DE2546906A1 - NEW ARYL ACID ACIDS THEIR PRODUCTION AND USE IN MEDICINAL PRODUCTS - Google Patents

Description

25A6906

SANDOZ-PATENT-GMBH
7850 Loerach

Case 100-4244

New -, their manufacture and use

The invention relates to new compounds of the formula I in which R .. denotes hydrogen or alkyl having 1-2 carbon atoms,
R_ hydrogen or halogen with atomic weight

below 80 means
R ₃ and R. each for hydrogen or together for

Oxygen stand and

Rc is hydrogen or alkyl of 1-4 carbon atoms means

or, if R_ and R- on the same carbon atom are bound

R ₅ and R_ together form an alkylene chain with 3 to 6 carbon atoms,

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or, if A stands for a (CH ₃ ) ₂ group, also

R. and R_ together form a bond and R-hydrogen means,

R _{6 represents} hydrogen or alkyl with 1-4 carbon atoms and

A represent a (CH ₀ ) group, wherein

η, if R ₃ and R together denote oxygen, denotes 0 or

n, if at least one of the substituents R ₅ , R ₆ and R- alkyl with 1-4 carbon atoms or Rc and R ₇ . together an alkylene chain with 3-6 carbon atoms

mean or if R _c , R _c and R- water ■ whether /

substance, R ₃ and R. together are oxygen and R _{2 is} halogen with an atomic weight of less than 80, is 1, or

n, if R ₃ and R ₄ together form oxygen or R and Rc together form a bond or if R ₂ denotes halogen with an atomic weight of less than 80 or if at least one of the substituents R., R ₅ , R _g and R-alkyl with

1-4 carbon atoms or

R ₅ and R ₇ together represent an alkylene chain with 3-6 carbon atoms, represents 2.

or, if R ₅ and R- are hydrogen, also. R and A together with the carbon atom to which they are attached form a 1,2-cycloal

- ^ y kylene group of the formula (CH ₂ ) J _n I form, in which

m 3 or, "- ^ *

if R ₃ and R. together represent oxygen, also means 4,

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R_ for hydrogen or, if R _{g is} hydrogen, also for alkyl with 1-4 carbon atoms,
and their salts, as well as processes for their preparation.

According to the invention, the new compounds of the formula I and their salts are obtained by

ä) for the preparation of compounds of the formula Ia, wherein
R ₁ and R _{2 have the} above meaning,

R? for hydrogen, alkyl with 1-4 carbon atoms

II
or, if R ₁ -. and R_ to the same coal

I I

atom are bound, R_ together with R_ represents an alkylene chain with 3-6 carbon atoms,

Rg for hydrogen or alkyl with 1-4 carbon atoms and

A ^{1 is} a (CH ₂ J _n I group, in which. .. η is 0 or 2 or

η; if at least one of the substituents R? rJ and

R ₇ alkyl with 1-4 carbon atoms or R and R ¹ '5

together an alkylene chain with 3-6 carbon atoms

or, if R _{g is} halogen with an atomic weight of less than 80, also for I.

or, if R _c and R-. Mean hydrogen, too

Rg and A together with the carbon atom to which they bound sin d, e ine 1,2-cycloalkylene group of the formula (CH ₅₎ Ij, wherein

4M Λτ Ail ^ J

m 3 or 4 means bil3en7

I I

R- stands for hydrogen or, if R _{g is} hydrogen, also stands for alkyl with 1-4 carbon atoms,

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Compounds of the formula II in which R ,, R _n , R _c , R, II ± /. ο 6

R and A have the above meaning, or their reactive acid derivatives are cyclized, or

b) for the preparation of compounds of the formula Ib, wherein

R. and R ^ have the above meaning, R * and R * each denote hydrogen, R; * ¹ denotes hydrogen or alkyl with 1-4 carbon atoms

or, if R_ and R- are bonded to the same carbon atom,

II I ^T
R_ and R_ "together form an alkylene chain with 3-6

Form carbon atoms,

Rg ¹ for hydrogen or alkyl with 1-4 carbon atoms and
A represents a (CH “) II group, in which

η, if at least one of the substituents R-,.

II II
R _fi and R ₇ alkyl with 1-4 carbon atoms

II τι
or R ₅ and R "together represent an alkylene chain

with 3-6 carbon atoms, represents 1, or

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η, if R _{2 is} halogen with an atomic weight below 80 or if at least one of the substituents

tuenten R ₁ , R * ¹ , R * ¹ and R ^ alkyl with 1-4

II II carbon atoms or R ₅ and R _g together

denote an alkylene chain with 3-6 carbon atoms, denotes 2

or, if R and R_ are hydrogen, also

II II

Rg and A together with the carbon atom

which they are bound to form a 1,2-cyclopentylene group of the formula (CH ₂ ΓΠ,

R _{7 represents} hydrogen or, if Rg ^{1 represents} hydrogen, also represents alkyl having 1 - 4 carbon atoms,

