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Naphthylene derivatives as cytochrome P450 inhibitors

An alkyl and alkenyl technology, applied in the field of novel heteroaryl-naphthyl-alkylamines and salts thereof, can solve the problems of lack of specificity, insufficient consideration of activity/toxicity ratio, limitations and the like

Inactive Publication Date: 2006-08-16
OSI PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Liarozole and other Cyp26 inhibitors inhibit other cytochrome P450-mediated responses and are therefore limited by their lack of specificity for other cytochrome P450 enzymes
This lack of specificity may account for the limited risk-benefit ratio observed in prostate cancer patients in the phase III trial of Liarozole (inadequate consideration of the activity / toxicity ratio by the FDA)

Method used

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  • Naphthylene derivatives as cytochrome P450 inhibitors
  • Naphthylene derivatives as cytochrome P450 inhibitors
  • Naphthylene derivatives as cytochrome P450 inhibitors

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preparation example Construction

[0302] In a typical preparation, a compound of formula II is reacted with CDI or CDT in a suitable solvent. Suitable solvents for the above methods include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, etc.; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrile; Such as dichloromethane (CH 2 Cl 2 ) or chloroform (CHCl 3 ). Mixtures of these solvents are used if desired. The preferred solvent depends on the substrate used and is chosen according to the nature of the substrate. The above process is carried out at a temperature of about -78°C to about 100°C. Preferably, the reaction is carried out at 22°C to about 80°C. The above-described methods of producing compounds of the invention are preferably carried out at about atmospheric pressure, although higher or lower pressures can be used if desired. Essentially, it is preferred to use equimolar amounts of the reactants, although higher or lower amounts can be used if desired.

[0303] C...

Embodiment 3-1a

[0596] Embodiment 3-1a (wherein X 1 = imidazol-1-yl, R 2 =CH 3 , R 3 = H, G 1 =N(CH 3 ) 2 , n 2 =0,n 3 = 1, R 4b and R 5b =CH 3 , n 4 = 1, and Q 1 =CO 2 CH 3 Compound of Formula I): The title compound was prepared according to General Synthetic Method D as described above, wherein in the compound of Formula II, R 2 =CH 3 , R 3 = H, G 1 =N(CH 3 ) 2 , n 2 =0,n 3 = 1, R 4b and R 5b =CH 3 , n 4 = 1, and Q 1 =CO 2 CH 3 . 1 H NMR (CDCl 3 , 200MHz) δ0.79(d, 3H, J=6.6Hz), 1.35(s, 6H), 2.27(s, 6H), 3.46-3.55(m, 1H), 3.70(s, 3H), 4.07(s , 2H), 5.05(d, 1H, J=10.6Hz), 7.00(s, 2H), 7.11-7.14(m, 1H), 7.17(d, 1H, J=5.2Hz), 7.26-7.30(m, 1H), 7.65 (d, 2H, J = 11.6 Hz), 7.72 (d, 2H, J = 8.8 Hz); MS (ES) 410.0 (M+1).

Embodiment 3-1b

[0597] Embodiment 3-1b (wherein X 1 = imidazol-1-yl, R 2 =CH 3 , R 3 = H, G 1 =N(CH 3 ) 2 , n 2 =0,n 3 = 1, R 4b and R 5b =CH 3 , n 4 = 1, and Q 1 =CO 2 CH 3 Compound of Formula I): The title compound was prepared according to General Synthetic Method D as described above, wherein in the compound of Formula II, R 2 =CH 3 , R 3 = H, G 1 =N(CH 3 ) 2 , n 2 =0,n 3 = 1, R 4b and R 5b =CH 3 , n 4 = 1, and Q 1 =CO 2 CH 3 1 H NMR (CDCl 3 , 200MHz) δ0.90(d, 3H, J=6.6Hz), 1.35(s, 6H), 2.21(s, 6H), 3.55-3.63(m, 1H), 3.70(s, 3H), 4.07(s , 2H), 5.09(d, 1H, J=9.8Hz), 7.01(d, 2H, J=9.6Hz), 7.10(s, 1H), 7.15(d, 1H, J=2.6Hz), 7.40(dd , 1H, J=1.4Hz, 8.6Hz), 7.67-7.71 (m, 4H); MS (ES) 410.0 (M+1).

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Abstract

The present invention discloses compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein n1, n2, n3, n4, G1, Q1, Z, R1, R2, R3, R4a, R4b, R5a, and R5b are as described herein , which inhibits the cytochrome P450 RAI enzyme and is useful for the treatment and / or prevention of a variety of diseases and conditions that respond to treatment with retinoids and naturally occurring retinoic acid.

Description

Background of the invention [0001] The present invention relates to novel heteroaryl-naphthyl-alkylamines and salts thereof, processes for their preparation and compositions comprising them. The novel compounds of the present invention are useful for inhibiting the cytochrome P450 RAI enzyme (Cyp26) in animals, including humans, for the treatment and / or prevention of multiple diseases that respond to treatment with retinoids and naturally occurring retinoic acids. diseases and conditions. [0002] It is known in the art that retinoic acid, retinoids, and pharmaceutical compositions including retinoic acid or retinoids as active ingredients play an important role in the regulation and differentiation of epithelial cells. Such regulatory and differentiation effects, including the ability to promote cell differentiation, apoptosis, and inhibit cell proliferation, make retinoic acid and retinoid compounds useful agents in the treatment of tumors and, for example, in the treatment...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/54C07D249/04C07C211/19A61P35/00A61K31/4164A61K31/4192
CPCC07D233/54C07D249/04A61P17/00A61P17/06A61P35/00A61P43/00C07D233/64A61K31/4164A61K31/4192
Inventor 瓦内萨·史密斯安托尼·尼格罗马克·米维希尔卡拉·切萨里奥帕特里夏·安妮·贝克阿林多·卢卡斯·卡斯特拉诺
Owner OSI PHARMA INC
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