Quinolone-and naphthridone carboxylic acid derivatives, process for their production, antibacterial

25 Pages·2013·1.94 MB·English

US005284842A
United States Patent [191
[11] Patent Number: 5,284,842
Petersen et al. I [45] Date of Patent: Feb. 8, 1994
[54] QUINOLONE- AND NAPI-ITI-IRIDONE Balsamo et al J. Med. Chem, 30, pp. 222-225 (1987).
CARBOXYLIC ACID DERIVATIVES, Auerbach et a1 Tetrahedron Letters No. 46, pp.
PROCESS FOR THEIR PRODUCTION,
4561-4564 (1973). '
ANTIBACTERIAL COMPOSITIONS AND
Giustiniani Gazz. Chim. Ital. 24, pp. 223-229 (1894).
FEED ADDITTVES CONTAINING THEM
Vasil’eva et a1. Zh, Org. Khim, 14, '(7), 1420 (1978)
[75] Inventors: Uwe Petersen, Leverkusen; Thomas English translation. ‘ ‘
Schenke, Bergisch Gladbach; Klaus Jacobsen et a]. Acta Chemica Scandinavica B 34 (1980),
Grolie; Michael Schriewer, both of pp. 319-326.
Odenthal; Ingo Haller, Wuppertal; Viscontini et a1. Helv. Chim. Acta, 50, 1967, pp.
Karl G. Metzger, Wuppertal; Rainer 1289-1293.
Endermann, Wuppertal; Gassman et al. J. Amer. Chem. Soc., 104, (1982), pp.
Hana-Joachim Zeiler, veiben, all of / 5849-5850.
Fed. Rep. of Germany
Wu et a]. J. Med. Pharm. Chem., 5, (1962), pp. 752-762.
[73] Assignee: Bayer Alrtien Domagala et al. J. Med. Chem., 31, (1988), pp. 503-506.
Leverkusen, Fed. Rep. of Germany
Primary Examiner-Badly Bernhardt
[2 1] Appl. No.: 931,746
Attorney, Agent, or Finn-Sprung Horn Kramer &
[22] Filed: Aug. 18, 1992 Woods
Related US. Application Data
[57] ABSTRACT
[60] Division of Ser. No. 699,880, May 14, 1991, Pat. No.
An antibacterially active quinolone or naph
5,173,484, which is a continuation-in-part of Ser. No.
thyridonecarboxylic acid derivative of the formula
298,459, Jan. 18, 1989, abandoned.
[30] Foreign Application Priority Data
R3 o
Feb. 5, 1988 [DE] Fed. Rep. of Germany ..... .. 3803478
Apr. 29, 1988 [DE] Fed. Rep. of Germany ..... .. 3814517
[51] Int. Cl.5 ................... .. A61K 31/47; CO7D 401/04
R‘ A N
[52] US. Cl. .................................. .. 514/187; 514/300; l
514/312; 546/5; 546/123; 546/156 R1
[58] Field ofSearch .................. .. 546/156, 5; 514/312,
in which >
5l4/235.2, 187; 544/128, 64
R1 stands for various organic radical,
[56] References Cited R2 stands for hydrogen, alkyl having 1 to 4 carbon
atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,
U.S. PATENT DOCUMENTS
R3 stands for hydrogen or amino,
4,382,892 5/ 1983 l-layakawa et a1. ............... .. 540/575 R‘ stands for a radical of the formula
4,508,724 4/ 1985 Taylor, Jr. et a1. .... .. 514/317
4,556,658 12/1985 Grohe et a1. . . . . . . . . . . .. 514/254
4,616,019 10/1986 Chu ........................... .. 514/254
4,638,067 1/ 1987 Culbertson et a1 ...... .. 546/15
4,649,144 3/1987 Matsumoto et a1 .......... .. 514/300
4,665,079 5/1987 Culbertson et a1 .... .. 514/312
4,666,920 5/ 1987 Grohe et a1. .............. .. 514/312
4,730,!!10 3/1988 Chu ....................... .. 514/254
' 4,735,944 4/1988 Bollinger .................. .. 514/278 A-stands for N or C—R5,
4,753,925 6/1988 Grohe et al .............. .. 514/254
4,771,054 9/1988 Domagala etal .... .. 514/312 wherein
4,771,055 9/1988 Domagala et al ........... .. 514/312 R5 stands for hydrogen, halogen methyl, cyano or nitro
4,774,246 9/1988 Chu ............................... .. 514/254 or else together with R1 can form a bridge of the
4,777,175 10/1988 Culbertsonet a1 .......... .. 514/300 structure
4,886,810 12/1989 Matsumoto et al. .......... .. 514/312
.4,927,926 5/ 1990 Corominas et a1. .... .. 546/156
4,952,695 8/1990 Grohe et al. .............. .. 546/156
4,962,112 10/1990 Roaen et a1. .. .... .. 514/300
5,039,683 8/1991 Nalranishi .......................... .. 546/156
FOREIGN PATENT DOCUMENTS
0275971 7/1988 European Pat. Off. .
