CA1122984A - Pyrido (3,2,1-jk) carbazol derivatives - Google Patents
Pyrido (3,2,1-jk) carbazol derivativesInfo
- Publication number
- CA1122984A CA1122984A CA315,257A CA315257A CA1122984A CA 1122984 A CA1122984 A CA 1122984A CA 315257 A CA315257 A CA 315257A CA 1122984 A CA1122984 A CA 1122984A
- Authority
- CA
- Canada
- Prior art keywords
- group
- carbazol
- hexahydro
- pyrido
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- 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
- C07D471/06—Peri-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles 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 carbon atoms of the ring system
Abstract
ABSTRACT OF THE DISCLOSURE
A pyrido[3,2,1-jk]carbazol derivative represented by the formula (I) (I) wherein R represents a hydroxy group, an alkoxy group which may be substituted with a halogen atom or with a 4-methyl-1-piperizinyl group, a hydrazino group or a
A pyrido[3,2,1-jk]carbazol derivative represented by the formula (I) (I) wherein R represents a hydroxy group, an alkoxy group which may be substituted with a halogen atom or with a 4-methyl-1-piperizinyl group, a hydrazino group or a
Description
llZ2,~34 1. Field of the Invention . .
This invention relates to pyrido[3,2,1-jk]carbazol derivatives represented by the formula (I) hereinafter defined and the pharmaceutically acceptable salts thereof which are useful as antimicrobial, anti-cancer and antiviral agents, a process for preparing the same and a pharmaceutical composition containing pyrido[3,2,1-jk]carbazol derivative.
This invention relates to pyrido[3,2,1-jk]carbazol derivatives represented by the formula (I) hereinafter defined and the pharmaceutically acceptable salts thereof which are useful as antimicrobial, anti-cancer and antiviral agents, a process for preparing the same and a pharmaceutical composition containing pyrido[3,2,1-jk]carbazol derivative.
2. DeScription of the Prior Art It is known that certain types of polyheterocyclic compounds exhibit antimicrobial activities. For example, Gerster et al U.S. Patent 3,917,609 discloses substituted derivatives of 1,2-dihydro-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline which are useful as antimicrobial agents or as intermediates for the preparation of antimicrobial agents.
Also, Gerster et al U.S. Patents 3,896,131; 3,985,882;
Also, Gerster et al U.S. Patents 3,896,131; 3,985,882;
3,969,463; 4,001,243 and 4,014,877 disclose 6,7-dihydro-1-oxo-lH, 5H-benzo[ij]quinolizine derivatives having antimicrobial activities.
However, the pyrido[3,2,1-jk]carbazol derivatives of the present invention are structurally different from these quinoline and quinoliæine compounds.
DETAILED DESCRIPTION OF T~IE INVENTION
.. . . . ...
The term "alkyl" as used herein refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl groups.
The term "alkoxy" as used herein refers to a straight or branched alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy groups.
1 The term "halogen" as used herein includes a chlorine atom, a bromine atom, an iodine atom and a fluorine atom.
The term "alkanoylamino" as used herein refers to a straight or branched alkanoylamine group having l to 4 carbon atoms such as an acetylamino group, a propanoylamino group, a butanoylamino group, an isobutanoylamino group and the like.
The term "an alkoxy group which may be-substituted with a halogen atom or with a 4-methyl-l-piperidinyl group" as used herein for R means the alkoxy group as defined above which may be substituted with a halogen atom or a 4~methyl-l-piperidinyl group and includes methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy, monochloromethoxy, 2-bromo-ethoxy, 3-bromopropoxy, 4-fluorobutoxy, 3-chloro-2-methyl-propoxy, 2-fluoroethoxy, 2-(4-methyl-l-piperidinyl)ethoxy, 3-(4-methyl-l-piperidinyl)propoxy, 4-(4-methyl-l-piperidiny].)-butoxy, 3-(~-methyl-l-piperidinyl)-2-methylpropoxy and the like groups.
The pyrido[3,2,l-jk]carbazol derivatives represented by the formula (I) above are novel compounds and these compounds as well as the pharmaceutical.ly acceptable salts thereof are useful as antimicrobial, anti-cancer and antiviral a~ents.
Representative compounds of the present invention included in the formula (I) are as follows:
Ethyl 7a,8,9,lO,ll,lla-hexahydro-4-oxo-4H-pyrido13,2,l-j~l-carbazol-5-carboxylate, 7a,8,9,lO,ll,l.la-hexahydro-4-oxo-4H-pyrido[3,2,l-jk]carbazol-5-carboxylic acid, Propyl 7a,8,9,lO,ll,lla-hexahydro-4-oxo-4H-pyrido[3,2,l-jk]-carbazol-5-carboxylate, Isopropyl 7a,~,9,lO,ll,lla-hexahydro-4-oxo-4H-pyrido[3,2,l-jk]carbazol-5-carboxylate, g~
12-Methyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]earbazol-5-carboxylie acid, 2-Propyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic aeid, 2-Isopropyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, Ethyl 2-methyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido L 3, 2 ,1- jk]carbazol-5-carboxylate, Propyl 2-nitro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-10pyrido[3,2,1-jk]carbazol-5-carboxylate, Methyl 2-amino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]earbazol-5-earboxylate, Butyl 2-aeetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]earbazol-5-carboxylate, Ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, Ethyl 1,3-dichloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-earboxylate, 2-Nitro-7a,8,9,10,11,11a-he~ahydro-4-oxo-4H-pyrido[3,2,1-20jk]earbazol-5-earboxylie aeid, 2-Amino-7a,8,9,10,11,11a-h~xahydro-4-oxo-4EI-pyrido[3,2,1-jk]earbazol-5-earboxylic acid, 2-Acetylamino-7a,8,9,10,11,1la-hexahydro-4-oxo-4H-pyri.do[3,2,1-jk]earbazol-5-earboxylie aeid, 2-Propanoylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylie aeid, 2-Isobutanoylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]earbazol-5-earboxylic acid, 2-Chloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-30jk]carbazol-5-earboxylic aeid, llZ;~ 4 1 2-Bromo-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyridoE3,2,1-jk]carbazol-5-carboxylic acid, 2-Iodo-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]-carbazol-5-carboxylic acid, 2-Fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, l-Fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, l-Chloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, 1,2-Dichloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid, 1,3-Dichloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, 1,3-Dimethyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-~k]carbazol-5-carboxylic acid, 1,2-Dimethyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4EI-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid, 1,2-Diacetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, Ethyl 2-methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-S-carboxylate, 2-Methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid, 1,2-Diethoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4~-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid, 2-Butoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, ~-Bromoethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, g~4 1 ~-Chloroethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-Bromoethyl 2-chloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4EI-pyridol3,2,1-jk]carbazol-5-carboxylate, ~-Chloroethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, y-Bromopropyl 2-fluoro-7a,8,9,10,11,1la-hexahydro-4-oxo-4H-pyridor3,2,1-jk]carbazol-5-carboxylate, ~-Fluoroethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyridol3,2,1-jk]carbazol-5-carboxylate, ~-Methyl-~-chloropropyl-7a,8,9,10,11,1~a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-Chloroethyl 2-methyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-Bromoethyl 2-methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, y-Bromopropyl 3-acetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, 1,3,-Dimethyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyr.ido[3,2,1,-jk]carbazol-5-carbohydrazide, 2-Methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid 5-nitrofur~urylidc-ne-hydra~ide, 7a,8,9,10,11,11a-Hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-carboxylic acid 5-nitrofurfurylidenehydrazide, ~-(4-Methyl-l-piperidinyl)ethyl 2-methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-(4-Methyl-l-piperidinyl)ethyl 7a,8,9,10,11,11a-hexahydro-
However, the pyrido[3,2,1-jk]carbazol derivatives of the present invention are structurally different from these quinoline and quinoliæine compounds.
DETAILED DESCRIPTION OF T~IE INVENTION
.. . . . ...
The term "alkyl" as used herein refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl groups.
The term "alkoxy" as used herein refers to a straight or branched alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy groups.
1 The term "halogen" as used herein includes a chlorine atom, a bromine atom, an iodine atom and a fluorine atom.
The term "alkanoylamino" as used herein refers to a straight or branched alkanoylamine group having l to 4 carbon atoms such as an acetylamino group, a propanoylamino group, a butanoylamino group, an isobutanoylamino group and the like.
The term "an alkoxy group which may be-substituted with a halogen atom or with a 4-methyl-l-piperidinyl group" as used herein for R means the alkoxy group as defined above which may be substituted with a halogen atom or a 4~methyl-l-piperidinyl group and includes methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy, monochloromethoxy, 2-bromo-ethoxy, 3-bromopropoxy, 4-fluorobutoxy, 3-chloro-2-methyl-propoxy, 2-fluoroethoxy, 2-(4-methyl-l-piperidinyl)ethoxy, 3-(4-methyl-l-piperidinyl)propoxy, 4-(4-methyl-l-piperidiny].)-butoxy, 3-(~-methyl-l-piperidinyl)-2-methylpropoxy and the like groups.
The pyrido[3,2,l-jk]carbazol derivatives represented by the formula (I) above are novel compounds and these compounds as well as the pharmaceutical.ly acceptable salts thereof are useful as antimicrobial, anti-cancer and antiviral a~ents.
Representative compounds of the present invention included in the formula (I) are as follows:
Ethyl 7a,8,9,lO,ll,lla-hexahydro-4-oxo-4H-pyrido13,2,l-j~l-carbazol-5-carboxylate, 7a,8,9,lO,ll,l.la-hexahydro-4-oxo-4H-pyrido[3,2,l-jk]carbazol-5-carboxylic acid, Propyl 7a,8,9,lO,ll,lla-hexahydro-4-oxo-4H-pyrido[3,2,l-jk]-carbazol-5-carboxylate, Isopropyl 7a,~,9,lO,ll,lla-hexahydro-4-oxo-4H-pyrido[3,2,l-jk]carbazol-5-carboxylate, g~
12-Methyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]earbazol-5-carboxylie acid, 2-Propyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic aeid, 2-Isopropyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, Ethyl 2-methyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido L 3, 2 ,1- jk]carbazol-5-carboxylate, Propyl 2-nitro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-10pyrido[3,2,1-jk]carbazol-5-carboxylate, Methyl 2-amino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]earbazol-5-earboxylate, Butyl 2-aeetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]earbazol-5-carboxylate, Ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, Ethyl 1,3-dichloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-earboxylate, 2-Nitro-7a,8,9,10,11,11a-he~ahydro-4-oxo-4H-pyrido[3,2,1-20jk]earbazol-5-earboxylie aeid, 2-Amino-7a,8,9,10,11,11a-h~xahydro-4-oxo-4EI-pyrido[3,2,1-jk]earbazol-5-earboxylic acid, 2-Acetylamino-7a,8,9,10,11,1la-hexahydro-4-oxo-4H-pyri.do[3,2,1-jk]earbazol-5-earboxylie aeid, 2-Propanoylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylie aeid, 2-Isobutanoylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]earbazol-5-earboxylic acid, 2-Chloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-30jk]carbazol-5-earboxylic aeid, llZ;~ 4 1 2-Bromo-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyridoE3,2,1-jk]carbazol-5-carboxylic acid, 2-Iodo-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]-carbazol-5-carboxylic acid, 2-Fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, l-Fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, l-Chloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, 1,2-Dichloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid, 1,3-Dichloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, 1,3-Dimethyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-~k]carbazol-5-carboxylic acid, 1,2-Dimethyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4EI-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid, 1,2-Diacetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, Ethyl 2-methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-S-carboxylate, 2-Methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid, 1,2-Diethoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4~-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid, 2-Butoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid, ~-Bromoethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, g~4 1 ~-Chloroethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-Bromoethyl 2-chloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4EI-pyridol3,2,1-jk]carbazol-5-carboxylate, ~-Chloroethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, y-Bromopropyl 2-fluoro-7a,8,9,10,11,1la-hexahydro-4-oxo-4H-pyridor3,2,1-jk]carbazol-5-carboxylate, ~-Fluoroethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyridol3,2,1-jk]carbazol-5-carboxylate, ~-Methyl-~-chloropropyl-7a,8,9,10,11,1~a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-Chloroethyl 2-methyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-Bromoethyl 2-methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, y-Bromopropyl 3-acetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, 1,3,-Dimethyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyr.ido[3,2,1,-jk]carbazol-5-carbohydrazide, 2-Methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid 5-nitrofur~urylidc-ne-hydra~ide, 7a,8,9,10,11,11a-Hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-carboxylic acid 5-nitrofurfurylidenehydrazide, ~-(4-Methyl-l-piperidinyl)ethyl 2-methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-(4-Methyl-l-piperidinyl)ethyl 7a,8,9,10,11,11a-hexahydro-
4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, 1 ~-(4-Methyl-l-piperidinyl)ethyl 1,3-dimethyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol 5-carboxylate, ~-Methyl-r-chloropropyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, 2-Fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carbohydrazide, 2-Fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid 5-nitrofurfurylidene-hydrazide, ~-(4-Methyl-l-piperazinyl)ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-(4-Methyl-l-piperidyl)methyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-(4-Methyl-l-piperidyl)ethyl 2-chloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4~1-pyrido[3,2,1-jk]carbazol-5-carboxylate, ~-(4-Methyl-l-piperidyljpropyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-~-oxo-41~-pyrido[3,2,1-jk]carbaYol-5-carboxylate, ~-Methyl-r-(4-methyl-1-piperidyl)propyl 2-fluoro-7a,8,9, lO,ll,lla-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-
5-carboxylate, and the like.
