GB2068363A - Substituted Benzhydrindanes - Google Patents

Abstract

Compounds of the general formula <IMAGE> (wherein R is hydrogen, alkyl, alkoxy, hydroxy, halogen or halogenoalkyl, R1 stands for alkyl, hydroxy, halogen, cyano, carboxyl, inorganic salts of carboxyl, carbalkoxy, or CON R4 R5 wherein R4 and R5 are hydrogen, alkyl, optionally substituted aryl, optionally substituted heterocycle or (CH2)n R6 wherein n stands for 1-5 and R6 stands for carboxyl, inorganic salts of carboxyl, carbalkoxy or CONR4R5; R2 stands for hydrogen or alkyl, m is the numeral zero or one, and R3 stands for an atom of oxygen or hydrogen with the proviso that m is zero when R3 is oxygen atom and m is one when R3 is hydrogen atom) are anti-inflammatory agents, antipyretics and analgesics.

Description

SPECIFICATION Substituted Benzhydrindanes, Process for Preparing Same and Pharmaceutical Compositions Containing said Compounds This invention relates to novel substituted benzhydrindanes, process for preparing same and compositions containing said compounds.

This invention more particularly relates to novel substituted benzhydrindanes of the general formula IX of the accompanying drawings wherein R is hydrogen, alkyl, alkoxy, hydroxy, halogen or halogenoalkyl, R, stands for alkyl, hydroxy, halogen, cyano. Carboxyl, inorganic salts of carboxyl, carbalkoxy, or CONR4R5 wherein R4 and R5 are hydrogen, alkyl, optionally substituted aryl, optionally substituted heterocycle or (CH2)n R6 wherein n stands for 1-5 and Re stands for carboxyl, inorganic salts of carboxyl, carbalkoxy or CONR4R5 R2 stands for hydrogen or alkyl, m is the numeral zero or one, and R3 stands for an atom of oxygen or hydrogen with the proviso that m is zero when R3 is oxygen atom and m is one when R3 is hydrogen atom.

This invention also relates to a process for preparing said compounds of formula IX and pharmaceutical compositions containing same.

It has been found by us that the compounds of the invention possess anti-inflammatory, antipyretic and analgestic properties. It is thus possible to prepare pharmaceutical compositions using the compounds of this invention with conventional pharmaceutically accepted carriers.

According to this invention there is provided compounds of the general formula IX wherein R is hydrogen, alkyl, alkoxy, hydroxy, halogen or halogenalkyl, R, stands for alkyl, hydroxy, halogen, cyano, carboxyl, inorganic salts of carboxyl, carbalkoxy, or CONR4R5 wherein R4 and R5 are hydrogen, alkyl, optionally substituted aryl, optionally substituted heterocycle or (CH2)n R8 wherein n stands for 1--5 and R6 stands for carboxyl, inorganic salts of carboxyl, carbalkoxy or CONR4R5.

R2 stands for hydrogen or alkyl, m is the numeral zero or one, and R3 stands for an atom of oxygen or hydrogen with the proviso that m is zero when R3 is oxygen atom and m is one when R3 is hydrogen atom.

There is also provided a process for preparing compounds of the general formula IX wherein R stands for hydrogen or alkyl, for example, methyl, ethyl, n-propyl, isopropyl or alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy or hydroxy or halogen, for example fluoro, chloro, bromo or halogenoalkyl, for example trifluoromethyl.

R, stands for alkyl, for example methyl, ethyl, n-propyl or hydroxy or halogen, for example chloro, bromo, or cyano or carboxyl or inorganic salts of carboxyl such as sodium salt, calcium salt or carbalkoxy, for example carbethoxy or CONR4R5 wherein R4 and R5 are hydrogen or alkyl, for example methyl, ethyl, n-propyl, or optionally substituted aryl for example phenyl, pchlorophenyl or optionally substituted heterocycle, for example, pyridyl, quinolyl or (CH2)nR5, wherein n stands for 1-5 and R0 stands for carboxyl or inorganic salts of carboxyl such as sodium salt, calcium salt or carbalkoxy, for example carbethoxy or CONR4R5.

