IE41615B1 - Substituted keto-acids and esters and pharmaceutical uses therof - Google Patents

Abstract

1489784 Pharmaceutically active substituted keto-acid derivatives SANDOZ Ltd 10 Oct 1974 [10 Oct 1973] 22272/77 Divided out of 1489783 Heading C2C The invention relates to the compound of formula or a salt thereof. This compound may be obtained by one of the following processes: (a) reacting a compound of Formula II with succinic acid anhydride, or (b) hydrolysing a compound of Formula III wherein R is alkyl of 1 to 4 carbon atoms. The preparation of the intermediate of Formula II is given in the parent Specification. This invention also comprises a pharmaceutical composition which contains as an active ingredient a compound of Formula I in association with a pharmaceutical carrier or diluent.

Description

The present invention relates to new heterocyclic compounds.

In accordance With the invention there are ! provided new compounds of formula I, wherein R^ is hydrogen, halogen of atomic number from 9 to 35 or alkyl of 1 to 4 carbon atoms, R2 is hydrogen or alkyl of 1 to 4 carbon atoms, each of Rg and is hydrogen, or 10 Rg and R^ together are oxygen, n is 2, 3 or 4, and A is ethylene or vinylene.

Further, in accordance with the invention a compound of formula I may be obtained by a process comprising a) reacting a compound of formula II, II wherein R^, Rg, R^ and A are as defined above, with a compound of formula III, X-CO-(CHo) -CO-O-Y III wherein n is as defined above, X is chlorine or bromine, and Y is alkyl of 1 to 5 carbon atoms, or X and Y together form a bond, or b) hydrolyzing a compound of formula lb, lb wherein R^, Rg, R^, A and n are as defined above, and Rg is alkyl of 1 to 4 carbon atoms, to produce a compound of formula Ia, -«?ίΐ2)η"ε00Η la wherein R^, Rg, R4, A and n are as defined above.

In the compounds of formula I R^ preferably signifies hydrogen or chlorine. R^ is preferably present in the 6 or 7 position of the ring structure. When R^ is lower alkyl, this preferably contains 1 to 4 carbon atoms and especially signifies methyl. The substituent Rg preferably signifies hydrogen. When Rg is lower alkyl, this contains, for example, 1 to 4 carbon atoms and especially signifies methyl or ethyl. Rg and together preferably signify oxygen, and n preferably denotes 2.

. Any carbon-containing radical not particularly defined herein preferably has up to 5 carbon atoms.

The reaction of a compound of formula II with a compound of formula III in accordance vrith process variant a) is preferably effected in the presence of an acid condensation agent. In accordance with a preferred method of the process the reaction may, for example, be effected in the presence of a Lewis acid in an inert organic solvent, e.g. a chlorinated hydrocarbon such as - 4 41615 methylene chloride or tetrachloroethane, or in carbon disulphide. A Friedel-Crafts reaction may be used.

Examples of suitable Lewis acids are aluminium trichloride or tin tetrachloride. The reaction of a compound of formula II with 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, toluene, xylene or tetraline. When the reaotion is effected in the presence of a Lewis acid, the reaction temperature preferably is between room temperature and the boiling temperature of the reaction mixture. reaction in the presence of a strong mineral acid is preferably effected at a temperature between about 50 and the case of the reaction in the presence of a strong T mineral acid any ester groupings -COOR2 , which may be present, may be simultaneously hydrolyzed, so that compounds of formula la. are obtained.

The hydrolysis of an ester of formula lb in accordance with process variant b) may be effected in accordance with the usual methods for ester hydrolysis.

For example, a compound of formula lb may be hydrolyzed 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.g. a mineral acid such as hydrochloric acid or sulphuric acid, or an organic sulphonic acid. The hydrolysis may be effected at a temperature between room temperature and about 100°C. An inert watermiscible organic solvent may be present.----------- The hydrolysis is preferably effected in an alkaline medium, e.g. with at least an equivalent amount of an aqueous alkali metal hydroxide solution at room temperature or at a slightly elevated temperature. Examples of organic Solvents which may be present are lower alcohols, acetone or cyclic ethers suc'n as tetrahydrofuran or dioxane.

