BE897208A - CARBOSTYRYLE COMPOUNDS - Google Patents

Abstract

The invention relates to novel carbostyryl derivatives and their salts, which have a peptic antiulcer action and are useful as an agent for treating peptic ulcers of the digestive system, for example stomach and duodenal ulcers. These derivatives correspond to the general formula (I), the carbostyryl derivative of the present invention in particular has a prophylactic and therapeutic action in the treatment of chronic ulcers.

Description

       

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  "Carbostyryl compounds" by the Company: OTSUKA PHARMACEUTICAL CO., LTD., 2-9, Kanda-Tsukasacho, Chiyoda-ku, TOKYO. (Japan).
 EMI1.1
 ----------- Priority of two patent applications filed in Japan, on July 5, 1982, under NO 117311/82 and on July 5, 1982, under NO 117312/82.

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   The present invention relates to a novel carbostyryl derivative with action against peptic ulcers, methods of preparing such a compound and a pharmaceutical composition for the treatment of peptic ulcers containing said carbostyryl derivative as an active ingredient.



   A new carbcstyryl derivative and its salt according to the present invention are represented by the general formula (1)
 EMI2.1
 in which,
R1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl (lower alkyl) group;

   
 EMI2.2
 i is a hydrogen atom, halogen atom, a benzoyloxy group (which may have halogen atoms as substituents), a hydroxyl group, a lower alkyl group or a lower alkoxy group;
R3 is a hydroxyl group, an amino group / which may bear, as a substituent, a cycloalkyl- (lower alkyl) group (which may bear, as substituent, a carboxy group, or a (lower alkoxy) carbonyl group on the cycloalkyl ring) ./, a lower alkoxy group, a (lower alkoxy) carbonyl (lower alkoxy) group, a benzoyl (lower alkoxy) group or a (lower alkanoyl) oxy- (lower alkoxy) group;

  
R4 is a hydrogen atom, a phenylsulfonyl group (which may have, as substituents, groups

  <Desc / Clms Page number 3>

 
 EMI3.1
 lower alkyl or halogen atoms), a lower alkyl group, a phenyl-lower group) which may have, as a substituent, a halogen atom on the phenyl ring), or a group of formula-COR / bùR est a lower alkyl group (which may have as substituents an amino group or a phenyl (lower alkoxy) carbonylamino group), a cycloalkyl group (which may have, as substituent, an amino (lower alkyl) group or a phenyl- (lower alkoxy group) ) -carbonylamino- (lower alkyl), on the cycloalkyl ring), a phenyl group (which may have 1 to 3 substituents chosen from the group comprising a halogen atom, a lower alkyl group,

   a lower alkoxy group, a nitro group, a
 EMI3.2
 amino group and a hydroxyl group, on the phenyl ring), a lower phenyl group) (which may have, as a substituent, a halogen atom on the phenyl ring), or a penta-or hexagonal unsaturated heterocyclic ring bearing 1 or 2 hetero atoms selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom (said heterocyclic ring may have a lower alkyl group as a substituent) 7; R is a hydrogen atom or a phenylsulfonyl group (which may have, as substituents, lower alkyl groups or halogen atoms);
A is a lower alkylene group;

   n is 0 or 1;
 EMI3.3
 / the carbon-carbon bond indicated by-C --- C,
 EMI3.4
 in the side chain of the formula COR3 L-UK N n N
 EMI3.5
 denotes a single or double carbon-carbon bond; the carbon-carbon bond between positions 3 and 4 of the carbo-styryl skeleton is a single or double bond;

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 the substitution position of the side chain
 EMI4.1
 rale of the formula COR 4 - n - \ RO
 EMI4.2
 is one of the positions 3, 4, 5, 6, 7 or 8 of the carbostyryl skeleton.



   A new carbostyryl derivative or its salt according to the present invention, represented by the general formula (1), is endowed with an action against peptic ulcer, and is useful as an agent for treating peptic ulcers of the digestive system, for example stomach and duodenal ulcers.



   The carbostyryl derivative of the present invention has in particular prophylactic and therapeutic effects in the treatment of chronic ulcers, for example the experimental ulcer caused by acetic acid and the ulcer caused by a caustic substance, while being slightly toxic and without side effects; thus, the carbostyryl derivative of the present invention is an agent of interest for the treatment of chronic ulcers.



   The carbostyryl derivative of the present invention also has the effect of increasing the endogenous prostaglandin E2 and thus it is useful as a prophylactic and therapeutic agent for the treatment of diseases by increasing the endogenous prostaglandin E2.



   For example, the carbostyryl derivative according to the present invention is useful as a prophylactic and therapeutic agent for the treatment of peptic ulcers by increasing the endogenous prostaglandin E2 in the gastric mucosa.



   The present invention proposes to provide a new derivative of carbostyryl and its salt, represented by the general formula (1), endowed with an action against peptic ulcer.

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 EMI5.1
 



  Another object of the present invention is to provide processes for said carbostyryl derivative and its salt of general formula (1).



  Yet another object of the present invention is to provide a pharmaceutical composition for the treatment of peptic ulcers, containing said carbostyryl derivative or its salt as an active ingredient.



  As the lower alkyl group mentioned in the present specification, mention may be made, by way of example, of a straight or branched chain alkyl group of 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl.



  As the lower alkenyl group mentioned in the present specification, there may be mentioned, by way of example, a straight or branched chain alkenyl group of 2 to 6 carbon atoms, for example vinyl, allyl, 2-butenyl, 3-butenyl, 1- methylallyl, 2-pentenyl or 2-hexenyl.



  As the lower alkynyl group mentioned in the present specification, mention may be made, by way of example, of a straight or branched chain alkynyl group of 2 to 6 carbon atoms, for example ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl or 2-hexynyl.



  As the lower alkylene group mentioned in the present specification, there may be mentioned by way of example a straight chain alkylene group of 1 to 6 carbon atoms, for example methylene, ethylene, trimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene or hexamethylene.



  As phenyl (lower alkyl) group mentioned in the present specification, there may be mentioned by way of example a phenylalkyl group in which the alkyl moiety is a straight or branched chain alkyl group of 1 to 6 carbon atoms, for example benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1, 1-dimethyl-2-

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 preparationphenylethyl, 5-phenylpentyl, 6-phenylhexyl or 2-methyl-3-phenylpropyl.



   As the cycloalkyl group mentioned in the present specification, mention may be made of a cycloalkyl group having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.



   As the lower alkoxy group mentioned in the present specification, mention may be made, by way of example, of a straight or branched chain alkoxy group of 1 to 6 carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy or hexyloxy.



   As the halogen atom mentioned in the present specification, mention may be made, by way of example, of a fluorine, chlorine, bromine or iodine atom.



   As phenyl- (lower alkoxy) carbonylamino group mentioned in the present specification, there may be mentioned by way of example a phenyl-alkoxycarbonylamino group in which the alkoxy moiety is a straight or branched chain alkoxy group of 1 to 6 carbon atoms, for example
 EMI6.1
 benzyloxycarbonylamino, 2-phenylethoxycarbonylamino, 1-ohenylethoxycarbonylamino, 3-phenylpropoxycarbonylamino, 4phenylbutoxycarbonylamino, 1, 1-dimethyl-2-phenylethoxycarbonylamino, 5-phenylpentyloxycarbonylamino-phenylcarbonyloxypropyl.



   As the lower alkyl group (which may have, as substituents, an amino group or a phenyl- (lower alkoxy) carbonylamino group) mentioned in the present specification, when the alkyl group does not carry a substituent, there may be mentioned by way of example the aforementioned lower alkyl group, while when the alkyl group carries substituents, mention may be made, for example, of a straight or branched chain alkyl group of 1 to 6 carbon atoms (comprising a phenyl-alkoxycarbonylaminino group in which the amino group or the alkoxy fragment contains 1 to 6 carbon atoms), for example aminomethyl,

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 2-aminoethyl, 2- or 3-aminopropyl, I-methyl-2-aminoethyl, 2-, 3-or 4-aminobutyl, 1, 1-dimethyl-2-aminobutyl, 2-or 3-aminopentyl,

     4-aminohexyl, benzyloxycarbonylaminomethyl, 2-benzyloxycarbonylaminoethyl, 2-benzyloxycarbonylaminopropyle, 3-benzyloxycarbonylaminopropyle, 4-benzyloxycarbonylaminobutyle, 3-benzyloxyaminocarbonyl-
 EMI7.1
 butyl, 5-benzyloxycarbonylaminopentyle, 6-benzyloxycarbonylaminohexyle, 2-phenylethoxycarbonylaminomethyl, 1-prenylethoxycarbonylaminomethyl, 2-amino) ethyl, 3-propyl, 2- (2-phenylethoxycarbonyl- (3-phenylpropoxycarbonylamino) ethyl, 4- (4-carbonylamino) ) butyl, 2- (5-phenylpen yloxycarbonylamino) - ethyl, 2- (6-phenylhexloxycarbonylamino) ethyl, 1,1-dimethyl-2- (benzyloxycarbonylamino) ethyl or (1,1-dimethyl-2-phenylethoxycarbonylamino) methyl.



   As phenyl group (which may have 1 to 3 substituents chosen from the group comprising a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group and a hydroxyl group on the phenyl ring), there may be mentioned by way of example a phenyl group (which may have 1 to 3 substituents chosen from the group comprising a halogen atom, an alkyl group of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 atoms of carbon, a nitro group, an amino group and a hydroxyl group, on the phenyl ring), for example phenyl, 2-3-or 4-chlorophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-iodophenyl, 3, 5-dichlorophenyl, 2, 6-dichlorophenyl,

     3-4dichlorophenyl, 3, 4-difluorophenyl, 3, 5-dibromophenyl, 2-, 3-or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 4-propylphenyl, 3-isopropylphenyl, 2-butylphenyl, 4- hexylphenyl, 3-pentylphenyl, 4-tert-butylphenyl, 3, 4-dimen-
 EMI7.2
 thylphenyl, 2,5-dimethylphenyl, 2-, 3- nyl, 2-, 3- -ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 2-pentyloxyphenyl, 4-

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 or 4-methoxyphen-tert-butoxyphenyl, 4-hexyloxyphenyl, 3, 4-dimethoxyphenyl, 3, 4-diethoxyphenyl, 2, 5-dimethoxyphenyl, 2-, 3-or 4-nitrophenyl, 2,

     4-dinitrophenyl, 2-, 3-or 4-amino-
 EMI8.1
 nyle, 2,4-diaminophenyl, 3-methyl-4-chlorophenyl, 2-chloro-6-methylhenyl, 2-methoxy-3-chlorophenyl, 3,4,5-tri-methoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trichlorophenyl, 2-, 3- or 4-hydroxyphenyl, 3,4-dihydroxyphenyl or 2,6-dihydroxyphenyl.



   As the phenyl- (lower alkyl) group (which may have, as substituents, halogen atoms on the phenyl ring), mentioned in the present specification, when there is no substituent on the phenyl ring, By way of example, mention may be made of the abovementioned phenyl- (lower alkyl) group, while when the phenyl nucleus carries substituents, mention may, for example, be made of a phenyl-alkyl group (having 1 to 3 halogen atoms as substituents of the phenyl nucleus, and the alkyl fragment carrying 1 to 6 carbon atoms), for example 2-, 3-or 4-chlorobenzyl, 2-, 3-or 4-fluorobenzyl, 2-, 3or 4-bromobenzyl, 2-, 3-or 4-iodobenzyl, 3,5-dichlorobenzyl, 2,6-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 3,5-dibromobenzyl, 3,4, 5-trichlorobenzyl,

   
 EMI8.2
 2- 2- 5- (3-chlorophenyl) ethyl, 2- (3, 4-dibromophenyl) ethyl, dichlorophenyl) ethyl, 1- (4-chlorophenyl) ethyl, 3- (2-fluorophenyl) propyl, 3- (3 , 4,5-trichlorophenyl) propyl, 4- (4-chlorophenyl) butyl, 1,1-dimethyl-2- (3-bromophenyl) ethyl,
 EMI8.3
 5- benzyl, 5- pentyl, 6- hexyl, 6- hexyl or (2,4-dichlorophenyl) 2-methyl-3- (4-chlorophenyl) propyl.



   As the cycloalkyl group (which may bear, as substituents, an amino- (lower alkyl) group or a phenyl (lower alkoxy) -carbonylamino- (lower alkyl) group, on the cycloalkyl ring), mentioned in the present specification, when the cycloalkyl group does not pre-

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 there is no substituent, the abovementioned cycloalkyl group may be mentioned as an example, while when the cycloalkyl group carries substituents, an example of a substituted cycloalkyl group of 3 to 8 carbon atoms in the cycloalkyl moiety (having an aminoalkyl group in which the alkyl fraction has from 1 to 6 carbon atoms or a phenyl- (lower alkoxy) - carbonylamino (lower alkyl) group in which the alkyl and alkoxy fractions each have from 1 to 6 carbon atoms,

   on the cycloalkyl ring), for example 3-aminoaminocyclopropyle, 3- (2-aminoethyl) cyclobutyl, 4- (1-aminoethyl) cyclopentyl, 2- (3-aminopropyl) cyclohexyl, 3- (4-aminobutyl) cyclohexyl, 4 -aminomethylcyclohexyl, 3- (5-aminopentyl) cycloheptyl, 2-benzyloxycarbonylaminomethylcyclopropyle,
 EMI9.1
 3 cyclobutyl, 3- oxycarbonylaminopropyl) cyclopentyl, 2- (2-benzyloxycarbonylaminoethyl) nylaminopropyl) cyclopentyl, 3- (4-benzyloxycarbonylamino-butyl) cyclohexyl, 4- (3-benzyloxycarbonylaminobutyl) cyclohexyl) 2- (5-benzyloxyxylcarbonyl) , 3- (6-benzyloxycarbonylaminohexyl) cycloheptyl, 4- (6-benzyloxycarbonylaminohexyl) cycloheptyl,

     5- (2-phenylethoxycarbonylaminomethyl) cycloheptyl, 4- (1-phenylethoxycarbonylaminomethyl) cyclooctyl, 2-f2- (2-phenylethoxycarbonylamino) -
 EMI9.2
 ethycyclooctyl, propylJcyclopropyle, cyclobutyle, 3-f4-pentyle, 4-22- 2-f2- 3El, 1-dimethyl-2- 4-il, 1-dimethyl-2-phenylethoxycarbonylJ-cyclohexyle, 2-benzyloxycarbonylmethylcyclooctyl, 4-benzyloxycarbonyl 3-
As the (lower alkoxy) carbonyl group mentioned in the present specification, there may be mentioned by way of example a straight chain alkoxycarbonyl group or

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 branched from 1 to 6 carbon atoms in the alkoxy moiety, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,

   pentyloxycarbonyl or hexyloxycarbonyl.



   As an amino- (lower alkyl) group mentioned in the present specification, there may be mentioned, by way of example, a straight or branched chain alkylamino group of 1 to 6 carbon atoms in the alkyl fragment, for example aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4aminobutyl, 1, 1-dimethyl-2-aminoethyl, 5-aminopentyl,
 EMI10.1
 6-aminohexyl or 2-methyl-3-aminopropyl.



  As the amino group to carry, as substituents, a cycloalkyl- (lower alkyl) group (which may bear as substituents a carboxy group or a (lower alkoxy) carbonyl group, on the cycloalkyl ring), mentioned herein can quote
 EMI10.2
 by way of example a substituted amino group, a lower cycloalkyl group), in which the alkyl moiety is a straight chain or branched alkylene group of 1 to 6 carbon atoms, and the cycloalkyl moiety is a cycloalkyl group from 3 to 8 carbon atoms (on the cycloalkyl ring can be substituted a carboxy group or an alkoxycarbonyl group of 1 to 6 atoms
 EMI10.3
 carbon in the alkoxy fragment) /, for example amino, cyclopropylmethylamino, 2-cyclobutylethylamino, 1-cyclopentylethylamino, 3-cyclohexylpropylamino,

   4-cycloheptylbutylamino, 5-cyclooctylpentylamino, 6-cyclohexylhexylamino, cyclohexylmethylamino, 2-methyl-3-cyclohexylpropylamino, (2-carboxycyclopropyl) methylamino, 2- ethylamino, 1- xycyclopentyl) propylamino 4- amino 3-carboxycycloheptyl) methylamino, 2- (4-caboxycycloheptyl) ethylamino, 1- (5-carboxycycloheptyl) ethylamino, 3- (4-carboxycyclooctyl) propylamino, 4- (2-

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 EMI11.1
 carboxycyclooctyl) butylamino, (4-carboxycyclohexyl) methylamino, 6- hexylamino, 5-ethoxycarbonylcyclobutyl) pentylamino, 4-cyclopentyl) butylamino, 3- propylamino, 2- 1- bonylcyclohexyl) methylamino, 2-methyl-propoxy propylamino, (5-methoxycarbonylcyclooctyl) methylamino or (4-methoxycarbonylcyclohexyl) methylamino.



   As the (lower alkoxy) carbonyl- (lower alkoxy) group mentioned in the present specification, an alkoxycarbonylalkoxy group in which the alkoxy moieties are straight or branched chain alkoxy groups of 1 to 6 carbon atoms may be mentioned by way of example. , for example methoxycarbonylmethoxy, 2-methoxycarbonylethoxy, 1-methoxycarbonylethoxy, 3-methoxycarbonylpropoxy, 4-methoxycarbonylbutoxy, 1, 1-dimethyl-2-methoxycarbonylethoxy, 5-methoxycarbonylpentyloxy, 6-methoxycaroxyoxycarbonyloxycarbonyloxy , 3-ethoxycarbonylpropoxy, 6-ethoxycarbonylhexyloxy, 2-propoxycarbonylethoxy, 4-propoxycarbonylbutoxy,

   5-butoxycarbonylpentyloxy, pentyloxycarbonylmethoxy, 1-pentyloxycarbonylethoxy, 1, 1-dimethyl-2-hexyloxycarbonylethoxy or 3-hexyloxycarbonylpropoxy.



   As the benzoyl- (lower alkoxy) group mentioned in the present specification, there may be mentioned by way of example a benzoyl-alkoxy group in which the alkoxy group is a straight or branched chain alkoxy group of 1 to 6 carbon atoms, for example example benzoylmethoxy, 2-benzoylétho-
 EMI11.2
 xy, 1-benzoylethoxy, 3-benzoylpropoxy, 4-benzoylbutoxy, 1, 1-dimethyl-2-benzoylethoxy, 5-benzoylpentyloxy, 6-ben-zoylhexyloxy or 2-methyl-3-benzoylpropoxy.



   As the (lower alkanoyl) group (lower alkoxy) mentioned in the present specification, an alkanoyloxyalkoxy group in which the

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 alkoxy moiety is a straight or branched chain alkoxy group of 1 to 6 carbon atoms, and the alkanoyloxv moiety is a straight chain or alkanoyloxy group
 EMI12.1
 mified from 1 to 6 carbon atoms, for example acetyloxy- / methoxy, 2-acetyloxyethoxy, l-acetyloxyethoxy, 3-acetvloxypropoxy, 4-acetyloxybutoxy, 1, 1-dimethyl-2-acetyloxy-ethoxv, 5-acetyloxypentyloxy, 6- acetyloxyhexyloxy, 2-methyl-3-acetyloxypropoxy, propionyloxymethoxy, 3-propionyloxypropoxy, 6-propionyloxyhexyloxy, 2-butyryloxyethoxy, 4-butyryloxybutoxy, 5-pentanoyloxypentyloxy, pentanoyloxymethoxy, tert-butylcarbon

   2- nyloxy) butylcarbonyloxy) propoxy, 4- butoxy, (tert-butylcarbo-1, 1-dimethyl-2- (tert-butylcarbonyloxy) ethoxy, hexanoyloxy-methoxy, 3-hexanoyloxypropoxy or 6- (tert-butylcarbonyloxy) - hexyloxy.



   As the lower alkanoyl group mentioned in the present specification, mention may be made, by way of example, of a straight or branched chain alkanoyl group of 1 to 6 carbon atoms, for example formyl, acetyl, propionyl, butyryl, isobutyryl, pentanole, tertio- butylcarbonyl or hexanoyl.



   As phenylsulfonyl group (which may bear, as substituents, lower alkyl groups or halogen atoms) mentioned in the present specification, mention may be made of a phenylsulfonyl group (which may bear, as substituents, alkyl groups of 1 to 6 atoms carbon or halogen atoms), for example phenylsul-
 EMI12.2
 fonyl, 4-methylphenylsulfonyl, 3-methylphenylsulfonyl, 2-methylphenylsulfonyl, 2-ethylphenylsulfonyl, 3-ethylphenylsulfonyl, 4-ethylphenylsulfonyl, 3-isopropylphenylsulfonyl, 4-hexylphenylsulfonyl 4-hexylphenylsulfonyl sulfonyl, 2-, 3-or 2-, 3-or 4iodophenylsulfonyl.

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   As the benzoyloxy group (which may carry halogen atoms as substituents) mentioned in the
 EMI13.1
 present specification, there may be mentioned by way of example the group 2-, 3-or 4-chlorobenzoyloxy, 2-, 3-or 4-fluorobenzoyloxy, 2-, 3-or 4-bromobenzoyloxy, or 2-, 3-or 4-iodobenzoyloxy.



   As the halogen atom mentioned in the present specification, mention may be made of chlorine, fluorine, bromine and iodine.



   As a penta-or hexagonal unsaturated heterocyclic ring having 1 or 2 hetero atoms selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom (said heterocyclic ring may carry a lower alkyl group having from 1 to 6 carbon atoms as substituent) mentioned in this specification, there may be mentioned by way of example the pyridyl, 2-methylpyridyl, 3-ethylpyridyl, 4-butylpyridyl, thienyl, 2-methylthienyl, 3-propylthienyl, pyrimidyl groups , 2-pentylpyri-
 EMI13.2
 midinyle, pyrrolyle, 3-methylpyrrolyle, 1-pyrazinyl, 4pentyl-l-pyrazinyle, pyrazolyle, 3-methylpyrazolyle, 4-ethylpyrazolyle, imidazolyle, 2-propylimidazolyle, 4-pentylimidazolyle, pyridazinyle, pyridazinyl, 4-methylpyrinyl oxazolyle, 4-butyloxazolyle,

   isoxazolyl, 4H-1,4-oxazinyl, thiazolyl, 4-methylthiazolyl, 2-ethylthiazolyl, 5-propylthiazolyl, isothiazolyl, 3-methylisothiazolyl, furyl, 3-methylfuryl, 2-ethylfuryl, 2-methyl, thianyl, 4-methyl 4-methylthianyl.



   The substitution position of the late- chain
 EMI13.3
 line of formula COR / R4 - (A) -CHC N \ R
 EMI13.4
 is any one of positions 3, 4, 5, 6, 7 or 8 of the carbostyryl skeleton.



   The new carbostyryl derivatives of the pre-

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 sente invention also include their optical isomers.



   The new carbostyryl derivatives of the present invention can be prepared by various methods, for example by a reaction process formula-I, as indicated in the following reaction scheme.

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 EMI15.1
 



  (Dream process C -3 ", - = CH - CH - -CH," \. ',' - ,, "- -" ii l't (In) (2) -77 A .. '- x 4f livdroiyse c ..., - -CHCH-XHCCR- '- -CHCH-NH - -CHCH- ao ide Cu 2 -' OË ./ (Ib) - '\' 2 2-2-1 7, Esterifi -Estërifieation orir. On cation '-o) -COOH s (4) / - ./ i û - -CCOH 1 3t (ld)' r '-X' -. on,, - LL'r. '.



  3) '/,' '/,'. - <- "--- <"/" '- /' - (3 l, n-. 2 -2

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 EMI16.1
 1 2 5 In this diagram, R, A, n and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above; R a lower alkyl group, a (lower alkoxy) carbonyl- (lower alkyl) group, a benzoyl (lower alkyl) group or an (lower alkanoyl) oxy (lower alkyl) group; R is a phenylsulfonyl group (which may have, as substituents, lower alkyl groups), a lower alkyl group or a phenyl- (lower alkyl) group (which may carry halogen atoms as
 EMI16.2
 6 substituents on the phenyl ring);

   R6 and R8 each represent a lower alkyl group respectively 7 3 "is a lower alkanoyl group; is an amine group may bear, as substituent, a cyclo group
8alkyl- (lower alkyl) (which may bear, as a substituent, a carboxy group or a (lower alkoxy) carbonyl group on the cycloalkylene ring /; and X is a halogen atom.



   Thus, the desired carbostyryl derivative can be prepared by hydrolysis of a compound of formula (2), and if desired, the product obtained can be acylated, alkyl, amidified, esterified or treated by a combination of these methods.



   The reaction for the preparation of a compound of formula (la) which is one of the desired compounds of the present invention by hydrolysis of a compound of formula (2) can be carried out in the presence of a suitable hydrolysis catalyst , for example a hydrohalic acid such as hydrochloric acid or hydrobromic acid; a mineral acid such as sulfuric acid or phosphoric acid; an alkaline inorganic compound, for example an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide;

   an alkali metal carbonate or hydrogen carbonate, for example sodium carbonate, potassium carbonate or sodium hydrogen carbonate in

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 the absence or presence of an appropriate solvent (for example water or a mixed solvent consisting of water and a lower alcohol such as methanol or ethanol), at 50-150 ° C., preferably 70-100 ° C. , for 3 to 24 hours.



   The compound of formula (la), (lc) or (l) can be acylated using a carboxylic acid of formula (3) to obtain the corresponding desired compound of formula (lb), (Id) or (lm), said acylation can be carried out by carrying out a conventional reaction for amide bond formation. In this case, said carboxylic acid of formula (3) can be an activated carboxylic acid.



   The amide bond formation reaction can be carried out by applying reaction conditions for a conventional amide bond formation reaction.



  For example, (a) a process using mixed acid anhydride, which is a process of reacting a carboxylic acid (3) with an alkylhalocarboxylic acid to obtain a mixed acid anhydride and then reacting this acid anhydride mixed with a compound (la), (lc) or (H); (b) a process using an activated ester or a process using an activated amide, which is a process which consists in converting a carboxylic acid (3) into an activated ester, for example p-nitrophenyl ester, N ester -hydroxysuccinimide or the ester of hydroxybenzotriazole; or to an activated amide, for example benzoxazoline-2-thione, then reacting said activated ester or activated amide with a compound of formula (la), (lc) or (If);

   (c) a process using a carbodiimide, which is a process which consists in dehydrocondensing a carboxylic acid (3) with a compound of general formula (la), (lc) or (1t) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole;

   (d) a process using a carboxylic acid halide which is a process which consists of

  <Desc / Clms Page number 18>

 converting a carboxylic acid (3) into a carboxylic acid halide, then reacting said halide with a compound of general formula (la), (lc) or (le) (e) as other methods, there may be mentioned for example a process consisting in converting a carboxylic acid (3) into a carboxylic acid anhydride using for example acetic anhydride as dehydrating agent, then reacting this carboxylic acid anhydride with a compound of general formula (la), (lc) or (if.);

     or a process consisting in reacting an ester of a carboxylic acid (3) and a lower alcohol with a compound of general formula (la), (lc) or (lB.) under high pressure and at a high temperature. It is also possible to use a process in which a carboxylic acid is activated with a phosphorus compound such as triphenylphosphine or diethyl chlorophosphate, then this activated carboxylic acid (3) is reacted with a compound of general formula (la), ( lc) or (lul).



   Mention may be made, as alkylhalogenacarboxylic acid used in the process using mixed acid anhydride, of methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate or chloroformate. isobutyl.



  The mixed acid anhydride is prepared by a Schotten-Baumann reaction, said mixed acid anhydride being reacted, without separation from the reaction system, with a compound of general formula (la), (lc) or (12 ) by giving a compound of general formula (lb), (Id) or (lm) according to the present invention. The Schotten-Baumann reaction is generally carried out in the presence of a basic compound.



  As basic compound, it is also possible to use any compound generally used in the SchottenBaumann reaction, for example an organic base such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine,

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 EMI19.1
 1, 5-diazabicycloÍ4, 3, OJnonene-5 (DBN), 1, 5-diazabicycle / 5, 4, Ojundecene-5 (DBU) or 1, 4-diazabicyclo / 2, 2, 2Joctane (DABCO); an inorganic basic compound such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate.



  This reaction is carried out at a temperature between -20 and 1000C, preferably between 0 and 500C, and the reaction time is from about 5 minutes to 10 hours, preferably from 5 minutes to 2 hours. The reaction of a mixed acid anhydride thus obtained with a compound of general formula (la), (lc) or (lS.) Is carried out between approximately - 20 to 150 C, preferably between 10 and 50 C, for approximately 5 minutes to 10 hours, preferably about 5 minutes to 5 hours. The process using mixed acid anhydride can be carried out without solvent, but a solvent is generally used.

   As solvent, use may also be made of any solvent commonly used in a process using mixed acid anhydride, in particular a halogenated hydrocarbon such as methylene chloride, chloroform or dichloroethane; an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran or dimethoxyethane; an ester such as methyl acetate or ethyl acetate; a polar aprotic solvent such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoryltriamide.

   To conduct the reaction, the ratio of the amount of carboxylic acid (3) to the amount of alkyl halogenocarboxylic acid to the amount of compound of general formula (1), (lc) or (1 #) is not particularly limited , and in general an at least equimolar amount of each of these reactants is used, preferably 1 to 2 times the molar amount of the alkylhalocarboxylic acid and of compound of general formula (1), (lc) or (lut ) compared to the carboxylic acid (3).



   To implement the above process

  <Desc / Clms Page number 20>

 of (b), which is a process using an activated ester or an activated amide, for example using benzoxazoline-2-thionamide, the reaction can be carried out in a suitable inert solvent which has no harmful effect on the reaction, for example a solvent analogous to that which can be used in the above-mentioned process using mixed acid anhydride or another solvent such as I-methyl-2-pyrrolidone, at a temperature of 0 to 150 C, preferably from 10 to 100 C, for 0.5 to 75 hours.



  As for the ratio of the amount of compound of general formula (la), (lc) or (lu), to the amount of benzoxazoline-2thionamide, it is at least an equimolar amount, preferably equimolar to 2 times the molar quantity of the last compound relative to the first. When using N-hydroxysuccinimide ester, a suitable basic compound, for example a basic compound which can be used in the above-mentioned process using the carboxylic acid halide (d) can also be used to advantageously conduct the reaction.



   To carry out the above-mentioned process using a carboxylic acid halide (d), a carboxylic acid (3) is reacted with a halogenating agent to prepare a carboxylic acid halide, and then said halide is reacted. carboxylic acid with a compound of general formula (la), (lc) or (lt), said carboxylic acid halide can be used with or without separation from the reaction system. The reaction of said carboxylic acid halide with a compound of general formula (la), (lc) or (l) can be carried out in the presence of a dehydrohalogenation agent in a solvent.

   As dehydrohalogenation agent, a common basic compound can be used, that is to say other than that used in the Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, a

  <Desc / Clms Page number 21>

 alkali metal alcoholate such as sodium methylate or sodium ethylate. An excess of compound of formula (la), (lc) or (l) can also be used as dehydrohalogenation agent.

