Note: Descriptions are shown in the official language in which they were submitted.
1341 161
The invention relates to quinolone- and naphthyri-
donecarboxylic acid derivatives which are substituted
in the 7-position by a cyclic amine radical which carries
a quaternary carbon atom, processes for their preparation,
and antibacterial agents and feed additives containing
them.
It has been fomnd that quinolone- and naphthyri-
donecarboxylic acid derivatives of the formula (I>
R3 O
OOR2 (I)
R4~~~N
R1
in which
~? 0
R1 stands for methyl, ethyl, propyl, isopropyl,
cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoro-
ethyl, methoxy, amino, methylamino, dimethyl-
amino, ethylamino,
R2 stands for hydrogen, alkyl having 1 to 4
carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-
methyl,
R3 stands for hydrogen or amino,
~'.5 R4 stands for a radical of the for~aula
X1
(CH~)~~(CHZ)h-Y (CH2)P~O
~N~~(CH2)m ~N~(CH2)m
.'s 0
X2
CHZ ~~X3
'i~(CH2)m
Le A 25 727
- 1 -
1341 161
wherein
p stands for 0, 1 or 2,
m stands for 1 or 2, where p + m together can be
1, Z or 3,
n stands for 1 or 2,
R'
if stands for N' , OR, SR,
. R"
R'
X~ stands for IV\ , OR, SR, halogen, CN, CONH2,
R'o
COOH or C~-C4-alkyl,
X2 and X3 can be identical or different and stand
for oxygen, sulphur, NH or N-CH3,
'IS R stands for hydrogen, C~-C3-alkyl or C~-C3-
acyl,
R' stands for Hydrogen, C~-C3-alkyl, allyl or~
propargyl and
R" stands for hydrogen, C~-C3-alkyl or C3-C6-
20 cycloalkyl,
where
R' + R" together can also denote the groups
-CH2CH2-0-CH2CH2- or -(CH2)k-, in which
k can stand for 3, 4 or 5,
where 3-amino-3-methyl-1-pyrrolidinyl is excluded
for R4, and
A stands for N or C-R5,
wherein
RS stands for hydrogen, halogen such as fluorine
or chlorine, methyl, cyano or vitro,
23189-6872
1 341 16'!
and their pharmaceut:a.cally utilizable hydrates and acid addi-
tion salts and also t~Y~e~ alkali metal salts, alkaline earth
metal salts, silver salts and guanidinium salts of the under-
lying carboxylic acidic have a high antibacterial action, in
particular in the gram--positive range.
In a preferred group of compounds if m=1 then p is
other than 1 when X1 i.s C1 - C4 alkyl.
They are therefore suitable as active compounds for
human and veterinary medicine, where the treatment of fish for
the therapy or proph,ylaxis of bacterial infections is also to
be counted as veterin<~ry medicine. ~Jses of such compounds for
such treatments and commercial packages comprising compounds
of the invention with :instructions for such uses are further
aspects of the invention.
Preferred compounds of the formula (I) are those in
which
R1 stands for ethyl, isopropyl, cyclopropyl, vinyl,
2-hydoxyethy:l, 2-fluoroethyl, amino, methylamino,
R2 stands for hydrogen, alkyl having 1 to 3 carbon
atoms or (~--methyl-2-oxo-1,3-dioxol-4-yl)-methyl,
R3 stands for hydrogen or amino,
R4 stands for a radical of the formula
_ 3 _
23189-6872
1 341 161
X~ 0
(CH2)P-.-~~(CHZ)n-r (CH2)P~
~N,.(CH2)m ~N/(CHq)m
X ~1
(CH2 P~_X3
/(CHy)m
N
wherein
p stands for 0,1 or 2,
m stands for 1 or 2, where p + m together can be 1,
2 or 3,
n stands for 1 or 2,
- 3a -
a
E:. 23189-6872
1341 161
R'
Y stands for N ~ , OR,
\ R"
R'
X1 stands for N ~ , OR, fluorine, chlorine or
C1-C2-alkyl,
X2 and X3 can be identical or different and
stand for oxylgen, sulphur or N-CH3,
1D R stands for hydrogen, C1-C2-alkyl or acetyl,
R' stands for hydrogen or C1-C2-alkyl, and
R" stands for hydrogen or C1-C2-alkyl,
where
R' + R" together also denote the groups
-CH2CH2-0-CH2CH2- or -(CH2)k, in which k can
stand for 3, 4 or 5,
and
A stands for IN or C-R5,
wherein
RS stands for hydrogen, halogen such as fluorine
or chlorine or methyl
and their pharmaceutically utilizable hydrates and acid
addition salts and also the alkali metal salts, alkaline
earth metal salts, silver salts and guanidinium salts.
Particularly preferred compounds of the formula
(I) are those in which
R1 stands for ethyl, isopropyl, cyclopropyl,
vinyl, 2-hydroxyethyl, 2-fluoroethyl, amino,
methylamino,
R2 stands for hydrogen or alkyl having 1 or 2
carbon atoms,
Le A 25 727
- 4 -
1341 1fi1
R3 stands for hydrogen,
R4 stands for a radical of the formula
x~
(CH2)P~(CH2)n-Y (CHZ)p l
~N~~(CH2')m ~N~(CH2)m
(CH2 ~~X3
i~(CH2)m
wherein
p stands for 0, 1 ar 2,
m stands for 1 or 2, where p + m together can
be
1, 2 or ,
3
n stands for 1,
R'
Y t f ~
d
s or N
an , OR or hydrogen,
s
2 0 ~R ~~
R'
X1 stands for N ~ , OR, chlorine or methyl,
R"
X2 and can be identical or different and
X3
st and oxy gen or N-CH3,
for
R stands for hydrogen or methyl,
R' stands for hydrogen or methyl,
R" stands for hydrogen or methyl and
and
A stands for N or C-R5
,
vherein
R5 stands for hydrogen, halogen, such as
fluorine or. chlorine
Le A 25 727
- 5 -
~'.v.
1341 161
and their pharmaceutically utilizable hydrates and acid addition
salts and also the alkali metal salts, alkaline earth metal
salts, silver salts and guanidinium salts.
A preferred group of compounds comprises those wherein
R1 represents cyclopropyl,
R2 and R3 represent hydrogen,
p and m stand for 1 or 2
n stands for 1,
Y represents OH, NH2, NH(CH3), NH(C2H5), N(CH3)2'
NH(~ ) or NH ((CH3)~.C-0-CO),
X~1 represents OH, CH3 or OCH3,
and X2 and X3 each represent oxygen.
Furthermore, it has been found that the compounds of
the formula (I) are obtained when compounds of the formula (II)
R3 0
COOR2 ~ (II)
Z ~J1 hl
~1
in which
Z stands for fluorine or chlorine and
R1, R2, R3 and A have the abovementioned meaning, are
reacted with compounds of the formula (III)
R4-H (III)
in which
R4 has the abovementioned meaning,
if appropriate in the presence of acid entrainers.
6
.,.,
Compounds of the structure (Ia)
R3 0
COORZ (Ia)
(CHZ)m-N
3~~ ( CH
2 )p
in which
R1, R2, R3, A, X2, X3, m and p have the abovementioned
meaning,
can also be prepared by reaction of a compound of the formula
(IV)
6a
1341 161
R3 0
COOR2
tCH2)m-N ~A I N I (IV)
°~t cH2 ~,.J ~ 1
R
S
in which
R 1, R2, R3, p,. m and 1 have the above-
mentioned meaning,
with a compound of the formula (V)
H-X2-CH2-CIH2-X3-H (V)
in which
X2 and X3 have the abovementioned meaning.
If, for example, 8-chloro-1-cyclopropyl-6,7-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and
3-ethylaminomethyl-3-Ihydroxy-.pyrrolidine are used as
starting substances, then the course of the reaction can
be represented by the following equation:
OOH C2H5-NN-CH NH base
1 H ~ - H--------..
30 C2H5-NH-CH2
HO ~~
The compounds of the formula (II) used as start-
ing substances are known or can be prepared by known
methods. Examples which may be mentioned are:
Le A 25 727
- 7 -
1341 161
7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid (German Patent Application
3,142,854),
1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid (European Patent Application 113,091),
8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid (German Patent Application
3,420,743),
1-cyclopropyl-6,7,8-t:rifluoro-1,4-dihydro-4-oxo-3-quino-
linecarboxylic acid (German Patent Application 3,318,145),
1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-
quinolinecarboxylic aicid,
6,7-difluoro-1-ethyl-~1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid,
7-chloro-6-fluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid,
7-chloro-6-fluoro-1,4.-dihydro-1-(2-hydroxyethyl)-4-oxo-
3-quinolinecarboxylic acid,
1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-8-vitro-4-
oxo-3-quinolinecarboxylic acid,
6,7-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid,
6,7-difluoro-1,4-dihydro-1-methoxy-4-oxo-3-quinoline-
carboxylic acid,
6,7-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quino-
linecarboxylic acid,
6,7-difluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinoline-
carboxylic acid,
6,7-difluoro-1-(4-fluoro-phenyl)-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid,
6,7-difluoro-1-(3,4-difluoro-phenyl)-1,4-dihydro-4-oxo-
3-quinolinecarboxylic acid,
7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid,
ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo
3-quino-linecarboxylate (German Patent Application
Le A 25 727
_ g _
1341 161
3,318,145),
9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-
C1,2,3-deJC1,47benzoa;acine-6-carboxylic acid (European
Patent Application 4T,005),
8,9-difluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzoCi,j)-
quinolicine-2-carboxylic acid,
7-chloro-6-fluoro-1-phenyl-1,4-dihydro-4-oxo-1,8-naphth-
yridine-3-carboxylic acid (European Patent Application
153,580>,
7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic acid (European Patent
Application 153,580),.