Compounds of formula III,

wherein R ₁ ,
own,

wherein R ₁ , R ₂ , R * ¹ , R ₇ ¹ and A ^{11 have the} above meaning

and R ₃ together represent oxygen and

stands for hydrogen or alkyl with 1-4 carbon atoms or, if R? and RiE ¹ to the same coal

III II substance atom are bound, R ₅ and R ₇

form an alkylene chain with 3-6 carbon atoms or
R] F and Rg ¹¹ together form a bond and

R ₃ ¹ is hydrogen, and

R _g V7asserstoff or, if R * ¹ and R ₃ ¹ together represent oxygen, a hydrolytically ab'spaltbaren radical / reduced and, if R ₀ is a hydrolytically cleavable

ο remainder means splitting it off at the same time,

or

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c) for the preparation of compounds of the formula Ic, wherein

R ₁ , R ~ and R have the above meaning and Rp ^{1 is} hydrogen or alkyl with 1-4 carbon atoms,

from compounds of the formula IV in which R-, R ₂ , R_ and Ry have the above meaning and R «denotes hydrogen or an acidolytically cleavable radical, water and, if R _{g stands} for an acidolytically cleavable radical, also cleaves this at the same time and

the compounds of formula I obtained, if desired converted into their salts.

In the compounds of the formula I, the substituent R _{1 is} preferably hydrogen or methyl. The substituent R "preferably represents hydrogen. If R "denotes a halogen as defined above, it preferably represents chlorine. The substituents R ₃ and R ₄ together preferably represent oxygen or each represent" hydrogen. If the substituents R ₁ -, R ₆ or R_ denote lower alkyl groups, these contain preferably 1-3 carbon atoms and, if A stands for a -CH _{- group or a -CH 2} -CH.- group, in particular represent ethyl or methyl and, if A stands for • a bond,. ..in particular .nP ^ opyl,. ,, isopropyl .. · ·, .., or ethyl. If R_ and R_ together form an alkylene chain, this preferably contains 5 carbon atoms Preference is given to an alkyl substituent in the 6-position or, if A stands for a CH ₂ group or a (CH ₂ ) ₂ group, also in the 7-position

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arranged. A preferably stands for a (CH ₂ ) "group or, together with R _g and the carbon atom to which they are attached, forms a cycloalkylene ring as defined above, which is preferably cis-linked to ring B.

The cyclization of the compounds of the formula II according to process a) according to the invention can be carried out by methods known per se. The reaction is preferably carried out in the presence of a strongly acidic condensing agent, optionally with the addition of an organic solvent which is inert under the reaction conditions, for example an aromatic or a chlorinated hydrocarbon. Strong acids such as, preferably, polyphosphoric acid, sulfuric acid or methanesulfonic acid / phosphorus pentoxide are suitable as acidic condensing agents. The reaction temperature can be between about 60 and 160 °. Instead of an acid of the formula II, its reactive derivatives can also be used for the cyclization. Suitable reactive derivatives of the acids of the formula II are, for example, their acid halides or mixed anhydrides of acids of the formula II and lower organic carboxylic acids or else lower alkyl esters of the acids of the formula. 'See acid chloride such as thionyl chloride converted into their acid chlorides and these then under the reaction conditions of a Friedel-Crafts reaction, for example in the presence of aluminum trichloride, in an organic solvent which is inert under the reaction conditions

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solvents are cyclized. The reaction conditions in the hydrolysis of the organometallic complex formed as an intermediate in the Friedel-Crafts reaction chosen so that any acid derivatives of the acetic acid group simultaneously become free acid groups be hydrolyzed.

The reduction according to the invention of compounds of the formula III can be carried out according to methods customary per se for the selective reduction of a double bond or a carbonyl group to the methylene group. Suitable reduction processes are, for example, if R ₀ water

Substance means the catalytic hydrogenation or, if R ₃ and R ₄ together represent oxygen, also reductions with nascent hydrogen, for example the reduction according to Clemmensen or the reduction method according to Wolff-Kishner and their modifications. Under the reaction conditions of the reduction methods according to .. Clemmensen or Wolf f-Kishner, any hydrolytically cleavable radicals R _ß , for example alkyl, in particular lower alkyl or aryl groups, are cleaved from the compounds of the formula III at the same time. The catalytic hydrogenation can be carried out, for example, in the presence of a catalyst in a solvent which is inert under the reaction conditions at a hydrogen pressure between about 1 and 5 at. And temperatures between about 10 and 100 °. Suitable catalysts are, for example, platinum or palladium catalysts or Raney nickel. Suitable solvents are, for example, lower alcohols or alcohol / water mixtures or, preferably, acetic acid. The hydrogenation is preferably carried out with the addition of a strong mineral acid such as, for example, sulfuric acid or perchloric acid or hydrogen chloride. the

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Reduction of the compounds of formula III with nascent Hydrogen can, for example, according to Clemmensen with amalgamated zinc / hydrochloric acid, optionally under Addition of an organic solvent which is inert under the reaction conditions / for example an aromatic one Hydrocarbon or a water-miscible solvent such as a lower one Alcohol. The reduction is preferably carried out at temperatures between 20 and about 120 °. According to the Wolff-Kishner method, the compounds of the formula III can initially be converted into their hydrazones transferred and then with strong bases such as alkali metal hydroxides or alcoholates are treated. The Wolff-Kishner Reduction is preferably based on the process variant carried out by Huang-Minlon by, for example, compounds of the formula III with hydrazine hydrate in the presence an alkali metal hydroxide and a high-boiling polar one which is inert under the reaction conditions Water-miscible organic solvent can react at temperatures between approx. 20 and 220 °.

