N6-substituted diarylalkyl adenosines, processes for their production and pharmaceutical compositions comprising the same

Claim 2

A compound having the following general formula 1: or a pharmaceutically acceptable addition salt thereof, wherein: R 1 is a hydrogen atom or a lower alkyl radical; Ar and Ar are each independently a phenyl radical; a phenyl radical substituted by one or more of the following: a halogen atom, a hydroxy group, a thiol group, a lower alkoxy radical, a lower thioalkoxy radical, a lower alkanoyloxy radical, a lower alkyl radical, a nitro group, an amino group, a lower S(O) n -alkyl radical in which n is 0, 1, or 2, a sulphonamide radical or trifluoromethyl; a 2-, 3-, or 4-pyridyl radical ; a 2- or 3-thienyl radical; or a -furanyl radical; A is a direct bond between the nitrogen and carbon atoms or is a straight or branched alkylene chain of from 1 to 8 carbon atoms optionally interrupted, at a position on the straight or branched chain inwardly of the two carbon atoms adjacent to the two terminal carbon atoms of the alkylene chain, by an oxygen atom, a sulphur atom or an NH group; X is a hydrogen atom, a hydroxy group, a lower alkyl radical, a lower carboalkoxy radical or a lower alkanoyloxy radical; Y is a hydrogen atom, a halogen atom, an -NR 2 R 3 radical, an -OR 2 radical or an -SR 2 in which R 2 and R 3 are independently a hydrogen atom, a lower alkyl radical or phenyl lower alkyl radical; Z is a hydrogen atom or a halogen atom; and R 2 ', R 3 ', and R 5 1 are each independently a hydrogen atom; an alkanoyl radical having from two to twelve carbon atoms in a straight or branched alkyl chain and which is optionally substituted by an amino radical; a benzoyl radical or a benzoyl radical substituted by a lower alkyl radical, a lower alkoxy radical, a halogen atom or a trifluoromethyl radical; R 5 ' additionally being chosen from a phosphate group, a hydrogen phosphate group, a dihydrogen phosphate group, an alkali or dialkali metal phosphate group, or an ammonium or diammonium phosphate group; and R 2 ' and R 3 ' optionally forming, when taken together, an alkylidene radical containing up to 20 carbon atoms, in which one carbon atom is bound to the two 0 atoms to form a 5-membered ring; wherein the terms lower alkyl, lower alkoxy, lower thioalkoxy, lower alkanoyloxy, and lower carboalkoxy refer to radicals which have a straight or branched alkyl portion of from 1 to 6 carbon atoms.

Claim 3

A compound according to Claim 1, wherein: R 1 and X are a hydrogen atom or a methyl radical; R 2 ' and R 3 ' are each independently a hydrogen atom, an acetyl group, a benzoyl group or, when taken together, an isopropylidene radical; R S ' is a hydrogen atom, a phosphate group, a hydrogen phosphate group, a dihydrogen phosphate group, a sodium phosphate or disodium phosphate group; and Z is a hydrogen atom or a fluorine atom.

Claim 4

A compound according to Claim 1 or 2 , wherein R 1 , R2' , R 3 ', R 5 ', X , and Z are each a hydrogen atom.

Claim 5

A compound according ot Claim 1, 2 or 3, wherein Y is a hydrogen atom, a halogen atom or -NR 2 R 3 where R 2 and R 3 are as defined in Claim 1.

Claim 6

A compound according to any preceding claim, wherein Y is a hydrogen atom, a chlorine atom or an amino group, and A is a straight of branched alkylene chain of from 1 to 4 carbon atoms.

Claim 7

A compound according to any preceding claim, wherein A is a methylene, and Ar and Ar are each a phenyl radical.

Claim 8

A compound according to Claim 6, and having the name: N 6 -(2,2-diphenylethyl)adenosine; N 6 -(3,3-diphenylpropyl)adenosine; N 6 -(2,2-diphenylethyl)-2-choroadenosine; N 6 -(2,2-diphenylethyl)-2-aminoadenosine; N 6 -(2,2-diphenylpropyl)adenosine; or a pharmaceutically acceptable addition salt thereof.