6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quino-
linecarboxylic acid (German Patent Application 3,409,922),
1-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid (German Patent Application 3,409,922),
6,7,8-trifluoro-1,4-clihydro-1-dimethylamino-4-oxo-3-
quinolinecarboxylic acid (German Patent Application
3,409,922>,
7-chloro-6-fluoro-1,4,-dihydro-8-vitro-4-oxo-1-phenyl-3-
quinolinecarboxylic acid,
7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-8-nitro-
4-oxo-3-quinolinecarboxylic acid,
6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-8-methyl-4-
oxo-3-quinolinecarbox:ylic acid,
6-chloro-7-fluoro-1-(4-fluorophenyl>-1,4-dihydro-4-oxo-
3-quinolinecarboxylic acid (European Patent Application
131,839),
6-chloro-7-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-
oxo-3-quinolinecarbox:ylic acid (European Patent Applica-
tion 131,839),
6,7,8-trifluoro-1-(4-~fluorophenyl)-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid (European Patent Application
154,780),
6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-
3-quinolinecarboxylic acid (European Patent Application
Le A 25 727
- 9 -
. ~ 1341 161
154,780),
6,7,8-trifluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinoline-
carboxylic acid (European Patent Application 154,780),
7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphth-
yridine-3-carboxylic acid,,
6,7-difluoro-1,4-dil,ydro-4-oxo-1-vinyl-3-quinoline-
carboxylic acid.
The compounds of the formula (III) used as starting compounds are
in some cases new and therefore an embodiment of the present invention.
Their preparation can be carried out by various
processes:
1. Ring-opening to form the hydroxyamines (3) is
carried out by reaction of the spiro-oxiranes protected
on the nitrogen (1> I:J. Med. Chem. 30, 222 (1987); US-P
4,508,724; EP 189,3707 with amines (2). Elimination of
the protective group yields starting compounds of the
formula (IIIa):
0 OH ,R'
t CH2 ) p ~ ,,R' ( CHZ ) p i CH2-N~., '
l
~N~(CH2)m f HN''R.. ~N~(CH2)m
8 B
(1) t2) t3)
B = C00-hlkyl, C:H2C6H5
~H ~R. ..
t CH2 ) p~CH2-N~..
~N~tCH2)m
H
(IIIa)
2. The cyclization of the succinic acid ester (4)
CTetrahedron Letters 46, 4561 (1973)7 with benzylamine
yields the alkyl 1-be~nzyl-3-hydroxy-5-oxo-pyrrolidine-3-
carboxylate (5) which, after reaction with an amine (2),
reacts to give the amide (6). Subsequent reduction with
LiAlH4 and hydrogenolytic elimination of the benzyl
Le A 25 727
- 10 -
1341 161
group yields starting compounds of the formula (IIIb):
NH2
Alkyl-0-C0~~\/~C:00-Alkyl
0
(4)
OH
00-Alkyl
~ (2)
N~
(5)
OH ,R' OH ,R'
N
Co N~.,
N/ N
_-. .. H
i
(6) (IIIb)
3. Reaction of the (1-benzyl-3-hydroxy-2,5-dioxo-
pyrrolidin-3-yl)-acetic acid (7) CGazz. Chim. Ital. 24,
226 (1984)J to give the amide (8) and subsequent reduc-
tion using LiAlH4 and elimination of the benzyl group
yields starting compounds of the formula (IIIc):
OH OH ,R'
_ 0-N
COON ~'R"
N ___.. N 0 ~ _--.
(~) (e)
' OH ,R'
N
H
Le A 25 727 (IIIc)
- 11 _
1341 161
4. 3-Hydroxy-3-methyl-pyrrolidine can be prepared
by LiAlH4 reduction of 4-hydroxy-4-methyl-pyrrolidin-2-
one CZh. Org. Khim. 14, 7, p. 1420 (1978)7 or by de-
benzylation of 1-benzyl-3-hydroxy-3-methyl-pyrrolidine
(EP 132,845).
5. Starting from cyclic oxoamines (9) which are
blocked by a protective group on the nitrogen, starting
compounds of the formulae (IIId), (IIIe) and (IIIf) can
be synthesized CActa Chem. Scand. 8 34, 319 (1980)7.
OH OH
(CH2~~ CH3N02 (CH2)p~~02 (CH2 ~~~NHZ
~N~~(CH2)m ~N~~(CH2)m ~. -~. '''~N~(CH2)m
N
B B
(9) (10) / llIId)
HCN or
(I:H3)3 SiCN
B = C00-lllkyl,
CH2-C6H5
i OH
2 0 ( CH2 )p~N
~N~~(CH2)m
B
~2
NHZ
(CH2)~OOH (CH2 H
~ [' ~ ~ -'
\Ni(CH ) ~N~(CH )
ICH2)p~N 2 m H 2 n
~N~I(CH2)m 8
g (13) (IIIe)
(12)
(CHi) NH2
~N~(CH2)m
H
(IIIf)
a 9c 777
- 12 _
1341 16'I '
6. The hydroxy group of the hydroxyamines (IIIa) -
(IIIf) can be alkylated or halogenated.
7. Ketals, thioketals or aminals can be prepared
from the cyclic oxoamines (9) CHelv. Chim. Acta 50, 1289
(1967)7.
By reaction of the spiro-oxiranes protected on
the nitrogen (1) with trimethylsilyl cyanide CJ. Amer.
Chem. Soc. 104, 5849 (1982>J, the isonitriles (14) can be
prepared which can be reacted by hydrolyzing and eliminat-
ing the protective gra~up to give the starting compounds
of the formula (IIIg):
(CH2)p
+ (CN3)3 SiCN -
~N~(CH2)m
B
(1)
NH2
( CHZ ~~~OH
N ~~t', IC
(CH2~~~OSi((:H3)3 -' Ni(CH )
2 m
i~(CH2)m
H
B
(14) (IIIp)
Examples of starting compounds of the formula
(III) which may be mentioned are the following compounds,
where chiral compound!. can be employed both as racemates
as well as pure enantiomeric substances:
3-aminomethyl-3-hydroxypyrrolidine,
3-acetylaminomethyl-3-hydroxypyrrolidine,
3-tert.-butoxycarbonyllaminomethyl-3-hydroxypyrrolidine,
3-hydroxy-3-methylaminomethylpyrrolidine,
3-ethylaminomethyl-3-hydroxypyrrolidine,
3-hydroxy-3-propylaminomethylpyrrolidine,
3-ethylaminomethyl-3-methoxypyrrolidine,
Le A 25 727
- 13 -
a
1 341 161
3-aminomethyl-3-fluoropyrrolidine,
3-aminomethyl-3-chloropyrrolidine,
3-fluoro-3-methylaminomethylpyrrolidine,
3-chloro-3-methylaminomethylpyrrolidine,
3-ethylaminomethyl-3-:Eluoropyrrolidine,
3-chloro-3-ethylaminomethylpyrrolidine,
3-hydroxy-3-methylpyrrolidine,
3-hydroxy-3-methoxymei:hylpyrrolidine,
3-methoxy-3-methylaminomethylpyrrolidine,
3-dimethylaminomethyl~-3-fluoropyrrolidine,
- 3-chloro-3-dimethylaminomethylpyrrolidine,
3-fluoromethyl-3-aminopyrrolidine,
3-ethoxy-3-ethylaminomethylpyrrolidine,
3-chloro-3-ethylaminomethylpyrrolidine,
3-ethylaminomethyl-3-~'luoropyrrolidine,
3-ethylaminomethyl-3-methylpyrrolidine,
3-ethylaminomethyl-3-mercaptopyrrolidine,
3-ethylaminomethyl-3-methylthiopyrrolidine,
3-acetoxy-3-ethylaminomethylpyrrolidine,
3-dimethylaminomethyl--3-hydroxypyrrolidine,
3-hydroxy-3-pyrrolidinomethylpyrrolidine, _
3-hydroxy-3-morpholinomethylpyrrolidine,
3-amino-3-ethylaminome~thylpyrrolidine,
3-acetylamino-3-ethylaminomethylpyrrolidine,
3-ethylaminomethyl-3-methylaminopyrrolidine,
3-dimethylamino-3-ethylaminomethylpyrrolidine,
3-amino-3-hydroxymethylpyrrolidine, ~ _ _
3-acetylamin.o-3-hydrox;ymethylpyrrolidine,
3-amino-3-methoxymethylpyrrolidine,
3-tert.-butoxycarbonylamino-3-methoxymethylpyrrolidine,
3-amino-3-methylthiome~thylpyrrolidine,
3-amino-3-mercaptomethylpyrrolidine,
3-cyclopropylaminomethyl-3-hydroxypyrrolidine,
3-isopropylaminomethyl-3-hydroxypyrrolidine,
1,4-dioxa-7-azaspiroC4..4Jnonane,
1-oxa-4,7-diazaspiroC4.4Jnonane,
4-methyl-1-oxa-4,7-diazaspiroC4.4Jnonane,
1-thia-4,7-diazaspiroC4.4Jnonane,
1,4,7-triazaspiroC4.4Jnonane,
1,4-dimethyl-1,4,7-triazaspiroC4.4Jnonane.
