CA1341161C - Quinolone- and naphthyridone carboxylic acid derivatives, process for their production, antibacterial compositions and feed additives containing them - Google Patents
Quinolone- and naphthyridone carboxylic acid derivatives, process for their production, antibacterial compositions and feed additives containing them Download PDFInfo
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- CA1341161C CA1341161C CA000590013A CA590013A CA1341161C CA 1341161 C CA1341161 C CA 1341161C CA 000590013 A CA000590013 A CA 000590013A CA 590013 A CA590013 A CA 590013A CA 1341161 C CA1341161 C CA 1341161C
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/10—Spiro-condensed systems
Abstract
An antibacterially active quinolone or naphthyridonecarboxylic acid derivative of the formula (see formula I) in which R1 stands for various organic radical, 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, R4 stands for a radical of the formula (see formula II) and wherein A stands for N or C-R5, R5 stands for hydrogen, halogen methyl, cyano or nitro or else together with R1 can form a bridge of the structure (see formula III) or a pharmaceutically utilizable hydrate, acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or guanidiniunu salt of the carboxylic acid when R2 is hydrogen.
Description
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>
OOR2 (I) R4~~~N
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 (CH~)~~(CHZ)h-Y (CH2)P~O
~N~~(CH2)m ~N~(CH2)m .'s 0 CHZ ~~X3 'i~(CH2)m Le A 25 727 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, 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 _ 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 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 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 , 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 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 ~'.v.
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) 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.
.,., Compounds of the structure (Ia) 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 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--------..
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-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 _ 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 . ~ 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 (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 group yields starting compounds of the formula (IIIb):
Alkyl-0-C0~~\/~C:00-Alkyl (4) OH
00-Alkyl ~ (2) N~
It has been fomnd that quinolone- and naphthyri-donecarboxylic acid derivatives of the formula (I>
OOR2 (I) R4~~~N
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 (CH~)~~(CHZ)h-Y (CH2)P~O
~N~~(CH2)m ~N~(CH2)m .'s 0 CHZ ~~X3 'i~(CH2)m Le A 25 727 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, 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 _ 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 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 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 , 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 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 ~'.v.
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) 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.
.,., Compounds of the structure (Ia) 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 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--------..
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-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 _ 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 . ~ 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 (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 group yields starting compounds of the formula (IIIb):
Alkyl-0-C0~~\/~C:00-Alkyl (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 _ 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, 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.
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 _ 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, 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) ( 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 a 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 -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 -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 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 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 N O Z e'~
E Z t'7 N Ls. U S
S U Z Z . . . ~ U
U U
t 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 Z
Le A 25 727 I ~
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 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 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 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 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, Le A 25 727 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 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 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.
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Le A 25 727 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 25 727 100 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
Le A 25 727 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
Le A 25 727 1 a~1 161 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 Le A 25 727 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 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 Le A 25 727 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 -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 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 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 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 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
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 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 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 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 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 OOH
>~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 OOH
~ N
HO~
F
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-a ~s ~»
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 YCOOH
J x HC 1 H N ~ N
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 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 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 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 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
HO
Le A 25 727 4$ -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
>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 (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
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 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-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 ~»
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.
Le A 25 727
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) ( 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 a 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 -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 -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 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 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 N O Z e'~
E Z t'7 N Ls. U S
S U Z Z . . . ~ U
U U
t 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 Z
Le A 25 727 I ~
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 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 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 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 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, Le A 25 727 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 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 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.
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Le A 25 727 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 25 727 100 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
Le A 25 727 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
Le A 25 727 1 a~1 161 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 Le A 25 727 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 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 Le A 25 727 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 -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 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 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 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 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
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 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 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 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 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 OOH
>~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 OOH
~ N
HO~
F
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-a ~s ~»
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 YCOOH
J x HC 1 H N ~ N
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 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 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 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 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
HO
Le A 25 727 4$ -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
>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 (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
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 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-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 ~»
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.
