AU3241093A

AU3241093A - Treatment of involuntary movements with 5HT-1A receptor agonists

Info

Publication number: AU3241093A
Application number: AU32410/93A
Authority: AU
Inventors: Martin Galvan
Original assignee: Merrell Dow Pharmaceuticals Inc
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 1992-01-07
Filing date: 1992-12-07
Publication date: 1993-08-03
Also published as: CA2126554A1; MX9300035A; ZA9312B; WO1993013766A1

Description

TREATMENT OF INVOLUNTARY MOVEMENTS WITH 5HT_1A RECEPTOR

AGONISTS

This invention relates to the new uses of a class of known 5HT_1A receptor agonists, and to the manufacture of these known compounds for their use as medicaments for their new uses.

More specifically, this invention relates to the

treatment of disease states which exhibit unwanted and abnormal involuntary movements such as those found in epilepsy, parkinsonism, Huntington's chorea, tardive

dyskinesia, Freidreich's ataxia, presenile dementia, and Gilles de la Tourette's syndrome, said treatment being effected with compounds of the formula

X Z

FORMULA I in which B is represented by a C_1-4 alkylene bridging group; Alk is represented by a linear alkylene bridging group containing from 2-8 carbon atoms which may optionally be mono-substituted at one carbon atom with a C_1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; D is represented by a bond or an ethenylene bridging group; X, Y, and Z are each independently represented by hydrogen, C_1-4 alkyl, phenyl, substituted phenyl or alkylphenyl in which the phenyl ring may be optionally substituted; R₁ is

represented by a substituent selected from the group

consisting of hydrogen, halogen, C_1-4 alkyl, C_1-5 alkoxy, CF₃, OCF_3, OH, NO₂, CN, -CONR₂R₃, -NR₂R₃, -COOR_4,

-OCH₂COOR₄, -CH₂SO₂NR₂R₃, and -SO₂NR_2R3; R₂ and R₃ are each independently represented by H or a C_1-4 alkyl; R₄ is

represented by H, C_1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; Het is represented by one of the following substituents:

in which R is represented by a substituent selected from the group consisting of hydrogen, halogen, C_1-4 alkyl, C_1-4 alkoxy, O-CH₂-C₅H₅, CF₃, OCF_3, OH, NO₂, CN, -CONR₅R₆,

-CH₂SO₂NR₅R₆, -SO₂NR₅R_6, -COOR₇ or -OCH₂COOR₇; R₅ and R₆ are each independently represented by H or C_1-4 alkyl; R₇ is represented by H, C_1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; A is represented by H, or C_1-4 alkyl; or a pharmaceutically acceptable salt thereof; with the proviso that when Het is an indolyl derivative, then R₁ is not a carbonyl derivative. Another specific aspect of this invention is the use in the manufacture of a medicament for treating disease states characterized by unwanted and abnormal involuntary movements with a compound of Formula I, said disease states being those of the group comprised of epilepsy, parkinsonism, Huntington's chorea, tardive dyskinesia, Freidreich's ataxia, presenile dementia, and Gilles de la Tourette's syndrome. The compounds encompassed by Formula I above may also be represented by the following subgeneric formulae:

in which R, A, B, Alk, D, X,Y, Z, and R₁ are as defined above.

These compounds mimic the effects of serotonin at the 5HT_1A and _1D receptor. They are useful in the treatment of anxiety, depression, migraine, stroke and hypertension. As used in this application: a) the term "halogen" refers to a fluorine, chlorine, or bromine atom. b) the terms "lower alkyl group and C_1-4 alkyl" refer to a branched or straight chained alkyl group containing from 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, etc. c) the terms "lower alkoxy group and C_1-4 alkoxy" refer to a straight or branched alkoxy group containing from 1-4 carbon atoms, such as methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, isobutoxy, etc. d) the term "substituted phenyl ring" refers to a phenyl moiety (C₆H₅) which is substituted with up to 3 substituents, each substituent is independently selected from the group consisting of halogens, C_1-4 alkyl, C_1-4 alkoxy, CF₃, OCF₃, OH, CN, and NO₂. These substituents may be the same or different and may be located at any of the ortho, meta, or para positions. e) the term "alkylphenyl substituent" refers to the

following structure, -(CH₂)_m-C₆H₅, in which m is an integer from 1-3. This phenyl ring may be substituted in the manner described immediately above. f) the term "pharmaceutically acceptable salt" refers to either a basic addition salt or an acid addition salt. g) the phrase "C_1-4 alkylene bridging group" refers to a methylene, ethylene, propylene, butylene, 1-methyl-ethylene, 2-methyl-ethylene, 2-methyl-propylene, 2-ethyl-ethylene, 1-ethyl-ethylene, etc. h) the term "ethenylene bridging group" refers to the following substituent:-CH=CH-. i) the term "Alk" refers to a linear alkylene group which may be represented by the following structure:

