NZ208607A

NZ208607A - Bicyclo(3.2.1)octane-3-carboxylic acid derivatives and therapeutic compositions

Info

Publication number: NZ208607A
Application number: NZ208607A
Authority: NZ
Inventors: R Boigegrain; J Chenu; J Simiand; J-C Vernieres
Original assignee: Sanofi Sa
Priority date: 1983-06-22
Filing date: 1984-06-21
Publication date: 1986-08-08
Also published as: JPS624378B2; KR870002052B1; EP0130882B1; HU191677B; DK280284A; ATE24711T1; PH22596A; ES532983A0; AR242370A1; DK280284D0; PL248314A1; NO158254C; DD235447A5; AU564961B2; OA07728A; FI842538A0; FR2547814B1; FR2547814A1; HUT34428A; IL71905A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £08607 208607 Priority Date(s): Complete Specification Filed: Class: £.<??. £ f/>.. ?/;< t] ..QAf&y/i# Publication Date: .... £.?. !^)9.]??!*.... , P.O. Journal, No: ...(P.X£ t Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "BICYCLO (3.2.1.) OCTANE CARBOXYLIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC APPLICATION THEREOF" I-jWE SANOFI, of 195 Route d'Espagne, Toulouse, France of French nationality hereby declare the invention, for which ~I/we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement ~1~ (followed by pa?e TA.> 208607 l<" This invention relates to new bicyclo(3.2.1.)-5 octane carboxylic acid derivatives, to a process for their preparation and to their application in human and veterinary medicine. The compounds of this invention have the following general structural formula: 10 COZ ) CDC (i) in which: 15 R represents a straight- or branched-chain lower alkyl radical, Z represents a group OX in which X is hydrogen or em alkali metal, or Z may also represent a group in which R^ and 20 R^, which may be the same or ^ different, represent hydrogen or a lower alkyl radical. By "lower alkyl radical" is meant a hydrocarbon radical having 1-4 carbon atoms. Said compounds may exist under the form of several 25 stereoisomers. This invention concerns both the individual isomers and their admixture. Compounds having the .same bicyclo octane carboxylic structure are known. Thus, BUCHTA and BILLENSTEIN (Ann. Chem., 1966, 692, 30 42-52) prepared compounds in which Z and R have the following meanings : /V ^ call V- 10 15 20 25 R Z COOC2H5 OC2H5 COOC2H5 OH COOH OH H OC2H5 H OH TAKEFUMI and OSAMU (Chem. Pharm. Bull., 1978, 26, 8, 2589-2593) effected the synthesis of derivatives in which R is H, and Z represents C^H^ or OCgH^. NELSON, Mc EVEN and LAWTON (J. Org. Chem., 1969, 34, 5, 1225-1229) prepared the following derivative: CE C0DC2H5 However, the derivatives described by BUCHTA et al., TAKEFUMI et al. , and NELSON et al were not submitted to any toxico-pharmacological investigation. This invention relates also to a process for the preparation of the aforesaid compounds of the formula (I) comprising converting methyl 8-oxo-bicyclo (3.2.1.) octane -3-carboxylate of the formula (II) c> COOCH. (II) via reduction and hydrolysis, to an acid of the formula (III) COQH , (III) converting resulting acid (III) wigh a strong base, to give an intermediate organo-metallic compound of the 30 formula (IV) 3 208607 COOH (IV) 10 15 20 25 30 in which B is an alkali metal, and then, by action of an alkyl halide R-X in which R has the aforesaid described meanings, converting said intermediate organo-metallic compound (IV) to a compound of the formula (I) in which Z represents OH. Theoonpounds of the formula (I) in which Z is other than OH are prepared by salification, esterification or amidification, according to conventional methods. The compound of the formula (II) was prepared according to the method disclosed by NELSON et al., (J. Org.Chem., 1969, 34, 1225-1229) used to prepare the ethyl ester. The reduction of said compound, to give the compound of the formula (III) , is effected by action of a reducing agent, typically potassium hydroxide and hydrazine. Said compound of the formula (III) was described by E. BUCHTA and co-workers (Ann.Chem., 1966, 692, 42, 52), but was prepared by the latter via a different route. The strong base used to obtain the compound of the formula (IV) may be sodamide, lithium diethylamide or lithium diisopropylamide. As a modification, it may be interesting -to convert the acid of the formula (III) to a derivative such as the nitrile or an ester, prior to reacting same with a strong base. - In this, the action of the organo-metallic compound and the alkyl halide provides a derivative having the general formula (V): v czx (V) « in which Y represents a nitrile or ester function, which 4 is then converted to a derivative of the formula (I), by conventional methods. The following non-limiting Examples Illustrate the invention. 