Le A 25 727
Claims (35)
1. A quinolone- or naphthyridonecarboxylic acid derivative of the formula (I) in which R1 stands for methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, 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, R4 stands for a radical of the formula 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, Y stands for , OR, SR, X1 stands for , OR, SR, CN, CONH2, COOH or C1-C4-alkyl, X2 and Y3 can be identical or different and stand for oxygen, sulphur, NH or N-CH3, R stands for hydrogen, methyl or C1-C3-acyl, R' stands for hydrogen, C1-C3-alkyl, allyl or propargyl and R" stands for hydrogen, C1-C3-alkyl or C3-C6-cycloalkyl, where R' + R" together can also denote the groups -CH2CH2-O-CH2CH2- or -(CH2)k-, in which k can stand for 3, 4 or 5, and A stands for N or C-R5, wherein R5 stands for hydrogen, halogen, methyl, cyano or nitro, a pharmaceutically utilizable hydrate or acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or a guanidinium salt of an underlying carboxylic acid.
2. A compound of they formula (I) according to claim 1, in which R1 stands for ethyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, amino, methylamino, R2 stands for hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R3 stands for hydrogen or amino, R4 stands for a radical of the formula 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, Y stands for , OR, X1 stands for , OR or C1-C2-alkyl, X2 and X3 can be identical or different and stand for oxygen, sulphur or N-CH3, R stands for hydrogen, methyl 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-O-CH2CH2- or -(CH2)k, in which k can stand for 3 , 4 or 5, and A stands for N or C-R5, wherein R5 stands for hydrogen, halogen or methyl.
a pharmaceutically utilizable hydrate or acid addition salt, alkali metal salt, alkalines earth metal salt, silver salt or guanidinium salt.
a pharmaceutically utilizable hydrate or acid addition salt, alkali metal salt, alkalines earth metal salt, silver salt or guanidinium salt.
3. A compound of the formula (I), according to claim 1, 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, R3 stands for hydrogen, R4 stands for a radical of the formula 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, Y stands for , OR
X1 stands for , OR or methyl, X2 and X3 can be identical or different and stand for oxygen or N-CH3, 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, wherein R5 stands for hydrogen or halogen, .a pharmaceutically utilizable hydrate or acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or guanidinium salt.
X1 stands for , OR or methyl, X2 and X3 can be identical or different and stand for oxygen or N-CH3, 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, wherein R5 stands for hydrogen or halogen, .a pharmaceutically utilizable hydrate or acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or guanidinium salt.
4. A compound of formula (I) as defined in claim 1, 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, or NH((CH3)3~C-O-CO), X1 represents OH, CH3 or OCH3, and X2 and X3 each represent oxygen.
5. A quinolone- or naphthyridonecarboxylic acid derivative of the formula (I) in which R1 stands for methyl, ethyl, propyl, isopropyl, cyclo-propyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, 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, R4 stands for a radical of the formula 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, Y stands for , OR, SR, X1 stands for , OR, SR, CN, CONH2 COOH, X2 and X3 can be identical or different and stand for oxygen, sulphur, NH or N-CH3, R stands for hydrogen, methyl or C1-C3-acyl, R' stands for hydrogen, C1-C3-alkyl, allyl or propargyl and R" stands for hydrogen, C1-C3-alkyl or C3-C6-cycloalkyl, where R' + R" together can also denote the groups -CH2CH2-O-CH2CH2- or -(CH2)k-, in which k can stand for 3, 4 or 5, and A stands for N or C-R5, wherein R5 stands for hydrogen, halogen, methyl, cyano or nitro a pharmaceutically utilizable hydrate or acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or a guanidinium salt of an underlying carboxylic acid.
6. A compound of the formula (I) according to claim 5, in which R1 stands for ethyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, amino, methylamino, R2 stands 7.or hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R3 stands for hydrogen or amino, R4 stands for a radical of the formula 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, Y stands for , OR, X1 stands for or OR
X2 and X3 can be identical or different and stand for oxygen, sulphur or N-CH3, R stands far hydrogen, methyl 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-O-CH2CH2- or -(CH2)k, in which k can stand for 3, 4 or 5, and A stands for N or C-R5, wherein R5 stands for hydrogen, halogen or methyl, a pharmaceutically utilizable hydrate or acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or guanidinium salt.
X2 and X3 can be identical or different and stand for oxygen, sulphur or N-CH3, R stands far hydrogen, methyl 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-O-CH2CH2- or -(CH2)k, in which k can stand for 3, 4 or 5, and A stands for N or C-R5, wherein R5 stands for hydrogen, halogen or methyl, a pharmaceutically utilizable hydrate or acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or guanidinium salt.
