Selective heterocyclic sphingosine 1 phosphate receptor modulators
Compounds that selectively modulate the sphingosine 1 phosphate receptor are provided including compounds which modulate subtype 1 of the S1P receptor. Methods of chiral synthesis of such compounds is provided. Uses, methods of treatment or prevention and methods of preparing inventive compositions including inventive compounds are provided in connection with the treatment or prevention of diseases, malconditions, and disorders for which modulation of the sphingosine 1 phosphate receptor is medically indicated.
1. A compound of Formula (I) or a pharmaceutically acceptable salt, ester, prodrug, homolog, tautomer, stereoisomer, or hydrate, or solvate thereof:
wherein
a dashed line signifies that a single bond or a double bond can be present, provided that there are two double bonds and three single bonds in the ring comprising A 1 , A 2 , and A 3 ;
A 1 , A 2 , and A 3 each independently is CH or S or N; provided that one of A 1 , A 2 , and A 3 is S;
R 1 is di-substituted phenyl or di-substituted pyridinyl where the phenyl and pyridinyl substituents are each independently selected from the group consisting of halo, nitro, cyano, perfluromethyl, fluorinated methyl, and C 1-4 -alkoxy; provided that if R 1 is di-substituted phenyl, such phenyl is para-substituted with C 1-4 -alkoxy;
R 2 is
wherein a wavy line indicates a point of attachment;
X is —NR′R″ or —OR′″;
R′ is H, C 1-4 alkyl, n-hydroxy C 1-4 alkyl, —SO 2 —R 3 , or —CO—R 3 ;
R″ is H, —SO 2 —R 5 , C 1-4 alkyl optionally substituted with 1 or more R 4 , or a ring moiety optionally substituted with R 6 wherein such ring moiety is piperidinyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazolyl, or phenyl;
R′″ is H, C 1-4 alkyl, or —CO—R 3
or R′ and R″ taken together with the nitrogen atom to which they are bound form a 4, 5, or 6 membered saturated heterocyclic ring containing 0 or 1 additional heteroatoms where such additional heteroatom is O or N wherein such heterocycle is optionally singly or multiply substituted with substituents independently selected from the group consisting of —OH, oxo, —NH 2 , n-hydroxy-C 1-4 alkyl, —COOH, —(CH 2 ) m —COOH, —(CH 2 ) m —COOR 3 , —N(R 3 R 3 ), and —(CH 2 ) m —CO—N(R 7 R 7 );
each R 3 is independently C 1-4 alkyl or H;
each R 4 is independently H, halo, OH, oxo, ═NH, NH 2 , —COOH, F, —NHR 3 , —N(R 7 R 7 ), —SO 2 —R 3 , —SO 2 —N(R 7 R 7 ), —N(R 3 )—SO 2 —R 3 , —COOR 3 , —OCO—R 3 , —CO—N(R 7 R 7 ), —N(R 3 )—COR 3 , C 1-3 alkyl, C 1-3 alkoxy, and a ring moiety optionally substituted with R 6 wherein such ring moiety is piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, benzimidazolyl, azetidinyl, cyclobutinyl, or phenyl;
each R 5 is independently R 4 , C 1-4 alkyl, C 3-6 cycloalkyl, or C 1-4 alkyl optionally substituted with 1 or more R 4 ;
each R 6 is independently halo, OH, —NH 2 , —NHR 3 , —N(R 3 R 3 ), —COOH, —COOR 3 , —NHCO—R 3 , each R 7 is independently C 1-4 alkyl or H, or two R 7 taken together with the nitrogen atom to which they are bound form a 4, 5, or 6 membered saturated heterocyclic ring containing 0 or 1 additional heteroatoms where such additional heteroatom is O or N wherein such heterocycle is optionally substituted with —OH, —NH 2 , —N(R 3 R 3 ), n-hydroxy C 1-4 alkyl, —(CH 2 ) m —COOH, or —(CH 2 ) m —COOR 3 ;
each m is independently 0, 1, 2, or 3.
2. The compound of claim 1 wherein the structure of Formula I is selected from the group consisting of formulas a-i through a-x:
3. The compound of claim 1 wherein A 1 is S.
4. The compound of claim 1 wherein A 2 is S.
5. The compound of claim 1 wherein A 3 is S.
6. The compound of claim 5 wherein A 1 is N and A 2 is CH or N.
7. The compound of claim 6 wherein A 2 is CH.
8. The compound of claim 6 wherein A 2 is N.
9. The compound of claim 1 wherein R 1 is
R 3 is C 2-4 alkyl; and Y is —CN, —Cl, —O—R 3 , or —CF 3 .
10. The compound of claim 9 wherein R 3 is isopropyl or ethyl.
11. The compound of claim 9 wherein Y is —CN or —O—C 2 H 5 .
12. The compound of claim 1 wherein R 2 is
13. The compound of claim 1 wherein R 2 is
14. The compound of claim 12 wherein R 2 is
15. The compound of claim 13 wherein R 2 is
16. The compound of claim 14 wherein R 2 is
17. The compound of claim 14 wherein R 2 is
18. The compound of claim 15 wherein R 2 is
19. The compound of claim 15 wherein R 2 is
20. The compound of claim 14 wherein the compound is substantially enantiomerically pure.
21. The compound of claim 1 wherein the compound has an EC 50 as an S1P receptor subtype 1 agonist which is at least ten times smaller than its EC 50 as an agonist of a mutant S1P receptor subtype 1 having a single mutation with respect to wild type S1P receptor subtype 1 such that the 101 st amino acid residue is changed from asparagine to alanine.