The elimination of water from the compounds of the formula IV according to process variant c) can be carried out in a manner known per se, for example by the action of suitable dehydrating agents on the compounds of the formula IV ₇

., optionally with the addition of one of the reaction. conditions inert organic solvent take place. Strong water-releasing agents, for example, can be used Acids or acid anhydrides or acid halides can be used. If R- is in the connections of the

.Formula IV for an acidolytically cleavable residue, for example an alkyl, especially lower alkyl or aryl group stands, the elimination of water is expedient

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for the simultaneous splitting off of the radical R _g by means of strong acids.

The compounds of the formula I obtained according to the invention can be in the form of the free acids or their salts are present. The free acids can be converted into their salts in a manner known per se and vice versa. If in the compounds of the formula I A and R. together with your carbon atom / on which they are bound to form a cycloalkylene ring defined above, the according to the invention Process obtained mixtures of cis and trans isomers in a manner known per se, for example separated by fractional crystallization.

The starting compounds can be obtained as follows:

a ¹ ) Compounds of the formula II can be obtained, for example, by adding compounds of the formula

III I mel V, where R ₃ , R ₅ , R ,, R_ and A have the above meaning and R ₁₀ and R ^. each denotes lower alkyl, hydrolyzed and, if desired, introduces a halogen atom R ₂ into the dicarboxylic acids obtained in a manner known per se. If desired, the acids of the formula II. Can be converted into derivatives, for example halides, in a manner known per se.

b ¹ ) Compounds of the formula V can be obtained, for example, by _{rearranging compounds of the formula VI f} in which R ₁ , R *, R *, R *, A ¹ and R _{10 have the} above meaning, »under oxidative conditions., Die- oxidative ——

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Rearrangement can take place according to methods known per se, for example by oxidizing compounds of the formula VI with thallium III trinitrate in the presence of a strong acid and an alcohol R ₁₁ OH.

c ¹ ) If R stands for methyl or ethyl, the compounds of the formula VI are preferably converted into compounds of the formula VII, in which R ,, R _c , R,., R _n , A and R _{nA have the} above meaning,

XDO / XU

transferred, split off from these by means of sodium methylate in a dipolar aprotic solvent, for example dimethyl sulfoxide, hydrochloric acid and the resulting compounds of the formula VIII, in which R ₁ , R ₅ , R _g , R ₇ , A and R _{10 have the} above meaning, by treatment with thallium -III-trinitrate converted into compounds of the formula V in the presence of an alcohol ^R _{lc, 0H.}

d ¹ ) Compounds of the formula VI can be obtained, for example, by mixing compounds of the formula IX in which R ₅ , R _g , R ₇ , A and R ^ _{0 have the} above meaning with compounds of the formula X in which R _{1 has the} above meaning ,

'·' ·· '.-. Under the conditions of a Friedel-Cräf tsr. '··· .. Acylated reaction.

e ¹ ) Compounds of the formula IX can be obtained, for example, by adding compounds of the formula XI, wherein R-, R ... and A ^x above

D XU

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Have meaning, R ^ ^v hydrogen or alkyl

IV

with 1-4 carbon atoms means and IC

IV I

for hydrogen or, if R _c and R ,, water

o ο

Substance mean, also stands for alkyl, reduced by catalytic hydrogenation and the

obtained compounds of the formula IXa, wherein

IV I IV I

R ₅ , Rg, R_, A and R _{10 have the} above meaning, if desired alkylated to give compounds of the formula IX which are disubstituted in the α-position to the ester group. For alkylation in the α-position to the ester group, the compounds of the formula IXa can be used in a manner known per se

IV manner with alkyl halides or, if R _{5 is} hydrogen, if desired also to introduce an R ₅ -R ₇ -A ^ y lenkette with CO -alkyl dihalides in the presence of strongly basic condensing agents, for example alkali metal amides or hydrides, are reacted.

f ') Compounds of the formula XI can be obtained, for example, by reacting compounds of the formula XII in which R _g , R ₇ and A have the above meaning with compounds of the mel XIII in which R 1 and R _{Q have the} above meaning. The reaction leads to isomeric mixtures of compounds of the formula XI and to isomeric compounds in which the ester group is arranged in the β-position to the double bond and which are converted into compounds of the formula IXa by catalytic hydrogenation.

