IE870022L - 1,1,4-trisubstituted butenes - Google Patents

Description

62 ; 80 _ 1 - NOVEL AMINO ACID DERIVATIVES Description summary of the invention The present invention relates to novel N-(butenvl-substituted) 25 azaheterocyclic carboxvlic acids of the general formula 1. r1«c=ch-ch2-ch2-r3 (i) R2 i wherein R represents phenyl optionally substituted by one, two or more substituents selected from the group consisting of halogen, lower-alkyl, and lower-alkoxy, R represents lower-alkylthienyl, lower-alkyl furanyl, lower-alkylpyridyl or lower-alkvlpyrrolyl, each 35 of which may be substituted with halogen, wherein the alkyl group is positioned ortho to the radical position of the thienyl furanyl, ■3 pyridinyl, or pyrrolyl group, and wherein R represents 3-carboxypiperidin-l-vl or 3-carboxy-l,2,5,6-tetrahydropyridin-l-ylor o ;; n O v/ salts, lower alky1 esters or amides thereof, wherein lower means that the alkyl or alkoxv group contains less than 8 carbon atoms. These compounds have interesting and valuable pharmacological properties.

BACKGROUND OF THE INVENTION In the last decade, intensive pharmacological research concerning y-aminobutyric acid (hereinafter designated GABA), a 10 neurotransmitter in the central nervous system, has taken place.

Increased GABA ergic activity is useful in the treatment of anxiety, pain, epilepsy and muscular and movement disorders. Furthermore, compounds having increased GABA ergic activity can be 15 used as sedatives.

In U.S. Patent Specification No. 4,383,999 (Smithkline Beckmann Corporation) some derivatives of N-(4-phenyl-3-butenvl)azahetero-cyclic carboxylic acids which have, furthermore, inter alia, phenyl, 20 D-fluorophenvl, cyclohexvl or thienyl in the 4-position, are described.

According to J. Pharm. Exp. Therap. 228 (1984). 109 et seq.. Nr(4,4-diphenyl-3~butenvl)nipecotic acid (designated SK&F 89976A), 25 JNI-(4,4-diphenyl=3~butenyl)guvacine (designated SK&F 100330A), N.- (4,4 diphenyl~3-butenvl)-B-homoproline (designated SK&F 100561) and !i-(4-phenyl-4«(2~thienyl)-3~butenyl) nipecotic acid (designated SK&F 100604J) are orallv-active inhibitors of GABA uptake.

CA-102:160041s discloses JN-(4,4-diphenyl~3-butenyl)-3-piperidine- carboxylic acid which is a specific GABA-uptake inhibitor.

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 possess useful pharmacological properties 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 and other neurological disorders and as 5 sedatives and hypnotics.

There are disclosed compounds wherein pyrrolyl is 2-pyrrolyl or 3-pyrrolyl, furanyl is 2-furanyl or 3 furanyl, pyridinyl (pyridyl) is 2-pyridyl, 3-pvridyl or 4-pvridyl, and thienyl is 2-thienvl or 10 3-thienyl.

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 preferred alkyl groups are methyl 15 and ethyl. The lower alkoxv group contains less than 8 carbon atoms, preferably less than 5 carbon atoms, and some preferred alkoxv groups are methoxy and ethoxy. Preferably, (lower alkyl)thienvl is 3-methylthien-2-yl . Specific examples of substituted groups R* and 2 R are H-methylpyrrol-2-vl and N.-methylpyrrol-3-yl.

