Pharmaceutical compositions with attenuated release of phenolic opioids

1. A pharmaceutical composition, which comprises a trypsin inhibitor and a compound of general formula (I)

X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 )  (I)

or a pharmaceutically acceptable salt thereof, in which:

X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );

R 1 represents a (1-4C)alkyl group;

R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group;

n represents 2 or 3;

R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and

R 5 represents a hydrogen atom, an N-acyl group, or a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.

2. The pharmaceutical composition of claim 1 , wherein the phenolic opioid is selected from oxymorphone, hydromorphone and morphine.

3. The pharmaceutical composition of claim 1 , wherein the compound of general formula (I) has a general formula (IV):

or a pharmaceutically acceptable salt thereof, in which:

R a is hydrogen or hydroxyl;

R b is oxo (═O) or hydroxyl;

the dashed line is a double bond or single bond;

R 1 represents a (1-4C)alkyl group;

R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group;

n represents 2 or 3;

R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and

R 5 represents a hydrogen atom, an N-acyl group, or a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.

4. The pharmaceutical composition of claim 1 , wherein R 1 represents a methyl or ethyl group.

5. The pharmaceutical composition of claim 1 , wherein each of R 2 and R 3 represents a hydrogen atom.

6. The pharmaceutical composition of claim 1 , wherein n represents 2.

7. The pharmaceutical composition of claim 1 , wherein R 4 represents —CH 2 CH 2 CH 2 NHC(═NH)(NH 2 ).

8. The pharmaceutical composition of claim 1 , wherein R 5 represents an N-acyl group.

9. The pharmaceutical composition of claim 8 , wherein the N-acyl group is an N-(1-4C)alkanoyl, N-benzoyl or N-piperonyl group.

10. The pharmaceutical composition of claim 1 , wherein R 5 is an acetyl, glycinyl or N-acetylglycinyl group.

11. The pharmaceutical composition of claim 10 , wherein R 5 is an acetyl group.

12. The pharmaceutical composition of claim 1 , wherein the group —C(O)—CH(R 4 )—NH(R 5 ) is N-acetylarginine.

13. The pharmaceutical composition of claim 1 , wherein X is hydromorphone; R 1 is methyl; each of R 2 and R 3 is a hydrogen atom; n is 2; R 4 is —CH 2 CH 2 CH 2 NHC(═NH)(NH 2 ); and R 5 represents an N-acetyl group.

14. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is derived from soybean.

15. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is an arginine mimic or a lysine mimic.

16. The pharmaceutical composition of claim 15 , wherein the arginine mimic or lysine mimic is a synthetic compound.

17. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is a compound of formula:

wherein:

Q 1 is selected from —O-Q 4 or -Q 4 -COOH, where Q 4 is C 1 -C 4 alkyl;

Q 2 is N or CH; and

Q 3 is aryl or substituted aryl.

18. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is a compound of formula:

wherein:

Q 5 is —C(O)—COOH or —NH-Q 6 -Q 7 -SO 2 —C 6 H 5 , where

Q 6 is —(CH 2 ) p —COOH;

Q 7 is —(CH 2 ) r —C 6 H 5 ; and

p is an integer from one to three; and

r is an integer from one to three.

19. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is selected from

(S)-ethyl 4-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperazine-1-carboxylate;

(S)-ethyl 4-(5-guanidino-2-(2,4,6-triisopropylphenylsulfonamido)pentanoyl)piperazine-1-carboxylate;

(S)-ethyl 1-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperidine-4-carboxylate;

(S)-ethyl 1-(5-guanidino-2-(2,4,6-triisopropylphenylsulfonamido)pentanoyl)piperidine-4-carboxylate;

(S)-6-(4-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperazin-1-yl)-6-oxohexanoic acid;

4-aminobenzimidamide;

3-(4-carbamimidoylphenyl)-2-oxopropanoic acid;

(S)-5-(4-carbamimidoylbenzylamino)-5-oxo-4(R)-4-phenyl-2-(phenylmethylsulfonamido)butanamido)pentanoic acid;

6-carbamimidoylnaphthalen-2-yl 4-(diaminomethyleneamino)benzoate; and

4,4′-(pentane-1,5-diylbis(oxy))dibenzimidamide.

