WO1992015301A1

WO1992015301A1 - Treatment of hypertension and peripheral vascular diseases

Info

Publication number: WO1992015301A1
Application number: PCT/DK1991/000060
Authority: WO
Inventors: Jens Kristian Perregaard; Nils Dragsted
Original assignee: H. Lundbeck A/S
Priority date: 1991-03-01
Filing date: 1991-03-01
Publication date: 1992-09-17
Also published as: JPH05505612A

Abstract

Described is a method for the treatment of hypertension in man, comprising the step of administration of a therapeutically effective amount of an 1-aryl-3-(4-piperidyl)-indole derivative having general formula (I), wherein R1 is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, lower alkylthio, trifluoromethyl, trifluoromethylthio, lower alkylsulfonyl, amino, lower alkylamino or lower dialkylamino; R is optionally substituted phenyl or a hetero aromatic group; and R2 is optionally hydroxyl substituted alkyl or alkenyl, or R2 is a group of formula (IV), wherein n is an integer from 2-6; W is oxygen, sulphur or N-R3, wherein R3 is H or alkyl; U is nitrogen or carbon; Z is -(CH¿2?)m-, m being 2 or 3, or Z is -CH=CH- or 1,2-phenylene, or Z is -COCH2-; V is oxygen, sulphur, CH2, or NR?4¿, wherein R4 is hydrogen, optionally substituted alkyl or alkenyl; to a patient in need thereof.

Description

TREATMENT OF HYPERTENSION AND PERIPHERAL VASCULAR DISEASES

Field of invention

The present invention relates to a method for the treatment of hypertension and peripheral vascular diseases in man, in which method a compound belonging to a certain class of 1-aryl-3-(4-piperidyl)-indole derivatives is administered in a therapeutically effective amount.

Background of the invention

US patent No 4,710,500 discloses in general optionally 5-substituted 1 -aryl-3- (1 ,2,3,6-tetr ahydro-4-pyridyl)- (III), 1 -aryl-3-(4-piperidyl)- (I^') or 1 -aryl-3-(1 -piperazi- nyl)indole (II) derivatives having the formulas:

in which formulas R' designates optionally substituted phenyl or a hetero aromatic group, R1^' is hydrogen or a substituent such as halogen, alkyl, alkoxy, cyano, nitro, etc., and R2^' is hydrogen, alkyl, alkenyl or a certain (hetero cycle) lower alkyl substituent. Most of the compounds are shown to be potent and long-lasting dopamine antagonists in vivo , and accordingly to be useful in the treatment of psychoses, and all the compounds are proven to be strong serotonin-S₂ (5-hydroxytryptamin-2; 5-HT₂) receptor antagonists in vivo indicating effects in the treatment of depression and negative symptoms of schizophrenia. The tests used to show blockade of dopaminergic activity in vivo were a catalepsy test and a methylphenidate test, both being at that time regarded as tests for dopaminergic activity. However, at present said two tests are considered to be a measure of the propensity of an antipsychotic compound to induce extrapyramidal side effects.

The compound of the above formula V wherin W is chloro, R^' is 4-fluorophenyl and R2^' is 2-(2-imidazolidinon-1-yl)ethyl is the known neuroleptic, sertindole, the neuroieptic activity of which is discribed in the co-pending US patent application No 07/508,240.

It is also mentioned in US patent No. 4,710,500 that due to the 5-HT₂ activity the compounds may be useful in the treatment of cardiovascular diseases.

However, though serotonin is proven to be a potent vasoconstrictor in the vascular system (Vanhoutte P.M., "Serotonin in the cardiovascular system" Raven Press, 1985) and this together with the antihypertensive effect of the first selective 5-HT₂ antagonist ketanserin (Awouters F., "The pharmacology of ketanserin, the first selective S₂ antagonist.", Drug. Dev. Res. 6 : 263-300, 1985) could suggest the beneficial role of 5-HT antagonists in antihypertensive therapy, the role of seroto¬ nin on the vascular system is very complex and not fully understood.