5 EXAMPLE 1 3-Methyl-bidyclo(3.2.1.)octane-3-carboxylic acid (Derivative n°l) a) Preparation ofmethyl8-oxo-bicYclo (3.2.1.) octane -3-carboxYlate_.of ^the_formula_£lI) 10 To a solution of 53 g (0.386 mole) freshly distilled N-cyclopentenyl pyrrolidine and 118 ml (0.85 mole) anhydrous triethylamine in 400 ml dry acetonitrile ,, is added, under a nitrogen atmosphere, a solution of 100 g (0.386 mole) methyl (i,p>-dibromoisobutyrate in 250 ml dry 15 acetonitrile, while maintaining the temperature of the mixture below 35°C. The reaction inixture is then heated to 60°C for 15 hours, after which acetic acid (28 ml) in water (150 ml) is added thereto, and the whole is refluxed for 1 hour. The acetonitrile is removed in vacuo, and 20 water (1000 ml) is added to the mixture. Repeated extractions with methylene chloride and distillation in vacuo give 45 g (Yield: 64%) of a product having a boiling point/0.5 mm fig of 110-114°C. b) Preparation of bicyclo(3.2.1.)octane -3-carboxylic 25 acid of the formula (III). A mixture of 32 g (0.176 mole) of the derivative of the formula (II) obtained in (a), 31 g potassium hydroxide, 21 ml 98% hydrazine hydrate and 220 ml diethylene glycol is gradually heated to 190°-200°C; after which 30 beating of the mixture As maintained at 200®C for a further 4 hours. The water and the methanol are removed by distillation in the course of this operation. 'The resulting mixture is poured over 1000 ml water. The aqueous solution is washed with ether and then made acidic 35 with concentrated hydrochloric acid. The acid of the 5 formula (III) is extracted with methylene chloride, to give 23.4 g colorless crystals (Yield: 87%) having a melting point of 94 °C. c) Pregaration_of_methYl_bicYcloX3i2ili^octane-32 The acid of the formula (III) obtained above in (b) (23 g, 0.15 mole) is refluxed for 20 hours with 75 ml dichloroethane, 22 ml methanol and 1 ml concentrated sulfuric acid. Ether (300 ml) is added in the cold, and 10 the resulting material is washed with water and then with 2N potassium bicarbonate. Distillation of the organic portion gives 23 g (Yield: 91%) methyl bicycl6(3.2. 1.)octane-3-carboxylate, having a boiling point/0.1 mn Hg of 64°—65®C. 15 d) Preparation of methyl_37methYl-bicyclo(3.2.1.)- octane-3-carboxylate Under a dry nitrogen atmosphere, 110 ml (0.17 mole) butyllithium dissolved in hexane (concentration 1.56 M) , 120 ml anhydrous tetrafuran (THF) are added to a three-20 necked flask. The solution is cooled to 0°C, and a solution of 17.2 g (0.17 mole) dried diisopropylamine in 30 ml THF is added thereto. This is stirred 15 minutes at 0°C, after which the material is cooled to -70° -B0°C, 23 g (0.137 mole) of the ester obtained in (c) dissolved 25 in 20 ml THF is slowly added thereto, and the mixture is then maintained at a temperature of -709 -80°C for 1 hour. 24.2 g (0.17 mole) methyl iodide in 25 ml hexa-methyl phosphoro-triamide (H.M.P.T.) is added at the same temperature. The temperature of the mixture is 30 allowed to warm to between -20° and -10°C, and the mixture is then left aside for 4 hours. The mixture is hydrolyzed. with water and then with benzene. The organic phase is washed repeatedly with a 10% hydrochloric acid solution, and then with 2N potassium 35 bicarbonate. The organic portion is removed; distillation 6 gives 24 g (Yield; 92%) methyl 3-methy 1-bicyclo(3.2. 1.) octane-3-carboxylate, b.p./0.05 mm Hg = 45°-.50°C. e) 3-MethYl-biCYcloX3i2ili^octane-3-carboxY3ic_acid 24 g of the ester obtained in Xd) (0.133 mole) are 5 refluxed at 160°C for 5 hours with 14.5 g potassium hydroxide and 1000 ml glycol. Water (200 ml) is then added in the cold, and the material is extracted with ether. The separated aqueous phase is made acidic. The acid is extracted with henzene, 10 to give 14 g colorless crystals (Yield: 62%) having a melting point of 109-110°C (Hexane). EXAMPLE 2 Sodium 3-methyl-blcyclo(3.2.1,)bctane-3-carboxylate (Derivative n°2) 15 16.8 g (0.01 mole) of the acid prepared above in Example 1 are added to a sodium methoxide solution prepared from 2.3 g sodium in methanol. The mixture is heated at 50°C for 15 minutes, and the methanol is then evaporated in vacuo. The colorless sodium 3-methyl-20 bicyclo(3.2.1.)octane-3-carboxylate crystals are washed with ether and dried (Yield: 95%). M.p. 270°C. EXAMPLE 3 3-Ethyl-blcyclo(3.2.1.)octane-3-carboxylic acid (Derivative n°3) 25 Using the procedure described in Example 1, the following compounds were prepared sequentially from the suitable reagents: methyl 3-ethyl-bicyclo(3.2.1.)octane-3-carboxylate (b.p./4.5 mm Hg)= 9l-92°C); and then 3-ethyl-bicyclo (3. 