20. The pharmaceutical composition of claim 1 , wherein the compound of general formula (I) comprises hydromorphone 3-(N-methyl-N-(2-N′-acetylarginylamino)) ethylcarbamate or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition of claim 1 , wherein:

X is oxymorphone;

R 1 represents methyl,

R 2 and R 3 each represents a hydrogen atom;

n represents 2;

R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and

R 5 represents N-acetyl.

22. The pharmaceutical composition of claim 1 , wherein:

X is morphine;

R 1 represents methyl,

R 2 and R 3 each represents a hydrogen atom;

n represents 2;

R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and

R 5 represents N-acetyl.

23. A pharmaceutical composition, which comprises a trypsin inhibitor and a compound of general formula (II):

X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 )  (II)

or a pharmaceutically acceptable salt thereof, in which:

X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );

R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;

each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;

each R 3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;

or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;

n represents an integer from 2 to 4;

R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and

R 5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.

24. The pharmaceutical composition of claim 23 , wherein the compound of general formula (II) has a general formula (V):

or a pharmaceutically acceptable salt thereof, in which:

R a is hydrogen or hydroxyl;

R b is oxo (═O) or hydroxyl;

the dashed line is a double bond or single bond;

R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;

each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;

each R 3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;

or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;

n represents an integer from 2 to 4;

R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and

R 5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.

25. The pharmaceutical composition of claim 23 , wherein the compound of general formula (II) has a general formula (III):

X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 )  (III)

or a pharmaceutically acceptable salt thereof, in which:

X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O )—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );

R 1 represents a (1-4C)alkyl group;

R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group;

n represents 2 or 3;

R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and

R 5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.

26. The pharmaceutical composition of claim 23 , wherein acyl is substituted acyl.

27. The pharmaceutical composition of claim 23 , wherein n is 2.

28. The pharmaceutical composition of claim 23 , wherein R 1 is methyl or ethyl.

29. The pharmaceutical composition of claim 23 , wherein R 5 is acetyl, benzoyl, malonyl, piperonyl, succinyl, N-acetylarginine or N-acetyllysine.

30. The pharmaceutical composition of claim 23 , wherein R 2 and R 3 are hydrogen.

31. The pharmaceutical composition of claim 23 , wherein R 2 and R 3 which are on the same carbon are alkyl.

32. The pharmaceutical composition of claim 23 , wherein R 2 and R 3 which are on the same carbon form a spirocycle.

33. The pharmaceutical composition of claim 23 , wherein R 2 and R 3 which are on the same carbon are methyl.

34. The pharmaceutical composition of claim 23 , wherein R 2 and R 3 can modulate a rate of intramolecular cyclization.

35. The pharmaceutical composition of claim 23 , wherein R 2 and R 3 comprise an electron-withdrawing group or an electron-donating group.

36. The pharmaceutical composition of claim 23 , wherein —[C(R 2 )(R 3 )] n - is selected from —CH(CH 2 F)CH(CH 2 F)—; —CH(CHF 2 )CH(CHF 2 )—; —CH(CF 3 )CH(CF 3 )—; —CH 2 CH(CF 3 )—; —CH 2 CH(CHF 2 )—; —CH 2 CH(CH 2 F)—; —CH 2 CH(F)CH 2 —; —CH 2 C(F 2 )CH 2 —; —CH 2 CH(C(O)NR 20 R 21 )—; —CH 2 CH(C(O)OR 22 )—; —CH 2 CH(C(O)OH)—; —CH(CH 2 F)CH 2 CH(CH 2 F)—; —CH(CHF 2 )CH 2 CH(CHF 2 )—; —CH(CF 3 )CH 2 CH(CF 3 )—; —CH 2 CH 2 CH(CF 3 )—; —CH 2 CH 2 CH(CHF 2 )—; —CH 2 CH 2 CH(CH 2 F)—; —CH 2 CH 2 CH(C(O) NR 23 R 24 )—; —CH 2 CH 2 CH(C(O)OR 25 )—; and —CH 2 CH 2 CH(C(O)OH)—, in which R 20 , R 21 , R 22 and R 23 each independently represents hydrogen or (1-6C)alkyl, and R 24 and R 25 each independently represents (1-6C)alkyl.

37. The pharmaceutical composition of claim 23 , wherein one of R 2 and R 3 is aminoacyl.

38. The pharmaceutical composition of claim 23 , wherein one of R 2 and R 3 is

wherein each R 10 is independently selected from hydrogen, alkyl, substituted alkyl, and acyl, and R 11 is alkyl or substituted alkyl.

