IE47209B1 - Improvements in or relating to organic compounds - Google Patents

Abstract

Indole compounds useful for the treatment of hypertension, of formula wherein n is 2 or 3, A is 1,4-cyclohexylidene or trimethylene and R1 is H or alkyl, or A together with NR1 is 4-piperidyl, R2 is hydrogen or alkyl, R3 is alkyl, cycloalkyl, amino, alkylamino, dialkylamino, phenylamino, unsubstituted or substituted phenyl or benzyl, pyridylmethyl or an heterocycle, R4 is hydrogen, chlorine, bromine or alkyl, R5 is hydrogen, alkyl, alkoxy or alkylthio, and X is -CO- or -CS, a process for their production which comprises a) acylating a compound of formula II wherein n, A and R1 to R5 are as defined above, or b) condensing a compound of formula III wherein n, R4 and R5 are as defined above, and Y is a leaving group, with a compound of formula IV wherein A, R1 to R3 and X are as defined above. n

Description

The present invention relates to new indole derivates, processes for their preparation, and pharmaceutical compositions containing them.

In accordance with the inventionthere are provided new compounds of formula I wherein n is 2 or 3, either A is trimethylene optionally substituted by (C^_4) alkyl or 1,4-cyclohexylidene and R^ is hydrogen or (C^_g) alkyl, or A together with R^ and the nitrogen atom to 10 which R-j· is bound, form a 4-piperidyl radical, R^ is hydrogen or (C^_g) alkyl, R3 is (C.j_4) alkyl; (C3_g)cycloalkyl; amino; (C.j_4) alkylamino; di (C^) alkylamino; phenylamino wherein the phenyl ring is unsubstituted or mono-, di- or trisubstituted independently by halogen, (C1_4)alkyl, (C^ ^lalkoxy or di (C^_4)alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C^_4)alkyl, (C^_4)alkoxy or di-(C^_4>alkylamino; 2-,3- or 4-pyridyImethyl ;or an aromatic - or 6-membered heterocycle containing one 0 heteroatom chosen from nitrogen, oxygen or sulphur and optionally additional one or two nitro gen atoms, is hydrogen, chlorine, bromine or (C^ alkyl, R,. is hydrogen, (C^^) alkyl, (C^^) alkoxy or (Cj_4)alkylthio, and X is -CO- or -CS-.

Any alkyl, alkoxy or alkylthio radical contains preferably two carbon atoms, especially one carbon atom. Halogen means fluorine, chlorine, bromine or iodine, especially chlorine.

When A is 1,4-cyclohexylidene, this may be cis or trans-l,4-cyclohexylidene.

When A is optionally substituted trimethylene, this is preferably either unsubstituted or mono25 substituted, conveniently at the middle carbon atom.

When and Rj are chosen from hydrogen or alkyl, these are preferably alkyl.

Conveniently A is optionally substituted trimethy lene or 1,4-cyclohexylidene. Preferably A is optionally substituted trimethylene.

When Rj is or contains a dialkylamino radical, the alkyl groups are preferably the same. When R3 is an optionally substituted phenyl or phenylamino radical, the substituents are conveniently identical.

Conveniently these radicals are unsubstituted or monosubstituted preferably in the para position. When Rj is a heterocycle, conveniently this contains one heteroatom chosen from nitrogen, oxygen or sulphur and optionally a second nitrogen atom, e.g. thienyl, furyl, pyrrolyl, pyridyl or pyrazinyl. Conveniently the heterocycle is bound to X by a ring carbon atom adjacent to a heteroatom.

Rj is preferably unsubstituted phenyl.

R^ and Rj are conveniently hydrogen.

X is conveniently -CO-.

