CA1038876A - Benzocycloheptathiophene derivatives - Google Patents
Benzocycloheptathiophene derivativesInfo
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- CA1038876A CA1038876A CA211,060A CA211060A CA1038876A CA 1038876 A CA1038876 A CA 1038876A CA 211060 A CA211060 A CA 211060A CA 1038876 A CA1038876 A CA 1038876A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
- C07D333/80—Seven-membered rings
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
BENZOCYCLOHEPTATHIOPHENE DERIVATIVES
Abstract of the Disclosure This invention provides new compounds of formula I, I
wherein R1 is hydrogen, halogen of atomic number from 9 to 35 or lower alkyl, R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, or R3 and R4 together are oxygen, n is 2, 3 or 4, and A is ethylene or vinylene, useful as antiphlogistics and anti-arthritics.
Abstract of the Disclosure This invention provides new compounds of formula I, I
wherein R1 is hydrogen, halogen of atomic number from 9 to 35 or lower alkyl, R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, or R3 and R4 together are oxygen, n is 2, 3 or 4, and A is ethylene or vinylene, useful as antiphlogistics and anti-arthritics.
Description
-. Case 100-4089 1~)315 876 : BENZOCYCLOHEPTATHIOPHENE DERIVATIVES
The present invention relates to new hetero-cyclic compounds.
In acsordance with the invantion there are provided new compounds of formula I, ( CH ~ ) n-COOR2 ,' ' X
S wherein Rl is hydrogen, halogen of atomlc number from 9 to 35 or lower alkyl, R2 is hydrogen or lower alkyl, each of R3 and P~4 is hydrogen, or R3 and R4 together are oxysen, n is ~, 3 ox 4, and A is ethylene or vinylene.
.
Further, in accordance wlth the invention a compound of formula I may be obtained by a process comprising a) reacting a compound of formula II, .
"~
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.~ ' ` ~038~76
The present invention relates to new hetero-cyclic compounds.
In acsordance with the invantion there are provided new compounds of formula I, ( CH ~ ) n-COOR2 ,' ' X
S wherein Rl is hydrogen, halogen of atomlc number from 9 to 35 or lower alkyl, R2 is hydrogen or lower alkyl, each of R3 and P~4 is hydrogen, or R3 and R4 together are oxysen, n is ~, 3 ox 4, and A is ethylene or vinylene.
.
Further, in accordance wlth the invention a compound of formula I may be obtained by a process comprising a) reacting a compound of formula II, .
"~
.
.~ ' ` ~038~76
2 - 100-4089 .
, ~/ II
wherein Rl, R3, R4 and A are as defined above, , . .
` ' with a compound o. formula III, ,, .
X-co-(cH2)n-co-o-y III
wherein n is as defined above, X i5 chlorine or bromtne, and Y .ts lower alkyl, or X and Y together form a bond, or b) hydrolyzing a compound of formula Ib, i I r Rl [~ C- 1 CH 2 ) 1~ CoOR2 .'` ~< .
whereln Rl, R3, R4, A and n ale as defined above, and R2 is lower alkyl, to produce a compound of foxmula Ia, ~' .~
, ~/ II
wherein Rl, R3, R4 and A are as defined above, , . .
` ' with a compound o. formula III, ,, .
X-co-(cH2)n-co-o-y III
wherein n is as defined above, X i5 chlorine or bromtne, and Y .ts lower alkyl, or X and Y together form a bond, or b) hydrolyzing a compound of formula Ib, i I r Rl [~ C- 1 CH 2 ) 1~ CoOR2 .'` ~< .
whereln Rl, R3, R4, A and n ale as defined above, and R2 is lower alkyl, to produce a compound of foxmula Ia, ~' .~
3~1~76 ~ 3 ~ 100-4089 Rl~ ~S~ (c}l2)n-coQH
4 3 wherein Rl, R3, R4, A and n are a~ defined above.
In the compounds of formula I R1 preferably si~nifies hydrogen or chlorine. R1 is preferably present ~- ~ in the 6 or 7 position of the rin~ structure. I~hen Rl i8 lower alk~l, this preferably contains 1 to ~ carbon atoms and ~specially signifies methyl. 'rh~ substituent R2 p~eferably slcJnifies hydrog~n. When R2 is lower alkyl, this contains, for example, 1 to ~ car~on atoms and especially si~nifies meth~l or ethyl. R3 and R4 to~ether preferably signify oxygen, and n preferably deno~es 2.
Any carbon-conta:ining radical not particularly define~ herein preferably has up to S carbon atoms.
; The reaction of a compound of formula II with a compound of formula IlI in ~ccordance with process variant a) is preferably effected in th~ presence o an acid condensation a~ent. In accordance with a preferred method of the process the react~on may, for example, be effected in the pre~ence of a Lewis acid in an inert or~anic ~olvent, e.g. a chlorinated hydrocarbon such as 3~76 - 4 - 100-~089 methylene chloride or tetrachloroethane, or in carbon disulphide. A Friedel-Crats reaction may be used.