2.1.) octane-3-carboxylic acid (M.P. Bl-82* C). 30 EXAMPLE 4 " 3-Isopropyl-bicyclo(3.2.1.)octane-3-carboxylic acid (Derivative n°4) Using the procedure described in Example lf the following conqpounds were prepared sequentially from the 35 suitable reagents : methyl 3-isopropyl-bicyclo(3.2.1.)- octane-3-carboxylate (b.p./5 mm Hg *= 94-96° C) / and then 3-isopropyl-bicyclo(3.2.1.)octane-3-carboxylic fccid, which has a melting point of 72-74°C. v EXAMPLE 5 3-Methyl-bicyclo (3 .-2.1.) octahe-3-carboxamlde (Derivative n°5) 7' 8.7 g (0.0517 mole) of acid prepared as described . in Example 1, dissolved in 50 ml dichloroethane and 10 ml thionyl chloride are refluxed for 5 hours. The resulting material is evaporated to dryness and the acid chloride is distilled in vacuo ^b.p./0.3 mm flg = 45-48°C). It is then added to a dichloroethane solution saturated with ammonia. After concentration to dryness, the amide is washed with water, to give 48 g colorless crystals (Yield: 56%) which have a melting point of 110-111°C (isopropyl ether) EXAMPLE 6 ' 3-Ethyl-bicyclo(3.2.1.)octane-3-carboxamide (Derivative n°6) / Using the procedure described in Example 5, 3-ethyl-bicyclo(3.2.1.)octane-3-carboxamide , M.P. = 101°C, was prepared from the confound of Example 3. EXAMPLE 7 3-Isopropyl-bicyclo(3.2.1.)octane-3-carboxamide (Derivative n°7) Using the procedure described in Example 5, 3-isopropyl-bicyclo (3.2. 1„}octane-3-rcarboxamide, M.p. = 142°C, was prepared from^the.compound of Example 4.. EXAMPLE 8 . N-Methyl 3-methyl-bicyclo(3.2.1.)octane-3-carboxamide (Derivative n°8) 7 g "(0.037 mole) of the acid chloride of 3-methyl-bicyclo(3.2.1.)octane-3-carboxylic acid prepared as described in Example 5, dissolved in 70 ml dfchloroethane, are treated with 46.6 g methylamine and 5.2 ml triethyl- 8 amine at a temperature of 0®C. The mixture is then left aside for 4 hours. After evaporation of the solvent, water (50 ml) is added, and the amide is extracted with ether and purified by percolation through a silica gel 5 column, to give 5.1 g colorless crystals (Yield: 76%) which have a melting point of 91°C. The results of toxicological and pharmacological tests reported below demonstrate the useful properties of the derivatives of this invention, particularly 10 their low toxicity and excellent tolerance, together with important anticonvulsant and antianoxemic properties. • Thus, this invention includes also within its scope a therapeutic composition having in particular anticonvulsant and antianoxemic activities, comprising, as 15 active ingredient, a derivative of the formula (I). All toxico-pharmacological tests were conducted in male mice of CHARLES RIVER <CD1) strain. Toxicological investigation The compounds of this invention benefit from an 20 excellent tolerance and a low toxicity. Thus, the LDc-q , determined orally in mice by the Finney method (Probit analysis. University Press Cambridge, 1971) is 3000 mg/kg for derivative n®5 and in excess of 1000 mg/kg for all compounds of this invention. 25 In addition, the tests conducted in the course of acute, chronic, subchronic, delayed toxicity tests and teratogenicity tests failed to provide evidence of any anomaly. Within the scope of this investigation, the sedative 30 activity of the compounds of this invention was determined; the rotating cylinder test was used for this purpose (Boissier, J.R., Therapie "1958, 13, 1074). This test is designed to evaluate the aptitude of the animals to coordinate their motions. It uses a wooden 35 cylinder (4.8 cm diameter) rotating at a speed of 4 rpm. 208607 The test is conducted with mice having a body weight of about 22 g. The products are administered orally to different groups of 10 animals. The latter are placed on the apparatus 15 minutes after administration of the 5 product. The percent mice which lose their equilibration reflex — i.e., which become incapable of maintaining themselves on the cylinder for a period of time of 2 minutes — is recorded. Using the Finney method, a neurotoxic dose 50 10 (NTD^q) is calculated , which dose expresses the mean level for the first neuromuscular attacks under the influence of the test material. The NTDj.q thus determined are the following: Compound n°2 = 600 mg/kg 15 5 = 365 mg/kg 6 =4 00 mg/kg 7 =230 mg/kg 8 =500 mg/kg Pharmacological investigation 20 I - AntigOjivuigao^_||g^iyity 1) Pentetrazole_test This test was conducted with groups of 10 mice kept fasting since the previous day and placed in individual cages, according to the method disclosed by Cheymol (J., 25 Acta Pharmacol., 1950, 2, 1-55). The treatments are conducted orally 15 minutes prior to the intraperitoneal injection of a pentetrazole solution (125 mg/kg). The percent protection against the tonic spasms is recorded. The efficient dosages 50 30 (ED^q) calculated according to the Finney method, expressed as mg/kg body weight, are as follows: Compound n°2 = 90 Compound n°7 = 120 5 = 53 8 = 115 6 = 75 10 For comparative purposes, the ED^q of sodium valproate, a highly efficient anticonvulsant agent, is 200 mg/kg. 2) §U£ramaximal_electric_shpck_. 