OTHER PUBLICATIONS or a pharmaceutically utilizable hydrate, acid addition
salt, alkali metal salt, alkaline earth metal salt, silver salt
Grohe et al, Chemical Abstracts, vol. 102, No. 78744
or guanidinium salt of the carboxylic acid when R2 is
(1984) (Abstract for DE 3318145, Nov. 22, 1984. hydrogen.
Grohe et al, Chemical Abstracts, vol. 101, No. 211165
(1984) (Abstract for DE 3248507, Jul. 5, 1984).
4 Claims, No Drawings
5,284,842
1
Y stands for
QUINOLONE- AND NAPHTHRIDONE
CARBOXYLIC ACID DERIVATIVES, PROCESS
FOR THEIR PRODUCI' ION, ANTIBACTERIAL /
COMPOSITIONS AND FEED ADDITIVES 5
CONTAINING THEM
This application is a division of application Ser. No.
OR, SR, halogen or hydrogen,
699,880, ?led May 14, 1991, now US. Pat. No.
X1 stands for
5,173,484, which is a continuation-in-part of application
Ser. No. 298,459, ?led Jan. 18, 1989, now abandoned.
The invention relates to quinolone- and naph
/.
thyridonecarboxylic acid derivatives which are substi
N.
tuted in the 7-position by a cyclic amine radical which
carries a quaternary carbon atom, processes for their 15
preparation, and antibacterial agents and feed additives
containing them. OR, SR, halogen, CN, CONHZ, COOH or C1-C4
It has been found that quinolone- and naph alkyl,
thyridonecarboxylic acid derivatives of the formula (I) X2 and X3 can be identical or different and stand for
20 oxygen, sulphur, NH or N-CH3, I
R stands for hydrogen, C1-C3-alkyl or C1-C3-acyl,
(I) R’ stands for hydrogen, C1—C3-alkyl, allyl or propargyl
and
R" stands for hydrogen, C1-C3-alkyl or C3-C6-cycloal
25
kyl,
where
R’+R” together can also denote the groups —CH2C
H2—O—CH2CH2—— 0r —(CH2)k—, in which
in which 30 k can stand for 3, 4 or 5,
R1 stands for methyl, ethyl, propyl, isopropyl, cyclo R'” stands for hydrogen or C1-C3~a1kyl,
propyl, vinyl, Z-hydroxyethyl, 2-fluoroethyl, me A stands for N or C—-R5,
thoxy, amino, methylamino, dimethylamino, wherein
ethylamino, phenyl, 4-?uorophenyl or 2,4 R5 stands for hydrogen, halogen such as ?uorine or
di?uorophenyl, 35
chlorine, methyl, cyano or nitro or else together with
R2 stands for hydrogen, alkyl having 1 to 4 carbon R1 can form a bridge of the structure
atoms or (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl,
R3 stands for hydrogen or amino,
R4 stands for a radical of the formula
“mt Nam»...