Compounds disclosed are, for examples N.-(4~(N.~methy 1 pyrrol-2-vl)-4-phenvlbut-3-en-l-yl)nipecotic acid, H~(4~(ji~methylpyrrol-2-yl)-4-phenylbut~3-en-l -yl)guvacine, 25 N.-(4-(N-methvlpyrrol-3-yl)-4-phenylbut~3-en-l-yl)nipecotic acid, N-(4-(N-methylpyrrol-3-yl)-4-phenylbut-3-en-l -yl)guvacine, j|-(4-(furan-2-yl)-4-phenylbut-3-en-l-vl)nipecotic acid, H-(4-(furan-2-yl)~4-phenylbut-3-en-l -vl)guvacine, j^-(4-(furan~3~yl)-4-phenylbut-3-en~l-yl)nipecotic acid, 30 N.-(4~(furan-3~yl)-4-phenylbut-3-en-l -yl)guvacine, j1-(4-phenyl»4-(pyridin-2-yl)but-3-en-l-yl)nipecotic acid, |i-(4-phenyl-4-(pyridin-2-yl)but-3-en-l -vl)guvacine, N.-(4-phenyl~4~(pyridin~3-yl)but-3-en-l-yl)nipecotic acid, N.-(4-phenyl-4-(pyridin-3-yl )but-3-en-l -yl)guvacine, 35 N.-(4-phenyl-4-(pvridin-4-yl)but~3-en-l-vl)nipecotic acid, N-(4-phenvl-4-(pyridin-4-yl)but-3-en- 1 -yl)guvacine, JM-(4-(2-methylphenyl )-4-(N.-methylpyrrol-2-yl )but=3-en-l-yl )nipecotic acid, N-(4-(2-methylphenyl)-4-(H.-methylpyrrol-2-yl)but-3-en-l -yl)guvacine, N|-(4-(2-methyl phenyl)-4- (N.-methyl pyrrol-2-yl )but-3-en-l-yl )nipecot ic acid, j^-(4-(2~methylphenyl)-4-(N-methylpyrrol-3-yl)but-3-en-l -yl)guvacine, 5 (4-(2-methylphenyl)-4-(pyridin-3-vl)but-2-en-l-vl)nipecotic acid, N-(4-(2-methylphenyl)-4-(pyridin-3-vl)but-2-en- 1 -yl)guvacine, N-(4-(2-methylphenvl)-4~(pyridin-3-yl)but-3-en-l-vl)nipecotic acid, N-(4~(2-methylphenyl)-4~(pvridin-3-yl)but-3~en-l -yl)guvacine, j|-(4~(3~methyl-2-thienyl)~4~phenylbut-3-en~l»yl)nipecotic acid, 10 Sf-(4-(3-methyl-2-thienvl)-4»phenylbut-3-en-l -yl)guvacine, and salts thereof.

Compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. 15 Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallisation.

One embodiment of this invention is non-toxic pharmaceuticallv acceptable salts of compounds of formula 1. Salts include those 20 derived from inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, maleic and phthalic acid.

Compounds of formula I may be prepared by H-alkvlation of a 25 compound of the general formula II H-R*3 (II) 13 3 wherein R has the same meaning as R with the proviso that the carboxv group is protected, for example, by an ester group, with a compound of the general formula III R1-C=CH-CH2-CH2X I (III) R2 12 wherein R and R are as defined in Claim 1P and X represents 5 halogen. This reaction may be carried out in an inert solvent in the presence of an alkali metal carbonate, for example, potassium carbonate at, for examplec, room temperaturefor from about 1 to 12 days. The solvent may conveniently be acetone or Mt,N~dimethylformamide«, Compounds of formula I may be prepared 10 by hydrolysis of the resulting ester, preferably at room temperature in a mixture of an aqueous sodium hydroxide solution and an alcohol such as methanol or ethanol for from about 0.5 to 4 hours.

Compounds of formula III may be prepared by reacting 15 the appropriate disubstituted ketones with a Grignard reagente. i „e. e, cyclopropyl magnesium bromide,, followed by ring opening of the intermediate cyclopropyl carbinol derivative by treatment with hydrogen bromide in acetic acid. Alternative conditions involve the use of trimethylsilyl chloride and 20 lithium iodide in? for examplee dichloromethane.

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 25 depending on the compound of formula I employed, on the mode of administration and on the therapy desired. However,, in generalf 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 30 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 compo sitions comprising a compound of formula I or a pharmaceutical-Iv 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 10 appear in conventional forms, for example» capsules or tablets.

The pharmaceutical carrier employed.may be conventional solid or liquid carriers. Examples of solid carriers are lactose, terra alba, sucrose., talc, gelatin, agarpectinr acacia,, magnesium stearate and stearic acid. Examples of liquid 15 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, 20 the preparation can be tablettedf, 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 may appear in the form of a 25 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 30 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 35 route being preferred.

The features disclosed in the foregoing description and in the following examples and claims may* both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.

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

Hereinafter T.l.c. is thin layer chromatography,. THF 10 is tetrahydrofuran and EtOH is ethanol.

Example 1 Cyclopropyl-(M-methylpyrrol-2-yl) pb.enylmethanol To a suspension of magnesium turnings (5.29 gP 0.22 mole) in anhydrous tetrahydrofuran (70 ml)P cyclopropyl bromide 15 (26.35 gF 0.22 mole) in tetrahydrofuran (50 ml) was added dropwise under nitrogen. The reaction mixture was heated at reflux for one hour after the initial exotherm had subsided before M-methylpyrrol-2-ylphenyIketone (13.3 gf 0.072 mole) (J.White and G. McGillivrav, JsOrg-Chem., (1977), 4_2f 4248f R. 20 Greenhouse and C. Ramirez, J.Org.Chem., (1985), 50 2961) in anhydrous tetrahydrofuran (50 ml) was introduced dropwise.

