CA 02257662 1999-O1-14
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WO 95132948 V PCT/EP95I02000
QUINOLINE DERIVATIVES AS TACHYKININ NK3 RECEPTOR ANTAGONISTS
The present invention relates to novel quinoline derivatives, processes for
their preparation and their use in medicine.
The mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK)
peptide family which also include Substance P (SP) and Neurokinin A (NKA).
Pharmacological and molecular biological evidence has shown the existence of
three
subtypes of TK receptor (NK1, NK2 and NK3) and NKB binds preferentially to the
NK3 receptor although it also recognises the other two receptors with lower
affinity
(Maggi et al , 1993, J. Auton. Pharmacol., 13, 23-93).
Selective peptidic NK3 receptor antagonists are known (Drapeau, 1990 Regul.
Pept., 31, 125-135), and findings with peptidic NK3 receptor agonists suggest
that
NKB, by activating the NK3 receptor, has a key role in the modulation of
neural input
in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem,
1993,
J.Phisiol., 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429;
Mccarson and Krause, 1994, J. Neurosci., 14 {2), 712-720; Arenas et al. 1991,
J.Neurosci., 11, 2332-8).
However, the peptide-like nature of the known antagonists makes them likely
to be too labile from a metabolic point of view to serve as practical
therapeutic
agents.
We have now discovered a novel class of selective, non-peptide NK3
antagonists which are far more stable from a metabolic point of view than the
known
peptidic NK3 receptor antagonists and are of potential therapeutic utility in
treating
pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-,
airway hyperreactivity, cough), skin disorders and itch (for example, atopic
dermatitis
and cutaneous wheat and flare), neurogenic inflammation and CNS disorders
(Parkinson's disease, movement disorders, anxiety and psychosis). These
disorders
are referred to hereinafter as the Primary Disorders.
The novel NK3 antagonists of the present invention are also of potential
therapeutic
utility in treating convulsive disorders (for example epilepsy), renal
disorders, urinary
incontinence, ocular inflammation, inflammatory pain, eating disorders (food
intake
inhibition), allergic rhinitis, neurodegenerative disorders (for example
Alzheimer's
disease), psoriasis, Huntington's disease, and depression (hereinafter
referred to as the
Secondary Disorders).
According to the present invention there is provided a compound, or a solvate
or salt thereof, of formula {I):
CA 02257662 1999-O1-14
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WO 95!32948 PC'T/EP95102000
R2 R
N-C -Ar
R R,
4
~N RS
in which:
Ar is an optionally substituted phenyl, naphthyl or CS_~ cycloalkdienyl group,
or an
optionally substituted single or fused ring heterocyclic group, having
aromatic
character, containing from 5 to I2 ring atoms and comprising up to four hetero-
atoms in the or each ring selected from S, O, N;
R is linear or branched C1_g alkyl, C3_~ cycloalkyl, Cø~ cycloalkylalkyl,
optionally
substituted phenyl or phenyl CI_6 alkyl, an optionally substituted five-
membered
heteroaromatic ring comprising up to four heteroatom selected from O and N,
hydrozy C1_6 alkyl, amino C1_6 alkyl, C1_6 alkylaminoalkyl, di C1_6
alkylaminoalkyl, C1_6 acylaminoalkyl, C1_6 alkoxyalkyl, C1_6 alkylcarbonyl,
carboxy, C1_6 alkoxyxcarbonyl, C1_6 alkoxycarbonyl C1_6 alkyl, aminocarbonyl,
Cl_6 alkylaminocarbonyl, di C1_6 alkylaminocarbonyl, halogeno C1_6 alkyl; or
is
a group -(CH2)p- when cyclized onto Ar, where p is 2 or 3.
Rl and R2, which may be the same or different, are independently hydrogen or
C1_6
linear or branched alkyl, or together form a -(CH2)n- group in which n
represents
3, 4, or 5; or RI together with R forms a group -(CH2)q-, in which q is 2, 3,
4 or
5.
R3 and R4, which may be the same or different, are independently hydrogen,
CI_6
linear or branched alkyl, C1_6 alkenyl, aryl, C1_6 alkoxy, hydroxy, halogen,
vitro,
cyano, carboxy, carbozamido, sulphonamido, C1_6 alkoxycarbonyl,
trifluoromethyl, acyloxy, phthalimido, amino, mono- and di-C1_6 alkylamino,
-O(CH2)rNT2, in which r is 2, 3, or 4 and T is hydrogen or CI_~ alkyl or it
forms with the adjacent nitrogen a group
V, V,
N ~ N
I
V (CH~ V (CH2
in which V and V 1 are independently hydrogen or oxygen and a is 0,1 or 2;
-O(CH2)s-OW2 in which s is 2, 3, or 4 and W is hydrogen or C1_6 alkyl;
hydroxyalkyl, aminoalkyl, mono-or di-alkylaminoalkyl, acylamino,
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WO 95!32948
alkwylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; with
up to four R3 substituents being present in the quinoline nucleus;
or R4 is a group -(CH2)r when cyclized onto Rg as aryl, in which t is 1, 2, or
3;
RS is branched or linear C1_6 alkyl, C3_~ cycloalkyl, Cø~ cycloalkylalkyl,
optionally
substituted aryl, or an optionally substituted single or fused ring
heterocyclic
group, having aromatic character, containing from 5 to 12 ring atoms and
comprising up to four hetero-atoms in the or each ring selected from S, O, N;
X is O, S, or N-C---N.
Examples of Ar are phenyl, optionally substituted by hydroxy, halogen, C1_6
alkoxy or C1_6 alkyl. Examples of halogen are chlorine and fluorine, an
example of
C1_6 alkoxy is methoxy and an example of C1_6 alkyl is methyl.
Examples of Ar as a heterocyclic group are thienyl and pyridyl.
Examples of Ar as a CS_~ cycloalkdienyl group is cyclohezadienyl.
Examples of R are as follows:
C1-g alkyl: methyl, ethyl, n-propyl, iso-propyl, n-butyl, hepryl;
phenyl C 1-6 alkyl: henry!;
hydroxy C1_6 alkyl: - CH20H, -CH2CH20H, CH(Me)OH;
amino C1_6 alkyl: -CH2NH2;
di C1_S alkylaminoalkyl: -CH2NMe2;
C1_6 alkoxylalkyl: CH20Me;
C 1 _6 alkylcarbonyl: COMB;
C1_6 alkoxycarbonyl: COOMe;
C 1 _6 alkoxycarbonyl C 1 _6 alkyl: CH2COOMe;
C1_6 alkylaminocarbonyl: CONHMe;
di C 1 _b alkylaminocarbonyl: CONMe2, CO( 1-pyrrolidinyl);
halogen C 1_6 alkyl: trifluoromethyl;
-(CH2)p- when cyclized onto Ar:
/ \
Example of R1 and R2 as C1_6 alkyl is methyl;
example of R1 together with R forming a group-(CH2)q- is spirocyclopentane.
Examples of R3 and R4 are methyl, ethyl, n-propyl, n-butyl, methoxy,
hydroxy, amino, chlorine, fluorine, bromine, acerylozy, 2-
(dimerylamino)ethoxy,
2-{1-phthaloyl)ethoxy, aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, phthaloyl,
dimethylaminopropoxy, dimethylaminoacerylamino, acerylamino,
dimethylaminomethyl and phenyl.
Examples of RS are cyclohexyl, phenyl optionally substituted as defined for
3
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WO 95!32948 p~'~95102000
Ar above; examples of RS as a heterocyclic group are fury!, thienyi, pyrryl,
thiazolyl,
benzofuryl and pyridyl.
A'preferred group of compounds of formula (n are those in which:
Ar is phenyl, optionally substituted by C1_6 alkyl or halogen; thienyi or a
C~~ cycloalkdienyl group;
R is C 1-6 alkyl, C 1 _6 alkoxycarbonyl, C 1 _6 alkylcarbonyl, hydrozy C 1-6
alkyl;
Rl and R2 are each hydrogen or C 1-6 alkyl;
R3 is hydrogen, hydrozy, halogen, C 1-6 alkoxy, C 1-6 alkyl;
R4 is hydrogen, C 1 _6 alkyl, C 1 _6 alkozy, hydroxy, amino, halogen,
aminoalkoxy, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl,
phthaloylalkozy, mono- or di-alkylaminoacylamino and acylamino; .
RS is phenyl, thienyi, fury!, pyrryi and thiazolyl.
A further preferred group of compounds of formula (I) are those in which:
Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl;
R is methyl, ethyl, n-propyl, -COOMe, -COMB;
R1 and R2 are each hydrogen or methyl;
R3 is hydrogen, methoxy, or hydroxy;
R4 is hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine,
dimethylaminoethoxy, 2-(1-phthaioyl)ethoxy, aminoethoxy, 2-(1-
pyrrolidinyl)ethoxy, dimethylaminopropoxy, dimethylaminoacetylamino,
acetylamino, and dimethylaminomethyl.
RS is phenyl, 2-thienyl, 2-fury!, 2-pyrryl, 2-thiazolyl and 3-thienyl;
and X is oxygen.
A preferred sub-group of compounds within the scope of formula (1) above is
of formula (Ia):
I z /R
N- \ Z
R H
~ 4
Rs w N ( Y (la)
in which:
R, R2, R3 and R4 are as defined in formula (>7, and Y and Z, which may be
the same or different, are each Ar as defined in formula (17.
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A particularly preferred group of compounds of formula (Ia) are those of
formula (Ib) in which the group R is oriented downward and H upward.
Z
N-C ~
R4 H
R
s ~ (ib)
'N Y
The compounds of formula (I) or their salts or solvates are preferably in
pharmaceutically acceptable or substantially pure form. By pharmaceutically
acceptable form is meant, inter alia, of a pharmaceutically acceptable level
of purity
excluding normal pharmaceutical additives such as diluents and carriers, and
including no material considered toxic at normal dosage levels.
A substantially pure form will generally contain at least 50% (excluding
normal
pharmaceutical additives), preferably 75%, more preferably 90% and still more
preferably 95% of the compound of formula (17 or its salt or solvate.
One preferred pharmaceutically acceptable form is the crystalline form,
including
such form in pharmaceutical composition. In the case of salts and solvates the
additional ionic and solvent moieties must also be non-toxic.
Examples of pharmaceutically acceptable salts of a compound of formula (17
include the acid addition salts with the conventional pharmaceutical acids,
for
example malefic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric,
salicylic,
citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic, and
methanesulphonic.
Examples of pharmaceutically acceptable solvates of a compound of formula
(I) include hydrates.
The compounds of formula (I) may have at least one asymmetric centre and
therefore may exist in more than one stereoisomeric form. T'he invention
extends to
all such forms and to mixtures thereof, including racemates.
The invention also provides a process for the preparation of a compound of
formula (17 which comprises reacting a compound of formula (I>I)
R'
~ z R'
H' N ~--Ar'
R' ~
in which R', R'1, R'2 and Ar' are R, Rl, R2 and Ar as defined for formula (I)
or a group or atom convertible to R, Rl, R2 and Ar, with a compound of formula
(B)
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PCT/EP95/02000
WO 95!32948
X' OH
i i R'4
R3 ~ ~N~R'
s
or an active derivative thereof, in which R'3, R'4, R'S and X' are R3, R4, RS
and X as defined for formula (17 or a group convertible to R3, R4, RS and X,
to form
a compound of formula (Ic)
R.
X' N At'
R'
i i R, ,
R~3 ~ 4
\N R's
(Ic)
and optionally thereafter performing one or more of the following steps:
(a) where R', R'1 to R'S, Ar' and X' are other than R, Rl to R5, Ar and X,
converting any one of R', R'1 to R'S, Ar' and X' to R, R1 to R5, Ar and X to
obtain a
compound of formula (1),
(b) where R', R' 1 to R'S, Ar' and X' are R, R 1 to R5, Ar and X, converting
any
one of R, R1 to R5, Ar and X to another R, R1 to R5, Ar and X, to obtain a
compound
of formula (17,
(c) forming a salt and/or solvate of the obtained compound of formula (Ic).
Suitable active derivatives of the compounds of formula (II] are acid halides
(preferably chlorides), acid azides or acid anhydrides. Another suitable
derivative is a
mixed anhydride formed between the acid and an alkyl chloroformate; another
suitable derivative is an activated ester such as a cyanomethyl ester,
thiophenyl ester,
p-nitrophenyl ester, p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester,
pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phtalimido ester,
N-
hydroxypiperidine ester, N-hydroxysuccinimide ester, N-hydrozy benzotriazole
ester;
or the carbozy group may be activated using a carbodiimide or N,N-
carbonyldiimidazole.
For example, in standard methods well known to those skilled in the art, the
compounds of formula (IZI) may be coupled:
(a) with an acid chloride in the presence of an inorganic or organic base in a
suitable aprotic solvent such as dimethylformamide (DMF} at a temperature in a
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WO 95!32948 PCT/EP95l02000
range from -70 to.50°C (preferably in a range from -10 to 20°C),
(b) with the acid in the presence of a suitable condensing agent, such as for
example N,N-carbonyl diimidazole (CD17 or a carbodiimide such as
dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N'-ethylcarbodiimide
S and N-hydroxybenzotriazole (HOBT) to maximise yields and avoid racemization
processes (Synthesis, 453, 1972) in an aprotic solvent such as a mixture of
acetonitrile
(MeCN) and tetrahydrofuran ~ in a ratio from 1 : 9 to 7 : 3, respectively, at
a
temperature in a range from -70 to 50°C (preferably in a range from -10
to 25°C)
(see Scheme 1 ),
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WO 95132948 PCT/EP95/02000
Scheme 1
O OH O N~2 COOMe
~At'
i i R' R Z COOMe R.