The compounds of formula' I may be isolated from the reaction mixture and purified in known manner. Free acid forms of formula la may be converted into salt forms thereof and vice' versa.. A suitable salt is the sodium salt.

The compounds of formula Ila, wherein- R^ and A are as defined above, used as starting materials, may, for example, be obtained by reducing a compound of formula lib, wherein R^ and A are as defined above.

The reduction may, for example, be effected in accordance with Clemmensen with amalgamated zinc/hydrochloric acid, or, when A is an ethylene group, also by treatment with sodium/alcohol.

Insofar as the production of the starting materials is not described, these are known or may be produced in accordance with known processes, or in a manner analogous to the processes described herein or to known processes.

In the following non-limitative Examples all temperatures are indicated in degrees Centigrade. i . ,11615 - 7 EXAMPLE 1: 4-(9,10-dihydro-4H-benzo Γ 4, 51cyclohepta[l,2-b]thiophen-2-yl)-4-oxobutyric acid 11.0 g of succinic acid anhydride are dissolved in 220 cc of anhydrous methylene ohloride with heating, the resulting solution is cooled to 20° and g of aluminium chloride are added portionwise. After stirring for 15 minutes at room temperature, a solution of 22.0 g of 9,10-dihydro-4H-benzo[4,5]cyclohepta[l,2-bJthiophene in 100 cc of anhydrous methylene chloride is added dropwise within 30 minutes, the resulting mixture is stirred for a further 45 minutes at room temperature and is poured on a mixture of 200 cc of concentrated hydrochloric acid and 200 g of ice. After adding 300 cc of methylene chloride, the entire mixture is heated for minutes on a water bath, is cooled, the methylene chloride is removed and the aqueous phase is further extracted with methylene chloride. The acidic portion is extracted fromihe combined methylene ohloride solutions with 0.5 normal caustic soda, the basic extract is acidified with 5 N hydrochloric acid and extracted with chloroform. The chloroform solutions are washed with water, dried over magnesium sulphate, filtered through active charcoal and evaporated to dryness. Tho title compound, obtained as solid residue, is recrystallized - 8 41615 from dimethyl formamide/acetone. M.P. 202 to 203°.

The starting material may be obtained as follows: .0 g of sodium are added portionwise to a 5 solution of 25.0 g of 9,10-dihydro-4H-benzo[4,5]eyelohepta[l,2-b]thiophen-4-one in 280 cc of anhydrous ethanol. After all the material is dissolved, the reaction mixture is heated to the boil for 2 3/2 hours and the solvent is evaporated at reduced pressure. 500 cc of ice water and 200 cc of methylene chloride are slowly added to the evaporation residue, the organic phase is separated and the aqueous solution is again extracted with methylene chloride. The combined organic solutions are washed with water until neutral, dried over sodium sulphate and concentrated by evaporation. The residue is crystallized from ethanol. M.P. of 9,10-dihydro-4Hbenzo[4,5Jcyclohepta[l,2-b]thiophene: 117 to 119°.

EXAMPLE 2: 4-(9,10-dihvdro-4-oxo-4H-benzoΓ4,5]~ cyclohepta[l,2-b]thlophen-2-vl)-4-oxobutyric S£id The title compound, having a M.P. of 167 to 168° (from ethanol/ether), is obtained by the process - 9 described in Example 1, from 12.2 g of succinic acid anhydride, 30 g of aluminium chloride and 15.0 g of 9,10-dihydro-4H-benzo[4,5]eyeloheptaf1,2-b]thiophen-4one in 320 cc of anhydrous methylene chloride.

EXAMPLE 3: 5-(4-oxo-4H-benzor4,5]cyclohepta[l,2-b)thiophen-2-yl)-5-oxovaleric acid The title compound, having a M.P. of 149 to 151°, (reerystallized twice from acetone) is obtained by the process described in Example 1, from 13.0 g of glutaric acid anhydride, 30 g of aluminium chloride and .0 g of 4H-benzo[4,5]cyclohepta[l,2-b]thiophen--4-one in 350 cc of anhydrous methylene chloride.