The present invention provides a process for the production of a compound of formula I as defined above, which comprises a) acylating a compound of formula II wherein n, A and R, to R_ are as defined above, 1 5 or b) condensing a compound of formula III (0Η2)η-ϊ ' (III) wherein n, R4 and Rg are as defined above, and Y is a leaving group, with a compound of formula IV wherein A, R^ to R^ and X are as defined above. Process a) may be effected in conventional manner for the production of amides or thio-amides from amines. For example there may be used, as acylating agent, a compound of formula V Z - X - Ri, (V) wherein X is as defined above,has the same signification as R^ but is other than amino, alkyl10 - 5 ' 47209 amino and optionally substituted phenylamino and Z is chlorine or bromine. The reaction may be effected conveniently in a solvent such as pyridine and at temperatures from 0 to 25°. Alternatively when R3 is amino, alkylamino or optionally substituted phenylamino, there may be used a compound of formula VI χ (VI) wherein X is as defined above and Rg is imino, alkylimino or optionally substituted phenylimino.

The reaction may be effected conveniently in a solvent such as dimethylformamide and at temperatures from 5 to 25°. A compound of formula VI wherein Rg is imino may be prepared in situ from potassium or sodium cyanate or thiocyanate, by treatment with acid , for example hydrochloric acid.

Process b) may be effected in conventional manner for a condensation reaction to produce a secondary or tertiary amine. Y is conveniently chlorine, bromine, iodine, tosyloxy or mesyloxy.

The reaction may be conveniently effected in acetone or dimethylformamide. Suitable reaction temperatures are from 20 to 150°.

The compounds of formula I may be isolated from the reaction mixture and purified in known manner. The free base forms may be converted ' into acid addition salt forms in the usual manner and vice versa. Suitable acids for salt formation are hydrochloric acid, oxalic acid, fumaric acidznaphthalene-25 sulphonic acid and naphthalene-1,5-disulphonic acid.

The starting material of formula II may be produced from a compound of formula III and a compound of formula VII Rn R, I2 I1 HN — A — NH (VII) wherein A, R^ and R^ are as defined above, in analogous manner to process b).

When the amine of formula VII is unsymmetrical, the conditions should be chosen to avoid the formation of the undesired corresponding compound produced by condensation at the nitrogen atom bearing the substituent. For this purpose the amine may be used in protected form of formula VIII (VIII) HN - A - N - R? wherein R^ is a protecting group, such as benzyl or benzyloxy, which may be removed from the resulting product, e.g. by hydrogenolysis. . 20 A starting material of formula Ila wherein A1 is -CH-CH_-CH_- or J 2 2 R8 -CHj-CH —CHj- and wherein Rg is alkyl and Rs n, Rj, R^ and Rg. are as defined above, may alternatively be produced by reducing a compound of formula IX wherein B is -CH(Rg)-CH2~ or -CH2~CH(Rg)and n, r R^, Rg and Rg are as defined above, e.g. by hydrogenation in the presence of Raney-nickel.

Any starting material of formula II wherein R^ and/or Rj is hydrogen may be converted into a corresponding compound wherein R^ and R^ are both alkyl, or R^ is alkyl and Rj is hydrogen under appropriate selective alkylation conditions.

The starting material of formula IV may be produced by acylating an amine of formula VII in analogous manner to process a). If desired, one nitrogen atom of an unsymmetrical amine may be protected to facilitate production of the desired product.

A starting material of formula IVa HN (IVa) II wherein X, R2 and R3 are as defined above and A together with R^ and the nitrogen atom to which R^ is bound, form a 4-piperidyl radical, may alternatively be produced by acylating 4-piperidone with a compound of formula V or VI and condensing the resulting compound of formula X (X) wherein X and R^ are as defined above, with a compound of formula XI R--NH (XI) wherein R2 is as defined above, under simultaneous reduction, e.g. with hydrogen in presence of a catalyst. Insofar as the production of any starting material is not particularly described, these are known or may be produced in conventional manner or in a manner analogous to that described above.

In the following non-limitative Examples all temperatures are indicated in degrees Centigrade.

