Novel polyamine derivatives

Claim 2

A compound of the general formula I RHN(CH₂) n NH(CH₂) m NH(CH₂) n NHR      (I) and the pharmaceutically acceptable salts thereof wherein n is an integer 2 to 6, m is an integer 3 to 12, and R is a C 1-6 saturated or unsaturated hydrocarbyl radical or -(CH₂) x -(Ar)-X wherein x is zero, one or two, Ar is phenyl or naphthyl, and X is H, C 1-6 alkoxy, halogen, C 1-4 alkyl, -S(O) x R₁ with R₁ being C 1-6 alkyl, with the proviso that R cannot be phenylmethyl where n is 2 and m is either 6 or 10.

Claim 3

A compound of claim 1 wherein m is an integer 6 to 9.

Claim 4

A compound of claim 2 wherein n is three.

Claim 5

A compound of claim 2 wherein R is benzyl.

Claim 6

A compound of claim 2 wherein R is phenyl.

Claim 7

A compound of claim 2 wherein R is phenylethyl.

Claim 8

A compound of claim2 2 wherein said compound is bis-benzyl-3-7-3.

Claim 9

A compound of claim 2 wherein said compound is bis-benzyl-3-6-3.

Claim 10

A compound of claim 2 wherein said compound is bis-benzyl-3-8-3.

Claim 11

A compound of the general formula I RHN(CH₂) n NH(CH₂) m NH(CH₂) n NHR      (I) and the pharmaceutically acceptable salts thereof wherein n is an integer 2 to 6, m is an integer 3 to 12, and R is a C₁-C₆ saturated or unsaturated hydrocarbyl radical or -(CH₂) x -(Ar)-X wherein x is zero, one or two, Ar is phenyl or naphthyl, and X is H, C₁-C₆ alkoxy, halogen, C₁-C₄ alkyl, -S(O) x R₁ with R₁ being C₁-C₆ alkyl, for use as a therapeutic agent.

Claim 12

A compound of the general formula I RHN(CH₂) n NH(CH₂) m NH(CH₂) n NHR      (I) and the pharmaceutically acceptable salts thereof wherein n is an integer 2 to 6, m is an integer 3 to 12, and R is a C₁-C₆ saturated or unsaturated hydrocarbyl radical or -(CH₂) x -(Ar)-X wherein x is zero, one or two, Ar is phenyl or naphthyl, and X is H, C₁-C₆ alkoxy, halogen, C₁-C₄ alkyl, -S(O) x R₁ with R₁ being C₁-C₆ alkyl, for use as a therapeutic agent.

Claim 13

A compound of claim 10 for use in a method for treating infections caused by protozoa.

Claim 14

A compound of claim 10 for use in a method according to claim 11 wherein the infection is caused by protozoa of the genera consisting of Plasmodium, Trypanosoma, including salivaria and stercoraria, Leishmania, Trichomonas, Babesia, Toxoplasma, and Theileria.

Claim 15

A compound of claim 10 for use in a method according to claim 12 wherein the host suffering from a protozoal infection is suffering from malaria or from Chaga's Disease.

Claim 16

A pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier or diluent.

Claim 17

A pharmaceutical composition according to claim 14 further comprising an ornithine decarboxylase inhibitor or an arginine decarboxylase inhibitor.

Claim 18

A pharmaceutical composition according to claim 15 comprising α-difluoromethyl ornithine or α-­difluoromethyl arginine.

Claim 19

A process for preparing a compound of the general formula I RHN(CH₂) n NH(CH₂) m NH(CH₂) n NHR      (I) and the pharmaceutically acceptable salts thereof wherein n is an integer 2 to 6, m is an integer 3 to 12, and R is a C₁-C₆ saturated or unsaturated hydrocarbyl radical or -(CH₂) x -(Ar)-X wherein x is zero, one or two, Ar is phenyl or naphthyl, and X is H, C₁-C₆ alkoxy, halogen, C₁-C₄ alkyl, -S(O) x R₁ with R₁ being C₁-C₆ alkyl, with the proviso that R cannot be phenylmethyl where n is 2 and m is either 6 or 10, comprising a) reaction of an appropriate N-protected tetramine with a compound of the formula Rʹ-halide wherein Rʹ is as defined for R in formula I except that when R is X-(Ar)-(CH₂) x , x cannot be zero, followed by deprotection of the N-terminal alkylated product; b) reductive alkylation of a compound of the formula H₂N(CH₂) n OH with an appropriate aldehyde Rʹ(CH₂) nʹ CHO wherein Rʹ is X-(Ar)-(CH₂) x with x being other than zero and nʹ is zero or a positive integer, N-protection and mesylation of the alkylated product and reaction of the N-protected and mesylated product with an N-­protected diamine of the formula Pro-NH(CH₂) m NH-Pro wherein Pro is an N-protecting group; c) N-aroylation of a partially N-protected tetramine with an aroyl chloride followed by reduction and deprotection of the N-aroylated product; d) for the production of a compound of the formula I wherein R is X-(Ar)-(CH₂) x wherein x is zero, reaction of an N-protected compound of the formula an appropriate dihaloalkane followed by deprotection, or e) for the production of a compound of the formula I wherein R is an unsaturated hydrocarbyl radical, reaction of an N-protected diamine mesylate with an N-protected amine bearing an appropriate unsaturated hydrocarbyl moiety followed by deprotection.

Claim 20

A process for preparing a compound of the general formula I RHN(CH₂) n NH(CH₂) m NH(CH₂) n NHR      (I) and the pharmaceutically acceptable salts thereof wherein n is an integer 2 to 6, m is an integer 3 to 12, and R is a C₁-C₆ saturated or unsaturated hydrocarbyl radical or -(CH₂) x -(Ar)-X wherein x is zero, one or two, Ar is phenyl or naphthyl, and X is H, C₁-C₆ alkoxy, halogen, C₁-C₄ alkyl, -S(O) x R₁ with R₁ being C₁-C₆ alkyl, with the proviso that R cannot be phenylmethyl where n is 2 and m is either 6 or 10, comprising a) reaction of an appropriate N-protected tetramine with a compound of the formula Rʹ-halide wherein Rʹ is as defined for R in formula I except that when R is X-(Ar)-(CH₂) x , x cannot be zero, followed by deprotection of the N-terminal alkylated product; b) reductive alkylation of a compound of the formula H₂N(CH₂) n OH with an appropriate aldehyde Rʹ(CH₂) nʹ CHO wherein Rʹ is X-(Ar)-(CH₂) x with x being other than zero and nʹ is zero or a positive integer, N-protection and mesylation of the alkylated product and reaction of the N-protected and mesylated product with an N-­protected diamine of the formula Pro-NH(CH₂) m NH-Pro wherein Pro is an N-protecting group; c) N-aroylation of a partially N-protected tetramine with an aroyl chloride followed by reduction and deprotection of the N-aroylated product; d) for the production of a compound of the formula I wherein R is X-(Ar)-(CH₂) x wherein x is zero, reaction of an N-protected compound of the formula an appropriate dihaloalkane followed by deprotection, or e) for the production of a compound of the formula I wherein R is an unsaturated hydrocarbyl radical, reaction of an N-protected diamine mesylate with an N-protected amine bearing an appropriate unsaturated hydrocarbyl moiety followed by deprotection.