1-(Aminoalkyl)-alpha, alpha-diaryl pyrrolidine-piperidine- and homopiperidine- acetamides and acetonitriles

Claim 2

A compound of general formula I: wherein: n is zero, one or two; A r 1 and A r 2 , which may be the same or different, are selected from 2-, 3- and 4-pyrido, phenyl and phenyl substituted by 1 to 3 radicals, which may be the same or different and selected from loweralkyl, loweralkoxy, halogen and trifluoromethyl; Y represents aminocarbonyl or cyano; x is from two to five; R represents hydrogen or loweralkyl; R and R 2 are selected from hydrogen, loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, loweralkoxy and phenyl-loweralkyl wherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy, and R 1 and R 2 may be the same or different, or, taken together with the adjacent nitrogen atom, may form a heterocyclic residue selected from pyrrolidino, piperidino, 4-phenylpiperidino, 2,6-diloweralkyl-piperidino, 4-hydroxy-4-phenylpiperidino, 4-cyano-4-phenylpiperidino, piperazino, 4-loweralkylpiperazino, 4-phenylpiperazino, (4-phenyl-loweralkyl)-piperazino and 4-morpholino radicals; or a pharmaceutically acceptable acid addition salt thereof.

Claim 3

A compound as claimed in Claim 1, wherein each of A r 1 and A r 2 represents a phenyl group.

Claim 4

A compound as claimed in Claim 1 or 2, wherein x is 2 or 3.

Claim 5

A compound as claimed in Claim 1, 2 or 3, wherein R 1 and R 2 both represent loweralkyl or, together with the adjacent nitrogen atom, form a pyrrolidino residue.

Claim 6

1-[2-(Dimethylamino)ethyl]-a,a-diphenyl-3-pyrrolidineacetonitrile, 1-[2-(dimethylamino)ethyl]-a,a-diphenyl-3-pyrrolidine- acetamide, 1-[3-(dimethylamino)propyl]-a,a-diphenyl-3-pyrrolidineacetamide, 1-[2-(diethylamino)ethyl]-α,α,-diphenyl-3-pyrrolidine- acetamide, a,a-dipheny1-1-[2-(1-pyrrolidinyl)ethyl]-3-pyrrolidineacetamide, 1-[2-(dimethylamino)ethyl]-a,a-diphenyl-3-piperidine- acetamide or 1-[2-(dimethylamino)ethyl]-a,a-diphenyl-4-piperidine- acetamide or a pharmaceutically acceptable acid addition salt thereof.

Claim 7

1-[2-(Dimethylamino)ethyl]-a,a-diphenyl-3-pyrrolidineacetonitrile, 1-[2-(dimethylamino)ethyl]-a,a-diphenyl-3-pyrrolidine- acetamide, 1-[3-(dimethylamino)propyl]-a,a-diphenyl-3-pyrrolidineacetamide, 1-[2-(diethylamino)ethyl]-α,α,-diphenyl-3-pyrrolidine- acetamide, a,a-dipheny1-1-[2-(1-pyrrolidinyl)ethyl]-3-pyrrolidineacetamide, 1-[2-(dimethylamino)ethyl]-a,a-diphenyl-3-piperidine- acetamide or 1-[2-(dimethylamino)ethyl]-a,a-diphenyl-4-piperidine- acetamide or a pharmaceutically acceptable acid addition salt thereof.

Claim 8

A compound having the formula wherein:

Claim 9

A compound having the formula wherein:

Claim 10

n is zero, one or two; Ar 1 and Ar 2 , which may be the same or different, are selected from 2-, 3- and 4-pyrido, phenyl and phenyl substituted by 1 to 3 radicals which may be the same or different and selected from loweralkyl, loweralkoxy, halogen and trifluoromethyl; Y represents aminocarbonyl or cyano; x is from two to five; R represents hydrogen or loweralkyl; R 1 and R 2 are selected from hydrogen, loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, loweralkoxy and phenyl-loweralkyl, wherein phenyl may be substituted by halogen, loweralkyl, or loweralkoxy, and R 1 and R 2 may be the same or different, or, taken together with the adjacent nitrogen atom, may form a heterocyclic residue selected from pyrrolidino, piperidino, 4-phenylpiperidino, 2,6-diloweralkyl-piperidino, 4-hydroxy-4-phenylpiperidino, 4-cyano-4-phenylpiperidino, piperazino, (4-loweralkyl)piperazino and 4-morpholino radicals; or a pharmaceutically acceptable acid addition salt thereof, for use in human or veterinary medicine.