7. A compound of the formula (I), according to claim 5, 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, R3 stands for hydrogen, R4 stands for a radical of the formula 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, ~
Y stands for , OR, X1 stands for or OR
X2 and X3 can be identical or different and stand for oxygen or N-CH3, 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, wherein R5 stands for hydrogen or halogen, a pharmaceutically utilizable hydrate or acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or guanidinium salt.
Y stands for , OR, X1 stands for or OR
X2 and X3 can be identical or different and stand for oxygen or N-CH3, 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, wherein R5 stands for hydrogen or halogen, a pharmaceutically utilizable hydrate or acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or guanidinium salt.
8. A compound of formula (I) as defined in claim 5, 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, or HH((CH3), C-O-CO), X1 represent OH, or OCH3, and X2 and X3 each represent oxygen.
9. 1-Cyclopropyl-7-(3-ethylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula
10. 8-Chloro-1-cyclopropyl-7-(3-ethylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula
11. 1-Cyclopropyl-7-(3-ethylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula
12. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxy-3-methlaminomethyl-1-pyrrolidinyl)-4-oxo-3-quinoline carboxylic acid of the formula
13. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxy-3-methlaminomethyl-1-pyrrolidinyl)-4-oxo-3-quinoline carboxylic acid of the formula
14. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxy-3-methyl-1-pyrrolidinyl)-4-oxo-3-quinoline carboxylic acid of the formula
15. 7-(3-Aminomethyl-3-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula
16. 7-(3-Aminomethyl-3-hydroxy-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula
17. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxy-3-dimethylaminomethyl-1-pyrrolidinyl)-4-oxo-3-quinoline-carboxylic acid of the formula
18. 1-Cyrlopropyl-7-(4-ethylaminomethyl-4-hydroxy-1-piperidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula
19. A pharmaceutically utilizable hydrate, acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or guaridinium salt of a compound according to any one of claims 9 to 18.
20. A process for preparing a compound of the formula (I), according to any one of claims 1 to 8, which process comprises:
(a) reacting a compound of the formula (II) in which Z stands for fluorine or chlorine and R1, R2, R3 arad A have the meaning indicated in any one of claims 1 to 8 with a compound of the formula {III) R4-H (III) in which R4 has the meaning indicated in any one of claims 1 to 8, if required, in the presence of an acid entrainer, or (b) to prepare a compound of the formula (Ia) in which R1, R2, R3, A, X2, X3, m and p have the meaning indicated in any one of claims 1 to 8, reacting a compound of the formula (IV) in which R1, R2, R3, A, m and p haves the meaning indicated in any one of claims 1 to 8, with a compound of the formula (V) H-X2-CH2-CH2-X3-H (V) in which X2 and X3 have the meaning indicated in any one of claims 1 to 8.
(a) reacting a compound of the formula (II) in which Z stands for fluorine or chlorine and R1, R2, R3 arad A have the meaning indicated in any one of claims 1 to 8 with a compound of the formula {III) R4-H (III) in which R4 has the meaning indicated in any one of claims 1 to 8, if required, in the presence of an acid entrainer, or (b) to prepare a compound of the formula (Ia) in which R1, R2, R3, A, X2, X3, m and p have the meaning indicated in any one of claims 1 to 8, reacting a compound of the formula (IV) in which R1, R2, R3, A, m and p haves the meaning indicated in any one of claims 1 to 8, with a compound of the formula (V) H-X2-CH2-CH2-X3-H (V) in which X2 and X3 have the meaning indicated in any one of claims 1 to 8.
21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 as the active ingredient in association with a pharmaceutically acceptable excipient, diluent or carrier.
22. A pharmaceutical composition according to claim 21, wherein the active ingredient comprises 0.1 to 99.5% by weight of the composition.
23. A composition according to claim 21, wherein the active ingredient is L-cyclopropyl-7-(3-ethylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid.
24. A composition according to claim 21, wherein the active ingredient is 8-chloro-1-cyclopropyl-7-(3-ethylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid.
25. A composite-on according to claim 21, wherein the active ingredient is 1-cyclopropyl-7-(3-ethylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid.
26. A composition according to claim 21, wherein the active ingredient is 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxy-3-methylaminomethyl-1-pyrrolidinyl)-4-oxo-3-quinoline carboxylic acid.