R2 stands for hydrogen or alkyl, for example methyl, ethyl, n-propyl, iropsopyl, m stands for a numeral 0 or 1 and R3 stands for a hydrogen atom or an oxygen atom with the proviso that m is zero when R3 is oxygen and m is 1 when R3 is hydrogen which comprises subjecting the compound of formula I to alkylation with a phenylethylhalide which may have a substitution 'R' wherein 'R' is as defined before to give a compound of formula II where R is as defined before, followed by subjecting the obtained compound of formula II to reduction in presence of reducing agents to give compounds of the general formula Ill where R is as defined before, followed by cyclization qf the same to give compound of formula IV where R is as defined before, whereafter the compound of formula IV is treated with an acid chloride or acid anhydride in the presence of Lewis acid like aluminum chloride to give a compound of formula Vlla or Vllc, respectively followed by treating the compounds of formula Vlla, with an oxidizing agent such as hypohalite to give compound of formula Vlib, the compound of formula Vllb being reduced using reducing agents like lithium aluminium hydride to give a compound of formula Vllla, the compound of formula Vllla being brominated with a brominating agent to give compound of formula Vlilb, the compound of formula Vlllb being subjected to reaction with a cyaniding agent like alkali cyanide in presence of solvent like dimethyl sulfoxide to give compounds of formula Vlilc, the compound of formula Vllle being alkylated using alkylation agents like alkyl halides in presence of a base and solvent like dimethyl sulfoxide to give a compound of formula Vlllg, when desired, converting the compound of formula Vlla, by reaction with sulphur and morpholine followed by alkaline hydrolysis to give compound of formula Vllld, the compound of formula Vllld being esterified using esterifying agents like alcohol in the presence of sulfuric acid to give compound of formula Vigil, which onalkylation using alkylation agents like alkyl halides in presence of a base and solvents like dimethyl sulfoxide is converted to give compound of formula Vlllj, and when desired, converting compound of formula Vllla by treatment with a reducing agent to give compound of formula Vllle the compound of formula Vllle being then converted by treatment with a chlorinating agent such as thionyl chloride to give the compound of formula Vlllf, the compound of formula Vlilf being treated with a cyaniding agent like alkali cyanide in presence of solvent like dimethyl sulfoxide to give a compound of formula Vlllg, the compound of formula Vllig or Vlllj being subjected to acid of alkaline hydrolysis to give compound formula Vlllh, and when desired converting the compound of formula IV where R is as defined before by treatment with ethyl oxalyl chloride in the presence of Lewis acid like aluminium chloride to give compound of formula Vlld which on alkaline hydrolysis gage compound of formula Vlle the compound of formula Vlle being treated with alkyl magnesium halide followed by treatment with a mineral acid and reduction to give compound of formula Vlllh, if desired the compounds of formulae Vllb and Vllc and also compounds of formulae Vlild and Vlllh are converted to the corresponding acid chlorides by treatment with thionyl chloride in presence of benzene, the obtained acid chlorides being reacted with ammonia or an amine like alkylamine, optionally, substituted arylamine or heterocyclic amine to give compound of formulae Vllf, Vllg, VI Ilk, or Villi respectively with the proviso that each of the above compounds of formula IV, Vlla, Vllb, Vllc, Vlld, Vlle, Vllf, Vllg, Vllla, Vlllb, Vlilc, Vllld, Vllle, Vlllg, Vlllh, Vllli, Vlllj, Vlllk and VIlil is isolable and the reactions can be terminated or continued at the production of any compound as desired and as indicated above.

The reaction involving alkylation of compound of formula I is preferably carried out under reflux using dioxane to give compound of formula II which on reduction using metal hydrides like sodium borehydride gave compound of formula 111.

However, we have also been able to cyclize the compound of formula II using polyphosphoric acid and this produced a mixture of compounds of formulae IV and V. it is possible to convert compound of formula V to compound of formula IV by a simple catalytic reduction using hydrogen as reducing agent. The catalysts can be platinum oxide or palladium on the carbon.

