Mu opioid receptor ligands: methods of use and synthesis

1. A compound of the formula (I):

wherein,

each R 1 , R 2 , and R 3 are independently alkyl substituted with aryl or heteroaryl, each of which is optionally substituted with 1-5 substituents selected from OR 6 , CN, NO 2 , NHR 7 , N(R 7 ) 2 , halo, CONHR 7 , CON(R 7 ) 2 , CO 2 R 8 , or C 1 alkyl;

X is O, or S;

R 4 is H, CON(R 7 ) 2 , CONHR 7 , CH 2 OH, CH(OH)CH═CH 2 , or C(O)NHCHR 10 CO 2 H;

each R 5 is independently H, alkyl, alkenyl, aryl, heteroaryl, acyl, P 1 , or C(O)CHR 10 NH 2 ;

each R 6 is independently H, alkyl, or P 3 ;

each R 7 is independently H, alkyl, acyl, or P 2 ;

each R 8 is independently H, alkyl, aralkyl, or heteroaralkyl;

each R 10 is independently an amino acid side chain;

each P 1 and P 2 is independently a nitrogen protecting group; and

each P 3 is independently an oxygen protecting group;

or pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein:

X is O;

R 1 is alkyl substituted with aryl, which is optionally substituted with 1-5 substituents selected from OR 6 , CN, NO 2 , NHR 7 , N(R 7 ) 2 , halo, CONHR 7 , CON(R 7 ) 2 , CO 2 R 8 , or C 1-6 alkyl;

R 4 is H, CON(R 7 ) 2 , C(O)NHCHR 10 CO 2 H, or CH 2 OH;

each R 5 is independently H, alkyl, acyl, P 1 , or C(O)CHR 10 NH 2 ;

each R 6 is independently H, alkyl, or P 3 ;

each R 7 is independently H, alkyl, acyl, or P 2 ;

each R 8 is independently H, alkyl, aralkyl, or heteroaralkyl;

each R 10 is independently an amino acid side chain;

each P 1 and P 2 is independently a nitrogen protecting group; and

each P 3 is independently an oxygen protecting group.

3. The compound of claim 1 , wherein:

X is O;

R 1 is alkyl substituted with aryl, which is optionally substituted with 1-5 substituents selected from OR 6 , CN, NO 2 , halo, or C 1-6 alkyl;

R 4 is H, CONHR 7 , or CH 2 OH;

each R 5 is independently H or alkyl;

each R 6 is independently H or alkyl;

R 7 is H, alkyl, or P 2 ; and

P 2 is a nitrogen protecting group.

4. The compound of claim 1 , wherein:

X is O;

R 1 is alkyl substituted with aryl, which is optionally substituted with 1-5 substituents selected from OH or C 1-6 alkyl; and

R 4 is H, CONH 2 , or CH 2 OH.

5. The compound of claim 1 , wherein:

X is O;

R 1 is C 1 alkyl substituted with phenyl, which is substituted at the 2- and 6-positions with Me and is substituted at the 4-position with OH; and

R 4 is H, CONH 2 , or CH 2 OH.

6. The compound of claim 1 having the formula (II):

wherein,

X is O;

R 4 is H, CON(R 7 ) 2 , CONHR 7 , CH 2 OH, or C(O)NHCHR 10 CO 2 H;

each R 5 is independently H, alkyl, acyl, P 1 , or C(O)CHR 10 NH 2 ;

each R 6 is independently H, alkyl, or P 3 ;

each R 7 is independently H, alkyl, acyl, or P 2 ;

each R 8 is independently H, alkyl, aralkyl, or heteroaralkyl;

each R 9 is independently OR 6 , CN, NO 2 , NHR 7 , N(R 7 ) 2 , halo, CONHR 7 , CON(R 7 ) 2 , CO 2 R 8 , or C 1 alkyl;

each R 10 is independently an amino acid side chain;

each n is independently 0, 1, 2, 3, 4, or 5;

each P 1 and P 2 is independently a nitrogen protecting group; and

each P 3 is independently an oxygen protecting group.