EXAMPLE 1 N-benzoyl-N'-[3- (3-indolyl) propyl ]-N'~ methy1-1,3-diaminopropane A solution of 10.1 g benzoyl chloride in ml anhydrous methylene chloride is added dropwise with stirring for 25 minutes between 0 and 10° to a solution of 14.5 g N-[3-(3-indolyl)propyl]N-methy1-1,3-diaminopropane in 150 ml anhydrous pyridine and the reddish clear solution is stirred for 2 hours at 0°. The reaction mixture is divided between a 2N sodium carbonate solution and methylene chloride, and the organic phase is washed, dried and evaporated. Chromatographic purification of the resinous product on aluminium oxide using methylene chloride with 0.1 to 0.3% of methanol yields the title coumpound. The naphthalene-2-sulfonate-dihydrate, obtained by conventional methods, melts at 73-74° after crystallization from methanol/water/ethyl acetate (1:1:1) .

The starting material may be obtained as follows : a) A mixture of 57 g trifluoroacetic acid and 105 g trifluoroacetic anhydride in 400 ml anhydrous acetonitrile are added dropwise to a stirred suspension of 95.1 g 3-(3-indolyl,propionic acid in 500 ml anhydrous acetonitrile and maintained with stirring at -15° for 30 minutes. - 10 Under good cooling 500 ml anhydrous pyridine are added between -20 and -15° and quickly 238 ml of a 4.2 N solution of anhydrous methylamine in acetonitrile. The mixture is warmed with stirring 5 at 0° for 15 minutes and maintained to 0° for 3 hours. 3-(3-indolyl)-N-methy1-propionamide (M.pt 97-98° after crystallization from methylene chloride/ethyl acetate) is obtained after working up. b) A solution of 60.6 g 3-(3-indolyl)-N-methy1-propiona10 mide in 500 ml anhydrous tetrahydrofuran are added dropwise at 25° for 15 minutes under nitrogen atmosphere to a suspension of 34. 2 g lithium aluminium hydride in 800 ml anhydrous tetrahydrofuran and maintained at 66° for 3 hours. N-methy1-3-(3-indolyl)15 propylamine (M.pt 81-82° after crystallization from methylene chloride/ethyl acetate) is obtained after working up. c) A mixture of 37.6 g N-methy1-3-(3-indolyl)-propylamine and 21,2 g acrylonitrile in 65 ml anhydrous 2o 1,2-dimethoxyethane are warmed with stirring at 60° for 2^2 hours. N- (2-cyanoethyl)-N-methy 1--3(3-indolyl)propylamine (M.pt 48-49° after crystallization from isopropyl ether) is obtained after working up. d) 36.2 g N-(2-cyanoethyl)-N-methy1-3-(3-indolyl)propyl amine are hydrogenated at normal pressure and at room temperature with 20 g Raney-nickel catalyst in 400 ml dioxan and 400 ml of a 10% ammonia solution. N-[3-(3-indolyl)propyl]-N-methyl-1,35 diaminopropane is obtained after working up.

M.pt of the neutral fumarate:180-181° (with decomposition) after crystallization from ethanol.