After heating the reaction mixture at reflux for 3 hours it was cooled and saturated, aqueous ammonium chloride solution (95 ml) and water (150 ml) were added. The mixture was extracted 25 with ethyl acetate (3 x 200 ml) and the combined sxtractis wGiTG dried (MgSO.). Flash chromatography of the residue on evaporation on silica gel eluting with heptane/tetrahydrofuran (9:1) provided the title compound as an oil (9.9 g, 4 6%) which solidified on standing. T.l.c,. rf = 0.35 (SiC^? heptane/THF 30 (7:3)).

Ring opening of cvclopropylcarhinols Method A I-Broino-4- (M-methvlpyrrol-2-yl) -4-phenylbut-3-ene Cyclopropyl-(M-methylpyrrol~2-yl)phenyImethanol was dissolved in acetic acid (60 ml) and a mixture of acetic acid 5 (30 ml) and 48% hydrobromic acid (15 m't) was added at 5°C. The mixture was stirred for 30 minutes and poured into water (300 ml). The resultant emulsion was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with saturated sodium bicarbonate solution and brine and dried 10 (Ha^SO^)„ The concentrate, containing some acetic acid, was passed through a silica column (Merck Art 9385) with heptane/tetrahydrofuran (19si) as eluent. After further flash chromatography in the same solvent system,, the pure bromide (2 isomer) was obtained. T.l.c. rf = 0.35 (Si02? heptane/TKF 15 (9:1)).

Method B (G. Balme,, G. Fournet and J. Gore,, Tetrahedron„ Lett. p (1905), 1907 4-(M-Hethylpyrrol-2-yl)°-4°phenylbut-3-en-l-yl chloride and iodide > Cyclopropyl-(N-methvlpyrrol-2-yl)phenyImethanol (6.46 gt, 28.4 mmol) was dissolved in dichloromethane (2 00 ml) and lithium iodide (4„5S g? 31.4 mmol) was introduced. The mixture was cooled to 0°C„ and chlorot rime thy Is i lane (3.6 ml,, 28.4 mmol) was added dropwise. After 2 hours at 0°C, the reaction 25 mixture was filtered and evaporated to a dark green oil (7.28 g)o Flash chromatography on silica gel (Merck Art 9385) eluting with heptane/tetrahydrofuran (19:1) provided the title compounds as an oil (6.3 gf 64%) (a mixture of E and Z isomers). T.l.c. rf = 0.29 (SiO^ * heptane/THF (9:1)).

R-N-(4-(N~MethvIpyrrol-2-yl)-4-phenylbut-3-en-l-y1)nipecotic acid ethyl ester 4-(M-Methylpyrrol-2-yl)-4-phenylbut-3-en-l-y1 chloride and iodide (3.0 gP 8.7 mmol) were dissolved in 5 anhydrous acetone (50 ml) and dried potassium carbonate (4.8 g„ 34.8 simol); sodium iodide (1.3 g„ 8.7 mmol) and the R-enantiomer of ethyl nipecotate (1.462 ge 9.3 mmol) (A.M. Akkerman et al., Rec.Trav.Chem„, 1951,, 70 e 899? G. Bettoni et al., Gazz„Chem,Ital., 1972, 102„ 189) was added. The suspension 10 was stirred at room temperature for 10 days P filtered and evaporated to a gummy residue which was purified by flash chromatography on silica gel (Merck Art 9385). Elution with heptane/tetrahydrofuran (19 si) provided the title ester (1.74 gc, 54%) as an oil„ T.l.c. rf = 0.06 (SiC^p heptane/THF (9:1)).

R-N- (4- (N-Methylpyrrol-2-yl) -4-pheny lbut--3-en--l-yl) nipecotic acid hydrochloride (MQ-05-0356) R-N-(4-(H-Methylpyrrol-2-vl)-4~phenvlbut-3-en-l-yl)nipecotic acid ethyl ester (1.74 gi( 4.7 mmol) was dissolved in ethanol K50 ml) and 10 N sodium hydroxide solution (8.9 ml) 20 was added. The solution was stirred at room temperature for 30 minutes and cooled to 0°C. The pH was adjusted to 5 with 4 N hydrochloric acid solution, and the solution was extracted with dichloromethane (4 x 25 ml). The combined extracts were washed with water (10 ml) and dried (MgSO^). The residue on 25 evaporation was treated with water (100 ml) and activated charcoal. Filtration through a millipore filter gave a solution which was freeze-dried to give the product as a cream solid (1.53 gf 82%). It was found that the E and Z isomers could be separated by HPLC.

