Nor-statine and nor-cyclostatine polypeptides

Claim 2

A compound of the formulae and and a pharmaceutically acceptable salt thereof, wherein Z is R 1 -(Y) m -(A) p , where R 1 is (C 1 -C 6 )alkyl, amino, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylamino, (C 1 -C 3 )alkoxy(C 2 -C 4 )alkyleneamino, carboxy(C 1 -C 4 )alkyl, hydroxy(C 2 -C 4 )-alkyleneamino, (C 1 -C 3 )alkoxyCOCH 2 N(CH 3 ), amino(C 1 -C 5 )alkyl, morpholino, piperidyl, hydroxypiperidino, 4- oxopiperidino, piperazino, 4-oxopiperidino ethylene ketal 4-(C 1 -C 3 )alkylpiperazino, thiomorpholino, thiomorpholino 1-oxide, thiomorpholino 1,1-dioxide, N-(C 1 -C 4 )alkoxycarbonylpiperidyl, 4-(C 1 -C 4 )-alkoxycarbonylpiperazino, 3-oxomorpholino, 3,5-dioxomorpholino, hydroxypyridyl, pyridyl, (s)-pyrrolid-2-yl, N-t-butoxycarbonyl-(s)-pyrrolid-2-yl, (C 1 -C 3 )alkoxycarbonyl-(s)-pyrrolid-2-yl or 4-(Ci-C 4 )alkanoylpiperazino; Y is C=O, P(OCH 3 ) = O or SO 2 ; A is N(CH 3 ), NH or 0; m and p are each integers of 0 or 1; M is phenyl, benzyl, naphthyl, thienyl, methoxyphenyl, hydroxyphenyl, chlorophenyl or (C 6 -C 7 )cycloalkyl; Q is methyl or hydrogen; R 2 is (C 1 -C 5 )alkyl, (C 1 -C 3 )alkylthio(C 1 -C 2 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 2 )alkyl, benzyloxy(C 1 -C 2 )alkyl, benzyl, hydroxy(C 1 -C 2 )alkyl, carboxy(C 1 -C 2 )alkyl, guanido(Ci-C 3 )alkyl, (C 1 -C 3 )alkylsulfinyl(C 1 -C 2 )alkyl, (C 1 -C 3 )-alkylsulfonyl(C 1 -C 2 )alkyl, 4-benzyloxycarbonylaminobutyl, 4-aminobutyl, imidazol-4-ylmethyl, N-t - butoxycarbonylimidazol-4-ylmethyl or carbamyl(C 1 -C 2 )alkyl; X is cyclohexyl, i-propyl or phenyl; W is (C 1 -C 3 )-alkyldi(Ci-C 2 )alkyl amino, CH|||OCO(C 1 -C 3 )alkylpiperidino, CH|||OH, C = O, CH|||N 3 , CH N3, CH NH 2 , CH|||NH 2 , C(CH 3 )|||OH, C(CH 3 ) OH, CH|||OCO(C 1 -C 2 )alkyl or CH|||OCO(C 1 -C 2 )alkylene CO 2 H; Z 1 is CH 2 0H or R-S-T where R is C=0, S is 0, NH, N(CH 3 ), CH 2 or a chemical bond linking R and T; T is (C 1 -C 5 )alkyl, hydroxy(C 1 -C 4 )alkyl, CONH-(C 1 -C 4 )alkyl, hydrogen, trifluoroethyl, (C 6 -C 7 )cycloalkyl, (C 6 -C 7 )-cycloalkylmethyl, phenyl, benzyl, amino(C 2 -C 5 )alkyl, 0-(C 1 -C 2 )alkyl hydroxylamino, morpholino, 4-(C 1 -C 2 )-alkylpiperazino or omega-di(C 1 -C 2 )alkylamino(C 3 -C 5 )alkyl; L is CH or N; R 5 is imidazol-4-ylmethyl or (C 2 -C 5 )-alkyl; and R 6 is (C 1 -C 4 )alkoxy or (C 1 -C 4 )alkylamino with the provi-so that when m is 0, p is 0; when A is O, Y is C=O; when T is CONH-(C 1 -C 4 )alkyl, S is NH, N(CH 3 ) or CH 2 ; and when T is (C 2 -C 5 )alkylamino, O-(C 1 -C 2 )-alkyl hydroxylamino, morpholino or 4-(C 1 -C 2 )alkylpiperazino, S is CH 2 or a chemical bond linking R and T.

Claim 3

A compound of claim 1, formula I, wherein Y is C=0, A is NH, Q is hydrogen, X is cyclohexyl, W is CH|||OH, R is C=O, T is benzyl or (Ci-C 5 )alkyl and m and p are each 1.