Examples of suitable Lewis acids are .
aluminium trichloride or tin tetrachloride. The re,action of a compound of formula II wit:h a compound of formula III may alternatively be effected in the presence of a strong mineral acid, e.g. polyphosphoric acid or ' phosphoric acid, There may be present an inert organic solvent, e.g. a hydrocarbon such as benzene, toluen~, xylene or tetraline. When the r~action is effec~ed in ~he pre.sence of a I,ewis ac.id, the reaction temperature pre~'erably .is between .r:oom tempf.3r~
; ature and the boiling temperature of the reacti.on mixture.
~ - The reaction in the presence of a strong mineral acid is preferably e:Efected at a '.emperature bet~een about 50 and 150~C. ~ Ir.
the case of the reaction i.n the presence of a strong mineral acid any ester groupings -COOR2 , which may be pr~sent, may be simultaneously hydrolyæed, so that com~
pounds of formula Ia are obtained.
The hydrolysis of an ester of formula Ib in accordance with process variant b) may be effected in accorclance with the usual methods for es~er hydrolysis.
For example, a compound of formula Ib may be hydrolyzed
In the compounds of formula I R1 preferably si~nifies hydrogen or chlorine. R1 is preferably present ~- ~ in the 6 or 7 position of the rin~ structure. I~hen Rl i8 lower alk~l, this preferably contains 1 to ~ carbon atoms and ~specially signifies methyl. 'rh~ substituent R2 p~eferably slcJnifies hydrog~n. When R2 is lower alkyl, this contains, for example, 1 to ~ car~on atoms and especially si~nifies meth~l or ethyl. R3 and R4 to~ether preferably signify oxygen, and n preferably deno~es 2.
Any carbon-conta:ining radical not particularly define~ herein preferably has up to S carbon atoms.
; The reaction of a compound of formula II with a compound of formula IlI in ~ccordance with process variant a) is preferably effected in th~ presence o an acid condensation a~ent. In accordance with a preferred method of the process the react~on may, for example, be effected in the pre~ence of a Lewis acid in an inert or~anic ~olvent, e.g. a chlorinated hydrocarbon such as 3~76 - 4 - 100-~089 methylene chloride or tetrachloroethane, or in carbon disulphide. A Friedel-Crats reaction may be used.
Examples of suitable Lewis acids are .
aluminium trichloride or tin tetrachloride. The re,action of a compound of formula II wit:h a compound of formula III may alternatively be effected in the presence of a strong mineral acid, e.g. polyphosphoric acid or ' phosphoric acid, There may be present an inert organic solvent, e.g. a hydrocarbon such as benzene, toluen~, xylene or tetraline. When the r~action is effec~ed in ~he pre.sence of a I,ewis ac.id, the reaction temperature pre~'erably .is between .r:oom tempf.3r~
; ature and the boiling temperature of the reacti.on mixture.
~ - The reaction in the presence of a strong mineral acid is preferably e:Efected at a '.emperature bet~een about 50 and 150~C. ~ Ir.
the case of the reaction i.n the presence of a strong mineral acid any ester groupings -COOR2 , which may be pr~sent, may be simultaneously hydrolyæed, so that com~
pounds of formula Ia are obtained.
The hydrolysis of an ester of formula Ib in accordance with process variant b) may be effected in accorclance with the usual methods for es~er hydrolysis.
For example, a compound of formula Ib may be hydrolyzed
- 5 - 100-40~9 ~1~38876 in the presence of a base, e.g. an alkali metal or alkaline earth metal hydroxide, or in the presence of an acid catalyst, e.CJ~ a mineral acid such as hydxochloric : acid or sulphuric acid, or an organlc sulphonic acid. The hydrolysis may be effected at a temperature between room temperature and about lOO~C:. An inert water-miscible organic solvent may be present. ~ The hydrolysis is preferably effected in an alkallne medium, e.g. with at least an equivalent amount of an aqueous alkall metal hydroxide so1ution at room temperature o~
a~ a sli~htly eleva~ed temperatu.re. Examples c)f organi.c solvents which may be present are lower alcohols, ac~etone or cycllc ethers such as tetrahy~ro-furan or dloxane.
Tne compounds of formula I may be lsolated from th~ reaction mixture and pur.ified in known manner.
F.ree acid forms of formula Ia may be converted into salt forms thereof and Vi ersa. A suitable salt is the sodi~ salt.
'rhe compounds of formula IIa, 1 ~ i IIa H H
wherein Rl and A are as defined above, used as starting materials, may, for example, be obtained by reducing a compound of formula II_, r~
a~ a sli~htly eleva~ed temperatu.re. Examples c)f organi.c solvents which may be present are lower alcohols, ac~etone or cycllc ethers such as tetrahy~ro-furan or dloxane.
Tne compounds of formula I may be lsolated from th~ reaction mixture and pur.ified in known manner.
F.ree acid forms of formula Ia may be converted into salt forms thereof and Vi ersa. A suitable salt is the sodi~ salt.
'rhe compounds of formula IIa, 1 ~ i IIa H H
wherein Rl and A are as defined above, used as starting materials, may, for example, be obtained by reducing a compound of formula II_, r~
- 6 - ~ 100~4089 ~03~3~376 1 C ~ ! 3 IIb wherein Rl and A are as def.ined above.