After preparing compound of formula IV, we have prepared the other derivatives in the order given above.

Thus from compound of formula IV, the following are prepared as shown below and these compounds conform to formula IX.

1. Compound IV--Vllc.

2. Compound lV-Vlla-Vllb-VlIIa-Vlllb Vllle--Vlllgg-Vlllh.

3. Compound IV-Vlla-VIlle-Vlllf-Vlllg- Vlllh.

4. Compound IV-Vlla-Vllld-Vlllc-Vlllj- Vlllh.

5. Compound IV--Vlldd-Vllle-Vlllh Each of the above compound can be isolated or the compound taken for the next conversion as desired.

In the conversion of compound of formula IV to compound of formula Vlla or Vllc, we have used aliphatic acid chloride and aliphatic dicarboxylic acid an hydride respectively.

Sodium hypohalite has been preferred as oxidizing agent to obtain compound of formula Vllb from Vlla. Phosphorous tribromide has been the preferred brominating agent to convert compound of formula Vllla to Vlllb. A preferred base in converting compound of formula Vlllc. to Vlilg or Vllli to Vlllj is sodium hydride.

We have employed as reducing agent, metal hydride like sodium borohydride or hydrogen in presence of suitable catalyst to convert compound of formula Vlla to Vllle.

We have also found that the compound formulae Vllb Vllc, Valid and Vlllh can be converted.

to the respective acid chlorides using thionyl chloride in the presence of benzene. It is still further possible to convert these acid chlorides to the amino derivatives of formula Vllf Vlig, Vlllk and Vllli respectively using suitable agents like ammonia or an amine like alkylamine, arylamine or heterocyclic amine.

It is to be remembered that the various conversions are described with reference to preferred agents only and the conversions are not limited to such agents only. Any chemical equivalent capable of giving the desired conversion is also within the purview of our conversions.

All the compounds reported in this specification are new. We tested the properties of several compounds and found them to possess the desired properties.

As an Example: We report below the properties details of one such compound.

Test compound: 4-(Benz[E]hydrindan-7-yl)-4- oxobutric acid has exhibited the following activities: Properties Teste: (a) Antiinflammatory ED 50:50 mg/kg/P.O; (Rat Paw Oedema model) LD 50:4 500 mg/kg/P.O.

(b) Antipyretic The effect lasts for 5 hours or more at 50 and 100 mg/kg p.o. in rats.

(c) Analgesic It exhibits 68% of the acitivity of aspirin at 200 mg/kg P.O. in mice.

The properties were determined by usual standards.

The invention is illustrated but not limited by the following examples: Examples 2. (2-Phenylethyl) cyclopentenone (II) To a solution of pyrrolidine enamine of cyclopentanone (40 g) in dry dioxane (200 ml) was added phenylethyl bromide (80 g) under nitrogen atmosphere and the mixture was refluxed for 20 hours. This was then cooled.

Water (200 ml) was added to it and the reflexing continued for another 3 hours. The solvent was removed under reduced pressure, the residue extracted with ether (3x1 00 ml) and the extract washed with water, sodium bicarbonate solution (10%) and water. The extract was dried over anhydrous sodium sulphate, concentrated and the residue distilled under reduced pressure to afford li; yield: 22g, bp,.5130--320; Benz[e]hydrindane (IV) To a cooled solution of 2-(2-phenylethyl) cyclopentanone (Il) (25 g) in methanol (200 ml) was added sodium boro-hydride (10 g) and the mixture was stirred at room temperature for 4 hours. Methanol was removed under vacuo, water was added and the product extracted with ether.

The ethereal extract was washed with water, dilute hydrochloric acid and water. It was dried over anhydrous sodium sulphate and concentrated to afford 2(2-phenylethyl) cyclopentanol (III),. This was cooled in ice bath and sulphuric acid (95 Ri 25 ml) was added portionwise with vigorous stirring and the stirring was then continued for 30 minutes. The mixture was cooled, water was added and the product extracted with ether. The ethereal extract was washed with water, sodium bicarbonate solution (10%) and water. It was dried over anhydrous sodium sulphate, concentrated and distilled under reduced pressure to afford IV; yield: 1 9 g; bp, 1260.

