Compositions and Methods for the Treatment of Multiple Sclerosis

1 . A method of treating a multiple sclerosis patient, the method comprising administering a therapeutically effective amount of a compound of the formula:

wherein,

R 1 is heteroalkyl, heterocycloalkyl, or heteroaryl;

R 2 , R 4 and R 6 are independently hydrogen, halogen, nitro, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, heterocycloalkyl or aryl;

R 3 , R 5 , and R 7 are independently hydrogen or C 1 -C 6 alkyl, or

R 3 and R 4 taken together with the carbon atoms to which they are attached form a phenyl ring, or

R 4 and R 5 taken together with the carbon atoms to which they are attached form a phenyl ring, or

R 5 and R 7 taken together with the carbon atoms to which they are attached form a phenyl ring; and

n 1 and n 2 are independently 0, 1 or 2;

or a pharmaceutically acceptable salt, a prodrug, or a mixture thereof.

2 . The method of claim 1 , wherein the amount is sufficient to prevent disability caused by disease progression.

3 . The method of claim 1 , wherein the amount is sufficient to reduce the frequency, severity, or duration of a relapse as compared to an untreated patient.

4 . The method of claim 1 , wherein the amount is sufficient to relieve one or more symptoms of multiple sclerosis.

5 . The method of claim 1 , wherein R 1 is —(CH 2 ) 2 N(CH 3 ) 2 .

6 . The method of claim 5 , wherein R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen, and R 2 is selected from —CH 3 , —CH 2 —CH 3 , —CH 2 —CH 2 —CH 3 , —F, —Cl, —I, —Br, —OH, —OCH 3 , —OCH 2 —CH 3 , —OCH 2 —CH 2 —CH 3 , —OCH 2 —CH 2 —N(CH 3 ) 2 , —OCH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NH 2 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NH—CH 2 —CH 2 —OH, —NHCOCH 3 , —NHCOC(CH 3 ) 3 , —NH—CH 2 —CH 2 —N(CH 3 ) 2 , —NH—CH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NO 2 , —CN, —SCH 3 , —SCH 2 CH 3 , —SCH 2 —CH 2 —CH 3 , and —SO 2 CH 3 .

7 . The method of claim 5 , wherein R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen, and R 4 is selected from —CH 3 , —CH 2 —CH 3 , —CH 2 —CH 2 —CH 3 , —F, —Cl, —I, —Br, —OH, —OCH 3 , —OCH 2 —CH 3 , —OCH 2 —CH 2 —CH 3 , —OCH 2 —CH 2 —N(CH 3 ) 2 , —OCH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NH 2 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NH—CH 2 —CH 2 —OH, —NHCOCH 3 , —NHCOC(CH 3 ) 3 , —NH—CH 2 —CH 2 —N(CH 3 ) 2 , —NH—CH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NO 2 , —CN, —SCH 3 , —SCH 2 CH 3 , —SCH 2 —CH 2 —CH 3 , and —SO 2 CH 3 .

8 . The method of claim 5 , wherein R 2 , R 3 , R 4 , R 5 , and R 7 are hydrogen, and R 6 is selected from —CH 3 , —CH 2 —CH 3 , —CH 2 —CH 2 —CH 3 , —F, —Cl, —I, —Br, —OH, —OCH 3 , —OCH 2 —CH 3 , —OCH 2 —CH 2 —CH 3 , —OCH 2 —CH 2 —N(CH 3 ) 2 , —OCH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NH 2 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NH—CH 2 —CH 2 —OH, —NHCOCH 3 , —NHCOC(CH 3 ) 3 , —NH—CH 2 —CH 2 —N(CH 3 ) 2 , —NH—CH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NO 2 , —CN, —SCH 3 , —SCH 2 CH 3 , —SCH 2 —CH 2 —CH 3 , and —SO 2 CH 3 .

9 . The method of claim 6 , wherein R 2 is attached to the dibenzisoquinoline ring structure at position 6 and is selected from —O(CH 2 ) 2 N(CH 3 ) 2 , —SCH 3 , —SCH 2 CH 3 , —N(CH 3 ) 2 , and —NH(CH 2 ) 2 N(CH 3 ) 2 , and wherein n 1 is 1.

10 . The method of claim 6 , wherein R 2 is attached to the dibenzisoquinoline ring structure at position 6 and is —OCH 2 CH 3 , and wherein n 1 is 1.

11 . The method of claim 1 , wherein R 1 is selected from —(CH 2 ) 2 N(CH 3 ) 2 , —(CH 2 ) 2 NHCH 3 , —(CH 2 ) 3 N(CH 3 ) 2 , —(CH 2 ) 2 NH(CH 2 ) 2 OH, —(CH 2 ) 3 N(CH 2 CH 2 OH) 2 , —(CH 2 ) 2 N(CH 2 ) 4 , —(CH 2 ) 2 N(CH 2 ) 5 , —(CH 2 ) 2 -(1-methyl-2-pyrrolidinyl), —CH 2 -(1-ethyl-2-pyrrolidinyl), -(1-ethyl-3-piperidinyl), —(CH 2 ) 2 —N-morpholinyl, —(CH 2 ) 2 —N-piperazinyl, —(CH 2 ) 2 -2-pyridyl, —CH 2 -2-pyridyl, —CH 2 -3-pyridyl, -(3-pyridyl), and -(p-N(CH 3 ) 2 )—C 6 H 5 ), and wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen.

12 . The method of claim 1 , wherein the compound, pharmaceutically acceptable salt, or prodrug comprises a component of a pharmaceutical composition suitable for administration to the patient.