   As solvent, other than that used in the above-mentioned Schotten-Baumann reaction, mention may be made of water, an alcohol such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, l ethyl cellosolve or methyl cellosolve; pyridine, acetone or acetonitrile; or a mixed solvent consisting of two or more of the above solvents. The ratio of the amount of compound of formula (la), (lc) or (l! L) to the amount of the carboxylic acid halide is not particularly limiting, and it can be chosen within a wide range and , in general, at least an equimolar amount is used, preferably an equimolar amount at 2 times the molar amount of the latter relative to the former.

   The reaction temperature is generally between -30 and 180oC, preferably between about 0 and 150C, and generally the reaction is finished after about 5 minutes to 30 hours.



   The carboxylic acid halide is prepared by reacting a carboxylic acid (3) with a halogenating agent in the presence or not of a solvent. As solvent, use may be made of any solvent which has no harmful effect on the reaction, for example an aromatic hydrocarbon such as benzene, toluene or xylene; a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetrachloride; an ether such as dioxane, tetrahydrofuran or diethyl ether;

   or a polar aprotic solvent such as dimethylformamide or dimethylsulfoxide. As the halogenating agent, a common halogenating agent can be used which can convert the hydroxyl group of the carboxylic acid, for example thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, penta-

  <Desc / Clms Page number 22>

 phosphorus chloride or phosphorus pentabromide.

   The ratio of the amount of the carboxylic acid (3) to the amount of the halogenating agent is not particularly limiting and it can be chosen over a wide range when the reaction is carried out in the absence of solvent, the latter being used in a large excess relative to the former, while in the presence of a solvent, the latter is used in an amount at least approximately equimolar, preferably 2 to 4 times the molar amount of the former. The reaction temperature and the reaction time are not particularly limiting, and in general, the reaction is carried out between approximately room temperature and 100 ° C., preferably between 50 and 80 ° C., for 30 minutes to 6 hours.



   In the above-mentioned process in which a carboxylic acid (3) is activated with a phosphorus compound such as triphenylphosphine or diethyl chlorophosphate, then the activated carboxylic acid (3) is reacted with a compound of formula (la) , (lc) or (liL), the reaction is carried out in an appropriate solvent.

   As solvent, use may be made of any solvent having no harmful effect on the reaction, and in particular a halogenated hydrocarbon such as methyl chloride, chloroform or dichloroethane; an aromatic hydrocarbon such as benzene, toluene or xylene; an ether such as diethyl ether, tetrahydrofuran or dimethoxyethane; an ester such as methyl acetate or ethyl acetate; a polar aprotic solvent such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoryl-triamide. In this reaction, the compound of formula (la), (lc) or (If) itself can serve as basic compound, and the reaction is preferably carried out when the compound of formula (la), (lc) or (read) is used in excess.

   If necessary, another basic compound can be used, for example an organic basic compound such as triethyl-

  <Desc / Clms Page number 23>

 
 EMI23.1
 amine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1, 5diazabicyclo / 4, 3, OJnonene-5 (DBN), 1, 5-diazabicycloj5, 4, Q / undecene- 5 (DBU) or 1, 4-diazabicycloL2, 2, 27octane (DABCO); an inorganic basic compound such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate. The reaction can be carried out between approximately 0 and 150 ° C., preferably between approximately 0 and 100 ° C., for approximately 1 to 30 hours.

   The ratio of the amount of compound of formula (la), (lc) or (l) to the amount of the phosphorus and carboxylic acid compound of formula (3), is generally at least an equimolar amount, preferably 1 to 3 times the molar amount of the latter compared to the former.



   In the reaction process formula-1, a compound of formula (la) or (lb) can be esterified with an alcohol to give the corresponding desired compound of formula (lc) or (ld).



   This esterification reaction can be carried out under reaction conditions analogous to those of a conventional esterification reaction, for example (i) by dehydrocondensation in the presence of a dehydrating agent in a solvent; or (ii) by reaction in the presence of an acidic or basic catalyst in a suitable solvent. As solvent used in process (i), there may be mentioned a halogenated hydrocarbon such as methylene chloride, chloroform or dichloroethane; an aromatic hydrocarbon such as benzene, toluene or xylene; an ether such as diethyl ether, tetrahydrofuran or dimethoxyethane; a polar aprotic solvent such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoryl-triamide.



   As dehydrating agent, mention may, for example, be made of dicyclohexylcarbodiimide or carbonyldiimidazole. The ratio of the amount of compound of formula

  <Desc / Clms Page number 24>

 (la) or (lb) the amount of alcohol of formula (4), corresponds to at least one equimolar amount, preferably equimolar to 1.5 times the molar amount of the latter relative to the first. The ratio of the amount of dehydrating agent used to the amount of compound of formula (la) or (lb) is at least an equimolar amount, preferably equimolar to 1.5 times the molar amount of the former relative to the latter.

   The reaction temperature is generally between room temperature and 150 C, preferably between 50 and 100 C, and the reaction is generally completed in 1 to 10 hours. As the acid catalyst used in the process of (ii), there may be mentioned an inorganic acid such as hydrochloric gas, concentrated sulfuric acid, a phosphoric acid, a polyphosphoric acid, boron trifluoride or perchloric acid; an organic acid such as trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, benzene sulfonic acid or ethane sulfonic acid; an acid anhydride such as trichloromethanesulfonic acid anhydride or trifluoromethane sulfonic acid anhydride; thionyl chloride;

   or acetonic dimethylacetal.



  In addition, an acidic ion exchange resin can also be used as a catalyst in the present invention. Any basic catalyst which is known in the art can be used as the basic catalyst, for example an inorganic basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, hydrogen carbonate. sodium, potassium hydrogen carbonate or silver carbonate; an alcoholate such as sodium methylate or sodium ethylate. This reaction can be carried out in the absence or in the presence of a solvent.

   As solvent to be used in the reaction, it is advantageous to have recourse to any solvent used in a conventional esterica reaction.

  <Desc / Clms Page number 25>

 tion, in particular an aromatic hydrocarbon such as benzene, toluene or xylene; a halogenated hydrocarbon such as dichloromethane, dichlorethane, chloroform or carbon tetrachloride; an ether such as diethyl ether, tetrahydrofuran, dioxane or the ethylene glycol monomethyl ether. In addition, the reaction can advantageously be carried out using a dehydrating agent such as anhydrous calcium chloride, anhydrous copper sulphate, anhydrous calcium sulphate or phosphorus pentoxide.

   The ratio of the amount of compound of formula (la) or (lb) to the amount of alcohol (4) is not particularly limiting, and can be chosen within a wide range; in the absence of solvent, alcohol (4) is used in a large excess, while in the presence of solvent, an equimolar amount is used at 5 times the molar amount, preferably at 2 times the molar amount of alcohol (4) to the amount of the compound of formula (la) or (lb). The reaction temperature is not particularly limited, and in general it is between -20 and 200 C, preferably between 0 and 150 C, and the reaction is generally completed in 1 to 20 hours.



   In the above formula-1 reaction process, a compound of formula (la) can be prepared by hydrolyzing a compound of formula (lb), (lc), (Id), (ln), (le) or (lm) in conditions analogous to those of the hydrolysis of a compound of formula (2). The reaction for forming the amide bond of a compound of formula (la) or (lb) can be carried out under conditions analogous to those of the reaction for forming an amide bond of a compound of formula (la), (le) or (if).



   The reaction of a compound of formula (la), (lez or (lc) with a compound of formula (5) is carried out until completion in the absence of a solvent or generally in the presence of an inert solvent at a temperature generally between room temperature and 2000C,

  <Desc / Clms Page number 26>

 preferably between room temperature and 120 C, for several hours to 24 hours.

   As the inert solvent, an ether such as dioxane, tetrahydrofuran or dimethyl ether of ethylene glycol can be used; an aromatic hydrocarbon such as benzene, toluene or xylene; a lower alcohol such as methanol, ethanol or isopropanol; a polar solvent such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoryl triamide, acetone or acetonitrile. The reaction can advantageously be carried out using a basic compound such as a deacidifying agent. As basic compound, there may be mentioned by way of example potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogencarbonate, sodium amide, sodium hydride, a tertiary amine such as triethylamine, tripropylamine, pyridine or quinoline.

   In addition, the reaction can be carried out by adding an alkali metal iodide such as potassium iodide or sodium iodide; or hexamethylphosphoryl-triamide as a reaction accelerator, if necessary. The ratio of the amount of compound of formula (la), (read) or (le) to the amount of compound of formula (5) is not particularly limiting and can be chosen within a wide range; in general, an equimolar amount to an excess is used, preferably an equimolar amount to 5 times the molar amount of the latter relative to the former.



   Under reaction conditions analogous to those used in the reaction of compound (1), (le) or (lut) with compound (5), the above-mentioned compound (lo), (lp) or (lq) can be sulfonylated to prepare a compound represented by the general formula

  <Desc / Clms Page number 27>

 
 EMI27.1
 
 EMI27.2
 in which R2, A, n and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above; and R 'is a phenylsulfonyl group (which may have, as substituents, lower alkyl groups or halogen atoms).
 EMI27.3
 



  Furthermore, among the compounds of general formula (1), a compound having a phenylsulfonyl group (which may bear, as substituents, lower alkyl groups) represented by R4 can be introduced into a compound represented by the general formula
 EMI27.4
 
 EMI27.5
 1 2 3 5 in which R, R2, R3, R ', A, n and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above, by a process under conditions analogous to those used in the acylation of the compound (la) with the compound (3).



   The compound (lr) thus obtained can be introduced into the compound (lo) by treatment with water, a lower alcohol such as methanol, ethanol or isopropanol, or with a mixed solvent consisting of water. and a lower alcohol, in the presence of a mineral acid such

  <Desc / Clms Page number 28>

 as sulfuric acid, hydrochloric acid or hydrobromic acid, between room temperature and 150 C, preferably between 60 and 120 C, for about 30 minutes to 15 hours.



   The compound of the present invention can also be prepared by methods represented by the following formula-II reaction process.

  <Desc / Clms Page number 29>

 
 EMI29.1
 



  (? Ci ... .- "- -" --''-- = - c /) /.



  - - 2 -.- CCCH "" "" '-. i, crr. aticr. from '/ liaison ce hycr:)' - ..



  -c "" "'." "-'. c (lay) <R-. 'nb.) ".)". c7lat 'link formation.'. cr smide '=' R '+ ix CCCH CCCH 3 ", -" - <-) ,, '""' '' "--.- i ls'i CH '¯sDer /' - T: ,, - 3 -," r. / '' 'C /' '"" - 2 F . n-- 21 '2 :)' t) 1 R c -c "'- c 71, / 1

  <Desc / Clms Page number 30>

 
 EMI30.1
 1 2 3'5 In this formula, R, R, R, R, R, X, A, n and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above.



   Thus, the compound of formula (6) is reacted with a compound of formula (7), then the intermediate compound formed is hydrolyzed; in addition, the product obtained is hydrolyzed, acylated, esterified or treated by a method of combining these reactions to obtain the desired carbostyryl derivative.



   The reaction of a compound of formula (6) with a compound of formula (7) can be carried out in the presence of a basic compound in an appropriate solvent. As basic compound used in the reaction, there may be mentioned an organic amine such as triethylamine-trimethylamine, pyridine, piperidine, N-methylmorpholine or 4-dimethylaminopyridine; an inorganic basic compound such as potassium hydroxide, sodium hydroxide, sodium hydride, sodium amide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or hydrogen carbonate potassium; an alkali metal salt of aliphatic fatty acid such as sodium or potassium acetate or sodium propionate;

   an alkali metal alcoholate such as sodium methylate or sodium ethylate.



   As solvent to be used in the reaction, there may be mentioned as examples an alcohol such as methanol, ethanol or isopropanol; a hydrocarbon such as hexane or cyclohexane; an ether such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran or diethyl ether; an ester such as ethyl acetate or methyl acetate; an aromatic hydrocarbon such as benzene, toluene or xylene; as well as water, acetic acid, acetic anhydride and pyridine./

  <Desc / Clms Page number 31>

 
The ratio of the amount of compound of formula (6) to the amount of compound of formula (7) is at least an equimolar amount, preferably equimolar to twice the molar amount of the latter relative to the former.



  The reaction is generally carried out between 50 and 200 C,
 EMI31.1
 preferably between 80 and 150 C, for about 30 minutes to 5 hours.



   By reacting a compound of formula (6) with a compound of formula (7), an intermediate product having the following formula is obtained:
 EMI31.2
 
 EMI31.3
 1, 5 / in which R, R2, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above., This intermediate product can easily be hydrolyzed by heating under reflux in a water-mixture acetone to obtain a compound of formula (lb '). The compound thus obtained of formula (lb ') can easily be converted into a compound of formula (la') under conditions analogous to those of the hydrolysis of a compound of formula (2) in the reaction process formulates- I mentioned above.



   In addition, a compound of formula (lb ') or (la') can also be esterified by a process analogous to that described in the esterification reaction of the reaction process formula I mentioned above, using a compound of formula (4) to prepare a corresponding compound of formula (ld ') or (le'), respectively. Furthermore,

  <Desc / Clms Page number 32>

 a compound of formula (la '), (le') or (il ') can also be acylated by a process analogous to that described in the acylation reaction of the above-mentioned reaction process formula-1, using a compound of formula ( 3), to prepare a corresponding compound of formula (lb '), (1d') or (lm ') respectively.



   A compound of formula (lb ') or (la') can be treated by a process analogous to that described in the amidation reaction of the reaction process formula I mentioned above to prepare a compound of formula (lu ') or (ln' ) respectively.



   The reaction of a compound of formula (la '), (1') or (le ') with a compound of formula (5) can be carried out under conditions analogous to those described in the reaction of a compound of formula ( la), (12) or (le) with a compound of formula (5) in the reaction process formula-I mentioned above.



   In addition, a compound of formula (le '), (ld'), (li ') or (ln') can be easily hydrolyzed to be introduced into a compound of formula (la ') by a process carried out in conditions analogous to those used in the hydrolysis reaction of a compound of formula (2) of the reaction process formula-I.



   The compound of general formula (lo '), (lp') or (lq ') can be introduced into a compound of general formula:
 EMI32.1
 
 EMI32.2
 1 2 3 41 in which R, R, R3, R ', A, n and the carbon-carbon bond between positions 3 and 4 of the skeleton

  <Desc / Clms Page number 33>

 carbostyryl are as defined above, by sulfonation under conditions analogous to those used in the reaction of (la '), (le') or (lt ') with a compound of formula (5).



   Among the compounds of general formula (1), those having a phenylsulfonyl group (which may carry, as
 EMI33.1
 substituents, lower alkyl groups or halogen atoms) and in which the carbon-carbon bond
 EMI33.2
 , / de-CH --- C of the side chain of formula / COR - (A) -CH --- C a double bond, can n \ N-R Ro
 EMI33.3
 introduced into a compound of general formula:
 EMI33.4
 
 EMI33.5
 2 in which R1, R, R, R, R ', A, n and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above, by acylation under conditions analogous to those used in the reaction of the compound of general formula (la) with the compound of formula (3).



   The compound of formula (lr ') can be introduced into a compound of formula (lo') under reaction conditions analogous to those used in the reaction of the compound of general formula (lr).



   Among the compounds of the present invention, those having a single bond in the carbon-carbon bond of -CH --- C in the side chain of formula

  <Desc / Clms Page number 34>

 
 EMI34.1
 3 - can be prepared by reduction of an NHR
CH --- C-COR Corresponding compound in which the carbon-carbon bond is a double bond, as indicated in the following reaction process formula-III.
 EMI34.2
 



  Reaction process formula-III /
 EMI34.3
 HORN).



  - n - = '.--- n- \ 1 R educt "- i 1 R2 Ri (l')
 EMI34.4
 zo in which R, R, R2, R, A, n and the carbon-carbon bond between the 3 and 4 of the carbostyryl skeleton are as defined above.



   The reduction reaction is generally carried out by catalytic reduction in the presence of an appropriate reduction catalyst. As catalyst to be used, mention may be made of the usual catalytic reduction catalysts, for example platinum, platinum oxide, palladium black, palladium on carbon or Raney nickel. The amount of catalyst used is generally in the range of about 0.2 to 0.5 times the weight of the compound of formula (1 ').



   The catalytic reduction is carried out in a solvent, for example water, methanol, ethanol, isopropanol, tetrahydrofuran or diethyl ether under pressure from 0.1 to 1 MPa, preferably 0.1 to 0.3 MPa of hydrogen gas, between -30 C and the boiling point of the solvent, preferably between OOC and about room temperature, with suitable stirring.



   In addition, a compound of the present invention can be converted to another compound of the present invention.

  <Desc / Clms Page number 35>

 vention by methods indicated in the reaction process formulas IV to VI below.



  / Formula-IVJ reaction process
 EMI35.1
 
 EMI35.2
 1 3 4 wherein R, R, A, n and the carbon-carbon bond between positions 3 and 4 of the carbostyryl backbone are as defined above; and R is a lower alkoxy group.



   The reaction aimed at obtaining a compound of formula (lf) from a compound of formula (le) is carried out by treatment of a compound of formula (le) in a solution of hydrobromic acid between 50 and 1500C for approximately 5 at 10 o'clock.
 EMI35.3
 formula-veg reaction process
 EMI35.4
 COR CCR - / "N-R -p! -R '' ->.



  0 alkylating agent 1i C: "R (1h) R
 EMI35.5
 234 where R, A, n and the carbon-carbon bond between positions 3 and 4 of the carbostyryl backbone are as defined above; zis a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl- (lower alkyl) group.

  <Desc / Clms Page number 36>

 
 EMI36.1
 



   The alkylation reaction of a compound of formula (Ig) is carried out in the presence of a basic compound such as sodium hydride, potassium hydride, metallic potassium, metallic sodium, sodium amide , potassium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, in a suitable solvent.



   As solvent to be used, there may be mentioned by way of example an ether such as dioxane, tetrahydrofuran, diethyl ether or dimethyl ether of diethylene glycol; an aromatic hydrocarbon such as benzene, toluene, xylene or chlorobenzene; a polar solvent such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoryl-triamide or ammoniacal water; or a mixture of these solvents.



    As alkylating agent, mention may be made of a halogenated alkyl of formula R-X (where Ril is as defined above; X is a halogen atom); dialkyl sulfate such as dimethyl sulfate or diethyl sulfate; a toluene sulfonate such as benzyl p-toluenesulfonate or methyl p-toluenesulfonate. The ratio of the amount of the alkylating agent to the amount of compound of formula (Ig) is not particularly limiting, and at least one equimolar amount is used, preferably equimolar to 2 times the molar amount of the first versus last.

   The reaction is generally carried out between about 0 and 70 ° C., preferably between 0 ° C. and room temperature, and it is generally completed in 30 minutes to 12 hours.

  <Desc / Clms Page number 37>

 
 EMI37.1
 / Formula-VI reaction process /
 EMI37.2
 C cc ('\) ïo' Peduction '-
 EMI37.3
 1 3 4 in which R, R2 L in which R, R, R, R, and n are as defined: J3 above.



   The dehydrogenation of a compound of formula (if) to obtain a compound of formula (lk) is carried out in a suitable solvent in the presence of a dehydrogenation agent. As dehydrogenation agent used, there may be mentioned a benzoquinone such as 2,3-dichloro-5, 6-dicyanobenzoquinone or 2,3, 5, 6-tetrachlorobenzoquinone (a common name is chloranile); a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide or bromine; a dehydrogenation catalyst such as selenium dioxide, palladium on carbon, palladium black, palladium oxide or Raney nickel.

   The ratio of the amount of the dehydrogenation agent used is not particularly limiting; in the case of the halogenating agent, 1 to 5 times the molar amount, preferably 1 to 2 times the molar amount of the halogenating agent are used relative to the compound of formula (li); in the case of the dehydrogenating agent, an excess of this agent is preferably generally used; in the case of other types of dehydrogenating agent, an amount equimolar to an excess is generally used.

   As solvent, there may be mentioned by way of example an ether such as dioxane, tetrahydrofuran, methoxyethanol or dimethoxyethane; an aromatic hydrocarbon such as benzene, toluene, xylene or cu-

  <Desc / Clms Page number 38>

 leads; a halogenated hydrocarbon such as dichloroethane, dichloromethane, chloroform or carbon tetrachloride; an alcohol such as butanol, amyl alcohol or hexanol; a polar protic solvent such as acetic acid; a polar aprotic solvent such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoryl-triamide. The reaction is generally carried out between room temperature and 300 C, preferably between room temperature and 200 C, and the reaction is complete in about 1 to 40 hours.



   In addition, the reduction of the compound of formula (Ik) to prepare a compound of formula (Ii) is carried out under usual catalytic reduction conditions in an appropriate solvent in the presence of a metal catalyst. As catalyst which is used, mention may be made, for example, of a metal catalyst such as palladium, palladium on carbon, platinum and Raney nickel. As solvent used, there may be mentioned as examples water, methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, hexane, cyclohexane, ethyl acetate and a mixture of these solvents.



   The catalytic reduction can be carried out under normal hydrogen pressure, or under pressure, generally under normal hydrogen pressure up to 1.96 MPa, preferably between normal hydrogen pressure and 0.98 MPa, between 0 and 150oC, preferably between room temperature and 100 C.



   Among the compounds of general formula (1),
 EMI38.1
 those having a hydroxyl group represented by the symbol o can also be prepared by dealkylation of a
R2, a compound in which R2 is a lower alkoxy group with an aqueous solution of hydrobromic acid under heating.



   Furthermore, the compound of general formula (1), having a hydroxyl group represented by the symbol
 EMI38.2
 o R, can also be prepared by hydrolysis of a compound

  <Desc / Clms Page number 39>

 
 EMI39.1
 0 of general formula (1) in which is a group
R2benzoyloxy (which may carry, as substituents, halogen atoms). The hydrolysis can be carried out in a suitable solvent in the presence of an acidic or basic compound. As solvent used, there may be mentioned as examples water, a lower alcohol such as methanol, ethanol or isopropanol; ethers such as dioxane or tetrahydrofuran; or a mixture of these solvents. As the acid used, mention may be made, by way of example, of mineral acids such as hydrochloric acid, hydrobromic acid or sulfuric acid.

   As basic compounds, there may be mentioned, by way of example, a metal hydroxide such as sodium hydroxide, potassium hydroxide or calcium hydroxide. The reaction is generally carried out between room temperature and 150 ° C., preferably
 EMI39.2
 between 80 and 120 C, and is generally completed in 1 to 15 hours.



   Among the compounds of general formula (1), those having a lower alkoxy group represented by the symbol R2 can be prepared by alkylation of a
 EMI39.3
 corresponding compound carrying a hydroxyl group represented by the symbol As alkylating agent used in the alkylation reaction, there may be mentioned, by way of example, a lower alkyl halide such as methyl iodide, chloride ethyl and tert-butyl bromide; dimethyl sulfate and diethyl sulfate. Other types of alkylating agent such as diazomethane can also be used.



   The reaction is carried out in an inert solvent, for example a ketone such as acetone or methyl ethyl ketone; an ether such as diethyl ether or dioxane; an aromatic hydrocarbon such as benzene, toluene or xylene; the water ; pyridine; dimethylformamide; dimethyl sulfoxide or hexamethylphosphoryl triamide.

  <Desc / Clms Page number 40>

 



   The alkylation can also be carried out using the basic compound used in the following acylation reaction. In addition, the alkylation can be carried out using silver oxide as the catalyst.



  The reaction is carried out at a temperature between 0 C and the boiling point of the solvent used. The ratio of the amount of the alkylating agent to the amount of the compound of formula (1), comprising a hydroxyl group
 EMI40.1
 2 represented by the symbol corresponds 1 to 3 times the molar quantity. The reaction is generally completed in 1 to 15 hours.



   Among the compounds of general formula (1), those having a benzoyloxy group (which may bear, as substituents, halogen atoms) can be prepared
 EMI40.2
 by acylation, i.e. benzoylation of a corresponding compound in which R is a hydroxyl group. As benzoylating agent used, there may be mentioned, by way of example, a benzoyl halide such as pchlorobenzoyl chloride and benzoyl chloride; benzoic anhydride and benzoic acid. When an acid anhydride or an acid halide is used as the acylating agent, the acylation reaction is carried out in the presence of a basic compound.

   As basic compound used, there may be mentioned, by way of example, an alkali metal such as metallic sodium or metallic potassium; an alkali metal hydroxide, carbonate or hydrogen carbonate; an aromatic amine such as pyridine or piperidine. The reaction is carried out in the absence or in the presence of a solvent, generally in an appropriate solvent. As solvent used, there may be mentioned as examples ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene, water and pyridine.



   The ratio of the acylating agent used to the

  <Desc / Clms Page number 41>

 amount of starting material is at least an equimolar amount and generally an equimolar amount to a large excess of the former over the latter. The reaction
 EMI41.1
 is carried out between 0 and 150 C and generally between 0 and 80 C. The reaction is completed in 0.5 to 10 hours. When an acid such as benzoic acid is used as an acylating agent, the reaction is advantageously carried out by adding a mineral acid such as sulfuric acid or hydrochloric acid; a sulfonic acid such as p-toluenesulfonic acid, benzenesulfonic acid or ethanesulfonic acid in the reaction system, and maintaining the reaction at a temperature of 50 to 120oC.



   Among the compounds of the present invention represented by the general formula (1), those having an atom
 EMI41.2
 1 of hydrogen represented by and also a carbon-carbon double bond between positions 3 and 4 of the carbostyryl skeleton can exist in tautomeric lactam-lactime form, as represented by the following equation:
 EMI41.3
 
 EMI41.4
 wherein R, R2, R3, A and n are as defined above.



   Among the compounds represented by the general formula (1), the compounds having an acid group can easily form salts with pharmaceutically acceptable bases. These bases include inorganic bases, for example metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; carbonates and hydrogen carbon

  <Desc / Clms Page number 42>

 alkali metal nates such as sodium carbonate and sodium hydrogencarbonate; alkali metal alcoholates such as sodium methylate and potassium ethylate.



   Alternatively, among the compounds represented by the general formula (1), the compounds having a basic group can easily form salts with pharmaceutically acceptable acids. These acids include inorganic acids, for example sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid; organic acids, for example acetic acid, p-toluene sulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid and benzoic acid.



   The compounds of the present invention obtained by the above methods can easily be isolated and purified from traces of the reaction system by conventional separation techniques, for example distillation, recrystallization, column chromatography, preparative thin layer chromatography, and extraction with solvent.



   The compound of general formula (2) used as starting material in the above-mentioned formula I reaction process is a new compound and it can be prepared according to the process shown in the following formula-VII reaction process.



  Reaction process formula-VII /
 EMI42.1
 

  <Desc / Clms Page number 43>

 
 EMI43.1
 In which and the carbon-carbon bond between positions 3 and 4 of the carbostyryl backbone are as defined above; and X is a halogen atom.



   The compound of general formula (2) is prepared by reacting the compound of general formula (8) with the compound of general formula (9). This reaction is carried out in an appropriate solvent, in the presence of a basic compound, between room temperature and 200 C, preferably between 60 and 100 C, for 1 to 24 hours.

   As inert solvent used, there may be mentioned, by way of example, ethers such as dioxane, tetrahydrofuran, dimethyl or diet-plic ethers of diethylene glycol; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; polar solvents such as dimethylformamide and dimethylsulfoxide.

   As basic compound, inorganic basic compounds can be used such as calcium carbonate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, amide of sodium, sodium hydride, potassium hydride, sodium methylate and sodium ethylate; tertiary amines such as triethylamine, tripropylamin, pyridine and quinoline; and other basic compounds selected from a wide range.



   The above reaction can be carried out by adding an alkali metal iodide such as potassium iodide or sodium iodide as a reaction accelerator.



   The ratio of the amount of compound (8) to the amount of compound (9) is not particularly limiting, and an equimolar amount is used to a large excess, preferably an equimolar amount

  <Desc / Clms Page number 44>

 at 5 times the molar amount, preferably an equimolar amount to 1.2 times the molar amount of the latter relative to the former.



   The compound represented by the other type of general formula (2) can be prepared from the compound (2) by methods in accordance with the reaction process formulas VIII and IX below.



  / Formula-VIII reaction process
 EMI44.1
 CCC VV // / '\' "r =) ') -C-C- \' - 'r'r-1 OCR Agent v -------- C 2 2 (2a) (2b)
 EMI44.2
 2 6 7 8 1 1 in which and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above.



   In the above-mentioned formula-VIII reaction process, the reaction of the compound (2a) with the alkylating agent can be carried out under conditions analogous to those mentioned with regard to the reaction of the compound (1g) with the alkylating agent according to the formula-V reaction process.



  / Formula-IX reaction process /
 EMI44.3
 CCOR C 7 CH R '. JCH, -C --- n-2- '. 1 t on .., '' '' 1: C c '' Reduction 'R (2c)
 EMI44.4
 where RI, A, n and the carbon-carbon bond

  <Desc / Clms Page number 45>

 between positions 3 and 4 of the carbostyryl skeleton are as defined above.



   Dehydrogenation and reduction in the reaction process formula-IX can be carried out under conditions analogous to those used in the dehydrogenation of compound (li) and reduction of compound (1k) according to the reaction process formula-VI.



   Certain compounds represented by the general formula (5) used as starting material in the reaction process formula-II are known, and still include new compounds, and these new compounds can be prepared by a process as represented by the reaction process formula -X next.



  Reaction process formula-j
 EMI45.1
 where z is as defined above.



   In the reaction process formula-X mentioned above, the reaction aiming to obtain the compound (11) by cyclization of the compound- (10) can be carried out in the presence of formamide N, N-disubstituted, and an acid catalyst (which is generally called Vilsmaier's reagent), in a suitable solvent or without solvent. As formamide N, Ndisubstituted, there may be mentioned by way of examples N, N-dimethylformamide, N, N-diethylformamide, N-ethyl-N-methylformamide and N-methyl-N-phenylformamide. Examples of acid catalysts include phosphorus oxychloride, thionyl chloride and phosgene.



  As solvent, mention may be made, by way of examples, of halogenated hydrocarbons such as chloroform, 1, 2-dichloroethane and 1, 2-dichlorethylene; aromatic hydrocarbons

  <Desc / Clms Page number 46>

 ticks such as chlorobenzene and 1,2-dichlorobenzene.



  The ratio of the amount of N, N-disubstituted formamide and the acid catalyst to the amount of the compound of formula
 EMI46.1
 general (10) can generally be a large excess, preferably 2 to 5 times the molar amount of the former and 5 to 10 times the molar amount of the latter relative to the compound (10). The reaction temperature can generally range from 0 to 150 C, preferably from about 50 to 100 C, and the reaction is complete in about 3 to 24 hours.



   The reaction aimed at obtaining the compound (6a) from the compound (11) is carried out by heating the compound (11) in the presence of a hydrohalic acid such as hydrochloric acid or hydrobromic acid; an inorganic acid such as sulfuric acid or phosphoric acid; an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide; or an inorganic alkaline compound such as sodium carbonate, potassium carbonate or potassium hydrogen carbonate; or an organic acid such as acetic acid, at a temperature of 50 to 150 C, preferably 70 to 120 C, for about 0.5 to 24 hours.



