WO1987000171A1

WO1987000171A1 - Amino acid derivatives

Info

Publication number: WO1987000171A1
Application number: PCT/DK1986/000076
Authority: WO
Inventors: Frederik Christian GRO^/NVALD; Claus BRA^ESTRUP
Original assignee: Novo Industri A/S
Priority date: 1985-06-26
Filing date: 1986-06-26
Publication date: 1987-01-15
Also published as: EP0236342A1; AU599326B2; JPS62503172A; ES8800927A1; FI870810A0; ES556659A0; ATE67196T1; DK156398C; PT82841B; CA1284503C; IE861702L; EP0236342B1; IE59084B1; ZA864608B; JPH07103116B2; LU90130I2; DK156398B; DK100887A; FI870810A; AU6133686A

Abstract

1-Aminobut-3-en derivatives having optionally substituted furanyl, thienyl, pyridyl and/or pyrrolyl in the 4-position and 3-carboxypiperidin-1-yl, 3-carboxytetrahydropyrid-1-yl or 3-carboxymethylpyrrolidin-1-yl in the 1-position potentiate GABA'ergic neurotransmission.

Description

AMINO ACID DERIVATIVES.

Summary of the invention

The present invention relates to novel N-(butenyl substituted) azaheterocyclic carboxylic acids of the general formula I

R¹-C=CH-CH₂-CH₂-R³ (I)

I R²

wherein R 1 and R2 are the same or different and each represents furanyl, thienyl, pyridyl or pyrrolyl each of which may be substituted one, two or three times by halogen

3 or lower alkyl, and R represents 3-carboxyρiperidin-l-yl,

3-carboxy-l,2,5,6-tetrahydropyrid-l-yl or 3- carboxymethylpyrrolidin-1-yl, or salts thereof.

Background of the invention

In the last decade, intensive pharmacological research concerning γ-aminobutyric acid (hereinafter designated GABA) , a neurotransmitter in the central nervous system,, has taken place. Increased GABA'ergic activity is useful in the treatment of anxiety, epilepsy and muscular and movement disorders. Furthermore, these compounds can be used: as sedatives.

In U.S. patent specification No. 4,383,999 (Smithkline Beckmann Corporation) some derivatives of N-(4- phenylbuten-3-yl)azaheterocyclic carboxylic acids which have, furthermore, inter alia, phenyl, 4-fluorophenyl, cyclohexyl or thienyl in the 4-position, are described. It is stated therein that the compounds are useful as inhibitors of GABA uptake.

According to J.Pharm.Exp.Therap. , 228 (1984), 109 et seq. , N-(4,4-diphenyl-3-butenyl)nipecotic acid (designated SK&F 89976A), N-(4,4-diphenyl-3-butenyl)guvacine (designated SK&F 100330A), N-(4,4-diphenyl-3-butenyl)-β-homoproline (designated SK&F 100561) and N-(4-phenyl-4-(2-thienyl)-3- butenyl)nipecotic acid (designated SK&F 100604J) are active inhibitors of GABA uptake.

Detailed practice of this invention It has now been found that novel compounds of the general formula I stated in Claim 1 below exhibit GABA uptake inhibitory properties and exert useful pharmacological effects on the central nervous system, i.e., a selective enhancement of GABA activity. Surprisingly, these effects are superior to those of previously known compounds. Compounds of formula I may be used for treatment of, for example, pain, anxiety, epilepsy, certain muscular and movement disorders, other neurological disorders and as sedatives and hypnotics. Herein furanyl is 2-furanyl or 3-furanyl, thienyl is 2-thienyl or 3-thienyl, pyridyl is 2-pyridyl, 3-pyridyl or 4-pyridyl and pyrrolyl is 2-pyrrolyl or 3-pyrrolyl. Furthermore, halogen is, preferably, chloro,. bromo and fluoro. The lower alkyl group contains less than 8 carbon atoms, preferably less than 5 carbon atoms, and some especially preferred alkyl grups are methyl and ethyl. Examples of preferred substituents R 1 and R2 are 3- methylthienyl, 4-methylthienyl and N-methylpyrrolyl.

Compounds of formula I are, for example: _ N-(4,4-di(furan-2-yl)but-3-enyl)nipecotic acid, N-(4,4-di(furan-3-yl)but-3-enyl)nipecotic acid, N-(4,4-di(thien-2-yl)but-3-enyl)nipecotic acid, N-(4,4-di(thien-3-yl)but-3-enyl)nipecotic acid, N-(4-(5-chlorothien-2-yl)-4-(thien-2-yl)but-3-enyl)nipecotic acid,

