Note: Descriptions are shown in the official language in which they were submitted.
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NEW GENERATION TRIPLE-TARGETING, CHIRAL, BROAD-SPECTRUM
ANTIMICROBIAL 7-SUBSTITUTED PIPERIDINO-QUINOLONE CARBOXYLIC ACID
DERIVATIVES, THEIR PREPARATION, COMPOSITIONS AND USE AS
MEDICAMENTS
Field of the Inyention:
The present invention relates to novel antimicrobial 7-substituted piperidino-
quinolone
to carboxylic acid derivatives and pharmaceutically acceptable salts thereof.
Methods of
preparation of the compounds of the invention, compositions of compounds of
the invention and
their use are also described.
Background of the Invention:
The fluoroquinolone group of antibiotics available since the early 1960s are
valuable as
antibacterial agents. There have been synthesized, developed and marketed
quinolone carboxylic
acid derivatives having various chemical structures. Nalidixic acid, the
progenitor of the series,
was used primarily as a urinary tract antiseptic. Later development provided
agents with broader
2o activity, increased potency against selected pathogens and improved
pharmacokinetic and '
pharmacodynamic properties.
From a medical utility viewpoint, the quinolones are classified as first-,
second-, and third-
generation compounds (Gootz T D et al, Chemistry & Mechanism of Action of the
Quhlolone
Antibacterials. In Andriole VT ed. The Quinolones, San Francisco, Academic
Press, 1998, 28-
80). First-generation compounds like piromidie acid and pipemidic acid
provided coverage for
gram-negative Enterobacteriaceae. The second-generation compounds are divided
into those
with enhanced but predominant gram-negative activity, against pathogens like
Escherischia coli
and Pseudonaonas aeruginosa, and those with balanced broad-spectrum activity
(norfloxacin,
pefloxaein, enoxacin, fleroxacin, lomefloxacin, ciprofloxacin, ofloxacin,
rufloxacin,
nadifloxacin). Norfloxacin, ofloxacin and ciprofloxacin have, therefore, been
used mainly for
treatment of diseases including urinary tract infections, gastrointestinal
infections, sexually
transmitted diseases and the like. Third-generation drugs (levofloxacin,
pazufloxacin,
sparfloxacin, clinafloxacin, sitafloxacin, trovafloxacin, tosufloxacin,
temafloxacin,
grepafloxacin, balofloxacin, moxifloxacin, gatifloxacin) are those with
enhanced activity against
gram-positive cocci (notably clinafloxacin, sitafloxaein, trovafloxacin for
Streptococcus
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pf2eunaoniae) and, for essentially all the third- generation quinolones,
activity also against gram-
negative Haemoplailus influerazae and Legionella pneumophila, and against
anaerobes and
atypical pathogens (Ball P, The Quinolone. History and Overview. In Andriole
VT ed. The
Quinolones, San Francisco, Academic Press, 1998, 1-28). Levofloxacin,
moxifloxacin and
gatifloxacin have, therefore, found use for community-acquired infections such
as those of the
upper and lower respiratory tract infections (RTI) like pneumonia, sinusitis
and pharyngitis, and
for skin and soft tissue infections (SSI) caused by gram-positive strains of
staphylococci,
pneumococci, streptococci and enterococci.
l0 The improvements seen in most of the third-generation drugs in current use
are generally
attributed to their uniqueness in inhibiting the bacterial targets, DNA gyrase
and topoisomerase
IV. Three categories of quinolone inhibition have been suggested. Type I
quinolones
(norfloxacin, enoxacin, fleroxacin, ciprofloxacin, lomefloxacin,
trovafloxacin, grepafloxacin,
ofloxacin and levofloxacin) indicated a preference for topoisomerase IV
inhibition. Type II
15 quinolones (nadifloxacin and sparfloxacin) indicated a preference for DNA
gyrase inhibition.
Type III quinolones to which some of the third-generation quinolones belong
(gatifloxacin,
pazufloxacin, moxifloxacin and clinafloxacin) display, however, a dual-
targeting property, and
equally influence DNA gyrase inhibition and topoisomerase 1V inhibition.
(Takei M et al,
Antimicrobial Agents and Chemotherapy, 2000; 45:3544-49). DNA gyrase is the
primary target
2o in bacteria, and thus is explained the weaker activity in gram-positive
bacteria of the preferred
topoisomerase IV-targeting second-generation quinolones like norfloxacin,
ciprofloxacin,
ofloxacin, and levofloxacin. The unusual activity of nadifloxacin described by
others, and further
significantly elaborated for S-(-)-nadifloxacin by us (cf our pending US
application Nos.
09/566,875, 09/850,669, WO 00/68229 and WO 01/85728), specially against gram
positive .S
25 auYeus, is now better understood in view of its being shown to be DNA-
gyrase targeting, which
is the first such report for a quinolone in S. aureus (Oizumi N et al, J .
Infect. Chemother, 2001;
7: 191-194). Some, but not all, third generation quinolones being primarily
topoisomerase IV-
targeting in gram-positive staphylococci, and DNA gyrase-targeting in gram-
positive S.
pneunaoniae, explains the advantages provided by the dual-targeting third-
generation quinolones
30 like moxifloxacin and gatifloxacin.
The evolution of quinolones from first-generation to second-generation to
third-generation
compounds has also been guided by structure-activity relationship studies. It
has been
determined by those in the art that certain structures with specific sites on
the quinolone ring
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functionalised have distinct advantages over others. Structure-activity
relationships of the
quinolones have been the subj ect of detailed study for more than a decade
(Asahina Y et al,
Recent Advances in Structure Activity Relationships in New Quinolones, Prog.
Drug Res., 1992,
38, 57-106) As a result of these studies, it has been determined by those in
the art that certain
structures, with specific sites on the quinolone ring functionalised, have
distinct advantages over
others. The structural feature that remains constant throughout the drug class
is the bicyclic
aromatic core consisting of 2 fused 6-membered rings. This core can contain a
carbon at the 8-
position, yielding a true quinolone, or a nitrogen which provides a ring
system technically
termed a naphthyridone, or an additional fused ring across the N-1 and C-8
positions yielding
tricyclic heterocycles, such as pyridobenzoxazines and benzoquinolizidines.
In the context of the current invention, the nature of the amine group at the
7-position takes on
special relevance. It is notable that in the cited second-generation
quinolones the piperazine ring
remains relatively constant and undisturbed as a 7-substituent, except for
alkylation on the distal
nitrogen, or less frequently on the ring carbons. In the third-generation
quinolones, the
continuing trend of use of a C-7 cyclic amino group is also almost universal.
The presence of a
second amine, in addition to the nitrogen bonded to C-7 of the quinolone
nucleus has been found
to be important. However, amongst these new quinolones, too, the frequent
employment of
mainly a C-7 piperazino or pyrrolidino variant is to be noted, but with only
one example of a C-7
piperidino substituent.
Only two of the above-cited quinolones, the second-generation nadifloxacin and
the third-
generation balofloxacin, have a C-7 piperidino substituent. Nadifloxacin with
a
hydroxypiperidine substituent at the C-7 position is notable for its being the
sole marketed a
modern quinolone without a distal amino group, but is merely a topical agent.
Balofloxacin has
an unusual 3-methylaminopiperidino substituent, which is, however, said to be
the contributing.
element to its lower activity against Enterobacteriaceae and Mycoplasttta
p>zeumottiae. Among
the recent fluoroquinolones which have been introduced commercially are
moxifloxacin and
gatifloxacin. Both these antibacterial agents have an 8-methoxy substituent in
the
fluoroquinolone core. As 7-substituents in the core, there is for moxifloxacin
a bicyclic .
pyrollidine as the amino moiety, and for gatifloxacin a substituted
pyrollidine as the amino
moiety. A more recently described olamufloxacin, which has been shown to have
activity in
marine models of system infections and urinary tract infections, has an 8-
methyl substituent in
its fluoroquinolone core in which the C-7 substituent is also a substituted
pyrollidiize. No
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commercially introduced fluoroquinolone or one that has commercial potential
is known in
which a piperidino group, substituted or unsubstituted, is introduced at the 7-
position of the
quinolone structure also having a methoxy group or methyl group at the 8-
position.
Since the 1960s, in an enormous worldwide effort, well more than 10,000
structurally- related
fluoroquinolone agents have been described in many hundreds of patents and j
ournal articles.
Despite the understanding of the need of a cyclic amine at the C-7 position,
the prior art appears
to have discounted the value of having a piperidino moiety, unsubstituted or
substituted, as a C-7
substituent. For instance, a 1992 review article (Asahina Y et al, vide infra)
indicates the
1o comparative low prior art interest in C-7 piperidino substituents, wherein
there are only 21
piperidino moieties cited in comparison to 188 piperazino moieties, and 74
pyrollidino moieties
out of a total of 578 C-7 amino moieties.
Just as there are structure-activity relationships, there are also structure-
side effect relationships
15 that have been determined. Side effects and adverse events related to N-1,
C-5, C-8 variants of
the quinolone core are generally those that contribute to increase in
theophylline interactions,
clastogenicity, phototoxicity, hepatotoxicity, cardiotoxicity, arthropathy and
tendonitis. Notable
is the pattern of (a) the N-1 cyclopropyl and C-8 fluorine, chlorine or
methoxy substituted
quinolone reported to show heightened cytotoxicity (Domagala J M, J.
Antimicrob. Chemother:,
20 1994; 33: 655-706), which can be modulated, however, by further structural
manipulation (Gootz
T D et al, vide infra), (b) the presence of halogen atoms (fluorine or
chlorine) at the C-8 position
(sparfloxacin, clinafloxacin) enhancing the tendency to induce
photosensitivity, (c) the N-1
difluorophenyl substituent in trovafloxacin and temafloxacin associated with
hepatotoxicity and
hemolytic anemia and (d) the C-5 methyl (grepafloxacin) and C-8 methoxy
substituent
25 (moxifloxacin, gatifloxacin) contributing to prolongation of the QT
interval and the Bevelopment
of a form of ventricular tachycardia known as torsade de pointes.
As important, if not more so, than the above-mentioned substituents of the
fluoroquinolone core
is the amine substituent at the C-7 site. G-7 pyrrolidines tend to show
increased cytotoxicity
30 over piperazino substituents, with the combination of 3-substituted
pyrrolidines at C-7 and
halogens at C-8 providing the most cytotoxic compounds.(Suto N J et al, J Med
Chem 1992;
35:4745-50; Mundell L A et al, Clin Infect Dis, 2001; 32(Suppl): 574) In the
second most
frequently encountered form of quinolone toxicity, namely adverse events
involving the CNS, it
4
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is the unsubstituted piperazines which correlate best with the degree of GABA-
binding
inhibition, closely followed by the pyrrolidinyl quinolones.
The incremental improvements that have resulted in moving from first- to
second- and third-
s generation quinolones are a consequence of the understanding of the
modulation brought about
by a combination of a fluoroquinolone core moiety with a C-7 amino
substituent. Although
certain substituents can impart improvements, whether on one hand in
antibacterial potency or
on the other in a minimised potential for adverse effect, it is the overall
characteristics of each
molecule derived from the interaction of all the substituents with each other
and with the specific
to nucleus employed that brings newer gains. Furthernzore, characteristics in
addition to those of
activity and side effects are central to the development of improved human
theraputants such as
selective molecular mechanisms of action, broader antibacterial coverage to
include anaerobes,
atypical and resistant pathogens, improved pharmacokinetics and
pharmacodynamics, and
devoid of class-identified toxicity features.
It is, thus, clear that the art has focussed on identifying new quinolones to
progress from earlier
generation compounds to the next generation compounds. Despite the progress
made, the full
promise of the quinolones has not yet been exploited.
Examples of bacterial infections resistant to antibiotic therapy have been
reported in the past;
they are now a significant threat to public health in the developed world. The
development of
microbial resistance is of increasing concern in medical science. "Resistance"
can be defined as
existence of organisms, within a population of a given microbial species, that
are less susceptible
to the action of a given antimicrobial agent. This resistance is of particular
concern in
environments such as hospitals and nursing homes, where relatively high rates
of infection and
intense use of antibacterials are common. Recent international conferences in
2002 on infectious
diseases organised by the Centres for Disease Control and Prevention, USA,
World Health
Organisation and other groups have highlighted ernergifZg infectious diseases,
in which the word
"emeygihg" refers to newly discovered infectious diseases or old ones that
have rebounded,
turned up iii new places, or become drug resistant.
The mechanisms of bacterial resistance to fluoroquinolones is generally
believed to function by
two principal categories, both resulting from chromosomal mutations (DC
Hooper, Drug Resis
Updat 1999; 2:38-55). One category is the alterations in drug target enzymes.
Fluoroquinolone
5
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resistance mutations generally occurring stepwise have been localized to
specific regions of the
paf°C and pai E genes (gf°lA and grlB in S. aureus) encoding
topoisomerase IV, and the gyrA and
gyrB genes encoding DNA gyrase. This clustering of mutations has defined the
quinolone
resistance determining regions (QRDRs) of these genes that are in proximity to
the apparent
enzyme active site and are thought likely to constitute a domain at which
quinolones interact
directly with the enzyme-DNA complex. The manner by which the emergence of
resistant
mutants can be prevented is receiving attention, but is as yet insufficiently
understood and
continues to be speculative. Studies with the C-8 methoxy fluoroquinolones
bearing a C-7
unsubstituted or 3-alkyl substituted piperazino substituent provide support to
the concept that
attack of both gyrase and topoisomerase IV equally would be ideal. In cases
where single point
mutation already exists, then a quinolone that would preferably potently
inhibit the primary more
essential target, whether gyrase or topoisomerase IV, would be better to
prevent the resistance
(Zhao et al, Proc. Natl. Acad. Sc. 1997; 94: 13991-13996). No similar study,
to our knowledge,
is available for compounds with a C-7 piperidino substituent, whether
unsubstituted or
substituted, in any quinolone core. The second category for bacterial
resistance to develop is
alterations that limit permeation of drug to the target. In S. au~eus the
elevated expression of the
norA gene is responsible for efflux-mediated resistance to quinolones. Factors
influencing the
decrease in activity of quinolones in efflux-mediated resistant mutants of S.
au~eus have been
suggested not to be hydrophobicity of the whole quinolone molecule, but rather
the bulkiness at
2o the C-7 substituent, and bulkiness and hydrophobicity at the C-8
substituent (Takenouchi T et al,
1996; 40:1835-42). Only two of forty quinolones included in this analysis bore
a C-7 amino-
substituted piperidino substituent. The effect of efflux was more pronounced
with the compound
bearing the 4-amino substituted piperidino substituent, its MIC value being 8
times more with an
efflux pump-bearing strain than with a non-efflux pump-bearing strain, as
compared with a 2
times more value for the 3-amino substituted piperidino substituent.
Surprisingly, unlike this
precedent, the present invention shows that appropriately substituted 4-amino
piperidine
substituents on different fluoroquinolone cores display potent efflux pump
inhibitory/uptake
facilitatory properties.
Stereochemistry-activity relationships are also of importance in
considerations regarding the
advancement of quinolones that can exist as isomers. For instance, S-(-)-
levofloxacin, as an
example of a compound in which the chiral centre.is close to the quinolone
nucleus, is from 8-
128 fold as potent as the R-(+)-enantiomer. Earlier work and our pending US
patent application
Nos. 09/566,875 and 09/850,669, WO 00/68229 and WO 01/85728 on nadifloxacin,
which like
6
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levofloxacin has a relatively similar chiral centre, also disclose the
superior profile of S-(-)-
nadifloxacin over the R-(+)-enantiomer. Chiral centres at C-7 that are at some
distance from the
quinolone nucleus are said to contribute less significantly to biological
activity. However, the
relative orientation of the methyl groups on the C-7 piperazine of
sparfloxacin is important for
bacterial enzymes versus mammalian enzyme selectivity. Sparfloxacin, bearing
methyl groups
with a cis-stereochemistry essential for its antibacterial activity, displays
dramatic differential
effects on mammalian topoisomerase-II with no or less interaction with the
mammalian enzyme,
in contrast to the t~~aris-isomer which does interact with the mammalian
enzyme, while however
retaining its antibacterial activity (Gootz T D et al., vide infra). Unlike
this prior art, the present
l0 invention once again surprisingly shows that stereochemical differences of
substituents on the C-
7 piperidino moiety, while dramatically affecting antibacterial activity, do
not significantly
influence cytotoxicity of mammalian cell lines, irrespective of whether the
differences are
enantiomeric or diastereomeric.
1s Both of the third-generation fluoroquinolone market introductions of
moxifloxacin and
gatifloxacin with improved activity against gram-positive pathogens, have an 8-
methoxy
substituent in the core fluoroquinolone nucleus. Even their coverage, however,
of staphylococci
is considered partial, as they possess weak antibacterial activity against
most of the methicillin-
resistant strains. Moreover, moxifloxacin and gatifloxacin have failed to show
therapeutically
20 relevant potency for recent widely reported ciprofloxacin-resistant and
levofloxacin-resistant
strains of pneumococci. In addition, the potency of newer fluoroquinolones
such as moxifloxacin
against gram-negative pathogenic bacteria such as E. coli and P. aerugihosa
has considerably
diminished.
25 Therefore, there is a need for newer orally effective fluoroquinolone
antibacterials with superior
potency not only against methicillin-resistant, macrolide-resistant and
fluoroquinolone-resistant
strains, viz. multidrug-resistant strains of gram-positive staphylococci and
pneumococci, but also
against gram-negative strains with potency comparable to ciprofloxacin and
levofloxacin, and
against the now so Balled emerging infectious diseases. Accordingly, numerous
studies are being
3o continuously conducted to address the disadvantages of the fluoroquinolones
having an 8-
methoxy substituent or 8-alkyl substituent or other 8-substituents to make
them considerably
more potent against bacterial pathogens, to increase their spectrum coverage
to include the
insufficiently addressed pathogens like mycobacteria, anaerobes, and
atypicals, to optimise their
7
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action towards bacterial molecular targets, to reduce their efflux or
facilitate their cellular uptake,
and to improve their oral bioavailability and toxicity profile.
Some 1,4-dihydroquinolone related moieties bearing an 8-methoxy substituent
are known in the
art to have antimicrobial activity and are described in the following
references:
U.S. Patent No. 4,638,067 to Culbertson, et al. on January 20, 1987; US Patent
No. 4,665,079 to
Culbertson, et al. on May 12, 1987; European Patent Application 0230295A2 of
Kyorin
Pharmaceutical Co. pub. July 29, 1987; European Patent Application 0241206A2
of Ube Ind
1o pub. October 14, 1987; U.S. Patent No. 4,822,801 to Domagala et al. on
April 18, 1989; U.S.
Patent No. 509 7032 to Domagala et al. on March 17, 1992; U.S. Patent No.
5,051,509 to
Nagano et al. on September 24, 1991; European Patent Application 0541086A1 of
Kaken
Pharmaceutical Co. published May 12, 1993; European Patent Application
0572259A1 of Ube
Ind. Published December 1, 1993; WO 1993-JP 1925 of Japan Tobacco, Inc., dated
December
28, 1993; European Patent Specification 0342675B 1 of Chugai Seiyaku
I~abushiki I~aisha
published January 25, 1995; Japanese Patent 6-145167 published May 24, 1994;
US Patent No.
5,607,942 of Clive Petersen et al. on March 4, 1997; PCT Patent Application
No.
PCT/K.R94/00005 to Korea Research Institute of Chemical Technology published
July 21, 1994;
U.S. Patent No. 5,677,316 to Hideki et al. on October 14, 1997; World Patent
W098/58923A1 to
zo Hagano et al. on June 23, 1998; US Patent No. 4,777,175 to Warner-Lambert
Co. on October 11,
1988; European Patent Application 0919553A1 of Daiichi Pharma Co. published
June 2, 1999;
US Patent No. 6,121,285 to Takemura et al., on September 19, 2000; US Patent
No. 6,329,391
B1 to Benoit Ledoussel et al. On December 11, 2001.
z5 Similarly some 1,4-dihydroquinolone related moieties bearing an 8-alkyl
substituent, in
particular an 8-methyl substituent, are known in the art to have antimicrobial
activity and are
described in the following references: US Patent No. 4,874,764 to Hiraki Ueda
et al., on October
17, 1989; US Patent No. 4,935,420 to Hiraki Ueda et al., on June 19, 1990, US
Patent No.
5,859,026 to Ito et al., on January 12, 1999 and European Patent application
0919553A1 of
3o Daichi Pharmaceutical Company 'published June 02, 1999; US Patent No.
6,121,285 to
Takemura et al., on September 19, 2000.
The methods of producing quinolone carboxylic acids bearing an 8-methoxy
substituent are also
to be found in the following references:
8
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U.S. Patent No. US 5,639,886 to Zerbes et al. on June 17, 1997; U.S. Patent
No. 5,869,661 to
Ochi et al. on February 9, 1999; and PCT Patent Application No. WO 99126940 to
Bayer
Aktiergesellschaft published June 3, 1999.
The methods of producing quinolone carboxylic acids bearing an 8-methyl
substituent are also to
be found in the following references: US Patent No. 5,859,026 to Ito et al.,
on January 12, 1999;
US Patent No. 6,121,285 to Takemura et al., on September 19, 2000.
European Patent application 0919553A1 of Daichi Pharmaceutical Company
published June 02,
1999.
io
A number of compounds having a cyclic amino moiety as substituents at the 7-
position of these
quinolone carboxylic acids are already known. In addition, many attempts have
been made to
modify the 7-cyclic amino moiety with various substituents to produce superior
compounds, and,
for example, a cyclic amino substituent such as 4-amino-1-piperidinyl group or
4-hydroxy-1-
piperidinyl group wherein the adjacent carbon atom to the amino or hydroxy
substituent is
further monosubstituted by an alkyl substituent is known, as hereinbelow
described in the
identified patent applications and patents.
For example PCT Patent Application WO 99/14214 and US Patent No. 6,329,391B1
discloses a
2o compound having a cyclic amino substituent of the formula
R3
~9
wherein each symbol is as defined in the specification of the above-mentioned
publication. For
the piperidino substituent at the 7-position of the quinolonecarboxylic acid,
the compounds
having substituents of 3-amino-4-methyl, 3-amino-4-4-dimethyl, 3-amino-4-
spirocyclopropyl, 3-
amino-6-cyclopropyl, are included in the preferred examples therein. However,
specific
examples of compounds having a substituent at the 7-position as piperidine of
the present
invention with a 4-amino or 4-hydroxy substituent with 2-alkyl, 3-alkyl, 5-
alkyl or 6-alkyl
substituents, or with geminal 3,3-dialkyl, or 3,5-dialkyl, or 3,3,5-trialkyl
substituents, located at a.
g.
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position adjacent to the substituent at the 4-position, are not disclosed.
What is more
compounds with a piperidine substituent at the 7-position as defined in the
cited patent
application above with a substituent in the 8-position as a methoxy group (R$
= OCH3) or as an
alkyl group (R$ = CH3, CZHS) and the substituent in the 6-position as a fluoro
group (R6 = F) are
s also not disclosed.
European Patent Application 241206A2 discloses a compound having a 7-cyclic
amino
substituent of the formula
COOH
with one meaning of Y being
R4 N-
wherein each symbol is as defined in the specification of the above-mentioned
publication at the
7-position of quinolonecarboxylic acid and the compounds having substituents
of 4-hydroxy-3-
methyl, 4-amino-3-methyl, or 4-methylamino-3-methyl are included as specific
examples
therein. However, specific examples of the compounds having a substituent at
the 7-position as
piperidine of the present invention with a 4-amino or 4-hydroxy substituent
with 2-alkyl or 6-
alkyl substituents, or with 3,3-dialkyl substituents, geminally located at a
position adjacent to the
substituent at the 4-position are not disclosed.
European Patent Application 039455381 discloses a compound for the treatment
of HIV
infections having a 7-cyclic amino substituent of the formula
R3
'~4
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wherein each symbol is as defined in the specification of the above-mentioned
publication at the
7-position of the quinolone carboxylic acid with a 4-amino substituent and a
single 3-alkyl
substituent or a 3-3-dialkyl substituent claimed. However, specific examples
of the compounds
having a substituent at the 7-position as piperidine of the present invention
with a 4-amino or 4-
hydroxy substituent with 2-alkyl, 3- alkyl, 5-alkyl or 6-alkyl substituents,
or with geminal 3,3-
dialkyl, or 3,5-dialkyl, or 3,3,5-trialkyl substituents, located at a position
adjacent to the
substituent at the 4-position are not disclosed. What is more, compounds with
a piperidine
substituent at the 7-position as defined in the cited patent application above
with a substituent in
the 8-position as a methoxy group (Q = C-OCH3) or as an alkyl group (Q = C-
CH3, C-CZHS) are
to also not disclosed.
European Patent Application 0304087A2 discloses a compound having a 7-cyclic
amino
substituent of the formula
R3
R~
n9
wherein each symbol is as defined in the specification of the above-mentioned
publication at the
7-position of the quinolone carboxylic acid with a 4-amino substituent and a
single 3-alkyl
substituent is claimed. However, specific examples of compounds having a
substituent at the 7-
position as piperidine of the present invention with a 4-amino or 4-hydroxy
substituent with 2-
alkyl, 3-alkyl, 5-alkyl or 6-alkyl substituents, or with geminal 3,3-dialkyl,
or 3,5-dialkyl, or
3,3,5-trialkyl substituents, located at a position adjacent to the substituent
at the 4-position are
not disclosed. What is more, compounds with a piperidine substituent at the 7-
position as
defined in the cited patent application above with a substituent in the 8-
position as a methoxy
group (X = C-OCH3) or as an alkyl group (X = C-CH3, C-C2H5) are also not
disclosed.
European Patent Application 0572259A1 discloses a compound having a 7-cyclic
amino
3o substituent of the formula
Rs
p COOH
( )~ p I
~ s ~N X
( )N' R
R7 N~( )m 11 '
R$
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wherein each symbol is as defined in the specification of the above-mentioned
publication at the
7-position of the quinolone carboxylic acid with a 4-amino piperidinyl moiety
wherein the amino
group is substituted with an aryl or aromatic hetero monocyclic group or a
fused aromatic group
and a single 3-alkyl substituent is disclosed. However, specific examples of
compounds having
a substituent at the 7-position as piperidine of the present invention with a
4-amino or 4-hydroxy
substituent with 2-alkyl, 3-alkyl, 5-alkyl or 6-alkyl substituents, or with
geminal 3,3-dialkyl, or
3,5-dialkyl, or.3,3,5-trialkyl substituents, located at a position adjacent to
the substituent at the 4-
position are not disclosed. What is more, compounds with a piperidine
substituent at the 7-
position as defined in the cited patent application above with a substituent
in the 8-position as a
1o methoxy group (X= C-OCH3) or as an alkyl group (X = C-CH3, C-C2H5) are also
not disclosed.
European Patent Application 0287951A2 discloses a compound having a 7-cyclic
amino
substituent as in the following formula
R,
R3 R~
Rh
'
Ri N-
Rj ~
in which one of the meanings of R2 is substituent which is a 5- to 9- membered
saturated or
unsaturated heterocyclic ring which may be substituted, wherein each symbol is
as defined in the
specification of the above-mentioned publication at the 7-position of the
quinolone carboxylic
acid with a 4-hydroxy piperidinyl moiety. However, specific examples of
compounds having a
substituent at the 7-position as piperidine of the present invention with a 4-
amino or 4-hydroxy
substituent with 2-alkyl, 3-alkyl, 5-alkyl or 6-alkyl substituents, or with
geminal 3,3-dialkyl, or
3,5-dialkyl, or 3,3,5-trialkyl substituents, located at a position adjacent to
the substituent at the 4-
position are not disclosed. What is more, compounds with a piperidine
substituent at the 7-
position as defined in the cited patent application above with a substituent
in the 8-position as a
methoxy group (R3 = OCH3) or as an alkyl group (R3 = CH3, CZHS) are also not
disclosed.
U.S. Patent No. 4,382,892 discloses a compound having a cyclic substituted
amino group
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Z = N-
R~
which is a 4- to 7- membered ring which may be substituted, wherein each
symbol is as defined
in the specification of the above-mentioned publication at the Z substituted
position of the
l0 quinolone carboxylic acid with a 4-amino 1-piperidinyl moiety, 4-
dimethylamino 1-piperidinyl
moiety and 4-hydroxy 1-piperidinyl moiety.
However, specific examples of compounds having a substituent at the 7-position
as piperidine of
the present invention with a 4-amino or 4-hydroxy substituent with 2-alkyl, 3-
alkyl, 5-alkyl or 6-
alkyl substituents, or with geminal 3,3-dialkyl, or 3,5-dialkyl, or 3,3,5-
trialkyl substituents,
located at a position adjacent to the substituent at the 4-position are not
disclosed.
The feature of the known 7-substituted piperidino derived compounds is that
they are said to
exhibit antimicrobial properties, but either no biological data is provided or
in cases where some
data is provided, such piperidino derivatives have been found to be inferior
in activity to those
derivatives bearing 7-piperazino or 7-pyrrolidino substituents. It is only
through our on-going
studies in recent years as described in our pending US patent applications
091566,875 and
09/850,669, WO 00/68229 and WO 01185728 that there has begun to be elaborated
the full
potential of a fluoroquinolone core bearing an unsubstituted or substituted 4-
hydroxy piperidino
substituent at the 7th position of the core fluoroquinolone for use in
clinical development as
medicaments for life-threatening old and new emerging infectious diseases.
Thus, the present inventors have extensively studied the subject by
introducing various
substituted piperidine groups in the 7-position of different fluoroquinolone
cores and
determining the microbiological/pharmacological properties of the compounds to
develop the
novel substituted piperidino compounds of the invention, which (a) show a
potent hitherto-
undescribed antibacterial potency against broad spectrum sensitive and
existing/emerging
resistant pathogenic strains, including [i-lactam-resistant, macrolide-
resistant and even
fluoroquinolone-resistant strains, mycobacteria, anaerobes and atypical
pathogens (b) prevent
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selection of resistant bacteria by apparently iilhibiting both DNA gyrase and
topoisomerase IV
equally, or by potently inhibiting the enzyme it targets, (c) are not subj
ected to efflux or have
facilitated uptake, (d) do not apparently act to merely form bacteriostatic
quinolone-
gyrase/topoisomerase-DNA complexes to inhibit cell growth, but also apparently
extend the
action to release the broken DNA ends to ensure cell death, (d) exhibit high
absorption and
improved pharmacokinetic properties in a living body, and (e) display a
favourable safety
profile. As a result, we have identified that the compounds of the general
formula I as defined
below wherein substituted piperidino groups are introduced into the 7-position
of the
fluoroquinolone nucleus can satisfy such a purpose.
l0
It is therefore, an aspect of the present invention to provide new non-chiral
and chiral 7-
substituted piperidino-quinolone carboxylic acid derivatives, of the formula
I, as defined below,
wluch show potent antibacterial activity against a broad range of pathogenic
microorganisms,
including both gram-positive and gram-negative strains with advantages of
activity against
resistant microorganisms, reduced toxicity, and improved pharmacology and
pharmacokinetics.
It is another aspect of the present invention to provide a process for
preparing 7-substituted
piperidino-quinolone carboxylic acid derivatives of the formula I.
It is a further aspect of the present invention to prepaxe the intermediates
that are necessary to
obtain the 7-substituted piperidino-quinolone carboxylic acid derivatives of
the formula I.
It is a further aspect of the present invention to provide compositions
containing 7-substituted
piperidino-quinolone carboxylic acid derivatives of the formula I as an active
component.
It is also an aspect of the invention to use the 7-substituted piperidino-
quinolone carboxylic acid
derivatives of the formula I of the invention and compositions containing them
as medicaments
for the treatment of infectious diseases.
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Summary of the Invention
This invention describes fluoroquinolones of the formula I
Y
RB
1o Formula I
wherein
Rl is C1_5 alkyl, substituted C1_s alkyl, C3_6 cycloalkyl, substituted C3_6
cycloalkyl, aryl, or
substituted aryl;
or when Q is CH and the nitrogen atom to which Rl is linked forms an
optionally substituted 5-,
6- or 7-membered ring with the carbon atom of Q, the ring optionally
containing one or more
hetero atoms selected from nitrogen, oxygen or sulfur atoms, said
heteroatom(s) represented by
T, preferably Rl is CH2CHz-, CHZT-, CHZCHZCHz-, CHZCH2T-, CHZTCHz-, TCHZT-,
TCHZCH2CHZCHz- CHZCHZCHZT-, CHZTCHZCHz_, or TCH2CHZT- where T represents NH,
O,
or S. If the ring is substituted, the substituent is as defined above for Rl,
Y is OR3 where
R3 is hydrogen;
R3 is Cl-Czo alkyl, such as straight chain or branched chain aliphatic
residues;
R3 is aralkyl;
R3 is CHZCH(NHz)COOH;
R3 is (CHz)"-CHRIO-OCORII or (CHz)p CHRIO-OCOZRII wherein Rl~ is H, or CH3; n
is 0-3 and
Rll is Cl-Czo alkyl, substituted Cl-C6 alkyl or aralkyl or Rl I is
-CH2 CH3
O\ /O
I~IO
or R3 is a,-aminoalkanoyl or an alkanoylalkyl group;
CA 02468190 2004-05-26
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or R3 is
-(CHZ)u-A Z
wherein A is CH or N, and when A is CH, Z is NH or NCH3, and when A is N, Z is
CH, 0, NH,
S, or NCH3 ; p is 0 - 2 ; q is 0 - 2; or
Y is NHRz, wherein R2 is H, C1_zo alkyl, C3_6 cycloalkyl, substituted C3_6
cycloalkyl, aryl,
substituted aryl, or heteroaryl, all of which heteroaryl residues may be
further substituted or
unsubstituted;
or Rz is an amino acid residue derived from one of the 20 naturally occurring
amino acids, or the
optically active isomers thereof, or the racemic mixtures thereof;
to RS is H, Cl_5 alkyl, C1_5 alkoxy, amino, C1_5 alkylamino, or Cl_5
acylamino;
Q is -N-, -C(R$)- (R$ being H, F, Cl, bromo, C1_4 alkyl or unsubstituted or
substituted Cl-4
alkoxy, wherein when the alkoxy group is substituted it is substituted by one
or more halogen
atoms such as F, Cl, or Br),
or when Q is CH and the nitrogen atom to which Rl is linked forms an
optionally substituted 5-,
6- or 7-membered ring with the carbon atom of Q, the ring optionally
containing one or more
hetero atoms selected from nitrogen, oxygen or sulfur atoms, said
heteroatom(s) represented by
T, preferably Rl is CH2CHz-, CHZT-, CHZCHzCHz-, CHZCH2T-, CHZTCHz-, TCH2T-,
TCHzCHZCHZCHz- CHZCHzCH2T-, CHZTCH2CHz_, or TCHzCHzT- where T represents NH,
O,
or S. If the ring is substituted, the substituent is as defined above for Rl.
2o X is OR4,
wherein R4 is hydrogen, Cl-Czo alkyl, glycosyl, aralkyl, C1-C6 alkanoyl,
aminoalkanoyl or an
amino acid residue derived from one of the 20 naturally occurnng amino acids,
or the optically
active isomers thereof, or the racemic mixtures thereof, or R4 is 1-
aminocyclohexylcarbonyl or
COORII wherein RI1 is as hereinbefore defined or R4 is -(CHz)"CHRIO-OCOORII
where Rlo
and Rll are as hereinbefore defined, or R4 is C6HilO6, POz(CH3)H, P03Hz,
POz(OCH3)H or
S03H thus giving respectively the gluconic acid, phosphonic acid, phosphoric
acid and sulfonic
acid ester derivatives of the compounds;
or X is NR6R~,
wherein R6 is H, Cl_zo alkyl, C3_6 cycloalkyl, aralkyl, Cl_zo alkanoyl, Cl-zo
alkoxycarbonyl,
3o aralkyloxycarbonyl, amino(C1_zo)alkanoyl, or an amino acid residue derived
from one of the 20
naturally occurring amino acids or the optically active isomers thereof, or
the racemic mixtures
thereof.
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The amino acid residue is derived from a single amino acid or from
combinations of amino acids
that form dipeptide, tripeptide or polypeptide amino acid unit residues,
wherein a terminal
carboxy group is optionally protected by Cl_4 alkyl or aralkyl groups and a
terminal amino group
is optionally protected by a t-Boc (tertiarybutyloxycarbonyl), F-Moc
(fluorenylmethoxycarbonyl)
or Cbz (benzyloxycarbonyl) group.
R6 may also be COORI I wherein Rll as hereinbefore defined or R6 is C6H11O6
thus giving the
gluconic acid ester derivative of the compounds.
R~ is H, Ci_6 alkyl, C3_6 cycloallcyl, aralkyl; C1_6 alkanoyl,
aralkyloxycarbonyl or amino(C1_ZO)
alkanoyl; or an amino acid residue derived from one of the 20 naturally
occurring amino acids or
1o the optically active isomers thereof, or the racemic mixtures thereof. The
amino acid residue is
derived from a single amino acid or from combinations of amino acids that form
dipeptide,
tripeptide or polypeptide amino acid unit residues, wherein a terminal carboxy
group is
optionally protected by Cl_4 alkyl or aralkyl groups and a terminal amino
group is optionally
protected by a t-Boc (tertiarybutyloxycarbonyl), F-Moc
(fluorenylmethoxycarbonyl) or Cbz
(benzyloxycarbonyl) group or R~ may be C6H11O6~
R$/R$' are substituents at the 3/3-position of the piperidino ring and are the
same or different and
represent H, C1_6 alkyl, substituted C1_6 alkyl, alkylamino, or aralkyl.
R9 is a substituent at the 4-position or 5-position of the piperidino ring and
represents H, CI_6
alkyl, Cl_5 alkylamino, Cl_3 dialkylamino, aryl, axalkyl or a trihaloalkyl.
This invention also includes optical isomers, diastereomers, enantiomers,
polymorphs,
pseudopolymorphs, pharmaceutically acceptable salts, hydrates, or
biohydrolyzable esters,
amides, or solvates of the fluoroquinolones of formula I and prodrugs of these
compounds. In
addition, compositions incorporating the compounds of the invention, or using
compounds of the
invention as starting material are also contemplated in this invention.
The new compounds of the invention have increased potency and bactericidal
activity that can be
attributed to the combinations of the respective Ri, Y, R5, and Q substituents
in the
fluoroquinolone cores and the respective X, Rg, RB~, and R9 substituents on
the 7-substituted
3o piperidino moieties introduced in the cores.
The compounds of the invention thus belong to a new generation of dual-
targeting, non-effluxed,
diastereomeric, enantiomorphic antimicrobial 7-substituted piperidino-
quinolone carboxylic acid
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derivatives. The compounds of the invention may be rightly called new
generation triple-
targeting, chiral, broad-spectrum antimicrobial agents.
Detailed Description of the Invention
The present invention encompasses certain compounds, dosage forms, and methods
of
administering the compounds, to a human or other animal subject. Specific
compounds and
compositions to be used in the invention must, accordingly, be
pharmaceutically acceptable. As
used herein, such a "pharmaceutically-acceptable" compound is one that is
suitable for use with
to humans and/or animals without undue adverse side effects (such as toxicity,
irritation, and
allergic response) commensurate with a reasonable benefit/risk ratio.
This invention describes fluoroquinolones of the formula I
Rg
2Q
Formula I
wherein
Rl is Cl_5 alkyl being unsubstituted or substituted with from 1 to 3 fluoro
atoms, C3_6 cycloalkyl
being unsubstituted or substituted with from 1 to 2 fluoro atoms, or aryl
being unsubstituted or
substituted with from 1 to 3 fluoro atoms;
or when Q is CH and the nitrogen atom to which Rl is linked forms an
optionally substituted 5-,
6- or 7-membered ring with the carbon atom of Q, the ring optionally
containing one or more
hetero atoms selected from nitrogen, oxygen or sulfur atoms, said
heteroatom(s) represented by
T, preferably R~ is CH2CH2-, CHZT-, CH2CH2CH2-, CH2CHaT-, CHzTCH2-, TCHZT-,
3o TCHZCHaCHaCH2- CHZCHZCHZT-, CHzTCHZCH2_, or TCH2CH2T- where T represents
NH, O,
or S. This 5- to 7- membered ring may be substituted with 1 or 2 of the same
substituents as
those defined above for Rl, preferably by one C1-Cs alkyl group.