7. The compound of claim 6 , wherein:

R 4 is H, CON(R 7 ) 2 , CONHR 7 , or CH 2 OH;

each R 5 is independently H, alkyl, or acyl;

each R 6 is independently H or alkyl;

each R 7 is independently H or alkyl;

each R 9 is independently OR 6 , CN, NO 2 , halo, or C 1-6 alkyl; and

each n is independently 0 1, 2, or 3.

8. The compound of claim 6 , wherein:

P 1 is a BOC or Fmoc;

P 2 is a solid support; and

P 3 is t-Bu, Bn, Me, or Ac.

9. The compound of claim 6 , wherein:

R 4 is H, CON(R 7 ) 2 , CONHR 7 , or CH 2 OH; each

R 5 is independently H, alkyl, acyl, or P 1 ;

each R 6 is independently H or P 3 ;

each R 7 is independently H or P 2 ;

each R 9 is independently OR 6 or C 1-6 alkyl;

each n is independently 0, 1, or 2;

P 1 is a BOC;

P 2 is a solid support; and

P 3 is t-Bu.

10. The compound of claim 6 , wherein:

R 4 is H, CONH 2 , or CH 2 OH;

each R 5 is independently H, P 1 , or C(O)CHR 10 NH 2 ; each R 6 is H or alkyl

each R 9 is C 1-6 alkyl or OR 6 ;

each R 10 is independently an amino acid side chain;

each n is independently 1, 2, or 3; and

P 1 is a nitrogen protecting group.

11. The compound of claim 1 that is formula (III):

wherein,

X is O;

R 9 is C 1-6 alkyl; and

n is 2.

12. The compound of claim 1 that is formula (IV):

wherein X is O.

13. The compound of claim 1 having the formula (V):

wherein

X is O; and

R 4 is CONH 2 , H, or CH 2 OH.

14. A method of making a compound of the formula (XIV):

comprising coupling compounds of formulas (XI) and (XIII),

with a ruthenium catalyst;

treating the resulting compound with peroxide and base under conditions sufficient to hydrolyze the thioester;

amidation or esterification of the resulting acid; and

treatment of the resulting compound with a deprotecting agent sufficient to remove protecting groups, giving a compound of the formula (XIV);

wherein,

each R 1 , R 2 , and R 3 is independently alkyl substituted with aryl or heteroaryl, each of which is optionally substituted with 1-5 substituents selected from OR 6 , CN, NO 2 , NHR 7 , N(R 7 ) 2 , halo, CONHR 7 , CON(R 7 ) 2 , CO 2 R 8 , or C 1-6 alkyl;

X is O;

R 4 is H, CON(R 7 ) 2 , CONHR 7 , CH 2 OH, or CH(OH)CH═CH 2 ;

each R 6 is independently H, alkyl, or P 3 ;

each R 7 is independently H, alkyl, acyl, or P 4 ;

each R 8 is independently H, alkyl, aralkyl, or heteroaralkyl;

each R 11 and R 12 are independently alkyl substituted with aryl or heteroaryl, each of which is optionally substituted with 1 - 5 substituents selected from OR 16 , CN, NO 2 , NHR 17 , N(R 17 ) 2 , halo, CONHR 17 , CON(R 17 ) 2 , CO 2 R 18 , or C 1-6 alkyl;

each R 16 is independently H, alkyl, or P 3 ;

each R 17 is independently H, alkyl, acyl, or P 4 ;

each R 18 is independently H, alkyl, aralkyl, or heteroaralkyl; each P 1 and P 4 is independently a nitrogen protecting group; each P 3 is independently an oxygen protecting group; and

P 5 is a sulfur protecting group.