N-(4,4-di(pyrid-3-yl)but-3-enyl)nipecotic acid, N-(4,4-di(5-methylpyrrol-2-yl)but-3-enyl)nipecotic acid, N-(4-(furan-2-yl)-4-(thien-2-yl)but-3-enyl)nipecotic acid, N-(4-(furan-3-yl)-4-(thien-3-yl)but-3-enyl)nipecotic acid, N-(4-(furan-2-yl)-4-(thien-3-yl)but-3-enyl)nipecotic acid, N-(4-(furan-3-yl)-4-(thien-2-yl)but-3-enyl)nipecotic acid, N-(4,4-di(furan-2-yl)but-3-enyl)guvacine, N-(4,4-di(furan-3-yl)but-3-enyl)guvacine, N-(4,4-di(thien-2-y1)but-3-enyl)guvacine, N-(4,4-di(thien-3-yl)but-3-enyl)guvacine, N-(4,4-di(pyrid-4-yl)but-3-enyl)guvacine, N-(4-(furan-2-yl)-4-(thien-2-yl) ut-3-enyl)guvacine, N-(4-(furan-3-yl)-4-(thien-3-yl)but-3-enyl)guvacine, N-(4-(furan-2-yl)-4-(thien-3-yl)but-3-enyl)guvacine, N-(4-(furan-3-yl)-4-( hien-2-yl)but-3-enyl)guvacine, N-(4,4-di(fur n-2-yl)but-3-enyl)-β-homoproline, N-(4,4-di(furan-3-yl)but-3-enyl)-β-homoproline, N-(4,4-di(thien-2-yl)but-3-enyl)-β-homoproline, N-(4,4-di(thien-3-yl)but-3-enyl) -β-homoproline, N-(4-(fur n-2-yl)-4-(thien-2-yl)but-3-enyl)-β-homoproline, N-(4-(furan-3-yl)-4-(thien-3-yl) ut-3-enyl)-β-homoproline, N-(4-(furan-2-yl)-4-(thien-3-yl)but-3-enyl)-β-homoproline, N-(4-(furan-3-yl) -4-(thien-2-yl)but-3-enyl)-β-homoproline, N-(4,4-di(3-methylthien-2-yl)but-3-enyl)guvacine, N-(4,4-di(3-methylthien-2-yl)but-3-enyl)nipecotic acid, N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-β-homoproline, N-(4-(3-methylthien-2-yl)-4-(thien-2-yl) )but-3-enyl)- guvacine,

N-(4-(3-methylthien-2-yl)-4-(thien-2-yl) )but-3-enyl)- nipecotic acid, N-(4-(3-methylthien-2-yl)-4-(thien-2-yl) )but-3-enyl)-β- homoproline,

N-(4-(N-methyl-pyrrol-2-yl) -4-(thien-2-yl) )but-3-enyl)- guvacine,

N-(4-(N-methyl-pyrrol-2-yl)-4-(thien-2-yl) )but-3-enyl)- nipecotic acid, N-(4-(N-methyl-pyrrol-2-yl)-4-(thien-2-yl) )but-3-enyl)-β- homoproline,

N-(4, 4-di(N-methyl-ρyrrol-2-yl)but-3-enyl)guvacine, N-(4 ,4-di(N-methyl-pyrrol-2-yl)but-3-enyl)nipecotic acid, N-(4 ,4-di(N-methyl-pyrrol-2-yl)but-3-enyl)-β-homoproline, N-(4-(3-bromo-thien-2-yl)-4-(thien-2-yl) )but-3-enyl)- nipecotic acid, and salts thereof. Compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallisation.

One embodiment of this invention is non-toxic pharmaceutically acceptable salts of compounds of formula I. Salts include those derived from inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, maleic and phthalic acid. Furthermore, salts include salts of the carboxylic acid group, for example sodium, potassium, calcium and magnesium salts and salts with a strong base such as triethylamine.

Compounds of formula I may be prepared by N-alkyla- tion of a compound of the general formula II

H-R'³ _m (II)

wherein R' has the same meaning as the above R with the proviso that the carboxy group is protected (for example, as an ester group), with a compound of the general formula III

R¹-C=CH-CH -CH X

I (III)

R²

wherein R 1 and R2 are as defined in Claim 1, and X represents halogen. This reaction may be carried out in an inert solvent in the presence of an alkali metal carbonate, for example, potassium carbonate, for example, at reflux temperature or lower temperature, for from about 8 to 24 hours. The solvent may conveniently be an alcohol, acetone or N,N- dimethylformamide. Thereafter, compounds of formula I may be prepared by hydrolysis of the resulting ester, for example by refluxing a mixture of an aqueous sodium hydroxide solution and an alcohol such as methanol or ethanol for from about 1 to 4 hours. Compounds of formula III may be prepared by reacting the corresponding disubstituted ketones of the general formula V

R¹-C0-R² _(V)

wherein R 1 and R2 each is as defined above, with a Grignard reagent, i.e., cyclopropyl magnesium bromide, followed by ring opening and dehydration of the intermediate carbinol derivative by treatment with hydrogen bromide in acetic acid.

