EP0000355A1

EP0000355A1 - New indole derivatives, processes for their preparation, and pharmaceutical compositions containing them.

Info

Publication number: EP0000355A1
Application number: EP78100274A
Authority: EP
Inventors: Paul Dr. Stadler; Franz Dr. Troxler
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1977-07-12
Filing date: 1978-06-29
Publication date: 1979-01-24
Also published as: DE2861502D1; JPS5436259A; ES471593A1; IL55116A; IT7850140A0; PH14993A; IL55116A0; PT68270A; EP0000355B1; CA1114381A; IE781382L; AU3793978A; NZ187813A; IE47209B1; FI782138A7; AU521641B2; DK300978A

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 R, is H or alkyl, or A together with NR, 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, R_s 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 R, 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, R, to R₃ and X are as defined above.

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_1-4) alkyl or 1,4-cyclohexylidene and R₁ is hydrogen or (C_1-5) alkyl, or A together with R₁ and the nitrogen atom to which R₁ is bound, form a 4-piperidyl radical,
R₂ is hydrogen or (C_1-5) alkyl,
^R ₃ is (C_1-4) alkyl; (C_3-6)cycloalkyl; amino; (Cl-4)alkylamino; di(C_1-4)alkylamino; phenylamino wherein the phenyl ring is unsubstituted or mono-, di- or trisubstituted independently by halogen, (C_1-4)alkyl, (C_1-4)alkoxy or di(C_l-4)alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C_1-4) alkyl, (C_1-4)alkoxy or di-(C_1-4)alkylamino; 2-,3- or 4-pyridylmethyl;or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur and optionally additional one or two nitrogen atoms,
R₄ is hydrogen, chlorine, bromine or (C_1-4)alkyl,
R₅ is hydrogen, (C_l-4)alkyl, (C_1-4)alkoxy or (C_1-4)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 monosubstituted, conveniently at the middle carbon atom.
When R₁ and R₂ are chosen from hydrogen or alkyl, these are preferably alkyl.
Conveniently A is optionally substituted trimethylene or 1,4-cyclohexylidene. Preferably A is optionally substituted trimethylene.
When R₃ is or contains a dialkylamino radical, the alkyl groups are preferably the same. When R₃is 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 R₃ 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.
R₃is preferably unsubstituted phenyl.
R₄ and R₅ 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 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.

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
wherein X is as defined above, R₃' has the same signification as R₃ but is other than amino, alkylamino 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 O to 25°. Alternatively when R₃ is amino, alkylamino or optionally substituted phenylamino, there may be used a compound of formula VI
wherein X is as defined above and R₆ 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 R₆ 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 acid naphthalene-2-sulphonic acid and naphthalene-l,5-disulphonic acid.
The starting material of formula II may be produced from a compound of formula III and a compound of formula VII
wherein A, R₁ and R₂ 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 R₁ substituent. For this purpose the amine may be used in protected form of formula VIII
wherein R₇ is a protecting group, such as benzyl or benzyloxy, which may be removed from the resulting product, e.g. by hydrogenolysis.
A starting material of formula IIa
wherein A^I is
or
and wherein R₈ is (C_1-4)alkyl and n, R₂, R₄ and ^R ₅ are as defined above, may alternatively be produced by reducing a compound of formula IX
wherein B is -CH(R₈)-CH₂- or -CH₂-CH(R₈)-and n, R₂, R₄, R₅ and R₈ are as defined above, e.g. by hydrogenation in the presence of Raney-nickel.
Any starting material of formula II wherein R₁ and/or R₂ is hydrogen may be converted into a corresponding compound wherein R₁ and R₂ are both alkyl, or R₁ is alkyl and R₂ 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
wherein X, R₂ and R₃ are as defined above and A^II together with R₁ and the nitrogen atom to which R₁ is bound, form a 4-piperidyl radical, may alternatively be produced by acylating 4-piperidone with a compound of formula _Vor VI and condensing the resulting compound of formula X
wherein X and R₃ are as defined above, with a compound of formula 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'- methyl-1,3-diaminopropane

A solution of 10.1 g benzoyl chloride in 15 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-methyl-l,3-diaminopropane in 150 ml anhydrous pyridine and the reddish clear solution is stirred for 2 hours at O°. 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. 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 at O° for 15 minutes and maintained to O° for 3 hours. 3-(3-indolyl)-N-methyl-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-methyl-propiona- 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-methyl-3-(3-indolyl)-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-methyl-3-(3-indolyl)-propylamine and 21,2 g acrylonitrile in 65 ml anhydrous 1,2-dimethoxyethane are warmed with stirring at 60° for 2 ¹/₂ hours.N-(2-cyanoethyl)-N-methyl-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-methyl-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-l,3-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 -CO- may be obtained in analogous manner to Example 1.

EXAMPLE 2: N-henlcarbamol-N'-[2-(3-indolyl)ethyl]-N'- methyl-1,3-diaminopropane

3 ml phenyl isocyanate are added dropwise between 5 and 10° and with stirring to a solution of 5.8 g N-[2-(3- indolyl) ethyl]-N-methyl-1,3-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-methyl-2-(3-indolyl)ethylamine which is worked up further directly.
b) Reduction of N-(2-cyanoethyl)-N-methyl-2-(3-indolyl)-ethylamine with Raney-Nickel catalyst yields the N-[2-(3-indolyl)ethyl]-N-methyl-1,3-diaminopropane (M.pt. of the fumarate 153-154°).

