US2015099806A1PendingUtilityA1
Compounds as l-cystine crystallization inhibitors and uses thereof
Est. expiryJun 10, 2031(~4.9 yrs left)· nominal 20-yr term from priority
C07C 321/14C07C 321/20A61K 31/095A61K 31/132A61P 13/12A61K 31/195A61K 31/225C07C 229/22C07C 321/18
61
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Claims
Abstract
A method of preventing or inhibiting L-cystine crystallization is disclosed, using the compounds of formula I: R 1a —[O] v -(-A-L-) m -A-[O] v —R 1b I wherein A, L, R 1a , R 1b , m, and v are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of conditions that are causally related to L-cystine crystallization, such as comprising (but not limited to) kidney stones.
Claims
exact text as granted — not AI-modified1 . A method for preventing, inhibiting, or slowing the growth of L-cystine crystallization comprising administering an effective amount of a compound of formula I:
R 1a —[O] v -(-A-L-) m -A-[O] v —R 1b I
or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein each A is independently
each X and Y is independently S, S(O), S(O) 2 , or C(R 5 )q;
each R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , and R 5 is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted cycloalkyl; the subscript q is 1 or 2;
the dotted bond is a single or a double bond;
provided that when one of X and Y is S, S(O), or S(O) 2 , then the dotted bond is a single bond;
L is —O—C 1 -C 6 alkylene-O—, —O-aryl-O—, or a group —O—(CH 2 —CH 2 -O—) t —; the subscript t is 1-10; the subscript m is 0-10; and
each R 1a and R 1b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted cycloalkyl; and each subscript v is 0 or 1.
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8 . A method according to claim 1 wherein the compound is of formula I; the subscript m is 0; the subscript v is 0; and the compound is according to formula II:
R 1a -A-R 1b II;
and wherein A, R 1a and R 1b are as in claim 1 .
9 . A method according to claim 1 , wherein the compound is of formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, or IIIg:
or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein
each R 1a and R 1b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted cycloalkyl;
each R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , and R 5 is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted cycloalkyl; and the subscript v is 0, 1, or 2.
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45 . The method of claim 1 , wherein the compound is according to formula IVa, IVb, IVc, IVd, IVe, IVf, Va, Vb, Vc, Vd, Ve, Vf, Vg, Vh, VIa, VIIb, VIIc, VIId, VIIa, VIIb, VIIc, VIId, XIIa, XIIb, XIIc, or XIId:
and wherein R 1a and R 1b are as in claim 1 ;
or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof.
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51 . The method of claim 1 , wherein one of R 1a and R 1b is H; and the other is alkyl or aryl.
52 . The method of claim 1 , wherein one of R 1a and R 1b is H; and the other is Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, or Ph.
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59 . The method of claim 1 , wherein each of R 1a and R 1b is alkyl, cycloalkyl, or aryl.
60 . The method of claim 1 , wherein each of R 1a and R 1b is independently Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, cyclohexyl, cyclopropyl, or Ph.
61 . The method of claim 1 , wherein each of R 1a and R 1b is alkenyl.
62 . The method of claim 1 , wherein each of R 1a and R 1b is alkynyl.
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68 . The method of claim 1 , wherein each of R 1a and R 1b is Ph.
69 . The method of claim 1 , wherein the compound is according to formula VIIIa, VIIIb, IXa, IXb, IXc, IXd, Xa, Xb, XI, XIIIa, XIIIb, XIIIc, XIIId, XIVa, XIVb, XIVc, XIVd, XVa, XVb, XVc, XVd, XVI, or XVII:
or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof.
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89 . The method of claim 1 , wherein the compound is one of the compounds listed in Table 1, wherein the compound # is 2, 3, 9, 10, 12, or 14.
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93 . A pharmaceutical composition for preventing, inhibiting, or slowing the growth of L-cystine crystallization comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound as defined in claim 1 .
94 . The composition of claim 93 wherein the carrier is a parenteral carrier, oral or topical carrier.
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96 . A method for preventing, inhibiting or slowing growth of L-cystine kidney-stone formation in a subject in need thereof, the method comprising administering a pharmaceutically effective amount of a compound as defined in claim 1 to the subject.
97 . A method of treating a subject having chronic kidney disease, comprising administering a pharmaceutically effective amount of a compound as defined in claim 1 .
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99 . A method for reducing a L-cystine crystal concentration in a human or animal comprising administering to a human or animal a pharmaceutically effective amount of a compound as defined in claim 1 .
100 . A method for treating a L-cystine crystal related condition in a human or animal comprising administering to a human or animal a pharmaceutically effective amount of a compound as defined in claim 1 .
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102 . The method or the combination according to claim 100 , wherein the L-cystine related condition is cystinuria or kidney stone disease.
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