7,8-bicycloakyl-chroman derivatives

1. A method of treating a subject suffering from neurodegenerative or neuroinflammatory disorders, comprising administering to said subject a therapeutically effective amount of a compound represented by Formula I:

wherein:

-A-B— is —CH 2 —(CH 2 ) 0-2 —; —CH—CH—; —CH 2 —O—; —CH 2 —S—; or CH 2 —N—;

n is 0 to 5;

V is C 7-12 -bicyclo[a.b.c]alkyl; C 7-12 -bicyclo[a.b.c]alkenyl; C 7-12 -heterobicyclo[a.b.c]alkyl; or C 7-12 -heterobicyclo[a.b.c]alkenyl; and a, b, and c are 0 to 6; and wherein the bicyclo ring is optionally substituted with one or more substituents selected from C 1-6 -alkyl, halogen, haloalkyl, carboxy, alkoxycarbonyl, cyano, hydroxy, alkoxy, thiol, and oxo;

R 1 is C 1-6 alkyl;

R 2 is C 1-20 alkyl; optionally substituted C 2-20 alkenyl; halogen; hydroxy; alkoxy; acyl; —C(O)OR; —S(O) 2 OR; —NR′R″; —NH—C(═NH 2 )—NR′R″; N—SO 2 R; —NHC(O)NR′R″; —N(OH)C(O)NR′R″; —SO 2 NR′R″; —C(O)NR′R″; —S(O) 0-3 R′″; —PO(OR) 2 ; triphenylphosphonium; trialkylphosphonium; optionally substituted aryl; or optionally substituted heterocyclyl;

R 3 is hydrogen; optionally substituted C 1-20 alkyl; C 2-20 alkenyl; hydroxyalkyl; acyl; glucoside; phosphoryl; phosphoryloxyalkyl; carboxyalkylcarbonyl; aminoalkylcarbonyl; or alkylketocarbonyl;

R 4 is hydrogen; halogen; nitro, cyano; optionally substituted C 1-6 alkyl; aryl, arakyl, heterocyclyl or heterocyclylalkyl all optionally substituted with alkyl, hydroxy, alkoxy, nitro, acyl, amino, oxo or —C(O)OR; optionally substituted alkenyl; hydroxy, alkoxy, nitro; —C(O)OR; —C(O)NR′R″; —NR′R″; —NHC(O)NR′R″; —NR′—SO 2 —R; —NH—C(═NH 2 )—NR′R″; —SO 2 NR′R″; or —P(O)(OR) 2 ; or

R 3 and R 4 taken together with the atoms to which they are attached form a heterocyclic ring;

R is hydrogen; optionally substituted alkyl; optionally substituted aryl; optionally substituted arylalkyl; optionally substituted cycloalkyl; or optionally substituted heterocyclyl;

R′ and R″ are independently of each other hydrogen; C 1-6 alkyl; hydroxyalkyl; aminoalkyl; optionally substituted aryl; or optionally substituted benzyl; or R′ and R″ taken together with the atom to which they are attached form a 5 to 8 membered aromatic, saturated or unsaturated ring, optionally incorporating one additional atom chosen from N, O, or S and optionally substituted with a substituent selected from the group consisting of C 1-6 alkyl, halo, cyano, alkylthio, lower alkoxy, phenyl, benzyl and carboxy; and

R′″ is optionally substituted C 1-6 alkyl; optionally substituted aryl; or optionally substituted heterocyclyl;

or stereoisomers, mixture of stereoisomers or pharmaceutically acceptable salts thereof.

2. A method of treating a subject suffering from neurodegenerative or neuroinflammatory disorders, comprising administering to said subject a therapeutically effective amount of one or more compounds selected from the group represented by the structures:

wherein R is hydrogen or C 1-4 alkyl;

or stereoisomers, mixture of stereoisomers or pharmaceutically acceptable salts thereof.

3. The method of claim 1 , wherein the subject is suffering from a neurodegenerative disorder selected from stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunctions, peripheral neuropathy/neuropathic pain, spinal cord injury, head injury and surgical trauma.

4. A method of inhibiting a lipoxygenase enzyme in a subject in need of such inhibition which comprises administering to said subject a therapeutically effective amount of a compound represented by Formula I:

wherein:

-A-B— is —CH 2 —(CH 2 ) 0-2 —; —CH═CH—; —CH 2 —O—; —CH 2 —S—; or —CH 2 —N—;

n is 0 to 5;

V is C 7-12 -bicyclo[a.b.c]alkyl; C 7-12 -bicyclo[a.b.c]alkenyl; C 7-12 -heterobicyclo[a.b.c]alkyl; or C 7-12 -heterobicyclo[a.b.c]alkenyl; and a, b, and c are 0 to 6; and wherein the bicyclo ring is optionally substituted with one or more substituents selected from C 1-6 -alkyl, halogen, haloalkyl, carboxy alkoxycarbonyl, cyano, hydroxy, alkoxy, thiol, and oxo;

R 1 is C 1-6 alkyl;