Le A 25 727 - 14 -
1341 161
The reaction of (II) with (III) is preferably
performed in a diluent such as dimethyl sulphoxide, N,N- '
dimethylformamide, hexamethylphosphoric triamide, sulpho-
lane, water, an alcohol such as methanol, ethanol, n- _
propanol, isopropanol, glycol monomethyl ether, aceto-
nitrile or pyridine. Mixtures of these diluents can
likewise be used.
All customary inorganic and organic acid-binding
agents can be used as acid binders. These preferably
include the alkali metal hydroxides, alkali metal car-
bonates, sodium hydride, organic amines and amidines.
Those which may be mentioned individually as being parti-
cularly suitable are: triethylamine, 1,4-diazabicyclo-
C2,2,2Joctane (DAeCO>, 1,8-diazabicycloC5,4,OJundec-7-ene
(O8U) or excess amine (III).
The reaction temperatures can be varied within a
relatively wide range. In general, the reaction is
carried out between about 20 and 200°C, preferably bet-
ween 80 and 180°C.
The reaction can be carried out at atmospheric
pressure, but also at elevated pressure. In general, the
reaction is carried out at pressures between about 1 and
about 100 bar, preferably between 1 and 10 bar.
When carrying out the process according to the
invention by method A, 1 to 15 moles, preferably 1 to 6
moles, of the amine (III) are employed per mole of car-
boxylic acid (II).
In addition to the compounds shown in the
examples, t+~e following may be mentioned individually as
.30 new active compounds:
9-fluoro-2,3-dihydro-10-(3-hydroxy-3-methylaminomethyl-
1-pyrrolidinyl)-3-methyl-7-oxo-7H-pyridoC1,2,3-deJCl,4J-
benzoxacine-6-carboxylic acid,
8-(3-ethylaminomethyl-3-hydroxy-1-pyrrolidinyl)-9-fluoro-
:35 6,7-dihydro-5-methyl-1-oxo-1H,SH-benzoCi,jJquinolicine-
2-carboxylic acid,
and furthermore the compounds shown in the following
table.
Le A 25 727 - 15 -
1341 161
Z.
a
- . . . . .
U
Z
Z
~r~
x
U
N
c"~ Z
S Z Z S = Z Z
N
S
O
O
U
O
O Z C = Z
_ N U
r7 ~ S I Z U N Z s
N V
a
s s . a
N
U
.r N r) ~f tff ~0 A
Z
Le A 25 727
- 16 -
1341 1fi1
x
U Z U U U Z U
i
i Z-
Z
et
Z N O - ~ - ~
N O x x
x U
Z Z
Z o
i
r~ x
x N
U U
N
x = x x z x x x
x
x x x x x N
U
N
\ / ~. ~ . . U
"" Z \ /
p. p .. N Cf e!
., ., ~.n .m'
Z
Le A 25 727
- 17 -
1341 161
z
z
z
Q v
N O
Z Z - O N O
U N Z Z t"7
Z U U U
Z
Z /~ Z
N f'7 f~ N
U S Z Z
U U N
U
M
S S Z Z Z Z Z Z
ciV Q~~i = Z S Z Z
_U _
N
N N
S Z
U U
s s
~ If9 ~0 t~ CD 0' O ., N
L .~ .r on .w .-i N N N
Z
Le A 25 727
- 18 -
X341 161
N O Z e'~
E Z t'7 N Ls. U S
S U Z Z . . . ~ U
U U
t
Z 2 Z
Z Z
i
Z
x x N
N N U
U U
S Z Z S Z S Z Z S
Z Z Z Z Z Z Z Z
N
S
t . s
c~ mn .o c. ao o, o
N N N N N N N F7
Z
Le A 25 727
- 19 -
I ~
Image
-20-
Image
- 21 -
1341 161
The compounds according to the invention show,
combined with low toxicity, a broad antibacterial spectrum
against gram-positives and gram-negative bacteria, in par-
ticular against Enterobacteriaceae; above all also against
those which are resistant to various antibiotics, such
as, for example, peniicillins, cephalosporins, aminoglyco-
sides, sulphonamides and tetracyclines.
These useful properties facilitate their use as
chemotherapeutic actiive compounds in medicine and also
as substances for then preservation of inorganic and
organic materials, in particular of organic materials of
all types, for example polymers, lubricants, dyes, fibres,
leather, paper and wood, and of foodstuffs and water.
The compounds. according to the invention are act-
ive against a very wide spectrum of microorganisms. Gram-
negative and gram-positive bacteria and bacteria-like
microorganisms can beg controlled with their aid, and the
diseases produced by these pathogens can also be prevented,
improved and/or cured.
The compounds. according to the invention are parti-
cularly active against bacteria and bacteria-like micro-
organisms. They are therefore particularly well suited in
human and veterinary medicine for the prophylaxis and
chemotherapy of local and systemic infections which are
produced by these pathogens.
For example, local and/or systemic diseases which
are caused by the following pathogens or by mixtures of
the following pathogens can be treated and/or prevented:
gram-positive cocci, for example staphylococci (Staph.
aureus, Staph. epidermidis) and streptococci (Street. aga-
lactiae, Street. faecalis, Street. pneumoniae, Street.
pyogenes); gram-negative cocci (Neisseria gonorrhoeae) and
also gram-negative rods such as Enterobacteriaceae, for
example Escherichia coli, Haemophilus influenzae, Citro-
bacter (Citrob. freundii, Citrob. divernis), Salmonella
and Shigella; furthermore Klebsiella (Klebs. pneumoniae,
Le A 25 727
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Klebs. oxytoca), Enterrobacter (Ent. aerogenes, Ent. agglo-
merans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr.
mirabilis, Pr. rettge~ri, Pr. vulgaris), Providencia,
Yersinia, and also the order Acinetobacter. Moreover,
the antibacterial sperctrum comprises the order Pseudomonas
(Ps. aeruginosa, Ps. maltophilia) and also strictly anae-
robic bacteria such as, for example, eacteroides fragilis,
representatives of the order Peptococcus, Peptostrepto-
coccus and also the order Clostridium; furthermore myco-
plasma (M. pneumoniaer, M. hominis, M. urealyticum> and also
mycobacteria, for example Mycobacterium tuberculosis.
The above enumeration of pathogens is merely by
way of example and in no way to be conceived as limiting.
Examples of diseases which may be caused by the said
pathogens or mixed infections and which may be prevented,
improved or cured by the compounds according to the in-
vention which may be mentioned are: infectious diseases in
humans, such as, for example, otitis, pharyngitis, pneu-
monia, peritonitis, p~yelonephritis, cystitis, endocardi-
tis, systemic infections, bronchitis (acute, chronic>,
septic infections, diseases of the upper airways, diffuse
panbronchiolitis, pulmonary emphysema, dysentery, enter-
itis, hepatic abscesses, urethritis, prostatitis, epididy-
mitis, gastrointestinal infections, bone and joint infec-
tions, cystic fibrosis, skin infections, post-operative
wound infections, abscesses, phlegmon, wound infections,
infected burns, scalds, infections in the oral region,
infections after dental operations, osteomyelitis, septic
arthritis, cholecystitis, peritonitis with appendicitis,
cholangitis, intra-abdominal abscesses, pancreatitis,
sinusitis, mastoiditis, mastitis, tonsillitis, typhus,
meningitis and infections of the nervous systems, sal-
pingitis, endometritis, genital infections, pelveoperi-
tonitis and eye infections.