From the appropriate compounds of formula II the following compounds of formula I wherein X is 10 -CO- may be obtained in analogous manner to Example 1. Ρ CM σ> μ* Η CO rH ΙΛ X l m n 1 X ® ι a U I l in I X II II II II π 0$ II S X X II II Η - - π rH rH rH >< ΰ d β o 0 Λ Λ 0. Λ CM CM II X II co X Ο I ιη X CM Ο I I I ι co co co XXX -ΙΓ I « I _1L co co CO It X Ιΐ W I, -Ρ nJ fi Λ1 χί φ Φ 0 Φ CM •P -P •Ρ -Ρ ω nJ nJ -Ρ β 0 XJ P •Η Ρ Χί CM nJ Μ β Di rH ε θ § Φ fi 9 CM 3 fi •P Cfl Η Φ nJ ,_, ,—, 0 _ fcn P Φ Φ ϋ fi 0 nJ w w φ Φ P ΪΡ nJ ni Ό θ' nJ X5 Λ X3 0 >< 0 χ: ρ Λ fi 10 ω -Ρ nJ • o •H •H •Ρ >ί ε X3 Xi & χ: ID co σ» Ο rH rH rH nJ ϋ Q m rH a ω •rl I rH in Ο rH CM 1 X Φ fi CM Φ \ rH rH Φ β •Ρ χί Φ β 4J φ nJ ι-Η Χί nJ •Η β CM ♦Η Ρ X β ε 0 0 fi 0 rH Μ χ: fi Φ* Xi ο φ ϋ) 0 0 ζΡ β Ρ Ρ 0 Λ Ό nj Ρ >1 >1 Ό ω Χί Χί >1 •Η Ή ♦Η χ} XI Π3 Π3 CM co *3* ιη 472θβ - 16 EXAMPLE 2: N-ghenylcarbamoyl-Nj.yX2-^3yindolyl2 e_thy_l_]_=Nj.y ESiLyl^lj^diaminopropj-ne ml phenyl Isocyanate are added dropwise between and 10° and with stirring to a solution of 5.8 g N-[2-(3indolyl) ethyl ]-N-methyl-l,3-diaminopropane in 25 ml anhydrous dimethylformamide. The solution is stirred for an hour between 10 and 15° and evaporated. The residue is dried in high vacuum and chromatographied on silicagel using methylene chloridewith 6 to 10% methanol,to yield the title compound (M.pt. of the hydrogen maleate 153-155° with decomposition after crystallization from alcohol/acetone) .

The starting material may be obtained as follows: a) Reaction of 3-[2-methylamino)ethyl]indole with acrylonitrile in dimethoxy-ethane yields the N-(2-cyanoethyl)-N-methy1-2-(3-indolyl)ethylamine which is worked up further directly. b) Reduction of N-(2-cyanoethyl)-N-methy1-2-(3-indolyl)ethylamine with Raney-Nickel catalyst yields the N- [2-(3-indolyl)ethyl]-N-methy1-1,3-diaminopropane (M.pt. of the fumarate 153-154°).

EXAMPLE 3 ; N-BenzoylytT y_[ 2-_(3yindolyl)ethyl_]_-lx^diaminoE£opane A solution of 8 g N-benzoyl-1,3-diaminopropane, 6,7 g 3-(2-bromoethyl) indole and 5 ml anhydrous triethylamine in 15 ml anhydrous dimethylformamide is maintained for 72 hours in nitrogen atmosphere. A dilute ammonia solution and methylene chloride are then added to the reaction mixture and the organic phase is dried and evaporated.The residue is chromatographied on silicagel using as eluant methylene chloride+ 5% methanol + 0.3% ammonia, to yield the title compound (M.pt. of the naphthalene-2-sulfonate 203-204° with decomposition after crystallization from ethanol).

The following compounds of formula may be obtained in analogous manner to Example 3 : 10 Table Ex. No.R2R3R4 M.Pt. a) -n-CgH? p-tolyl H 181-183° X) 1 2 3) b) -CHg p-methoxyphenyl H 133-135° 15 3) c) -CIi3 p-chlorophenyl H 161-163° -° a) -CH3 phenyl H 122-124° J) e) CHg 2-furyl H 95-96° f) -CH3 phenyl Br 148-150° 1) 3) 1) hydrogen oxalate 2) naphthalene-2-sulfonate 3) with decomposition - 18 EXEMPLE 4: From the appropriate 4-amino-piperidines and 2-(3-indolyDethyl bromide or 3- (3-indolyl)propyl bromide, the following compounds of formula H may be obtained in analogous manner to Example 3: T a b 1 e EX. NO. nR2R3 M.pt. a) 2 -ch3 phenyl 131-133° 3) b) 3 -CIIj phenyl 201-203° 3) c) 2 iso-C,H_ 4 9 phenyl 152-154 2) 3) d) 2 H phenyl 151-152 35 e) 2 -ch3 phenylamino ' 58-60" f) 2 H dimethylamino - 119-120° 1) naphthalene-2-sulfanate 2) hydrochloride 3) with decomposition The compounds of formula I exhibit pharmacological activity in animals. In particular, the compounds exhibit anti-hypertensive activity, as indicated by 72 0 9 standard tests, e.g. in the awake renal hypertonic Grollman rat upon administration of 1 to 50 rng/kg animal body weight of the compounds,and in the awake renal hypertonic Goldblatt dog upon administration of 1 to 10 mg/kg animal body weight of the compounds.