EXAMPLE 3: N-Benzoyl-N'-[2-(3-indolyl)ethyl-13-diamino- propane

A solution of 8 g N-benzoyl-l,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 :

EXEMPLE 4:

From the appropriate 4-amino-piperidines and 2-(3-indolyl)ethyl bromide or 3-(3-indolyl)propyl bromide, the following compounds of formula
may be obtained in analogous manner to Example 3:
The compounds of formula I exhibit pharmacological activity in animals. In particular, the compounds exhibit anti-hypertensive activity, as indicated by standard tests, e.g. in the awake renal hypertonic Grollman rat upon administration of 1 to 50 mg/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 lO to about 2000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about2,5 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, R₁ is hydrogen or (C_1-5)alkyl, R₂is hydrogen or (C_1-5)alkyl, R₃is phenyl or benzyl unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C_1-4)alkyl, (C_1-4)alkoxy or di-(C_1-4)alkylamino; (C3-6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R₄ is hydrogen, chlorine, bromine or (C_1-4)alkyl, R₅ is hydrogen, (C_1-4)alkyl, (C_1-4)alkoxy, or (C_1-4)alkylthio, and X is -CO-.
In another group of compounds n is 2, either A is trimethylene and R₁ is hydrogen or (C_1-5) alkyl, or A together with R₁ and the nitrogen atom to which R₁ is bound form a 4-piperidyl radical, and R₂ is hydrogen or (C_1-5)alkyl, R₃ is (C_1-4)alkyl; phenyl unsubstituted or mono-, di- or trisubstituted independently by halogen, (C_1-4)alkyl or (C_1-4)alkoxy; (C_3-6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R₄ is hydrogen, chlorine, bromine or (C_1-4)alkyl, R_Sis hydrogen, (C_1-4)alkyl or (C_1-4)alkoxy, and X is -CO- or -CS.

Claims

1) A compound of formula I

wherein n is 2 or 3, either A is trimethylene optionally substituted by (C_1-4)alkyl or 1, 4-cyclohexylidene and R₁ is hydrogen or (C_1-5) alkyl, or A together with R₁ and the nitrogen atom to which R₁ is bound, form a 4-piperidyl radical,

R₂ is hydrogen or (C_1-5)alkyl,

R3 is (C_1-4) alkyl; (C_3-6)cycloalkyl; amino; (C_1-4)alkylamino; di(C_l-4)alkylamino; phenylamino wherein the phenyl ring is unsubstituted or mono-, di- or trisubstituted independently by halogen, (C_1-4)alkyl, (C_1-4)alkoxy or di(C_l-4)alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C_1-4)alkyl, (C_1-4)alkoxy or di-(C_1-4)alkylamino; 2-,3- or 4-pyridylmethyl;or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur and optionally additional one or two nitrogen atoms,

R₄ is hydrogen, chlorine,bromine or (C_1-4)alkyl,

R₅ is hydrogen, (C_1-4)alkyl, (C_1-4)alkoxy or (C_1-4)alkylthio, and X is -CO- or -CS-.

2) A compound of claim 1 wherein n is 3,

A is trimethylene,

R₁ is hydrogen or (C_1-5) alkyl,

R₂is hydrogen or (C_1-5)alkyl,

R₃is phenyl or benzyl unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C_1-4)alkyl, (C_1-4)alkoxy or di-(C_1-4)alkylamino; (C_3-6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur,

R₄is hydrogen, chlorine, bromine or (C_1-4)alkyl,

R₅ is hydrogen, (C_1-4)alkyl, (C_1-4)alkoxy, or (^C _l-4) alkylthio, and X is -CO-.

3) A compound of claim 1 wherein n is 2 either A is trimethylene and R₁ is hydrogen or (C_1-5) alkyl,

or A together with R₁ and the nitrogen atom to which R₁ is bound form a 4-piperidyl radical,

R₂ is hydrogen or (C_1-5) alkyl,

^R ₃ is (C_1-4)alkyl; phenyl unsubstituted or mono-, di- or trisubstituted independently by halogen, (C_1-4)alkyl or (C_1-4)alkoxy; (C_3-6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur

R₄ is hydrogen, chlorine, bromine or (C_1-4)alkyl,

R₅ is hydrogen, (C_1-4)alkyl or (C_1-4)alkoxy, and X is -CO- or -CS-.

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

5) A compound of claim 1 which is N-methyl-N-benzoyl-N'-methyl-N'-[2-(3-indolyl)ethyl]-2-methyl-1,3-diaminopropane.

6) A compound of any one of claims 1 to 5 in free base form.

7) A compound of any one of claims 1 to 5 in acid addition salt form.

8) A process for the production of a compound of formula I as defined in claim 1, which comprises

a) acylating a compound of formula II

wherein n, A and R₁ to R₅ are as defined in claim 1, or

b) condensing a compound of formula III

wherein n, R₄ and R₅ are as defined in claim 1, and Y is a leaving group, with a compound of formula IV

wherein A, R₁ to R₃ and X are as defined in claim 1.

9) A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.