It has been found that there is a poor correlation between 5-HT2 receptor antago¬ nism and the antihypertensive potential of a number of drugs. Accordingly the suggestion that the antihypertensive effect of ketanserin is due to the 5-HT₂ antagonistic activity do not seem valid (Cohen et al 1983 and Kalkman et al. 1983 as reviewed in Saxena P.R. and Wouters W., "Interferences with 5-hydroxytryp- tamine" in : Pharmacology of antihypertensive therapeutics, Handb. Exp. Pharm. 93, Springer Verlag. p. 533-558, 1990). The antihypertensive effect of ketanserin has later been shown to correlate with the α-adrenolytic action of ketanserin, and Vanhoutte (1985) has stated that serotonin has an amplifying effect on other vasoconstrictory agents, e.g. on norepinephrine.

Several authors suggest, and this is now the recognized concept, that the antihyper- tensive effect is a result of the α-adrenoreceptor antagonistic activity or of a combination of 5-HT₂ receptor and α-adrenoreceptor antagonistic activi-ties (Saxena P.R. and Wouters W., 1990).

Surprisingly, it has now been found that certain 1-aryl-3-(4-piperidyl)-indole derivatives having the above general formula I' in addition to the 5-HT₂ receptor antagonistic activity have also α-adrenoreceptor antagonistic activity. Furthermore they have been found to be non-cataleptic and to have antihypertensive activity.

Disclosure of the invention

The present invention provides a method for the treatment of hypertension and peripheral vascular diseases in man comprising the step of administration of a therapeutically effective amount of an 1-aryl-3-(4-piperidyl)-indole derivative having the generel formula:

wherein R1 is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, lower alkylthio, trifluoromethyl, trifluoromethylthio, lower alkylsulfonyl, amino, lower alkylamino or lower dialkylamino;

R is phenyl optionally substituted with one or more substituents independently selected from the following: halogen, lower alkyl, lower alkoxy, hydroxy, trifluoro¬ methyl, and cyano, or R is a hetero aromatic group, preferably 2-thienyl, 3-thienyl, 2- furoyl, 3-furoyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl; and R2 is hydrogen, cycloalkyl, lower alkyl or lower alkenyl, optionally substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid having from two to twentyfour carbon atoms inclusive, or R2 is a group of the formula IV :

wherein n is an integer from 2 - 6;

W is oxygen, sulphur or N-R3, wherein R3 is H, lower alkyl or cycloalkyl

U is nitrogen or carbon;

Z is -(CH₂)m-, m being 2 or 3, or Z is -CH=CH- or 1 ,2-phenylene optionally substi- tuted with halogen or trifluoromethyl, or Z is -COCH₂- or -CSCH₂-;

V is oxygen, sulphur, CH₂, or NR4 , wherein R is hydrogen, lower alkyl optionally substituted with one or two hydroxy groups, lower alkenyl or a cycioalkylmethyl group, said cycloalkyl having from three to six carbon atoms inclusive; or a pharmaceutically acceptable acid addition salt thereof to a patient in need thereof.

The term "lower alkyl" is intended to mean a straight or branched alkyl group having from one to four carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, etc. Lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylamino and lower dialkylamino similarly designate such groups wherein the alkyl moiety is a lower alkyl group as defined above.

Lower alkenyl is intended to mean an alkenyl group containing from 2 to 4 carbon atoms, for example ethenyl, 1-propenyl, 2-butenyl, etc.

The Z-group -COCH₂- or -CSCH₂- may be oriented in either direction in the ring.

Some of the compounds of the general formula I may exist in optical isomers thereof; and the administration of such optical isomers is also embraced by the method of the invention. The pharmaceutically acceptable acid addition salts of the compounds used in the invention are salts formed with non-toxic organic or inorganic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The compounds of the formula I and the pharmaceutically acceptable acid addition salts thereof may be administered in any suitable way, e.g. orally or parenterally, and the compounds may be presented in any suitable form for such administration, eg. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.

An effective daily dose of a compound of the formula I or a pharmaceutically acceptable salt thereof is from 1.0 μg/Kg to 1.0 ng/Kg body weight.