Compounds of formula I are useful because they possess pharmacological activity in man. In particular, the compounds of formula I are useful as inhibitors of GABA uptake.

For the above indications, the dosage will vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired. However, in general, satisfactory results are obtained with a dosage of from about 15 mg to about 2 g of compounds of formula I, conveniently given from 1 to 5 times daily, optionally in sustained release form. Usually, dosage forms suitable for oral administration comprise from about 25 mg to about 1 g of the compounds of formula I admixed with a pharmaceutical carrier or diluent. No toxic effects have been observed at these levels.

The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit approximately the same order of activity as the free base forms.

This invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent. The compositions of this invention may be prepared by conventional techniques to appear in conventional forms, for example, capsules or tablets. The pharmaceutical carrier employed may be conven¬ tional solid or liquid carriers. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil_^ and water. Similarly, the carrier or diluent may include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. If a solid carrier for oral administration is used, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but, usually, will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation mey appear in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension. The. pharmaceutical compositions of this invention can be made following the conventional techniques of the pharmaceutical industry involving mixing, granulating and compressing or variously mixing and dissolving the ingredients as appropriate to give the desired end product.

The route of administration may be any route which effectively transports the active compound to the appropriate . or desired place, such as orally or parenterally, the oral route being preferred.

Any novel feature or combination of features described herein is considered essential.

The process for preparing compounds of formula I and preparations containing them is further illustrated in the following examples, which, however are not to be. construed as limiting. The examples illustrate some preferred embodiments.

Example 1 a) To a suspension of 1.3^" g of magnesium in 20 ml of anhydrous tetrahydrofuran, 8.0 g of cyclopropyl bromide in 15 ml of anhydrous tetrahydrofuran was added under nitrogen. The reaction mixture was kept under reflux for 1 hour and then cooled to ambient temperature. To the reaction mixture, 5.4 g of di(thien-2-yl)ketone dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise. After refluxing for 30 minutes, the reaction mixture was chilled and_ 35 ml of a con¬ centrated ammonium chloride solution was carefully added. To the resulting mixture, 50 ml of water was added and the suspension was extracted twice with 50 ml of ether. The ether extracts were washed with water, dried and evaporated leaving 7.6 g of an oil.

The crude product was dissolved in 60 ml of acetic acid and a mixture of 30 ml of acetic acid and 15 ml of 48% hydrobromic acid was added at 5°C. The mixture was stirred for 30 minutes and then poured into 300 ml of water. The resulting emulsion was extracted twice with 100 ml of ether. The ether extracts were washed with water, dried and evaporated leaving 8.5 g of an oil.

From this oil, 5.2 g of 4,4-di(thien-2-yl)but-3- enyl bromide having a boiling point (hereinafter b.p.) of 137°C (0.05 mm Hg) was obtained by fractional distillation in vacuum. b) A suspension of 5.0 g of 4 ,4-di(thien-2-yl)but- 3-enyl bromide, 3.4 g of nipecotic acid ethyl ester and 3.3 g of potassium carbonate in 150 ml of dry acetone was kept under reflux for 15 hours. The reaction mixture was - evaporated and, after addition of 30 ml of water, the resulting solution was extracted twice with 50 ml of ethyl acetate. The ethyl acetate extracts were dried 'and evaporated leaving 7.3 g of an oil. By column chromatography on silica gel using methanol as eluent, N-(4,4-di(thien-2-yl)but-3- enyl)nipecotic acid ethyl ester was isolated.

5.3 g of this compound was dissolved in 100 ml of ethanol and 200 ml of an 8 N sodium hydroxide solution was added. The mixture was heated at reflux for 1 hour, cooled and acidified by adding 10% hydrochloric acid. The resulting solution was evaporated and 100 ml of water was added to the residue. The resulting acid solution was extracted with ethyl acetate and the dried extract was evaporated to give N-(4,4- di(thien-2-yl)buten-3-yl)nipecotic acid which after crystallization from ethyl acetate had a melting point (hereinafter m.p.) of 62 - 64°C (decomposition).

Example 2 A solution of 34 ml of n-butyllithium in 30 ml of anhydrous ether was cooled to -65°C under nitrogen and 5.3 ml of 3-bromothiophen in 10 ml anhydrous ether was added dropwise over a period of 10 min. The reaction mixture was stirred at -65°C for 1 hour and 2.7 ml of ethyl 4-bromo- butyrate in 10 ml of anhydrous ether was added slowly. The reaction was stirred for 4 hours while the temperature raised to -20°C. 20 ml water was added and the mixture was stirred for 5 minutes after which the aqueous layer was removed. The ether layer was washed with 20 ml of water and the combined aqueous phases were extracted with 50 ml of ether. The combined organic phases were dried over anhydrous sodium sulfate which after evaporation yielded 9 g. of l-bromo-4,4- di(3-methylthien-2-yl)but-3-en as an oil. This compound was without further purification used for coupling with ethyl nipecolate following the procedure according to b) in Example 1 whereby N-(4,4-di(3-methylthien-2-yl)but-3-en)nipecotic acid hydrochloride was obtained.