-(CH₂)_p-CHL-(CH₂)_s, in which p and s are each independently represented by an integer from 0-7 and L is represented by H, C_1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted, with the proviso that the sum p and s is from 1-7. Representative examples of such linear alkylene groups include ethylene, propylene, butylene, hexylene, δ-benzyl- pentylene, β-ethyl-heptylene, α-phenyl-propylene, β-benzyl- pentylene, α-methylpentylene, α-methylbutylene, etc. For the purposes of this application, the α-carbon should be

considered to be the carbon atom immediately adjacent to the carbon atom bearing the Y-substituent. j) the term "indolyl derivative" refers to a compound in which Het is represented by:

k) the term "benzodioxan" derivative refers to a compound in which Het is represented by:

l) the term carbonyl derivative refers to one of the

following substituents: -CONR₂R₃, -COOR₄, -OCH₂COOR₄,

-CONR₅R₆, -COOR₇, -OCH₂COOR₇. m) the term C_1-5 alkoxy refers to:

a straight or branched alkoxy group containing from 1-5 carbon atoms, such as methoxy, ethoxy, n-propoxy,

isopropoxy, n-butoxy, isobutoxy, n-pentoxy, etc.

The expression "pharmaceutically acceptable acid addition salts" is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tri- carboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic,

succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as

methanesulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.

The expression "pharmaceutically acceptable basic addition salts" is intended to -apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by Formula I or any of its intermediates.

Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides;

ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. Either the mono- or di-basic salts can be formed with those compounds. Some of the compounds of Formula I contain one or more asymmetric centers and will therefore exist as enantiomers and diastereomers. Any reference in this application to one of the compounds represented by Formula I, or any intermediate thereof, should be construed as covering a specific optical isomer, a racemic mixture or a diastereomeric mixture. The specific optical isomers can be synthesized or can be separated and recovered by techniques known in the art such as chromatography on chiral stationary phases, resolution via chiral salt formation and subsequent

separation by selective crystallization, or enzymatic hydrolysis using stereoselective esterases as is known in the art. Alternatively, a chirally pure starting material may be utilized. Those compounds of Formula I in which D is an ethenylene bridging group will also exist as geometric isomers. Any reference to these compounds should be construed as

referring to either the cis isomer, the trans isomer or a mixture of these isomers.

All of the compounds of Formula la contain an indole. This indole may be optionally substituted as is indicated by the presence of the R substituent. When R is represented by a substituent other than hydrogen, there can be up to 3 such non-hydrogen substituents occurring on the indole ring. These substituents may appear at any of positions 2, 4, 5, 6, or 7. The 1-position of the indole may also be optionally substituted as indicated by the A substituent. All of the compounds represented by Formula lb contain a benzodioxan. This benzodioxan may be optionally substituted as indicated by the R substituent. When R is represented by a substituent other than hydrogen, there can be up to 3 such non-hydrogen substituents occurring on the benzodioxan.

These substituent may be located at any of positions 3, 5, 6, 7 or 8.

All of the compounds of Formula I contain a phenyl ring adjacent to the amide substituent. This phenyl ring may also be substituted as is indicated by the R₁ substituent. When R₁ is represented by a substituent other than hydrogen, there can be up to 3 such non-hydrogen substituents occurring on the phenyl ring. These substituents can be the same or different and can be located at any of the ortho, meta, or para positions. As noted above, if Het is represented by an indolyl derivative, then R₁ should not be represented by a carbonyl derivative.