Y is OR3 where
R3 is hydrogen;
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R3 is C1-Czo alkyl, such as straight chain or branched chain aliphatic
residues such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl or
their branched chain
isomers;
R3 is aralkyl such as benzyl, phenethyl, or phenylpropyl;
R3 is CHZCH(NHz)COOH;
R3 is (CHz)"-CHRIO-OCORII or (CHz)"-CHRIO-OCOZRII wherein Rlo is H, or CH3; n
is 0-3 and
Rll is Ci-Czo alkyl as hereinbefore defined, or substituted C1-C6 alkyl with
substituents such as
hydroxy, halogen, amino, or mercapto; or aralkyl such as benzyl; phenethyl,
phenylpropyl or
Rll is
-CHz CH3
O\ /O
Ij ISO
or R3 is a-aminoalkanoyl such as a-aminopropionyl or R3 is alkanoylalkyl group
such as
acetoxymethyl, acetoxyethyl, pivaloyloxy-methyl, or pivaloyloxyethyl group;
or R3 is
-(CHZ)n-A Z
~-()q
wherein A is CH or N, and when A is CH, Z is NH or NCH3, and when A is N, Z is
CH, O, NH,
S, or NCH3 ; p is 0 - 2 ; q is 0 - 2, preferably it is a group such as N-
methylpiperidin-4-yl,
pyrrolidin-2-yl-ethyl, piperidin-2-yl-ethyl, or morpholin-2-yl-ethyl; or
Y is NHRz, wherein RZ is H, CI_zo alkyl such as straight chain or branched
chain aliphatic
residues as defined above, C3_~ cycloalkyl, substituted C3_6 cycloalkyl
wherein the substituent is
Cl_z alkyl such as methyl or ethyl or trifluoroalkyl such as trifluoromethyl
or halogen such as
fluorine, chlorine, bromine or Rz is aryl such as unsubstituted or substituted
phenyl wherein the
substituent is Cl_3 alkyl, CI_3 alkoxy, amino, or halogen; heteroaryl such as
pyridyl, pyrimidinyl,
quinolinyl, isoquinolinyl, furyl, oxazolinyl, thiazolyl, or thiadiazolyl, all
of which heteroaryl
residues may be further substituted or unsubstituted, wherein the substituent
is methyl or ethyl;
or Rz is an amino acid residue derived from one of the 20 naturally occurring
amino acids viz.
alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic
acid, glycine, histidine,
3o isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,
threonine, tryptophan,
tyrosine and valine, or the optically active isomers thereof, or the racemic
mixtures thereof;
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RS is H, C1_5 alkyl, Cl_s alkoxy, amino, Cl_5 alkylamino such as-NHCH3,
N(CH3)z, and the like;
or acylamino such as -NHCOCH3, -NHCOC(CH3)3, and the like;
Q is -N-, -C(R$)- (R$ being H, F, Cl, bromo, methoxy, Cl_4 alkyl, or
unsubstituted or substituted
C1_4 alkoxy, wherein when the alkoxy is substituted it is substituted by one
or more halogen
atoms such as F, Cl, or Br), or when Q is CH and the nitrogen atom to which Rl
is linked forms
an optionally substituted 5-, 6- or 7-membered ring with the carbon atom of Q,
the ring
optionally containing one or more hetero atoms selected from nitrogen, oxygen
or sulfur atoms,
said heteroatom(s) represented by T, preferably Rl is CHZCHz-, CHZT-,
CH2CHZCHz-,
CHZCHZT-, CHZTCHz-, TCH2T-, TCHZCHzCHZCHz- CHZCHZCHZT-, CHZTCHzCHz_, or
io TCH2CHZT- where T represents NH, O, or S. If the ring is substituted, the
substituent is as
defined above for Ri. This 5- to 7- membered ring may be substituted with 1 or
2 of the same
substituents as those defined above for Rl, preferably by one Cl-CS alkyl
group.
X is OR4
wherein R4 is hydrogen, C1-Czo alkyl as hereinbefore defined, glycosyl,
aralkyl such as benzyl;
or Cl-C6 alkanoyl such as acetyl, propionyl, pivaloyl, stearoyl, or
nonadecanoyl or
aminoalkanoyl such as aminoacetyl, aminopropionyl and the like or an amino
acid residue
derived from one of the 20 naturally occurring amino acids viz. alanine,
arginine, asparagine,
aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine,
isoleucine, leucine, lysine,
methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine
and valine, or the
optically active isomers thereof, or the racemic mixtures thereof; or R4 is 1-
aminocyclohexylcarbonyl or COORII wherein Rll is as hereinbefore defined or R4
is -(CHz)ri
CHRIO-OCOORII where Rlo and Rll are as hereinbefore defined, or R4 is C6H11O6,
POz(CH3)H,
PO3Hz, POz(OCH3)H or SO3H thus giving respectively the gluconic acid,
phosphonic acid,
phosphoric acid and sulfonic acid ester derivatives of the compounds;
or X is NR6R~,
wherein R6 is H, Cl_zo alkyl as hereinbefore defined, C3_s cycloalkyl, aralkyl
such as benzyl,
a
phenethyl, or phenylpropyl; C1_zo alkanoyl such as COCH3, COCHZCH3, or
COC(CH3)3, or C1_zo
alkoxycarbonyl such as COOCH3, COOCH2CH3, or COOC(CH3)3; aralkyloxycarbonyl
such as
benzyloxycarbonyl, or amino(Cl_zo)alkanoyl such as aminoacetyl, aminopropionyl
and the like,
or an amino acid residue derived from one of the 20 naturally occurring amino
acids or the
optically active isomers thereof, or the racemic mixtures thereof. The amino
acid residue is
derived from alanine, axginine, asparagine, aspartic acid, cysteine,
glutamine, glutamic acid,
glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
proline, serine,
threonine, tryptophan, tyrosine or valine. The amino acid residue is derived
from a single amino
2o
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acid or from combinations of amino acids that form dipeptide, tripeptide or
polypeptide amino
acid unit residues wherein a terminal carboxy group is optionally protected by
C1_4 alkyl or
aralkyl groups and a terminal amino group is optionally protected by a t-Boc
(teritarybutyloxycarbonyl), F-Moc (fluorenylmethoxycarbonyl) or Cbz
(benzyloxycarbonyl)
group or R6 may also be COORII wherein Rll is as hereinbefore defined or R6 is
C6H11O6 thus
giving the gluconic acid ester derivative of the compounds.
R~ is H, Cl_6 alkyl as hereinbefore defined, C3_6 cycloalkyl, aralkyl such as
benzyl, phenethyl, or
phenylpropyl; C1_6 alkanoyl such as COCH3, COCH2CH3, COC(CH3)3,
aralkyloxycarbonyl such
as benzyloxycarbonyl or amino (C1_zo)alkanoyl such as aminoacetyl,
aminopropionyl, etc.; or an
1o amino acid residue derived from one of the 20 naturally occurring amino
acids or the optically
active isomers thereof, or the racemic mixtures thereof. The amino acid
residue is derived from
alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic
acid, glycine, histidine,
isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,
threonine, tryptophan,
tyrosine or valine. The amino acid residue is derived from a single amino acid
or from
combinations of amino acids that form dipeptide, tripeptide or polypeptide
amino acid unit
residues, wherein a terminal carboxy group is optionally protected by Cl_4
alkyl or aralkyl groups
and a terminal amino group is optionally protected by a t-Boc
(teritarybutyloxycarbonyl), F-Moc
(fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl) group or
R~ may be C6H11O6 thus giving the gluconic acid ester derivative of the
compounds.
2o R$/R$' are substituents at the 3/3-position of the piperidino ring and are
the same or different and
represent H, C1_6 alkyl, substituted C1_6 alkyl wherein the substituent is
amino, hydroxy, halogen
such as one or more fluorine, chlorine, or bromine atoms; alkylamino, or
arallcyl such as benzyl.
R9 is a substituent at the 4-position or 5-position of the piperidino ring and
represents H, C1-6
alkyl, C1_5 alkylamino, Cl_3 dialkylamino or aryl, aralkyl such as benzyl or
phenethyl or a
trihaloalkyl such as trifluoromethyl.
As used herein aryl is substituted or unsubstituted phenyl. The phenyl, alkyl,
and cycloalkyl
group may be substituted at one or more positions by the usual aromatic
substituents such as
halogen namely F, Cl, or Br; allcyl such as methyl, ethyl, trifluoromethyl,
etc. Substituted phenyl
groups include such as halophenyl, trifluoromethylphenyl, monofluorophenyl, 2-
fluorophenyl, 4
fluorophenyl, or 2,4 difluorophenyl.
This invention also includes optical isomers, diastereomers, enantiomers,
polymorphs,
pseudopolymorphs, pharmaceutically acceptable salts, hydrates, or
biohydrolyzable esters,
amides, imides, or solvates of the fluoroquinolones of formula I and prodrugs
of these
2n
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compounds. A pseudopolymorph is a polymorph that differs from a true polymorph
by the
incorporation of solvent.
It has been found that the compounds of this invention, and compositions
containing these
compounds, are effective antimicrobial agents which are a new generation of
antibacterial
agents, in particular a new generation of respiratory antibacterials,
effective against multidrug-
resistant pathogens with broad spectrum coverage of gram-positive and gram-
negative microbes,
such as sensitive and fluoroquinolone-resistant pneumococci, staphylococci,
streptococci,
anaerobes, enterococci and atypical pathogens. hi addition, the compounds of
the invention have
1o potent cidal action for fluoroquinolone-resistant strains. The compounds of
the invention have
the preferred potential to address the unmet need for orally effective drugs
for the treatment of
multidrug-resistant pneumococcal infections like life-threatening pneumoniae
and menngitis, to
which pediatric and geriatric patients are vulnerable. They are unusually
cidal for viridans
streptococci, which are the causative groups of strains responsible for
bacteremias, soft tissue
infections, abscesses, sepsis and endocarditis. They are potential
antitubercular agents against
sensitive and resistant mycobacteria. The combination of physicochemical
parameters
contributed to the fluoroquinolone molecules by the location, hydrogen-
acceptor/-donor
properties, spatial bulk, hydrophobicity, stereochemical orientation of the
different contributing
substituents at the respective positions surprisingly provide compounds of the
invention that are
2o not effluxed by efflux pump bearing strains or have better uptake through
bacterial cellular
membranes. The above described physicochemical parameters also contribute to
their unusually
favourable drugability properties. They are orally effective with once-a-day
potential. They have
favourable penetration into tissues like the lung, liver, kidney and heart
over serum thus enabling
the targeting of organ-specific infections. They are relatively non-
phototoxic, with favourable
cytotoxicity and cardiotoxicity profiles which are usually the problem
toxicities displayed by the
fluoroquinolone class of compounds.
Among compounds that fall within the compounds of the aforementioned general
formula,
optically active compounds and diastereomeric isomers, each having the
substituent in a specific
3o stereo and three-dimensional spatial orientation have both excellent
antibacterial activity and
high safety features.
The compounds of the invention are sufficiently basic to form acid addition
salts. The
compounds are useful both in the free base form and the form of acid addition
salts, and both
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forms are within the purview of the invention. The acid addition salts are in
some cases a more
convenient form for use. Examples of appropriate acid addition salts include,
but are not limited
to acetate, benzenesulfonate, fixxnarate, hydrochloride, hydrobromide,
hydroiodide,
hydrogensulfate, isethionate, lactate, malate, maleate, malonate,
methanesulfonate, pamoate
(embonate), phosphate/diphosphate, stearate, succinate, sulfate, tartrate,
trifluoroacetate,
trifluoromethanesulfonate, p-toluenesulfonate, and the like. Preferred acid
addition salts include
halides, sulfonates, carboxylates, phosphates, and the like. However, other
appropriate
pharmaceutically acceptable salts within the scope of the invention are those
derived from other
mineral acids, organic acids and amino acids. The amino acid may be selected
from one of the 20
to naturally occurring amino acids: alanine, arginine, asparagine, aspartic
acid, cysteine, glutamine,
glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine,
phenylalanine, proline,
serine, threonine, tryptophan, tyrosine or valine or the optically active
isomers thereof or the
racemic mixtures thereof or dipeptides, tripeptides and polypeptides derived
from the
monoaminoacid units thereof. The compounds of the invention are also
sufficiently acidic to
form alkaline/base addition salts. Preferred allcali/base addition salts
include the alkali metal salts
(such as sodium and potassium), alkaline earth metal salts (such as magnesium
and calcium),
inorganic salts, such as anunonium, substituted ammonium, choline and organic
base salts from
basic amines such as diethanolamine, ethylenediamine, guanidine or
heterocyclic amines such as
piperidine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, morpholine,
piperazine, N-methyl
piperazine and the like or basic amino acids such as optically pure and
racemic isomers of
arginine, lysine, histidine, tryptophan and the like.
In practice, the use of the salt form inherently amounts to the use of the
base form of the active.
Acids used to prepare acid addition salts include preferably those, which
produce, when
combined with the free base, pharmaceutically acceptable salts. These salts
have anions that are
relatively innocuous to the animal organism, such as a mammal, in
pharmaceutical doses of the
salts so that the beneficial property inherent in the free base are not
vitiated by any side effects
ascribable to the acid's anions.
The pharmaceutically acceptable acid addition salts of compounds of the
formula I are prepared
in a conventional manner by treating a solution or suspension of the free base
of formula I with
about one chemical equivalent of a pharmaceutically acceptable acid such as an
inorganic acid or
organic acid. Conventional concentration and recrystallization techniques are
employed in
isolating the salts.
23
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For example, the free base can be dissolved in an aqueous alcohol solution
containing the
appropriate acid and the salt is isolated by evaporation of the solution.
Alternatively, they may be
prepared by reacting the free base with an acid in an organic solvent so that
the salt separates
directly. Where separation of the salt is difficult, it can be precipitated
with a second organic
solvent, or can be obtained by concentration of the solution.
Although pharmaceutically acceptable salts of the basic compounds are
preferred, all acid
addition salts are within the scope of the present invention. All acid
addition salts are useful as
1o sources of the free base form, even if the particular salt per se is
desired only as an intermediate
product. For example, when the salt is formed only for purposes of
purification or identification,
or when it is used as an intermediate in preparing a pharmaceutically
acceptable salt by ion
exchange procedures, these salts are clearly contemplated to be a part of this
invention.
is The amino moiety of piperidine is a potential point of formation for the
subject compounds of a
pharmaceutically acceptable anionic salt; such salts are included in the
subject invention
compounds. Preferred salts are acid addition salts with, for example, HCI,
CH3COOH,
CH3S03H, HCOOH, CF3COOH, gluconic acid, C1_ZO straight chain or branched
alkanoic acids or
one of the 20 naturally occurring amino acids as hereinbefore defined or
dipeptide, tripeptide or
20 polypeptide derivatives of the monoaminoacid units thereof.
"Host" is a substrate capable of sustaining a microbe, preferably it is a
living organism, and most
preferably an animal, more preferably a mammal, and more preferably still a
human.
2s "Biohydrolyzable amides" are aminoacyl, acylamino, or other amides of the
compounds of the
invention, where the amide does not essentially interfere, preferably does not
interfere, with the
activity of the compound, or where the amide is readily converted in vivo by a
host to yield an
active compound.
30 "Biohydrolyzable imides" are imides of the compounds of the invention,
where the imide does
not essentially interfere, preferably does not interfere, with the activity of
the compound, or
where the imide is readily converted in vivo by a host to yield an active
compound. Preferred
imides are hydroxyimides.
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"Biohydrolyzable esters" are esters of the compounds of the invention, where
the ester does not
essentially interfere, preferably does not interfere, with the antimicrobial
activity of the
compound, or where the ester is readily converted in a host to yield an active
compound. Many
such esters are known in the art. Such esters include lower alkyl esters,
lower acyloxy-alkyl
esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxynethyl,
pivaloyloxylmethyl and
pivaloyloxylethyl esters); lactonyl esters (such as phthalidyl and
thiophthalidyl esters) lower
alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl,
ethoxycarbonyloxyethyl and
isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and
alkylacylaminoalkyl
esters (such as acetamidomethyl esters) and alkyl amino acid esters.
The illustration of specific protected forms and other derivatives of the
formula 1 compounds are
not intended to be limiting. The application of other useful protecting
groups, salt forms, etc. is
within the ability of the skilled artisan.
"Optical isomer", "stereoisomer", "diastereomer" "polyrnorph"
"pseudopolyrnorph", "hydrates"
and "solvates" as referred to herein have the standard art recognized
meanings. Solvates are
generally formed during the process of crystallization when molar or submolar
amounts of the
solvents get incorporated into the crystal structure of the compound.
2o The compounds of the invention may contain chiral center(s), thus any such
compound includes
and contemplates each optical isomer, diastereomer or enantiomer thereof, in
purified or
substantially purified form, and mixtures thereof, including racemic mixtures.
The compounds of the invention may have one or more chiral centers. As a
result, one may
selectively prepare one optical isomer, including diastereomer and enantiomer,
over another, for
example by use of chiral starting materials, catalysts or solvents, one may
prepare both
stereoisomers or both optical isomers, including diastereomers and enantiomers
at once (a
racemic mixture). Since the compounds of the invention may exist as racemic
mixtures, mixtures
of optical isomers, including diastereomers and enantiomers, or stereoisomers,
they may be
separated using known methods, such as chiral resolution, chiral
chromatography and the like.
3o In addition, it is recognized that one optical isomer, including
diastereomer and enantiomer, or
stereoisomer may have favorable properties over the other. Thus when
disclosing and claiming
the invention, when one racemic mixture is disclosed, it is clearly
contemplated that both optical
isomers, including diastereomers and enantiomers, or stereoisomers
substantially free of the
other are disclosed and claimed as well.
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As used herein, a quinolone derivative includes prodrugs of a quinolone.
The preferred compounds of the invention are those compounds of Formula I
which are
composed of on one hand the following core fluoroquinolone moieties displayed
below minus
the respective 7-amino substituent:
0 CHI 0
F / COZ H H H
N
20 0 NH2 0
H H H
w
F
0 0 0
H H F / COz H
N
Cy H5 ~ F
/
F
H H H
so
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CHI 0
H H H
is ~ F
0 CH3 0
H F / Cpz H F / COZ H
~N N N
25 ~/
0
3o F / C02 H H H
. ~ JI
'N N
F ,.. .
F
0 O O O O
F / COZ H F F
/ ~ OOH / ~ OOH
N F ~ N. ~ F ~ N
so 0~ ~ C~H~ ~ C2Hs C~HS
U
F / i OH F
27 F
F
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It is preferred that one of the following amines can be combined with the core
fluoroquinolone
moieties as shown above. The prefix "c" represents cyclo:
CH C H CH NH
3 2 5 2 2 C F'
HN~OH HN OH HN OH HN OH HN~OH
CH CH3
iso-C H
CH3 CH3 CH3 ~-C3H7
HN~OH
HN OH HN OH HN OH HN OH
CH
ISO-C4H9 CH3 CH3 CZHS z 5
HN OH
CH
2 5
CH CH CH CH
3 3 3 3
HN NHz HN~NH HN~NHCH HN~NHC H HN, ,--NHc-C H
2 3 2 5 3 5
CH CH CH CH CH
3 2 5 2 5 °2 5 2 5
~ ( )
HN N CH3 z HN NHz HN NHCH3 HN NHC2H5 HN NHc-C31
CzHS CH3 CH3 CH3 CH3 CH3 CH3 CH CH
3 3
25HN N(CH3)zHN NHz HN NHCH3 HN NHCzHS HN~NHc-C H
3 5
CH
CH CH CH CH CH CH 3 CH3
3 3 3 3 3 3
HN. )--N(CH3)z HN~NHCOCH3 HN, ,--NHCOOCH2C6H5 HN NHCOO-t-C4H9
CH C H CH C H CH C H CH3 CzHs CzHS CzHs
2 5 3 2 5 3 2 5
HN~NHz HN~NHCH3 HN~NHc-C3H5 HN N(CH3)z HN NHz
28
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CH
CH CH CH
3 3 3
HN NHz HN NHCH3 HN NHC2H5 HN NHc-C3H5
CH
CH3 CH3 CH3 s
l0
CH CH CH CH C H CH C H
3 3 3 3 2 5 3 2 5
HN N(CH3)z HN NH HN NH HN NH
z z z
CH3 CH CH C H
3 3 2 5
including their optical isomers and diastereomers.
The combinations of the above mentioned cores and the above mentioned amines
provide the
fluoroquinolone compounds of the invention.
The following exemplary compounds are made using the procedures described
herein and
variations thereof which are within the purview of the skilled artisan's
practice. The examples
below do not limit the invention, but rather serve to illustrate some of
embodiments of the
invention.
In the following tables (Tables 1 - 16), there are provided some examples of
the compounds of
the invention. The lower case "c" represents "cyclo".
Table 1
H
CH.
Hi
Q = C-H, C-(C1-CZ) allcyl, C-OCH3, C-F or N, and when Q is CH and the nitrogen
atom to which
Rl is linked forms substituted 6 membered ring with the carbon atom of Q and
Rl are C-
CHZCHZC*H(CH3) or C-OCHZCH(CH3);
29
R9 i
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Rl = CZHS, c-C3H5, or C6H3Fz(2,,4), and when Q is CH and the nitrogen atom to
which RI is
linked forms substituted 6 membered ring with the carbon atom of Q and Rl are
C-
CHaCHZC*H(CH3) or C-OCHZCH(CH3);
RS = H, CH3, or NHz ;
Rg = H, or CH3;
R9 = H, or CH3;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Rl RS R$ R9 Isomer
C-H C-C3H5 H H H cis + trans
C-H c-C3H5 H H H cis
C-H c-C3H5 H H H traps
C-H c-C3H5 H CH3 H ()
C-H c-C3H5 H CH3 H (+)
C-H C-C3H5 H CH3 H (-)
C-H c-C3H5 CH3 H H traps
C-H c-C3H5 CH3 CH3 H (+)
C-H c-C3H5 CH3 CH3 H (+)
C-H c-C3H5 CH3 CH3 H (-)
C-CH3 CZHS H H H cis + traps
C-CH3 CZHS H H H cis
C-CH3 CZHS H H H ~~s
C-CH3 CZHS H CH3 H (+)
C-CH3 C2H5 H CH3 H (+)
C-CH3 CZHS H CH3 H (-)
C-CH3 c-C3H5 H H H cis + traps
C-CH3 c-C3H5 H H H cis
C-CHI c-C3H5 H H H traps
C-CH3 c-C3H5 H CH3 H (+)
C-CH3 c-C3H5 H CH3 H (+)
C-CH3 c-C3H5 H CH3 H (-)
C-CH3 c-C3H5 NHz H H cis + traps
C-CH3 c-C3H5 NHz H H cis
C-CH3 c-C3H5 NHZ H H traps
C-CH3 c-C3H5 NHz CH3 H (+)
C-CH3 c-C3H5 NHz CH3 H (+)
C-CH3 c-C3H5 NHz CH3 H (-)
C-CH3 C6H3Fz(2,4)H H H cis + traps
C-CH3 C6H3Fz(2,4)H H H cis
C-CH3 C6H3Fz(2,4)H H H traps
C-CH3 C6H3Fz(2,4)H CH3 H (+)
C-CH3 C6H3Fz(2,4)H CH3 H (+)
C-CH3 C6H3Fz(2,4)H CH3 H (-)
C-CZHS CZHS H H H cis + traps
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C-CzHs CZHS H H H cis
C-CzHs CZHS H H H traps
C-CZHS CZHS H CH3 H (+)
C-CzHs CZHS H CH3 H (+)
C-CZHS C2H5 H CH3 H (-)
C-C2H5 c-C3H5 H H H cis + traps
C-CZHS C-C3H5 H H H cis
C-CZHS c-C3H5 H H H traps
C-CZHS c-C3H5 H CH3 H (+)
C_CzHs c_C3H5 H CH3 H (+)
C-C2H5 c-C3H5 H CH3 H (-)
C-CZHS C6H3Fz(2,4H H H cis + traps
C-CZHS C6H3Fz(2,4H H H cis
C-CzHs C6H3Fz H H H traps
2,4)
C_CzHs C6H3Fz(~,4)H CH3 H
C_CzHs C6H3Fz(2,4)H CH3 H (+)
C_CzHs C6H3Fz(2,4)H CH3 H (-)
C-OCH3 c-C3H5 H H CH3 mixtures A+B
C-OCH3 c-C3H5 H H CH3 mixtare A of
isomers
C-OCH3 c-C3H5 H H CH3 mixture B of
isomers
C-OCH3 c-C3H5 H CH3 H
C-OCH3 c-CsHs H CH3 H (+)
C-OCH3 c-C3H5 H CH3 H (-)
C-OCH3 c-C3H5 H CH3 CH3 mixtures of
isomers
C-OCH3 C-C3H5 NHz H CH3 mixture A of
isomers
C-OCH3 c-C3H5 NHz H CH3 mixture B of
isomers
C-OCH3 c-C3H5 NHz H CH3 mixtures A+B
C-OCH3 c-C3H5 NHz CH3 H (+)
C-OCH3 c-C3H5 NHz CH3 H (+)
C-OCH3 c-C3H5 NHz CH3 H ' (-)
C-OCH3 c-C3H5 NHz CH3 CH3 mixtures of
isomers
C-OCH3 C6H3Fz(2,4)H CH3 H (+)
C-OCH3 C6H3Fz H CH3 H (+)
2,4)
C-OCH3 C6H3Fz(2,4)H CH3 H (-)
C-OCH3 C6H3Fz(2,4)NHz CH3 H (+)
C-OCH3 C6H3Fz(2,4)NHz CHs H (+)
C-OCH3 C6H3Fz(2,4)NHz CH3 H (-)
C-F c-C3H5 H CH3 H (+)
C-F c-C3H5 H CH3 H (+)
C-F c-C3H5 H CH3 H O
C-F c-C3H5 CH3 CH3 H (+)
C-F c-C3H5 CH3 CH3 H (+)
C-F c-C3H5 CH3 CH3 H (-)
C-F C-C3H5 NHz H CH3 mixtures A+B
C-F C-C3H5 NHz H CH3 mixture A of
isomers
C-F c-C3H5 NHz H CH3 mixture B of
isomers
C-F c-C3H5 NHz CH3 H (+)
C-F c-C3H5 NHz CH3 H (+)
C-F C-C3H5 NHz CH3 H (-)
m
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N c-C3H5 H H CH3 mixtures A+B
N c-C3H5 H H CH3 mixture A of
isomers
N c-C3H5 H H CH3 mixture B of
isomers
N c-C3H5 H CH3 H ()
N c-C3H5 H CH3 H (+)
N c-C3H5 H CH3 H (-)
N c-C3H5 CH3 CH3 H (+)
N c-C3H5 CH3 CH3 H (+)
N c-C3H5 CH3 CH3 H (-)
N C6H3F2(2,4)H H CH3 mixtures A+B
N C~H3F2(2,4)H H CH3 mixture A of
isomers
N C~H3F2(2,4)H H CH3 ~x~'e B of
isomers
N C6H3F2(2,4)H CH3 H ~ ()
N C6H3F2(2,4)H CH3 H (+)
N C6H3F2(2,4H CH3 H (-)
N C6H3Fz(2,4)CH3 CH3 H (+-)
N C6H3F2(2,4)CH3 CH3 H (+)
N C6H3F2(2,4)CH3 CH3 H (-)
C-CHZCHZC*H(CH3) H H H cis + traps
C-CH2CHZC*H(CH3 H H H cis
C-CH2CHZC*H(CH3) H H H traps
C-CH2CHZC*H(CH3) H H CH3 mixtures A+B
C-CHZCHZC*H(CH3) H CH3 H ()
C-CH2CHZC'~H(CH3) H CH3 H (+)
C-CH2CHZC*H(CH3) H CH3 H (-)
C-OCHaCH(CH3) H H H cis + traps
C-OCHZCH(CH3) H H H cis
C-OCH2CH(CH3) H H H
C-OCH2CH(CH3) H H CH3 mixtures A+B
C-OCH2CH(CH3) H CH3 H ()
C-OCHZCH(CH3) H CH3 H (+)
C-OCH2CH(CH3) H CH3 H (-)
Table 2
COOH
CH
CH3H
Q = C-H, C-CH3, C-OCH3, C-F or N, and when Q is CH and the nitrogen atom to
which RI is
linked forms substituted 6 membered ring with the carbon atom of Q and Rl are
C-
CHZCHZC*H(CH3) or C-OCHZCH(CH3);
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Rl = CzHs, c-C3Hs, or C6H3Fz(2,4), and when Q is CH and the nitrogen atom to
which Rl is
linked forms substituted 6 membered ring with the carbon atom of Q and Rl are
C-
CHZCHZC*H(CH3) or C-OCHZCH(CH3);
Rs = H, CH3, or NHz;
R8 = H, or CH3;
R9 = H, or CH3;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Q Rl RS R$ R9 Isomers
C-H c-C3Hs H H H cis + traps
C-H c-C3Hs H H H cis
C-H c-C3Hs H H H traps
C-H c-C3Hs H CH3 H ()
C-H c-C3Hs H CH3 H (+)
C-H c-C3Hs H CH3 H (-)
C-H c-C3Hs CH3 H H cis + traps
C-H c-C3Hs CH3 H H cis
C-H c-C3Hs CH3 H H traps
C-H c-C3Hs CH3 CH3 H (+)
C-H c-C3Hs CH3 CH3 H (+)
C-H c-C3Hs CH3 CH3 H (-)
C-CH3 c-C3Hs H H H cis + traps
C-CH3 c-C3Hs H H H cis
C-CH3 c-C3Hs H H H traps
C-OCH3 C2Hs H H CH3 mixture A
of isomers
C-OCH3 C2Hs H H CH3 mixture B
of isomers
C-OCH3 c-C3Hs H H CH3 mixture A+B
C-OCH3 c-C3Hs H H CH3 mixture A
of isomers
C-OCH3 c-C3Hs H H CH3 mixture B
of isomers
C-OCH3 c-C3Hs NHz H CH3 mixture A+B
C-OCH3~ c-C3Hs NHz H CH3 mixture A
of isomers
C-OCH3 c-C3Hs NHz H CH3 mixture B
of isomers
C-F c-C3Hs NHz H CH3 mixture A+B
C-F c-C3Hs NHz H CH3 mixture A
of isomers
C-F c-C3Hs NHz H CH3 rnix~'e B
of isomers
C-F G-C3H5 NHz CH3 H (-!-)
C-F c-C3Hs NHz CH3 H (+)
C-F c-C3Hs NHz CH3 H (-)
N c-C3Hs H H H cis + traps
N c-C3Hs H H H cis
N c-C3Hs H H H traps
c-C3Hs H H CH3 mixture A+B
c-C3Hs H H CH3 mixture A
of isomers
c-C3Hs H H I CH3 I mixture
B of isomers
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N c-C3H5 H CH3 H (+)
N c-C3H5 H CH3 H (+)
N c-C3H5 H CH3 H (-)
N C~H3FZ(2,4) H H H cis + trans
N ~C6H3Fz(2,4)H H H cis
N C~H3F2(2,4) H H H Trans
N C6H3F2(2,4) H H CH3 Mixture A+B
N CgH3F2(2,4 H H CHI mixture A of
isomers
N C6H3F2(2,4) H H CH3 mixture B of
isomers
N C6H3F2 2,4) H CH3 H ()
N C6H3F2(2,4) H CH3 H (+)
N C6H3F2(2,4) H CH3 H (-)
C-CHZCH2C*H(CH3) H H H cis + traps
C-CHZCHZC*H(CH3) H H H cis
C-CH2CH2C*H(CH3) H H H traps
C-CH2CHZC*H(CH3) H H CH3 mixture A+B
C-CHZCHZC*H(CH3) H H CH3 mixture A of
isomers
C-CHZCHZC*H(CH3) H H CH3 mixture B of
isomers
C-CHzCH2C*H(CH3) H CH3 H ()
C-CH2CHZC*H(CH3) H CH3 H (+)
C-CHZCHZC*H(CH3) H CH3 H (-)
C-OCHZCH(CH3) H H H cis + traps
C-OCHZCH(CH3) H H H cis
C-OCHzCH(CH3) H H H traps
C-OCHzCH(CH3) H H CH3 mixture A+B
C-OCHZCH(CH3) H H CH3 ~x~'e A of
isomers
C-OCHZCH(CH3) H H CH3 mixture B of
isomers
C-OCHZCH(CH3) H CH3 H (+)
C-OCHZCH(CH3) H CH3 H (+)
C-OCHZCH(CH3) H CH3 H ~ (-)
Table 3
COOH
CH
C2H5H
Q = C-H, C-CH3, C-OCH3, C-F or N, and when Q is CH and the nitrogen atom to
which R1 is
linked forms substituted 6 membered ring with the carbon atom of Q and Ri are
C-
CHZCHZC*H(CH3) or C-OCHZCH(CH3);
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Rl = c-C3Hs, or C6H3F2(2,4), and when Q is CH and the nitrogen atom to which
Rl is linked
forms substituted 6 membered ring with the carbon atom of Q and Rl are C-
CHaCH2C*H(CH3)
or C-OCHaCH(CH3);
Rs = H, CH3, or NH2;
R8 = H, or CH3;
R9 = H, or CH3;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Q RI RS R8 R9 Isomers
C-H C-C3H5 H CH3 H ()
C-H c-C3Hs H CH3 H (+)
C-H C-C3H5 H CH3 H (-)
C-H c-C3Hs CH3 CH3 H (+)
C_H c-C3Hs CH3 CH3 H (+)
C_H c-C3Hs CH3 CH3 H (-)
C-CH3 c-CsHs H CH3 H (+)
C-CH3 c-C3Hs H CH3 H (+)
C-CH3 c-C3Hs H CH3 H (-)
C-OCH3 c-C3Hs H H CH3 mixture A of
isomers
C-OCH3 c-C3Hs H H CH3 mixture B of
isomers
C-OCH3 c-C3Hs NH2 H CH3 mixture A+B
C-OCH3 c-C3Hs NHZ H CH3 mixture A of
isomers
C-OCH3 c-C3H5 NHZ H CH3 mixture B of
isomers
C-F c-C3Hs NHZ CH3 H (+)
C-F c_C3H5 NH2 CH3 H (+)
C-F c-C3Hs NH2 CH3 H (-)
C-F c-C3Hs NH2 H CH3 mixture A+B
C-F C-C3H5 NHZ H CH3 rruxtux'e A
of isomers
C-F c-C3H5 NH2 H CH3 r~xriu'e B of
isomers
N c-C3Hs H H H cis + trans
N c-C3Hs H H H cis
N c-C3Hs H H H traps
N c_C3Hs H CH3 H
N c_C3Hs H CH3 H (+)
N c_C3Hs H CH3 H (-)
N C6H3F2(2,4)H H H cis + traps
N C6H3F2(2,4)H H H cis
N C6H3Fz(2,4)H H H traps
N C6H3F2(2,4)H CH3 H (+)
N C6HsFa(2,4)H CH3 H (+)
N C6H3F2(~,4)H CH3 H (-)
C-CHZCH2C*H(CH3) H CH3 H (+)
C-CH2CHZC*H(CH3) H CH3 H (+) .
C-CH2CHZC*H(CH3) H CH3 H (-)
C-OCHZCH(CH3) H CH3 H
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C-OCHZCH(CH3) I H I CH3 ~ H ~ ( )
C-OCH~CH(CH~) H CH3 H (-)
Table 4
CH3
H~
1
IS
Q = C-H, C-OCH3, C-F or N, and when Q is CH and the nitrogen atom to which R1
is linked
forms substituted 6 membered ring with the carbon atom of Q and Rl are C-
CHZCHZC*H(CH3)
or C-OCHZCH(CH3);
Rl = c-C3H5, or C6H3Fz(2,4), and when Q is CH and the nitrogen atom to which
Rl is linked
2o forms substituted 6 membered ring with the caxbon atom of Q and Rl are C-
CHZCHZC*H(CH3)
or C-OCHZCH(CH3);
R5 = H, CH3, or NH2;
R$ = H, or CH3;
R9 = H, or CH3;
25 and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Rl RS Rg R9 Isomer
C-H C-C3H5 H~ CH3 H
C-H c-C3H5 H CH3 H (+)
C_H c-C3H5 H CH3 H (-)
C_H c-C3H5 CH3 CH3 H (+)
C-H c-C3H5 CH3 CH3 H (+)
C_H c-C3H5 CH3 CH3 H (-)
C-OCH3 c-C3Hs H H CH3 mixture A+B
C-OCH3 c-C3H5 H H CH3 mixture A
of isomers
C-OCH3 c-C3H5 H H CH3 mixture B
of isomers
C-OCH3 c-CsHs H H CH3 mixture A+B
C-OCH3 c-C3H5 H H CH3 mixture A
of isomers
C-OCH3 c-C3H5 H H CH3 ~x~'e B of
isomers
C-OCH3 c-C3H5 NHZ H CH3 mixture A+B
C-OCH3 c-C3H5 NHZ H CH3 ~x~'e A of
isomers
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C-OCH3 c-C3H5 NH2 H CH3 mixture B
of isomers
C-OCH3 c-C3H5 NHz H CH3 mixture A+B
C-OCH3 C-C3H5 NHZ H CH3 mixture A
of isomers
C-OCH3 C-C3H5 NHz H CH3 mixtuxe B
of isomers
C-OCH3 c-C3H5 NHz CH3 H ()
C-OCH3 c-C3H5 NHz CH3 H (+)
C-OCH3 c-C3HS NHz CH3 H (-)
C-F e-C3H5 NHz H CH3 mixture A+B
C-F c-C3H5 NHZ H CH3 mixture A
of isomers
C-F c-C3HS NHZ H CH3 mixture B
of isomers
C-F c-C3H~ NHz CH3 H (+_)
C-F c-C3H5 NHz CH3 H (+)
C-F c-C3H5 NHz CH3 H (-)
N c-C3H5 H H H cis + traps
N c-C3H5 H H H cis
N c-C3H5 H H H traps
N c-C3H5 H CH3 H ()
N c-C3H5 H CH3 H (+)
N c-C3H5 H CH3 H (-)
N C6H3Fz(2,4)H H H
cis + traps
N C6H3Fz(2,4)H H H cis
N C~H3Fz(2,4)H H H traps
N C6H3Fz(2,4)H CH3 H (+-)
N C6H3Fz(2,4)H CH3 H (+)
N C6H3Fz(2,4)H CH3 H (-)
C-CHZC HZC*H(CH3)H CH3 H ()
C-CHZCH2C*H(CH3) H CH3 H (+)
C-CHzCHzC*H(CH3) H CHI H (-)
C-OCH2CH(CH3) H CH3 H )
C-OCHZCH(CH3) H CH3 H +
C-OCHZCH(CH3) H CH3 H (-)
Table 5
OOH
CH3
~- ......t....... "1
IQ-1~ Ra T
Q = C-H, C-CH3, C-OCH3, C-F or N, and when Q is CH and the nitrogen atom to
which Rl is
linked forms substituted 6 membered ring with the carbon atom of Q and Rl axe
C-
CHZCHZC*H(CH3) or C-OCHZCH(CH3);
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Rl = c-C3H5, or C6H3Fz(2,4), and when Q is CH and the nitrogen atom to which
Rl is linked.
forms substituted 6 membered ring with the carbon atom of Q and Rl are C-
CHZCHZC*H(CH3)
or C-OCHZCH(CH3);
Rs = H, CH3, or NHz;
R$ = H, or CH3;
R9 = H, or CH3;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Q Rl RS R$ R9 Isomers
C-H C-C3Hs H CH3 H ()
C-H c-C3Hs H CH3 H (+)
C-H C-C3Hg H CH3 H (-)
C-H c-C3Hs CH3 CH3 H ()
C-H C-C3Hs CH3 CH3 H (+)
C-H c-C3Hs CH3 CH3 H (-)
C-CH3 C-C3Hs H H H cis + traps
C-CH3 c-C3Hs H H H cis
C-CH3 c-C3Hs H H H traps
C-CH3 c-C3Hs H CH3 H ()
C-CH3 c-CHs H CH3 H (+)
C-CH3 c-C3Hs H CH3 H (-)
C-OCH3 c-C3Hs H H H cis + traps
C-OCH3 c-C3Hs H H H cis
C-OCH3 c-C3Hs H H H traps
C-OCH3 c-C3Hs H H CH3 mixtures A+B
C-OCH3 c-C3Hs H H CH3 mixture A of
isomers
C-OCH3 c-C3Hs H H CH3 mixture B of
isomers
C-OCH3 c-C3Hs H CH3 H (+)
C-OCH3 c-C3Hs H CH3 H (+)
C-OCH3 c-C3Hs H CH3 H (-)
C-OCH3 c-C3Hs NHz H H cis + traps
C-OCH3 c-C3Hs NHz H H cis
C-OCH3 c-C3Hs NHz H H traps
C-OCH3 c-C3Hs NHz H CH3 mixture A+B
C-OCH3 c-C3Hs NHZ H CH3 mixture A of
isomers
C-OCH3 c-C3Hs NHZ H CH3 mixture B of
isomers
C-OCH3 c-C3Hs NHz CH3 H (-!-)
C-OCH3 c-C3Hs NHz CH3 H (+)
C-OCH3 c-C3Hs NHz CH3 H (-)
C-F c-C3Hs CH3 CH3 H ()
C-F c-C3Hs CH3 CH3 H +
C-F c-C3Hs CH3 CH3 H
C-F e-C3Hs NHz H H ~is+trans
C-F c-C3Hs NHz H H
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C-F C-C3H5 NHz H H trans
C-F c-C3H5 NHz H CH3 mixtures A+B
C-F C-C3H5 NHz H CH3 mixture A of
isomers
C-F C-C3H5 NHZ H CH3 mixture B of
isomers
C-F c-C3H5 NHz CH3 H ()
C-F c_C3H5 NHz CHs H +
C-F c-C3H5 NHz CH3 H
N C-C3H5 H H H eis + trans
N c-C3H5 H H H eis
N c-C3H5 H H H trans
N c-C3H5 H CH3 H ()
N c-C3H5 H CH3 H +
N c-C3H5 H CH3 H
N C6H3Fz(2,4)H H H ois + traps
N C6H3Fz(2,4H H H eis
N C6H3Fz H H H traps
2,4)
N C6H3Fz(2,4)H CH3 H ()
N C6H3Fz(2,4)H CH3 H +
N C6H3Fz(2,4)H CH3 H -)
C-CHzCH 2C*H(CH3) H CH3 H
C-CHZCHzC*H(CH3) H CH3 H +)
C-CHZCHZC*H(CH3) H CH3 H
C-OCH2CH(CH3) H H H cis+trans
C-OCH2CH(CH3) H H H ~;S
C-OCHZCH(CH3) H H H traps
C-OCHZCH(CH3) H CH3 H ()
C-OCHzCH(CH3) H CH3 H (+)
C-OCH2CH(CH3) H CH3 H (-)
Table 6
H
C.