The following (4H-benzo Γ 4,5]eyelohepta[1,2-b]thiophen-2-yl)oxocarboxylic acid derivatives may also be obtained in a manner analogous to that described in Example 1, by reaction of the corresponding 4H-benzo[4,5jcyclohepta[l,2-b]thiophene derivatives with the corresponding dicarboxylic acid anhydrides: •μ fi (0 P w a o y P <0 Ή 0} £ a ω c o +j id § ϋ to § 1) x Ό c a Oi e o o 0 0 0 Tf O σι m O > CM CM P I M CO CO σι r- CM P H « • A Oi & £ £ £ [4,5]cyclohepta[l,2-b]thiophen-2-yl)ο Ό N -H fi 0 ai id Λ ι o Μ Ή if u I >i 0 -P X fi 0Λ I 0 •a· X — 0 I I if if 1 tf 1 (0 1 cd 1 (0 1 id 0 a) X! A 1 rd P P P P b Pl 1 P 6 Pi CU Pi fit 0< 0 CM & r—i Q) 0 Φ Φ a) Ti *>, Φ 43 XJ A 43 A Λ A P 43 1 0 0 0 0 0 +3 uu 0 CM P rH P rH P r—< 1 (0 P *» 0 u y υ Φ 43 P y P >1 >1 >1 >1 ΪΧ 1 rH Pl >1 LU 0 0 0 0 0 CM >1 Φ y 10 ι—η r—ι J—I I"! r·^ u I A |—1 P tn in in in tn P CM 0 in «» u u * uu 1 rH s Φ Tf Tf Tf Tf Tf (0 fi y Tf 43 uu uu uu uu P Φ >1 uu 0 0 tf 0 tf 0 tf 0 tf 0 tf Pi 43 y 0 tf P N Ή N P N P N P N P Φ Pi r-i N P y fi 0 fi υ fi U fi o fi υ 43 0 in fi y >1 Q) (0 Φ (0 Φ (0 Φ rd Φ (0 0 P *» φ y 43 43 Λ 43 43 P 43 Tf A *. r-i 1 U ι υ ι υ 1 0 ι υ 0 P uu ι y in K p ffi P £ Ρ ffi «rl ffi Ή >1 r-i 0 ffi P u Tf p Tf p Tf p Tf p Tf p 0 A N tf Tf p tf 1 ΪΧ 1 ΣΧ I ΪΧ 1 >1 I tx r-τ i fi P 1 UU tpl 0 P 0 P 0 P 0 P 0 P in CM Φ 2 0 P S 3 X fi X fi X fi X fi X fi ·» u A fi X fi N <0 0 A 0 A 0 43 0 43 0 43 Tf P 1 9*3 1 0 1 0 1 0 i 0 1 0 uu uu w y 1 0 Φ y Tf X X Tf X Tf X Tf % 0 (0 Tf P Tf X A ·£ 1 0 I 0 1 0 1 0 1 0 N P 1 P I 0 1 0 0 J rH | rH | rH 1 0 1 fi Ol 0 5x 0 I ffi P P Th >tTf > P Tl· Φ tf 5! P P P Tf Tf o« tf 1 Xi 1 X* 1 43 1 tf I 43 P 43 tf fi tf 1 1 fi » P P P >1~ i 0 0 > >I ο υ A Ρ φ P Φ rH Φ P 41 rH B 10 P 43 0 