Claim 11

n is zero, one or two; Ar 1 and Ar 2 , which may be the same or different, are selected from 2-, 3- and 4-pyrido, phenyl and phenyl substituted by 1 to 3 radicals which may be the same or different and selected from loweralkyl, loweralkoxy, halogen and trifluoromethyl; Y represents aminocarbonyl or cyano; x is from two to five; R represents hydrogen or loweralkyl; R 1 and R 2 are selected from hydrogen, loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, loweralkoxy and phenyl-loweralkyl, wherein phenyl may be substituted by halogen, loweralkyl, or loweralkoxy, and R 1 and R 2 may be the same or different, or, taken together with the adjacent nitrogen atom, may form a heterocyclic residue selected from pyrrolidino, piperidino, 4-phenylpiperidino, 2,6-diloweralkyl-piperidino, 4-hydroxy-4-phenylpiperidino, 4-cyano-4-phenylpiperidino, piperazino, (4-loweralkyl)piperazino and 4-morpholino radicals; or a pharmaceutically acceptable acid addition salt thereof, for use in human or veterinary medicine.

Claim 12

A compound as claimed in any one of Claims 2 to 6 for use in human or veterinary medicine.

Claim 13

A therapeutic composition for the treatment of cardiac arrhythmias comprising a) an effective amount of a compound selected from the group having the formula: wherein: n is zero, one or two; Ar 1 and Ar 2 , which may be the same or different, are selected from 2-, 3- and 4-pyrido, phenyl and phenyl substituted by 1 to 3 radicals which may be the same or different and selected from loweralkyl, loweralkoxy, halogen and trifluoromethyl; Y represents aminocarbonyl or cyano; x is from two to five; R represents hydrogen or loweralkyl; R 1 and R 2 are selected from hydrogen, loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, loweralkoxy and phenyl-loweralkyl wherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy, and R 1 and R 2 may be the same or different, or, taken together with the adjacent nitrogen atom, may form a heterocyclic residue selected from pyrrolidino, piperidino, 4-phenylpiperidino, 2,6-diloweralkyl-piperidino, 4-hydroxy-4-phenylpiperidino, 4-cyano-4-phenylpiperazino, (4-phenyl-loweralkyD-piperazino or 4-morpholino radicals, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier therefor.

Claim 14

A therapeutic composition for the treatment of cardiac arrhythmias comprising a) an effective amount of a compound selected from the group having the formula: wherein: n is zero, one or two; Ar 1 and Ar 2 , which may be the same or different, are selected from 2-, 3- and 4-pyrido, phenyl and phenyl substituted by 1 to 3 radicals which may be the same or different and selected from loweralkyl, loweralkoxy, halogen and trifluoromethyl; Y represents aminocarbonyl or cyano; x is from two to five; R represents hydrogen or loweralkyl; R 1 and R 2 are selected from hydrogen, loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, loweralkoxy and phenyl-loweralkyl wherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy, and R 1 and R 2 may be the same or different, or, taken together with the adjacent nitrogen atom, may form a heterocyclic residue selected from pyrrolidino, piperidino, 4-phenylpiperidino, 2,6-diloweralkyl-piperidino, 4-hydroxy-4-phenylpiperidino, 4-cyano-4-phenylpiperazino, (4-phenyl-loweralkyD-piperazino or 4-morpholino radicals, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier therefor.

Claim 15

A therapeutic composition for the treatment of cardiac arrhythmias comprising a) an effective amount of a compound as claimed in any one of Claims 2to5 and b) a pharmaceutically acceptable carrier therefor.

Claim 16

The use of a compound of general formula I wherein: n is zero, one or two; A r 1 and A r 2 , which may be the same or different, are selected from 2-, 3- and 4-pyrido, phenyl and phenyl substituted by 1 to 3 radicals, which may be the same or different and selected from loweralkyl, loweralkoxy, halogen and trifluoromethyl; Y represents aminocarbonyl or cyano; x is from two to five; R represents hydrogen or loweralkyl; R 1 and R 2 are selected from hydrogen, loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, loweralkoxy and phenyl-loweralkyl wherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy, and R and R 2 may be the same or different, or, taken together with the adjacent nitrogen atom, may form a heterocyclic residue selected from pyrrolidino, piperidino, 4-phenylpiperidino, 2,6-diloweralkyl-piperidino, 4-hydroxy-4-phenylpiperidino, 4-cyano-4-phenylpiperidino, piperazino, 4-loweralkylpiperazino, 4-phenylpiperazino, (4-phenyl-loweralkyl)-piperazino and 4-morpholino radicals; or a pharmaceutically acceptable acid addition salt thereof, in the manufacture of a cardiac antiarrhythmic agent.