   The compound (8) used for the starting material in the reaction process formula-VII can be prepared by a process in accordance with the reaction process formula-XI below.

  <Desc / Clms Page number 47>

 
 EMI47.1
 Reaction process formula-XI /
 EMI47.2
 o .-- -CCCH - n '-.



  ., -'.- L - '2 - - (12)) (121 Heduction - C-X tv-aloénation A 11') .., n R'R '.



  R 2 R 1 R (15)
 EMI47.3
 1 2 wherein R, R, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl backbone g are as defined above; is a lower alkyl group or a group of formula 0 is a halogen atom.-N 0 In the reaction process formula-XI mentioned above, the reaction of compound (12) with compound (13) can be carried out under very analogous to those of the esterification reaction of compound (la) or (lb) with compound (4) of the reaction process formula-I.



  The compound (14) thus obtained by esterification can be converted into the corresponding compound (15) by reduction of the compound (14). In addition, the compound (15) can also be prepared directly by reduction of the compound (12). These reductions can be accomplished using a conventional hydrogenation reducing agent.

  <Desc / Clms Page number 48>

 



  Examples of reduction-hydrogenation agents that may be mentioned include sodium borohydride, lithium aluminum hydride and diborane. The amount of the reducing agent by hydrogenation is generally at least an equimolar amount, preferably an equimolar amount to 3 times the molar amount, relative to the amount of the compound (12) or (14). When lithium aluminum hydride is used as the hydrogenation reduction agent, the same weight amount of the reducing agent is preferably used as the amount of compound (12) or (14).

   The reduction is generally carried out in a suitable solvent such as water; a lower alcohol, for example methanol, ethanol or isopropanol; an ether, for example tetrahydrofuran, diethyl ether or diglyme, between about -60 and 50 C, preferably between -30 C and room temperature, for about 10 minutes to 5 hours. When using lithium aluminum hydride or diborane as the reducing agent, an anhydrous solvent such as diethyl ether, tetrahydrofuran or diglyme is preferably used.



   The halogenation reaction of the compound (15) to prepare the compound (8) can be carried out under the reaction conditions used in the conventional halogenation reaction, for example by reaction of the compound (15) with a halogenating agent in a inert solvent or solvent-free.



   As halogenating agent, mention may be made, by way of examples, of hydrohalic acids such as hydrochloric acid or hydrobromic acid; N, N-dimethyl-1, 2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride or thionyl chloride. As inert solvent, there may be mentioned an ether such as dioxane or tetrahydrofuran; a halogenated hydrocarbon such as chloro-

  <Desc / Clms Page number 49>

 form, methylene chloride or carbon tetrachloride. The ratio of the amount of the compound (15) to the amount of the halogenating agent can be at least an equimolar amount, generally a large excess of the latter relative to the former.

   The reaction is generally carried out between room temperature and about 150 C, preferably between room temperature and 80 C, for about 1 to 6 hours.



   Certain carboxylic acid compounds (12) and their ester compounds (14) used as starting materials in the above-mentioned formula-XI reaction process include new compounds and these new compounds can be prepared by methods as represented by the following formula-XII to XVI reaction process. reaction process formula-XII /
 EMI49.1
 
 EMI49.2
 ? 10 where is as defined above; is an atom of hy-
R2drogen or a lower alkyl group.



   In the above-mentioned formula-XII reaction process, the reduction of the nitro group of the compound (16) is carried out under conditions generally used in the reduction of the nitro group, for example (a) by a process using a catalytic reduction catalyst in a solvent suitable inert, or (b) by a process using a mixture of metal or metal salt with an acid, or a metal or metal salt with an alkali metal hydroxide, sulfide or ammonium salt as reducing agent, in an inert solvent.



   When implementing a process (a) using

  <Desc / Clms Page number 50>

 catalytic reduction, examples of the solvent used are water; alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol; ethers such as diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; hydrocarbons such as hexane and cyclohexane; esters such as methyl acetate, ethyl acetate, and aprotic solvents such as N, N-dimethylformamide. Examples of catalytic reduction catalysts include palladium, palladium black, palladium on carbon, platinum, platinum oxide, copper chromite and Raney nickel.



   The ratio of the amount of catalyst to the amount of compound (16) can be 0.02 to 1.00 times (by weight) the amount of the former relative to the latter.



  The reaction is generally carried out between -20 and 150 ° C., preferably between OOC and approximately room temperature, under hydrogen pressure of 0.1 to 1.0 MPa for approximately 30 minutes to 10 hours. When a process (b) is used, a combination of iron, zinc, tin or stannic chloride with a mineral acid such as hydrochloric acid or sulfuric acid can be used as the reducing agent; or a combination of iron, ferrous sulfate, zinc or tin with an alkali metal hydroxide such as sodium hydroxide, a sulfide such as ammonium sulfide, ammonia water or an ammonium salt such as ammonium chloride. As inert solvent, mention may be made of water, acetic acid, methanol, ethanol and dioxane.

   The reaction temperature and the reaction time can be chosen according to the type of catalyst used; for example, in the case of the combination of ferrous sulfate with ammoniacal water, the reduction is advantageously carried out at a temperature of about 50 to 150 ° C., for 30 minutes to 10 hours. The amount of the reducing agent used is generally about

  <Desc / Clms Page number 51>

 minus an equimolar amount, preferably an equimolar amount to 5 times the molar amount relative to the amount of compound (16). The reaction of the compound (17) with the compound (18) can be carried out in the presence of a basic compound, in an appropriate solvent.

   As the basic compound, an inorganic basic compound such as sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, sodium methylate or the like can be used. sodium ethoxide; or an amine such as triethylamine, pyridine, α-picoline, N, N-dimethylaniline, N-methylmorpholine, piperidine or pyrrolidine. As the solvent, an ether such as dioxane, tetrahydrofuran, a glyme or a diglyme can be used; an aromatic hydrocarbon such as toluene or xylene; a lower alcohol such as methanol, ethanol or isopropanol; a polar solvent such as dimethyl sulfoxide or dimethylformamide.

   The reaction is carried out between room temperature and 150 ° C., preferably between 60 and 120 ° C., for approximately 1 to 24 hours. The ratio of the amount of compound (17) to the amount of compound (18) is not particularly limiting and an equimolar amount is used to a large excess, preferably an equimolar amount to 5 times the amount of the latter by compared to the first.



  Reaction process formula-XIII /
 EMI51.1
 CCCH --c I -, - 'y d r o 1 7T s e' R '. iq I, 2'-gl 2 t 11 2'i 2 ""; : 12 CO 11 2 (20) (20a) (12a)
 EMI51.2
 2 where R is as defined above; and R is a lower alkyl group.

  <Desc / Clms Page number 52>

 



   The reaction represented by the reaction process formula-XIII mentioned above is carried out by reacting the compound (20) with an acylating agent represented
 EMI52.1
 ted by the general formula RCOX CO) O / in which 11 Ril is as defined above; is an atom or (Rd'halogen), then the compound (20a) obtained is hydrolyzed to obtain the compound (12a). The reaction of compound (20) with the acylating agent represented by the formula RCOX or (RIICO) is carried out in the presence or in the absence of basic compound.

   As basic compound, there may be mentioned, as examples, alkali metals such as metallic sodium and metallic potassium; hydroxides, carbonates and hydrogen carbonates of these alkali metals; and aromatic amines such as pyridine and piperidine. The reaction is carried out in the absence or in the presence of a solvent. As solvent, mention may be made, by way of examples, of ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; the water ; and pyridine.



   The ratio of the amount of acylating agent
 EMI52.2
 represented by the general formula R COX CO) O used in the amount of the compound represented by the general formula (20) is at least a molar amount of the first relative to the last, and in general an equimo-
 EMI52.3
 much to the excess of the former over the latter.



  The reaction is carried out at a temperature of 0 to 200 ° C., in general from 0 to 150 ° C. It is completed in 0.5 to 10 hours.



  The hydrolysis reaction of the compound (20a) is carried out in aqueous solution, in the presence of a hydrolysis catalyst, for example an alkali metal hydroxide such as potassium hydroxide and sodium hydroxide; alkali metal compounds such as sodium carbonate, potassium carbonate and hydrogen carbonate

  <Desc / Clms Page number 53>

 
 EMI53.1
 sodium, between 50 and 150oC, preferably between 70 and 100 C for about 0.5 to 10 hours.



  / Reaction process formula-XIV /
 EMI53.2
 / '---- C- 3.



  '12 (23) I'1 C, '/' t / 1/1 (21) / (23) Hydroivse 'a /' i / I C C '-' 3'3 (12b)
 EMI53.3
 129 where R, A, n, X and the carbon-carbon bond between positions 3 and 4 of the carbostyryl backbone are 12 as defined above; is a residue of aromatic amine.



   In the above-mentioned formula-XIV reaction process, the reaction of the compound (21) with the aromatic amine (22) is carried out in the absence or in the presence of an appropriate solvent. As the solvent, any inert solvent is used which does not adversely affect the reaction, for example a halogenated hydrocarbon such as chloroform, methylene chloride, dichloromethane or carbon tetrachloride; an ether such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; an alcohol such as methanol, ethanol, isopropanol or

  <Desc / Clms Page number 54>

 butanol; an ester such as methyl acetate, ethyl acetate; a polar aprotic solvent such as N, N-diiaethylformamide, dimethylsulfoxide or hexamethylphosohoryl-triamide.

   As aromatic amine, mention may be made of pyridine or quinoline. The amount of aromatic amine used is at least an equimolar amount, preferably a large excess relative to the amount of compound (21). The reaction is carried out at a temperature of 50 to 200 C, preferably between 70 and 150 C for about 3 to 10 hours.



   The hydrolysis of the compound (23) thus obtained is carried out in water, in the presence of a basic inorganic compound such as sodium hydroxide or hydroxide of
 EMI54.1
 potassium at a temperature between room temperature and 150 C for 1 to 10 hours.



  The esterification of the compound (23) with the compound (13) is carried out in the presence of a basic compound in the presence or in the absence of a solvent. As solvent, there may be mentioned a halogenated hydrocarbon such as methylene chloride, chloroform or dichloroethane; an aromatic hydrocarbon such as benzene, toluene or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; or a polar aprotic solvent such as N, N-dimethylformamide, dimethylsulfoxide or hexamethylphosphoryl-triamide.



  As basic catalyst, there may be mentioned, by way of example, an organic basic compound such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methyl
 EMI54.2
 thylmorpholine, 4-dimethylaminopyridine, 1, 5-diazabicycle4, 3, Q7nonene-5 (DBN), 1, 5-diazabicyclo / 5, 4, Q7undêcène-5 (DBU) or 1, 4-diazabicyclof2, 2, 27-octane (DABCO); or an inorganic basic compound such as potassium carbonate, sodium carbonate or sodium or potassium hydrogen carbonate.



   The ratio of the amount of basic compound to

  <Desc / Clms Page number 55>

 the amount of compound (23) can be at least an equimolar amount, preferably an equimolar amount to 1.5 times the molar amount of the former to the amount of the latter. The ratio of the amount of compound (13) to the amount of compound (23) can be at least an equimolar amount, preferably a large excess, of the former relative to the latter. The reaction is generally carried out between room temperature and 150 C, preferably between about 50 and 100 C, for 30 minutes to 10 hours in general.
 EMI55.1
 



  Reaction process formula-XV /
 EMI55.2
 or 1-J 'J'-D' '-' * - '"CCX'." "" '' '' '' '-' t CZclisat on CC .. \ itration .-- / - r (2.



  (POT / - "2 Mc r '" "
 EMI55.3
 where R and X are as defined above; X is a hydrogen atom or a halogen atom.



   In the reaction process formula-XV mentioned above, the reaction of the compound (24) with the compound (25) or (26) is called the Friedel-Crafts reaction, and it generally takes place in an appropriate solvent in the presence of an acid. of Lewis. As solvent used, it is also advantageous to have recourse to any solvent used in this type of reaction, and examples include carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane and carbon tetrachloride.

   As Lewis acid, any Lewis acid can also be used

  <Desc / Clms Page number 56>

 which is used in this type of reaction, examples of which include aluminum chloride, zinc chloride iron chloride, tin chloride, boron tribromide, boron trifluoride and concentrated sulfuric acid. The amount. Lewis acid used can be any amount and is generally about 2 to 6 times the molar amount, preferably 3 to 4 times the molar amount based on the amount of the compound (24).



  The ratio of the amount of compound (25) or (26) to the amount of compound (24) is generally at least an equimolar amount, preferably an equimolar amount to 3 times the molar amount of the former relative to the latter. The reaction temperature is generally from - 50 to 120 C, preferably from 0 to 70 C, and the reaction time varies depending on the type of catalyst and the reaction temperature, but it is generally 30 minutes
 EMI56.1
 at 24 hours. The nitration of the compound (27) thus obtained is carried out under conditions analogous to those of a conventional nitration of an aromatic hydrocarbon, for example using a nitration agent, in the absence or in the presence of a solvent inert appropriate.

   As the inert solvent, examples include acetic acid, acetic anhydride and concentrated sulfuric acid. Mention may be made, as nitration agent, of fuming nitric acid, concentrated nitric acid, a mixed acid consisting of nitric acid and another acid (for example sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride), a mixture of an alkali metal nitrate such as potassium nitrate, or sodium nitrate, with a mineral acid such as sulfuric acid. The amount of nitrating agent used is an equimolar amount or greater, and in general this is a large excess over the amount of the compound (27).

   The reaction is preferably carried out between -10 ° C. and room temperature, for 5 minutes to 4 hours.

  <Desc / Clms Page number 57>

 



  The compound (28) thus obtained is then reduced and cyclized to introduce the compound (12d). This reaction is carried out under conditions analogous to those of the reduction reaction of compound (16) of the reaction process formula-XI. When this reaction is carried out by (a) a process using catalytic reduction, the reaction temperature is preferably 0 to 50 ° C., and the reaction is advantageously carried out in the presence of a basic compound such as hydroxide. sodium or potassium hydroxide.



  When the reaction is carried out by (b) a process using a mixture of metal or metal salt with an acid, the reaction is generally carried out between -50 and 1000C for 0.5 to 10 hours. For example, when a mixture of stannous chloride and hydrochloric acid is used as a reducing agent, the reduction can advantageously be carried out between about -20 and 50 C. The amount of the reducing agent used is at least an equimolar amount , generally an amount equal to 3 times the molar amount relative to the amount of the starting material.

   According to the above-mentioned reaction, the nitro group of the compound (28) is reduced and at the same time, the cyclization of the compound (28) is carried out giving the compound (12d). It should be noted that when the process (a) is carried out using the catalytic catalyst, it happens that the carbonyl group is reduced to the methylene group by reduction, and the reaction conditions can be conveniently chosen in the process. aim of avoiding this undesirable transformation of the carbonyl group.

  <Desc / Clms Page number 58>

 
 EMI58.1
 / process
 EMI58.2
 1 .. stars 1 r cR f '' -rY ri ',, -' ** .- .. "- / '1 r.



  J cm H
 EMI58.3
 whereR, R, R as defined In the reaction process formula-XVI mentioned above, the reaction of the compound (29) with the compound (30) is generally carried out in the presence of a dehydrohalogenation agent, in the absence or in the presence of an appropriate solvent.

   As dehydrohalogenation agent, a basic compound is generally used, for example an organic basic compound such as triethylamine, trimethylamine,
 EMI58.4
 pyridine, dimethylaniline, N-methyl-morpholine, 4-dimethylaminopyridine, 1, 5-diazabicycloL4, 3, OJnonene-5 (DBN), 1, 5-diazabicycloL5, 4, OJundecene-5 (DBU) or 1,4-diazabicycloL2,2,2 / octane (DABCO); an alkali metal compound such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, hydride potassium; silver carbonate; an alkali metal alcoholate such as sodium methylate or sodium ethylate.

   Compound (30) can also be used as a dehydrohalogenation agent when used in a large excess. As the solvent used, examples include a halogenated hydrocarbon such as methylene chloride, chloroform or dichloroethane; an aromatic hydrocarbon such as /

  <Desc / Clms Page number 59>

 benzene, toluene or xylene; an ether such as diethyl ether, tetrahydrofuran or dimethoxyethane; an ester such as methyl acetate or ethyl acetate; a polar aprotic solvent such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoryltriamide; pyridine, acetone, acetonitrile, an alcohol such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve or methyl-cellosolve;

   or a mixed solvent consisting of two or more of the solvents.



   The ratio of the amount of the compound (29) to the amount of the compound (30) is not particularly limiting and can be chosen within a wide range; in general, at least an equimolar amount is used, preferably an equimolar amount at 5 times the molar amount of the latter relative to the former. The reaction is generally carried out between -30 and 180 C, preferably between about 0 and 150 C, for 5 minutes to 30 hours.



   The cyclization reaction of the compound (31) is carried out in the absence or in the presence of an appropriate solvent, in the presence of an acid. As the acid, there is no particular limitation in the choice, but in general one can use a common organic or inorganic acid, for example hydrochloric acid, hydrobromic acid, sulfuric acid; a Lewis acid such as aluminum chloride, boron trifluoride or titanium tetrachloride; an organic acid such as formic acid, acetic acid, ethanesulfonic acid or p-toluenesulfonic acid. Among these acids, it is preferred to use an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid.

   The amount of acid used is not particularly limited, and in general an equivalent amount by weight is used, preferably 10 to 50 times the weight of the acid relative to the compound (31).

  <Desc / Clms Page number 60>

 



   As the solvent, a common inert solvent can be used, for example water, an alcohol such as methanol, ethanol, or propanol; an ether such as dioxane or tetrahydrofuran; an aromatic hydrocarbon such as benzene, toluene or xylene; a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride, a polar aprotic solvent such as acetone, dimethylsulfoxide, dimethylformamide or hexamethylphosphoryl-triamide.



  Among these solvents, lower alcohols, ethers, water-soluble solvents such as acetone, dimethylsulfoxide, dimethylformamide and hexamethylphosphoryl-triamide are preferred.



   The reaction is generally carried out between 0 and
 EMI60.1
 100 C, preferably between room temperature and 60 C, for generally about 5 minutes to 6 hours.



  Compounds (19a), (19b) can also be introduced into compounds (19) and (12) respectively by the alkylation process, as indicated in the reaction process formula-V and by the dehydrogenation reaction process -reduction as indicated in the reaction process formulas-VI and IX.



   The compound (15) as an intermediate product and the compound (8) of the reaction process formula-XI and the compound (21) as starting material in the reaction process formula-XIV can be prepared respectively by methods according to the following reaction formulas XVII to XXI.

  <Desc / Clms Page number 61>

 
 EMI61.1
 / Reaction process formula-XVII /
 EMI61.2
 '' --1-J ".



  ,;; 'c', 1, - f1c) ',), t' y /.



  . '/'.



  0
 EMI61.3
 where R, X, X 'and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above.



  The reaction of the compound (32) with the compound (25) or (26) can be carried out under conditions analogous to those indicated in the reaction of the compound (24) with the compound (25) or (26) of the reaction process formulaXV. The reaction is generally carried out between 20 and 120 C, preferably between 40 and 70 C, and the reaction time generally ranges from 30 minutes to 24 hours depending on the type of starting materials and the type of catalyst.



  / Formula-XVIII reaction process /
 EMI61.4
 1 duc - duction ', r --- \. "- '. J -, í \ -'-. J u - J -' J .. Il n on educil- (34) (6)
 EMI61.5
 where R, R, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are like

  <Desc / Clms Page number 62>

 
 EMI62.1
 1 2 'defined above;

   and a hydrogen atom, a
 EMI62.2
 lower alkyl group or a group of formula 0 -N 'P
 EMI62.3
 The reaction for obtaining the compound (6) by reduction of the compound (34) is carried out under conditions analogous to those used in the reaction for obtaining the compound (15) by reduction of the compound (12) from the reaction process formula-XI, and analogues to those used in the reaction for obtaining the compound (1 ") by catalytic reduction of the compound (1 ') in the reaction process formula-III.



   Various methods can be used to reduce compound (6) to compound (15); for example, it is preferably possible to use a reduction process using a reduction-hydrogenation agent. Examples of reduction-hydrogenation agents include sodium aluminum hydride, lithium aluminum tri-tert-butoxyaluminum hydride, diisobutylaluminum hydride, (1,1-) hydride. dimethyl-1-diisopropylmethyl) boron and sodium borohydride.



   The amount of the reducing-hydrogenating agent is generally an amount equivalent by weight to the amount of the compound (6). The reduction reaction is carried out in a suitable solvent, for example diethyl ether, tetrahydrofuran or diglyme, between -60 and SO'C, preferably between -30 C and room temperature.



  The reaction is completed in 10 minutes to 5 hours.

  <Desc / Clms Page number 63>

 
 EMI63.1
 Formula XIX process ZProcess-7
 EMI63.2
 
 EMI63.3
 0 where A, n and X are as defined above.



   The cyclization reaction of the compound (35) is carried out under conditions analogous to those used in the cyclization reaction of the compound (10) of the reaction process formula-X. In addition, the reaction for obtaining the compound (8b) from the compound (36) is carried out under conditions analogous to those used in the reaction for obtaining the compound (6a) from the compound (11) in the process. reaction formula-X.
 EMI63.4
 



  Reaction process formula-XX /
 EMI63.5
 1 '-'- -. f r- - - - /,, 2--.



  (37) (33) (Se)
 EMI63.6
 where and X are as defined above.



   In the above-mentioned formula-XX reaction process, the halogenation reaction of the compound (37) is carried out in a suitable solvent by treating the compound (37) with a halogenating agent. As the halogenating agent, examples include halogen molecules, for example chlorine or bromine; N-halosuccinimides, such as N-chlorosuccinimide and N-bromosuccinimide; sulfuryl chloride; halides of

  <Desc / Clms Page number 64>

 copper for example copper chloride and copper bromide. As the solvent used, examples include halogenated hydrocarbons such as dichloromethane, dichlorethane, chloroform and carbon tetrachloride; ethers such as diethyl ether, tetrahydrofuran and dioxane; and acetic acid.



   The ratio of the amount of the halogenating agent to the amount of the compound (37) is an equimolar amount to a large excess, preferably an equimolar amount to 1.2 times the molar amount of the former. The reaction is generally carried out between OOC and about the boiling point of the solvent, preferably between room temperature and 40 C. The reaction generally ends in 1 to 10 hours. It can be carried out using a peroxide such as benzoyl peroxide or hydrogen peroxide as a reaction initiator.



   The reaction for obtaining the compound (8c) by cyclization of the compound (38) can be carried out in an appropriate solvent, in the presence of a condensing agent.



   As the condensing agent used, examples include Lewis acids such as phosphorus pentoxide, hydrofluoric acid, sulfuric acid, polyphosphoric acid, aluminum chloride and tin chloride. As the solvent, examples include halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane ethers such as diethyl ether and dioxane; aromatic hydrocarbons such as nitrobenzene and chlorobenzene.



  The ratio of the amount of compound (38) to the amount of the condensing agent is not particularly limited, and in general an equimolar amount can be used at 10 times said amount, preferably 3 to 6 times the molar amount of the latter compared to the former. The reaction is generally carried out between 50 and 250 C, preferably between 70 and 200 C, for about 20 minutes

  <Desc / Clms Page number 65>

 6 hours./ Reaction process formula XXI /
 EMI65.1
 where R1, R2, X and the carbon-carbon bond between positions 3 and 4 of the carbostyryl backbone are as defined above; and R13 is a lower alkanoyl group.



   In the reaction process formula XXI mentioned above, the reaction of the compound (8) with the compound (39) is preferably carried out using a basic compound as dehydrohalogenation agent, in an appropriate solvent, at a temperature between room temperature and 200 C, preferably between room temperature and 150 C, for a few hours to 15 hours.

   As the solvent used, examples include lower alcohols such as methanol, ethanol, and isopropanol; ethers such as diethyl ether, tetrahydrofuran, dioxane, monomethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimer

  <Desc / Clms Page number 66>

 thylformamide, dimethyl sulfoxide, hexamethylphosphoryl triamide and acetic anhydride.

   As basic compounds, examples include basic inorganic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and carbonate d 'silver ; alkali metals such as sodium and potassium; sodium amide; sodium hydride; alkali metal alcoholates such as sodium methylate, sodium ethylate and potassium ethylate; tertiary amines such as triethylamine, tripropylamin, pyridine, quinoline, N, N-dimethylaniline and N-methylmorpholine.



  In the above-mentioned reaction, an alkali metal iodide, for example potassium iodide or sodium iodide, can be used as the reaction accelerator.



   The ratio of the amount of compound (8) to the amount of compound (39) is not particularly limited, and at least one equimolar amount is generally used, preferably 1 to 5 times the molar amount of the latter relative to the former .



   The compound (40) thus obtained is hydrolyzed to form the compound (15). This hydrolysis reaction is carried out in the presence of a hydrohalic acid such as hydrochloric acid or hydrobromic acid; a mineral acid such as sulfuric acid or phosphoric acid; an alkali metal hydroxide such as sodium hydroxide, an alkali metal carbonate such as sodium carbonate or potassium carbonate; of an alkali metal hydrogencarbonate such as sodium hydrogencarbonate, generally between 50 and 150oC, preferably between 70 and 100C, for 3 to 24 hours under heating.



   Compounds (15) and (8) can also be converted into other types of compounds of formulas (15) and (8) by methods in accordance with the N-alkyla- process.

  <Desc / Clms Page number 67>

 
 EMI67.1
 tion, as indicated in the reaction processes formulas-V and VIII, and the dehydrogenation process and the reduction process, as indicated in the reaction process formulas-VI and IX.



  The compound of general formula (12) of the reaction process formula-XI can also be prepared by a process, for example the reaction process formula-XXII.



  Reaction process formula-XXII /
 EMI67.2
 ,, - COOR H 2 "-N a '' '- //' N / '0 R2 R (41) R2 Ri (43) ,, c'Li.-CCOOH / n 1 l'1 1 R2 R2 Hydrolysis yc /// 1 R2
 EMI67.3
 where R, A, X and the carbon-carbon bond between the

  <Desc / Clms Page number 68>

 
 EMI68.1
 positions 3 and 4 of the carbostyryl skeleton are as 14 defined an alkyl group is not equal to 1.



   The reaction of the compound of general formula (41) with the compound of general formula (42) can be carried out under conditions analogous to those used in the reaction of the compound of general formula (8) with the compound of general formula (9).



   The hydrolysis of the compound of general formula (43) can be carried out under conditions analogous to those used in the hydrolysis of the compound of general formula (2).



  * The reaction of the compound of general formula (41) with a metallic cyanide of general formula (44) is carried out in an appropriate solvent. As the metallic cyanide of general formula (44), examples include potassium cyanide, sodium cyanide, silver cyanide, copper cyanide and calcium cyanide.



  As the solvent, examples include water; lower alcohols such as methanol, ethanol and isopropanol; and a mixed solvent consisting of water and these alcohols. The total amount of metallic cyanide of general formula (44) which is used is at least an equimolar amount, preferably 1 to 1.5 times the molar amount relative to the amount of the compound of general formula (41). The reaction is generally carried out between
 EMI68.2
 room temperature and 150 C, preferably between about 50 and 120 C, for 30 minutes to 10 hours.



  The hydrolysis of the compound of general formula (45) can be carried out under conditions analogous to those used in the hydrolysis of the compound of general formula (2).



   The carbostyryl derivatives of the present invention can also be prepared by a process as represented by the reaction process formula-XXIII

  <Desc / Clms Page number 69>

 following.



    The reaction process formula-XXIIIJ
 EMI69.1
 It JL t L '* i, - CO. c 0i 0 R2 R R (+1) 'CCOH Hydrolysis -. nt-nt-N-R NH "'-: t2 (48)
 EMI69.2
 i? 4'14 where R, R, R, A, n ', X' and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above.



   The reaction of the compound of general formula (41) with the compound of general formula (46) can be carried out under conditions analogous to those used in the reaction of the compound of general formula (8) with the compound of general formula (9).



   The hydrolysis of the compound of general formula (47) can be carried out under conditions analogous to those used in the hydrolysis of the compound of general formula (2).



   The reaction of the compound of general formula (48) with the compound of general formula (49) can be carried out in the absence or in the presence of an appropriate solvent, in the presence of a basic compound. As the solvent used, examples include ethers such as dioxane,

  <Desc / Clms Page number 70>

 tetrahydrofuran, ethylene glycol dimethyl ether and diethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; polar solvents such as dimethylsulfoxide, dimethylformamide, hexamethylphosphoryltriamide and acetone.

   As basic compounds, there may be mentioned as examples the inorganic basic compounds such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide, sodium amide and sodium hydride; basic organic compounds such as triethylamine, tripropylamine, pyridine and quinoline.



   The reaction is generally carried out between room temperature and 200 C, preferably between room temperature and 150 C, for 1 to 30 hours.



   The reaction can advantageously be carried out by adding an alkali metal iodide such as potassium iodide or sodium iodide; or hexamethylphosphoryl-triamide as a reaction accelerator.



   The amount of the compound of general formula (49) which is used can generally be an equimolar amount to a large excess, preferably an equimolar amount to 5 times the molar amount relative to the amount of the compound of formula general (48).



   By carrying out the reactions for increasing the number of carbon atoms in the reaction process formula-XI mentioned above / '(12) or (14) # (15) # (8) 7 and the reaction process formula-XXII (41) # (43) (12e) or (41) (45) (12f) J by repeating them several times, the desired carbostyryl derivative represented by the general formula can be prepared:

  <Desc / Clms Page number 71>

 
 EMI71.1
 wherein R1, R ", A, n ', X and the carbon-carbon bond between positions 3 and 4 of the carbostyryl backbone are as defined above, having the predetermined number of carbon atoms.



   The carbostyryl derivatives of the present invention are useful as peptic anti-ulcer agents, and can be used in the form of general preparations of pharmaceutical compositions with the usual pharmaceutically acceptable carriers. Examples of pharmaceutically acceptable carriers which are used in the desired form of the pharmaceutical compositions include diluents or excipients such as fillers, diluents, binders, wetting agents, disintegrating agents, surfactants and lubricants.



   No particular limitation exists as regards the unit forms of administration and the compositions can be chosen in any desired unit form comprising tablets, pills, powders, liquors, suspensions, emulsions, granules, capsules, suppositories and injections (solutions, suspensions, etc.).



   To form tablets, it is possible to use supports which are widely used in this field, for example excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc; binders such as water, ethanol, propanol, a simple syrup, a glucose solution, a starch solution, a gelatin solution, carboxymethylcellulose,

  <Desc / Clms Page number 72>

 shellac, methylcellulose, calcium phosphate and polyvinylpyrrolidone;

   disintegrating agents such as dried starch, sodium alginate, agar powder, laminaria powder, sodium hydrogencarbonate, calcium carbonate, esters of polyoxyethylene sorbitan fatty acids, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose; disintegration inhibitors such as sucrose, stearin, coconut butter and hydrogenated oils; absorption accelerators such as quaternary ammonium bases and sodium lauryl sulfate; wetting agents such as glycerin and starch; adsorption agents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; and lubricants such as purified talc, salts of stearic acid, boric acid powder and polyethylene glycols.