7-Acetyl-benz[e]hydrindano (Vlla) A suspension of anhydrous aluminium chloride (12 g) indry dichloromethane (1 50 ml) was cooled to OOC and to this was added a mixture aF benz[e]hydrindane (lV) (10.4 g) and acetylchloride j5. 16 g) dropwise. It was then allowed to stir at room temperature for 4 hours. It was cooled, the complex was decomposed with water and the product extracted with ether. The extract was washed with water, diluted hydrochloric acid and water. It was dried over anhydrous sodium sulphate, concentrated and distilled under reduced pressure to furnish Vlla; yield: 12.5 g; bop10 14648o.

Benz[e]hydrindane-7-carboxylic Acid (Vllb) Sodium hypobromite was prepared by adding bromine (6 ml) to ice-cold solution of sodium hydroxide (17.7 g) in water (70 ml) To a solution of 7-acetyl-benz[e]hydrindane (Vlla) (4 g) in dioxane (5 ml) was added sodium hypobromite solution siowly at 5-1 00C and the mixture was stirred for one hour. The temperature was slowly raised to 400C and kept at this temperature for 2 hours. The excess of sodium hypobromite was decomposed by adding aqueous sodium bisulphite solution (5%). It was then acidified with concentrated hydrochloric acid and the product extracted with ether.The extract was washed with water, dried over anhydrous sodium sulphate and concentrated to give a residue which crystallised from alcohol to afford Vllb; yields: 2.6 g mp 21620o.

7-Hydroxymethyl-benz[e]hydrindane (Vllla) To a suspension of lithium aluminum hydride (6 g) in dry ether (200 ml) was added a solution of benz[e]hydrindane-7-carboxylic acid (Vllb) (10 g) in dry ether (100 ml) and the mixture was stirred overnight. It was then decomposed with aqueous sodium hydroxide solution (10%) and the ethereal layer was decanted. The organic layer was washed with diluted hydrochloric acid and water, dried over anhydrous sodium sulphate, concentrated and the residue distilled under reduced pressure to give Vllla; Yield: 8g, bpr 0 18486 .

7-Cyanomethyl-benz[e]hydrindane (Vll Ic) .

To an ice-cold solution of 7- hydroxym ethyl- benz[e]hydrindane (Vllla) (9 g) in anhydrous benzene was added phosphorus tribromide (4 ml) dropwise over a period of 30 minutes. The mixture was allowed to stir overnight; water was added to it and benzene layer was separated. The organic layer was washed with water, sodium bicarbonate solution (10%) and water. It was dried over anhydrous sodium sulphate and concentrated in vacuo to give 7-bromomethylbenz[e]hydrindane (Vlllb). This was then taken up in anhydrous dimethylsulphoxide (50 ml) and added dropwise to a suspension of sodium cyanide (3.6 g) in anhydrous dimethylsulfoxide (100 ml) under stirring over a period of 30 minutes. The mixture was then allowed to stir overnight. It was diluted with water and extracted with ether.The extract was washed with water, dried over anhydrous sodium sulphate, concentrated and the residue distilled under reduced pressure to give Vlilc yield: 6.7g bp20 16466 .

2(Benz[e]hydrindan-7-yl)propionitrile (VilIg) (a). To a suspension of sodium hydride (1.75 g; 50 /O) in anhydrous dimethylsulfoxide (20 ml) was added a solution of 7-cyanomethylbenz[e]hydrindan (Vlllc) (6.30 g) in anhydrous dimethylsulfoxide (20 ml) under stirring. The reaction mixture was allowed to stir for 4 hours, cooled in ice-bath and methyl iodide (5 ml) was added to it. Another portion of methyl iodide (5 ml) was added after stirring for 2 hours and the stirring was continued overnight. Water was added to the reaction mixture and the product was extracted with ether. The extract was washed with water, dried over anhydrous sodium sulphate, concentrated and purified through a column of silica gel (50 g) using benzene as eluant.