13 . A method of treating a patient having a neurological lesion associated with multiple sclerosis, the method comprising administering a therapeutically effective amount of a compound of the formula:

wherein,

R 1 is heteroalkyl, heterocycloalkyl, or heteroaryl;

R 2 , R 4 and R 6 are independently hydrogen, halogen, nitro, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, heterocycloalkyl or aryl;

R 3 , R 5 , and R 7 are independently hydrogen or C 1 -C 6 alkyl, or

R 3 and R 4 taken together with the carbon atoms to which they are attached form a phenyl ring, or

R 4 and R 5 taken together with the carbon atoms to which they are attached form a phenyl ring, or

R 5 and R 7 taken together with the carbon atoms to which they are attached form a phenyl ring; and

n 1 and n 2 are independently 0, 1 or 2;

or a pharmaceutically acceptable salt, a prodrug, or a mixture thereof.

14 . The method of claim 13 , wherein the patient exhibits no neurologic impairment or disability as measured by a clinical rating scale.

15 . The method of claim 14 , wherein the amount is sufficient to prevent progression to clinically symptomatic multiple sclerosis as measured by the clinical rating scale.

16 . The method of claim 13 , wherein the patient exhibits no more than minimal neurologic impairment or disability as measured by a clinical rating scale.

17 . The method of claim 16 , wherein the amount is sufficient to prevent disease progression as measured by the clinical rating scale.

18 . The method of claim 13 , wherein R 1 is —(CH 2 ) 2 N(CH 3 ) 2 .

19 . The method of claim 18 , wherein R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen, and R 2 is selected from —CH 3 , —CH 2 —CH 3 , —CH 2 —CH 2 —CH 3 , —F, —Cl, —I, —Br, —OH, —OCH 3 , —OCH 2 —CH 3 , —OCH 2 —CH 2 —CH 3 , —OCH 2 —CH 2 —N(CH 3 ) 2 , —OCH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NH 2 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NH—CH 2 —CH 2 —OH, —NHCOCH 3 , —NHCOC(CH 3 ) 3 , —NH—CH 2 —CH 2 —N(CH 3 ) 2 , —NH—CH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NO 2 , —CN, —SCH 3 , —SCH 2 CH 3 , —SCH 2 —CH 2 —CH 3 , and —SO 2 CH 3 .

20 . The method of claim 18 , wherein R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen, and R 4 is selected from —CH 3 , —CH 2 —CH 3 , —CH 2 —CH 2 —CH 3 , —F, —Cl, —I, —Br, —OH, —OCH 3 , —OCH 2 —CH 3 , —OCH 2 —CH 2 —CH 3 , —OCH 2 —CH 2 —N(CH 3 ) 2 , —OCH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NH 2 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NH—CH 2 —CH 2 —OH, —NHCOCH 3 , —NHCOC(CH 3 ) 3 , —NH—CH 2 —CH 2 —N(CH 3 ) 2 , —NH—CH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NO 2 , —CN, —SCH 3 , —SCH 2 CH 3 , —SCH 2 —CH 2 —CH 3 , and —SO 2 CH 3 .

21 . The method of claim 18 , wherein R 2 , R 3 , R 4 , R 5 , and R 7 are hydrogen, and R 6 is selected from —CH 3 , —CH 2 —CH 3 , —CH 2 —CH 2 —CH 3 , —F, —Cl, —I, —Br, —OH, —OCH 3 , —OCH 2 —CH 3 , —OCH 2 —CH 2 —CH 3 , —OCH 2 —CH 2 —N(CH 3 ) 2 , —OCH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NH 2 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NH—CH 2 —CH 2 —OH, —NHCOCH 3 , —NHCOC(CH 3 ) 3 , —NH—CH 2 —CH 2 —N(CH 3 ) 2 , —NH—CH 2 —CH 2 —N(CH 2 CH 3 ) 2 , —NO 2 , —CN, —SCH 3 , —SCH 2 CH 3 , —SCH 2 —CH 2 —CH 3 , and —SO 2 CH 3 .

22 . The method of claim 19 , wherein R 2 is attached to the dibenzisoquinoline ring structure at position 6 and is selected from —O(CH 2 ) 2 N(CH 3 ) 2 , —SCH 3 , —SCH 2 CH 3 , —N(CH 3 ) 2 , and —NH(CH 2 ) 2 N(CH 3 ) 2 , and wherein n 1 is 1.

23 . The method of claim 19 , wherein R 2 is attached to the dibenzisoquinoline ring structure at position 6 and is —OCH 2 CH 3 , and wherein n1 is 1.

24 . The method of claim 13 , wherein R 1 is selected from —(CH 2 ) 2 N(CH 3 ) 2 , —(CH 2 ) 2 NHCH 3 , —(CH 2 ) 3 N(CH 3 ) 2 , —(CH 2 ) 2 NH(CH 2 ) 2 OH, —(CH 2 ) 3 N(CH 2 CH 2 OH) 2 , —(CH 2 ) 2 N(CH 2 ) 4 , —(CH 2 ) 2 N(CH 2 ) 5 , —(CH 2 ) 2 -(1-methyl-2-pyrrolidinyl), —CH 2 -(1-ethyl-2-pyrrolidinyl), -(1-ethyl-3-piperidinyl), —(CH 2 ) 2 —N-morpholinyl, —(CH 2 ) 2 —N-piperazinyl, —(CH 2 ) 2 -2-pyridyl, —CH 2 ) 2 -pyridyl, —CH 2 -3-pyridyl, -(3-pyridyl), and -(p-N(CH 3 ) 2 )—C 6 H 5 ), and wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen.

25 . The method of claim 13 , wherein the compound, pharmaceutically acceptable salt, or prodrug comprises a component of a pharmaceutical composition suitable for administration to the patient.