The reduction may, for example, be ef~ected in accord-ance with Cle~nensen with ama.lgamated zinc/hydrochloric acid, cr, when A is an e~hylene ~roup, also by treatme.nt .~ 5 wi.th sodtumJalcohol.
Insofar as the production of the starting nlaterials is not descri.bed, these are known or may be produced ~n acco~clallce w.tth known processe.s, or in a manner analogous to the processes described here:ln or to known proc~sses.
In the followi.ng non l.tmi.tative Examples ali temperatur~s are indicated in degrees Cent.igrade.
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~ - 7 - 100-40~9 ` 1~38~76 EX~MPLE lo 4-(9,10-clih~lro-4E _enzo~4,5IcYclohePta ]thiophen-2-Y.ll-~-oxobutYric acid ll.o g of succinic acid anhydride are dissol~ed in 220 cc of anhydrous methylene chloride with heating, the resulting solution is cooled to 20 and 30 g of aluminium chloride are added portionwis~. ~fter stirring for 15 minutes at room temperature, a solution o 22.0 g o~ 9,10-dihydro-4~-benzoC~,5]cyclohepta[1,2~b~^-thiop~erle in 100 cc of cmhyc'~ous methylene c~h~o.rid~ is ~0 added dropwise within 30 m:inutes, the result~ g mixture .is stlrred for a furt'her 45 rtlinutes at room ~emperature and i~ poured on a mi.xture oE 200 cc of concentrated hydrochloric acid and 200 g of i.ce. Aft.er add:ing 300 cc of methylene chloride, the entire mixtuxe is heated for 15 r.~inutes Gn a water bath, is cooled, the methylell~
chlori.de is rernoved and the aqUeOII~ phase is ~urther ex-tracted with methylene c'hloride. ~'he acidlc porti.orl is extracted rom~he col~bined met'hylene chlo~ide so~utions with 0.5 normal caustic soda, the basic extract is acidif.ied with 5 ~ hydrochloric acid and extracted wi.th chloroform. The chloroform solutions are washed with water, dried over magnesium sulphate, filtered through active charcoal and evaporated to dryness. The title compound, obtainea as solid residue, is recrystallized - - 8 - 1~0-~089 ~0;~8~7~;
; from dimethyl formamide/acetone. M~P. 202 to 203.
The starting material may be obtained as follows:
25.0 g of sodium are added portionwise to a solution of 25.0 g of 9,10-dihyc~o-4H-benzo~4,5~c~clo-he.pta~l,2-b~thiophen-4-one in 280 cc o~ anhydrous ethanol. After all the material is di.ssolved, the reaction mixture i.s heated to the boil for 2 y2 hours and the solvent is evaporated at reduced pressure. 500 cc of i~e water and 200 CC! of me~.hy.~ene chloride ~re slowly ; added to the evapo.ratioxl.re~iclue, the org~lnic p~as~ .iJ
sepclrated and the ac~ueous solution is again ext:racted with methy:Lene chlo~ide. The co~ined or~anic! solutions a~e washed with water until neutral, c~ri.ed over sodium su:Lphate and concentrated by evaporat.ion. The residue i.s crystallized ~rom ethanol. ~.P. of 9,lO~dihydro-4H-benzo[4,5lcyclohep-ta[1,2-blthiophene: 117 to ].19.
; EX~MPLE 2. 4 ~9,10-_ih~d~o _ o o-4H=benzo~4,5~-~yclohepta~1,2-b]thiophe~ oxobut~-.ic acid The title compound, having a M.P. of 167 to 168 ~from ethanol/ether), is obtained by the process ~- ~ 9 ~ 100-408 1~38876 described in Example 1, from 12.2 g of succinic acid anhydride, 30 g of aluminium chlori.de and 15.0 g o 9,10-dihydro-4H-benzo[4,5 I cyclohepta~l,2-bIthiophen-4-one i-n 320 cc of anhydrous methylene chloride.
_XAMP~E 3: 5-(4-oxo-4H-benzo~4,5¦cyclohepta Ll ,2 bl-thiophen-2-yl)-5 oxovaleric acid .
'The title compound, having a M.P. of 149 to 151, (recr~stallizecl twice ~rom acetone) is obtained by the proce~s described in Example 1, ~rom 13.0 ~ o lQ glutaric acid anhydride, 30 g of aluminium chloride and 15.0 g of 4E-benzo[4,5¦cyclohepta~1,2-b¦thiophen~4-one in 350 cc of anhydrous methylene chloride~
. The following ~H-~enzor~,51cyclohepta-~1,2-bIt.hiophen-2-yl)oxocarboxylic acid derivatives may also be obtai.ned in a manner analogous to that described in Example 1, by reaction of the corresponding 4H-benzo-~4,5Icyclohepta~1,2-bIthiophene derivatives with the corresponding dicarboxylic acid anhydrideso - 10 - 100-408~
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~11 ~ ~i r-i r-i ~I r-i ~ 100-4089 1(~3~876 EX~MP~E 15: 4-(9,10-dih~dro-4-oxo-4H-benzo~,5l-- cyclohepta~l,2-b~thiophen-2-yl)-4-oxo-butyric acid methyl ester A solution of 6.3 cc of succinic acid ~ 5 monomethyl ester chloride in 100 cc of anhydrous car~on ; disulphide is added dropwise at 0 to a suspension of 10.0 g of 9,10-dihydro-4H-benzo~4,5lcyclohepta~1,2-b]-thiophen-4-one and 30.0 g of anhydrous aluminium chloride in 200 cc o~ anhydrous carbon disulphide, the reaction mixturc~ is skirred fox a further 6 hours at room tem-perature, 23.3 g of tin tetrachloride are added dropwise thereto at 20 to 25 and stirring is continued at room temperature for 15 hours. The reaction mixture is su~-seguently heated to 50 for 2 hours, cooled, poured on 500 cc. . of 5 N hydrochloric acid and extracted with chloroform. The organic phases are washed with 5 ~
hydrochloric acid and w.ith water, dried over magnesium sulphate and concentrated by evaporation. The evapora-tion residue is dissolved in 300 cc of methylene ch~oride, filtered through silica gel and evaporated to dryness.