   In the case of the preparation of tablets, they can also be coated with the usual coating materials in order to obtain tablets coated with sugar, tablets coated with a gelatin film, tablets coated with enteric coatings, tablets coated with films. or double-coated tablets as well as multi-coated tablets.



   To obtain the form of pills, one can use any support which is known and widely used in this field, for example excipients such as glucose, lactose, starch, coconut butter, hydrogenated vegetable oils, kaolin and talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; disintegrating agents such as kelp and agar.



   To obtain the form of suppositories, it is also possible to use supports which are known and widely used in this field, for example polyethylenes.

  <Desc / Clms Page number 73>

 lene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides.



   To obtain the form of preparations for injection, solutions and suspensions are sterilized which are preferably isotonic with blood. To obtain preparations for injection in the form of solutions, emulsions and suspensions, it is also possible to use any support which is known and widely used in this field, for example water, ethyl alcohol, propylene glycol , ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol and fatty acid esters of polyoxyethylene sorbitan. In this case, suitable amounts of sodium chloride, glucose or glycerin can be added to the desired injection preparations to make them isotonic.

   In addition, dissolving agents, buffers, pain relievers, colorants, preservatives, perfumes, seasoning agents, sweeteners and other drugs can be added to the desired preparations if necessary.



   The amount of the carbostyryl derivatives of the present invention which the peptic antiulcer composition of the present invention must contain is not particularly limited, and it can be chosen within a wide range, generally ranging from 1 to 70%, preferably from 5 to 50% by weight of the total composition.



   The peptic anti-ulcer agent of the present invention can be used in various forms of preparation depending on age, sex, degree of symptoms and other conditions, without limitation. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally; the preparations for injection are administered intravenously alone or they are administered as a mixture with

  <Desc / Clms Page number 74>

 standard injection transfusion solutions such as glucose solutions and amino acid solutions; if necessary, the preparations for injection are administered alone by the intramuscular, intracutaneous, subcutaneous or intraperitoneal route; suppositories are administered rectally.



   The dosage of the peptic anti-ulcer agent of the present invention can be advantageously chosen according to the use, the age of the patient, sex and other conditions as well as the degree of the symptoms, and generally the pharmaceutical compositions contain 0.6. at 50 mg / kg of body weight / day of the carbostyryl derivative of general formula (1) or its salt. In addition, the active ingredient may be contained in an amount of 10 to 1000 mg in the form of a unit administration dose.



   The present invention will be explained in more detail with reference to the following examples in which the preparation of the compounds to be used for the starting materials are presented in the form of Reference Examples and the preparation of the compounds of the invention are represented in the forms Examples.



  Reference example 1.



   100 g of m-aminobenzoic acid are suspended in 1 liter of ether, then 44.6 g of p-ethoxyacrylyl chloride are added dropwise in the solution at room temperature with stirring. This reaction mixture is kept at 40 ° C. for 5 hours, then the precipitate formed in the reaction mixture is filtered off.



  The crystals are washed with water three times, dried and recrystallized from methanol to obtain 60 g of m-carboxy-N- (ss-ethoxyacryloyl) aniline in the form of colorless cotton-like crystals. Melting point: 200, 5-202, 0 C.



  Reference example 2.



   A 50 g mixture of 3-phephium is cooled to 0 C.

  <Desc / Clms Page number 75>

 melyler nylpropionate 51, 6 g of chloracetyl chloride and 250 ml of dichloromethane. The mixture is stirred between 0 and 10OC and 122 g of aluminum chloride are gradually added to the mixture. The reaction mixture is then stirred at room temperature for 2 hours. The reaction mixture is left to stand overnight, then it is poured into a mixture of ice and concentrated hydrochloric acid and then it is extracted with chloroform. The chloroform phase is washed with water, dried, then the chloroform is removed from the reaction mixture by distillation.

   The residue thus obtained is crystallized by addition of isopropyl ether, and the crystals formed are filtered off, then recrystallized from ethanol to obtain 53.4 g of methyl 3- (4-chloroacetylphenyl) propionate in the form of needle crystals.



  Melting point: 90, 0-92, 0 C.



  Reference example 3.



   36.2 g of methyl 3- (4-chloroacetylphenyl) propionate are dissolved in 300 ml of concentrated sulfuric acid, then 20.9 g of fuming nitric acid (d = l, 52) under ice cooling and stirring. The reaction mixture is further stirred at room temperature for 3 hours, then poured into an ice-water mixture, and extracted with chloroform. The chloroform phase is washed with water, dried and the chloroform is distilled off. The residue thus obtained is purified by chromatography on a column of silica gel, then it is crystallized by addition of ether.



  The crystals formed are collected by filtration and recrystallized from methanol to obtain 26.7 g of methyl 3- (4-carboxy-2-nitrophenyl) propionate in the form of light yellow prismatic crystals. Melting point: 120.0-122.0 ° C



    Example 4.



   To a solution containing 467 g of

  <Desc / Clms Page number 76>

 chloracetyl chloride in 400 ml of dichloromethane, 735 g of aluminum chloride in 3 equal portions at a temperature below 30 C with stirring. Then added 200 g of carbostyryl at the same temperature with stirring. The reaction mixture is heated at reflux for 6 hours, then it is poured into a mixture of ice and concentrated hydrochloric acid and the crystals formed are collected by filtration.

   The crystals are washed with methanol, then with hot methanol to obtain 153 g of 6-chloroacetylcarbostyryl. The mother liquor is concentrated to dryness and the residue obtained is purified by chromatography on a column of silica gel, then it is recrystallized from methanol to obtain 35.41 g of 8chloroacetylcarbostyryl in the form of light yellow crystals. Melting point: 177, 5-179, 0 C.



  Reference example 5.
 EMI76.1
 



  30 g of 8-chloroacetylcarbostyryl are mixed with 300 ml of pyridine and this mixture is heated between 80 and 90 C for 2.5 hours with stirring. The reaction mixture is cooled with ice and the crystals thus precipitated are collected by filtration, washed with ether and recrystallized from methanol to obtain 40.85 g of 8- (a-pyridinium-acetyl chloride) ) -carbostyryl in the form of colorless needle-like crystals. Melting point: 261, 5-264, 0 C (decomposition).



  Reference example 6.



   To a solution containing 29.5 g of methyl m-aminobenzoate in 300 ml of diethyl ether is added dropwise between 17 and 27 ° C. with stirring, 11.53 g of ss-ethoxyacrylic acid chloride. When the addition is complete, the reaction mixture is further stirred at room temperature for one hour, then the crystals thus precipitated are collected by filtration. The crystals are washed with ether, and the crude crystals are dissolved in chloroform, then the chloroform solution is washed

  <Desc / Clms Page number 77>

 with 0.5 N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride.

   The chloroform solution is dried, then the chloroform is distilled off, and the residue thus obtained is purified by chromatography on a column of silica gel, then it is recrystallized from methanol to obtain 13.63 g of m-methoxycarbonyl-N- ( ss-ethoxyacryloyl) aniline in the form of colorless prismatic crystals. Melting point: 108-110 C.



  Reference example 7.
 EMI77.1
 



  (a) 60 g of 6-acetyl) carbostyryl are suspended in 0.5 kg of pyridine, then this suspension is stirred at a temperature of 80 to 90 ° C. for 2 hours, then stirring is continued under cooling with ice for 1 hour. The crystals thus precipitated are collected by filtration and recrystallized from methanol to obtain 70 g of 6- (a-pyridinium) carbostyryl chloride hydrostate in the form of colorless needle-like crystals. Melting point: above 300 C.



   (b) 69.7 g of 6- (a-pyridinium-acetyl) carbostyryl chloride and 65 g of sodium hydroxide are dissolved in 0.6 liters of water, and this solution is stirred at 60 to 70 C for 3 hours. The pH of the reaction mixture is then adjusted to about 2 by the addition of concentrated hydrochloric acid. The crystals thus precipitated are collected by filtration and recrystallized from dimethylformamide to obtain 41.4 g of 6-carboxycarbostyryl in the form of a light brown powdery product.



  Melting point: above 300 C.



  Reference example 8.



   By a process analogous to that described in Reference Example 7, using an appropriate starting material, the following compound is obtained:

  <Desc / Clms Page number 78>

 6-carboxy-3, 4-dihydrocarbostyryl, powdery product of light yellowish color (in dimethylformamide) Melting point: above 300 C.



  8-carboxycarbostyryl, colorless needle-like crystals (in a methanolchloroform mixture)
 EMI78.1
 Melting point: above 320 C.



  NMR (dimethyl sulfoxide) 6.57 (d, J = 9.5 Hz, 1 H), 7.25 (t, J = 8.0 Hz, 1 H), 7.44 (d, d, J = 8, 0 Hz, 1.5 Hz, 1 H), 7.98 (d, J = 9.5 Hz, 1 H), 8.14 (d, d, J = 8.0 Hz, 1.5 Hz, 1 H).



  Reference example 9.



   10 g of 6-carboxy-3,4-dihydrocarbostyryl and 6.0 g of N-hydroxysuccinimide are suspended in 200 ml of dioxane. A solution containing 12.4 g of dicyclohexylcarbodiimide is then added there dropwise.
 EMI78.2
 in 50 ml of dioxane under ice cooling with stirring. The reaction mixture is further stirred for 4 hours at 90 ° C. At the end of the reaction, the reaction mixture is left to stand so that it cools to room temperature, and the precipitated crystals are filtered off, then concentrated to dry the filtrate obtained. The residue is recrystallized from a dimethylformamide-ethanol mixture to obtain 10.8 g of succinimide 3,4-dihydrocarbostyryl-6-carboxylate in the form of crystals analogous to colorless flakes. Melting point: 234, 5-236 C.



    Reference example 10.



   8 g of m-carboxy-N- (ss-ethoxyacryloyl) aniline are added to 80 ml of concentrated sulfuric acid, the mixture is stirred at room temperature for 2 hours, then at 50 ° C. for 1 hour. The reaction mixture is poured into an ice-water mixture and the pH of the resulting mixture is adjusted to 3-4 using an aqueous solution of hydro-

  <Desc / Clms Page number 79>

 sodium ion ION. The precipitated crystals are collected by filtration and recrystallized from dimethylformamide to obtain 4.26 g of 5-carboxycarbostyryl in the form of a light yellowish pulverulent product. Melting point: above 320oC.



  NMR (DMSO) 6.58 (d, J = 9.5 Hz, 1 H), 7, 40-7, 80 (m, 3 H), 8, 69 (d, J = 9.5 Hz, 1 H ).



  Reference example 11.



   5 g of methyl 3- (4-carboxy-2nitrophenyl) propionate, 8.87 ml of a methanolic solution of 2.226 N sodium hydroxide, 100 ml of methanol and 1 g of catalyst are mixed well together. 5% Pd on C (50% in water) and this mixture is reduced catalytically at room temperature and at atmospheric pressure. The catalyst is then separated from the reaction mixture by filtration, and the pH of the filtrate is adjusted to about pH = 1, by addition of concentrated hydrochloric acid. The precipitated crystals are collected by filtration and recrystallized from methanol to obtain 3.62 g of 7-carboxy-3,4-dihydrocarbostyryl in the form of colorless needle-like crystals. Melting point: above 320 C.



  RMN (DMSO) 2, 33-2, 60 (m, 2 H), 2.77-3, 05 (m, 2 H), 7.21 (d, J = 8.5 Hz, 1 H), 7 , 38-7, 53 (m, 2H), 10.15 (s, 1H).



  Reference example 12.



   10 g of m-methoxycarbonyl-N- (ss-ethoxyacryloyl) -aniline are gradually added to 100 ml of concentrated sulfuric acid, and this mixture is stirred at room temperature for 2 hours, then at 45 ° C. for 4 hours.



  The reaction mixture is poured into a mixture of ice and water, and the precipitated crystals are collected by filtration and washed with water. The crude crystals thus obtained are recrystallized from a methanol-chloroform mixture to obtain 6.97 g of 5-methoxycarbonylcarbostyryl.



  Melting point: 277, 5-279, 0 C.

  <Desc / Clms Page number 80>

 



  Reference example 13.



   2 g of 5-carboxycarbostyryl are suspended in 30 ml of water, then a 10 N aqueous solution of sodium hydroxide is added to dissolve the crystals. 500 mg of catalyst containing 10% platinum on carbon are added to this solution, and this mixture is reduced catalytically with hydrogen gas under pressure of 0.29-0.39 MPa at 70 C. At the end of the reaction, the catalyst is separated from the reaction mixture by filtration, then the pH of the filtrate is adjusted to about pH = 1 by addition of concentrated hydrochloric acid. The precipitated crystals are filtered off and recrystallized from methanol to obtain 820 mg of 5-carboxy-3,4-dihydrocarbostyryl in the form of colorless needle-like crystals.



  Melting point: 309-311 C.



  Reference example 14.



   2 g of 5-carboxycarbostyryl are suspended in 100 ml of methanol, and the hydrochloric gas is saturated by bubbling it through this suspension, then the reaction mixture is heated at reflux for 3 hours. The reaction mixture is concentrated to half its initial volume, and the precipitated crystals are collected by filtration. The crystals are purified by chromatography on a silica gel column, and they are recrystallized from a methanol-chloroform mixture to obtain 230 mg of 5-methoxycarbonylcarbostyryl in the form of a colorless pulverulent product. Melting point: 277, 5- 2790C.



  Reference example 15.



   2 g of 8- (a-pyridinium-acetyl) -carbostyryl chloride are dissolved in 20 ml of methanol, and 1.01 g of DBU (1, 5-diazabicyclo / 5, 4, OJundecane-5) and heated to reflux for 1 hour. The reaction mixture is concentrated to dryness and water, chloroform and IN hydrochloric acid are added to the residue. The chloroform phase is washed

  <Desc / Clms Page number 81>

 mique with water, with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in this order, and dried.

   The chloroform is distilled off, the residue thus obtained is purified by chromatography on a column of silica gel, then it is recrystallized from methanol to obtain 130 mg of 8-methoxycarbonylcarbostyryl in the form of colorless needle-like crystals. Melting point: 140-1420C.



  Reference example 16.



   34 g of 3-formylcarbostyryl are suspended in 800 ml of methanol, and 7.4 g of sodium borohydride is gradually added thereto under ice-cooling with stirring. The reaction mixture is further stirred under ice cooling for 3 hours. The precipitated crystals are collected by filtration and recrystallized from methanol to obtain 33.2 g of 3-hy-
 EMI81.1
 droxymethylcarbostyryl in the form of colorless prismatic crystals. Melting point: 238-239, Reference example 17.



   16 g of aluminum hydride are suspended
 EMI81.2
 and lithium in 200 ml of dried tetrahydrofuran, then 16 g of 3-methoxycarbonylcarbostyryl are added thereto at room temperature with stirring. The reaction mixture is further stirred for 5 hours at room temperature.



  The excess aluminum hydride and lithium are decomposed in the reaction mixture by dropwise addition of ethyl acetate. In addition, water is added to the reaction mixture which is concentrated under reduced pressure to obtain a residue. Dilute sulfuric acid is added to the residue and the precipitated crystals are collected by filtration and recrystallized from methanol to give 3.7 g of 3-hydroxymethylcarbostyryl in the form of colorless prismatic crystals. Melting point: 238-239.5 C.

  <Desc / Clms Page number 82>

 



  Reference Examples 18 to 22.



   By a process analogous to that described in Reference Examples 16 and 17, using an appropriate starting material, the compounds shown in Table 1 below are prepared.
 EMI82.1
 

  <Desc / Clms Page number 83>

 



  TABLE 1
 EMI83.1
 
 <tb>
 <tb> Position <SEP> from <SEP> Liaison <SEP> carbon <SEP> Form
 <tb> carbon-substitution <SEP> between <SEP> crystalline <SEP>
 <tb> Example <SEP> from <SEP> the <SEP> chain <SEP> them <SEP> positions <SEP> Point <SEP> from <SEP> fusion <SEP> (A)
 <tb> l <SEP> 1 <SEP> 2 <SEP> lateral <SEP> 3 <SEP> and <SEP> 4 <SEP> Solvent <SEP> (C)
 <tb> reference <SEP> R + <SEP> R- <SEP> - <SEP> (A) N-Di2Ott
 <tb> Crystals.

    <SEP> acicu- <SEP> Acetone <SEP> 196 <SEP> - <SEP> 197
 <tb> 18 <SEP> H <SEP> 6-OCH3, <SEP> 3 <SEP> Double <SEP> link <SEP> laires <SEP> slightly <SEP> yellowish
 <tb> 19 <SEP> H <SEP> H <SEP> 3 <SEP> Simple <SEP> link <SEP> Shout <SEP> staux <SEP> prisma-Acetate <SEP> ethyl <SEP> 104.5 <SEP> - <SEP> 105.5
 <tb> ticks <SEP> colorless - hexane
 <tb> res
 <tb> Crystals <SEP> aci-
 <tb> 20 <SEP> it <SEP> 4 <SEP> Double <SEP> link <SEP> eyepieces <SEP> inco- <SEP> Methanol
 <tb> lores <SEP> -chloroform <SEP> 272 <SEP> - <SEP> 274.5 <SEP> -
 <tb> 21 <SEP> H <SEP> H <SEP> 6 <SEP> Simple <SEP> link <SEP> Crystals <SEP> aci- <SEP> Acetone <SEP> 175.5 <SEP> - <SEP> 177.5 <SEP> eyepieces Colorless <SEP>
 <tb> 22 <SEP> H <SEP> H <SEP> 4 <SEP> Simple <SEP> liaicon <SEP> Crystals <SEP> aci- <SEP> Ether <SEP> 221.5 <SEP> - <SEP> 222,

  5 <SEP> eyepieces Colorless <SEP>
 <tb> 23 <SEP> H <SEP> f) <SEP> 4 <SEP> Double <SEP> link <SEP> Crystals <SEP> prisma- <SEP> Ethanol <SEP> 170 <SEP> - <SEP> 171.5
 <tb> ticks <SEP> brownish
 <tb> clear
 <tb>
 

  <Desc / Clms Page number 84>

 Reference example 24.



   50 ml of 47% hydrobromic acid are added to 5 g of 3-hydroxymethylcarbostyryl, and the mixture is stirred at 70-80 C for 3 hours. After cooling the mixture, the precipitated crystals are collected by filtration and recrystallized from methanol to obtain 6 g of 3-bromomethylcarbostyryl in the form of colorless needle-like crystals. Melting point: 218.5-2190C (decomposition).



  Reference example 25.



   3 g of 3-hydroxymethylcarbostyryl are suspended in 100 ml of chloroform, then a solution containing 2 g of thionyl chloride in 20 ml of chloroform is added dropwise at room temperature and with stirring. The reaction mixture is further stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure and the residue obtained is recrystallized from methanol to obtain
 EMI84.1
 2.9 g of 3-chlorornethylcarbostyryl in the form of colorless needle-like crystals. Melting point: 204-205 C.



  Reference example 26.



   2.8 g of 2-chloro-3-chloromethylquinoline are dissolved in 30 ml of acetic acid and the solution is heated under reflux for 2 hours. The reaction mixture is poured into water and the precipitated crystals are collected by filtration, and they are recrystallized from methanol to obtain 2.1 g of 3-chloromethylcarbostyryl in the form of colorless needle-like crystals. Melting point: 204-2050C.



  Examples of Reference 27 to 40.



   By a process analogous to that described in Reference Examples 24 to 26, using an appropriate starting material, the compounds indicated in Table 2 below are prepared.

  <Desc / Clms Page number 85>

 
 EMI85.1
 rl'A TABLHAU
 EMI85.2
 
 <tb>
 <tb> B], <SEP> 1Example <SEP> from <SEP> Position <SEP> from <SEP> Liaison <SEP> carbon <SEP> - <SEP> Form <SEP> Solvent <SEP> from <SEP> Point
 <tb> substitution <SEP> carbon <SEP> between <SEP> crystalline <SEP> rocristal- <SEP> from
 <tb> Reference <SEP> from <SEP> the <SEP> string <SEP>
 <tb> lateral <SEP>
 <tb> R1 <SEP> R2 <SEP> X <SEP> - <SEP> (A) n-CH2X <SEP> 3 <SEP> and <SEP> 4 <SEP> (C.) <SEP> (A)
 <tb> Crystals <SEP> aci-
 <tb> 27 <SEP> H <SEP> 6-OCH <SEP> Hr <SEP> 3 <SEP> Double <SEP> link <SEP> eyepieces <SEP> the- <SEP> Acetone <SEP> 212 <SEP> - <SEP> 212,

  5
 <tb> 3 <SEP> yellowish
 <tb> Crystals <SEP> aci-
 <tb> 28 <SEP> H <SEP> H <SEP> Br <SEP> 3 <SEP> Simple <SEP> link <SEP> eyepieces <SEP> in- <SEP> Acetate <SEP> of ethyl <SEP> 138 <SEP> - <SEP> 140.5
 <tb> colores-hexane
 <tb> Crystals <SEP> aci-
 <tb> 29 <SEP> H <SEP> H <SEP> Cl <SEP> 4 <SEP> Double <SEP> link <SEP> eyepieces <SEP> in- <SEP> Methanol <SEP> 252 <SEP> - <SEP> 254
 <tb> colores-chloroforma
 <tb> Crystals <SEP> aci-
 <tb> 30 <SEP> H <SEP> H <SEP> Br <SEP> 4 <SEP> Double <SEP> link <SEP> eyepieces <SEP> in-Methanol <SEP> 265-266 <SEP>
 <tb> colors <SEP> -chloroform
 <tb> Crystals <SEP> aci-
 <tb> 31 <SEP> H <SEP> H <SEP> Br <SEP> 6 <SEP> Simple <SEP> link <SEP> Culars <SEP> in- <SEP> Acetone <SEP> 190 <SEP> - <SEP> 191
 <tb> colors <SEP> (decomp.)

  
 <tb> Crystals <SEP> aci-
 <tb> 32 <SEP> If <SEP> Br <SEP> 4 <SEP> Double <SEP> link <SEP> eyepieces <SEP> bru- <SEP> Ethanol <SEP> 127 <SEP> - <SEP> 130
 <tb> 2 <SEP> 5 <SEP> nâtres
 <tb> Crystals <SEP> aci-
 <tb> 33 <SEP> H <SEP> 6-OCIL <SEP> Hr <SEP> 4 <SEP> Double <SEP> link <SEP> eyepieces <SEP> jau- <SEP> Ethanol <SEP> 248 <SEP> - <SEP> 250.5
 <tb> 3 <SEP> nâteres <SEP> (decomp.)
 <tb>
 

  <Desc / Clms Page number 86>

 TABLE 2 (Continued)
 EMI86.1
 
 <tb>
 <tb> Position <SEP> from <SEP> Liaison <SEP> carbon- <SEP> Form <SEP> Solvent <SEP> from <SEP> Point
 <tb> substitution <SEP> carbon <SEP> between <SEP> crystalline <SEP> recrystal- <SEP> from
 <tb> Example <SEP> from <SEP> from <SEP> the <SEP> string <SEP> them <SEP> positions <SEP> reading <SEP> fusion <SEP> (A)

  
 <tb> reference <SEP> lateral <SEP> "
 <tb> RÚ <SEP>
 <tb> Re <SEP> X <SEP> 34 <SEP> H <SEP> 8-Cl <SEP> Br <SEP> 4 <SEP> Double <SEP> link <SEP> Crystals <SEP> aci- <SEP> Ethanol <SEP> 206 <SEP> - <SEP> 208 <SEP> eyepieces <SEP>
 <tb> bru- <SEP> nâtres
 <tb> Product <SEP> sprayed- <SEP>
 <tb> 35 <SEP> l <SEP> o-C2H5 <SEP> br <SEP> 4 <SEP> Double <SEP> link <SEP> rulent <SEP> Dimethyl- <SEP> 195 <SEP> - <SEP> 200
 <tb> formamide
 <tb> cau
 <tb> Crystals <SEP> aci-
 <tb> 36 <SEP> it <SEP> H <SEP> Cl <SEP> 3 <SEP> Double <SEP> link <SEP> eyepieces <SEP> Ethanol <SEP> 165.5 <SEP> - <SEP> 166 <SEP> CH2
 colorless <tb>
 <tb> Crystals <SEP> taken-
 <tb> 37 <SEP> H <SEP> H <SEP> Cl <SEP> lt <SEP> Double <SEP> link <SEP> matics <SEP> Methanol <SEP> 186 <SEP> - <SEP> 187 <SEP> CH2
 <tb> brownish
 <tb> 38 <SEP> CH3 <SEP> H <SEP> Br <SEP> 3 <SEP> Double <SEP> link <SEP> C)

    <SEP> L <SEP>
 <tb> 39 <SEP> H <SEP> H <SEP> Br <SEP> 4 <SEP> Double <SEP> link <SEP> Crystals <SEP> aci- <SEP> Ethanol <SEP> 173 <SEP> - <SEP> 174 <SEP> CH
 <tb> eyepieces <SEP> brownish
 <tb> 40 <SEP> H <SEP> If <SEP> Br <SEP> 4 <SEP> Double <SEP> link <SEP> Crystals <SEP> aci- <SEP> Ethanol <SEP> 155 <SEP> - <SEP> 156 <SEP> CH2CH2
 <tb> eyepieces
 colorless <tb>
 <tb>
 

  <Desc / Clms Page number 87>

 Example of Reference 41
Sodium ethylate is prepared from 1.5 g of metallic sodium and 150 ml of dry ethanol, then 12 g of diethyl acetamidemalonate are added thereto and the mixture is stirred at room temperature for one hour. 12 g of 4-bromoethylcarbostyryl are added to this reaction mixture, then the reaction mixture is heated to reflux for 2 hours.

   The ethanol is removed from the reaction mixture and to the residue thus obtained is added water to precipitate the crystals. The crystals are collected by filtration, then recrystallized from ethanol to obtain 13 g of ethyl 2-acetamido-2-carboethoxy-3- (2-quinolone-4-yl) propionate in the form of colorless prismatic crystals .



  Melting point: 224-226'C (decomposition).



  Examples of Reference 42 to 59
By a process analogous to that described in Reference Example 41, using an appropriate starting material, compounds are prepared as shown in the following Table 3.
 EMI87.1
 

  <Desc / Clms Page number 88>

 



  T A B L E A U 3
 EMI88.1
 1'0.



  (k "la c of formula COOH Example of- (A) -CHC-CCOr reference R1 aiso n 2 i. .'n 42 Il!! C2115 COCH C2H5 3 Double 1. i" L,; OIl - 3 43 CI! H 44 H 6-0cri, C2H, 5 325 3 2 5 3 2 5 45 Ci H 46 2 5 25 325 47-CH Double bond 49-Cil H C2H H Double bond 2 49 '- "3 50 HH C2H5 COCH C2 5 Double 51 HH 52-C2Hc 25 54 H 8-CH'C

  <Desc / Clms Page number 89>

 
 EMI89.1
 TADUAU 3 (continued)
 EMI89.2
 
 <tb>
 <tb> 51. <SEP> l <SEP>: <SEP> ion <SEP> from <SEP>: <SEP> sluxitil <SEP>: <SEP> ubonExample <SEP> from <SEP> Solvent <SEP> from
 <tb> reference <SEP> Form <SEP> crystalline <SEP> recrystallization <SEP> Point <SEP> from <SEP> fusion <SEP> (OC.
 <tb>



  42 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 228 <SEP> - <SEP> 230 <SEP> (decomp.)
 <tb> 43 <SEP> Crystals <SEP> flaky Colorless <SEP> <SEP> Ethanol <SEP> 190. <SEP> 5-192 <SEP>
 <tb> 44 <SEP> Product Powdery <SEP> <SEP> white <SEP> Acetate <SEP> ethyl <SEP> 207 <SEP> - <SEP> 209 <SEP> (decomp.)
 <tb> 45 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol <SEP> 191 <SEP> - <SEP> 192.5
 <tb> 46 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol <SEP> 204-205
 <tb> 47 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol <SEP> 176 <SEP> - <SEP> 178.5
 <tb> 48 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 161-163
 <tb> 49 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 155-157
 <tb> 50 <SEP> Crystals <SEP> granular Colorless <SEP> <SEP> Ethanol <SEP> 210-213 <SEP> (dócomp.)

    <SEP> 1 / 2-1IO <SEP>
 <tb> 51 <SEP> Product Powdery <SEP> Colorless <SEP> <SEP> Ethanol <SEP> 264 <SEP> - <SEP> 265 <SEP> (decomp.)
 <tb> 52 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ligroine-ethanol <SEP> 153 <SEP> - <SEP> 154
 <tb> 53 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ligroine <SEP> 107 <SEP> - <SEP> 110
 <tb> 54 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 211, <SEP> 5 <SEP> - <SEP> 212, <SEP> 5 <SEP>
 <tb>
 

  <Desc / Clms Page number 90>

 TABLE 3 (Continued)
 EMI90.1
 . de d1iúne de fomulc cooir - C-COUX Excle de x) Ext reference 1 2 6 7 8 "" tLcns 3 e't 4 n RR l 3-n 55 H 8-Cl C2H5 COCH3 C2 4 Double bond 56 Il 8 -C2II5 CH COCH3 Double bond 57 il 6-OCH- I 58 If fi Cn COCH3 C2H5 4 Double l. i. or.



  59 Il Double bond Cep

  <Desc / Clms Page number 91>

 osiu. we ac snuGU. LueionTABLEAU 3 (Continued)
 EMI91.1
 
 <tb>
 <tb> Example <SEP> from <SEP> Form <SEP> crystalline <SEP> Solvent <SEP> from <SEP> Point <SEP> from <SEP> fusion <SEP> Salt
 <tb> reference <SEP> recrystallization <SEP> (C)
 <tb> 55 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol <SEP> l88-190
 <tb> 56 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 192, <SEP> 5-195 <SEP>
 <tb> 57 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 207-208, <SEP> 5 <SEP>
 <tb> 58 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 156-158
 <tb> 59 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol-water <SEP> 182-183
 <tb>
 

  <Desc / Clms Page number 92>

 Reference Example 60
5.6 g of 2-acetamido-2-carboethoxy-3- (2-quinolone-3-yl) are dissolved

   ethyl propionate in 150 ml of tetrahydrofuran, then added thereto at room temperature with stirring 0.8 g of 50% sodium hydride in oil. Then 4.5 g of methyl iodide are added dropwise to the reaction mixture at room temperature and with stirring for 3 hours. At the end of the reaction, the reaction mixture is concentrated under reduced pressure, and the residue is poured into water, and the precipitated crystals are collected by filtration. Recrystallized from an ethanol-water mixture to obtain 3.5 g of ethyl 2-acetamido-2-carboethoxy-3- (1-methyl-2-quinolone-3-yl) -propionate in the form of crystals in the form colorless glitter. Melting point: 190, 5-192 C.



   By a process analogous to that described in Reference Example 60, the compounds of Reference Examples 44 - 47, 50 51 and 58 are prepared.



  Reference Example 61
1.9 g of aluminum and lithium hydride are suspended in 100 ml of dehydrated tetrahydrofuran, then 1.9 g of 3-carboxycarbostyryl are added at room temperature with stirring, then the reaction mixture is continuously stirred at room temperature overnight.