Example 2 M-(4-(M-Methylpvrrol-2-yl)-4-phenylbut-3-en-l-yl)nipecotic acid ethyl ester l-Bromo-4-(N-methylpyrrol-2-yl)-4-phenvlbut-3-ene 5 (4.58 g, 15.9 mmol) was dissolved in anhydrous acetone (115 ml) and dried potassium carbonate (8.78 g, 53.5 mmol) was introduced,, followed by ethyl nipecotate (3.25 gt. 20.7 mmol). The reaction mixture was stirred at room temperature for 12 days* filtered and evaporated to give a brown oil (6.4 g). 10 Column chromatography on silica gel (Merck Art 15111) eluting with heptane/tetrahydrofuran (19:1) provided the title compound as an oil (3.68 g,, 63%). T.l.c. rf = 0.31 (SiO^# THF/heptane (3:7)).

N-(4-l^~Metbylpyrrol-2-yl)-4-phenylbut-3-en-l-yl)nipecotic acid hydrochloride (NQ-05-0165) N-(4-(N-Methylpyrrol-2-y1)-4-phenylbut-3-en-1-yl)nipecotic acid ethyl ester (2.75. ge 7.5 mmol) was dissolved in ethanol (,70 ml). 10 N sodium hydroxide solution (14 ml) was 20 introducedt, and the solution was stirred for 30 minutes at room temperature before being cooled to 0°C. The pH was adjusted to 7 with 4 N hydrochloric acid solution,, and the reaction mixture was extracted with dichloromethane (4 x 100 ml) (emulsion). The combined organic extracts were washed with a mixture of 25 saturated brine (20 ml) and water (20 ml). The layers were separated, and the aqueous phase was washed with dichloromethane (100 ml). The combined extracts were dried (Na^SO^) and filtred through "hyflo"„ The filtrate was evaporated and the residue dissolved in 150 ml water, 30 decolourised (charcoal) and freeze dried. The title amino acid was obtained as a dense white powder-(Z isomer) (1.83 g, 72%). T.l.c. rf = 0 o 33 (Si02, dichloromethane/methanol (4:1)).

Example 3 2-Benzoyl-N-ethylpyrrole 2-Benzoylpyrrole (ref. as in Example 1) (10.27 g, 5 0.06 mole) was dissolved in dry N,,N-dimethylformamide (120 ml) and combined with sodium hydride (2.016 gf 0.084 mole) (60% oil dispersion) in dry N,N-dimethylformamide (120 ml). The reaction mixture was stirred at room temperature for 18 hours and water (100 ml) was added. The reaction mixture was extracted with 10 diethyl ether (3 x 100 ml) and the combined extracts were washed with water (200 ml). The organic layer was dried (MgSO^) and evaporated to give the title compound as an oil (11.74 gc, 98%). T.l.c. rf = 0.53 (Si0^f, dichloromethane/methanol (98:2)).

This ketone was converted into a mixture of 4-(N-15 ethylpyrrol-2-yl)-4-phenylbut-3-en~l-yl chloride and iodide by the method described in Example 1 (using Method B) R-N-((4-N-Ethylpyrrol~2-yl)~4-phenylbut-3-en-l-yl)nipecotic acid ethyl ester 4-(W-Ethylpyrrol-2-yl)-4-phenvlbut-3-en-l-vl chloride 20 and iodide (3.16 gf 9 mmol) were dissolved in anhydrous acetone (50 ml) and dried potassium carbonate (4.97 ge 36 nunol), sodium iodide (2.7 gf 18 mmol) and the R-enantiomer of ethyl nipecotate (1.93 g, 13.7 mmol) were introduced. The suspension was stirred at room temperature for 10 days, filtered and 25 evaporated to a residue. The residue was purified by column chromatography on silica gel (Merck Art 9385) eluting with heptane/tetrahydrofuran (19:1), providing the title ester (1.50 gf 4 3%) as a gum. T.l.c. rf = 0.21 (SiC^/ heptane/THF (4:1)).

R^N- ( ( 4-N-Ethylpyrrol-2-yl) - 4-phenylbut-3-en-l-yI)nipecotic acid R—N—((4-N-EthylpYrrol-2-yl)-4-phenylhut-3-en-l~ yl)nipecotic acid ethyl ester (0.14 gs 0.4 mmol) was hvdrolysed 5 by the method outlined in Example 1- The title acid was obtained as a freeze-dried solid (Z isomer) (54 mg„ 33%) ; xn.p. 56.5 - 60°C (decomposition).