The amino-alkylene chain connecting the benzodioxan or indole with the terminal phenyl ring may be further

substituted as indicated by the X, Y, and Z substituents. X, Y, and Z may be represented by the same substituents or differing substituents. As noted above, Alk is represented by a linear alkylene group. This alkylene group may be further substituted with only one alkyl, phenyl or alkylphenyl substituent. This one substituent may occur on any one carbon atom of the alkylene chain. Examples of compounds encompassed by the present invention include: a) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-heptanamide; b) 7-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-octanamide; c) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-phenyl- heptanamide; d) 5-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-hexanamide; e) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-heptanamide; f) 4-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-pentanamide; g) 6-[[2-(5-Methoxy-1H-indol-3-yl)ethyl]aminό]-N-[4- (trifluoromethyl)phenyl]-heptanamide; h) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]methylamino]-N-[4- (trifluoromethyl)phenyl]-heptanamide; i) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(2- methoxyphenyl)-heptanamide; j) 6- [ [2-(5-Carboxamido-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-heptanamide; k) 6-[[2-(1H-Indol-3-yl)ethyl]amino]-N-[4-(trifluoro- methyl)phenyl]-hexanamide; l) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4-(1- propyl)phenyl]-hexanamide; m) 5-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4-(1- propyloxy)phenyl]-hexanamide; n) 6-[2-[(2,3-Dihydro-1,4-benzodioxin-2-yl)ethyl]amino]-N- phenyl-hexanamide; o) 6-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4- (trifluoromethyl)phenyl]-heptanamide; p) 6-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4- methoxyphenyl)-heptanamide; q) 6-[[(2,3-Dihydro-1,4-benzodioxin-2-yl)methyl]-methyl amino]-N-[4-(trifluoromethyl)phenyl]-hexanamide; r) 6-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[2- (trifluoromethyl)phenyl]-hexanamide; s) 7-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyyl)-heptanamide; t) 7-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(2- methoxyphenyl)-heptanamide; u) 6-[[2-(4-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-heptanamide; v) 6-[[2-(5-Chloro-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-heptanamide; w) 7-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(3- methoxyphenyl)-octanamide; x) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[2- (trifluoromethyl)phenyl]-hexanamide; y) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[3- (trifluoromethyl)phenyl]-hexanamide; z) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-4-methyl-N- (4-methoxyphenyl)-hexanamide; aa) 6-[[3-(5-Hydroxy-1H-indol-3-yl)propyl]amino]-N-(4- methoxyphenyl)-hexanamide; bb) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(3- methoxyphenyl)-hexanamide; cc ) 6-[[2-(5-Hydroxy-1-methyl-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-hexanamide; dd) 6-[(2,3-Dihydro-8-methoxy-l,4-benzodioxin-2- yl)methylamino]-N-(4-methoxyphenyl)-hexanamide; ee) 5-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4- (trifluoromethyl)phenyl]-pentanamide; ff) 4-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4- methoxyphenyl)-butanamide; gg) 7-[[2-(5-Methoxy-1H-indol-3-yl)ethyl]-methylamino]-N- (4-methoxyphenyl)-octanamide; hh) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-2-hexenamide. ii) 7-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4- trifluoromethyl)phenyl]-heptanamide. Examples of preferred 5HT_1A receptor agonists include: a) 5-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4- (trifluoromethyl)phenyl]-pentanamide; b) 6-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[2- (trifluoromethyl)phenyl]-hexanamide; c) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-heptanamide; d) 7-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-octanamide; e) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-phenyl- heptanamide; f) 5-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-hexanamide; g) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-heptanamide; h) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-hexanamide; i) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(3,4- dimethoxyphenyl)-heptanamide; j) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-octanamide; k) 4-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- ( trifluoromethyl)phenyl]-pentanamide; l) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(2- methoxyphenyl)-heptanamide; m) 5-[(2,3-Dihydro-1,4-benzodioxin-2(S)-yl)methylamino]-N- (4-chlorophenyl)-pentanamide; n) 5-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N- (3,4-dichlorophenyl ) -pentanamide ; o) 5-[(2 ,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4- dimethylaminophenyl)-pentanamide; p) 6-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4- methoxyphenyl)-hexanamide; q) 7-[2-[(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-phenyl- heptanamide.