The pyrido[3,2,1-jk]carbazol compounds of the present invention represented by the formula (I) can be prepared by various alternative procedures. A typical process for the preparation of the compounds of the formula (I? can be illustrated by the following Reaction Scheme-I.
1 Reaction Scheme-I
_ H
( )n ~ ~O + R'OCH=C/
(II) tIII) ~COR
n ~ COR (Y)n~3/COR
(IV) ll~a 11\ / 8 (I) wherein Y, R and n are as defined above, R may be the same or different, and R' represents an alkyl group.
The above process can be illustrated hereinafter in greater detail.
The compounds of the ormulae (II) and (III) used as starting materials in the above process are known compounds or can be easily prepared in accordance with the known procedures.
The reaction between the compound of the formula (II) and the compound of the formula (III) can be effected in the absence of solvents or in the presence of solvents such as methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide and the like, preferably in the absence of solvents.
The compound of the formula (III) can be used in excess amounts over the equimolar amount relative to the compounds 1~2~
1 f the formula (II), preferably in an equimolar amount in the absence of solvents and in an amount of from 1.1 to 1.5 mol per mol of the compound of the formula (II) in the presence of solvents. The reaction can generally be carried out at a temperature of from room temperature (about 15 to 30C) to about 150C, preferably 100 to 130C, for a period of from about 0.5 to about 6 hours thereby easily yielding the compound represented by the formula (IV).
The subsequent cyclization reaction of the thus obtained compound of the formula (IV) can be effected in accordance with a conventional cyclization reaction, for example, a method comprising heating the compound of the formula (IV) or a cyclization method using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid and the like. When the cylization is effected by heating, it is preferred to heat the compound of the formula (IV) in a solvent such as high boiling point hydro-carbons or high boiling point ethers, for example, tetralin diphenyl ether, diethylene glycol dimethyl ether, etc. at a temperature of about 100 to about 250C, preferably 150 to 200C for a period of about 0.5 to about 6 hours. When the cyclization is effected usiny an acidic substance, the cyclization can be effected in the presence of the acid substance in an approximately equimolar amount to a large excess amount, preferably 10 to 20 molar excess amount, relative to the amount of the compound of the formula (IV) at a temperature of about 100 to about 150C for a period of about 0.5 to about
The pyrido[3,2,1-jk]carbazol compounds of the present invention represented by the formula (I) can be prepared by various alternative procedures. A typical process for the preparation of the compounds of the formula (I? can be illustrated by the following Reaction Scheme-I.
1 Reaction Scheme-I
_ H
( )n ~ ~O + R'OCH=C/
(II) tIII) ~COR
n ~ COR (Y)n~3/COR
(IV) ll~a 11\ / 8 (I) wherein Y, R and n are as defined above, R may be the same or different, and R' represents an alkyl group.
The above process can be illustrated hereinafter in greater detail.
The compounds of the ormulae (II) and (III) used as starting materials in the above process are known compounds or can be easily prepared in accordance with the known procedures.
The reaction between the compound of the formula (II) and the compound of the formula (III) can be effected in the absence of solvents or in the presence of solvents such as methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide and the like, preferably in the absence of solvents.
The compound of the formula (III) can be used in excess amounts over the equimolar amount relative to the compounds 1~2~
1 f the formula (II), preferably in an equimolar amount in the absence of solvents and in an amount of from 1.1 to 1.5 mol per mol of the compound of the formula (II) in the presence of solvents. The reaction can generally be carried out at a temperature of from room temperature (about 15 to 30C) to about 150C, preferably 100 to 130C, for a period of from about 0.5 to about 6 hours thereby easily yielding the compound represented by the formula (IV).
The subsequent cyclization reaction of the thus obtained compound of the formula (IV) can be effected in accordance with a conventional cyclization reaction, for example, a method comprising heating the compound of the formula (IV) or a cyclization method using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid and the like. When the cylization is effected by heating, it is preferred to heat the compound of the formula (IV) in a solvent such as high boiling point hydro-carbons or high boiling point ethers, for example, tetralin diphenyl ether, diethylene glycol dimethyl ether, etc. at a temperature of about 100 to about 250C, preferably 150 to 200C for a period of about 0.5 to about 6 hours. When the cyclization is effected usiny an acidic substance, the cyclization can be effected in the presence of the acid substance in an approximately equimolar amount to a large excess amount, preferably 10 to 20 molar excess amount, relative to the amount of the compound of the formula (IV) at a temperature of about 100 to about 150C for a period of about 0.5 to about
6 hours, whereby the desired pyrido[3,2,1-jk]carbazol derivatives of the formula (I) can be produced advantageously.
llZ'~
1 The compounds of the formula (I) wherein R represents an alkoxy group which may be substituted with a halogen ato~ or A ~ p , pe ~ iJ ~` n y I
e~ a 4-methyl-1-pipeE-i inyl group, or a hydroxy group, i.e., the compounds of the formula (Ia) or (Ib), can be produced from each other by hydrolysis or esterification as shown by the Reaction Scheme - II below.
Reaction Scheme - II
(Y)n / COR Hydrolysis (Y)n COOH
Ester fication (Ia) (Ib) wherein Y and n are as defined above, and R2 represents an alkoxy group which may be substituted with a halogen akom or a p;pe r i d l'n y I
4-methyl-1-~ptri~h~t group.
In the above Reaction Scheme - II, the hydrolysis of the compound of the formula (Ia) into the compound of the formula (Ib) can be achieved by a conventional hydrolysis procedure in the presence of a usual catalyst, for example, a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, or an inorganic or organic acid such as sulfuric acid, hydrochloric acid, nitric acid, acetic acid, an aromatic sulfuric acid and the like. The hydrolysis can be carried out in a solvent such as water, methanol, ethanol, isopropanol, acetonel methyl ethyl ketone, dioxane, ethylene glycol, acetic acid and the like at a temperature of g~ ~
1 from room temperature to about 200C, preferably 50 to 150~C
for a period of about 0.5 to about 6 hours.
The esterification of the compound of the formula (Ib~
into the compound of the formula (Ia) can be achieved by a usual esterification procedure, for example, a method using a carboxylic acid, an acid halide or an acid anhydride.
The esterification using the carboxylic acid [Formula (Ib)] can be carried out in the presence of a catalyst generally used in the esterification, for example, an inorganic acid such as hydrogen chloride gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid,- boron trifluoride, perchloric acid and the like, an organic acid such as trifluoroacetic acid, trichloromethanesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, benzene-sulfonic acid, ethanesulfonic acid and the like, an acid anhydride such as trichloromethanesulfonic anhydride, trifluoro-methanesulfonic anhydride and the like, or thionyl chloride and the like.
The esterification reaction can be carried out in the presence or absence o~ a solvent. Examples of solvents which can be used are aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogena-ted hydrocarbons such as dichloro-methane dichloroethane, chloroform, carbon tetrachloride and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether and the like.
The amount of an alcohol having the formula R OH
wherein R2 is as defined above, used in the esterification is not critical and can be over an approximately equimolar amount relative to the compound of the formula (Ib), but is preferably a molar excess amount in the absence of solvents and is about 1 1 to about 5 mols, preferably 1 to 2 mols, per mol of the compound of the formula (Ib). This esterification can be carried out at a temperature of about -20 to about 200C, preferably 0 to 150C for a period of about 0.5 to about 6 hours.
The esterification using an acid halide of the compound of the formula (Ib) can be achieved by reacting an acid halide, which is prepared from the compound of the formula (Ib) and a suitable halogenating agent, with an alcohol of the formula R20H wherein R is as defined above.
The halogenation reaction between the compound of the formula (Ib) and the halogenating agent can be conducted in the presence or absence of solvents. Suitable examples of halogenating agents are thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide and the like. Suitable examples of solvents which can be used in the halogenation reaction are aromatic hydro-carbons such as benzene, toluene, xylene and the like, halogen-ated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and the like. The halogenating agent can be used in a large molar excess amount relative to the compound of the formula (Ib) in the absence of solvents, or in an amount of at least an equimolar amount, preferably 1 to 2 mols, per mol of the compound of the formula (Ib) in the presence of solvents. The halogenation reaction can be conducted at a temperature of from room temperature to about 100C, preferably room temperature to 50C, for about 1 to 3 hours.
The reaction between the acid halide of the compound of the formula (Ib) prepared above and an alcohol of the 1~2'~84 1 formula R2O~ wherein R2 is as defined above can be carried out with or without using solvents in the presence of a hydrogen halide acceptor. Suitable examples of solvents are aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogenated hydrocarbons such as dichloromethane, dichloroethane~
chloroform, carbon tetrachloride and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and the like, pyridine and the like. Suitable examples of hydrogen halide acceptors are inorganic basic compounds such as sodium carbonate, sodium bicarbonate, potassium carbonate and the like, and tertiary amines such as triethylamine, pyridine, quinoline, N,N-dimethylaniline and the like. Such hydrogen halide acceptors aan be used in an amount of at least equimolar amount, preferably 1 to 2 mols, per mol of the acid halide of the compound of the formula (Ib). The reaction can be carried out at a temperature of about -10C
to about 50C, preferably 0C to room temperature, for a period of about 30 minutes to about 6 hours.
The alcohol of the formula R2OI1 can be used in a large molar excess relative to the acid halide of the compound of the formula ~Ib) when the reaction is carried out in the absence oE solvent, or in an amount of at least equimolar amount, preferably 1 to 2 mols, per mol of the acid halide of the compound o~ the formula (Ib) when the reaction is carried out in a solvent.