The compounds are therefore indicated for use as anti-hypertensives. For this use an indicated daily dose is from about 10 to about 2000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 2,5 to about 1000 mg, or in sustained release form.

A particularly interesting compound is the Example 1 compound.

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

The invention also provides a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. A suitable pharmaceutical form is a capsule.

In one group of compounds n is 3, A is trimethylene, is hydrogen or (C1_5)alkyl, R2 is hydrogen or (C^g) alkyl, Rj is phenyl or benzyl unsubstituted or mono-, di- or trisubstituted independently by -20 halogen, hydroxy, (C^_4)alkyl, (C^_4)alkoxy or di(Cj_4)alkylamino; (C^_(,)oycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R4 is hydrogen, chlorine, bromine or (C^_4>alkyl, is hydrogen, (C1_4)alkyl, (C^ alkoxy, or (C^) alkylthio, and X is -CO-, In another group of compounds n is 2, either A is trimethylene and R^ is hydrogen or (C^ alkyl, or A together with R^ and the nitrogen atom to which is bound form a 4-p.iperidyl radical, and R^ is hydrogen or (C^_^)alkyl, is (C^_4)alkyl; phenyl unsubstituted or mono-, di- or trisubstituted independently by halogen, (C4_4)alkyl or (C^_4)alkoxy; (C-j_g) cycloalkyl; or an aromatic 5- or G-membcred hetcrocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R4 is hydrogen, chlorine, bromine or (C^_4)alkyl, R^ is hydrogen, (C^_4)alky1 or (C^_4)alkoxy, and X is -CO- or -CS,

Claims (40)

1. C L A .I_M S 1) A process for tlie production of a compound of formula I wherein n is 2 or 3, either A is trimethylene optionally substituted by 5 (C^^) alkyl or 1,4-cyclohexylidene and is hydrogen or fC^_ 5 ) alkyl, or A together with R^ and the nitrogen atom to which R^ is bound, form a 4-piperidyl radical, R 2 is hydrogen or (C 1 _ g )alkyl, χθ r is (C^_ 4 ) alkyl; (C 3 _ g ) cycloalkyl; amino; (C )alkylamino; di(C^^) alkylamino; phenylamino wherein the phenyl ring is unsubstituted or mono-, di- or trisubstituted independently by halogen, alkyl, (C )alkoxy or di(C^_ 4 )alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C ^Jalkyl, (C^_ 4 )alkoxy or di-(C^_ 4 )alkyl2q amino; 2-,3- or 4-pyridyImethyl;or an aromatic 5- or G-mcinbered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sul4 7 2 0 9 phur and optionally additional one or two nitro gen atoms , R 4 is hydrogen, chlorine, bromine or (C 1 _ 4 )alkyl, Rj is hydrogen, (C^_ 4 )alkyl, (C^_ 4 )alkoxy or (C 1-4 )alkylthio, and X is -CO- or -CS-, which comprises a) acylating a compound of formula II wherein n, A and R to Rj are as defined above, or b) condensing a compound of formula III 5 < ri 1 H ' (III) 4 wherein n, R 4 and li 5 are as defined above, 5 and Y is a leaving group, with a compound of formula IV R , I 2 I 1 HN - Λ - N - X - R (IV wherein A, to Rj and X are as defined recte. 4720

2. ) A process for the production of a compound of formula I as defined in claim 1 substantially as hereinbefore des cribed with reference to any one of the examples.

3. ) A compound of formula I as defined in claim 1 whenever produced by a process as claimed in claim. 1 or 2.