Claim 4

The compound of claim 2, wherein R 1 is morpholino, M is 2-thienyl, R 2 is CH 3 SCH 2 -, S is 0 and T is i-propyl.

Claim 5

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is n-propyl, S is O and T is i- propyl.

Claim 6

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is CH 3 SCH 2 -, S is O and T is i- propyl.

Claim 7

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is n-butyl, S is 0 and T is methyl.

Claim 8

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is n-butyl, S is NH and T is methyl.

Claim 9

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is n-butyl, S is a chemical bond linking R and T and T is CH 2 CH(CH 3 )2.

Claim 10

The compound of claim 2, wherein R 1 is 2-pyrrolidyl, M is phenyl, R 2 is CH3SCH2-, S is 0 and T is i- propyl.

Claim 11

The compound of claim 2, wherein R 1 is 4-pyridyl, M is phenyl, R 2 is CH 2 SCH 2 -, S is O and T is i- propyl.

Claim 12

The compound of claim 2, wherein R 1 is piperazino, M is phenyl, R 2 is CH 3 SCH 2 -, S is O and T is i- propyl.

Claim 13

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is CH3SCH2-, S is a chemical bond linking R and T and T is -CH 2 CH(CH 3 ) 2 .

Claim 14

The compound of claim 2, wherein R 1 is 4-hydroxypiperidino, M is phenyl, R 2 is CH 3 SCH 2 -, S is O and T is i-propyl.

Claim 15

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is HOCH 2 -, S is O and T is i- propyl.

Claim 16

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is CH 2 O(CH 2 ) 2 )-, S is 0 and T is i-propyl.

Claim 17

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is CH3SCH2-, S is O and T is benzyl.

Claim 18

The compound of claim 2, wherein R 1 is morpholino, M is 4-hydroxyphenyl, R 2 is CH 3 SCH 2 -, S is O and T is i-propyl.

Claim 19

The compound of claim 2, wherein R 1 is morpholino, M is 4-methoxyphenyl, R 2 is n-butyl, S is 0 and T is methyl.

Claim 20

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is methyl, S is 0 and T is i-propyl.

Claim 21

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is n-butyl, S is 0 and T is i- propyl.

Claim 22

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is n-butyl, S is O and T is i- propyl.

Claim 23

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is CH 3 OCH 2 -, S is O and T is i- propyl.

Claim 24

The compound of claim 2, wherein R 1 is morpholino, M is phenyl, R 2 is CH 3 CH 2 OCH 2 -, S is 0 and T is i-propyl.

Claim 25

A compound of claim 1, formula I, wherein M is phenyl, S is a chemical bond linking R and T, T is (C 1 -C 5 )alkyl and R is C = O.

Claim 26

A method of treating hypertension in a mammal which comprises administering to said mammal an antihypertensive effective amount of a compound according to claim 1.

Claim 27

A pharmaceutical composition comprising an antihypertensive effective amount of a compound according to claim 1 and a pharmaceutically acceptable diluent or carrier.