39. The pharmaceutical composition of claim 23 , wherein one of R 2 and R 3 is

wherein R 10 is selected from hydrogen, alkyl, substituted alkyl, and acyl.

40. The pharmaceutical composition claim 39 , wherein R 10 is acyl.

41. The pharmaceutical composition of claim 23 , wherein the trypsin inhibitor is derived from soybean.

42. The pharmaceutical composition of claim 23 , wherein the trypsin inhibitor is an arginine mimic or a lysine mimic.

43. The pharmaceutical composition of claim 42 , wherein the arginine mimic or lysine mimic is a synthetic compound.

44. The pharmaceutical composition of claim 23 , wherein the trypsin inhibitor is a compound of formula:

wherein:

Q 1 is selected from —O-Q 4 or -Q 4 —COOH, where Q 4 is C 1 -C 4 alkyl;

Q 2 is N or CH; and

Q 3 is aryl or substituted aryl.

45. The pharmaceutical composition of claim 23 , wherein the trypsin inhibitor is a compound of formula:

wherein:

Q 5 is —C(O)—COOH or —NH-Q 6 -Q 7 -SO 2 —C 6 H 5 , where Q 6 is —(CH 2 ) p —COOH;

Q 7 is —(CH 2 ) r —C 6 H 5 ; and

p is an integer from one to three; and

r is an integer from one to three.

46. The pharmaceutical composition of claim 23 , wherein the trypsin inhibitor is selected from

(S)-ethyl 4-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperazine-1-carboxylate;

(S)-ethyl 4-(5-guanidino-2-(2,4,6-triisopropylphenylsulfonamido)pentanoyl)piperazine-1-carboxylate;

(S)-ethyl 1-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperidine-4-carboxylate;

(S)-ethyl 1-(5-guanidino-2-(2,4,6-triisopropylphenylsulfonamido)pentanoyl)piperidine-4-carboxylate;

(S)-6-(4-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperazin-1-yl)-6-oxohexanoic acid;

4-aminobenzimidamide;

3-(4-carbamimidoylphenyl)-2-oxopropanoic acid;

(S)-5-(4-carbamimidoylbenzylamino)-5-oxo-4-(R)-4-phenyl-2-(phenylmethylsulfonamido)butanamido)pentanoic acid;

6-carbamimidoylnaphthalen-2-yl 4-(diaminomethyleneamino)benzoate; and

4,4′-(pentane-1,5-diylbis(oxy))dibenzimidamide.

47. The pharmaceutical composition of claim 25 , wherein the compound of general formula (III) has a general formula (VI):

or a pharmaceutically acceptable salt thereof, in which:

R a is hydrogen or hydroxyl;

R b is oxo (═O) or hydroxyl;

the dashed line is a double bond or single bond;

R 1 represents a (1-4C)alkyl group;

R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group;

n represents 2 or 3;

R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and

R 5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.

48. The pharmaceutical composition of claim 25 , wherein acyl is substituted acyl.

49. The pharmaceutical composition of claim 25 , wherein R 5 is acetyl, benzoyl, malonyl, piperonyl, succinyl, N-acetylarginine or N -acetyllysine.

50. A pharmaceutical composition comprising:

a phenolic opioid prodrug comprising a trypsin-labile moiety that provides enzymatically-controlled release of a phenolic opioid, and

a trypsin inhibitor that mediates the enzymatically-controlled release of the phenolic opioid from the prodrug so as to attenuate enzymatic cleavage of the prodrug.

51. A method of treating or preventing pain in a patient in need thereof, which comprises administering to the patient an effective amount of a pharmaceutical composition of claim 1 .

52. A method for reducing drug abuse potential of a composition containing a phenolic opioid prodrug, the method comprising:

combining a phenolic opioid prodrug comprising a trypsin-labile moiety that provides enzymatically-controlled release of a phenolic opioid with a trypsin inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the phenolic opioid from the prodrug,

wherein the trypsin inhibitor reduces the ability of a user to release a phenolic opioid from the phenolic opioid prodrug by addition of the enzyme.

53. The method of claim 52 , wherein the phenolic opioid prodrug is a compound of formulae I-VI and the enzyme inhibitor is a trypsin inhibitor.

54. A method of treating or preventing pain in a patient in need thereof, which comprises administering to the patient an effective amount of a pharmaceutical composition of claim 23 .