6-Aminomorphinane Derivatives, Method for the Production and Use Thereof

a technology of aminomorphinane and derivatives, applied in the field of6aminomorphinane derivatives, can solve the problems of significant disadvantages of treatment, risks such as bleeding, infections or cartilage damage, and injections into affected tissue or joints, and achieves the effects of reducing side effects and toxicity, reducing the risk of bleeding, and prolonging the analgesic effect period

Inactive Publication Date: 2009-08-20
CHIRONWELLS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0065]In addition, it was surprisingly found that the compounds of this invention have a very long analgesically effective period. This enables a lower dosage and less frequent administration of the medicament, which results in a lower rate of side effects and toxicity as well as a higher readiness of patients to take the medicament.

Problems solved by technology

The type of application (injection) represents a significant disadvantage of the treatment.
Repeated injections into the affected tissue or joint are associated with risks such as bleeding, infections or cartilage damage.

Method used

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  • 6-Aminomorphinane Derivatives, Method for the Production and Use Thereof
  • 6-Aminomorphinane Derivatives, Method for the Production and Use Thereof
  • 6-Aminomorphinane Derivatives, Method for the Production and Use Thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of (4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-ylamino)-acetic acid-tert.-butylester (Compound 1) and (4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-ylamino)-acetic acid-tert.-butylester (Compound 2).

[0090]

[0091]A solution of 14-O-methyloxymorphone hydrobromide (H. Schmidhammer et al., Helv. Chim. Acta 1990, Vol. 71, pp. 1179-1783) (2.36 g, 5.96 mmol) and glycine-tert.-butylester hydrochloride (1.11 g, 6.62 mmol) in absolute MeOH (100 ml) was stirred for 1 hour under N2 at room temperature. Then a solution of NaCNBH3 (0.55 g, 8.75 mmol) in MeOH (50 ml) was added in drops over 20 min. and the solution stirred further under N2 at room temperature. After 19 h H2O (20 ml) was added and the mixture evaporated. The residue was mixed with H2O (400 ml), alkalized with concentrated ammonia, saturated with NaCl and extracted with Et2O (1×100 ml, 3×50 ml). The combined organic phases were washed with H2O (1×200 ml) and saturated NaCl solution (1×200 ml), dried (N...

example 2

Synthesis of (4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-ylamino)-acetic acid sesqui(trifluoroacetate) (Compound 3•1,5 TFA)

[0094]

[0095]A mixture of Compound 1 (0.18 g, 0.42 mmol) and 30% trifluoroacetic acid (TFA) in CH2Cl2 (7 ml) was stirred at room temperature for 9 h and then evaporated. The residue (0.26 g of orange foam resin) was crystallised out of i-PrOH / Et2O / MeOH. The expected bis(trifluoroacetate) is not obtained, but instead the sesqui(trifluoroacetate), which has been proven by several elementary analyses. Yield 0.13 g (57%) of beige 3•1,5 TFA: Fp >190° C. (Brkd.); IR (KBr): 3428 (OH), 1677 (C═O) cm−1; 1H-NMR (D2O): δ 6.90 (d, J=8.4, 1 arom. H); 6.81 (d, J=8.4, 1 arom. H); 4.47 (dd, 3J=3.0, 4J=1.0, H—C(5)); 3.87 (d, J=1.4, C(6)-NH—CH2) 3.35 (s, CH3O—C(14)); 2.94 (s, CH3N); ESI-MS: m / z 375 (M++1).

example 3

Synthesis of (4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-ylamino)-acetic acid sesqui(trifluoroacetate) (Compound 41, 5 TFA)

[0096]

[0097]A mixture of Compound 2 (0.30 g, 0.70 mmol) and 30% trifluoroacetic acid (TFA) in CH2Cl2 (11 ml) was stirred at room temperature for 5 h and then evaporated. The residue (0.43 g of yellow foam resin) was crystallised out of i-PrOH / Et2O / MeOH. The expected bis(trifluoroacetate) is not obtained, but instead the sesqui(trifluoroacetate), which has been proven by several elementary analyses. Yield 0.21 g (55%) of beige 4•1,5 TFA: Fp >210° C. (Brkd.); IR (KBr): 3419 (OH), 1677 (C═O) cm−1; 1H-NMR (D2O): δ 6.89 (d, J=8.6, 1 arom. H); 6.83 (d, J=8.6, 1 arom. H); 4.90 (d, J=7.8, H—C(5)); 4.04 (s, C(6)-NH—CH2—); 3.32 (s, CH3O—C(14)); 2.91 (s, CH3N); ESI-MS: m / z 375 (M++1).

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Abstract

This invention relates to compounds of the formula (I).

Description

PRIORITY CLAIM[0001]This is a continuation of U.S. application Ser. No. 10 / 499,133, filed Jun. 17, 2004, which is a U.S. national stage of PCT International Application No. PCT / EP02 / 14343, filed Dec. 16, 2002, which claims priority of German Application No. 101 61 963.4, filed Dec. 17, 2001. The contents of these applications in their entirety are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]This invention relates to a class of 6-amino-morphinan compounds which can be used as highly active analgesics. This invention also relates to their pharmaceutically acceptable salts and easily accessible derivatives (e.g. esters or amides of the amino acid derivatives), to a process for their manufacture and their application in the manufacture of pharmaceutical specialities.[0003]The existence of opioid receptors as receptors of the central nervous system (CNS), which transfer an analgesic effect, has been clearly proven. These receptors are subdivided into three subtypes,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/485C07D489/08A61P25/00A61P1/00A61P1/04A61P1/10A61P1/12A61P1/16A61P3/04A61P5/40A61P7/10A61P9/00A61P9/08A61P9/10A61P11/00A61P13/12A61P15/00A61P19/00A61P19/02A61P21/00A61P23/00A61P25/04A61P25/06A61P25/18A61P25/22A61P25/32A61P25/36A61P29/00A61P29/02A61P35/00A61P37/02A61P37/04A61P37/06C07D489/09
CPCC07D489/08A61K31/485A61P1/00A61P1/04A61P1/10A61P1/12A61P1/16A61P11/00A61P13/12A61P15/00A61P19/00A61P19/02A61P21/00A61P23/00A61P23/02A61P25/00A61P25/02A61P25/04A61P25/06A61P25/18A61P25/22A61P25/32A61P25/36A61P29/00A61P29/02A61P35/00A61P3/04A61P37/02A61P37/04A61P37/06A61P5/40A61P7/10A61P9/00A61P9/08A61P9/10
Inventor SCHUTZ, JOHANNESSCHMIDHAMMER, HELMUT
Owner CHIRONWELLS
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