22. The compound of claim 21 wherein the compound has an EC 50 as an S1P receptor subtype 1 agonist which is at least twenty times smaller than its EC 50 as an agonist of a mutant form of S1P receptor subtype 1 having a single mutation with respect to wild type S 1P receptor subtype 1 such that the 101 st amino acid residue is changed from asparagine to alanine.
23. The compound of claim 1 wherein the compound has a therapeutic index of at least 5 as measured in rats following 5 or 14 days of dosing with the compound where the therapeutic index is the ratio of the dose achieving less than or equal to 10% increase in lung to terminal body weight at the conclusion of such 5 or 14 days and the dose achieving 50% lymphopenia.
24. The compound of claim 23 wherein the therapeutic index is at least 10.
25. The compound of claim 23 wherein the therapeutic index is at least 20.
26. The compound of claim 23 wherein the therapeutic index for the compound is greater than the therapeutic index for the enantiomer of the compound.
27. The compound of claim 26 wherein the therapeutic index for the compound is at least 150% of the therapeutic index for the enantiomer of the compound.
28. The compound of claim 9 wherein Y is Cl.
29. The compound of claim 9 wherein Y is CF 3 .
30. The compound of claim 9 wherein Y is CN.
31. The compound of claim 1 wherein X is —NR′R″.
32. The compound of claim 1 wherein X is —OR′″.
33. The compound of claim 32 wherein X is —OH.
34. The compound of claim 32 wherein X is —OCO—R 3 .
35. The compound of claim 34 wherein R 3 is C 1-3 alkyl.
36. The compound of claim 31 wherein R′ is H.
37. The compound of claim 31 wherein R′ is —COR 3 .
38. The compound of claim 31 wherein R′ is —SO 2 —R 3 .
39. The compound of claim 31 wherein R″ is H.
40. The compound of claim 31 wherein R″ is —SO 2 —R 5 .
41. The compound of claim 31 wherein R″ is C 1-4 alkyl optionally substituted with 1 or more R 4 .
42. The compound of claim 31 wherein R″ is —(CR a R b ) n —R 4 ; each R a and each R b is independently selected from the group consisting of H, hydroxyl and methyl or R a and R b bound to the same carbon taken together are oxo; and n is 0, 1, 2, or 3.
43. The compound of claim 42 wherein n is 2.
44. The compound of claim 43 wherein R 4 is —OH, —NH 2 , —NHR 3 , —N(R 7 R 7 ), or —COOH.
45. The compound of claim 40 wherein R 5 is C 1-4 alkyl optionally substituted with 1 or more R 4 .
46. The compound of claim 9 wherein Y is CN.
47. The compound of claim 45 wherein R 5 is —C 2 H 5 —N(R 7 R 7 ) or —CH 2 —CO—N(R 7 R 7 ).
48. The compound of claim 46 wherein R 5 is C 2 H 5 —O—R 3 .
49. The compound of claim 31 wherein X is —NH—CO—N(R 7 R 7 ).
50. The compound of claim 1 wherein the compound is selected from:
or any pharmaceutically acceptable salt, ester, prodrug, homolog, tautomer, stereoisomer, or hydrate, or solvate thereof.
51. The compound of claim 50 wherein the compound is selected from compounds:
or any pharmaceutically acceptable salt, ester, prodrug, homolog, tautomer, stereoisomer, or hydrate, or solvate thereof.
52. A pharmaceutical composition comprising the compound as in any one of claims 1 - 51 and suitable excipient.
53. A pharmaceutical composition comprising the compound as in any one of claims 1 - 51 and a second medicament.
54. The composition of claim 53 wherein the second medicament is medically indicated for the treatment of multiple sclerosis, transplant rejection, or acute respiratory distress syndrome.
55. A method of activation or agonism of a sphingosine-1-phosphate receptor subtype 1 comprising contacting the receptor subtype 1 with an effective amount of the compound as any in one of claims 1 - 51 or the composition of claims 52 or 53 .
56. The method of claim 55 wherein the compound activates or agonizes the sphingosine-1-phosphate receptor subtype 1 to a greater extent than the compound activates or agonizes a sphingosine-1-phosphate receptor subtype 3.
57. The method of claim 56 wherein the sphingosine-1-phosphate receptor subtype 1 is disposed within a living mammal.
58. A method of treatment of a malcondition in a patient for which activation or agonism of an sphingosine-1-phosphate receptor subtype 1 is medically indicated, comprising administering an effective amount of the compound as in any one of claims 1 - 51 to the patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient wherein the malcondition is selected from multiple sclerosis, transplant rejection, acute respiratory distress syndrome, ulcerative colitis, influenza, Crohn's disease and adult respiratory distress syndrome.
59. The compound of claim 15 wherein the compound is substantially enantiomerically pure.