The compounds used in the method of the invention are known to be 5-HT2- receptor antagonist and have now been shown to be active in an in vitro test for binding to α-preceptors, these two activities together indicating clinical vasodilation. Furthermore they have been found to have effects in measurements of the blood pressure in vivo in rats, and they have been found not to induce catalepsy or only induce weak catalepsy which is today regarded as indicative of extrapyramidal side effects. It is indeed very surprising that the present compounds are non-cataleptic whereas the compounds of the formulas II and HI of the above US patent have proved to be cataleptic (cf. the pharmacological data in the following) and the mechanisms behind this are not fully understood. Accordingly the compounds of the present invention are believed to be useful in the treatment of hypertension and peripheral vascular diseases without causing extrapyramidal side effects. Though US patent No 4,710,511 generally comprises the 3-(4-piperidyl) com¬ pounds of the formula I disclosed above, only five compounds have been specifi¬ cally disclosed, i.e. 1-(4-fluorophenyl)-5-methyl-3-(1-methyl-4-piperidyl)-1 H-indole, hydrobromide, designated Lu 21-037, 1 -(4-fluorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-1 H-indole, designated Lu 23-086,

1 -(4-fluorophenyl)-3-[1 -[2-(2-pyrrolidinσn-1 -yl)ethyl]-4-piperidyl]-5-trifluoro-methyl- 1 H-indole, fumarate, designated Lu 23-158, 1 -(4-fluorophenyl)-3-(1 -methyl-4-pϊperidyl)-5-trifluoromethyl-1 H-indole, oxalate, designated Lu 21-131,

5-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidyl]-1H- indole, sertindole.

Accordingly the 1-aryl-3-(4-piperidyl)-indole derivatives used in the method according to the invention having the generel formula I as defined above, provided that in case R is 4-fluorophenyl: R2 may not be CH₃ when R1 is CH₃ or CF₃, R1 may not be hydrogen or chloro when R is an 1-(2- imidazolidinon-1-ylethyl) group and R1 may not be CF₃ when R is an 1-(1-pyrrolidin-2-on-ylethyl) group; are novel compounds.

The compounds of the formula I used in the invention may be prepared according to methods (b), (c), or (d) described in US patent No. 4,710,500. 2-pyrrolidin- thiones are prepared from the corresponding lactame derivatives according to Iitterature methods (BuII.Soc.Chim.Belg. 87, 223, 229, 299, 525 (1978)) by using Lawesson^'s reagent or phosphorous pentasulphide at appropriate temperatures. lmidazolidin-2-thion derivatives are prepared by ringclosure reactions from properly substituted ethylendiamines with carbondisulphide, thiophosgen or corresponding thiocarbonyl precursor compounds.

The acid addition salts of the compounds used in the invention are easily prepared by methods well known in the art. The base is reacted with either the calculated amount of organic or inorganic acid in an aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling, or an excess of the acid in an aqueous immiscible solvent such as ethyl ether or chloro¬ form with the desired salt separating directly. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts. In addition to the above known substances, the following compounds were pre¬ pared according to methods (b), (c), or (d) described in US patent No. 4,710,500 , or from the corresponding lactame derivatives according to litterature methods (Bull.Soc.Chim.Belg. 87, 223, 229, 299, 525 (1978)) by using Lawesson ^'s reagent 5 or phosphorous pentasulphide at appropriate temperatures:

5-chloro-1 -(4-fluorophenyl)-3-[1 -(2-hydroxyethyl)-4-piperidyl]-1 H-indole, hydro¬ chloride, 1 MP : 266-269° C

5-chloro-1 -(4-fluorophenyl)-3-[1 -[2-(2-oxazolidinon-1 -yl)ethyl]-4-piperidyl]-1 H- indole, fumarate, 2, MP : 203-205° C o 5-chloro-1 -(4-fluorophenyl)-3-[1 -[2-(3-methyl-2-imidazolidinon-1 -yl)ethyl]-4- piperidyl]-1 H-indole, fumarate, 3, MP : 198-199° C 5-chloro-1 -(4-f luorophenyl)-3-[1 -[2-(2-pyrrolidinon-1 -yl)ethyl]-4-piperidyl]-1 H- indole, fumarate, 4, MP : 209-211 ° C

1 -(4-fluorophenyl)-3-[1 -[2-(3-methyl-2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-5- 5 trifluoromethyl-1 H-indole, 5, MP : 144-145° C

1 -(4-fluorophenyl)-3-[1 -[2-(2-oxazolidinon-1 -yl)ethyl]-4-piperidyl]-5-triflouro-methyl- 1 H-indole, fumarate, 6, MP : 212-213° C

5-chloro-1 -(4-fluorophenyl)-3-[1 -[2-(2-pyrrolidinthion-1 -yl)ethyl]-4-piperidyl]-1 H- indole, fumarate, 7, MP : 195-199° C o 1 -(4-fluorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-5-methyl- sulfonyl-1 H-indole, fumarate, 8, MP : 188-192° C

5-chloro-1 -(4-fluorophenyl)-3-[1 -[6-(2-pyrrolidinon-1 -yl)-1 -hexyl]-4-piperidyl]-1 H- indole.hydrochloride, 9, MP : 123-128° C

5-chloro-1-(4-fluorophenyl)-3-(4-piperidyl)-1 H-indole, fumarate, 10 , MP : 196- 5 201° C.