Ft I H N~Ar pCC. HOBT , ~ ~ R~4 '
w wN~R,s R,~ R3 \ \ I
MeCN/THF 3:7 ~N~ ~R'
o-20°C
(II) (III) (Ic)
S (c) with a mixed anhydride generated in situ from the acid and an alkyl (for
example isopropyl) chloroformate in a suitable aprotic solvent such as
dichloromethane at a temperature in a range from -70 to 50°C
(preferably in a range
from -20 to 20°C).
It will be appreciated that a compound of formula (Ic) may be converted to a
compound of formula (I), or one compound of formula (I) may be converted to
another compound of formula (1), by interconversion of suitable substituents.
Thus,
certain compounds of formula (I) and (Ic) are useful intermediates in forming
other
compounds of the present invention.
For example R'2 may be hydrogen and converted to R2 alkyl group, for example
methyl, by conventional amide alkylation procedures (Zabicky, The chemistry of
amides; lnterscience, London, 1970, p. 749). When X' is oxygen, it may be
converted
to X sulphur by standard thioamide formation reagents, such as P2S5 CChem.
Rev.,
61, 45, 1961 or Angew. Chem., 78, 517, 1966) or the Lawesson reagent
(Tetrahedron,
41, 5061, 1985). When Ar' or R'S is a methoxy substituted phenyl, it may be
converted to another Ar' or R'S hydroxy substituted phenyl by standard
demethylation
procedures via Lewis acids, such as boron tribromide.(Synthesis, 249, 1983) or
mineral acids, such as hydrobromic or hydroiodic acid. When R is an
alkoxycarbonyl
group, for example methoxycarbonyl, it may be converted to another R, such as
ethozycarbonyl by transesterification with an appropriate alcohol at a
temperature in a
range from 20 to 120°C, carboxy by hydrolysis in acidic or basic
medium,
aminocarbonyl, aikylaminocarbonyl or dialkylaminocarbonyl by transamidation
with
ammonia, a primary amine or a secondary amine in methanol as solvent at a
temperature in a range from 10 to 120°C, optionally in the presence of
a catalytic
amount of NaCN (J. Org. Chem., 52, 2033, 1987) or by using trimethylaluminium
(Me3Al) (Tetrahedron Letters, 48, 4171,1977), hydroxymethyl by a selective
metal
hydride reduction, such as lithium borohydride reduction (Tetrahedron, 35,
567,
1979) or sodium borohydride reduction in THF + MeOH (Bull. Chem. Soc. Japan,
57, 1948, 1984 or Synth. Common., 12, 463, 1982), alkylcarbonyl by acyl
chloride
formation and subsequent reaction with alkylmagnesium halides in THF as
solvent at
8
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WO 95132948 PCT/EP95102000
a temperature in a range from -78 to 30°C (Tetrahedron Leuers,
4303,1979) or with
alkylcadmium halides or dialkylcadmium in the presence of MgCl2 or LiCl (.l.
Org.
Chem., 47, 2590, 1982). Another group which R' as methozycarbonyl can be
converted into is a substituted heteroaromatic ring, such as an oxadiazole (J
Med
Chem., 34, 2726,1991).
Scheme 2 summarizes some of the above described procedures to convert a
compound of formula (Ic) or (1) in which X' is oxygen, R' is COOMe, Ar' and
R'1 to
R'S are as described for formula {I) to another compound of formula (1).
Scheme 2
R.z COOMe
O N~Ar
R'
i i R'~ '
R.a w wN I R,s
Me COOMe !R~2 ~ ~ ~~~~ Meth. MeOH R~z CONHMe
O N~Ar NaH. 0°C. THF ~. 80°C. 4 h O N~Ar
R'
3
R i i I R;R.' 1p~3 ~, oMe) ~ I R 4Rn
~N~R, B&3 LBHd. THF a
s ~~ ~~ N R s
R'
O N'z COOMe re~nc O N 2 CA pH
10°.G HC~ 1) NH
R, R~~ re6~c. t n ) MeC(GE1)3 , ~ R 4R',
HO ~ ~ R~a ~
R~ ~N N R s
~N R s R~z COOH ~ z O
N
o N~Ar o N~Ar
i i R;R,' i i R;R,'
R.s w wN~R.s R.s w wN~R~s
~ MeMgBr. TNF. -78'C
R~z COMB
O N~Ar
R'~
i i R',
R,s ~ ~N I R,s
The compounds of formula (I) may be converted into their pharmaceutically
acceptable acid addition salts by reaction with the appropriate organic or
mineral
acids.
Solvates of the compounds of formula (I) may be formed by crystallization or
recrystallization from the appropriate solvent. For example, hydrates may be
formed
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by crystallization or recrystallization from aqueous solutions, or solutions
in organic
solvents containing water.
Also salts or solvates of the compounds of formula (n which are not
pharmaceutically
acceptable may be useful as intermediates in the production of
pharmaceutically
acceptable salts or solvates. Accordingly such salts or solvates also form
part of this
invention.
As mentioned before, the compounds of formula (17 may exist in more than
one stereoisomeric form and the process of the invention may produce racemates
as
well as enantiomerically pure forms. To obtain pure enantiomers, appropriate
enantiomerically pure primary or secondary amines of formula (Illd) or (Ille)
R~2 R~ R 2 R.
H'N~Ar' H'N~Ar'
R., R~~
(IBd) (iBe)
are reacted with compounds of formula (In, to obtain compounds of formula (Td)
or
(1'e).
R' R'
i 2 R, i z R,
x N~Ar X~ N~Ar'
v i R',sR'' i i
R~s ~ R,s
~N R'S \ 'N R~s
(hd) (he)
Compounds of formula (1~d) or (I'e) may subsequently be converted to
compounds of formula (Id) or (Ie) by the methods of conversion mentioned
before.
2 R ~ R
X N~Ar N~Ar
i i R4R' ~ ~ R R,
R3 ~ R3
~N RS ~ ~N RS
(Id) (le)
Compounds of formula (In are known compounds or can be prepared from
known compounds by known methods.
For example, the compound of formula (In, in which X' is oxygen, R'3, R'4
CA 02257662 1999-O1-14
WO 95132948 PCTIEP95/02000
and R'S are hydrogen is described in Pfitzinger,1. Prakr. Chem., 38, 582, 1882
and in
Pfitzinger, J. Prak~ Chem., 56, 293,1897; the compound of formula (In, in
which X'
is oxygen, R'3 and R'4 are hydrogen and R'S is 2-pyridyl is described in
Risaliti, Ric.
Scienr_, 28, 561, 1958; the compound of formula (II], in which X' is oxygen,
R'3 and
R'4 are hydrogen and R'S is o-, m- and p-chlorophenyl, o-fluorophenyl and 3,4-
dichlorophenyl are described in Brown et aZ, J:. Am. Chem. Soc., 68,
2705,1946; the
compound of formula (II), in which X' is oxygen, R'3 and R'4 are hydrogen and
R'S is
p-methozyphenyl is described in Ciusa and Ltlaatto, Gazz Chim. Ital., 44,
64,1914;
the compound of formula (Il), in which X' is oxygen, R'3 and R'4 are hydrogen
and
R'S is m-trifluoromethylphenyl is described in Shargier and Lalezari, J. Chem.
Eng.
Data, 8, 276,1963; the compound of formula (1~, in which X' is oxygen, R'3 and
R'4
are hydrogen and R'S is p-fluorophenyl is described in Bu Hoi et al., Rec
Trav. Chim_,
68, 781, 1949; the compound of formula (In, in which X' is oxygen, R'3 and R'4
are
hydrogen and R'S is p-methylphenyl is described in Prevost et al., Compt:
Rend.
Acad Sci.> 258, 954, 1964; the compound of formula (In, in which X' is oxygen,
R'3
and R'4 are hydrogen and R'S is p-bromophenyl is described in Nicolai et al.,
Eur. J.
Med Chem, 27, 977,1992; the compound of formula (In in which X' is oxygen, R'4
and R'S are hydrogen and R'3 is 6-methyl is described in Buchmann and Howton,
J.
Am. Chem. Soc., 68, 2718, 1946; the compound of formula (137, in which X' is
oxygen, R'4 and R'S are hydrogen and R'3 is 8-vitro is described in Buchmann
et al, J
Am_ Chem. Soc., 69, 380,1947; the compound of formula (In, in which X' is
oxygen,
R'4 is hydrogen, R'3 is 6-chloro, R'S is p-chlorophenyl is described in Lutz
et al., .l.
Am. Chem Soc., 68, 1813,1946; the compound of formula (I17, in which X' is
oxygen, R'3 and R'4 are hydrogen and R'S is 2-thiazolyl is described in Eur.
Pat
Appl. EP 112,776; compounds of formula (In, in which X' is oxygen, R'3 is 8-
trifluoromethyl, R'4 is hydrogen and R'S are phenyl, o- and p-fluorophenyl,
3,4-
dichlorophenyl, p-methoxyphenyl are described in Nicolai et a~, Eur. .1. Med
Chem.,
27, 977,1992; compounds of formula (in, in which X' is oxygen, R'3 is 6-bromo,
R'4
is hydrogen and R'S are phenyl or p-fluorophenyl are described in Nicolai et
al., Eur.
J. Med Chem., 27, 977,1992; other compounds of formula (II? are described in
Ger.
Offen DE 3,721,222 and in Eur. Pat Appl. EP 384,313.
Compounds of formula (III, (Ifld) and (I>Te) are commercially available
compounds or can be prepared from known compounds by known methods (for
example, compounds of formula (B17 in which R' is alkozycarbonyl, R' 1 and R'2
are
hydrogen and Ar' is as defined for the compounds of formula (n, are described
in
Liebigs Ann. der Chemie, 523, 199, 1936).
The activity of the compounds of formula (I) as NK3 receptor antagonists in
standard tests indicates that they are of potential therapeutic utility in the
treatment of
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WO 95!32948 PCTIEP95/02000
both the Primary and Secondary Disorders herein before referred to.
The discovery that NK3 receptor antagonists have potential therapeutic utility
in
treating the Secondary Disorders is new, and in a further aspect of the
present
invention there is provided the use of an NK3 receptor antagonist for the
treatment of
the Secondary Disorders. There is also provided the use of an NK3 receptor
antagonist in the manufacture of a medicament for the treaunent of any of the
Secondary Disorders.
The present invention also provides a compound of formula (I), or a
pharmaceutically
acceptable salt or solvate thereof, for use as an active therapeutic
substance.
The present invention further provides a pharmaceutical composition
comprising a compound of formula (1), or a pharmaceutically acceptable salt or
solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides the use of a compound of formula (1), or
a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a
IS medicament for the treatment of the Primary and Secondary Disorders.
Such a medicament, and a composition of this invention, may be prepared by
admixture of a compound of the invention with an appropriate carrier. It may
contain
a diluent, binder, filler, disintegrant, flavouring agent, colouring agent,
lubricant or
preservative in conventional manner.
These conventional excipients may be employed for example as in the
preparation of compositions of known agents for treating the conditions.
Preferably, a pharmaceutical composition of the invention is in unit dosage
form and in a form adapted for use in the medical or veterinarial fields. For
example,
such preparations may be in a pack form accompanied by written or printed
instructions for use as an agent in the treatment of the conditions.
The suitable dosage range for the compounds of the invention depends on the
compound to be employed and on the condition of the patient It will also
depend,
inter alia, upon the relation of potency to absorbability and the frequency
and route of
administration.
The compound or composition of the invention may be formulated for
administration by any route, and is preferably in unit dosage form or in a
form that a
human patient may administer to himself in a single dosage. Advantageously,
the
composition is suitable for oral, rectal, topical, parenteral, intravenous or
intramuscular administration. Preparations may be designed to give slow
release of
the active ingredient.
Compositions may, for example, be in the form of tablets, capsules, sachets,
vials, powders, granules, lozenges, reconstitutable powders, or liquid
preparations, for
example solutions or suspensions, or suppositories.
The compositions, for example those suitable for oral administration, may
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WO 95!32948 PCT/EP95/02000
contain conventional ezcipients such as binding agents, for example syrup,
acacia.,
gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example
lactose,
sugar, maize-starch, calcium phosphate, sorbitol or glyci.ne; tabletting
lubricants, for
example magnesium stearate; disintegrants, for example starch,
polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose;
or
pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
Solid compositions may be obtained by conventional methods of blending,
filling, tabletting or the like. Repeated blending operations may be used to
distribute
the active agent throughout those compositions employing large quantities of
fillers.
When the composition is in the form of a tablet, powder, or lozenge, any
carrier
suitable for formulating solid pharnnaceutical compositions may be used,
examples
being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and
chalk.
Tablets may be coated according to methods well known in normal pharmaceutical
practice, in particular with an enteric coating. The composition may also be
in the
form of an ingestible capsule, for example of gelatin containing the compound,
if
desired with a carrier or other excipients.
Compositions for oral administration as liquids may be in the form of, for
example, emulsions, syrups, or elixirs, or may be presented as a dry product
for
reconstitution with water or other suitable vehicle before use. Such liquid
compositions may contain conventional additives such as suspending agents, for
example sorbitol, syrup, methyl cellulose, gelatin, hydrozyethylcellulose,
carbozymethylcellulose, aluminium stearate gel, hydrogenated edible fats;
emulsifying agents, for example lecithin, sorbitan monooleate, or acacia;
aqueous or
non-aqueous vehicles, which include edible oils, for example almond oil,
fractionated
coconut oil, oily esters, for example esters of glycerine, or propylene
glycol, or ethyl
alcohol, glycerine, water or normal saline; preservatives, for example methyl
or
propyl p-hydrozybenzoate or sorbic acid; and if desired conventional
flavouring or
colouring agents.