R 2 is C 1-20 alkyl; optionally substituted C 2-20 alkenyl; halogen; hydroxy; alkoxy; acyl; —C(O)OR; —S(O) 2 OR; —NR′R″; —NH—C(═NH 2 )—NR′R″; —N—SO 2 R; —NHC(O)NR′R″; —N(OH)C(O)NR′R″; —SO 2 NR′R″; —C(O)NR′R″; —S(O) 0-2 R′″; —PO(OR) 2 ; triphenylphosphonium; trialkylphosphonium; optionally substituted aryl; or optionally substituted heterocyclyl;

R 3 is hydrogen; optionally substituted C 1-20 alkyl; C 2-20 alkenyl; hydroxyalkyl; acyl; glucoside; phosphoryl; phosphoryloxyalkyl; carboxyalkylcarbonyl; aminoalkylcarbonyl; or alkylketocarbonyl;

R 4 is hydrogen; halogen; nitro; cyano; optionally substituted C 1-6 alkyl; aryl, arakyl, heterocyclyl or heterocyclylalkyl all optionally substituted with alkyl, hydroxy, alkoxy, nitro, acyl, amino, oxo or —C(O)OR; optionally substituted alkenyl; hydroxy; alkoxy; nitro; —C(O)OR; —C(O)NR′R″; —NR′R″; —NHC(O)NR′R″; —NR′—SO 2 —R; —NH—C(═NH 2 )—NR′R″; —SO 2 NR′R″; or —P(O)(OR) 2 ; or

R 3 and R 4 taken together with the atoms to which they are attached form a heterocyclic ring;

R is hydrogen; optionally substituted alkyl; optionally substituted aryl; optionally substituted arylalkyl; optionally substituted cycloalkyl; or optionally substituted heterocyclyl;

R′ and R″ are independently of each other hydrogen; C 1-6 alkyl; hydroxyalkyl; aminoalkyl; optionally substituted aryl; or optionally substituted benzyl; or R′ and R″ taken together with the atom to which they are attached form a 5 to 8 membered aromatic, saturated or unsaturated ring, optionally incorporating one additional atom chosen from N, O, or S and optionally substituted with a substituent selected from the group consisting of C 1-6 alkyl, halo, cyano, alkylthio, lower alkoxy, phenyl, benzyl and carboxy; and

R′″ is optionally substituted C 1-6 alkyl; optionally substituted aryl; or optionally substituted heterocyclyl;

or stereoisomers, mixture of stereoisomers or pharmaceutically acceptable salts thereof.

5. The method of claim 4 , wherein the subject is a mammal suffering from asthma or chronic obstructive disease (COPD), arthritis, rheumatoid arthritis, osteoarthritis, allergic rhinitis, psoriasis, atherosclerosis, or diabetes.

6. The method of claim 1 , wherein the compound is selected from:

3-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H -benzo[h]chromen-2-yl)-propionic acid methyl ester;

3-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H -benzo[h]chroman-2-yl)-propionic acid;

2,2,-Dimethyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-6-ol;

3-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-propano-2H-benzo[h]chromen -2-yl)-propionic acid methyl ester;

2-Methyl-2-[3-(thiazol-2-ylsulfanyl)-propyl]-3,4,7,8,9,10-hexahydro-7,10-methano -2H-benzo[h]chromen-6-ol;

[3-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H -benzo[h]chromen-2-yl)-propyl]-phosphonic acid dimethyl ester;

[3-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H -benzo[h]chromen-2-yl)-propyl]-phosphonic acid;

3-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H -benzo[h]chromen-2-yl)-propionic acid methyl ester;

4-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexehydro-7,10-methano-2H -benzo[h]chromen-2-yl)-butane-1-sulfonic acid dimethylamide;

2-(3-Hydroxy-propyl)-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H -benzo[h]chromen-6-ol;

2-(3-Chloro-propyl)-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H -benzo[h]chromen-6-ol

2,2-Dimethyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-6-ol;

-(2-Chloro-ethyl)-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H -benzo[h]chromen-6-ol;

2-Methyl-2-thiazol-2-yl-3,4,7,8,9,10-hexahydro-7,10-methano-2H -benzo[h]chromen-6-ol;

2,2-Dimethyl-3,4,7,8,9,10-hexahydro-7,10-ethano-2H-benzo[h]chromen-6-ol;

3-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-ethano-2H-benzo[h]chromen -2-yl)-propionic acid;

2-(3-Chloro-propyl)-2-methyl-3,4,7,8,9,10-hexahydro-7,10-ethano-2H -benzo[h]chromen-6-ol;

4-(6-Hydroxy-2,2-dimethyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H -benzo[h]chromen-5-ylmethylene)-2-methyl-5-propyl-2,4-dihydro-pyrazol-3-one;

and single stereoisomers and mixtures of stereoisomers, or the pharmaceutically acceptable salts thereof.

7. The method of claim 1 , wherein the compound is selected from the group represented by the following structures:

or single stereoisomers and mixtures of stereoisomers, or the pharmaceutically acceptable salts thereof.