27. A composition according to claim 21, wherein the active ingredient is 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxy-3-methylaminomethyl-1-pyrrolidinyl)-4-oxo-3-quinoline carboxylic acid.
28. A composition according to claim 21, wherein the active ingredient is 7-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxy-3-methyl-1-pyrrolidinyl)-4-oxo-3-quinoline carboxylic acid.
29. A composition according to claim 21, wherein the active ingredient is 7-(3-aminomethyl-3-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid.
30. A composition according to claim 21, wherein the active ingredient is 7-(3-aminomethyl-3-hydroxy-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid.
31. A composition according to claim 21 wherein the active ingredient is 1-cyclopropyl-6, 8-difluoro-1,4-dihydro-7-(3-hydroxy-3-dimethylaminomethyl-1-pyrrolidinyl)-4-oxo-3-quinoline carboxylic acid.
32. A composition according to claim 21 wherein the active ingredient is 1-cyclopropyl-7-(4-ethylaminomethyl-4-hydroxy-1-piperidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid.
33. A process for preparing a pharmaceutical composition comprising a compound according to any one of claims 1 to 18 as the active ingredient which process comprises admixing the active ingredient with a pharmaceutically acceptable excipient, diluent or carrier.
34. Use of a compound as defined in any one of claims 1 to 18 to combat a bacterial. infection in an mammal.
35. A commercial package comprising a pharmaceutically effective amount of a compound as defined in any one of claims 1 to 18 together with instructions for use thereof to combat a bacterial infection in a mammal.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3803478.6 | 1988-02-05 | ||
| DE3803478 | 1988-02-05 | ||
| DEP3814517.0 | 1988-04-29 | ||
| DE3814517A DE3814517A1 (en) | 1988-02-05 | 1988-04-29 | CHINOLON AND NAPHTHYRIDONE CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND ANTIBACTERIAL AGENTS AND FOOD ADDITIVES CONTAINING THE SAME |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1341161C true CA1341161C (en) | 2001-01-02 |
Family
ID=25864593
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000590013A Expired - Fee Related CA1341161C (en) | 1988-02-05 | 1989-02-03 | Quinolone- and naphthyridone carboxylic acid derivatives, process for their production, antibacterial compositions and feed additives containing them |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0326916A3 (en) |
| JP (1) | JP2788043B2 (en) |
| KR (1) | KR0136792B1 (en) |
| CA (1) | CA1341161C (en) |
| DE (1) | DE3814517A1 (en) |
| FI (1) | FI94524C (en) |
| HU (1) | HUT55357A (en) |
| PT (1) | PT89614B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5137892A (en) * | 1990-12-12 | 1992-08-11 | Abbott Laboratories | Quinoline, naphthyridine and pyridobenzoxazine derivatives |
| FR2673426B1 (en) * | 1991-03-01 | 1993-07-16 | Bouchara Sa | NEW QUINOLONES, THEIR PREPARATION PROCESS AND THE CLOSING COMPOSITIONS. |
| FR2674854B1 (en) * | 1991-04-04 | 1995-03-03 | Bouchara | NEW QUINOLONES THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS THEREOF. |
| FR2675144B1 (en) * | 1991-04-10 | 1995-06-16 | Bouchara Sa | NEW DIFLUORINATED QUINOLONES - THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
| EP0541086A1 (en) * | 1991-11-08 | 1993-05-12 | Kaken Pharmaceutical Co., Ltd. | Antibacterial 6-fluoro-quinolones having an oxime group on the substituent in position 7 |
| EP0677522A4 (en) * | 1992-12-28 | 1995-12-27 | Yoshitomi Pharmaceutical | 8-methoxyquinolonecarboxylic acid derivative. |