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g ¹ ) Compounds of the formula III in which R _fi denotes a hydrolytically cleavable radical can be obtained from the corresponding acids.

h ¹ ) Compounds of the formula III in which R ₄

III
and R ₅ together form a bond can be obtained, for example, by reducing _{the keto group to the hydroxy group in corresponding compounds of the formula III in which R 4} and R are jointly oxygen, and then splitting off water from the hydroxy compounds obtained.

i ¹ ) Compounds of the formula IV can be obtained from corresponding compounds of the formula Ia by reducing the keto group to the hydroxyl group _{in these, if desired after introducing an acidolytically cleavable radical R g.}

If the preparation of the starting compounds is not described, these are known or according to methods known per se or analogously to those described here or analogously to per se known processes can be produced.

The compounds of the formula I and their physiologically tolerable salts are characterized by interesting pharmacological properties and can therefore be used as medicinal products.

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In animal experiments, the compounds show in particular anti-inflammatory properties and inhibit E.g. edema formation in rats in the carrageenan paw edema test.

The compounds of the formula I show analgesic properties and inhibit in animal experiments for example the phenylbenzoquinone syndrome in mice.

Due to their anti-inflammatory properties, the compounds can be used as anti-inflammatory agents or to inhibit exudation in inflammation or edema use.

Because of their analgesic effectiveness, the substances can be used to treat pain different genesis used v / earth.

As medicaments, the compounds of the formula I and their salts can be used together with customary pharmaceutical auxiliaries in pharmaceutical preparations, such as tablets, capsules or Solutions, be included. These pharmaceutical preparations can be prepared according to methods known per se getting produced.

In the following examples, which explain the invention in more detail, but none of its scope If you want to limit the temperature, all temperatures are given in degrees Celsius.

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Example 1;

To 200 g of polyphosphoric acid are added with stirring at 100 ° 17.8 g of 5- (4-carboxymethylphenyl) -3-methylvaleric acid admitted. The reaction mixture is one hour at Stirred 100 °, cooled to about 60 ° and added dropwise 100 ml of water. Then the reaction mixture is on ice poured, extracted with methylene chloride, the methylene chloride extract washed with water and dried over sodium sulfate dried. The 6,7,8,9-tetrahydro-7-methyl-9-oxo-5H-benzocyclohepten-2-acetic acid obtained after concentrating the solvent is purified by chromatography on silica gel. Mp. Of the title compound - 107 ° (from acetonitrile). M.p. of the cyclohexylammonium salt the title compound 135-137 ° (from acetonitrile).

The starting material can be obtained as follows:

a) To a solution of sodium methylate (prepared from 67 g of sodium) in 1000 ml of methanol is a Solution of 292 g (diethylphosphono) acetic acid methyl ester in 200 ml of methanol at 0 - 5 ° below Stir added dropwise. The mixture is stirred at 0-5 ° for 15 minutes, and a solution of 215 g of benzyl acetone is added dropwise in 200 ml of methanol and allowed to stir at room temperature for 18 hours. Then 55 ml , Acetic acid was added dropwise, the solution was concentrated, diluted with water and extracted with ether. Of the Ether extract is washed with 3% sodium bicarbonate solution and dried over sodium sulfate and narrowed. The remaining 3-methyl-5-

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methyl phenylpent-2-enoate is purified by distillation. Kp ₁₁ = 132-135 °.

The methyl 3-methyl-5-phenylpent-2-enoate obtained above is dissolved in 1.5 liters of ethanol and with the addition of 10 g of palladium-carbon (10%) 1 at. Hydrogen pressure and 25 ° hydrogenated. After the calculated amount of hydrogen has been taken up, it is filtered and the solution concentrated. The remaining 5-phenyl-3-methylvaleric acid methyl ester is purified by distillation. Kp_ __ 98 - 101 °.

b) In a suspension of 46.5 g of aluminum chloride in 250 ml of methylene chloride is stirred at 0-5 ° a solution of 20.6 g of methyl S-phenyl-3-methylvalerate and 14.7 g of acetyl chloride in 50 ml of methylene chloride were added dropwise over 10 minutes. The solution is stirred for 3 hours at room temperature and then poured onto ice / water. The mixture is extracted with methylene chloride, the extract is washed with water and dried over sodium sulfate and narrowed. The remaining crude methyl 5- (4-acetylphenyl) -3-methylvalerate is processed directly.

c) To a solution of 32.2 g of thallium III trinitrate and 10 ml of 70% aqueous perchloric acid in 200 ml of methanol is a solution of 17.2 g of 5- (4-acetylphenyl) -3-methylvaleric acid methyl ester in 100 ml of methanol were added. The reaction mixture is stirred at room temperature for 16 hours, filtered, the filtrate then with Diluted water and extracted with chloroform. After concentrating the washed with water, dried over sodium

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The crude methyl 5- (4-carbomethoxymethylphenyl) -3-methylvalerate, which is purified by distillation, remains on the sulfate-dried chloroform phase. Kp _{n nt} . = 174 - 178 °.

d) To a solution of 19.3 g of methyl 5- (4-carbomethoxymethylphenyl) -3-methylvalerate a solution of 20 g of potassium hydroxide in 40 ml of water is added to 200 ml of methanol and the mixture is refluxed for 2 hours heated. The solution is then concentrated, diluted with water and acidified with 2N hydrochloric acid and extracted with ether. The crude 5- (4-carboxymethylphenyl) -3-methylvaleric acid obtained after concentrating the ether extract is recrystallized from ether / hexane. M.p. 100-102 °.