  The excess aluminum hydride and lithium are broken down by dropwise addition of ethyl acetate. Then, the reaction mixture is acidified by adding dilute sulfuric acid. After removing the tetrahydrofuran by distillation under reduced pressure, the precipitated crystals are collected by filtration. They are recrystallized from methanol to obtain 0.5 g of 3-hydroxymethylcarbostyril in the form of colorless prismatic crystals. Melting point: 238-239y5 OC.



   By a process analogous to that described in Reference Example 61, using a suitable starting material.

  <Desc / Clms Page number 93>

 appropriate, the compounds of Reference Examples 18-23 are prepared.



  Reference Example 62
30 9 of acetoacetanilide are dissolved in 30 ml of chloroform, then a solution containing 27 g of bromine-in 30 ml of chloroform is added dropwise at room temperature with stirring. At the end of the addition of the bromine, the reaction mixture is heated to reflux for 30 minutes. The reaction mixture is concentrated under reduced pressure, the residue obtained is added to 70 ml of concentrated sulfuric acid with stirring. We conduct the operation of addi-
 EMI93.1
 tion by keeping the interior of the container between 70 and 75 ° C., then the whole mixture is stirred at 95 ° C. for 30 minutes.



  The reaction mixture is poured into an ice-water mixture and the precipitated crystals are collected by filtration. They are recrystallized from a methanol-chloroform mixture to obtain
 EMI93.2
 nir 20 of 4-bromomethylcarbostyryl in the form of colorless needle-like crystals. Melting point: 265-266
By a process analogous to that described in Reference Example 62, using an appropriate starting material, the compounds of Reference Examples 24, 25, 27-29 and 31-38 are prepared.



  Reference Example 63
2.2 g of 3-chloromethyl-6-methoxycarbostyryl are dissolved in 20 ml of acetic anhydride, then 12 g of potassium acetate are added thereto and the mixture is stirred at 60 to 70 ° C. for 3 hours. The reaction mixture is poured into an ice-water mixture and the precipitated crystals are collected by filtration. They are recrystallized from acetone to obtain 2 g of 3-acetoxymethyl-6-methoxycarbostyril in the form of colorless prismatic crystals. Melting point: 166-168 C.



  Example of Reference 64
2 g of 3-acetoxymethylcarbostyril are dissolved in 30 ml of methanol containing 0.6 g of sodium hydroxide, then

  <Desc / Clms Page number 94>

 the mixture is heated at reflux for 3 hours. After removing the methanol by distillation, water is added to the residue thus obtained and the precipitated crystals are collected by filtration. They are recrystallized from acetone to obtain 1.3 g of 3-hydroxymethyl-6-methoxycarbostyryl in the form of needle-like crystals of light yellowish color.



  Melting point: 196-197 C.



   By a process analogous to that described in Reference Example 64, using an appropriate starting material, the compounds of Reference Examples 16 and 19 to 23 are prepared.



  Reference Example 65 (a) 175 ml of water, 10.5 g of ferrous sulfate heptahydrate, 0.5 ml of concentrated hydrochloric acid and 6 g of o-nitrobenzaldehyde are placed in a four-pipe flask. heat the flask to 90 ° C in a water bath. 25 ml of an aqueous ammonia solution are added all at once to the reaction mixture contained in the flask, with stirring, then another 30 ml of ammonia water are added three times every 2 minutes. At the end of the addition of the ammonia water, the reaction mixture is left to distill immediately with steam. The distillate is collected in an amount of 250 ml twice separately. The first distillate is cooled and the precipitated crystals are collected by filtration.

   The mother liquor obtained from the first distillate is combined with the second distillate, and this mixture is saturated with sodium chloride, then it is extracted with ether. The ether extract is dried with sodium sulfate and the ether is distilled off. The residue thus obtained is combined with the crystals precipitated in the first distillate and the mixture is dried to obtain 2.9 g of o-aminobenzaldehyde in the form of crystals analogous to colorless flakes. Melting point: 38-39 OC.



   (b) 2 g of malonic acid are dissolved in 15 ml of pyridine, then 1.2 g of o-aminobenzaldehyde are added thereto and

  <Desc / Clms Page number 95>

 2 ml of piperidine, and the mixture is stirred at 90 ° C. for 5 hours. The reaction mixture is poured into an aqueous hydrochloric acid solution and the precipitated crystals are collected by filtration. They are recrystallized from a methanol-chloroform mixture to obtain 1.2 g of 3-carboxycarbostyryl in the form of colorless needle-like crystals.



  Melting point: above 300 OC Reference example 66
140 ml of acetic anhydride are added to 60 g of satine and the mixture is heated to reflux for 4 hours.



  The reaction mixture is cooled, and the precipitated crystals are collected by filtration, and washed with ether to obtain 58 g of N-acetylisatin.



   58 g of the above-mentioned N-acetylisatin are added to a solution containing 30 g of sodium hydroxide in 1.5 liters of water and the mixture is heated at reflux for 1 hour. The reaction mixture is then cooled to a certain degree, then activated carbon is added and further heated to reflux for 30 minutes. The activated carbon is removed from the reaction mixture by filtration while the mixture is hot, and the mother liquor is cooled, then 6N hydrochloric acid is added to the mother liquor to adjust its pH to 3-4. The precipitated crystals are collected by filtration, washed with water and dried to obtain 45 g of 4-carboxycarbostyryl. Melting point: above 300 C.



  Reference Example 67 (a) Under ice cooling and with stirring, 322 ml of phosphorus oxychloride are added dropwise to 96 ml of N, N-dimethylformamide. At the same temperature, 67.5 9 of acetanilide are added thereto and the mixture is stirred at 75 ° C. for 18.5 hours. It is poured onto ice and the precipitated crystals are collected by filtration and dried. By recrystallization from ethyl acetate, 55.2 g of 2-chloro-3-formylcarbostyryl is obtained in the form

  <Desc / Clms Page number 96>

 yellowish needle-like crystals. Melting point: 149-151 OC.



   (b) to 37 g of 2-chloro-3-formylquinoline, 600 ml of 4N hydrochloric acid are added and the mixture is heated at reflux for 1 hour. After cooling the reaction mixture, the precipitated crystals are separated therefrom by filtration, and they are recrystallized from an ethanol-chloroform mixture to obtain 34 g of 3-formylcarbostyryl in the form of needle-like crystals of light yellowish color.



  Melting point: 308-309 C.



   (c) 2.7 g of 3-formylcarbostyryl are dissolved in 150 ml of tetrahydrofuran, then 0.8 g of a 50% solution in sodium hydride oil is added to it at room temperature and with stirring . Then 4.5 g of methyl iodide are added dropwise at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, the residue thus obtained is poured into water and the precipitated crystals are collected by filtration. They are recrystallized from ethanol to obtain 1.7 g of 1-myethyl-3-formylcarbostyryl in the form of acicular crystals of brownish yellow. Melting point: 211-214 C.



  Reference Example 68
With stirring at 0 ° C., 64.4 ml of phosphorus oxychloride containing 11.6 ml of N, N-dimethylformamide are added dropwise. At the same temperature, 18.4 g of Nphenyl-3-chloropropionamide are added thereto, and the reaction mixture is further stirred at 75-80 OC for 10 hours. The reaction mixture is poured into an ice-water mixture, and the precipitated crystals are collected by filtration. They are recrystallized from ethanol to obtain 6.7 g of 2-chloro-3-chloromethylquinoline in the form of colorless prismatic crystals.



  Melting point: 116-118 C.



  Example of Reference 69
Heated 17 g of 4-formylcarbostyryl, 18 g of Nacetylglycine, 7 g of anhydrous sodium acetate and 100 ml of an-

  <Desc / Clms Page number 97>

 acetic hydride at 110 OC to obtain a homogeneous solution, then the solution is heated to reflux for 1.5 hours.



  After cooling the reaction mixture, it is poured into cold water and the precipitated crystals are collected by filtration. The crystals are washed with cold water, then recrystallized from an ethanol-chloroform mixture to obtain 10 g of 4- (1, 2-dihydro-2-oxo-4-quinolylidene) - 2-methyl-5-oxazolone semi-hydrated. Melting point: 275-277 OC (decomposition).



  Reference Examples 70-71
By a process analogous to that described in Reference Example 69, using an appropriate starting material, the compounds shown in Table 4 below are prepared.
 EMI97.1
 

  <Desc / Clms Page number 98>

 



  Table4
 EMI98.1
 Position Example of carbon substitution between .. '"Heference spitions''ormccs R o /' \ 68 CH- (Lthanol-chlorolorm) [Salt: A1 / 2.



  "3'3 203 bond (Ethanol)

  <Desc / Clms Page number 99>

 
 EMI99.1
 Example 1.



  To 5 g of 2-acetamido-2-carboxy-3- (2-quinolone-4-yl) ethyl propionate is added 150 ml of hydrochloric acid from Liai carbonc- Po: i. ntà 20 ao and the mixture is heated to reflux for 9 hours.



  The reaction mixture is concentrated under reduced pressure, the residue is recrystallized from an ethanol-water mixture to obtain 3.2 g of 2-amino-3- (2-quinolone-4-yl) propionic acid hydrochloride in the form colorless prismatic crystals. Melting point: 220-225 OC (decomposition).



    Example 2
1.6 g of 2-amino-3- (2-quinolone-3-yl) propionic acid hydrochloride and 2.4 g of potassium carbonate are dissolved in 60 ml of acetone with 30 ml of water, then a solution containing 1.2 g of p-chlorobenzoyl in 10 ml of acetone is added dropwise to this mixture, cooling with ice and stirring. The reaction is continued under ice cooling for 2 hours. After removing the acetone by distillation, water is added to the residue to remove the insoluble matter by filtration.

   The filtrate is acidified by addition of hydrochloric acid and the precipitated crystals are collected by filtration. By recrystallization from an ethanol-water mixture, 1.5 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-3-yl) propionic acid is obtained in the form of a white powder. Melting point: 270-271.5 C (decomposition).



    Example 3
1.5 g of 2-amino-3- (6-methoxy-2-quinolone-3-yl) propionic acid hydrochloride are dissolved in a solution containing 0.8 g of sodium hydroxide in 25 ml of water then, while cooling with ice, 1 g of p-chlorobenzoyl chloride is added dropwise, while stirring. The reaction is carried out by addition of an IN aqueous solution of sodium hydroxide and p-chlorobenzoyl chloride until the starting material has disappeared from the reaction mixture when a sample of the reaction mixture is examined by chromium

  <Desc / Clms Page number 100>

 thin layer matography. At the end of the reaction, the reaction mixture is acidified with hydrochloric acid, and the precipitated crystals are collected by filtration.



  The crystals are washed with ether and then recrystallized from a methanol-water mixture to obtain 0.7 9 of 2- (4-chlorobenzoylamino) -3- (6-methoxy-2-quinolone-3-yl acid) ) propionic in the form of a yellowish powder. Fusion point
 EMI100.1
 234, 5 (decomposition).



  Example 4
2 g of 2 amino-3- (6-hydroxy-2-quinolone-3-yl) propionic acid hydrochloride are suspended in 50 ml of 1-methyl-2-pyrrolidone, then 2.2 g of 3- (4-chlorobenzoyl) -benzoxazoline-2-thione and stirred at room temperature for 3 days. The reaction mixture is poured into ice water and the precipitated crystals are collected by filtration. The crystals are dissolved in a 1N aqueous solution of sodium hydroxide and acidified with 10% hydrochloric acid, then the precipitated crystals are collected by filtration. The crystals are dried and washed with chloroform.

   They are recrystallized from a methanol-water mixture to obtain 1.5 g of 2- (4-chlorobenzoyl-amino) -3- (6-hydroxy-2-quinolone-3-yl) -propionic acid in the form of a clear yellowish powder. Melting point: 223-227 OC-decomposition).



    Example 5
1.2 g of 2-amino-3- (2-quinolone-3-yl) propionic acid, 1.3 g of DCC Ldicyclohexylcarbodiimidev and 1.0 of p-chlorobenzoic acid are suspended. in 10 ml of dioxane, and the suspension is stirred between 60 and 70 OC for 5 hours. At the end of the reaction, the solvent is distilled off, then the ether residue is added and the precipitated crystals are filtered off. The filtrate is concentrated, the residue obtained is dissolved in chloroform and washed with water and with a saturated aqueous solution of sodium chloride. The chloroform phase is dried with sodium sulfate, then the solvent is distilled off.

   We re-

  <Desc / Clms Page number 101>

 crystallize the residue in an ethanol-water mixture to obtain 350 mg of 2- (4-chlorobenzoylamino) -3- (2-quinolone-3-yl) propionic acid in the form of a white powder. Melting point: 270-271.5 C (decomposition).



  Example 6
1.2 g of 2-amino-3- (2-quinolone-3-yl) propionic acid and 0.8 ml of triethylamine are suspended in 10 ml of tetrahydrofuran, then added dropwise, with stirring and at room temperature a solution containing 1.0 g of diethyl chlorophosphate in 10 ml of tetrahydrofuran, and the reaction mixture is stirred at room temperature for 3 hours. A solution containing 1.0 g of p-chlorobenzoic acid in 10 ml of tetrahydrofuran is added dropwise to this reaction mixture and the whole reaction mixture is again stirred at room temperature for 10 hours.

   At the end of the reaction, the precipitated crystals are collected by filtration, the filtrate is concentrated and a saturated aqueous solution of sodium hydrogencarbonate is poured into the residue, then extraction is carried out with chloroform. The organic phase is washed with water and a saturated aqueous solution of sodium chloride, and dried with sodium sulfate. The solvent is distilled off and the residue is recrystallized from an ethanol-water mixture to obtain 0.9 g of 2- (4-chlorobenzoyl-amino) -3- (2-quinolone-3-yl) -propionic acid under the shape of a white powder. Melting point: 270-271.5 OC (decomposition).



    Example 7
To a solution containing 4.84 g of p-chlorobenzoic acid and 4 ml of triethylamine in 50 ml of dimethylformamide, a solution containing 3.87 g of isobutyl chloroformate in 2 ml of dimethylformamide is added dropwise. The reaction mixture is stirred at room temperature for 30 minutes, then a solution containing 6.03 g of 2-amino-3- (2-quinolone-

  <Desc / Clms Page number 102>

 3-yl) propionic acid in 3 ml of dimethylformamide and the mixture is stirred at room temperature for 30 minutes, then between 50 and 60 OC for 1 hour. The reaction mixture is poured into a large amount of a saturated aqueous sodium chloride solution, extracted with chloroform, washed with water and dried.

   The solvent is distilled off and the crude crystals obtained are recrystallized from an ethanol-water mixture to obtain 3.7 g of 2- (4-chloro-benzoylamino) -3- (2-quinolone-3-yl) propionic acid in the form of a white powder. Melting point: 270-271.5 OC (decomposition).



  Example 8
1.66 g of ethyl p-chlorobenzoate, 0.5 g of sodium ethylate and 2.09 g of 2-amino-3- (2-quinolone-3 acid) are added to 100 ml of ethanol. -yl) propionic and all the mixture is placed in an autoclave. The reaction is carried out under pressure of 11 MPa between 140 and 150 OC for 6 hours. At the end of the reaction, the reaction mixture is cooled and concentrated under reduced pressure. The residue is dissolved in 200 ml of chloroform, washed with a 1% aqueous potassium carbonate solution, dilute hydrochloric acid and water, in this order, then the chloroform phase is dried with sulphate sodium.

   The solvent is distilled off, and the residue is recrystallized from an ethanol-water mixture to obtain 300 mg of 2- (4-chlorobenzoylamino) -3- (2-quinolone-3-yl) propionic acid in the form of a white powder. Melting point: 270-271, 5 OC.



  (decomposition).



    Examples 9 to 32
By a process analogous to that described in Example 1, using an appropriate starting material, the compounds indicated in Table 5 below are prepared.
 EMI102.1
 

  <Desc / Clms Page number 103>

 



    TABLE 5 Position of the side chain substitution
 EMI103.1
 -'J-t-L. i ' <AJLt. II'J.



  - Ci / -carbon n h; np1e) "'2 9 H II bond'" bond 11 bond "'-" 3 Double Prnduit bond' '3 "" 4 bond 14 Prismatic crystals bond 15 C Powder product bond 16 CH = CH bond 17 18 Powder product \ -' bond 19 bond 20 bond 21 bond 22 H II Granular crystals bond 23 H) bond

  <Desc / Clms Page number 104>

 
 EMI104.1
 l / (continued)
 EMI104.2
 
 <tb>
 <tb> 3tSolvent <SEP> from
 <tb> Example <SEP> re-distribution <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt <SEP> (A) n
 <tb> 9 <SEP> M & thanol-acetone <SEP> 271 <SEP> - <SEP> 272 <SEP> (decomp.) <SEP> HCl
 <tb> 10 <SEP> Ethanol <SEP> 218 <SEP> - <SEP> 225 <SEP> (decomp.) <SEP> HCl
 <tb> 11 <SEP> Hau <SEP> 293 <SEP> - <SEP> 295 <SEP> (decomp.) <SEP> HCl.

    <SEP> 1/2 <SEP> -H2O
 <tb> 12 <SEP> Ean <SEP> higher <SEP> to <SEP> 300 <SEP> HBr
 <tb> 1 "5 <SEP> Ethanol-other <SEP> 237 <SEP> - <SEP> 238 <SEP> (decomp.) <SEP> HCl. <SEP> 1/4-H2O
 <tb> 14 <SEP> Ethanol <SEP> 175 <SEP> - <SEP> 178 <SEP> (decomp.) <SEP> Hcl.H2O
 <tb> 15 <SEP> Methanol <SEP> 255 <SEP> - <SEP> 260 <SEP> (decomp.) <SEP> HCl
 <tb> 16 <SEP> Ethanol <SEP> 166 <SEP> - <SEP> 161 <SEP> (decomp.) <SEP> HCl.H2O
 <tb> 17 <SEP> Methanol <SEP> 218 <SEP> - <SEP> 221 <SEP> (decomp.) <SEP> H2O
 <tb> 18 <SEP> Ethanol <SEP> 166 <SEP> - <SEP> 169 <SEP> (decomp.) <SEP> HCl
 <tb> 19 <SEP> u <SEP> higher <SEP> to <SEP> 300 <SEP> HC1 <SEP>
 <tb> 20 <SEP> Water <SEP> 257 <SEP> - <SEP> 260 <SEP> (decomp.) <SEP> HCl.H2O
 <tb> 21 <SEP> Methanol-ether <SEP> 290 <SEP> - <SEP> 292 <SEP> (decomp.)

    <SEP> HBr.1 / 2-H2O
 <tb> 22 <SEP> Methanol-ether <SEP> 283 <SEP> - <SEP> 285 <SEP> (decomp.) <SEP> HCl
 <tb> 23 <SEP> Ethanol <SEP> 208 <SEP> - <SEP> 210 <SEP> (decomp.) <SEP> HCl
 <tb>
 

  <Desc / Clms Page number 105>

 TABLE 5 (continued)
 EMI105.1
 Substitution position of Carbon bond ,, COOII-carbon - (A) -CHCH ,, positions ..... n1 I 24 white 25 - "" CAIQ bond Procluit 26 I 8-Cil Powdered product 27 i 28 1l Double bond 29 4 Double bond Product 30 I 31 Double bond Powder product 32 Double bond Powder product

  <Desc / Clms Page number 106>

 the side chain TABLE 5 (continued)
 EMI106.1
 
 <tb>
 <tb> Solvent <SEP> from
 <tb> Example <SEP> recrystallization <SEP> Point <SEP> from <SEP> fusion <SEP> (OC) <SEP> Type <SEP> from <SEP> oneself <SEP> (A) <SEP>
 <tb> 24 <SEP> Ethanol <SEP> 244 <SEP> - <SEP> 246 <SEP> (decomp.)

    <SEP> HCl
 <tb> 25 <SEP> Ethanol <SEP> 168 <SEP> - <SEP> 170 <SEP> (decomp.) <SEP> HCl.2 / 3-H2
 <tb> 26 <SEP> Ethanol <SEP> 229 <SEP> - <SEP> 231 <SEP> (decomp.) <SEP> HCl.2 / 3-H2O
 <tb> 27 <SEP> Ethanol <SEP> 246-28 <SEP> (decomp.) <SEP> HC1 <SEP>
 <tb> 28 <SEP> Ethanol <SEP> 260-261 <SEP> (decomp.) <SEP> HCl <SEP>
 <tb> 29 <SEP> Ethanol <SEP> Superior <SEP> to <SEP> 320 <SEP> HCl
 <tb> 30 <SEP> Dimethvlformamide <SEP> Superior <SEP> to <SEP> 300 <SEP> HCl
 <tb> - <SEP> water <SEP>
 <tb> 31 <SEP> CH2 <SEP> CH2 (+)
 <tb> 32 <SEP> Water <SEP> 296-298 <SEP> (decomp.) <SEP> HC1 <SEP> CM2 <SEP>
 <tb> (+) <SEP> N <SEP> 1R <SEP> & <SEP> (DMSO) <SEP> 8. <SEP> 60 <SEP> (2H, <SEP> b <SEP> s), <SEP> 7. <SEP> 00 <SEP> - <SEP> 8.00 <SEP> (4H, <SEP> m), <SEP> 6. <SEP> 52 <SEP> (l1, <SEP> s), <SEP> 3. <SEP> 80 <SEP> - <SEP> 4.10 <SEP> (1H, m)
 <tb> 2. <SEP> 70-3. <SEP> 10 <SEP> (2H, <SEP> m), <SEP> 1.

    <SEP> 50-2. <SEP> 20 <SEP> (4H, <SEP> m).
 <tb>
 

  <Desc / Clms Page number 107>

 



  Examples 33 to 126
By a process analogous to that described in any one of Examples 2 and 5 to 8, using an appropriate starting material, the compounds indicated in Table 6 below are prepared.
 EMI107.1
 

  <Desc / Clms Page number 108>

 
 EMI108.1
 



  '1' ^ HL sn).) Side chain
 EMI108.2
 col-13 - (A) cilc 'C f)). nc- / - c .- l'X) \ Il; )) Ex 33 34 il ti OH COCIfc 3 2 35! C 35 11 011 o 3f, 0- 2 37 il c o-L 2 37 il Il OH CO -.- Cl C 2 2 38 H, 2 2 39 H) H CH "..



  40 '' \ -C1 C 41 H -OC 42 H, CH 43 H Cl 44 H '-C1 CH 45 011 T) oiible 2 4 "! NH. CH 2 2 2 2 46 HH OH CO (CH) H) 2 47 jl -Cl CH \ - c HH 1 i.,) ...



  -

  <Desc / Clms Page number 109>

   H A U @@@@@ (continued)
 EMI109.1
 
 <tb>
 <tb> Solvent <SEP> from
 <tb> Example <SEP> Close <SEP> oristalline <SEP> recrystallization <SEP> Point <SEP> from <SEP> rasion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> 33 <SEP> Product <SEP> Powdery <SEP> slightly <SEP> Water <SEP> 228 <SEP> - <SEP> 231 <SEP> (decomp.)
 <tb> yellowish
 <tb> 34 <SEP> Product Powdery <SEP> <SEP> white <SEP> Water <SEP> 212 <SEP> - <SEP> 215 <SEP> (decomp.)
 <tb> 35 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 261 <SEP> - <SEP> 264 <SEP> (decomp.)
 <tb> 36 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 255 <SEP> - <SEP> 257, <SEP> 5 <SEP> (decomp.) <SEP> - <SEP>
 <tb> 37 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Acetate <SEP> ethyl- <SEP> 201.5 <SEP> - <SEP> 203,

    <SEP> 5 <SEP> (keycornp.) <SEP> - <SEP>
 <tb> hexane
 <tb> 38 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-ether <SEP> 190 <SEP> - <SEP> 192 <SEP> (decomp.)
 <tb> 39 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 250 <SEP> - <SEP> 253 <SEP> (decomp.)
 <tb> 40 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 246 <SEP> - <SEP> 247, <SEP> 5 <SEP> (df'comp.)
 <tb> 41 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 249 <SEP> - <SEP> 251 <SEP> (decomp.)
 <tb> 42 <SEP> Crystals <SEP> prismatic <SEP> Ethanol <SEP> 280 <SEP> - <SEP> 282 <SEP> (decomp.) <SEP> H2O
 colorless <tb>
 <tb> 43 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol-chloroform <SEP> 288 <SEP> - <SEP> 290 <SEP> (decomp.)

    <SEP> 1/2-H2O
 <tb> 44 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Methanol-chloroform <SEP> 275 <SEP> - <SEP> 276.5 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 45 <SEP> Product <SEP> cotton <SEP> white <SEP> ethanol <SEP> 250 <SEP> - <SEP> 252 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 46 <SEP> Product Powdery <SEP> <SEP> white <SEP> Kethanol <SEP> 270 <SEP> - <SEP> 271 <SEP> (decomp.) <SEP> H2r. <SEP> 1/2-H2O
 <tb> 47 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol-water <SEP> 256 <SEP> - <SEP> 257 <SEP> (decomp.)
 <tb> 48 <SEP> Crystals <SEP> acicular <SEP> colorless <SEP> Methanol-water <SEP> 263 <SEP> - <SEP> 267 <SEP> (decomp.) <SEP> -
 <tb>
 

  <Desc / Clms Page number 110>

 TABLE 6 (CONTINUED)
 EMI110.1
 Position cladiaTnc] - ucd- (A) "coi.

   ! "49 r 'Exo C'1 Exomr) 49 C 50 [!' OtI C0 - nr 2 51 [Il Oit -OCH OCII3 3 52! Oi OCH OCII3 - / -Cl 4 Double C)) 55} - Cn 55 if -N]) on-CHC il'5c> - (1113 56 C) [H -Cl son-C) 54 = ci 2 55 Il 011 c, 0 110 57 C.,) VCl 4 Double CH- 1 F 2 259-cl '"= CH H -Cl son-CH, /' 3-Cil 2 60-CHOsCH -C1 on-CHCH 6] -CH-3 C1 CH.



  60 -Cll .., C; ::, CII Il 0]; [; coJi C1 4 Double lhJÌ. 6on -Cil, Cil: - 62) Cl CH "- 'I t) 61-Cil il 011 62 il 0 c i.

  <Desc / Clms Page number 111>

 suTABLEAU6 (continued)
 EMI111.1
 
 <tb>
 <tb> Example <SEP> Form <SEP> crystalline <SEP> Solvent <SEP> from <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> soil
 <tb> recrystallization
 <tb> 49 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol-water <SEP> 270.5 <SEP> - <SEP> 271.5 <SEP> (decomp.)
 <tb> 50 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 287 <SEP> - <SEP> 288.5 <SEP> (decomp.)
 <tb> -cau
 <tb> 51 <SEP> Product Powdery <SEP> <SEP> white <SEP> Acetone-water <SEP> 259 <SEP> - <SEP> 261 <SEP> (decomp.)
 <tb> 52 <SEP> Product <SEP> pulveral <SEP> white <SEP> Methanol <SEP> 256 <SEP> - <SEP> 258 <SEP> (decomp.)

  
 <tb> 53 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide
 <tb> cau <SEP> 287 <SEP> - <SEP> 289 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 54 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 278 <SEP> - <SEP> 280 <SEP> (decomp.) <SEP> -
 <tb> - <SEP>
 <tb> eau55 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 290 <SEP> - <SEP> 291 <SEP> (decomp.) <SEP> -
 <tb> - <SEP> water
 <tb> 56 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 278 <SEP> - <SEP> 280 <SEP> (decomp.) <SEP> -
 <tb> - <SEP>
 <tb> eau57 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol <SEP> 247 <SEP> - <SEP> 249 <SEP> (decomp.)

  
 <tb> 58 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 134 <SEP> - <SEP> 148
 <tb> 59 <SEP> Product Powdery <SEP> <SEP> disgust <SEP> Acetate <SEP> ethyl <SEP> 130 <SEP> - <SEP> 135
 <tb> yellow
 <tb> 60 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Methanol-water <SEP> 271 <SEP> - <SEP> 272 <SEP> (decomp.) <SEP> H2O
 <tb> 61 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol-water <SEP> 230 <SEP> - <SEP> 231 <SEP> (decomp.) <SEP> H2O
 <tb> 62 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Dimethylformamide <SEP> higher <SEP> to <SEP> 300
 <tb> (H) <SEP> HMR <SEP> (DMSO) <SEP>;

    <SEP> 1.17 <SEP> (8H, t), <SEP> 3.00 <SEP> - <SEP> 3.70 <SEP> (2H, <SEP> m), <SEP> 4.18 <SEP> (2H, <SEP> 7. <SEP> d = <SEP> 7Hz), <SEP> 4.50 <SEP> - <SEP> 5.80 <SEP> (1H, <SEP> m),
 <tb> C, <SEP> 53 <SEP> (lll, <SEP> s), <SEP> 7, <SEP> 10- <SEP> P, <SEP> (T <SEP> () <SEP> (8f), <SEP> nl), <SEP> 8, <SEP> H8 <SEP> (1H, <SEP> d, <SEP> J = <SEP> 7.5Hz).
 <tb>
 

  <Desc / Clms Page number 112>

 
 EMI112.1
 



  TAn) uLc)
 EMI112.2
 f'uf. suffered '. coit3 la ci))) lateral, 13-0 2 I 8-). "NHn '-''-' '' '' n 2 63 H H-Onn -C1 64)) -C1 65 -Cl 6 Sinpie 66, 67 3 Double, 'G-OCII) 9 f 2 0' 69 2 72 (H 2 73 Ctt ,. --'- son-0) Il 011 I! 4 Doub1 e'UilÜ; on / "74-CnCfCn n 73 C 21!,. It -CI12C! I "- 75-CiC-CH 76-0 77! 5 Double oiible

  <Desc / Clms Page number 113>

 i:

   AU6 (TABLE 6 (continued)
 EMI113.1
 Solvent Ex) du) 63 the product eiylformamido j, tin ^ ttre-, (garlic 64 Hrpulvcrulcnt -eau 65 Powdered product 65 66 white product Methanol-acetone 271 h7) 'rr. '"' 'Te 68'-reduced 293-295 (decomp.) 1IC1. 1 / 2-11 2 0 69 powdery reduced Br 70 colorless Ethanol-ethcr 7 Colorless crystals Ethanol-water O 72 colorless Ethanol 175 73 white Mthanol 7'1 Crystals]) 75 Product 76 Powdery product, white 77 Product

  <Desc / Clms Page number 114>

 deTABLEAU6 (Continued)
 EMI114.1
 you. idonae snL '.-l ,,,. rijOOGCOI nGlLera'Lc "-) unLt.'L '' COU] po'jit - temple.." - '= - <78 t 79 il H-OH O1 -5 2 79 11 13- () Il 011 Il 5 Doiil) l. e 2 80 il il OH il 6 Sinpie C)) 2 81 H 8-OCH OH 3 3 82 11 6-OCH J-Cl 83 I J-Cl CH 2 84 il 2 84 H -CH 2 85 H if -OCH) ) - 3 'LOCH 87 fl C25 -OCH 3 2 ocii 3 87 fi Il oc il ocli 3 I) forget.

   e- (Il] cil 2 5 3 88 H "Cl" 89 -Cl C)) Cl 9 H -Oft "" "- '" 2 --c ... ,, - 9 1 Oif 2 4

  <Desc / Clms Page number 115>

 
 EMI115.1
 TAi'Lì 6 (continued)
 EMI115.2
 Solvent from Example r. of fusion (C) i p 1 78 l'rodui 1 t 79 l'rndui.