AH 3 8 Ρ ε ε >< ε >i P ίΧ *3* U P X ρ >< 0 X tf I 1 1 i 1 1 1 tf 1 1 0 >t tf 0 tf 1 1 0 1 CM tO CM co CM r* cm 1 CM OH 0 tf 1 1 1 CM Tf 1 Ο 1 I | 1 1 1' 1 O i X P — p O Tf O 1 1 H fi 0 fi 0 fi 0 fi rH fi 0 >1 in y P 1 P fi 0 1 ·. φ p Φ Ρ Φ Ρ Φ * Φ 1 P * (0 ·»*-» * Φ Ρ os A tf A tf A tf 43 σι xi Tf EJ Tf 01 P σι 43 ny p 1 Οι >i Pi >i 0« a I Qi 1 43 uu 0 i >1 1 Pi 0 0 43 0 43 0 xi 0 0 0 0 0 0 P 0 1 0 0 A 1 Μ Ρ P P •ri P Ρ P P P P X N P P CM P P P CM ο a tf XJ tf 43 tf 43 0 xi 0 0 fi 0 1 0 43 7 1· Η XI 1 P 1 P 1 P rH P rH 1 Φ P P fi fi P 1 fi A — o — O t-' O — Α- 43 Tf 43 fi A Φ P r-i ο φ Ο 43 Η 43 rH 43 rH 43 ν 43 υ ι 1 A y 43 PA p A | | * 1 - 1 * 1 1 — W 0 1 Pi 1 1 ·» Pl tO CM σι cm σι cm 01 CM Γ- CM tO P Tf X to 0 to CM σι 0 •w» u u **-* *—* ·» >1 *-* 0 *—’P *-* u *-* P t Ρ 1 P 1 P 1 rH 1 rH 1 I 1 1 1 43 1 p1 ί UU Tf uu Tf uu Tf uu Tf ·_» Tf CM Tf Tf Tf p uu ID 4-> I - 11 EXAMPLE 15: 4-(9,10-dihydro-4-oxo-4H-benzof4,51 cyclohepta[l,2-b]thiophen-2-yl)-4-oxobutyric acid methyl ester A solution of 6.3 cc of succinic acid monomethyl ester chloride in 100 cc of anhydrous carbon disulphide is added dropwise at 0° to a suspension of 10.0 g of 9,10-dihydro-4H-behzo[4,5lcyclohepta[l,2-blthiophen-4-one and 30.0 g of anhydrous aluminium chloride in 200 cc of anhydrous carbon disulphide, the reaction mixture is stirred for a further 6 hours at room temperature, 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 subsequently 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 H hydrochloric acid and with water, dried over magnesium sulphate and concentrated by evaporation. The evaporation residue is dissolved in 300 cc of methylene chloride, filtered through silica gel and evaporated to dryness.