1 -(4-fluorophenyl)-3-(4-piperidyl)-5-trifluoromethyl-1 H-indole, hydrochloride, 11 MP : 281-284° C

1 -(4-fluorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-5-trif,uoro- methyl-1 H-indole, 12, MP : 169-171° C o 1 -(4-fluorophenyl)-3-[1 -[6-(2-pyrrolidinon-1 -yl)-1 -hexyl]-4-piperidyl]-5-trif luoromethy l-1 H-indole,oxalate, 13, MP : 85-87° C

5-chloro-1 -(4-fluorophenyl)-3-[1 -[2-[3-(2-propyl)-2-imidazolidinon-1 -yl]ethyl]-4- piperidyl]-1 H-indole, oxalate, 14, MP : 92-96° C 5-fiuoro-1-(4-fluorophenyl)-3-(4-piperidyt)-1 H-indole, fumarate, 15 , MP : 198-

200° C

5-f iuoro-1 -(4-fluorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-1 H- indole, oxalate, 16, MP : 188-190° C 5-fIuoro-1 -(4-f luorophenyl)-3-[1 -[2-(2-pyrrolidinon-1 -y l)ethyl]-4-piperidyl]-1 H-indole, fumarate, 17, MP : 178-180° C

5-fluoro-1 -(4-fluorophenyl)-3-[1 -[2-[3-(2-propyl)-2-imidazolidinon-1 -yl]ethyl]-4- piperidyl]-1 H-indole, fumarate, 18, MP : 115-120° C

5-chloro-1 -(4-fluorophenyl)-3-[1 -[5-(2-imidazolidinon-1 -yl)-1 -pentyl]-4-piperidyl]-1 H- indole, oxalate, 19, MP : 145-147° C

5-chloro-1 -(4-fluorophenyl)-3-[1 -[4-(2-imidazolidinon-1 -yl)-1 -butyl]-4-piperidyl]-1 H- indole, oxalate, 20, MP : 178-179° C

5-chIoro-1-(4-fluorophenyl)-3-[1-[6-(2-imidazolidinon-1-yl)-1-hexyl]-4-piperidyl]-1H- indole, oxalate, 21, MP : 156-158° C 5-chloro-1 -(4-fluorophenyl)-3-[1 -[2-(hydantoin-2-yl)ethyl]-4-piperidyl]-1 H-indole,

22, MP : 174-176° C

5-fluoro-1 -(4-fluorophenyl)-3-[1 -[6-(2-pyrrolidinon-1 -yl)-1 -hexyl]-4-piperidyl]-1 H- indole, 23, oil

1 -(4-fluorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-5-methyl-1 H- indole, 24, MP : 187-189° C

1 -(4-fiuorophenyl)-3-[1 -[2-[3-(2-propyl)-2-imidazolidinon-1 -yl]ethyl]-4-piperidyl]-5- methyl-1 H-indole, hydrochloride, hydrate, 25, MP : 214-215° C 1 -(4-fluorophenyl)-3-[1-[2-(2-pyrrolidinon-1 -yl)ethyl]-4-piperidyl]-5-methyl-1 H- indole, hydrochloride, hemihydrate, 26, 265-266°C 1-(4-fluorophenyl)-3-[1-[2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl]-4-piperidyl]-5- trifluoromethyl-1 H-indole, 27, MP : 99-100° C

3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-1 -(3-thienyl)-1 H-indole, oxalate 28, MP : 139-140° C^*

1 -(4-f luorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-5-methoxy-1 H- indole, 29, MP : 167° C

5-fluoro-3-[1 -[2-[3-(2-propyl)-2-imidazolidinon-1 -yl]ethyl]-4-piperidyl]-1 -(3-thienyl)- 1 H-indole, oxalate, hemihydrate, 30, MP : 95-97° C