  Hothanol-ether 80 81 Colorless needle crystals Ethanol 264 82 Product, 83 fast 84 rrn <) 85 White product Ethanol-water 284 8G Prod. white Ethanol-water 200-205 O 87 rulent 0 - ethanol 88 Prf.



  - 89 ent 90 t''ro. O 9) j 271,> 5- 1, l t 1-

  <Desc / Clms Page number 116>

 ; t-iTABLEAU6 (Continued)
 EMI116.1
 oi la coi3 a] 3 l14 n-3 el 92 il c 1.



  4 93 1'112N "2 2 94 1 Oif I) otible 3 t'o subsU-LuLionde la ch le li.



  , L ..



  97 2 98 Cil oit (Il () \ -Cil 2 1 "92 '-Cl% 94" "Otf" /) y - r 11 95 H n 0! ! C0- /) 4 tub'-nn Cf) N 2 M "" On 9 -rilicii- / -ci 98 '99 Cf) -CL l) Cif 101'f -Cl 101 103 --... -CI M4 - - '"-.



  105 H -Cl.



  JOC)) -'- '.



  1OG

  <Desc / Clms Page number 117>

 
 EMI117.1
 . 6 (suitc)
 EMI117.2
 
 <tb>
 <tb>;. <SEP>; <SEP> Example <SEP> Close <SEP> crystalline <SEP> Solvent <SEP> from <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> or <SEP> salt
 <tb> recrystallization
 <tb> 92 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamide <SEP> 278 <SEP> - <SEP> 279 <SEP> (decomp.)
 <tb> jaunâtze <SEP> -water
 <tb> 93 <SEP> Product Powdery <SEP> <SEP> white <SEP> Water <SEP> 320 <SEP> (decomp.) <SEP> - <SEP>
 <tb> 94 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 261 <SEP> - <SEP> 263 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 95 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 298-299 <SEP> (docomp.) <SEP> 1/2-H <SEP> O
 <tb> 96 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-cau <SEP> 283 <SEP> - <SEP> 286 <SEP> (decomp.)

  
 <tb> 97 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-cau <SEP> 280.5 <SEP> - <SEP> 282.5 <SEP> (decomp.) <SEP> H2O
 <tb> 98 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Ethanol <SEP> 234.5 <SEP> - <SEP> 236 <SEP> (decomp.)
 <tb> yellowish
 <tb> 99 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 208-211 <SEP>
 <tb> 100 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 226 <SEP> - <SEP> 228 <SEP> (decomp.)
 <tb> 101 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamaide <SEP> Superior <SEP> to <SEP> 300
 <tb> yellowish <SEP> - <SEP> water
 <tb> 102 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 298 <SEP> - <SEP> 299 <SEP> (decomp.)
 <tb> - <SEP> water
 <tb> 103 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 303 <SEP> - <SEP> 305 <SEP> (decomp.)

  
 <tb> - <SEP>
 <tb> eau104 <SEP> Product Powdery <SEP> <SEP> yellow-browned <SEP> Ethanol-chloroform <SEP> 241.5 <SEP> - <SEP> 242.5 <SEP> (decomp.)
 <tb> 105 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> -water <SEP> 275 <SEP> - <SEP> 280 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 106 <SEP> cijataux <SEP> acicular Colorless <SEP> <SEP> Ethanol- <SEP> water <SEP> 220.5 <SEP> - <SEP> 222 <SEP> (decomp.)
 <tb>
 

  <Desc / Clms Page number 118>

 
 EMI118.1
 '' '' '' '' '' - "'h
 EMI118.2
 i'oi ". nj, ...



  , .-]. ! 1C 'iac'h. nc -)., ath'rtc LUit ..



  - (Co,. , n1 ') 107 CH 5 108' -C'L 2 LAW) il t -CI 'UO Il tt) -Cl 2 5 Hl Q-CtCH 112 Il Il 011 4 Double bond - 112 "' CH ,, -'- son-Cf) 011 Co Cl-12l 2-2 114 HH OH CO-j CH 2 114 I OQ 1 4.) m) 2 C, '") L7 COOCH -C1 119 18 CO- -C). iso-CHCH 1) -Cl e., CH ..



  '-n c 1. 4 2 2 119 11 11 ocii occ (Cil co- "i \\ - ci. 4 I) YES)' l 0 iai S0, 2 tt 3 3 2)

  <Desc / Clms Page number 119>

 (uuiLc) TABLE 6 (continued)
 EMI119.1
 
 <tb>
 <tb> Solvent <SEP> from <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> Example <SEP> Form <SEP> crystalline <SEP> recrystallization
 <tb> 107 <SEP> Product Powdery <SEP> <SEP> white <SEP> Acetate <SEP> ethyl <SEP> 135-137 <SEP> (decomp.) <SEP> 1 / 3- <SEP> 0
 <tb> ¯ <SEP> he-wane <SEP>
 <tb> 108 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol-water <SEP> 180.5 <SEP> - <SEP> 182
 <tb> 109 <SEP> Crystals <SEP> acicular <SEP> slightly <SEP> Ethanol-chloroform <SEP> 258 <SEP> - <SEP> 260 <SEP> (decomp.)
 <tb> youths
 <tb> 110 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 212, <SEP> 5-214 <SEP> (decomp.)

  
 <tb> 111 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 227.5 <SEP> - <SEP> 229 <SEP> (decomp.)
 <tb> 112 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 254 <SEP> - <SEP> 256 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> -water
 <tb> 113 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 293, <SEP> 5 <SEP> - <SEP> 294.5 <SEP> (decomp.) <SEP> 1/4-H2O
 <tb> 114 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 279 <SEP> - <SEP> 280 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 115 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 284 <SEP> - <SEP> 285.5 <SEP> (decomp.) <SEP> 2/3-H2O
 <tb> 116 <SEP> Product <SEP> pulverulent <SEP> white <SEP> Ethanol-water <SEP> 276-277 <SEP> (d6comp.) <SEP> 1 / 2-1p20 <SEP>
 <tb> 117 <SEP> Crystals <SEP> granular <SEP> white <SEP> Ethanol <SEP> 202.5 <SEP> - <SEP> 204,

  5
 <tb> 113 <SEP> Prnit Powdery <SEP> <SEP> white <SEP> Ethanol-chloroform <SEP> 256 <SEP> - <SEP> 257.5 <SEP> (decomp.)
 <tb> i. <SEP> i) <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 217-220 <SEP> (decomp.) <SEP>
 <tb>
 

  <Desc / Clms Page number 120>

 
 EMI120.1
 TALi all. ut. iondcJachainc laLcratc Po (A) Cil --- C'col -C01t3 fAt ir g. n '- "- CHC Example - 120 H -Cl 4 Double jjaison-CiCH 121 -C1 CH 2 122 -Cl un-CHCH 2 3 1 1. -Cl CH.' -C1 -CI CU 2 '5 -Cl 4 Doubla CH 2 2' 2G -Cl '+ Double bond-CHpCH 2 2

  <Desc / Clms Page number 121>

 ) ':

   TABLE 6 (continued)
 EMI121.1
 
 <tb>
 <tb> So] <SEP> before <SEP>: <SEP> from <SEP>
 <tb> Example <SEP> Form <SEP> crystalline <SEP> recrystallization <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> 120 <SEP> Crystals <SEP> prismatic <SEP> slightly <SEP> Ethanol-chloroform <SEP> 261 <SEP> - <SEP> 262 <SEP> (decomp.)
 <tb> yellowish
 <tb> 121 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamide <SEP> 315.5 <SEP> - <SEP> 318 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> nobody.

    <SEP> trG-eau <SEP>
 <tb> 122 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 294 <SEP> - <SEP> 295 <SEP> (decomp.)
 <tb> l2i <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 278-280 <SEP> (ddcomp.) - <SEP>
 <tb> 124 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 302 <SEP> - <SEP> 303 <SEP> (decomp.)
 <tb> 125 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide- <SEP> 279, <SEP> 5-280.5 <SEP> (decomp.) <SEP> water
 <tb> 126 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide- <SEP> 295-296 <SEP> (decomp.)
 <tb> water
 <tb>
 

  <Desc / Clms Page number 122>

 Examples 127 to 220
By a process analogous to that described in Example 3, using an appropriate starting material, the compounds indicated in Table 7 below are prepared.

   
 EMI122.1
 

  <Desc / Clms Page number 123>

 
 EMI123.1
 



  't'AHLiAU)' OSi. snt.'st.



  ] lat. lc Li, - =. U.'r] 4 \. L. n lé Example)) 127) i, '-) 129 Cff', '\ Sinplc lLrLsol) 130 if 11 Oit CO-' 130 il il oit c 0 - J (. -CI12 (; [; I: 132 il f) al [-Cl 133 H nH-) 1H C)) ".



  135 Il 011 e 136 137 c,) -Cl 139 Il lf OII 1 \ Dou1) 18, U. i1i. sound - 138 H. -Cl 2 2 139) NH.



  Q),], zo H -Cl (i Cl c

  <Desc / Clms Page number 124>

 
7TABLE 7 (continued)
 EMI124.1
 
 <tb>
 <tb> Solvent <SEP> from
 <tb> Example <SEP> Form <SEP> crystalline <SEP> recrystallization <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> soil
 <tb> t
 <tb> 127 <SEP> Product <SEP> powder <SEP> slightly <SEP> Water <SEP> 228 <SEP> - <SEP> 231 <SEP> (decomp.)
 <tb> 128 <SEP> Product Powdery <SEP> <SEP> white <SEP> Water <SEP> 212-215 <SEP> (dncomp.) <SEP>
 <tb> 129 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 261 <SEP> - <SEP> 264 <SEP> (decomp.)
 <tb> 130 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 255 <SEP> - <SEP> 257.5 <SEP> (decomp.)
 <tb> Crystals <SEP> prismatic Colorless <SEP> <SEP> Acetate <SEP> ethyl <SEP> 201, <SEP> 5-203, <SEP> 5 <SEP> (dccomp.)

  - <SEP>
 <tb> -hexane
 <tb> 132 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-ether <SEP> 190 <SEP> - <SEP> 192 <SEP> (decomp.)
 <tb> 133 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 250-253 <SEP> (deco) <SEP> np.) <SEP>
 <tb> 134 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethnnol <SEP> 246-2 / 17, <SEP> 5 <SEP> (dccornp.)
 <tb> 135 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Ethanol <SEP> 249 <SEP> - <SEP> 251 <SEP> (decomp.)
 <tb> 136 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 280 <SEP> - <SEP> 282 <SEP> (decomp.) <SEP> H2O
 <tb> 137 <SEP> Product <SEP> polveruleat <SEP> blane <SEP> Methanol-chloroform <SEP> 288 <SEP> - <SEP> 290 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 138 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Methanol-chloroform <SEP> 275 <SEP> - <SEP> 276.5 <SEP> (decomp.)

    <SEP> 1/2-H2O
 <tb> 139 <SEP> Product Cottony <SEP> Colorless <SEP> <SEP> Methanol <SEP> 250 <SEP> - <SEP> 252 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 140 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Methanol <SEP> 270 <SEP> - <SEP> 271 <SEP> (decomp.) <SEP> HBr. <SEP> 1/2-H2O
 <tb> 141 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol-water <SEP> 256 <SEP> - <SEP> 257 <SEP> (decomp.)
 <tb> 142 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Methanol-water <SEP> 265 <SEP> - <SEP> 267 <SEP> (decomp.)
 <tb>
 

  <Desc / Clms Page number 125>

 Vableau7 (CONTINUED)
 EMI125.1
 Positon su) '' nL. of n i-3c l. ; i Coli-Cil 1li1l COH'c.



  1 n'C "= - = - C-N)" "'' '' -" = 'r-n. l 143 ff /) y = / Cl 1 -Br ison-CfC)) .. 'OCH 146) -OCiI., -'-' "- CH 14 OCH '" "0 C HIC - Il) \.



  149 f J C)) 145 '-'''- 2']) C1 4 ruble. ".



  153 152)) C1 'on-CC) 155 152' - '154-CHC = CH) i' '' - C 149 15 151 ("Il3 il 0 1 '.) 5 -CI12 {) II 011 C; 0. Ji - '>> - C l 1 \. L. Jo1. 1J, lLli,; on -CII'JCII:' Doiil) le 15G Il If Ol! CO .... / í J-Cl r ']; ) ouble li. éli: ÏoI1 -C Il, /) Il. '' - 2 154-cil 2 oli Cl 4 I) oi. ibl c. ,, 155- ("Il 011 2 156

  <Desc / Clms Page number 126>

 from TABLE 7 (continued)
 EMI126.1
 
 <tb>
 <tb> Example <SEP> Form <SEP> crystalline <SEP> Solvent <SEP> from <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> recrystallization
 <tb> 143 <SEP> Product <SEP> powder <SEP> blane <SEP> Methanol-water <SEP> 270.5 <SEP> - <SEP> 271.5 <SEP> (decomp.) <SEP> 1/4-H2O
 <tb> 144 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Dimethylformamide <SEP> 287 <SEP> - <SEP> 288.5 <SEP> (decomp.)

    <SEP> 1/2-H2O
 <tb> - <SEP>
 <tb> eau145 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Acetone-water <SEP> 259 <SEP> - <SEP> 261 <SEP> (decomp.) <SEP> -
 <tb> 146 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Methanol <SEP> 256 <SEP> - <SEP> 258 <SEP> (decomp.) <SEP> -
 <tb> 147 <SEP>
 <tb> Produ-eau
 <tb> 148 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 278 <SEP> - <SEP> 280 <SEP> (decomp.) <SEP> -
 <tb> - <SEP> water
 <tb> 149 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 290 <SEP> - <SEP> 291 <SEP> (decomp.) <SEP> -
 <tb> - <SEP>
 <tb> eau150 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 240 <SEP> - <SEP> 242 <SEP> (decomp.) <SEP> -
 <tb> - <SEP> water
 <tb> 151 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol <SEP> 247 <SEP> - <SEP> 249 <SEP> (decomp.)

    <SEP> -
 <tb> 152 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 134 <SEP> - <SEP> 138 <SEP> 1/2-H2O <SEP> (+++)
 <tb> 153 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Acetate <SEP> ethyl <SEP> 130 <SEP> - <SEP> 135 <SEP> Yellowish
 <tb> 154 <SEP> Crystals <SEP> ociculatros Colorless <SEP> <SEP> Methanol-water <SEP> 271 <SEP> - <SEP> 272 <SEP> (decomp.) <SEP> H2O
 <tb> 155 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Methanol-cau <SEP> 230-231 <SEP> (decomp.) <SEP> H2O
 <tb> 156 <SEP> Crystals <SEP> asical Colorless <SEP> <SEP> Dimethylformamide <SEP> upper <SEP> to <SEP> 300 <SEP> -
 <tb> - <SEP> water
 <tb> (41-) <SEP>
 <tb> @@@ <SEP> & 6.53 <SEP> (1H, <SEP> s), <SEP> 7.10-8.00 <SEP> (5H, <SEP> m), <SEP> 8.68 <SEP> (1H, <SEP> 0.0 = 7.5Hz)
 <tb>
 

  <Desc / Clms Page number 127>

 
 EMI127.1
 T) ')
 EMI127.2
 Horn;

   l3 157 - (A) -C! I --- C '"1 [;' osiLLons]; and 4. -CII --- (, / (A) c 1 l) c 11 1 ')' -" "160 3-Cil L6 1.



  ) ,,) "M '" <, '--- 7 -Cl 2 j58 C1 aon-C)) CH 159' -C 166 16'7 2115-C) II 16 j [) 4-Cil 2 2.



  , - 1 ,. CH t63 u.



  ],] 5 L.



  ) on-CHCH 167 i69-CH C) t70-f non-f CH .. '.' "2

  <Desc / Clms Page number 128>

 
 EMI128.1
 1 T
 EMI128.2
 
 <tb>
 <tb>; <SEP> Example <SEP> Form <SEP> crystalline <SEP> Solvent <SEP> from <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> recrystallization
 <tb> 157 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamide <SEP> 299 <SEP> - <SEP> 300 <SEP> (decomp.) <SEP> -
 <tb> - <SEP>
 <tb> water158 <SEP> Product Powdery <SEP> <SEP> colorless <SEP> Dimethylformamide <SEP> Superior <SEP> to <SEP> 300 <SEP> -
 <tb> 159 <SEP> Product Powdery <SEP> <SEP> colorless <SEP> Ethanol <SEP> 251 <SEP> - <SEP> 252 <SEP> (dcomp.) <SEP> -
 <tb> 160 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol-acetone <SEP> 271 <SEP> - <SEP> 272 <SEP> (decomp.)

    <SEP> HCl
 <tb> 161 <SEP> Product <SEP> granular <SEP> white <SEP> Ethanol <SEP> 218 <SEP> - <SEP> 225 <SEP> (decomp.) <SEP> HCl
 <tb> 162 <SEP> Product Powdery <SEP> <SEP> colorless <SEP> Water <SEP> 293 <SEP> - <SEP> 295 <SEP> (decomp.) <SEP> HCl. <SEP> 1/2-H2O
 <tb> 163 <SEP> Product Powdery <SEP> <SEP> yellow <SEP> Water <SEP> Superior <SEP> to <SEP> 300 <SEP> HBr
 <tb> 164 <SEP> Product Powdery <SEP> Colorless <SEP> <SEP> Ethanol-ether <SEP> 237 <SEP> - <SEP> 238 <SEP> (decomp.) <SEP> HCl.1 / 4-H2O
 <tb> 165 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol-water <SEP> 220 <SEP> - <SEP> 225 <SEP> é <SEP> (decomp.) <SEP> HCl.H2O
 <tb> 166 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 175 <SEP> - <SEP> 178 <SEP> (decomp.) <SEP> HCl.

    <SEP> H2O
 <tb> 167 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 255 <SEP> - <SEP> 260 <SEP> (decomp.) <SEP> HCl
 <tb> 168 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 166 <SEP> - <SEP> 171 <SEP> (decomp.) <SEP> HCl.H2O
 <tb> 169 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 218 <SEP> - <SEP> 221 <SEP> (decomp.) <SEP> H2O
 <tb> 170 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 166 <SEP> - <SEP> 169 <SEP> (decomp.) <SEP> HCl
 <tb> 171 <SEP> Product Powdery <SEP> Colorless <SEP> <SEP> Water <SEP> Superior <SEP> to <SEP> 300 <SEP> HCl
 <tb>
 

  <Desc / Clms Page number 129>

 
 EMI129.1
 t'o '. ".. su'.



  ('ctarh.'tinc'., 2 COi! I - (A C .... t ...



  2 iompio "P '' - CH - C 3 2 3 2 173 74)" 175 '3 17li 3 Double sound 178! 1/9 if -CH 4 Double bond. CH 80 -OCH C) OCH 3 182 i 11 -OCH c ocii 181 CI J. 8iJ Il JI ail CO {-'-- \\ -011 4 Doublo li: \ ì. ; -Clì? CII: 'Double-eyelash cliCl 1' "" 0) -OH -C) cl 185

  <Desc / Clms Page number 130>

 iU. cTABLEAU7 (continued)
 EMI130.1
 
 <tb>
 <tb> Example <SEP> Form <SEP> crystalline <SEP> Solvent <SEP> from <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> soil
 <tb> 172 <SEP> Product Powdery <SEP> Colorless <SEP> <SEP> Water <SEP> 257 <SEP> - <SEP> 260 <SEP> (decomp.) <SEP> Hcl.H2O
 <tb> 173 <SEP> Product Powdery <SEP> Colorless <SEP> <SEP> Methanol-ether <SEP> 290 <SEP> - <SEP> 292 <SEP> (decomp.) <SEP> HBr.1 / 2-H2O
 <tb> Crystals <SEP> granclaires Colorless <SEP> <SEP> Methanol-ether <SEP> 283 <SEP> - <SEP> 285 <SEP> (decomp.)

    <SEP> HCl
 <tb> 175 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol <SEP> 264 <SEP> - <SEP> 265 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 176 <SEP> the .- night Powdery <SEP> <SEP>: <SEP> yellows <SEP>: <SEP> rc <SEP> Methanol-water <SEP> 270-271. <SEP> 5 <SEP> (do'comp.)
 <tb> 177 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Methanol-water <SEP> 223 <SEP> - <SEP> 227 <SEP> (decom.)
 <tb> yellow
 <tb> 178 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 208 <SEP> - <SEP> 210 <SEP> (decomp.)
 <tb> 179 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 284 <SEP> - <SEP> 286 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 180 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 200 <SEP> - <SEP> 205 <SEP> (decomp.)

    <SEP> 1/4-H2O
 <tb> 181 <SEP> Product Powdery <SEP> <SEP> white <SEP> Acét <SEP> ate <SEP> ethyl <SEP> 206 <SEP> - <SEP> 208.5 <SEP> (decomp.)
 <tb> - <SEP> ethanol <SEP>
 <tb> 182 <SEP> Product <SEP> pulveculent <SEP> slightly <SEP> Dimethylformamide <SEP> 278 <SEP> - <SEP> 279 <SEP> (decomp.)
 <tb> d .. '. <SEP> unatro "pau <SEP>
 <tb> 183 <SEP> Product Powdery <SEP> <SEP> white <SEP> Water <SEP> 281 <SEP> - <SEP> 282 <SEP> (decomp.)
 <tb> 184 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 305.5 <SEP> - <SEP> 306.5 <SEP> (decomp.) <SEP> 2/3-H2O
 <tb> 185 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Ethanol <SEP> 271.5 <SEP> - <SEP> 272.5 <SEP> (decomp.) <SEP> H2O
 <tb> yellow
 <tb>
 

  <Desc / Clms Page number 131>

 
 EMI131.1
 '1' -)
 EMI131.2
 roHiU.



  DcL't HubsLituUon <.'iiaî. ze 1r '".



  , ,, - C.-CHC "r." N '"t) On3 nl.



  187 188 ll3C 18C 19 - 2 2 8) <"'y - N H /): t90 0'" 191. - -01.



  2 'o "-CH.



  3 '-' "- / 2 '0 2 1. 94 c il il 011 c 0 2 5 195 11 11 rlli2 Co-ci e" t "-Cl' '"' "H-NHCH- -Cl json-CHCH) - <-... -Cl 1S 3 3 1 -C1 2 -

  <Desc / Clms Page number 132>

 : il) TABLE7 (continued)
 EMI132.1
 
 <tb>
 <tb> Solvent <SEP> from
 <tb> Example <SEP> Form <SEP> crystalline <SEP> recrystallization <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> 186 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamide <SEP> 278 <SEP> - <SEP> 279 <SEP> (decomp.) <SEP> yellowish <SEP> -water
 <tb> 187 <SEP> Product Powdery <SEP> <SEP> white <SEP> Water <SEP> 320 <SEP> (decomp.) <SEP> -
 <tb> 188 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 261 <SEP> - <SEP> 263 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 189 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 298 <SEP> - <SEP> 299 <SEP> (decomp.)

    <SEP> 1/2-H2O
 <tb> 190 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-cau <SEP> 283-286 <SEP> (decomp.) <SEP> 1/2-H <SEP> 0 <SEP>
 <tb> 191 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-cau <SEP> 280.5 <SEP> - <SEP> 282.5 <SEP> (decomp.) <SEP> H2O
 <tb> 192 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Ethanol <SEP> 234.5 <SEP> - <SEP> 236 <SEP> (decomp.)
 <tb> Yellowish
 <tb> 193 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 208-211 <SEP>
 <tb> 194 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 226 <SEP> - <SEP> 228 <SEP> (decomp.)
 <tb> 195 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamide <SEP> Superior <SEP> to <SEP> 300
 <tb> yellow
 <tb> 196 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 298 <SEP> - <SEP> 299 <SEP> (decomp.)

    <SEP> -
 <tb> - <SEP> water
 <tb> 197 <SEP> Product Powdery <SEP> <SEP> launch <SEP> Dimethylformamide <SEP> 303 <SEP> - <SEP> 305 <SEP> (decomp.) <SEP> -
 <tb> - <SEP>
 <tb> eau198 <SEP> Product Powdery <SEP> <SEP> yellow <SEP> Ethanol-chloroform <SEP> 241.5 <SEP> - <SEP> 242.5 <SEP> (decomp.) <SEP> brownish
 <tb> 199 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 275 <SEP> - <SEP> 280 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 200 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol-water <SEP> 220, <SEP> 5 <SEP> - <SEP> 222 <SEP> (decomp.) <SEP> - <SEP>
 <tb>
 

  <Desc / Clms Page number 133>

 
 EMI133.1
 'iliLiir' "" '')
 EMI133.2
 li L C,]: -CI-1 E't'u. '. subst-i fi 113 If c) string] '.



  0 InLcraJe '. nt 4 - C -.....



  3 con3 C,) "-so 2 5 2 2 2" 0 -Cl C)) j 2 203 Cil t -Cl 3 207 11 011 a L-; 0 1-1 208 11 11 011 c o 4 I) OIlt) l- f '-Ji Se n-cil 2 ("Il ,, 204 C1,) -" - 205 C' is 206 4 Double c \.



  S "] C) - 210" "OH '' CH 211 li Il OCH -Cl t- 2) CO- / '-Cl C 213 il If OCH' -Cl a

  <Desc / Clms Page number 134>

 jLLioTABLEAU7 (continued)
 EMI134.1
 
 <tb>
 <tb> Solvent <SEP> from
 <tb> Example <SEP> Form <SEP> crystalline <SEP> recrystallization <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> soil
 <tb> 201 <SEP> Product Powdery <SEP> <SEP> white <SEP> Acetate <SEP> ethyl <SEP> 135 <SEP> - <SEP> 137 <SEP> (decomp.) <SEP> 1/3-H2O
 <tb> - <SEP> hC'X8Iltl <SEP>
 <tb> 202 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol-water <SEP> 180.5 <SEP> - <SEP> 182
 <tb> 203 <SEP> Crystals <SEP> acicular <SEP> slight- <SEP> Ethanol-chloroform <SEP> 258 <SEP> - <SEP> 260 <SEP> (decomp.)
 <tb> ment <SEP> jannâtres
 <tb> 204 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 212.5 <SEP> - <SEP> 214 <SEP> (decomp.)

  
 <tb> 205 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol water <SEP> 227.5 <SEP> - <SEP> 229 <SEP> (decomp.)
 <tb> 206 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 254 <SEP> - <SEP> 256 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> - <SEP>
 <tb> eau207 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Ethanol-water <SEP> 293.5 <SEP> - <SEP> 294.5 <SEP> (decomp.) <SEP> 1/4-H2O
 <tb> 208 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 279 <SEP> - <SEP> 280 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 209 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 284 <SEP> - <SEP> 285.5 <SEP> (decomp.) <SEP> 2/3-H2O
 <tb> 210 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 276-277 <SEP> (decomp.) <SEP> 1 / 2-1120 <SEP>
 <tb> 211 <SEP> Crystals <SEP> granular <SEP> white <SEP> Ethanol <SEP> 202,

  5 <SEP> - <SEP> 204.5
 <tb> 212 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-chloroform <SEP> 256 <SEP> - <SEP> 257.5 <SEP> (decomp.)
 <tb> 213 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 217 <SEP> - <SEP> 220 <SEP> (dòcomp.) <SEP> - <SEP>
 <tb>
 

  <Desc / Clms Page number 135>

 
 EMI135.1
 T). JiJ)
 EMI135.2
 Position uuhst.'it.



  (A) i n r-xo. ci-Cil! ,, "--NUR '' L .. -CHC, E-xe.



  2J4 -Cl 4 Double 2 2] -Cl C \. 'Y'- 2 "y-Cl G Il 6-OCI] oit 27' -Cl 4 Double CH 218 il 6 -Cl \ -C1 Double Link-CHCH 2 219 CH. 11 OH -Cl ", 220 11 '-Cl CH 2 2

  <Desc / Clms Page number 136>

 tr.) TABLE 7 (continued)
 EMI136.1
 
 <tb>
 <tb> Example <SEP> Form <SEP> existalline <SEP> Solvent <SEP> from <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> recrystallization
 <tb> 214 <SEP> Crystals <SEP> prismatic <SEP> slightly <SEP> Ethanol-chloroform <SEP> 261 <SEP> - <SEP> 262 <SEP> (decomp.) <SEP> yellowed. <SEP> sorts <SEP>
 <tb> 215 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamide <SEP> 315.5 <SEP> - <SEP> 318 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> brownish.

    <SEP> -water
 <tb> 216 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 294 <SEP> - <SEP> 295 <SEP> (decomp.) <SEP> -
 <tb> 217 <SEP> Product Powdery <SEP> <SEP>; <SEP> white <SEP> Ethanol-water <SEP> 278 <SEP> - <SEP> 280 <SEP> (decomp.)
 <tb> 218 <SEP> Product <SEP> pulverized. <SEP> white <SEP> Ethanol-water <SEP> 302 <SEP> - <SEP> 303 <SEP> (decomp.) <SEP> -
 <tb> 219 <SEP> Product Powdery <SEP> <SEP> white
 <tb> 220 <SEP> Product <SEP> powder <SEP> white
 <tb>
 

  <Desc / Clms Page number 137>

 
 EMI137.1
 Examples 221 to 314
By a process analogous to that described in Example 4, using an appropriate starting material, the compounds shown in Table 8 below are prepared.
 EMI137.2
 

  <Desc / Clms Page number 138>

 
 EMI138.1
 



  TAiiLAU 8 col-t3 - (A) cilc '4 Pu s') d).') 'I'nclat t-.') Con3.



  N 2 H "R 224 11 11 oit 0-3) ') -.



  2 22 U); OH YES on-.



  2 2 222 Il H CH 2 2 2 2 223 CH]) 0, 3 '-Cl CH 22 27), 0 CO 229 H' -OCH CH 1-) Ollbl e Cil 230 11 011 2 2o CH 2j -Cl -Cl -, ..), 4 Double C)) 2 2 234 I). ) -Cl H 2., 0-, n-CH.-, "'Cl (H cbz OCH.' '' /

  <Desc / Clms Page number 139>

 :;). TABLE8 (continued)
 EMI139.1
 
 <tb>
 <tb> Solvent <SEP> from
 <tb> Example <SEP> Form <SEP> crystalline <SEP> recrystal <SEP> isation <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> 221 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Water <SEP> 228 <SEP> - <SEP> 231 <SEP> (decomp.)
 <tb> yellowish
 <tb> 222 <SEP> Product Powdery <SEP> <SEP> white <SEP> Water <SEP> 212 <SEP> - <SEP> 215 <SEP> (decomp.)
 <tb> 223 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 261 <SEP> - <SEP> 264 <SEP> (decomp.)

