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4-aminothiazole derivs, their preparation and their use as inhibitors of cyclin-dependent kinases

A technology of alkyl and alkynyl, which is applied in the field of pharmaceutical compositions of aminothiazole compounds, and can solve problems such as CDK activity imbalance

Inactive Publication Date: 2000-12-13
AGOURON PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The p21 protein also appears to transmit p53 tumor suppressor signals to CDKs; thus, approximately 50% of p53 mutations in all human cancers may indirectly lead to deregulation of CDK activity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0071] Example A(1): (4-amino-2-phenylamino-thiazol-5-yl)-(3-nitrophenyl)-methanone

[0072] Sodium (188 mg, 8.20 mmol) was carefully dissolved in methanol (9 mL) at 0 °C following the procedure described by Gewald et al., J. Prakt. Chem., Vol. 35 (1967), pp. 97-104 , and allowed to warm to room temperature. The resulting solution was added portionwise to a mixture of cyanamide (345 mg, 8.20 mmol) and phenyl isothiocyanate (0.98 mL, 8.2 mmol), with evolution of heat. 2-Bromo-3'-nitroacetophenone (2.00 g, 8.2 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (150 mL). The tan solid was filtered out, washed with water and a small amount of ether, dried in vacuo, and recrystallized from ethanol to obtain 2.17 g (52% yield) of the title compound as dark brown crystals with a melting point (mp) of 186-187°C. 1 H NMR (DMSO-d 6 ): δ10.95(1H, s), 8.44(1H, t, J=1.9Hz), 8.54-8.22(2H, bs), 8.34(1H, ddd, J=8.2, 1...

Embodiment B

[0100] Example B: [4-amino-2-(p-tolylamino)-thiazole-5-carbonyl]-phenyl benzoate

[0101] First, the intermediate product S-(4-benzoyloxyphenylacetyl)-N'-cyano- N"-p-tolyl-isothiourea. Sodium (6.7 mg, 0.29 mmol) was carefully dissolved in methanol (0.5 mL) and allowed to cool to room temperature. To the resulting solution was added p-toluene ester (43 mg, 0.29 mmol) and cyanamide (12 mg, 0.29 mmol). After 1 hour, 4-bromoacetophenone benzoate (92 mg, 0.29 mmol) was added and the resulting mixture was stirred at room temperature overnight The mixture was then diluted with water (10 mL). The resulting tan solid was filtered off, washed with water and a small amount of ether, dried in vacuo, and recrystallized from ethanol / chloroform to obtain 63 mg (51% yield) of S- Raw material of (4-benzoyloxyphenylacetyl)-N′-cyano-N″-p-tolyl-isothiourea (white needle-like crystals): 1 H NMR (DMSO-d 6 ): δ 8.10-8.04 (2H, m), 7.72 (1H, ddd, J = 7.5, 1.8, 1.8Hz), 7.67-7.54 (4H, m), 7.20 (2...

Embodiment C

[0103] Example C(1): 4-[4-Amino-5-(4-methoxy-benzoyl)-thiazol-2-ylamino]-benzoic acid methyl ester

[0104] To a mixture of 4-methoxycarbonylphenyl isothiocyanate (82 mg, 0.5 mmol) and cyanamide (23 mg, 0.55 mmol) in acetonitrile (5 mL) was added potassium tert-butoxide (61 mg, 0.55 mmol) in tert-butanol (5 mL). After standing at room temperature for 30 minutes, 2-bromo-4'-methoxy-acetophenone (115 mg, 0.5 mmol) was added. After standing at room temperature for 2 hours, the reaction mixture was diluted with water (50 mL). The product was collected by filtration, washed with water and ether, and dried in vacuo to obtain 172 mg (90% yield) of a yellow solid. 1 H NMR (DMSO-d 6): δ 8.00 (2H, d, J = 8.2Hz), 7.84 (2H, d, J = 8.2Hz), 7.72 (2H, d, J = 8.2Hz), 7.10 (2H, d, J = 8.2Hz) , 3.90 (6H, s).FABMS (MH+): 384. Analytical calculated value: C 19 h 17 N 3 o 4 5·0.5H 2 O: C, 57.36; H, 4.71; N, 10.56; S, 8.06. Found: C, 56.97; H, 4.74; N, 10.51; S, 8.07.

[0105] Example C...

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Abstract

This invention is directed to aminothiazole compounds of formula (I) wherein R<1> is a substituted or unsubstituted group selected from: C1-6-alkyl; C1-6-alkenyl; C1-6-alkynyl; C1-6-alkoxyl; C1-6-alcohol; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; carbonyl; ether; (C1-6-alkyl)-carbonyl; (C1-6-alkyl)-aryl; (C1-6-alkyl)-cycloalkyl; (C1-6-alkyl)-(C1-6-alkoxyl); aryl-(C1-6-alkoxyl); thioether; thiol; and sulfonyl; wherein when R<1> is substituted, each substituent independently is a halogen; haloalkyl; C1-6-alkyl; C1-6-alkenyl; C1-6-alkynyl; hydroxyl; C1-6-alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; or carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; and R<2 >is a carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure having a substituent at the position adjacent to the point of attachment, which ring structure is optionally further substituted, where each substituent of R<2> independently is a halogen; haloalkyl; C1-6-alkyl; C1-6-alkenyl; C1-6-alkynyl; hydroxyl; C1-6-alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; or carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; or a pharmaceutically acceptable salt of a compound of formula (I), or a prodrug or pharmaceutically active metabolite of a compound of formula (I) or pharmaceutically acceptable salt thereof, for inhibiting cyclin-dependent kinases (CDKs), such as CDK1, CDK2, CDK4, and CDK6.

Description

[0001] Cross References to Related Applications [0002] This regular application claims priority to US Provisional Application 60 / 063,634, filed October 27, 1997, and US Provisional Application 60 / 063,666, filed October 28, 1997. field of invention [0003] The present invention relates to pharmaceutical compositions containing aminothiazole compounds for the inhibition of cyclin-dependent kinases (CDKs), such as CDK1, CDK2, CDK4 and CDK6. The present invention also relates to the therapeutic or prophylactic use of pharmaceutical compositions containing the compounds, and methods of treating malignant tumors and other diseases by administering effective doses of these compounds. Background of the invention [0004] Uncontrolled cell proliferation is a hallmark of cancer. Cell proliferation in response to various stimuli is manifested as an abnormal cell division cycle by which cells multiply and divide. Tumor cells often have...

Claims

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Application Information

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IPC IPC(8): C07D277/20A61K31/426A61K31/427A61K31/4439A61K31/454A61K31/496A61K31/551A61P35/00A61P43/00C07D213/00C07D235/00C07D277/42C07D277/56C07D333/00C07D417/06C07D417/12C07D417/14C07D521/00
CPCC07D417/06C07D231/12C07D417/14C07D249/08C07D417/12C07D277/42C07D233/56A61P35/00A61P43/00
Inventor W·K·M·钟储少嵩R·K·杜瓦迪伊李琳肖薇杨怡
Owner AGOURON PHARMA INC
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