Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis

摘要

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.

主权项

1. 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 to the patient, at a frequency and for a duration of time sufficient to provide a beneficial effect, an effective amount of a compound having the structure of Formula I-R or I-S or a pharmaceutically acceptable salt, ester, hydrate or solvate thereof:wherein
X is —NR′R″ or —OR′″; Y is —CN, —Cl, or —CF3; R′ is H, C1-4 alkyl, n-hydroxy C1-4 alkyl, —SO2—R1, or —CO—R1; R″ is H, —SO2—R3, C1-4 alkyl optionally substituted with 1 or more R2, or a ring moiety optionally substituted with R4 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, —NH2, n-hydroxy-C1-4 alkyl, —COOH, —(CH2)m—COOH, —(CH2)m—COOR1, —N(R1R1), and —(CH2)m—CO—N(R5R5); R′″ is H, C1-4 alkyl, or —CO—R1; each R1 is independently C1-4 alkyl or H; each R2 is independently H, halo, OH, oxo, ═NH, NH2, —COOH, F, —NHR1, —N(R5R5), —SO2—R1, —SO2—N(R5R5), —N(R1)—SO2—R1, —COOR1, —OCO—R1, —CO—N(R5R5), —N(R1)—COR1, C1-3 alkyl, C1-3 alkoxy, and a ring moiety optionally substituted with R4 wherein such ring moiety is piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, benzimidazolyl, azetidinyl, cyclobutinyl, or phenyl; each R3 is independently R2, C1-4 alkyl, C3-6 cycloalkyl, or C1-4 alkyl optionally substituted with 1 or more R2; each R4 is independently halo, OH, —NH2, —NHR1, —N(R1R1), —COOH, —COOR1, —NHCO—R1, each R5 is independently C1-4 alkyl or H, or two R5 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, —NH2, —N(R1R1), n-hydroxy C1-4 alkyl, —(CH2)m—COOH, —(CH2)m—COOR1; and each m is independently 0, 1, 2, or 3.