Preferred 5HT_1D Agonists include: a) 5-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4- ( trifluoromethyl)phenyl]-pentanamide; b) 5-[(2,3-Dihydro-1,4-benzodioxin-2(S)-yl)methylamino]-N- (4-chlorophenyl)-pentanamide; c) 5-[(2,3-Dihydro-1,4-benzodιoxin-2(S)-yl)methyl amino]-

N-[4-(trifluoromethyl)phenyl]-pentanamide; d) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[3- (trifluoromethyl)phenyl]-hexanamide; e) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-hexanamide; f) 5-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[phenyl]- hexanamide. The compounds of Formula la can be prepared using techniques known in the art. One suitable method is disclosed below in Reaction Scheme I:

As is depicted, the initial step in the reaction is to carry out an amidation reaction between the acid derivative of structure 1 and N,O-dimethylhydroxylamine, thereby producing the amido-derivative depicted by structure 3. This amido-derivative is subjected to a Grignard reaction thereby producing the compound of structure 5. The desired product of Formula la is then produced by carrying out a reductive animation between the compound of structure 5 and the indole derivative of structure 6.

The appropriate acid derivative to utilize as a starting material is one in which Alk, D, R₁, and Z are represented by the same substituents as is desired in the final product of Formula la. Methods for producing these acid derivatives are known in the art. For example, see Leznoff, C.C. and Goldwasser, J.M. Tetrahedron Letters, 1875-1878 (1977) and Leznoff C.C. and Goldwasser, J.M., Can. J. Chem., 56, 1562- 1568 (1978). The amidation reaction of Step A can be carried out using techniques known in the art. Typically approximately equivalent amounts of the acid derivative and N,O-dimethyl- hydroxylamine are contacted in the presence of an approximately equivalent amount of a peptide coupling reagent such as isobutylchloroformate. The amidation is also typically carried out in the presence of an approximately equivalent amount of a base such as triethylamine, 4-ethylmorpholine, or 4-methylmorpholine. The reaction is typically carried out in an aprotic solvent such as tetrahydrofuran or dichloro- methane for a period of time ranging from 1 to 24 hours. The reaction is typically carried out at a temperature range of from -20° to 20°C. The resulting amide derivative of structure 3 can be recovered from the reaction zone by extraction with

dichloromethane. It may then be purified by recrystallization from a solvent system such as ethyl acetate/hexane. Alternatively, it may be purified by flash chromatography utilizing an eluting agent such as a mixture of ethyl acetate and hexane. In Step B, this amide derivative is subjected to a

Grignard reaction in which the Grignard reagent is as described by structure 4 in which Y is as in Formula la and is represented by the same substituent as is desired in the final product. Typically, the amide of structure 3 is contacted with an excess of the Grignard reagent (2.0 to 3.0 equivalents) in an ethereal solvent such as ether or

tetrahydrofuran at -78ºC The reaction is warmed to room temperature and stirred for 8 to 36 hours. The resulting ketone derivative of structure 5 can be recovered by

extraction. It may then be purified by flash chromatography with an eluting agent such as a 50:50 mixture of ethyl acetate and hexane.

In Step C, a reductive amination is carried out between the ketone or aldehyde derivative of structure 5 and the indole derivative of structure 6 in which R, A, X, and B are as in Formula la and are represented by the same

substituents as is desired in the final product. Several of these indoles are items of commerce and methods for producing other indole derivatives are known in the art. For example, see Lloyd, D.H., Nichols, J. Orq. Chem. 51, 4294- 4295 (1986); Naito, T. et al., Synthesis, 778-780 (1989); Webb, C, US Patent 4,252,803; Abramovitch, R.A., Shapiro, D., J. Chem. Soc. 4589 (1956); Demerson, CA. et al;, J . Med. Chem. 31, 1344-50 (1988). The reductive amination is carried out using techniques known in the art. Typically the hydrochloric acid or maleic acid salt of the indole derivative of structure 6 is

contacted with an equivalent or a slight excess of the compound of structure 5. The reductive amination is carried out in the presence of an excess of sodium cyanoborohydride (about 1.5 equivalents). The reaction is typically carried out in an alcoholic solvent such as methanol at a concentration of 0.1 molar. The reaction is carried out at room temperature for a period of time ranging from 1 to 7 days. The resulting product of Formula la can be recovered by the addition of sodium bicarbonate and water followed by

extraction with a 1:4 mixture of 2-propanol and dichloromethane. It may be purified by flash chromatography with an eluting system such as 5:20:80 triethylamine:ethanol:ethyl acetate.

Alternatively, the compounds of structure 5 can also be prepared according to the procedures described in Journal of Medicinal Chemistry, 26(4), 494 (1983) and in Int. J. Pept. Protein Res., 22, 284 (1983).