45
|
and their pharmaceutically utilizable hydrates and acid
addition salts and also the alkali metal salts, alkaline
earth metal salts, silver salts and guanidinium salts of the
underlying carboxylic acids, have a high antibacterial
action, in particular in the gram-positive range.
55 They are therefore suitable as active compounds for
human and veterinary medicine, the treatment of ?sh
for the therapy or prophylaxis of bacterial infections
being included in the term veterinary medicine.
Preferred compounds of the formula (I) are those in
which
R1 stands for ethyl, isopropyl, cyclopropyl, vinyl, 2
hydroxyethyl, 2-?uoroethyl, amino, methylamino,
excluding 3-amino-3-methyl-l-pyrrolidinyl,
phenyl, 4-?uorophenyl or 2,4-di?uorophenyl,
wherein
p stands for 0, l or 2, 65 R2 stands for hydrogen, alkyl having 1 to 3 carbon
m stands for l or 2, where p+m together can be 1, 2 or atoms or (S-methyl-Z-oxo-l,3-dioxol-4-yl)methyl,
39 R3 stands for hydrogen or amino,
n stands for 1 or 2, R4 stands for a radical of the formula
5,284,842
4 .
Particularly preferred compounds of the formula (I)
are those in which
R1 stands for ethyl, isopropyl, cyclopropyl, vinyl, 2- -
hydroxyethyl, Z-?uoroethyl, amino, methylamino,
Rm't NACHZ)". phenyl, 4-fluorophenyl or 2,4-di?uorophenyl,
R2 stands for hydrogen or alkyl having 1 or 2 carbon
, |
atoms,
R3 stands for hydrogen,
10 R4 stands for a radical of the formula
XI
15
X“
(CH1), X3
20
excluding 3-amino-3-methyl-l-pyrrolidinyl,
wherein
25
p stands for 0, 1 or 2,
m stands for l or 2, where p+m together can be 1, 2 or
3,
(CH2); X3
it stands for 1 or 2,
Y stands for
excluding 3-amino-3-methyl-l-pyrrolidinyl,
35 wherein
p stands for 0, 1 or 2,
OR, or hydrogen,
m stands for l or 2, where p+m together can be 1, 2 or
X1 stands for
3!
n stands for 1,
Y stands for
OR, ?uorine, chlorine or C1-C2-alkyl, 45
X2 and X3 can be identical or different and stand for
oxygen, sulphur or N-CH3,
R stands for hydrogen, C1-C2-alkyl or acetyl, OR or hydrogen,
R' stands for hydrogen or C1-C2-alkyl, and X1 stands for
R" stands for hydrogen or C1—C;-alkyl, 50
where
R’+R” together also denote vthe groups —CH2C
H2-O-—CH2CH2-- or —(CH2)k, in which k can
stand for 3, 4 or 5,
R’” stands for hydrogen or C1-C2-alkyl and 55
A stands for N or C—R5, OR, chlorine or methyl,
wherein X2 and X3 can be identical or different and stand for
R5 stands for hydrogen, halogen such as ?uorine or
oxygen or N--CH3,
chlorine or methyl or else together with R1 can form R stands for hydrogen or methyl,
a bridge of the structure
R’ stands for hydrogen or methyl,
R" stands for hydrogen or methyl,
R'” stands for hydrogen or methyl and
A stands for N or C—-R5,
65 wherein
and their pharmaceutically utilizable hydrates and acid R5 stands for hydrogen, halogen, such as ?uorine or
addition salts and also the alkali metal salts, alkaline chlorine or else together with R1 can form a bridge of
earth metal salts, silver salts and guanidinium salts. the structure
5,284,842
6
starting substances, then the course of the reaction can
be represented by the following equation:
it’
and their pharmaceutically utilizable hydrates and acid
F COOH
addition salts and also the alkali metal salts, alkaline I +
earth metal salts, silver salts and guanidinium salts.
