Therapeutic methods

1. A method for treating a disease or condition associated with dopamine deficiency in a mammal in need of such treatment comprising administering a compound that binds to RXR to the mammal, provided the compound that binds to RXR is not bexarotene, wherein the compound that binds to RXR is a compound of formula XXX:

wherein:

the bond represented by --- is a single bond or a double bond;

ring B is optionally substituted with one or more (i.e., 1, 2, or 3) groups independently selected from halo, hydroxy, carboxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, —B(OH) 2 , and —SO 3 H, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, is optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O);

D is

and

ring A is a phenyl ring or a 6-membered heteroaryl ring other than pyridyl, which phenyl ring or 6-membered heteroaryl ring other than pyridyl is optionally substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, —B(OH) 2 , and —SO 3 H, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, is optionally substituted with one or more groups independently selected from halo, hydroxy, carboxy, nitro, cyano, oxo (═O), —B(OH) 2 , and —SO 3 H;

or a pharmaceutically acceptable salt thereof, wherein the disease or condition associated with dopamine deficiency is Parkinson's disease.

2. The method of claim 1 wherein the compound that binds to RXR is a compound of formula II:

wherein:

R 1 is H, halo, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, is optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O);

the bond represented by --- is a single bond or a double bond;

D is

and

at least one of one of R 2 , R 3 , and R 4 is —COOH, —B(OH) 2 , or —SO 3 H; and the remaining R 2 , R 3 , and R 4 are each independently selected from H, —COOH, —B(OH) 2 , —SO 3 H, halo, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, is optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O);

or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 wherein R 1 is H, halo, hydroxy, cyano, nitro, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, is optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O).

4. The method of claim 2 wherein R 1 is halo, hydroxy, cyano, nitro, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, is optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O).

5. The method of claim 2 wherein the bond represented by --- is a single bond.

6. The method of claim 2 wherein the bond represented by --- is a double bond.

7. The method of claim 2 wherein one of R 2 , R 3 , and R 4 is COOH.

8. The method of claim 2 wherein one of R 2 , R 3 , and R 4 is —SO 3 H.

9. The method of claim 2 wherein at least one of one of R 2 , R 3 , and R 4 is —COOH or —SO 3 H; and the remaining R 2 , R 3 , and R 4 are each independently selected from —COOH, —SO 3 H, halo, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, is optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O).

10. The method of claim 1 wherein the compound has the formula:

wherein R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, thiol, halogen, —CO 2 H, —CO 2 (C 1-6 alkyl), —SO 3 H, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 , or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 wherein the compound is a compound having the formula:

having the following substituents at each of positions R 1 , R 2 , R 3 , R 4 :

Compound #

R 1

R 2

R 3

R 4

2

CO 2 H

H

H

CO 2 H

3

H

NO 2

CO 2 H

H

4

H

CO 2 H

CO 2 H

H

5

H

CO 2 H

CO 2 H

CO 2 H

6

F

F

CO 2 H

H

7

H

F

CO 2 H

F.

12. A method for treating a disease or condition associated with dopamine deficiency in a mammal in need of such treatment comprising administering a compound that binds to RXR to the mammal, wherein the compound that binds to RXR is a compound selected from:

or a pharmaceutically acceptable salt thereof, wherein the disease or condition associated with dopamine deficiency is Parkinson's disease.

13. A method for treating a disease or condition associated with dopamine deficiency in a mammal in need of such treatment comprising administering a compound that binds to RXR to the mammal, provided the compound that binds to RXR is not bexarotene, wherein the compound that binds to RXR is a compound of formula IV:

wherein:

ring A is a phenyl ring or a 6-membered heteroaryl ring other than pyridyl, which phenyl ring or 6-membered heteroaryl ring other than pyridyl is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, is optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, and oxo (═O);

R 2 is —COOH, —B(OH) 2 , or —SO 3 H; and

D is

or a pharmaceutically acceptable salt thereof, wherein the disease or condition associated with dopamine deficiency is Parkinson's disease.

14. The method of claim 13 wherein ring A is a phenyl ring substituted with one or more groups independently selected from halo, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy, is optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, and oxo (═O).

15. The method of claim 13 wherein R 2 is —COOH.

16. A method for treating a disease or condition associated with dopamine deficiency in a mammal in need of such treatment comprising administering a compound that binds to RXR to the mammal, wherein the compound that binds to RXR is compound

or a pharmaceutically acceptable salt thereof, wherein the disease or condition associated with dopamine deficiency is Parkinson's disease.