5-fluoro-3-[1-[2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl]-4-piperidyl]-1-(2-thienyl)- 1 H-indole, dioxalate, 31, MP : 173-174° C 5-bromo-1 -(4-fluorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-1 H- indole, 32, MP : 171-172° C

1 -(4-fluorophenyl)-3-[1 -[2-[3-(2-propyl)-2-imidazolidinon-1 -yl]ethyl]-4-piperidyl]-1 H- indole, hydrochloride, 33, MP : 226-227° C 5 5-chloro-1 -(4-fluorophenyl)-3-[1 -[3-(2-imidazolidinon-1 -yl)-1 -propyl]-4-piperidyl]-1 H- indole, fumarate, 34, MP : 203-205° C

In the following example the preparation of an imidazolidin-2-thion derivative is shown :

EXAMPLE 1

l o 5-chloro-1 -(4-fluorophenyl)-3-[1 -[2-(2-imidazolidinthion-1 -yl)ethyl]-4-piperidyl]-1 H- indole, oxalate, 35, MP : 150° C

To a solution of 5-chloro-1 -(4-f luorophenyl)-3-(4-piperidyl)-1 H-indole (25 g) in N- methyl-2-pyrrolidone (150 ml) were added chloroacetonitrile (6 g) and triethylamine (10 ml). The reaction mixture was heated at 60° C for one hour and subsequently

1 poured onto crushed ice. The precipitated 5-chloro-3-(1-cyanomethyl-4-piperidyl)-1-

(4-fluorophenyl)-1 H-indole was filtered off and washed with water. Yield 20 g. MP : 170-172° C.

A solution of the thus isolated cyanomethylderivative (24 g) in dry THF (150 ml) was added dropwise to a previously prepared solution of AIH₃ (from 8 g of UAIH₄ and 8

20 g of AICI3) in dry diethyl ether (250 ml). The mixture was heated at reflux for one hour and finally hydrolyzed by carefully adding a cone, aqueous solution of NaOH (10 ml) under simultaneous cooling. Inorganic salts were filtered off and were subsequently carefully washed with hot dichloromethane (2 x 100 ml), the com¬ bined organic phases were dried (anh. MgS0₄) and finally evaporated leaving 3-[1- 5 (2-aminoethyl)-4-piperidyl]-5-chloro-1-(4-fluorophenyl)-1 H-indole (25 g) as an oil. Without further purification this product (12 g) and triethylamine (4.2 g) were heated in 1 ,1 ,1-trichloroethane (100 ml) at 50-55° C. A solution of chloroacetonitrile (3.6 g ) in 1 ,1 ,1-trichloroethane (10 ml) were added dropwise during 10 minutes. The mixture was heated for another 4 hours at 50° C. Ethyl acetate (200 ml) was added 0 and the mixture was poured into ice cooled dil. aqueous NaOH solution (400 ml). The organic phase was separated, washed with brine, dried (anh. MgS0₄) and the solvents evaporated leaving 5-chloro-3-[1-[2-(N-cyanomethyl)aminoethyl]-4- piperidyl]-1-(4-fluorophenyl)-1 H-indole (14 g) as an oil.

The oil thus isolated was dissolved in dry THF (100 ml) and added dropwise to a previously prepared solution of AIH₃ (from 6 g of LiAIH₄ and 6 g of AICI₃) in dry dϊethyl ether (200 ml). The mixture was refluxed for one hour and finally hydrolyzed by cautiously adding a cone, aqueous solution of NaOH (8 ml) under simultaneous cooling. Inorganic salts were filtered off and were subsequently washed with hot dichloromethane (2 x 100 ml). The combined organic phases were dried (anh. MgS0₄) and finally evaporated leaving 3-[1-[N-(2-aminoethyl)-2-aminoethyl]-4- piperidyl]-5-chloro-1-(4-fluorophenyI)-1 H-indole (8.5 g) as an oil. This oil (4.5 g) was dissolved in 1-pentanol (50 ml) and carbondisulphide (5 ml) was added. After stirring for 2 hours at room temperature the resulting suspension was heated to 140° C for 1.5 hours. Excess CS₂ was flushed away by a gentle stream of N₂ gas. Finally most of the 1-pentanol was evaporated at reduced pressure. The remaining oil was purified by column chromatography on silica gel (eluted with ethyl acetate/- ethanol/triethylamme - 80/20/4). The oxalate salt of the title compound 35 crystallized from acetone. Yield 250 mg. MP : 150° C.