Claim 28

Claims for the following contracting States: GR, ES

Claim 29

A process for preparing a compound of the formulae and wherein Z is R 1 -(Y) m -(A) p , where R 1 is (C 1 -C 6 )alkyl, amino, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylamino, (C 1 -C 3 )alkoxy(C 2 -C 4 )alkyleneamino, carboxy(C 1 -C 4 )alkyl, hydroxy(C 2 -C 4 )alkyleneamino, (Ci-C 3 )alkoxyCOCH 2 N(CH 3 ), amino(C 1 -C 5 )alkyl, morpholino, piperidyl, hydroxypiperidino, 4-oxopiperidino, piperazino, 4-oxopiperidino ethylene ketal 4-(C 1 -C 3 )alkylpiperazino, thiomorpholino, thiomorpholino 1-oxide, thiomorpholino 1,1-dioxide, N-(C 1 -C 4 )-alkoxycarbonylpiperidyl, 4-(C 1 -C 4 )alkoxycarbonylpiperazino, 3-oxomorpholino, 3,5-dioxomorpholino, hydroxypyridyl, pyridyl, (s)-pyrrolid-2-yl, N-t-butoxycarbonyl-(s)-pyrrolid-2-yl, (C 1 -C 3 )alkoxycarbonyl-(s)-pyrrolid-2-yl or 4-(C 1 -C 4 )alkanoylpiperazino; Y is C = 0, P(OCH 3 ) = 0 or SO 2 ; A is N(CH 3 ), NH or 0; m and p are each integers of 0 or 1; M is phenyl, benzyl, naphthyl, thienyl, methoxyphenyl, hydroxyphenyl, chlorophenyl or (C 6 -C 7 )cycloalkyl; Q is methyl or hydrogen; R 2 is (C 1 -C 5 )alkyl, (C 1 -C 3 )alkylthio(C 1 -C 2 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 2 )alkyl, benzyloxy(C 1 -C 2 )alkyl, benzyl, hydroxy(Ci-C 2 )alkyl, carboxy(C 1 -C 2 )alkyl, guanido(C 1 -C 3 )alkyl, (Ci-C 3 )-alkylsulfinyl(C 1 -C 2 )alkyl, (C 1 -C 3 )alkylsulfonyl(C 1 -C 2 )alkyl, 4-benzyloxycarbonylaminobutyl, 4-aminobutyl, imidazol-4-ylmethyl, N-t -butoxycarbonylimidazol-4-ylmethyl or carbamyl(C 1 -C 2 )alkyl; X is cyclohexyl, i- propyl or phenyl; W is CH|||OCO (C 1 -C 3 )alkyldi(C 1 -C 2 )alkylamino, CH|||OCO(C 1 -C 3 )alkylpiperidino, CH|||OH, C=O, CH|||N 3 , CH N 3 , CH NH 2 , CH|||NH 2 , C(CH 3 )|||OH, C(CH 3 ) OH, CH|||OCO(C 1 -C 2 )alkyl or CH|||OCO(C 1 -C 2 )alkylene C0 2 H; Z 1 is CH 2 0H or R-S-T where R is C=O, S is 0, NH, N(CH 3 ), CH 2 or a chemical bond linking R and T; T is (C 1 -C 5 )alkyl, hydroxy(C 1 -C 4 )alkyl, CONH-(C 1 -C 4 )alkyl, hydrogen, trifluoroethyl, (C 6 -C 7 )cycloalkyl, (C 6 -C 7 )cycloalkylmethyl, phenyl, benzyl, amino(C 2 -C 5 )alkyl, O-(C 1 -C 2 )alkyl hydroxylamino, morpholino, 4-(C 1 -C 2 )alkylpiperazino or omega-di(C 1 -C 2 )alkylamino(C 3 -C 5 )alkyl; L is CH or N; R 5 is imidazol-4-ylmethyl or (C 2 -C 5 )alkyl; and R 6 is (C 1 -C 4 )alkoxy or (C 1 -C 4 )alkylamino with the proviso that when m is 0, p is 0; when A is 0, Y is C=O; when T is CONH-(C 1 -C 4 ) alkyl, S is NH, N(CH 3 ) or CH 2 ; and when T is (C 2 -C 5 ) alkylamino, O-(C 1 -C 2 )alkyl hydroxylamino, morpholino or 4-(C 1 -C 2 )alkylpiperazino, S is CH 2 or a chemical bond linking R and T, characterized by the formation of an amide bond, C(O)N, by dehydrative-coupling wherein the functional groups not involved in the reaction may be blocked, followed by the optional steps of 1) selectively removing the blocking groups 2) oxidizing a sulfide group to sulfoxide or sulfone 3) oxidizing W wherein it is CH|||||OH or CH OH to C = 0 4) acylating W wherein it is CH|||||OH and, if desired, making a pharmaceutically acceptable salt of the product.