Furthermore, it has been found that the compounds
F N
of the formula (I) are obtained when compounds of the 10 Cl 5
formula (II)
a3 p (11)
F / I I coon2 15 CzHs NH _ CH1 NH hue
—HP 5
HO
Z A N
,1,
0
II
20 F COOH
in which
Z stands for ?uorine or chlorine and
R1, R2, R3 and A have the abovementioned meaning,
are reacted with compounds of the formula (III) ‘ C2H5—NH—CH2 N Cl Nf
R4_H (III) 25 H0
in which The compounds of the formula (II) used as starting
R4 has the abovementioned meaning,
substances are known or can be prepared by known
if appropriate in the presence of acid entrainers. 3O
methods. Examples which may be mentioned are:
Compounds of the structure (la) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3
quinolinecarboxylic acid (German Patent Applica
R3 0 (la) tion 3,142,854),
II 1-cyclopropyl-6,7-di?uoro-l,4-dihydro-4-oxo-3
F coonl
I I 35 quinolinecarboxylic acid (European Patent Applica
tion 113,091),
z
x (cum-N A T: 8.chloro-l-cyclopropyl-6,7-di?uoro-1,4-dihydro-4-oxo
[ R,” R 1 3-quinolinecarboxylic acid (German Patent Applica
tion 3,420,743),
x; (CH2), ,0
1-cyclopropyl-6,7,8-tri?uoro-1,4dihydro-4-oxo-3
in which quinolinecarboxylic acid (German Patent Applica
R1, R2, R3, R’”, A, X2, X3, m and p have the abovemen tion 3,318,145),
l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4
tioned meaning, ,
can also be prepared by reaction of a compound of the 45 oxo-3-quinolinecarboxylic acid,
formula (IV) 6,7-di?uoro-l-ethyl-l,4-dihydro-4-oxo-3-quinolinecar
boxylic acid,
7-chloro-6-?uoro-l-ethyl-1,4-dihydro4-oxo-3
(1V)
quinolinecarboxylic acid,
7-chloro-6-tluoro-L4-dihydro-l-(2~hydroxyethyl)-4
oxo-3-quinolinecarboxylic acid,
l-cyclopropyl-7-chloro~6-?uoro-l,4-dihydro-8-nitro4
cH2)m_ N
oxo-3-quinolinecarboxylic acid,
O
6,7-di?uoro-l-(2-tluoroethyl)-1,4-dihydro-4-oxo-3
(CH2); 55 quinolinecarboxylic acid,
6, 7-ditluoro- 1,4-dihydro- l-methoxy-4-oxo-3
in which quinolinecarboxylic acid,
R‘, R2, R3, R'”, A, m and p have the above-mentioned 6,7-difluoro- l ,4-dihydro- l~methylamino-4-oxo-3
meaning,
quinolinecarboxylic acid,
with a compound of the formula (V) 60 6,7-di?uoro~1,4-dihydro4-oxo-l-phenyl-3
quinolinecarboxylic acid,
H—-X2—CH2—CH2—X3-—H (V)
6,7-di?uoro-1-(4-?uoro-phenyl)-1,4-dihydro-4-oxo-3
in which quinolinecarboxylic acid,
X2 and X3 have the abovementioned meaning. 65 6,7-di?uor0-l’(3,4~di?uoro-phenyl)-l,4-dihydro-4-oxo
If, for example, S-chloro-l-cyclopropyl-6,7-dilluoro 3-quinolinecarboxylic acid,
l,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 3 7-chloro-l-cyclopropyl-6-tluoro-l,4-dihydros4-oxo—l,8
ethylaminomethyl-3-hydroxy-pyrrolidine are used as naphthyridine-3-carboxylic acid,
5,284,842
7 8
ethyl l~cyclopropy1-6,7,8-trifluoro-1,4-dihydro-4-oxo—
continued
3-quino-linecarboxylate (German Patent Application
R,
3,318,145),
9,lO-di?uoro-2,3-dihydro-3-methyl-7-oxo-7H
