Compounds and methods for treatment of systemic lupus erythematosus
View Patent ↗Small molecule compounds are provided for treating lupus as are methods of treating lupus using these compounds.
1. A method of treating systemic lupus erythematosus (SLE) in a patient comprising administering to the patient a compound in an amount and manner effective to reduce one or more sign or symptom of SLE selected from the group consisting of serum levels of anti-double stranded DNA antibodies, serum levels of anti-double stranded DNA antibodies that cross react with N methyl D aspartate receptor, lupus nephrotoxicity, lupus neurotoxicity, neuropsychiatric lupus and lupus cognitive impairment, wherein the compound has the structure:
wherein:
m=1-6;
R 1 is quinoline or isoquinoline, partially or fully hydrated, and optionally substituted with R′, OR′, SR′, (CH 2 ) n′ NHR′ or (CH 2 ) n′ N(R′) 2 , wherein n′=0-6, and R′ is independently H, or branched or unbranched C 1-6 alkyl or heteroalkyl;
R 2 is (i) keto or thioketo; or (ii) R″, OR″, SR″, NHR″ or N(R″) 2 , wherein R″ is independently H, or branched or unbranched C 1-6 alkyl or heteroalkyl;
R 3 and R 4 are, independently, H or (CH 2 ) n R where R is aryl and n=1-6;
R 5 is (CH 2 ) n′″ N(R 3 ) 2 or (CH 2 ) n′″ COX wherein X is R′″, OR′″, SR′″, NHR′″ or N(R′″) 2 , wherein n′″=0-6, and R′″ is independently H, or branched or unbranched C 1-6 alkyl or heteroalkyl; and
R 6 is quinoline or isoquinoline, partially or fully hydrated, and optionally substituted with R IV , OR IV , SR IV , (CH 2 ) nIV NHR IV or (CH 2 ) nIV N(R IV ) 2 , wherein n IV =0-6, and R IV is independently H, or branched or unbranched C 1-6 alkyl or heteroalkyl;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein R 1 has the structure
where ( ) represents the point of attachment to the molecular scaffold.
3. The method of claim 1 , wherein R 2 is OH.
4. The method of claim 1 , wherein R 3 is benzyl.
5. The method of claim 1 , wherein R 4 is H.
6. The method of claim 1 , wherein R 5 is (CH 2 ) 2 NH 2 .
7. The method of claim 1 , wherein m=1.
8. The method of claim 1 , wherein R 6 has the structure
where ( ) represents the point of attachment to the molecular scaffold.
9. The method of claim 1 , wherein the compound has the structure
or a pharmaceutically acceptable salt thereof.
10. A method of treating systemic lupus erythematosus (SLE) in a patient comprising detecting anti-double stranded DNA antibodies in serum from the patient and administering to the patient in whom anti-double stranded DNA antibodies are detected a compound in an amount and manner effective to treat SLE, wherein the compound has the structure:
wherein:
m=1-6;
R 1 is quinoline or isoquinoline, partially or fully hydrated, and optionally substituted with R′, OR′, SR′, (CH 2 ) n′ NHR′ or (CH 2 ) n′ N(R′) 2 , wherein n′=0-6, and R′ is independently H, or branched or unbranched C 1-6 alkyl or heteroalkyl;
R 2 is (i) keto or thioketo; or (ii) R″, OR″, SR″, NHR″ or N(R″) 2 , wherein R″ is independently H, or branched or unbranched C 1-6 alkyl or heteroalkyl;
R 3 and R 4 are, independently, H or (CH 2 ) n R where R is aryl and n=1-6;
R 5 is (CH 2 ) n′″ N(R 3 ) 2 or (CH 2 ) n′″ COX wherein X is R′″, OR′″, SR′″NHR′″ or N(R′″) 2 , wherein n′″=0-6, and R′″ is independently H, or branched or unbranched C 1-6 alkyl or heteroalkyl; and
R 6 is quinoline or isoquinoline, partially or fully hydrated, and optionally substituted with R IV , OR IV , SR IV , (CH 2 ) nIV NHR IV or (CH 2 ) nIV N(R IV ) 2 , wherein n IV =0-6, and R IV is independently H, or branched or unbranched C 1-6 alkyl or heteroalkyl;
or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 , wherein R 1 has the structure
where ( ) represents the point of attachment to the molecular scaffold.
12. The method of claim 10 , wherein R 2 is OH.
13. The method of claim 10 , wherein R 3 is benzyl.
14. The method of claim 10 , wherein R 4 is H.
15. The method of claim 10 , wherein R 5 is (CH 2 ) 2 NH 2 .
16. The method of claim 10 , wherein m=1.
17. The method of claim 10 , wherein R 6 has the structure
where ( ) represents the point of attachment to the molecular scaffold.
18. The method of claim 10 , wherein the compound has the structure
or a pharmaceutically acceptable salt thereof.
19. The method of claim 10 , wherein the anti-double stranded DNA antibodies cross react with N methyl D aspartate receptor.