5 This experiment is conducted according to the test of Swinyard et al., (Am.J.Pharmacol., Ther., 1952, 168-175). The treatments are administered orally to groups of 10 mice, 30 minutes prior to the supramaximal electro-shock (dc current, 50 HZ, 60 volts, for 0.4 sec.) 10 supplied by intra-auricular electrodes. The number of animals in each group which fail to exhibit a tonic hyperextension on transcranial electric stimulation is recorded, and the (as mg/kg) is determined. Compound n°2 = 400 15 5 = 210 6 = 210 7 = 260 B = 310 3) Bicuculline_test 20 This test was conducted according to the method dis closed by P£rez de la Mora and Tapia (Biochem. Pharmacol., 1973, 19, 303-310). The treatments were administered orally to groups of 10 mice, 30 minutes prior to intra- : venous bicuculline injection (0.65 mg/kg). The onset of 25 the tonic convulsions was noted during the 30 minutes that followed the bicuculline injection. The ED^q (mg/kg) thus determined are as follows: Compound n°5 = 68 6 = 61 30 7 = 145 8 = 75 4) ^-Mercagtogrogionic_acid_test ^-Mercaptopropionic acid is an inhibitor of glutamate-decarboxylase (GAD), en enzyme which catalyzes 20^601 n the conversion of glutamate to y -aminobutyric acid (GABA). Its action is thus reflected by a decrease of the GABA level and by the onset of generalized tonic-clonic fits 3-4 minutes after_ . its administration. 5 ^-Mercaptopropionic acid was administered to the mice by the I.P. route, at a dosage of 60 mg/kg. The treatment for the test compounds is administered orally 15 minutes prior to the (V -mercaptopropionic acid injection. The EDj-q (as mg/kg) thus determined are as follows: 10 Compound n°2 — 90 5 = 30 6 = 60 7 = 120 8 = 70 15 II - ^ntianoxe^ig_§gJiyitY This activity was investigated using the confinement anoxemia method. Mice (20 per group) are placed in a hermetically sealed, xiormobaric, normoxic , 200 ml enclosure 20 (glass jar). All treatments are administered intraperi-toneally, immediately prior introduction into the enclosure. The animal is considered dead at the time of the respiratory arrest. Since the jars chosen are very small, the motor 25 activity of the animals is extremely reduced which, theoretically, rules out any possible positive result due to a sedative effect. The survival time of all the animals is noted in each group. This time is increased by a factor of 15% for 30 derivative n°2, and of 25% for derivative n°5. It is apparent from the above toxicological and pharmacological investigations that the therapeutic index of the compounds of this invention is highly favourable because, as was found for all the compounds, the toxic 35 and neurotoxic dosages are very remote from the ED^'s. 2 08 6 0 7 12 In addition, the compounds of this invention possess interesting anticonvulsant and antianoxemic activities which make them highly therapeutically valuable. The therapeutic composition may be formulated, for oral administration, as tablets, coated tablets, capsules, drops, granules or syrups. It may also be formulated, for rectal administration, as suppositories and, for parenteral administration, as injectable solutions. Each unit dose contains advantageously 0.050 - 0.500 g active ingredient, the daily dosage regimen varying from 0.050 g to 3.00 g active ingredient, depending on the age of the patient and on the severity of the condition treated. Non-limiting Examples of pharmaceutical formulations of the therapeutic composition of this invention are given below: 1. Tablets Derivative n°2 : 0.200 g Excipient : calcium silicate, polyvinyl pyrro- lidone, magnesium stearate, talc, corn starch, titanium dioxide, cellulose acetophthalate. 2. Coated tablets Derivative n°5 : 0.100 g Excipient : levilite starch, gelatin, magnesium stearate, shellac, talc, gumarabic, sucrose, titanium dioxide. 3. Capsules Derivative n°6 : 0.150 g Excipient : Talc, magnesium stearate. 4. Syrup ' Derivative n°5 : 1.00 g Flavoured excipient, sufficient to make 100 ml. </div>