The pyrido[3,2,1-jk]carbazol derivatives represented by the formula (I) wherein R represents a hydrazin~ group or a -NHN=CH ~ NO2 group, i.e., the compounds of the formula (Id) or (Ie), can also be prepared by the following Reaction Scheme - III.
112'~
1 Reaction Scheme - III
N
~ + NH2NH2 )~\
(Ic) (V) n ~ CONHNH2 I l CHO NO
G' 2 (Id) (VI) zo ~ )n~ CON~IN=c~l ~3 2 \
(Ie) wherein Y and n are as defined above, and R3 represents an alkoxy group.
The reaction of the compound of the formula (Ic) with hydrazine of the formula (V) can be carried out in a solvent.
-13- ~
8~
1 Examples of solvents are aromatic hydrocarbons such as benzene, toluene, xylene and the li~e, lower alcohols such as methanol, ethanol, propanol and the like, ethers such as diethyl ether, tetrahydro~uran, dioxane, ethylene glycol monomethyl ether and the like, dimethyl sulfoxide dimethylformamide and the like.
The reaction can be carried out under pressurized conditions, i.e., at a pressure of about 1 to about 10 atms., preferably 1 to 5 atms., at a temperature of about 50 to about 150C, preferably 60 to 100C for a period of about 1 to about 5 hours, using at least an equimolar amount, preferably 1 to 2 mols, of hydrazine of the formula (V) per mol of the compound of the formula (Ic).
The subsequent reaction of the compound of the formula (Id) thus obtained and the compound of the formula (IV) can be carried out in a solvent. Examples of solvents which can be used are lower alcohols such as methanol, ethanol, propanol and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether and the like, dimethyl sulfoxide, dimethylformamide and the like.
The reaction can be carried out a temperature of from about room temperature to about 120C, preferably 50 to 100C for a period of about 10 minutes to about 1 hour using at least an equimolar amount, preferably 1 to 2 mols, of the compound of the formula (IV) per mol of the compound of the formula (Id).
The compound of the formula (I) wherein R represents y; p er'cl ~ n y/
an alkoxy group substituted with a 4-methyl-1-pi~rizi~l group, i.e., the compounds of the formula (Ig) below can also be prepared by the Reaction Scheme - IV.
3~
1 Reaction Scheme - IV
(Y)n ~ COR
(If) (VII) (Y) n O
~ ~ COR
~, (Ig) wherein Y and n are as defined above, R4 represents an alkoxy group substituted with a halogen atom and R5 represents an Pl pt~ r ~ ~J l n~/
A7 alkoxy group substituted with a 4-methyl-1-pipe~l group.
The reaction of the compound of the formula (If) Y- tnæ ~ y/,Pl'p~r l'C/~ e with ~-me~h~}~e#~A~e of the formula (VII) can be carried out in a solvent in the presence of a basic compound~ Examples of solvents which can be used are aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether and the like, dimethyl sulfoxide, dimethylformamide and the like. Examples of basic compounds which can be used are ~2'~8~
1 sodium amide, potassium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and the like.
The reaction of the compound of the formula (If) f~ ~f~ /p;per~dihe with~ of the formula (VII) can be carried out at a temperature of about 50 to about 200C, preferably 80 to 150C, for a period of about 2 to about 10 hours. In this 4~ h y ip ~ ~e r i Cl I t) e reaction, ~-~m~try~p~per~h~ of the formula (VII) and the basic compound can be used in an amount of at least an equimolar 1~ amount, preferably 1 to 2 mols, per mol of the compound of the formula (If).
The compounds of the formula (I) wherein Y represents an amino group, an alkanoylamino group, a hydrogen atom or a halogen atom can also be prepared from the compound of the formula (I) wherein Y represents a nitro group, i.e., the compounds of the formula (Ih) by the following Reaction Scheme - V.
8~
1 Reaction Scheme - V
. _ .
(O2N)n o (H2N)n Reduction (Ih) / (Ii) 1~ /
Sandmeyer Reaction 101 . ~ \ ~
R CNH)n (Y')n ~ COR ~ ~ COR
(Ik) wherein R and n are as defined above, R6 represents an alkyl group and Y' represents a hydrogen atom or a halogen atom.
In the alternative procedures shown in the Reaction Scheme - V above, the reduction reaction of the compound of the formula (Ih) can be conducted using (1) a conventional reduc.ing agent such as a combination of iron and hydrochloric acid ; zinc and acetic acid; tin or stannous chloride and hydrochloric acid; or the like in at least an equimolar amount, preferably 3 to 5 mols, per mol of the compound of the formula llZ~ 34 1 (Ih) or (2) a convention~ hydrogenation catalyst such as palladium black, palladium carbon, Raney nickel, platinum dioxide and the like. The reduction proceeds advantageously in water, an alcohol such as methanol, ethanol, isopropanol and the like, acetic acid, etc., at a temperature of about 0 to about 150C, preferably 50 to 100C in the presence of the reducing agent described above or at a temperature of about 0 to about 100C, preferably at room temperature in a hydrogen atmosphere under atmospheric pressure or pressuri~ed conditions in the presence of the hydrogenation catalyst described above.
The Sandmeyer reaction of the compound of the formula (Ii) in Reaction Scheme - V can be effected by diazotizing the compound of the formula (Ii) with an aqueous solution of sodium nitrite and hydrochloric acid or sulfuric acid at a temperature of about -30C to room temperature and then reacting the resulting diazo compound with ethanol, cuprous chloride, cuprous bromide, potassium iodide, bromine or tetrafluoroboron hydride at a temperature of about 0 to about 100C.
The acylation reaction of the compounds of the formula (Ii) in Reaction Schc-~me - V can generally be conducted with or without using an inert solvent, for example, pyridine, chloroform, water and the like using an acid anhydride or an acid halide of an aliphatic acid as an acylating agent in the presence of a basic compound such as a ter-tiary amine, for example, pyridine, triethylamine, trimethylamine and the like, an alkali metal bicarbonate or hydroxide, for example, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and the like, at a temperature of about 0 to about 100C, preferably 0 to room temperature. The acylating agent is advantageously used in an amount at least an equimolar amount, preferably 1 to 5 mols, per mol of the compound of the formula (Ii).
~a34 1 Further, the compounds of the present invention - represented by the formula (I) wherein Y represents an alkyl group can also be prepared by Wittig reaction from the compounds of the formula (I) wherein Y represents a halogen atom obtained as described above. Also, the compounds of the formula (I) wherein Y represents a halogen atom or a nitro group can be prepared from the eompound of the formula (I) wherein Y
represents a hydrogen atom by usual halogenation or nitration, respectively, using a eonventional halogenating agent or 1~ nitrating agent.
The pyrido[3,2,1-jk]carbazol derivatives represented by the formula (I) prepared as described above can form pharmaceutieally aeceptable salts with acids when the compound of the formula (I) has a basic group, and the present invention ineludes within its seope sueh pharmaceutieally aeeeptable salts. The pharmaeeutieally aeeeptable aeids whieh ean be used for the salt formation ean be various organie or inorganie aeids, for example, hydrochlorie aeid, sulfurie acid, nitrie acid, hydrobromie acid, phosphorie aeid, aeetic acid, oxalie aeid, malonie aeid, succinie aeid, maleie aeid, fumarie aeid, malie aeid, mandelie aeid, ethànesulfOnie aeid, p-toluenesulfonie aeid and the like.
The eompounds of the formula (I) wherein R represents a hydroxy group, i.e., a earboxylie aeid, can be eonverted into a eorresponding carboxylate by reaeting the carboxylie acid with a pharmaeeutieally aeeeptable basic eompound. Examples of basie compounds are inorganic basie eompounds sueh as sodium hydroxide, potassium hydroxide, ealeium hydroxide, aluminum hydroxide, sodium biearbonate and the like and organie basie P ~ r ~
eompounds such as morpholine, piperazine, pyridine, ~ri~ine, ethylamine, dimethylamine, triethylamine, aniline and the like.
~8~
1 The pyrido[3,2,1-jk]carbazol derivatives and the salts thereof representea by the formula (I~ obtained as described above can be isolated from the respective reaction mi~tures upon completion and purified by conventional procedures, for example, solvent extraction, dilution method, precipitation method, recrystallization method, column chromatography, preparative thin layer chromatography and the like.
As is apparent to those skilled in the art, the pyrido~3,2,1-jk]carbazol derivatives of the formula (I) can exist in optically active forms and the present invention includes such optical isomers within the scope of the invention.
In using the compounds of the present invention of the formula (I) and the salts thereof as therapeutic agents, these compounds can be formulated into pharmaceutical compositions together with ordinary pharmaceutically acceptable carriers. Suitable carriers which can be used are, for example, diluents or excipients such as fillers, extenders, binders, wetting agents, disinte~rants, surface activc agents and lubricants which are usually employed to prepare such drugs depending on the type of dosaye forms.
Various dosage forms of the therapeutic agerlts as an antimicrobial a~ent can be selected according -to the purpose of the therapy. T~pical dosage forms which can be used are tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, and injectable preparations (solutions, suspensions, etc.).
In molding a pharmaceutical composition containing the compounds of the formula (I) or the pharmaceutically acceptable salt thereof as an active ingredient into a tablet form, a wide range of carriers known in the art can be used.
~12'~8'1 1 Examp].es of suitable carriers include excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline celluslose and silicic acid, binders such as water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, meth~l cellulose, potassium phosphate and polyvinyl pyrrolidone, disintegran-ts such as dried-starch, sodium aliginate, agar powder, laminaria powder, sodium hydrogen carbonate, calcium carbonate, Tween, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose, disintegration inhibitors such as white sugar, stearic acid qlyceryl ester, cacao butter and hydrogenated oils, absorption promotors such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerol and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as purified talc, stearic acid salts, boric acid powder, Macrogol (trade name for a polyethylene glycol produced by Shinetsu Chemical Industry Co., Ltd.) and solid polyethylene glycol.
The tablets, if desired, can be coated, and made into sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or tablets comprising two or rnore layers.
In molding the pharmaceutical composition into pills, a wide variety of conventional carriers known in the art can be used. Examples of suitable carriers are excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar.
~f 71~ ~9 D ~ ~ A~
1~2~ 34 1 In molding the pharmaceutical composition into a suppository form, a wide variety of carriers known in the art ean be used. Examples of suitable carriers include polyethylene glycol, caeao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.
When the pharmaceutical composition is formulated into an injectable preparation, the resulting solution and suspension are preferably sterilized, and are isotonic with respect to the blood. In formulating the pharmaceutical composition into the form of a solution or suspension, all diluents eustomarily used in the art can be used. Examples of suitable diluents are water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose or glycerol may be ineorporated into a therapeutic agent, e.g., as a nephr:itis treating agent in an amount sufficient to prepare isotonie solutions. The therapeutic agent may further eontain ordinary dissolving aids, buffers, pain-al~ev:Lating agents, and preservatives, and optionally colourincJ agents, perfumes, flavors, sweeteners, and other drucJs.
The amount of the compouncl of the formula (I) and the pharmaceut.ically aceeptahle salts thereof of this invention as an active ingredient to be incorporated into a pharmaceutieal eomposition useful as an antimierobial agent is not partieularly limited, and can vary over a wide range. A suitable therepeutieally effeetive amount of the compound of the general formula (I) and the pharmaceutically acceptable salts thereof of this invention is usually about l to about 70~
by weight, preferably 5 to 50~ by weight, based on the entire composition~
~l~'Zg84 1 There is no particular restriction on the manner of using the therapeutic agent as a nephritis treating agent, and the therapeutic agent can be administered by routes suitable for the particular forms of the therapeutic agent. For example, the tablets, pills, liquid preparations, suspensions, emulsions, granules, and capsules are orally administered. The injectable preparations are intravenously administered either alone or together with ordinary auxiliary agents such as glucose and amino acids. Furthermore, as required, the therapeutic agent can be singly administered intramuscularly, intracutaneously, subcutaneously, or intraperitoneally. The suppository is administered intrarectally.