pyrido[l,2,3-de][1,4]benzoxacine-6-carboxy1ic
acid
(CH2)m
(European Patent Application 47,005), N/
8,9-di?uoro-6,7-dihydro-5-methyl-1-oxo-1H,5I-I-ben I
zo[i,j]quinolicine-2~carboxylic acid, B
7-chloro-6-?uoro-l-phenyl-1,4-dihydro-4-oxo-L8 (3)
naphthyridine-3-carboxylic acid‘ (European Patent /
Application 153,580),
7-chloro-6-?uoro- 1-(4-?uorophenyl)-1,4-dihydro-4»
oxo-1,S-naphthyridine-3-carboxylic acid (European OH
Patent Application 153,580), (CH2);
6,7,8-tri?uoro-1,4-dihydro-1-methy1amino-4-oxo-3
quinolinecarboxylic acid (German Patent Applica
tion 3,409,922),
l-amino-6,7,8-tri?uoro-1,4-dihydro-4-oxo-3
(Illa)
quinolinecarboxylic acid (German Patent Applica B = COO-Alkyl, CHZC6H5
tion 3,409,922), 20
6,7,8-tri?uoro-1,4-dihydro-1-dimethylamino-4-ox0-3 1 2. The cyclization of the succinic acid ester (4) [Tet
quinolinecarboxylic acid (German Patent Applica rahedron Letters 46, 4561 (1973)] with benzylamine
yields the alkyl 1-benzyl-3-hydroxy-S-oxo-pyrrolidine
tion 3,409,922),
7-chloro-6-?uoro-1,4-dihydro-8-nitro-4-oxo-l-phenyl 3-carboxylate (5) which, after reaction with an amine
3-quinolinecarboxylic acid, 25 (2), reacts to give the amide (6). Subsequent reduction
7-ch1oro-6-?uoro-1-(4-?uorophenyl)-1,4-dihydro~8 with LiAlH4 and hydrogenolytic elimination of the
nitro-4-oxo-3-quinolinecarboxylic acid, benzyl group yields starting compounds of the formula
6,7-di?uoro-1—(4-?uorophenyl)-1,4-dihydro~8-methyl-4 (IIIb):
oxo—3-quinolinecarboxylie acid,
6-chloro-7-fluor0-1-(4-?uorophenyl)-l,4~dihydro-4 3O Q?“
oxo-3-quinolinecarboxylic acid (European Patent
Application 131,839),
6-chloro-7-?uoro-l-(2,4»difluorophenyl)-1,4-dihydro-4 Alkyl-O-CO 2 3C OO -Alk y] ———é
oxo-3-quino1inecarboxylic acid (European Patent
Application 131,839), 35 o
(4)
6,7, 8-tri?uoro-l-(4-f1uorophenyl)-1,4-dihydro-4-oxo-3
quinolinecarboxylic acid (European Patent Applica OH
tion 154,780), COO-Alkyl
6,7,8-tri?uoro-l-(2,4-di?uorophenyl)-l,4-dihydro-4
i1»
oxo-3-quinolinecarboxylic acid (European Patent
0 N
Application 154,780),
6,7,8-trifluoro-1,4-dihydro-4-oxo-1-phenyl-3
quinolinecarboxylic acid (European Patent Applica
tion 154,780),
7-chloro-1-ethyl-6-?uoro-1,4-dihydro-4-oxo-l,8-naph 45
thyridine-3-carboxylic acid,
6,7-difluoro-1,4-dihydro-4-oxo-l-vinyl-3-quinolinecar
boxylic acid.
The compounds of the formula (III) used as starting
compounds are in some cases new and therefore an 50
embodiment of the present invention.
Their preparation can be carried out by various pro
cesses:
l. Ring-opening to form the hydroxyamines (3) is
carried out by reaction of the spiro-oxiranes protected 55
on the nitrogen (l) [1. Med. Chem, 30, 222 (1987); US.
(6)
Pat. No. 4,508,724; EP 189,370] with amines (2). Elimi
nation of the protective group yields starting com
pounds of the formula (IIIa):
0
R,
CH +A
( 2)p + HN _}
(lIIb)
|\ N/(cH2)m \.
