Compounds as L-cystine crystallization inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-10759748-B2
Application number	US-201815926657-A
Country	US
Kind code	B2
Filing date	Mar 20, 2018
Priority date	Jun 10, 2011
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

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.

First claim

What is claimed is:

1. 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; and

wherein if:
1) the compound of formula I is formula IIIg,
2) R 1a , R 1b , R 3a , and R 3b are all H,
3) the subscript v of formula IIIg is 0, and
4) one of R 2a and R 4a is Me,

then the other of R 2a and R 4a is not H; and
wherein the compound of formula I is not formula XIIId.

2. The method according to claim 1 wherein the compound is of formula I; and A is:

and wherein R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 4a , R 4b and R 5 are as in claim 1 .

3. The 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 .

4. The 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.

5. 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, VIb, VIc, VId, 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.

6. The method of claim 1 , wherein one of R 1a and R 1b is H; and the other is alkyl or aryl.

7. 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, cyclohexyl, cyclopropyl, or Ph.

8. The method of claim 1 , wherein each of R 1a and R 1b is alkyl, cycloalkyl, or aryl.

9. 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, or Ph.

10. The method of claim 1 , wherein each of R 1a and R 1b is alkenyl or each of R 1a and R 1b is alkynyl.

11. The method of claim 1 , wherein each of R 1a and R 1b is Ph.

12. The method of claim 1 , wherein the compound is according to formula VIIIa, VIIIb, IXa, IXb, IXc, IXd, Xa, Xb, XI, XIIIa, XIIIb, XIIIc, XIVa, XIVb, XIVc, XIVd, XVa, XVb, XVc, XVd, XVI, or XVII:

or

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof.

13. The method of claim 1 , wherein the compound is one of the compounds listed in Table 1, wherein the compound # is 2, 9, 10, 12, or 14.

14. 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 .

15. The composition of claim 14 wherein the carrier is a parenteral carrier, oral or topical carrier.

16. 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.

17. A method of treating a subject having chronic kidney disease, comprising administering a pharmaceutically effective amount of a compound as defined in claim 1 .

18. 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 .

19. A method for treating a L-cystine crystal related

Assignees

• Univ New York

Inventors

• Ward Michael D
• Zhu Zina

Classifications

• A61K31/195 Primary

  having an amino group · CPC title

• A61K31/095

  Sulfur, selenium, or tellurium compounds, e.g. thiols · CPC title

• A61K31/132

  having two or more amino groups, e.g. spermidine, putrescine · CPC title

• C07C321/14

  of an acyclic saturated carbon skeleton · CPC title

• A61P13/12

  of the kidneys · CPC title