Q = C-(C1-Cz) alkyl, C-OCH3, C-F or N;
Rl = CzHs, C-C3Hs, or C6H3Fz(2,4);
RS = H, or NHz;
R8 = H, CH3, or CzHS;
R9 = H, CH3, or C2Hs;
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and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Q Rl RS R$ R9 Isomers
C-CH3 CZHS H H H cis + trams
C-CH3 C6H3Fz(2,4)H H H cis + tr~ans
C-CzHs CZHS H H H cis + tr-ans
C-CZHs c-C3Hs H H H cis + traps
'
C-CZHs C6H3Fz(2,4)H H H cis + tr-ans
C-OCH3 c-C3Hs H H H cis + traps
C-OCH3 c-C3Hs H H H Cis
C-OCH3 c-C3Hs H H H Traps
C-OCH3 c-C3Hs H H CZHs mixture A+B
C-OCH3 c-C3H5 H H CZHs ~x~'e A of isomers
C-OCH3 c-C3H5 H H CZHs ~x~.n'e B of
isomers
C-OCH3 c-C3Hs H CH3 H ~ ()
C-OCH3 c-C3Hs H CH3 H (+)
C-OCH3 c-C3Hs H CH3 H (-)
C-OCH3 c-C3Hs H CH3 CH3 mixtare of isomers
C-OCH3 c-C3Hs H CH3 CZHs ~x~'e of isomers
C-OCH3 c-C3Hs H CH3 CZHs mixture of isomers
C-OCH3 c-C3Hs H CZHs H
C-OCH3 c-C3Hs H CZHs H (+)
C-OCH3 c-C3Hs H CZHs H (-)
C-OCH3 c-C3Hs H CH3 H (-)
C-OCH3 c-C3Hs NHz H H cis + traps
C-OCH3 c-C3Hs NHz H H cis
C-OCH3 c-C3Hs NHz H H Traps
C-OCH3 c-C3Hs NHz H CzHs mixture A+B
C-OCH3 c-C3H5 NHz H CzHS texture A of
isomers
C-OCH3 c-C3Hs NHz H CZHS ~xt~e B of isomers
C-OCH3 C-C3H5 NHz CH3 H ()
C-OCH3 c-C3Hs NHz CH3 H (+)
C-OCH3 c-C3Hs NHz CH3 H (-)
C-OCH3 c-C3Hs NHz CH3 CH3 mixture of isomers
C-OCH3 c-C3Hs NHz CH3 CzHs ~~'e of isomers
C-OCH3 c-C3Hs NHz CzHs H
C-OCH3 c-C3Hs NHz CZHs H (+)
C-OCH3 c-C3Hs NHz CzHs H (-)
C-F c-C3Hs NHz H H cis + traps
C-F C-C3H5 NHz H H cis
C-F c-C3Hs NHz H H traps
C-F c-C3Hs NHz H CZHs mixture A+B
C-F c-C3H5 NHz H CZHS mixture A of
isomers
C-F C-C3H5 NHz H CzHs mixture B of
isomers
C-F c-C3Hs NHz CH3 H (+)
C-F c_C3Hs NHz CH3 H (+)
C_F c_C3Hs ~z CH3 H (-)
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C-F c-C3Hs NHZ CH3 CH3 mixture of isomers
C-F c-C3Hs NH2 CH3 CZHs mixture of isomers
C-F c-C3Hs NHZ CZHs H ()
C-F c-C3Hs NH2 CZHs H (+)
C-F c-C3Hs NHZ C2Hs H (-)
N c-C3Hs H H H cis + traps
N c-CHs H H H cis
N c-C3Hs H H H traps
N C6H3F2(2,4 H H H cis + traps
N C6H3F2 2,4) H H H cis
N C6H3F2(2,4) H H I ~ traps
H
Table 7
S
H
I
T
Q = C-OCH3, or C-F, and when Q is CH and the nitrogen atom to which R1 is
linked forms
substituted 6 membered ring with the carbon atom of Q and Rl is C-OCHZCH(CH3);
Rl = c-C3Hs and when Q is CH and the nitrogen atom to which Rl is linked forms
substituted 6
membered ring with the carbon atom of Q and Rl is C-OCHZCH(CH3);
Rs = H, or NHZ;
R$ = H, or CH3;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Q Rt RS R8 Isomer
C-OCH3 c-C3Hs H H cis +
traps
C-OCH3 c-C3Hs H H cis
C-OCH3 c-C3Hs H H traps
C-OCH3 c-CsHs H CH3 ()
C-OCH3 c-C3Hs H CH3 (+)
C-OCH3 c-C3Hs H CH3 (-)
C-OCH3 c-C3Hs NHZ H cis +
traps
C-OCH3 c-C3Hs NHZ H cis
C-OCH3 c-C3Hs NHZ H traps
C-OCH3 C-C3Hs NHZ CH3 ()
C-OCH3 c-C3Hs NHZ ~ CH3 ~ (+)
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C-OCH3 c-C3Hs NHz CH3 (-)
C-F c-C3Hs NHz H cis +
traps
C-F c-C3Hs NHz H cis
C-F c-C3Hs NHz H traps
C-F c-C3Hs NHz CH3 (+_)
C-F c-C3Hs NHz CH3 (+)
C-F c-C3Hs NHz CH3 (-)
C-OCH2CH(CH3 H H cis +
traps
C-OCHZCH(CH3) H H cis
C-OCHZCH(CH3) H H traps
Table 8
Cz
15 Q = C-OCH3;
Rl = c_C3Hs:
Rs = H, or NHz;
R8 = H, or CH3;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Q Rl RS Rg Isomer
C-OCH3 c-C3Hs H H ~;S+trans
C-OCH3 c-C3Hs H H ~;S
C-OCH3 c-C3Hs H H traps
C-OCH3 c-CsHs H CH3 ()
C-OCH3 c-C3Hs H CH3 (+)
C-OCH3 c-C3Hs H CH3
C-OCH3 c-C3Hs NHZ H cis+trans
C-OCH3 c-C3Hs NHz H
C-OCH3 c-C3Hs NHz H traps
C-OCH3 c-C3Hs NHz CH3 ()
C-OCH3 c-C3Hs NHz CH3 (+)
C-OCH3 c-C3Hs NHz CH3
42
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C2H
Table 9
CH3~
,i ..... .......
CH3 T
Q = C-OCH3;
Ri = c_CsHs~
R5 = H, or NHZ;
R$ = H, or CH3;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Rl RS R8 Isomer
C-OCH3 c-C3H5 H H cis +
trans
C-OCH3 c-C3Hs H H cis
C-OCH3 c-C3Hs H H ~a~
C-OCH3 c-C3Hs H CH3 ()
C-OCH3 c-C3H5 H CH3 (+)
C-OCH3 c-C3Hs H CH3 (-)
C-OCH3 c-C3H5 NHZ H cis +
trans
C-OCH3 c-C3Hs NHZ H cis
C-OCH3 C-C3H5 NHZ H traps
C-OCH3 c-C3Hs NHZ CH3 ()
C-OCH3 c-C3Hs NHZ CHs (+)
C-OCH3 c-C3Hs NH2 I CHs ~ (-)
Table 10
OOH
CH,
R6H
Q = C-OCH3, or C-F;
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Rs = H, or NHz;
R6 = COCH3, CO-(O-Cz-C4 alkyl), COOCH2C6Hs, amino C1_4 alkanoyl, carboxy amino
Cl-a
alkanoyl, dipeptidoalkanoyl wherein the terminal amino group is unprotected or
protected with a
t-Boc-protecting group.
Q Rs ~ R6 Isomer
C-OCH3 H COCH3 ()
C-OCH3 H COOC2Hs ()
C-OCH3 H COOC2Hs (+)
C-OCH3 H COOC2Hs (-)
C-OCH3 H COOC(CH3)3 ()
C-OCH3 H COOC(CH3)3 (+)
C-OCH3 H COOL CH3)3 (-)
C-OCH3 H COOCHZC6Hs ()
C-OCH3 H COOCHzC6Hs (+)
C-OCH3 H COOCHzC6Hs (-)
C-OCH3 H COC*H(CH3)NHz mixture
C-OCH3 H COC*H(NHz)CH(CH3 z mixture
C-OCH3 H COCH2CH(NHz)COOH mixture
C-OCH3 H COC*H(CH3)NHCOC*H(CH3)NH-t-Bocmixture
C-OCH3 H COC*H(CH3)NHCOC*H(CH3 NHz mixture
C-F NHz COCH3 mixture
Table 11
15
Y = NHz, NHRz, wherein Rz is H, Cl_z alkyl; or Y is OR3 where R3 is CI_4 alkyl
(branched or
unbranched); CHzC6Hs; Cz-C3 carboxylic acid and their Cl-C4 alkyl esters
(unbranched or
branched); or five or six member heterocycle (unsubstituted or substituted);
or oc-aminoalkanoyl
such as x-aminopropionyl;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Y Isomers
~z
NHCH3 ()
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NHCZHS ()
NHCH(CH3 COOH ()
OCH3 ()
OCZHS - ( ).
OC3H~(n) ()
OC3H~(i (+_)
OC4H9(n) ()
OCHZC6H5 ()
OCHZCOOH ()
OCH20COCH3 (~
OCHZOCOCH(CH3)Z
OCHZOCOC CH3 3 (+)
OCHZCHZOCOCH3 ()
OCHZCHZOCOC(CH3 3
O-(N-methyl-4- iperidinyl(+)
1- yrrolidinyl (-!-)
1- i eridinyl (+)
1-piperazinyl ()
1-mo holin 1 (+)
OCH2CH(NHZ)COOH (+) I
Table 12
to
h~
T
Q = C-(C1-Cz) alkyl, C-OCH3, C-F or N, and when Q is CH and the nitrogen atom
to which R1 is
linked forms substituted 6 membered ring with the carbon atom of Q and Rl is C-
CH2CHzC*H(CH3);
Rl = C2H5, c-C3H5, or C6H3FZ(2,4), and when Q is CH and the nitrogen atom to
which Rl is
linked forms substituted 6 membered ring with the carbon atom of Q and Rl is C-
CHZCH2C*H(CH3);
RS = H, or NH2;
2o R$ = H, C3-C4 alkyl (unbranched or branched), CH2C6H5 , or CF3;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
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Q Rl RS R8 Isomers
C-CH3 CzHs H H -
C-CH3 C6H3F2 H H
2,4
C-CZHS CZHS H H
C-C2H5 c-C3H5 H H
C-CZHS C6H3Fa H H
2,4
C-OCH3 c-C3H5 H n-C3H~ cis+trans
C-OCH3 c-C3H5 H i-C3H~ cis+trans
C-OCH3 c-C3H5 H n-C4H9 cis+trans
C-OCH3 c-C3H5 H i-C4H~ cis+trans
C-OCH3 c-C3H5 H CHZC6H5 cis+trans
C-OCH3 c-C3H5 H CF3 cis+trans
C-OCH3 c-C3H5 NH2 CF3 cis+trans
C-F c-C3H5 NHZ CF3 cis+trans
N I C6H3F2(2,4)H CF3 I cis+trans
I ~
Table 13
CI
OH
R9 ~
Q = C-H, C-(C1-C2) alkyl, C-OCH3, C-F or N, and when Q is CH and the nitrogen
atom to which
Rl is linked forms substituted 6 membered ring with the carbon atom of Q and
Rl are C-
CHZCHZC*H(CH3) or C-OCHZCH(CH3);
Rl = CZHS, c-C3H5, or C6H3F2(2,4), and when Q is CH and the nitrogen atom to
which Rl is
linked forms substituted 6 membered ring with the carbon atom of Q and Rl are
C-
CH2CH2C*H(CH3) or C-OCHZCH(CH3);
2o RS = H, or NH2;
R8 = H, CHs, or C2H5;
R9 = H, CH3, or CZHS;
and . optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs 'thereof.
Q R1 RS R8 R9 Isomer
C-H c-C3H5 H H H cis +
traps
C-H c-C3H5 H H H cis
C-H C-C3H5 H H H traps
~
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C-H ~ c-C3H5 H H CH3 mixture
C-H c-C3H5 H CH3 H
C-CH3 CZHS H H H cis +
traps
C-CH3 CZHS H H H cis
C-CH3 C2H5 H H H ixans
C-CH3 C2H5 H CH3 H cis +
traps
C-CH3 c-C3H5 H H H cis +
traps
C-CH3 c-C3H5 H H H cis
C-CH3 c-C3H5 H H H traps
C-CH3 c-C3H5 H CH3 H cis +
traps
C-CH3 c-C3H5 NHZ H H cis +
- traps
C-CH3 c-C3H5 NHz H H cis
C-CH3 c-C3H5 NHz H H ~'a~
C-CH3 C6H3Fz(2,4)H H H cis +
traps
C-CH3 C6H3Fz(2,4)H H H cis
C-CH3 C6H3Fz 2,4 H H H pans
C-CH3 C6H3Fz(2,4)H CH3 H cis +
traps
C-CZHS C2H5 H H H cis +
traps
C-CzHs , CzHs H H H _ cis
-
C-CZHS CZHS H H H traps
C-C2H5 CZHS H CH3 H cis +
traps
C-C2H5 c-C3H5 H H H cis +
traps
C-CZHS c-C3H5 H H H cis
C-CZH~ c-C3H5 H H H ~,a
C-CZHS c-C3H5 H CH3 H
C-CZHS C6H3F2(2,4)H H H cis +
traps
C-CZHS C6H3F2 2,,4)H H H Cis
C-CZHS C6H3F2(2,4)H H H Traps
C-CZHS C6H3Fz(2,4)H CH3 H
C-OCH3 c-C3H5 H H H cis +
traps
C-OCH3 c-C3H5 H H H Cis
C-OCH3 c-C3H5 H H H Traps
C-OCH3 c-C3H5 H H CH3 mixtures
C-OCH3 c-C3H5 H H CH3 mixtures
C-OCH3 c-C3H5 H H CH3 mixtures
C-OCH3 c-C3H5 H CH3 H
C-OCH3 c-C3H5 H CH3 CH3 mixtures
C-OCH3 c-C3H5 H CzHS H
C-OCH3 c-C3H5 H CZHS CH3 mixtures
C-OCH3 c-C3H5 H CZHS C2H5 mixtures
C-OCH3 c-C3H5 NHz H H cis +
traps
C-OCH3 c-C3H5 NHz H H cis
C-OCH3 c-C3H5 NHz H H traps
C-OCH3 c-C3H5 NHz H CH3 mixtures
C-OCH3 c-C3H5 NHz CH3 H +
-
C-OCH3 C-C3H5 NHz CH3 CH3 mixtures
C-OCH3 c-CsHs ~z CzHs H +
C-OCH3 C-C3H5 NHz C2H5 CH3 mixtures
C-OCH3 c_C3H5 NHZ C2H5 CZHS fixtures
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C-F c-C3H5 H H CH3 mixtures
C-F c-C3H5 H H H
C-F c-C3H5 H CH3 H
C-F c-C3H5 NHZ H H cis+trans
C-F c-C3H5 NHa H CH3 mixture
C-F c-C3H5 NH2 CH3 H
C-F c-C3H5 NHz CZHS H
N c-C3H5 H H H cis
+ trans
N c-C3H5 H H H cis
N c-C3Hs H H H traps
N c-C3H5 H H CH3 yes
N c-C3H5 H CH3 H -!-
N C6H3F2(2,4)H H H cis
+ traps
N C6H3F2(2,4)H H H cis
N C6H3F2(2,4)H H H traps
N C6H3Fz(2,4)H H CH3 mixtures
N C6H3F2(2,4 H CH3 H -!-
C-OCHZCH(CH3) H H H cis+trans
C-OCHZCH H H CH3 mixtures
CH3)
C-OCH2CH(CH3) H CH3 ~ H ~ -!-
Table 14
10
H
R9 T
Q = C-H, C-(C1-CZ) alkyl, C-OCH3, C-F or N, and when Q is CH and the nitrogen
atom to which
Ri is linked forms substituted 6 membered ring with the carbon atom of Q and
Rl is C-
OCHZCH(CH3);
Rl = C1_2 alkyl, c-C3H5, or C~H3F2(2,4), and when Q is CH and the nitrogen
atom to Which Rl is
linked forms substituted 6 membered ring with the carbon atom of Q and Rl is C-
OCHZCH(CH3);
2o RS = H, or NH2;
R9 = H, or CZHS;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
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Q Rl RS R9 Isomers
C-H CH3 H H cis+trans
C-CH3 c-C3H5 H H cis+trans
C-CH3 c-C3H5 NHz H cis+trans
C-CH3 CZHS H H cis+trans
C-CH3 C6H3Fz H H cis+trans
2,4)
C-CzHs CZHS ~ H H cis+trans
C-CZHS c-C3H5 H H cis+trans
C-C2H5 C6H3Fz(2,4H H cis+trans
C-OCH3 c-C3H5 H H cis+trans
C-OCH3 c-C3H5 H CzHs Mixture
C-OCH3 c-C3H5 NHz H cis+trans
C-OCH3 c-C3H5 NHz CzHs Mixture
C-F C-C3H5 NHz H cis+trans
N c-C3H5 H H cis+trans
N C6H3Fz(2,4)H H cis+trans
C- OCHzCH(CH3) H H cis+trans
Table 15
OH
HZNCH2
HG
T
Q = C-H, C-OCH3, C-F or N, and when Q is CH and the nitrogen atom to which Rl
is linked
forms substituted 6 membered ring with the carbon atom of Q and Rl is C-
OCHZCH(CH3);
Rl = c-C3H5, or C6H3Fz(2,4), and when Q is CH and the nitrogen atom to which
Rl is linked
forms substituted 6 mernbered ring with the carbon atom of Q and Rl is C-
OCHzCH(CH3);
RS = H, CH3, or NHz;
and optical isomers, pharmaceutically acceptable salts, hydrates,
biohydrolyzable esters,
polymorphs and pseudomorphs thereof.
Q R1 RS Isomers
C-H c-C3H5 H cis+trans
C-H c-C3H5 CH3 cis+trans
C-OCH3 c-C3H5 H cis+trans
' C-F c-C3H5 CH3 cis+irans
C-F C-C3H5 NHz cis+trans
N c-C3H5 H cis+trans
N C6H3Fz(2,4)H cis+lrans
C- OCH ZCH CHs) H cis+trans
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Table 16
H
HzN
Q = C-CH3, or C-C2Hs;
T
Rl = CZHs, c-C3Hs, or C- C6H3Fa(2,4);
and pharmaceutically acceptable salts, hydrates, biohydrolyzable esters,
polymorphs and
pseudomorphs thereof.
Q Ri
C-CH3 CZHs
C-CH3 c-C3Hs
C-CH3 C6H3F2(2,4
C_CzHs Calls
C_CzHs c_CsHs
C-CaHs CsH3Fa(~~4)
2o Particularly preferred compounds of the invention are those where Q is C-
OCH3 and C-CH3. A
list of these preferred compounds are given below under the heading of
specific compounds of
the invention.
Specific co~nponnds of the invention
1. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-metho~y-7-(4-amino-3-methyl-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid (mixture of cis and traps isomers) and its salts;
2. tratis -1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-
piperidinyl)
4-oxo-quinoline-3-carboxylic acid (racemic mixture of 4R, 3R and 4S, 3S) and
its salts;
3. traps-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid (4R, 3R) and its salts;
4. traps-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid (4S, 3S) and its salts;
5. cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-
piperidinyl)-4
oxo-quinoline-3-carboxylic acid (racemic mixture of 4S, 3R and 4R, 3S) and its
salts;
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6. cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid (4S, 3R) and its salts;
7. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid (mixture of cis and trans isomers) and its salts;
8. 1-Cyclopropyl-6-fluoro-1,4-dihydxo-8-methoxy-7-(4-methylamino-3-methyl-1-
piperidiliyl)-
4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
9. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
10. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylainino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
11. 1-Cyclopropyl-6-fluoro-1,4-dihydxo-8-methoxy-7-(4-cyclopropylamino-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
12. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-ethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
13. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
14. 1-Cyclopropyl-6-fluoro-1,4-dihydxo-8-methoxy-7-(4-dimethylamino-3-ethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
15. 1-Ethyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-oxo-
2o quinoline-3-carboxylic acid and its isomers and its salts;
16. 1-(2,4-Difluorophenyl)-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
17. (+)-1-Cyclopropyl-6-fl, uoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-
1-piperidinyl)-
4-oxo-quinoline-3-carboxylic acid, its salts and its polymorphs;
18. (~)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid hydrochloride and its polymorphs;
19. (~)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid methane sulfonate and its polymorphs;
20. (~)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid gluconate and its polymorphs;
21. (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid, its salts and its polymoprhs;
22. (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid hydrochloride and its polymorphs;
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23. (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid methane sulfonate and its polymorphs;
24. (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid gluconate and its polymorphs;
25. (-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid, its salts and its polymorphs;
26. (-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid hydrochloride and its polymorphs;
27. (-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid methane sulfonate and its polymorphs;
28. (-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid gluconate and its polymorphs;
29. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-acetylamino-3,3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
i5 30.1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-carbethoxyamino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
31. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4 t-butyloxycarbonylamino-
3,3-dimethyl-
1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
32. (~)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-
benzyloxycarbonylamino-3,3-
dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its salts;
33. (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-
benzyloxycarbonylamino-3,3-
dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its salts;
34. (-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-
benzyloxycarbonylamino-3,3-
dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its salts;
35.1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,3-dimethyl-
1
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
36. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
37. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3,3-
dimethyl-1-
3o piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
38. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
39. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3-methyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid, its isomers, and its salts;
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40. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-ethyl-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid, its isomers, and its salts;
41. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3-ethyl-
3-methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid, its isomers, and its salts;
42. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethyamino-3-ethyl-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
43. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-diethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
44. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3, 5-dimethyl-1-
pip eridinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
45. 1-Cyclopropyl-6-fluoro-1,4- dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
46. 1-Ethyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
47.1-Cyclopropyl-6-fluoro-1~,4-dihydro-8-methoxy-7-(4-ethylamino-3,5-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
48. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-3, 5-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
49. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3, 5-
dimethyl-1-
2o piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
50. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3,5-trimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
51. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3,5-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
52.1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-3,5-
diethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid, its isomers, and its salts;
53. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid (mixture of cis and traps
isomers) and its
salts;
54. traps-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid (racemic mixture of 4R, 3R and
4S, 3S) and
its salts;
55. tr~ans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-rnethoxy-7-(4-amino-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid (4R, 3R) and its salts;
53
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56. tf°ans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-
amino-3-methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid (4S, 3S) and its salts;
57. cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid (racemic mixture of 4S, 3R and
4R, 3S) and
its salts;
58. cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid (4S, 3R) and its salts;
59. cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid (4R, 3S) and its salts;
60.5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
61. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
62. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-
3-methyl-
1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
63 . 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3
-methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
64. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-1-
pip eridinyl)-
4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
65.5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-
ethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
66. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8 -rnethoxy-7-(4-
cyclopropylamino-3-ethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
67. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-
ethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
68. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
69. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-acetylamino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
70.5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-
ethoxycarbonylamino-3,3-
dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and
its salts;
71. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-t-butoxycarbonyl
amino-3,3-
dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and
its salts;
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72. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-
benzyloxycarbonyl amino-
3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers
and its salts;
73. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3, 3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
74. 5-Amino-1-cyclopropyl-6-fluoro-1;4-dihydro-8-methoxy-7-(4-ethylamino-3, 3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
75. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-
3, 3-
dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and
its salts;
76. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-
3,3-dimethyl-
1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
77. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid, its isomers, and its salts;
78. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-
ethyl-3
methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid, its isomers, and its
salts;
79.5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-
3-methyl
3-ethyl-1- piperidinyl)-4-oxo-quinoline-3-carboxylic acid, its isomers, and
its salts;
80. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-
methyl-3-
ethyl-1- piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and
its salts;
81: 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-
diethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
82. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,5-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
83. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3,5-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
84.5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-ethylamino-3,5-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
85. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-cyclopropylamino-
3,5-
dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers arid
its salts;
86. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-
3,5-dimethyl-
3o 1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
8 7. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3, 3, 5-
trimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
88. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-ethyl-
3,5-dimethyl-
1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
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89. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3-methyl-
3,5-diethyl-
1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
90. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl -7-(4-amino-1-piperidinyl)-4-
oxo-quinoline-3-
carboxylic acid and its salts;
91. 1- Cyclopropyl -6-fluoro-8-methyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-
4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
92. cis/trans-1- Cyclopropyl -6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
93. cis-1- Cyclopropyl -6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-
1,4-dihydro-4-
to oxo-quinoline-3-carboxylic acid and its isomers and its salts;
94. trans-1- Cyclopropyl -6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-
piperidinyl)-1,4-dihydro-
4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
95. (~)-1- Cyclopropyl -6-fluoro-8-methyl-7-(4-hydroxy-3,3-dimethyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
15 96. cis/trans-1- Cyclopropyl -6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
97. trasZS-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl -7-(4-amino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers, its salts and its polymorphs;
98. tYans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl -7-(4-amino-3-methyl-1-
piperidinyl)-4-
20 oxo-quinoline-3-carboxylic acid hydrochloride and its polymorphs;
99. cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
100. cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl -7-(4-amino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride and its polynorphs;
25 101. ( ~ )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid, its salts and its polymorphs;
10~. ( ~ )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride and its
polymorphs;
103. ( ~ )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-
1-
3o piperidinyl)-4-oxo-quinoline-3-carboxylic acid methane sulfonate and its
polymorphs;
104. ( ~ )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid gluconate and its polymorphs;
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105. (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid, its salts and its polymorphs;
106. ( + )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride and its
polymorphs;
107. ( + )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid methane sulfonate and its
polymorphs;
108. ( + )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid gluconate and its polymorphs;
109. (-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its salts;
I10. ( - )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-
1
piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride and its
polymorphs;
111. ( - )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-
1
piperidinyl)-4-oxo-quinoline-3-carboxylic acid methane sulfonate and its
polymorphs;
112. ( - )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid gluconate and its polymorphs;
113. 1-Cyclopropyl-6-fluoro-1,4-dihydro 8-methyl -7-(4-methylamino-3-methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
114. 1-Cyclopropyl-6-fluoro-1,4-dihydro -8-methyl -7-(4-dimethylamino-3-methyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
115. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl -7-(4-ethylamino-3,3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
116. 1-Cyclopropyl-6-fluoro-1,4-dihydro -8-methyl -7-(4-dimethylamino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
117. 1-Cyclopropyl-6-fluoro-8-ethyl-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-
oxo-quinoline-
3-carboxylic acid and its isomers and its salts;
118. 1- Cyclopropyl -6-fluoro-8-ethyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-
4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
119. cis/trans-1- Cyclopropyl -6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
120. cis-1- Cyclopropyl -6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-
1,4-dihydro-
4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
121. trans-1- Cyclopropyl -6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
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122. (~)-1- Cyclopropyl -6-fluoro-8-ethyl-7-(4-hydroxy-3,3-dimethyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
123. cis/trans-1- Cyclopropyl -6-fluoro-8-ethyl-7-(4-hydroxy-3-ethyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
124. trans-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl -7-(4-amino-3-methyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
125. cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-$-ethyl-7-(4-amino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
126. ( ~ )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-
1-
l0 piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its salts;
127. (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid and its salts;
128. (-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid and its salts;
15 129. t~~ans-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl -7-(4-amino-
3-methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
130. cis-1-5-Amino-I-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
131. ( ~ )-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-
dimethyl-1-
2o piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its salts;
132. (+)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its salts;
133. (-)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its salts;
25 134. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
135. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
13 6. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-ethyl-1-
piperidinyl)-4-
30 oxo-quinoline-3-carboxylic acid and its isomers and its salts;
137. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-ethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
138. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-n-propyl-1-
piperidinyl)-
4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
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139. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-
isopropyl 1-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
140. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-
isobutyl 1-1-
piperidhlyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
141. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-aminomethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
142. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3-
aminomethyl-
1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
143. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3-dimethyl-1-
to piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
144. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
145. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,5-dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
15 146. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,5-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
147. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3,5-trimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
148. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-3,3,5-
trimethyl-
20 1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its
salts;
149. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and isomers and its salts;
150. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
25 151. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-trifluoro
methyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
152. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-hydroxy-4-
trifluoro
methyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and its isomers and
its salts;
153. 1-Ethyl-6-fluoro-8-methyl-7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-
quinoline-3-
30 carboxylic acid and its isomers and its salts;
154. 1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-
quinoline-3-
carboxylic acid and its isomers and its salts;
155. cis/trans-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-
1,4-dihydro-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
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156. cis-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
157. traps-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
158. cis/traps-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-
1,4-dihydro-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
159. cis-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
160. traps-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-
dihydro-4-
to oxo-quinoline-3-carboxylic acid and its isomers and its salts;
161. (~)-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-
dihydro-4-
oxo-quinoline-3-carboxylic acid and its salts;
162. (+)-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-
dihydro-4-
oxo-quinoline-3-carboxylic acid and its salts;
15 163. (-)-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-piperidinyl)-
1,4-dihydro-4-
oxo-quinoline-3-carboxylic acid and its salts;
164. (~)-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-
1,4-dihydro-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
165. cis/traps-1-Ethyl-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-piperidinyl)-
1,4-dihydro-4-
20 oxo-quinoline-3-carboxylic acid and its isomers and its salts;
166. cis/traps-1-Ethyl-6-fluoro-8-methyl-7-(4-amino-3-ethyl-1-piperidinyl)-1,4-
dihydro-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
167. 1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
25 168. 1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-1-piperidinyl)-
1,4-dihydro-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts;
169. cis/traps-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-
piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
170. cis-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-
piperidinyl)-1,4-
3o dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
171. traps-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-methyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
172. cis/traps-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-
1-
piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and
its salts;
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173. cis-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
174. traps-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-
piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
175. (~)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its salts;
176. (+)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its salts;
177. (-)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-
l0 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its salts;
178. (~)-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3,3-dimethyl-1-
piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
179. cis/traps-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-
piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
15 180. cisltrans-1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7-(4-amino-3-ethyl-
1-piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
181. 1,8-Diethyl-6-fluoro -7-(4-amino-1-piperidinyl)-1,4-dihydro-4-oxo-
quinoline-3-
carboxylic acid and its isomers and its salts;
182. 1,8-Diethyl-6-fluoro -7-(4-hydroxy-1-piperidinyl)-1,4-dihydro-4-oxo-
quinoline-3-
2o carboxylic acid and its isomers and its salts;
183. cisltrans-1,8-Diethyl-6-fluoro -7-(4-amino-3-methyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
184, cis-1,8-Diethyl-6-fluoro -7-(4-amino-3-methyl-1-piperidinyl)-1,4-dihydro-
4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
25 185. traps-1,8-Diethyl-6-fluoro -7-(4-amino-3-methyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
186. cis/trans-1,8-Diethyl-6-fluoro -7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
187. cis-1,8-Diethyl-6-fluoro -7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
30 quinoline-3-carboxylic acid and its isomers and its salts;
188. traps-1,8-Diethyl-6-fluoro -7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
189. (~)-1,8-Diethyl -6-fluoro -7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its salts;
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190. (+)-1,8-Diethyl -6-fluoro -7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its salts;
191. (-)-1,8-Diethyl -6-fluoro -7-(4-amino-3,3-dimethyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its salts;
192. (~)-1,8-Diethyl -6-fluoro-7-(4-hydroxy-3,3-dimethyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
193. cis/trans-1,8-Diethyl -6-fluoro -7-(4-hydroxy-3-ethyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
194. cis/trans-1,8-Diethyl -6-fluoro- -7-(4-amino-3-ethyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
195. 1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
196. 1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-1-pip eridinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts;
197. cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-methyl-1-
piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
198. cis-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-methyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
199. trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-methyl-1-
piperidinyl)-1,4-
2o dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
200. cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-
piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
201. cis-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
202. trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-methyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
203. (~)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its salts;
204. (+)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its salts;
205. (-)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its salts;
206. (~)-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3,3-dimethyl-1-
piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
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207. cis/trans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-hydroxy-3-ethyl-1-
piperidinyl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
208. cisltrans-1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-(4-amino-3-ethyl-1-
piperidinyl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid and its isomers and its salts;
Some preferred compounds of the invention are:
(~)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its polymorphs.
(~)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride and its polymorphs..
(~)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid methane sulfonate and its polymorphs..
(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid gluconate and its polymorphs..
(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its polymorphs..
(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride and its polymorphs..
2o (+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid methane sulfonate and its polyrnorphs..
(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid gluconate and its polymorphs..
(-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its polymorphs..
(-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride and its polymorphs..
(-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid methane sulfonate and its polymorphs..
(-)-1-Cyclopropyl-6-fluoro-1,4-dihydro- 8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid gluconate and its polymorphs..
cis/trans-1- Cyclopropyl -6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-
piperidinyl)-1,4-dihydro-
4-oxo-quinoline-3-carboxylic acid and its isomers and its salts.
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cis-1- Cyclopropyl -6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts. ,
traps-1- Cyclopropyl -6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-
1,4-dihydro-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts.
cis/trans-1- Cyclopropyl -6-fluoro-8-methyl-7-(4-hydroxy-3-ethyl-1-
piperidinyl)-1,4-dihydro-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts.
tf~atas-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl -7-(4-amino-3-methyl-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts. .
traps-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl -7-(4-amino-3-methyl-1-
piperidinyl)-4-oxo-
to quinoline-3-carboxylic acid hydrochloride and its polymorphs.
cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid and its isomers and its salts.
cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid hydrochloride and its polymorphs.
( ~ )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its polymorphs..
( ~ )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride and its polyrnorphs..
( ~ )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid methane sulfonate and its polymorphs..
( ~ )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid gluconate and its polymorphs;
( + )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its polymorphs..
( + )-1-Cyelopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride and its polymorphs..
( + )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid methane sulfonate and its polymorphs..
( + )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid gluconate and its polyrnorphs;
( - )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its polymorphs..
( - )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride and its polymorphs..
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( - )-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid methane sulfonate and its polymorphs;
(-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid gluconate and its polymorphs;
1-Cyclopropyl-6-fluoro-1,4-dihydro -8-methyl -7-(4-dimethylamino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid and its isomers and its salts.
Other preferred compounds of the invention include:
l0 Crystalline polymorphic form of (~)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-
amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid
hydrochloride-Polymorph
A1
Crystalline polymorphic form of (~)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-
amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid
hydrochloride -Polymorph
15 A2:
Crystalline polymorphic form of (-)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-amino-
3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride-
Polymorph Al:
2o Crystalline polymorphic form of (-)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-amino-
3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride-
Polymorph A2:
Crystalline polymorphic form of (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-
amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid
hydrochloride-Polymorph
25 A1:
Crystalline polymorphic form of (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-
amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid
hydrochloride-Polymorph
A2:
Another embodiment of the invention encompasses a process to make the
compounds of the
invention, which comprises the following general methods.
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General Methods
In general, the fluoroquinolone compounds were prepared by heating the
appropriate 6,7-dihalo
fluoroquinolone core moiety (bearing either a free 3 carboxylic acid or a 3
carboxylic acid ester
or an 03 04 borane chelate) or the appropriate 8,9-dihalo fluoroquinolone core
moiety (bearing
an O-B-diacetoxy borane) with the appropriate, 4-substituted/unsubstituted
amino/hydroxy-3-
substituted/unsubstituted piperidine moiety in an organic solvent, optionally
in the presence of a
base at 50° - 120°C, preferably 50 - 90°C for 4 - 72 hr
preferably 16 - 24 hr and isolating the
product. Suitable solvents include acetone, alcohol, acetonitrile, dimethyl
sulphoxide, N,N-
dimethylformamide, preferably acetonitrile or dimethyl sulphoxide. Suitable
bases include
1o triethylamine, pyridine, 1,S-diazabicyclo[4.3.0]non-5-ene (DBN), 1,7-
diazabicyclo[5.4.0]undec-
7-ene (DBE, preferably triethylamine. When the amino function of the 7
piperidino substituent
bears am alkoxycarbonyl or aralkyloxycarbonyl as a protecting group, the
protecting group is
removed by treatment with aqueous alkali or inorganic acid at~30 - 120
°C, preferably 30 - 80 °C
for 4 - 12 hours, preferably 4 - 6 hours and isolating the product.
Method 1
1-Cyclopropyl-6-fluoro-7-{(4-aminolsubstituted amino /disubstituted
amino/hydroxy-3
alkyl/3,3-dialkyl/3,5-dialkyl)1-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-
carboxylic acid and
isomers were prepared by heating a mixture of 1-cyclopropyl-6-fluoro-7-chloro-
1,4-dihydro-4-
oxo-quinoline-3-carboxylic acid with appropriate {4-(amino/ substituted
amino/disubstituted
amino/hydroxy -3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl))piperidine in
an organic solvent
optionally in the presence of a base at 50° - 120°C, preferably
90°C for 4- 72 hr. The solvent
may be selected from acetone, alcohol, acetonitrile, dimethyl sulphoxide, N,N-
dimethylformamide preferably acetonitrile or dimethyl sulphoxide. The base may
be selected
from triethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,7-
diazabicyclo[5.4.0]undec-7-ene (DBT~, preferably triethylamine.
Method 2
1-Cyclopropyl-6-fluoro-8-methoxy-7-{(4-amino/substituted amino/ disubstituted
amino/
3o hydroxy -3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)-1-piperidinyl)-1,4-
dihydro-4-oxo-
quinoline-3-carboxylic acid and isomers were prepared by a procedure described
in Method 1
by using [1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-
carboxylate-
03,04]difluoroboron chelate and appropriate {4-(amino/ substituted
amino/disubstituted
amino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl)}piperidine followed by
hydrolysis of the
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obtained boron complex in presence of base such as aqueous sodium hydroxide,
aqueous
potassium hydroxide, triethylamine, diisopropylethylamine in solvents such as
acetonitrile,
methyl alcohol, ethyl alcohol.
Method 3
5-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-{(4-amino/substituted amino/
disubstituted
amino/ hydroxy -3-alkyl/3,3-dialky113,5-dialkyl/3,3,5-trialkyl)1-1-
piperidinyl) -1,4-dihydro -4-
oxo-quinoline-3-carboxylic acid and isomers were prepared by a procedure
described in Method
1 by using 5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy--1,4-dihydro-4-oxo-
quinoline-3-
to carboxylic acid and appropriate {4-(amino/ substituted amino/disubstituted
amino/ hydroxy -3-
alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)} piperidine.
Method 4
9-Fluoro-5-methyl-6,7-dihydro-8-(3/4/S-substituted-4-hydroxyl-1-piperidinyl)-1-
oxo-1H,SH
benzo[i,j]quinolizine-2-carboxylic acid its isomers were prepared by a
procedure described in
Method 1 by using (0-B)-diacetoxy-{S-(-)-8,9-difluoro-5-methyl-6,7-dihydro-1-
oxo-1H,SH-
benzo[i,j] quinolizine-2-carboxy}borane and appropriate 3/4/5-substituted-4-
hydroxy piperidine
and optionally hydrolyzing the obtained boron complex in the presence of a
base.
Method 5
1-Cyclopropyl-6-fluoro-7-{(4-amino/substituted amino/ disubstituted amino/
hydroxy -3-
alkyl/3,3-dialkyl/3,5-dialkyl)1-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-
naphthyridone-3-carboxylic
acid and isomers were prepared by a procedure described in Method 1 by using 1-
cyclopropyl-
7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridone-3-carboxylic acid and
appropriate {4-
amino/ substituted amino/disubstituted amino/hydroxy-3-alkyl/3,3-dialkyl/3,5-
dialkyl)}piperidine.
Method 6
1-(2,4-Difluorophenyl)-6-fluoro-7-{(4-amino/substituted amino/ disubstituted
amino/ hydroxy-3-
3o alkyl/3,3-dialkyl/3,5-dialkyl)1-1-piperidinyl)-1,4-dihydro-4-oxo-1,8-
naphthyridone-3-carboxylic
acid and isomers were prepared by a procedure described in Method 1 by using
ethyl-1-
(difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridone-3-
carboxylate and
appropriate {4-amino/ substituted amino/disubstituted amino/hydroxy-3-
alkyl/3,3-dialkyl/3,5-
dialkyl}piperidine.
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Method 7
1-Cyclopropyl-6-fluoro-8-methoxy-7-[4-amino-3-alkyl/3,3-dialkyl/3,5-dialkyl-1-
piperidinyl}-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and enantiomers were prepared by
hydrolysis of
racemic or optically active I-cyclopropyl-6-fluoro-I,4-dihydro-8-methoxy-7- f
4-
benzyloxycarbonylamino/ t-butyloxycarbonylamino/ ethoxycarbonylamino-3-
alkyl/3,3-
diallcyl/3,5-dialkyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid with
aqueous alkali
preferably aqueous sodium hydroxide or inorganic acid such as hydrochloric
acid at ambient
temperature for 2-12 hr.
Method 8
1-Cyclopropyl-6-fluoro -8-methyl-7-{4-amino/substituted amino/ disubstituted
amino/ hydroxy -
3-alkyl/3,3-dialkyl-1-piperidinyl}- 1,4-dihydro-4-oxo-quinoline-3-carboxylic
acid and isomers
were prepared by a procedure described in Method 1 by using [1-cyclopropyl-6,7-
difluoro-8-
methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04] difluoroboron chelate
and
appropriate {4-amino/ substituted amino/disubstituted aminolhydroxy-3-
alkyl/3,3-
dialkyl}piperidine and optionally hydrolyzing the obtained boron complex in
the presence of a
base.
Method 9
1-Cyclopropyl-6-fluoro -8-ethyl-7-{4-amino/substituted amino/ disubstituted
amino/ hydroxy -3-
2o alky113,3-dialkyl-1-piperidinyl}- 1,4-dihydro-4-oxo-quinoline-3-carboxylic
acid and isomers
were prepared by a procedure described in Method 1 by using [1-cyclopropyl-6,7-
difluoro-8-
ethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04] difluoroboron chelate
and appropriate
{4-amino/ substituted amino/disubstituted arninol hydroxy -3-alkyl/3,3-
dialkyl}piperidine and
optionally hydrolyzing the obtained boron complex in the presence of a base.