The compounds of this invention may also be administered by a non-oral
route. In accordance with routine pharmaceutical procedure, the compositions
may
be formulated, for example for rectal administration as a suppository. They
may also
be formulated for presentation in an injectable form in an aqueous or non-
aqueous
solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g.
sterile
pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
The liquid
may contain bacteriostatic agents, anti-oxidants or other preservatives,
buffers or
solutes to render the solution isotonic with the blood, thickening agents,
suspending
agents or other pharmaceutically acceptable additives. Such forms will be
presented
in unit dose form such as ampoules or disposable injection devices or in mufti-
dose
forms such as a bottle from which the appropriate dose may be withdrawn or a
solid
13
CA 02257662 1999-O1-14
WO 95132948 PCT/EP95/02000
form or concentrate.which can be used to prepare an injectable formulation.
The compounds of this invention may also be administered by inhalation, via
the nasal or oral routes. Such administration can be carried out with a spray
formulation comprising a compound of the invention and a suitable carrier,
optionally
suspended in, for example, a hydrocarbon propellant.
Preferred spray formulations comprise micronised compound particles in
combination with a surfactant, solvent or a dispersing agent to prevent the
sedimentation of suspended particles. Preferably, the compound particle size
is from
about 2 to 10 microns.
A further mode of administration of the compounds of the invention
comprises transdermal delivery utilising a skin-patch formulation. A preferned
formulation comprises a compound of the invention dispersed in a pressure
sensitive
adhesive which adheres to the skin, thereby permitting the compound to diffuse
from
the adhesive through the skin for delivery to the patient. For a constant rate
of
percutaneous absorption, pressure sensitive adhesives known in the art such as
natural
rubber or silicone can be used.
As mentioned above, the effective dose of compound depends on the
particular compound employed, the condition of the patient and on the
frequency and
route of administration. A unit dose will generally contain from 20 to 1000 mg
and
preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200,
250, 300,
350, 400, 450, or 500 mg. The composition may be administered once or more
times
a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg
adult will
normally be in the range 100 to 3000 mg. Alternatively the unit dose will
contain
from 2 to 20 mg of active ingredient and be administered in multiples, if
desired, to
give the preceding daily dose.
No unacceptable toxicological effects are expected with compounds of the
invention when administered in accordance with the invention.
The present invention also provides a method for the treatment and/or
prophylazis of the Primary and Secondary Conditions in mammals, particularly
humans, which comprises administering to the mammal in need of such treatment
andlor prophylaxis an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt or solvate thereof.
The invention ftuther provides a method for the treatment and/or prophylaxis
of the
Secondary Conditions in mammals, particularly humans, which comprises
administering to the mammal in need of such treatment and/or prophylaxis an
effective amount of an NK3 receptor antagonist
The activity of the compounds of the present invention, as NK3 ligands, is
determined by their ability to inhibit the binding of the radiolabelled NK3
ligands,
[125_[Me-Phe7)-NKB or [3H]-Senktide, to guinea-pig and human NK3 receptors
14
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WO 95/32948 PCTlEP95/02000
(Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEES,
299(1 ), 90-
95; Chung et al, 1994, Biochem. Biophys. Res. Co~nmun., 198(3), 967-972).
The binding assays utilized allow the determination of the concentration of
the
individual compound required to reduce by SO% the [I25~-[Me_phe7]-NKB and
[3H]-Senktide specific binding to NK3 receptor in equilibrium conditions
(IC50).
Binding assays provide for each compound tested a mean IC50 value of 2-5
separate
experiments performed in duplicate or triplicate. The most potent compounds of
the
present invention show ICSp values in the range 1-1000 nM; in particular, in
guinea-
pig cortex membranes by displacement of [3H]-Senktide, the compounds of the
Examples 22, 47, 48, and 85 display Kis (nM) of 5.6, 8.8, I2.0 and 4.8
respectively
(n=3). The NK3-antagonist activity of the compounds of the present invention
is
determined by their ability to inhibit senktide-induced contraction of the
guinea-pig
ileum (Maggi et a1,1990, Br. .l. Pharmacol.,101, 996-1000) and rabbit isolated
iris
sphincter muscle (Hall et al., 1991, Eur. !. Pharmacol.,199, 9-14) and human
NK3
receptors-mediated Ca'~"~' mobilization (Mochizuki et x1,1994, ,l. Biol. Chem,
269,
9651-9658). Guinea-pig and rabbit in-vitro functional assays provide for each
compound tested a mean KB value of 3-8 separate experiments, where KB is the
concentration of the individual compound required to produce a 2-fold
rightward shift
in the concentration-response curve of senktide. Human receptor functional
assay
allows the determination of the concentration of the individual compound
required to
reduce by 50% (ICSO values) the Ca'~"~' mobilization induced by the agonist
NKB. In
this assay, the compounds of the present invention behave as antagonists.
The therapeutic potential of the compounds of the present invention in
treating the
conditions can be assessed using rodent disease models.
The following Descriptions illustrate the preparation of the intermediates,
whereas the Examples illustrate the preparation of the compounds of the
present
invention. The compounds of the Examples are summarised in the Tables 1 to 6
35
DESCRIP'ITON 1
2-phenylquinoline-4-carboxylic acid chloride
CA 02257662 1999-O1-14
WO 95!32948 PCTIEP95102000
11.7 ml ( 136.3 mmol) of ozalyl chloride were dissolved in 150 ml of CH2CI2.
The
solution was cooled at -10°C and 20 g (80.2 mmol) of commercially
available 2-
phenylquinoline-4-carboxylic acid were added portionwise. The reaction mi~ure
was
left overnight at room temperature and then evaporated to dryness to yield 22
g of the
title compound, used without further purification.
C 16H 1 OC1N0
M.W. = 267.76
DESCRIPTION 2
7-methoxy-2-phenylquinoline-4-carboxylic acid
5 g (28.2 mmol) of 6-methozyisatin, 4 ml (33.8 mmol) of acetophenone and 5.2 g
(92.6 mmol) of potassium hydroxide were dissolved in 22.9 ml of abs. EtOH and
the
slurry heated at 80°C for 42 hours. After cooling of the reaction
mixture, 50 ml of
water were added and the solution extracted with 50 ml of Et20. The ice-cooled
aqueous phase was acidified to pH 1 with 37% HCl and the precipitate collected
by
filtration and washed with water.
The solid obtained was dried in-vacuo at 40°C to yield 7.0 g of the
title compound.
C17H13N03
M.P. = 226-228°C
M.W. = 279.30
Elemental analysis: Calcd. C,73.11; H,4.69; N,5.01;
Found C,72.07; H,4.59; N,4.90.
LR. (KBr): 3420; 1630 cm-1.
DESCRIPTION 3
7-methoxy-2-phenylquinoline-4-carboxylic acid chloride
2.8 ml (32.3 mmol) of ozalyl chloride were dissolved in 60 ml of CH2Cl2. The
solution was cooled at -10°C and 6 g (19.0 mmol) of 7-methozy-2-
phenylquinoline-
4-carboxylic acid were added portionwise. The reaction mixture was left
overnight at
room temperature and then evaporated to dryness to yield 7 g of the title
compound,
used without further purification.
C 17H 12CIN02
M.W. = 297.74
DESCRIPTION 4
7-hydroxy-2-phenylquinoline-4-carboxylic acid hydroiodide
16
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WO 95132948 PCT/EP95/02000
1.5 g (5.4 mmol) of 7-methoxy-2-phenylquinoline-4-carboxylic acid were added
portionwise to 50 ml of 57% aqueous HI. The reaction mixture was refluxed and
vigourously stirred for 5 hours; then it was evaporated in-vacuo to dryness to
yield
2.1 g of the title compound.
CI6H11N03. HI
M.W. = 393.17
LR. (KBr): 3120; 1650; 1620 cm-1.
DESCRIPTION 5
~(2-thienyl)quinoline-4-carboxylic acid
5 g (34.0 mmol) of isatin, 4.4 ml (40.8 mmol) of 2-acetylthiophene and 6.3 g (
112.2
mmol) of potassium hydroxide were dissolved in 40 ml of abs. EtOH and the
slurry
heated at 80°C for 16 hours. After cooling of the reaction mixture, 50
ml of water
were added and the solution extracted with 50 ml of Et20. The ice-cooled
aqueous
phase was acidified to pH 1 with 37% HCl and the precipitate collected by
filtration
and washed with water.
The crude product obtained was dried in-vacuo at 40°C and triturated
with EtOAc to
yield 4.8 g of the title compound.
C 14H9N02S
M.P. = 181-183°C
M.W. = 255.29
LR. (KBr): 1620 cm-1.
300 MHz 1H-NMR (DMSO-d6): b 8.60 (d, 1H); 8.45 (s, IH); 8.10 (m, 2H); 7.78 (m,
2H); 7.68 (t, 1H); 7.22 (m, 1H).
DESCRIPTION 6
Z-(2-furyl)quinoline-4-carboxylic acid
5 g (34.0 mmol) of isatin, 4 ml (40.8 mmol) of 2-acetylfuran and 6.3 g (112.2
mmol)
of potassium hydroxide were dissolved in 40.9 ml of abs. EtOH and the slurry
heated
at 80°C for 12 hours. After cooling of the reaction mixture, 50 ml of
water were
added and the solution extracted with 50 ml of Et20. The ice-cooled aqueous
phase
was acidified to pH 1 with 37% HCl and the precipitate collected by filtration
and
washed with water. The crude product obtained was dried in-vacuo at
40°C to yield
8.5 g of the title compound.
C 14H9N03
17
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WO 95132948 PCT/EP95/02000 '
M.W. = 239.23
DESCRIPTTON 7
~-(2-furyl)quinoline-4-carboxylic acid chloride
5.2 ml (60.4 mmol) of ozalyl chloride were dissolved in 70 ml of CH2Cl2. The
solution was cooled at -10°C and 8.5 g (35.5 mmol) of 2-(2-
furyl)quinoline-4-
carbozylic acid were added portionwise. The reaction mixture was left
overnight at
room temperature and then evaporated to dryness to yield 9.2 g of the title
compound,
used without further purification.
C 14H8C1N02
M.W. = 257.78
DESCRIPTTON 8
2-(4-pyridyl)quinoline-4-carboxylic acid hydrochloride
5 g (34.0 mmol) of isatin, 4.5 ml (40.8 mmol) of 4-acetylpyridine and 6.3 g
(112.2
mmol) of potassium hydroxide were dissolved in 40 ml of abs. EtOH and the
slurry
heated at 80°C for 12 hours. After cooling of the reaction mixture, 50
ml of water
were added and the solution extracted with 50 ml of Et20. The ice-cooled
aqueous
phase was acidified to pH 1 with 37% HCl and the precipitate collected by
filtration
and washed with water.
The aqueous solution was evaporated in-vacuo to dryness, the residue
triturated with
EtOH and filtered off. Evaporation of the solvent afforded 6.0 g of the crude
title
compound. This product was combined with the previously obtained precipitate
and
recrystallized from toluene containing traces of MeOH to yield 4.5 g of the
title
compound.
C15H10N202 - HCl
M.P. = 297-301°C
M.W. = 286.72
LR. (KBr): 1705; 1635; 1610 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 8.90 (d, 2H); 8.70 (m, 2H); 8.50 (s, 2H); 8.28 (d,
1H); 7.89 (dt, 2H).
18
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WO 95!32948 PCTIEP95I02000
DESCRIPTION 9
2-(4-pyridyl)quinoiine-4-carboxylic acid chloride hydrochloride
1.3 ml (10.4 mmol) of ozalyl chloride were dissolved in 60 ml of CH2C12. The
solution was cooled at -10°C and 3.0 g (14.4 mmol) of 2-(4-
pyridyl}quinoline-4-
carbozylic acid hydrochloride were added portionwise. The reaction mixture was
left
72 hours at room temperature and then evaporated to dryness to yield 4.0 g of
the title
compound, used without further purification.
C l5HgC1N20 ~ HCl
M.W. = 305.22
EXAMPLE 1
(R,S~N-<a-methylbenzyl~~-phenylquinoline-4-rarboxamide
1.2 ml (9.4 mmol) of (R.,S) a-methylbenzylamine and 1.6 mi (11.7 mmol) of
triethylamine (TEA) were dissolved, under nitrogen athmosphere, in 50 ml of a
1:1
mixture of dry CH2C12 and CH3CN.
2.0 g (7.8 mmol) of 2-phenylquinoline-4-carbonylchloride, dissolved in 50 ml
of a
1:4 mixture of dry CH2Cl2 and DMF, were added dropwise to the ice-cooled
solution
of the amines and the reaction was kept at 0°- 5°C for 1 hour
and left at room
temperature overnight.
The reaction mixture was evaporated in-vacuo to dryness, the residue was
dissolved
in EtOAc and washed twice with a sat. sol. of NaHC03. The organic layer was
separated, dried over Na2S04, filtered and evaporated in-vacuo to dryness.
The residual oil was crystallized from EtOAc to yield 1.1 g of the title
compound as a
white solid.
C24H20N20
M.P. = 156-157°C
M.W. = 352.43
Elemental analysis: Calcd. C,81.79; H,5.72; N,?.95;
Found C,81.99; H,5.69; N,7.89.
LR. (KBr): 3240;1645 cm-1.
300 MHz 1H-NMR (DMSO-d6): b 9.29 (d, 1H); 8.32 (d, 2H); 8.13 (d, 1H); 8.13 (s,
1H); 8.06 (d, 1H); 7.81 (ddd, 1H); 7.68-7.52
(m, 4H); 7.47 (d, 2H); 7.39 (dd, 2H); 7.27 (dd,
1H); 5.30 (dq, 1H); 1.52 (d, 3H).
