IE43917B1 - 4-(9,10-dihydro-4h-benzo/4,5/cyclohepta/1,2-b/thiophen-4-ylidine piperidines - Google Patents

Abstract

Case 100-4362 n4-(9,10-Dihydro-4H-Benzo4,5!Cyclcohepta1,2-b!Thiophen- 4-Ylidene)Piperidine Compounds This invention provides new compounds of formula I, (I) wherein R1 is hydrogen or alkyl, and R2 is alkyl, useful as analgesics.

Description

This invention relates to benzocycloheptathiophenes.

The present invention provides compounds of formula I, wherein R^ is hydrogen or alkyl of 1 to 4 carbon atoms, is alkyl of 1 to 4 carbon atoms.

When R^ is alkyl, it is preferably methyl or ethyl.

R2 is preferably in the 6 or 7 position of the benzo[4,5]cyclohepta[1,2-b]thiophene nucleus. R2 is preferably } methyl. £ Especially preferred compounds are those wherein R^ is hydrogen or methyl, and R2 is methyl in the 6 or 7 position.

The present invention also provides a process for the production of compounds of formula I which comprises a) for the production of a compound of formula la, R2 is as defined above, splitting off water from a compound of formula IX, I wherein R^ and R^ are as defined above, or b) for the production of a compound of formula lb, λ o C i « is tt w J· * lb wherein Rg is as defined above, splitting off the group Rg from a compound of formula III III wherein Rg is as defined above, and Rg is a group capable of being split off.

Process a) may be effected in conventional manner for the dehydration of analogous carbinols, for example using a suitable dehydrating agent optionally in the presence of an inert solvent, e.g. a lower alcohol. As dehydrating agents may be used for example mineral acids, or strong organic acids or anhydrides thereof or acid halides thereof. ' Process b) may be effected in conventional manner for the splitting off of an amino protecting group from a heterocyclic amine, for example using hydrogenolytic methods or solvolytic, especially hydrolytic methods. Suitable groups which may be split off under solvolytic or hydrolytic conditions include alkoxycarbonyl, especially lower alkoxycarbonyl, aryloxycarbonyl, or nitrile. The solvolysis may, according to the type of group Ro used, be preferably effected in an acid medium, for example in the presence of a strong mineral acid or in an alkaline medium, for example in the presence of 1C an inorganic base. Suitable groups which may be split off under hydrogenolytic conditions include, for example optionally substituted benzyl groups. The hydrogenolysis may be effected in conventional manner, for example using catalytic hydrogenation in the presence of a platinium or palladium catalyst.

The starting materials may be obtained, for example, as follows ία') Compounds of formula II may be obtained by reacting a ketone of formula IV wherein 1?2 is as defined above, with a Grianard compound of formula V, V x-Mg ta-R' wherein R^ is as defined above, and X is chlorine, bromine or iodine the resulting complex being then hydrolysed, b') Compounds of formula III may be obtained by (i) reacting a ketone of formula IV with a Grignard compound of formula VI X-Mg N-R '4 VI wherein is methyl or a group capable of being split off under hydrogenolytic conditions, and X is as defined above the resulting complex being hydrolysed, and (ii) splitting off water from the resulting product in a manner analogous to process a), and (iii) converting any group which is methyl in the resulting product in conventional manner, e.g. using a chloroformic ester, or bromocyanide, into a group R^ which is capable of being split off under solvolytic conditions.

Insofar as the production of any starting material is not particularly described these compounds are known. 2917 or may be produced and purified in accordance with known processes, or in a manner analogous to processes described herein, e.g. in the Examples, or to known * processes.

Free base forms of compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation include hydrochloric acid, and fumaric acid.

In the following Examples ill temperatures are in degrees Centigrade and are uncorrected.