Method 10
5-Amino-1-cyclopropyl-6-fluoro -8-methyl-7-{4-amino/substituted amino/
disubstituted amino/
hydroxy -3-alkyl/3,3-dialkyl-1-piperidinyl}-1,4-dihydro -4-oxo-quinoline-3-
carboxylic acid and
3o isomers were prepared by a procedure described in Method 1 by using [5-
amino-1-cyclopropyl-
6,7-difluoro-8-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-
03,04]difluoroboron chelate
and appropriate f 4-amino/ substituted amino/disubstituted amino/ hydroxy -3-
alkyl/3,3-
diallcyl}piperidine and optionally hydrolyzing the obtained boron complex in
the presence of a
base.
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Method 11
1-Ethyl-6-fluoro-8-methyl-7-f4-amino/substituted amino/ disubstituted amino/
hydroxy -3-
alkyl/3,3-diallcyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylic
acid and isomers
were prepared by a procedure described in Method 1 by using [1-ethyl-6,7-
difluoro -8-methyl-
1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04]difluoroboron chelate and
appropriate {4-
amino/ substituted amino/disubstituted amino/ hydroxy -3-alkyl/3,3-
dialkyl}piperidine and
optionally hydrolyzing the obtained boron complex in the presence of a base.
1o Method 12
1,8-Diethyl-6-fluoro-7-~4-amino/substituted amino/ disubstituted amino/
hydroxy -3-alkyl/3,3-
dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and
isomers were prepared
by a procedure described in Method 1 by using [1,8-diethyl-6,7-difluoxo -1,4-
dihydro-4-oxo-
quinoline-3-carboxylate-03,04]difluoroboron chelate and appropriate {4-amino/
substituted
amino/disubstituted amino/ hydroxy -3-alkyl/3,3-dialkyl}piperidine and
optionally hydrolyzing
the obtained boron complex in the presence of a base.
Method 13
1-(2,4-Difluorophenyl)-6-fluoro-8-methyl-7- f 4-amino/substituted amino/
disubstituted amino/
hydroxy -3-alkyl/3,3-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-
carboxylic acid and
isomers were prepared by a procedure described in Method 1 by using [1-(2,4-
Difluorophenyl)-
6,7-difluoro -8-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-
03,04]difluoroboron chelate
and appropriate f 4-amino/ substituted amino/disubstituted amino/ hydroxy -3-
alkyll3,3-
dialkyl}piperidine and optionally hydrolyzing the obtained boron complex in
the presence of a
base.
Method 14
1-(2,4-Difluorophenyl)-6-fluoro-8-ethyl-7-{4-amino/substituted amino/
disubstituted amino/
hydroxy -3-alkyl/3,3-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-
carboxylic acid and
isomers were prepared by a procedure described in Method 1 by using [1-(2,4-
Difluorophenyl)-
6,7-difluoxo-8-ethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04]
difluoroboron chelate
and appropriate {4-amino/ substituted amino/disubstituted amino/ hydroxy -3-
alkyl/3,3-
dialkyl}piperidine and optionally hydrolyzing the obtained boron complex in
the presence of a
base.
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Another aspect of the invention are novel amines that can be used to prepare
the compounds of
formula 1. The amines are listed below and the methods for their preparation
are included in
parenthesis alongside each one of them as follows:
4-Amino-3,3-dimethylpiperidine (prepared as in Preparation 10, step 2) and
optical enantiomers
thereof (prepared as in Preparation 37 and Preparation 38)
4-Methylamino-3,3-dimethylpiperidine (prepared as in Preparation 11) and
optical enantiomers
thereof (can be prepared by methods known to those skilled in the art);
4-Ethylamino-3,3-dimethylpiperidine (prepared as in Preparation 12) and
optical enantiomers
to thereof (can be prepared by methods known to those skilled in the art);
4-Cyclopropylamino-3,3-dimethylpiperidine (prepared as in Preparation I3) and
optical
enantiomers thereof (can be prepared by methods known to those skilled in the
art);
4-Dimethylamino-3,3-dimethylpiperidine (prepared as in Preparation 14) and
optical
enantiomers thereof (can be prepared by methods known to those skilled in the
art);
4-Benzylamino -3,3-dimethylpiperidine and optical enantiomers thereof (can be
prepared by
methods known to those skilled in the art);
4-Acetylamino-3,3-dimethylpiperidine (prepared as in Preparation 16) and
optical enantiomers
thereof (can be prepared by methods known to those skilled in the art);
4-Carbethoxyamino-3,3-dimethylpiperidine (prepared as in Preparation 15) and
optical
2o enantiomers thereof (can be prepared by methods known to those skilled in
the art);,
(~)-4 t-Butyloxycarbonylamino -3,3-dimethylpiperidine (can be prepared
according to
Preparation 19, step 7 using the racemic mixture of isomers in place of the
optical enantiomer)
(+)-4-t-Butyloxycarbonylamino -3,3-dimethylpiperidine (prepared according to
Preparation 19,
step 7);
(-)-4 t-Butyloxycarbonylamino-3,3-dimethylpiperidine (prepared according to
Preparation 19,
step 7);
4-Benzyloxycarbonylamino-3,3-dimethylpiperidine (prepared as in Preparation
18) and optical
enantiomers thereof (can be prepared by methods known to those skilled in the
art);
4-Amino- 1-benzyl- 3,3-dimethylpiperidine (prepared as in Preparation 10, step
2)and optical
3o enantiomers thereof (can be prepared by methods known to those skilled in
the art);
4-Amino- 1-carbethoxy- 3,3-dimethylpiperidine and optical enantiomers thereof
(can be
prepared by methods known to those skilled in the art);
4-Amino- 1 t-butyloxycarbonyl- 3,3-dimethylpiperidine (prepared as in
Preparation 18, step 2)
and optical enantiomers thereof (can be prepared by methods known to those
skilled in the axt);
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(~)- 4-Amino-1-benzyloxycarbonyl- 3,3-dimethylpiperidine (prepared as in
Preparation 19, step
2);
(+)- 4-Amino-1-benzyloxycarbonyl- 3,3-dimethylpiperidine (prepared as in
Preparation 19, step
3); and
(-)- 4-Amino-1-benzyloxycarbonyl- 3,3-dimethylpiperidine (prepared as in
Preparation 19, step
4);
4-Amino-1-carbethoxy-3-methylpiperidine (prepared as in Preparation 1, step
1);
4-Amino-3,5-diethyl-3-methylpiperidine (prepared as in Preparation 32);
4-Amino-1-carbethoxy-3,5-dimethylpiperidine (prepared as in Preparation 25,
step 2);
4-Amino-1-benzyl-3,5-diethyl-3-methylpiperidine (prepared as in Preparation
32);
4-Amino-3,5-dimethyl-3-ethylpiperidine (prepaxed as in Preparation 33);
4-Amino-1-benzyl-3,5-dimethyl-3-ethylpiperidine (prepared as in Preparation
33);
4-Amino-3,5-diethylpiperidine (prepared as in Preparation 30);
4-Amino-1-benzyl-3,5-diethylpiperidine (prepared as in Preparation 30);
4-Amino-3,3,5-trimethylpiperidine (prepared as in Preparation 31);
4-Amino-3,3-diethylpiperidine (prepared as in Preparation 24);
4-Amino-1-benzyl-3,3-diethylpiperidine (prepared as in Preparation 24);
4-Amino-3,5-dimethylpiperidine (prepared as in Preparation 25);
Mixture of isomers of 4-amino-1-carbethoxy-3,5-dimethylpiperidine (prepared as
in Preparation
25, step 1);
4-Amino-3-ethyl-3-methylpiperidine (prepared as in Preparation 20);
4-Amino-1-benzyl-3-ethyl-3-methylpiperidine (prepared as in Preparation 20);
4-Acetylamino-1-benzyl-3,3-dimethyl piperidine (prepared as in Preparation
16);
cis or t~asas-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine (prepared
as in Preparation
34, step 4);
cis-4-t-Butyloxycarbonylamino-3-methylpiperidine (prepared as in Preparation
35);
trans-4-t-Butyloxycarbonylamino-3-rnethylpiperidine (prepared as in
Preparation 36);
1-Benzyl-4-carbethoxyamino-3,3-dimethyl piperidine (prepared as in Preparation
15);
1-Benzyl-4-cyclopropylamino-3-ethyl-3-methylpiperidine (prepared as in
Preparation 22);
1-Benzyl-4-methylamino-3-ethyl-3-methylpiperidine (prepared as in Preparation
21);
1-Benzyl-4-dimethylawino-3-ethyl-3-methylpiperidine (prepared as in
Preparation 23);
1-Carbethoxy-4-ethylamino-3-methylpiperidine (prepared as in Preparation 3,
step 1);
4-Cyclopropylamino-3-methylpiperidine (prepared as in Preparation 4, step 2);
I-Carbethoxy-4-cyclopropylamino-3-methylpiperidine (prepared as in Preparation
4, step 2);
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1-Carbethoxy-4-dimethylamino-3-methylpiperidine (prepared as in Preparation 5,
step 1);
4-Cyclopropylamino-3-ethylpiperidine (prepared as in Preparation 8);
4-Cyclopropylamino-3-ethyl-3-methylpiperidine (prepared as in Preparation 22);
4-Cyclopropylamino-3,5-dimethylpiperidine (prepared as in Preparation 28);
4-Dimethylamino-3-ethylpiperidine (prepared as in Preparation 9);
4-Dimethylamino-3-methylpiperidine (prepared as in Preparation 5, step 2);
4-Dimethylamino-3,5-dimethylpiperidine (prepared as in Preparation 29);
4-Dimethylamino-3-ethyl-3-Methylpiperidine (prepared as in Preparation 23);
4-Methylamino-3-methylpiperidine (prepared as in Preparation 2, step 2);
l0 4-Ethylamino-3-methylpiperidine (prepared as in Preparation 3, step 2);
4-Methylamino-3-ethylpiperidine (prepared as in Preparation 7);
4-Methylamino-3-ethyl-3-methylpiperidine (prepared as in Preparation 21);
4-Methylamino-3,5-dimethylpiperidine (prepared as in Preparation 26);
4-Ethylamino-3,5-dimethylpiperidine (prepared as in Preparation 27);
In addition, the invention also provides novel intermediate amines that can be
used to prepare
the amines listed above. The novel intermediate amines are listed below and
the methods for
their preparation are included in parenthesis alongside each one of them as
follows:
3,3-Dimethyl-4-piperidone (prepared as in Preparation 17);
1- t-Butyloxycarbonyl-3,3-dimethyl-4-piperidone (prepared as in Preparation
18, step 1);
1- Benzyloxycarbonyl-3,3-dimethyl-4-piperidone (prepared as in Preparation 19,
step 1);
(~)-4-Benzyloxycarbonylamino-1 tbutyloxycarbonyl-3,3-dimethylpiperidine
(prepared as in
Preparation 18, step 3);
(+)-1- Benzyloxycarbonyl-4-tbutyloxycarbonylamino-3,3-dimethylpiperidine
(prepared as in
Preparation 19, step 5);
(-)-1-Benzyloxycarbonyl- -4 t-butyloxycarbonylamino-3,3-dimethylpiperidine
(prepared as in
Preparation 19, step 6);
1-Carbethoxy-3,5-dimethyl-4-piperidone (prepared as in Preparation 25, step
1);
3,3,5-Trimethyl-4-piperidone (prepared as in Preparation 31); ,_
Ethyl-1-benzyl-3-methyl-4-oxo-piperidine-3-carboxylate (prepared as in
Preparation 34, step 1);
The above mentioned novel intermediates are used to prepare the novel amines
of the invention.
The intermediates can be classified as (a) the unprotected dialkyl or trialkyl
4-piperidones, (b)
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the dialkyl or trialkyl 1-N protected 4-piperidones and (c) the dialkyl 1-N
protected, 4-protected
amino piperidines.
The unprotected diallcyl or trialkyl 4-piperidone intermediates can be used to
prepare the
corresponding amines by using the known art of transforming a carbonyl
functionality to an
amine functionality by using reagents such as ammonimm acetate, methyl amine
hydrocholide,
ethyl amine hydrochloride, cyclopropyl amine etc to form an imino
functionality which upon
subsequent reduction can produce desired amine after reduction. The reducing
agents can be
selected from sodium cyano borohydride or palladium on carbon in a solvent
such as methanol,
ethanol, ethyl acetate etc.
The dialkyl or trialkyl 1-N protected 4-piperidones are used to prepare the
corresponding
deprotected amines by using the known art of deprotection such as
hydrogenolysis to deprotect a
benzyloxycarbonyl moiety or a benzyl moiety by stirnng the intermediate in the
presence of ,
catalysts and a hydrogen source. The catalyst can be selected from palladium
on carbon,
palladium hydroxide on carbon and hydrogen source can be selected from
hydrogen gas or
ammonium formate, cyclohexene, in solvents such as methanol ethanol, ethyl
acetate etc.
The dialkyl 1-N protected, 4-protected amino piperidines can be used to
prepare the
2o corresponding deprotected amines by using the known art of deprotection as
described. in the
previous paragraph to remove a benzyloxycarbonyl or a benzyl moiety and the
known art of
removing a butyloxycarbonyl group by stirring the intermediate, in the
presence of inorganic
acids such as concentrated hydrochloric acid or organic acids such as
trifluoro acetic acid in
solvents such as tetrahydrofuran, dioxane etc.
The preparations 1 - 38 include examples of the specific preparative methods
used of how to use
the described amine intermediates for the preparation of the corresponding
novel amines of the
invention.
3o The pharmaceutically acceptable acid addition salts of compounds of the
formula I are prepared
in a conventional manner by treating a solution or suspension of the free base
of the formula I
with about one chemical equivalent of a pharmaceutically acceptable acid such
as an inorganic
acid or organic acid. Conventional concentration and recrystallization
techniques are employed
in isolating the salts. For example, the free base can be dissolved in an
aqueous alcohol solution
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containing the appropriate acid and the salt is isolated by evaporation of the
solution.
Alternatively, they may be prepared by reacting the free base with an acid in
an organic solvent
so that the salt separates directly. Where separation of the salt is
difficult, it can be precipitated
with a second organic solvent, or can be obtained by concentration of the
solution. Examples of
appropriate acid addition salts include, but are not limited to acetate,
benzenesulfonate, fumarate,
hydrochloride, hydrobromide, hydroiodide, hydrogensulfate, isethionate,
lactate, malate,
maleate, malonate, methanesulfonate, pamoate (embonate),
phosphate/diphosphate, stearate,
succinate, sulfate, tartrate, trifluoroacetate, trifluoromethanesulfonate, p-
toluenesulfonate, and
the like. Preferred acid addition salts include halides, sulfonates,
carboxylates, phosphates, and
l0 the like. However, other appropriate pharmaceutically acceptable salts
within the scope of the
invention are those derived from other mineral acids, organic acids and amino
acids. The amino
acid may be selected from one of the 20 naturally occurring amino acids:
alanine, arginine,
asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine,
histidine, isoleucine,
leucine, lysine, methionine, phenylalanine, proline, serine, threonine,
tryptophan, tyrosine or
valine or the optically active isomers thereof or the racemic mixtures thereof
or dipeptides,
tripeptides and polypeptides derived from the monoaminoacid units thereof.
The pharmaceutically acceptable alkali/base addition salts of compounds of
formula I may be
prepared by conventional methods from the corresponding acids e.g. by reaction
with about one
2o equimolar amount of an alkali/base. Preferred alkali/base addition salts
include the alkali metal
salts (such as sodium and potassium), alkaline earth metal salts (such as
magnesium and
calcium), inorganic salts, such as ammonium, substituted ammonium, choline and
organic base
salts from basic amines such as diethanolamine, N-methyl glucamine,
ethylenediamine,
guanidine or heterocyclic amines such as piperidine, hydroxyethylpyrrolidine,
hydroxyethylpiperidine, morpholine, piperazine, N-methyl piperazine and the
like or basic amino
acids such as optically pure and racemic isomers of arginine, lysine,
histidine, tryptophan and the
like.
The hydrates, pseudopolymorphs, polyrnorphs and solvates of all the compounds
of the
3o invention are also included and are prepared by conventional methods.
The present invention also encompasses the process of making the intermediate
amines, as
illustrated in the detailed preparations that are used in the condensation
with the fluoroquinolone
nucleus. For instance, the 3-substituted-4-aminopiperidine intermediates can
exist as a mixture
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of cis and traps isomers and the mixture was prepared by the procedure
described in Preparation
1. The mixture of cis and traps isomers of 4-amino-3-methylpiperidine was
prepared by a
sequence as described in Preparation 34. Each cis and tra~is isomer is a
racemic mixture and can
be resolved into optically active enantiomeric forms by the usual methods of
optical resolution
of amines known to those skilled in the art. Other 3-substituted-4-
aminopiperidines were
synthesised using a similar method.
The 4-amino-3,5-dimethylpiperidine intermediate was obtained in the following
manner. 4-
Amino-1-carbethoxy-3,5-dimethylpiperidine (a mixture of isomers) was prepared
according to
to the procedure described in Preparation 25 and separated by silica gel
column chromatography
into the two major mixtures of isomers, one mixture designated as upper
mixture A and the
. other designated as lower mixture B of isomers. Conformations of these
mixtures of isomers
were not assigned. Using any one of the mixtures of isomers of 4-amino-3,5-
dimethylpiperidine,
some compounds of the invention can be prepared by condensing the respective
mixture of
isomers of 4-amino-3,5-dimethyl-piperidine with [1-cyclopropyl-6,7-difluoro-
1,4-dihydro-8
methoxy-4-oxo-quinoline-3-carboxylate-03,04]difluoroboron chelate, as
exemplified in the
" section on examples described later in this specification.
The present invention also encompasses an antiinfective composition for the
treatment of
2o humans and animals in need of prophylaxix and/or therapy for systemic or
topical infections
especially resistant gram-positive organism infections, gram-negative organism
infections,
mycobacterial infections and nosocomial pathogen infections, which composition
comprises an
amount of a compound of the invention, the derivatives, isomers, salts,
polymorphs,
pseudopolymorphs, and hydrates thereof, substantially sufficient to eradicate
said infection, but
not to cause any undue side effects. Compounds and compositions of this
invention can be
administered to humans and animals who are at risk of being infected, for
example a compound
or composition of this invention can be administered to a patient prior to
and/or after surgery.
In addition the compounds of the invention have superior bactericidal activity
against
pneumococci and streptococci of various groups. Cidal features available in
such molecules add
to their clinical attractiveness as it would offer clinicians a valuable
treatment option to treat a
broader range of infections caused by staphylococci, MRSA, MRSE, pneumococci,
streptococci,
mycobacteria and diverse range of anaerobic bacteria of clinical importance in
a situation such as
patients allergic to 13-lactam or possibility of infections due to macrolide
resistant strains of
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streptococci and pneumococci or MRSA/QRSA. For anaerobic bacterial infections,
currently
available treatment options are rather limited due to reasons such as
inadequate potency or gaps
in the spectrum of anaerobic pathogens covered. Such is the case with
macrolides. With (3-
lactam antibacterials, the major shortcoming is their liability to a variety
of [3-lactamases, the
drug inactivating enzymes elaborated by commonly encountered anaerobic
pathogens. Older
fluoroquinolones such as ciprofloxacin, levofloxacin, pefloxacin also suffered
due to inadequate
anti-anaerobic potency. The molecules of invention demonstrate several
distinct gains in
antimicrobial properties against anaerobic pathogens vis-a-vis earlier
antibacterial agents of the
(3-lactam, rnacrolide and fluoroquinolone classes.
to
It has been found that the compounds of this invention, and compositions
containing these
compounds, are effective antimicrobial agents against a broad range of
pathogenic
microorganisms with advantages in low susceptibility to ,microbial resistance,
reduced toxicity,
and improved pharmacology.
Moreover, the molecules of the invention, chiral compounds, salts, polymorphs,
pseudopolymorphs and hydrates thereof, also retain the other valuable
features, of being
bactericidal to fluoroquinolone resistant staphylococci (QRSA with resistant
gyrase) and even to
staphylococcal and pneumococcal isolates possessing Nor A efflux pumps and
other efflux
pumps. The compounds of the invention also display efflux pump inhibitory
activity. A
combination of all these properties coupled with overall good safety and
tolerability observed in
a new molecule renders them worthy of therapeutic use in humans and animals.
By virtue of
such features, they have considerable advantages over existing fluoroquinolone
antibacterials, in
particular in the treatment of respiratory diseases and infections of skin and
soft tissue.
The above list of pathogens is merely by way of example and is in no way to be
interpreted as
limiting. Streptococci are implicated as one of the most common pathogens, in
both the pediatric
and adult population in diverse infectionsldiseases. Examples which may be
mentioned of
diseases, which can thus be prevented, alleviated andlor cured by the
formulations according to
the invention include but are not limited to are meningitis, otitis externa,
otitis media;
pharyngitis; pneumonia; life-threatening bacteremia, peritonitis;
pyelonephritis; cystitis;
endocarditis; systemic infections; bronchitis; arthritis; local infections;
and septic diseases.
Several molecules of the present inventions also exhibit impressive gains in
potency against
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Mycobacte~~ium tuberculosis and therefore of potential value in the treatment
of latent and
recalcitrant mycobacterial infections such as tuberculosis.
These findings have an important implication from the point of view of the
systemic use of the
compounds of the invention in view of their superior potency, superior
bactericidal activity,
expanded biospectrum, better bioavailability and improved tolerability which
are now enabled to
be administered systemically in therapeutically effective doses.
Utilizing the compounds of the invention or the substantially optically pure
or optically pure
isomers, the derivatives and salts thereof, whether in systemic or topical
dosage form, results in
1o clearer dose-related definitions of efficacy, diminished toxic effects and
accordingly an
improved therapeutic index.
The present invention encompasses certain compounds, dosage forms, and methods
of
administering the compounds to a human or other animal subject. Specific
compounds and
compositions to be used in the invention must, accordingly, be
pharmaceutically acceptable. As
used herein, such a "pharmaceutically acceptable" component is one that is
suitable for use with
humans and / or animals without undue adverse side effects (such as toxicity,
irritation, and
allergic response) commensurate with a reasonable benefitlrisk ratio.
2o The pharmaceutical compositions are prepared according to conventional
procedures used by
persons skilled in the art to make stable and effective compositions. In the
solid, liquid,
parenteral and topical dosage forms, an effective amount of the active
compound or the active
ingredient is any amount, which produces the desired results.
For the purpose of this invention the pharmaceutical compositions may contain
the active
compounds of the invention, their derivatives, salts and hydrates thereof, in
a form to be
administered alone, but generally in a form to be administered in admixture
with a
pharmaceutical carrier selected with regard to the intended route of
administration and standard
pharmaceutical practice. Suitable carriers which can be used are, for example,
diluents or
excipients such as fillers, extenders, binders, emollients, wetting agents,
disintegrants, surface
active agents and lubricants which are usually employed to prepare such drugs
depending on the
type of dosage form.
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Any suitable route of achninistration may be employed for providing the
patient with an effective
dosage of the compound of the invention their derivatives, salts and hydrates
thereof. For
example, oral, rectal, paxenteral (subcutaneous, intramuscular, intravenous),
transdermal, topical
and like forms of administration may be employed. Dosage forms include
(solutions,
suspensions, etc) tablets, pills, powders, troches, dispersions, suspensions,
emulsions, solutions,
capsules, injectable preparations, patches, ointments, creams, lotions,
shampoos and the like.
The prophylactic or therapeutic dose of the compounds of the invention, their
derivatives, salts
or hydrates thereof, in the acute or chronic management of disease will vary
with the severity of
condition to be treated, and the route of administration. In addition, the
dose, and perhaps the
dose frequency, will also vary according to the age, body weight and response
of the individual
patient. In general, the total daily dose range, for the compounds of the
invention, the
derivatives, salts or hydrates thereof, for the conditions described herein,
is from about 200 mg
to about 1500 mg, in single or divided doses. Preferably, a daily dose range
should be between
about 400 mg to 1200 mg, in single or divided dosage, while most preferably a
daily dose range
should be between about 500 mg to about 1000 mg in divided dosage. While
intramuscular
administration may be a single dose or up to 3 divided doses, intravenous
administration can
include a continuous drip. It may be necessary to use dosages outside these
ranges in some cases
as will be apparent to those skilled in the art. Further, it is noted that the
clinician or treating
physician will know how and when to interrupt, adjust, or terminate therapy in
conjunction with
individual patient's response. The term "an amount sufficient to eradicate
such infections but
insufficient to cause undue side effects" is encompassed by the above -
described dosage amount
and dose frequency schedule.
Pharmaceutical compositions of the present invention suitable for oral
administration may be
presented as discrete units such as capsules, cachets, or tablets, or aerosol
sprays, each
containing a predetermined amount of the active ingredient, as a powder or
granules, or as a
solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-
water emulsion, or
a water-in-oil liquid emulsion. Such compositions may be prepared by any of
the methods of
pharmacy, but all methods include the step of bringing into association the
active ingredient with
the carrier, which constitutes one or more necessary ingredients. In general,
the compositions
are prepared by uniformly and intimately admixing the active ingredient with
liquid Garners or
finely divided solid carriers or both, and then, if necessary, shaping the
product into the desired
presentation.
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The compositions of the present invention include compositions such as
suspensions, solutions,
elixirs, aerosols, and solid dosage forms. Carriers as described in general
above are commonly
used in the case of oral solid preparations (such as powders, capsules and
tablets), with the oral
solid preparations being preferred over the oral liquid preparations. The most
preferred oral
solid preparation is tablets.
Because of their ease of administration, tablets and capsules represent the
most advantageous
oral dosage unit form, in which case solid pharmaceutical earners are
employed. Examples of
suitable carriers include excipients such as lactose, white sugar, sodium
chloride, glucose
1o solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose
and silicic acid, binders
such as water, ethanol, propanol, simple syrup, glucose, starch solution,
gelatin solution,
carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and
polyvinyl
pyrrolidone, disintegrants such as dried starch, sodium alginate, agar powder,
laminaria powder,
sodium hydrogen carbonate, calcium carbonate, Tween (fatty acid ester of
polyoxyethylenesorbitan), sodium lauryl sulfate, stearic acid monoglyceride,
starch, and lactose,
disintegration inhibitors such as white sugar, stearic acid glyceryl ester,
cacao butter and
hydrogenated oils, absorption promoters such as quaternary ammonium bases and
sodium lauryl
sulfate, humectants such as glycerol and starch, absorbents such as starch,
lactose, kaolin,
bentonite and colloidal silicic acid, and lubricants such as purified talc,
stearic acid salts, boric
acid powder, polyethylene glycol and solid polyethylene glycol.
The tablet, if desired, can be coated, and made into sugar-coated tablets,
gelatin-coated tablets,
enteric-coated tablets, film-coated tablets, or tablets comprising two or more
layers.
If desired, tablets may be coated by standard aqueous or non-aqueous
techniques.
In molding the pharmaceutical composition into pills, a wide variety of
conventional carriers
known in the art can be used. Examples of suitable carriers are excipients
such as glucose,
lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc,
binders such as gum arabic
powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as
laminaria and agar.
In molding the pharmaceutical composition into a suppository form, a wide
variety of earners
known in the art can be used. Examples of suitable carriers include
polyethylene glycol, cacao
butter, higher alcohols, gelatin, and semi-synthetic glycerides.
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A second preferred method is parenterally for intramuscular, intravenous or
subcutaneous
administration.
A third preferred route of administration is topically, for which creams,
ointments, shampoos,
lotions, dusting powders and the like are well suited. Generally, an effective
amount of the
compound according to tlus invention in a topical form is from about 0.1% w/w
to about 10
w/w of the total composition. Preferably, the effective amount of the compound
of the invention
is 1 % w/w of the total composition.
In addition to the common dosage forms set out above, the compounds of the
present invention
may also be administered by controlled release means and/or delivery devices
such as those
described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123 and
4,008,719; the
disclosures of which are hereby incorporated by reference.
is Desirably, each tablet contains from about 200 mg to about 1500 mg of the
active ingredient.
Most preferably, the tablet, cachet or capsule contains either one of three
dosages, about 200 mg,
about 400 mg, or about 600 mg of the active ingredient.
When the pharmaceutical composition is formulated into an injectable
preparation, in
2o formulating the pharmaceutical composition into the form of a solution or
suspension, all
diluents customarily used in the art can be used. Examples of suitable
diluents are water, ethyl
alcohol, polypropylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene
sorbitol, and
sorbitan esters. Sodium chloride, glucose or glycerol may be incorporated into
a therapeutic
agent.
The antimicrobial pharmaceutical composition may further contain ordinary
dissolving aids,
buffers, pain-alleviating agents, and preservatives, and optionally coloring
agents, perfumes,
flavors, sweeteners, and other drugs.
For topical application, there are employed as non-sprayable forms, viscous to
semi-solid or
3o solid forms comprising a carrier compatible with topical application and
having a dynamic
viscosity preferably greater than water. Suitable formulations include but are
not limited to
solutions, suspensions, emulsions, creams, ointments, powders, liniments,
salves, aerosols, etc.,
which are, if desired, sterilized or mixed with auxiliary agents, e.g.
preservatives, antioxidants,
stabilizers, wetting agents, buffers or salts for influencing osmotic
pressuxe, etc. For topical
so
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application, also suitable are sprayable aerosol preparations wherein the
active ingredient
preferably in combination with a solid or liquid inert carrier material.
A specific embodiment of the invention is the preparation of storage stable
compositions of the
compounds of the invention of formula I. Such stable compositions can be
advantageously made
through the use of selective stabilizers. Different stabilizers are known to
those skilled in the art
of making pharmaceutical compositions. Of special utility for making storage
stable
compositions of the compound of the invention of formula I, stabilizers such
as disodium
ethylenediaminetetraacetic acid (EDTA), tromethamine, cyclodextrins such as
gannna-
to cyclodextrin, hydroxy-propyl-gamma-cyclodextrin have been found to be
useful.
In a specific embodiment of the invention, the pharmaceutical compositions
contain an effective
amount of the active compounds of the invention, its derivatives, salts or
hydrates thereof
described in this specification as hereinbefore described in admixture with a
pharmaceutically
acceptable carrier, diluent or excipients, and optionally other therapeutic
ingredients.
The invention is further defined by reference to the following examples
describing in detail the
preparation of the composition of the present invention as well as their
utility. It will be apparent
to those skilled in the art that many modifications, both to materials and
methods may be
practiced without departing from the purpose and scope of this invention.
The following preparations and examples illustrate the methods of preparation
of the compounds
of the invention and are provided only as examples, but not to limit the scope
of the compounds
of the invention.
General preparation for synthesisin~ 1-benzyl-3-alkyl-4-piperidones
A method for preparing a 3-alkyl substituted-1-benzyl-4-piperidone comprising
the steps of:
1) treating ethyl-1-benzyl-4-oxo-piperidine-3-carboxylate hydrochloride with a
base such as
3o potassium tert-butoxide, potassium hydroxide, preferably potassium
hydroxide in an organic
solvent ; such as diethyl ether, dioxane, tetrahydrofuran, N,N-
dimethylformamide or mixtures
thereof, preferably 1:1 mixture of tetrahydrafuran and N,N-dimethylformamide,
2) adding alkyl halide under stirring at a temperature between 25°C -
65 °C, preferably 25°C - 40
°C for 1-12 hrs, preferably 2-3 hrs; and
sl
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3) heating with inorganic acid such as hydrochloric acid, sulfuric acid,
preferably hydrochloric
acid, in the presence of solvent such as water, dioxane , N, N-
dimethylformamide, preferably
water or dioxane at ~0 °C -120 °C, preferably 90 °C -110
°C for 5-36 hrs, preferably 24 - 36 hrs,
and isolating the product.
General preparation for synthesising 1-benzyl-3,3-dialkyl/3,5-dialkyl/3,3,5-
trialkyl-4
piperidones
A method for preparing a 3,3-dialkyl/3,5-dialkyl/ 3,3,5-trialkyl substituted-1-
benzyl-4-
piperidone comprising the steps of:
1) treating 1-benzyl-4-piperidone or ethyl-3-alkyl-1-benzyl-4-oxo-piperidine-3-
carboxylate or
3,3-dialkyl-1-benzyl-4-piperidones in an organic solvent such as dioxane, N, N-
dimethylformamide, tetrahydrofuran, preferably tetrahydrofuran or dioxane with
a base such as
potassium tert-butoxide, sodium hydride, n-butyl lithium, preferably sodium
hydride or
potassium tent-butoxide;
2) adding an alkyl halide selected from C1-C6 lower alkyl/ allcenyl
iodideslbromides such as
methyl iodide, ethyl iodides, allyl bromide, propargyl bromide etc or C1-C6
aralkyl
iodides/bromides/chlorides such as benzyl bromide, benzyl chloride etc under
stirring at
temperature a between -10 °C to 45 °C , preferably -10 °C
to 35 °C for 12 - 24 hrs, preferably
12 - 16 hrs, and isolating the product.
General preparation for s~nthesisin~ 3-alkyl/3 3-dialkyl/3 5-dialkyl/3 3 5-
trialk
amino~peridines
A method for preparing a 3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl
substituted-4-
amino/methylamino/ethylamino / cyclopropylamino/dimethylamino-piperidine
comprising the
steps of:
1) treating a 3-alkyl 3,3-dialkyl/3,5-dialkyl/ 3,3,5-trialkyl substituted-1-
benzyl-4-piperidone
with an amine such as ammonium acetate (ammona source), rnethylamine
hydrochloride,
3o ethylamine hydrochloride, cyclopropylamine, dimethylamine hydrochloride in
an organic
solvent such as methanol, ethanol, preferably methanol, at a temperature
between 10 °C to 35°C,
preferably 20 °C to 35°C, for 1 - 6 hrs, preferably 3 - 4 hrs;
2) adding sodium cyano borohydride at temperature between 0 °C to 60
°C , preferably 0 °C to
°C and isolating the product by evaporating the solvent under vacuum;
35 3) treating the isolated product with a catalyst such as palladium
hydroxide, palladium on carbon
or platinum, preferably palladium on carbon, in an organic solvent, such as
methanol, ethanol,
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ethyl acetate, preferably methanol in presence of hydrogen or hydrogen sources
such as
hydrogen gas, ammonium formate, cyclohexene, preferably hydrogen gas, ammonium
formate,
at temperature between 30 °C to 60 °C, preferably 30 °C
to 45 °C and isolating the product.
Preparation 1
4-Amino-3-methylpi eridine
Step-1: 4-Amino-1-carbethoxy_3-meth~~peridine:
Ethyl chloroformate (3.0 g, 26.7 mmol) was added to a stirred solution of 1-
benzyl-3-methyl-4-
l0 piperidinone (2.0 g, 9.85 mmol) in benzene (30 ml) at ambient temperature.
The obtained
reaction mixture was refluxed with stirnng for 6 hr and concentrated to
dryness to give 1-
carbethoxy-3-methyl-4-piperidone as oil. Yield 1.4 g (77 %), C9H15N03,m/z 186
(M+1).
Ammoniurri acetate (5 g, 64.93 mmol) was added to the stirred solution of 1-
carbethoxy-3-
methyl-4-piperidone (1.4 g, 7.56 mmol) in methanol (25 ml) and stirring was
continued for 3 hr
at ambient temperature. The resulting mixture was cooled at 0°C and
sodium cyanoborohydride
(0.5 g, 7.93 mmol) was added to it. Cooling was removed after 10 min. and
resulting mixture
was stirred for 6 hr at ambient temperature. The reaction mixture was
concentrated to dryness,
triturated with water, acidified with conc. HCl (pH 3 ~ 4) and extracted with
ethyl acetate to
remove impurities. The aqueous layer was basified with 1 M sodium hydroxide
solution (pH
~10) and extracted with ethyl acetate. Ethyl acetate extract was dried
(Na2S04) and concentrated
to dryness to furnish 4-amino-1-carbethoxy-3-methylpiperidine. Yield 1.0 g (72
%), C9H18N202,
m/z 187 (M+1), PMR (CDC13): 0.94 (dd, 3H), 1.22 (m, 1H), 1.26 (t, 3H), 1.6 (m,
1H), 1.82
(m,lH), 2.4 (m,lH), 2.82 (m, 1H), 3.34 (m, 2H), 3.64 (m, 1H) 4.14 (q, 2H).
Ste~2; 4-Amino-3-methylpiperidine:
4-Amino-1-carbethoxy-3-methylpiperidine (1.0 g, 5.73 mmol) was suspended in 5
M NaOH
solution (10 ml), stirred at 120 °C for 6 hr, cooled, extracted with
ethyl acetate, dried (Na2S04)
and concentrated to dryness to afford 4-amino-3-methylpiperidine. Yield 0.2 g
(34 %), C6H14N2,
m/z 115 (M+1), PMR (CDCl3): 0.94 (m, 3H), 1.22 - 1.8 (m, 3H), 1.88 (m, 1H),
2.22 (m, 1H),
2.7 (m, 1H), 3.0 (m, 2H).
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Preparation 2
4-Methylamino-3-methylpiperidine
Stet-l: 1-Carbethoxy 4-methylamino-3-methy~iperidine-
Methylamine hydrochloride (10 g, 148 mmol) was added to the stirred solution
of 1-carbethoxy-
3-methyl-4-piperidone (7 g, 37.83 mmol) obtained as described in Preparation
1, in methanol (50
ml) followed by 8.3g (148 mmol) KOH. Stirnng was continued for 3 hr at ambient
temperature.
The resulting mixture was cooled at 0°C and sodium cyanoborohydride
(3.0 g, 46.0 mmol) was
added to it. Cooling was removed after 10 min. and resulting mixture was
stirred for 12 hr at
to ambient temperature. The reaction mixture was concentxated to dryness,
triturated with water,
acidified with conc. HCl (pH 3 ~ 4) and extracted with ethyl acetate to remove
impurities. The
aqueous layer was basified with 1 M sodium hydroxide solution (pH ~10) and
extracted with
ethyl acetate. Ethyl acetate extract was dried (NazS04) and concentrated to
dryness to give 1-
carbethoxy-4-methylamino-3-methylpiperidine. Yield 4.0 g (50 %), CloHzoN20z,
rn/z 201
(M+1), PMR (CDC13): 0.92 (dd, 3H), I.26 (t, 3H), 1.54 (m, 1H), 2.1 (m, 2H),
2.34 (s, 3H), 2.62
(m, 1 H), 2.86 (m, 1 H), 3 .06 (m, 1 H), 3 .46 (m, 1 H), 3 .72 (m, 1 H), 4.1
(q, 2H).
Step-2: 4-Methylamino-3-methy~iperidine
1-Carbethoxy-4-methylamino-3-methylpiperidine (4.0 g, 18.34 mmol) was
suspended in 5 M
NaOH solution (15 ml), stirred at 110°C for 24 hr, cooled, extracted
with ethyl acetate, dried
(NazS04) and concentrated to dryness to afford 4-methylamino-3-methyl-
piperidine. Yield I.8 g
(77 %), C~Hl6Nz, mlz 129 (M+1), PMR (CDCl3): 0.92 (dd, 3H), 1.54 (m, 1H), 2.12
(m, 2H), 2.38
(s, 3H), 2.6 (m, 1H), 2.8 (m, 1H), 3.02 (m,lH), 3.42 (m,lH), 3.68 (m,lH).
Preparation 3
4-Ethylamino-3-methylpiperidine
Step-1: 1-Carbethoxy-4-eth~lamino-3-methylpi~eridine
Ethylamine hydrochloride (S g, 61.34 mmol) was added to the stirred solution
of 1-carbethoxy-
3-methyl-4-piperidone (3.5 g, 18.9 mrnol) obtained as described in Preparation
l, in methanol
(30 ml) followed by 3.43g (61.34 mmol) KOH. Stirring was continued for 3 hr at
ambient
temperature. The resulting mixture was cooled at 0°C and sodium
cyanoborohydride (1.4 g,
22.22 mmol) Was added to it. Cooling was removed after 10 min. and resulting
mixture was
stirred for 16 hr at ambient temperature. The reaction mixture was
concentrated to dryness,
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triturated with water, acidified with conc. HCl (pH 3 ~ 4) and extracted with
ethyl acetate to
remove impurities. The aqueous layer was basified with 1 M sodium hydroxide
solution (pH
~10) and extracted with ethyl acetate. Ethyl acetate extract was dried
(NazS04) and concentrated
to dryness to give 1-carbethoxy-4-ethylamino-3-methylpiperidine. Yield 2.3 g
(54 %),
CllHzzN20z,m/z 215 (M+1).
Steb-2: 4-Eth~amino-3-meth~piperidine
1-Carbethoxy-4-ethylamino-3-methylpiperidine (2.3 g, 10.74 mmol) was suspended
in 5 M
NaOH solution (15 ml), stirred at 110°C for 120 hr, cooled, extracted
with ethyl acetate, dried
to (NazS04) and concentrated to dryness to afford 4-ethylamino-3-
methylpiperidine. Yield 0.7 g
(46 %), C8H18Nz, m/z 143, (M+1).
Preparation 4
4-Cyclopro~ylamino-3-methylpiperidine
Step-1 ~ 1-Carbethoxy-4-c~propylamino-3-methylpiperidine:
Cyclopropylarnine (10 g, 169.5 mmol) was added 'to the stirred solution of 1-
carbethoxy-3-
methyl-4-piperidone (7.0 g, 37.83 mmol) obtained as described in Preparation
1, in methanol (50
ml) and stirring was continued for 12 hr at ambient temperature. The resulting
mixture was
cooled at 0°C and sodium cyanoborohydride (3.0 g, 46.0 mmol) was added
to it. Cooling was
removed after 10 min. and stirring was continued for 12 hr at ambient
temperature. The reaction
mixture was concentrated to dryness, triturated with water, acidified with
conc. HCl (pH 3 ~ 4)
and extracted with ethyl acetate to remove impurities. The aqueous layer was
basified with 1 M
sodium hydroxide solution (pH ~10) and extracted with ethyl acetate. Ethyl
acetate extract was
dried (NazS04) and concentrated to dryness to afford 1-carbethoxy-4-
cyclopropylamino-3-
methylpiperidine. Yield 6.0 g (70 %), Cl2HzzNzOz, n~z 227 (M+1), PMR (CDC13):
0.38 (m, 4H),
0.88 (dd, 3H), 1.28 (t, 3H), 1.54 (m, 1H), 2.06 (m, 2H), 2.32 (m, 1H), 2.48
(m, 1H), 2.84 (m,
1H), 3.06 (m, 1H), 3.72 (m, 1H), 3.88 - 4.24 (m, 2H).