Vlllg was obtained as a viscous oil after distillation under reduced pressure; yield: 4.5 g; bp15 172-74.

(b) (i). To a solution of 7-acetylbenz[e]hydrindane (Vlla) (5 g) in methanol (100 ml) was added sodium borohydride (2 g) in two portion and the mixture stirred for 6 hours.

Solvents was removed under vacuo, the complex was decomposed by adding water and the product extracted with ether. The extract was washed with water,,dried over anhydrous sodium sulphate, concentrated and the residue distilled under reduced pressure to give 1 (benz[e]hydrindan-7-yl)ethanol (Vllle); yield: 4.2 g; bop10 142-440.

(ii) To a cooled solution of Vllle (4 g) in anhydrous benzene (50 ml) was added thionyl chloride (2 ml) and the mixture allowed to stir overnight. Excess of thionyl chloride was decomposed by water and benzene layer was separated. The organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated to yield 1 (benz[e]hydrindan-7yl)ethyl chloride (Vlllf). This was taken up in anhydrous dimethyl sulfoxide (20 ml) and added dropwise to a suspension of sodium cyanide (2 g) in anhydrous dimethylsulfoxide (25 ml) and it was then stirred overnight-. Water was added to the reaction mixture and the product extracted with ether. The extract was washed with water, dried over anhydrous sodium sulphate and concentrate to yield Vlllg as a viscous oil.

Benzte]hydrindane-7-acetic Acid (valid) A mixture of 7-acetyl-benz[e]hydrindane (Vila) (6 g), sulphur (1 g) and morpholine (3 ml) were heated at 1 400C for 12 hours. It was then decomposed with water and extracted with ether.

The extract was washed w.ith water, dried over anhydrous sodium sulphate and concentrated to give a viscous liquid. This was then chromatographed on a column of silica gel (100 g) using benzene as eluant to give an intermediate compound which was refluxed for 15 hours with ethanolic potassium hydroxide (75 ml: 10%).

Ethanol was removed under vacuo, the residue was taken up in water, the aqueous layer was washed with ether to remove unreacted starting materials and then acidified. The product was extracted with ether, the extract washed with water, dried over anhydrous sodium sulphate and concentrated. The residue thus obtained was chromatographed on a column of silica gel (60 g) using benzene as eluant to give a viscous oil which was distilled under reduced pressure to yield Vllld; yield: 3.5 g. bp O 15860 .

Benz[e] hydrindane-7-acetic Acid Ethylestsr (Vllli) A mixture of-benz[e]hydrindane-7-acetic acid (Vllld) (4.2 g), absolute ethanol (7 cc), dichloroethane (100 ml) and sulphuric acid (0.5 ml) were refluxed for 4 hours. This was then poured into water, the organic layer was separated, the aqueous layer extracted with ether and the combined organic layer was washed with water, sodium bicarbonate solution (10%) and water. It was dried over anhydrous sodium sulphate concentrated and the residue distilled under reduced pressure to give VIllI; yield: 4.2 g: bp,, 135--400.

2-Benz[e] hydrindan-7-vl) Propionic Acid Ethyl Ester (VEllj) To a suspension of sodium hydride (300 mg.

50% suspension) in anhydrous dimethylsulfoxide (3 ml) was added benz[e]hydrindane. 7-acetic acid ethyl ester (Vlili) (1 g) and the mixture was stirred for 6 hours. The reaction mixture was cooled in icebath; methyl iodine (1 ml) was added to it and the stirring was continued for another 4 hours. It was then decomposed with water and the product extract with ether. The ethereal extract was washed with water, dried over anhydrous sodium sulphate and concentrated.

The residue thus obtained was chromatographed on a column of silica gel (15 g) using hexanebenzene (90:10) as eluant. Vlllj was obtained as a viscous liquid; yield: 800 mg.

