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(s) -2-benzyl-3- ( (3r, 4r) -4- (3 -carbamo ylphenyl) -3, 4-dimethylpiperidinyl) propanoic acid and salt therof as antagonists of the opioid receptors

An opioid receptor, IA-S-3 technology, applied in the direction of antitoxins, anti-inflammatory agents, non-central analgesics, etc., can solve the problems of lack of specificity and peripheral selective side effects of intestinal obstruction.

Inactive Publication Date: 2012-07-11
APOLOR CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These prior art methods have deficiencies, such as lack of specificity for postoperative or postpartum ileus
Most currently known opioid receptor antagonist treatments are not peripherally selective and potentially have undesired side effects due to penetration into the CNS

Method used

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  • (s) -2-benzyl-3- ( (3r, 4r) -4- (3 -carbamo ylphenyl) -3, 4-dimethylpiperidinyl) propanoic acid and salt therof as antagonists of the opioid receptors
  • (s) -2-benzyl-3- ( (3r, 4r) -4- (3 -carbamo ylphenyl) -3, 4-dimethylpiperidinyl) propanoic acid and salt therof as antagonists of the opioid receptors
  • (s) -2-benzyl-3- ( (3r, 4r) -4- (3 -carbamo ylphenyl) -3, 4-dimethylpiperidinyl) propanoic acid and salt therof as antagonists of the opioid receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Example 1: (S)-2-benzyl-3-((3R,4R)-4-(3-carbamoylphenyl)-3,4-dimethylpiperidin-1-yl)propionic acid Preparation of lithium(4a)

[0139] plan 1

[0140]

[0141] a.(S)-2-benzyl-3-((3R,4R)-3,4-dimethyl-4-(3-(trifluoromethyl-sulfonyloxy)phenyl)piperidine- 1-base) preparation of methyl propionate (2)

[0142]

[0143] To (S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]propionic acid methyl ester (1) (5.00g, 0.0131mol) (see Werner et al., J.Org.Chem, 1996, 61, 587-597) in dichloromethane (70mL, 1mol) was added triethylamine (3.03mL, 0.0218 mol), then N-phenylbis(trifluoromethanesulfonimide) (7.02 g, 0.0196 mol) / dichloromethane (70 mL) was added dropwise. The mixture was stirred overnight at room temperature. LCMS indicated the reaction was complete. NaOH (1 N) was added and the mixture was stirred for 30 minutes. The resulting layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with N...

Embodiment 2

[0150] Example 2: (S)-2-benzyl-3-((3R,4R)-4-(3-carbamoylphenyl)-3,4-dimethylpiperidin-1-yl)propionic acid Preparation of sodium (4b)

[0151] Scenario 2

[0152]

[0153]

[0154] a.(S)-2-benzyl-3-((3R,4R)-3,4-dimethyl-4-(3-(trifluoromethyl-sulfonyloxy)phenyl)piperidine- 1-base) preparation of methyl propionate (2)

[0155] Example 1a was repeated except that the reaction was scaled up to use 40.0 g (0.1 mol) of (S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3 , methyl 4-dimethylpiperidin-1-yl]propionate (1) / dichloromethane (560mL), triethylamine (24.25mL, 0.174mol) and N-phenylbis(trifluoromethanesulfonyl imine) (56.2 g, 0.157 mol) / dichloromethane (70 mL). Obtained 50 g (93%) of (S)-2-benzyl-3-((3R,4R)-3,4-dimethyl-4-(3-(trifluoromethyl-sulfonyloxy)phenyl )piperidin-1-yl)methyl propionate (2) as a pale yellow oil. 1 H NMR (CDCl 3 ), δ0.68(d, J=7Hz, 3H), 1.29(s, 3H), 1.55(m, 1H), 1.96(m, 1H), 2.25(m, 1H), 2.39(m, 2H), 2.47(m, 1H), 2.68(m, 2H), 2.79(m, 2H), 2.93(m, 2...

Embodiment 3

[0160] Example 3: (S)-2-Benzyl-3-((3R,4R)-4-(3-carbamoylphenyl)-3,4-dimethylpiperidin-1-yl)propionic acid Preparation of Trifluoroacetate (4c)

[0161] Option 3

[0162]

[0163] a.(S)-tert-butyl 2-benzyl-3-((3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)propionate ( 1a) Preparation

[0164] Di-tert-butoxy-N,N-dimethylmethylamine (30 mL, 0.1.mol, 4 equiv) was added dropwise to (S)-2-benzyl-3-((3R,4R)- 4-(3-Hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)propanoic acid (5) (see Werner et al., J.Org.Chem. 1996, 61, 587-597) (10.3 g, 0.028803 mol, 1 eq) in suspension in refluxing toluene (100 mL). The mixture was heated to reflux for 8 hours. The mixture was then cooled to room temperature, poured into 1N aqueous sodium hydroxide solution, and extracted. The crude product was purified by column chromatography (hexane / ethyl acetate 8:2) to give compound 1a (3.65 g, 31%). 1 H NMR (DMSO), δ0.65(d, J=7Hz, 3H), 1.20(s, 3H), 1.23(s, 9H), 1.48(d, J=13Hz, 1H), 1.92(dd, J= 7...

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Abstract

Novel 3,4-disubstituted-4-(3-carbamoylphenyl)-piperidinylpropanoic acid compounds and their salts, including pharmaceutically acceptable salts, pharmaceutical compositions and methods of their use are disclosed. The novel compounds are useful, inter alia, as antagonists of opioid receptors.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application 61 / 184,891, filed June 8, 2009, and US Application 12 / 795,095, filed June 7, 2010, both of which are hereby incorporated by reference in their entirety. technical field [0003] The present invention relates to substituted piperidinylpropionic acid compounds that affect the opioid receptor system. More particularly, the present invention relates to 3,4-disubstituted-4-(3-carbamoylphenyl)piperidinylpropionic acid compounds and their use, inter alia, as opioid receptor antagonists. Background technique [0004] It is well known that opioid drugs target three classes of endogenous opioid receptors (ie mu, delta and kappa receptors) in biological systems. Various opiates such as morphine are mu opioid receptor agonists that are commonly used as analgesics to treat severe pain because they activate mu opioids primarily (but not exclusively) in the central nervo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/34A61K31/451A61P1/00A61P25/04
CPCC07D211/34A61P1/00A61P1/04A61P1/06A61P1/08A61P1/10A61P25/02A61P25/04A61P29/00A61P39/02A61P43/00C07D211/16A61K31/451
Inventor R.E.多尔B.勒鲍唐尼克
Owner APOLOR CORP
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