Example 2: 5 _i 6 _i 7 _i 8-Tetrahγdro-6 _i cc-dimethγl28-oxonaghthalin-2-acetic acid

4- [4- (1-carboxyethyl) phenyl] -2-methylbutyric acid cyclized with polyphosphoric acid analogously to Example 1. Mp. Of the cyclohexylammonium salt of the title compound 196 ° (from methanol / ether).

The starting material can be obtained as follows:

a) 2-methyl-4- (4-propionylphenyl) butyric acid methyl

ester, prepared analogously to Example Ib from methyl 4-phenyl-2-methylbutyrate and Propionylchloriä,

- ¹⁵⁴ ° -

b) To a solution of 76.8 g of 2-methyl-4- (4-propionyl-

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phenyl) butyric acid methyl ester in 1 liter of anhydrous Ether are added to 193 g of phosphorus pentachloride and the mixture for 16 hours • Stirred at room temperature, then refluxed for one hour. The mix will slowly poured onto ice, stirred for one hour and extracted with ether. The after evaporation of the Ether extract obtained 4- [4- (1-chloro-1-propenyl) -phenyl] -2-methylbutyric acid methyl ester is distilled under vacuum (Kugelrohr), bp 160-170 °.

c) To a solution of 78 g of 4- [4- (1-chloro-1-propenyl) phenyl] ~ 2-methylbutyric acid methyl ester 78 g of sodium methylate are added in 500 ml of dimethyl sulfoxide and the solution is added for 2 hours at room temperature stirred, neutralized with 180 ml of 50% sulfuric acid. The mixture is diluted with water and extracted with ether. The ether extract is washed with water, dried over sodium sulfate and evaporated. The remaining, oily 2-methyl-4 [4- (1-propynyl) phenyl] butyric acid methyl ester is processed directly.

d) To a solution of 124 g of thallium trinitrate trihydrate in 400 ml of methanol, a solution of 64 g of 2-methyl-4- [4- (1-propynyl) phenyl] butyric acid methyl ester is obtained while cooling with ice admitted. The mixture is stirred for one hour at room temperature, filtered, the filtrate diluted with 1 liter of water and extracted with methylene chloride. The methylene

• The chloride extract is washed with water over sodium sulfate dried, evaporated and the remaining 4 [4- (1-carbomethoxyethyl) phenyl] -2-methylbutyric acid methyl ester distilled in a bulb tube,

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160-170 °.

e) 4- [4- (1-carboxyethyl) phenyl] -2-methyl butyric acid is produced analogously to Example 1d. Mp. 107 109 ° (from hexane / ether).

Example 3;

4-Carboxymethyl-ß-isobutyldihydrocinnamic acid is analogous Example 1 cyclized. M.p. of the cyclohexylarainalses the title compound 140-142 ° (from methanol / ether).

The starting material can be obtained as follows:

a) In a suspension of 100 g of zinc dust and something crystalline iodine in 100 ml of benzene is a solution of at reflux temperature with stirring 16.2 g of 3'-methylbutyrophenone and 18 g of methyl bromoacetate added dropwise in 100 ml of benzene for 30 minutes. The solution is refluxed for 2 hours heated, cooled to room temperature, filtered, diluted with 2% hydrochloric acid and with Aether extracted. The extract is washed with water, dried over sodium sulfate and concentrated. The crude ß-hydroxy-ß-isobutyldihydrocinnamate is processed directly.

A solution of 18.9 g of ß-hydroxy-ß-isobutyldihydrocinnamate and 2.5 g of p-toluenesulfonic acid in 400 ml of benzene are refluxed for 2 hours (water separator) heated. The cooled solution is washed with 1% sodium bicarbonate solution,

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dried over sodium sulfate and concentrated. The crude mixture of unsaturated ß-isobutyldihydrocinnamate is processed directly.

15.8 g of the mixture of unsaturated esters obtained above are dissolved in 400 ml of ethanol and taken under Addition of 0.3 g of platinum (IV) oxide catalyst at 1 atm. Hydrogen pressure and 25 ° hydrogenated. After admission the calculated amount of hydrogen is filtered and the solution is concentrated. The leftover ß-isobutyldihydrocinnamate is distilled at 91-100 ° / 0.02 mm.

b) Analogously to Example Ib - Id 4-carboxymethyl-ß-isobutyldihydrocinnamic acid is obtained from the above product produced, m.p. 143-147 °.