The dosage of the antimicrobial agent is suitably selected according to the purpose of use, the symptoms, etc.
Usually, a preferred dosage of the compound of this invention is about 10 mg to 5 g/body per day in 3 to 4 multiple doses.
The present invention is further illustrated by the following Reference Examples (preparation of starting materials) and Examples, but they are not to he construed as limiting the scope of this invention. The antimi.crobial activity o typical compouncls of the present invention are also shown in Examples.
Unless otherwise indicated, all parts, percents and ratios are by weight.
Reference Example 1 12.6 g of p-fluoroaniline was dissolved in 100 mQ
of ethanol and a catalytic amount of p-toluenesulfonic acid was added thereto. 9.8 g of cyclohexanone was then added dropwise to the mixture at room temperature. After completion of the addition, the mixture was stirred at room temperature for one hour and concentrated under reduced pressure. Dilute sulfuric l~ Zf~ 8 4 1 acid prepared from 190 mQ of water and 20 m~ of concentrated sulfuric acid was added to the residue and the mixture was heated at 110C for 15 minutes on an oil bath to precipitate light orange crystals. The crystals thus formed were filtered, washed 3 times with water and dried to obtain 17.4 g of 6-fluoro-1,2,3,4-tetrahydrocarbazol which was identified by NMR spectrum.
Reference Example 2 10 g of 6-fluoro-1,2,3,4-tetrahydrocarbazol was dissolved in 75 mQ of glacial acetic acid and 15 g of tin metal was added to the solution. The mixture was heated on an oil bath while refluxing and then 50 m~ of concentrated hydrochloric acid was added dropwise thereto. The color of the reaction system changed from orange color to colorless with vigorous generation of hydrogen. After reaction for 3.5 hours, any excess of tin metal was removed by filtration, and the filtrate was concentrated. 50 mQ of water was added to the residue, and the mixture was rendered alkaline with 4 N sodium hydroxide and f~ extracted with diethyl ether. The ether layer was dried over C~ e~ r~a ~ ~ c( anhydrous sodium sulfate, filtered and concentrt~e* to obtain 10 g of 6-fluoro-1,2,3,~,10,l1-hexahydrocarbazol as white crystals having a melting point of 80-83C. The production of the above compound was confirmed by NMR spectrum.
_xample 1 9 g of ethyl ethoxymethylenemalonate was added to 8 g of 6-fluoro-1,2,3,4,10,11-hexahydrocarbazol and the mixture was heated at 110C on an oil bath during which time distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 minutes, 100 g of polyphosphoric acid was added thereto followed by heating at 140C for 30 minutes. After completion of the reaction, the 112~34 1 reaction mixture was poured into 500 rnQ of water to ob-tain light brown crystals which were then recrystallized from a mixture of benzene-hexane (1:1) to obtain 14 g of ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]-carbazol-5-carboxylate as white plates having a melting point of 97-98C.
Example 2 21.6 g of ethyl ethoxymethylenemalonate was added to 17.5 g of 1,2,3,4,10,11-hexahydrocarbazol and the mixture was heated at 110C on an oil bath for 30 minutes while stirring, during which time distillation of ethanol was observed. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide was added to the mixture and the mixture was allowed to react on an oil bath at 140C for 45 minutes. After completion of the reaction, the mixture was allowed to cool to room temperatur~ and poured into 400 mQ of water, followed by rendering the mixture neutral with 40% aqueous sodium hydroxide to precipitate light purple crystals. The crystals thus obtained were recrystallized from benzene-hexane (1:1) to obtain 32 g of ethyl 7a,8,9,10,11,11a-hexahydro-4-oxo-4~1-pyrido[3,2,1-jk]carbaæol-5-carboxylate having a melting point of 71-73C.
Example 3 8.36 g (0.0387 mol) of ethyl ethoxymethylenemalonate was added to 7.32 g (0.0387 mol) of 6-methyl-1,2,3,4,10,11-hexahydrocarbaæol and the mixture was heated on an oil bath at 110C, during which time distillation of ethanol was observed.
After heating the mixture at the same temperature as above, 100 g of polyphosphoric acid was added thereto followed by heating at 140~C for 40 minutes. After completion of the ~3~3~
reaction, the reaction mixture was poured into 200 mQ of water and the resulting mixture was rendered neutral with 20% aqueous sodium hydroxide while cooling to precipitate light brown crystals which were recrystallized from benzene-hexane (1:1) to obtain 12 g of ethyl 2-methyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate as colorless plates having a melting point of 107-109C.
Examples 4-17 .
In the same manner as described in the above Examples, the following compounds having various substituents shown in Table 1 below were prepared. The melting point and the crystal form of the resulting products are also shown in Table 1.
COR
Rl ~ , o U~ ~ C ~ ~o ~ o ~ s~ x s~ X ~ s~
O ~ ~ ~ X ~ d O O O
N 3 ~ 3 ~ 3 ~ 3 3 o Q. 3 3 o ~ ~ 3 ~ ~ o ,_ o ~1 ~ O O O ~-- ~ O
O ~ O ~ td ~) 1~ ~ OQ) ~ O
c c C s ~ c t~ ,t~ C
~C ,_ O U ~ N N N N N N N N 14 ~1 .~ ~ 0~
aJ a~ a~ ~ ~ ~ ~ ooLr) LO g ~
N N N N N NN O r-l a N ¦ C~
K ~ zoN z o ~;
K I ~N
O O O O O O :r: X
.
~0 X ~ cn o .1 8~
.
o U~
u~ . a~
h ~ Z o O
O r~ ,~
~ rd ~ h h U~ o t~,1 O
U-- ~ ~ U U
.o O ~ ?
t~ U I I I .s:: I O
.~ ~ o ~ ~ ~ o ~ ,_1 ~C~ h ~ O
r~
h h h F4 ~: O
'~'J U ~z;
U~ 0 O ~N U
r-l Z
Q, U~
~ Z
--2~--1 EXample 18 140 mQ of a 10~ aqueous sodium hydroxide solution was added to 10 g of ethyl 2~fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H pyrido[3,2,1-jk]carbazol-5-carboxylate, followed by heat-refluxing for 40 minutes. The crystals of the above starting material were dissolved to give a uniform solution.
The solution was treated with activated carbon while hot, and filtered. The filtrate was cooled, and adjusted to pH 2 with concentrated hydrochloric acid to obtain 8 g of white crystals.
The resulting crystals were recrystallized from ethanol to give 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]-carbazol-5-carboxylic acid as white needles having a melting point of 281-282C.
Example 19 250 mQ of a 10% aqueous sodium hydroxide solution was added to 28 g of ethyl 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, followed by heat-refluxing for 2 hours. The reaction system changed from a suspension state to a uniform solution as the reaction proceeded.
200 mQ of water was added to the reaction mixture which was then filtered, and the filtrate was rendered acidic with concentrated hydrochloric acid to precipitate light yellow crystals. The crystals were separated by filtration, washed successively with water and a small amount of ethanol, dried and recrystallized from chloroform-hexane (1:1 by volume) to obtain 16 g of 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1--jk]-carbazol-S-carboxylic acid as light yellow amorphous crystals having a meltin~ point of 238 - 241C.
Example 20 _ _ 70 mQ of a 10~ aqueous sodium hydroxide solution was ~iZ~8'~
1 added '~o 4 g of ethyl 2-methyl-7a,8,9,10,11,11a-hexallydro-4-oxo-4EI-pyrido [ 3,2,1-jk]carbazol-5-carboxylate. The mixture was heat-refluxed for 1.5 hours, allowed to cool to room temperature and filtered. ~he filtrate was cooled and adjusted to a pH of 2 with concentrated hydrochloric acid to obtain 3.2 g of light yellow crystals. Recrystallization from ethanol gave 2-methyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid as needle crystals having a melting point of 188 - 190C.
Examples_21 to 24 In the same manner as described in Examples 18 to 20, the following compounds having the substituents shown in Table 2 below were prepared. The melting point and the crystal form of the resulting products are also shown in Table 2.
o ICOR
~3 Table 2 Example R R R R Melting Crystal Form Nos. 1 2 3 Point (Recrystallization Solvent) ( C) 21 OH H OCEI3 EI 198-200 Light Yellow Amorphous (Chloroform - Hexane) 22 OH El CQ H 219-221 Light Yellow Amorphous (Chloroform - Hexane) 23 OH CH3 H CH3 216-217 Light Brown Needles (Ethanol) 24 OH F H H 215-217 Light Yellow Plates (Ethanol) ~8~
1 Example 25 6 g of 3-nitro-7a,8,9,10,11,11a-hexahydro-4-oxo-~H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid was dissolved in 100 mQ of a 2% aqueous potassium hydroxide solution and the solution was catalytically reduced by the Parr method (3 kg/cm2) in the presence of 5 g of Raney nickel. After completion of the reduction, the mixture was filtered and the filter cake on the filter paper was washed with water and the combined filtrate and the washing was rendered neutral with glacial acetic acid to precipitate brown crystals. The resulting crystals were filtered, washed with water, dried and recrystal-lized from DMF-H20 to obtain 3.7 g of 3-amino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid having a melting point of 253 - ~C- (with decomposition).
Example 26 .
2.84 g of 3-amino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid was dissolved in 50 mQ of a 2~ aqueous potassium hydroxide, and acetic anhydride was added dropwise thereto while ice cooling whereby orange-colored crystals were precipitated. The resultin~
erystals were separated by ~iltration, washed with water and reeryctallized from dimethylformamide-water to obtain 3 g o~
3-acetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid having a melting point o~ 187-190C.
Exa_ple_?7 6 g of 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]earbazol-5-carboxylic acid was dissolved in 35 mQ of concentrated su]furic acid and stirred while coolin~ with ice, followed by dropwise addition of a mixture of 4.3 mQ of-concentrated nitric acid having a specific gravity 1.42 and ~2~
1 15 mQ of the concentrated sulfuric acid. After completion of the addition, the resulting mixture was stirred for one hour at room temperature and poured into 200 g of ice to precipita-te yellow crystals. RecrystallizatiOn from dimethylformamide-water gave 7 g of 3-nitro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid having a melting point of 251-253C.
Example 28 5.64 g of 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,]-jk]carbazol--5-carboxylic acid was suspended in 60 mQ of chloroform and 4.5 g of phosphorus pentachloride was S~ S p~nS l'c~, added to the 3U_pC~5~ at room temperature. After allowing the mixture to react at room temperature for 30 minutes, the solvent was removed under reduced pressure to obtain a carboxylic acid chloride as a light brown oily substance. 60 mQ of chloroform was added to the resuling carboxylic acid chloride, and 3 g of ethylenebromohydrin was added dropwise to the solution.
~fter stirring the mixture for olle hour at room tempera-ture, 50 mQ of a saturated aqueous solution of po~ass i.UIIl carbonate was added to the mixture and the chlorofol^m layer was scparated.
The ahloxoform lay~r WclS washed with water, clried over an~ydrous sodium sulfate and the chloroform was removed to obtain 6.7 g of ~-bromoethyl 2-fluoro-7a,8,9,10,11,1:La-hexahydro-4-oxo-~H-pyrido[3,2,1-jk]carbazol-5-carboxylate. Recrystallization from toluene gave a product as white plate crystals having a melting point of 126-t~70C
Example 29 .. ..