EXAMPLE 1: 4y_(9 ^lO-dihydro-T^methyl^AH^benzo£<,5]_ S®t!lXiSiES.Ei§iUS A solution of 21.5 g of 9,10-dihydro-7-methyl5 4-(l-methyl-4-piperidyl)-4H-benzo[4,5]cyclo,hepta[l ,2-b] thiophen-4-ol in 210 ml of acetic acid anhydride is heated to the boil for 18 hours, is concetrated by evaporation at reduced pressure and the residue is poured onto 1 litre of icewater. The resulting solution is adjusted to pH 14 with caustic sodf. -!olutic">., stirred for 30 minutes at room temperature and extracted with methylene chloride. The extracts are washed neutral with water, dried over potassium carbonate, and- concentrated by evaporation. The resulting residue is dissolved in 500 ml of methylene chloride and is filtered over 200 g of aluminium oxide of activity II-III. After concentrating the solvent by evaporation, the title compound remaining as residue is converted into its fumarate in methanol and is recrystallized once. M.Pt.: 200° - 201°.

The starting material may be produced as follows:a) A solution of 52 ml of bromine in 300 ml of benzene and a solution of 5.0 g of α,α-azoisobutyronitrile are simultaneously added dropwise within 40 minutes to a boiling solution of 131 g of 2,4-dlmethyl-benzonitrile in 600 ml of anhydrous benzene. The reaction - 7 25 <23*7 mixture is stirred for 3.5 hours at the boiling temperature and for 12 hours at room temperature. At 70° 183 ml of triethyl phosphite are added dropwise during the course of 30 minutes while stirring, and the temperature is slowly raised to 115° - 120°, whereupon the resulting ethyl bromide is distilled off with the benzene. Stirring is continued at this temperature for 3 hours. The reaction mixture is fractionated in a high vacuum, whereupon a mixture of (2-cyano-5-methylbenzyl)- and (4-eyan.o-3-mei.hylbenzyl)phosphonic acid diethyl esters is obtained at 165° - 172°/O.l Torr. b) A solution of 15.7 g of the mixture, obtained in step a) and 65 g of 2-thiophenaldehvde are added dropwise during the course of approximately 20 minutes to a suspension of 37 g of sodium methylate in 1000 ml of Ν,Ν-dimethyl^formamide at 35° to 40°. The reaction mixture is stirred for another hour at 40°, cooled to 20° and poured into icewater. The organic products are extracted with ether and the extracts are washed i with saturated common salt solution, dried over / magnesium sulphate and concentrated by evaporation.

The volatile components are removed in a high vacuum at 100° - 110° and a mixture of 4-methyl-2-[2-(2thienyl)vinyl)benzonitrile and 2-methyl-4-[2-(28 £ 3 9 1 ? thienyl)vinyl]benzonitrile is obtained. The 2-methyl isomer is separated by crystallisation in ethanol from the mixture and the enriched 4-methyl-2-[2-(2thienyl)vinyl]benzonitrile is distilled in a high vacuum. i B.Pt. - 210° - 22O°/O.l Torr. c) A solution of 45 g of the distillate obtained in step b) in 500 ml Of anhydrous ethanol is hydrogenated in the presence of 15 g of 5% palladium on charcoal at 100° and 25 Atm for'24 hours. After filtering and LO concentrating the filtrate by evaporation, the hydrogenation product, 4-methyl-2-[2-(2-thienyl)ethyl] benzonitrile containing a small amount of 2-methyl4-[2-(2-thienyl)ethyl]benzonitrile is further worked up without any purification. d) A solution of 33 g of the product obtained in step c) in 50 ml of diethylene glycol monoethyl ether is added dropwise to a solution of 74 g of potassium hydroxide in 200 ml of diethylene glycol monoethyl ether at 180° within 30 minutes. The reaction mixture is stirred for 3 hours at the same temperature, cooled to 100°, and poured into 1 litre of water. The resulting solution is washed with ether (after cooling to room temperature). The aqueous solution is £ 3 χ 7 adjusted to pli 1 with 4 N sulphuric acid white cooling and is extracted several tines with ether. The extracts are washed with water, dried over magnesium sulphate and concentrated by evaporation. The residue is dissolved in 1 litre of methylene chloride, filtered through silica gel and concentrated by evaporation. 4-methyl-2-[2-(2-thienyl)ethyl]benzoic acid (slightly contaminated with 2-methyl~4-[2-(2-thienyl)ethyl]benzoic acid) crystallizes from tha evaporation residue from ether/petroleum ether. M.Pt.: 75° - 7S°. e) A mixture of 22 g of 4-methyl-2-[2-(2-thienyl)ethyl]benzoic acid and 110 g of polyphosphoric acid is stirred for 20 minutes at 30°, cooled, poured into 300 mi of water and is extracted several times with ether. The ethereal solutions are washed with water, % ammonia solution and again with water, are dried over magnesium sulphate and concentrated by evaporation.

