Piperazine benzothiazoles as agents for the treatment of cerebral ischemic disorders or CNS disorders

1. A piperazine benzothiazole compound having formula I

as well as its tautomers, its geometrical isomers, its optically active forms as an enantiomer, a diastereomer and as a racemate, as well as pharmaceutically acceptable salts thereof, wherein

R is selected from the group comprising or consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl aryl, heteroaryl, C 1 -C 6 -alkyl heteroaryl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkenyl aryl, C 2 -C 6 -alkenyl heteroaryl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkynyl aryl, C 2 -C 6 -alkynyl heteroaryl, C 3 -C 8 -cycloalkyl, heterocycloalkyl, C 1 -C 6 -alkyl cycloalkyl, C 1 -C 6 -alkyl heterocycloalkyl, C 1 -C 6 -alkyl carboxy, acyl, C 1 -C 6 -alkyl acyl, acyloxy, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl alkoxy, alkoxycarbonyl, C 1 -C 6 -alkyl alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkyl aminocarbonyl, acylamino, C 1 -C 6 -alkyl acylamino, ureido, C 1 -C 6 -alkyl ureido, amino, C 1 -C 6 -alkyl amino, sulfonyloxy, C 1 -C 6 -alkyl sulfonyloxy, sulfonyl, C 1 -C 6 -alkyl sulfonyl, sulfinyl, C 1 -C 6 -alkyl sulfinyl, sulfanyl, C 1 -C 6 -alkyl sulfanyl, sulfonylamino, and C 1 -C 6 -alkyl sulfonylamino;

R 1 is selected from the group comprising or consisting of H, halogen, cyano, nitro, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl-aryl, aryl or heteroaryl, C 1 -C 6 -alkyl-heteroaryl, -C(O)-OR 2 , -C(O)-R 2 , -C(O)-NR 2 R 2′ , and -(SO 2 )R 2 , with

R 2 and R 2′ being independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, C 1 -C 6 -alkyl aryl, C 1 C 6 -alkyl heteroaryl and combinations mixtures thereof; and

n is an integer from 0 to 3.

2. The piperazine benzothiazole compound according to claim 1 , wherein R 1 is hydrogen.

3. The piperazine benzothiazole compound according to claim 1 , wherein R is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, aminocarbonyl, C 1 -C 6 -alkyl alkoxycarbonyl, C 1 -C 6 -alkyl alkoxy, C 1 -C 6 -alkyl acyloxy, alkoxycarbonyl, and C 1 -C 6 -alkyl aminocarbonyl.

4. The piperazine benzothiazole compound according to claim 3 , wherein R is H, or C 1 -C 3 alkyl, in particular a methyl or an ethyl moiety, or C 1 -C 6 -alkyl alkoxy.

5. The piperazine benzothiazole compound according to claim 1 , wherein n is 1.

6. The piperazine benzothiazole compound according to claim 1 selected from the group consisting of:

1,3-benzothiazol-2-yl[2-({4-[(4-methylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl]acetonitrile,

1,3-benzothiazol-2-yl[2-({4-[(4-benzyl-piperazin-1-yl)methyl]-benzyl}oxy)pyrimidin-4-yl]acetonitrile,

1,3-benzothiazol-2-yl(2-{[4-(piperazin-1-ylmethyl)benzyl]oxy}pyrimidin-4-yl)acetonitrile,

1,3-benzothiazol-2-yl[2-({4-[(4-formylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl]acetonitrile,

[2-({4-[(4-acetylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl](1,3-benzothiazol-2-yl)acetonitrile,

(3H-Benzothiazol-2-ylidene)-{2-[4-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-ylmethyl)-benzyloxy]-pyrimidin-4-yl}-acetonitrile,

4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazine-1-carboxylic acid methyl ester,

2-[4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazin-1-yl]-acetamide,

(2-{4-[4-(2-Amino-acetyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4-yl)-(3H-benzothiazol-2-ylidene)-acetonitrile,

[4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazin-1-yl]-acetic acid methyl ester,

(3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4-yl)-acetonitrile,

4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazine-1-carboxylic acid dimethylamide,

(3H-Benzothiazol-2-ylidene)-{2-[4-(4-ethyl-piperazin-1-ylmethyl)-benzyloxy]-pyrimidin-4-yl}-acetonitrile, and

(3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4-yl)-acetonitrile.

7. A pharmaceutical composition, comprising:

a therapeutically effective amount of the piperazine benzothiazole compound according to claim 1 with a pharmaceutically acceptable carrier.

8. A method of treating ischemia, comprising:

administering a therapeutically effective amount of the pharmaceutical composition according to claim 7 to a subject in need of treatment for ischemia.

9. A process for the preparation of a piperazine benzothiazole compound claimed in claim 1 , comprising:

reacting a pyrimidinylbenzothiazole compound of formula (IV)

with a piperazinyl alcohol compound of formula (V)

wherein R, R 1 and n are as defined in claim 1 , thereby preparing the piperazine benzothiazole compound of claim 1 .