PHARMACOLOGY

The compounds used in the invention were tested in accordance with well recogni- zed and reliable test methods. The tests were as follows:

CATALEPSY TEST

Evaluation of catalepsy is made according to Arnt ( Eur. J. Pharmacol. _Q,, 47 -55 (1983)). Test compound is given s.c. in different doses. The rat (170 - 240 g ) is placed on a vertical wire mesh ( mesh diameter 12 mm ). The rat is considered cataleptic if it remains immobile for more than 15 sec. The maximum number of rats showing catalepsy within the first 6 hours is recorded for each dose group. The results are recorded in fractions and an ED₅₀ value is calculated by means of log- probit analysis. The results are shown in table 1.

The following corresponding 1-aryl-3-(1 ,2,3,6-tetrahydrpyridyl)- or 1-aryl-3-(pipera- zinyl)indole derivatives which are analogues of sertindole and compound No 12, respectively, were included in the test as comparing compounds: A) 1 -(4-Fluorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-1 ,2,3,6-tetrahydropyridi n-4-yl]-5-trifluoromethyl-1 H-indole

B) 5-Chloro-1 -(4-f luorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-1 ,2,3,6- tetrahydro-4-pyridyl]-1 H-indole

C) 5-Chloro-1 -(4-fluorophenyl)-3-[4-[2-(2-imidazolidinon-1 -yl)ethyl]-1 -piperazinyl]- 1 H-indole

TABLE 1 Cataleptic Activity

Further ED50 values of corresponding 1-aryl-3-(1 ,2,3,6-tetrahydro-4-pyridyl)- or 1- aryl-3-(1-piperazinyl)indole derivatives are given in US patent No 4,710,500.

EFFECTS ON BLOOD PRESSURE IN SPONTANEOUSLY HYPERTEN¬ SIVE RATS

The test is used for the determination of the ability of a compound to increase or decrease the blood pressure in conscious spontaneously hypertensive rats (SHR). Materials

Rats : Male SHR having a body weight of 250-350 g.

Polyethylene catheters : Portex No. 800/100/200/ = PP 50; ID 0.58 mm;

OD 0.96mm. Restraint boxes Pressure transducers : Bell & Howell or Druck Transducers.

Procedure

The femoral arteriy of the male SHR is cannulated in ether anaestesia for blood pressure recording. After a stabilisation period of 1.5 hours after discontinuation of the anaestesia, initial blood pressure curves are recorded and the systolic (SAP) and the diastolic (DAP) pressure determined.

Test substance (5mg/kg) is injected i.p. and the pressure curve recorded for one hour. SAP and DAP are calculated in percent of mean initial values at different times (10, 20, 30, 40, 50 and 60 minutes) after the injection. At least two SHR are used per dose level. The mean maximum change is used for estimating the effects of the drug.

The results are shown in the following table II. The known substances prazosin, and ritanserin are included in the test for comparison purposes.

INHIBITION OF 3H-PRAZOSIN BINDING TO C _Λ ADRENOCEPTORS

IN RAT BRAIN IN VITRO

By this method the inhibition of the binding of 3H-Prazosin (0.25 nM) to αi adreno- ceptors in membranes from rat brain is determined in vitro. Method and results in Hyttel & Larsen, J. Neurochem, 44, 1615-1622, 1985; Skarsfeldt & Hyttel, Eυr. J. Pharmacol. 125, 323-340, 1986. Procedure

Male Wistar (Mo Wist) rats (125-200 g) are sacrificed and brain tissue is dissected and weighed. The tissue is homogenized (Ultra Turrax, 10 sec.) in 10 ml of ice-cold 50 nM Tris buffer pH 7.7 (at 25°C). The homogenate is centrifuged twice at 20,000 g for 10 min. at 4°C with rehomogenization of the pellet in 10 ml ice-cold buffer. The final pellet is homogenized in 400 vol (w/v) ice-cold buffer.