The following compounds of the formula Ia mentioned in Table 1 are also carried out analogously to Example 1-3 Cyclization of corresponding compounds of the formula II obtained:

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^R l ^R 2 H T a b e 1 (CH ^R 7 CH ₃ 1 e 1 H A ¹ 118 - 100-4244 120 M.p. 4th - 170 ° (Z) E.g.
No. H H H G-CH ₃ 5-CH-CH ₂ -CH ₃ »I. H -CH ₂ - 99 - 101 O O 3A H H H 6-CH ₂ -CH ₂ -CH ₃ H ta ta -CH ₂ - 73 - 75 ° O 138 ° [ol _D - 15 ° 3B H H H H H - (CH ₂ ) ₀ - 94 - 96 ° 136 ° [cc3 _D + 14 ° ^
- 190 ° (Z) ⁺ ο
: ^ T) 3C H H H H H -CH ₂ - CHA * 176 3D H H H 6-CK ₃ H 151 - 153 - 179 ° 3E ° H H H 6-CH ₂ -CH ₃ CHA * 196 3F °° CH ₃ H H H -CH ₂ - 128 - 131 - 199 ° 3G CH ₃ H H 6-CH ₂ CH ₃ H -CH ₂ - CHA * 167 3H CH ₃ H K 7-CH ₃ H
V T ₃ ) 134 - 136 3J ° H H H 7-CH ₃
2 ⁾ 5 i ^CH 2 -CH ₂ - CHA * 136- 3K H H H - (CHj) ₂ CHA *
CHA * 134-
186 3L ^A ta ta H
H (CHj) ₀ 3N

cis-Fcrm °° trans-form * cyclohexylammonium salt

Δ (-) - (7R) -form ^ΔΔ (+) - (7S) -form

Z = with decomposition

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Example 4 _;

5.4 g of 6-ethy1-5,6,7,8-tetrahydro-8-oxonaphthalene-2-acetic acid are dissolved in 150 ml of acetic acid and, with the addition of 1 g of palladium / carbon (10%) and 2 ml of 70% -iger aqueous perchloric acid at 4 atm. hydrogen pressure and 45 ° hydrogenated. After the calculated amount of hydrogen has been taken up, it is filtered, 2 g of sodium acetate are added and the solution is concentrated. The residue is partitioned between ether and water, the ether extract is dried over sodium sulfate and evaporated. The remaining 6-Ethyl-5,6 , 1,8-tetrahydronaphthalene-2-acetic acid is recrystallized from hexane and melts at 64-66 °.

Analogously to Example 4, the following compounds of the formula Ib listed in the table are also obtained by reduction of the corresponding keto compounds obtained:

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Example ". No. ^R l ^R 2 «I R ^1
R 4 tab hurry 2 II
^R 6 MCH H
H H A ¹¹ 100-4244 4A H H H H R ^11
R 5 R ¹¹
R ₇ H H -CH ₂ - M.p. 4B H H H H H 6-CH ₃ H H -CH ₂ - 90 - 92 ° 4C H H H H H * "*** 3 H H . - (CH ₃ J ₂ - DPA ** 126 - 129 ° 4 E ' H H H H H 7-CH ₃ H H -CH ₂ - 109-111 ° 4F ° H H H H H 6-CH ₂ -CH ₂ -CH ₃ H
\ 78 - 80 ° 4G
4H CH ₃
CH ₃ H
H H
H H
H H H ((CH -CH ₂ - CHA * 166 - 169 ° co
α
co
30th
-Ρ "»
O 4 y CH ₃ H H H H
H 6-CH ₃
6 — CH -— CH- - (CH ₂ J ₂ - 93 - 95 °
84 - 87 ° 4K CH ₃ H H H H ^{1 7} " ^CH 3 - (CH ₂ J ₂ - CHA * 166 - 169 ° fs)
co 4L CH ₃ H H H H 7-CH ₃ -CH ₃ - (CH ₂ J ₂ - CHA * 143 - 146 ° 4M ^Δ H H H H H H - (CH ₂ J ₂ - CHA * 187 - 190 ° 4 N ^ΔΔ H H H H H 7-CH ₃ f 139-142 °, [al _D = -20 ° 40 ° CH ₃ H H H H 7-CH ₃ 2>] 141-143 °, [cc] _D = + 23 ° 4 p CH ₃ H H H H H -CH ₂ CHA * 19 2 - 195 ° H 6-CH ₂ -CH ₂ -CH ₃ DPA ** 136-137 °

cis form

(-) - (7R) -Forxn

CHA «* cyclohexylane monium salt

(+) - (7Sj-form

** DPA = (1,3-dihydroxy-2-hydroxymethyl-2-propyl) ammonium salt

- 24 - 100-4244

Example 5:

5/9 g 6,7,8,9-tetrahydro-9-hydroxy-7-methyl-5H-benzocyclohepten-2-acetic acid is dissolved in 50 ml of benzene, 1 g of p ~ toluenesulfonic acid is added and the solution Boiled under reflux for 3 hours. The solution is made with water diluted, extracted with benzene, the benzene extract washed with water, dried over sodium sulfate and evaporated. The crude 6,7-dihydro-7-methyl ~ 5H-benzocyclohepten-2-acetic acid is purified by chromatography on silica gel. M.p. of title compound 80 - 82 ° (from hexane).