Claim 9

A process for the preparation of a compound as claimed in Claim 1, which process comprises reacting a compound of the following general formula: with an amine of the following general formula: in the presence of a base, and, if desired, converting the resulting free base to a pharmaceutically acceptable acid addition salt; wherein Hal is a halogen atom, and A, X, Y, Z, Ar, Ar 1 , R 1 , R 2 ', R 3 ' and R 5 ' are as defined in Claim 1.

Claim 10

A process for the preparation of a compound as claimed in Claim 1, wherein Y is an -NR 2 R 3 radical, an -OR 2 radical or an -SR 2 radical, which process comprises displacing the chlorine atom in a compound of the formula with Y-H, wherein Y is as defined above, Ac is acetyl and R 1 , R 2 and R 3 are as defined in Claim 1; optionally removing the acetyl groups with ammonium hydroxide, and, if desired, converting the resulting free base to a pharmaceutically acceptable acid addition salt.

Claim 11

A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in any one of Claims 1 to 7, together with a pharmaceutically acceptable carrier.

Claim 12

CLAIMS (for the Contracting State:AT)

Claim 13

A process for the preparation of a compound having the following general formula 1; or a pharmaceutically acceptable addition salt thereof, wherein: R 1 is a hydrogen atom or a lower alkyl radical; Ar and Ar 1 are each independently a phenyl radical; a phenyl radical substituted by one or more of the following: a halogen atan, a hydroxy group, a thiol group, a lower alkoxy radical, a lower thioalkoxy radical, a lower alkanoyloxy radical, a lower alkyl radical, a nitro group, an amino group, a lower S(O)n-alkyl radical in which n is 0, 1, or 2, a sulphonamide radical or trifluoromethyl; a 2-, 3-, or 4-pyridyl radical; a 2- or 3-thienyl radical; or a -furanyl radical; A is a direct bond between the nitrogen and carbon atoms or is a straight or branched alkylene chain of from 1 to 8 carbon atoms optionally interrupted, at a position on the straight or branched chain inwardly of the two carbon atoms adjacent to the two terminal carbon atoms of the alkylene chain, by an oxygen atan, a sulphur atom or an NH group; X is a hydrogen atom, a hydroxy group, a lower alkyl radical, a lower carboalkoxy radical or a lower alkanoyloxy radical; Y is a hydrogen atom, a halogen atom, an -NR 2 R 3 radical, an -OR 2 radical or an -SR 2 in which R 2 and R 3 are independently a hydrogen atom, a lower alkyl radical or phenyl lower alkyl radical; Z is a hydrogen atom or a halogen atom; and R 2 1 , R 3 ', and R 5 ' are each independently a hydrogen atom; an alkanoyl radical having from two to twelve carbon atoms in a straight or branched alkyl chain and which is optionally substituted by an amino radical; a benzoyl radical or a benzoyl radical substituted by a lower alkyl radical, a lower alkoxy radical, a halogen atom or a trifluoromethyl radical; R S ' additionally being chosen from a phosphate group, a hydrogen phosphate group, a dihydrogen phosphate group, an alkali or dialkali metal phosphate group, or an ammonium or diammonium phosphate group; and R 2 1 and R 3 1 optionally forming, when taken together, an alkylidene radical containing up to 20 carbon atoms, in which one carbon atom is bound to the two O atoms to form a 5-membered ring; wherein the terms lower alkyl, lower alkoxy, lower thioalkoxy, lower alkanoyloxy, and lower carboalkoxy refer to radicals which have a straight or branched alkyl portion of from 1 to 6 carbon atoms; which process comprises reacting a compound of the following general formula: wherein Hal is a halogen atom, with an amine of the following general formula: in the presence of a base, and, if desired, converting the resulting free base to a pharmaceutically acceptable acid addition salt.