  
 <tb> 224 <SEP> Product <SEP> pulveral <SEP> blane <SEP> Ethanol <SEP> 255 <SEP> - <SEP> 257.5 <SEP> (decomp.)
 <tb> 225 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Acetate <SEP> ethyl <SEP> 201.5 <SEP> - <SEP> 203.5 <SEP> (decomp.) <SEP> -
 <tb> - <SEP> hexnne
 <tb> 226 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Ethanol-ether <SEP> 190 <SEP> - <SEP> 192 <SEP> (decomp.)
 <tb> 277 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 250 <SEP> - <SEP> 253 <SEP> (decomp.)
 <tb> 228 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 246 <SEP> - <SEP> 247.5 <SEP> (decomp.)
 <tb> 229 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 249 <SEP> - <SEP> 251 <SEP> (decomp.)
 <tb> 230 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 280 <SEP> - <SEP> 282 <SEP> (decomp.)

    <SEP> H2O
 <tb> Prol <SEP> Product Powdery <SEP> <SEP> blane <SEP> Methanol-chloroform <SEP> 288 <SEP> - <SEP> 290 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 232 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Methanol-chloroform <SEP> 275 <SEP> - <SEP> 276.5 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 233 <SEP> Product <SEP> cotounneux Colorless <SEP> <SEP> Methanol <SEP> 250 <SEP> - <SEP> 252 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 234 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 270 <SEP> - <SEP> 271 <SEP> (decomp.) <SEP> HBr. <SEP> 1/2-H2O
 <tb> 235 <SEP> Product Powdery <SEP> <SEP> white <SEP> Mothnnol-eau <SEP> 256-257 <SEP> (dccomp.) <SEP>
 <tb> 236 <SEP> Crystals <SEP> acicalaria Colorless <SEP> <SEP> Methanol-water <SEP> 265 <SEP> - <SEP> 267 <SEP> (decomp.) <SEP> -
 <tb>
 

  <Desc / Clms Page number 140>

 
 EMI140.1
 TA8L; -.). d, .- NW. ac-i.



  VS <CAt 4. . , - -CIC.,.



  VS).



  238 11 -Hr '23 <)) -OCH OCtf., Oell3 240 \} - OCH., 'Ison OC eye HC. 'COJ /. 4 Double \., ...



  244 245 Cf) CO - C1 240 011 c 0 I) oiibl ocit 3 24 C))) -C.



  3,242 11 11,011 0 2; 4 3 011 c, 0 2 244 011 c 0 21 2 ioiible 2zl5 1 011 0 C'l 41 2 4 011 cci 2 5 247-C) CH -C1 2 2 248-CHC- 0 249-Cli 011 Co ci 2 I ) otble-Liai soi 249-0- Cl 20 Cl. - ") - CH."

  <Desc / Clms Page number 141>

 
 EMI141.1
 1 TAnu-AUH
 EMI141.2
 
 <tb>
 <tb>; <SEP>: <SEP>: Solvent <SEP> from
 <tb> Example <SEP> Form <SEP> crystalline <SEP> recrystallization <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> in <SEP> salt
 <tb> 237 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol-water <SEP> 270.5-271.5 <SEP> (decomp.) <SEP> 1/4-H2O
 <tb> 238 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 287 <SEP> - <SEP> 288.5 <SEP> (decomp.)
 <tb> - <SEP>
 <tb> eau239 <SEP> Product Powdery <SEP> <SEP> white <SEP> Acetone-water <SEP> 259 <SEP> - <SEP> 261 <SEP> (decomp.)

  
 <tb> 210 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 256 <SEP> - <SEP> 258 <SEP> (decomp.)
 <tb> 241 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 287 <SEP> - <SEP> 289 <SEP> (decomp.)
 <tb> - <SEP>
 <tb> eau242 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 278 <SEP> - <SEP> 280 <SEP> (decomp.)
 <tb> - <SEP> water
 <tb> 243 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 290 <SEP> - <SEP> 291 <SEP> (decomp.)
 <tb> - <SEP>
 <tb> eau244 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Dimethylformamide <SEP> 240 <SEP> - <SEP> 242 <SEP> (decomp.)
 <tb> - <SEP> water
 <tb> 245 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol <SEP> 247 <SEP> - <SEP> 249 <SEP> (decomp.)

  
 <tb> 246 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 13-138 <SEP> 1 / 2-11 <SEP> 0 <SEP> ('' '+' '' ') <SEP>
 <tb> 247 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Acetate <SEP> ethyl <SEP> 130 <SEP> - <SEP> 135 <SEP> yellowish
 <tb> 248 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Methanol-3au <SEP> 271 <SEP> - <SEP> 272 <SEP> (decomp.) <SEP> H2O
 <tb> 249 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol-water <SEP> 230 <SEP> - <SEP> 231 <SEP> (decomp.) <SEP> H2O
 <tb> 250 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Dimethylformamide <SEP> Superior <SEP> ü <SEP> 300
 <tb> - <SEP>
 <tb> water (++++) <SEP> EZP <SEP> (DFSO);

    <SEP> 1.17 <SEP> (2H, <SEP> t), <SEP> 3.00-3.70 <SEP> (2H, m), <SEP> 4.18 <SEP> (2H, <SEP> q, <SEP> J = 7Hz), <SEP> 4.50-5.80 <SEP> (1H, <SEP> m)
 <tb> 6.5, <SEP> (1H, <SEP> s), <SEP> 7.10-8.00 <SEP> (8H, <SEP> m), <SEP> 8.88 <SEP> (1H, <SEP> d, <SEP> J = 7.9 <SEP> Hz).
 <tb>
 

  <Desc / Clms Page number 142>

 
 EMI142.1
 



  TAiif.



  S)) CIC f-i f) lêlt C i. vs.'.



  COH., 1 C r l> 251 '-CI.



  252 -C1. CH 253, H -C1 nH 2 254, 2 255 CU 256 c) -o (-. Il 3 011 il 257 3 258 oil il 259 (Dil il- ("Il 2 ci] 256 J1 6-00) 257 tf 6 -Otf 257 259 .'on-C) 260 on-OH) 262-CCHCtL, 263-CH, O 264-Cj- 'CH 265 H 2GS

  <Desc / Clms Page number 143>

 
LAU 8TABLEAU8 (continued)
 EMI143.1
 
 <tb>
 <tb> Solvent <SEP> from <SEP>
 <tb> Example <SEP> Form <SEP> crystalline <SEP> recrystallization <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> 251 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamide <SEP> 299 <SEP> - <SEP> 300 <SEP> (decomp.) <SEP> yellowish <SEP> -water
 <tb> Dimethylformamide <SEP> superior <SEP> ü <SEP> 300
 <tb> 252 <SEP> Product Powdery <SEP> Colorless <SEP> <SEP> - <SEP>
 <tb> 253 <SEP> Product Powdery <SEP> Colorless <SEP> <SEP> Ethanol <SEP> 251 <SEP> - <SEP> 252 <SEP> (decomp.)

  
 <tb> 254 <SEP> the product Powdery <SEP> <SEP> white <SEP> Methanol-acetone <SEP> 271 <SEP> - <SEP> 272 <SEP> (decomp.) <SEP> HCl
 <tb> 255 <SEP> Product <SEP> granular <SEP> white <SEP> Ethanol <SEP> 218 <SEP> - <SEP> 225 <SEP> (decomp.) <SEP> HCl
 <tb> 256 <SEP> Product Powdery <SEP> <SEP> colorless <SEP> Water <SEP> 293 <SEP> - <SEP> 295 <SEP> (decomp.) <SEP> HCl.1 / 2-H2O
 <tb> 257 <SEP> Product Powdery <SEP> <SEP> yellowish <SEP> Water <SEP> Superior <SEP> to <SEP> 300 <SEP> HBr
 <tb> 258 <SEP> Product Powdery <SEP> Colorless <SEP> <SEP> Ethanol-ether <SEP> 237 <SEP> - <SEP> 238 <SEP> (decomp.) <SEP> Hcl.1 / 4-H2O
 <tb> 259 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol-water <SEP> 220 <SEP> - <SEP> 225 <SEP> (decomp.) <SEP> HCl.H2O
 <tb> 2 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 175 <SEP> - <SEP> 178 <SEP> (decomp.)

    <SEP> HCl.H2O
 <tb> 261 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Methanol <SEP> 255 <SEP> - <SEP> 260 <SEP> (decomp.) <SEP> HCl
 <tb> 262 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol <SEP> 166-171 <SEP> (decomp.) <SEP> HCl. <SEP> IL20 <SEP>
 <tb> 263 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 218 <SEP> - <SEP> 221 <SEP> (decomp.) <SEP> H2O
 <tb> 264 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 166-169 <SEP> (decomp.) <SEP> IICl <SEP>
 <tb> 265 <SEP> Product Powdery <SEP> Colorless <SEP> <SEP> Water <SEP> Superior <SEP> to <SEP> 300 <SEP> HCl
 <tb>
 

  <Desc / Clms Page number 144>

 
 EMI144.1
 TABJ.) 'PosiLi substitution dc Ja cha. rnc, ,,,, fjartjtXK.'c'Dtt'L- 'lat-craic'), C)) / con (A) -CHC ,.



  -] 'r. ; x: mpl (j 11'- ', - 266!' 3-OCH 2 267! '8-011 -son-Cf 2 268 il H 2 269 H 5 Doubl 3 3 270 il 6-o (, ii 011 Co- "/ - \, - ci 3 I) oiibl. e lieiisoti-Cil ce il- '3 2 271 ouble 2 27] il 6-OH -C1 272 CH 272 Il Il 011 II 3 Sim::> le l. iiÜson -CII ') CII:: - 273 HH 011 r CO - CH., 2 / j'. "-) 274 -OCH C) OCH 275 H -OCH CH 2 3. CH 'Cl 277 H H -Cl CH \ Ci 2 Cl 2 278 H -OH' "" "" "COCH,,. ,,, ',,,.



  2 4

  <Desc / Clms Page number 145>

 : IN TABLE 8 (continued)
 EMI145.1
 Fnr EXClllp] 0 266 Produced in O 267 268 Crintaux 269 Crystals Ethanol 26-265 270 Product: pul \ / <'-rulcnt.



  271 Product 5 (decomp.) 272 Ethanol product 208 274 White ethanol-water product 275 Powder product - 276 yellowish 277 0 278 0 '/ <) nt-Ethanol 0 yellows

  <Desc / Clms Page number 146>

 
 EMI146.1
 T / \ LL 8 (Suit-. ..., Pos. J. On de; subsLit.'uLion Ict
 EMI146.2
 L carbon - C n1 ') 280'I) -Cl 280 8-Cil c 0 28] "-... M CH 2 2 282 H'1 <"2 J / 283 011 co- 'N 284 Il 4 Doiit) l. E liai coJJ ----- Jj 1 -Cil CII / 284 H CH-"' 285 2 ii ir, on 2 COCf -'- C ') VS)).



  286 Cf C] I 287 o "','" "CO - Cl on-CH. '? 288) CH' 289 -CI 2 290" "-" "CH- <'\) - C1 CH' "'29 L Il H-N) - -...' -Cl 2 Cool'Cl 2 292 CH '29- -C1 3 Double 29. H \ 4 Double 2

  <Desc / Clms Page number 147>

 ! 1lcTABLEAU8 (continued)
 EMI147.1
 
 <tb>
 <tb> Solvent <SEP>
 <tb> ofExample <SEP> Form <SEP> crystalline <SEP> recrystallization <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> soil
 <tb> 280 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamide <SEP> 278 <SEP> - <SEP> 279 <SEP> (decomp.) <SEP> -
 <tb> 281 <SEP> Product Powdery <SEP> <SEP> white <SEP> Water <SEP> 320 <SEP> (decomp.) <SEP> -
 <tb> 282 <SEP> Product Powdery <SEP> <SEP> white <SEP> Methanol <SEP> 261 <SEP> - <SEP> 263 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 283 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 298 <SEP> - <SEP> 299 <SEP> (decomp.)

    <SEP> 1/2-H2O
 <tb> 284 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> -water <SEP> 283 <SEP> - <SEP> 286 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 285 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 280.5 <SEP> - <SEP> 282.5 <SEP> (decomp.) <SEP> H2O
 <tb> 286 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Ethanol <SEP> 234.5 <SEP> - <SEP> 236 <SEP> (decomp.) <SEP> yellowish
 <tb> 287 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 208 <SEP> - <SEP> 211 <SEP> -
 <tb> 288 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 226 <SEP> - <SEP> 228 <SEP> (decomp.)

    <SEP> -
 <tb> 289 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamide <SEP> Superior <SEP> ü <SEP> 200 <SEP> yellowish <SEP> -water
 <tb> 290 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 298 <SEP> - <SEP> 299 <SEP> (decomp.) <SEP> -
 <tb> - <SEP> water
 <tb> 291 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformaide <SEP> 303 <SEP> -305 <SEP> (decomp.) <SEP> -
 <tb> - <SEP>
 <tb> water292 <SEP> Product <SEP>
 <tb> brownish
 <tb> 293 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 275 <SEP> - <SEP> 280 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 294 <SEP> Crystals <SEP> acicular Colorless <SEP> <SEP> Ethanol-water <SEP> 220.5 <SEP> - <SEP> 222 <SEP> (decomp.) <SEP> -
 <tb>
 

  <Desc / Clms Page number 148>

 
 EMI148.1
 TAHLr Posj. su). '.



  * L latëralc nL) "" '' s'.



  R3 ni ') J.: x 295 C)' 011 0 296 n-C)) '-Cl C)' "'4 29-7 -C1 2 <-Cl Cff 30 GI13 2 299 ("Il 4 e;) OQ it i '"' C MirCOOCfr-4 2 il 011- (, Il CI [011 JOUI) l E.



  2 it. L s 0 1'l 302) 'C1, j0j) 4 Double CH 2 305! -Cl 06 "" OCHCO - / '/ CO- <') -C1 CH 307 H' 'CH. o

  <Desc / Clms Page number 149>

 : IN TABLE 8 (continued)
 EMI149.1
 
 <tb>
 <tb> Solvent <SEP> from
 <tb> Example <SEP> Form <SEP> crystalline <SEP> recrystallization <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> 295 <SEP> 5 <SEP> Product Powdery <SEP> <SEP> white <SEP> Acetate <SEP> ethyl <SEP> 135 <SEP> - <SEP> 137 <SEP> (decomp.) <SEP> 1/3-H2O
 <tb> - <SEP> hexano
 <tb> 296 <SEP> Crystals <SEP> prismatic Colorless <SEP> <SEP> Ethanol-water <SEP> 180, <SEP>? -182 <SEP>
 <tb> 297 <SEP> Crystals <SEP> acicular <SEP> slightly <SEP> Ethanol-chloroform <SEP> 258 <SEP> - <SEP> 260 <SEP> (decomp.)
 <tb> yellowish
 <tb> 298 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 212.5 <SEP> - <SEP> 214 <SEP> (decomp.)

  
 <tb> 290 <SEP> Product <SEP> pulveculent <SEP> white <SEP> Ethanol-water <SEP> 227.5 <SEP> - <SEP> 229 <SEP> (decomp.)
 <tb> 300 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide <SEP> 254 <SEP> - <SEP> 256 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> - <SEP>
 <tb> eau301 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 293.5 <SEP> - <SEP> 294.5 <SEP> (decomp.) <SEP> 1/4-H2O
 <tb> 3 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 279 <SEP> - <SEP> 280 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> 303 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 284 <SEP> - <SEP> 285.5 <SEP> (decomp.) <SEP> 2/3-H2O
 <tb> 304 <SEP>
 <tb> Produ303 <SEP> Crystals <SEP> granular <SEP> white <SEP> Ethanol <SEP> 202.5 <SEP> - <SEP> 204,

  5 <SEP> -
 <tb> 306 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-chloroform <SEP> 256 <SEP> - <SEP> 257.5 <SEP> (decomp.)
 <tb> 307 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol <SEP> 217-220 <SEP> (decomp.) <SEP>
 <tb>
 

  <Desc / Clms Page number 150>

 
 EMI150.1
 TABLE g (uite) biuticn de la clkd'l1c 1dllralc -) hC) fA '\ COR nl rut 308: -Cl 4 Double bond-Cil 2 ju9 li 6-011 OH CO- -Cl 4 Double bond-Cil 2 310 \ ) -C1 4 Double bond-Cil 3 2 3n -Cl 2 5 2 312 H 6-OCO- <-C1 -C1 4 Double bond-Ci 2:

   3 -Cl CH Ci 2 314 OH CO- / F'0-Cl Double bond-CH 2 2

  <Desc / Clms Page number 151>

 
PositTABLEAU8 (continued)
 EMI151.1
 
 <tb>
 <tb> Example <SEP> Form <SEP> crystalline <SEP> Solvent <SEP> from <SEP> Point <SEP> from <SEP> fusion <SEP> (C) <SEP> Type <SEP> from <SEP> salt
 <tb> recrystallization
 <tb> 308 <SEP> Crystals <SEP> pragmatic <SEP> slightly <SEP> Ethanol-chloroform <SEP> 261 <SEP> - <SEP> 262 <SEP> (decomp.)
 <tb> yellowish
 <tb> 309 <SEP> Product Powdery <SEP> <SEP> slightly <SEP> Dimethylformamide <SEP> 315.5-318 <SEP> (decomp.) <SEP> 1/2-H2O
 <tb> brownish <SEP> -water
 <tb> 310 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 294-295 <SEP> (dccomp.) <SEP>
 <tb> 311 <SEP> Product Powdery <SEP> <SEP> white <SEP> Ethanol-water <SEP> 278 <SEP> - <SEP> 280 <SEP> (decomp.)

  
 <tb> 312 <SEP> Product Powdery <SEP> <SEP> blane <SEP> Ethanol-water <SEP> 302 <SEP> - <SEP> 303 <SEP> (decomp.)
 <tb> 313 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide- <SEP> 279.5-280.5 <SEP> (decomp.)
 <tb> water
 <tb> 314 <SEP> Product Powdery <SEP> <SEP> white <SEP> Dimethylformamide- <SEP> 295-296 <SEP> (decomp.)
 <tb> water
 <tb>
 

  <Desc / Clms Page number 152>

 Example 315
20% of S-formyl-8-methoxycarbostyryl, 18 g of N-acetylgycin, 7 g of anhydrous sodium acetate and 100 ml of acetic anhydride are mixed with heating to 110 ° C. to form a homogeneous solution, then the mixture is heated to reflux for 1.5 hours. When the reaction is complete, the reaction mixture is cooled, and cold water is added to the mixture, then the precipitated crystals are collected by filtration.

   The crystals are washed with cold water to obtain crude azolactone. In a mixture of 100 ml of water and 300 ml of acetone, the crude azolactone is added and the whole mixture is heated under reflux for 5 hours. The acetone is distilled off, and cold water is added to the residue thus obtained to form crude crystals. The crude crystals thus obtained are collected by filtration. The crude crystals are then dissolved in an aqueous solution of sodium hydrogencarbonate, and the insoluble materials are removed by filtration.

   The filtrate is treated with activated carbon, it is acidified with hydrochloric acid, then the precipitated crystals are collected by filtration and they are recrystallized from ethanol to obtain 10 g of 2-acetylamino-3- acid ( 8-methoxy-2-quinolone-5-yl) acrylic in the form of colorless needle-like crystals. Melting point: 264-265 OC (decomposition).



   By a process analogous to that described in Example 315, using an appropriate starting material, the compounds of Examples 104, 105 and 109 are prepared.



  Example 316
To 6 g of 2-amino-3- (6-methoxy-2-quinolone-3-yl) propionic acid hydrochloride are added 60 ml of 47% hydrobromic acid, and the mixture is heated at reflux for 7 hours. . After cooling the reaction mixture, the precipitated crystals are collected by filtration, then they are recrystallized from water to obtain 1.8 g of 2-amino-3- (6-hydroxy-2-quinolone-3 acid hydrobromide -yl) propionic

  <Desc / Clms Page number 153>

 in the form of a yellowish powder. Melting point: above 300 C.



    Example 317
5 g of 2-amino-3- (2-quinolone-4-yl) propionic acid hydrochloride are dissolved in 150 ml of water. To this solution is added 1 g of 10% palladium on carbon, then it is made to adsorb hydrogen gas at 70 ° C. at atmospheric pressure. The catalyst is removed from the reaction mixture by filtration, then the filtrate is concentrated under reduced pressure. The residue thus obtained is recrystallized by adding acetone, then recrystallized from an ethanol-ether mixture to obtain 3.6 g of hydrochloride
 EMI153.1
 2-amino-3- 4-dihydroquinoline-2-one-4-yl) propionic acid in the form of a white powder. Melting point (3.237-238 OC (decomposition).



    Example 318
4 g of 2- amino-3- (2-quinolone-4-yl) propionic acid hydrochloride are suspended in 50 ml of methanol.



  5.3 g of thionyl chloride are added dropwise thereto, under cooling with ice and with stirring, and the reaction mixture is stirred at room temperature for approximately 16 hours. Methanol and thionyl chloride are removed by distillation under reduced pressure, then the residue obtained is recrystallized from a methanol-acetone mixture to obtain 2.4 g of 2-amÅano-3- (2-quinolone-4-yl) propionate methyl in the form of a white powder. Melting point: 208 - 211 OC (decomposition).



    Example 319
1.8 g of 2- (4-methoxybenzoyl) amino-3- (2-quinolone-3-yl) propionic acid are dissolved in 100 ml of ethanol and then introduced into this solution until the gas is saturated hydrochloric under ice cooling and stirring. The reaction mixture is then heated for 5 hours and, at the end of the reaction, the solvent is distilled off under reduced pressure, and the residue obtained is recrystallized.

  <Desc / Clms Page number 154>

 kept in an ethyl acetate-ethanol mixture to obtain 1.5 g of 2- (4-methoxybenzoyl) amino-3- (2-quinolone-3-yl) ethyl propionate in the form of a powder white. Melting point: 206-208, 5 C.



   By a process analogous to that described in the above-mentioned Example 319, using an appropriate starting material, the compounds of Examples 44 and 87 are obtained.



    Example 320
To 2.7 g of 2-acetylamino-3- (2-quinolin-4-yl) propionic acid, 30 ml of 20% hydrochloric acid are added and the mixture is heated at reflux for 3 hours. The reaction mixture is concentrated under reduced pressure to dryness and the residue obtained is recrystallized from an ethanol water mixture to obtain 1.9 g of 2-amino-3- (2-quinolone-4-yl) propionic acid hydrochloride hydrated under form of colorless prismatic crystals. Melting point: 220-225 OC (decomposition).



   By a process analogous to that described in the above-mentioned Example 320, using an appropriate starting material, the compounds of Examples 9 to 34 are prepared.



    Example 321
6 g of 2-amino-3- (8-methoxy-2-quinolone-5-yl) acrylic acid hydrochloride are dissolved in 100 ml of an IN aqueous solution of sodium hydroxide. 2 g of Raney nickel are added to this solution and the hydrogenation is carried out at room temperature under pressure of 0.3 MPa. The catalyst is filtered off, the mother liquor is neutralized with acetic acid, and left to stand in a refrigerator; the precipitated crystals are collected by filtration.



  Recrystallized from water to obtain 2 g of 2-amino-3- (8-methoxy-2-quinolone-5-yl) propionic acid hydrochloride in the form of a colorless powder. Melting point: 257 - 260 Oc (decomposition).



   By a process analogous to that described in the above-mentioned Example 321, using a suitable starting material.

  <Desc / Clms Page number 155>

 Propriée, preparing the compounds of Examples 1, 2.9 to 19, and 21 to 126.



  Example 322
2.8 g of 2- (4-chlorobenzoyl) amino- 3- (2-quinolone-3-yl) propionic acid are dissolved in 50 ml of N, N-dimethylformamide. To this solution are added 1 9 of 50% sodium hydride in oil at room temperature with stirring, then the mixture is further stirred for 30 minutes. Under ice cooling and with stirring, 1.5 g of methyl iodide are added to the mixture.

   At the end of the reaction, the reaction mixture is concentrated under reduced pressure and the residue is dissolved in water. This solution is acidified with concentrated hydrochloric acid, the precipitated crystals are collected by filtration and recrystallized from ethanol to give 0.5 g of 2- (4-chlorobenzoyl) amino-3- (1- methyl-2-quinolone-3-yl) propionic acid in the form of a white powder. Melting point: 246-247.5 OC (decomposition).



   By a process analogous to that described in the above-mentioned Example 322, using a suitable starting material, the compounds of Examples 10, 14 to 18, 57 to 61.67, 72 to 76, 98 to 100, 104 are prepared. 106 to 111 and 125.



  Example 323
To 4 g of 2-amino-3- (6-methoxy-2-quinolone-4-yl) propionic acid hydrochloride, 50 ml of 48% hydrobromic acid are added and the mixture is heated at reflux for 4 hours. . After cooling the reaction mixture, the precipitated crystals are collected by filtration and dissolved in an aqueous solution of sodium hydroxide. The solution is then acidified with hydrochloric acid and the precipitated crystals are collected by filtration. They are recrystallized from a dimethylformamide-water mixture to obtain 2.2 g of 2-amino-3- (6-hydroxy-2-quinolone-4-yl) hydrochloride propionic acid in the form of a white powder. Melting point: above 300 C.

  <Desc / Clms Page number 156>

 



    Example 324
2.0 g of 2-amino-3- (6-hydroxy-2-quinolone-4-yl) propionic acid hydrochloride and 4.89 of potassium carbonate are dissolved in 100 ml of acetone with 50 ml of 'water. 2.7 g of p-chlorobenzoyl chloride are added dropwise to this mixture while cooling with ice, with stirring.



  The reaction is continued for 3 hours under ice cooling and with stirring. The acetone is distilled off, the residue obtained is diluted with water, and acidified with hydrochloric acid. The precipitated crystals are collected by filtration. They are recrystallized from an ethanol-water mixture to obtain 1.5 g of 2- (4-chlorobenzoylamino) -3-i6- (4-chlorobenzoyloxy) -2-quinolone-4-y propionic acid in the form of 'a powdery product of
 EMI156.1
 their white. Melting point: 302 Example 325
1.8 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) propionic acid are dissolved in 80 ml of N, N-dimethylformamide. 0.6 g of triethylamine is added to this solution.



  Then, while cooling with ice and stirring, 0.8 g of isobutyl chloroformate is added to the above-mentioned mixture. Under the same temperature conditions, 10 ml of an N, N-dimethylformamide solution containing 0.4 g of ammonia are added dropwise to the reaction mixture, and the mixture is stirred for 3 hours. After removing the N, N-dimethylformamide by distillation, water is added to the residue, precipitated crystals are collected by filtration and washed with an aqueous solution of sodium hydroxide. They are recrystallized from a mixture of dimethylformamide and water to obtain 0.7 g of 2- (4-chlorobenzoylamino) -3- (2-quinoline-4-yl) propionamide in the form of a powdered product light yellowish. Melting point: above 300 C.



   Using a process analogous to that described in Example 325, using an appropriate starting material, the compounds of Examples 102 and 103 are prepared.

  <Desc / Clms Page number 157>

   example 326
1.9 g of 2- (4-chlorobenzoylamino) - 3- (2-quinolone-4-yl) propionic acid are dissolved in 20 ml of HMPA. 3 ml of an aqueous solution containing 0.3 g of sodium hydroxide are added dropwise to this solution and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into ice water, then the precipitated crystals are collected by filtration.

   They are recrystallized from ethanol to obtain 0.5 g of 2- (4-chlorobenzoylamino) - 3- (2-quinolone-4-yl) methoxycarbonylmethyl propionate in the form of white granular crystals. Melting point: 202.5-204.5oC.



   Using a process analogous to that described in Example 326, using an appropriate starting material, the compounds of Examples 118 and 119 are prepared.



  Example 327
1.8 g of 2-amino-3- (2-quinolone-4-yl) propionic acid hydrochloride are dissolved in a solution containing 0.8 g of sodium hydroxide in acetone. While stirring at room temperature, 1.3 g of pchlorobenzenesulfonyl chloride are added thereto and the whole reaction mixture is stirred at room temperature for 3 hours. The precipitated crystals are filtered off and the filtrate is acidified with hydrochloric acid. The precipitated crystals are collected by filtration and recrystallized from
 EMI157.1
 a dimethylformamide-water mixture to obtain 1.6 g of 2-14-chlorobenzenesulfonylamino-3-nic acid in the form of a white powder.

   Melting point: 299 - 300 oe (decomposition).
 EMI157.2
 Examples 328 to 333
By a process analogous to that described in Example 327, using an appropriate starting material, the compounds shown in Table 9 below are prepared.
 EMI157.3
 

  <Desc / Clms Page number 158>

 
 EMI158.1
 TAAUO
 EMI158.2
 i'sitinnsut.'S.- ,. tiLudGJa lateral challle,. ,,. pose, -) -f N-t 1 '1') link '' "'' link 329 H H -Ctf .. oub ').



  '3 330 ci] 3 331 cil "-liaison'" "2 *. '. / 332 H -Cl)))," \ i / liaison 333 H TAELEAt Ty) "Example Crystalline form j dT.)'.



  Crystalline fori7ic 328 329 32nd Ivorulous rrfiduit U) '. foT ') nmi. ') 329 Prnduit v6rnlcnl' ').) 330 Crystals prisl 236-237, 5 (decomp.) 331 Prismatic crystals 5 (c1écornp.) 332 3¯ \ 3 ProJuiLpuJvcrulcnLtjJanc] cotp.)

  <Desc / Clms Page number 159>

 Example of film-coated tablets
 EMI159.1
 
 <tb>
 <tb> Acid <SEP> 2- <SEP> (4-chlorobenzoylamino) -3- <SEP> (2-quinolone <SEP>
 <tb> 3-yl) <SEP> propionic <SEP> 150 <SEP> g
 <tb> Avicel <SEP> (brand <SEP> from <SEP> manufactures <SEP> of <SEP> cellulose
 <tb> microcrystalline, <SEP> manufactured <SEP> by <SEP> Asahi
 <tb> Chemical <SEP> Industries, <SEP> Ltd.

    <SEP>) <SEP> 40 <SEP> g
 <tb> Starch <SEP> from <SEP> corn <SEP> 30 <SEP> 9
 <tb> Stearate <SEP> from <SEP> magnesium <SEP> 2 <SEP> g <SEP>
 <tb> Hydroxypropylmethylcellulose <SEP> 10 <SEP> g
 <tb> Polyethylene glycol <SEP> 6000 <SEP> 3 <SEP> g
 <tb> Oil <SEP> from <SEP> castor <SEP> 40 <SEP> g
 <tb> Methanol <SEP> 40 <SEP> g
 <tb>
 
2- (4-chlorobenzoylamino) -3- (2-quinolone-3-yl) propionic acid, Avicel, mars starch and magnesium stearate are mixed together and ground, then the mixture obtained is compressed in tablets using a 10 mm punch. The tablets obtained are coated with a coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol 6000, castor oil and methanol, to obtain tablets coated with a film.