Those compounds of structure 5 wherein Y = H can be made from the bromides of structure 8 (depicted below in Reaction Scheme II)by procedures known in the art. For example see Kornblum, N. et al., J. Am. Chem. Soc., 81, 4113-4114 (1959) and Ganem, B., Boeckman, R.K., Tetrahedron Letters, 917-920 (1974). In a typical procedure, approximately equimolar amounts of bromides of structure 8 (where Y = H and Alk, D, Z, and R₁, are as required structure 5) and sodium bicarbonate are stirred in dimethylsulfoxide (0.1-0.3 M) with a catalytic amount of potassium iodide. The mixture is typically heated under a nitrogen atmosphere at a

temperature of from 100 to 150°C for 2 - 10 hours. The resulting aldehyde derivative of structure 5 (Y=H) can be recovered by addition of water and extraction with diethyl ether. It may be purified by flash chromatography utilizing an eluant mixture such as 50:50 ethyl acetate:hexane.

The benzodioxan derivatives of Formula lb can also be prepared by techniques known in the art. One suitable method is disclosed below in Reaction Scheme II:

REACTION SCHEME I I

Formula lb

As is depicted above, the compounds of Formula lb are prepared by carrying out an N-alkylation between a

benzodioxan derivative as described by structure 7 in which R, X and B are as in Formula lb and an alkylhalide

derivative as described by structure 8 in which Alk, D, R₁, Y and Z are as in Formula lb and Hal is a halogen. The appropriate benzodioxan derivative to use is one in which R, X and B are represented by the same substituents as is desired in the final product. Methods for producing these benzodioxans are known in the art. For example, see Dewar, G.H. et al., Eur. J. Med. Chem. Chim. Ther. 18, 286-289 (1983); Shapero, M., et al., J. Med. Chem. 12, 326-329. The appropriate alkylhalide derivative of structure 8 to use is one in which Y, Z, Alk, D and Ri are represented by the same substituents as is desired in the final product. Methods for producing the alkylhalide derivatives are known in the art. For example, see Stirling, C.J.M., Journal of the Chemical Society, 4531-4536 (1958), and Stirling, C.J.M., Journal of the Chemical Society, 255-262 (1960).

The N-alkylation reaction is carried out using

techniques known in the art. Typically approximately equimolar amounts of the reactants are contacted in a polar, aprotic solvent such as dimethylformamide or dimethylsulfoxide. The reaction is usually carried out for a period of time ranging from 30 minutes to 8 hours at a temperature range of 50 to 100°C The desired product of Formula lb can be recovered by extraction after saturated aqueous sodium bicarbonate has been added to the reaction. It may then be purified by recrystallization from a solvent system such as ethanol:ethyl acetate and/or it may be purified by flash chromatography with an eluting agent such as 10:90

ethanol:ethyl acetate.

Alternatively, the compounds of Formula lb can be prepared by the procedure outlined above in Reaction Scheme I. The only modification is that the benzodioxan derivative of structure 7 is utilized rather than the indole derivative of structure 6. Likewise, the compounds of Formula la in which R is H can be prepared by the method disclosed in Reaction Scheme II, but substituting the appropriate indole starting material for the benzodioxan of structure 7. The compounds of Formula I are serotonin 5HT_1A receptor agonists and it is now discovered that they will be useful in the treatment of unwanted and abnormal involuntary movements such as those found in epilepsy, parkinsonism, Huntington's chorea, tardive dyskinesia, Freidreich's ataxia, presenile dementia, and Gilles de la Tourette's syndrome.

Serotonin 5HT_1A receptors are present on many different types of neurones in the mammalian brain. Activation of these receptors with serotonin or novel synthetic agonists has inhibitory actions on neuronal function. Thus, it has been shown that agonists at 5HT_1A receptors increase the membrane permeability for potassium ions leading to a hyperpolarization of the neuronal membrane potential and a decrease in membrane resistance. Such a hyperpolarization reduces the probability of the cell membrane potential reaching the threshold for action potential discharge and is thus intrinsically inhibitory in nature. In cells which are spontaneously discharging, activation of 5HT_1A receptors leads to a decrease in discharge rate; in quiescent cells, the membrane potential is moved to more negative levels.

Electrophysiological experiments on single neurones in the rat hippocampus, dorsolateral septal nucleus and raphe nucleus show that the these compounds hyperpolarize the neuronal membrane potential and inhibit neuronal activity.