MS (FI; source 200 °C; 70 V; 200 mA): 352 (M+.); 337; 232; 204; 77.
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EXAMPLE 2
S-(+)-N-(a-methylbenzyl)-~.phenylquinoline-4-carboxamide
Prepared as Ex. 1 from 1.2 ml (9.4 mmol) of S-(-)-a-methylbenzylamine, 1.6 ml
{11.7 mmol) of TEA, 2.0 g (7.8 mmol) of 2-phenylquinoline-4-carbonylchloride
in
100 ml of a mixture of CH2C12, CH3CN and DMF.
The work-up of the reaction mixture was carried out in the same manner as
described
in Ex. 1. The residual oil was crystallized from EtOAc to yield 1.1 g of the
title
compound.
C24H20N20
M.P. = 161-162°C
M.W. = 352.43
~a~D20 - + 25 (C = 0.5, DMF)
LR. (KBr): 3240; 1645 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 9.29 (d, 1H); 8:32 (d, 2H); 8.13 (d, 1H); 8.13 (s,
1H); 8.06 (d, 1H); 7.81 (ddd, 1H); 7.68-7.52 {m,
4H); 7.47 (d, 2H); 7.39 (dd, 2H); 7.27 (dd, 1H);
5.30 (dq, 1H); 1.52 (d, 3H).
MS spactra was identical to that of the Ex. 1.
EXAMPLE 3
R-(-~N-(a-methylbenzyl)-~-phenylquinoline-4-rarboxamide
Prepared as Ex. 1 from 1.2 ml (9.4 mmol) of R-{+)-a-methylbenzylamine, 1.6 ml
(11.7 mmol) of TEA and 2.0 g (7.8 mmol) of 2-phenylquinoline-4-
carbonylchloride
in 100 ml of a mixture of CH2Cl2, CH3CN and DMF. The work-up of the reaction
mixture was carried out in the same manner as described in Ex. 1. The residual
oil
was crystallized from EtOAc to yield 1.1 g of the title compound.
C24H20N20
M.P. = 158-160°C
M.W. = 352.43
~a~D20 = _ ~5 {C = 0.5, DMF)
LR. (KBr): 3240; 1645 cm-1.
The 1H-NMR and MS spectra were identical to those of the Ex. 1 and Ez. 2.
CA 02257662 1999-O1-14
WO 95132948 PCT/EP95/02000
EXAMPLE 4
(R,SAN-(a-(methoxycarbonyl)benryl]-2-phenylquinoIine-4-rarboxamide
2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic acid were dissolved, under
nitrogen athmosphere, in 130 ml of dry THF and 100 ml of CH3CN.
2.0 g (9.9 mmol) of (D,L) methyl phenylglicinate hydrochloride and 1.5 ml
(10.7
mmol) of TEA were added and the reaction mixture was cooled at 5°C.
2.5 g ( 12.1 mmol) of dicyclohexylcarbodiimide (DCC), dissolved in 10 ml of
dry
CH2C12, were added dropwise and the solution was allowed to reach room
temperature, stirred for 5 hours and left overnight
The precipitated dicyclohexylurea was filtered off and the solution was
evaporated in
varuo to dryness. The residue was dissolved in CH2C12 and then washed with
H20.
The organic layer was separated, dried over Na2S04 and evaporated in-vacuo to
dryness to obtain 6.0 g of a crude product which was dissolved in 20 ml of
CH2C12
and left overnight Some more dicyclohexylurea precipitated and was filtered
off.
The solution was evaporated in-vacuo to dryness and the residue flash
chromatographed on 230-400 mesh silica gel, eluting with a mixture of
hezanelethyl
acetate 3:2 containing 0.5% NH40H. The crude solid obtained was triturated
with
warm i-Pr20, filtered, washed and dried to yield 1.1 g of the title compound.
C25H20N203
M.P. = 170-172°C
M. W. = 396.45
Elemental analysis: Calcd. C,75.74; H,5.09; N,7.07;
Found C,75.88; H,5.12; N,7.06.
LR. (nujol): 3240; 1750; 1670 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 9.72 (d, 1H); 8.28 (dd, 2H); 8.20 (dd, 1H); 8.13
(dd, 1H); 8.11 (s, 1H); 7.83 (ddd, 1H); 7.66
(ddd, 1H); 7.60-7.50 (m, SH); 7.47-7.37 (m,
3H); 5.78 (d, 1H); 3.72 (s, 3H).
MS (EI; source 200 °C; 70 V; 200 mA): 396 (M+.); 337; 232; 204.
EXAMPLE 5
(+~(SAN-[a-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-rarboxamide
21
CA 02257662 1999-O1-14
w0 95!32948 PCTIEP95l02000
2.0 g (8.0 mmol). of 2-phenylquinoline-4-carboxylic acid were dissolved, under
nitrogen athmosphere, in 70 ml of dry THF and 30 ml of CH3CN.
1.7 g (8.4 mmol) of (L) methyl phenylglicinate hydrochloride, 1.1 ml (9.9
mmol) of
N-methylmorpholine and 2.1 g (15.5 mmol) of N-hydrozybenzotriazole (HOB'I~
were added and the reaction mixture was cooled at 0°C.
1.85 g (9.0 mmol) of I7CC, dissolved in 10 ml of CH2Cl2, were added dropwise
and
the solution was kept at 0°- 5°C for 1 hour and then at room
temperature for 2 hours.
The precipitated dicyclohexylurea was filtered off and the solution evaporated
in-
vacuo to dryness. The residue was dissolved in CH2C12 and washed with H20,
sat.
sol. NaHC03, 5% citric acid, sat sol. NaHC03 and sat. sol. NaCl.
The organic layer was separated, dried over Na2S04 and evaporated in-vacuo to
dryness; the residue was dissolved in 20 ml of CH2C12 and left overnight. Some
more
dicyclohezylurea precipitated and was filtered off.
The solution was evaporated in-vacuo to dryness to obtain 2.6 g of a crude
product
which was triturated with petroleum ether, filtered, washed with i-Pr20 and
then
recrystallized from 70 m1 of i-PrOH to yield 1.7 g of the title compound.
C25H20N203
M.P. = 180-181° C
M.W. = 396.45
LR. (nujol): 3300; 1750; 1640 cm-1.
[a]D20 = .~2.0 (C = 0.5, MeOH).
The 1H-NMR and MS spectra were identical to those of Ex. 4.
EXAMPLE 6
(-~(R)-N-[a-(methoxyrarbonyl)henry!]-2-phenylquinoline-4-carboxamide
Prepared as Ex. 5 from 2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic
acid, 1.7
g (8.4 mmol) of (D) methyl phenylglicinate hydrochloride, 1.1 ml (9.9 mmol) of
N
methylmorpholine, 2.1 g (15.5 mmol) of HOBT and 1.85g (9.0 mmol) of DCC in 70
ml of dry THF and 30 ml of CH3CN.
The work-up of the reaction mixture was carried out in the same manner as
described
in Ex. 5. The crude product obtained (3.5 g ) was triturated twice with warm i-
Pr20,
filtered, washed and then recrystallized from 80 ml of i-PrOH to yield 2.3 g
of the
title compound.
C25H2pN203
M.P. = 180-181°C
M.W. = 396.45
LR. (nujol): 3300; 1750; 1640 cm-1
22
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WD 95132948 PCT/EP95/02000
~a]D20 = ..42.0 (C = 0.5, MeOH).
The 1H-NMR and MS spectra wem identical to those of Exs. 4 and 5.
EXAMPLE 7
(R,S)-N-hoc-{methoxycarbonyl)benzyl]-7-methoxy-2-phenylquinoline-4-
carboxamide
1.0 g {5.0 mmol) of (D,L) methyl phenylglicinate hydrochloride were dissolved,
under nitrogen athmosphere, in 30 ml of dry DMF.
2.5 g (18.1 mmol) of anhydrous potassium carbonate were added and the solution
.
cooled at 0°C.
0.7 g (2.3 mmol) of the compound of Description 3, dissolved in 25 ml of dry
DMF,
were added dropwise and the solution was kept at 0°- 5°C for 1
hour and at room
temperature overnight
The reaction mixture was evaporated in-vacuo to dryness and the residue was
dissolved in EtOAc and washed twice with H20. The organic layer was separated,
dried over Na2S04, filtered and evaporated in-vacuo to dryness.
The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting
with
a mixture of hezanelethyl acetate 3:2 containing 0.5% NH40H to afford 0.1 g of
the
crude product which was triturated with i-Pr20 to yield 0.08 g of the title
compound.
C26H22N204
M.P. = 187-190°C
M.W. = 426.48
LR. {KBr): 3220; 1750; 1660; 1620 cm-l.
300 MHz 1H-NMR (CDC13): b : 8.13-8.08 (m, 3H); 7.80 (s, 1H); 7.55-7.38 (m,
9H);
7.21 (dd, 1H); 7.02 (d broad, H); 5.88 (d, 1H); 3.97
(s,3H); 3.80 (s, 3H).
MS (EI; source 200 °C; 70 V; 200 mA): 426 (M+.); 367 ; 262 ; 234;
191;77.
EXAMPLE 8
(R,SAN-joc-(methoxycarbonyl)benzyl]-7-hydroxy-~phenylquinoline-4-
carboxamide
Prepared as Ex. 5 from 2.1 g (5.3 mmol) of the compound of Description 4, 1.08
g
(5.3 mmol) of (D,L) methyl phenylglicinate hydrochloride, 1.5 ml ( 10.7 mmol)
of
TEA, 1.7 g (12.5 mmol) of HOBT and 1.2 g (5.8 mmol) of DCC in 70 ml of dry THF
and 30 ml of CH3CN.
The work-up of the reaction mixture was carried out in the same manner as
described
23
Y CA 02257662 1999-O1-14
WO 95132948 PCTlEP95/02000
in Ex. 5. The crude product obtained was triturated with i-Pr20 and then
recrystallized twice from i-PrOH to yield 0.06 g of the title compound. .
C25H20N204
M.P. = 256-257°C
M.W. = 412.45
LR. (KBr): 3270; 1750; 1650; 1620 cm' 1.
300 MHz 1H-NMR (DMSO-d6): 8 10.30 (s broad, 1H); 9.64 (d, 1H); 8.22 (d, ZH);
8.04 (d, 1H); 7.85 (s, 1H); 7.60-7.34 (m, 9H);
7.21 (dd, IH); 5.74 (d, 1H); 3.71 (s, 3H).
MS (EI; source 200 °C; 70 V; 200 mA): 412 (M+.); 353; 248; 220;
77.
EXAMPLE 9
(R,S)-N-[a-(carboxy)benzyl]-7-methoxy-2-phenyIquinoline-4-carboxamide
hydrochloride
0.18 g (0.4 mmol) of the product of Ex. 7 were dissolved in 10 ml of 10% HC1
and 5
ml of dioxane. The reaction mixture was refluxed and stirred for 3 hours, then
evaporated in-vacuo to dryness.
The crude product was triturated with warm EtOAc (containing a few drops of
EtOH)
to yield 0.16 g of the title compound.
C25H20N204-HCl
M.P. = 228-230°C
M.W. = 448.91
LR. (KBr): 3180; 1735; 1655; 1630 cm' 1.
300 MHz 1H-NMR (DMSO-d6): 8 9.6 (d, 1H); 8.26 (dd, 2H); 8.14 (d, 1H); 7.98 (s,
1H); 7.63-7.52 (m, 6H); 7.46-7.36 (m, 3H); 7.33
(dd, IH); 5.66 (d, 1H); 3.98 (s, 3H).
MS (EI; source 200 °C; 70 V; 200 mA): 412 (M+.); 368 ; 262; 234; 191;
77.
EXAMPLE 10
(R,S)-N-[a-(methylaminocarbonyl)benzyl]-2-phenylquinoIine-4-carboxamide
0.45 g (1.1 mmol) of the product of Ex. 4 were dissolved in 40 ml of 33%
MeNH2/EtOH; a catalitic amount of NaCN was added and the reaction mixture was
heated at 70°C for 1 hour in a parr apparatus. The internal pressure
used to 40 psi.
The solution was evaporated in-vacuo to dryness and the residue was triturated
with
water, filtered, dried and recrystallized from a mixture of i-PrOH (50 ml) and
EtOH
(30 ml) to yield 0.2 g of the title compound.
24
. CA 02257662 1999-O1-14
WO 95132948 PCTIEP95I02000
C25H21N302
M.P. = 261-263°C
M.W. = 395.47
Elemental analysis: Calcd. C,75.93; H,5.35; N,10.63;
Found C,75.65; H,5.34; N,10.55.
LR. (KBr): 3300; 3270; 1660; 1635 cm-1.
300 MHz 1H-NMR (DMSO-d6): S 9.48 (d, 1H); 8.33-8.25 (m, 3H); 8.18-8.10 (m,
3H); 7.80 (ddd, 1H); 7.68-7.50 (m, 6H); 7.40-
7.28 (m, 3H); 5.75 (d, 1H); 2.63 (d,3H).
MS (EI; source 200 °C; 70 V; 200 mA): 395 (M+.); 337; 232; 204;
77.
EXAMPLE 11
(R,SAN-[a-(methoxycarbonyl)benryl]-~.(~thienyl)quinoline-4-rarboxamide
Prepared as Ex. 5 from 2.0 g (7.3 mmol) of 2-(2-thienyl)quinoline-4-carboxylic
acid,
1.7 g (8.4 mmol) of (D,L) methyl phenylglicinate hydrochloride, 1.1 ml (10
mmol) of
N-methylmorpholine, 2.1 g (15.5 mmol) of HOBT and 1.85 g (9.0 mmol) of DCC in
70 ml of dry THF, 30 ml of CH3CN and IO ml of CH2C12.
