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Novel heterocycles

A general formula and compound technology, which can be used in medical preparations containing active ingredients, allergic diseases, metabolic diseases, etc., and can solve problems such as side effects

Inactive Publication Date: 2011-02-02
ORCHID CHEM & PHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] A major problem with the use of compounds disclosed in patents US 5,622,977, WO99 / 50262, US 6,410,563 and US 5,712,298 as PDE4 inhibitors is the side effect of vomiting observed in some volunteers

Method used

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Experimental program
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Embodiment approach

[0271] According to another embodiment of the present invention, there is provided a method for preparing a novel heterocyclic compound of formula (I),

[0272]

[0273] wherein B represents pyridine and R represents a halogen atom, which can be prepared by transforming compounds of formula (Ia), wherein all symbols are as defined above.

[0274]

[0275] The compound of formula (Ia) was prepared following the procedures described in our PCT / IB03 / 01289.

[0276] with or without the presence of solvents such as toluene, xylene, tetrahydrofuran, di alkanes, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, diphenyl ether, etc., or mixtures thereof, with or without catalytic amounts of dimethylformamide or N,N-dimethylaniline or N, Compounds of formula (Ia) are converted using halogenating agents such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride and the like in the presence of N-diethylaniline and the like. T...

preparation example 1

[0334] Synthesis of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-amine

[0335]

[0336] At 0-10°C, 4-chloro-6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidine (5.5g, 13.33mmol, according to PCT / IB03 / 02879 described process preparation) THF (500ml) solution is fed continuously into ammonia gas and reaches 30 hours, stirs simultaneously. After completion of the reaction, THF was completely distilled in vacuo, water (100ml) was added and the reaction mixture was extracted with ethyl acetate (3x200ml). The combined organic layers were washed with brine (150ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl ) pyrimidin-4-amine (3.6 g, yield 87.79%).

[0337] Prepare the following compounds according to the above process

[0338]

Embodiment 3

[0340] Synthesis of 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonyl chloride

[0341]

[0342] To chlorosulfonic acid solution (605mmol, 40.4ml) was slowly added 4-chloro-6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidine (5.0g, 12.1 mmol, prepared according to the procedure described in PCT / IB03 / 02879), stirring was continued at 0°C until the addition was complete. The reaction mixture was then continued to stir at 32 °C until TLC confirmed the completion of the reaction. The resulting reaction was then slowly poured onto crushed ice under vigorous stirring, and the resulting solid was filtered, washed well with water (100ml), and extracted with ethyl acetate (3x200ml). The combined organic layers were washed with brine (150ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoro Methyl)pyrimidin-5-yl}benzenesulfonyl chloride ...

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Abstract

Described are novel heterocyclic compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof. These compounds are useful in the treatment of immunological diseases, inflammation, pain disorder, rheumatoid arthritis,osteoporosis,multiple myeloma,uveititis,acute and chronic myelogenous leukemia,atherosclerosis,cancer,cachexia,ischemic-induced cell damage,pancreatic beta cell destruction,osteoarthritis,rheumatoid spondylitis,gouty arthritis,inflammatory bowel disease,ARDS,psoriasis,Crohn's disease,allergic rhinitis,ulcerative colitis,anaphylaxis,contact dermatitis,muscle degeneration,asthma,COPD,bone resorption diseases,multiple sclerosis,sepsis,septic shock,toxic shock syndrome and fever. More particularly these compounds are useful as PDE4 inhibitors and are useful for treating PDE4 mediated diseases.

Description

technical field [0001] The present invention relates to novel general formula (I) heterocyclic compounds, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and Its composition, metabolites and prodrugs. [0002] [0003] The present invention also relates to a process for the preparation of the aforementioned novel heterocyclic compounds of general formula (I). [0004] The novel heterocyclic compounds of the present invention can be used in the treatment of inflammation and immunological diseases. Specifically, the compounds of the invention are useful in the treatment of cancer, inflammatory and immunological diseases which are caused by cytokines such as TNF-α, IL-1, IL-6, IL-1β, IL-8, IL-12 and Cyclooxygenases such as COX-1, COX-2 and COX-3 are mediated. More particularly, the compounds of the present invention are suitable as PDE4 inhibitors for the treatment of PDE4-mediated diseases, such...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07D401/12A61K31/505C07D403/04C07D403/12C07D213/30C07D401/04C07D239/32
CPCC07D239/42A61K31/5377C07D265/28C07D401/04A61P1/00A61P1/04A61P1/18A61P11/00A61P11/02A61P11/04A61P11/06A61P11/16A61P17/00A61P17/02A61P17/06A61P19/02A61P19/08A61P19/10A61P21/00A61P25/00A61P25/04A61P27/16A61P29/00A61P31/04A61P31/12A61P31/16A61P31/18A61P31/22A61P33/06A61P35/00A61P35/02A61P35/04A61P37/00A61P37/08A61P43/00A61P5/00A61P7/00A61P9/00A61P9/10A61P3/10C07D403/04
Inventor V·A·S·S·斯里尼瓦司R·塔迪帕斯G·V·R·夏尔马T·萨帕尼姆图D·P·巴奇亚拉杰V·卡查迪亚K·纳拉斯姆罕S·N·塔拉S·拉加戈帕尔S·纳拉亚南V·帕拉梅斯瓦兰V·贾纳萨南姆M·纳拉亚南姆S·加德U·拉马钱德兰G·巴拉苏布拉马尼安N·苏伦德兰L·S·维什瓦卡尔马S·萨克塞纳G·O·雷迪
Owner ORCHID CHEM & PHARM LTD
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