3 g of ~-bromoethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido~3,2,1-jk]carbazol-5-carboxylate was added to a suspension of 1 g of 4-methylpiperidine and 0.4 g ~84 1 f sodium amide in 30 mQ of toluene, and the mix-ture was heated for 5 hours while refluxing. After the reaction had been completed as confirmed by the thin layer chromatography, a saturated aqueous solution of sodium carbonate was added to the reaction mixture and the toluene layer was separated. The toluene layer was dried over anhydrous sodium sulfate, concentrated to a volume of 15 mQ and hydrogen chloride gas was introduced into the solution, followed by removal of toluene under reduced pressure. 10 mQ of diethyl ether was added to the resulting residue and the mixture was triturated to obtain 2.3 g of ~-(4-methyl-1-piperidinyl)ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate hydrochloride as colorless amorphous crystals having a melting point of 187-192C.
Example 30 2 g of ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate was dissolved in 80 mQ of rnethanol, and 5 mQ of hydrazine hydrate was added thereto. The mixture was then heated while refluxing. The precipitated yello needle crystals were separated by Eiltration, and recrystallized from ethanol to obtain 1.7 g oE 2-~luoro-7a,8,9,10,11,11a-hexahydro-~-oxo-~EI-pyrido[3,2,1-jk]carbazol-5-carbohydra 2 ide monohydrate.
Example 31 20 mQ of ethanol was added to 1.6 g of the hydrazide prepared as described in Example 30, and 0.8 g of 5-nitro-2-furaldehyde was added to the solution while heat-refluxing. The mixture was then heat-refluxed for 10 minutes, and the yellow crystals precipitated was filtered after cooling/ washed with ethanol and dried to obtain 1.8 g of 2-fluoro-7a,8,9,10,11,11a~
hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid '3~3~
1 5-nitrofurfurylidene hydrazide as colorless amorphous crystals having a melting point of 293~2~4~C (with decomposition).
Antimicrobial Activity .
1. Test Method The antimicrobial activity of the following test compounds on various test organisms listed below was determined by the serial dilution method on agar plate and the minimum inhibitory concentration (mcg/m~) obtained are shown in Table 4 below.
~O 2. Test Organisms A. Bacillus subtilis ATCC 6633 B. Bacillus anthracis C. Bacillus cereus ATCC 11778 D. Staphyrococcus aurellS FDA 209p E. Staphyrococcus aureus Newmann F. Streptococcus faecalis IFO 12580 G. Streptomyces viridans H. Sarcina lutea ATCC 9341 I. Micrococcus flavus ATCC 10240a ~O J. Serratia marcescens ATCC 14756 K. Salmonella typhimurium kh L. Enterbactor cloacae 2 M. Enterbactor aero~enes IFO 12979 N. Klebsiella pneumoniae ST-101 O. Esherichia coli NIHJ
P. Esherichia coli NIHJ JC-2 Q. Proteus mirabilis 1287 R. Pseudomonas aeruginosa ATCC 10145 S. Candida albicans KYU
llZ'~
1 The compounds of the formula (I) wherein R represents an alkoxy group which may be substituted with a halogen ato~ or A ~ p , pe ~ iJ ~` n y I
e~ a 4-methyl-1-pipeE-i inyl group, or a hydroxy group, i.e., the compounds of the formula (Ia) or (Ib), can be produced from each other by hydrolysis or esterification as shown by the Reaction Scheme - II below.
Reaction Scheme - II
(Y)n / COR Hydrolysis (Y)n COOH
Ester fication (Ia) (Ib) wherein Y and n are as defined above, and R2 represents an alkoxy group which may be substituted with a halogen akom or a p;pe r i d l'n y I
4-methyl-1-~ptri~h~t group.
In the above Reaction Scheme - II, the hydrolysis of the compound of the formula (Ia) into the compound of the formula (Ib) can be achieved by a conventional hydrolysis procedure in the presence of a usual catalyst, for example, a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, or an inorganic or organic acid such as sulfuric acid, hydrochloric acid, nitric acid, acetic acid, an aromatic sulfuric acid and the like. The hydrolysis can be carried out in a solvent such as water, methanol, ethanol, isopropanol, acetonel methyl ethyl ketone, dioxane, ethylene glycol, acetic acid and the like at a temperature of g~ ~
1 from room temperature to about 200C, preferably 50 to 150~C
for a period of about 0.5 to about 6 hours.
The esterification of the compound of the formula (Ib~
into the compound of the formula (Ia) can be achieved by a usual esterification procedure, for example, a method using a carboxylic acid, an acid halide or an acid anhydride.
The esterification using the carboxylic acid [Formula (Ib)] can be carried out in the presence of a catalyst generally used in the esterification, for example, an inorganic acid such as hydrogen chloride gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid,- boron trifluoride, perchloric acid and the like, an organic acid such as trifluoroacetic acid, trichloromethanesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, benzene-sulfonic acid, ethanesulfonic acid and the like, an acid anhydride such as trichloromethanesulfonic anhydride, trifluoro-methanesulfonic anhydride and the like, or thionyl chloride and the like.
The esterification reaction can be carried out in the presence or absence o~ a solvent. Examples of solvents which can be used are aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogena-ted hydrocarbons such as dichloro-methane dichloroethane, chloroform, carbon tetrachloride and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether and the like.
The amount of an alcohol having the formula R OH
wherein R2 is as defined above, used in the esterification is not critical and can be over an approximately equimolar amount relative to the compound of the formula (Ib), but is preferably a molar excess amount in the absence of solvents and is about 1 1 to about 5 mols, preferably 1 to 2 mols, per mol of the compound of the formula (Ib). This esterification can be carried out at a temperature of about -20 to about 200C, preferably 0 to 150C for a period of about 0.5 to about 6 hours.
The esterification using an acid halide of the compound of the formula (Ib) can be achieved by reacting an acid halide, which is prepared from the compound of the formula (Ib) and a suitable halogenating agent, with an alcohol of the formula R20H wherein R is as defined above.
The halogenation reaction between the compound of the formula (Ib) and the halogenating agent can be conducted in the presence or absence of solvents. Suitable examples of halogenating agents are thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide and the like. Suitable examples of solvents which can be used in the halogenation reaction are aromatic hydro-carbons such as benzene, toluene, xylene and the like, halogen-ated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and the like. The halogenating agent can be used in a large molar excess amount relative to the compound of the formula (Ib) in the absence of solvents, or in an amount of at least an equimolar amount, preferably 1 to 2 mols, per mol of the compound of the formula (Ib) in the presence of solvents. The halogenation reaction can be conducted at a temperature of from room temperature to about 100C, preferably room temperature to 50C, for about 1 to 3 hours.
The reaction between the acid halide of the compound of the formula (Ib) prepared above and an alcohol of the 1~2'~84 1 formula R2O~ wherein R2 is as defined above can be carried out with or without using solvents in the presence of a hydrogen halide acceptor. Suitable examples of solvents are aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogenated hydrocarbons such as dichloromethane, dichloroethane~
chloroform, carbon tetrachloride and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and the like, pyridine and the like. Suitable examples of hydrogen halide acceptors are inorganic basic compounds such as sodium carbonate, sodium bicarbonate, potassium carbonate and the like, and tertiary amines such as triethylamine, pyridine, quinoline, N,N-dimethylaniline and the like. Such hydrogen halide acceptors aan be used in an amount of at least equimolar amount, preferably 1 to 2 mols, per mol of the acid halide of the compound of the formula (Ib). The reaction can be carried out at a temperature of about -10C
to about 50C, preferably 0C to room temperature, for a period of about 30 minutes to about 6 hours.
The alcohol of the formula R2OI1 can be used in a large molar excess relative to the acid halide of the compound of the formula ~Ib) when the reaction is carried out in the absence oE solvent, or in an amount of at least equimolar amount, preferably 1 to 2 mols, per mol of the acid halide of the compound o~ the formula (Ib) when the reaction is carried out in a solvent.
The pyrido[3,2,1-jk]carbazol derivatives represented by the formula (I) wherein R represents a hydrazin~ group or a -NHN=CH ~ NO2 group, i.e., the compounds of the formula (Id) or (Ie), can also be prepared by the following Reaction Scheme - III.
112'~
1 Reaction Scheme - III
N
~ + NH2NH2 )~\
(Ic) (V) n ~ CONHNH2 I l CHO NO
G' 2 (Id) (VI) zo ~ )n~ CON~IN=c~l ~3 2 \
(Ie) wherein Y and n are as defined above, and R3 represents an alkoxy group.
The reaction of the compound of the formula (Ic) with hydrazine of the formula (V) can be carried out in a solvent.
-13- ~
8~
1 Examples of solvents are aromatic hydrocarbons such as benzene, toluene, xylene and the li~e, lower alcohols such as methanol, ethanol, propanol and the like, ethers such as diethyl ether, tetrahydro~uran, dioxane, ethylene glycol monomethyl ether and the like, dimethyl sulfoxide dimethylformamide and the like.
The reaction can be carried out under pressurized conditions, i.e., at a pressure of about 1 to about 10 atms., preferably 1 to 5 atms., at a temperature of about 50 to about 150C, preferably 60 to 100C for a period of about 1 to about 5 hours, using at least an equimolar amount, preferably 1 to 2 mols, of hydrazine of the formula (V) per mol of the compound of the formula (Ic).
The subsequent reaction of the compound of the formula (Id) thus obtained and the compound of the formula (IV) can be carried out in a solvent. Examples of solvents which can be used are lower alcohols such as methanol, ethanol, propanol and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether and the like, dimethyl sulfoxide, dimethylformamide and the like.
The reaction can be carried out a temperature of from about room temperature to about 120C, preferably 50 to 100C for a period of about 10 minutes to about 1 hour using at least an equimolar amount, preferably 1 to 2 mols, of the compound of the formula (IV) per mol of the compound of the formula (Id).
The compound of the formula (I) wherein R represents y; p er'cl ~ n y/
an alkoxy group substituted with a 4-methyl-1-pi~rizi~l group, i.e., the compounds of the formula (Ig) below can also be prepared by the Reaction Scheme - IV.
3~
1 Reaction Scheme - IV
(Y)n ~ COR
(If) (VII) (Y) n O
~ ~ COR
~, (Ig) wherein Y and n are as defined above, R4 represents an alkoxy group substituted with a halogen atom and R5 represents an Pl pt~ r ~ ~J l n~/
A7 alkoxy group substituted with a 4-methyl-1-pipe~l group.
The reaction of the compound of the formula (If) Y- tnæ ~ y/,Pl'p~r l'C/~ e with ~-me~h~}~e#~A~e of the formula (VII) can be carried out in a solvent in the presence of a basic compound~ Examples of solvents which can be used are aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether and the like, dimethyl sulfoxide, dimethylformamide and the like. Examples of basic compounds which can be used are ~2'~8~
1 sodium amide, potassium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and the like.
The reaction of the compound of the formula (If) f~ ~f~ /p;per~dihe with~ of the formula (VII) can be carried out at a temperature of about 50 to about 200C, preferably 80 to 150C, for a period of about 2 to about 10 hours. In this 4~ h y ip ~ ~e r i Cl I t) e reaction, ~-~m~try~p~per~h~ of the formula (VII) and the basic compound can be used in an amount of at least an equimolar 1~ amount, preferably 1 to 2 mols, per mol of the compound of the formula (If).