In addition to humans, bacterial infections can
also be treated in other species. Examples which may be
l.e A 25 727
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mentioned are:
pig: coli-diarrhoea, enterotoxaemia, sepsis, dysentery,
salmonellosis, mastitis-metritis-agalactia syndrome,
mastitis; ruminants (cow, sheep, goat): diarrhoea, sepsis,
bronchopneumonia, salmonellosis, pasteurellosis,
mycoplasmosis, genital infections;
horse: bronchopneumonias, joint-ill, puerperal and post-
puerperal infections, salmonellosis;
dog and cat; bronchopneumonia, diarrhoea, dermatitis,
otitis, urinary tract infections, prostatitis;
poultry (hen, turkey, quail, pigeon, ornamental birds and
others): mycoplasmosis, E. coli infections, chronic airway
diseases, salmonellosis, pasteurellosis, psittacosis.
Bacterial diseases in the rearing and keeping of
productive and ornamental fish can likewise be treated,
where the antibacterial spectrum is widened beyond the
previously mentioned pathogens to further pathogens such
as, for example, Pasteurel.la, Rucella, Campylobacter,
Listeria, Erysipelothrix, Corynebacteria, Borrelia, Trepo-
nema, Nocardia, Rickettsia, Yersinia and Aeromonas,
Edwardsiella and Vibria.
The present 'invention includes pharmaceutical pre-
parations which contain one or more according to the
invention or which consist of one or more active
compounds according i:o the invention in addition to non-
toxic, inert pharmaceautically suitable excipients and
processes for the production of these preparations.
The present ~'invention also includes pharmaceuti-
cal preparations in dosage units. This means that the
preparations are in the form of individual portions, for
example tablets, dragees, capsules, pills, suppositories
and ampoules, whose active compound content corresponds
to a fraction or a multiple of an individual dose. The
dosage units may contain, for example, 1, 2, 3 or 4
individual doses or 1/2, 1/3 or 1/4 of an individual dose.
An individual dose preferably contains the amount of
Le A 25 727
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141 161
active compound which is administered in one application
and which usually corresponds to a whole, a half, a third
or a quarter of a daily dose.
Non-toxic, inert pharmaceutically suitable
excipients are taken to mean solid, semi-solid or liquid
diluents, fillers or formulation auxiliaries of any type.
Preferred pharmaceutical preparations which may be
mentioned are tablets, dragees, capsules, pills, granules,
suppositories, solutilons, suspensions and emulsions,
pastes, ointments, gels, creams, lotions, powders or sprays.
Tablets, dragees, capsules, pills and granules may
contain the active compounds) in addition to the custom-
ary excipients, such as (a) fillers and extenders, for
example starches, lactose, sucrose, glucose, mannitol and
silica, (b) binders, for example carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidone, (c) humectants,
for example glycerol,, (d) disintegrants, for example agar-
agar, calcium carbonate and sodium carbonate, (e) solu-
tion retardants, for example paraffin and (f> absorption
accelerators, for example quaternary ammonium compounds,
(g) wetting agents, for example cetyl alcohol, glycerol
monostearate, (h) adsorption agents, for example kaolin
and bentonite and (i) lubricants, for example talc, cal-
cium stearate and magnesium stearate and solid polyethy-
lene glycols or mixtures of the substances mentioned
under (a) to (i).
The tablets, dragees, capsules, pills and gran-
ules may be provided with the customary coatings and
shells containing, if appropriate, opacifying agents and
can be so composed that they release the active com-
pound(s), if appropriate with a delay, only or preferably
in a certain part of the intestinal tract, in which case,
for example, polymeric substances and waxes can be used
as embedding materials.
If appropriate, the active compounds) may also
be present in micro-encapsulated form with one or more
Le A 25 727
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1341 161
of the abovementioned excipients.
In addition to the active compounds>, supposi-
tories may contain the customary water-soluble or water-
insoluble excipients,, for example polyethylene glycols,
fats, for example cocoa fat and higher esters (for
example C14-alcohol with C16-fatty acid) or mixtures
of these substances.
Ointments, pastes, creams and gels may contain
the customary excipients in addition to the active com-
pound(s), for example animal and vegetable fats, waxes,
paraffins, starch, tragacanth, cellulose derivatives,
polyethylene glycols,, silicones, bentonites, silica, talc
and zinc oxide or mixtures of these substances.
Powders and :;prays may contain the customary
excipients in addition to the active compounds>, for
example lactose, talc;, silica, aluminium hydroxide,
calcium silicate and polyamide powder or mixtures of
these substances. Sprays may additionally contain the
customary propellants., for example chlorofluorohydro-
carbons.
Solutions and emulsions may contain the cust-
omary excipients, such as solvents, solubilizers and emul-
sifiers, for example water, ethyl alcohol, isopropyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils, in particular cottonseed oil,
groundnut oil, maize germ oil, olive oil, castor oil and
sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of
sorbitan or mixtures of these substances in addition to
the active compound(s).
For parenteral administration, the solutions and
emulsions may also be present in sterile and blood-
isotonic form.
Suspensions may contain the customary excipients,
such as liquid diluents, for example water, ethyl alcohol,
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1341 161
propylene glycol, suspending agents, for example ethoxyla-
ted isostearyl alcoh~ols, polyoxyethylene sorbitol and
sorbitan esters, microcrystalline cellulose, aluminium
metahydroxide, bentoinite, agar-agar and tragacanth or
mixtures of these substances in addition to the active
compound(s).
The said formulation forms may also contain
colorants, preservatives and also odour-improving and
flavour-improving additives, for example peppermint oil
and eucalyptus oil and sweeteners, for example saccharin.
The therapeutically active compounds should pre-
ferably be present in the abovementioned pharmaceutical
preparations in a concentration of about 0.1 to 99.5, pre-
ferably of about 0.5 to 95% by weight, of the total mixture.
The abovementioned pharmaceutical preparations may
also contain further pharmaceutical active compounds in
addition to the compounds according to the invention.
The preparation of the abovementioned pharma-
ceutical preparation:; takes place in a customary manner
by known methods, for example by mixing the active com-
pound s) with the excipient(s).
The preparations mentioned may be used in humans
and animals either orally, rectally, parenterally (intra-
venously, intramuscularly, subcutaneously), intracister-
nally, intravaginally, intraperitoneally, locally (powders,
ointments, drops) and for the therapy of infections in
hollow spaces and body cavities. Suitable preparations
are injection solutions, solutions and suspensions for
oral therapy, gels, pour-on formulations, emulsions, oint-
ments or drops. For local therapy, ophthalmological and
dermatological formulations, silver salts and other salts,
ear drops, eye ointments, powders or solutions may be
used. In animals, the administration may also take place
in suitable formulations via the feed or drinking water.
Furthermore, gels, powders, tablets, delayed-release
tablets, premixes, concentrates, granules, pellets,
Le A 25 727
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1341 161
boli, capsules, aerosols, sprays and inhalants may be used
in humans and animals. Furthermore, the compounds accord-
ing to the invention may be incorporated into other
excipients such as, 'for example, plastics, (plastic chains
for local therapy), collagen or bone cement.
In general, it has proved advantageous both in
human and veterinary medicine to administer the active
compounds) according to the invention in total amounts
of about 0.5 to about 500, preferably 5 to 100 mg/kg of
body weight every 24 hours, if appropriate in the form of
several individual doses, to attain the desired results.
An individual dose preferably contains the active com-
pound(s> according to the invention in amounts of about 1
to about 80, in partiicular 3 to 30 mg/kg of body weight.
However, it may be necessary to depart from the dosages
mentioned, depending on the type and the body weight of
the subject to be trerated, the nature and severity of the
disease, the type of preparation and the administration
of the medicament and also the time period or interval
within which the administration takes place.
Thus in some cases it may be sufficient to manage
with less than the ab~ovementioned amount of active com-
pound, whereas in other cases the abovementioned amount of
active compound must be exceeded. The optimum dosage
required in each case and the type of administration of
the active compounds can easily be established by anyone
skilled in the art on the basis of his expert knowledge.
The new compounds rnay be given in the customary
concentrations and preparations together with the feed or
feed preparations or with the drinking water. Infection
by gram-negative or gram-positive bacteria can thus be
prevented, improved and/or cured and promotion of growth
and an improvement in the utilization of the feed can thus
be achieved.
The minimum inhibitory concentrations (MIC)
were determined by the serial dilution method on
Le A 25 727
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1341 161
iso-sensitest agar (Oxoid). A series of agar plates which
contained concentrations of the active compound decreasing
in double dilutions in each case were prepared for each
test substance. The agar plates were inoculated using a
mufti-point inoculator (Denley). For the inoculation,
overnight cultures of the pathogen were used which were
previously diluted i~n such a way that each inoculation
point contained about 104 colony-forming particles. The
inoculated agar plates were incubated at 37°C and the
bacterial growth was read off after about 20 hours. The
MIC value (ug/ml) indicates the lowest active compound
concentration with which no bacterial growth could be
detected using the naked eye.
In the table below, the MIC values of some of
the compounds according to the invention are indicated
in comparison to ciprofloxacin and norfloxacin.