Step-2' 4-Cyclopropylamino-3-methylpiperidine:
1-Carbethoxy-4-cyclopropylamino-3-methylpiperidine (6.0 g, 26.66 mmol) was
suspended in 5
M NaOH solution (20 ml), stirred at 130°C for 120 hr, cooled and
extracted with ethyl acetate.
Ethyl acetate extract was dried (NazSOa) and concentrated to dryness to afford
a mixture of
starting material (3.0 g) and 4-cyclopropylamino-3-methylpiperidine, which
were separated by
silica column chromatography. Yield 1.0 g (35 %), C9H18Nz, m1z 155, (M+1).
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Preparation 5
4-Dimethylamino-3-meth~~ ep ridine
Step-1: 1-Carbethoxy-4-dimethylamino-3-rnethylpineridine:
Paraformaldehyde (S.lg) was added to the stirred solution of 4-amino-1-
carbethoxy-3-
methylpiperidine (3.5 g, 18.8 rmnol) in methanol (100 ml) at 0°C and
sodium cyanoborohydride
(1.7 g, 27.0 mmol) was added to it. Then, acetic acid (1 ml) was added to the
resulting mixture
and stirring was continued for 96 hr at ambient temperature. The reaction
mixture was
concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3
~ 4) and extracted
to with ethyl acetate to remove impurities. The aqueous layer was basified
with 1 M sodium
hydroxide solution (pH ~10) and extracted with ethyl acetate. Ethyl acetate
extract was dried
(Na2S04) and concentrated to dryness to give 1-carbethoxy-4-dimethylamino-3-
methylpiperidine. Yield 3.5 g (88 %), C11HZZN2O2, m/z 215 (M+1).
Step-2:4-Dimethylamino-3-methylpiperidine
1-Carbethoxy-4-dimethylamino-3-methylpiperidine (3.5 g, 16.3 mmol) was
suspended in 5 M
NaOH solution (20 ml), stirred at 110°C for 48 hr, cooled, extracted
with ethyl acetate, dried
(NaZS04) and concentrated to dryness to afford 4-dimethylamino-3-
methylpiperidine. Yield 1.0
g (43 %), C8H18N2, m/z 143 (M+1), PMR (CDCl3): 0.96 (dd, 3H), 1.3 (m, 1H), 1.5
(m, 1H), 1.74
(m, 1H), 2.08 (m, 1H), 2.24 (s, 6H), 2.38 (m, 1H), 2.61. (bs, 1H, D20
exchangeable), 2.86 (m,
1H), 3.16 (m, 1H), 3.68 (m, 1H).
Preparation 6
4-Amino-3-ethylpiperidine
Ethyl, chloroformate (37.49 g, 346 mmol) was added to a stirred solution of 1-
benzyl-3-ethyl-4-
piperidone (24.0 g, 110 mmol) in benzene (200 ml) at ambient temperature. The
obtained
reaction mixture was refluxed with stirring for 16 hr and concentrated to
dryness to give 1-
carbethoxy-3-ethylpiperidin-4-one as oil. Yield 21 g (96 %), CloH1~N03, m/z
200 (M+1).
Ammonium acetate (33 g) was added to the stirred solution of 1-carbethoxy-3-
ethyl-4-
piperidinone (8.2 g, 41 mmol) in methanol (125 ml) and stirring was continued
for 3 hr at
ambient temperature. The resulting mixture was cooled at 0°C and sodium
cyanoborohydride
(2.5 g, 39 mmol) was added to it. Cooling was removed after 10 min. and
resulting mixture was
stirred for 6 hr at ambient temperature. The reaction mixture was concentrated
to dryness,
triturated with water, acidified with conc. HCl (pH 3 ~ 4) and extracted with
ethyl acetate to
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remove impurities. The aqueous layer was basified with 1 M sodium hydroxide
solution (pH
~10) and extracted with ethyl acetate. Ethyl acetate extract was dried
(NaaS04) and concentrated
to dryness to furnish crude 4-amino-1-carbethoxy-3-ethylpiperidine, which was
used as such in
the next step.
4-Amino-1-carbethoxy-3-ethylpiperidine was suspended in 5 M NaOH solution (36
ml), stirred
at 120°C for 120 hr, cooled, extracted with ethyl acetate, dried
(Na2S04) and concentrated to
dryness to afford 4-amino-3-ethylpiperidine. Yield 3.1 g (59.6 %), C~Hl6Na,
m/z 129 (M+1).
Preparation 7e
l0 4-Methylamino-3-eth~piperidine
Methylamine hydrochloride (17 g, 252 mmol) was added to the stirred solution
of 1-carbethoxy-
3-ethyl-4-piperidone (10 g, 50 mmol) in methanol (150 ml) followed by 14.1 g
(252 mmol)
KOH. Stirring was continued for 3 hr at ambient temperature. The resulting
mixture was cooled
at 0°C and sodium cyanoborohydride (4.72 g, 75 mmol) was added to it.
Cooling was removed
after 10 min. and resulting mixture was stirred for 12 hr at ambient
temperature. The reaction
mixture was concentrated to dryness, triturated with water, acidified with
conc. HCl (pH 3 ~ 4)
and extracted with ethyl acetate to remove impurities. The aqueous layer was
basified with 1 M
sodium hydroxide solution (pH ~10) and extracted with ethyl acetate. Ethyl
acetate extract was
dried (NazSO4) and concentrated to dryness to give crude 1-carbethoxy-4-
methylamino-3-
ethylpiperidine. The obtained crude 1-carbethoxy-4-methylamino-3-
ethylpiperidine was
suspended in 7 M NaOH solution (50 rnl), stirred at 110°C for 230 hr,
cooled, extracted with
ethyl acetate, dried (Na2S04) and concentrated to dryness to afford 4-
methylamino-3-ethyl-
piperidine. Yield 3.5 g (50 %), C8H18N~, m/z 142 (1VI+1).
Preparation S
4-Cyclopro~ylamino-3-ethylpiperidine
Cyclopropylamine (14.25 g, 250 mmol) was added to the stirred solution of 1-
carbethoxy-3-
ethyl-4-piperidone (10 g, 50 rmnol) in methanol (100 ml) and stirnng was
continued for 12 hr at
ambient temperature. The resulting mixture was cooled at 0°C and sodium
cyanoborohydride
(3.9 g, 62 mrnol) was added to it. Cooling was removed after 10 min. and
stirring was continued
for 12 hr at ambient temperature. The reaction mixture was concentrated to
dryness, triturated
with water, acidified with conc. HCl (pH 3 ~ 4) and extracted with ethyl
acetate to remove
impurities. The aqueous layer was basified with 1 M sodium hydroxide solution
(pH ~10) and
extracted with ethyl acetate. Ethyl acetate extract was dried (NaZS04) and
concentrated to
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dryness to afford crude 1-carbethoxy-4-cyclopropylamino-3-ethyl piperidine.
The obtained crude
1-carbethoxy-4-cyclopropylamino-3-ethylpiperidine was suspended in 7 M NaOH
solution (30
ml), stirred at 130°C for 160 hr, cooled and extracted with ethyl
acetate. Ethyl acetate extract
was dried (Na2S04) and concentrated to dryness to afford 4-cyclopropylamino-3-
ethyl -
piperidine. Yield 5.7 g (67 %), CloHzoNa, m/z 169, (M+1).
Preparation 9
4-Dimethylamino-3-eth~piperidine
Sodium cyanoborohydride (3.2 g, 50.8 mmol) was added to the stirred suspension
of N-
tert.-butoxycarbonyl-3-ethyl-4-piperidone (8 g, 35 mmol), N,N-dimethylamine
hydrochloride
(14 g, 172 rmnol) and I~OH (9.6 g, 172 mmol) in methanol (50 ml) at
0°C. The resulting mixture
was stirred for 4 hr at ambient temperature. The reaction mixture was
concentrated to dryness,
triturated with water, acidified with conc. HCl (pH 3 ~ 4) and extracted with
ethyl acetate to
remove impurities. The aqueous layer was basified with 1 M sodium hydroxide
solution (pH
~10) and extracted with ethyl acetate. Ethyl acetate extract was dried
(NaZS04) and concentrated
to dryness to give 4-dimethylamino-3-ethylpiperidine. Yield 2.3 g (37 %),
C9H2°N2, m/z 157
(M+1).
Preparation 10
4-Amino-3 3-dimethylpiperidine
2o Step-1 ~ 1-Benzyl-3 3-dimethyl-4-piperidone
Method -A:
To a solution of 1-benzyl-4-piperidone (1 kg, 5.3 mol) in 7 liter THF, was
added simultaneously
potassimn tert-butoxide ( 1.25 kg, 11.16 mol) in eight equal lots, and methyl
iodide (1.5 kg,
10.56 mol) diluted with 1 liter THF, over a period of four hours between
temperature 0 to 10 °C.
The reaction mixture was slowly allowed to warm upto to 35 °C and
maintained for 4 hours. The
reaction mixture was diluted with 4 liter saturated aqueous sodium chloride
solution. The organic
layer was separated. The aqueous layer was washed with 2.0 liter chloroform.
Combined organic
layer was concentrated to provide a crude product in 1.23 kg quantity.
3Q
The crude product was distilled at 3 mm vacuum, and 160 °C fraction
distillate was collected in
a quantity of 800 gm. To the distillate, 1 liter concentrated HCl was added to
provide a clear
solution. The solution obtained was concentrated to dryness. The solid
obtained was
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recrystallised from 2 liter isopropanol to afford hydrochloride salt of 1-
benzyl-3, 3-dimethyl-4-
piperidone (720 gm).
The solid was dissolved in 2 liter water and treated with 800 ml aqueous
ammonia. The basic
solution obtained was extracted with 2 X 2 liter CHC13. Concentration of the
combined organic
layer afforded 1-benzyl- 3,3 -dimethyl -4- piperidone (490 gm, 42% yield)
having spectral data
as given below:
C14H19N0 m/z = 218 (ES+1)
PMR (CDC13): 1.18 (s, 6H); 2.40 (s, 2H); 2.45 (t, 2H); 2.65 (t, 2H); 3.60 ( s,
2H); 7.38 (m, SH).
Method-B
1-Benzyl-4-piperidone (100 gm, 0.53 mol) diluted with 100 ml THF was added to
a suspension
of 60% NaH (42 g, 1.05 mol) in 700 ml THF at -10 to -5 °C. The mixture
was stirred for 1 hour
and methyl iodide (150 gm, 1.06 rnol) diluted in 50 ml THF was added,
maintaining the
temperature between -3 to -10 °C. The resultant mixture was stirred.
Ethyl acetate (800 ml) was
added to the reaction mixture followed addition of 300 ml water. The organic
layer was
separated washed with 2 x 300 ml water and concentrated under vacumn to obtain
a syrup. The
syrup was triturated with 200 ml hexane. the mass was filtered at room
temperature over celite
and the filtrate concentrated to afford a 121 gm of crude compound. The crude
compound upon
high vacuum distillation afforded 85 g distillate. To the distillate (50 gm)
was charged 50 ml of-
concentrated hydrochloric acid. The suspension was stirred for 15 minutes and
hydrochloric acid
was evaporated under vacuum to obtain a thick residue. Isopropanol (50 ml) was
added to this
residue and was evaporated under vacuum to obtain a solid. The solid was
dissolved in 200 ml
isopropanol under reflux and stirring, and cooled under stirring to effect
crystallization. The
crystalline solid was filtered under suction at 20-30 °C to give a
white crystalline compound as
hydrochloride salt of 1-benzyl- 3,3 -dimethyl-4- piperidone. The solid was
dissolved in 100 ml
water and made alkaline with aqueous ammonia solution to pH 10-11. Alkaline
aqueous phase
was extracted with SO ml chloroform thrice. Combined organic extract was
washed with water,
dried over sodium sulfate and then evaporated under vacuum to afford 28 g
(80%) compound as
an oil.
m/z (M+1) 218.
NMR (CDC13): 1.18 (s, 6H,); 2.40 (s, 2H); 2.45(t, 2H); 2.65 (t, 2H); 3.60 (s,
2H); 7.38 (m,SH).
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Step-2: 4-Amino-3,3-dimethylpiperidine:
Ammonium acetate (3.5 g, 45.45 mmol) was added to the stirred solution of 1-
benzyl-3,3-
dimethyl-4-piperidone (2.0 g, 9.2 mmol), in methanol (20 ml) and stirring was
continued for 3
hr at ambient temperature. The resulting mixture was cooled at 0°C and
sodium
cyanoborohydride (0.58 g, 9.2 mmol) was added. Cooling was removed after 10
min. and
resulting mixture was stirred for 6 hr at ambient temperature. The reaction
mixture was
concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3
~ 4) and extracted
with ethyl acetate to remove impurities. The aqueous layer was basified with 1
M sodium
hydroxide solution (pH ~10) and extracted with ethyl acetate. Ethyl acetate
extract was dried
(Na2S04) and concentrated to dryness to furnish 4-amino-1-benzyl-3,3-dimethyl
piperidine.
Yield, 1.6 g (77 %), C14HZZN2, m/z 219 (M+1), PMR (CDC13): 0.84 (s, 3H), 0.98
(s, 3H), 1.48
(bs, 2H, D20 exchangeable), 1.66 (m, 2H), 2.04 (m, 2H), 2.42 (m, 2H), 2.86 (m,
1H), 3.46 (dd,
2H), 7.32 (m, SH).
A mixture of 20% Pd(OH)z on carbon (0.3 g) and 4-amino-1-benzyl-3,3-
dimethylpiperidine (1.6
g, 7.33 mmol) in methanol (25 ml) was stirred in hydrogen atmosphere (1 atm.)
at 30°C for 6 hr.
The catalyst was filtered off, washed with methanol and filtrate was
concentrated to dryness to
afford 4-amino-3,3-dimethylpiperidine. Yield 0.7 g (75 %), C~H16N2, mlz 129
(M+1), PMR
(CDC13): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H, DzO exchangeable), 2.26 -
2.68 (m, 4H), 3.06
(m, 1H), 3.52 (bs, 1H, D20 exchangeable).
Preparation 11
4-Methylamino-3 3-dimethylpiperidine
Potassium hydroxide (12.85 g, 230 mmol) was added to the stirred solution of
methylamine
hydrochloride (15.5 g, 230.0 mmol) in methanol (100 ml) and stirring was
continued for 30 min
at 30°C. 1-Benzyl-3,3-dimethyl-4-piperidone (5 g, 23.0 rnmol), was
added to the resulting
mixture and stirred for 6 hr. Sodium cyanoborohydride (1.45 g, 23.0 mmol) was
added to it and
reaction mixture was stirred for 15 hr. The reaction mixture was concentrated
to dryness,
triturated with water, extracted with chloroform, dried (NaZS04) and
concentrated to give 1-
benzyl-4-methylamino-3,3-dimethylpiperidine. Yield 5.3 g (99 %), C15H24N2, m/z
233 (M+1),
PMR (CDC13): 0.9 (s, 3H), 1.0 (s, 3H), 1.38 (m, 2H), 1.54 (bs, 1H, DZO
exchangeable), 1.68 -
2.1 (m, 4H), 2.4 (s, 3H), 2.86 (m, 1H), 3.4 (dd, 2H), 7.3 (m, SH).
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A mixture of 20% Pd(OH)2 on carbon , (0.15 g) and 1-benzyl-4-methylamino-3,3-
dimethylpiperidine (0.5 g, 2.1 mmol) in methanol (10 ml) was stirred in
hydrogen atmosphere (1
atm.) at 60°C for 6 hr. The catalyst was filtered off, washed with
methanol and filtrate was
concentrated to dryness to afford 4-methylamino-3,3-dimethyl-piperidine. Yield
0.3 g (99 %),
C$Hl$N2, m/z 143 (M+1), PMR (CDCl3): 0.88 (s, 6H), 1.24 (m, 2H), 1.8 (bs, 2H,
D20
exchangeable), 1.8 (m, 1H), 2.1 (m, 1H), 2.4 (s, 3H), 2.6 (d, 2H), 2.86 (m,
1H).
Preparation 12
4-Ethylamino-3, 3-dimethylpiperidine
l0 Potassium hydroxide (4.6 g, 83.0 mmol) was added to the stirred solution of
ethylamine
hydrochloride (6.8 g, 83.0 mmol) in methanol (70 ml) and stirring was
continued for 30 min at
30°C. 1-benzyl-3,3-dimethyl-4-piperidone (3.5 g, 16.6 mmol) ), was
added to the resulting
mixture and stirred for 6 hr. Sodium cyanoborohydride (1.0 g, 16.6 mmol) was
added to it and
reaction mixture was stirred for 15 hr. The reaction mixture was concentrated
to dryness,
triturated with water, extracted with chloroform, dried (NaZS04) and
concentrated to give 1-
benzyl-4-ethylamino-3,3-dimethylpiperidine. Yield 3.8 g (88 %), C16H26N2, m/z
247 (M+1),
PMR (CDCl3): 0.9 (s, 3H), 1.06 (s, 3H), 1.18 - 1.38 (m, SH), 1.64 - 2.8 (m,
6H), 2.94 (m, 1H),
3.44 (dd, 2H), 7.2 (m, SH).
2o A mixture of 20% Pd(OH)Z on carbon (0.4 g) and 1-benzyl-4-ethylamino-3,3-
dimethylpiperidine
(1.3 g, 5.3 mmol) in methanol (10 ml) was stirred in hydrogen atmosphere (1
atm.) at ambient
temperature for 15 hr. The catalyst was filtered off, washed with methanol and
filtrate was
concentrated to dryness to afford 4-ethylamino-3,3-dimethylpiperidine. Yield
0.8 g (97 %),
C9HzaN2, m1z 157 (M+1), PMR (CDC13): 0.9 (s, 3H), 1.06 (s, 3H), 1.18 - 1.38
(m, SH), 1.85 (bs,
2H, DZO exchangeable), 1.64 - 2.8 (m, 6H), 2.94 (m, 1H).
Preparation 13
4-Cyclopropylamino-3,3-dimeth~piperidine
1-Benzyl-3,3-dimethyl-4-piperidone (10.0 g, 46.0 xmnol), was added to the
stirred solution
3o cyclopropylamine (13.1 g, 230.0 mmol) in methanol (150 ml) and stirred for
6 hr. Sodium
cyanoborohydride (2.9 g, 46.0 mmol) was added to it and reaction mixture was
stirred for 15 hr.
The reaction mixture was concentrated to dryness, triturated with water,
extracted with
chloroform, dried (NaZS04) and concentrated. The obtained crude product was
purified over
silica gel column. Eluted from 5 % ethyl acetate in hexane gave 1-benzyl-4-
cyclopropylamino-
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3,3-dimethyl piperidine. Yield 8.0 g (67.3 %), Cl~H2gN2, m/z 259 (M+1), PMR
(CDC13): 0.4 (m,
2H), 0.82 (s, 3H), 1.06 (s, 3H), I.16 (m, 2H), I.5 (bs, 1H, D20 exchangeable),
I.7 (m, 2H), I.9 -
2.95 (m, 5H), 3.3 - 3.6 (m, 3H), 7.22 (m, SH).
A mixture of 20% Pd(OH)2 on carbon (0.5 g) and 1-benzyl-4-cyclopropyl-amino-
3,3-
dimethylpiperidine (2.0 g, 7.7 mmol) in methanol (20 ml) was stirred in
hydrogen atmosphere (1
atm.) at 60°C for 48 hr. The catalyst was filtered off, washed with
methanol and filtrate was
concentrated to dryness to afford 4-cyclopropylamino-3,3-dimethylpiperidine.
Yield 1.2 g (92
%), CloH2oN2, mlz 169 (M+1), PMR (CDC13): 0.42 (m, 2H), 0.84 (s, 3H), 0.9 (s,
3H), 1.22 (m,
2H), 1.7 (bs, 2H, D20 exchangeable), 1.94 (m, 2H), 2.1 - 2.72 (m, SH), 3.08
(m, 1H).
Preparation 14
4-Dimethylamino-3,3-dimeth,~lpiperidine
Formaldehyde solution (47 %, 10 g) was added to the stirred solution of 4-
amino- 1-benzyl-3,3-
dimethylpiperidine (2.0 g, 9.2 mmol) in methanol (20 ml) at 0°C and
sodium cyanoborohydnide
(0.5 g, 9.2 mmol) was added to it. Then, acetic acid (2 ml) was added to the
resulting mixture
and stirring was continued for 24 hr at ambient temperature. The reaction
mixture was
concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3
~ 4) and extracted
with ethyl acetate to remove impurities. The aqueous layer was basified with 1
M sodium
2o hydroxide solution (pH ~10) and extracted with ethyl acetate. Ethyl acetate
extract was dried
(Na2SO4) and concentrated to give 1-benzyl-4-dimethylamino-3,3-
dimethylpiperidine. Yield 1.9
g (84 %), C16H26N2~ 1~Z 247 (M+1).
A mixture of 20% Pd(OH)Z on carbon (0.3 g) and 1-benzyl-4-dimethylamino-3,3-
dimethylpiperidine (4.5 g, 6.0 mmol) in methanol (20 ml) was stirred in
hydrogen atmosphere (1
atm.) for 48 hr at room temperature. The catalyst was filtered off, washed
with methanol and
filtrate was concentrated to afford 4-dimethylamino-3,3-dimethylpiperidine.
Yield 1.6 g (95 %),
C9HZON2, m/z 157 (M+1).
Preparation 15
4-Carbethox amino-3,3-dimethYlpiperidine
Ethyl chlorofonnate (2 ml) was added to a stirred solution of 4-amino-1-benzyl-
3,3-
dimethylpiperidine (1.6 g, 7.33 mmol) and triethylaanine (2 ml) in methylene
chloride (25 ml) at
ambient temperature, stirring was continued for 1 hr concentrated to dryness,
triturated with
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water, extracted with ethyl acetate, dried (NazS04) and concentrated to give 1-
benzyl-4-
carbethoxyamino-3,3-dimethyl piperidine as oil. Yield 1.3 g (62 %),
Cl~Hz6Nz0z, m/z 291
(M+1), PMR (CDC13): 0.98 (s, 3H), 1.2 (t, 6H), 1.78 (m, 2H), 2.42 (m, 2H),
2.82 (m, 2H), 3.6 (d,
2H), 3.9 (m,~ 1H), 4.1 (q, 2H), 4.8 (bs, 1H), 7.54 (m, 5H).
A mixture of 20% Pd(OH)z on carbon (0.3 g) and 1-benzyl-4-carbethoxyamino-3,3-
dimethylpiperidine (1.3 g, 4.48 mmol) in methanol (15 ml) was stirred in
hydrogen atmosphere
(1 atm.) at 30°C for 3 hr. The catalyst was filtered off, washed with
methanol and filtrate was
concentrated to dryness to afford 4-carbethoxyamino-3,3-dimethylpiperidine.
Yield 0.8 g (90 %),
1o CloHzoNzOz, m/z 201 (M+1).
Preparation 16
4-Acetylamino-3,3-dimethylpiperidine
Acetic anhydride (3 ml) was added to a stirred solution of 4-amino-1-benzyl-
3,3-
dimethylpiperidine (2.0 g, 9.17 mmol) in pyridine (5 ml) and stirred for 1 hr.
The reaction
mixture was concentrated to furnish 4-acetylamino-1-benzyl-3,3-dimethyl
piperidine as an oil.
Yield 1.8 g (76 %), C16Hz4Nz0, m/z 261 (M+1), PMR (CDC13): 0.84 (s, 3H), 0.98
(s, 3H), 1.64
(m, 2H), 2.02 (s, 3H), 2.12 (m, 2H), 2.44 (d, 1H), 2.84 (d, 1H), 3.44 (d, 2H),
3.7 (m, 1H), 5.3 (bs,
1H), 7.31 (m, SH).
A mixture of 20% Pd(OH)z on carbon (0.3 g) and 4-acetylamino-1-benzyl-3,3-
dimethyl
piperidine (1.8 g, 6.92 mmol) in methanol (20 ml) was stirred in hydrogen
atmosphere (1 atm.) at
35°C for 6 hr. The catalyst was filtered off, washed with methanol and
filtrate was concentrated
to dryness to afford 4-acetylamino-3,3-dimethylpiperidine. Yield 1.0 g (90 %),
C9H1gN20, m/z
171 (M+1).
Preparation 17
3 3-Dimethyl-4-piperidone
1-Benzyl-3,3-dimethyl-4-piperidone 275 g (1.26 mol), was dissolved in 1.0 L.
methanol. The
solution was transferred to a Parr reactor after adding 10% palladium on
carbon (25 g). The
reaction mixture was stirred under 300 psi hydrogen pressure at 60°C
until chromatography
showed complete conversion. The reaction mixture was filtered and the residue
washed with
methanol (200 ml). The filtrate was concentrated to dryness to afford 3,3 -
dimethyl-4-piperidone
(158 g) which was used as such for the preparation of either 4-
benzyloxycarbonylamino-3,3-
dimethylpiperidine or 4-t-butyloxycarbonylamino-3,3-dimethylpiperidine.
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Preparation 18
(~1-4-Benzyloxycarbonylamino-3,3-dimethyl~peridine
Step-I : 1- t-Butyloxycarbonyl-3,3-dimethyl-4:piperidone
Di-t-butyldicarbonate (430 g, 1.97 mol) was added to a stirred solution of 3,3-
dimethyl-4-
piperidone (262 g, 2.06 mol) and triethylamine (175 g, 1.73 mol) in 600 ml
dichloromethane at
0-10°C over a period of 1 hour. Cooling was removed and the reaction
mixture was stirred at 20-
30°C for 30 min. The reaction mixture was concentrated to dryness and
the residue was triturated
with hexane (250 ml) and filtered to give I-t-butyloxycarbonyl-3,3-dimethyl-4-
piperidone (352
1o g) in 76% yield.
m/z (M+1) 228.
NMR(CDC13): 0.8 (s, 3H); 0.95 (s,3H); 1.50 (s, 9H); 1.5-1.8 (m, 2H); 2.5-2.9
(m, 2H); 3.4-3.8
(m, 2H); 4.05 (bs, 1H), 4.6 (d,lH), 5.05(s, 2H), 7.4 (s,SH).
Step-2: 4-Amino 1 t-but~~carbonyl- 3,3-dimethylpiperidine:
Ammonium acetate (700 g, 9.09 mol) was added to a stirred solution of 1 t-
butyloxy carbonyl-
3,3-dimethyl-4-piperidone (352 g, 1.55 mol) in methanol (1.0 L). The
suspension was stirred for
3 hr at 20-30°C. The reaction mixture was cooled to 0 °C and
sodiumcyanoborohydride (45 g,
0.71 mol) was added portion wise over 30 minutes. Cooling was removed and the
suspension
2o was stirred for 12 hr at 20-30°C. The reaction mixture was
concentrated to dryness, stirred with
water (2.0 L) and extracted with 1.0 L X 3 dichloromethane. Combined organic
extract was
washed with water and dried over sodium sulfate. Evaporation of organic
solvent afforded the
product.
Step-3: 4-Benzylox~carbon~lamino-1 t-butylox c~arbonyl-3,3=dimethylpiperidine:
Benzyl chloroformate (50% in toluene, 450 ml, I.57 mol) was added to a stirred
suspension of 4-
amino-1-t-butyloxycarbonyl-3,3-dimethylpiperidine (365 g ) as prepared above
and NaHC03
(150 g, 1.78 mol) in dry tetrahydrofuran (1.5 L). The reaction mixture was
stirred for 20 hr at
35°C. The reaction mixture was diluted with 3.5 L water and was
extracted with 2.0 L X 2 ethyl
acetate. Combined organic extract was washed with water, dried over Na2S04 and
concentrated
to dryness. The residue was subjected to chromatography on a silica gel column
to give 4-
benzyloxycarbonylamino-1 t-butyloxycarbonyl -3,3-dimethylpiperidine in 63%
(350 g) yield.
m/z 363 (M+1).
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NMR(CDCl3): 0.8 (s, 3H); 0.95 (s, 3H); 1.5 (s, 9H); 1.5-1.8 (m, 2H);2.5-2.9
(m, 2H); 3.4-3.8 (m,
2H); 4.05 (bs,lH); 4.6 (d, 1H); 5.05 (s, 2H); 7.4 (s, 5H)
Step-4: 4-Benzyloxycarbonylamino-3,3-dimethylpiperidine:
6 N HCl (200 ml) was added to a stirred solution of 4-benzyloxycarbonylamino-1-
t-
butyloxycarbonyl-3,3-dirnethylpiperidine (350 g, 0.96 mol) in dioxane (200
ml). The resulting
mixture was stirred for 1 hr and concentrated to dryness. The resultant
residue was treated with
water (3,0 L) water and was extracted with 1.0 L X 2 ethyl acetate. The
aqueous layer was
basified with 2 M aqueous NaOH and extracted with 2.5 L X 2 dichloromethane.
Combined
to organic extract was washed with water, dried over Na2S04 and concentrated
to afford 4-
benzyloxycarbonylamino-3,3-dimethylpiperidine in 89% (224 g) yield.
m/z (M+1) 263.
NMR (CDC13): 0.88 (s, 6H); 1.2-1.5 (m, 2H); 1.6-1.8 (m, 1H); 2.4-2.7 (m,
3H);'2.9-3.1 (m, 1H);
3.4-3.6 (m, 1H); 4.7 (s, 1H), 5.1 (s, 2H); 7.40 ( s, 5H).
Preparation 19
(+~and~~4-t-Butyloxycarbonylamino -3,3-dimethylpiperidine
Ste,~-1: 1- Benz~ycarbonyl-3,3-dimethyl-4-piperidone:
2o Method A
3,3-dimethyl-4-piperidone (157 g, 1.24 rnol) was dissolved in 750 L.
tetrahydrofuran and was
charged with solid NaHC03 (115 g , 1.37 mol) . The reaction mixture was
stirred and under
stirnng addition of 50% benzyl chloroformate in toluene (470 ml, 1.37 mol) was
made at 0
to 10°C temperature. To the reaction mixture 1.0 L water was added and
the resulting mixture
was extracted with 500 ml X 3 ethyl acetate. Combined organic extract was
washed with water,
dried over sodium sulfate and concentrated in vacuo to give a residue which
was subjected to
silica gel column chromatography to give 272 g titled compound.
mlz (M+1) 262.
NMR(CDCl3): 1.18 (s, 6H); 2.50 (t, 2H); 3.50(s, 2H); 3.80 (t, 2H); 5.20 (s,
2H); 7.40 (s,SH).
Method B
1-Benzyl-3,3-dimethyl-4.-piperidone (255 g , 1.175 mol) was dissolved in 800
rnl toluene. To
the clear solution was charged 50°/'° benzyl chloroformate in
toluene (441 ml, 1.29 mol). The
reaction mixture was stirred at temperature between 80-85°C for 4-5
hrs. The reaction mixture
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was concentrated under vacuum. Crude product was purified by silica gel column
chromatograhy
to give 292 g (95°!°) titled compound.
m/z (M+1) 262.
NMR (CDC13): 1.18 (s, 6H); 2.50 (t, 2H); 3.50(s, 2H); 3.80 (t, 2H); 5.20 (s,
2H); 7.40 (s,SH).
Step-2: 4-Amino-1 benzyloxycarbonyl- 3 3-dimethylpiperidine~
1-Benzyloxycarbonyl-3,3-dimethyl-4-piperidone (290 g, 1.11 mol) was dissolved
in methanol
(1.5 L) and under stirring addition of ammonium acetate (600 g, 7.80 mol ) was
made at 30-
35°C. The reaction mixture was stirred for 5 hrs. Sodium
cyanoborohydride (35 g, 0.55 mol) was
1o added portion wise to the suspension. over 0.5 hrs by maintaining
temperature between 0- 10°C.
The reaction mixture was stirred for 6-7 hrs. After completion of reaction,
solvent was
evaporated under reduced pressure and addition of 3.00 L water was made under
stirring. The
reaction mixture was stirred for 15 minutes. It was extracted with 1.5 L X 2
CHC13 . Combined
organic extract was evaporated under vacuum. The residue was dissolved in 3 N
HCl till pH 1
and was extracted with 500 ml X 2 dichloromethane. The aqueous layer was
basified with 300
ml aqueous ammonia solution (23-25%) to pH 10-11 and then was extracted with
1.5 L X 3
dichloromethane. Combined organic extract was washed with water and was dried,
over sodium
sulfate. Evaporation of organic solvent afforded 225 g (77%) title compound.
m/z (M+1) 263.
2o NMR (CDC13) DZO exchange: 0.80 (s, 3H); 0.98 (s, 3H); 1.40-1.78 (m, 2H);
2.50 (dt, 2H); 2.90
(m, 1H); 3.80 (t,lH); 4.18 (t, 1H), 5.18 (s,2H); 7.40 (s, 5H).
Step-3: (+1-4-Amino-1-benz~ycarbonyl-3,3-dimethylpiperidine:
4-Amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine (200 g, 0.76 mol) was
dissolved in 2.4 L
2-3% aqueous ethyl alcohol (moisture content 2.6% by Karl Fischer titration)
and L-(+)-tartaric
acid (110 g, 0.73mo1) was added to the solution at 65-70 °C. The
reaction mixture was heated
under stirring for half an hour at 65-70 °C. The reaction mixture was
cooled under stirring
between 20-30°C. The solid was filtered and the wet cake was washed
with additional 675 ml
ethyl alcohol.
Resultant 'solid A' was treated separately to obtain (-) isomer of 4-amino-1-
benzyloxycarbonyl-
3,3-dimethyl- piperidine as described in Step-4.
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The filtrate was concentrated under vacuum to obtain a 'solid B'. The 'solid
B' was treated with
aqueous KZC03 solution made by dissolving 112 g KZC03 in 1.2 L water and was
extracted with
750 rnl chloroform thrice, Combined organic extract was washed with 200 ml
water and dried
over sodium sulfate. Evaporation of organic solvent afforded 71 g (71% ) as an
oil. The
compound was subjected to a second resolution by dissolving it ( 70 g, 0.267
molj in 840 ml 2-3
aqueous ethyl alcohol (moisture content, 2.6 %) under stirring and resultant
solution was
treated with (40 g, 0.267 mol) D-(-)-tartaric acid at 60-70°C. The
reaction mixture was agitated
at 6S-70 °C for half an hour. The reaction mass was cooled and was
filtered at 20-30°C. The wet
cake was washed with 210 ml additional ethyl alcohol to afford a crystalline
salt. The resultant
to wet solid was treated with aqueous KZC03 solution made by dissolving 81 g
KZC03 in 0.81 L
water and was extracted with 750 ml X 3 chloroform. Combine organic extract
was washed with
200 ml water and was dried over sodium sulfate. Evaporation of organic solvent
afforded 57 g
(86%) as an oil.
m/z (M+1) 263.
NMR(CDC13) Da0 exchange: 0.80 (s, 3H); 0.98 (s, 3H); 1.40-1.78 (m, 2H); 2.50
(dt,~~ 2H); 2.90
(m, 1H); 3.80 (t,lH); 4.I8 (t, 1H), 5.18 (s,2H); 7.40 (s, SH).
~ajDZS value +30.60' (c=l, CHC13), percentage of isomers ratio 98.07: 1.93
determined by HPLC
of Mosher amide analogue.
2o The process of the resolution is further repeated on the free base till the
unwanted chiral isomer
falls below 0.5% limit by HPLC analysis.
Step-4: (-1- 4-Amino-1-benzyloxycarbonyl- 3,3-dimethylpiperidine
The 'solid A' obtained in. Step-3 was treated with aqueous KZC03 solution made
by dissolving
164 g KZC03 in 1.6 L water and was extracted with 750 ml chloroform thrice.
Combined organic
extract was washed with 200 ml water and dried over sodium sulfate.
Evaporation of organic
solvent afforded 85 g (85%) as an oil.
The compound was subjected to a second resolution by dissolving it (84 g, 0.32
mol} in 1.0 L
2-3 % aqueous ethyl alcohol (moisture content, 2.6 %) under stirring and
resultant solution was
treated with L-(+)-tartaric acid (46 g, 0.307 mol) at 60-70°C. The
reaction mixture was agitated
at 65-70°C for half an hour. The reaction mass was cooled and was
filtered at 20-30°C. The wet
cake was washed with 250 ml additional ethyl alcohol to afford a crystalline
salt. The resultant
white solid was treated with aqueous KZC03 solution made by dissolving 93 g
KZC03 in 1.0 L
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water and was extracted with 750 ml X 3 chloroform. Combined organic extract
was washed
with 200 ml water and was dried over sodimn sulfate. Evaporation of organic
solvent afforded
71 g (83 %) as an oil.
~a~DZS value -31.80° (c=1, CHCl3), percentage of isomers ratio
96.37:3.63 determined by HPLC
s of Mosher amide analogue.
The process of the resolution is further repeated on the free base till the
unvcranted chiral isomer
falls below 0.5% limit by HPLC analysis.
l0 Step-5: (+)-1- Benz~oxycarbonyl-4-~butylox ca~ylamino-3,3-
dimethylpiperidine:
To a solution of (+)-4-amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine (55 g,
0.209 mol)
was dissolved in 500 L dichloromethane was added triethylamine (22.2 g, 0.209
mol) followed
by di-t-butyl carbonate (45.8 g, 0.209 mol) dissolved in 200 ml
dichloromethane while
maintaining temperature between 5- 10°C, under stirnng. The reaction
was maintained at 25-
15 35°C. After completion of reaction the reaction mixture was diluted
with 1.0 L water and layers
were separated. Combined organic extract was dried over sodium sulfate and was
evaporated to
dryness to obtain 76 g of product.
mlz (M+1) 363.
NMR(CDCl3) D20 exchange: 0.80 (s, 3H); 0.98 (s, 3H); 1.45 (s, 9H); 1.70 (m,
1H); 2.70 (m,
20 1H); 2.90 (t,lH); 3.40 (t, 1H), 3.80 (t,lH); 4.18 (t, 1H); 4.4 (d,lH), 5.1
(s, 2H); 7.40 (s,SH).
[oc]DZS value +16.28° (c=l, CHC13).
Step-6' (-)-1-Benzyloxycarbonyl- -4-t-butyloxycarbonylamino-3,3-
dimethylpiperidine
The compound was prepared as per procedure described for its (+) isomer in
quantitative yield.
25 [a,~DZS value -15.86° (c=1, CHC13).
StepT7. (+)-4 t-Butvloxycarbonylamino -3,3-dimethylpiperidine:
(+)-1- Benzyloxycarbonyl-4 t-butyloxycarbonylamino-3,3-dimethylpiperidine (75
g, 0.207 mol)
was dissolved in 500 ml methanol and the solution was transferred to a Parr
reactor. Wet 10%
3o palladium on carbon (7.5 g) was added to the solution and was stirred at
200 psi hydrogen
pressure. Reaction progress was monitored on TLC and reaction was completed in
3-4 hrs. The
reaction mixture was filtered as soon as it was completed. The residue was
washed with 100 ml
methanol. Filtrate was evaporated to dryness to afford the required product
(47 g) in quantitative
yield.
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m/z (M+1) 229.
NMR(CDC13): 0.95 (bs, 6H); 1.45-1.6 (m, lOH); 1.6-1.8 (m, 1H); 2.4 (d, 1H);
2.5-2.7 (m, 2H);
3.05 (m,lH); 3.3-3.5 (m, 1H), 4.4 (m,lH).
Step-8: (~)-4 t-Butyloxycarbonylamino-3,3-dimeth~piperidine
The compound was prepared as per procedure described for its (+) isomer.
mlz (M+1) 229.
NMR(CDC13): 0.95 (bs, 6H); 1.45-1.6 (m, lOH); 1.6-1.8 (m, 1H); 2.4 (d, 1H);
2.5-2.7 (m, 2H);
3.05 (m,lH); 3.3-3.5 (m, 1H), 4.4 (m,lH).
to
Preparation 20
4-Arnino-3-ethyl-3-meth~piperidine
Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred solution of 1-
benzyl-3-ethyl-3-
methyl-4-piperidinone (0.9 g, 3.9 mmol) in methanol (20 ml) and stirring was
continued for 3 hr
at ambient temperature. The resulting mixture was cooled at 0°C and
sodium cyanoborohydride
(0.2 g, 3.1 mmol) was added to it. Cooling was removed after 10 min. and
resulting mixture was
stirred for 6 hr at ambient temperature. The reaction mixture was concentrated
to dryness,
triturated with water, acidified with conc. HCl (pH 3 ~ 4) and extracted with
ethyl acetate to
remove impurities. The aqueous layer was basified with 1 M sodium hydroxide
solution (pH
~10) and extracted with ethyl acetate. Ethyl acetate extract was dried
(Na2S04) and concentrated
to dryness to furnish 4-amino-1-benzyl-3-ethyl-3-methylpiperidine. Yield 0.6 g
(66 %),
C15H24N2~~Z 233 (M+1).
A mixture of 20% Pd(OH)2 on carbon (0.2 g) and 4-amino-1-benzyl-3-ethyl-3-
methylpiperidine
(0.6 g, 2.58 mmol) in methanol (210 ml) was stirred in hydrogen atmosphere (1
atm.) at 30°C for
6 hr. The catalyst was filtered off, washed with methanol and filtrate was
concentrated to dryness
to afford 4-amino-3-ethyl-3-methylpiperidine. Yield 0.27 g (74 %), C8H18N2,
m/z 143 (M+1).