The title compound crystalli.zes from benzene/petroleum ether and is recrystallized once from ether. M.P.
97 - ~8.
~ - 12 - 1~0-4089 1~3~87~i EXRMPLE 160 4-(4-oxo-4H-benzoL4,5¦cyclo~epta~1,2 b~-thiophen-2-yl3-4~ogobutyric acid methyl ester The title compound is produced in a manner analogous to that described in E,xample 1, from 10.0 g of 4H-benzoC4,5lcyclohepta[1,2-b]thiophen-4-one, 30.0 g of anhydrous aluminium chloride and 23.3 g of tin tetrachloride and 6.3 cc of succinic acid monomethyl ester chloride in 300 cc of anhydrous carbon disulphide;
the title compound is recrystall.ized from ether. M.P.
1~ - 145.
.
; The following (4H-b~rlzoC4~5lcyclohepta-[1,2-b]thiophen-2-yl)oxocarboxylic acid es-ter deriva-tives ma~ also be obtained in a manner analogous to that , 15 described in Example 15 or 16, by reaction of the corres-ponding 4H-benzo[4,5~cycloheptaC1,2-blthiophene deriva-tives with the corresponding dicarboxylic acid mono-alkyl ester halideso .;
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~38876 ~X~MP~E 26: 5-(4-oxo-4H-benzo[4,~1cyclohepta~1,2-b¦-thiophen-2-yl)-5-oxovaleric acid A mixture of lO.O g of 4H-benzot4,5~-cyclohepta[l,2-b]thiophen-4-one, 6.3 cc of succinic ; 5- acid monomethyl ester chloride and 80 g of polyp~osphoric acid is first stirred or one hour at 80 and then for 3 hours at 120-130, is cooled to 90, 100 cc of water are added thereto and stirring is continued at the same temperature for a further hour. After cooling to room temperature, the reaction mixture is pouxed on 400 cc of ice water, is extracted with methylene chloride, the organlc solutions are washed with water, dried over sodium sulphate and concentrated by evaporation. The title compound is crystallized 'rom the evaporation resi-due with acetone and is recrystallized once. M.P. 149-151.
EX~MPLE 27: 4-(9,lO-dihYdro-4-oxo-4H-banzo~4~5l-cyclohepta[l,2-blthiophen-2-Yl~-4-oxo-butYric acid [process variant b)~
A solution of 3.0 g of 4-(9,10-dihydro-4-oxo-4H-benzo[4,51cycloheptal1,2-blthiophen-2-yl)-4-oxobutyric acid methyl est~r and l.S g of potassium , - .
. - 15 - 100-~089 1~)38876 hydroxide in 60 cc of dioxane and 30 cc o~ water is stirred at room temperatuxe for 3 hours, dilution is effected with 200 cc of water ancL the pH of the solution is adjusted to 1 with concentrated hydrochloric acid at 10 - 15. The resulting title compound is extracted with methylene chloride, the organic solution i~ washed with water, dried over magnesium sulphate, concentrated by evaporation, and the title compound is recrystallized from dimethyl formamide/acetone. M.P. 1.67-168.
The (4H-benzo~,51cyclo~epta~1,.2~b}-th.iophen-2-yl)oxocarboxylic acid derivatives described in Examples 1 to 14 may also be obtained in a manner analogous to that described in Example 27, ~y hydrol~sis of the corresponding (4H-benzo~4,5]cyclohepta~1,2-b¦-thiophen-2-yl)oxocarboxylic acid l~wer alkyl ester derivatives which may be produced in accordance with Example 15 or 16.
~38~76 The compounds of formula I exhibit pharmacological activity. In particular the compounds exhibit anti-phlogistic activity, as indicated in standarcl tests, for example by an inhibition of oedema formation in the carrageen paw oedema test in rats. and in the subchronic granuloma cyst test in rats.
The compounds are therefore indicated for use as anti-phlogistic agents.. For this use an indicated daily dose is from about 100 to about 1000 mg~ conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 25 to about 500 mg, or in sustained release form.
Additionally the compounds exhibit anti-arthritic activity, as indicated in standard tests, for example in the Freund adjuvant arthritis latent period test in rats by an inhibition of swelling.