25
35
Le A 25 727
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1341 161
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Le A 25 727
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1341 161
Preparation Examples for intermediate compounds of the
formula (III):
Example A
3-Ethylaminomethyl-3-hydroxypyrrolidine
a) Ethyl 5-aza-1-oxa;spiroC2,47heptane-5-carboxylate
23.5 g (107 mmol> of trimethylsulphoxonium
iodide and 3.3 g of :;odium hydride (80% strength in
paraffin oil> are initially introduced and 80 ml of
absolute dimethyl sul.~phoxide are added dropwise at 10°C.
The mixture is stirred for an hour at room temperature
and 15.7 g (100 mmol) of ethyl 3-oxopyrrolidine-1-car-
boxylate CJ. Med. Pharm. Chem. 5, 752 (1962)7 in 20 ml
of absolute dimethyl sulphoxide are then added dropwise
in the course of 15 minutes. The mixture is stirred for
one hour at room temperature, poured onto a mixture of
ice and saturated sodium chloride solution and extracted
using diethyl ether. The ether solutions are washed with
sodium chloride solution, dried over Na2S04, concen-
trated and distilled.
Yield: 6 g
Boiling point: 80°C/0.15 mbar
b) Ethyl 3-ethylaminomethyl-3-hydroxypyrrolidine-1-
carboxylate
8 g (46.7 mmol) of ethyl 5-aza-1-oxaspiroC2,47-
heptane-5-carboxylate are added dropwise to 50 ml of
ethylamine solution (50% in water) and the mixture is
stirred overnight at room temperature. It is concen-
trated and the residue is distilled.
Yield: 8 g
Boiling point: 130°C/0.05 mbar
c) 3-Ethylaminomethyl-3-hydroxypyrrolidine
7.7 g (35.6 mmol) of ethyl 3-ethylaminomethyl-3-
hydroxypyrrolidine-1-carboxylate are heated under reflux
overnight with 22 g of 8a(0H)2 . 8H20 in 220 ml of water.
The mixture is filtered off with suction from BaC03 and
concentrated. The residue is boiled five times using
Le A 25 727
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1341 161
100 ml of dioxane each time, and the dioxane solution is
concentrated and distilled.
Yield: 4.2 g
Boiling point: 70-75'°C/0.1 mbar
Example B
3-Aminomet;hyl-3-hydroxypyrrolidine
a) 3-Aminomethyl-1-benzyl-3-hydroxypyrrolidine
9.7 g (51.3 mmol> of 5-benzyl-5-aza-1-oxaspiro-
C2,47heptane (US Patent 4,508,724) are added dropWise to
50 ml of ammonia solution (25%) and the mixture is
stirred overnight at room temperature. The batch is then
concentrated and the residue is distilled.
Yield: 4.4 g
Boiling point: 134°C/0.4 mbar
b) 3-Aminomethyl-3-hydroxypyrrolidine
3.9 g (18.9 mmol> of 3-aminomethyl-1-benzyl-3-
hydroxypyrrolidine in 25 ml of methanol are hydrogenated
using 1 g of palladium/active carbon (10%) at 90°C and
95 bar. The catalyst: is filtered off, the filtrate is
concentrated and the residue is distilled.
Yield: 1.2 g
Boiling point: 80°C/C1.14 mbar
Example C
3-Ethylaminomethyl-3-~hydroxypyrrolidine
a> 1-Benzyl-3-ethylaminomethyl-3-hydroxypyrrolidine
10.2 g (53.9 mmol> of 5-benzyl-5-aza-1-oxaspiro-
C2,47heptane are added dropwise to b0 ml of aqueous
ethylamine solution (50%) and the mixture is stirred over-
night at room temperature. The batch is then concentra-
ted and the residue is distilled.
Yield: 10.7 g
Boiling point: 120°C/0.18 mbar
b> 3-Ethylaminomethyl-3-hydroxypyrrolidine
10 g (42.7 mmol) of 1-benzyl-3-ethylaminomethyl-
3-hydroxypyrrolidine in 60 ml of methanol are hydrogena-
ted using 2 g of palladium/active carbon (10%) at 92°C
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1341 161
and 107 bar. The catalyst is filtered off, the filtrate
is concentrated and the residue is distilled.
Yield: 4.8 g
Boiling point: 74°C/0.08 mbar
Example D
3-Hydroxy-3-methylaminomethylpyrrolidine dihydrochloride
a) 1-Benzyl-3-hydroxy-3-methylaminomethylpyrrolidine
dihydrochloride
10.2 g (58.3 mmol) of 5-benzyl-5-aza-1-oxaspiro-
C2,47heptane are added dropwise to 70 ml of aqueous
methylamine solution (30%) and the mixture is stirred
overnight at room temperature. The batch is then con-
centrated and the residue is distilled.
Yield: 8.8 g
Boiling point: 145oC,/0.35 mbar
The distillate is dissolved in dilute hydro-
chloric acid and the solution is concentrated. The
crystalline residue is triturated with isopropanol, fil-
tered off with suction and dried.
Yield: 7.3 g
Melting point: 202oC
b> 3-Hydroxy-3-methyl.aminomethylpyrrolidine dihydro-
chloride
6.9 g (23.5 mmol) of 1-benzyl-3-hydroxy-3-methyl-
aminomethylpyrrolidine dihydrochloride in 100 ml of
methanol are hydrogenated on 2 g of palladium/active
carbon (10X) at 80oC and 100 bar. The catalyst is
filtered off with suction, the solution is concentrated
and the residue is triturated with butanol. The crystal-
line salt is filtered off with suction, washed with
acetone and dried.
Yield: 4 g
Melting point: 231-232°C
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Example E
3-Cyclopropylaminomet:hyl-3-hydroxypyrrolidine dihydro-
chloride
a) 1-Benzyl-3-cyclopropylaminomethyl-3-hydroxypyrrolidine
dihydrochloride
9.7 g (51.3 mmol) of 5-benzyl-5-aza-1-oxaspiro-
C2,47heptane are added dropwise to 9.7 g (0.17 mol> of
cyclopropylamine in 4.0 ml of water and the mixture is
stirred overnight at room temperature. The batch is then
concentrated and the residue is distilled.
Yield: 8 g
Boiling point: 130°C/0.08 mbar
The distillate is dissolved in dilute hydro-
chloric acid and the solution is concentrated. The
residue which crystallizes is triturated with acetone,
filtered off with suction and dried.
Yield: 8.3 g
Melting point: 182-184oC
b> 3-Cyclopropylaminomethyl-3-hydroxypyrrolidine dihydro-
chloride
7.9 g (24.7 mmol) of 1-benzyl-3-cyclopropylamino-
methyl-3-hydroxypyrrolidine dihydrochloride in 100 ml of
methanol are hydrogenated on 2 g of palladium/active
carbon (10%) at 50°C and 100 bar. The product is
filtered off with suction and concentrated, and the
residue is triturated with butanol. The crystalline salt
is filtered off with suction, washed with acetone and
dried.
Yield: 3.4 g
Example F
3-Aminomethyl-3-hydroxypiperidine
a) Methyl 5-aza-1-oxaspiroC2,5Joctane-5-carboxylate
23.5 g (107 mmol) of trimethylsulphoxonium iodide
and 3.4 g (100 mmol) of NaH (80% in paraffin oil) are
initially introduced and 80 ml of absolute dimethyl
sulphoxide are added dropwise at 10°C. The mixture is
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1341 161
stirred for one hour at room temperature and 15.8 g
(100 enrol) of methyl 3-piperidone-1-carboxylate CActa
Chem. Scand. 8 30, ('1976>, page 8847 are then added drop-
wise in the course oif 15 minutes. The mixture is
stirred for one hour at room temperature, poured onto a
mixture of ice and saturated sodium chloride solution and
extracted using diethyl ether. The ether solution is
washed with sodium chloride solution, dried over Na2S04,
concentrated and distilled.
Yield: 8 g
Boiling point: 68oC/0.15 mbar
b) Methyl 3-aminomethyl-3-hydroxypiperidine-1-carboxylate
9.1 g (53.2 mmol> of methyl 5-aza-1-oxaspiro-
C2,5Joctane-5-carboxylate are added dropwise to 50 ml of
ammonia solution (25%> and the mixture is stirred over-
night at room temperature. It is then concentrated and
the residue is distilled.
Yield: 5.6 g
Boiling point: 103°C/0.1 mbar
c) 3-Aminomethyl-3-hydroxypiperidine
5.1 g (27.1 mmol) of methyl 3-aminomethyl-3-
hydroxypiperidine-1-carboxylate are heated overnight
under reflux with 15.8 g of Ba(OH)2 . 8H20 in 150 ml of
water. The product is filtered off from BaC03 with
suction and concentrated. The residue is boiled five
times using 70 ml of dioxane each time, and the dioxane
solutions are concentrated and distilled.