The title compound crystallizes from benzene/petroleum ether and is recrystallized once from ether. M.P. - 98°.

EXAMPLE 16: 4-(4-oxo-4H-benzor4,5lcvcloheptafl,2-hlthiophen-2-yl)-4-oxobutyric acid methyl ester The title compound is produced in a manner 5 analogous to that described in Example 1, from 10.0 g of 4H-benzo[4,5Icyclohepta[1,2-blthiophen-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 recrystallized from ether. M.P. 144 - 145°.

The following (4H-benzo[4,5]cyclohepta[l,2-b]thiophen-2-yl)oxocarboxylic acid ester derivatives may also be obtained in a manner analogous to that described in Example 15 or 16, by reaction of the corres ponding 4H-benzo[4,5]cyclohepta[l,2-b]thiophene derivatives with the corresponding dicarboxylic acid monoalkyl ester halides: II -μ u £ II ti II 44 1! Ul II II II υ ii u rH II ti II υ ii d n 0 11 >1II xs ii Pi II II * II ui II 44 II μ II ti If ε !! V 11 Cd Ii II 11 11 I I I -(4-oxo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-oxobutyric acid ethyl ester I l ti ti 1 ti 1 £ 0 X3 1 1 ti 44 -P •P 0 CU X- +1 , 1 ap Cu k Oik 43 O H OtM Γ—· 0 0 0 0 0 Φ CU •d >1 φ A XJ 4J 43 -P 43 +i O 43 1 43 4J 1 O 0 0 0 O 0 •d 44 OI o ra OJ rH 0 H 0 rH 0 A C"> t rM 0) X 0 0 O 44 XI £ υ rH id »H id H >1 t—> 1 Φ *-* k 0 >4 O >1 O id A - OJ 43 0 >t ti 0 e-'Xj x: r^43 1 X CU r-) 33 44 *P tn 4-> in 4J tn 4J Ol H O in +J Pi 0 * 0 *· 0 x 0 X 1—( •d - 0) 0 0 β *r ε ** ε iH ti 43 2L e 43 U-l i_t 44 44 QH 003 0 03 Ο Ό ti CU r-*> Ο Ό H >i N «d N -d N -d 4-i 0 XI H -4 0 -P £ 0 £ O £ O CU x: 1 β 9 >l £ 0 ti 0 ti 0 ti 0 o k Oi a) nJ OX3 Λ Λ 43 XJ k •Η 0 X Λ . 1—1 1 ι υ 1 ° 1 0 O 0 O 44 H 1 0 in £ ffi-d SB «d S3 -d rH 4J id 0 *—· a ή x Μ· k *r k k O 0 O 0 ti ar M *r 03 1 >i l id 1 >1 >1 0 p—n 44 1 >i *—* *d 0 +1 0 -P O 4J O in h CU k0 Έ X £ X £ X £ r—> r4 * id 0 0 tJ ti 0X1 0 Λ ΟΛ in id *4* 43 xi 44 °-9 £ „ 1 0 1 0 1 0 -XJ ‘-’-P O 0 1 0 0 O *f X *r X ’T X *J* 4-i O 0 H 0 ar X A -H 1 0 1 o I o 0 n e υ 1 0 I o 0 I H I Η 1 O £ idH 0 1 W k k M' >1*1* >ι*1* N 03 0 03 O >1 M as· *1* CU 03 1 43 1 43 1 £-d XJ *d «-«xi Ό 1 t ti >1— 4-i +i 0 O ι υ in 4J 0 o Α «Η 0 Ή 0 H 43 ti S3 ti - 0 43 rt X 0 Ή id e >< ε id 1 M* g •rt >, O X 03 1 1 1 1 1 SB O I 0 l—l •a ι 1 0 1 OJ kD OJ CO OJ M* «d O -d O 03 1 tM *1* 1 O 1 1 ! 1 I 1 k X k N -d ο 1 i to rH £ 0 £ O £ O >t ο id £ O rt β 0 1 - 0 k 0 k 0 k «Ρ I 44 0 ti a k-χ σ» 43 03 XJ 03 xj 03 £ M1 3 43 m 43 03 H 1 Pi >i CU id CU >tja I XI 1 0 1 b. >. >1 0 0 43 0 43 O 43 O O 0 W -d O 0 43 1 k Ή •d *d •d -d •d X k x *i· k Μ rt •d oi OXS 03 XJ 03 Xi *O O O 0 I 0 0 43 03 1 rH +J 1 -P 1 -P 1 1 Η 1 Ο H 3 -P 1 £ 43«-· o»-» O r-1 Ο M* x: *r X ti r~1 r— O 0 ΟΛ Η Λ rH 43 rH 1 υ ι 0 > Η 43 I I * 1 * 1 **—a 1 ~ I 0 1 1 x CU 1X5 OJ σ\ οι σι oi Ci H tO rH *** X vo ts Ct 0 ·—* a. «a ·»—- x >1 *— >1 —' 0 'a-' X Ή I rH 1 H 1 Η 1 1 1 t 1 1 1 rH 1 43 «ί «—' *T U_. 3* t-i *r oi *1* OI in in I—1 kD 44 Ο H OJ oi Oi oi m Oi *3» oi in oi EXAMPLE 26; 5-(4-oxo-4H-benzo[4,5lcvclohepta(l,2-blthiophen-2-yl)-5-oxovaleric acid A mixture of 10.0 g of 4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-one, 6.3 cc of succinic acid monomethyl ester chloride and 80 g of polyphosphoric acid is first stirred for one hour at 80° and then for 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 poured on 400 cc of ice water, is extracted with methylene chloride, the organic solutions are washed with water, dried over sodium sulphate and concentrated by evaporation. The title compound is crystallized from the evaporation resi15 due with acetone and is recrystallized once. M.P. 149151°.

