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Sulfonyl urea derivatives and their use in control of interleukin-1 activity

A compound, C1-C6 technology, applied in the direction of sulfonylurea active ingredients, organic compound preparation, organic active ingredients, etc., can solve joint pain, diffuse myalgia, anorexia and other problems

Inactive Publication Date: 2000-02-23
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Subcutaneous IL-1 can cause fever, lethargy, anorexia, diffuse myalgia, arthralgia, headache, and with increased use, hypotension

Method used

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  • Sulfonyl urea derivatives and their use in control of interleukin-1 activity

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Experimental program
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preparation example Construction

[0150] The following reaction schemes illustrate the preparation of the present invention. Unless otherwise stated, n, A, B, D, E and G in these reaction schemes and in the discussion that follows are as defined above.

[0151] Preparation A

[0152] Preparation B

[0153] Preparation C

[0154] Preparation D

[0155] plan 1 In Reaction 1 of Preparation A, the compound of formula XII is mixed with triphosgene in such as triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5,4,0]undec-7-ene, etc. Base, and in the presence of an aprotic solvent such as tetrahydrofuran, benzene or dichloromethane, the compound of formula XII is converted into the corresponding isocyanate compound of formula XI. The mixture is stirred and heated to reflux for about 1 to about 3 hours, preferably about 2 hours.

[0156]In reaction 1 of Preparation B, the compound of formula XIV is converted to the corresponding sulfonamide compound of formula XIII by the following method: at a te...

Embodiment 1

[0333] Example 11-(4-chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxyl-1-methylethyl)-benzenesulfonyl]-

[0334] Urea

[0335] To a stirred solution of 2-(3-aminosulfonylphenyl)-propan-2-ol (26.5 g) in tetrahydrofuran was added sodium hydride (5.2 g of a 60% dispersion in mineral oil) in portions. Once hydrogen evolution had ceased, 4-chloro-2,6-diisopropylphenylisocyanate (30.8 g) was added in one portion and the resulting mixture was heated at reflux for 12 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The resulting foam was dissolved in water, made basic with 1N sodium hydroxide, and extracted with two 1:1 portions of ether / hexane. The aqueous layer was acidified with 1N hydrochloric acid and the resulting white solid was filtered, washed with water and dried. This gave 50 g of a white solid, which was recrystallized from wet ethyl acetate / hexane to give the title compound, mp 160.5-162.0°C.

Embodiment 2

[0337] Example 21-(4-chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxycyclopentyl)-benzenesulfonyl]-urea

[0338] 3-1-Hydroxycyclopentyl-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenylisocyanate. mp: 155°C.

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Abstract

A compound of formula (I) wherein R<1> and R<2> are as defined in the description, R<2> being an aromatic group, useful in the treatment and condition selected from the group consisting of the group meningitis and salpingitis, septic shock, disseminated intravascular coagulation, and / or adult respiratory distress syndrome, acute or chronic inflammation, arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease, auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis, periodonate diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation tumors which produce IL-1 as an autocrine growth factor, cachexia, Alzeimer's disease, percussion injury, depression, atherosclerosis, osteoporosis in a mammal, including a human.

Description

Background of the invention [0001] The present invention relates to substituted urea derivatives for use in the treatment of inflammation of the joints, central nervous system, gastrointestinal tract, endocardium, pericardium, lung, eye, ear, skin and genitourinary system. More particularly, the present invention relates to aryl and heteroaryl substituted sulfonylureas which are useful inhibitors of the processing and release of interleukin-1α and interleukin-1β. [0002] The status of IL-1 as an important mediator of inflammation is based on numerous studies demonstrating the pro-inflammatory activity of this cytokine. These effects in vivo were demonstrated to be stimulation of cartilage resorption, induction of leukocyte recruitment response and acute phase response, and generation of a febrile and shock-like state. These changes mediated by IL-1 binding to its receptor include regulation of adhesion molecules and chemokines, stimulation of metalloproteinase synthesis, pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/20A61K31/357A61K31/4164A61K31/64A61P1/00A61P9/10A61P19/10A61P25/00A61P29/00A61P37/00C07C311/54C07C311/60C07C317/14C07C323/67C07D209/08C07D235/08C07D307/64C07D317/18C07D333/20C07D333/34C07D335/06C07D407/04C07D409/04
CPCC07C2102/10C07D307/64C07C311/60C07C2101/08C07C317/14C07C323/67C07C2101/02C07C2101/14C07D209/08C07D317/18C07D333/34C07C2101/04C07C2601/02C07C2601/04C07C2601/08C07C2601/14C07C2602/10A61P1/00A61P19/00A61P19/02A61P19/10A61P25/00A61P25/24A61P25/28A61P29/00A61P35/00A61P37/00A61P9/10A61P3/10C07C311/54
Inventor M·A·多姆布罗斯基J·F·艾戈勒
Owner PFIZER INC
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