Claim 14

A process for the preparation of a compound having the following general formula 1; or a pharmaceutically acceptable addition salt thereof, wherein: R 1 is a hydrogen atom or a lower alkyl radical; Ar and Ar 1 are each independently a phenyl radical; a phenyl radical substituted by one or more of the following: a halogen atan, a hydroxy group, a thiol group, a lower alkoxy radical, a lower thioalkoxy radical, a lower alkanoyloxy radical, a lower alkyl radical, a nitro group, an amino group, a lower S(O)n-alkyl radical in which n is 0, 1, or 2, a sulphonamide radical or trifluoromethyl; a 2-, 3-, or 4-pyridyl radical; a 2- or 3-thienyl radical; or a -furanyl radical; A is a direct bond between the nitrogen and carbon atoms or is a straight or branched alkylene chain of from 1 to 8 carbon atoms optionally interrupted, at a position on the straight or branched chain inwardly of the two carbon atoms adjacent to the two terminal carbon atoms of the alkylene chain, by an oxygen atan, a sulphur atom or an NH group; X is a hydrogen atom, a hydroxy group, a lower alkyl radical, a lower carboalkoxy radical or a lower alkanoyloxy radical; Y is a hydrogen atom, a halogen atom, an -NR 2 R 3 radical, an -OR 2 radical or an -SR 2 in which R 2 and R 3 are independently a hydrogen atom, a lower alkyl radical or phenyl lower alkyl radical; Z is a hydrogen atom or a halogen atom; and R 2 1 , R 3 ', and R 5 ' are each independently a hydrogen atom; an alkanoyl radical having from two to twelve carbon atoms in a straight or branched alkyl chain and which is optionally substituted by an amino radical; a benzoyl radical or a benzoyl radical substituted by a lower alkyl radical, a lower alkoxy radical, a halogen atom or a trifluoromethyl radical; R S ' additionally being chosen from a phosphate group, a hydrogen phosphate group, a dihydrogen phosphate group, an alkali or dialkali metal phosphate group, or an ammonium or diammonium phosphate group; and R 2 1 and R 3 1 optionally forming, when taken together, an alkylidene radical containing up to 20 carbon atoms, in which one carbon atom is bound to the two O atoms to form a 5-membered ring; wherein the terms lower alkyl, lower alkoxy, lower thioalkoxy, lower alkanoyloxy, and lower carboalkoxy refer to radicals which have a straight or branched alkyl portion of from 1 to 6 carbon atoms; which process comprises reacting a compound of the following general formula: wherein Hal is a halogen atom, with an amine of the following general formula: in the presence of a base, and, if desired, converting the resulting free base to a pharmaceutically acceptable acid addition salt.

Claim 15

A process for the preparation of a compound of the formula 1 as defined in Claim 1, wherein Y is an -NR 2 R 3 radical, an -OR 2 radical or an -SR 2 radical, which process comprises displacing the chlorine atom in a compound of the formula with Y-H, wherein Y is as defined above, Ac is acetyl, and R 1 , R 2 and R 3 are as defined in Claim 1; optionally removing the acetyl groups with ammonium hydroxide, and, if desired, converting the resulting free base to a pharmaceutically acceptable acid addition sat.

Claim 16

A process according to Claim 1 or 2, wherein: R 1 and X are a hydrogen atom, or a methyl radical; R 2 ' and R 3 ' are each independently a hydrogen atom, an acetyl group, a benzoyl group or, when taken together, an isopropylidene radical; R 5 ' is a hydrogen atom, a phosphate group, a hydrogen phosphate group, a dihydrogen group, a sodium phosphate or disodium phosphate group; and Z is a hydrogen atom or a fluorine atom.

Claim 17

A process according to any preceding claim, wherein R 1 , R 2 1, R 3 1, R 5 ', X and Z are each a hydrogen atom.

Claim 18

A process according to any preceding claim, wherein Y is a hydrogen atom, a halogen atom or -NR 2 R 3 where R 2 and R3 are as defined in Claim 1.

Claim 19

A process according to any preceding claim, wherein Y is a hydrogen atom, a chlorine atom or an amino group, and A is a straight or branched alkylene chain of from 1 to 4 carbon atoms.

Claim 20

A process according to any preceding claim, wherein A is a methylene, and Ar and Ar 1 are each a phenyl radical.

Claim 21

A process according to Claim 1 or to any one of Claims 3 to 7 when appendant to Claim 1, for preparing the compound having the name N 6 -(2,2-diphenylethyl)adenosine; N 6 -(3,3-diphenylpropyl)adenosine; N -( 2 ,2-diphenylethyl)-2-chloroadenosine; N 6 -(2,2-diphenylethyl)-2-aminoadenosine; N 6 -(2,2-diphenylpropyl)adenosine; or a pharmaceutically acceptable addition salt thereof.

Claim 22

A process for preparing a pharmaceutical composition, which process comprises combining an effective amount of a compound prepared by a process according to any preceding claim, with a pharmaceutically acceptable carrier.