Claim 30

A process for preparing a compound of the formulae and wherein Z is R 1 -(Y) m -(A) p , where R 1 is (C 1 -C 6 )alkyl, amino, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylamino, (C 1 -C 3 )alkoxy(C 2 -C 4 )alkyleneamino, carboxy(C 1 -C 4 )alkyl, hydroxy(C 2 -C 4 )alkyleneamino, (Ci-C 3 )alkoxyCOCH 2 N(CH 3 ), amino(C 1 -C 5 )alkyl, morpholino, piperidyl, hydroxypiperidino, 4-oxopiperidino, piperazino, 4-oxopiperidino ethylene ketal 4-(C 1 -C 3 )alkylpiperazino, thiomorpholino, thiomorpholino 1-oxide, thiomorpholino 1,1-dioxide, N-(C 1 -C 4 )-alkoxycarbonylpiperidyl, 4-(C 1 -C 4 )alkoxycarbonylpiperazino, 3-oxomorpholino, 3,5-dioxomorpholino, hydroxypyridyl, pyridyl, (s)-pyrrolid-2-yl, N-t-butoxycarbonyl-(s)-pyrrolid-2-yl, (C 1 -C 3 )alkoxycarbonyl-(s)-pyrrolid-2-yl or 4-(C 1 -C 4 )alkanoylpiperazino; Y is C = 0, P(OCH 3 ) = 0 or SO 2 ; A is N(CH 3 ), NH or 0; m and p are each integers of 0 or 1; M is phenyl, benzyl, naphthyl, thienyl, methoxyphenyl, hydroxyphenyl, chlorophenyl or (C 6 -C 7 )cycloalkyl; Q is methyl or hydrogen; R 2 is (C 1 -C 5 )alkyl, (C 1 -C 3 )alkylthio(C 1 -C 2 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 2 )alkyl, benzyloxy(C 1 -C 2 )alkyl, benzyl, hydroxy(Ci-C 2 )alkyl, carboxy(C 1 -C 2 )alkyl, guanido(C 1 -C 3 )alkyl, (Ci-C 3 )-alkylsulfinyl(C 1 -C 2 )alkyl, (C 1 -C 3 )alkylsulfonyl(C 1 -C 2 )alkyl, 4-benzyloxycarbonylaminobutyl, 4-aminobutyl, imidazol-4-ylmethyl, N-t -butoxycarbonylimidazol-4-ylmethyl or carbamyl(C 1 -C 2 )alkyl; X is cyclohexyl, i- propyl or phenyl; W is CH|||OCO (C 1 -C 3 )alkyldi(C 1 -C 2 )alkylamino, CH|||OCO(C 1 -C 3 )alkylpiperidino, CH|||OH, C=O, CH|||N 3 , CH N 3 , CH NH 2 , CH|||NH 2 , C(CH 3 )|||OH, C(CH 3 ) OH, CH|||OCO(C 1 -C 2 )alkyl or CH|||OCO(C 1 -C 2 )alkylene C0 2 H; Z 1 is CH 2 0H or R-S-T where R is C=O, S is 0, NH, N(CH 3 ), CH 2 or a chemical bond linking R and T; T is (C 1 -C 5 )alkyl, hydroxy(C 1 -C 4 )alkyl, CONH-(C 1 -C 4 )alkyl, hydrogen, trifluoroethyl, (C 6 -C 7 )cycloalkyl, (C 6 -C 7 )cycloalkylmethyl, phenyl, benzyl, amino(C 2 -C 5 )alkyl, O-(C 1 -C 2 )alkyl hydroxylamino, morpholino, 4-(C 1 -C 2 )alkylpiperazino or omega-di(C 1 -C 2 )alkylamino(C 3 -C 5 )alkyl; L is CH or N; R 5 is imidazol-4-ylmethyl or (C 2 -C 5 )alkyl; and R 6 is (C 1 -C 4 )alkoxy or (C 1 -C 4 )alkylamino with the proviso that when m is 0, p is 0; when A is 0, Y is C=O; when T is CONH-(C 1 -C 4 ) alkyl, S is NH, N(CH 3 ) or CH 2 ; and when T is (C 2 -C 5 ) alkylamino, O-(C 1 -C 2 )alkyl hydroxylamino, morpholino or 4-(C 1 -C 2 )alkylpiperazino, S is CH 2 or a chemical bond linking R and T, characterized by the formation of an amide bond, C(O)N, by dehydrative-coupling wherein the functional groups not involved in the reaction may be blocked, followed by the optional steps of 1) selectively removing the blocking groups 2) oxidizing a sulfide group to sulfoxide or sulfone 3) oxidizing W wherein it is CH|||||OH or CH OH to C = 0 4) acylating W wherein it is CH|||||OH and, if desired, making a pharmaceutically acceptable salt of the product.

Claim 31

The process of claim 1, formula I, wherein the amide bond is formed between the fragments.

Claim 32

The process of claim 1, formula 1, wherein the amide bond is formed between the fragments

Claim 33

The process of claim 1, formula II, wherein the amide bond is formed between the fragments

Claim 34

The process of claim 1, wherein the coupling reagent is 1-hydroxybenzotriazole and dicyclohexylcarbodiimide.

Claim 35

The process of claim 1, wherein the coupling reagent is 1-hydroxybenzotriazole and dimethylaminopropyl ethyl carbodiimide.

Claim 36

The process of claim 1, wherein the optional step of oxidation of a sulfide group is carrried out with m-chloroperbenzoic acid.

Claim 37

The process of claim 1, wherein the optional step of oxidation of CH||||||OH or CH OHis carried out with pyridum dichromate and acetic anhydride.

Claim 38

The process of claim 1, wherein the optional step of acylation CH||||||OH is carried out with an acid and the coupling reagents of claim 5 or 6, or an acid halide and an organic tertiary amine.