EXAMPLE 27; 4-(9,10-dihydro-4-oxo-4H-benzor4,5lcycloheptari.2-blthiophen-2-yl)-4-oxobutyric acid (process variant b)] A solution of 3.0 g of 4-(9,lO-dihydro-4oxo-4H-benzo[4,5]cyclohepta[l,2-bIthiophen-2-yl)-4oxobutyric acid methyl ester and 1.5 g of potassium hydroxide in 60 cc of dioxane and 30 cc of water is stirred at room temperature for 3 hours, dilution is effected with 200 cc of water and the pH of the solution is adjusted to 1 with concentrated hydrochloric acid at -15°. The resulting title compound is extracted with methylene chloride, the organic solution is washed with water, dried over magnesium sulphate, concentrated hy evaporation, and the title compound is recrystallized from dimethyl formamide/acetone. M.P. 167-168°.

The (4H-benzot4,5]cyclohepta[l,2-bIthiophen-2-yl)oxocarboxylxc acid derivatives described in Examples 1 to 14 may also be obtained in a manner analogous to that described in Example 27, by hydrolysis of the corresponding (4H-benzo[4,5]cyclohepta[l,2-b]15 thiophen-2-yl)oxocarboxylxc acid lower alkyl ester derivatives which may be produced in accordance with Example 15 or 16.

The compounds of formula I exhibit pharmacological activity. In particular the compounds exhibit antiphlogistic activity, as indicated in standard 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 5OQng, 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. j 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 is hydrogen may alternatively be administered---41615 - 17 10 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 orz when it is a compound of formula I wherein Pg is hydrogen, alternatively in pharmaceutically acceptable salt form; in association with a pharmaceutical carrier oi- diluent. Such compositions may be in the form of, for example, a solution or a tablet.

In a group of compounds R^ is in the 6 or 7 position of the tricyclic ring and preferably is hydrogen or halogen. 4-(3,10-dihydro-4-oxo-4H-benzo[4,5]cyclohepta-[l,2-b]thiophen-2-yl)-4-oxobutyric acid haiZe’ been found to be especially interesting.

In one group of compounds Rg and R^ are hydrogen. In another group of compounds Rg and together are oxygen.

Claims (5)

1. CLAIMS ‘ 1. A process for the production of a compound of formula I, wherein R^ is hydrogen, halogen of atomic number 5 from 9 to 35 or alkyl of I to 4 carbon atoms, Rg is hydrogen or alkyl of 1 to 4 carbon atoms, each of Rg and R^ is hydrogen, or Rg and R^ together are oxygen, lu n is 2, 3 or 4, and A is ethylene or vinylene, which comprises a) reacting a compound of formula II, II wherein R^, Rg, and Λ are as defined above, with a compound of formula III, X-CO-(CH-) -CO-O-Y III

2. A process for the production of a compound of formula I, as stated in claim 1, substantially as herein before described with reference to any one of the Examples. 5 3. A compound of formula I, whenever produced by a process according to claim 1 or 2,

3. To 34 in free form. 36., A compound according to any one of claims 3 to 8 wherein Rg is hydrogen or any one of claims 9 to 22 in salt form. 37. A pharmaceutical composition comprising a compound according to any one of claims 3 to 34 in free form or when it is a compound of formula I wherein R 2 is hydrogen alternatively in pharmaceutically