The work-up of the reaction mixture was carried out in the same manner as
described
in Ez. 5. The crude product obtained was crystallized from EtOAc and then
recrystallized from abs. EtOH to yield 0.9 g of the title compound.
C23H18N203S
M.P. = 178-180°C
M.W. = 402.47
Elemental analysis: Calcd. C,68.64; H,4.51; N;6.96;
Found C,67.50; H,4.99; N,7.43.
LR. (KBr): 3300; 1745; 1645 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 9.70 (d, 1H); 8.12 (d, 1H); 8.08 (s, 1H); 8.04 (d,
1H); 8.02 (d, 1H); 7.19 (t, 1H); 7.76 (d, 1H);
7.62 (t, 1H); 7.53 (d, 2H); 7.46-7.37 (m, 3H); 7.3
(dd, 1H); 5.68 (d, 1H); 3.68 (s, 3H).
MS (FI; source 200 °C; 70 V; 200 mA): 402 (M+.); 343; 238; 210; 77.
EXAMPLE 12
(R,SAN-(oc-(methoxycarbonyl)benzyI]-2-(2-furyl)quinoline-4-rarboxamide
Prepared as Ex. 1 from 7.2 g (35.5 mmol) of (D,L) methyl phenylglicinate
hydrochloride, 12.4 ml (88.8 mmol) of TEA and 9.1 g (35.5 mmol) of crude 2-(2-
CA 02257662 1999-O1-14
WO 95!32948 PGT/EP95102000
fury!)quinoline-4-carbonylchloride in 350 ml of a mixture of CH2C12, CH3CN and
DMF. The work-up of the reaction mixture was carried out in the same manner as
described in Ex. 1. The crude product obtained was triturated with MeOH to
yield 3.3
g of the title compound.
C23H18N204
M.P. = 178-180°C
M.W. = 386.405
Elemental analysis: Calcd. C,71.49; H,4.70; N,7.25;
Found C,71.67; H,4.74; N,7.17.
LR. (KBr): 3300; 1750; 1650 cm-1.
300 MHz IH-NMR (DMSO-d6): S 9.72 (d, 1H); 8,12 (d, 1H); 8.06 (d, 1H); 7.96
(dd,
1H); 7.92 (s, 1H); 7.80 (ddd, 1H); 7.62 (ddd,
1H); 7.52 (dd, 2H); 7.45-7.35 (m, 4H); 6.73 (dd,
1H); 5.77 (d, 1H); 3.74 (s, 3H).
MS (EI; source 200 °C; 70 V; 200 mA): 386 (M+.); 327; 222; 194;
77.
EXAMPLE 13
(R,S)-N-[oc-(methoxycarbonyI)benryl]-2-{4-pyridyl~uinoline-4-carboxamide
Prepared as Ez. 1 from 3.4 g ( 16.7 mmol) of (D,L) methyl phenylglicinate
hydrochloride, 3.9 ml (27.8 mmol) of TEA and 3.0 g (11.1 mmol) of 2-(4-
pyridyl)quinoline-4-carbonylchloride in 100 ml of a mixture of CH2C12, CH3CN
and
DMF. The work-up of the reaction mixture was carried out in the same manner as
described in Ex. 1. The crude product obtained was recrystallized three times
from
EtOAc to yield 1.9 g of the title compound.
C24H 19N303
M.P. = 172-174°C
M.W. = 397.43
Elemental analysis: Calcd. C,72.53; H,4.82; N,10.57;
Found C,71.87; H,4.87; N,10.44.
LR. (KBr): 3240; 1750; 1670 cm-1.
300 MHz IH-NMR (DMSO-d6): 8 9.74 (d, 1H); 8.79 (dd, 2H); 8.27-8.17 (m, SH);
7.89 (ddd, 1H); 7.74 (ddd, IH); 7.54 (dd, 2H);
7.47-7.38 (m, 3H); 5.8 (d. 1H); 3.75 (s, 3H).
MS (EI; source 200 °C; 70 V; 200 mA): 397 (M+.); 338; 233; 205;
77.
EXAMPLE 14
{R,SAN-[a-(methoxyrarbonyl)-2-thieny!methyl]-2-phenylquinoline-4-
26
CA 02257662 1999-O1-14
WO 95132948 PCT/EP95/02000
carboxamide
Prepared as Ex. 1 from 1.94 g (9.4 mmol) of (D,L) methyl thienylglicinate
hfdrochloride, 2.7 ml (19.5 mmol) of TEA and 2.0 g (7.8 mmol) of 2-
phenylquinoline-4-carbonylchloride in 100 ml of a mixture of CH2C12, CH3CN and
DMF. The work-up of the reaction mixture was carried out in the same manner as
described in Ex. 1. The crude product obtained was recrystallized three times
from
EtOAc to yield 0.66 g of the title compound.
C23H18N203S
M.P: = 144-145°C
M.W. = 402.47
Elemental analysis: Calcd. C,68.64; H,4.51; N,6.96;
Found C,68.81; H,4.46; N,6.96.
LR. (KBr): 3295; 1745; 1640 cm-I.
300 MHz IH-NMR (CDC13): 8 8.25 (dd, 1H); 8.22 (dd, 1H); 8.17 (dd, 2H); 7.95
(s,
1H); 7.78 (ddd, 1H); 7.60 (ddd, 1H); 7.56-7.45 (m,
3H); 7.35 (dd,lH) ; 7.20 (d, 1H); 7.05 (dd, 1H); 7.05
(s broad, 1H); 6.22 (d, 1H); 3.9 (s, 3H).
MS (EI; source 200 °C; 70 V; 200 mA): 402 (M+.); 343; 232; 204.
EXAMPLE 15
(R,SAN-[a-(methoxycarbonylmethyl)benzyl]-2-phenylquinoline-4-carboxamide
Prepared as Ez. 5 from 1.39 g (5.60 mmol) of 2-phenylquinoline-4-carboxylic
acid,
1.2 g (5.60 mmol) of (R,S) methyl 3-amino-3-phenylpropionate hydrochloride,
0.78
ml (5.60 mmol ) of TEA, 1.51 g (11.2 mmol) of HOBT and 2.31 g (11.2 mmol) of
DCC in IO ml of dry THF, 4 ml of CH3CN and 7 ml of CH2CI2. The work-up of the
reaction mixture was carried out in the same manner as described in Ex. 5. The
crude
product obtained was dissolved in CH2CI2 and Ieft at 0°C overnight Some
more
dicyclohexylurea precipitated and was filtered off.
The solution was evaporated in-vacuo to dryness to obtain 1.4 g of a crude
product
which was triturated with a mixture of i-Pr2Olacetone 99:1 to yield 1.2 g of
the title
compound as a white solid.
C26H22N203
M.P. = 156-158°C
M.W. = 410.47
Elemental analysis: Calcd. C,76.07; H,5.40; N,6.82;
Found C,75.77; H,5.3$; N,6.94.
27
CA 02257662 1999-O1-14
WO 95!32948 ' ' PCT/EP95I02000 ,
LR. (KBr): 3295; 1755; 1645; 1590; 1530 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 9.40 (d, 1H); 8.29 (dd, 2H); 8.14 (d, 1H); 8.07
(d,
1H); 8.04 (s, 1H); 7.83 {ddd, 1H); 7.66-7.52 (m,
4H); 7.50 (d, 2H); 7.40 (dd, 2H); 7.31 (ddd, 1H);
5.60 (dt, 1H); 3.65 {s, 3H); 3.04-2.89 (m, 2H).
MS (EI; source 200 °C; 70 V; 200 mA): 410 (M+.); 337; 233; 205.
28
CA 02257662 1999-O1-14
WO 95/32948 PCT/EP95l02000
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CA 02257662 1999-O1-14
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61
CA 02257662 1999-O1-14
WO 95/32948 PCT/EP95I02000
E~~AMPLE 93
(R,S)-N-(a-(Methoxycarbonyl)benzyl]-2-(p-chlorophenyl)quinoline-4
carboxamide
2 g (7.0 mmol) of 2-(p-chlorophenyl)quinoline-4-carboxylic acid and 1.7 ml (
15.4
mmol) of N-methylmorpholine were dissolved, under nitrogen athmosphere, in 50
ml
of dry THF.
The solution was cooled to -20°C and 0.91 ml (7.0 mmol) of isobutyl
chloroformate
were added. After 20 minutes, 2.12 g (10.5 mmol) of methyl (R,S)
phenylglycinate
hydrochloride and 1.3 ml (11.9 mmol) of N-methylmorpholine, dissolved in 30 ml
of
dry THF, were added and the reation mixture was stirred at room temperature
OVeIrllght
ml of H20 were added and the reaction mixture was evaporated in vacuo to
dryness. The residue was dissolved in Et20, washed with a saturated solution
of
NaHC03, separated, dried over Na2S04 and evaporated in vacuo to dryness.
The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting
with
a mixture of hezane/isopropyl ether 7 : 3 to afford 0.9 g of crude product,
which was
recrystallized three times with iPr02/toluene to yield 0.5 g of the title
compound.
C25H 190203
M.P. = 170-172 °C
M.W. = 430.90
Elemental analysis: Calcd. C, 69.72; H, 4.45; N, 6.50
Found C, 69.82; H, 4.47; N, 6.48
LR. {KBr): 3280; 1740; 1670; 1635; 1590; 1530 cm-1.
300 MHz 1H-NMR (DMSO-d6): 9.71 (d, 1H); 8.32 (d, 2H); 8.21 (d, 1H); 8.13 (d,
1H); 8.13 (s, 1H); 7.85 (dd, 1H); 7.67 {dd, 1H);
7.63 (d, 2H); 7.53 (dd, 2H); 7.46-7.38 (m, 3H);
5.79 (d, 1H); 3.74 (s, 3H).
MS (EI; source 200 °C;70 eV; 200 ~A): 430 (M+.); 371; 266; 238;
203.
ExAMPIrE 94
(RAN-[a-(Methoxycarbonyl~4-methoxybenzyl]-2-phenylquinoIine-4
carboxamide
0.62 g (1.5 mmol) of (R}-N-[a-(methozycarbonyl)-4-hydrozybenzyl]-2-
phenylquinoline-4-carboxamide (compound of Ez. 83) were dissolved in 30 ml of
dry
acetone and 2 ml of dry DMF; 0.14 g (0.75 mmol) of K2C03 were added and the
reaction mixture was stirred for 30 minutes.
0.093 ml ( 1.5 mmol) of methyl iodide were added at room temperature and the
reaction mixture was heated at 40 °C for 4 hours. 0.104 g (0.75 mmol)
of K2C03 and
62
CA 02257662 1999-O1-14
WO 95132948 PCT/EP95102000
0.093 ml (1.5 mmol) of methyl iodide were added again, and the mixture
refluxed for
additional 6 hours.
The mixture was evaporated in vacuo to dryness, dissolved in EtOAc and washed
with H20. The organic layer, dried over Na2S04, was evaporated in vacuo to
dryness. The residue was recrystallized from Et20 to yield 0.45 g of the title
compound.
C26H22N204
M.P. = 160-162 °C
M.W. = 426.48
Elemental analysis: Calcd. C, 73.22; H, 5.20; N, 6.57
Found C, 73.01; H, 5.20; N, 6.48
LR. (KBr): 3210; 1?50; 1635; 1625; 1590; 1530; 1515 cm-1
300 MHz 1H-NMR (DMSO-d6): 9.65 (d, 1H); 8.28 (d, 2H); 8.21 (d, 1H); 8.14 (d,
1H); 8.10 (s, 1H); 7.84 (dd, 1H); 7.67 (dd, 1H);
7.61-7.49 (m, 3H); 7.44 (d, 2H); 6.98 (d, 2H);
4.70 (d, 1H); 3.79 (s, 3H); 3.76 (s, 3H).
MS (FI; source 200 °C;70 eV; 200 ~A): 426 (M+.); 367; 232; 204.
EXAMPLE 95
(R,S)-N-[a-(Methoxycarbonyl)-a-(methyl)benzyl]-N-methyl-2-phenylquinoIine-
4-carboxamide hydrochloride
0.50 g (1.3 mmol) of (R,S)-N-[a-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-
carboxamide (compound of Ez. 4) were dissolved, under nitrogen athmosphere, in
10
ml of dry DMF.
The solution was cooled to 0 °C and 0.052 g (1.3 mmol) of NaH (60%)
were added;
after 20 minutes at 0 °C the temperature was raised to r.t and 0.09 ml
(1.4 mmol) of
MeI were added. The reation mixture was stirred at room temperature overnight,
then
the procedure was repeated by adding additional 0.052 g ( 1.3 mmol) of NaH
(60%)
and 0.1 ml ( 1.6 mmol) of MeI.
After 6 hours at room temperature, 10 ml of saturated solution of NH4C1 were
added
and the reaction mixture was evaporated in vacuo to dryness. The residue was
dissolved in CH2Cl2 and washed with water-, the organic layer was separated,
dried
over Na2S04 and evaporated in vacuo to dryness.
The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting
with
a mixture of hexane/ethyl acetate 3 : 2 containing 0.5% of conc. NH40H to
afford
0.18 ~ of a crude product which was dissolved in Et20 and treated with
HCIIEt20 to
yield 0.15 g of the title compound.
C27H24N203~HC1
M.W. = 460.96
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LR. (KBr): 1745; 1640; 1610 cm-1
MS (EI; source 200 °C;70 eV; 200 ~.A): 424 (M+.); 365; 232; 204.
EXAMPLE 96
(R,S)-N-[a-(Methylcarbonyl)benzyl]-2-phenylquinoline-4-carboxamide
0.27 ml (3.1 mmol) of ozalyl chloride were dissolved, under nitrogen
athmospheru, in
2.3 ml of dry CH2C12.