65
| 3. Reaction of the (l-benzyl-3-hydroxy-2,5-dioxopyr
B rolidin-3-yl)-acetic acid (7) [Gazz. Chim. Ital. 24, 226
(1) (2) (1984)] to give the amide (8) and subsequent reduction
5,284,842
9 10
using LiAlI-h and elimination of the benzyl group yields continua
starting compounds of the formula (1110): R’
on /
N
CH coon 5 l l \ R"
E N
o N §Q H
(1110)
10 4. 3-Hydroxy-3-methyl-pyrrol1_ d1_ ne can be prepared
by LiAlH4 reduction of 4-hydroxy-4-methyl-pyrrolidin
(7) 2-one [Zh. Org. Khim. 14, 7, p. 1420 (1978)] or by
> debenzylation of l-benzyl-3-hydroxy-3-methyl-pyrroli
on /R' 15 dine (EP 132,345).
£j/\C0—N 5. Starting from cyclic oxoamines (9) which are
\ H blocked by a protective group on the nitrogen, starting
0 \ R a 5 compounds of the formulae (IIld), (IIIe) and (Hit) can
N o be synthesized [Acta Chem. Scand. B 34, 319 (1980)].
(CH2), ——-f cHsNoz (cm), N02 (cum NH2
(8) k a |\ _—l/\ a 9 |\
/(CH2)m ,(CH2)m ,(CH2)m
N N N
B| Bl / H
(9) HCN or (10) (111d)
13 = COO-Alkyl, (CH3)3SiCN
CH2-C6H5
OH
(CH2), CN
l\ N/(CH2)m
I
B
NH; NH; NH;
(011k2), , CN (c11k2) , coon —> (CHk1), A» 0“
N,<cnz)m N,(¢H1)m N/(cm).
I l H
B B
(12) (13) (IIle)
(1110
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) [Helv. Chim. Acta 50, 1289
(1967)].
By reaction of the spiro-oxiranes protected on the
nitrogen (l) with trimethylsilyl cyanide [J. Amer.
65 Chem. Soc. 104, 5849 (1982)], the isonitriles (14) can be
prepared which can be reacted by hydrolyzing and
eliminating the protective group to give the starting
compounds of the formula (Illg):
5,284,842
11 12
B-dimethylamino-3-ethylaminomethylpyrrolidine,
3-amino-3-hydroxymethylpyrrolidine,
0
3-acetylamino-3-hydroxymethylpyrrolidine,
(cl-12).’ +>
3-amin0-3-methoxymethylpyrrolidine,
+ (cl'lslasicN ———>
k ,(Cl-mm 3-tert.butoxycarbonylamino-3-methoxymethylpyrroli
N dine,
l
B 3-amino-3-methylthiomethylpyrrolidine,
(1) 3-amino-3-mercaptomethylpyrrolidine,
10
3-cyclopropylaminomethyl-3-hydroxypyrrolidine,
I NC NR2 3-isopropylaminomethyl-3-hydroxypyrrolidine,
(CHk2)P _/*(/CH\2o)smi (c?3)3 (cH‘2\)p /(CH2)m l,4-dioxa-7-azaspiro[4.4]nonane,
l-oxa-4,7-diazaspiro[4.4]nonane,
N N
l | 4-methyl- l -oxa-4,7~diazaspiro [4.4]nonane,
B H 1-thia-4,7-diazaspiro[4.4]nonane,
(14) (1112)
l,4,7-triazaspiro[4.4]nonane,
1,4-dimethyl- l,4,7-triazaspiro[4.4]nonane.
Examples of starting compounds of the formula (III) 20
The reaction of (II) with (III) is preferably performed
which may be mentioned are the following compounds,
in a diluent such as dimethyl sulphoxide, N,N-dimethyl
where chiral compounds can be employed both as race
formamide, hexamethylphosphoric triamide, sulpho
mates as well as pure enantiomeric substances:
3-aminomethyl-3-hydroxypyrrolidine, 25 lane, water, an alcohol such as methanol, ethanol, n
propanol, isopropanol, glycol monomethyl ether, aceto
3-acetylaminomethyl-S-hydroxypyrrolidine,
nitrile or pyridine. Mixtures of these diluents can like
3-tert.-butoxycarbonylaminomethyl-3-hydroxypyrroli
wise be used.
dine,
All customary inorganic and organic acid-binding
3~hydroxy-3-methylaminomethylpyrrolidine,
agents can be used as acid binders. These preferably
3-ethylaminomethyl-B-hydroxypyrrolidine,
include the alkali metal hydroxides, alkali metal carbon
3~hydroxy-3-propylaminomethylpyrrolidine,
ates, sodium hydride, organic amines and amidines.