2-Benz] hydrindan-7-yl Prop ironic Acid (VI llh) A) mixture of 2(benz[e]hydrindan-7-yl) propionic acid ethyl ester (Vlllj) (500 mg) and ethanolic potassium hydroxide (309/0, 10 ml) was refluxed for 3 hours. Ethanol was then removed under reduced pressure, water was added to it, the residue acidified and extracted with either. The ethereal extract was washed with water, dried over anhydrous sodium sulphate, concentrated and purified through a column of silica gel (20 g) using benzene as eluant. Vlllh was obtained as a viscous liquid which on cooling in defreezer over several days gave a low melting solid; yield 300 mg.

B) A mixture of 2-(benz[ejhydrindan-7-yl) propionitrile (Vlllg) (2 g) and a solution of potassium hydroxide (2 g) in ethylene glycol (20 ml) was refluxed for 20 hours. This was then diluted with water, washed with ether to remove unreacted material and the alkaline solution acidified with concentrated hydrochloric acid. The product was extracted with ether, the extract washed with water, dried over anhydrous sodium sulphate and concentrated. The residue thus obtained was purified through a column of silica gel (15 g) using benzene as eluant. Vlllh was obtained as a viscous liquid which on cooling in defreezer over several days gave a low melting solid; yield: 1.6 g.

Claims (1)

1. Claims

   1. Compounds of the general formula IX wherein R is hydrogen, alkyl, alkoxy, hydroxy, halogen or halogenoalkyl, R, stands for alkyl, hydroxy, halogen, cyano, carboxyl, inorganic salts of carboxyl, carbalkoxy, or CONR4R6, wherein R4 and R5 are hydrogen, alkyl, optionally substituted aryl, optionally substituted heterocycle or (CH2)n R8 wherein n stands for 1-5 and R, stands for carboxyl, inorganic salts of carboxyl, carbalkoxy or CONR4R6; R2 stands for hydrogen or alkyl, m is the numeral zero or one, and R3 stands for an atom of oxygen or hydrogen with the proviso that m is zero when R3 is oxygen atom and m is one when R3 is hydrogen atom.

   2. A process for preparing compounds of the general formula IX wherein R stands for hydrogen or alkyl, for example, methyl, ethyl, n-propyl, isopropyl or alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy or hydroxy or halogen, for example fluoro, chloro, bromo or halogenoalkyl, for example trifluoro-methyl.

   R' stands for alkyl, for example methyl, ethyl, n-propyl, or hydroxy or halogen, for example chloro, boromo- or cyano or carboxyl or inorganic salts of carboxyl such as sodium salt, calcium salt or carbalkoxy, for example carbethoxy or CONR4R5 wherein R4 and R6 are hydrogen or alkyl, for example methyl, ethyl, n-propyl or optionally substituted aryl, for example phenyl, pchlorophenyl or optionally substituted heterocycle, for example, pyridyl, quinolyl or (CH2)n R6 wherein n stands for 1-5 and R6 stands for carboxyl or inorganic salts of carboxyl such as sodium salt, calcium salt or carbalkoxy, for example carbethoxy or CONR4R5.