Claim 17

The use of a compound of general formula I wherein: n is zero, one or two; A r 1 and A r 2 , which may be the same or different, are selected from 2-, 3- and 4-pyrido, phenyl and phenyl substituted by 1 to 3 radicals, which may be the same or different and selected from loweralkyl, loweralkoxy, halogen and trifluoromethyl; Y represents aminocarbonyl or cyano; x is from two to five; R represents hydrogen or loweralkyl; R 1 and R 2 are selected from hydrogen, loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, loweralkoxy and phenyl-loweralkyl wherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy, and R and R 2 may be the same or different, or, taken together with the adjacent nitrogen atom, may form a heterocyclic residue selected from pyrrolidino, piperidino, 4-phenylpiperidino, 2,6-diloweralkyl-piperidino, 4-hydroxy-4-phenylpiperidino, 4-cyano-4-phenylpiperidino, piperazino, 4-loweralkylpiperazino, 4-phenylpiperazino, (4-phenyl-loweralkyl)-piperazino and 4-morpholino radicals; or a pharmaceutically acceptable acid addition salt thereof, in the manufacture of a cardiac antiarrhythmic agent.

Claim 18

The use of a compound as claimed in any one of Claims 1 to 5 in the manufacture of a cardiac antiarrhythmic agent. CLAIMS FOR THE DESIGNATED STATE: AT

Claim 19

A process for the preparation of a compound of general formula I wherein: n is zero, one or two; Ar 1 and Ar 2 , which may be the same or different, are selected from 2-, 3- and 4-pyrido, phenyl and phenyl substituted by 1 to 3 radicals, which may be the same or different and selected from loweralkyl, loweralkoxy, halogen and trifluoromethyl; Y represents aminocarbonyl or cyano; x is from two to five; R represents hydrogen or loweralkyl; R 1 and R 2 are selected from hydrogen, loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, loweralkoxy and phenyl-loweralkyl wherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy, and R 1 and R 2 may be the same or different, or, taken together with the adjacent nitrogen atom, may form a heterocyclic residue selected from pyrrolidino, piperidino, 4-phenylpiperidino, 2,6-diloweralkyl-piperidino, 4-hydroxy-4-phenylpiperidino, 4-cyano-4-phenylpiperidino, piperazino, 4-loweralk y l-piperazino, 4-phenylpiperazino, (4-phenyl-loweralkyl)-piperazino and 4-morpholino radicals; or a pnarma- ceutically acceptable acid addition salt thereof, the process comprising (A) either reacting a compound of general formula II wherein n, Ar 1 , Ar2, Y and R are as defined for general formula I above, with a compound of general formula (III) wherein halo represents a halogen atom, x is as defined in formula I above and R 1A and R 2A are as defined for R 1 and R 2 respectively in formula I, provided that R 1A and/or R 2A cannot be hydrogen or unprotected piperazine, but can additionally represent a halogen atom or, together with the adjacent nitrogen atom form 1-phthalimido, 4 substituted piperazine or loweralkyl , and subsequently, when either or loweralkyl both of R 1A and R 2A represent a substituent not within the definition of either or both of R 1 and R 2 , converting a substituent defined by R 1A to a substituent defined by R 1 and/or converting a substituent defined by R 2A to a substituent defined by R 2 , to obtain a compound as defined in general formula I ; (B) or reacting a compound of general formula IV wherein R, R 1 , R 2 , x and n are as defined for general formula I above, first with a compound of general formula V wherein halo represents a halogen atom and W represents a loweralkyl or phenyl group, the phenyl group optionally being substituted by one or more non-interfering radicals, and then with a compound of general formula VI wherein M + represents an alkali metal ion and Ar 1 and Ar 2 are as defined for general formula I above, to obtain a compound as defined in general formula I, except that -Y represents -CN; (C) and in either case optionally converting a compound of general formula I so formed into another compound of formula I and/or into a salt thereof.