S-ethylaminomethyl-3-methoxypyrrolidine, Those which may be mentioned individually as being
35
S-aminomethyl-3-fluoropyrrolidine, particularly suitable are: tn'ethylamine, 1,4-diazabicy
3-aminomethyl-3-chloropyrrolidine, clo[2,2,2]octane (DABCO), l,8-diazabicyclo[5,4,0]un
3-?uoro-3-methylaminomethylpyrrolidine, dec-7-ene (DBU) or excess amine (III).
3-chloro-3-methylaminomethylpyrrolidine, The reaction temperatures can be varied within a
3-ethylaminomethyl-3-?uoropyrro1idine, relatively wide range. In general, the reaction is carried
3-chloro-3-ethylaminomethylpyrrolidine, out between about 20° and 200° C., preferably between
80° and 180° C.
3-hydroxy-3-methylpyrrolidine,
The reaction can be carried out at atmospheric pres
3-hydroxy-3-methoxymethylpyrrolidine, 45
sure, but also at elevated pressure. In general, the reac
3-methoxy-3-methylaminomethylpyrrolidine,
tion is carried out at pressures between about 1 and
3-dimethylaminomethyl-3-?uoropyrrolidine,
about 100 bar, preferably between 1 and 10 bar.
3-chloro-3-dimethylaminomethylpyrrolidine,
When carrying out the process according to the in
3-fluoromethyl-3-aminopyrrolidine, 50
vention by method A, 1 to 15 moles, preferably 1 to 6
3-ethoxy-3-ethylaminomethylpyrrolidine,
moles, of the amine (III) are employed per mole of
3-chl0ro-3-ethylarninomethylpyrrolidine, carboxylic acid (II).
3-ethylaminomethyl-3-?uoropyrrolidine, In addition to the compounds shown in the examples,
55
3-ethylaminomethyl-3-methylpyrrolidine, the following may be mentioned individually as new
3-ethylaminomethyl~3-mercaptopyrrolidine, active compounds:
9-fluoro-2,3-dihydro-l0-(3-hydroxy-3—
B-ethylaminomethyl-3-methylthiopyrrolidine,
methylaminomethyl-l-pyrrolidinyl)-3-methyl-7-oxo
3-acetoxy-3-ethylaminomethylpyrrolidine,
7H-pyrido[l,2,3-de][l,4]benzoxacine-6-carboxylic
3-dimethylaminomethyl-3-hydroxypyrrolidine,
acid,
3-hydroxy-3-pyrrolidinomethylpyrrolidine,
8-(3-ethylaminomethyl-3-hydroxy-l-pyrro1idinyl)-9
3-hydroxy-3-morpholinomethylpyrrolidine,
3-amino-3-ethylaminomethylpyrrolidine, 65
]quinolicine-2-carboxylic acid,
3~acetylamino-3-ethylaminomethylpyrrolidine,
and furthermore the compounds shown in the following
3-ethylaminomethyl-3-methy1aminopyrrolidine,
table.

5,284,842
17 18
-continued
R3 0
Nr. R1 R2 R3 R‘ A
38 n H H " N
39 " CH
H2N—CH2
N
no
40 " H n " CF
41 " H H " CC]
42 [>_ (canal-CH1 CH
N
no
43 H H " CF
The compounds according to the invention show,
combined with low toxicity, a broad antibacterial spec I and also strictly anaerobic bacteria such as, for example,
trum against gram-positive and gram-negative bacteria, Bacteroides fragilis, representatives of the order Pepto
in particular against Enterobacteriaceae; above all also 30 coccus, Peptostreptococcus and also the order Clostrid
against those which are resistant to various antibiotics, ium; furthermore mycoplasma (M. pneumoniae, M.
such as, for example, penicillins, cephalosporins, amino homim's, M. urealyticum) and also mycobacteria, for
glycosides, sulphonamides ‘and tetracyclines. example Mycobacterium tuberculosis.