15. A method of making a compound of formula (XVII):

comprising coupling compounds of formulas (XI) and (XIII)

with a ruthenium catalyst;

treating the resulting compound with peroxide and base under conditions sufficient to hydrolyze the thioester; and

reacting the free hydroxyls with an oxygen protecting group to give a compound of formula (XVIII)

coupling the compound of formula (XVIII) with an alcohol of formula R 13 (CHOH)CHOR 16 ; and

treating the resulting compound with a deprotecting agent sufficient to remove protecting groups to give a compound of formula (XVII);

wherein,

each R 1 , R 2 , and R 3 is independently alkyl substituted with aryl or heteroaryl, each of which is optionally substituted with 1-5 substituents selected from OR 6 , CN, NO 2 , NHR 7 , N(R 7 ) 2 , halo, CONHR 7 , CON(R 7 ) 2 , CO 2 R 8 , or C 1-6 alkyl;

each R 6 is independently H, alkyl, or P 3 ;

each R 7 is independently H, alkyl, acyl, or P 4 ;

each R 8 is independently H, alkyl, aralkyl, or heteroaralkyl;

each R 11 , R 12 , and R 13 is independently alkyl substituted with aryl or heteroaryl,

each of which is optionally substituted with 1-5 substituents selected from OR 16 , CN, NO 2 , NHR 17 , N(R 17 ) 2 , halo, CONHR 17 , CON(R 17 ) 2 CO 2 R 18 , or C 1-6 alkyl;

each R 16 is independently H, alkyl, or P 3 ;

each R 17 is independently H, alkyl, acyl, or P 4 ;

each R 18 is independently H, alkyl, aralkyl, or heteroaralkyl;

each P 1 and P 4 is independently a nitrogen protecting group;

each P 3 is independently an oxygen protecting group; and

P 5 is a sulfur protecting group.

16. A composition comprising a compound of formula (I) in claim 1 and a pharmaceutically acceptable carrier.

17. A compound of formula (XIX):

wherein,

each R 1 , R 2 , and R 3 is independently alkyl substituted with aryl or heteroaryl,

each of which is optionally substituted with 1-5 substituents selected from OR 6 , CN, NO 2 , NHR 7 , N(R 7 ) 2i halo, CONHR 7 , CON(R 7 ) 2 , CO 2 R 8 , or C 1-6 alkyl;

X is O, or S;

R 4 is H, CON(R 7 ) 2 , CONHR 7 , CH 2 OH, CH(OH)CH═CH2, or C(O)NHCHR 10 CO 2 H; each R 5 is independently H, alkyl, alkenyl, aryl, heteroaryl, acyl, P 1 , or C(O)CHR 10 NH 2 ;

each R 6 is independently H, alkyl, or P 3 ;

each R 7 is independently H, alkyl, acyl, or P 2 ;

each R 8 is independently H, alkyl, aralkyl, or heteroaralkyl;

each R 10 is independently an amino acid side chain;

each P 1 and P 2 is independently a nitrogen protecting group;

each P 3 is independently an oxygen protecting group; and

or pharmaceutically acceptable salts thereof.

18. The compound of claim 17 wherein:

X is O;

R 1 is alkyl substituted with aryl, which is optionally substituted with 1-5 substituents selected from OR 6 , CN, NO 2 , NHR 7 , N(R 7 ) 2 , halo, CONHR 7 , CON(R 7 ) 2 , CO 2 R 8 , or C 1-6 alkyl;

R 4 is H, CON(R 7 ) 2 , C(O)NHCHR 10 CO 2 H, or CH 2 OH; and

each R 5 is independently H, alkyl, acyl, P 1 , or C(O)CHR 10 NH 2 ;

each R 10 is independently an amino acid side chain.

19. The compound of claim 17 , wherein:

X is O;

R 1 is alkyl substituted with aryl, which is optionally substituted with 1-5 substituents selected from OR 6 , CN, NO 2 , halo, or C 1-6 alkyl;

R 4 is H, CONHR 7 , or CH 2 OH;

each R 5 is independently H or alkyl;

each R 6 is independently H or alkyl; and

R 7 is H, alkyl, or P 2 .