4. ) A compound of formula I as defined in claim 1. 47309

5. ) A compound of claim 4 which is N-benzoyl-N'-[3(3-indolyl)propyl]-N’-methy1-1,3-diaminopropane.

6. ) A compound of claim 4 wherein X is CO.

7. ) A compound of claim 6 wherein n, Rg, A, Rg, Rg, 5 R^ and Rg are respectively 2, IJ, -(CHg)g~, dig, phenyl, Η, H.

8. ) A compound of claim 6 wherein n, Rj , A, Rg, Rg, R^ and Rg are respectively 2, H, - (Cllg)g-, ~CIIg, phenyl, H, 4-OCglIg. 30

9. ) A compound of claim 6 wherein n, R , A, Rg, Rg, R^ and Rg are respectively 3, H, -(CHg)g-, --CHg, phenyl, -CHg, Ii.

10. ) A compound of claim C wherein n, Rg, A, Rg, Rg, R^ and Rg are respectively 3, H, -(CHg)g-, -CHg, phenyl, 15 II, 6-SCIIg.

11. ) Λ compound of claim 6 wherein n, Rg, A, Rg, Rg, R^ and Rg are respectively 3, II, -(CHg)g-, -CHg, phenyl, H, 5-OCH,. 3 '

12. ) A compound of claim 6 wherein n, Rg, A, Rg, Rg, 2o R4 and Rg are respectively 3, Η, -(CHg)g-, “CHg, phenyl, II, 4-OCHg.

13. ) A compound of claim 6 wherein n, Rg, A, Rg, Rg, IL and R are respectively 3, H, —(CII O ) _—, C,H , phenyl, 4 j 2 ’ 2 □ II, II. 25

14. ) A compound of claim 6 wherein n, Rg, A, Rg , Rg, R and R r are respectively 3, -CHg, -(CHg)g-, dig, phenyl, II, II. -25

15. ) Λ compound of claim R. and R_ are respectively 3, 4 o phenyl, Η. H.

16. ) Λ compound of claim R^ and Rg are respectively 3, Η, H.

17. ) Λ compound of claim R^ and Rg are respectively 2, Η, H.

18. ) Λ conii>ound of claim R^ and (Rg are respectively 2, II, H.

19. ) Λ compound of claim and Rg are respectively 3, trimethoxybenzyl. Η, II.

20. ) A compound of claim R, and R_ are respectively 3, 4 b phenyl, Η, H.

21. ) A compound of claim R^ and Rg are respectively 2, Η, H.

22. ) A compound of claim R^ and R r are respectively 2, amino, II, II.

23. ) A compound of claim R^ and Rg are respectively 2, phenyl, II, II. 6 wherein n, Rg, A, R 2 , Rg, -n-C 3 H 7 , -(CHg) -, -CHg, 6 wherein n, Rg , A, Rg , Rg, II, -(CII 2 )g-, -CHg, benzyl, 6 wherein n, Rg, A, Rg , Rg, Η, , -dig, phenyl, H' ''H 6 wherein n, 1^, A, It,, Rg , Η, /“λ.-- , ” cn 3, phenyl, H- ’ Cwherein n, Rg, A, Rg , Rg, II, -(CII 2 )g-, -CHg, 3,4,56 wherein n, Rg , A , P.g , Rg , II, -(CH 2 )g-, CHg, o-chloro6 wherein n, Rg, A, Rg , Rg, H, -(CHgJg-, H, diethylamino, 6 wherein n, P.g, A, Rg , Rg, H, “(CH 2 )g-, -CHg, dimethyl6 wherein n, Rg, A, Rg, Rg, H, -( CH 2^3 - ' ~ CII 3' P-rcefch°xy47209 -26

24. ) A compound of claimθ and Rj are respectively 3, H, aminophenyl, Η, H.

25. ) A compound of claim 6 R^ and Rj are respectively 3, II, Η, H.

26. ) A compound of claims R^ and Rj are respectively 2, II, p-tolyl, II, H.

27. ) A compound of claim 6 I’ 4 and R,. are respectively 3, H, phenyl, II, H.