The starting material can be obtained as follows:

a) 6,7,8,9 ~ Tetrahydro-7-methyl-9-oxo-5H-benzocyclohepten-2-acetic acid (6.3 g) is dissolved in 90 ml of methanol and 4.1 g of sodium borohydride in small portions added over 10 minutes with stirring at room temperature. The solution is stirred for 30 minutes, diluted with water, acidified with IN hydrochloric acid and the crude 6,7,8,9-tetrahydro-9-hydroxy-7-methyl-5H-benzocyclohepten-2-acetic acid filtered off. M.p. of the crude product 161-163 °.

60 9840/1129

100-4244

CH-COOH

CH-COOH

CH-COOH

III

CH-COOH

CH-COOH

CH COOR

III

III

CH-COOR,

609840/1 129 ORIGINAL iNSPECTED

.1 * 5

COOR

10

CH-COOR 11

R,

VI

VII

R-

R,

COOR

10

C - C-R,

VIII

f ^OOR

R.

COOR _1Λ .IV. / 10

IXa R-CH ₂ -CO-Cl

XI

¹ SLa
Jiv

XII

O Rf

(C ₂ H ₅ O) ₂ -Ρ — CH-COOR ₁₀

XIII

609840/1129
ORIGiNAL INSPECTED

Claims (1)