Example 4 N- (4- (H-Methylpyrrol-2-yl) -4-pheny lbut-3-en-l~yl) guvacine 10 methyl ester 4- (M-Methylpyrrol-2~yl) -4-phenylbut-3-en-l-yl chloride and iodide (1.46 g, 4.3 mmol) (Example 1) were dissolved in anhydrous acetone (30 ml) and dried potassium carbonate (2.37 g, 17.2 mmol),. sodium iodide (0.645 4.3 15 mmol) and guvacine methyl ester hydrochloride. (0.995 gg 5.6 mmol) were added. The suspension was stirred at room temperature for 5 davsf and worked up as described in Example 1 to give the ytitle ester (1.1 g, 72%) as a fawn oil (mixture of E and Z isomers). T.l.c. rf = 0.05 (SiC^r heptane/THF (9:1)).

N-(4-(N-Methylpyrrol-2-yl)-4-phenylbut-3-en-1-vl)guvacine hydrochloride (mixture of S and Z isomers) (MQ-05-0387) N-(4-(M-(Methylpvrrol-2-yl)-4-phenylbut-3-en-l-yl)guvacine (1.02 g, 2.9 mmol) was hydrolysed by the method outlined in Example 1. The title acid was obtained as a freeze 25 dried solid (0.64 g, 52%) ; melting point: 81.5 - 84°C (E and Z isomers).

N- (4- (H-Methylpyrrol-2-yl) -4-phenylbut-3^-en-l-yl) guvacine methyl ester l-Bromo-4~-(M-methylpyrrol-2-yl) -4-phenylbut~3-ene (0.60 gP 2.08 mmol) was dissolved in anhydrous acetone- (20 ml) 5 and dried potassium carbonate (1.10 ge 8 mmol) was introduced, followed by guvacine methyl ester hydrochloride (0.37 g, 2.08 mmol)* The reaction mixture was stirred at room temperature for 10 days and worked up as described in Example 1 to give the title ester (Z isomer) (380 mg, 52%) as an oil. T.l.c. rf = 10 0.32 (SiC>2 „ heptane/THF (9:1)) N-(4-(M-Methylpyrrol-2-yl)-4-phenylbut-3-en-l-vl)guvacine hydrochloride (Z-isomer) M?-^05-0227 N-(4-(N~Methylpyrrol~2~yl)-4-phenvlbut-3-en~l= yl)guvacine methyl ester was hydrolysed by the method outlined 15 in Example 1. The title acid was obtained as a freeze dried white powder (60 mgt, 38%)? melting point? 70°C.

Example 5 > Cyclopropvlphenvl-(4-pyridyl)methanol Magnesium turnings (2.65 g£, 0.109 mole) in dry 20 tetrahydrofuran (50 ml) was treated dropwise with cyclopropyl bromide (13.2 mlP 0.109 mole). The reaction mixture was heated at reflux for 1 hour after the initial exotherm had subsided^ and then 4-benzoylpyridine (10 g„ 0.0545 mole) was introduced. Heating at reflux was continued for 2 hours, the reaction 25 mixture was cooled and saturated ammonium chloride solution (70 ml) was added. This aqueous phase was extracted with ethyl acetate (3 x 200 ml) and the combined extracts were dried (MgSO^). Evaporation gave a crude solid residue (6.23 g) which as recrystallized from toluene to give the title alcohol (2.57 g, 21%) , m.p. 171 - 172°C. T.l.c. rf = 0.065 (SiO^? THF/heptane (3:7)). l-Bromo-4-pheny1-4-(4-pyridyl)but-3-ene Cyclopropvlphenyl-4~(4-pyridy1)methanol (2.4 g„ 10.6 mmol) was dissolved in acetic acid (25 ml). The solution was cooled to 0°C. A 47% solution of hydrogen bromide (5 ml) was added and the reaction mixture was stirred at room temperature for 3.5 hours, and at 40°C for 1 hour. The reaction mixture was 10 poured into water (100 ml) and this aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution (40 ml) and saturated brine (40 ml) and dried (MgSO^). Evaporation gave a crude product (3.26 g) which was purified by flash 15 chromatography on silica gel (Merck Art 9385). Elution with heptane/ethyl acetate (7:3) provided an oil (1.38 gf 45%) which solidified on standing. T.l.c. rf = 0.13 (SiO^? heptane/ethyl acetate (7:3)). i N-(4-Phenyl-4-(4-pyridyl)but-3-en-l-yl)nipecotic acidg ethyl 20 ester l-Bromo-4-phenyl-4-(4-pyridyl)but-3-ene (1.0 gp 3.5 mmol) f ethyl nipecotate (0.72 g? 4.6 mmol) and potassium carbonate (1.93 g„ 14.0 mmol) were stirred at room temperature for 5 days. The reaction mixture was filtered,, and evaporated 25 to a residue which was purified by flash chromatography on silica gel (Merck Art 9385). Elution with dichloromethane/ethanol/25% ammonium solution (190:9:1) provided the title compound as an oil. T.l.c. rf - 0.23 (SiO^f CH2Cl2/EtOH/NH3 (190:9:1)).