Preparation 21
4-Methylamino-3-ethyl-3-meth~pit~eridine
Potassium hydroxide (15.45 g, 276 mmol) was added to the stirred solution of
methylamine
hydrochloride (18.54 g, 276 nnnol) in methanol (100 ml) and stirring was
continued for 30 min
at 30°C. 1-benzyl-3-ethyl-3-methyl-4-piperidinone (8 g, 34.6 mmol) was
added to the resulting
mixture and stirred for 6 hr. Sodium cyanoborohydride (2.18 g, 34.6 mmol) was
added to it and
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reaction mixture was stirred for 15 hr. The reaction mixture was concentrated
to dryness,
triturated with water, extracted with chloroform, dried (NazS04) and
concentrated to give 1-
benzyl-4-methylamino-3-ethyl-3-methylpiperidine. Yield 6 g (67 %), C16Hz6Nz,
m/z 247 (M+1).
s A mixture of 20% Pd(OH)z on carbon (0.7 g) and 1-benzyl-4-methylamino-3-
ethyl-3-methyl
piperidine (6 g, 24.39 mmol) in methanol (60 ml) was stirred in hydrogen
atmosphere (1 atm.) at
60°C for 6 hr. The catalyst was filtered off, washed with methanol and
filtrate was concentrated
to dryness to afford 4-methylamino-3-ethyl-3-methylpiperidine. Yield 2.5 g (66
%), C9HzoNz,
m/z 157 (M+1).
l0 Preparation 22
4-Cyclopropylamino-3-ethyl-3-meth~pi ep riding
1-Benzyl-3-ethyl-3-methyl-4-piperidinone (4.2 g, 18.18 mmol) was added to the
stirred solution
cyclopropylamine (6.5 g, 115 mmol) in methanol (100 ml) and stirred for 6 hr.
Sodium
cyanoborohydride (1.14 g, 18.18 rnmol) was added to it and reaction mixture
was stirred for 15
15 hr. The reaction mixture was concentrated to dryness, triturated with
water, extracted with
chloroform, dried (NazS04) and concentrated to furnish crude 1-benzyl-4-
cyclopropylamino-3-
ethyl-3-methylpiperidine. Yield 4g (88%), C18Hz8Nz,m/z 273 (M+1).
A mixture of 20% Pd(OH)z on carbon (0.5 g) and 1-benzyl-4-cyclopropylamino-3-
ethyl-3-
2o methylpiperidine (3.54 g, 13.00 mmol) in methanol ( 70 ml) was stirred in
hydrogen atmosphere
(1 atm.) at 60°C for 48 hr. The catalyst was filtered off, washed with
methanol and filtrate was
concentrated to dryness to afford 4-cyclopropylamino-3-ethyl-3-
methylpiperidine. Yield 2.3 g
93%), CllHzzNz,m/z 183 (M+1).
ZS Preparation 23
4-Dimethylamino-3-Ethyl-3-Methyl ep riding
Paraformaldehyde (10 g) was added to the stirred solution of 4-amino-1-benzyl-
3-ethyl-3-
methylpiperidine (8.0 g, 34 mmol) in methanol (100 ml) at 0°C and
sodium cyanoborohydride
(2.14 g, 34 mmol) was added to it. Then, acetic acid (2 ml) was added to the
resulting mixture
3o and stirring was continued for 24 hr at ambient temperature. The reaction
mixture was
concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3
~ 4) and extracted
with ethyl acetate to remove impurities. The aqueous layer was basified with 1
M sodium
hydroxide solution (pH ~10) and extracted with ethyl acetate. Ethyl acetate
extract was dried
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(NaZS04) and concentrated to give 1-benzyl-4-dimethylamino-3-ethyl-3-
methylpiperidine. Yield
6 g (67 %), C1~H28N2, m/z 261 (M+1).
A mixture of 20% Pd(OH)2 on carbon (0.7 g) and 1-benzyl-4-dimethylamino-3-
ethyl-3-methyl
piperidine (6 g; 23 mmol) in methanol (50 ml) was stirred in hydrogen
atmosphere (1 atm.) for
48 hr at room temperature. The catalyst was filtered off, washed with methanol
a~ld filtrate was
concentrated to afford 4-dimethylamino-3-ethyl-3-methylpiperidine. Yield 2.8 g
(72 %),
C1oH22N2,m/z 171 (M+1).
Preparation 24
to 4-Amino-3,3-dieth,~~lp~eridine
Ammonium acetate (7.85 g, 102 mmol) was added to the stirred solution of 1-
benzyl-3,3-diethyl
piperidin-4-one (5.0 g, 20.40 mmol) in methanol (100 ml) and stirring was
continued for 3 hr at
ambient temperature. The resulting mixture was cooled at 0°C and sodium
cyanoborohydride
(1.3 g, 20.40 mmol) was added to it. Cooling was removed after 10 min. and
resulting mixture
was stirred for 6 hr at ambient temperature. The reaction mixture was
concentrated to dryness,
triturated with water, acidified with conc. HCI (pH 3 ~ 4) and extracted with
ethyl acetate to
remove impurities. The aqueous layer was basified with 1 M sodium hydroxide
solution (pH
~10) and extracted with ethyl acetate. Ethyl acetate extract was dried
(Na2SO4) and concentrated
to dryness to furnish 4-amino-1-benzyl-3,3-diethyl piperidine. Yield 8.2 g (82
%), C16Hz6N2, m/z
247 (M+1), PMR (CDC13): 0.84 (s, 3H), 0.98 (s, 3H), 1.48 (bs, 2H, DZO
exchangeable), 1.66 (m,
2H), 2.04 (m, 2H), 2.42 (m, 2H), 2.86 (m, 1H), 3.46 (dd, 2H), 7.32 (m, SH).
A mixture of 20% Pd(OH)2 on carbon (0.8 g) and 4-amino-1-benzyl-3,3-
diethylpiperidine (B.Og,
32.52 mmol) in methanol (100 ml) was stirred in hydrogen atmosphere (1 atm.)
at 30°C for 6 hr.
The catalyst was filtered off, washed with methanol and filtrate was
concentrated to dryness to
afford 4-amino-3,3-diethylpiperidine. Yield 4.8g (94.60 %), C9HZONZ, m/z I57
(M+1), PMR
(CDCl3): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H, D2O exchangeable), 2.26 -
2.68 (m, 4H), 3.06
(m, 1H), 3.52 (bs, 1H, DZO exchangeable).
Preparation 25
4-Amino-3,5-dimethylpiperidine
Std-1: Mixture of isomers of 4-amino-1-carbethoxy-3,5-dimethylpiperidine:
Ethyl chloroformate (10.0 g, 90 mmol) was added to a stirred solution of 1-
benzyl-3,5-dimethyl
4-piperidinone (5.0 g, 24 mmol) in benzene (20 rnl), refluxed with stirnng for
6 hr and
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concentrated to dryness to give 1-carbethoxy-3,5-dimethyl-4-piperidinone as
oil. Yield 4.51 g
(90 %), CloH1~N03, m/z 200 (M+1).
Ammonium acetate (20 g) was added to the stirred solution of 1-carbethoxy-3,5-
dimethyl-4-
piperidinone (4.5 g, 22.5 mmol) in methanol (200 ml) and stirred for 3 hr. The
resulting mixture
was cooled at 0°C and sodium cyanoborohydride (1.4 g, 22.5 mmol) was
added to it. Cooling
was removed and stirring was for 3 hr at 35°C. The reaction mixture was
concentrated, triturated
with water, acidified with conc. HCl (pH 3 ~ 4) and extracted with ethyl
acetate to remove
impurities. The aqueous layer was basified with 1 M sodium hydroxide solution
(pH ~10) and
1o extracted with ethyl acetate. Ethyl acetate extract was dried (Na2S04) and
concentrated to give 4-
amino-1-carbethoxy-3,5-dimethylpiperidine. The obtained 4-amino-1-carbethoxy-
3,5-
dimethylpiperidine was subjected to silica gel column chromatography. Elution
with 5%
methanol in chloroform furnished a solid, which was a mixture of
stereoisomers, conformational
analysis of which was not obtained.
Yield 3.5 g (77 %), m.p. 218-20°C, CioH18N202, m1z 201 (M+1).
Step-2: Separation of isomers of 4-amino-1-carbethoxy-3 5-dimethylpiperidine~
4-Amino-1-carbethoxy-3,5-dimethylpiperidine obtained as per procedure
described in Step-1
was subjected to silica gel column chromatography. Elution with chloroform
gave "upper"
mixture of isomers of 4-amino-1-carbethoxy-3,5-dimethylpiperidine m.p. 248-
50°C,
zo CIOHI$N202, m/z 201 (M+1), PMR (CDC13): 0.94 (m, 6H), 1.16 (t, 3H), 1.78
(m, 1H), 2.02 (m,
1H), 2.06 (bs, 2H, D20 exchangeable), 2.72 (m, 2H), 2.86 (m, 1H), 3.74 (m,
2H), 4.12 (q, 2H).
Further elution with 5 % methanol in chloroform furnished "lower" mixture of
isomers of 4-
amino-1-carbethoxy-3,5-dimethylpiperidine m.p. 236-40°C, CloH1gN202,
m/z 201 (M+1), PMR
(CD30D): 0.88 (m, 6H), 1.16 (t, 3H), 1.82 (m, 1H), 2.1 (m, 1H), 2.5 (m, 2H),
2.94 - 3.15 (m,
3H), 3.96 (q, 2H).
Step-3: Mixture of isomers of 4-amino-3,5-dimeth~~peridine (Mixtures A+B~
A mixture of isomers of 4-amino-1-carbethoxy-3,5-dimethylpiperidine (10 g, 51
mmol) obtained
3o by a procedure as described in step-1, was stirred in 5 M NaOH solution
(100 ml) at 100°C for
48 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated
to afford mixture of
isomers of 4-amino-3,5-dimethylpiperidine as oil as "mixture A + B". Yield 5.1
g (80 %),
C~Hl6Nz,m/z 129 (M+1).
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Step-4: "Upper" mixture of isomers of 4-amino-3 5-dimethyl~iperidine (Mixture
A of isomers
A "upper" mixture of isomers of 4-amino-1-carbethoxy-3,5-dimethylpiperidine
(1.5 g, 7.5
mmol) obtained as described in Step-2, was stirred in 5 M NaOH solution (10
ml) at 100°C for
48 hr, cooled, extracted with ethyl acetate, dried (Na2S04) and concentrated
to afford "upper"
mixture of isomers of 4-amino-3,5-dimethyl piperidine as oil as mixture A of
isomers, of which
the conformational analysis was not obtained. Yield 0.72 g (76 %), C~H16N2,
m1z 129 (M+1),
PMR (CDC13): 0.94 (m, 6H), 1.7 (bs, 3H, DZO exchangeable), 1.78 (m, 1H), 2.02
(m, 1H), 2.5 -
2.8 (m, 4H), 2.86 (m, l H).
to Step-5: "Lower" mixture of isomers of 4-amino-3 5-dimethylpiperidine
(Mixture B of isomers
A "lower" mixture of isomers of 4-amino-1-carbethoxy-3,5-dimethylpiperidine
(1,0 g, 5.0
mmol) obtained by a procedure as described in step-2, was stirred in 5 M NaOH
solution (10 ml)
at 100°C for 48 hr, cooled, extracted with ethyl acetate, dried
(NazS04) and concentrated to
afford "lower" mixture of isomers of 4-amino-3,5-dimethylpiperidine as an oil
as mixture B of
isomers, of which the conformational analysis was not obtained. Yield 0.51 g
(80 %), C~HISNz,
n~/z 129 (M+1).
Preparation 26
4-Methylamino-3,5-Dimethypi~eridine
Powdered KOH (0.92 g, 16.44 nunol) was added in portions to the stirred
solution of
2o rnethylamine hydrochloride (1.11 g, 16.44 mmol) in methanol (20 ml) at 0-
5°C and 1-
carbethoxy-3,5-dimethyl-4-piperidinone (2.2 g, 1.1 mmol),obtained by a
procedure as described
in Example 25 (Step-1) , was added in portions to it. The resulting reaction
mixture was stirred
for 45 min at 10°C and a solution of sodium cyanoboro-hydride (0.7 g,
1.1 mmol) in methanol (5
ml) was added dropwise to it. Cooling was removed and stirring was for 24 hr
at 30°C. T'he
reaction mixture was basified with 20% KOH solution, filtered (to remove
insoluble impurities)
and filtrate was concentrated to dryness. The obtained residue was dissolved
in water and
extracted with chloroform. Chloroform layer was extracted with 50% HCl and
acid layer was
basified with 20% KOH solution. The separated oil was extracted with
chloroform, dried
(Na2S04) and concentrated to give a Mixtures A+B of 4-methylamino-1-carbethoxy-
3,5-
3o dimethylpiperidine. Yield 1.34 g (60 %), CIIHzzNzOa, m/z 214 (M+1).
Mixtures A+B of 4-methylamino-1-carbethoxy-3,5-dimethylpiperidine (1.3 g, 0.6
mmol) was
stirred in a mixture of 10% NaOH solution (20 ml) and ethyl alcohol (10 ml) at
100°C for 120 hr,
cooled, extracted with ethyl acetate, dried (NazS04) and concentrated to
afford a Mixtures A+B
of 4-methylamino-3,5-dimethylpiperidine. Yield 0.61 g (70 %), CgHlgNz, m/z 143
(M+1).
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Mixture A of isomers and Mixture B of isomers of 4-methylamino-3,5-
dimethylpiperidine were
prepared by separation technique at 4-methylamino-1-carbethoxy-3,5-
dimethylpiperidiiie stage
by using silica gel column chromatography similar as described in Preparation
25 (Step-2)
followed by aqueous sodium hydroxide mediated hydrolysis.
Preparation 27
4-Ethylamino-3,5-dimethylpiperidine
Powdered KOH (2.8g, 50 mmol) was added in portions to the stirred solution of
ethylamine
hydrochloride (4.0 g, 50 rmnol) in methanol (50 ml) and 1-carbethoxy-3,5-
dimethyl-4-
piperidinone (5.0 g, 25.12 mmol) obtained by a procedure as described in
Example 25 (Step-1),
was added to it. The resulting reaction mixture was stirred for 6 hr. A
solution of sodium
cyanoborohydride (1.6 g, 25.12 rnmol) in methanol (I O ml) was added dropwise
to it and stirring
was continued for 16 hr. The reaction mixture was concentrated to dryness. The
obtained residue
was dissolved in water and extracted with chloroform. Chloroform layer was
extracted with 50%
HCl and acid layer was basified with KOH (20%) solution. The oil thus
separated was extracted
with chloroform, dried (NazS04) and concentrated to give Mixtures A +B of 4-
ethylamino-1-
carbethoxy-3,5-dimethylpiperidine as an oil. Yield 5.6, g (97.7 %),
C12H24N202~ ~z 229 (M+1).
The similarly obtained Mixtures A+B of 4-ethylamino-1-carbethoxy-3,5-
dimethylpiperidine was
separated over silica gel column chromatography. Elution from 5% methanol in
chloroform gave
Mixture A of isomers of 4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine as
oil. Yield 2.1 g
(36 %), C12H24N2~2, ~z 229 (M+1), PMR (CDC13): 0.94 (dd, 6H), 1.25 (t, 3H),
1.5 - 2.1 (3H,
m, Dz0 exchangeable), 2.38 (m, 1H), 2.72 (m, 2H), 3.3 - 3.8 (m, 3H), 3.64 (s,
1H), 4.12 (q, 2H).
Further elution from 5 % methanol in chloroform furnished Mixture B of isomers
of 4-
ethylamino-1-carbethoxy-3,5-dimethylpiperidine as oil. Yield 2.1 g (36 %),
C12H24N202, m/z
229 (M+1), PMR (CDC13): 0.92 (dd, 6H), 1.18 (t, 3H), 1.48 (bs,lH, Dz0
exchangeable), 1.68
(m, 1H), 2.02 (m, 1H), 2.3 (m, 1H), 2.4 - 2.68 (m,-3H), 3.0 (dd, 1H), 3.82
(dd, 1H), 3.95 (m,
1H), 4.12 (rn, 2H).
The Mixture A of isomers of 4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine
(2.1 g, 0.92
3o mmol) was stirred in 5 N NaOH solution (20 ml) at 100°C for 96 hr,
cooled, extracted with ethyl
acetate, dried (NazS04) and concentrated to afford Mixture A of isomers of 4-
ethylamino-3,5-
dimethyl piperidine as oil. Yield 1.34 g (93.2 %), CgHzoNz, m1z 157 (M+1), PMR
(CDC13): 0.94
(dd, 9H), 1.45 (m, 1H), 1.66 (m, 1H), 1.94 (m, 3H, D20 exchangeable), 2.36 (m,
1H), 2.44 - 2.74
(m, 3H), 3.0 (dd, 1H), 3.5 (m, 1H).
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The Mixture B of isomers of 4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine
(2.1 g, 0.92
mmol) was stirred in 5 N NaOH solution (20 ml) at 100°C for 96 hr,
cooled, extracted with ethyl
acetate, dried (Na2S04) and concentrated to afford Mixture B of isomers 4-
ethylamino-3,5-
dimethylpiperidine as oil. Yield 1.34 g (93.2 %), C9HZONz, m/z 157 (M+1), PMR
(CDCl3): 0.94
(dd, 6H), 1.12 (t, 3H), 1.5 - 1.8 (m, 3H, D20 exchangeable), 1.9 (m, 1H), 2.28
(m, 2H), 2.46 (m,
1 H), 2. 62 - 3. 0 (m, 4H).
Preparation 28
4-Cyclopropylamino-3,5-dimethypi eridine
to A solution of cyclopropylamine (71.6 g, 126 mmol) and 1-carbethoxy-3,S-
dimethyl-4-
piperidinone (50 g, 26 mmol) obtained by a procedure as described in Example
25 (Step-1), in
methanol (500 ml) was stirred for 6 hr at ambient temperature. Sodium
cyanoboxohydride (16 g,
26 mmol) was added in portions to the resulting mixture and stirring was
continued fox 16 hr.
The reaction mixture was concentrated to dryness. The obtained residue was
dissolved in water
and extracted with chloroform. Chloroform layer was extracted with 6N HCl and
HCl extract
was basified with aqueous KOH (20 %) solution. The oil thus separated was
extracted with
chlorofornl, dried (NaZS04) and concentrated to give a mixture of Mixtures A+B
of 1-
carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine as oil. Yield 58 g (96
%), C13H24NZO2,
m/z 241 (M+1).
The similarly obtained Mixture A+B of 1-carbethoxy-4-cyclopropylamino-3,5-
dimethylpiperidine was separated over silica gel column chromatography. Elute
from 5% ethyl
acetate in hexane gave Mixture A of isomers of 1-carbethoxy-4-cyclopropyamino-
3,5-
dimethylpiperidine as oil. C13Hz4N2O2, m/z 241 (M+1), PMR (GDCl3): 0.88 - 1.17
(m, lOH),
1.3 (t, 3H), 1.74 (bs, 1H, Da0 exchangeable), 2.48 - 2.82 (m, 4H), 3.26 - 3.85
(m, 2H), 4.18 (q,
2H), 4.42 (bm, 2H).
Further elution from 5% ethyl acetate in hexane furnished Mixture B of isomers
of 1-carbethoxy-
4-cyclopropylamino-3,5-dimethylpiperidine as oil. C13H24N2O2~ n'~z 241 (M+1),
PMR (CDC13):
0.78 - 1.08 (m, l OH), 1.15 (t, 3H), 1.48 - 2.1 (m, 4H, D20 exchangeable),
2.32 - 2.82 (m, 2H),
3.24 - 3.82 (m, 2H), 4.04 - 4.25 (m, 3H).
Mixture A of isomers of 1-carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine
( 3.5 g, 1.45
mmol) was stirred in 5 N NaOH solution ( 25 ml) at 100°C for hr,
cooled, extracted with ethyl
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acetate, dried (Na2S04) and concentrated to afford Mixture A of isomers of 4-
cyclopropylamino-
3,5-dimethyl piperidine as oil. Yield 2.1 g ( 85%), ClnH2oN2, m/z 169 (M+1).
The Mixture B of isomers of 1-carbethoxy-4-cyclopropylamino-3,5-
dimethylpiperidine (2.8 g,
1.16 mmol) was stirred in a mixture 5 N NaOH solution (20 ml) and ethyl
alcohol (5 ml) at
100°C for 120 hr, cooled, extracted with ethyl acetate, dried (Na2S04)
and concentrated to afford
Mixture B of isomers of 4-cyclopropylamino-3,5-dimethylpiperidine as an oil.
Yield 1.6 g (84
%), CloH2oN2, m/z 169 (M+1) PMR (CDCl3): 0.82 - 1.05 (m, lOH), 1.5 (m, H),
1.75 (m, H,),
2.16 - 2.3~ (m, 3H), 2.65 (m, 1H), 2.78 (m, 1H), 3.02 (m, 1H), 3.4I (m, 1H),
3.64 (m, 1H).
to
Preparation 29
4-Dimethylamino-3,5-dimethylpi eridine
Potassium hydroxide (3.86 g) was added to the stirred solution of N,N-
dimethylamine
hydrochloride (5.63 g, 69.0 mmol) in methanol (20 ml) and stirnng was
continued for 30 min at
30 °C. 1-benzyl-3,5-methyl-4-piperidinone (3 g, 13.8 mmol) was added to
the stirred mixture
and refluxed for 48 hr. Reaction mixture was cooled at 30 °C and sodium
cyanoborohydride
(0.87 g, 13.8 rninol) was added. The resulting reaction mixture was stirred
for 24 hr at 70 °C.
The reaction mixture was concentrated to dryness, triturated with water,
extracted with
chloroform, dried (NaZS04) and concentrated to give Mixtures A+B of 1-benzyl-4-
2o dimethylamino-3,5-dimethylpiperidine. Yield 2.7 g (79.4 %), C16Hz6Nz, m1z
247 (M+1).
A mixture of 20% Pd(OH)2 on carbon (0.5 g) and Mixtures A+B of 1-benzyl-4-
dimethylamino-
3,5-dimethylpiperidine (2.7 g, 10.1 mmol) in methanol (50 ml) was stirred in
hydrogen
atmosphere (1 atm.) at 60 °C for 48 hr. The catalyst was filtered off,
washed with methanol and
filtrate was concentrated to dryness to afford Mixtures A +B of 4-
dimethylamino-3,5-
dimethylpiperidine. Yield 0.9 g (52.6 %), C9HZON2, m/z 157 (M+1).
Mixture A of isomers and Mixture B of isomers of 4-dimethylamino-3,5-
dimethylpiperidine
were prepared by separation technique at 1-benzyl-4-dimethylamino-3,5-
dimethylpiperidine
stage by using silica gel column chromatography followed by debenzylation by
using catalytic
palladium hydroxide on carbon.
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Preparation 30
4-Amino-3,5-diethyl~ eridine
Ammonium acetate (10 g, 130mmo1) was added to the stirred solution of 1-benzyl-
3,5-diethyl-4-
piperidone (3.5 g, 14.3 mmol) in methanol (SO ml) and stirring was continued
for 4 hr at ambient
temperature. The resulting mixture was cooled at 0°C and sodium
cyanoborohydride (0.45 g,
7.14 rninol) was added to it. Cooling was removed after 10 min. and resulting
mixture was
stirred for 10 hr at ambient temperature. The reaction mixture was
concentrated to dryness,
triturated with water, acidified with conc. HCl (pH 2) and extracted with
ethyl acetate to remove
impurities. The aqueous layer was basified with 1M sodium hydroxide solution
(pH 10) and
1o extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and
concentrated to
dryness to furnish 4-aminx-1-benzyl-3,5-diethylpiperidine.
Yield 3.4 g (97 %), C16H26N2~ ~z 247 (M+1).
A mixture of 5% Pd on carbon (0.5 g) and 4-amino-1-benzyl-3,5-
diethylpiperidine (3.4 g, 13.82
mmol) in methanol (25 ml) was stirred in hydrogen atmosphere (3 atm.) at 60
°C for 6 hr. The
catalyst was filtered off, washed with methanol and filtrate was concentrated
to dryness to afford
4-amino-3,5-diethylpiperidine as an oil. Yield 1.4 g (64.5 %), C9HZON2, m/z
157 (M+1).
Preparation 31
4-Amino-3,3,5-trimethylpiperidine
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 1-benzyl-3,3,5-trimethyl-4-
piperidone (1.5 g,
6.5 mmol) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) at
30°C for 6 hr. The
catalyst was filtered off, washed with methanol and filtrate was concentrated
to dryness to afford
3,3,5-trimethyl-4-piperidinone. Yield 0.8 g (88 %), C8H15N0, m/z 142 (M+1).
Ammonium acetate (2.5 g, 32.46mmo1) was added to the stirred solution of 3,3,5-
trimethyl-4-
piperidone (0.8 g, 5.67 mmol) in methanol (20 ml) and stirring was continued
for 3 hr at ambient
temperature. The resulting mixture was cooled at 0°C and sodium
cyanoborohydride (0.25 g,
3.96 mmol) Was added to it. Cooling was removed after 10 min. and resulting
mixture was
stirred for 6 hr at ambient temperature. The reaction mixture was concentrated
to dryness,
triturated with water, acidified with conc. HCl (pH 3 ~ 4) and extracted with
ethyl acetate to
remove impurities. The aqueous layer was basified with 1 M sodium hydroxide
solution (pH
~10) and extracted with ethyl acetate. Ethyl acetate extract was dried
(NaaS04) and concentrated
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to dryness to furnish 4-amino-3,3,5-trimethylpiperidine. Yield 0.45 g (54 %),
CgHlsNz, m/z 143
(M+1).
Preparation 32
4-Amino-3,5-diethyl-3-methylpiperidine
Ammonium acetate (8.0 g, 104 nunol) was added to the stirred solution of 1-
benzyl-3,5-diethyl-
3-methyl-4~piperidone (2.5 g, 9.65 mmol) in methanol (25 ml) and stirring was
continued for 24
hr at ambient temperature. The resulting mixture was cooled at 0 °C and
sodium
cyanoborohydride (0.69 g, 11.2 mmol) was added to it. Cooling was removed
after 10 min. and
resulting mixture was stirred for 20 hr at ambient temperature. The reaction
mixture was
l0 concentrated to dryness, triturated with water, acidified with conc. HCl
(pH 2) and extracted with
ethyl acetate to remove impurities. The aqueous layer was basified with 1M
sodium hydroxide
solution (pH 9) and extracted with ethyl acetate. Ethyl acetate extract was
dried (NazS04) and
concentrated to dryness to furnish 4-amino-1-benzyl-3,5-diethyl-3-
methylpiperidine as an oil.
Yield 2.1 g (84 %), CI~HzBNz, mlz 261 (M+1).
A mixture of 20% Pd(OH)z on carbon (0.3 g) and 4-amino-1-benzyl-3,5-
diethyl-3-methylpiperidine (2.1 g, 8.07 mmol) in methanol (50 ml) was stirred
in hydrogen
atmosphere (4 atm.) at 45 °C for 4 hr. The catalyst was filtered off,
washed with methanol and
filtrate was concentrated to dryness to afford 4-amino-3,5-diethyl-3-methyl-
piperidine as an oil.
2o Yield 1.2 g (88 %), CloHzzNz, mlz 171 (M+1).
Preparation 33
4-Amino-3,5-dimeth 1-y_3-ethylpiperidine
Ammonium acetate (2.5 g, 32.46mmol) was added to the stirred solution of 1-
benzyl-3,5-
dimethyl-3-ethyl-4-piperidone (3.0 g, 12.25 mmol) in methanol (40 ml) and
stirnng was
continued for 20 hr at ambient temperature. The resulting mixture was cooled
at 0°C and sodium
cyanoborohydride (0.8 g, 12.7 mmol) was added to it. Cooling was removed after
10 min, and
resulting mixture was stirred for 20 hr at ambient temperature. The reaction
mixture was
concentrated to dryness, triturated with water, acidified with conc. HCl (pH
2) and extracted with
ethyl acetate to remove impurities. The aqueous layer was basified with 1M
sodium hydroxide
solution (pH 9) and extracted with ethyl acetate. Ethyl acetate extract was
dried (NazSO~) and
concentrated to dryness to furnish 4-amino-1-benzyl-3,5-dimethyl-3-
ethylpiperidine.
Yield 2.2 g (73 %), C1gH26N2, m/z 247 (M+1).
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A mixture of 20% Pd(OH)z on carbon (0.4 g) and 4-amino-1-benzyl-3,5-dimethyl-3-
ethylpiperidine (2.2 g, 8.9 mmol) in methanol (15 rnl) was stirred in hydrogen
atmosphere (1
atm.) at 60°C for IO hr. The catalyst was filtered off, washed with
methanol and filtrate was
concentrated to dryness to afford 4-amino-3,5-dimethyl-3-ethylpiperidine as a
semi solid.
S Yield 1.1 g (79 %), C9H2oN2, m/z 157 (M+1).
Preparation 34
cis or trafas-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine:
Step-l: Ethyl-1-benzyl-3-methyl-4-oxo-piperidine-3-carboxylate:
l0 Ethyl -1-benzyl-4-oxo-piperidine -3-carboxylate hydrochloride (150 g, 0.504
mol) was
suspended in a solvent mixture of 750 ml THF and 750 ml DMF at room
temperature. Addition
of powdered KOH (56 g, I.0 mol) was made in two equal Iots keeping half an
hour interval
between two additions. To a clear reaction mixture methyl iodide (78 g, 0.55
mol) was added
over period of 10 minutes and it was stirred for three hours at room
temperature. The reaction
15 was quenched by adding 4 ltr water followed by 1.5 ltr diethyl ether.
Layers were separated.
Organic layer was washed with water and dried over NazS04. Evaporation of
organic solvent
afforded a liquid, which was passed through a silica gel column to give 86 g
(61%), titled
compound.
mass (ES+) 276, Molecular Formula C16H21N03,
2o H1NMR (CDC13) 1.2 (s, 3H), 1.25 (t, 2H), 2.15 (d, 1H), 2.35-2.5 (m, 2H),
2.9 (d, 2H), 3.45 (d,
1H), 3.6 (s, 2H), 4.12-4.3 (m, 2H), 7.3 (s, SH).
Step-2: 1-Benzyl-3-meth~piperidone:
Ethyl-1-benzyl-3-methyl-4-oxo-piperidine-3-carboxylate (85 g, 0.31 mol) was
dissolved in conc
25 HCl (82 ml, 0.77 mol) and the reaction mixture was heated to 100 °C
for 32 hrs. Solvent was
removed under reduced pressure and the resulting solid Was dissolved in the
300 ml CHC13 and
400 ml pet ether was added to this order stirring to provide a solid. The
solid was filter and was
dissolved in 400 ml ethyl acetate and organic layer was washed with 10% NaOH
aqueous
solution. Layers were separated and concentration of organic layer afforded 48
g ( 75%) oil as a
30 titled product.
mass (ES+) 204, Molecular Formula C13H1~N0,
H1NMR (CDC13) 1.0 (d, 3H), 2.1 (t, 1H), 2.3-2.5 (m, 2H), 2.6-2.8 (m, 2H), 3.0-
3.2 (m, 2H), 3.6
(s, 2H), 7.4 (s, SH).
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Step-3: 4-Amino-1-bend-3-methy~iperidine:
Ammonium acetate (178.3 g, 2.3I mol) was charged to a solution of 1-benzyl-3-
methyl-4-
piperidone (47 g, 0.232 mol) in 500 ml methanol. The suspension was stirred
for 4 hours at room
temperature. Sodium cyanoborohydride (7.3 g, 0.116 mol) was added in lots at
10 °C and it was
stirred for 1 hour.
Solvent was removed under vacuum and resultant solid was suspended in 500 ml
water and
acidified with dilute aqueous HCI. It was extracted with 200m1 X 2 chloroform
and layers were
separated. Aqueous layer was basified with ammonia solution to pH 9 and
extracted with 500 ml
l0 X 3 CHC13. Drying of organic layer over NaZSO~ and evaporation afforded 44
g (92%) titled
product as an oil, which was used directly for further reaction.
Step -4: cis or tr~afis-4-t-Bu~lox c~arbonylamino-1-benzyl-3-methylpiperidine:
Di-tert-butyloxydicarbonate (45 g, 0.206 mol) was charged in lots to a
solution of 4-amino-1-
is benzyl-3-methylpiperidine (42 g, 0.206 mol) and 300 ml CHZCIz followed by 5
ml triethylamine.
Reaction was worked up after 90 minutes by adding 300 ml water and layers were
separated
Drying of organic layer over NazS04 and evaporation yielded mixture of cis and
traps isomers in
unequal proportion which when subjected to silica gel column chromatography
with 10% ethyl
acetate and hexane yielded 14 g of cis isomer and 11 g t3~ayzs isomer and 19
gm mixture of both
2o isomers of titled compound.
For cis isomer:
mass (ESA) 305, Molecular Formula C1gH28N2Oz,
H1NMR (CDC13) 0.95 (d, 3H), 1.45 (s, 9H), 1.7-1.8 (m, 2H), 2.0-2.2 (m, 2H),
2.35-2.5 (m, 2H),
3.5 (d, 2H), 3.7-3.8(bs, 1H), 4.5 (bs, 1H), 7.3 (s, SH).
25 For traps isomer:
mass (ES+) 305, Molecular Formula ClgHzBNzOz,'
H1NMR (CDCl3) 0.90 (d, 3H), 1.45 (s, 9H), 1.7-1.8 (t, 2H), 1.9-2.1 (m, 2H),
2.8-2.9 (m, 2H), 3.1
(m, 1H), 3.45(s, 2H), 4.3 (m, 1H), 7.3 (s, SH).
30 Preparation 35
cis-4-t-Butyloxycarbonylamino-3-rnethylpiperidine:
cis-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine(13 g, .042 mol) was
dissolved in
170 ml methanol and transferred to the Parr pressure xeactor after addition of
1.3 g of Pd(OH)z
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on carbon. The rqcytoion mixture stirred fox 6 hrs at 400 psi pressure at 50
°C. Catalyst was
removed by filtration and eavaporation of the solvent afforded 8.7 g ( 95%) of
titled compound.
mass (ES+) 215, Molecular Formula Cl lHzzN20z,
H1NMR (CDC13) 0.90 (d, 3H), 1.45 (s, 9H), 1.7 (m, 2H), 2.0 (m, 2H), 2.8 (m,
2H), 3.8 (bs, 1H),
4.7 (bs, 1H).
Preparation 36
trans-4-t-Butylox c~axbonylamino-3-methylpineridine~
trans-4-t-Butyloxycarbonylamino-3-methylpiperidine was obtained as per
procedure depicted in
preparation 000 by using trans-4-t-Butyloxycarbonylamino-1-benzyl-3-
methylpiperidine in the
l0 place of cis-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine in 96%
yield.
mass (ES+) 215, Molecular Formula CllHzzNz~z,
H1NMR (CDC13) 0.90 (d, 3H), 1.40 (s, 9H), 1.9 (m, 2H), 2.8 (m, 2H), 3.1 (m,
2H), 3.4 (s, 1H),
4.3 (m, 1H).
Preparation 37
(-)-4-Amino-3,3-dimethylpiperidine
A mixture of 10% palladium on carbon (7.5 g) and (-)- 4-amino-1-
benzyloxycarbonyl- 3,3-
dimethylpiperidine ( cf. Preparation 19, Step 4, 50 g, 191.0 mmol) in methanol
(500 1111) was
stirred under hydrogen atmosphere (30 atm.) at 30 °C for 6 hr. The
catalyst was filtered off,
washed with 100 ml methanol and filtrate was concentrated to dryness to afford
(-)-4-amino-3,3-
dimethylpiperidine, which was further purified by vacuum distillation to give
16.8 (71 %) titled
compound.
C~Hl6Nz, mlz 129 (M+1), PMR (CDC13): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H,
Dz~
exchangeable), 2.26 - 2.68 (m, 4H), 3.06 (m, 1H), 3.52 (bs, 1H, DzQ
exchangeable). [a]DZS value
-31.72 (c = l, CHC13).
Preparation 38
1+)-4-Amino-3,3-dimethylpiperidine
The titled compound was prepared by the procedure described in Preparation 37,
by using (+)- 4-
amino-1-benzyloxycarbonyl- 3,3-dimethylpiperidine (cf. Preparation 19, Step 3,
44 g, 168.0
3o mmol), to give 15.0 (70%) titled compound.
C~Hl6Nz, m/z 129 (M+1), PMR (CDC13): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H,
D20
exchangeable), 2.26 - 2.68 (m, 4H), 3.06 (m, 1H), 3.52 (bs, 1H, D20
exchangeable). [a,]D2s value
+ 32.34 (c=l, CHC13).
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Example 1
1-Cyclo ropyl-6-fluoro-1 4-dihydro-8-methoxy-7-(4-amino-3-methyl-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid
A mixture of [1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-quinoline-
3-
carboxylate-03,04]difluoroboron chelate (0..1 g, 0.29 mmol) and 4-amino-3-
methylpiperidine
(0.2 g, 1.75 rninol) in acetonitrile (20 mI) was refluxed for 6 hr. The
reaction mixture was
concentrated to dryness. The obtained residue was treated with triethylamine
(3 ml) and ethanol
(15 ml) and refluxed for 16 hr. The resulting mixture was concentrated to
dryness; the solid thus
obtained was triturated with water (10 ml), filtered, washed with water, dried
and purified by
to preparative HPLC to furnish the required pxoduct. Yield 0.04 g (35%),
m.p.238-40°C,
CZOH24FN304, m/z 390 (M+1), PMR (CD30D): 0.84-1.42 (m, 7H), 1.8-2.4 (m, 3H),
3.02 (m,
1H), 3.18-3.72 (m, 4H), 3.8 (s, 3H), 4.18 (m, 1H), 7.82 (d, 1H), 8.9 (s, 1H).
Example 2
t~a~s-1-Cyclobropyl-6-fluoro-14-dihYdro-8-methoxy-7-(4-amino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where tYaras-4-
amino-3-
methylpiperidine was used in place of 4-amino-3-methylpiperidine. Yield 35%,
m.p.240-42°C,
C2oH24FN3O4, m/z 390 (M+~l).
2o Example 3
cis-1-cyclopropyl-6-fluoro-1 4-dihydro-8-methoxy-7 ~4-amino-3-methyl-1-pip
eridinyl)-4-oxo-
quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example l, where cis-4-
amino-3-
methylpiperidine was used in place of 4-amino-3-methylpiperidine Yield 35%,
m.p.246-50°C,
C2oHZ4N3O4F, m/z 390 (M+1).
Example 4
1-Cyclohropyl-6-fluoro-1 4-dihydro-8-methoxy-7-(4-methylamino-3-methyl-1-
piperidinyl)-4
oxo-guinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where- 4-
methylamino-3
methylpiperidine was used in place of 4-amino-3-methylpiperidine. Yield 50 %,
m.p.240°C
(decomp.), CZIHzsFN304, m/z 404 (M+1).
Example 5
1-Cvclopropyl-6-fluoro-1 4-dihydro-8-methox~7-(4-ethylamino-3-methyl-1-
pirperidinyl)-4-oxo
quinoline-3-carboxylic acid
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It was prepared in a similar manner as described in Example 1, where 4-
ethylamino-3-
methylpiperidine was used in place of 4-amino-3-methylpiperidine. Yield 52 %,
m.p.160-62°C,
CazHasFN30a~ ~z 418 (M+1).
Example 6
1-Cyclopropyl-6-fluoro-1 4-dihydro-8-methox -7~-(4-c_yclopropylamino-3-metal-1-
piperidin
4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where 4-
cyclopropyl amino-3-
methylpiperidine was used in place of 4-amino-3-methylpiperidine. Yield 60 %,
m.p.182-84°C,
C23H28FN3O4, m/z 430 (M+1).
to Example 7
1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dirnethylarnino-3-methyl-
1=piperidinyl)-4
oxo-quinoline-3-carboxylic acid
It was prepared in a similar mannex as described in Example 1, where 4-
dimethyl amino-3-
methylpiperidine was used in place of 4-amino-3-methylpiperidine. Yield 74 %,
m.p.180-82°C,
C22HZ8FN304, m/z 418 (M+I), PMR (CD30D): 0.88-1.28 (rn, 7H), I.8-2.3 (m, 3H),
2.92 (s, 6H),
2.66-3.62 (m, SH), 3.76 (s, 3H), 4.14 (m, 1H), 7.68(d, 1H), 8.78 (s, 1H).
Example 8
1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7,~4-ethoxycarbonylamino-3 3-
dimethyl-I-
2o piperidinyll-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example l, where 4-1-
carbethoxy amino-3,3-
dimethyl piperidine was used in place of 4-amino-3-methyl-piperidine. Yield 16
%, m.p.222°C,
Cz4H3oFNs4s, m/z 476 (M+1), PMR
(CDC13): 1.04 (m, 9H), 1.26 (m, 4H), 1.86 (m, 2H), 3.02 - 3.68 (m, 4H), 3.72
(s, 3H), 4.02 (m,
1H), 4.16 (q, 2H), 4.58 (m, 1H), 7.86 (d, 1H), 8.82 (s, 1H), 14.8 (s, IH, D20
exchangeable).
Example 9
(~1-1-C~clopropyl-6-fluoro-1,4-dih~dro-8-methoxy-7~4-benzyloxycarbon~lamino-3
3-
dimethyl-1-p~eridinyl)-4-oxo-quinoline-3-carbox hy--c acid
3o It was prepared in a similar manner as described in Example l, where 4-(~)-
benzyloxy
carbonylamino-3,3-dimethylpiperidine was used in place of 4-amino-3-
methylpiperidine. Yield
47 %, m.p.158-60°C, C29H32fN3O6, m/z 538 (M+1), PMR (CDC13): 1.0 (s,
6H), 1.26 (m, 4H),
1.84 (rn, 2H), 3.04 - 3.7 (m, 4H), 3.76 (s, 3H), 4.06 (m, 1H), 4.72 (m, 1H),
5.18 (s, 1H), 7.4 (m,
5H), 7.86 (d, 1H), 8.84 (s, 1H), 14.8 (s, 1H, D20 exchangeable).