The compounds are therefore further-indicated for use as anti-arthritis agents. For this use an indicated daily dose is from about 100 to about 1000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 25 about 500 mg, or in sustained release form.
Compounds of formula I wherein Rl is hydrogen may alternatively be administered _ _ ~ 3~3~376 in pharmaceutically acceptable salt form. Such salt forms exhibit the same order of activity as the free forms and are readily prepared in conventional manner.
; The present invention provides pharmaceutical composition comprising a compound of formula I in free form or, when it is a compound of formula I
wherein R2 is hydrogen, alternatively in pharma-ceutically acceptable salt form~ in association ~ith a pharmaceutical carrier or diluent. Such compositions may be in the form of~ for example~ a solution or a tablet.
In a group of compounds Rl is in the 6 or
The reduction may, for example, be ef~ected in accord-ance with Cle~nensen with ama.lgamated zinc/hydrochloric acid, cr, when A is an e~hylene ~roup, also by treatme.nt .~ 5 wi.th sodtumJalcohol.
Insofar as the production of the starting nlaterials is not descri.bed, these are known or may be produced ~n acco~clallce w.tth known processe.s, or in a manner analogous to the processes described here:ln or to known proc~sses.
In the followi.ng non l.tmi.tative Examples ali temperatur~s are indicated in degrees Cent.igrade.
--` .
~ - 7 - 100-40~9 ` 1~38~76 EX~MPLE lo 4-(9,10-clih~lro-4E _enzo~4,5IcYclohePta ]thiophen-2-Y.ll-~-oxobutYric acid ll.o g of succinic acid anhydride are dissol~ed in 220 cc of anhydrous methylene chloride with heating, the resulting solution is cooled to 20 and 30 g of aluminium chloride are added portionwis~. ~fter stirring for 15 minutes at room temperature, a solution o 22.0 g o~ 9,10-dihydro-4~-benzoC~,5]cyclohepta[1,2~b~^-thiop~erle in 100 cc of cmhyc'~ous methylene c~h~o.rid~ is ~0 added dropwise within 30 m:inutes, the result~ g mixture .is stlrred for a furt'her 45 rtlinutes at room ~emperature and i~ poured on a mi.xture oE 200 cc of concentrated hydrochloric acid and 200 g of i.ce. Aft.er add:ing 300 cc of methylene chloride, the entire mixtuxe is heated for 15 r.~inutes Gn a water bath, is cooled, the methylell~
chlori.de is rernoved and the aqUeOII~ phase is ~urther ex-tracted with methylene c'hloride. ~'he acidlc porti.orl is extracted rom~he col~bined met'hylene chlo~ide so~utions with 0.5 normal caustic soda, the basic extract is acidif.ied with 5 ~ hydrochloric acid and extracted wi.th chloroform. The chloroform solutions are washed with water, dried over magnesium sulphate, filtered through active charcoal and evaporated to dryness. The title compound, obtainea as solid residue, is recrystallized - - 8 - 1~0-~089 ~0;~8~7~;
; from dimethyl formamide/acetone. M~P. 202 to 203.
The starting material may be obtained as follows:
25.0 g of sodium are added portionwise to a solution of 25.0 g of 9,10-dihyc~o-4H-benzo~4,5~c~clo-he.pta~l,2-b~thiophen-4-one in 280 cc o~ anhydrous ethanol. After all the material is di.ssolved, the reaction mixture i.s heated to the boil for 2 y2 hours and the solvent is evaporated at reduced pressure. 500 cc of i~e water and 200 CC! of me~.hy.~ene chloride ~re slowly ; added to the evapo.ratioxl.re~iclue, the org~lnic p~as~ .iJ
sepclrated and the ac~ueous solution is again ext:racted with methy:Lene chlo~ide. The co~ined or~anic! solutions a~e washed with water until neutral, c~ri.ed over sodium su:Lphate and concentrated by evaporat.ion. The residue i.s crystallized ~rom ethanol. ~.P. of 9,lO~dihydro-4H-benzo[4,5lcyclohep-ta[1,2-blthiophene: 117 to ].19.
; EX~MPLE 2. 4 ~9,10-_ih~d~o _ o o-4H=benzo~4,5~-~yclohepta~1,2-b]thiophe~ oxobut~-.ic acid The title compound, having a M.P. of 167 to 168 ~from ethanol/ether), is obtained by the process ~- ~ 9 ~ 100-408 1~38876 described in Example 1, from 12.2 g of succinic acid anhydride, 30 g of aluminium chlori.de and 15.0 g o 9,10-dihydro-4H-benzo[4,5 I cyclohepta~l,2-bIthiophen-4-one i-n 320 cc of anhydrous methylene chloride.
_XAMP~E 3: 5-(4-oxo-4H-benzo~4,5¦cyclohepta Ll ,2 bl-thiophen-2-yl)-5 oxovaleric acid .