The compounds of the formula (I) wherein Y represents an amino group, an alkanoylamino group, a hydrogen atom or a halogen atom can also be prepared from the compound of the formula (I) wherein Y represents a nitro group, i.e., the compounds of the formula (Ih) by the following Reaction Scheme - V.
8~
1 Reaction Scheme - V
. _ .
(O2N)n o (H2N)n Reduction (Ih) / (Ii) 1~ /
Sandmeyer Reaction 101 . ~ \ ~
R CNH)n (Y')n ~ COR ~ ~ COR
(Ik) wherein R and n are as defined above, R6 represents an alkyl group and Y' represents a hydrogen atom or a halogen atom.
In the alternative procedures shown in the Reaction Scheme - V above, the reduction reaction of the compound of the formula (Ih) can be conducted using (1) a conventional reduc.ing agent such as a combination of iron and hydrochloric acid ; zinc and acetic acid; tin or stannous chloride and hydrochloric acid; or the like in at least an equimolar amount, preferably 3 to 5 mols, per mol of the compound of the formula llZ~ 34 1 (Ih) or (2) a convention~ hydrogenation catalyst such as palladium black, palladium carbon, Raney nickel, platinum dioxide and the like. The reduction proceeds advantageously in water, an alcohol such as methanol, ethanol, isopropanol and the like, acetic acid, etc., at a temperature of about 0 to about 150C, preferably 50 to 100C in the presence of the reducing agent described above or at a temperature of about 0 to about 100C, preferably at room temperature in a hydrogen atmosphere under atmospheric pressure or pressuri~ed conditions in the presence of the hydrogenation catalyst described above.
The Sandmeyer reaction of the compound of the formula (Ii) in Reaction Scheme - V can be effected by diazotizing the compound of the formula (Ii) with an aqueous solution of sodium nitrite and hydrochloric acid or sulfuric acid at a temperature of about -30C to room temperature and then reacting the resulting diazo compound with ethanol, cuprous chloride, cuprous bromide, potassium iodide, bromine or tetrafluoroboron hydride at a temperature of about 0 to about 100C.
The acylation reaction of the compounds of the formula (Ii) in Reaction Schc-~me - V can generally be conducted with or without using an inert solvent, for example, pyridine, chloroform, water and the like using an acid anhydride or an acid halide of an aliphatic acid as an acylating agent in the presence of a basic compound such as a ter-tiary amine, for example, pyridine, triethylamine, trimethylamine and the like, an alkali metal bicarbonate or hydroxide, for example, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and the like, at a temperature of about 0 to about 100C, preferably 0 to room temperature. The acylating agent is advantageously used in an amount at least an equimolar amount, preferably 1 to 5 mols, per mol of the compound of the formula (Ii).
~a34 1 Further, the compounds of the present invention - represented by the formula (I) wherein Y represents an alkyl group can also be prepared by Wittig reaction from the compounds of the formula (I) wherein Y represents a halogen atom obtained as described above. Also, the compounds of the formula (I) wherein Y represents a halogen atom or a nitro group can be prepared from the eompound of the formula (I) wherein Y
represents a hydrogen atom by usual halogenation or nitration, respectively, using a eonventional halogenating agent or 1~ nitrating agent.
The pyrido[3,2,1-jk]carbazol derivatives represented by the formula (I) prepared as described above can form pharmaceutieally aeceptable salts with acids when the compound of the formula (I) has a basic group, and the present invention ineludes within its seope sueh pharmaceutieally aeeeptable salts. The pharmaeeutieally aeeeptable aeids whieh ean be used for the salt formation ean be various organie or inorganie aeids, for example, hydrochlorie aeid, sulfurie acid, nitrie acid, hydrobromie acid, phosphorie aeid, aeetic acid, oxalie aeid, malonie aeid, succinie aeid, maleie aeid, fumarie aeid, malie aeid, mandelie aeid, ethànesulfOnie aeid, p-toluenesulfonie aeid and the like.
The eompounds of the formula (I) wherein R represents a hydroxy group, i.e., a earboxylie aeid, can be eonverted into a eorresponding carboxylate by reaeting the carboxylie acid with a pharmaeeutieally aeeeptable basic eompound. Examples of basie compounds are inorganic basie eompounds sueh as sodium hydroxide, potassium hydroxide, ealeium hydroxide, aluminum hydroxide, sodium biearbonate and the like and organie basie P ~ r ~
eompounds such as morpholine, piperazine, pyridine, ~ri~ine, ethylamine, dimethylamine, triethylamine, aniline and the like.
~8~
1 The pyrido[3,2,1-jk]carbazol derivatives and the salts thereof representea by the formula (I~ obtained as described above can be isolated from the respective reaction mi~tures upon completion and purified by conventional procedures, for example, solvent extraction, dilution method, precipitation method, recrystallization method, column chromatography, preparative thin layer chromatography and the like.
As is apparent to those skilled in the art, the pyrido~3,2,1-jk]carbazol derivatives of the formula (I) can exist in optically active forms and the present invention includes such optical isomers within the scope of the invention.
In using the compounds of the present invention of the formula (I) and the salts thereof as therapeutic agents, these compounds can be formulated into pharmaceutical compositions together with ordinary pharmaceutically acceptable carriers. Suitable carriers which can be used are, for example, diluents or excipients such as fillers, extenders, binders, wetting agents, disinte~rants, surface activc agents and lubricants which are usually employed to prepare such drugs depending on the type of dosaye forms.
Various dosage forms of the therapeutic agerlts as an antimicrobial a~ent can be selected according -to the purpose of the therapy. T~pical dosage forms which can be used are tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, and injectable preparations (solutions, suspensions, etc.).
In molding a pharmaceutical composition containing the compounds of the formula (I) or the pharmaceutically acceptable salt thereof as an active ingredient into a tablet form, a wide range of carriers known in the art can be used.
~12'~8'1 1 Examp].es of suitable carriers include excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline celluslose and silicic acid, binders such as water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, meth~l cellulose, potassium phosphate and polyvinyl pyrrolidone, disintegran-ts such as dried-starch, sodium aliginate, agar powder, laminaria powder, sodium hydrogen carbonate, calcium carbonate, Tween, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose, disintegration inhibitors such as white sugar, stearic acid qlyceryl ester, cacao butter and hydrogenated oils, absorption promotors such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerol and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as purified talc, stearic acid salts, boric acid powder, Macrogol (trade name for a polyethylene glycol produced by Shinetsu Chemical Industry Co., Ltd.) and solid polyethylene glycol.
The tablets, if desired, can be coated, and made into sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or tablets comprising two or rnore layers.
In molding the pharmaceutical composition into pills, a wide variety of conventional carriers known in the art can be used. Examples of suitable carriers are excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar.
~f 71~ ~9 D ~ ~ A~
1~2~ 34 1 In molding the pharmaceutical composition into a suppository form, a wide variety of carriers known in the art ean be used. Examples of suitable carriers include polyethylene glycol, caeao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.
When the pharmaceutical composition is formulated into an injectable preparation, the resulting solution and suspension are preferably sterilized, and are isotonic with respect to the blood. In formulating the pharmaceutical composition into the form of a solution or suspension, all diluents eustomarily used in the art can be used. Examples of suitable diluents are water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose or glycerol may be ineorporated into a therapeutic agent, e.g., as a nephr:itis treating agent in an amount sufficient to prepare isotonie solutions. The therapeutic agent may further eontain ordinary dissolving aids, buffers, pain-al~ev:Lating agents, and preservatives, and optionally colourincJ agents, perfumes, flavors, sweeteners, and other drucJs.
The amount of the compouncl of the formula (I) and the pharmaceut.ically aceeptahle salts thereof of this invention as an active ingredient to be incorporated into a pharmaceutieal eomposition useful as an antimierobial agent is not partieularly limited, and can vary over a wide range. A suitable therepeutieally effeetive amount of the compound of the general formula (I) and the pharmaceutically acceptable salts thereof of this invention is usually about l to about 70~
by weight, preferably 5 to 50~ by weight, based on the entire composition~
~l~'Zg84 1 There is no particular restriction on the manner of using the therapeutic agent as a nephritis treating agent, and the therapeutic agent can be administered by routes suitable for the particular forms of the therapeutic agent. For example, the tablets, pills, liquid preparations, suspensions, emulsions, granules, and capsules are orally administered. The injectable preparations are intravenously administered either alone or together with ordinary auxiliary agents such as glucose and amino acids. Furthermore, as required, the therapeutic agent can be singly administered intramuscularly, intracutaneously, subcutaneously, or intraperitoneally. The suppository is administered intrarectally.
The dosage of the antimicrobial agent is suitably selected according to the purpose of use, the symptoms, etc.
Usually, a preferred dosage of the compound of this invention is about 10 mg to 5 g/body per day in 3 to 4 multiple doses.
The present invention is further illustrated by the following Reference Examples (preparation of starting materials) and Examples, but they are not to he construed as limiting the scope of this invention. The antimi.crobial activity o typical compouncls of the present invention are also shown in Examples.
Unless otherwise indicated, all parts, percents and ratios are by weight.
Reference Example 1 12.6 g of p-fluoroaniline was dissolved in 100 mQ
of ethanol and a catalytic amount of p-toluenesulfonic acid was added thereto. 9.8 g of cyclohexanone was then added dropwise to the mixture at room temperature. After completion of the addition, the mixture was stirred at room temperature for one hour and concentrated under reduced pressure. Dilute sulfuric l~ Zf~ 8 4 1 acid prepared from 190 mQ of water and 20 m~ of concentrated sulfuric acid was added to the residue and the mixture was heated at 110C for 15 minutes on an oil bath to precipitate light orange crystals. The crystals thus formed were filtered, washed 3 times with water and dried to obtain 17.4 g of 6-fluoro-1,2,3,4-tetrahydrocarbazol which was identified by NMR spectrum.
Reference Example 2 10 g of 6-fluoro-1,2,3,4-tetrahydrocarbazol was dissolved in 75 mQ of glacial acetic acid and 15 g of tin metal was added to the solution. The mixture was heated on an oil bath while refluxing and then 50 m~ of concentrated hydrochloric acid was added dropwise thereto. The color of the reaction system changed from orange color to colorless with vigorous generation of hydrogen. After reaction for 3.5 hours, any excess of tin metal was removed by filtration, and the filtrate was concentrated. 50 mQ of water was added to the residue, and the mixture was rendered alkaline with 4 N sodium hydroxide and f~ extracted with diethyl ether. The ether layer was dried over C~ e~ r~a ~ ~ c( anhydrous sodium sulfate, filtered and concentrt~e* to obtain 10 g of 6-fluoro-1,2,3,~,10,l1-hexahydrocarbazol as white crystals having a melting point of 80-83C. The production of the above compound was confirmed by NMR spectrum.
_xample 1 9 g of ethyl ethoxymethylenemalonate was added to 8 g of 6-fluoro-1,2,3,4,10,11-hexahydrocarbazol and the mixture was heated at 110C on an oil bath during which time distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 minutes, 100 g of polyphosphoric acid was added thereto followed by heating at 140C for 30 minutes. After completion of the reaction, the 112~34 1 reaction mixture was poured into 500 rnQ of water to ob-tain light brown crystals which were then recrystallized from a mixture of benzene-hexane (1:1) to obtain 14 g of ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]-carbazol-5-carboxylate as white plates having a melting point of 97-98C.