28. ) A compound of claim 6 I< 4 and Rj are respectively 2, II, phenyl, II, II.

29. ) A compound of claim θ and Rj are respectively 3, H, methoxyphenyl·. Η, II.

30. ) Λ compound of claim 6 I? 4 and Rj are respectively 3, II, trimethoxyphenyl, Η, H.

31. ) A compound of claim 6 R^ and Rj are respectively 3,H, phenyl, [I, II.

32. ) k compound of claim 6 R. an< 3 R are respectively 2, H, 4 5 wherein n, R^ , A, P- 2 , Rj, -(CH 2 ) 3 “, -CHj, p-dimethylwherein n, R , A, Rj, R^, -(CII ? ) 3 -, -CIIj, m-tolyl, wherein n, P^, A, Rj, Rj, -(αι 2 ) 3 -, -n-c 3 H 7 , wherein n, , A, P_ 2 , Rj, - (CH 2 )j-, “CHj, m-chlorowherein n, R , A, Rj, Rj, -(CHjJj-, “CHj, p-chlorowherein n, R , A, Rj, Rj, -(CH 2 )j-, “CHj, 3,5-diwherein η, P^, A, , , -(CH 2 )j-, -CHj, 3,4,5wherein n, R , A, Rj, Rj, '( ch 2^3'' -C,, 3' °“ methox y“ wherein n, R^, A, Rj, Rj, -(CH 2 )j-, -CHj, 2-furyl, II, II. 4 7 2 0 9 - 27

33. ) Λ compound of claim 6 wherein n, R^, A, Rg , R_,, R^ and Rg are respectively 3, II, -CHg, 2-furyl, Η, H.

34. ) A compound of claim 6 wherein n, R^ , A, Pg , Rg, R^ and Rg are respectively 3, II, ~( CH 2^3~' “CHg, 2-thienyl, H. H

35. ) A compound of claim 6 wherein n, R^, A, Pg , Rg R 4 and Rg are respectively 3, H, -(CHg)g-, -CHg, 2-pyridyl Η, H. 10

36. ) A compound of claim 6 wherein n, R^, A, R 2 , Rg R 4 and Rg are respectively 3, H, -(CH 2 )g-, -CHg, 3-pyridyl Η, H.

37. ) A compound of claim 6 wherein n, Rg , A, Rg , Rg, R 4 and Rg are respectively 3, H, -(CH 2 )g~, -CHg, 4-pyridyl 15 Η, H. 3¾) A compound of claim 6 wherein n, Rg, A, Rg , Rg, R 4 and Rg are respectively 3, II, ~(CH 2 )g~, “CHg, pyrazinyl Η, II.

38. 39) A compound of claim 6 wherein n, Itg , A, Rg , Rg, 20 R 4 and Rg are respectively 3, H, -(CH 2 )g-, -CHg, 2-pyridyl methyl,.II, H.

39. 40) A compound of claim 6 wherein n, Rg, A, Rg, Rg, R 4 and Rg are respectively 3, II, - (CHg)g-, -CHg, 2-pyrrolyl, II, II.

