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Substituted pyrimidines as prostaglandin D2 receptor antagonists

A compound and pyrimidine technology, applied in the field of substituted pyrimidine compounds, can solve the problems of discontinuation of niacin treatment, influence of patients' compliance with doctor's orders, etc.

Inactive Publication Date: 2013-04-10
AVENTIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These symptoms negatively impact patient compliance and, in severe cases, lead to discontinuation of niacin therapy

Method used

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  • Substituted pyrimidines as prostaglandin D2 receptor antagonists
  • Substituted pyrimidines as prostaglandin D2 receptor antagonists
  • Substituted pyrimidines as prostaglandin D2 receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136] 4-{2-Methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-morpholine-2-carboxylic acid trifluoroacetate

[0137]

[0138] 1A. 2-Methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl trifluoromethanesulfonate

[0139]

[0140] At room temperature, mix 2-methoxy-6-trifluoromethanesulfonyl-pyrimidin-4-yl trifluoromethanesulfonate (105 mg, 0.26 mol) and 2-(4-trifluoromethoxy-phenyl) -CH of ethylamine (53mg, 0.26mmol) 2 Cl 2 (3 mL) and the solution was stirred overnight. More 2-(4-trifluoromethoxy-phenyl)-ethylamine (ca. 100 mg) was added. After 2 hours, LC / MS indicated that the reaction was complete. The reaction mixture was concentrated in vacuo and the crude product was used in the next step without further purification. LC Rt: 1.19 min; MS 462 (M+1).

[0141] 1B. 4-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-morpholine-2-carboxylic acid ethyl ester

[0142]

[0143] At 95°C, 2-methoxy-6-[2-(4-trifl...

Embodiment 2

[0149] (4-{2-Methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-piperazin-1-yl)-acetic acid tri Trifluoroacetate

[0150]

[0151] 2A. [4-(6-{tert-butoxycarbonyl-[2-(4-trifluoromethoxy-phenyl)-ethyl]-amino}-2-methoxy-pyrimidin-4-yl)- Piperazin-1-yl]-ethyl acetate

[0152]

[0153] At 40°C, trifluoromethanesulfonic acid 6-{tert-butoxycarbonyl-[2-(4-trifluoromethoxy-phenyl)-ethyl]-amino}-2-methoxy-pyrimidine-4 CH 2 Cl 2 (5 mL) and the solution was heated overnight. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel with MeOH / CH 2 Cl 2 (2-3%) eluted to give the title product (37 mg, 36%). LC Rt: 3.59 min; MS 584 (M+1).

[0154] 2B.(4-{2-Methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-piperazin-1-yl)- Ethyl acetate hydrochloride

[0155]

[0156] At room temperature, [4-(6-{tert-butoxycarbonyl-[2-(4-trifluoromethoxy-phenyl)-ethyl]-amino}-2-methoxy-pyrimidin-4-yl )-piperazin-1-yl]-ethyl ...

Embodiment 3

[0162] 1-{2-Methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-piperidine-2-carboxylic acid trifluoroacetate

[0163]

[0164] 3A.1-(6-{tert-butoxycarbonyl-[2-(4-trifluoromethoxy-phenyl)-ethyl]-amino}-2-methoxy-pyrimidin-4-yl)-piper Ethyl pyridine-2-carboxylate

[0165]

[0166] At 85 ° C, trifluoromethanesulfonic acid 6-{tert-butoxycarbonyl-[2-(4-trifluoromethoxy-phenyl)-ethyl]-amino}-2-methoxy-pyrimidine-4 A solution of the -yl ester (144 mg, 0.26 mmol) and ethyl piperidine-2-carboxylate hydrochloride (99 mg, 0.51 mmol) and DIEA (89 μL, 0.51 mmol) in DMF (3 mL) was heated overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH 2 Cl 2 and water. The two layers were separated, and the organic layer was washed with 10% citric acid, saturated NaHCO 3 , water and saturated brine, washed with Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was purified on silica gel eluting with EtOAc / heptane (...

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Abstract

The present invention is directed to a substituted pyrimidine compound of formula (I) as set forth herein, or an enantiomer thereof, or a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound. The invention also includes a method of treatment of a patient by the administration of a pharmaceutically effective amount of such a compound. Formula (I), wherein m and n, independently of each other, are selected from the integers 0, 1, 2 or 3; X and Y, independently of each other, are selected from CRR, NR or O, wherein X and Y cannot both be O; or X and Y, taken together with the bond between them, form a phenyl group optionally substituted by one to four R groups; each Z, independently of each other, is CRR; R, R and R, independently of each other, are selected from the group consisting of H, halogen, aryl, amino, optionally substituted alkyl, optionally substituted alkoxy, and carboxy; wherein optionally substituted alkyl, may be substituted by one to three of the same or different of halogen, carboxy, cyano, hydroxy, amino or aryl.

Description

field of invention [0001] The present invention relates to substituted pyrimidine compounds, their preparation methods, pharmaceutical compositions containing such compounds, and their pharmaceutical applications in the treatment of disease symptoms that can be regulated by inhibiting prostaglandin D2 receptors. Background of the invention [0002] The results of local allergen challenge in patients with allergic rhinitis, bronchial asthma, allergic conjunctivitis and atopic dermatitis showed that prostaglandin D2 "(PGD2)" levels rise rapidly. PGD2 has many inflammatory effects, such as increased vascular permeability of the conjunctiva and skin, increased nasal airway resistance, airway constriction, and eosinophil infiltration of the conjunctiva and trachea. [0003] PGD2, the major cyclooxygenase product of arachidonic acid, is produced from mast cells under immune-challenging conditions. [Lewis, RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ II, prostaglandi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/505A61P11/00
CPCC07D403/04A61P1/04A61P11/00A61P11/02A61P11/06A61P17/00A61P19/02A61P27/00A61P27/02A61P27/12A61P27/14A61P31/00A61P3/06A61P37/00A61P37/08A61P43/00A61P9/00A61P9/10A61P9/14A61P3/10A61K31/5377A61K31/506A61K45/06A61K2300/00
Inventor K.J.哈里斯J.C.阿奎亚沈伟国赵志城G.B.波利G.斯托克洛萨Y-M.乔伊-斯莱德斯基S.莱林D.斯特芬尼C.加德纳
Owner AVENTIS PHARMA INC
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