The solution was cooled to -55 °C and 0.22 ml (3.1 mmol) of DMSO,
dissolved in
0.7 ml of dry CH2C12, were added dropwise maintaining the temperature below -
50 °
C. The reaction was stirred at -55°C for 7 minutes then 0.97 g (2.5
mmol) of (R,S)-N-
[a-(1-hydroxyethyl)benzyl]-2-phenylquinoline-4-carbozamide (compound of Ez.
17), dissolved in 25 ml of dry CH2C12, were added keeping the temperature
between
-50 and -55 °C.
After 30 minutes at -55 °C, 1.9 ml ( 13.6 mmol) of TEA were added
without
exceeding -40 °C, then the reaction mixture was allowed to reach room
temperature
and stirred for additional 15 minutes.
The reaction was quenched with 5 ml of H20 and extracted with CH2Cl2; the
organic
layer was washed with H20, 20% citric acid, saturated solution of NaHC03 and
brine; the organic layer was separated, dried over Na2S04 and evaporated in
vacuo to
dryness.
The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting
with
a mixture of hexane/ethyl acetate 70 : 30 containing 0.5% of conc. NH40H to
afford
0.64 g of a crude product which was trittuated with warm i-Pr20/i-PrOH 2 : 1,
_
filtered, washed and dried to yield 0.5 g of the title compound.
C25H20N202
M.P. = 160-161 °C
M.W. = 380.45
Elemental analysis: Calcd. C, 78.93; H, 5.30; N, 7.36;
Found C, 79.01; H, 5.31; N, 7.27.
LR. (KBr): 3400; 3265; 1725; 1660; 1640; 1592 cm-l.
300 MHz IH-NMR (DMSO-d6): 9.60 (d, 1H); 8.29 (d, 2H); 8.I7 (d, 1H); 8.14 (d,
1H); 8.12 (s, 1H); 7.82 (dd, 1H); 7.65 (dd, 1H);
7.61-7.51 (m, 5H); 7.48-7.36 (m, 3H); 2.19 (s, 3H).
MS (EI; source 200 °C;70 eV; 200 ~.A): 380 (M+.); 337; 232; 204.
EXAMPLE 97
(R,S)-N-[a-(2-Hydroxyethyl)benryl]-2-phenylquinoline-4-carboxamide
0.7 g (1.7 mmol) of (R,S)-N-[a-(methoxycarbonylmethyl)benzyl]-2-
phenylquinoline-
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4-carboxamide (compound of Ex. 15) were dissolved, under nitrogen athmosphere,
in
50 ml of t-BuOH and 2 ml of MeOH.
60 mg (1.6 mmol) of NaBH4 were added in 15 minutes to the boiling solution.
The
reaction mixture was refluxed for 6 hours, quenched with 5 ml of saturated
solution
of NH4C1 and then evaporated in vacuo to dryness. The residue was dissolved in
CH2Cl2 and washed with brine; the organic layer was separated, dried over
Na2S04
and evaporated in vacuo to dryness.
The crude product was flash chromatographed on 230-400 mesh silica gel,
eluting
with Et20 containing 0.5% of conc. NH40H and then crystallized from i-PrOH to
yield 0.19 g of the title compound.
C25H22N202
M.P. = 167-169 °C
M.W. = 382.47
Elemental analysis: Calcd. C, 78.52; H, 5.80; N, 7.32;
Found C, 78.49; H, 5.79; N, 7.29.
LR. (KBr): 3360; 1650; 1592 cm-I.
300 MHz 1H-NMR (DMSO-d6): 9.30 (d, IH); 8.31 (d, 2H); 8.13 (d, 1H); 8.10 (s,
IH); 8.03 (d, 1H); 7.81 (dd, 1H); ?.64-7.51 (m,
4H); 7.46 (d, 2H); 7.39 (dd, 2H); 7.29 (dd, 1H);
5.30 (dt, 1H); 4.61 (t, 1H); 3.61-3.41 (m, 2H);
2.11-1.86 (m, 2H).
MS (EI; source 200 °C;70 eV; 200 p.A): 382 (M+.); 337; 232; 204.
EXAMPLE 98
(S)-N-(a-Ethylbenryl~3-(2-dimethylaminoethoxy)-2-phenylquinoline-4
rarboxamide hydrochloride
0.62 g (1.6 mmol) of (S)-N-(a-ethylbenryl)-3-hydroxy-2-phenylquinoline-4-
carboxamide (compound of Ex. 85) were dissolved in 30 ml of dry DMF.
0.58 g (4.0 mmol) of dimethylaminoethylchloride hydrochloride and 0.56 g (4.0
mmol) of K2C03 were added and the reaction mixture was refluxed for 20 hours.
The K2CO3 was filtered off and the mixture was evaporated in vacuo to dryness,
dissolved in AcOEt and washed with H20 and with 20°Xo citric acid. The
aqueous
layer was made alkaline with 2 N NaOH and extracted with EtOAc; the organic
layer
was washed with brine, separated, dried over Na2S04 and evaporated in vacuo to
dryness.
The residue was flash chromatographed on 230-400 mesh silica gel, eluting with
CH2C12/MeOH 98 : 2 containinJ 0.4% of conc. NH40H and then with
CH2C12/MeOH 86 : 10 containing 0.6% of conc. NH40H to yield 85 mg of a crude
product which was dissolved in EtOAc and treated with HCUEt20 to obtain 75 mg
of
CA 02257662 1999-O1-14
WU 95!32948 PCT/EP95/02000
the title compound.
C29H31 N302.HC1
M.P. = 70 °C dec.
M.W. = 490.05
LR. (nujol): 3600; 3100; 1650; 1550 cm-1. .
300 MHz 1H-NMR (DMSO-d6): 10.28 (s br, 1H); 9.50 (d, 1H); 8.10 (d, 1H); 7.96
(dd, 2H); 7.78 (m, 1H); 7.67-7.61 (m, 2H); 7.61-
7.51 (m, 3H); 7.49-7.39 (m, 4H); 7.33 (dd, 1H);
5.08 (dt, 1H); 3.90 (t, 2H); 2.96 (dt, 2H); 2.49 (s,
6H); 1.85 (m, 2H); 0.97 (t, 3H).
MS (FAB POS, thioglycerol matrix, Xe gas, 8 KeV, source 50 °C): 454
(MFi+)
EXAMPLE 99
(S)-N-(a-Ethylbenzyl)-3-acetylamino-2-phenylquinoline-4-carboxamide
0.40 g (1.05 mmol) of (S)-N-(a-ethylbenzyl)-3-amino-2-phenylquinoline-4-
carboxamide (compound of Ex. 69) were heated in 25 ml of acetic anhydride at
70 °C
for 1 hour and then at 100 °C for additional 3 hours.
The reaction mixture was then evaporated in vacuo to dryness and the residue
dissolved in EtOAc; the solution was washed with water, saturated solution of
NaHC03, brine, dried over Na2S04 and evaporated in vacuo to dryness.
The crude product (0.39 g) was purified by silica gel flash column
chromato~aphy,
eluting with a mixture of hexanelEtOAclconc. NH40H, 70 : 30 : 0.5,
respectively, to
afford 0.2 g of a pure compound which was recrystallized from acetone to yield
0.14
g of the title compound.
C27H25N302
M.P. = 268-269 °C
M.W. = 423.52
Elemental analysis: Calcd. C, 76.57; H, 5.95; N, 9.92;
Found C, 76.38; H, 5.98; N, 9.90.
LR. (KBr): 3230; 1670; 1640; 1555; 1525 cm-1.
300 MHz 1H-NMR (DMSO-d6): 9.65 (s, 1H); 9.05 (d, 1H); 8.10 (d, 1H); 7.80 (t,
1H); 7.70-7.50 (m, 4H); 7.45-7.20 (m, 8H); 5.08
(dt, 1H); 1.85 (m, 2H); 1.60 (s, 3H); 0.97 (t, 3H).
MS (EI; source 200 °C;70 eV; 200 ~A): 423 (M+.); 381; 334; 289; 261;
247; 218.
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WO 95!32948
EXAMPLE 100
(-~(S)-N-(a-EthyIbenryl~3-(3-dimethylaminopropoxy)-2-phenylquinoline-4
rarboxamide hydrochloride
1.2 g (3.1 mmol) of (-)-(S)-N-(a-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-
carboxamide (compound of Ex. 85) were dissolved in 15 ml of dry THF.
1.0 g (8.2 mmol) of 3-dimethylaminopropylchlotide, dissolved in 10 ml of Et20,
1.3
g (9.4 mmol) of K2C03 and 0.16 g of KI were added and the reaction mixture was
stirred at room temperature for 30 minutes and then refluzed for 2 hours.
Further 0.77 g (6.3 mmol), 1.0 g (8.2 mmol), 0.6 g (4.9 mmol) and additional
0.6 g
{4.9 mmol) of 3-dimethylaminopropylchloride, dissolved each time in 10 ml of
Et20,
and some KI were added every 12 hours and the reaction refluxed.
The K2C03 was filtered off and the mixture was evaporated in-vacuo to dryness,
dissolved in EtOAc and washed with H20 and with 20% citric acid. The aqueous
layer was made alkaline with 2 N NaOH and extracted with EtOAc; the organic
layer
was washed with brine, separated, dried over Na2S04 and evaporated in-vacuo to
dryness.
The residue was flash chromatographed on 230-400 mesh silica gel, eluting with
CH2C12/MeOH 95: 5 containing 0.5% of conc. NH40H to yield 0.9 g of a crude
product which was dissolved in EtOAc and treated with HCllEt20 to obtain 0.62
g of
the title compound.
C30H33N302-HCl
M.P. = 108°C dec.
M.W. = 504.08
[a]D2° _ - 16.0 (c = 0.5, MeOH)
LR. (KBr): 3400; 3080; 1655; 1545 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 10.55 (s br, 1H); 9.35 (d, 1H); 8.09 (d, 1H); 7.92
(dd, 2H); 7.76 (ddd, 1H); 7.65-7.51 (m, 5H); 7.48-
7.40 (m, 4H); ?.31 (dd, IH); 5.10 {dt, 1H); 3.72-
3.62 (m, 2H); 2.75-2.60 (m, 2H); 2.58 (d, 3I~; 2.56
(d, 3H); 1.90-1.67 (m, 4H); 1.00 (t, 3H).
MS (EI; source 180 °C; 70 V; 200 mA): 467 (M+.); 466; 395; 58.
EXAMPLE 101
(-~(S)-N-(a-Ethylbenzyl)-3-[2-(1-phthaloyl~thoxy]-2-phenylquinoline-4
carboxamide hydrochloride
1.9 ~ (5.0 mmol) of (-)-(S)-N-{a-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-
carboxamide (compound of Ex. 85) were dissolved in 20 ml of dry THF.
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3.8 g (14.9 mmol) .of 2-phthalimidoethylbromide, dissolved in IS ml of THF,
2.0 g
( 14.5 mmol) of K2C03 and 0.25 g of KI were added and the reaction mixture was
stirred at room temperature for 2.5 hours and then refluxed for 2 hours.
1.9 g (7.4 mmol) of 2-phthalimidoethylbromide and some KI were added and the
reaction was refluxed for additional 3.5 hours.
0.5 g (2.0 mmol) of 2-phthalimidoethylbromide and some KI were added again and
the mixture was reffuzed for 5 hours.
The K2C03 was filtered off and the mixture was evaporated in-vacuo to dryness,
dissolved in CH2C12 and washed with H20. The organic Iayer was dried over
Na2S04 and evaporated in-vacuo to dryness.
The residue was flash chromatographed on 23(1-400 mesh silica gel, eluting
with
hexaneBtOAc 80 : 20 containing 0.5% of conc. NH40H and then hezanelEtOAc 60
40 containing 0.5% of conc. NH40H to afford 2.6 g of a purified product which
was
trittlrated with iPr20 to yield 2.5 g of the title compound.
C35H29N304
M.P. = 172-175°C
M.W. = 555.64
[a]D2° _ - 16.3 (c = 0.5, MeOH)
LR. (KBr): 3280; 3060; 2960; 1780; 1715; 1660; 1530 cm-l.
300 MHz 1H-NMR (DMSO-d6): 8 9.27 (d, 1H); 8.03 (d, 1H); 7.92-7.84 {m, 4H);
7.78-7.69 (m, 3H); 7.60-7.53 (m, 2H); 7.46-7.38
(m, 4H); 7.27 (dd, 1H); 7.13-7.04 (m, 3H); 4.96 (dt,
1H); 3.92-3.78 (m, 2H); 3.72-3.55 (m, 2H); 1.78
(dq, 2H); 0.93 (t, 3H).
MS (EI; source 180 °C; 70 V; 200 mA): 555 (M+.), 526, 421, 174.
EXAMPLE 102
(-)-(S)-N-{a-Ethylbenryl)-3-(2-aminoethoxy)-~phenylquinoIine-4-carboxamide
hydrochloride
2.2 g (3.9 mmol) of (-)-{S)-N-(a-ethylbenzyl}-3-[2-(1-phthaloyl~thoxy]-2-
phenyl
quinoline-4-carboxamide hydrochloride (compound of Ex. 101) were dissolved in
150 ml of 96% EtOH and 0.38 ml (7.8 mmol) of hydrazine hydrate were added to
the
boiling solution, which was then refluxed for 4 hours.
Further 0.4 ml (8.2 mmol), 0.2 ml (4.1 mmol), 0.2 ml (4.1 mmol), 0.4 ml (8.2
mmol)
and 0.4 ml (8.2 mmol) of hydrazine hydrate were added every 12 hours and the
reaction mixture was maintained refluxed.
