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Kappa agonist compounds and pharmaceutical formulations thereof

a technology of agonists and compounds, applied in the field of compounds, can solve the problems of well-known, undesirable and potentially dangerous dependence-forming side effects of opioids

Inactive Publication Date: 2003-06-03
APOLOR CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These opioids have well-known, undesirable and potentially dangerous dependence forming side effects.

Method used

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  • Kappa agonist compounds and pharmaceutical formulations thereof
  • Kappa agonist compounds and pharmaceutical formulations thereof
  • Kappa agonist compounds and pharmaceutical formulations thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

(R)-4-(Phenylmethyl)-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyridinyl)methyl] piperazine hydrochloride [(R)-1 HCl]

ADL-01-0147-9

The compound (R)-1 HCl was prepared following the literature procedure.sup.3 in 54% yield; mp 168.degree.-170.degree. C.; .sup.1 H NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.65 (4H, m), 1.95-3.00 (6H, m), 3.10-3.80 (9H, m), 4.35 (1H, m), 4.70 (1H, m), 7.00 (1H, m), 7.30 (7H, m); MS (FAB) 448 (M+H).sup.+ ; Anal. Calcd for C.sub.24 H.sub.29 Cl.sub.2 N.sub.3 O.2HCl.H.sub.2 O: C, 53.64; H, 6.19; N, 7.82. Found: C, 53.69; H, 5.88; N, 7.49.

example 2

(R)-1-[(3,4-Dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperazine hydrochloride [(R)-2HCl]

ADL-01-0047-9

The compound was prepared by the catalytic hydrogenation of (R)-1 HCl following the procedure described in the above reference. The product was isolated as a free base as clear oil in 81% yield and the dihydrochloride salt was prepared from 1M ethereal HCl; .sup.1 H NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.67 (4H, m), 1.95-3.10 (6H, m), 3.10-3.80 (7H, m), 4.30 (1H, m), 4.65(1H, m), 7.05 (1H, m), 7.35 (3H, m); MS (FAB) 356 (M+H).sup.'.

example 3

(R)-4-Methanesulfonyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)met hyl]piperazine hydrochloride [(R)-3a HCl]

ADL-01-0039-6

To the solution of (R)-2 (712 mg, 2 mmol in 10 ml CH.sub.2 Cl.sub.2), methanesulfonyl chloride (573 mg, 5 mmol) and pyridine (1 ml) were added at 0.degree. C., stirred overnight at that temperature, the solution was washed with aq. 5% K.sub.2 CO.sub.3 solution, extracted with dichloromethane, dried and evaporated solvent to give crude oil. This material was purified by flash column chromatography on silica gel, eluting with dichloromethane-methanol-ammonia (100:5:1), to give the free base, which was dissolved into 2 ml of dichloromethane and HCl (3 ml, 1M in Et.sub.2 O) was added to afford a white salt (R)-3a HCl (600 mg, 69%): mp 130.degree.-132.degree. C.; .sup.1 H NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.61-1.85 (4H, m), 2.38-2.65 (6H, m), 2.72 (3H, s), 2.80-3.06 (2H, m), 3.15-3.36 (1H, m), 3.50-3.96 (4H, m), 4.48-4.93 (1H, m), 7.00-7.10 (1H, m),...

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Abstract

Compounds having kappa opioid agonist activity, compositions containing them and method of using them as analgesics are provided.The compounds of formulae I, II, III and IV have the structure:wherein:X, X4, X5, X7, X9;R1, R2, R3, R4; andY, Z and n are as described in the specification.

Description

BACKGROUND OF THE INVENTION1. Field of the InventionThis invention relates to compounds, to processes of their preparation, to pharmaceutical compositions containing than and to their medical use as agonists at kappa opioid receptors.2. Reported DevelopmentsOpium and its derivatives are potent analgesics that also have other pharmacological effects, and exert their effects by interacting with high-affinity receptors.It has been shown by investigators that there are at least three major opioid receptor types in the central nervous system (hereinafter CNS) and in the periphery. These receptors, known as mu (.mu.), delta (.delta.) and kappa (.kappa.), have distinct pharmacological profiles, anatomical distributions and functions. [See, for example: Wood, P. L., Neuropharmacology, 21, 487-497,1982; Simon, E. J., Med. Res. Rev., 11, 357-374, 1991; Lutz et al, J. Recept. Res. 12, 267-286; and Mansour et al, Opioid I, ed. Herz,. A. (Springer, Berlin) pp. 79-106, 1993.] The .delta. receptor...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/4439A61K31/403A61K31/4427A61K31/404C07D241/00C07D241/04C07D209/42C07D209/00C07D213/56C07D213/00C07D295/12A61K31/40A61K31/496A61P25/04C07D207/09C07D209/08C07D209/18C07D403/06C07D403/12
CPCA61K31/404A61K31/4439A61P25/04C07D209/42C07D213/56C07D241/04
Inventor KRUSE, LAWRENCE I.CHANG, AN-CHIHDEHAVEN-HUDKINS, DIANE L.FARRAR, JOHN J.GAUL, FORRESTKUMAR, VIRENDRAMARELLA, MICHAEL ANTHONYMAYCOCK, ALAN L.ZHANG, WEI YUAN
Owner APOLOR CORP