/ O H D 3 U t> 100-4244 claims 1. Process for the preparation of new compounds of the formula I. CH-COOH where R ₁ denotes hydrogen or alkyl with 1-2 carbon atoms, R_ denotes hydrogen or halogen with an atomic weight of less than 80, R_ and R- each represent hydrogen or together represent oxygen and R_ denotes hydrogen or alkyl with 1-4 carbon atoms or, if
are bonded to a fuel atom, and R_ to the same Koh R ₅ and R ₇ together represent an alkylene chain with 3-6 carbon atoms, or, if A is a (CH ₃ ) ^ - group, R- and R ₅ together also form a bond and R_ means hydrogen Rg for hydrogen or alkyl with 1-4 carbon atoms and
A represents a (CH ₂₎ group are wherein 609840/1129 ORIGINAL INSPECTED 100-4244 η, if R ₃ and R ₄ together denote oxygen, denotes 0 or n, if at least one of the substituents R ₅ , R ₆ and R _{7 are} alkyl with 1-4 carbon atoms or R ₅ and R ₇ together are an alkylene chain with 3-6 carbon atoms or if R ₅ , R _g and R _{7 are} hydrogen, R ₃ and R ₄ together denotes oxygen and R ₂ denotes halogen with an atomic weight of less than 80, denotes 1, or n, if R ₃ and R ₄ together form oxygen or R 4 and R _{5 together form a bond or if R 2 is} halogen with an atomic weight of less than 80 or if at least one of the substituents R 1, R 1, R 1 and R 1 is alkyl with 1-4 Carbon atoms or R ₅ and R_ together represent an alkylene chain with 3 - 6 carbon atoms, for 2_ stands or, if R ₅ and R are hydrogen, also R- and A together with the carbon atom, 6th to which they are bound, single, 2- Cycloalkylene group of the formula (CH ₃ ) T form in which
m 3 or, if R ₃ and R ₄ together represent oxygen, also means 4, R _{7 represents} hydrogen or, if Rg represents hydrogen, also represents alkyl with 1-4 carbon atoms, 09840/1129 -29 100-4244 and their salts, characterized / that one ä) for the preparation of compounds of the formula Ia, Yes ^R 2 wherein R] L and 1 * 2 have the above meaning, rI for hydrogen, alkyl with 1-4 carbon atoms II men or, if R ,. and R_ to the same co- I are bonded to a lenstoffatom, R ₅ together with R * for an alkylene chain with 3 - 6 carbons material atoms stands for hydrogen material atoms and * for hydrogen or alkyl with 1-4 carbons A for a (CH ₂ ) I group, wherein. n ^{1 is} 0 or 2 or η, if at least one of the substituents R ?, rJ I ί> T ° and R alkyl has 1-4 carbon atoms or R ^ I 5 and R ^ together denote an alkylene chain with 3-6 carbon atoms or, if R denotes halogen with an atomic weight of less than 80, also denotes 1 or, if R ₅ and R ₇ denote hydrogen, also R * and A ¹ together with the carbon atom, ο to which they are attached form a e 1, 2-cycloalkylene group of the formula (CH _{2) m} Ij wherein 609840/1129 ORIOlNAL INSPECTED 100-4244 ro means 3 or 4, form, R _{7 represents} hydrogen or, if R * represents hydrogen, also represents alkyl with 1-4 carbon atoms, Compounds of formula II, CH-COOH II wherein R ₁ , R ₂ , R *, Rg, R * and Λ ^{1 have the} above meaning, or their reactive acid derivatives cyclislert, or b) for the preparation of compounds of the formula Ib, 609840/1129 ORIGINAL INSPECTED - 31 - 100-4244 R ₁ CH-COOH Ib wherein R ₁ and R _{2 have the} above meanings, and Rl each denotes hydrogen, P denotes hydrogen or alkyl having 1-4 carbon atoms or, if R * ¹ and R * are bonded to the same carbon atom, II II Rr and R ₇ together represent an alkylene chain with Form 3-6 carbon atoms, g ¹ for hydrogen or alkyl with 1-4 carbon atoms and
represent a (CH ₂ J _n II group, wherein η, if at least one of the substituents R * ¹ , R * ¹ and rI ^{1 is} alkyl with 1 - 4 carbon II II atoms of matter or R_ and R- together one Alkylene chain with 3-6 carbon atoms, represents 1, or η, if R _{2 is} halogen with an atomic weight below or if at least one of the substituents R ₁ , R * ¹ , R * ¹ and F * ^{1 is} alkyl J. ο b II with 1-4 carbon atoms or R ₁ - II and R_ together denote an alkylene chain with 3-6 carbon atoms, denotes 2 609840/1129 100-4244 or, if R ₅ and R _{7 are} hydrogen, even II
R. II and A together with the carbon atom to which they are attached form a 1,2-cyclopentylene group of the formula (CH ₂ ) -], for hydrogen or, if R * ^{1 is} hydrogen, also for alkyl with 1-4 carbon atoms, Compounds of formula III, CH COOR III wherein R ₁ , have R, R and A above meaning R. and R ₃ ″ together represent oxygen and R _{5 represents} hydrogen or alkyl with 1-4 carbon atoms or, if IL and R ₇ to the same carbon I ^T I II are atom-bound, R _1. * And R_ form an alkylene chain with 3-6 carbon atoms or
R- and R _n . form a bond together and II stands for hydrogen and II II R- together Hydrogen or, if R ₄ and ^ _ are oxygen, means a hydrolytically cleavable radical, reduced and, if R _{0 is} a hydrolytically cleavable ο Remainder means splitting it off at the same time, or 609840 / -1129 ORIGINAL INSPECTED 100-4244 c) for the preparation of compounds of the formula Ic, III Ic wherein ₂ and R3 have the above meaning and denotes hydrogen or alkyl with 1-4 carbon atoms, from compounds of the formula IV, III CH-COOR, IV where R Besit zen R- and R_ above meaning and R is hydrogen or an acidolytically removable radical means, water and, if Rg is an acidolytically removable group, and at the same time these splits 609840/1129 ^"34 - 100-4244 the compounds of formula I obtained, if desired converted into their salts. 60 98 4 0/1129 Germany-West ~ 35 - 100-4244 (2. New compounds of the formula I, ^R l R ₃ R ₄ r R ₅ , ^ X "^" CH-COOH R ₇ ^R 2 wherein R. is hydrogen or alkyl of 1-2 carbon atoms means R »hydrogen or calogen with atomic weight below 80 means R- and R- each stand for hydrogen or together for oxygen and
R is hydrogen or alkyl of 1-4 carbon atoms or, if R ₅ and R ₇ are bonded to the same carbon atom,
Rf. And R ₇ together an alkylene chain with Form 3-6 carbon atoms,
or, if A stands for a (CH ₂ ) ₂ group, also R. and R ₁ . form a bond together and 4 ο R _{3 is} hydrogen,
R, for hydrogen or alkyl with 1-4 carbon fuel atoms and
Λ represent a (CH ₂ ) group, wherein n, if R, and R. together denote oxygen, stands for 0 or B09840 / 1 1 29 ORIGINAL INSPECTED 2 5 Λ 6 9 O 6 - 36 - 100-4244 η, if at least one of the substituents ^R 5 * ^R 6 ^{and R} 7 ^{Al5 <} yl ^with 1-4 carbon atoms or R _r and R _ß together represent an alkylene chain with 3-6 carbon atoms or if R ^, Rg and R _{7 are} hydrogen, Rj and R ₄ together denotes oxygen and R ₂ denotes halogen with an atomic weight of less than 80, denotes 1, or n, if R ₃ and R together are oxygen or R and R_ together form a bond or if R- is halogen with an atomic weight of less than 80 or if at least one of the substituents Rw R _r , R _g and R is alkyl 1-4 carbon atoms or R ₅ and R ₇ together represent an alkylene chain with 3-6 carbon atoms, represents 2 or, if R _r and R_ are hydrogen, also K, and A together with the carbon atom to which they are bonded form a 1,2-cycloalkyl group of the formula (CH ₂ ) Γ, in which m 3 or, " if R ~ and R. together stand for oxygen, also 4 means R _{7 stands} for hydrogen or, if R ^ is hydrogen, also stands for alkyl with 1 - 4 carbon atoms, and their salts. 609840/1 129 -37- 100- 3 · Remedies identified by the fact that they Compounds of the formula I or their salts. SANDOZ-PATENT-GMBH 609840/1129