The reaction mixture was then evaporated in-vacuo to dryness, dissolved in 20
ml
HBO, cooled and acidified with 10 ml conc. HCI.
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The mixture was boiled for I hour and cooled; the phthalydrazide was filtered
off.
The aqueous layer was washed with EtOAc and then made alkaline with 2 N NaOH
and extracted with EtOAc; the organic layer was washed with brine, separated,
dried
over Na2S04 and evaporated in-vacuo to dryness.
The residue was flash chromatoaraphed on 230-400 mesh silica gel, eluting with
EtOAc/MeOH 96: 4 containing 1.2% of conc. NH40H to afford a purified product
which was dissolved in EtOAc and treated with HCl/Et20 to yield 1.2 g of the
title
compound.
C27H27N302.HC1
M.P. = 119°C dec.
M.W. = 462.00
(a]DZ° - _ 19.4 (c = 0.5, MeOH)
LR. (KBr): 3400; 3080; 1640; 1545 cm-l.
300 MHz IH-NMR (DMSO-d6): 8 9.45 (d, 1H); 8.09 (d, 1H); 8.00 (dd, IH); 7.94 (s
br, 3H); 7.76 (ddd, 1H); 7.65-7.51 (m, 4H); 7.48-
7.40 (m, 3H); 7.31 (dd, 1H); 5.09 (dt, 1H); 3.83 (t,
2H); 2.?2 (m, 2H); 1.93-1.80 (m, 2H); 0.99 (t, 3H).
MS (FAB POS, thioglycerol matrix; Xe gas, 8 keV; source SO °C): 426
(MH+).
EXAMPLE 103
(+)-(S)-N-(a-Ethylbenzyl)-3-(2-(1-pyrrolidinyl)ethoxy]-2-phenylquinoline-4
carboxamide hydrochloride
2.0 g (5.2 mmol) of (-)-(S)-N-(a-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-
carboxamide (compound of Ex. 85) were dissolved in 25 ml of dry THF.
1.0 g (7.5 mmol) of 2-pyrrolidinoethylchloride and 2.2 g (15.9 mmol) of K2C03
were added and the reaction mixture was stirred at room temperature for 30
rrrinutes
and then retluxed; 1.1 g (8.2 mmol) of 2-pyrrolidinoethylchloride were added
to the
boiling solution which was refluxed overnight.
The K2C03 was filtered off and the mixture was evaporated in-vacuo to dryness,
dissolved in EtOAc and washed with H20 and 20% citric acid. The aqueous layer
was made alkaline with 2 N NaOH and extracted with EtOAc; the organic layer
was
washed with brine, separated, dried over Na2S04 and evaporated in-vacuo to
dryness.
The residue was flash chromato~raphed on 230-400 mesh silica gel, eluting with
CH2C12/MeOH 97: 3 containing 0.5% of conc. NH40H to yield 1.8 g of a purified
product which was dissolved in EtOAc and treated with HCI/Et20 to yield 2.0 g
of
the title compound.
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C31H33N302 . HCl
M.P. = 110-115 °C (dec.)
M.W. = 516.08
[a]DZO _ + 4.5 (c = 0.5, MeOH)
LR. (KBr): 3400; 3080; 1655; 1545 cm-1.
300 MHz 1H-NMR (DMSO-d6): b 10.50 (s br, 1H); 9.50 (d, 1H); 8.10 (d, 1H); 7.96
(dd, 2H); 7.78 (ddd, 1H); 7.68-7.30 (m, lOH); 5.10
(dt, 1H); 3.90 (m, 2H); 3.20 (m, 2H); 3.00 (m, 2H);
2.65 (m, 2H); 1.95-1.65 (m, 6H); 1.94 (t, 3H).
MS (EI; source 180 °C; 70 V; 200 mA): 479 (M+.); 478; 383; 97; 84.
EXAMPLE 104
(-~(S)-N-(a-Ethylbenzyl)-3-(dimethylaminoacetylamino~2-phenylquinoline-4-
carboxamide
1.1 g (2.8 mmol) of (-)-(S)-N-(a-ethylbenzyl)-3-amino-2-phenylquinoline-4-
carboxamide (compound of Ex. 69) were dissolved, under nitrogen atmosphere, in
10
ml of warm toluene. 0.96 g (5.6 mmol) of chloroacetic anhydride, dissolved in
5 ml
of toluene, were dropped and the solution was refluxed for 1 hour.
The reaction mixture was evaporated in-vacuo to dryness, suspended in 10 ml of
CH2Cl2 and dropped in 5 ml of ice-cooled 28% Me2NH/EtOH.
The solution was stirred at room temperature overnight, then 15 ml of 28%
Me2NH/EtOH were added and the reaction mixture was heated at 60 °C in a
purr --
apparatus.
The mixture was evaporated in-vacuo to dryness, dissolved in 20% citric acid
and
washed with EtOAc. The aqueous layer was basified with 2 N NaOH and extracted
with EtOAc; the organic layer was washed with brine, separated, dried over
Na2S04
and evaporated in-vacuo to dryness to afford 1.4 g of the crude product.
This product was triturated with warm i-Pr20 to yield 0.86 g of the title
compound.
C29H341'1402
M.P. = 189-191 °C
M.W. = 466.59
[a]DZO = _ 63.1 (c = 0.5, MeOH)
LR. (KBr): 3230; 3180; 1670; 1630; 1540 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 9.41 (s, 1H); 8.97 (d, 1H), 8.08 (d, 1H); 7.81
(dd,
1H); 7.70-7.59 (m, 4H); 7.49-7.26 (m, 8H); 5.00
(dt, 1H); 2.55 (s, 2H); 1.97 (s, 3H); 1.90-1.65 (m,
2H); 0.93 (t, 3H).
MS (FI; source 180 °C; 70 V; 200 mA): 466 (M+.); 331; 58.
CA 02257662 1999-O1-14
WO 95!32948 PCT/EF95/02000
EXAMPLE 105
N-(a,a-Dimethylbenzyl)-3-hydroay-2-phenylqninoline-4-
carboaamide
2.0 g (7.5 mmol) of 3-hydroxy-2-phenylquinoline-4-carboxylic acid were
dissolved, under nitrogen atmosphere, in 70 ml of dry THF and 30 ml of
CH3 CN.
1.02 g (7.5 mmol) of cumylamine and 1.12 g (8.3 mmol) of N-
hydroxybenzotriazole (HOBT) were added and the reaction mixture was
cooled at -10°C.
1.71 g (8.3 mmol) of DCC, dissolved in 20 ml of CH2C12, were added
dropwise and the solution was kept at -5°- 0°C for 2 hours and
then at
room temperature overnight. The precipitated dicycloheaylurea was
filtered off and the solution evaporated in-uacuo to dryness. The residue
was dissolved in CH2C12 and washed with H20, sat. sol. NaHC03, 5%
citric acid, sat. sol. NaHC03 and brine.
The organic layer was separated, dried over Na2S04 and evaporated in-
uacuo to dryness; the residue was dissolved in 20 ml of CH2C12 and left
overnight. Some more dicyclohexylurea precipitated and was filtered off.
The solution was evaporated in-uacuo to dryness to obtain 1.4 g of a crude
product which was flash chromatographed on 230-400 mesh silica gel,
eluting initially with hexaneIEtOAc 9/1 and then hexanelEtOAc 8/2 to
afford 0.4 g of the purified product which was recrystallized twice from i-
PrOH to yield 0.15 g of the title compound.
C25H22N202
M.P. = 166-169°C dec.
M.W. = 382.47
LR. (nujol): 3200; 1650; 1580; 1535 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 9.56 (s, 1H); 8.92 (s br, 1H); 8.00-7.94 (m,
3H); 7.76 (d br, 1H); 7.63-7.45 (m, 7H); 7.36 (dd;
2H); 7.24 (dd, 1H); 1.72 (s, 6H).
MS (EI; source 180 °C; 70 V; 200 mA): 382 (M+.); 264; 247; 219;
119.
EXAMPLE 106
N-(a,a-Dimethylbenzyl)-3-amino-2-phenyiquinoline-4-carboaamide
2.0 g (7.6 mmol) of 3-amino-2-phenylquinoline-4-carboxylic acid were
dissolved, under nitrogen atmosphere, in 70 ml of dry THF and 30 ml of
CH3CN.
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WO 95/32948 PCT/EP95/02000
1.02 g (7.6 mmol) of cumylamine and 1.12 g (8.3 mmol) of N-
hydroxybenzotriazole (HOBT) were added and the reaction mixture was
cooled at -10°C.
1.72 g (8.3 mmol) of DCC, dissolved in 20 ml of CH2C12, were added
dropwise and the solution was kept at -5°- 0°C for 2 hours and
then at
room temperature overnight. The precipitated dicyclohegylurea was
filtered off and the solution evaporated in-vacuo to dryness. The residue
was dissolved in CH2C12 and washed with H20, sat. sol. NaHC03, 5%
citric acid, sat. sol. NaHC03 and brine.
The organic layer was separated, dried over Na2S04 and evaporated in-
vacuo to dryness; the residue was dissolved in 20 ml of CH2C12 and left
'overnight. Some more dicyclohexylurea precipitated and was filtered off.
The solution was evaporated in-vacuo to dryness to obtain 2.0 g of a crude
product which was flash chromatographed on 230-400 mesh silica gel,
eluting with hexane/EtOAc 6/4 containing 1% of conc. NH40H to afford
0.9 g of the purified product which was recrystallized from hexanelEtOAc
1/1 and then from i-PrOH to yield 0.45 g of the title compound.
C25H23N30
M.P. = 166-168°C
M.W. = 381.48
LR. (nujol): 3460; 3360; 3220; 1667; 1605; 1527 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 9.05 (s, 1H); 7.87 (dd, 1H); 7.74-7.68 (m, 3H);
7.64-7.42 (m, 7H); 7.37 (dd, 2H); 7.24 (dd, 1H);
4.74 (s, 2H); 1.71 (s,6H).
MS (EI; source 180 °C; 70 V; 200 mA): 381 (M+.); 263; 218; 119.
EXAMPLE 107
(-)-(S)-N-(a-Ethylbenzyl)-5-methyl-2-phenylqninoline-4-
carbozamide
0.80 g (3.04 mmol) of 5-methyl-2-phenylquinoline-4-carboxylic and were
dissolved, under nitrogen atmosphere, in 30 ml of dry THF and 12 ml of
CH3CN.
0.43 g (3.20 mmol) of (S)-(-~a-ethylbenzylamine and 0.78 g (5.78 mmol) of
N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was
cooled at -10°C.
0.69 g (3.34 mmol) of DCC, dissolved in 5 ml of CH2C12, were added
dropwise and the solution was kept at -5°- 0°C for 2 hours and
then at
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WO 95!32948 PCT/EP95/02000
room temperature overnight. The precipitated dicyclohexylurea was
filtered off and the solution evaporated in-uacuo to dryness. The residue
was dissolved in CH2Cl2 and washed with H20, sat. sol. NaHC03, 5%
citric acid, sat. sol. NaHC03 and brine.
The organic layer was separated, dried over Na2S04 and evaporated in-
uacuo to dryness; the residue was dissolved in 10 ml of CH2C12 and left
overnight. Some more dicyclohexylurea precipitated and was filtered off.
The solution was evaporated in-vacuo to dryness to obtain L15 g of a
crude product which was flash chromatographed on 230-400 mesh silica
gel, eluting with hexanelEtOAc 6/2 containing 0.5% of conc. NH40H to
a$'ord 0.47 g of the purified product which was recrystallized from i-Pr20
containing some drops of EtOAc to yield 0.36 g of the title compound as a
white powder.
C26H24N20
M.P. = 189-192 °C
M.W. _ 380.49
[a]D~ _ - 3.8 (c = 0.5, MeOH)
LR. (KBr): 3280; 3070; 3020; 1635; 1545 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 9.20 (d, 1H); 8.23 (d, 2H); 7.93 (d, 1H);
7.78 (s, 1H); 7.20-7.70 (m, lOH); 5.00 (dt,
1H); 2.38 (s broad, 3H); 1.70-1.90 (m, 2H);
0.95 (t, 3H).
MS (EI; source 180 °C; 70 V; 200 mA): 380 (M+.); 246; 218.
F~~LE 108
(R,S)-N-[oc-(1-Hydrnayethyl)benzyl]-3-methyl-2-phenylquinoline-4-
carboaamide
Prepared as described in Ex. 1, starting from 11.08 g ( 39.33 mmol) of
crude 3-methyl-2-phenylquinoline-4-carbonylchloride, 4.87 g (32.20 mmol)
of 1-phenyl-2-hydroxypropylamine and 10.33 ml (74.14 mmol) of TEA in
150 ml of a 1:1 mixture of dry CH2C12 and CH3CN.
The precipitated TEA hydrochloride was filtered off and the filtrate
concentrated in-uacuo to dryness; the residue was dissolved in CH2C12
(100 ml) and washed with a sat. sol. of NaHC03, 20 % citric acid and
brine. The organic solution was dried over Na2S04 and evaporated in-
uacuo to dryness to obtain 13.23 g of an oil, which was crystallized from i-
Pr02 ( 100 ml) containing 6 ml of i-PrOH to yield 9.14 g of the title
73
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- . . ,
WO 95!32948 PCT/EP95/02000
compound as an off white solid.
C26H24N202
M.P. = 163-165 °C
M.W. = 396.49
LR. (nujol): 3400; 3260; 1635; 1580 cm-1.