5HT_1A receptors, as observed in autoradiographical experiments on mammalian brain, are located in many parts of the mammalian brain, including the cortex and the limbic system. Abnormal neuronal function in such brain areas is thought to underlie many types of seizure discharges and so inhibition of these neurons can be of use in the treatment of seizure discharge. These would include Grand Mal and Petit Mal epilepsy, partial and complex seizures of known and unknown origin. The anti-seizure activity of these compounds has been shown by their ability to antagonize pentylenetetrazole-induced seizures in mice, a standard method for the evaluation of antiepileptic drugs (Krall, et al., 1978).

It has also been postulated that a reduction in neuronal inhibition can contribute to motor disturbances and impaired motor coordination in a number of neurological disorders.

Since 5HT_1A receptor agonists can inhibit neuronal activity, these compounds are to be found as being useful in the treatment of Parkinson's disease, Huntington's chorea, and such other diseases where tremor and/or involuntary

movements occur. It is possible to demonstrate an action of these compounds on tremor and motor coordination by their ability to block oxotremorine-induced tremor in rats. A beneficial effect in Parkinson's disease could be

demonstrated by administration to primates, which have previously been intoxicated with the specific neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP specifically destroys the dopamine-containing neurons in the substantia nigra of primates and humans and causes motor disorders which resemble those seen in idiopathic

Parkinson's disease.

In order to exhibit this neuroprotective effect, it is necessary that the compounds be administered to the patient in an effective amount. The dosage range at which these compounds exhibit this effect can vary widely depending upon the severity of the patient's condition, the particular compound being administered, the route of administration, the co-administration of other therapeutic agents, and the presence of other underlying disease states. Typically, the compounds will be administered at a dosage range of from 0.01 mg/kg/day to about 100 mg/kg/day. Repetitive daily administration may be desirable and will vary with the conditions described above. However, the compounds are typically administered from 1 to 4 times daily or as a continuous intravenous infusion.

Pharmaceutical compositions can be manufactured

utilizing techniques known in the art. Typically a thera- peutically effective amount of a compound of Formula I will be admixed with a pharmaceutically acceptable carrier, suitable for dosing at the appropriate dosage regimens as determined by the attending diagnostician.

For oral administration , the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or

emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations. In another embodiment, the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.

For parenteral administration the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a

suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art.

The compounds of this invention can also be administered topically. This can be accomplished by simply preparing a solution of the compound to be administered, preferably using a solvent known to promote transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Some suitable transdermal devices are described in U.S. Pat. Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,894. These devices generally contain a backing member which defines one of its face surfaces, an active agent permeable adhesive layer defining the other face surface and at least one reservoir containing the active agent interposed between the face surfaces. Alternatively, the active agent may be contained in a plurality of microcapsules distributed throughout the permeable adhesive layer. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. In another device for transdermally administering the compounds in accordance with the present invention, the pharmaceutically active compound is contained in a matrix from which it is delivered in the desired gradual, constant and controlled rate. The matrix is permeable to the release of the compound through diffusion or microporous flow. The release is rate controlling. Such a system, which requires no membrane is described in U.S. Pat. No. 3,921,636. At least two types of release are possible in these systems. Release by diffusion occurs when the matrix is non-porous. The pharmaceutically effective compound dissolves in and diffuses through the matrix itself. Release by microporous flow occurs when the pharmaceutically effective compound is transported through a liquid phase in the pores of the matrix.

Examples are presented in European Patent Application No. 91 114 456.6, filed August 28, 1991, entitled "Serotonin 5-HT_1A and 5-HT_1D Antagonists", published April 8, 1992, under No. 0 478 954 Al, and in South African Patent 91/6710, published May 27, 1992. These patent applications, and all publication references cited herein, are hereby incorporated by reference in order to further illustrate the invention. These examples should not be construed as limiting the scope of the invention in any manner.