The resulting residue is purified by column chromatography over 600 g of neutral aluminium oxide activity stage II-XII with methylene chloride as eluant and the resulting 9,10-dihydro-7-methyi-4H- / benzo[4,5]cyclohepta[l,2-b]thiophen-4-one is used in the next reaction stage without further purification. ζ 3 9 ί 7 f) Portions of 10 ml of anhydrous tetrahydrofuran are added to 3.1 g of magnesium filings and the latter are then catalysed with iodine and 1 to 2 drops of ethylene bromide. Upon commencement of the reaction, a solution of 17.4 g of 4-chloro-l-me'thylpiperidine in 70 ml of anhydrous tetrahydrofuran is added dropwise such that the reaction is maintained. After the dropwise addition, the reaction mixture is stirred for 2 hours at the boiling temperature, cooled to ° and then at ahis vemperature a solution of 15.o g of 9,10-dlhydro-7-methyl-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one (obtained in step d] in 60 ml of anhydrous tetrahydrofuran is added dropwise. The reaction mixture is subsequently stirred at room. temperature for 2 hours, poured into 300 ml of 2OS ammonium chloride solution and extracted with ether several times. The ethereal solutions are washed with water, dried over potassium carbonate and concentrated by evaporation. The 9,l0-dihydro-7-methyl-4-(1-methyl20 4-piperidyl)-4H-benzo[4,5]cyclohepta(l,2-b]thiophen4-ol remaining as solid residue is reerystallized from ether/petroleum ether. M.Pt.! 151° - 154° (sintering 147°). 3 017 In analogous manner to Example 1, the iolloving 4-(9,10-dihydro-4II-benzo[4,5]cycloheptai1,2-b]th.iophen4-yliden)-1-alkylaiperidine derivatives may be obtained by splitting off water from the corresponding 9,10-dihydro5 4-(l-alkyl-4-piperidyl)-4H-benzo[4,5)cyolohepta[1,2-b]thiophen-4-ols, whereir in formula I:- Sx, No.R1 ' R2 --— M.Pt. --- IA ch3 6-CH3 KEu*: Z** *** from 200° ID CH3 8-CH3 HPu*: Z** from 231° 1CC2H5 7-CH3 *** · ID nC4Hg 7-CH3 ★ A* * HFu = Hydrogenfumarat ** Z = Decomposition *** = Elemental C and H analysis agrees with calculated, value (free base form) EXAMPLE 2: ^-^g^lO-dihydro-VgmethylgiK-benzo(4^51cyclohggta (,1 j.2-b)_fhioghen-42yliderie) piperidine A solution of 8.0 g of chloroformic acid ethyl ester in 30 ml of anhydrous benzene is added dropwise within 30 minutes to a solution, preheated to 40°, of .9 g of 4-(9,10-dihydro-7-methyl-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidine in 150 ml of anhydrous benzene. The reaction mixture is stirred for one hour at the same temperature and for 3 hours at the boil, is cooled to-room temperature and washed with 0.5 N hydrochloric acid, and water. Ths o^nzene oolufi-; is dried over sodium sulphate and concentrated by evaporation to yield crude 4--(9,10-dihydro-7-methyl-4Hbe nzo[4,5]cyclohepta[1,2-b]thi oph en-4-y1idene)-115 piperidinecarboxylic acid ethyl ester. g of crude 4-(9,10-dihydro-7-methyl-4H-benzo [4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-l-piperidinecarboxylic acid ethyl ester is taken up in 250 ml of 48¾ hydrobromic acid and is heated to the boil for 30 minutes. Upon cooling, the reaction solution is diluted with water, made alkaline with concentrated caustic soda solution and is extracted with methylene chloride. The organic solution is washed with water, dried over sodium sulphate and concentrated by evaporation. The title 2 9X7 compound remaining as residue is converted into the hydrogen fumarate. M.Pt.: decomposition from 210° (ethanol).