40. 43) A compound of claim 6 wherein η, K , A, Rg , Rg, R 4 and Rg are respectively 2, -CHg, -CHg-CH-CHg-, -CHg, CHg phenyl, Η, II. -23 42) A compound of claim 6 wherein n, R , A, R 2 , Rg , R^ and Rg are respectively 2, It, - (Cil 2 ) -, -CHg, 4-hydroxy phenyl, Η, II, 43) A compound of claim 6 wherein n, R^, A, R^ , R 3r 5 R^ and Rg are respectively 3, H, -(CH 2 )g-, -CHg, 4-hydroxy phenyl, H, II. R 4 44) A compound of claim 6 wherein η , H, -(CH 2 ) 3 -, f A / t t -CH 3 , phenyl, and Rg are respectively 3, H, 6-CH 3 , 45) A compound of claim 6 wherein η , R^, A, Rg, Rg, R 4 and Rg are respectively 3, H, -(CH 2 ) 3 -, -CHg , phenyl, H, 5-CH 3 . 46) A compound of claim 6 wherein η, Rl, A, R 2 , R 3 , R 4 and R_ □ are respectively 3, ii, -{ch 2 ) 3 -, - dig , phenyl, , 4-ΟΠ 3 . 47) Λ compound of claim 6 wherein η, R x , A, R 2 , Rg, R 4 and Rg are respectively 3, II, -(CH 2 ) 3 -, -C 2 Hg, phenyl, II, II. 48) A compound of claim 6 which is N-phenylcarba- moyl-N'-I 2-(3-indolyl)ethyl]-Ν'-methy1-1,3 -diaminopropane 49) A compound of claim 4 wherein A is optionally substituted methylene. 50) Λ compound of claim 4 which is N-Benzoyl-N'~ [2-(3-indolyl) ethyl)-1,3-diaminopropane. -29 51) Λ compound of claim 4 having the formula 52) A compound of claim 51 wherein I< 2 , R^ and R^ are respectively -n-CjII^, p-tolyl, II. 5 53) A compound of claim 51 wherein R^, and R^ are respectively -CH 3 , p-methoxyphenyl, H. 54) A compound of claim 51 wherein 1^, R^ and R^ are respectively -CH 3 , p-chlorophenyl, H. 55) A compound of claim 51 wherein > R 3 and R ^ 10 are respectively -CH 3 , phenyl, H. 56) A compound of claim 51 wherein R%r R 3 ant ^ R 4 are respectively -CH 3 , 2-furyl, H. 57) A compound of claim 51 wherein R 2 , Rj and R^ are respectively —CII^, phenyl, Br. 15 58) A compound of claim 4 having the formula II wherein t? 2 and R 3 are as defined in claim 1. 59) A compound of claim 58 wherein -n, R 2 and R 3 are respectively 2, -CH 3 , phenyl. - 30 60) A compound of claim 5θ wherein -n, Rg and Rg are respectively 3, -CHg, phenyl. 61) A compound of claim 58 wherein -n, Rg and Rg are respectively 2, iso-C 4 H g , phenyl. 62) A compound of claim 58 wherein -n, Rg and Rg are respectively 2, II, phenyl. 63) A compound of claim 5 8 wherein -η, Rg and Rg are respectively 2, “CHg, phenylamino. 64) A compound of claim 58 wherein -n, R and R ~ J are respectively 2, H, dimethylamino. 65) A compound of claim 4 wherein n is 3, A is trimethylene, Rg is hydrogen or (Cg_g)alkyl, Rg is hydrogen or (Cg_g)alkyl, Rg is phenyl or benzyl unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (Cg^) alkyl, (Cg_^) alkoxy or di-(Cg_ 4 ) alky lamino; (Cg_g)cycloaikyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R^ is hydrogen, chlorine, bromine or (Cg_ 4 )alkyl, R 5 is hydrogen, (Cg_ 4 )alkyl, (Cg_ 4 )alkoxy, or (Cg_ 4 ) alkylthio, and X is -CO-. 10 r 5 and 10 r 5 and 66) A compound of claim 1 wherein n is 2 A is trimethylene and R^ is hydrogen or (Cj_ 5 ) alkyl, A together with and the nitrogen atom to which is bound form a 4-piperidyl radical, is hydrogen or (C^_g)alkyl, is (Cj_ 4 )alkyl; phenyl unsubstituted or mono-, di- or trisubstituted independently by halogen, (C^ ^)alkyl or (C^_ 4 )alkoxy; (C 3 _g)eycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur is hydrogen, chlorine, bromine or (C^_ 4 )alkyl, is hydrogen, (C^_ 4 )alkyl or (C^^) alkoxy, X is -CO- or -CS67) A compound of any one of claims 3 to 66 in free base form. 68) A compound of any one of claims 3 to 66 in acid addition suit form. 69) A pharmaceutical composition comprising a compound according to any one of claims 3 to 66 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.