R_f = 0.38 (MeOH; silicagel)

Examples 3 - 11 The compounds of formula I stated in table I, below, were prepared analogously to the method described in Example 1 (method A) and Example 2 (method B) . Table I

Exam¬ m. . ple: R

1- R. ^R3 °C

3 4-methylthien-2-yl 4-methylthien-2-yl nipecotic acid 60-63

4 5-methylthien-2-yl 5-methylthien-2-yl nipecotic acid 72-76

5 3-methylthien-2-yl 5-methylthien-2-yl nipecotic acid 57-60

6 3-methylthien-2-yl 5-methylthien-2-yl guvacine 40-42

7 thien-2-yl 3-methylthien-2-yl nipecotic acid 86-88

8 thien-2-yl 3-methylthien-2-yl guvacine 84-88

9 N-methylpyrrol-2-yl N-methylpyrrol-2-yl nipecotic acid 44

10 5-chloro-4-methylthien-2 -yl 5-chloro-4-methylthien-2-yl nipecotic acid 78-82

11 thien-2-yl 3-methylthien-2-yl β-homoproline oil

In Examples 5 through 8 and 11, Method A was used and in the remaining examples. Method B was used. The compounds prepared were hydrochlorides (HC1).

Example 12

Preparation of Capsules.

Ingredients Mg per Capsule J-(4,4-di(thien-2-yl)but-3-enyl)nipecotic acid 125 Magnesium stearate 2

Lactose 200

The above ingredients are thoroughly mixed and placed into hard gelatin capsules. Such capsules are administered orally to subjects in need of treatment from 1 - 5 times daily to enhance GABA'ergicactivity in the central nervous system.

Example 13

Preparation of Tablets.

Ingredients Mg per Tablet N-(4,4-di(thien-2-yl)but-3-enyl)nipecotic acid 200 Corn starch 46 Polyvinyl pyrrolidone .12 Magnesium stearate ].

The compound is thoroughly mixed with two thirds of the corn starch and granulated. The granules obtained are dried, mixed with the remaining ingredients and compressed into tablets.

The capsules or tablets thus prepared are administered orally. Similarly, other compounds of formula I can be used. Pharmacological test

GABA-uptake was measured essentially as described by Fjalland (Acta Pharmacol. et. toxicol. (1978), 4_2, 73 - 76) using 25 M of 3H-GABA as substrate. The results obtained appears from the following table.

Compound IC_c-, (nM)

SKF 100330 A 380

N-(4,4-di(3-methylthien-2-yl)buten-3-yl)- nipecotic acid, HC1 90 N-(4-(thien-2-yl)-4-(3-methylthien-2-yl)- buten-3-yl)-β-homoproline, HC1 70

N-(4,4-di(N-methylpyrrol-2-yl)buten-3-yl)- nipecotic acid, HC1 60

N-(4-(thien-2-yl)-4-(3-methylthien-2-yl)- buten-3-yl)nipecotic acid, HC1 110

The obtained values are means from 2 separate experiments using 3 - 5 different concentrations of test compound.

Claims

C l a i s

1. l-Aminobut-3-en derivatives of formula I

R¹-C=CH-CH₂-CH₂-R³ (I)

R² -

wherein R 1 and R2 are the same or different and each represents furanyl, thienyl, pyridyl or pyrrolyl each of which may be substituted one, two or three times by halogen or lower alkyl, and R 3 represents 3-carboxypiperιdm-l-yl,

3-carboxy-l,2,5,6-tetrahydropyrid-l-yl or 3-carboxymethyl- pyrrolidin-1-yl, or salts thereof.

2. Derivatives according to claim 1, c h a - r a c t e r i z e d in that the substituents are chloro or methyl.

3... Derivatives according to claim 1 or 2, where- m R 1 and R2 each is thienyl optionally substituted by lower alkyl.

4. Derivatives as prepared in any of the above examples.

5. Pharmaceutical compositions containing a com¬ pound of formula I stated in any one of the preceding claims.

6. Compositions according to claim 5, c a ¬ r a c t e r i z e d in that they contain from about 25 mg to about 1 g of the compound.

7. A process for preparing compounds of formula I stated in claim 1 or a salt thereof, c h a r a c t e r - i z e d in hydrolysing a compound of the general formula IV

wherein R 1 and R2 each are as defi.ned above and R^!3 has the

3 same meaning as the above R with the proviso that the carboxy group is protected, and, if desired, converting a compound of formula I into a salt thereof or convert¬ ing a salt into a compound of formula I.