Incubation tubes kept on ice in triplicate receive 100 μl of drug solution in water (or water for total binding) and 4000μl of tissue suspension (final tissue content corresponds to 10 mg original tissue). The binding experiment is initiated by ι o addition of 100 μl of 3H-Prazosin (final concentration 0.25 nM) and by placing the tubes in a 25°C water bath. After incubation for 20 min. the samples are filtered under vacuum (0-50 mBar) through Whatman GF/F filters (25 mm). The tubes are rinsed with 5 ml ice-cold buffer which then are poured on the filters. Thereafter, the filters are washed with 5 ml of buffer. The filters are placed in counting vials and 4

15 ml of appropriate scintillation fluid (e.g. PicofluorT -|5) are added. After shaking for 1 h and storage 2 hrs in the dark the content of radioactivity is determined by liquid scintillation counting. Specific binding is obtained by subtracting the nonspecific binding in the presence of 1 μM of Prazosin.

For determination of the inhibition of binding five concentrations of drugs covering 3 20 decades are used.

The measured cpm are plotted against drug concentration on semilogarithmic paper and the best fitting S-shaped curve is drawn. The IC₅₀ value is determined as the concentration at which the binding is 50% of the total binding in control samples minus the nonspecific binding in the presence of 1 μM of Prazosin.

5 3H-Prazosin = [furoyl-5-3H]-Prazosin from New England Nuclear, specific activity approximately 20 Ci/mmol. TABLE 2 Effects on blood pressure and inhibition of prazosin binding to α-i receptors of drugs

N.D. : Not determined.

It is seen from table 2 that the compounds of the invention are strong in vitro αi- antagonists and that they have strong antihypertensive effects in vivo in the tests used and it appears from table 1 that the compounds of the invention are without or substantially without cataleptic activity and accordinly being lacking the extrapyra¬ midal side effects probably associated with the corresponding known 3-(1 ,2,3,6- tetrahydro-4-pyridyl) and 3-(1-piperazinyl) derivatives. Consequetly, they are considered to be useful in the treatment of hypertension and peripheral vascular diseases in humans. FORMULATION EXAMPLES

The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting maschine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients.

Solutions for injections may be prepared by solving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilization of the solution and filling in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.

Typical examples of recipes for the formulations of the invention are as follows:

1 ) Tablets containing 0,5 milligrams of sertindole calculated as the free base: Sertindole 0.5 mg Lactose 18 mg

Potato starch 27 mg

Saccharose 58 mg

Sorbitol 3 mg

Talcum 5 mg Gelatine 2 mg

Povidone 1 mg

Magnesium stearate 0.5 mg 2) Tablets containing 1 milligrams of compound No 3 calculated as the free base:

4) Solution for injection containing per milliliter: Sertindole 0.2 mg

Acetic acid 17.9 mg

Sterile water ad 1 ml

5) Solution for injection containing per milliliter:

Claims

1. A method for the treatment of hypertension in man comprising the step of administration of a therapeutically effective amount of an 1 -aryl-3-(4-piperidyl)- indole derivative having the generel formula:

wherein

R1 is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, lower alkylthio, trifluoromethyl, trifluoromethylthio, lower alkylsulfonyl, amino, lower alkylamino or lower dialkylamino; R is phenyl optionally substituted with one or more substituents independently selected from the following: halogen, lower alkyl, lower alkoxy, hydroxy, trifluoro¬ methyl, and cyano, or R is a hetero aromatic group, preferably 2-thienyl, 3-thienyl, 2- furoyl, 3-furoyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl; and R2 is hydrogen, cycloalkyl, lower alkyl or lower alkenyl, optionally substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid having from two to twentyfour carbon atoms inclusive, or R2 is a group of the formula IV :

wherein n is an integer from 2 - 6;

W is oxygen, sulphur or N-R3, wherein R3 is H, lower alkyl or cycloalkyl

U is nitrogen or carbon;

Z is -(CH₂)m-. m being 2 or 3, or Z is -CH=CH- or 1 ,2-phenylene optionally substi tuted with halogen or trifluoromethyl, or Z is -COCH₂- or -CSCH₂-;

V is oxygen, sulphur, CH₂, or NR4 , wherein R4 is hydrogen, lower alkyl optionally substituted with one or two hydroxy groups, lower alkenyl or a cycloalkylmethyl group, said cycloalkyl having from three to six carbon atoms inclusive; or a pharmaceutically acceptable acid addition salt thereof to a patient in need thereof.