SPHINGOSINE 1 PHOSPHATE RECEPTOR MODULATORS AND METHODS OF CHIRAL SYNTHESIS
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 are 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 having the structure of Formula I-R or I-S or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof:
wherein
X is —NR′R″ or —OR″′;
Y is —CN, —Cl, or —CF 3 ;
R′ is H, C 1-4 alkyl, n-hydroxy C 1-4 alkyl, —SO 2 —R 1 , or —CO—R 1 ;
R″ is H, —SO 2 —R 3 , C 1-4 alkyl optionally substituted with 1 or more R 2 , or a ring moiety optionally substituted with R 4 wherein such ring moiety is piperidinyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazolyl, or phenyl;
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 1 , —N(R 1 R 1 ), and —(CH 2 ) m —CO—N(R 5 R 5 );
R″′ is H, C 1-4 alkyl, or —CO—R 1 ;
each R 1 is independently C 1-4 alkyl or H;
each R 2 is independently H, halo, OH, oxo, ═NH, NH 2 , —COOH, F, —NHR 1 , —N(R 5 R 5 ),—SO 2 —R 1 , —SO 2 —N(R 5 R 5 ), —N(R 1 )—SO 2 —R 1 , —COOR 1 , —OCO—R 1 , —CO—N(R 5 R 5 ), —N(R 1 )—COR 1 , C 1-3 alkyl, C 1-3 alkoxy, and a ring moiety optionally substituted with R 4 wherein such ring moiety is piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, benzimidazolyl, azetidinyl, cyclobutinyl, or phenyl;
each R 3 is independently R 2 , C 1-4 alkyl, C 3-6 cycloalkyl, or C 1-4 alkyl optionally substituted with 1 or more R 2 ;
each R 4 is independently halo, OH, —NH 2 , —NHR 1 , —N(R 1 R 1 ), —COOH, —COOR 1 , —NHCO—R 1 ; each R 5 is independently C 1-4 alkyl or H, or two R 5 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 1 R 1 ), n-hydroxy C 1-4 alkyl, —(CH 2 ) m —COOH, —(CH 2 ) m —COOR 1 ; and
each m is independently 0, 1, 2, or 3.
2 . The compound of claim 1 wherein the compound has the structure of Formula I-R or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.
3 . The compound of claim 1 wherein the compound has the structure of Formula I-S or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.
4 . The compound of claim 1 wherein the compound is substantially enantiomerically pure.
5 - 9 . (canceled)
10 . The compound of claim 1 wherein Y is Cl.
11 . The compound of claim 1 wherein Y is CF 3 .
12 . The compound of claim 1 wherein Y is CN.
13 . The compound of claim 1 wherein X is —NR′R″.
14 . The compound of claim 1 wherein X is —OR″′.
15 . The compound of claim 14 wherein X is —OH.
16 . The compound of claim 14 wherein X is —OCO—R 1 .
17 . The compound of claim 16 wherein R 1 is C 1-3 alkyl.
18 . The compound of claim 13 wherein R′ is H.
19 . The compound of claim 13 wherein R′ is —COR 1 .
20 . The compound of claim 13 wherein R′ is —SO 2 —R′.
21 . The compound of claim 13 wherein R″ is H.
22 . The compound of claim 13 wherein R″ is —SO 2 —R 3 .
23 . The compound of claim 13 wherein R″ is C 1-4 alkyl optionally substituted with 1 or more R 2 .
24 . The compound of claim 13 wherein R″ is —(CR a R b ) n —R 2 ; 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.
25 . The compound of claim 24 wherein n is 2.
26 . The compound of claim 25 wherein R 2 is —OH, —NH 2 , —NHR 1 , —N(R 5 R 5 ), or —COOH.
27 . The compound of claim 22 wherein R 3 is C 1-4 alkyl optionally substituted with 1 or more R 2 .
28 . The compound of claim 22 wherein Y is CN.
29 . The compound of claim 27 wherein R 3 is —C 2 H 5 —N((R 5 R 5 ) or —CH 2 —CO—N(R 5 R 5 ).
30 . The compound of claim 28 wherein R 3 is C 2 H 5 —O—R 1 .
31 . The compound of claim 12 wherein X is —NH—CO—N(R 5 R 5 ).
32 . The compound of claim 1 wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.
33 . The compound of claim 32 selected from the group consisting of:
or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.
34 . A pharmaceutical composition comprising a compound of claim 1 and a suitable excipient.
35 . A pharmaceutical combination comprising a compound of claim 1 and a second medicament.
36 . The combination of claim 35 wherein the second medicament is medically indicated for the treatment of multiple sclerosis, transplant rejection, or acute respiratory distress syndrome.
37 . (canceled)
38 . 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 of claim 1 or the composition of claim 34 .
39 . The method of claim 38 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.
40 . The method of claim 38 wherein the sphingosine-1-phosphate receptor subtype 1 is disposed within a living mammal.
41 . 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 of claim 1 to the patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient.
42 . The method of claim 41 wherein selective activation or agonism of an S1P subtype 1 receptor with respect to other subtypes of S1P receptor is medically indicated.
43 . The method of claim 41 wherein the malcondition comprises multiple sclerosis, transplant rejection, acute respiratory distress syndrome, ulcerative colitis, influenza, Crohn's disease or adult respiratory distress syndrome.
44 - 60 . (canceled)