Claims

WHAT IS CLAIMED IS:

1. The use in the manufacture of a medicament for treating disease states exhibiting unwanted and abnormal involuntary movements in epilepsy, parkinsonism,

Huntington's chorea, tardive dyskinesia, Freidreich's ataxia, presenile dementia, and Gilles de la Tourette's syndrome, effected with a compound of the formula

in which B is represented by a C_1-4 alkylene bridging group; Alk is represented by a linear alkylene bridging group containing from 2-8 carbon atoms which may optionally be mono-substituted at one carbon atom with a C_1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; D is represented by a bond or an ethenylene bridging group; X, Y, and Z are each independently represented by hydrogen, C_1-4 alkyl, phenyl, substituted phenyl or alkylphenyl in which the phenyl ring may be optionally substituted; R₁ is represented by a

substituent selected from the group consisting of hydrogen, halogen, C_1-4 alkyl, C_1-5 alkoxy, CF₃, OCF₃, OH, NO₂, CN, -CONR₂R₃, -NR₂R₃, -COOR₄, -OCH₂COOR₄,

-CH₂SO₂NR₂R₃, and -SO₂NR₂R₃; R₂ and R₃ are each

independently represented by H or a C_1-4 alkyl; R₄ is represented by H, C_1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; Het is represented by one of the following substituents: in which R is represented by a substituent selected from the group consisting of hydrogen, halogen, C_1-4 alkyl, C_1-4 alkoxy, O-CH₂-C₆H₅, CF₃, OCF₃, OH, NO₂, CN, -CONR₅R₆, -CH₂SO₂NR₅R₆, -SO₂NR₅R₆, -COOR₇ or -OCH₂COOR₇; R₅ and R₆ are each independently represented by H or C_1-4 alkyl; R₇ is represented by H, C_1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; A is represented by H, or C_1-4 alkyl; or a pharmaceutically acceptable salt thereof; with the proviso that when Het is an indolyl derivative, then R₁ is not a carbonyl derivative.

2. The use of a compound according to Claim 1, wherein the compound is

5-[(2,3-dihydro-1,4-benzodioxin-2(S)-yl)methylamino]-N- (4-chlorophenyl)-pentanamide, monohydrochloride,

5-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4- methylphenyl)-pentanamide, monohydrochloride,

5-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-4- phenyl-pentanamide, monohydrochloride,

5-[(2 ,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-4- fluorophenyl)-pentanamide, monohydrochloride,

6-[[2-(5-carboxamido-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-heptanamide, hemifumarate, 6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-[2-(trifluoromethyl)phenyl]-hexanamide, hydrochloride,

7-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-phenyl- heptanamide, hydrochloride,

6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-heptanamide,

7-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-octanamide,

6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-phenyl- heptanamide,

5-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-hexanamide; or

6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-heptanamide.

3. The process for treating disease states which exhibit unwanted and abnormal involuntary movements in epilepsy, parkinsonism, Huntington's chorea, tardive dyskinesia, Freidreich's ataxia, presenile dementia, and Gilles de la Tourette's syndrome, said treatment being effected with a therapeutically effective amount of a compound of the formula

substituent selected from the group consisting of hydrogen, halogen, C_1-4 alkyl, C_1-5 alkoxy, CF₃, OCF₃. OH, NO₂, CN, -CONR₂R₃, -NR₂R₃, -COOR_4, -OCH₂COOR₄,

-CH₂SO₂NR₂R₃, and -SO₂NR₂R₃; R₂ and R₃ are each

independently represented by H or a C_1-4 alkyl; R₄ is represented by H, C_1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; Het is represented by one of the following substituents:

in which R is represented by a substituent selected from the group consisting of hydrogen, halogen, C_1-4 alkyl, C_1-4 alkoxy, O-CH₂-C₆H₅, CF₃, OCF₃, OH, NO₂, CN, -CONR₅R₆, -CH₂SO₂NR₅R₆, -SO₂NR₅R_6, -COOR₇ or -OCH₂COOR₇; R₅ and R₆ are each independently represented by H or C_1-4 alkyl; R₇ is represented by H, C_1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; A is represented by H, or C_1-4 alkyl; or a pharmaceutically acceptable salt thereof; with the proviso that when Het is an indolyl derivative, then R₁ is not a carbonyl derivative.

4. The process according to Claim 3, wherein the compound is

5-[(2,3-dihydro-1,4-benzodioxin-2(S)-yl)methylamino]-N-

(4-chlorophenyl)-pentanamide, monohydrochloride,

5-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4- fluorophenyl)-pentanamide, monohydrochloride,

6-[[2-(5-carboxamido-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-heptanamide, hemifumarate,

6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-[2-(trifluoromethyl)phenyl]-hexanamide, hydrochloride,

7-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-octanamide,

6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-phenyl- heptanamide,

6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-heptanamide.