E~X,A1VH'LE 109
(R,S)-N-[a-(Methylcarbonyl)benzyl]-3-methyl-2-phenylqninoline-4-
carbozamide
Prepared as described in Ezample 96, starting from 3.25 g (25.60 mmol) of
ozalyl chloride, 3.88 g (49.66 mmol) of DMSO, 8.2 g (20.68 mmol) of (R,S~
N-[a-( I-hydroxyethyl)benzyl]-3-methyl-2-phenylquinoline-4-carbogamide
(compound of E$. 108) and 15.72 ml (112.76 mmol) of TEA in 230 ml of
dry CH2C12.
The reaction was quenched with 40 ml of H20 and the organic layer
separated and washed with 20% citric acid, sat. sol. NaHC03 and brine.
The organic solution was dried over Na2S04 and evaporated in-vacuo to
dryness to a$'ord 9.4 g of the crude title compound as an oil. This residual
oil was flash chromatographed on 230-400 mesh silica gel, eluting with a
mixture of hezanelethyl acetate 70 : 30 containing 1% of conc. NH40H to
afford 7.7 g of the purified product which was crystallized from a mixture
of EtOAc/hexane 1 : 3 respectively, to yield 6.0 g of the pure title
compound.
C26H22N202
M.P. = 156-158 °C
M.W. = 394.48
LR. (nujol): 3270; 3180; 1735; 1725; 1660; 1630; 1527; 1460 cm-1.
300 MHz 1H-NMR (DMSO-d6): b 9.53 (d, 1H); 8.01 (d, 1H); 7.73 (dd, IH);
7.62-7.35 (m, 12H); 5.97 (d, 1H); 2.30 (s br, 3H);
2.18 {s, 3H).
MS (EI; source 180 °C; 70 V; 200 mA): 394 (M+.); 352; 351; 246; 218;
217.
EXAMPLE lI0
(R,S)-N-[a-(Ethyl)-4-pyridy!methyl]-2-phenylqninoline-4
carbozamide
4.12 g (16_52 mmol) of 2-phenylquinoline-4-carboxylic acid were dissolved,
74
CA 02257662 1999-O1-14
WO 95!32948 PCT/EP95/02000
under nitrogen atmosphere, in 40 ml of dry CH2C12 and 30 ml of THF.
1.50 g (11.01 mmol) of 1-(4-pyridyl~n-propyl amine and 2.23 g (16.52
mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction
mixture was cooled at 0°C.
3.41 g (16.52 mmol) of DCC, dissolved in 26 ml of dry CH2C12, were added
dropwise and the solution was kept at 0°C for 2 hours and then stirred
at
room temperature for 36 hours. The precipitated dicyclohexylurea was
filtezed off and the solution evaporated in-vacuo to dryness. The residue
was dissolved in 100 ml of CH2C12 and washed with H20, 10°Xo K2C03,
5°lo citric acid and brine.
The organic layer was separated, dried over Na2S04 and evaporated in-
vacuo to dryness; the residue was dissolved in 30 ml of CH2C12 and left
overnight. Some more dicyclohexylurea precipitated and was filtered off
The solution was evaporated in-vacuo to dryness to obtain 3.5 g of a crude
product which was recrystallized three times from i-PrOH to yield 0.91 g
of the title compound.
C24H21N30
M.P. = 218-219 °C
M.W. = 367.45
LR. (KBr): 3260; 3064; 1648; 1595; 1545; 1350 cm-1.
300 MHz 1H-NMR (DMSO-d6): 8 9.33 (d, 1H); 8.58 (d, 2H); 8.33 (dd, 2H); 8.15
(d, IH); 8.14 (s, 1H); 8.03 (d, 1H); 7.82 (dd, 1H);
7.66-7.52 (m, 4H); 7.47 (d, 2H); 5.05 (dt, IH); 1.85
(dq, 2H); 1.00 (t, 3H).
MS (EI; source 180 °C; 70 V; 200 mA): 367 (M+.); 338; 232; 204.
EXAMPLE 111
(R,S)-N-[a-(Ethyl)-2-thieny!methyl]-2-phenylquinoline-4
carboaamide
1.40 g (8.00 mmol) of 1-(2-thienyl~n-propyl amine hydrochloride and 2.45
ml (17.60 mmol) of TEA were dissolved, under nitrogen atmosphere, in 50
ml of dry CH2C12 and 30 ml of CH3CN.
2.0 g (8.00 mmol) of 2-phenylquinoline-4-carboxylic acid and 1.30 g (9.60
mmol) of N-hydroxybenzotriazole (HOBT) were added.
2.48 g (12.00 mmol) of DCC, dissolved in 30 ml of dry CH2Cl2, were added
dropwise and the solution was stirred at room temperature for 36 hours.
CA 02257662 1999-O1-14
WO 95132948 PCTIEP95102000
50 mI of 10% HCl were added and the solution stirred for aditional 2
hours. The precipitated dicyclohexylurea was filtered off and the organic
layer washed with 10% citric acid and 10% K2C03.
The organic layer was separated, dried over Na2S04 and evaporated in-
vacuo to dryness. The crude product was flash chromatographed on 230-
400 mesh silica gel, eluting with a mixture of hexanelEtOAc/CH2C12 80
15 : 0.5 to afford 2.0 g of a yellow oil which was crystallized from a
mixture of tolueneJhexane to yield 0.9 g of the pure title compound as
white crystals.
C23H20N20S
M.P. = 134-137 °C
M.W. = 372.49
LR. (KBr): 3230; 3060; 1630; 1590; 1545 cm-I.
300 MHz 1H-NMR (DMSO-d6): 8 9.33 (d, 1H); 8.30 (dd, 2H); 8.15 (d, 1H); 8.13
(d, 1H); 8.08 (s, 1H); 7.84 (ddd, 1H); 7.68-7.51 (m,
4H); 7.44 (dd, 1H); 7.11 (d, 1H); 7.02 (dd, 1H);
5.33 (dt, 1H); 2.10-1.88 (m, 2H); 1.05 (t, 3H).
MS (EI; source 180 °C; 70 V; 200 mA): 372 (M+.); 343; 232; 204.
EXAMPLE I12
(+)-(S)-N-(a-Ethylbenzyl)-3-dimethylaminomethyl-2
phenylquinoline-4-carbozamide hydrochloride
5.60 g (21.27 mmol) of 3-methyl-2-phenylquinoline-4-carboxylic acid were
dissolved in 100 ml of dichloroethane.
7.60 g (42.50 mmol) of N-bromosuccinimide and 0.52 g (2.00 mmol) of
dibenzoyl peroxide were added and the solution refluzed for 24 hours.
The reaction mixture was evaporated in-vacuo to dryness, suspended in
100 ml of 33% Me2NH/EtOH and stirred overnight at room temperature.
The solution was evaporated in-vacuo to dryness, dissolved in 50 ml of
20% K2C03 and evaporated again in-vacuo to dryness. 50 ml of water
were added to the residue and the solution, acidified with 37% HCl, was
evaporated in-vacuo to dryness.
The crude residue and 10.8 ml (77.20 mmol) of TEA were dissolved in 50
ml of CH2C12, 50 ml of THF and 100 ml of CH3CN.
3.00 g (22.20 mmol) of (S)-(-)-a-ethylbenzylamine, 0.78 g (5.78 mmol) of N-
hydroxybenzotriazole (HOBT) and 11.9 g (57.90 mmol) of DCC were added
and the solution was stirred at room temperature overnight.
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WO 95/32948 PCT/EP95/02000
The precipitated dicyclohexylurea was filtered off and the organic layer
evaporated in-vacuo to dryness.
The brown oily residue was dissolved in 100 ml of CHZC12 and the
precipitate was filtered off. The filtrate was extracted three times with
40% citric acid. The acqueous layer, basified with solid K2C03, was
extracted with CH2C12; the organic solution dried over Na2S04 and
evaporated in-vacuo to dryness afforded 10 g of a brown oil.
The crude product was flash chromatographed on 230-400 mesh silica gel,
eluting with a mixture of i-Pr20/CH2Cl2 9 : 1 to afford 2.5 g of a white
solid which was dissolved in toluene and left overnight.
The DCU precipitated was filtered and the solution, treated with
ethanolic HCl, was evaporated in-vacuo to dryness. The crude product was
recrystallized from a mixture of toluenelEtOH to yield 0.7 g of the pure
title compound as colourless crystals.
C28H29N30-HCl
M.P. = 164-167 °C
M.W. = 460.02
[a]D~ _ + 25.3 (c = 1, MeOH)
LR. (KBr): 3440; 3150; 3020; 2560; 2460; 1650; 1540 cm-1.
300 MHz 1H-NMR (DMSO-dg, 353 K): b 9.70 (s br, 1H); 8.10 (d, 1H); 7.85
(dd, 1H); 7.80 (s br, 1H}; 7.70-7.10 (m, 12H);
5.15 (dt, 1H); 4.38-4.20 (m, 2H}; 2.30 (s,
3H); 2.22 (s, 6H); 2.10-1.82 (m, 2H); 1.00 (t,
3H).
MS (EI; source 180 °C; 70 V; 200 mA): 423 (M+.), 380, 288.
EXAMPLE 113
(S)-N-(a-Ethylbenzyl)-3-methyl-7-methozy-2-phenylquinoline-4
carbozamide
Prepared as described in Ex. 1, starting from 1.27 g ( 4.09 mmol) of crude
3-methyl-7-methoxy-2-phenylquinoline-4-carbonylchloride, 0.55 g {4.09
mmol) of (S~(-~a-ethylbenzylamine and 1.71 ml ( 12.27 mmol) of TEA in
24 ml of dry CH2Cl2 and 1 ml of DMF to help solubility. The reaction
mixture was stirred 12 hours at room temperture.
After being concentrated in-vacuo to dryness, the residue was dissolved in
CH2C12 (30 ml) and washed with 10°lo NaHC03, 5% citric acid and
brine.
The organic solution was dried over Na2S04 and evaporated in-vacuo to
dryness to obtain 1.87 g of a crude product, which was flash
chromatographed on 230-400 mesh silica gel, eluting with a mixture of
77
CA 02257662 1999-O1-14
~ ~ i ,
WO 95/32948 PCT/EP95/02000
hexanelEtOAc 70 : 30 to afford 0.350 g of a yellow oil.
C27H26N202
M.W. = 410.51
LR. (KBr): 3240; 2965; 2930; 1635; 1535; 1220 cm-I.
FXAr~LE 114
(S)-N-(oc-Ethylbenzyl)-&amino-5-methyl-2-phenylquinoline-4-
carboaamide . _
0.75 g (2.64 mmol) of 3-amino-5-methyl-2-phenylquinoline-4-carboxylic
and were dissolved, under nitrogen atmosphere, in 30 ml of dry THF and
ml of CH3CN.
0.38 g (2.83 mmol) of (S)-(-~a-ethylbenzylamine and 0.69 g (5.I8 mmol) of
N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was
cooled at -10°C.
0.61 g (2.97 mmol) of DCC, dissolved in 5 ml of CH2C12, were added .
dropwise and the solution was kept at -5°- 0°C for 2 hours,
heated at 50 °C
for 4 hours and then left at room temperature overnight.
The precipitated dicyclohexylurea was filtered off and the solution
evaporated in-vacuo to dryness: The residue was dissolved in CH2C12 and
washed with H20, sat. sol. NaHC03, 5% citric acid, sat. sol. NaHC03 and
brine.
The organic layer was separated, dried over Na2S04 and evaporated in-
vacuo to dryness; the residue was dissolved in 10 ml of CH2C12 and left
overnight. Some more dicyclohexylurea precipitated and was filtered off.
The solution was evaporated in-vdcuo to dryness to obtain 0.86 g of a
crude product which was flash chromatographed on 230-400 mesh silica
gel, eluting with CH2C12/MeOH/conc. NH40H, 90 : 10 : 0.5 respectively,
to afford 0.41 g of the title compound as an oil.
C26H25N30
M.W. = 395.50
LR. (I~r): 3480; 3390; 3230; 3020; 1635; 1615; 1545 cm-I.
EXAMPLE 115
(S)-N-(oc-Ethylbenzyl)-3-methoay-5-methyl-2-phenylquinoline-4
carboaamide
1.29 g (4.40 mmol) of 3-methoxy-5-methyl-2-phenylquinoline-4-carboxylic
78
CA 02257662 1999-O1-14
WO 95!32948 PCT/EP95/02000
acid were dissolved, under nitrogen atmosphere, in 40 ml of dry THF and
20 ml of CH3CN.
0.63 g (4.62 mmol) of (S)-(-~a-ethylbenzylamine and 1.13 g (8.36 mmol) of
N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was
cooled at -10°C.
1.0 g (4.84 mmol) of DCC, dissolved in 5 ml of CH2C12, were added
dropwise and the solution was kept at -5°- 0°C for 2 hours,
heated at 50 °C
for 4 hours and then Ieft at room temperature overnight.
The precipitated dicyclohexylurea was filtered off and the solution
evaporated in-uacuo to dryness. The residue was dissolved in CH2CI2 and
washed with H20, sat. sol. NaHC03, 5% citric acid, sat. sol. NaHC03 and
brine.
The organic layer was separated, dried over Na2S04 and evaporated in-
uacuo to dryness; the residue was dissolved in 20 ml of CH2C12 and left
overnight. Some more dicyclohexylurea precipitated and was filtered off.
The solution was evaporated in-uacuo to dryness to obtain 2.45 g of a
crude product which was flash chromatographed on 230-400 mesh silica
gel, eluting with hexane/EtOAc 7 : 2 containing 0.5% of conc. NH40H, to
afford 0.28 g of the title compound as an oil.
C27H26N2~2
M.W. = 410.52
LR. (KBr): 3270; 3020; 1635; 1535 cm-1.
79
CA 02257662 1999-O1-14
WO 95!32948 PCT/EP95102000
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