   R2 stands for hydrogen or alkyl, for example methyl, ethyl, n-propyl, isopropyl, m stands for a numeral 0 or 1 and R3 stands for a hydrogen atom or an oxygen atom with the proviso that m is zero when R3 is oxygen and m is 1 and R3 is hydrogen which comprises subjecting the compound of formula I to alkylation with a phenylethylhalide which may have a substitution 'R' wherein 'R' is as defined before to give a compound of formula II wherein R is as defined before, followed by subjecting the obtained compound of formula II to reduction in presence of reducing agents to give compound of the general formula Ill wherein R is as defined before, followed by cyclization of the same to give compound of formula IV where R is as defined before, whereafter the compound of formula IV is treated with an acid chloride or acid anhydride in the presence of Lewis acid like aluminium chloride to give a compound of formula Vlla or Vllc respectively followed by treating the compound of formula Vlla, with an oxidizing agent such as a hypohalite to give compound of formula Vllb, the compound of formula Vllb being reduced using reducing agents like lithium aluminum hydroxide to give a compound of formula Vllla, the compound of formula Villa being brominated with a brominating agent to give compound of formula Vllib, the compound of formula Vlllb being subjected to reaction with a cyaniding agent like alkali cyanide in presence of solvent like dimethyl sulfoxide to give compound of formula Villc, the compound of formula Vlilc being alkylated using alkylation agents like alkyl halides in presence of a base and solvent like dimethyl sulfoxide to give a compound of formula Vlllg, when desired, converting the compound of formula Vlla, by reaction with sulphur and morpholine followed by alkaline hydrolysis to give compound of formula VI lid, the compound of formula Vllld being esterified using esterifying agents like alcohol in the presence of sulfuric acid to give compound of formula Villi, which on alkylation using alkylation agents like alkyl halides in presence of a base and solvent like dimethyl sulfoxide is converted to give compound of formula Vlllj, and when desired, converting compound of formula Vlla, by treatment with a reducing agent to give compound of formula Vllle, the compound of formula Vllle being then converted by treatment with a chlorinating agent such as thionyl chloride to give a compound of formula Vlllf, the compound of formula Vlilf being treated with a cyaniding agent like alkali cyanide in presence of solvent like dimethyl sulfoxide to give a compound of formula Villi, the compound of formula Vlllg or Vlilj being subjected to acid or alkaline hydrolysis to give compound of formula Vlllh, and when desired converting the compound of formula IV where R is as defined before by treatment with ethyl oxalyl chloride in the presence of Lewis acid like aluminum chloride to give compound of formula Vlld which on alkaline hydrolysis gave compound of formula Vlle, the compound of formula Vlle being treated with alkyl magnesium halide followed by treatment with a mineral acid and reduction to give compound of formula Vlilh, if desired the compounds of formula Vllb and Vllc and also compounds of formulae Vlild and Vlllh are converted to the corresponding acid chlorides by treatment with thionyl chloride in presence of benzene, the obtained acid chlorides being reacted with ammonia or an amine like alkylamine, optionally substituted arylamine or heterocyclic amine to give compound of formulae Vllf, Vllg, Vlllk or Vllli respectively with the proviso that each of the above compounds of formula IV, Vlla, Vllb, Vllc, Vlld, Vlle, Vllf, Vllg, Vllla, Vlllb, Vlllc, Valid, Vlile, Vlilf, Vlilg, Vlllh, Vllli, Vlllj, Vlilk and VIlli is isolable and the reactions can be terminated or continued at the production of any compound as desired and as indicted above.

   3. A modification of the process as claimed in Claim 2 wherein the compound of formula IV is produced in admixture with compound of formula V by cyclization or compound of formula II using polyphosphoric acid and wherein the compound of formula V is converted to compound of formula IV by reduction with hydrogen using reducing catalyst like platinum oxide or palladium on carbon.

   4. A method as claimed in Claim 2 wherein the compound of formula Vlle is treated with alkyl magnesium halide to give intermediate compound which on subsequent dehydration with a mineral acid followed by reduction with hydrogen in presence of a catalyst such as platinum oxide or palladium on carbon furnished compounds of the general formula Vlllh.

   5. A process for preparing compounds of general formula IX wherein R, R1, R2, R3 and m are as defined before substantially as herein described.

   6. Pharmaceutical compositions having at least one compound of the formula IX wherein R, Rr, R2, R3 and m are as herein defined in conjunction with a pharmaceutically acceptable carrier therefor.

   7. 7-acetyl-benz[e]hydrindane.

   8. Benz[e]hydrindane-7-carboxylic acid.

   9. 7-hydroxymethyl-benz[e] hydrindane.

   10. 7-cyanomethylbenz[e]hydrindane.

   11. 2-(benz[e] hydrindane-7-yl) propionitrile.

   12. Benz[e]hydrindane-7-acetic acid.

   13. Benz[ejhydrindane-7-acetic acid ethyl ester.

   14. 2-Benz[e]hydrindane-7-yl-propionic acid ethyl ester.

   1.5. 2-Benz[e]hydrindane-7-yl-propionic acid.

   1 6. A process as claimed in Claim 2 and substantially as hereinbefore described with reference to the Examples.