Example 2 21.6 g of ethyl ethoxymethylenemalonate was added to 17.5 g of 1,2,3,4,10,11-hexahydrocarbazol and the mixture was heated at 110C on an oil bath for 30 minutes while stirring, during which time distillation of ethanol was observed. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide was added to the mixture and the mixture was allowed to react on an oil bath at 140C for 45 minutes. After completion of the reaction, the mixture was allowed to cool to room temperatur~ and poured into 400 mQ of water, followed by rendering the mixture neutral with 40% aqueous sodium hydroxide to precipitate light purple crystals. The crystals thus obtained were recrystallized from benzene-hexane (1:1) to obtain 32 g of ethyl 7a,8,9,10,11,11a-hexahydro-4-oxo-4~1-pyrido[3,2,1-jk]carbaæol-5-carboxylate having a melting point of 71-73C.
Example 3 8.36 g (0.0387 mol) of ethyl ethoxymethylenemalonate was added to 7.32 g (0.0387 mol) of 6-methyl-1,2,3,4,10,11-hexahydrocarbaæol and the mixture was heated on an oil bath at 110C, during which time distillation of ethanol was observed.
After heating the mixture at the same temperature as above, 100 g of polyphosphoric acid was added thereto followed by heating at 140~C for 40 minutes. After completion of the ~3~3~
reaction, the reaction mixture was poured into 200 mQ of water and the resulting mixture was rendered neutral with 20% aqueous sodium hydroxide while cooling to precipitate light brown crystals which were recrystallized from benzene-hexane (1:1) to obtain 12 g of ethyl 2-methyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate as colorless plates having a melting point of 107-109C.
Examples 4-17 .
In the same manner as described in the above Examples, the following compounds having various substituents shown in Table 1 below were prepared. The melting point and the crystal form of the resulting products are also shown in Table 1.
COR
Rl ~ , o U~ ~ C ~ ~o ~ o ~ s~ x s~ X ~ s~
O ~ ~ ~ X ~ d O O O
N 3 ~ 3 ~ 3 ~ 3 3 o Q. 3 3 o ~ ~ 3 ~ ~ o ,_ o ~1 ~ O O O ~-- ~ O
O ~ O ~ td ~) 1~ ~ OQ) ~ O
c c C s ~ c t~ ,t~ C
~C ,_ O U ~ N N N N N N N N 14 ~1 .~ ~ 0~
aJ a~ a~ ~ ~ ~ ~ ooLr) LO g ~
N N N N N NN O r-l a N ¦ C~
K ~ zoN z o ~;
K I ~N
O O O O O O :r: X
.
~0 X ~ cn o .1 8~
.
o U~
u~ . a~
h ~ Z o O
O r~ ,~
~ rd ~ h h U~ o t~,1 O
U-- ~ ~ U U
.o O ~ ?
t~ U I I I .s:: I O
.~ ~ o ~ ~ ~ o ~ ,_1 ~C~ h ~ O
r~
h h h F4 ~: O
'~'J U ~z;
U~ 0 O ~N U
r-l Z
Q, U~
~ Z
--2~--1 EXample 18 140 mQ of a 10~ aqueous sodium hydroxide solution was added to 10 g of ethyl 2~fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H pyrido[3,2,1-jk]carbazol-5-carboxylate, followed by heat-refluxing for 40 minutes. The crystals of the above starting material were dissolved to give a uniform solution.
The solution was treated with activated carbon while hot, and filtered. The filtrate was cooled, and adjusted to pH 2 with concentrated hydrochloric acid to obtain 8 g of white crystals.
The resulting crystals were recrystallized from ethanol to give 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]-carbazol-5-carboxylic acid as white needles having a melting point of 281-282C.
Example 19 250 mQ of a 10% aqueous sodium hydroxide solution was added to 28 g of ethyl 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate, followed by heat-refluxing for 2 hours. The reaction system changed from a suspension state to a uniform solution as the reaction proceeded.
200 mQ of water was added to the reaction mixture which was then filtered, and the filtrate was rendered acidic with concentrated hydrochloric acid to precipitate light yellow crystals. The crystals were separated by filtration, washed successively with water and a small amount of ethanol, dried and recrystallized from chloroform-hexane (1:1 by volume) to obtain 16 g of 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1--jk]-carbazol-S-carboxylic acid as light yellow amorphous crystals having a meltin~ point of 238 - 241C.
Example 20 _ _ 70 mQ of a 10~ aqueous sodium hydroxide solution was ~iZ~8'~
1 added '~o 4 g of ethyl 2-methyl-7a,8,9,10,11,11a-hexallydro-4-oxo-4EI-pyrido [ 3,2,1-jk]carbazol-5-carboxylate. The mixture was heat-refluxed for 1.5 hours, allowed to cool to room temperature and filtered. ~he filtrate was cooled and adjusted to a pH of 2 with concentrated hydrochloric acid to obtain 3.2 g of light yellow crystals. Recrystallization from ethanol gave 2-methyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid as needle crystals having a melting point of 188 - 190C.
Examples_21 to 24 In the same manner as described in Examples 18 to 20, the following compounds having the substituents shown in Table 2 below were prepared. The melting point and the crystal form of the resulting products are also shown in Table 2.
o ICOR
~3 Table 2 Example R R R R Melting Crystal Form Nos. 1 2 3 Point (Recrystallization Solvent) ( C) 21 OH H OCEI3 EI 198-200 Light Yellow Amorphous (Chloroform - Hexane) 22 OH El CQ H 219-221 Light Yellow Amorphous (Chloroform - Hexane) 23 OH CH3 H CH3 216-217 Light Brown Needles (Ethanol) 24 OH F H H 215-217 Light Yellow Plates (Ethanol) ~8~
1 Example 25 6 g of 3-nitro-7a,8,9,10,11,11a-hexahydro-4-oxo-~H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid was dissolved in 100 mQ of a 2% aqueous potassium hydroxide solution and the solution was catalytically reduced by the Parr method (3 kg/cm2) in the presence of 5 g of Raney nickel. After completion of the reduction, the mixture was filtered and the filter cake on the filter paper was washed with water and the combined filtrate and the washing was rendered neutral with glacial acetic acid to precipitate brown crystals. The resulting crystals were filtered, washed with water, dried and recrystal-lized from DMF-H20 to obtain 3.7 g of 3-amino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid having a melting point of 253 - ~C- (with decomposition).
Example 26 .
2.84 g of 3-amino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid was dissolved in 50 mQ of a 2~ aqueous potassium hydroxide, and acetic anhydride was added dropwise thereto while ice cooling whereby orange-colored crystals were precipitated. The resultin~
erystals were separated by ~iltration, washed with water and reeryctallized from dimethylformamide-water to obtain 3 g o~
3-acetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid having a melting point o~ 187-190C.
Exa_ple_?7 6 g of 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]earbazol-5-carboxylic acid was dissolved in 35 mQ of concentrated su]furic acid and stirred while coolin~ with ice, followed by dropwise addition of a mixture of 4.3 mQ of-concentrated nitric acid having a specific gravity 1.42 and ~2~
1 15 mQ of the concentrated sulfuric acid. After completion of the addition, the resulting mixture was stirred for one hour at room temperature and poured into 200 g of ice to precipita-te yellow crystals. RecrystallizatiOn from dimethylformamide-water gave 7 g of 3-nitro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid having a melting point of 251-253C.
Example 28 5.64 g of 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,]-jk]carbazol--5-carboxylic acid was suspended in 60 mQ of chloroform and 4.5 g of phosphorus pentachloride was S~ S p~nS l'c~, added to the 3U_pC~5~ at room temperature. After allowing the mixture to react at room temperature for 30 minutes, the solvent was removed under reduced pressure to obtain a carboxylic acid chloride as a light brown oily substance. 60 mQ of chloroform was added to the resuling carboxylic acid chloride, and 3 g of ethylenebromohydrin was added dropwise to the solution.
~fter stirring the mixture for olle hour at room tempera-ture, 50 mQ of a saturated aqueous solution of po~ass i.UIIl carbonate was added to the mixture and the chlorofol^m layer was scparated.
The ahloxoform lay~r WclS washed with water, clried over an~ydrous sodium sulfate and the chloroform was removed to obtain 6.7 g of ~-bromoethyl 2-fluoro-7a,8,9,10,11,1:La-hexahydro-4-oxo-~H-pyrido[3,2,1-jk]carbazol-5-carboxylate. Recrystallization from toluene gave a product as white plate crystals having a melting point of 126-t~70C
Example 29 .. ..
3 g of ~-bromoethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido~3,2,1-jk]carbazol-5-carboxylate was added to a suspension of 1 g of 4-methylpiperidine and 0.4 g ~84 1 f sodium amide in 30 mQ of toluene, and the mix-ture was heated for 5 hours while refluxing. After the reaction had been completed as confirmed by the thin layer chromatography, a saturated aqueous solution of sodium carbonate was added to the reaction mixture and the toluene layer was separated. The toluene layer was dried over anhydrous sodium sulfate, concentrated to a volume of 15 mQ and hydrogen chloride gas was introduced into the solution, followed by removal of toluene under reduced pressure. 10 mQ of diethyl ether was added to the resulting residue and the mixture was triturated to obtain 2.3 g of ~-(4-methyl-1-piperidinyl)ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate hydrochloride as colorless amorphous crystals having a melting point of 187-192C.
Example 30 2 g of ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate was dissolved in 80 mQ of rnethanol, and 5 mQ of hydrazine hydrate was added thereto. The mixture was then heated while refluxing. The precipitated yello needle crystals were separated by Eiltration, and recrystallized from ethanol to obtain 1.7 g oE 2-~luoro-7a,8,9,10,11,11a-hexahydro-~-oxo-~EI-pyrido[3,2,1-jk]carbazol-5-carbohydra 2 ide monohydrate.
Example 31 20 mQ of ethanol was added to 1.6 g of the hydrazide prepared as described in Example 30, and 0.8 g of 5-nitro-2-furaldehyde was added to the solution while heat-refluxing. The mixture was then heat-refluxed for 10 minutes, and the yellow crystals precipitated was filtered after cooling/ washed with ethanol and dried to obtain 1.8 g of 2-fluoro-7a,8,9,10,11,11a~
hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid '3~3~
1 5-nitrofurfurylidene hydrazide as colorless amorphous crystals having a melting point of 293~2~4~C (with decomposition).
Antimicrobial Activity .
1. Test Method The antimicrobial activity of the following test compounds on various test organisms listed below was determined by the serial dilution method on agar plate and the minimum inhibitory concentration (mcg/m~) obtained are shown in Table 4 below.
~O 2. Test Organisms A. Bacillus subtilis ATCC 6633 B. Bacillus anthracis C. Bacillus cereus ATCC 11778 D. Staphyrococcus aurellS FDA 209p E. Staphyrococcus aureus Newmann F. Streptococcus faecalis IFO 12580 G. Streptomyces viridans H. Sarcina lutea ATCC 9341 I. Micrococcus flavus ATCC 10240a ~O J. Serratia marcescens ATCC 14756 K. Salmonella typhimurium kh L. Enterbactor cloacae 2 M. Enterbactor aero~enes IFO 12979 N. Klebsiella pneumoniae ST-101 O. Esherichia coli NIHJ
P. Esherichia coli NIHJ JC-2 Q. Proteus mirabilis 1287 R. Pseudomonas aeruginosa ATCC 10145 S. Candida albicans KYU
Claims (43)
- claim 1 continued...
wherein Y, n and R are as defined above, and cyclizing the resulting compound of the formula (IV). - 2. A process as claimed in claim 1, wherein the compound of the formula (III) is used in excess amounts over the equimolar amount relative to the compound of the formula (II).
- 3. A process as claimed in claim 1, wherein the compound of the formula (III) is used in an equimolar amount.