EXAMPLE 3; CapauleS-Conteining £~1S£ic~dihydro27pmethyly £5l!i®2"Ol£'.5T_cyclohe£ta.£li2-32].thioc>hen~4-_ ylide ne me thyljsiperidine Compos! tion: 4-(9,20-dihydro-7-m.-.-.thyl-4H-benso [4,51cycioheota'1,2-:/ thicphen-4y 1 i d r. e)-l-msth"lpj.p <_· r i d i n e Powdered lactose Corn Starch Magnesium stearate Highly dispersed silicic acid 1.0 mg/dc.-e 72.5 .0 1.0 » 0.5 The ingredients were mixed and filled into capsules (hard gelatine). 43Si? t The compounds of formula T exhibit pharmacological activity. In-particular the compounds of formula I in general exhibit analgesic activity as indicated, for example, in standard tests, for example in the mouse on p.o. administration of from 0.5 to 20 mg/kg animal body weight in the phenylbenzoquinone syndrome test and in the mouse on p.o. or s.c. administration of from 3 to 50 mg/kg animal body weight in the tail flick test.

The compounds wherein R^ is hydrogen or’ methyl exhibit activity greater than expected for such compounds in the above tests.

The compounds of formula I are therefore indicated for use as analgesics, possibly for the treatment of acute or chronic pains.

For this use an- indicated daily dose Is from about 10 to about 100 mg, conveniently administered in divided doses in unit dosage form containing from about 0.5 to about 50 mg, or in sustained release form.

Additionally the compounds exhibit antagonism against various biogenic amines, as indicated in standard tests, for example histaminolytic, serotonin and/or acetylcholine antagonistic properties in well known histamine, serotonin and acetylcholine toxicity tests in guinea pigs on administration s.c. of from 0.01 to 20 mg/kg animal body weight. £3527 The compounds arc- therefore furth.·:. indicated for use as antaminic agents, possibly as an anti-histaminic or for the treatment of migraine. For this use an indicated daily dose is £-om about 10 to about 100 mg, conveniently administered in divided doses in unit dosage form containing from about 0.5 to about 50 mg, or in sustained release form.

The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.

Such acid addition salt forms exhibit the same .order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.

A group of compounds comprise those of formula I other than 4-(9,10-dihydro-6-methyl-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidine. A subrgroup comprises compounds of formula I other than those wherein R^ is hydrogen or methyl.

In another group of compounds R^ is methyl. In a sub-group R^ is hydrogen. In another sub-group R^ is alkyl.

The Example 1 compound shows particularly interesting activity. - 16 Further the. present invention also provides a process for the production of a pharmaceutical composition which comprises mixing a compound of formula I in free base form or in pharmceutically acceptable acid addition salt form in a purity sufficient for pharmaceutical acceptability with a pharmaceutical carrier or diluent.

The pharmaceutical compositions may be in a appropriate solid or liquid form for enteral, preferably oral, or parenteral application. If desired retard agents may be present..Examples of such pharmaceutical compositions for enteral application «re powders, granulates, tablets, capsules, dragees, syrups... drops, and suppositories, and for parenteral application are injectable solutions, or injectable aqueous or oil-based suspensions. For oral application unit dosage forms such as tablets containing 0.5, 1, 2 or 5 mg of compound per dose are particularly suitable.