Yield: 1.8 g
Boiling point: 63°C/0.05 mbar
Example G
3-Hydroxy-3-methylaminomethylpiperidine
a) Methyl 3-hydroxy-3-methylaminomethylpiperidine-1-
carboxylate
9.3 g (54.3 ~nmol> of methyl 5-aza-1-oxaspiro-
C2,5Joctane-5-carboxylate are added dropwise to 50 ml of
methylamine solution (25% in water) and the mixture is
i a a 7S 777
- 35 -
1341 161
stirred overnight at room temperature. It is then con-
centrated and the re:;idue is distilled.
Yield: 9.2 g
Boiling point: 83-95°C/0.1 mbar
b) 3-Hydroxy-3-methylaminomethylpiperidine
8.7 g (43 mmol) of methyl 3-hydroxy-3-methyl-
aminomethylpiperidine-1-carboxylate are heated overnight
under reflux with 24 g of Ba(OH)2 . 8H20 in 240 ml of
water. The product is filtered off from BaC03 with suc-
tion and concentrated. The residue is boiled five times
using 100 ml of diox<~ne each time, and the dioxane
solution is concentr<~ted and distilled.
Yield: 4.2 g
Boiling point: 56°C/0.05 mbar
Example H
3-Ethylaminomethyl-3-~hydroxypiperidine
a> Methyl 3-ethylaminomethyl-3-hydroxypiperidine-1-
carboxylate
9.3 g (54.3 mmol> of methyl 5-aza-1-oxaspiro-
C2,57octane-5-carboxylate are added dropwise to 50 ml of
ethylamine solution (50% strength in water) and the mix-
ture is stirred overnight at room temperature. It is
then concentrated and the residue is distilled.
Yield: 11.2 g
Boiling point: 104-1018°C/0.2 mbar
b) 3-Ethylaminomethyl-3-hydroxypiperidine
10 g (46.2 mmol) of methyl 3-ethylaminomethyl-3-
hydroxypiperidine-1-carboxylate are heated under reflux
overnight with 28.5 g of Ba(OH)2 . 8H20 in 280 ml of
water. The product is filtered off from BaC03 with
suction and concentrated. The residue is boiled five
times using 120 ml of dioxane each time, and the dioxane
solution is concentrated and distilled.
Yield: 4.5 g
Boiling point: 70°C/0.09 mbar
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1341 161
Example I
4-Aminomethyl-4-hydroxypiperidine dihydrochloride
a> Ethyl 4-aminomethyl-4-hydroxypiperidine-1-carboxylate
13.4 g (72.3 mmol) of ethyl 6-aza-1-oxaspiro-
C2,SJoctane-6-carboxylate (European Patent Application
189,370) are added dropwise to 60 ml of ammonia solution
(25%) and the mixture is stirred overnight at room tem-
perature. It is then concentrated and distilled.
Yield: 8.1 g
Boiling point: 110-130°C/0.04 mbar
b) 4-Aminomethyl-4-hydroxypiperidine dihydrochloride
1 g (4.9 mmol.> of ethyl 4-aminomethyl-4-hydroxy-
piperidine-1-carboxyl.ate is heated overnight under
reflux with 10 ml of concentrated hydrochloric acid. The
product is concentrated, and the crystals are triturated
with acetone, filtered off with suction and dried in a
vacuum desiccator over P4010.
Yield: 1 g
Melting point: 230-23.3oC
Example J
4-Hydroxy-4-methylaminomethylpiperidine dihydrochloride
a) Ethyl 4-hydroxy-4-~methylaminomethylpiperidine-1-
carboxylate
5.2 g (28 mmol) of ethyl 6-aza-1-oxaspiroC2,5J-
octane-6-carboxylate are added dropwise to 30 ml of
methylamine solution (25% in water) and the mixture is
stirred overnight at room temperature. It is then con-
centrated and recrystallized from petroleum ether
(hygroscopic crystals).
Yield: 3.3 g
b) 4-Hydroxy-4-methylaminomethylpiperidine dihydro-
chloride
3 g (13.9 mmol) of ethyl 4-hydroxy-4-methylamino
methylpiperidine-1-carboxylate are heated overnight under
reflux with 30 ml of concentrated hydrochloric acid. The
product is concentrated, and the crystals are stirred
i a a ~S
- 3l -
1341 161
with acetone, filtered off with suction and dried in a
vacuum desiccator over P4010~
Yield: 2.7 g
Melting point: 236-238°C
Example K
4-Dimethylaminomethyl-4-hydroxypiperidine dihydrochloride
a) Ethyl 4-dimethylaminomethyl-4-hydroxypiperidine-1-
carboxylate
5.2 g (28 mmol) of ethyl 6-axa-1-oxaspiroC2,5J-
octane-6-carboxylate are added dropwise to 30 ml of
dimethylamine solution (40% in water) and the mixture is
stirred overnight at room temperature. It is then con-
centrated and distillled.
Yield: 5.2 g
Soiling point: 150-1li5°C/3 mbar
b) 4-Dimethylaminomethyl-4-hydroxypiperidine dihydro-
chloride
4.5 g (19.4 mmol> of ethyl 4-dimethylaminomethyl-
4-hydroxypiperidine-'I-carboxylate are heated overnight
under reflux with 35 ml of concentrated hydrochloric acid.
The product is concentrated, and the crystals are tri-
turated with acetone,, filtered off pith suction and
dried in a vacuum des~iccator over P4010.
Yield: 4.1 g
Melting point: 224-227°C
Example L
4-Ethylaminomethyl-4-~hydroxypiperidine dihydrochloride
a) Ethyl 4-ethylaminomethyl-4-hydroxypiperidine-1-
carboxylate
5.7 g (30.8 mmol) of ethyl 6-aza-1-oxaspiro-
C2,5Joctane-6-carboxylate are added dropwise to 30 ml of
ethylamine solution (50% in water) and the mixture is
stirred overnight at room temperature. It is then con-
centrated and distilled.
Yield: 5.5 g
Soiling point: 100-104°C/0.01 mbar
Le A 25 727
- 38 -
1 X41 16 1
b) 4-Ethylaminomethyll-4-hydroxypiperidine dihydrochloride
4.6 g (20 mmol) of ethyl 4-ethylaminomethyl-4-
hydroxypiperidine-1-carboxylate are heated overnight
under reflux with 35 ml of concentrated hydrochloric acid.
The product is concentrated, and the crystals are tri-
turated with acetone,, filtered off with suction and dried
in a vacuum desiccator over P4010.
Yield: 4.2 g
Melting point: 225-229°C
Example M
3-Hydroxy-3-methylpyrrolidine
g (78.4 mmol> of 1-benzyl-3-hydroxy-3-methyl-
pyrrolidine (European Patent Application 132,845) are
dissolved in 150 ml of ethanol and hydrogenated on 2 g
15 of palladium/active carbon (10% Pd) at 90°C and 100 bar.
The catalyst is subsequently filtered off with suction,
the filtrate is concentrated and the residue is distilled.
Yield: 4.6 g
Boiling point: 60-64°C/0.08 mbar
Example N
3-Dimethylaminomethyl-3-hydroxypyrrolidine
a> 1-Benzyl-3-dimethylaminomethyl-3-hydroxypyrrolidine
9.6 g (50 mmol) of 5-benzyl-5-aza-1-oxaspiroC2,47-
heptane are added dropwise to 50 ml of dimethylamine
solution (50X) and the mixture is stirred overnight at
room temperature. The batch is then concentrated and the
residue is distilled.
Yield: 10.3 g
Boiling point: 94°C/0.05 mbar
b) 3-Dimethylaminomethyl-3-hydroxypyrrolidine
9.4 g (39 mma~l) of 1-benzyl-3-dimethylamino-
nrethyl-3-hydroxypyrra~lidine in 60 ml of methanol are
hydrogenated using 2 g of palladium/active carbon (5%> at
100°C and 90 bar. The catalyst is filtered off, the
filtrate is concentrated and the residue is distilled.
Yield: 4.3 g
Le A 25 727
- 39 -
1341 161
Boiling point: 51°C/i0.06 mbar.
Example 0
3-Hydroxy-3-methoxymethylpyrrolidine
a) 1-Benzyl-3-hydroxy-3-methoxymethylpyrrolidine
26.8 g (0.14 mol) of 5-benzyl-1-oxa-5-azaspiro
C2,47heptane are heated overnight under reflux with
2.6 ml (14 mmol) of :30% strength sodium methoxide solu-
tion in 200 ml of ab;;olute methanol. The product is
concentrated and disvtilled.
Yield: 25.6 g (83% of theory)
Boiling point: 107-1'12°C/0.15 mbar
b) 3-Hydroxy-3-methoxymethylpyrrolidine
10 g (45 mmol.) of 1-benzyl-3-hydroxy-3-methoxy-
methylpyrrolidine are hydrogenated using 3 g of Pd/active
carbon (10% Pd) in 200 ml of methanol at 100°C and 100
bar. The catalyst i:; filtered off with suction, the
filtrate is concentrated and the residue is distilled.