| AU4272793A (en) * | 1993-04-24 | 1994-11-21 | Korea Research Institute Of Chemical Technology | Novel quinolone carboxylic acid derivatives and process for preparing the same |
| KR950018003A (en) * | 1993-12-09 | 1995-07-22 | 스미스클라인 비참 피엘씨 | Novel quinolone derivatives and methods for their preparation |
| TW425394B (en) | 1996-04-24 | 2001-03-11 | Daiichi Seiyaku Co | Antimicrobial quinolone derivatives having 3-(N-cycloalkyl) aminomethylpyrrolidine group |
| PT1666477E (en) | 2003-09-10 | 2013-08-28 | Kyorin Seiyaku Kk | 7-(4-substituted 3- cyclopropylaminomethyl-1- pyrrolidinyl) q uinolonecarboxylic acid derivative |
| EP2149571A4 (en) | 2007-05-24 | 2010-09-01 | Kyorin Seiyaku Kk | Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position |
| DE102012006884A1 (en) * | 2012-04-04 | 2013-10-10 | Merck Patent Gmbh | Cyclic amides as MetAP-2 inhibitors |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2188317A (en) | 1938-01-04 | 1940-01-30 | Ellsworth F Seaman | Noncarbonizing arc resistant material |
| US4508724A (en) * | 1984-02-03 | 1985-04-02 | A. H. Robins Company, Inc. | Aryloxymethylpyrrolidinols and piperidinols having antidepressant, antiarrhythmic or hypotensive activity |
| JPS61137885A (en) * | 1984-12-08 | 1986-06-25 | Dainippon Pharmaceut Co Ltd | 1,8-naphthylidine derivative, its ester and salt |
| US4657913A (en) * | 1985-04-18 | 1987-04-14 | Warner-Lambert Company | Trifluoro- quinoline -3- carboxylic acids and their use as anti-bacterial agents |
| JPH0696572B2 (en) * | 1985-07-17 | 1994-11-30 | 大日本製薬株式会社 | Pyridonecarboxylic acid derivatives, their esters and their salts |
| JPH0753715B2 (en) * | 1986-02-25 | 1995-06-07 | 大塚製薬株式会社 | Benzoheterocyclic compound |
| DE3705621C2 (en) * | 1986-02-25 | 1997-01-09 | Otsuka Pharma Co Ltd | Heterocyclic substituted quinolonecarboxylic acid derivatives |
| EP0241206A3 (en) * | 1986-03-31 | 1989-05-10 | Sankyo Company Limited | Quinoline-3-carboxylic acid derivatives, their preparation and use |
| JPS63198664A (en) * | 1986-03-31 | 1988-08-17 | Sankyo Co Ltd | Quinolonecarboxylic acid derivative |
| EP0242789A3 (en) * | 1986-04-25 | 1990-09-05 | Dainippon Pharmaceutical Co., Ltd. | Novel quinoline derivates and processes for preparation thereof |
| US4771055A (en) * | 1986-07-28 | 1988-09-13 | Warner-Lambert Company | 7-[[3-(aminomethyl)-3-alkyl]-1-pyrrolidinyl]-quinoline-carboxylic acids |
| FR2634483B2 (en) * | 1987-12-29 | 1994-03-04 | Esteve Labor Dr | DERIVATIVES OF ACIDS 7- (1-AZETIDINYL) -1,4-DIHYDRO-4-OXOQUINOLEINE-3-CARBOXYLIQUES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
-
1988
- 1988-04-29 DE DE3814517A patent/DE3814517A1/en not_active Withdrawn
-
1989
- 1989-01-25 EP EP89101242A patent/EP0326916A3/en not_active Withdrawn
- 1989-01-31 JP JP1019946A patent/JP2788043B2/en not_active Expired - Lifetime
- 1989-02-02 FI FI890503A patent/FI94524C/en not_active IP Right Cessation
- 1989-02-03 CA CA000590013A patent/CA1341161C/en not_active Expired - Fee Related
- 1989-02-03 PT PT89614A patent/PT89614B/en not_active IP Right Cessation
- 1989-02-03 HU HU906247A patent/HUT55357A/en unknown
- 1989-02-04 KR KR1019890001321A patent/KR0136792B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0326916A2 (en) | 1989-08-09 |
| DE3814517A1 (en) | 1989-08-17 |
| KR890012996A (en) | 1989-09-20 |
| FI94524C (en) | 1995-09-25 |
| EP0326916A3 (en) | 1990-05-16 |
| FI94524B (en) | 1995-06-15 |
| HUT55357A (en) | 1991-05-28 |
| JP2788043B2 (en) | 1998-08-20 |
| KR0136792B1 (en) | 1998-04-25 |
| PT89614B (en) | 1994-01-31 |
| PT89614A (en) | 1989-10-04 |
| FI890503A0 (en) | 1989-02-02 |
| JPH01226883A (en) | 1989-09-11 |
| FI890503A (en) | 1989-08-06 |
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