The production of the pharmaceutical compositions may be effected in conventional manner known in the galenical art, using solid or liquid pharmaceutical diluents or carriers. Solid carriers or diluents include physiologically tolerable substances like mannitol, lactose, starch, organic or inorganic calcium salts.

If a retard effect is required, then the release of the active agent may be delayed using physiologically neutral polymers such as cellulose derivatives, or synthetic polymers^, fatty alcohols, and other waxy substances known in the art. The conventional substances for the production of suppositories may be'used. As liquid pharmaceutical carriers or diluents there may be used water, ethanol or physiologically tolerable Oils. Additionally, other pharmaceutical diluents and carriers may be used, for example the usual tabletting agents such as binding agents, e.g. polyvinyl pyrrolidone, dispersing agents, lubricating agents such as magnesium stearate, and preserving agents, buffering substances, and flavouring agents.

Claims (10)

1. CLAIMS 1. A process for the' production of a compound of formula I, wherein R^ is hydrogen or alkyl of 1 to 4 carbon atoms, is alkyl of 1 to 4 carbon atoms. which comprises a) for the production of a compound of formula la. wherein R 1 is alkyl of 1 to 4 carbon atoms, and R 2 is as defined above, splitting off water from a compound of formula II, I wherein R^ and R^ are as defined above, or 5 b) for the production of a compound of formula lb, H wherein R„ is as defined above, z > splitting off the group R^ from a compound of } formula III, wherein R 2 is as defined above, and Rg is a group capable of being split off.

2. A process for the production of a compound of formula I, as stateu in claim 1, substantially as haxai-.ibefore described with reference-to any one of the Examples.

3. A compound of formula I, whenever produced by a process according to claim 1 or 2.

4. A compound of formula X, as defined in claim 1.

5. A compound of claim 4 which is 4-(9,10-dihydro7-methyl-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)1-methyIpiperidine. δ.

6. A compound of claim 4 which is 4-(9,10-dihydro7- methyl-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)piperidine.

7. A compound of claim 4 which is 4-{9,10-dihydro8- methyl-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)1-methyIpiperidine. 42917 7.

8. A compound of claim 4 which is 4-{9,10-dihydro6- methyl-4H-benzo[4,5}cyclohepta[l,2-b]thiophen-4-ylidene)1-methylpiperidine. * 8.

9. A compound of claim 4 which is 4-,10-diL.ydro5 7-methyl-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)1-ethylpiperidine. 1θ· A compound of claim 4 which is 4-(9,10-dihydro7- methyl-4K-benzo[4,5)cyclohepta Ll,2-b]thiophen-4-ylidene) 1-n-butylpiperidine. iO ll. A compound of claim 4 other than 4-(9,10-dihydro6-methyl-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene) piperidine . 12. A compound of claim 4, wherein R^ is hydrogen, and R 2 is methyl. 15 1 3. A compound of claim 11, wherein R^ is hydrogen, and R 2 is methyl. 14. A compound of claim 4, wherein R. is alkyl, and 1 ί R 2 is methyl. f £391^ t 15- A compound of claim 4, wherein R^ is other than hydrogen of methyl. 16. A compound according to any one of claims 3 to 15 in free base form. , 5 17. A compound according to any one of claims 3 to 15 in acid addition salt form. 18. A pharmaceutical composition comprising a compound according to any one of claims 3 to 15 in free base form or in pharmaceutically acceptable acid addition 9. 10 salt form as active agent in association with a pharmaceutical carrier or diluent. 19. A pharmaceutical composition according to claim 18 in unit dosage form' containing from 0,5 to 50 mg of I the active compound.

10. 15 20. A pharmaceutical composition substantially as hereinbefore described. 21. A process for the production of a pharmaceutical composition which comprises mixing a compound of claim 4 in free base form or in pharmaceutically acceptable 20 acid addition salt form in a purity sufficient for pharmaceutical acceptability with a pharmaceutical carrier or diluent. 45017 22. A pharmaceutical composition whenever prepared by a process according to claim 21.