These useful properties facilitate their use as chemo The above enumeration of pathogens is merely by
therapeutically active compounds in medicine and also way of example and in no way to be conceived as limit
as substances for the preservation of inorganic and or ing. Examples of diseases which may be caused by the
ganic materials, in particular of organic materials of all said pathogens or mixed infections and which may be
types, for example polymers, lubricants, dyes, ?bers, prevented, improved or cured by the compounds ac
leather, paper and wood, and of foodstuffs and water. cording to the invention which may be mentioned are:
The compounds according to the invention are active infectious diseases in humans, such as, for example,
against a very wide spectrum of microorganisms. otitis, pharyngitis, pneumonia, peritonitis, pyelonephri
Gram-negative and gram-positive bacteria and bacteria tis, cystitis, endocarditis, systemic infections, bronchitis
lilte microorganisms can be controlled with their aid, (acute, chronic), septic infections, diseases of the upper
and the diseases produced by these pathogens can also airways, diffuse panbronchiolitis, pulmonary emphy
be prevented, improved and/or cured. 45 sema, dysentery, enteritis, hepatic abscesses, urethritis,
The compounds according to the invention are par prostatitis, epididymitis, gastrointestinal infections,
ticularly active against bacteria and bacteria-like micro bone and joint infections, cystic ?brosis, skin infections,
organisms. They are therefore particularly well suited post-operative wound infections, abscesses, phlegmon,
in human and veterinary medicine for the prophylaxis wound infections, infected burns, scalds, infections in
and chemotherapy of local and systemic infections the oral region, infections after dental operations, osteo
which are produced by these pathogens. myelitis, septic arthritis, cholecystitis, peritonitis with
For example, local and/or systemic diseases which appendicitis, cholangitis, intra-abdominal abscesses,
are caused by the following pathogens or by mixtures of pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis,
the following pathogens can be treated and/or pre typhus, meningitis and infections of the nervous sys
vented: gram-positive cocci, for example staphylococci 55 tems, salpingitis, endometritis, genital infections, pel
(Staph. aureus, Staph. epidennidis) and streptococci veoperitonitis and eye infections.
(Strept. agalactiae, Strept. faecalis, Strept. pneumaniae,
In addition to humans, bacterial infections can also be
Strept. pyogenes); gram-negative cocci (Neisseria gonor treated in other species. Examples which may be men
rhoeae) and also gram~negative rods such as Enterobac tioned are: pig: coli-diarrhoea, enterotoxaemia, sepsis,
teriaceae, for example Escherichia coli, Haemophilus dysentery, salmonellosis, mastitis-metritis-agalactia syn
in?uenzae, Citrobacter (Citmb. freundii, Citrob. diver drome, mastitis; ruminants (cow, sheep, goat): diar
nis), Salmonella and Shigella; furthermore Klebsiella rhoea, sepsis, bronchopneumonia, salmonellosis, pas
(Klebs. pneumoniae, Klebs oxytoca), Enterobacter (Ent. teurellosis, mycoplasmosis, genital infections; horse:
aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. bronchopneumonias, joint-ill, puerperal and post-puerp
marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulga 65 eral infections, salmonellosis; dog and cat; broncho
ris), Providencia, Yersinia, and also the order Acineto pneumonia, diarrhoea, dermatitis, otitis, urinary tract
bacter. Moreover, the antibacterial spectrum comprises infections, prostatitis; poultry (hen, turkey, quail, pi
the order Pseudomonas (Ps. aeruginosa, Ps. maltaphilia) geon, ornamental birds and others): mycoplasmosis, E.