Claim 20

A process for the preparation of a compound of general formula I wherein: n is zero, one or two; Ar 1 and Ar 2 , which may be the same or different, are selected from 2-, 3- and 4-pyrido, phenyl and phenyl substituted by 1 to 3 radicals, which may be the same or different and selected from loweralkyl, loweralkoxy, halogen and trifluoromethyl; Y represents aminocarbonyl or cyano; x is from two to five; R represents hydrogen or loweralkyl; R 1 and R 2 are selected from hydrogen, loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, loweralkoxy and phenyl-loweralkyl wherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy, and R 1 and R 2 may be the same or different, or, taken together with the adjacent nitrogen atom, may form a heterocyclic residue selected from pyrrolidino, piperidino, 4-phenylpiperidino, 2,6-diloweralkyl-piperidino, 4-hydroxy-4-phenylpiperidino, 4-cyano-4-phenylpiperidino, piperazino, 4-loweralk y l-piperazino, 4-phenylpiperazino, (4-phenyl-loweralkyl)-piperazino and 4-morpholino radicals; or a pnarma- ceutically acceptable acid addition salt thereof, the process comprising (A) either reacting a compound of general formula II wherein n, Ar 1 , Ar2, Y and R are as defined for general formula I above, with a compound of general formula (III) wherein halo represents a halogen atom, x is as defined in formula I above and R 1A and R 2A are as defined for R 1 and R 2 respectively in formula I, provided that R 1A and/or R 2A cannot be hydrogen or unprotected piperazine, but can additionally represent a halogen atom or, together with the adjacent nitrogen atom form 1-phthalimido, 4 substituted piperazine or loweralkyl , and subsequently, when either or loweralkyl both of R 1A and R 2A represent a substituent not within the definition of either or both of R 1 and R 2 , converting a substituent defined by R 1A to a substituent defined by R 1 and/or converting a substituent defined by R 2A to a substituent defined by R 2 , to obtain a compound as defined in general formula I ; (B) or reacting a compound of general formula IV wherein R, R 1 , R 2 , x and n are as defined for general formula I above, first with a compound of general formula V wherein halo represents a halogen atom and W represents a loweralkyl or phenyl group, the phenyl group optionally being substituted by one or more non-interfering radicals, and then with a compound of general formula VI wherein M + represents an alkali metal ion and Ar 1 and Ar 2 are as defined for general formula I above, to obtain a compound as defined in general formula I, except that -Y represents -CN; (C) and in either case optionally converting a compound of general formula I so formed into another compound of formula I and/or into a salt thereof.

Claim 21

A process as claimed in Claim 1, wherein each of A r 1 and Ar 2 represents a phenyl group.

Claim 22

A process as claimed in Claim 1 or 2, wherein x is 2 or 3.

Claim 23

A process as claimed in Claim 1, 2 or 3, wherein R 1 and R 2 both represent loweralkyl or, together with the adjacent nitrogen atom, form a pyrrolidino residue.

Claim 24

A process for the preparation of 1-[2-(dimethyl- amino)ethyl]-a,a-diphenyl-3-pyrrolidineacetonitrile, or a salt thereof, which comprises either reacting a,a-diphenyl-3-pyrrolidineacetonitrile with 2-(dimethyl-(amino)ethyl chloride or reacting 1-[2-(dimethyl- amino)ethyl]-3-pyrrolidinol first with methylsulphonyl chloride and then with diphenylacetonitrile, and in either case optionally forming a salt thereof.

Claim 25

A process for the preparation of 1-[2-(dimethyl- amino)ethyl]-a,a-diphenyl-3-pyrrolidineacetonitrile, or a salt thereof, which comprises either reacting a,a-diphenyl-3-pyrrolidineacetonitrile with 2-(dimethyl-(amino)ethyl chloride or reacting 1-[2-(dimethyl- amino)ethyl]-3-pyrrolidinol first with methylsulphonyl chloride and then with diphenylacetonitrile, and in either case optionally forming a salt thereof.