'The title compound, having a M.P. of 149 to 151, (recr~stallizecl twice ~rom acetone) is obtained by the proce~s described in Example 1, ~rom 13.0 ~ o lQ glutaric acid anhydride, 30 g of aluminium chloride and 15.0 g of 4E-benzo[4,5¦cyclohepta~1,2-b¦thiophen~4-one in 350 cc of anhydrous methylene chloride~
. The following ~H-~enzor~,51cyclohepta-~1,2-bIt.hiophen-2-yl)oxocarboxylic acid derivatives may also be obtai.ned in a manner analogous to that described in Example 1, by reaction of the corresponding 4H-benzo-~4,5Icyclohepta~1,2-bIthiophene derivatives with the corresponding dicarboxylic acid anhydrideso - 10 - 100-408~
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~11 ~ ~i r-i r-i ~I r-i ~ 100-4089 1(~3~876 EX~MP~E 15: 4-(9,10-dih~dro-4-oxo-4H-benzo~,5l-- cyclohepta~l,2-b~thiophen-2-yl)-4-oxo-butyric acid methyl ester A solution of 6.3 cc of succinic acid ~ 5 monomethyl ester chloride in 100 cc of anhydrous car~on ; disulphide is added dropwise at 0 to a suspension of 10.0 g of 9,10-dihydro-4H-benzo~4,5lcyclohepta~1,2-b]-thiophen-4-one and 30.0 g of anhydrous aluminium chloride in 200 cc o~ anhydrous carbon disulphide, the reaction mixturc~ is skirred fox a further 6 hours at room tem-perature, 23.3 g of tin tetrachloride are added dropwise thereto at 20 to 25 and stirring is continued at room temperature for 15 hours. The reaction mixture is su~-seguently heated to 50 for 2 hours, cooled, poured on 500 cc. . of 5 N hydrochloric acid and extracted with chloroform. The organic phases are washed with 5 ~
hydrochloric acid and w.ith water, dried over magnesium sulphate and concentrated by evaporation. The evapora-tion residue is dissolved in 300 cc of methylene ch~oride, filtered through silica gel and evaporated to dryness.
The title compound crystalli.zes from benzene/petroleum ether and is recrystallized once from ether. M.P.
97 - ~8.
~ - 12 - 1~0-4089 1~3~87~i EXRMPLE 160 4-(4-oxo-4H-benzoL4,5¦cyclo~epta~1,2 b~-thiophen-2-yl3-4~ogobutyric acid methyl ester The title compound is produced in a manner analogous to that described in E,xample 1, from 10.0 g of 4H-benzoC4,5lcyclohepta[1,2-b]thiophen-4-one, 30.0 g of anhydrous aluminium chloride and 23.3 g of tin tetrachloride and 6.3 cc of succinic acid monomethyl ester chloride in 300 cc of anhydrous carbon disulphide;
the title compound is recrystall.ized from ether. M.P.
1~ - 145.
.
; The following (4H-b~rlzoC4~5lcyclohepta-[1,2-b]thiophen-2-yl)oxocarboxylic acid es-ter deriva-tives ma~ also be obtained in a manner analogous to that , 15 described in Example 15 or 16, by reaction of the corres-ponding 4H-benzo[4,5~cycloheptaC1,2-blthiophene deriva-tives with the corresponding dicarboxylic acid mono-alkyl ester halideso .;
- 13 - 100-408~1 1~338876 m 11 ,, ~11 ~ 11 ~q 1, ~ 11 8,' . Il , U , ~Q
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i - 14 - 1~0-408~
~38876 ~X~MP~E 26: 5-(4-oxo-4H-benzo[4,~1cyclohepta~1,2-b¦-thiophen-2-yl)-5-oxovaleric acid A mixture of lO.O g of 4H-benzot4,5~-cyclohepta[l,2-b]thiophen-4-one, 6.3 cc of succinic ; 5- acid monomethyl ester chloride and 80 g of polyp~osphoric acid is first stirred or one hour at 80 and then for 3 hours at 120-130, is cooled to 90, 100 cc of water are added thereto and stirring is continued at the same temperature for a further hour. After cooling to room temperature, the reaction mixture is pouxed on 400 cc of ice water, is extracted with methylene chloride, the organlc solutions are washed with water, dried over sodium sulphate and concentrated by evaporation. The title compound is crystallized 'rom the evaporation resi-due with acetone and is recrystallized once. M.P. 149-151.
EX~MPLE 27: 4-(9,lO-dihYdro-4-oxo-4H-banzo~4~5l-cyclohepta[l,2-blthiophen-2-Yl~-4-oxo-butYric acid [process variant b)~
A solution of 3.0 g of 4-(9,10-dihydro-4-oxo-4H-benzo[4,51cycloheptal1,2-blthiophen-2-yl)-4-oxobutyric acid methyl est~r and l.S g of potassium , - .
. - 15 - 100-~089 1~)38876 hydroxide in 60 cc of dioxane and 30 cc o~ water is stirred at room temperatuxe for 3 hours, dilution is effected with 200 cc of water ancL the pH of the solution is adjusted to 1 with concentrated hydrochloric acid at 10 - 15. The resulting title compound is extracted with methylene chloride, the organic solution i~ washed with water, dried over magnesium sulphate, concentrated by evaporation, and the title compound is recrystallized from dimethyl formamide/acetone. M.P. 1.67-168.