N-(4-Phenyl-4-(4-pyridyl)but-3-en-i-yl)nipecotic acid hydrochloride (N0^05-^0358 - M-(4-Phenyl-4-(4-pyridyl)but-3-en~l-y1)nipecotic acid ethyl ester was hydrolysed by the method outlined in Example 1. 5 The title acid was obtained as a freeze dried solid.

Example 6 2~Methylphenyl"4~pyridylmethanol Magnesium turnings (3.2 gP 0.131 mole) in dry tetrahydrof uran (50 ml) were treated dropwise with 2-10 bromotoluene (15 gP 0 = 087 mole). The reaction mixture was heated at reflux for 1 hour after the initial reflux had subsided. After cooling,, 4-pyridylcarboxaldehyde (14.38 q,, 0.131 mole) in dry tetrahydrofuran (30 ml) was introduced slowly„ and subsequently the reaction mixture was heated at 15 reflux for 2 hours. The reaction was worked up as in Example 5 (Grignard reaction) to give the title alcohol (5.92 gf 34%). T.l.c. rf = 0.24 (SiC>2 / ethyl acetate). 4-(2-Methylbenzoyl)pyridine Pyridinium chlorochrornate (9.29 gf 43.1 mmol) was 20 dissolved in dichloromethane (50 ml) and a solution of 2-methylphenyl-4-pyridylmethanol (5.72 gf 28.7 mmol) in dichloromethane (30 ml) was added. The reaction mixture became dark immediatelyr and was stirred for 2 hours at room temperature. Diethyl ether (3 50 ml) was addedP and the reaction 25 mixture was filtered through "hyflo" and evaporated to a dark oil (11.26 g). Flash chromatography on silica gel (Merck Art 9385) eluting with heptane/tetrahydrofuran (4:1) provided the title compound (2.74 g, 48%) as an oil. T.l.c. rf = 0.45 (SiC^, ethyl acetate).

This ketone was converted into l-bromo-4-(2-5 methylphenyl)-4-(4-pyridyl)but-3-ene"by the method described in Example 1 (Method A).

N"(4 - (2-Methylphenyl)-4°(4-pyridyl)but-3-en-l-yl)nipecotic acid ethyl ester l-Bromo-4-(2-methylphenyl)-4-(4-pyridyl)but-3-ene 10 (1.9 g? 7.6 mmol) was dissolved in anhydrous acetone (30 ml) and dried potassium carbonate (4,2 g„ 30.4 mmol) and ethyl mipecotate (2.39 gf 15.2 mmol) were introduced. The suspension was stirred at room temperature for 18 hours, filtered and evaporated to a residue. The residue was purified by ""flash8' 15 chromatography on silica gel (Merck Art 9385) eluting with heptane/tetrahydrofuran (7^3) to provide the title ester (0.67 gt. 41%) as a reddish oil (a mixture of E and Z isomers). T.l.c. rf = 0.08 (Si02; heptane/THF (7:3)).

M-(4-(2-Methylphenyl)-4-(4-pyridyl)but-3-en-l-yl)nipecotic acid N- (4 - (2--Methylphenyl) -4- (4-pyridyl)but-3-en-1- yl)nipecotic acid ethyl ester (0.67 g„ 1.8 mmol) was dissolved in ethanol (20 ml) and 10 N sodium hydroxide solution (3-42 ml) was added. The solution was stirred at room temperature for 0.5 hours, and the pH was adjusted to 5 with 4 N hydrochloric acid. 25 The solution was applied to a column of Dowex 50WX8 ion exchange resin (H' form). E3 ution with water followed by dilute ammonia solution provided the title acid (180 mg, 30%).

Example 7 2-Methylphenyl- ( 3-methyl-2--fchienyl)methanol The title compound was prepared from 2-bromotoluene (35.55 gP 0-208 mole), magnesium turnings (5.1 g, 0.208 mole) 5 and 3-methylthiophene-2-aldehyde (23.6 g, 0.187 mole) by the method described in Example 5, using diethyl ether (150 ml) as solvent. The yield was 36.0 g (88%). T.l.c. rf = 0.39 (SiC^, heptane/THF (7:3)). 3-Methy1-2-(2-methylbenzoyl)thiophene 2-Methylphenyl-(3~methyl~2~thienyl)methanol (36.0 g,, 0.165 mole) was dissolved in dichloromethane (400 ml) and manganese dioxide (58 g, 0.667 mole) was added. The reaction mixture was heated at reflux for 18 hours, cooled and further manganese dioxide (30 g, 0.34 mole) was introduced; reflux was continued for a further 18 hours. The mixture was filtred and evaporated to a residue (32 g) which was distilled iri vacuo (0.2 mm Hg). Fractions boiling at -100 - 120°C (4.8 g) and 120 -132°C (21,0' g) were collected,, giving the title compound as an oil (25.8 g, 72%).