Claim 26

A process for the preparation of 1-[2-(dimethyl- amino)ethy1]-a,a-diphenyl-3-pyrrolidineacetamide, or a salt thereof, which comprises either reacting a,a-diphenyl-3-pyrrolidinylacetamide with 2-(dimethylamino)ethyl chloride or reacting 1-[2-(dimethylamino)-ethyl]-3-pyrrolidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolyzing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 27

A process for the preparation of 1-[2-(dimethyl- amino)ethy1]-a,a-diphenyl-3-pyrrolidineacetamide, or a salt thereof, which comprises either reacting a,a-diphenyl-3-pyrrolidinylacetamide with 2-(dimethylamino)ethyl chloride or reacting 1-[2-(dimethylamino)-ethyl]-3-pyrrolidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolyzing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 28

A process for the preparation of 1-[2-(dimethyl- amino)propyl]-a,a-diphenyl-3-pyrrolidineacetamide, or a salt thereof, which comprises either reacting a,a-diphenyl-3-pyrrolidinylacetamide with 2-(dimethylamino)propyl chloride or reacting 1-[2-(dimethylamino)-propyl]-3-pyrrolidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolysing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 29

A process for the preparation of 1-[2-(dimethyl- amino)propyl]-a,a-diphenyl-3-pyrrolidineacetamide, or a salt thereof, which comprises either reacting a,a-diphenyl-3-pyrrolidinylacetamide with 2-(dimethylamino)propyl chloride or reacting 1-[2-(dimethylamino)-propyl]-3-pyrrolidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolysing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 30

A process for the preparation of 1-[2-(diethyl- amino)ethyl]-a,a-diphenyl-3-pyrrolidineacetamide, or a salt thereof, which comprises either reacting a,a-diphenyl-3-pyrrolidinylacetamide with 2-(diethylamino)ethyl chloride or reacting 1-[2-(diethylamino)-propyl]-3-pyrrolidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolysing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 31

A process for the preparation of 1-[2-(diethyl- amino)ethyl]-a,a-diphenyl-3-pyrrolidineacetamide, or a salt thereof, which comprises either reacting a,a-diphenyl-3-pyrrolidinylacetamide with 2-(diethylamino)ethyl chloride or reacting 1-[2-(diethylamino)-propyl]-3-pyrrolidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolysing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 32

A process for the preparation of 1-[2-(1-pyrrolidinyl)ethyl]-a,a-diphenyl-3-pyrrolidineacet- amide, or a salt thereof, which comprises either reacting a,a-diphenyl-3-pyrrolidinylacetamide with 2-(1-pyrrolidinyl)ethyl chloride or reacting 1-[2-(1-pyrrolidinyl)ethyl]-3-pyrrolidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolysing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 33

A process for the preparation of 1-[2-(1-pyrrolidinyl)ethyl]-a,a-diphenyl-3-pyrrolidineacet- amide, or a salt thereof, which comprises either reacting a,a-diphenyl-3-pyrrolidinylacetamide with 2-(1-pyrrolidinyl)ethyl chloride or reacting 1-[2-(1-pyrrolidinyl)ethyl]-3-pyrrolidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolysing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 34

A process for the preparation of 1-[2-(dimethyl- amino)ethyl]-a,a-diphenyl-3-piperidineacetamide, or a salt thereof, which comprises either reacting a,a-diphenyl-3-piperidinylacetamide with 2-(dimethylamino)ethyl chloride or reacting 1-[2-(dimethylamino)-ethyl]-3-piperidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolysing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 35

A process for the preparation of 1-[2-(dimethyl- amino)ethyl]-a,a-diphenyl-3-piperidineacetamide, or a salt thereof, which comprises either reacting a,a-diphenyl-3-piperidinylacetamide with 2-(dimethylamino)ethyl chloride or reacting 1-[2-(dimethylamino)-ethyl]-3-piperidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolysing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 36

A process for the preparation of 1-[2-(dimethyl- amino)ethyl]-a,a-diphenyl-4-piperidineacetamide, or a salt thereof, which comprises either reacting a,a-diphenyl-4-piperidinylacetamide with 2-(dimethylamino)ethyl chloride or reacting 1-[2-(dimethylamino)-ethyl]-4-piperidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolysing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.

Claim 37

A process for the preparation of 1-[2-(dimethyl- amino)ethyl]-a,a-diphenyl-4-piperidineacetamide, or a salt thereof, which comprises either reacting a,a-diphenyl-4-piperidinylacetamide with 2-(dimethylamino)ethyl chloride or reacting 1-[2-(dimethylamino)-ethyl]-4-piperidinol first with methylsulphonyl chloride and then with diphenylacetonitrile and subsequently hydrolysing the product to the corresponding acetamide, and in either case optionally forming a salt thereof.