Yield: 4.7 g (80% of theory)
Boiling point: 65°C/0.4 mbar
Example P
3-tert.-Butoxycarbonylaminomethyl-3-hydroxypyrrolidine
a) 1-Benzyl-3-tert.-butoxycarbonylaminomethyl-3-hydroxy-
pyrrolidine
3.2 g (80 mmol) of NaOH are dissolved in 40 ml of
water, 15.6 g (75 mmol) of 3-aminomethyl-1-benzyl-3-
hydroxypyrrolidine and 50 ml of tert.-butanol are added
and 17.7 g (79 mmol) of di-tert.-butyl Bicarbonate are
added dropwise at room temperature. After stirring over-
night at room temperature, the product is filtered off
with suction, the crystals are washed with CH2Cl2 and the
filtrate is extracted using CH2Cl2. The extracts are
dried over K2C03 and concentrated, and the residue is
recrystallized from diisopropyl ether.
Yield: 19.1 g (83% of theory)
Melting point: 117-119°C
Le A 25 727
- 40 -
1 X41 161
b) 3-tert.-Butoxycarbonylaminomethyl-3-hydroxypyrrolidine
18.7 g (61 mmol) of 1-benzyl-3-tert.-butoxy-
carbonylaminomethyl-3-hydroxypyrrolidine are dissolved
in 120 ml of methanol and hydrogenated on 3 g of 5%
strength Pd/active carbon at 90°C and 100 bar. The
catalyst is filtered off, the filtrate is concentrated
and the residue is recrystallized from ethyl acetate.
Yield: 9.2 g (70% of theory)
Melting point: 124-127°C
Example Q
3-Methoxy-3-methylaminomethylpyrrolidine
a) 1-Benzyl-3-benzylmethylaminomethyl-3-hydroxy-
pyrrolidine
18.2 g (95 mmol) of 5-benzyl-1-oxa-5-azaspiro-
C2,4Jheptane are added dropwise to 15.6 ml (0.115 mol)
of benzylmethylamine in 300 ml of water and the mixture
is stirred for 15 hours at room temperature. The product
is extracted using Cl~2Cl2, the extracts are dried
using K2C03 and concentrated, and incipient distilla-
tion is carried out up to 160°C (oil bath temperature).
Crude yield: 27.1 g
GC purity: 100%
b) 1-Benzyl-3-benzylmethylaminomethyl-3-methoxy-
pyrrolidine
26 g (83 mmol.) of crude 1-benzyl-3-benzylmethyl-
aminomethyl-3-hydroxypyrrolidine in 50 ml of absolute
tetrahydrofuran are added dropwise to 4 g of 80% strength
sodium hydride in 100 ml of absolute tetrahydrofuran and
the mixture is heated under reflux during this. After
completion of hydrogen evolution, 12.4 g (87 mmol) of
methyl iodide are slowly added dropwise and the mixture
is subsequently heated overnight under reflux. The pro-
duct is poured into iice eater and extracted using toluene,
the extract is dried over K2C03 and concentrated, and
the residue is distilled.
Yield: 16.5 g
Le A 25 727
- 41 -
1341 161
Boiling range: 140-173°C/0.1-0.23 mbar
After repeated distillation:
Yield: 9.1 g (26% of theory)
GC purity: 80%
S Boiling point: 141°C/0.07 mbar
c) 3-Methoxy-3-methylaminomethylpyrrolidine
8.4 g (20 mm~ol) of 80% strength 1-benzyl-3-
benzylmethylaminomethyl-3-methoxypyrrolidine are dis-
solved in 100 ml of methanol, 4.4 ml of concentrated
hydrochloric acid arse added and the mixture is hydro-
genated on 4 g of 10% strength Pd/active carbon at 80°C
and 120 bar. The catalyst is filtered off, the solu-
tion is concentrated,, a solution of 3 g of KOH in 50 ml
of methanol are added, KCl is filtered off and the
solution is concentrated. The residue is taken up in
CHCl3 again, the mixl:ure is filtered, the solution is
concentrated and the residue is distilled.
Yield: 1.7 g (59% of theory)
Boiling point: 33°C/0.08 mbar
Example 1
O
1/C OOH
C2H5_~..OH2 w
2 5 HO ~~
A mixture of 1.4 g (5 mmol) of 1-cyclopropyl-
6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid, 1.1 g (10 mmol) of 1,4-diazabicycloC2.2.2Joctane
and 0.8 g (5.5 cnmol) of 3-ethylaminomethyl-3-hydroxy-
pyrrolidine in 10 ml of acetonitrile and 5 ml of di-
methylformamide is heated under reflux for 1 hour. The
suspension is concentrated in vacuo, the residue is
stirred well with water, and the remaining precipitate
is filtered off with suction, washed with water, dried
and recrystallized from glycol monomethyl ether.
Le A 25 727
- 42 -
1 341 16 1
Yield: 1.2 g (59X of theory) of 1-cyclopropyl-7-(3-ethyl-
aminomethyl-3-hydroxy-1-pyrrolidinyl)-6,8-difluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid of melting point
230-232° (with decomposition).
Example 2
C2H5-NH-CHI, x HC1
Ho
1.1 g (10 mmol> of 1,4-diazabicycloC2.2.27octane
and 0.8 g (5.5 mmol) of 3-ethylaminomethyl-3-hydroxy-
pyrrolidine are added to 1.5 g (5 mmol) of 8-chloro-1-
cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid in 1C1 ml of acetonitrile and 5 ml of
dimethylformamide and the mixture is heated under reflux
for 1 hour. The suspension is concentrated, and the
residue is filtered °~ff with suction, washed with water
and brought into ,solution with a little 1:1 hydrochloric
acid. The hydrochloride is precipitated by the addition
of ethanol. It is filtered off with suction, washed with
ethanol and dried at 100° in vacuo.
Yield: 1.3 g (56.5% of theory) of 8-chloro-1-cyclopropyl-
7-(3-ethylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6-fluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochlor-
ide of melting point 222-223° (with decomposition).
Example 3
3 0 ooH
C2H5_NH_CH2
HO
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3
quinolinecarboxylic acid is reacted analogously to
Le A 25 727
- 43 -
1 X41 161
Example 1 to give 1-cyclopropyl-7-(3-ethylaminomethyl-3-
hydroxy-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid of melting point 202-207°.
Example 4
0
1/C OOH
CH3-1KH-CH2 ~,~J~ ~w
HO C l~
1.5 g (5 mmol) of 8-chloro-1-cyclopropyl-6,7-
difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are
heated under reflux for 1 hour with 2.2 g (20 mmol) of
1,4-diazabicycloC2.2.27octane and 1.12 g (5.5 mmol) of
3-hydroxy-3-methylaminomethylpyrrolidine dihydrochloride
in 10 ml of acetonitrile and 5 ml of dimethylformamide.
The suspension is concentrated, the residue is stirred
with water and the undissolved product is filtered off
with suction, washed with water and dried. The crude
product obtained (1.'~7 g) is recrystallized from
dimethylformamide.
Yield: 1.55 g (75.7% of theory) of 8-chloro-1-cyclo-
propyl-b-fluoro-1,4-dihydro-7-(3-hydroxy-3-methylamino-
methyl-1-pyrrolidinyl.)-4-oxo-3-quinolinecarboxylic acid
of melting point 26b-268° (with decomposition).
Example 5
OOH
CH3-NN-C'.H x HC 1
H~
1-Cyclopropyl.-6,7,8-trifluoro-1,4-dihydro-4-oxo-
3-quinolinecarboxylic; acid is reacted analogously to
Example 4, the crude product obtained (1.75 g) is dis
solved in 10 ml of 1:1 hydrochloric acid, and the
Le A 25 727
- 44 -
141 161
hydrochloride is precipitated by adding ethanol, filtered
off with suction, washed with ethanol and dried at 100° in
vacuo.
Yield: 1.2 g (56X of theory) of 1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-7-(3-hydroxy-3-methylaminomethyl-1-
pyrrolidinyl)-4-oxo-:5-quinolinecarboxylic acid hydro-
chloride of melting point 274-276° (with decomposition).
Example 6
0
OOH
C2H5-NH-CHZ
>~N N
H ~~------~~O
95 3.3 g (30 mmol) of 1,4-diazabicycloC2.2.2Joctane
and 2.5 g (11 mmol) of 4-ethylaminomethyl-4-hydroxy-
piperidine dihydrochloride are added to 2.65 g (10 mmol)
of 1-cyclopropyl-6,7-~difluoro-1,4-dihydro-4-oxo-3-quino-
linecarboxylic acid in a mixture of 20 ml of acetonitrile
and 10 ml of dimethylformamide and the mixture is heated
under reflux for 1 hour. The suspension is concentrated,
the residue is stirred with water (pH 7), and the pre-
cipitate is filtered off with suction, washed with water,
dried and recrystallized from dimethylformamide.
Yield: 3.03 g (75.2X of theory) of 1-cyclopropyl-7-(4-
ethylaminomethyl-4-hydroxy-1-piperidinyl)-6-fluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid of melting point
258-259° (with decomposition).