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Example-10
(~)-1-Cyclopropyl-6-fluoro-1 4-dihydro-8-method-7-(4-amino-3 3- dimethyl-1
~iperidinyl)-4
oxo-quinoline-3-carboxylic acid
4-Benzyloxycarbonylamino-3,3-dimethyl piperidine (100 g, 0.381 mol) was
suspended in 200
ml acetonitrile under stirring. To the solution was added (1-cyclopropyl-6, 7-
difluoro-8-
methoxy-1, 4-dihydro-4-oxo-quinoline-3-carboxylate 03, 04) difluoroboron
chelate (65 g, 0.189
mol) and stirring was started at temperature between 25-35°C. The
reaction mixture was stirred
for 4-5 hrs at this temperature. After the reaction was completed, the solvent
was removed under
vacuum to dryness to obtain a solid. To~the solid was charged 200 ml ethyl
alcohol followed by
tniethylamine (20 g, 0.198 mol). The reaction mixture was stirred at reflux
temperature for 2-3
hrs. The solution was left overnight at 25-35°C. The solid separated in
the reaction mixture was
filtered and washed with 50 ml ethanol. The filtered solid was stirred with
reflex at 100-110 °C
in concentrated hydrochloric acid (250 ml) for 2 hr. The resulting solution
was taken to dryness
by evaporating the acid order vacuum to obtain a residue. To the residue was
added 1 L acetone
and the suspension stirred for 1 hr. The resulting solid was filtered and
washed with acetone. The
residue was suspended in 600 ml chloroform and was refluxed for 30 minutes.
The suspension
was filtered and the residue washed with chloroform. The residue was suspended
in methanol
(600 ml) and was stirred at 30-35°C for 30 minutes. 'The suspension was
filtered to obtain a
solid, which was dissolved in 1 L water under stirring at 60- 70 °C.
The pH of the solution was
adjusted between 8.0-9.0 by adding 30% aqueous sodium hydroxide solution. The
reaction
mixture was extracted with 600 m1 X 2 chloroform. The organic layers were
combined and
washed with water, dried over NaZSOa and evaporated under reduced pressure to
afford a solid
which was further triturated with methyl alcohol and filtered to give 43 g (56
%) titled
compound.
mlz (M+1) 404, mp 222-224 °C
NMR (CDCl3): 0.95-1.3 (m, lOH); 1.7-1.8 (m, 2H); 2.6 (t, 1H); 3.0 (dd, 1H);
3.3 (m,2H); 3.6
(m, 1H), (3.7 s,3H); 4.02 (m, 1H), 7.9 (d,lH); 8.8 (s, 1H).
3o An alternate procedure to prepare this compound is by a method similar to
that described in
Example 1 where 4-amino-3,3-dimethylpiperidine was used in place of 4-amino-3-
methylpiperidine.
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A second alternate procedure to prepare this compound is by treating 1-
cyclopropyl-6-fluoro-
1,4-dihydro-8-methoxy-7-(4-1-carbethoxyamino-3,3-dimethyl-1-piperidinyl)-4-oxo-
quinoline-3-
carboxylic acid [obtained from condensation of 1-cyclopropyl-6,7-difluoro-1,4-
dihydro-8-
methoxy-4-oxo-quinoline-3-carboxylic acid difluoroborane chelate and 4-1-
carbethoxyamino-
3,3-dimethylpiperidine] (2.0 g, 4.0 mmol) under reflux with aqueous NaOH
(0.6M, 100 ml) for 4 .
hr with stirnng, filtered and the residue dried. The obtained crude product
was adjusted to pH 3-
S by 3 N HCI, concentrated, triturated with acetone and crystallisation from
methanol furnished
the required product.
Exam lp eel l
to (~)-1-Cyclopropyl-6-fluoro-1,4-dil~dro-8-methoxy-7-(4-amino-3,3-
dimeth~p~eridinyl)-4-
oxo-quinoline-3-carboxylic acid. Hydrochloride
The hydrochloride salt was obtained by modifying the procedure in Example 10
after obtaining
the solid residue from filtration of the suspension in methanol before
dissolving in water and
adjusting the pH to 8.9 by adding 30% aqueous sodium hydroxide solution. The
residue obtained
from filtration of the suspension from methanol was dissolved in 2.0 ltr at
reflux temperature. It
was then filtered hot and concentrated to approximately one fourth of its
volume and left
overnight. The crystals obtained were filtered at 25-35°C and were
dried in an oven at 70-80°C
under pump vacuum to yield 38.0 g (48 %) titled compound.
mp 256 -260°C,
NMR (CD30D): selected values 1.0-1.5 (m, 2H); 1.20 (d, 6H); 1.21-1.30 (m, 2H);
1.90-2.20 (m,
2H); 3.6-3.7 (m, 1H); 3.8 (s,3H); 4.20 (m, 1H), 7.8 (d,lH); 8.9 (s, 1H).
Example 12
(~)-1-Cyclopro~yl-6-fluoro-1 4-dihydro-8-methox~4-amino-3 3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid methanesulfonate
6.50 Grams (16.13 mol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-
amino-3,3-
dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid were suspended in 65
ml of isopropyl
alcohol. The suspension was heated to 70- 80°C under stirring and then
1.90 g (19.79 mol)
methanesulfonic acid was added. The reaction mixture Was heated at reflux for
30 minutes. It
3o was cooled to 30- 35°C and filtered. The solid was washed with 10 ml
isopropyl alcohol and
dried for 16 hrs in oven under vacuum at 50°C to give 6.80 g (84%)
titled compound, mp 286 -
290°C,
NMR (CD30D): selected values 1.0-1.5 (m, 2H); 1.20 (d, 6H); 1.9-2.2 (m, 2H);
2.7 (s,
IIS
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3H); 3.2-3.7 (m, 4H); 3.8 (s,3H); 4.20 (m, 1H), 7.8 (d,lH); 8.9 (s, 1H).
Example 13
(+)-1-CYclopro~yl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3 3-dimethyl-1-
~iperidinylL
oxo-quinoline-3-carboxylic acid. gluconate
To a suspension of 2.50 g (6.20 mol) 1-cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-
amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and 50 ml
isopropyl
alcohol was added 2.4 ml (1.50 g, 7.64 mol) 50% aqueous D-gluconic acid at
80°C under
l0 stirnng. The clear solution was stirred for 30 minute at this temperature,
and cooled to 30-35°C
to give a solid. The solid was filtered and washed with lOml isopropyl
alcohol. The obtained
solid was crystallized from methanol to give 2.0 g (54%) of the gluconate
salt.
mp. 160-162 °C.
Exam lp a 14
(+)- 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride
(+)-3,3-Dimethyl-4 t-butyloxycarbonylamino piperidine (46 g, 0.201mo1) was
suspended in 200
ml acetonitrile under stirnng. To the solution was added (1-cyclopropyl-6,7-
difluoro-8-
methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylate 03, O4) difluoroboron
chelate (35 g, 0.102
2o mol) and the reaction mixture was stirred for 24 hrs between 25-35
°C temperature.
Triethylamine (10.3 g, 0.102 mol) was added to the reaction mixture and it was
stirred at 80-
85°C temperature for 4-5 hrs. After reaction was completed, solvent was
removed under vacuum
to dryness to obtain a residue. To the residue was charged 200 ml ethyl
alcohol followed by
triethylamine (12.32 g, 0.122 mol). The reaction mixture was stirred at reflux
temperature for 5-6
hrs. The solution was left overnight at 25-35°C. The solid separated in
the reaction mixture was
filtered and washed with 50 ml ethanol. The solid was stirred with
concentrated hydrochloric
acid (100 ml) for 1 hr. The resulting solution was taken to dryness by
evaporating the acid under
vacuum to obtain a residue. To the residue was added 600 ml acetone and the
suspension stirred
for 1 hr. The resulting solid was filtered and washed with acetone. The solid
was suspended in
3o 300 mI chloroform and was refluxed fox 30 minutes. The suspension was
filtered and was
washed with chloroform. The wet solid was suspended in methanol 100 ml and was
stirred at 30-
35°C for 30 minutes. The reaction mixture was filtered. The residue was
dissolved in 1.3 L
methanol at reflux temperature. It was filtered hot and concentrated to
approximately one fourth
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of its volume and was left overnight. Crystals obtained were filtered at 25-
35°C and were dried
in an oven at 70-80°C under vacuum to yield 15 g (33.5%) titled
compound., mp 256 -260°C,
NMR(CD30D): 0.95-1.3 (m, lOH); 1.90-2.20 (m, 2H); 3.15-3.4(m, SH); 3.8 (s,3H);
4.20 (m,
1H), 7.8 (d,lH); 8.9 (s, 1H).
[a]Das value +132.0° (c=1, methanol).
The enantiomeric purity was established by making N-t-butyloxycarbonylalanine
derivative
of(+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl) -4-
oxo-quinoline-3-carboxylic acid. This derivative was analyzed on HPLC against
N-t-
l0 butyloxycarbonylalanine derivative of racemic 1-cyclopropyl-6-fluoro-1,4-
dihydro-8-methoxy-
7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid.
The ratio of enantiomers was fotuld to be 98.49:1.50.
Example - 15
~)-1-Cyclopropyl-6-fluoro-1,4-dih~dro-8-methox~7-(4-amino-3,3-
dimeth~piperidinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride
The compound was prepared in 30% yield as per procedure described for its (+)
isomer.[a]DZs
value -127.27° (c=1, methanol).
Enantiomeric purity was established by making N-t-butyloxycarbonylalanine
derivative of (-)-
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid. This derivative was analyzed on HPLC against N-t-
butyloxycarbonylalanine derivative of racemic 1-cyclopropyl-6-fluoro-1,4-
dihydro-8-methoxy-
7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid. The
ratio of
enantiomers was found to be 96.37:3.62.
Example - 16
(+)- 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methox~7-(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid
8.50 Grams (19.34 mrnol) of (+)- 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-
7-(4-amino-
3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride
were dissolved in
250 ml water under stirring. The solution pH was adjusted between 8.0-9.0 by
adding 30%
aqueous sodium hydroxide solution. The reaction mixture was extracted with 200
ml X 2
chloroform. Combined organic layer was washed with water, dried over NaaS04
and evaporated
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under reduced pressure to afford a solid which was further triturated with
isopropyl alcohol and
filtered to give 7.34 g (94%) above mentioned compound, mp 221-224°C.
NMR (CDC13): 0.95-1.3 (m, lOH); 1.7-1.8 (m, 2H); 2.6 (t, 1H); 3.0 (dd, 1H);
3.3 (m,2H); 3.6
(m, 1 H), (3. 7 s, 3H); 4. 02 (m, 1 H), 7.9 (d, l H); 8. 8 (s, 1 H).
[a,]DZS value +133.84° (c=1, chloroform).
Example - 17
(-)- 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methox ~-~7- 4-amino-3,3-dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid
Similarly, by using the procedure mentioned above, 8.40 g (19.11 rmnol) of (-)-
1-cyclopropyl-6-
fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-pip eridinyl)-4-oxo-
quinoline-3-
carboxylic acid hydrochloride was converted to 6.65 g (86%) titled compound.
mp 222-225°C,
~a~DZS value-125.06°(c=1, chloroform).
Example - 18
M5 (+)-1-C~propyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3 ,3 -dimethyl-1-
piperidiny~-4-oxo-quinoline-3-carboxylic acid. Methanesulfonate
6.50 Grams (16.13 mmol) of (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-
(4-amino-
3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboXylic acid were suspended
in 65 ml of
isopropyl alcohol. The suspension was heated to 70- 80°C under stirnng
and then 1.90 g ( 19.79
mmol) methanesulfonic acid was added. The reaction mixture became clear for a
moment and a
solid was separated. The suspension was heated at reflux for 30 minutes. It
was cooled to 30-
35°C and filtered. The solid was washed with 10 ml isopropyl alcohol
and dried for 16 hrs in
oven under vacuum at 50°C to give 6.80 g (84%) titled compound, mp 286 -
290°C,
NMK (CD30D): 0.95-1.25 (m, 10H); I.95-2.20 (m, 2H); 2.7 (s, 3H); 3.2-3.4 (m,
4H); 3.6-3.7
(m, 1H); 3.8 (s, 3H); 4.20 (m, 1H), 7.8 (d,lH); 8.9 (s, 1H).
~a~DZS value +113.97° (c=1, methanol).
Example - 19
~)-1-Cyclopro~ 1-~6-fluoro-1,4-dihydro-8-methox~(4-amino-3,3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid methanesulfonate
Similarly, by using the procedure mentioned above, 6.30 g (15.63 mmol) of (-)-
1-cyclopropyl-6-
fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-
quinoline-3-
carboxylic acid was converted to 5.60 g (72%) titled compound, mp 288-
290°C
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[a,~D2s value -112.41° (c=l, methanol).
Example 20
(+)-1-C~clopro~yl-6-fluoro-1 4-dihydro-8-methox~(4-amino-3,3-dimeth~l-
~iperidin~l-4-
oxo-quinoline-3-carboxylic acid ~luconate
To a suspension of 2.50 g (6.20 mmol) (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-
amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid and 50 ml
isopropyl
alcohol was added 2.4 ml (1.50 g, 7.64 mmol) 50% aqueous D=gluconic acid at
80°G under
stirring. The clear solution was stirred for 30 minute at this temperature,
cooled to 30-35°C to
give a solid. The solid was filtered and washed with 10 ml isopropyl alcohol.
he obtained solid
was crystallized from methanol to give 2.0 g (54%) gluconate salt of (+)-1-
cyclopropyl-6-fluoro-
1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-
carboxylic
acid, mp 158-60°C
Example - 21
(-)-1-C~clopro~yl-6-fluoro-1 4-dihydro-8-methox T-~7-(4-amino-3,3-dimethyl-1-
piperidinyl)- 4-oxo-quinoline-3-carbox~ic acid ~luconate
Similarly, by using the procedure mentioned above, 2.20 g (54.60 mmol) of (-)-
1-cyclopropyl-6-
fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-
quinoline-3-
carboxylic acid was converted to 1.65 g (50%) titled compound, rnp 154-
156°C.
Example 22
1-CXclopronyl-6-fluoro-1 4-dihydro-8-methoxy-7-(4-acetylamino-3 3-dirnethyl-1-
piperidinyl)-4
oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described, in Example 1, where 4-
acylamino-3,3-
dimethylpiperidine was used in place of 4-amino-3-methylpiperidine. Yield 20%,
m.p.194-96°C,
Cz3H2sFN3~s~ m1z 446 (M+1).
Example 23
1-Cycloprobyl-6-fluoro-1 4-dihydro-8-methoxy-7-(4 t-butyloxycarbonylamino-3 3-
dimethyl-1-
3o piperidinyl))-4-oxo-quinoline-3-carboxylic acid
Di-t-butoxycarbonate (0.32 g, 1.1 mmol) was added to a stirred solution of 1-
cyclopropyl-6-
fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)}-4-oxo-
quinoline-3-
carboxylic acid (0.3 g, 7.4 mmol) in dioxane (10 ml) and water (5 ml) at
ambient temperature
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and stirring was continued for 14 hr and concentrated to dryness. The obtained
solid was
dissolved in ethyl acetate, washed with water, dried (NaZS04) and concentrated
to give titled
product. Yield 72 %, m.p.218-20°C, C26H34FN306, ~z 504 (M+1).
Example 24
1-C~clopro~rl-6-fluoro-1 4-dihydro-8-methoxy-7-(4-methylamino-3 3-dimethyl-1-
piperidinyl))
4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where 4-
methylamino-3,3-
dimethylpiperidine was used.in place of 4-amino-3-methylpiperidine Yield 50 %,
m.p.246-48°C,
to CZZHzsFN304, m/z 418 (M+1).
Example 25
1-Cyclo~propyl-6-fluoro-1 4-dihydro-8-methox~(4-ethylamino-3 3-dimethyl-1-
piperidinyl)I
4-oxo-~,uinoline-3-carboxylic acid
15 It was prepared in a similar manner as described in Example 1, where 4-
ethylamino-3,3-
dimethylpiperidine was used in place of 4-amino-3-methylpiperidine Yield 60 %,
m.p.230-32°C,
C23H30fN3~4, ~z 432 (M+1).
Example 26
1 C, c~ lopro~yl-6-fluoro-1 4-dihvdro-8-methoxy-7-(4-cyclopropylamino-3,3-
dimethyl-1-
2o piperidin~ ~-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where 4-
cyclopropyl amino-3,3-
dimethylpiperidine was used in place of 4-amino-3-methylpiperidine Yield 31 %,
m.p.190-92°C,
C24H30fN3~4~ Wz 444 (M+1), PMR (CDCl3): 1.22 (6H, s), 0.8-1.48 (8H, m), 1.88
(2H, m),
2.28-3.7 (6H, m), 3.72 (s, 3H), 4.06 (m, 1H), 7.74 (d, 1H), 8.74 (s, 1H), 14.7
(bs, 1H, D20
25 exchangeable).
Example 27
1 Cyclopropyl-6-fluoro-1 4-dihydro-8-methoxy-7-(4-dimethylamino-3 3-dimethyl-1
pi ep ridinyl)-4-oxo-auinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where 4-
dimethyl amino-3,3-
3o dimethylpiperidine was used in place of 4-amino-3-methylpiperidine Yield 35
%, m.p.210°C,
Cz3g3oFN3pa, m/z 432 (M+1), PMR (CDC13): 1.02 (d, 6H), 0.92-1.4 (m, 4H), 1.8
(m, 2H), 2.32
(s, 6H) 2.28-3.65 (m, SH), 3.68 (s, 3H), 4.01 (m, 1H, m), 7.68 (d, 1H), 8.86
(s, 1H), 14.9 (bs, 1H,
D20 exchangeable).
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Example 28
1-Cyclopropyl-6-fluoro-1 4-dihydro-8-methoxy-7-(4-amino-3-ethyl-3-methyl-1-
~iperidinyl}-4
oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where 4-amino-3-
ethyl-3
methylpiperidine was used in place of 4-amino-3-methylpiperidine. m.p.152-54
°C,
CazH28FN304, m/z 418 (M+1).
Example 29
1-C r~clopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-met~lamino-3-ethyl-3-
methyl-I
piperidinyl)~-4-oxo-quinoline-3-carboxylic acid
to It was prepared in a similar mamier as described in Example _l, where 4-
methylamino-3-ethyl-3-
methylpiperidine was used in place of 4-amino-3-methylpiperidine m.p. 182-84
°C,
Cz3H3oFN3~4, m/z 432 (M+1).
Example 30
1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methox ~-y-7-(4-cyclopropylamino-3-ethyl-
3-methyl-1-
piperidinyl)1-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where 4-
cyclopropyl amino-3-
ethyl-3-methylpiperidine was used in place of 4-amino-3-methylpiperidine m.p.
210-12°C,
C25H32FN304, ~z 458 (M+1).
Example 31
1-cyclopro~yl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-ethyl-3-
methyl-1
~peridinyl)-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example l, where 4-
dimethyl amino-3-ethyl
3-methylpiperidine was used in place of ~ 4-amino-3-methylpiperidine, m.p.2l 0-
12 °C,
C24H32F'N3~4~ m1z 446 (M+1).
Example 32
Mixtures A+B of 1-cvclopropvl-6-fluoro-1,4-dihvdro-8-methoxv-7-(4-amino-3,5-
dimeth~-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar mamler as described in Example 1, where 4-amino-
3,5-
dimethylpiperidine was used in place of 4-amino-3-methylpiperidine, m.p.178-
80°C,
C2iHz6FN304, m/z 404 (M+1).
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Example 33
Mixture A of isomers of 1-cyclopro~yl-6-fluoro-1,4-dihydro-8-methox T-~7-(4-
amino-3,5-
dimethyl-1-piperidinyl)-4-oxo-guinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where Mixture A
of isomers of 4-
amino-3,5-dimethylpiperidine was used in place of 4-amino-3-methylpiperidine,
m.p. 238-40°C,
CZIHz6FN304, m/z 404 (M+1).
Exam lp a 34
Mixture B of isomers of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-
amino-3,5-
l0 dimeth~~beridin~)-4-oxo-~uinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where Mixture B
of isomers of 4-
amino-3,5-dimethylpiperidine was used in place of 4-amino-3-methylpiperidine,
m.p. 200-04°C,
C21H26~304~ ~z 404 (M+1).
Example 35
Mixtures A+B of lcycl~ropyl-6-fluoro-1,4-dihydro-8-methoxy-7-{4-methylamino-
3,5-
dimethyl-1-~peridinyl))-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where 4-
methylamino-3,5-
dimethylpiperidine was used in place of 4-amino-3-methylpiperidine, m.p. 268-
72°C,
CzzHzaFN3C4, ~z 418 (M+1).
2o Example 36.
Mixture A of isomers of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methox~r-7-(4-
methylamino-3,5-
dimethyl-1-~peridinyl)-4-oxo-guinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where Mixture A
of isomers of 4
wmethylamino-3,5-dimethylpiperidine was used in place of 4-amino-3-
methylpiperidine,
CZZH2aFN304, m/z 418 (M+1).
Example 37
Mixture B of isomers of 1-cyclopropyl-6-fluoro-1 4-dihydro-8-methox~4-
methylamino-3 5
dimethyl-1-piperidinyl)-4-oxo-duinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where Mixture A
of isomers of 4-
3o methylamino-3,5-dimethylpiperidine was used in place of 4-amino-3-
methylpiperidine,
CZZH28FN3O4, mlz 418 (M+1).
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Example 38
Mixture A of isomers of 1-cycloprouyl-6-fluoro-1,4-dihydro-S-methoxy-7-(4-
ethylamino-3,5
dimethXl_-1-piberidinyl) -4-oxo-auinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where Mixture A
of isomers of 4-
methylamino-3,5-dimethylpipenidine was used in place of 4-amino-3-
methylpiperidine, rn.p.
250-52°C, C23H30~N304~ ~z 432 (M+1).
Example 39
Mixture B of isomers of 1-c clue opropyl-6-fluoro-1,4-dihydro-8-methox~7-(4-
ethylamino-3,5-
dimethyl-1-piperidinyll-4-oxo-quinoline-3-carboxylic acid
l0 Tt was prepared in a similar manner as described in Example 1, where
Mixture B of isomers of 4-
methylamino-3,5-dimethylpiperidine was used in place of 4-amino-3-
methylpiperidine, m.p.
250-55°C, Cz3H3oFN3O4, m/z 432 (M+1).
Example 40
Mixture A of isomers of 1-cvclopronyl-6-fluoro-1 4-dihydro-8-methox~(4-
cyclopropylamino-
3 5-dimeth~-1 piperidinyll-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where Mixture A
of isomers of 4-
cyclopropyl amino-3,5-dimethylpiperidine was used in place of 4-amino-3-methyl-
piperidine,
C2dH3oFN304, m/z 444 (M+1)
2p Example 41
Mixture B of isomers of 1-cyclopro~yl-6-fluoro-1 4-dihydro-8-methoxy-7-(4-
cYclopropylamino
3 5-dimethyl-1-pi~peridin~l-4-oxo-g-uinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where Mixture B
of isomers of 4
cyclopropyl amino-3,5-dimethylpiperidine was used in place of 4-amino-3-methyl-
piperidine,
m.p. 240-42°C, C24H30FN3~4~ ~z 444 (M+1)
Example 42
1-Cyclo~ronyl-6-fluoro-1 4-dihydro-8-methoxy_7-(4-amino-3,3 5-trimethyl-1-
piperidinyl)-4
oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 1, where 4-amino-
3,3,5-
trimethylpiperidine was used in place of 4-amino-3-methylpiperidine, m.p. 218-
20°C,
C22Ii28FN3O4, m/z 418 (M+I).
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Example 43
5-Amino-1-c clopropyl-6-fluoro-1,4-dihydro-8-methox~t-7-(4-methylamino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid
A suspension of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-
quinoline-3-
carboxylic acid (0.17 g, 0.55 mmol), 3,3-dimethyl-4-methylamino piperidine
(0.15 g, 1.06
mmol) and triethylamine (lg, 10 mmol) in a mixture of dimethylsulfoxide (10
ml) and
acetonitrile (10 ml) was heated at 70°C for 18 hr. Acetonitrile was
distilled off, filtered to
remove suspended impurities, diluted with water (5 ml). The precipitate thus
separated was
filtered, washed with water, dried and purified by silicagel column
chromatography. Elute from a
to mixture of ethyl acetate and methanol furnished the required product. Yield
0.12 g (50 %),
m.p.250°C (decomp.), Cz2H29FN404, m/z 433 (M+1), PMR (DMSO-d6): 0.9 (m,
2H), 1.0 (m,
2H), 1.0 (s, 3H), 1.1 (s, 3H), 1.8 - 2.0 (m, 2H), 2.6 (s, 3H), 2.8 - 3.2 (m,
4H), 3.5 (s, 3H), 3.6 (s,
3H), 3.65 (m, 1H), 4.0 (m, 1H), 7.2 (bs, 2H, D20 exchangeable), 8.6 (s, 1H).
Exam lp a 44
5-Amino-1-cyclopro~yl-6-fluoro-1 4-dihydro-8-methox ~-~7-(4-amino-3-methyl-1-
piperidin~)-4-
oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-amino-
3-
methylpiperidine was used in place of 3,3-dimethyl-4-methylaminopiperidine.
Yield 40 %,
2o m.p.260-62°C, CzpH25FN4O4, m/z 405 (M+1), PMR (CD30D): 0.8-1.18 (m,
7H), 1.8 - 2.2 (m,
3H), 2.82 - 3.54 (m, 5H), 3.6 (s, 3H), 4.01 (m, 1H), 8.62 (s, 1H).
Example 45
5-Amino-1-cycl~ropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methylamino-3-methyl-
1-
~ueridinyl)-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-
methylamino-3-
methylpiperidine was used in place of 3,3-dimethyl-4-methylamino piperidine.
Yield 30 %,
m.p.228-30°C (decomp.), C2lHz~FN404, m/z 419 (M+1).
3o Example 46
5-Amino-1-cyclopro~yl-6-fluoro-1 4-dihydro-8-methox~7-4-ethylamino-3-methyl-1
piperidinyl)-4-oxo-quinoline-3-carbox lic acid
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It was prepared in a similar manner as described in Example 43, where 4-ethyl
amino-3-
methylpiperidine was used in place of 3,3-dimethyl-4-methylamino piperidine.
Yield 35 %,
m.p.230-32°C, C22H29FN4~4~ ~z 433 (M+1).
Example 47
5-Amino-1-c clo~ropyl-6-fluoro-1,4-dihydro-8-methox~7-(4-cyclopropylamino-3-
methyl-I-
piperidin~)-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-cyclo
propylamino-3-
methylpiperidine was used in place of 3,3-dimethyl-4-methyl aminopiperidine.
Yield 35 %,
to rn.p.218-20°C, Cz3H29fN4O4, m/z 445 (M+1).
Exam lp a 48
5-Amino-I-cyclopro~yl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3-
methyl-1-
~peridinyll-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-
dimethylamino-3-
methylpiperidine was used in place of 3,3-dimethyl-4-methylamino piperidine.
Yield 30 %,
m.p.210°C, CZZHZ9FN4O4, m/z 433 (M+1), PMR (CD30D): 0.81-1.22 (m, 7H),
1.8-2.25 (m, 3H),
2.92 (s, 6H), 2.61-3.52 (m, SH), 3.61 (s, 3H), 4.04 (m, 1H), 8.62 (s, 1H).
2o Example 49
5-Amino-1-c~clopropyl-6-fluoro-1 4-dihydro-8-methoxy-7-(4-amino-3,3-dimethyl-1-
pit~eridinyl)-4-oxo-q_uinoline-3-carboxylic acid
It was prepared in a similar mariner as described in Example 44, where 4-amino-
3,3-
dimethylpiperidine was used in place of 3,3-dimethyl-4-methylaminopiperidine,
m.p.205°C,
CZ1H27FN4O4, m/z 419 (M+1), PMR (DMSO-db): 0.8 (m, 2H), 1.0 (m, 2H), 1.0 (s,
3H), 1.1 (s,
3H), 1.4 - 1.6 (m, 2H), 2.6 - 2.8 (m, 4H), 3.6 (s, 3H), 3.65 (m, 1H), 4.0 (m,
1H), 6.2 (bs, 2H,
D20 exchangeable), 7.2 (bs, 2H, DZO exchangeable), 8.6 (s, 1H).
Example 50
5- -Amino-1-cyclopro~yl-6-fluoro-1 4-dihydro-8-methox~7-(4-ethylamino-3 3-
dimethyl-1-
pi ep ridinyl)~-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-
ethylamino-3,3-
dimethylpiperidine was used in place of 3,3-dimethyl-4-methyl-aminopiperidine,
m.p.205°C
(decomp.), Cz3H31FN4O4, m/z 447 (M+1), PMR (CDCl3): 0.8 (m, 2H), 1.0 (m, 2H),
1.05 (s, 3H),
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1.1 (s, 3H), 1.2 (t, 3H), 1.6 - 2.0 (m, 2H), 2.4 - 2.8 (m, 6H), 3.5 (s, 3H),
3.6 (m, 1H), 3.9 (m,
1H), 6.4 (bs, 2H, D~,O exchangeable), 8.4 (bs, 1H, D20 exchangeable), 8.8 (s,
1H).
Example 51
5-Amino-1-c,~propyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-dimethylamino-3,3-
dimeth,
piperidin~)-4-oxo-~uinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-
dimethylamino-3,3-
dimethylpiperidine was used in place of 3,3-dimethyl-4-methyl-aminopiperidine,
m.p.178°C
(decomp.), C23H31FN404, ~z 447 (M+1).
to
Example 52
Mixture A of isomers of 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-
(4-amino-
3,5-dimethyl-1-piperidiny~-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where Mixture
A of isomers of
4-amino-3,5-dimethylpiperidine was used in place of 3,3-dimethyl-4-methylamino
piperidine,
m.p.238-40°C, CzIHZ~FN404, m/z 419 (M+1),
Example 53
2o Mixture B of isomers of 5-Amino-1-cyclopropyl-6-fluoro-1 4-dihydro-8-
methoxy-7-(4-amino-
3 5-dimethyl-l~iperidin~)-4-oxo-duinoline-3-carboxylic acid
It was prepared in a similar masmer as described in Example 43, where Mixture
B of isomers of
4-amino-3,5-dimethylpiperidine was used in place of 3,3-dimethyl-4-methylamino-
piperidine,
m.p. 248-50°C (decomp.), CZ1HZ~FN404, m/z 419 (M+1),
Example 54
5-Amino-1-cyclopro~yl-6-fluoro-1 4-dihydro-8-methoxy-7-f4-methylamino-3,5-
dimethyl-1
~peridinyl)-4-oxo-c~uinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-
methylamino-3,5-
3o dimethylpiperidine was used in place of 3,3-dimethyl-4-
methylaminopiperidine, m.p. 224-26°C,
CZZHz9FN404, m/z 433 (M+1).
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Example 55
Mixture A of isomers of 5-amino-1-cyclopropyl-6-fluoro-1 4-dihydro-8-methoxy-7-
(4
methylamino-3 5-dimeth~-l~iperidinyll-4-oxo-c~uinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where Mixture
A of isomers of
4-methylamino-3,5-dimethylpiperidine was used in place of 3,3-dimethyl-4
methylaminopiperidine, Cz2Ha9FNa04, mlz 433 (M+1).
Example 56
Mixture B of isomers of 5-amino-1-c~pro~yl-6-fluoro-1 4-dihydro-8-methoxy-7-(4-
l0 methylamino-3 5-dimethyl-1-~peridin~)-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar mamier as described in Example 43, where Mixture
B of isomers of
4-methylamino-3,5-dimethylpiperidine was used in place of 3,3-dimethyl-4-
methyl-
aminopiperidine, C22H29FN4~4~ ~z 433 (M+1).
Example 57
Mixture A of isomers of 5-amino-1-c~propyl-6-fluoro-1 4-dihydro-8-methoxy-7-(4
ethylamino-3 5-dimethyll-l-piperidin~)-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where Mixture
A of isomers of
4-ethylamino-3,5-dimethylpiperidine was used in place of 3,3-dimethyl-4-methyl
2o aminopiperidine. Yield 52% m.p. 202-4 °C, C23H31FN404, m/z 447
(1VI+1).
Example 58
Mixture B of isomers of 5-amino-1-cyclopro~yl-6-fluoro-1 4-dihydro-8-methoxy-7-
(4
ethylamino-3 5-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where Mixture
B of isomers of
4-ethylasnino-3,5-dimethylpiperidine was used . in place of 3,3-dimethyl-4-
methyl-
aminopiperidine. Yield 80 %, m.p. 255-58°C, Ca3H31FN4O4, m/z 447 (M+1).
Example 59
Mixture A of isomers of 5-amino-1-cyclopropyl-6-fluoro-1 4-dihydro-8-methoxy-7-
(4-
~clopro~ylamino-3 5-dimethyl-1-~peridin~)-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where Mixture
A of isomers of
4-cyclopropylamino-3,5-dimethylpiperidine was used in place of 3,3-dimethyl-4-
methylaminopiperidine, CZaIi31FN4~4, mlz 459 (M+1)
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Example 60
Mixture B of isomers of 5-Amino-1-c cl~propyl-6-fluoro-1,4-dihydro-8-methoxy-7-
(4-
cyclo~ropylamino-3 5-dimethyl-1-~peridinyll -4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where Mixture
B of isomers of
4-cyclopropylamino-3,5-dimethylpiperidine was used in place of 3,3-dimethyl-4-
methylaminopiperidine, m.p. 248°C, C24H31FN4C4~ ~z 459 (M+1)
Example 61
to 5-Amino-1-c~lopro~yl-6-fluoro-14-dihydro-8-methoxy-7-(4-amino-3-ethyl-3-
meth
~peridin~rl)-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-amino-
3-ethyl-3-
methylpiperidine was used in place of 3,3-dimethyl-4-methylaminopiperidine,
m.p. 210 °C
(decompose), CZZH29FN4C4~ ~z 433 (M+1).
Example 62
5-Amino-1-cyclopropyl-6-fluoro-1 4-dihvdro-8-methoxy-7-(4-rnethylamino-3-ethyl-
3-methyl-1
piperidiny~)-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-
methylamino-3-ethyl-
3-methylpiperidine was used in place of 3,3-dimethyl-4-methylaminopiperidine,
m.p. 164-66 °C,
C23H31fN4~4~ ~z 447 (M+1).
Example 63
5-Amino-1-cyclopro~yl-6-fluoro-1 4-di~dro-8-methoxy-7-(4-cyclopropylamino-3-
ethyl-3
methyl-1-piperidinyl)}-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-
cyclopropyl amino-3-
ethyl-3-methylpiperidine was used in place of 3,3-dimethyl-4-
methylaminopiperidine, m.p. 186-
88 °C, CZSH33FN404, m/z 473 (M+1).
Example 64
5-Amino-1-cyclonropyl-6-fluoro-14-dihydro-8-methox~(4-dimethyamino-3-ethyl-3-
methyl
1-piperidin ~l -4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-
dimethyl amino-3-
ethyl-3-methylpiperidine was used in place of 3,3-dimethyl-4-
methylaminopiperidine, m.p. 194-
96 °C, CZq.H33~4o4, ~z 461 (M+1).
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Example 65
5-Amino-1-cyclopro~yl-6-fluoro-1 4-dihydro-8-methox~4-amino-3,3,5-Trimethyl-1
piperidinyll-4-oxo-quinoline-3-carboxylic acid
It was prepared in a similar manner as described in Example 43, where 4-amino-
3,3,5-
trimethylpiperidine was used in place of 3,3-dimethyl-4-methylaminopiperidine,
m.p. 248-52 °C,
C22H29F'N404, ~z 433 (M+1).
Example - 66
1o t~~ahs-1-~clopro~yl-6-fluoro-1 4-dihydro-8-meths 7-(4-amino-3-methyl-1-
piperidinyl) -4-
oxo-quinoline-3-carboxylic acid.
A mixture of [1-cyclopropyl-6,7-difluoro-8-methyl -1,4-dihydro-4-oxo-quinoline-
3-carboxylate-
O3,O4] difluoroboron (0.5 g,1.52 mmol), and t~ahs-4-amino-3-methylpiperidine
(0.86 g, 7.64
mmol) in 10, ml acetonitrile was heated to reflux for 8 hr. The reaction
mixture was concentrated
to dryness. The obtained residue was treated withl0 ml ethanol and
triethylamine (0.154 m1,1.52
mmol) and refluxed for 3 hr. Solvent was evaporated to dryness under reduced
pressure and the
residue was purified on preparative HPLC to give titled product, m. p. 223-
225°C CZ°Hz4FN3O3,
m/z 374 (M+1), PMR (CD30D): 0.85 (m, 2H), 1.05 (d, 3H), 1.2 (m, 2H), 1.7-
2.1(m, 3H), 2.8 (s,
3H), 2.9-3.1(m, 3H), 3.3-3.4(m,2H), 4.25 (m, 1H),7.8(d,lH), 8.9(s,lH).
Example - 67
cis 1 C.yclopro~yl-6-fluoro-1 4-dihydro-8-meth(4-amino-3-methyl-1-piperidinyl)-
4-oxo-
quinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 66, by using
cis-4-amino-
3-methylpiperidine, m. p. 224-228 °C, CzoHz4FN30s, m/z 374 (M+1), PMR
(CD30D): 0.8-1.0
(m, 2H), 1.15 (d,3H), 1.15-1.25(m, 2H),1.8-2.3(m, 3H), 2.8 (s, 3H),3.1-3.4(m,
3H), 3.4-
3.6(m,2H), 4.25 (m, 1H),7.8(d,lH), 8.9(s,lH).
Example - 68
(+__) 1 Cycl~robyl-6-fluoro-1 4-dihydro-8-methyl-7-(4-amino-3 3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 66, by using
(~)-4-amino-
3,3-dimethylpiperidine, m. p. 198 - 200 °C CZIHzsFN303, m/z 388 (M+1),
PMR (CD30D): 0.8-
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1.1 (m, 2H), 1.10 (d, 6H), 1.1-1.4 (m, 2H),1.9-2.2 (m, 2H), 2.8 (s, 3H), 2.9-
3.1(m, 1H), 3.2-3.4
(m,3H), 4.3 (m, 1H),7.8 (d,lH), 8.9 (s,lH).
Example - 69
(-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-
~~eridinyl)-4-oxo-
quinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 66, by using
(-)-4-amino-
3,3-dimethylpiperidine, m. p. 195-198 °C, CZ1H26FN303~ ~z 388 (M+1).
Exam lp e70
+)-1-C~propyl-6-fluoro-1,4-dih~methyl-7-(4-amino-3,3-dirneth~-1-piperidinyl)4-
oxo-
duinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 66, by using
(+)-4-amino-
3,3-dimethylpiperidine, m. p. 195-198 °C, CZIHasFN3O3, m/z 388 (M+1).
Example - 71
1-Cyclopropyl-6-fluoro-1,4-dihydro 8-meth -7-(4-methylamino-3-meth~pperidinyl)-
4-
oxo-quinoline-3-carboxylic acid.
2o The compound was prepared by a procedure as described in Example 66, by
using 4-
methylamino-3-methylpiperidine, rn. p 233-235 °C, CZ1H26FN303, m/z 388
(M+1), PMR
(CD30D): 0.8-1.4 (m, 7H), 1.9-2.4 (m, 3H), 2.8 (s, 3H), 2.9 (s, 3H), 3.2-3.7
(m, SH), 4.3 (m,
1H),7.9 (d,lH), 8.9 (s,lH).
Example - 72
1-Cyclo~ro~yl-6-fluoro-1,4-dihydro -8-methyl -7-(4-dimetl~lamino-3-methyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 66, by using
4-
dimethylamino-3-methylpiperidine, m. p. 221 °C, CZZHZ8FN3O3, m/z 402
(M+1), PMR
(CD30D): 0.8-1.4 (m, 7H), 2.0-2.2 (m, 2H),2.5 (m, 2H), 2.8 (s, 3H), 3.0 (s,
6H), 3.2-3.7 (m,4H),
4.4 (m, IH),7.8 (d,IH), 8.95 (s,lH).
Exam lp e'73
I-~clopropyl-6-fluoro-1 4-dihydro-8-methyl -7-(4-ethylamino-3,3-dimethyl-I-
biperidinyl)-4-
oxo-quinoline-3-carboxylic acid.
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The compound was prepared by a procedure as described in Example 66, by using
4-ethylamino-
3,3-dimethylpiperidine, m. p. 20I-203 °C, CzsHs°FNsO3, m/z 4I6
(M+1), PMR (CD30D): 0.8-
1.1 (m, 2H), ~1.2-1.5 (m, 11H),2.0-2.2 (m, 2H), 2.8 (s, 3H), 2.9-3.5 (m, 7H),
4.3 (m, 1H),7.9
(d,lH), 9.0 (s,lH).
Exam lmp e74
1-Cyclopropyl-6-fluoro-1,4-dihydro -8-methyl -7-(4-dirnethylamino-3 3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 66, by using
4-
lo dimethylamino-3,3-dimethylpiperidine, m. p. 209-210 °C, C~3H29FN3O3,
n~/z 416 (M+1), PMR
(CD3OD): 0.8-1.0 (m, 2H), 1.05-1.40 (gin, 8H),2.0-2.2 (m, 2H), 2.8-3.1 (m,
lOH), 3.2-3.6 (m,
3H), 4.3 (m,1H), 7.9 (d, l H), 9.0 (s,1H).