Claims

<div class="application article clearfix printTableText" id="claims">
2 08 607
13
5. Injectable solution 

Derivative n°7 ; 0.150 g 

Isotonic solvent, sufficient to make 5 ml
6. Suppository 

Derivative n°8 : 0.100 g 

Semi-synthetic semi-glycerides, to make 1 suppository. 

In view of its neuropsychotropic activity spectrum, endowed with substantial anticonvulsant and antianoxemic effects while respecting the patient's alertness, the therapeutic composition will be advantageously used, 

both in adults and in children, for the treatment of acute or chronic thymic disorders such as cyclothymia, manic-depressive psychosis, manic fits, depressive conditions, relapsing melancholia, in various psychotic manifestations, in mood and behavioral disorders, in sleeping disorders and in any forms of epilepsy, as wsll as in the case cf disorders -related to cerebral ageing. 

208607 

14 

WHAT +/WE CLAIM 1S:- 

C L h I M -6 

1. Bicyclo(3.2.1.)octarve-3-carbaxylic acid derivatives, having the following general formula: 

CDC - 

in which: 

R represents a straight- or branched-chain lower alkyl radical 

Z represents a group OX in which X is hydrogen or an alkali metal, or Z may also represent a group in which R1 and 

R2/ which may be the same or different, are hydrogen or a lower alkyl radical. 

2. Process for the preparation of derivatives of the formula (I) as defined in claim 1, comprising converting methyl 8-oxo-bicyclo (3.2.1.) octane-3-carboxylate having the formula: 

(II) 

<III) ; 

reacting the acid of the formula (III) with a strong base to give an intermediate organometallic compound having th£ formula: 

CDC - 

in which B is an alkali metal and, by action of an alkyl halide R-X in which R has the meaning given in claim 1, converting compound (IV) to a 

CD 

COOCH. 

to an acid of the formula 

Q 

COOH 

208607 

15 

canpound of the formula (I) In which Z is OH, and preparing according to conventional methods the compounds of the formula (I) in which Z is other than OH. 

3. Process as claimed in claim 2, wherein the derivative of the formula (III) is prepared by reacting methyl 8-oxo-bicyclo (3.2.1.) o'ctane-3-carboxylate with potassium hydroxide and hydrazine. 

4. Process as claimed in claim 2, wherein, according to a modification, the acid of the formula (III) may be substituted with the nitrile or an ester, thus giving a compound of the formula (V) which is then converted to a compound of the formula (I) by conventional means. 

5. Therapeutic composition having in particular anticonvulsant and antianoxemic activities, comprising as active ingredient a compound as claimed in claim 1. 

6. Therapeutic composition as claimed in claim 5, formulated in a form suitable for oral , parenteral or rectal administration, the active ingredient being combined with a therapeutically administrable vehicle.
7. Therapeutic composition as claimed in claim 6, in unit dosage form, each unit dose containing 0.050 -0.500 g active ingredient. 

BALDWIN, SON &. CAREY 

attorneys for the applicants 

© 



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