4. A compound of formula I, as defined in claim 1. 5. A compound of claim 4 wherein R^ is the 6 10 or 7 position. 6. A compound of claim 4 or 5 wherein R^ is hydrogen or halogen. 7. A compound of claim 4,5 or 6 wherein A is ethylene. 15 8. A compound of claim 4,5 or 6 wherein A is vinylene. 9. The compound of claim 4 which is 4-(9,10dihydro-4H-benzo[4,5]cyclohepta-Γ1,2-b]thiophen-2-yl)-4 -oxobutyric acid. 20 10. The compound of claim 4 which is 4-(9,10dihydro-4-oxo-4H-benzo[4,5]-cyclohepta[1,2-b]thiophen2—yl)-4-oxobutyric acid. 11. The compound of claim 4 which is 5-(4-oxo4H-benzo[4,5]cyclohepta[1,2-b]-thiophen-2-yl)-5-oxo25 valeric acid. 21 41615 12. The compound of claim 4 which is 4-(4oxo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-4-oxo· butyric acid. 13. The compound of claim 4 which is 4-(65 chloro-9,10-dihydro-4-oxo-4H-benzo[4,5]cyclohepta-[1,2b]thiophen-2-yl)-4-oxobutyric acid. 14. The compound of claim 4 which is 4-(9, 10-dihydro-6-methyl-4-oxo-4H-benzo[4,5]cyclohepta-[1,2b]thiophen-2-yl)-4-oxobutyric acid. 10 15. The compound of claim 4 which is 4-(9,10 dihydro-8-methyl-4-oxo-4H-benzo[4,5]cyclohepta-[1,2-b] thiophen-2-yl)-4-oxobutyric acid. 16. The compound of claim 4 which is 4-(9,10 dihydro-7-methyl-4-oxo-4H-benzO[4,5]cyclohepta-[1,2-b] 15 thiophen-2-yl)-4-oxobutyric acid. 17. The compound of claim 4 which is 4-(7chloro-9,10-dihydro-4-oxo-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-2-yl)-4-oxobutyric acid. 18. The compound of claim 4 which is 4-(620 chloro-4-oxo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen2-yl)-4-oxobutyric acid. 19. The compound of claim 4 which is 4-(4Hbenzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-4-oxobutyric acid. 20. The compound of claim 4 which is 4-(6chloro-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-4-oxobutyric acid. 21. The compound of claim 4 which is 4-(65 fluoro-9,10-dihydro-4-oxo-4H-benzo[4,5]cyclohepta[1,2-b3 thiophen-2-yl)-4-oxobutyric acid. 22. The compound of claim 4 which is 6-(9, 10-dihydro-4-oxo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-6-oxocaproic acid. 10 23. The compound of claim 4 which is 4-(9, 10-dihydro-4-oxo-4H-benzo[4,5]-cyclohepta[1,2—b]— thiophen-2-yl)-4-oxobutyric acid methyl ester. 24. The compound of claim 4 which is 4-(4oxo-4II-benzo[4,5]cyclohepta[1,2-b]-thiophen-2-yl)-4-oxo15 butyric acid methyl ester. 25. The compound of claim 4 which is 4-(4oxo-4H-bonzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-4oxobutyric acid ethyl ester. 26. The compound of claim 4 which is 4-(620 chloro-9,10-dihydro-4-oxo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-4-oxobutyric acid methyl ester. 27. The compound of claim 4 which is 4-(9, 10-dihydro-6-methyl-4-oxo-4II-benzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-4-oxobutyric acid methyl ester. 28. The compound of claim 4 which is 4-(9,10>’ dihydro-8-methyl-4-oxo-4H-benzo[4,5]cyclohepta-[1,2-b] thiophen-2-yl)-4-oxobutyric acid methyl ester. 29. The compound of claim 4 which is 4-(9,10dihydro-4H-benzo[4,5]cyclohepta[1,2-b)thiopheh-2-yl)-4oxobutyric acid ethyl ester. 30. The compound of claim 4 which is 4-(6chloro-4-oxo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen2-yl)-4-oxobutyric acid methyl ester. 31. The compound of claim 4 which is 5-(4oxo-4H-benzo[4,5]cyclohepta[1,2-b)thiophen-2-yl)-5-oxovaleric acid methyl ester. 32. The compound of claim 4 which is 4-(6fluoro-9,10-dihydro-4-oxo-4H-benzo[4,5)cyclohepta[l,2-b]thiophen-2-yl)-4-oxobutyric acid methyl ester. 33. The compound of claim 4 which is 6-(9,10dihydro-4-oxo-4H-benzo[4,5]cyclohepta[1,2-b)-thiophen2-yl)-6-oxocaproic acid n-butyl ester. 34. A compound of any one of claims 9 to 22 in alkyl (of 1 to 4 carbon atoms) ester form. 35. A compound according to any one of claims 4 n wherein n X Y X is as defined above, is chlorine or bromine, and is alkyl of 1 to 5 carbon atoms, or and Y together form a bond, or b) hydrolyzing a compound of formula lb, wherein R^, Rg, R^, A and n are as defined above, and R 2 is alkyl of 1 to 4. carbon atoms, to produce a compound of formula la,

5. Addition salt form in association with a pharmaceutical carrier or diluent.