Example - 75
trar~.s-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-ethyl -7-(4-amino-3-methyl-1-
piperidinyl) -4-oxo-
auinoline-3-carboxylic acid.
A mixture of [1-cyclopropyl-6,7-difluoro=8-ethyl -1,4-dihydro-4-oxo-quinoline-
3-carboxylate-
03,04] difluoroboron (0.5 g,1.49 mmol), and trafZS-4-amino-3-methylpiperidine
(0.86 g, 7.64
mmol) in 10 ml acetonitrile was heated to reflux for 8 hr. The reaction
mixture was concentrated
to dryness. The obtained residue was treated withl0 ml ethanol and
triethylamine (0.154 nil, 1.52
mmol) and refluxed for 3 hr. Solvent was evaporated to dryness under reduced
pressure and the
residue was purified on'preparative HPLC to give titled product, CZ1H26FN3O3~
~z 388 (M+1),
PMR (CD30D): 0.9-1.3 (m, lOH), 1.8-2.2 (m, 2H), 2.9-3.7 (m, SH), 4.2 (m, 1H),
7.9 (d,lH), 9.0
(s,1H).
2S Example - 76
cis-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-et~l-7-(4-amino-3-methyl-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 75, by using
cis-4-amino-
3-methylpiperidine, CZIHa6FN3O3, m/z 388 (M+1),
3o PMR (CD3OD): 0.8-1.4 (m, lOH), 1.8-2.4 (m, 3H), 3.0-3.8 (m, 9H), 4.2 (m,
1H), 7.9 ~(d,lH), 9.0
(s,1H).
Example - 77
(+__)-1-Cyclopropyl-6-fluoro-1 4-dihydro-8-ethyl-7-(4-amino-3,3-dimeth~-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid.
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The compound was prepared by a procedure as described in Example 75, by using
(~)-4-amino-
3,3-dimethylpiperidine, C22H28FN3O3, m/z 402 (M+1), PMR (CD30D): 0.8-1.3 (m,
13H), 1.6-
2.0 (m, 2H), 2.7-3 .0 (m, 2H), 3 .0-3 .8 (m, 5H), 4.1 (m, 1 H), 7. 8 (d, l H),
8.9 (s, l H).
Example - 78
(-)-1-Cyclopro~yl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-3, 3-dimethyl-1-pip
eridinyl)-4-oxo-
quinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 75, by using
(-)-4-amino-3,3-dimethylpiperidine, CZaH2gFN303, m/z 402 (M+1).
to
Example - 79
(+)-1-Cyclopro~yl-6-fluoro-1 4-dihydro-8-ethyl-7-~-amino-3,3-
dimeth~piperidinyl)4-oxo-
quinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 75, by using
(+)-4-amino-
3,3-dimethylpiperidine, C22H28FN303, m/z 402 (M+1).
Example - 80
1-Cycl~ro~yl-6-fluoro-1,4-dihydro-8-ethyl-7-(4-amino-1-piperidinyl)-4-oxo-
quinoline-3-
caxboxylic acid.
2o The compound was prepared by a procedure as described in Example 75, by
using 4-
aminopiperidine, m.p. 248-249°CC2oH24FN303, m/z 374 (M+1),
PMR (CD30D)aelected values 0.9 (m, 2H), 1.1 (t, 3H), 1.3 (m, 2H), 1.7-2.2 (m,
4H), 3.6 (m,
2H), 4.2 (m,lH), 7.9(d,lH), 9.0 (s, 1H).
Example 81
tans-5-Amino-1-cyclopropyl-6-fluoro-1 4-dihydro-8-meth~4-amino-3-meth-1-
piperidinyl) -4-oxo-quinoline-3-carboxylic acid.
A mixture of [1-cyclopropyl-6,7-difluoro-8-methyl -1,4-dihydro-4-oxo-quinoline-
3-carboxylate-
03,04] difluoroboron (0.5 g, 1.46 mmol), and traras-4-amino-3-
methylpiperidirie (0.86 g, 7.64
mmol) in 10 ml acetonitrile was heated to reflux for 8 hr. The reaction
mixture was concentrated
to dryness. The obtained residue was treated withl0 ml ethanol and
triethylamine (0.154 m1,1.52
mmol) and refluxed for 3 hr. Solvent was evaporated to dryness under reduced
pressure and the
residue was purified on preparative HPLC to give titled product, CzoH25FN403,
m/z 389 (M+1),
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Example 82
cis-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-~-amino-3-methyl-1
piperidin
4-oxo-q-uinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 81, by using
cis-4-amino-
3-methylpiperidine, C2°HZSFN4~3, m/z 389 (M+1).
Example 83
(+__)-5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-
dimeth
pit°eridin~)-4-oxo-quinoline-3-carboxylic acid.
to The compound was prepared by a procedure as described in Example 81, by
using (~)-4-amino-
3,3-dimethylpiperidine, C21HZ~FNøO3, m/z 403 (M+1).
Example 84
~~5-Amino-1-cyclopropyl-6-fluoro-1 4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-
1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 81, by using
(-)-4-amino-3,3-dimethylpiperidine, CZ1HZ~FN~03, m/z 403 (M+1).
2o Example 85
(+)-5-Amino-1-cycloprotwl-6-fluoro-1 4-dihydro-8-methyl-7-(4-amino-3,3-
dimethyl-1-
piperidi~l)4-oxo-quinoline-3-carboxylic acid.
The compound was prepared by a procedure as described in Example 81, by using -
(+)-4-amino-
3,3-dimethylpiperidine, CZIHz~FN~03, m/z 403 (M+1).
Example 86
cis-1-Cyclopropyl-6-fluoro-1 4-dihydro-8-methyl-7- 4-amino-3-methyl-1-
piperidinyl)-4-oxo-
quinoline-3-carboxylic acid hydrochloride.
A mixture of [1-cyclopropyl-6,7-difluoro-8-methyl -1,4-dihydro-4-oxo-quinoline-
3-carboxylate-
03,04] difluoroboron (2.4 g, 7.34 mmol), and cis-4-t-butyloxycarbonylamino-3-
methylpiperidine
(4.45 g, 20.8 mmol) in 10 ml acetonitrile was stirred at 50 °C for 30
hr. The reaction mixture was
concentrated to dryness. The obtained residue was treated with 10 ml ethanol
and 1 ml
triethylamine and refluxed for 1 hr. Solvent was evaporated to dryness under
vacuum and the
residue was purified by silica gel column chromatoghraphy using 3 % methanol
chloroform
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solvent mixture as an eluent to give a crude product. The crude product was
dissolved in 10 ml
conc HCl and stirred for 30 minutes. The solvent was evaporated under vacuum.
The resultant
solid was dissolved in methanol and re-crystallized by adding ethyl acetate to
provide titled
compound 1.56 g (52%) yield as a solid.
m. p. 255-260 °C CZ°H2sFN303C1, m/z 374 (M+1),
PMR (CD30D): 0.95 (m, 2H), 1.2 (d, 3H), 1.2-1.4 (m, 2H), 1.8-2.4 (m, 3H), 2.8
(s, 3H), 3.2-3.4
(m, 3H), 3.5-3.7 (m, 2H), 4.3 (m, 1H),7.8 (d,lH), 9.0 (s,lH).
Example 87
io traps-1-Cyclopro~yl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3-methyl-1-
~peridin~)-4-oxo-
auinoline-3-carboxylic acid hydrochloride.
The compound was prepared by a procedure described in Example 86 by using
t~a~zs-4-t-
butyloxycarbonylamino-3-methylpiperidine instead cis-4-t-butyloxycarbonylamino-
3-
methylpiperidine.
Yield : 56% m. p. 262-265 °C CZ°HZSFN303C1, m/z 374 (M+1).
Example 88
cis/traps-1-Cyclopropyl-6-fluoro-8-meth(4-hvdroxy-3-methyl-1-piperidinyl)-1,4-
dihydro-4
oxoquinoline-3-carboxylic acid.
The compomzd was prepared by a procedure described in Example 86 by using
cis/trans-4-
hydroxy-3-methylpiperidine instead of traps-4-amino-3-methylpieridine and
product was
purified on preparative HPLC to give titled product.
M. p. 202-206 °C, mass (ES+) 375, Molecular Formula CZ°H23FN2O4,
H1NMR (CD30D) 0.92 (s,
2H), 1.04 (d, 3H), 1.22-1.38 (m, 2H), 1.62-1.82 (m, 2H), 1.82-2.10 (m, 2H),
2.8 (s, 3H), 2.90-
3.24 (m, 4H), 3.95 (q, 1H), 4.30 (m, 1H), 7.80-7.88 (d, 1H), 8.95 (s, 1H).
Example 89
3o cis -1-Cyclopr~yl-6-fluoro-8-methyl-7-(4-hydroxy-3-methyl-1-piperidinyl)-
1,4-dihydro-4-
oxoquinoline-3-carboxylic acid.
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The compound was prepared by a procedure described in Example 86 by using cis-
4-hydroxy-3-
methylpiperidine instead of traps-4-amino-3-methylpieridine and product was
purified on
preparative HPLC to give titled product.
M. p. 206-210 °C, mass (ES~ 375, Molecular Formula
CZ°Hz3FN204,
H1NMR (CD30D) 0.92 (s, 2H), 1.04 (d, 3H), 1.22-1.38 (m, 2H), 1.62-1.82 (m,
2H), 1.82-2.10
(m, 2H), 2.8 (s, 3H), 3.0-3.15 (s, 1H), 3.22-3.40 (s, 1H), 3.50-3.62 (m, 2H),
4.0-4.10 (q, 1H),
4.10-4.20 (m, 1H), 7.80-7.88 (d, 1H), 8.95 (s, 1H).
Example 90
l0 tf-ans 1 Cycloprop_yl-6-fluoro-8-meth-7-(4-h~droxy-3-methyl-1-piperidinyl)-
1,4-dihydro-4-
oxoc~uinoline-3-carboxylic acid.
The compound was prepared by a procedure described in Example 86 by using
traps-4-hydroxy-
3-methylpiperidine instead of traps-4-amino-3-methylpieridine and product was
purified on
preparative HPLC to give titled product.
M. p. 214-216 °C, mass (ES+) 375, Molecular Formula
Cz°Hz3FNa04,
HiNMR (CD3OD) 0.92 (s, 2H), 1.04 (d, 3H), 1.22-1.38 (m, 2H), 1.62-1.82 (m,
2H), 1.82-2.10
(m, 2H), 2.8 (s, 3H), 3.0-3.15 (s, 1H), 3.22-3.40 (s, 1H), 3.50-3.62 (m, 2H),
4.0-4.10 (q, 1H),
4.10-4.20 (m, 1H), 7.80-7.88 (d, 1H), 8.95 (s, 1H). '
Example 91
cis l tans 1 Cycloprotwl 6 fluoro 8 methyl 7 (4-hydrox~-3-ethyl-1-piperidinyl)-
1 4-dihydro-
4-oxoe~uinoline-3-carboxylic acid.
The 'compound was prepared by a procedure described in Example 86 by using
cis/trans-4-
hydroxy-3-ethylpiperidine instead of traps-4-amino-3-methylpieridine and
product was purified
on preparative HPLC to give titled product.
m. p. 185-190 °C, mass (ES+) 389, Molecular Formula CzlHzsFNzO4~
H1NMR (CD30D) 0.92-1.02 (m, 7H), 1.22-2.18 (m, 4H), 2.78 (s, 3H), 2.90-3.72
(m, 4H), 4.15
(q, 1H), 7.85-7.98 (d, 1H), 8.95 (s, 1H).
Example 92
cis l traps 1 Cyclopropyl 6 fluoro 8 ethyl 7 (4 hydroxy-3-ethyl-1-uiperidinyl)-
1 4-dihydro-4
oxoquinoline-3-carboxylic acid.
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The compotmd was prepared by a procedure described in Example 86 by using
cis/trans-4-
hydroxy-3-ethylpiperidine instead of traps-4-amino-3-methylpieridine and
product was purified
on preparative HPLC to give titled product.
m. p. 170-I72 °C, mass (ES+) 403, Molecular Formula CZZHz~FNZ04,
H1NMR (CD30D) 0.92-1.02 (m, 10H), 1.22-2.18 (m, 6H), 2.80-3.62 (m, 4H), 4.0-
4.22 (m, 2H),
7.86-8.02 (d, 1H), 8.95 (s, 1H).
Example 93
cis l tf°ayas -1-C cl~_opropyl-6-fluoro-8-methoxy-(4-hydroxy-3-methyl-1-
piperidinyl)-1,4-dihydro-
l0 4-oxoquinoline-3-carboxylic acid.
The compound was prepared by a procedure described in Example 1 by using
cis/trans-4-
hydroxy-3-methylpiperidine instead of 4-amino-3-methylpiperidine and product
was purified on
preparative HPLC to give titled product.
m. p. 114-216 °C, mass (ES+) 391, Molecular Formula Cz°Hz3FNzO5,
is H~NMR (CDC13) 1.00-1.12 (m, 4H), 1.20-1.32 (d, 3H), 1.78-2.22 (m, 3H), 2.20-
2.70 (m, 4H),
3.58-3.80 (s,3H), 4.00- 4.18 (m, 1H), 7.82-8.0 (d, 1H), 8.82 (s, 1H).
Example 94
cis l t~ahs -1-CKclopro~yl-6-fluoro-8-methox~7- (4-hydroxy-3-ethyl-1-
piperidinyl)-1,4-
20 dih~dro-4-oxoguinoline-3-carboxylic acid.
The compound was prepared by a procedure described in Example 1 by using
cis/trans-4-
hydroxy-3-ethylpiperidine instead of 4-amino-3-methylpiperidine and product
was purified on
preparative HPLC to give titled pxoduct.
m. p. 188-190 °C, mass (ES+) 405, Molecular Formula CzlHzsFNzOs,
25 H1NMR (CHCl3) 0.98-1.05 (t, 3H), 1.06-1.58 (m, 4H), 1.60-2.02 (m, 3H), 3.30
(s, 3H), 3.60-
3.75 (m, 4H), 3.75-3.90 (q, 3H), 4.00- 4.20 (m, 2H), 7.85-7.98 (d, 1H), 8.80
(s, 1H).'
Exam lie 95
cis lt3°ans -5-Amino-1-cyclopro~yl-6-fluoro-8-methoxy-7- (4-hydroxy-3-
metl~l-1-piperidinyl)
30 ls4-dihydro-4-oxoquinoline-3-carboxylic acid.
The above compound was prepared by a procedure described in Example 43 by
using cis/trans-
4-hydroxy-3-methylpiperidine instead of 3,3-dimethyl-4-methylaminopiperidine
and product
was purified on preparative HPLC to give titled product.
m, p. 240-244 °C, mass (ES+) 406, Molecular Formula CzoHz4FN30s.
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Example 96
cis l trafzs -5-Amino-1-c~propyl-6-fluoro-8-methoxy-7~4-hydroxy-3-ether-1-
p~eridin~)
11 4-dihydro-4-oxoauinoline-3-carboxylic acid.
The above compound was prepared by a procedure described in Example 43 by
using cis/trans-
4-hydroxy-3-ethylpiperidine instead of 3,3-dimethyl-4-methylaminopiperidine
and product was
purified on preparative HPLC to give titled product.
m. p. 217-19 °C, mass (ES+) 420, Molecular Formula C~1H26FN305,
H1NMR (CDC13) 0.82 (d, 2H), 1.02 (t, 3H),1.18 (d, 2H), 3.18-3.40 (m, 4H), 3.60
(s, 3H), 3.90-
l0 4.02 (q, 2H), 4.18 (m, 1H), 8.70 (s, 1H).
Exam lp a 97
(~)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3 3-dimethvl-1-1-
~peridinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride
15 The product obtained in example 68 (1 gm; 2.58 mmol) was suspended in 10 ml
ethanol and
ethanolic hydrochloric acid (2.6 ml) was added at a temperature between 20-30
°C under stirring.
To this solution, 20 ml ether was added after 30 minutes and the solid
separated was filtered and
dried under vacuum. Yield - 0.89 gm (83 %). m. p. 242-244 °C,
C21H26FN303.HC1, m/z 388
(M+1).
Similarly by using above procedure other inorganic acid salts are made.
Example 98
(-)-1-Cyclo~ropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimeth~-1-
piperidinyl -4-oxo-
quinoline-3-carboxylic acid hydrochloride.
The product obtained in example 69 (1 gm; 2.58 mmol) was suspended in 10 ml
ethanol
and ethanolic hydrochloric acid (2.6 ml) was added at a temperature between 20-
30 °C under
stirring. To this solution, 20 ml ether was added after 30 minutes and the
solid separated was
filtered and dried under vacuum. Yield - 0.91 gm (83 %). m. p.( by DSC) 300
°C,
3o CZIH2sFNs03.HC1, m/z 388 (M+1), [ a.]DZS value = -278.14° (c = 0.5,
methanol ).
Similarly by using above procedure other inorganic acid salts are made.
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Example 99
(+)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(4-amino-3,3-dimethyl-1-pi
ep ridinyl)-4-
oxo-quinoline-3-carboxylic acid hydrochloride.
The product obtained in example 70 (1 gm; 2.58 mmol) was suspended in 10 ml
ethanol and
ethanolic hydrochloric acid (2.6 ml) was added at a temperature between 20-30
°C under stirring.
To this solution, 20 ml ether was added after 30 minutes and the solid
separated was filtered and
dried under vacuum. Yield - 0.86 g1n (83 %). m. p. ( by DSC) 300°C,
CZ1H~6FN303.HC1, m/z
388 (M+1), [ a,]DZS value =+ 275° (c = 0.5, methanol).
to
Similarly by using above procedure other inorganic acid salts axe made.
Example 100
(+)-1-Cyclopro~yl-6-fluoro-1 4-dihydro-8-methyl-7-(4-amino-3 3-dimethyl-1-
piperidinyl)-4-
oxo-quinoline-3-carboxylic acid methane sulfonate.
The product obtained in example 68 (1 gm; 2.58 mmol) was suspended in 10 ml
isopropyl
alcohol. The reaction mixture was heated to 70 to 80 °C. Methane
sulfonic acid (0.25 g, 2.6
mmol) was added. The reaction mixture was cooled after 30 minutes f refluxing
and was filtered
at 10 to 20 °C, dried under vacuum.,Yield - 0.76 gm (60 %).
C21H26FN303.CH4SO3, m/z 388
(M+1).
Similarly by using above procedure other organic acid salts are made.
Example 101
~ -wclopro~yl-6-fluoro-1 4-dihydro-8-methyl-7-(4-amino-3 3-dimethyl-1-
piperidinyl)-4-oxo-
q,uinoline-3-carboxylic acid methane sulfonate.
The product obtained in example 69 (1 gm; 2.58 mmol) was suspended in 10 ml
isopropyl
alcohol. The reaction mixture was heated to 70 to 80 °C. Methane
sulfonic acid (0.25 g, 2.6
mmol) was added. The reaction mixture was cooled after 30 minutes f refluxing
and was filtered
at 10 to 20 °C, dried under vacuum. Yield - 0.80 gm (64%).
C21H26FN3O3.CH4SO3, m/z 388
(M+1).
Similarly by using above procedure other organic acid salts are made.
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Exam lp a 102
(+)-1-Cyclo~ropyl-6-fluoro-1 4-dihydro-8-methyl-7-(4-amino-3 3-dimethyl-1-~i
eridin~yl,~ 4-
oxo-quinoline-3-carboxylic acid methane sulfanate
The product obtained in example 70 (1 gm; 2.58 mmol) was suspended in 10 ml
isopropyl
alcohol. The reaction mixture was heated to 70 to 80 °C. Methan
sulfonic acid (0.25 g, 2.6
mmol) was added. The reaction mixture was cooled after 30 minutes f refluxing
and was filtered
at 10 to 20 °C, dried under vacuum. Yield-0.83 gm (66%).
C21H26FN3~3~CHaSO3, m/z 388
(M+1).
Similarly by using above procedure other organic acid salts are made.
TEST EXAMPLE -1
X-ray Diffraction Analysis
300 mg of racemic or optically active 1-cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-
amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid
hydrochloride was thinly
spread on a sample holder. X-ray diffraction analyses (40kv x 40 mA Rigaku
D/max 2200) were
performed under the conditions listed below:
Scan speed 5°/ min
Sampling time 7 min
Scan mode: continuous
2A/6 reflection
Cu target (Ni filter)
TEST EXAMPLE 2
Differential Seannin~ Calorimetr~Analysis
Thermal analysis of racemic or optically active 1-c~cl,~ro~yl-6-fluoro-1,4-
dihydro-8-methoxy
7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-auinoline-3-carboxylic acid
hydrochloride:
For the Differential Scanning Calorimetry, PERKINELMER DSC-7 system was used.
3 to 5 mg
of the sample was weighed into the aluminum pan, which was then press sealed
with an
aluminum lid. The sample was tested by heating from 30 °C to 350
°C at a rate of 10 °C/min.
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TEST EXAMPLE -3
Infra-Red Spectrum
Infra-Red spetrum analysis of racemic or opticall~active 1-cyclopropyl-6-
fluoro-1 4-dihydro-8-
methoxy-7-(4-amino-3,3-dimethyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic
acid
hydrochloride:
A I~Br pellet of the sample (2% wlw) was scanned on Broker FT-IR
spectrophotometer. The
instrument was calibrated with polystyrene film. Scan range 4000 cm 1 to 400
cm 1. Resolution 2
crri 1. Scan time 16 scans.
l0
Example 103
Crystalline polymorphic form of (~)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-
amino-3,3-dimethyl-1-~peridinyl -4-oxo-quinoline-3-carboxylic acid
hydrochloride-Pol~rph
A1:
50 gm of (~)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride was dissolved in
4.0 liter methanol
at reflux temperature. The clear solution was filtered through a celite bed
and the resultant
solution was concentrated to approximately 1 liter, cooled to a temperature
between 25-35 °C
2o and filtered under suction after 12 hours. The solid obtained was further
dried at 70°G under
vacuum to provide crystalline material (35.6 gm).
The polymorph was characterized by the following analytical data.
Differential Scanning Colorimetry (DSC):
Endotherm at 252.33 °C (onset at 246.19 °C) exotherm at 205.0
(onset at 200.68 °C) and 259.00
°C (onset at 255.83 °C).
X-ra~powder diffraction:
(20 values): 11.16 + 0.2 ,12.06 + 0.2 ,13.74 + 0.2 ,15.06 + 02 ,16.46 ~ 02
,18.60 ~ 02 , ?1.72 ~
0.2 , 22.44 + 0.2 , 23.72 + 0.2 X4.66 + 0.2 X5.90 ~ 0.2 , 30.08 ~ OZ , 3258 ~
02 .
1R values (cm 1): 3442, 2957, 1728, 1623, 1512, 1460, 1318, 1277, 1184, 1056,
938.
Example 104
Crystalline polymorphic form of (+)-1-Cyclopropyl-6-fluoro-1 4-dihydxo-8-
methoxy-7 ~4-
arnino-3 3-dimethyl-1-p~eridinyl)-4-oxo-quinoline-3-carboxylic acid
hydrochloride -Pol~morph
A2:
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3 gm of (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride salt was
dissolved in 15 ml of
water at reflux temperature, allowed to crystallize by cooling to a
temperature between 25-35 °C
and filtered under suction. The solid obtained was further dried at
70°C under vacuum to provide
crystalline material (2.8 gm).
The polymorph was characterized by the following analytical data.
Differential Scanning Colorimetr~(DSC):
Endothenn at 144.66 (onset 115.25) and 254.83 °C (onset at 251.00
°C), exotherm at 211.33
to (onset at 208.35 °C) and 259.66 °C (onset at 257.18
°C).
X-ray powder diffraction
(20 values): 8.58 + 0.2,13.08 +0.2 ,14.9 +0.2 ,16.72 + 02 ,18.34+ 0.2 ,22.68 +
02 , 25.38 + 02 ,
25.92+0.2,27.6+0.2,28.18 +0.2 .
IR values (cW 1): 3476, 3332, 2880, 1712, 1619, 1528, 1448, 1329, 1273, 1234,
1180, 1066,
1035,989.
Example-1 OS
Crystalline polyrnorphic form of (-)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-
amino-3 3-dimet~l-1-~ ep riding)-4-oxo-quinoline-3-carboxylic acid
hydrochloride-Pol~rph
2o Al:
30 gm of (-)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride was dissolved in
3.0 liter methanol
at reflux temperature. The clear solution was filtered through a celite bed
and the resultant
solution was concentrated to approximately 500 ml, cooled to a temperature
between 25-35 °C
and filtered under suction. The solid obtained was fiuther dried at
70°C under vacuum to provide
crystalline material (24.0 gm).
The polyrnorph was characterized by the following analytical data.
Differential Scanning Colorimetr~(DSC):
Endotherm at 126.5 OC (onset 93.94 OC) and 252.50 °C (onset at 245.14
°C), exotherm at 202.83
(onset at 200.02 °C) and 257.17 °C (onset at 255.66 °C).
X-ra~powder diffraction : Crystalline nature.
(28 values): 11.30 + 0.2 ,12.06 + 0.2 ,13.64 + 0.2 ,14.4 + Q2 ,15.16 + 02
,16.48 + 02 , 18.52 ~
0.2 , 21.48 _+ 0.2 , 22.72 + 0.2 ,23.94 _+ 0.2 ,24.76 +02 ,26.42 + Q2 ,30.24 +
Q2 , X60 + 02 .
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IR values (cm 1): 3363, 2957, 1727, 1625, 1512, 1461, 1377, 1323, 1289, 1183,
1056, 942.
Example 106
Crystalline polyrnor~hic form of (~-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-
methoxy-7-(4-
amino-3 3-dimethyl-1-~peridinyl)-4-oxo-quinoline-3-carbolic acid hydrochloride-
Polylnorph
A2:
5 gm of (-)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride was dissolved in
10 ml mixture of
l0 50% aqueous iso-propanol at reflux temperature, cooled to a temperature
between 25 - 35 °C
and filtered under suction. The solid obtained was further dried at
70°C under vacuum to provide
crystalline material (2.78 gm).
The polymorph was characterized by the following analytical data.
Example 107
Crystalline polymorphic form of (+)-1-Cycl~ropyl-6-fluoro-1 4-dihydro-8-
rnethoxy-7-(4
amino-3 3-dimethyl-1-piperidi~l)-4-oxo-quinoline-3-carboxylic acid
hydrochloride-Polymorlh
Al:
30 gm of (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride was dissolved in
3.0 liter methanol
at reflux temperature. The clear solution was filtered through a celite bed
and the resultant
solution was concentrated to approximately 500 ml, cooled to a temperature
between 25-35 °C
and filtered under suction, The solid obtained was further dried at
70°C under vacuum to provide
crystalline material (24.0 gm).
The polymorph was characterized by the following analytical data.
Differential Scanning Colorimetry (DSC):
Endotherm at 131.5 °C (onset 92.32 °C) and 253.33 °C
(onset at 248.28 °C), exotherm at 204.0
°C (onset at 200.8 °C) and 258.0 °C (onset at 256.83
°C).
X-ra~powder diffraction : (2~ values): 11.34 +0.2 ,12.08 + 02 ,13.68 + 02 ,
1444 + 02 , 15.18
+ 0.2, 16.50 + 0.2, 18.56 + 0.2 ,21.50 + 0.2 ,22.76 + 0.2 ,2=i.98 + Q2 ,24.78
+ 02 , 25.24 ~ 02 ,
30.28+0.2,30.64+0.2,32.52 +02 .
IR values (cm 1): 3653, 3369, 2960, 1727, 1627, 1511, 1465, 1377, 1331, 1279,
1183, 1058, 940.
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Example 108
Crystalline pol~rphic form of (+)-1-Cyclopropyl-6-fluoro-1,4-dihXdro-8-
methox~4
amino-3,3-dimethyl-1-~peridinyl)-4-oxo-quinoline-3-carboxylic acid
hydrochloride-Polymomh
A2:
5 gm of (+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-amino-3,3-
dimethyl-1-
piperidinyl)-4-oxo-quinoline-3-carboxylic acid hydrochloride was dissolved in
10 ml mixture of
SO% aqueous iso-propanol at reflux temperature, cooled to a temperature
between 25 - 35 °C
to and filtered under suction. The solid obtained was further dried at
70°C under vacuum to provide
crystalline material (3.40 gm).
The polymorph was characterized by the following analytical data.
Differential Scanning Colorimetr~~DSC~
Endotherm at 136.66 °C (onset 101.0 °C) and 256.83 °C
(onset at 251.92 °C) exotherm at 201.50
°C (onset at 198.60 °C) and 261.16 °C (onset at 259.83
°C).
X-ray powder diffraction
(28 values): 7.00 + 0.2 , 7.66 + 0.2 ,8.00 + 0.2 ,12.32 + 02 ,12.72 ~ 02
,13.58 ~ 02 , 1a:88 ~ 02 ,
15.36 +0.2,16.08 +0.2,18.38 +0.2 ,19.36 +02 ,20.58 + 02 ,23.18 ~ Q2 ,25.40 ~
02 , x.72 ~
0.2,72.82+0.2,29.80+0.2 X0.60+0.2 ,32.28+0.2 ,36.94 ~Q2 .
2o IR values (cm 1): 3401, 2845, 2632, 171 l, 1621, 1537, 1458, 1378, 1321,
1275, 1207, 1061, 989,
806.
BIOLQGICAL EXAMPLES
as
Microbiological and pharmacological studies can be used to determine the
relative potency, and
the profile of specificity of the compounds of the invention as antibacterial
agent with a
spectrum of activity as described in the specification above.
3o In the following examples, the compounds of the invention are numbered as
per the list of the
specific compounds of the invention described earlier in the text.
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BIOLOGICAL EXAMPLE 1
In-vitro Antimicrobial Tests
The comparative antimicrobial activity of representative compounds of the
invention and
reference compounds against various sensitive and resistant microorganisms is
given in Tables
17 to 20. The test method was in accordance with the standard NCCLS protocol
(Methods for
Dilution Antimicrobial Susceptibility Tests for Bacteria that grow
Aerobicially, Approved
Standards, M7-A5, Fifth Edition, January 2000).
l0 The antibacterial activities (minimmn inhibitory concentration: MIC,
mcg/ml) were determined
by using the two-fold serial agar dilution method~recommended by NCCLS. The
media used for
preculture and main culture were Txyptic Soya broth (Difco) and Mueller Hinton
medium
(Difco), respectively. The Mueller Hinton agar was supplemented with 5% sheep
blood for
streptococci. Overnight cultures were diluted with buffered saline (pH 7.2) to
the final cell
density of 5 x 106-10~ CFU/ml, and each bacterial suspension was applied with
a replicator
(Denley's rnultipoint inoculator, UK) onto a series of Mueller-Hinton agar
plates containing
antibacterial agents at various concentrations. Final inoculum was
approximately 104 CFU/spot.
The plates were incubated for 18 hrs at 37° C. The MIC was defined as
the lowest concentration
of an antibacterial agent that inhibits the development of visible microbial
growth on agar. The
results obtained axe shown in tables 17 to 20.
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Table 17
Activi~ Against Fluoroquinolone Sensitive Strains.
Compound MSSA S. pheuf3aofaiaeS. saf~guisE. faecalisE. P.
No. ATCC ATCC 49619 ATCC ATCC coli aef~ugifaosa
25923 10556* 29212 ATCC 27853
25922
MICs
g /
ml)
1 0.05 0.2 - - 0.05
17 0.4 1.56 - - 0.4 -
18 0.05 0.05 0.1 0.1 0.2 6.25
22 0.05 0.05 0.1 0.1 0.2 6.25
26 0.05 0.1 0.1 0.1 0.2 6.25
30 0.05 0.1 - - 0.05 -
46 0.05 0.1 - - 0.1 -
48 1.56 >6.25 - - 6.25 -
70 0.05 0.2 - - 0.4 -
75 0.05 0.2 - - 0.2 -
92 0.1 - - - 0.05 -
93 0.003 0.025 0.05 0.05 0.2 3.12
94 0.003 0.025 0.025 0.1 0.2 3.12
95 0.003 0.025 0.025 0.05 0.2 3.12
97 0.012 0.1 0.2 0.2 0.4 12.5
98 0.025 0.05 0.025 0.1 0.006 1.56
100 0.025 0.05 0.025 0.1 0.00123.12
102 0.025 0.025 0.025 0.05 0.025 3.12
106 0.025 0.1 0.1 0.2 0.05 6.25
110 0.025 0.025 0.05 0.05 0.025 1.56
114 0.05 0.05 - - 0.05 -
120 0.1 0.8 - - 0.8 -
131 0.8 - - - 1.56 -
133 0.025 0.2 - - 0.4 -
145 0.025 0.4 - - 1.56 -
147 <0.006 0.1 - - 0.4 -
Levofloxacin0.2 0.8 1.56 0.8 0.025 3.12
Moxifloxacin0.05 0.2 0.4 0.2 ~ 0.05~ 6.25
* S.sanguis 10556 belongs to the group of Viridans Streptococci. 3 other
strains of the group
S. or-alis 900, S.salivaris 1062 arid S.mitis 1303 provided similar MICs
ranging from 0.025 - 0.40
~g / ml in comparison to the reference compounds which had MIC values ranging
from 0.1 -
3.12 .
15
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Table 18
Activit~gainst Fluoroquinolone-Resistant Strains.
Compound MRSA FQ S, pneumoniaeCipro Cipro
No. 032 718 S. S. mitis
sanguis938
941
MICs
(pg
/ ml)
18 0.8 0.8 0.4 1.56
22 0.8 0.4 0.2 0.8
26 0.8 0.8 0.4 1.56
93 0.2 0.8 0.4 0.4
94 0.2 0.8 0.4 0.4
95 0.2 0.8 0.4 0.4
97 0.8 3.12 3.12 3.12
98 1.56 1.56 3.12 1.56
100 1.56 1.56 3.12 1.56
102 0.8 0.8 1.56 1.56
106 1.56 1.56 6.25 6.25
110 0.4 0.4 1.56 0.8
Levofloxacin6.25 12.5 12.5 25.0
Moxifloxacin3.12 3.12 ~ 6.25 6.25
~ I ~
Table 19
Activity Against Trovafloxacin-Resistant and Vancomycin-Resistant Enterococci
Compound No. Trova-ResistV R E***
MRSE** 110 336
MICs ( I ml
93 0.4 3.12
94 0.4 3.12
95 0.4 3.12
Ref.com .1* 1.56 6.25
~
Ref.comp.2* 1.56 6.25
Ref.comp.3* 1.56 6.25
* Ref. Comp. 1, 2 and 3 are reference compounds cited in our pending US patent
application
l0 09/850,669 and WO 01/85728
Ref. Comp.l is S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy-3-methylpiperidin-1-yl)-
5-methyl-
1-oxo-1H,SH-benzo[i, j]quinolizine-2-carboxylic acid (mixture of cis racemate
and trans
racemate)
Ref. Comp. 2 is S-(-)-9-fluoro-6,7-dihydro-8- f cis-4-(RS)-hydroxy-3-(RS)-
methylpiperidin-1-
15 yl]-5-methyl-1-oxo-1H,SH-benzo[i, j]quinolizine-2-carboxylic acid.
Ref. Comp. 3 is S-(-)-9-fluoro-6,7-dihydro-8- f trans-4-(RS)-hydroxy-3-(RS)-
methylpiperidin-1-yl}-5-methyl-1-oxo-1H,SH-benzo[i, j]quinolizine-2-carboxylic
acid
** MRSE stands for fraethicillin-resistant S. epiderniidis
*** VRE stands for vancomycin-resistant Enter-ococcus faecium
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Table 20
Activit~Against Clinical Isolate MRSA 5076 with Mutations in DNA Gyrase and
Topoisomerase IV as well as bearing an Efflux Pump
Compound S. aureus (sensitive)MRSA 5076 MRSA 5076 +
No. ATCC 25293 (triple resistance)efflux inhibitor
rese ine
MICs ( l ml
18 0.05 3.12 1.56
22 0.05 1.56 1.56
26 0.05 3.12 1.56
95 0.003 0.2 0.2
110 0.05 0.8 0.8
Ciprofloxacin0.8 100 25.0
Moxifloxacin0.05 12.5 6.25
The data shows that the reference compounds, which although are active against
sensitive
staphylococci, are rendered quite unattractive due to serious loss in their
potency against clinical
isolate MRSA 5076 expressing triple fluoroquinolone-resistance mechanisms. The
fold
difference between the MIC values for each compound in the last two columns
indicates the
l0 effect of the efflux pump mechanism on the susceptibility of the strains to
the respective
compounds. The compounds of the invention are 4-fold to 500-fold more potent
than the
reference compounds against the resistant strain as seen in column 3.
Resistance to Resistance Development
Compound No. 18 was evaluated in comparison with Moxifloxacin and
Trovafloxacin in terms
of resistance to resistance development on sequential transfer / passages
through respective drug-
containing media. Initially all the three drugs had comparable activity
against MRSA 5027 (0.4
pg/ml). However, after 10 passages in drug containing medium, MIC for
Moxifloxacin and
Trovafloxacin was 6.25 p,g/ml and 50 ~g/ml respectively, while compound No. 18
showed no
elevation and remained 0.4 p,g/ml. The data indicates that compound No. 18 has
a remarkable
property of resisting the development and selection of MRSA strains resistant
to it and is
significantly less likely to select resistant mutants in a clinical scenario,
thus obviating the risk of
treatment failure in patients.
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BIOLOGICAL EXAMPLE 2
Irz-vivo Antimicrobial Tests
Protocol for Systemic Infection Model
The iyz vivo efficacy was studied through mouse septicemia model of infection
in Swiss male
and female mice ( 4 weeks old, 20 + 2g weight) using 6 animals in each group.
Infective
to organisms were inoculated intraperitonially. Compound were administered by
oral route 1 hour
and 5 hours post-infection. By Probit analysis protective doses were
calculated from the survival
rate on day 7 in terms of EDso (50% survival dose) values. Appropriate
comparators were
included in the study.
Table 22
In-vivo Activity Against Multidru~-Resistant (MDRI Pneumococcal Infections
COMPOUND EDSO p.o. (mglkg)
MDR
S. p~ceumorziae
718*
18 30
22 20
26 50
100 30
102 30
110 20
Levofloxacin> 100
Moxifloxacin> 100
Gatifloxacin> 100
* Resistant to 13-lactams, macrolides and fluoroquinolones
BIOLOGICAL EXAMPLE 3
Acute Toxicity
Each test compound or reference compound was administered orally to groups of
10 Swiss mice
(body weight: 22-26 gms) each, whereby its acute toxicity was investigated.
The compounds
were administered in solution form. As a result it was found that the median
lethal dose (LDso)
values of compounds 18, 19 and 20 were 650 mg/kg, 600 mg/kg and 650 mg/kg
respectively.
The LDso of reference compound moxifloxacin was 600 mg/kg. On the,basis of
data of EDso
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values (provided in table 22) the therapeutic index (LDso/EDSO) for the test
compounds is 3.0 to
7.5 times higher than that for moxifloxacin.
BIOLOGICAL EXAMPLE 4
Cytotoxicity
Protocol for cytotoxicity test
Compounds were evaluated for their cytotoxic potential against two celllines
viz. J 744 (mouse
l0 macrophage) and V79 (Chinese Hamster Lung). Cells were gromn for 3 - 4 days
in a culture
flask using D-MEM (Dulbecco's Modified Eagle Medium) supplemented with 10%
fetal bovine
serum~(FBS). Freshly grown cells were distributed in microtiter plates at a
cell density of 105-
106 cells / well and allowed to adhere and form monolayer by incubating the
microtiter plate at
37°C for 24 hrs. Medium from each well was aspirated and replaced with
fresh D-MEM
15 (supplemented with 2.5% FBS) containing various concentrations of
compounds. Following 3
hrs. of drug exposure, cells were washed with D-MEM and incubated further for
96 hrs.
Cytotoxic effects of drugs were monitored through daily microscopic
observation and by
ascertaining the metabolic status through redox indicator Alamar blue. Healthy
actively
metabolising cells bring about colour change of Alamar blue from blue to pink
within an
20 overnight incubation. Cytotoxic drugs inhibit this reaction resulting into
blue coloured wells.
Minimum drug concentration inhibiting Alarnar blue color change i.e. resulting
into blue
coloured wells for a given drug is considered cytotoxic concentration.
Table 23
Compound J 744 Macrophage
No. V 79 CHL
C totoxic concentration
me /ml
18 >1000 >1000
22 >1000 1000
26 >1000 >1000
g3 >1000 >1000
g4 >1000 >1000
g5 >1000 >1000
97 >1000 >1000
gg 1000 250
100 1000 125
102 1000 750
106 >1000 >1000
110 1000 250
Trovafloxacin500 62.5 -120
149
CA 02468190 2004-05-26
WO 03/050107 PCT/IN02/00232
BIOLOGICAL EXAMPLE 5
Phototoxicitv
Six groups of healthy Swiss Albino mice consisting of 6 males per group were
orally
administered with a single dose of a compound of the invention or a reference
compound at dose
levels of 50, 100, 200, 300 and 400 mg/kg. The stock solutions for different
doses were prepared
freshly on the day of experimentation. Appropriate concentration of each dose
was chosen to
give a constant dosage volume of 0.3-0.4 ml/20g body weight of mouse. The
treated mice were
exposed to UVA light source immediately after dosing for 4 hours and for 4
consecutive days.
to The mean light intensity in the LTVA chamber was adjusted to 0.9-1.2
mWlcm2. The total
irradiation dose was approximately 18 Joules/cm2 /day. A phototoxic dose is
one which causes
ear erythema and oeadema. The phototoxic doses of compounds 18, 19 and 20 of
the present
invention were greater than 500 mg/kg, whereas the phototoxic dose for
reference compound
sparfloxacin was 25 mglkg, thus indicating that the compounds of the present
invention induced
no phototoxicity.
150