The (4H-benzo~,51cyclo~epta~1,.2~b}-th.iophen-2-yl)oxocarboxylic acid derivatives described in Examples 1 to 14 may also be obtained in a manner analogous to that described in Example 27, ~y hydrol~sis of the corresponding (4H-benzo~4,5]cyclohepta~1,2-b¦-thiophen-2-yl)oxocarboxylic acid l~wer alkyl ester derivatives which may be produced in accordance with Example 15 or 16.
~38~76 The compounds of formula I exhibit pharmacological activity. In particular the compounds exhibit anti-phlogistic activity, as indicated in standarcl tests, for example by an inhibition of oedema formation in the carrageen paw oedema test in rats. and in the subchronic granuloma cyst test in rats.
The compounds are therefore indicated for use as anti-phlogistic agents.. For this use an indicated daily dose is from about 100 to about 1000 mg~ conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 25 to about 500 mg, or in sustained release form.
Additionally the compounds exhibit anti-arthritic activity, as indicated in standard tests, for example in the Freund adjuvant arthritis latent period test in rats by an inhibition of swelling.
The compounds are therefore further-indicated for use as anti-arthritis agents. For this use an indicated daily dose is from about 100 to about 1000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 25 about 500 mg, or in sustained release form.
Compounds of formula I wherein Rl is hydrogen may alternatively be administered _ _ ~ 3~3~376 in pharmaceutically acceptable salt form. Such salt forms exhibit the same order of activity as the free forms and are readily prepared in conventional manner.
; The present invention provides pharmaceutical composition comprising a compound of formula I in free form or, when it is a compound of formula I
wherein R2 is hydrogen, alternatively in pharma-ceutically acceptable salt form~ in association ~ith a pharmaceutical carrier or diluent. Such compositions may be in the form of~ for example~ a solution or a tablet.
In a group of compounds Rl is in the 6 or
7 position of the trlcyclic ring and preferably is ; hydrogen or halogen.
4-(9~10-dihydro-4-oxo-4H-benzo~4,5~cyclo-hepta-~1,2-b~thiophen-2-yl)-4-oxobutyric acid have been found to be especially interesting.
In one group of compounds R3 and R4 are hydrogen. In another group of compounds R3 and R4 to-gether are oxygen.
4-(9~10-dihydro-4-oxo-4H-benzo~4,5~cyclo-hepta-~1,2-b~thiophen-2-yl)-4-oxobutyric acid have been found to be especially interesting.
In one group of compounds R3 and R4 are hydrogen. In another group of compounds R3 and R4 to-gether are oxygen.
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a compound of formula I, I
wherein R1 is hydrogen, halogen of atomic number from 9 to 35 or lower alkyl, R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, or R3 and R4 together are oxygen, n is 2, 3 or 4, and A is ethylene or vinylene, which comprises a) reacting a compound of formula II, II
wherein R1, R3, R4 and A are as defined above, with a compound of formula III, X-CO-(CH2)n-CO-O-Y III
wherein n is as defined above, X is chlorine or bromine, and Y is lower alkyl, or X and Y together form a bond, or b) hydrolyzing a compound of formula Ib, Ib wherein R1, R3, R4, A and n are as defined above, and R? is lower alkyl, to produce a compound of formula Ia, Ia wherein R1, R3, R4, A and n are as defined above, and, where required, converting the resulting compound into a pharmaceutically acceptable acid addition salt thereof.
wherein R1 is hydrogen, halogen of atomic number from 9 to 35 or lower alkyl, R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, or R3 and R4 together are oxygen, n is 2, 3 or 4, and A is ethylene or vinylene, which comprises a) reacting a compound of formula II, II
wherein R1, R3, R4 and A are as defined above, with a compound of formula III, X-CO-(CH2)n-CO-O-Y III
wherein n is as defined above, X is chlorine or bromine, and Y is lower alkyl, or X and Y together form a bond, or b) hydrolyzing a compound of formula Ib, Ib wherein R1, R3, R4, A and n are as defined above, and R? is lower alkyl, to produce a compound of formula Ia, Ia wherein R1, R3, R4, A and n are as defined above, and, where required, converting the resulting compound into a pharmaceutically acceptable acid addition salt thereof.
2. A process for the production of a compound of formula I, as stated in Claim 1, according to process variant a) and, where required, converting the resulting compound into a pharmaceutically acceptable acid addi-tion salt thereof.
3. A process for the production of a compound of formula Ia according to process variant b) as defined in Claim 1 and, where required, converting the resulting compound into a pharmaceutically acceptable acid addi-tion salt thereof.
4. A process according to Claim 2, for the production of a compound of formula I wherein each of R1 and R2 is hydrogen, R3 and R4 together are oxygen, n is 2 and A is -CH2-CH2-.
5. A process according to Claim 3, for the production of a compound of formula Ia wherein each of R1 and R2 is hydrogen, R3 and R4 together are oxygen, n is 2 and A is -CH2-CH2-.
6. A compound of formula I
I
wherein R1 is hydrogen, halogen of atomic number from 9 to 35 or lower alkyl, R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, or R3 and R4 together are oxygen, n is 2, 3 or 4, and A is ethylene or vinylene, whenever produced by the process of Claim 1.