Example 7
35
0
OOH
C2H5-NH-CH2
~ N
HO~
F
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-
a ~s ~»
- 45 -
1341 161
3-quinolinecarboxylic acid is employed analogously to
Example 6 and 1-cyclopropyl-7-(4-ethylaminomethyl-4-
hydroxy-1-piperidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid of melting point 270-280° (with
decomposition) are obtained.
Example 8
O
~ I '1/'COOH
CH3-NH-CH2% n w
HO ~(~'N
1-Cyclopropyl.-b,7-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid is reacted with 4-hydroxy-4-
methylaminomethylpipearidine dihydrochloride analogously
to Example 6 to give 1-cyclopropyl-b-fluoro-1,4-dihydro-
7-(4-hydroxy-4-methyl.aminomethyl-1-piperidinyl)-4-oxo-3-
quinolinecarboxylic acid of melting point 162° (with
decomposition>.
Example 9
0
YCOOH
J x HC 1
H N ~ N
CH3-NH-CHI
1-Cyclopropyl-b,7-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid is reacted analogously to
Example 2 with 3-hydroxy-3-methylaminomethylpiperidine
to give 1-cyclopropyl-b-fluoro-1,4-dihydro-7-(3-hydroxy-
3-methylaminomethyl-1-piperidinyl)-4-oxo-3-quinoline-
carboxylic acid hydrochloride of melting point 293-296°
(with decomposition).
Le A 25 727
- 46 -
1341 161
Example 10
C2H,~-NH-C
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid is reacted analogously to
Example 1 with 3-eth;ylaminomethyl-3-hydroxypiperidine to
give 1-cyclopropyl-7-(3-ethylaminomethyl-3-hydroxy-1-
piperidinyl)-b-fluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid of melting point 199-203oC (with decom-
position).
Example 11
0
YCOOH
CH3%~ ~ N
H ~(~J~O
1.3 g (5 mmol.) of 1-cyclopropyl-6,7-difluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid are heated under
reflux for 1 hour with 1.1 g (10 mmol> of 1,4-diazabi-
cycloC2.2.2Joctane and 540 mg (5.4 mmol) of 3-hydroxy-3-
methylpyrrolidine in 10 ml of acetonitrile and 5 ml of
dimethylformamide. 1'he suspension is concentrated, the
residue is stirred wiith water, and the precipitate is
filtered off with suction, washed with water, recrystal-
lined from dimethylformamide and dried at 100° in vacuo.
Yield: 1.4 g (81X of theory) of 1-cyclopropyl-b-fluoro-
1,4-dihydro-7-(3-hydroxy-3-methyl-1-pyrrolidinyl)-4-oxo-
3-quinolinecarboxylic acid of melting point 315-320°
(with decomposition>.
le A 25 727
- 47 -
1341 161
Example 12
ooH
-fl
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid is reacted analogously to
Example 11 with 1,4-dioxa-7-azaspiroC4.4Jnonane to give
1-cyclopropyl-7-(1,4-dioxa-7-azaspiroC4.4Jnon-7-yl)-6-
fluoro-1,4-dihydro-4--oxo-3-quinolinecarboxylic acid of
melting point 229-230°.
Example 13
0
I 1/COOH
N
2 g of 1-cyclopropyl-7-(1,4-dioxa-7-azaspiro-
C4.4Jnon-7-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid are suspended in 100 ml of methanol and
stirred for 2 hours a~t room temperature with 100 ml of
1:1 hydrochloric acidl, The suspension is concentrated
and the residue is recrystallized from dimethylformamide.
Yield: 1 g (52% of theory) of 1-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-7-<3-oxo-1-pyrrolidinyl)-3-quinoline-
carboxylic acid of melting point 286-2880 (with decom-
position).
Example 14
OOH
3 5 H2N-CH2
HO
Le A 25 727
4$ -
1 X41 161
3-Aminomethyl-3-hydroxypyrrolidine is reacted
according to Example 1 to give 7-(3-aminomethyl-3-
hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid of melting point
248°C (with decomposition).
Mass spectrum: m/e 379 (M+), 361 (379-H20>, 344 (361-
F), 44 (C02), 41 (C3H5), 18 (H20).
Example 15
O
~ ooH
w
~2_CH2 ~ I NJ
HO~~ Ci
8-Chloro-1-c;yclopropyl-6,7-difluoro-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid is reacted analogously
to Example 14, the product obtained is purified by
chromatography on silica gel using dichloromethane/
methanol/20% aqueous ammonia solution (2:4:1) as eluent
and 7-(3-aminomethyl~-3-hydroxy-1-pyrrolidinyl)-8-chloro-
1-cyclopropyl-b-fluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid of melting point 240-243°C (with decom-
position) are obtained.
FAB mass spectrum: m/e 396 C(M+H)+7, 368 C(M+H-CO)+7
Example 16
o
COOH
CH3
>N-CH2 /~ ' N
CH3 x HCl
Ho
1.42 g (5 mmol> of 1-cyclopropyl-6,7,8-trifluoro-
1,4-dihydroxy-4-oxo-3-quinolinecarboxylic acid are heated
under reflux for 1 hour in a mixture of 10 ml of aceto-
nitrite and 5 ml of dimethylformamide and 0.8 g (5.6 mmol)
of 3-hydroxy-3-dimethylaminomethyl-pyrrolidine and 1.1 g
a 7S 777
- 49 -
1341 161
(10 mmol) of 1,4-diazabicycloC2,2,2Joctane. The suspen-
sion is concentrated,, water is added to the residue and
the mixture is acidiified with dilute hydrochloric acid
(1:1). The salt which crystallizes out is filtered off
with suction and recrystallized from dimethylformamide.
Yield: 1.1 g (50X of theory) of 1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-7-(3-hydroxy-3-dimethylaminomethyl-1-
pyrrolidinyl>-4-oxo-'_i-quinolinecarboxylic acid hydro-
chloride of melting point 292-295oC (with decomposi-
tion).
Example 17
D-NH-cH
H
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-
3-quinolinecarboxylic acid is reacted analogously to
Example 6 with 3-cyclopropylaminomethyl-3-hydroxypyrroli-
dine dihydrochloride to give 1-cyclopropyl-7-(3-cyclo-
propylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6,8-difluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting
point 161-162° (with decomposition).
Example 18
O
OOH
R-NH-CH2
Ho C1~
s) R = (CH3) 3C-O-CO
b) R ~ H x HC1
a) A mixture of 6 g (20 mmol) of 8-chloro-1-cyclo-
propyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-
Le A 25 727
- 50 -
1341 161
carboxylic acid, 2.5 g (22.7 mmol) of 1,4-diazabicyclo-
C2.2.2Joctane and 4.2 g (20 smol) of 3-test.-butoxy-
carbonylaminomethyl-'_>-hydroxypyrrolidine in 40 ml of
acetonitrile and 20 ml of dimethylformamide is heated
under reflux for 3 hours. The solution is concentrated
in vacuo, the residue' is stirred with water, and the un-
dissolved precipitates is filtered off with suction,
washed with water and dried.
Yield: 9.8 g (99% of theory) of crude 7-(3-test.-butoxy-
carbonylaminomethyl-3~-hydroxy-1-pyrrolidinyl)-8-chloro-
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid,
melting point: 192°C (with decomposition) (after re-
crystallization from ethanol).
b> 9.5 g (19 mmol) of the product from Example 18a>
are stirred for 30 minutes at room temperature in 300 ml
of 1:1 hydrochloric acid. The mixture is filtered and
the filtrate is concentrated at 35°C/12 mbar. The
residue is recrystallized from glycol monomethyl ether.
Yield: 4.3 g (52% of theory) of 7-(3-aminomethyl-3-
hydroxy-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydro-
chloride of melting point 147-150oC (with decomposi-
tion); purity: 93% pure (by HPLC).
Example 19
O
COOH
I i
CH3oCH2 /~ ~ -'~
3 0 HO
3-Hydroxy-3-methoxymethylpyrrolidine is reacted
analogously to Example 1 and 1-cyclopropyl-6,8-difluoro-
1,4-dihydro-7-(3-hydroxy-3-methoxymethyl-1-pyrrolidinyl)-
4-oxo-3-quinolinecarboxylic acid of melting point 230-
232° (with decomposition) (recrystallized from
a ~s ~»
- 51 -
1341 161
dimethylformamide) is obtained.
Example 20
O
\ ~ I COON
CH3-NH-CH2 ~~Ni
CH30 'F
3-Methoxy-3-methylaminomethylpyrrolidine is
reacted analogously 'to Example 1 and 1-cyclopropyl-6,8-
difluoro-1,4-dihydro-7-(3-methoxy-3-methylaminomethyl-1-
pyrrolidinyl)-4-oxo-:3-quinolinecarboxylic acid of melting
point 245-247oC (with decomposition) (recrystallized
from dimethylformamide> are obtained.
20
30
Le A 25 727
52