The ketone was converted into l-bromo-4-(2- methylphenyl)-4-(3-methyl-2-thieny1)but-3-ene by the method described in Example 1 (Method A) R-N-(4-(2-Methylphenyl)-4-(3-methy1-2-thienvl)but-3-en-l-yl)nipecotic acid ethyl ester l-Bromo-4-(2-methylphenyl>-4-(3-methy1-2- thienyl)but-3-ene (3.0 g, 9.34 mmol) was dissolved in anhydrous acetone (4 0 ml) and dried potassium"carbonate (1.38 g, 10 mmol) potassium iodide (0.2 g, 1 mmol) and the R-enantiomer of ethyl nipecotate (1,57 g f 10 mmol) were introduced. The suspension was stirred at room temperature for 18 hours, filtered, and evaporated to a residue. The residue was purified by "flash" chromatography on silica gel (Merck Art 9385) eluting with 5 heptane/tetrahydrofuran {4 zl)e to provide the title ester (2.4 g65%) as an oil. T.l.c. rf = 0.40 (Si02, heptane/THF (7:3)).

R-N-(4-(2-Methylphenyl)-4-(3-methyl~2-thienyl)but-3-en~l-yl)nipecotic acid (MO-05-0340) R-N-(4-(Z-Methylphenyl)-4-(3-methyl-2-thienyl)but-3-10 en-l-yl)nipecotic acid ethyl ester (1.4 g, 3.52 mmol) was hydrolysed by the method outlined in Example 1. The title acid was obtained as a solid (1.1 gL, 85%); melting point: 65 - 67°C.

Example 8 Cyclopropyl-2-furylphenylmethanol To a suspension of magnesium turnings (0.26 g, 10.5 mmol) in anhydrous tetrahydrofuran (5 ml) cyclopropyl bromide (1.28 g£, 10.5 mmol) in tetrahydrof uran (5 ml) was added dropwise under nitrogen. The reaction mixture was heated at reflux for 1 hour after the initial exotherm had subsided 20 before 2-benzoylfuran (12 g, 7.0 mmol) was added as a solution in tetrahydrofuran (10 ml). The reaction mixture was worked up as described in Example 1 to give the title alcohol as an oil. T.l.c. rf = 0.23 (SiC^, heptane/THF (7:3)).

This compound was converted directly into l-bromo-4-25 (2-furanyl)-4-phenylbut-3-ene by the method described in Example 1 (Method A).

N-( 4-( 2-Furanvl)-4 -pheny lbut-3-en-l-y 1) nipecotic acid ethyl ester l-Bromo-4-(2-furanyl)-4-phenylbut-3-ene (0.23 g, 0.83 mmol) was dissolved in anhydrous acetone (10 ml) and dried 5 potassium carbonate (0.46 g, 3.32 mmol) was addedf followed by ethyl nipecotate (0.16 g, 1 mmol). The suspension was stirred at room temperature for 9 dayse filtered and evaporated to a •residue. The residue was purified by column chromatography on silica gel (Merch Art 9385), eluting with heptane/tetrahydro-10 furan (7:3), to provide the title ester (140 mg, 47%) as an oil. T.l.c. rf = 0.36 (SiO^? heptane/THF (7:3)).

N- (4 - (2-Furanyl) -4-phenylbut-3-ene-l-yl) nipecotic acid N- (4- (2-Furanyl) -4-phenylbut-3-en-l~yl) nipecotic acid ethyl ester (130 mgP 0-36 mmol) was hydrolysed by the method 15 described in Example 1. The title acid was obtained as a freeze dried solid. T.l.c. rf = 0.43 (SiC^r methanol).

Example 9 ' Preparation of Capsules, Ingredients . Mg per Capsule N-(4-(N-methylpyrrol-2- yl)-4-phenylbut-3-en-l~yl)nipecotic acid Magnesium stearate Lactose The cibove ingredients are thoroughly mixed and placed 25 into hard gelatin capsu-les. Such capsules are administered orally to subjects in need of treatment from 1-5 times daily to enhance GABAsergic activity in the central nervous system. 125 2 200 Example 10 Preparation of Tablets.

Ingredients Mg per Tablet N-(4-(M-methylpyrrol-2-5 yl)-4-phenylbut-3-en-l-yl)nipecotic acid Corn starch Polyvinyl pyrrolidone Magnesium stearate - The compound is thoroughly mixed with two thirds of 10 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. 200 4 6 12 1 PHARMACOLOGICAL TEST Introduction The convulsions induced by loud noise in the DBA/2 strain of mice is regarded as a reliable model for evaluating anciepileptic drug effects,, cf. E.N. Petersen et al.; Psvchopharmacol. 83 (1984),, 24 0 ? and A„G. Chapman et al.: Arzmeim.-Forsch. jLO (1S84) 1261. The Rotarod and Traction tests were used to evaluate the sedative properties of the test drugs.