  Example of coated tablets
 EMI159.2
 
 <tb>
 <tb> Acid <SEP> 2- <SEP> (4-chlorobenzoylamino) -3- <SEP> (2-quinolone- <SEP>
 <tb> 4-yl) <SEP> propionic <SEP> 150 <SEP> g
 <tb> Acid Citric <SEP> <SEP> 1.0 <SEP> g
 <tb> Lactose <SEP> 33, <SEP> 5 <SEP> g <SEP>
 <tb> Phosphate <SEP> dicalcium <SEP> 70, <SEP> 0 <SEP> 9 <SEP>
 <tb> Pluronic <SEP> F-68 <SEP> 30, <SEP> 0 <SEP> 9 <SEP>
 <tb> Lauryl-sulfate <SEP> from <SEP> sodium <SEP> 15, <SEP> 0 <SEP> g <SEP>
 <tb> Polyvinylpyrrolidone <SEP> 15, <SEP> 0 <SEP> g <SEP>
 <tb> Polyethylene glycol <SEP> (Carbowax <SEP> 1500) <SEP> 4, <SEP> 5 <SEP> g <SEP>
 <tb> Polyethylene glycol <SEP> (Carbowax <SEP> 6000) <SEP> 45, <SEP> 0 <SEP> g <SEP>
 <tb> Starch <SEP> from <SEP> but <SEP> 30, <SEP> 0 <SEP> g <SEP>
 <tb> Laurylsulfate <SEP> from <SEP> sodium <SEP> sec <SEP> 3,

    <SEP> 0 <SEP> g.
 <tb> Stearate <SEP> from <SEP> magnesium <SEP> sec <SEP> 3, <SEP> 0 <SEP> g <SEP>
 <tb> Ethanol <SEP> q. <SEP> s. <SEP>
 <tb>
 

  <Desc / Clms Page number 160>

 



   2- (4-chlorobenzoylamino) -3- (2-quinolone-4yl) -propionic acid, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed together and the mixture obtained is passed through a No. 60 sieve and then the mixture having passed through the sieve is granulated in the wet state with an alcoholic solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. The granulated product is transformed into a large pasty lump by possible addition of ethanol. Corn starch is added and the mixture is well mixed until uniform granules are formed. The granules are passed through a Nol sieve, and those having passed through the sieve are placed on a tray and dried at 100 ° C. in an oven for 12 to 14 hours.

   The dried granules are passed through the N016 sieve (mesh opening of 1.19 mm) and those having passed through the sieve are added with dehydrated sodium lauryl sulfate and dehydrated magnesium stearate, then the whole mixture is well mixed and compressed to the form desired using a tablet press to give tablets to be used as the cores of the coated tablets. The cores are treated with a varnish, and their treated surface is coated with talc to prevent the surface from absorbing moisture. The treated surface of the cores is further coated with a layer of primary coating, then with a varnish, so that there are a sufficient number of layers to obtain coated tablets for oral administration.

   In order for the coated cores of the tablets to take a completely spherical shape and to make the treated surface smooth, the coated tablets are further coated with primary coating layers and leveling coating layers. The coated tablets are color coated until the desired surface color is obtained. After drying the coated tablets, their surface is polished to give them a uniform gloss.



  Example of preparation of composition for injection
 EMI160.1
 
 <tb>
 <tb> Acid <SEP> 2- <SEP> (4-chlorobenzoylamino) <SEP> -3- <SEP> (1-methyl- <SEP>
 quinolone-3-yl) <SEP> propionic <SEP> 5, <SEP> 0 <SEP> g <SEP>
 <tb>
 

  <Desc / Clms Page number 161>

 
 EMI161.1
 
 <tb>
 <tb> Polyethylene glycol <SEP> (weight <SEP> molecular <SEP>:

    <SEP> 4000) <SEP> 0, <SEP> 3 <SEP> g <SEP>
 <tb> Chloride <SEP> from <SEP> sodium <SEP> 0, <SEP> 9 <SEP> g <SEP>
 <tb> Monooleate <SEP> from <SEP> polyoxyethylene-sorbitan <SEP> 0, <SEP> 4 <SEP> 9 <SEP>
 <tb> Metabisulfite <SEP> from <SEP> sodium <SEP> 0, <SEP> 1 <SEP> g <SEP>
 <tb> f \ léthylparaben <SEP> 0, <SEP> 18 <SEP> 9 <SEP>
 <tb> Propylparaben <SEP> 0, <SEP> 02 <SEP> g <SEP>
 <tb> Water <SEP> distilled <SEP> for <SEP> injection <SEP> 100 <SEP> ml <SEP>
 <tb>
 
The above-mentioned methylparaben, propylparaben, sodium metabisulfite and sodium chloride are dissolved in half of the above-mentioned distilled water at 80 ° C. with stirring. The solution obtained is cooled to 40 ° C. and the compound, the polyethylene glycol and the polyoxyethylenesorbitan monooleate are dissolved, in this order, in the above-mentioned solution.

   The remainder of the distilled water for injection is added to the solution thus obtained to obtain the predetermined volume of composition for injection, and is sterilized by filtration using an appropriate filter paper to prepare a preparation for injection.



  Pharmacological test (1) Compound to be tested
1. 2- (4-Chlorobenzoylamino) -3- (2-quinolone-3-yl) propionic acid
 EMI161.2
 2. 2-Benzoylamino-3- acid 3. 2-Cyclohexylcarbonylamino-3- propionic acid 4. 2- (4-chlorobenzoylamino) -3- (1-methyl-2-quinolone-) acid
3-yl) propionic 5. Acid 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) propionic
 EMI161.3
 6. 2-Benzoylamino-3- acid 7. 2-Benzoylamino-3- (2-quinolone-4-yl) -propionicpropionic acid 8. 2- (4-chlorobenzoylamino) -3- (1-allyl-2-quinolone acid) -
4-yl) propionic 9. 2- (4-chlorobenzoylamino) -3- (1-propargyl-2-quinoline-4-yl) propionic acid

  <Desc / Clms Page number 162>

 10. 2- (4-Chlorobenzoylamino) -3- (1-Benzyl-2-quinolone-) acid
4-yl) propionic 11.

   Acid 2- (4-chlorobenzoylamino) -3- (1-n-butyl-2-quinolone-
4-yl) propionic 12. Acid 2- (4-chlorobenzoylamino) -3- (8-hydroxy-2-quinolone-
5-yl) propionic 13. Acid 2- (4-chlorobenzoylamino) -3- (8-methoxy-2-quinolone-
5-yl) propionic
 EMI162.1
 14. 2- 4-yl) propionic acid 15. 4-12- (4 - carboxycyclohexyl-lp-methylaminocarbonyl) (4-chlorobenzoylamino) ethyl / -carbostyrile 16. 4-L2- (4- &alpha; -ethoxycarbonylcyclohexyl-1 -ss-methylaminocarbonyl) -2- (4-chlorobenzoylamino) ethylcarbostyril 17. Acid 2- (4 - aminomethylcyclohexylcarbonylamino) -3- (2-quinolone-4-yl) propionic 18. Acid 2- (3-chlorobenzoylamino) -3- (2-quinolone-4-yl) propionic 19. Acid 2- (2-chlorobenzoylamino) -3- (2-quinolone-4-yl) propionic 20.

   Acid 2- (2,4-dichlorobenzoylamino) -3- (2-quinolone-4-yl) propionic 21. Acid 2- (4-methoxybenzoylamino) -3- (2-quinolone-3-yl) propionic 22. Acid 2 - (3,4,5-trimethoxybenzoylamino) -3- (2-quinolone-
4-yl) propionic 23. Acid 2- (2,4-dimethylbenzoylamino) -3- (2-quinolone-4-yl) propionic
 EMI162.2
 o 24. 2- (4-nitrobenzoylamino) -3- propionic acid 25. 2- (4-aminobenzoylamino) -3- (2-quinolone-4-yl) propionic acid 26. 2- (4- hydroxybenzoylamino) -3- (2-quinolone-4-yl) propionic

  <Desc / Clms Page number 163>

 27. 2- (4-Chlorobenzylcarbonylamino-3- (2-quinolone-4-yl) propionic acid 280 2-Benzylcarbonylamino-3- (2-quinolone-4-yl) propionic acid
 EMI163.1
 29. 2-Propionic acid 30. 2-Propionic acid 31.

   2- (4-methyl-thioazole-5-ylcarbonylamino) acid -
 EMI163.2
 3- propionic 32. Acid 2- (2-quinolone-4-yl) propionic 33. Acid 2- (4-chlorobenzoylamino) -3- (2-quinolone-3-yl) acrylic 34. 2-cyclohexylcarbonylamino acid 3- (1-ethyl-2-quinolone-
4-yl) propionic
 EMI163.3
 35. 2-Benzoylamino-3-propionic acid 36. 2- (4-Chlorobenzenesulfonylamino) -3- (2-quinolone-) acid
4-yl) propionic 37. 2- (Cyclopropylcarbonylamino) -3- (2-quinolone-4-yl) propionic acid.



   Reference compound:
Sucralfate = basic aluminum salt of sucrose hydrogen sulphate (administered twice a day at a rate of 1000 mg / kg each administration, for 9 days).



   (2) Test method
Under ether anesthesia, a rat's belly is cut to remove the stomach. Using a microsyringe, 15 ml of 30% acetic acid are injected from the side of the serous membrane to the submucosal membrane of the bifurcation of the anterior wall of the ventricle and vestibule of the pylorus. The portion of the bifurcation that received the injection is kept compressed for a few seconds to prevent leakage of the injected fluid. The

  <Desc / Clms Page number 164>

 an incised portion of the belly is sutured, and the rat is fasted overnight, then an oral test compound is administered at a dose of 10 mg / kg / day each time, twice a day, ie in the morning and in the evening, for 9 days.

   Four hours after the last administration, the rat is sacrificed by dislocation of the column, then its stomach is enucleated and fixed by injection of 10 ml of 1% formalin solution. The stomach is cut along the line of great curvature and the area of ulceration (hereinafter referred to as an ulceration index) is measured using an orthoscopic microscope (magnification x10),
 EMI164.1
 and calculating the therapeutic index of the test compound a-
 EMI164.2
 1 near the following formula Lindioe group of the reference group j- '. ggj Therapeutic index == -------- L Reference group ulceration indexj
 EMI164.3
 (A rat from the reference group receives water or a 0.5% aqueous solution of carboxymethylcellulose).



  The results of the tests are given in the following table.

  <Desc / Clms Page number 165>

 
 EMI165.1
 



  The are presented in the TABLE
 EMI165.2
 
 <tb>
 <tb>: <SEP> LInComposer <SEP> test <SEP> Rate <SEP> cura- <SEP> Compound <SEP> test <SEP> rate <SEP> curaNo, <SEP>
 <tb> 1 <SEP>
 <tb> 2 <SEP>
 <tb> tif <SEP> (3 <SEP> 25.0 <SEP> 23 <SEP> 15.0
 <tb> 4 <SEP> 38.1 <SEP> 24 <SEP> 21.3
 <tb> 5 <SEP> 38.5 <SEP> 25 <SEP> 24.8
 <tb> 5 <SEP> 25.0 <SEP> 23 <SEP> 15.0
 <tb> 4 <SEP> 38.1 <SEP> 24 <SEP> 21.3
 <tb> 5 <SEP> 38.5 <SEP> 25 <SEP> 24.8
 <tb> 6 <SEP> 28.1 <SEP> 26 <SEP> 21.0
 <tb> 7 <SEP> 33.0 <SEP> 27 <SEP> 25.2
 <tb> 3 <SEP> 16.8 <SEP> 28 <SEP> 17.8
 <tb> 9 <SEP> 27.6 <SEP> 29 <SEP> 23.2
 <tb> 10 <SEP> 13.7 <SEP> 30 <SEP> 17.6
 <tb> 11 <SEP> 22. <SEP> 3 <SEP> 31 <SEP> 20.

    <SEP> 0 <SEP>
 <tb> 12 <SEP> 17.7 <SEP> 32 <SEP> 22.3
 <tb> 13 <SEP> 18.2 <SEP> 33 <SEP> 18.7
 <tb> 14 <SEP> 28.3 <SEP> 34 <SEP> 23.6
 <tb> 15 <SEP> 16, <SEP> 5 <SEP> 35 <SEP> 19, <SEP> 6 <SEP>
 <tb> 16 <SEP> 13.4 <SEP> 36 <SEP> 18.1
 <tb> 17 <SEP> 22.1 <SEP> 37 <SEP> 28.9
 <tb> 18 <SEP> 25.3 <SEP> Compound <SEP> from <SEP> reference
 <tb> Sucralfate <SEP> 29.0
 <tb> 19 <SEP> 12 <SEP>: <SEP> 4 <SEP>
 <tb> 20 <SEP> 22. <SEP> 3
 <tb>



    

Claims (1)

 CLAIMS 1. New carbostyryl derivatives and their salts, characterized in that they correspond to the general formula,  EMI166.1  wherein R is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl- (lower alkyl) group; R2 is a hydrogen atom, a halogen atom, a benzoyloxy group (which may carry halogen atoms as substituents), a hydroxyl group, a lower alkyl group or a lower alkoxy group;    R3 is a hydroxyl group, an amino group which may bear, as a substituent, a cycloalkyl- (lower alkyl) group (which may carry, as substituents, a carboxy group or a (lower alkoxy) carbonyl group on the cycloalkyl nucleus /, a lower alkoxy group, a (lower alkoxy) carbonyl- (lower alkoxy) group, a benzoyl- (lower alkoxy) group or a group  EMI166.2  (lower alkanoyl) oxy- (lower alkoxy) 4 is a hydrogen atom, a phenylsulfonyl group (which may have, as substituents, lower alkyl groups or halogen atoms), a lower alkyl group, a phenyl- may carry, as substituents, atoms on the phenyl nucleus), or a group of formula-COR5 / in which R5 is a lower alkyl group (which may carry,  as substituents, an amino group or a phenyl- (lower alkoxy) carbonylamino group), a cyclo- group  <Desc / Clms Page number 167>  alkyl (which may bear, substituent, an amino- (lower alkyl) group or a phenyl- (lower alkoxy) carbonyl-amino- (lower alkyl) group, on the cycloalkyl ring), a phenyl group (which may bear 1 with 3 substituents chosen from a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group and a hydroxyl group, on the phenyl ring), a phenyl- (lower alkyl) group , (which can carry, as substituents, halogen atoms on the phenyl nucleus),  or a penta-or hexagonal unsaturated heterocyclic ring having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (said heterocyclic ring may have lower alkyl groups as substituents); RU is a hydrogen atom or a phenylsulfonyl group (which may bear, as substituents, lower alkyl groups or halogen atoms);  EMI167.1  A is a lower alkylene group n is 0 or 1;  EMI167.2  the carbon-carbon bond indicated by-C --- C. of the side chain of formula CO cop- - (A) -CHC \. Lli.  R R  EMI167.3  denotes a single or double carbon-carbon bond; the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton is a single or double bond; the substitution position of the lat chain. formula rale  EMI167.4  is any of the positions 3,4, 5, 6,7 or 8 of the  <Desc / Clms Page number 168>  carbostyryl skeleton.  (b) New carbostyryl derivative represented by the general formula:  EMI168.1  wherein R is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl- (lower alkyl) group;  EMI168.2  2 is a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a halogen atom, or a benzoyloxy group (which may carry halogen atoms as substituents);  EMI168.3  Q is a hydroxyl rump, a halogen atom, an oxy group (lower alkanoyl) or a group 1  EMI168.4  of formula  EMI168.5    EMI168.6  / 4 b / in which and are alkyl groups when A is a lower alkylene group;  is a lower alkanoyl group when n is 0 or; the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton is a single or double bond;  EMI168.7  the substitution position of the side chain of formula- (A) -CH-R is any one of the positions n 2 1 3, 4, 5, 6, 7 or 8 of the carbostyryl skeleton.  2. New carbostyryl derivative, characterized in that it is represented by the general formula  <Desc / Clms Page number 169>    EMI169.1    1 2 3 4 in which R, R, R, R, A, n, the carbon-carbon bond of the side chain, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton and the substitution substitution position the side chains are as defined in claim 1 (a) above.  3. New carbostyryl derivative, characterized in that it is represented by the general formula  EMI169.2    EMI169.3  123 in which R, R, RA, n and the carbon bond ne of the side chain and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton, and the position of substitution of the side chain are as defined in claim 1 (b).  4. Carbostyryl derivative according to claim 2, characterized in that n is equal to 0.  5. Carbostyryl derivative according to claim 2, characterized in that n is equal to 1.  6. Carbostyryl derivative according to claim 4, characterized in that R is a hydrogen atom.  7. Carbostyryl derivative according to claim  EMI169.4  Q 4, characterized in that it is a phenylsulfonyl group (which may bear, as substituents, lower alkyl groups or halogen atoms).  <Desc / Clms Page number 170>    8. Carbostyryl derivative according to claim 6, characterized in that R3 is a hydroxyl group.  9. Carbostyryl derivative according to claim 6, characterized in that R3 is a lower alkoxy group, a (lower alkoxy) carbonyl- (lower alkoxy) group, a benzoyl- (lower alkoxy) group or an oxy (lower alkanoyl) group - (lower alkoxy).  10. Carbostyryl derivative according to claim 6, characterized in that R3 is an amino group "which can carry, as substituent, a cycloalkyl- (lower alkyl) group (which can carry, as substituents, a carboxy group or a group (lower alkoxy) carbonyl on the cycloalkyl ring) -7.    11. Carbostyryl derivative according to claim 8 or 9 or 10, characterized in that R4 is a hydrogen atom.  12. Carbostyryl derivative according to one of claims 8,9 and 10, characterized in that R4 is a lower alkyl group, a phenyl- (lower alkyl) group (which may carry, as substituents, halogen atoms on the phenyl ring), or a phenylsulfonyl group (which may carry, as substituents, lower alkyl groups or halogen atoms).  13. Carbostyryl derivative according to claim 8, characterized in that R4 is a group of formula -COR (in which R5 is as defined in claim 1).  14. Carbostyryl derivative according to claim 9, characterized in that R4 is a group of formula  EMI170.1  5 5 -COR (in which is as defined in claim 1).  15. Carbostyryl derivative according to claim 10, characterized in that R4 is a group of  EMI170.2  5-COR formula 16. Carbostyryl derivative according to claims 13 or 14, characterized in that R5 is a group  <Desc / Clms Page number 171>  phenyl (which can bear 1 to 3 substituents chosen from a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group and a hydroxyl group, on the phenyl ring).  17. Carbostyryl derivative according to claim 16, characterized in that R5 is a phenyl group having 1 to 3 halogen atoms as substituents on the phenyl ring.  18. Carbostyryl derivative according to claim 13 or 14, characterized in that R5 is a cycloalkyl group (which may carry, as substituents, an amino- (lower alkyl) group or a phenyl- (lower alkoxy) carbonylaminoyalkyl group), on the cycloalkyl ring).  19. Carbostyryl derivative according to the claim  EMI171.1  tion 13 or 14, in that is a lower alkyl group (which may bear, as substituents, an amino group or a phenyl- (lower alkoxy) carbonylamino group).  20. Carbostyryl derivative as claimed  EMI171.2  2 cation 16, characterized in that is a hydrogen atom.  21. Carbostyryl derivative as claimed  EMI171.3  2 cation 16, in that is a hydroxyl group, a lower alkyl group, a benzoyloxy group (which may have halogen atoms as substituents), a halogen atom or a lower alkoxy group.  22. Carbostyryl derivative according to claim 20, characterized in that R is a hydrogen atom or a lower alkyl group.  23. Carbostyryl derivative according to claim 20, characterized in that R is a lower alkenyl group, a lower alkynyl group or a phenyl- (lower alkyl) group.  24. Carbostyryl derivative according to claim 21, characterized in that the substituted position  <Desc / Clms Page number 172>  of the side chain of formula  EMI172.1  is position 3 or 4 of the carbostyryl skeleton.  25. Carbostyryl derivative according to claim 22, characterized in that the substituted position of the side chain of formula  EMI172.2  is position 3 or 4 of the carbostyryl skeleton.  26. Carbostyryl derivative according to claim 22, characterized in that the substituted position of the side chain of formula  EMI172.3  is position 5, 6,7 or 8 of the carbostyryl skeleton.  27. Carbostyryl derivative according to claim 23, characterized in that the substituted position of the side chain of formula  EMI172.4  is position 3 or 4 of the carbostyryl skeleton.  EMI172.5   28. Carbostyryl derivative according to claim 1, characterized in that the carbon-  EMI172.6  carbon of-CH --- C'de Il of formula p3 Ur, Il - n 4 "Ra  EMI172.7  is a simple bond.  <Desc / Clms Page number 173>    EMI173.1   29. Carbostyryl derivative according to claim 25, characterized in that the carbon-  EMI173.2  carbon of-CH - C the side chain of formula coa3 COR3 (A) (-cc \ o il.  EMI173.3  is a simple bond. 30. of carbostyryl according to claim 27, characterized in that the carbon-carbon bond  EMI173.4  de-CH --- C of the side chain - of formula, - (A), - CHc ,, rJ-R "  EMI173.5  is a simple bond. 31. Carbostyryl derivative according to claim 25, characterized in that the carbon-  EMI173.6  carbon of -CH --- C the side chain of formula COR - (A) n R \  EMI173.7  is a double bond. 32. Carbostyryl derivative according to claim 29, characterized in that the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton is a double bond. 33. of carbostyryl according to claim 30, characterized in that the carbon-carbon bond between positions 3 and 4 of the skeleton of  <Desc / Clms Page number 174>  carbostyryl is a double bond.  34. Carbostyryl derivative according to claim 29, characterized in that the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton is a single bond.  35. Carbostyryl derivative according to claim 30, characterized in that the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton is a single bond.  36. Carbostyryl derivative according to claim 17, characterized in that R2 is a hydrogen atom, R is a hydrogen atom or a lower alkyl group, and the substituted position of the side chain of formula  EMI174.1  is position 3 or 4 of the carbostyryl skeleton.  37. Carbostyryl derivative as claimed  EMI174.2  cation 35, characterized in that the carbon-  EMI174.3  carbon of-CH --- C the side chain - 'of formula crut - (A) -CrC N-R -  EMI174.4  is a single bond and the carbon bond between positions 3 and 4 of the carbostyryl backbone is a double bond.  38. Carbostyryl derivative as claimed  EMI174.5  cation 35, characterized in that the carbon-  EMI174.6  carbon of-CH --- C the side chain - of formula CCR - CA) li- \ R  <Desc / Clms Page number 175>  is a single bond, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl backbone is also a single bond.  39. 2- (4-Chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid.  EMI175.1   40. 2-Methyl-2-propionic acid.  41. 2- (4-Chlorobenzoylamino) -3- (1-ethyl-2-quinolone-4-yl) propionic acid.  42. 2-Benzoylamino-3- (1-ethyl-2-cuinolone-4-yl) -propionic acid.  43. Process for the preparation of a carbostyryl derivative corresponding to the following general formula:  EMI175.2  wherein R is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl- (lower alkyl) group; R2 is a hydrogen atom, a halogen atom, a benzoyloxy group (which may carry halogen atoms as substituents), a hydroxyl group, a lower alkyl group or a lower alkoxy group;    R3 is a hydroxyl group, an amino group Z which can carry, as a substituent, a cycloalkyl- (lower alkyl) group (which can carry, as substituents, a carboxy group or a (lower alkoxy) carbcnyl group on the cycloalkyl ring) / , a lower alkoxy group, a (lower alkoxy) carbonyl- (lower alkoxy) group, a benzoyl- (lower alkoxy) group or a (lower alkanoyl) oxy- (lower alkoxy) group;    <Desc / Clms Page number 176>    EMI176.1  4 is a hydrogen atom, a phenylsulfonyl group (which may bear, as substituents, lower alkyl groups or halogen atoms), a lower alkyl group, a phenyl- (lower alkyl) group (which may carry, as substituents, halogen atoms on the phenyl ring), or a group of formula-COR5 / in which R5 is a lower alkyl group (which may have, as substituents, an amino group or a phenyl- (lower alkoxy) group carbonylamino), a cycloalkyl group (which may bear, as a substituent, an amino-lower alkyl group) or a phenyl- (lower alkoxy) carbonyl-amino- (lower alkyl) group, on the 2nd cycloalkyl ring), UD phenyl group ( which can carry 1 to 3 substituents chosen from a halogen atom,  a lower alkyl group, a lower alkoxy group, a nitro group, an amino group and a hydroxyl group, on the phenyl ring), a phenyl- (lower alkyl) group, (which may bear, as substituents, atoms of halogen on the phenyl ring), or a penta-or hexagonal unsaturated heterocyclic ring having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (said heterocyclic ring may have lower alkyl groups as substituents) g; R is a hydrogen atom or a phenylsulfonyl group (which may bear, as substituents, lower alkyl groups or halogen atoms);  EMI176.2  A is a lower alkylene group n is 0 or 1;    EMI176.3  the carbon-carbon bond indicated by-C --- C the side chain of formula. - n \ 1 &commat; R il \ R0; denotes a single or double carbon-carbon bond; the carbon-carbon bond between positions 3 and 4  <Desc / Clms Page number 177>  carbostyryl backbone is a single or double bond; the substitution position of the side chain of formula  EMI177.1  is any one of the positions 3,4, 5,6, 7 or 8 of the carbostyryl skeleton, characterized in that a compound corresponding to the general formula is reacted B-NH-R0 in which B is a group of formula,  EMI177.2    EMI177.3  123 (in which R,, and the carbon-carbon bond indicated by-CH - C the chain 'l a-% side, and carbon-carbon between positions 3 and 4 of the carbostyryl skeleton are identical to the definition given above ;  and the substitution position of the side chain of formula,  EMI177.4  is any one of the positions 3,4, 5,6, 7 or 8 of the carbostyryl skeleton, or a symbol E- (in which  <Desc / Clms Page number 178>  E is a substituted cyclo (lower alkyl) -lower alkyl group, the cycloalkyl group possibly carrying as a substituent a carboxy or lower alkoxy carbon group) J, with a compound of general formula, D-COOK In which D has a given meaning for R5 or is a group of formula,  EMI178.1    EMI178.2  1 2 4 0 (in which R, R, R, R, A, n, the carbon bond (in which RR, R-crone indicated by-CH --- C / in the side chain, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above;  and the substitution position of the side chain of formula,  EMI178.3  is any one of the positions 3,4, 5,6, 7, 8 of the carbostyrylet skeleton 7, provided that when the symbol B is a group of formula,  EMI178.4    <Desc / Clms Page number 179>  D has one of the meanings given for R5; or alternatively when the symbol B has one of the meanings given for the symbol E, D is a group of formula,  EMI179.1   44.  Process for the preparation of a carbostyryl derivative corresponding to the following general formula:  EMI179.2    EMI179.3  1 2 4 0 / in which R, R, R, A, n, the carbon- RCarbone indicated by -CH --- C in the side chain, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above; and the substitution position of the side chain of formula,  EMI179.4  is any of the positions 3,4,5,6,7 or 8  EMI179.5  carbostyryl skeleton;  I R31 is a lower alkyl group, a (lower alkoxy) carbonyl (lower alkyl) group, a benzoyl group  <Desc / Clms Page number 180>  lower alkyl or an (lower alkanoyl) oxy lower alkyl group, characterized in that a compound of general formula is reacted,  EMI180.1    EMI180.2  1 2 4 0 S where R, A, n, the carbon-carbon bond indicated by -CH --- C in the side chain, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined  EMI180.3  above; and the chain substitution position  EMI180.4  CL-OH - -CHC R R  EMI180.5  is any one of positions 3, 4, 5, 6, 7, 8 of the carbostyryl skeleton 7, with a compound corresponding to the general formula, R3'-OH / in which z is as defined above 7.  45. Process for the preparation of a carbostyryl derivative corresponding to the general formula,  EMI180.6    EMI180.7  r / in which A, n, the carbon-carbon bond R, indicated by -CH --- C in the side chain, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above.  <Desc / Clms Page number 181>  above ; and the substitution position of the side chain of formula,  EMI181.1  is any one of the positions 3,4, 5,6, 7 or 8 of the carbostyryl skeleton, characterized in that a compound corresponding to the general formula is hydrolyzed,  EMI181.2    EMI181.3  / in which R, A, n, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above;  R is a group of formula,  EMI181.4    EMI181.5  (wherein and are each a lower alkyl group respectively; R7 is an alkanoyl group  EMI181.6  lower) or a group of formula, 3 / 'CC2 this NHR is  EMI181.7  3 4 (in which are as defined above; provided that when R3 is a hydroxyl group, R is not a hydrogen atom); and the substitution position of the side chain of formula, - (A) -R is any one of the positions 3,4, 5,6, 7 or 8  <Desc / Clms Page number 182>  of the carbostyryl skeleton.  46. Process for the preparation of a carbostyryl derivative corresponding to the general formula,  EMI182.1    EMI182.2  1 2 3 0 / in which, n, the carbon-carbon bond indicated by -CH-C. in the side chain, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above  EMI182.3  above ;  A R a halogen atom, a phenyl sulfonyl group I (which may have as substituents, lower alkyl groups), a lower alkyl group or a phenyl lower alkyl group (which may have as substituents halogen atoms on the phenyl ring); and the substitution position of the side chain of formula,  EMI182.4  and any one of the positions 3,4, 5,6, 7 or 8 of the carbostyryl skeleton, characterized in that a compound corresponding to the, general formula is reacted,  EMI182.5    <Desc / Clms Page number 183>    EMI183.1  1 2 3 0 / in which A, n, the carbon bond- 1 R, R, R R, carbon indicated by -CH --- C in the side chain, and the carbon-carbon bond between positions 3 and 4 of the carbostyryl skeleton are as defined above;  and the substitution position of the side chain of formula,  EMI183.2    EMI183.3  and any one of positions 3, 4, 5, 6, 7 or 8, of the carbostyryl skeleton 7, with a compound corresponding to the general formula, R-X 4 'in which R' is as defined above; and X  EMI183.4  an atom. halogen 7-47. Process for the preparation of a carbostyryl derivative corresponding to the general formula,  EMI183.5    EMI183.6  1 2 6 7 8 / in which and the link R, R If R R R, A, n, carbon-carbon between positions 3 and 4 of the carbostyryl skeleton are as defined above;  EMI183.7  and the substitution position of the side chain  EMI183.8  of formula, cr'C r '"n'8. \ CCR \ C (CD8, L L  EMI183.9  is any one of positions 3, 4, 5, 6, 7 or 8 of the carbostyryl7 skeleton,  <Desc / Clms Page number 184>    EMI184.1  characterized by reacting a compound corresponding to the formula  EMI184.2    EMI184.3  / in which R, R, carbon-carbon Z in which R R A, n, and la-L between positions 3 and 4 of the carbostyryl skeleton are as defined above; X is a halogen atom and the substitution position of the side chain of is any one of positions 3, 4, 5, 6, 7 or 8 of the carbostyryi-ej skeleton, with a compound corresponding to the general formula ,  EMI184.4    EMI184.5  6 7 8 and are as defined above- 48.  Pharmaceutical composition having in particular an activity in the treatment of peptic ulcers, characterized in that it contains a type of active principle a carbostyryl derivative as claimed in claim l (a).