20. The compound of claim 17 , wherein:

X is O;

R 1 is alkyl substituted with aryl, which is optionally substituted with 1-5 substituents selected from OH or C 1-6 alkyl; and

R 4 is H, CONH 2 , or CH 2 OH.

21. The compound of claim 17 , wherein:

X is O;

R 1 is C 1 alkyl substituted with phenyl, which is substituted at the 2- and 6-positions with Me and is substituted at the 4-position with OH; and

R 4 is H, CONH 2 , or CH 2 OH.

22. The compound of claim 17 having the formula (XX):

wherein,

X is O;

R 4 is H, CON(R 7 ) 2 , CONHR 7 , CH 2 OH, or C(O)NHCHR 10 CO 2 H; each R 5 is independently H, alkyl, acyl, P 1 , or C(O)CHR 10 NH 2 ; each R 6 is independently H, alkyl, or P 3 ;

each R 7 is independently H, alkyl, acyl; or P 2 ;

each R 8 is independently H, alkyl, aralkyl, or heteroaralkyl;

each R 9 is independently OR 6 , CN, NO 2 , NHR 7 , N(R 7 ) 2 , halo, CONHR 7 , CON(R 7 ) 2 ,

CO 2 R 8 , or C 1-6 alkyl;

each R 10 is independently an amino acid side chain;

each n is independently 0, 1, 2, 3, 4, or 5;

each P 1 and P 2 is independently a nitrogen protecting group; and each P 3 is independently an oxygen protecting group.

23. The compound of claim 22 , wherein:

R 4 is H, CON(R 7 ) 2 , CONHR 7 , or CH 2 OH;

each R 5 is independently H, alkyl, or acyl; each

R 6 is independently H or alkyl;

each R 7 is independently H or alkyl;

each R 9 is independently OR 6 , CN, NO 2 , halo, or C 1-6 alkyl; and

each n is independently 0 1, 2, or 3.

24. The compound of claim 22 , wherein:

R 4 is H, CON(R 7 ) 2 , CONHR 7 , or CH 2 OH;

each R 5 is independently H, alkyl, acyl, or P 1 ; each

R 6 is independently H or P 3 ;

each R 7 is independently H or P 2 ;

each R 9 is independently OR 6 or C 1-6 alkyl; each

n is independently 0 or 1;

P 1 is a BOC;

P 2 is a solid support; and

P 3 is t-Bu.

25. The compound of claim 22 , wherein:

R 4 is H, CONH 2 , or CH 2 OH;

each R 5 is independently H, P 1 , or C(O)CHR 10 NH 2 ; each R 6 is H or alkyl

each R 9 is C 1-6 alkyl or OR 6 ;

each R 10 is independently an amino acid side chain; each n is independently 1, 2, or 3; and

P 1 is a nitrogen protecting group.

26. The compound of claim 17 having the formula (XXI):

wherein,

X is O;

R 4 is H, CONH 2 , or CH 2 OH;

R 9 is C 1-6 alkyl; and

n is 2.

27. A composition comprising a compound of formula (XIX) in claim 17 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

28. A method of activating a mu opioid receptor (MOR) in a subject comprising administering a compound of formula (I) in claim 1 or a compound of formula (XIX) in claim 17 or pharmaceutically acceptable salts thereof.

29. A method of activating a mu opioid receptor (MOR), in a subject comprising administering a composition comprising a compound of formula (I) in claim 1 or a compound of formula (XIX) in claim 17 or pharmaceutically acceptable salts thereof.

30. A method of treating pain in a subject, comprising administering to the subject a compound of formula (I) in claim 1 or of formula (XIX) in claim 17 or pharmaceutically acceptable salts thereof.

31. A library of compounds of formula (I) in claim 1 or formula (XIX) in claim 17 .