US2013231326A1PendingUtilityA1
Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
Est. expiryNov 13, 2029(~3.3 yrs left)· nominal 20-yr term from priority
Inventors:Esther MartinboroughMarcus F. BoehmAdam YeagerJunko TamiyaLiming HuangEnugurthi BrahmacharyManisha MoorjaniGregg TimonyJennifer L. BrooksRobert James PeachFiona Lorraine ScottMichael Allen Hanson
A61P 37/06A61P 43/00A61P 31/16A61P 25/00A61P 29/00A61P 11/00A61P 1/00A61P 1/04C07D 413/14A61K 31/4245C07D 413/12C07D 413/10A61K 31/454C07D 417/12A61K 2300/00C07D 271/06C07C 245/14A61K 31/5377C07C 311/13A61K 31/496A61K 45/06A61K 31/427C07C 255/58A61K 31/425A01N 43/78
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 . 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;
R′″ is H, C 1-4 alkyl, or —CO—R 1
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 );
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 ;
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 . The compound of claim 4 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.
6 . The compound of claim 5 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 S1P receptor subtype 1 such that the 101 st amino acid residue is changed from asparagine to alanine.
7 . 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.
8 . The compound of claim 7 wherein the therapeutic index is at least 10.
9 . The compound of claim 7 wherein the therapeutic index is at least 20.
10 . The compound of claim 7 wherein the therapeutic index for the compound is greater than the therapeutic index for the enantiomer of the compound.
11 . The compound of claim 10 wherein the therapeutic index for the compound is at least 150% of the therapeutic index for the enantiomer of the compound.
12 . The compound of claim 1 wherein Y is Cl.
13 . The compound of claim 1 wherein Y is CF 3 .
14 . The compound of claim 1 wherein Y is CN.
15 . The compound of claim 1 wherein X is —NR′R″.
16 . The compound of claim 1 wherein X is —OR′″.
17 . The compound of claim 16 wherein X is —OH.
18 . The compound of claim 16 wherein X is —OCO—R 1 .
19 . The compound of claim 18 wherein R 1 is C 1-3 alkyl.
20 . The compound of claim 15 wherein R′ is H.
21 . The compound of claim 15 wherein R′ is —COR 1 .
22 . The compound of claim 15 wherein R′ is —SO 2 —R 1 .
23 . The compound of claim 15 wherein R″ is H.
24 . The compound of claim 15 wherein R″ is —SO 2 —R 3 .
25 . The compound of claim 15 wherein R″ is C 1-4 alkyl optionally substituted with 1 or more R 2 .
26 . The compound of claim 15 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.
27 . The compound of claim 26 wherein n is 2.
28 . The compound of claim 27 wherein R 2 is —OH, —NH 2 , —NHR 1 , —N(R 5 R 5 ), or —COOH.
29 . The compound of claim 24 wherein R 3 is C 1-4 alkyl optionally substituted with 1 or more R 2 .
30 . The compound of claim 24 wherein Y is CN.
31 . The compound of claim 29 wherein R 3 is —C 2 H 5 —N((R 5 R 5 ) or —CH 2 —CO—N(R 5 R 5 ).
32 . The compound of claim 30 wherein R 3 is C 2 H 5 —O—R 1 .
33 . The compound of claim 14 wherein X is —NH—CO—N(R 5 R 5 ).
34 . The compound of claim 1 wherein the compound is selected from compounds 1-252:
or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.
35 . The compound of claim 34 selected from the group consisting of compounds 50, 86 and 139:
or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.
36 . The compound of claim 34 selected from the group consisting of compounds 163 and, 186:
or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.
37 . The compound of claim 34 selected from the group consisting of compounds 211, 234, and 241:
or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.
38 . A pharmaceutical composition comprising a compound of claim 1 and a suitable excipient.
39 . A pharmaceutical composition comprising the compound of claim 1 and a second medicament.
40 . The composition of claim 41 wherein the second medicament is medically indicated for the treatment of multiple sclerosis, transplant rejection, or acute respiratory distress syndrome.
41 . (canceled)
42 . 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 .
43 . The method of claim 42 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.
44 . The method of claim 42 wherein the sphingosine-1-phosphate receptor subtype 1 is disposed within a living mammal.
45 . 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.
46 . The method of claim 45 wherein selective activation or agonism of an S1P subtype 1 receptor with respect to other subtypes of S1P receptor is medically indicated.
47 . The method of claim 45 wherein the malcondition comprises multiple sclerosis, transplant rejection, acute respiratory distress syndrome, ulcerative colitis, influenza, Crohn's disease or adult respiratory distress syndrome.
48 . A method for the synthesis of a compound comprising an indane moiety having a chiral carbon in the five-membered ring of the indane moiety where the compound is enantiomerically enriched with respect to the chiral carbon, the method comprising the steps of
(i) providing a compound comprising an indane moiety where the ring carbon of the five-membered ring of the indane moiety where chiral substitution is desired is oxo substituted at such carbon; (ii) reacting such compound with a chiral reagent selected from the group consisting of a Corey Bakshita Shibata-oxazaborolidine and a chiral sulfinamide of the form RS(═O)NH 2 where R is selected from the group consisting of t-butyl, branched C 2-6 alkyl and C 3-8 cycloalkyl; and (iii) forming a chiral center at the indane moiety carbon previously bound to the oxo group by either reacting such compound with a suitable reducing agent along with the chiral reagent in step (ii) or reacting the result of the reaction of such compound with a suitable reducing agent.
49 - 67 . (canceled)
68 . A compound selected from the group consisting of:
69 . A method for the synthesis of a compound comprising an indane moiety having a chiral carbon in the five-membered ring of the indane moiety where the compound is enantiomerically enriched with respect to the chiral carbon, the method comprising a step of providing a compound of claim 68 .
70 . The method of claim 69 wherein the compound comprising an indane moiety having a chiral carbon in the five-membered ring of the indane moiety is a compound of the Formula III-R or III-S:
wherein X is as defined in claim 1 .
71 . The method of claim 70 wherein the compound of the Formula III-R or III-S is a compound of claim 1 .Cited by (0)
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