- 4. A process as claimed in claim 1, wherein the compound of the formula (III) is used in an amount of from 1.1 to 1.5 mol per mol of the compound of the formula (II).
- 5. A process as claimed in claim 1, wherein the reaction is carried out at a temperature of from room temperature to about 150°C.
- 6. A process as claimed in claim 5, wherein the reaction is carried out at a temperature of about 100°C to about 130°C.
- 7. A process as claimed in claim 1, wherein the reaction is carried out for a period of from about 0.5 to about 6 hours.
- 8. A process as claimed in claim 1, wherein said cyclization is carried out in a high boiling point hydrocarbon or a high boiling point ether.
- 9. A process as claimed in claim 8, wherein said high boiling point hydrocarbon or ether is selected from the group consisting of tetralin diphenyl ether, diethylene glycol and dimethyl ether.
- 10. A process as claimed in claim 1, wherein said cyclization is carried out at a temperature of about 100°C to about 250°C.
- 11. A process as claimed in claim 10, wherein said cyclization is carried out at a temperature of about 150°C to about 200°C.
- 12. A process as claimed in claim 1, wherein said cyclization is carried out for a period of about 0.5 to about 6 hours.
- 13. A process as claimed in claim 1, wherein the cyclization is carried out in the presence of an acidic substance.
- 14. A process as claimed in claim 13, wherein said acidic substance is selected from the group consisting of phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, su].furic acid, and polyphosphoric acid.
- 15. A process as claimed in claim 13, wherein said acidic substance is used in an approximately equimolar amount to a large excess amount relative to the amount of the compound of the formula (IV).
- 16. A process as claimed in claim 15, wherein said acidic substance is used in a 10 to 20 molar excess amount relative to the amount of the compound of the formula (IV).
- 17. A process as claimed in claim 13, wherein said cyclization is carried out at a temperature of about 100 to about 150°C.
- 18. A process as claimed in claim 13, wherein said cyclization is carried out for a period of about 0.5 to about 6 hours.
19. A compound of the formula (I) as defined in claim 1 and pharmaceutically acceptable salts thereof, whenever prepared - Claim 19 continued...
by a process as claimed in claim 1 or an obvious chemical equivalent thereof. - 20. A process as claimed in claim 1 wherein Y represents a halogen atom.
- 21. A compound of the general formula (I) as defined in claim 1 wherein Y represents a halogen atom whenever prepared by a process as claimed in claim 20 or an obvious chemical equivalent thereof.
- 22. A process as claimed in claim 1 wherein Y represents an alkoxy group, a nitro group, an amino group, an alkanoylamino group or an alkyl group.
- 23. A compound of the general formula (I) as defined in claim 1 wherein Y represents an alkoxy group, a nitro group, an amino group, an alkanoylamino group or an alkyl group, whenever prepared by a process as claimed in claim 22 or an obvious chemical equivalent thereof.
- 24. A process as claimed in claim 20 whercin R represents a hydroxy group.
- 25. A compound of the general formula (I) as defined in claim 1 wherein R represents a hydroxy group and Y represents a halogen atom whenever prepared by a process as claimed in claim 24 or an obvious chemical equivalent thereof.
- 26. A process as claimed in claim 20 wherein R represents an alkoxy group which may be substituted with a halogen atom or a 4-methyl-1-piperidinyl group; a hydrazino group or a group.
- 27. A compound of the general formula (I) as defined in claim 1 wherein Y represents a halogen atom and R is defined in claim 26, whenever prepared by a process as claimed in claim 26 or an obvious chemical equivalent thereof.
- 28. A process as claimed in claim 22 and R represents a hydroxy group.
- 29. A compound of the general formula (I) as defined in claim 1 wherein Y represents an alkoxy group, a nitro group, an amino group, an alkanoylamino group or an alkyl group, and R
represents a hydroxy group, whenever prepared by a process as claimed in claim 28 or an obvious chemical equivalent thereof. - 30. A process as claimed in claim 1 for preparing 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrldo-[3,2,1-jk]carbazol-5-carboxylic acid which comprises reacting ethyl ethoxymethyl-enemalonate with 6-fluoro-1,2,3,4,10,11-hexahydrocarbazol and cyclizing the resulting compound.
- 31. 2-Fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid which comprises reacting ethyl ethoxymethylenemalonate with 6-fluoro-1,2,3,4,10,11-hexahydrocarbazol and cyclizing the resulting compound whenever prepared by a process as claimed in claim 30 or an obvious chemical equivalent thereof.
- 32. A process as claimed in claim 1 for preparing 1-chloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylie acid which comprises reacting ethyl ethoxymethyl-enemalonate with 6-chloro-1,2,3,4,10,11-hexahydrocarbazol and cyclizing the resulting compound.
- 33. 1-Chloro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid which comprises reacting ethyl ethoxymethylenemalonate with 6-chloro-1,2,3,4,10,11-hexahydrocarbazol and cyclizing the resulting compound whenever prepared by a process as claimed in claim 32 or an obvious chemical equivalent thereof.
- 34. A process as claimed in claim 1 for preparing 2-methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid which comprises reacting ethyl ethoxymethylene-malonate with 6-methoxy-1,2,3,4,10,11-hexahydrocarbazol and cyclizing the resulting compound.
- 35. 2-Methoxy-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid which comprises reacting ethyl ethoxymethylenemalonate with 6-methoxy-1,2,3,4,10,11-hexahydrocarbazol and cyclizing the resulting compound whenever prepared by a process as claimed in claim 34 or an obvious chemical equivalent thereof.
- 36. A process as c]aimed in claim 1 for preparing 7a,8,9, 10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid which comprises reacting ethyl ethoxymethyl-enemalonate with 1,2,3,4,10,11-hexahydrocarbazol and cyclizing the resulting compound.
- 37. 7a,3,9,10,11,11a-Hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]-carbazol-5-carboxylic acid which comprises reacting ethyl ethoxymethylenemalonate with 1,2,3,4,10,11-hexahydrocarbazol and cyclizing the resulting compound whenever prepared by a process as claimed in claim 36 or an obvious chemical equivalent thereof.
- 38. A process as claimed in claim 1 for preparing 1,3-dimethyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]-carbazol-5-carboxylic acid which comprises reacting ethyl ethoxy-methylenemalonate with 4,6,-dimethyl-1,2,3,4,10,11-hexahydro-carbazol and cyclizing the resulting compound.
- 39. 1,3-Dimethyl-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid which comprises reacting ethyl ethoxymethylenemalonate with 4,6-dimethyl-1,2,3,4,10,11-hexahydrocarbazol and cyclizing the resulting compound whenever prepared by a process as claimed in claim 38 or an obvious chemical equivalent thereof.
- 40. A process as claimed in claim for preparing ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]-carbazol-5-carboxylate which comprises reacting ethyl ethoxy-methylenemalonate with 6-fluoro-1,2,3,4,10,11-hexahydrocarbazol.
- 41. Ethyl-2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylate which comprises reacting ethyl ethoxymethylenemalonate with 6-fluoro-1,2,3,4,10,11-hexahydrocarbazol whenever prepared by a process as claimed in claim 40 or an obvious chemical equivalent thereof.
- 42. A process as claimed in claim 1 for preparing 3-acetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]-carbazol-5-carboxylic acid which comprises reacting ethyl ethoxymethylenemalonate with 6-amino-1,2,3,4,10,11-hexahydro-carbazol and cyclizing the resulting product.
- 43. 3-Acetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido-[3,2,1-jk]carbazol-5-carboxylic acid which comprises reacting laim 43 continued...
ethyl ethoxymethylenemalonate with 6-amino-1,2,3,4,10,11-hexahydrocarbazol and cyclizing the resulting product whenever prepared by a process as claimed in claim 42 or an obvious chemical equivalent thereof.
1. A process for preparing a pyrido[3,2,1-jk]carbazol derivative represented by the formula (I):
(I) wherein R represents a hydroxy group, an alkoxy group which may be substituted with a halogen atom or with a 4-methyl-1-piper-idinyl group, a hydrazino group or a group, Y represents an alkoxy group, a halogen atom, a nitro group, an amino group, an alkanoylamino group or alkyl group, and n is 0, 1 or 2; and pharmaceutically acceptable salts thereof, which comprises reacting a compound represented by the formula (II):
(II) wherein Y and n are as defined above, with a compound represented by the formula (III):
(III) wherein R is as defined above and may be the same or different, and R' represents an alkyl group, to produce a compound of the formula (IV):
(IV)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP137418/77 | 1977-11-15 | ||
| JP52137418A JPS584717B2 (en) | 1977-11-15 | 1977-11-15 | Pyrido[3,2,1-jk]carbazole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1122984A true CA1122984A (en) | 1982-05-04 |
Family
ID=15198157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA315,257A Expired CA1122984A (en) | 1977-11-15 | 1978-10-31 | Pyrido (3,2,1-jk) carbazol derivatives |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS584717B2 (en) |
| BE (1) | BE872000A (en) |
| CA (1) | CA1122984A (en) |
| CH (1) | CH638808A5 (en) |
| DE (1) | DE2849158A1 (en) |
| FR (1) | FR2408606A1 (en) |
| GB (1) | GB2009731B (en) |
| IT (1) | IT1111363B (en) |
| NL (1) | NL7811239A (en) |
| SE (1) | SE437519B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS588396B2 (en) * | 1978-08-11 | 1983-02-15 | 大塚製薬株式会社 | Pyrido[3,2,1↓-jk]carbazole derivative |
| US4380543A (en) * | 1981-11-06 | 1983-04-19 | Riker Laboratories, Inc. | Antimicrobial 8-cyano-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acids |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE793524A (en) * | 1971-12-30 | 1973-06-29 | Riker Laboratories Inc | BENZOQUINOLIZINE-CARBOXYLIC ACIDS AND THEIR DERIVATIVES |
| US3917609A (en) * | 1973-06-27 | 1975-11-04 | Minnesota Mining & Mfg | Pyrroloquinoline carboxylic acids and derivatives |
-
1977
- 1977-11-15 JP JP52137418A patent/JPS584717B2/en not_active Expired
-
1978
- 1978-10-31 CA CA315,257A patent/CA1122984A/en not_active Expired
- 1978-11-08 GB GB7843756A patent/GB2009731B/en not_active Expired
- 1978-11-10 CH CH1159478A patent/CH638808A5/en not_active IP Right Cessation
- 1978-11-13 IT IT51875/78A patent/IT1111363B/en active
- 1978-11-13 DE DE19782849158 patent/DE2849158A1/en not_active Ceased
- 1978-11-14 NL NL7811239A patent/NL7811239A/en not_active Application Discontinuation
- 1978-11-14 SE SE7811762A patent/SE437519B/en not_active IP Right Cessation
- 1978-11-14 BE BE191720A patent/BE872000A/en not_active IP Right Cessation
- 1978-11-15 FR FR7832269A patent/FR2408606A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| GB2009731B (en) | 1982-05-12 |
| SE437519B (en) | 1985-03-04 |
| SE7811762L (en) | 1979-05-16 |
| NL7811239A (en) | 1979-05-17 |
| IT7851875A0 (en) | 1978-11-13 |
| JPS5473797A (en) | 1979-06-13 |
| JPS584717B2 (en) | 1983-01-27 |
| BE872000A (en) | 1979-05-14 |
| CH638808A5 (en) | 1983-10-14 |
| IT1111363B (en) | 1986-01-13 |
| GB2009731A (en) | 1979-06-20 |
| DE2849158A1 (en) | 1979-05-17 |
| FR2408606B1 (en) | 1981-07-03 |
| FR2408606A1 (en) | 1979-06-08 |
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