I
wherein R1 is hydrogen, halogen of atomic number from 9 to 35 or lower alkyl, R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, or R3 and R4 together are oxygen, n is 2, 3 or 4, and A is ethylene or vinylene, whenever produced by the process of Claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1439673A CH581130A5 (en) | 1973-10-10 | 1973-10-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1038876A true CA1038876A (en) | 1978-09-19 |
Family
ID=4400474
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA211,060A Expired CA1038876A (en) | 1973-10-10 | 1974-10-09 | Benzocycloheptathiophene derivatives |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5082052A (en) |
| AT (1) | AT352107B (en) |
| AU (1) | AU498690B2 (en) |
| BE (1) | BE820943A (en) |
| CA (1) | CA1038876A (en) |
| DD (1) | DD113910A5 (en) |
| DE (1) | DE2441592A1 (en) |
| DK (1) | DK135809B (en) |
| ES (2) | ES430790A1 (en) |
| FI (1) | FI286574A (en) |
| FR (1) | FR2247226B1 (en) |
| GB (2) | GB1489784A (en) |
| HU (1) | HU170505B (en) |
| IE (1) | IE41615B1 (en) |
| IL (1) | IL45814A (en) |
| NL (1) | NL7413107A (en) |
| NO (1) | NO743556L (en) |
| PH (1) | PH10997A (en) |
| SE (1) | SE392272B (en) |
| SU (1) | SU548210A3 (en) |
| ZA (1) | ZA746444B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2803984A1 (en) * | 1977-02-08 | 1978-08-10 | Sandoz Ag | OXAMIC ACID DERIVATIVES, THEIR PRODUCTION AND USE |
| CN102471326B (en) * | 2009-07-28 | 2015-04-29 | 日本脏器制药株式会社 | Method for producing thiabenzoazulene propionic acid derivative |
-
1974
- 1974-08-30 DE DE2441592A patent/DE2441592A1/en not_active Withdrawn
- 1974-09-30 SE SE7412312A patent/SE392272B/en unknown
- 1974-10-01 NO NO743556A patent/NO743556L/no unknown
- 1974-10-01 FI FI2865/74A patent/FI286574A/fi unknown
- 1974-10-01 DK DK516174AA patent/DK135809B/en unknown
- 1974-10-03 PH PH16387A patent/PH10997A/en unknown
- 1974-10-04 NL NL7413107A patent/NL7413107A/en not_active Application Discontinuation
- 1974-10-08 HU HUSA2699A patent/HU170505B/hu unknown
- 1974-10-08 IE IE2090/74A patent/IE41615B1/en unknown
- 1974-10-08 DD DD181560A patent/DD113910A5/xx unknown
- 1974-10-08 ES ES430790A patent/ES430790A1/en not_active Expired
- 1974-10-09 IL IL45814A patent/IL45814A/en unknown
- 1974-10-09 ZA ZA00746444A patent/ZA746444B/en unknown
- 1974-10-09 CA CA211,060A patent/CA1038876A/en not_active Expired
- 1974-10-09 JP JP49115668A patent/JPS5082052A/ja active Pending
- 1974-10-09 AU AU74141/74A patent/AU498690B2/en not_active Expired
- 1974-10-09 SU SU2065450A patent/SU548210A3/en active
- 1974-10-09 AT AT810174A patent/AT352107B/en not_active IP Right Cessation
- 1974-10-10 FR FR7434103A patent/FR2247226B1/fr not_active Expired
- 1974-10-10 GB GB22272/77A patent/GB1489784A/en not_active Expired
- 1974-10-10 GB GB43893/74A patent/GB1489783A/en not_active Expired
- 1974-10-10 BE BE149425A patent/BE820943A/en unknown
-
1976
- 1976-07-01 ES ES449429A patent/ES449429A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2247226A1 (en) | 1975-05-09 |
| NO743556L (en) | 1975-05-05 |
| IE41615B1 (en) | 1980-02-13 |
| HU170505B (en) | 1977-06-28 |
| DD113910A5 (en) | 1975-07-05 |
| FR2247226B1 (en) | 1978-07-28 |
| NL7413107A (en) | 1975-04-14 |
| SE392272B (en) | 1977-03-21 |
| IL45814A (en) | 1978-06-15 |
| ES430790A1 (en) | 1977-04-16 |
| SU548210A3 (en) | 1977-02-25 |
| FI286574A (en) | 1975-04-11 |
| IE41615L (en) | 1975-04-10 |
| AT352107B (en) | 1979-09-10 |
| DK516174A (en) | 1975-06-09 |
| PH10997A (en) | 1977-10-20 |
| GB1489784A (en) | 1977-10-26 |
| ES449429A1 (en) | 1977-12-01 |
| AU7414174A (en) | 1976-04-15 |
| IL45814A0 (en) | 1974-12-31 |
| DE2441592A1 (en) | 1975-04-17 |
| ATA810174A (en) | 1979-02-15 |
| BE820943A (en) | 1975-04-10 |
| GB1489783A (en) | 1977-10-26 |
| DK135809B (en) | 1977-06-27 |
| DK135809C (en) | 1977-11-28 |
| ZA746444B (en) | 1976-05-26 |
| JPS5082052A (en) | 1975-07-03 |
| AU498690B2 (en) | 1979-03-22 |
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