Claims
- 1. A method for the treatment of pruritus in a patient comprising administering to said patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof whereinn=1-3; R1 and R2 are independently=CH3; —(CH2)m, where m=4-8, —CH2CH(OH)(CH2)2—; —CH2CH(F)(CH2)2—; —(CH2)2O(CH2)2—; or —(CH2)2CH═CHCH2—; Ar=unsubstituted or mono-, or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH3, SO2CH3, CF3, amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl diphenyl methyl; or 9-fluorene; Z is —P(O)(OBn)2; —P(O)(OH)2; —(CH2)pC(O)NHOH; —(CH2)pCO2H; —SO2CH3; —SO2NH2; —CO(CH2)pCH(NH2)(CO2H); —COCH(NH2)(CH2)pCO2H; —CO2CH3; —CONH2; —(CH2)pO(CH2)pCO2H; —(CH2)pO(CH2)pCONHOH; —(CH2)pNHSO2CH3; —(CH2)pNHC(S)NHCH(CO2H)(CH2)pCO2H; —(CH2)pSO3H; or or Z is wherein p=0-20; R3=—H or —Ac; X2=—CO2H; —NHSO2CH3; NHP(O)(OBn)2; NHP(O)(OH)2; —OP(O)(OBn)2; or OP(O)(OH)2; X and Y are independently —CH2NHSO2CH3, —CH2NHP(O)(OBn)2, —CH2NHP(O)(OH)2, —CH2OP(O)(OBn)2, —CH2OP(O)(OH)2, —(CH2)qO(CH2)qCO2H, —(CH2)qO(CH2)qSO3H, —(CH2)qO(CH2)CHNHOH, —CH2NHC(S)NHCH(CO2H)(CH2)qCO2H, or wherein q=1-20 r=1-20 R4=—H or —Ac X3=—CO2H; —NHSO2CH3; —NHP(O)(OBn)2; —NHP(O)(OH)2; —OP(O)(OBn)2; or —OP(O)(OH)2 in a pharmaceutically acceptable carrier.
- 2. A compound which is selected from the group consisting of:Methyl-4-[-2-glycyl-4-(trifluoromethylphenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylate; Methyl-4-[(2-[N,N-bis-methylsulfonamido]-4-trifluoromethyphenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylate dihydrochloride; Methyl-4-[(2-[N-methylsulfonamido]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[(2-[N,N-bis-methylsulfonamido]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[(2-[N-methylamino)sulfamyl]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[-4-[N-methylamino)sulfamyl]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate hydrochloride; 4-Trifluoroacetyl-1-[(trans-3-furanacyrlate]-2-(R,S)-(1-pyrrolidinyl)methyl]piperazine hydrochloride; 4-Trifluoroacetyl-1-[(-4-trifluoromethylphenyl)acetyl]-2-(R,S)-(1-pyrrolidinyl)methyl]piperazine hydrochloride; Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R,S)-[(4′-methylpiperazinecarboxylate)methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[(4-a,a,a-trifluoromethylphenyl)acetyl]-3-(R,S)-[3-(S)-(4′-a,a,a-trifluoro methylphenylacetate)-1-(pyrrolidinyl)methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethyl-3′,4′-dichlorophenyl acetate)methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[(2-nitro-4-a,a,a-trifluoromethylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidine methanol)methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[(4-methylsulphonylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethyl-4′-methylsulphonylphenylacetate)methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[(4-methylsulphonylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethanol) methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[(2-amino-4-a,a,a-trifluoromethylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidine methanol)methyl]-1-piperazinecarboxylate hydrochloride; Methyl-4-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3′,4′-dichlorophenylacetate)-1-(pyrrolidinyl)methyl]-1-piperazinecarboxylate hydrochloride; 4-Acetyl-1-[3-(N-methylsulfonamido)phenyl]acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride; 4-Acetyl-1-[(2-acetylamidophenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride; 4-Acetyl-1-[(4-acetylamidophenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride; 4-Acetyl-1-[(4-methylsulfonyl]phenyl)acetyl]-2-(R,S)-[3-(S)-(4′-methylsulfonyl phenyl acetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride; 4-Acetyl-1-[(4-a,a,a-trifluoromethylphenyl)acetyl]-2-(R,S)-[3-(S)-(4′-a,a,a-trifluoromethylphenyl acetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride; 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3′,4′-dichlorophenylacetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride; 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethyl-3′,4′-dichlorophenylacetate)methyl]piperazine hydrochloride; 4-Acetyl-1-[(4-trifluoromethylphenyl)acetyl]-2-(R,S)-[2-(S)-pyrrolidinemethyl-4′-trifluoromethylphenylacetate)methyl]piperazine hydrochloride; 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]piperazine hydrochloride; 4-Acetyl-1-[(4-methylsulphonylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethyl-4′-methylsulphonylphenylacetate)methyl]piperazine hydrochloride; 4-Acetyl-1-[(4-methylsulphonylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethanol) methyl]piperazine hydrochloride; 4-Acetyl-1-[(4-trifluoromethylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethanol) methyl]piperazine hydrochloride; 4-Formyl-1-[(2-N-methylsulfamylphenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride; 4-Carbonylimidazole-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride; 