Methods Male DBA/2 mice (8 t 1 g) were used in all experiments- The animals were pretrained on the Rotarod (6 rpm; rod diameter 2-5 cm) for 1 minute. The compounds tested were injected intraperitoneally. Twenty-five minutes later, the animals underwent a 2 minutes' test on the Rotarod. The number of failures to stay on the rod was counted. An error rate higher than 10 was assigned the maximum score of 10.

Immediately after the Rotarod test, the animals were tested in 5 a Traction test{, cf. Psychopharmacol. above. In this test, the animal was required to maintain grasp on a thin rod (diameter 2.5 mm) with the forepaws for five seconds and, within this period of time, to show a traction response (grasping onto the rod with one of the hindlegs). The performance on the test was 10 based on the absence or presence of the traction response with the 5 seconds" test period. Finally, after the Traction test, the animals were individually placed in a chamber in which they were exposed for 30 seconds to a 14 kHz sinus tone at 111 dB. During this period of timef the following behaviors were noted: 15 "Wild running"f clonic convulsions and death.

Drugs The compounds tested were dissolved in distilled water or suspended in 5% chremophore. The injection volume was 0.2 ml/mouse.

Results obtained In table I, below, the ratio ED,-^ Rotarod/ED^^ tonic convulsions is given for the compounds tested. NO-O5-034 0 is R-N-(4 -(2-methylphenyl)-4-(3-methyl-2-thienyl)but-3-en-1-y1)nipecotic acid and NO-05-0356 is R-N-(4-(N-methylpyrrol-2-25 yl)-4-phenylbut-3-en-l-yl)nipecotic acid. - 22 -Table I Compound Ratio N0-05-0340 8 N0-05-0356 21 SK&F 100330A 1 SK&F 89976A SK&F 100561 7 The features disclosed in the foregoing description and in the following claims may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.

Claims (12)

Claims - 23 -

1. A compound comprising a phenylbuten derivative of the general formula I 5 r1-c=ch-ch2-ch2-r3 (i) R2 i 10 wherein R represents phenyl optionally substituted by one, two or more substituents selected from the group consisting of halogen, 2 lower-alkyl, and lower-alkoxy, R represents lower-alkylthienyl, lower-alkyl furanyl, lower-alkylpyridyl or lower-alkylpyrrolyl, each of which may be substituted with halogen, wherein the alkyl group is 15 positioned ortho to the radical position of the thienyl furanyl, 3 pyridinyl, or pyrrolyl group, and wherein R represents 3-carboxvpiperidin-l-yl or 3-carboxy-l,2,5,5 tetrahydropyridin-l-yl or salts, lower alkyl esters or amides thereof, wherein lower means that the alkyl or alkoxv group contains less than 8 carbon atoms. 20 3

2. A compound according to Claim 1, wherein R is 3-carboxv-piperidin-l-vl or 3-carboxv-l,2,5,6 tetrahydropvridin-l~yl. 2

3. A compound according to Claim 1 or 2, wherein R represents 25 pyrrolyl, furanyl, or thienyl each of which is substituted with an alkyl ortho to the radical position. i

4. A compound according to Claim 1 wherein R~ is 2-methylpnenyl, 2 3 R is 3-methylthien-2-vl and R is nipecotic acid. 30 1 2

5. A compound according to Claim 1, wherein R is phenyl, R is 3 N-methylpyrrol-2-y1 and R is nipecotic acid. i 2

6. A compound according to Claim 1, wherein R~ is phenyl, R is 3 35 ^.-methylpyrrol —2-y 1 and R is guvacine. 1 2

7. A compound according to Claim 1, wherein R is phenyl, R is 3 Ji-ethyl-pyrrol-2-y 1 and R is nipecotic acid. - 24 -

8. A pharmaceutical composition containing a compound according to any one of the preceding claims or a salt, ester or amide thereof.

9. A composition according to Claim 8, which contains from 25 mg 5 to 1 g of the compound in dosage unit form.

10. The use of a compound according to any one of Claims 1 to 7 for the manufacture of a medicament for treating a central nervous system ailment. 10

11. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for treating a central nervous system ailment in the form of a pharmaceutical composition thereof, in which is present a pharmaceuticallv acceptable carrier or diluent. 15

12. A compound according to claim 1 substantially as herein described by way of Example. TONKINS & CO. 20 25 30 35