4-Allyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride; 4-Acetyl-1-[(2-pyridyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride; 4-Formyl-1-[(2-pyridyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine hydrochloride; Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(S)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxlate hydrochloride; 4-Methanesulfonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-methanesulfonate-1-(pyrrolidinyl) methyl]piperazine hydrochloride; 4-Methylsulphonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3′,4′ dichloro phenyl acetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride; 4-Methylsulphonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(3-(S)-hydroxy-1-pyrrolidinyl) methyl]piperazine hydrochloride; 4-Methylsulphonyl-1-[(4-α,α,α-triflouromethylphenyl)acetyl]-2-(R,S)-[3-(S)-(4′-a,a,a-triflouro methylphenyl acetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride; 4-Methylsulphonyl-1-[(4-α,α,α-triflouromethylphenyl)acetyl]-2-(R,S)-[(3-(S)-hydroxy-1-pyrrolidinyl)methyl]piperazine hydrochloride; 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(S)-[(3′-(S)-hydroxy-1-pyrrolidine)methyl]-piperazine hydrochloride; 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(3′-(R)-hydroxy-1-pyrrolidine)methyl]-piperazine hydrochloride; and 4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(S)-[(3′-(R)-hydroxy-1-pyrrolidine)methyl]-piperazine hydrochloride.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. application Ser. No. 09/372,191, filed Aug. 11, 1999, now U.S. Pat. No. 6,239,154, issued on May 29, 2001, which is a continuation-in-part of U.S. application Ser. No. 09/150,369, filed Sep. 9, 1998, now U.S. Pat. No. 6,303,611, issued on Oct. 16, 2001, which is a continuation-in-part of U.S. application Ser. No. 09/034,661, filed Mar. 3, 1998, now U.S. Pat. No. 5,945,443, issued on Aug. 31, 1999, which is a divisional of U.S. application Ser. No. 08/899,086, filed Jul. 23, 1997, now U.S. Pat. No. 5,744,458, issued on Apr. 28, 1998, which is a divisional of U.S. application Ser. No. 09/796,078, filed Feb. 5, 1997, now U.S. Pat. No. 5,688,955, issued on Nov. 18, 1997, which is a continuation-in-part of U.S. application Ser. No. 08/612,680, filed Mar. 8, 1996, now U.S. Pat. No. 5,646,151, issued on Jul. 8, 1997.
US Referenced Citations (33)
Foreign Referenced Citations (27)
Number |
Date |
Country |
0 108 602 |
May 1984 |
EP |
0 147 085 |
Dec 1984 |
EP |
0 233 793 |
Jan 1987 |
EP |
0 254 545 |
Jan 1988 |
EP |
0 260 555 |
Mar 1988 |
EP |
0 261 842 |
Mar 1988 |
EP |
0 372 466 |
Jun 1988 |
EP |
0 330 461 |
Feb 1989 |
EP |
0 330 467 |
Feb 1989 |
EP |
0 325 406 |
Jul 1989 |
EP |
0 330 469 |
Aug 1989 |
EP |
0 333 427 |
Sep 1989 |
EP |
0 366 327 |
Oct 1989 |
EP |
0 356 247 |
Feb 1990 |
EP |
0 393 696 |
Apr 1990 |
EP |
0 398 720 |
Nov 1990 |
EP |
0 409 489 |
Jan 1991 |
EP |
0 483 580 |
Oct 1991 |
EP |
0 577 847 |
Jan 1994 |
EP |
0 752 246 |
Jan 1997 |
EP |
0 207 773 |
Jun 1986 |
WO |
WO 9007502 |
Jul 1990 |
WO |
WO 9220657 |
May 1992 |
WO |
WO 9418165 |
Aug 1994 |
WO |
WO 9503308 |
Feb 1995 |
WO |
WO 9606077 |
Feb 1996 |
WO |
WO 9606078 |
Feb 1996 |
WO |
Non-Patent Literature Citations (11)
Entry |
Freeman et al, “Naphto and Benzo Analogues of the κ Opioid Agonist trans-(±)-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide,” J. Med. Chem., 1991, 34(6), 1891-1896. |
Rajagopalan, P. et al., “DuP 747: Structure activity relationship study,” Bioorganic & Medicinal Chemistry Letters, 1992, 2(7), 721-726. |
Raynor et al., “Pharmacological Characterization of the Cloned κ-, δ-, and μ-Opioid Receptors,” Molecular Pharmacol., 1994, 45, 330-334. |
Szmuszkovicz et al., “Benzeneacetamide Amines: Structurally Novel Non-mμ Opioids,” Journal of Medicinal Chemistry, 1982, 25(10), 1125-6. |
Wheeler-Aceto et al., “Standardization of the rat paw formalin test for the evaluation of analgesics,” Psychopharmacology, 1991, 104, 35-44. |
McMahon et al., TINS, vol. 15, No. 12: 497-501, (1992), Itching for an Explanation. |
Bernstein et al., Journal of Investigative Dermatology, vol. 78, No. 2: 82-83 (1982), Antipruritic Effect of an Opiate Antagonist, Naloxone Hydrochloride. |
Ballantyne et al., Pain, vol. 33, No. 2: 149-160 (1988), Itching After Epidural and Spinal Opiates. |
J.D. Bernhard, J. Am. Acad. Derm. vol. 24, No. 2, part 1: 309-310 (Feb. 1991), Itching In the Nineties. |
Magerl Ph.D., Walter, IASP Newsletter, Sep./Oct. 1996: 1-10, Neural Mechanisms of Itch Sensation. |
Thomas et al., Brain Research, 695: 267-270 (1995), Microinjection of Morphine Into the Rat Medullary Dorsal Horn Produces a Dose-Dependent Increase in Facial Scratching. |
Continuation in Parts (3)
|
Number |
Date |
Country |
Parent |
09/150369 |
Sep 1998 |
US |
Child |
09/372191 |
|
US |
Parent |
09/034661 |
Mar 1998 |
US |
Child |
09/150369 |
|
US |
Parent |
08/612680 |
Mar 1996 |
US |
Child |
08/796078 |
|
US |