Substituted phenoxy aminothiazolones as estrogen related receptor-alpha modulators

An alkoxy and alkyl technology, applied in the field of substituted phenoxyaminothiazolones used as estrogen-related receptor-α modulators, can solve problems such as unknown molecular mechanisms

Inactive Publication Date: 2010-03-24
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Giving estrogen to postmenopausal osteoporosis patients found that it has an anabolic effect on bone growth (Pacifici, R.J.BoneMiner.Res.1996, 11(8), 1043-1051), but due to ER-α and ER-β knockout Skeletal defects in animals are mild, estrogenic effects are usually mediated, so the molecular mechanism of this anabolic effect is unknown

Method used

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  • Substituted phenoxy aminothiazolones as estrogen related receptor-alpha modulators
  • Substituted phenoxy aminothiazolones as estrogen related receptor-alpha modulators
  • Substituted phenoxy aminothiazolones as estrogen related receptor-alpha modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0265] 4-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrile

[0266]

[0267] A. Preparation of 4-(4-formyl-2-methoxy-phenoxy)-3-trifluoromethyl- Benzonitrile. 1 H NMR (400Hz, CDCl 3 ) 10.00(s, 1H), 8.00(m, 1H), 7.68(dd, 1H), 7.58-7.53(m, 2H), 7.29(d, 1H), 6.75(d, 1H), 3.83(s, 3H) ;LC / MS(m / z)[M+1] + 322.1(C 16 h 11 f 3 NO 3 The calculated value of , 322.06).

[0268] B. Preparation of 4-[ 4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrile. 1 H NMR (400Hz, DMSO-d6) 8.96 (bs, NH), 8.74 (bs, NH), 8.32 (d, 1H), 7.99 (dd, 1H), 7.65 (d, 1H), 7.47 (d, 1H) , 7.36(d, 1H), 7.24(d, 1H), 6.89(d, 1H), 3.88(s, 3H); LC / MS(m / z)[M+1] + 420.0 (C 19 h 13 f 3 N 3 o 3 S, 420.38).

Embodiment 2

[0270] 4-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-chloro-benzonitrile

[0271]

[0272] A. Using general procedure A, 4-(2-chloro-4-cyanophenoxy)-3-methoxybenzaldehyde was prepared from vanillin and 3-chloro-4-fluorobenzonitrile. 1 H NMR (400Hz, CDCl 3 )δ9.95(s, 1H), 7.76(d, 1H), 7.56(br s, 1H), 7.50(d, 1H), 7.45(br d, 1H), 7.15(d, 1H), 6.78(d , 1H), 3.90 (s, 3H).

[0273] B. Preparation of 4-[4-(2- Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-chloro-benzonitrile. 1 H NMR (400Hz, DMSO-d6) δ9.47 (bs, NH), 9.21 (bs, NH), 8.17 (d, 1H), 7.70 (dd, 1H), 7.64 (s, 1H), 7.46 (d, 1H), 7.32(d, 1H), 7.23(dd, 1H), 6.81(d, 1H), 3.79(s, 3H); LC / MS(m / z)[M+1] + 386.0 (C 18 h 13 ClN 3 o 3 Calculated value of S, 386.82).

Embodiment 3

[0275] 4-[2-Chloro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

[0276]

[0277] A. Preparation of 4-[2-chloro-4-(2,4-dioxo-thiazole) from 3-chloro-4-hydroxybenzaldehyde and 4-fluoro-3-trifluoromethylbenzonitrile using general method A Alk-5-ylidenemethyl)-phenoxy]-3-trifluoromethylbenzonitrile. 1 H NMR (400MHz, CDCl 3 )δ9.99(s, 1H), 8.06(d, J=1.96Hz), 8.02(d, J=1.96Hz, 1H), 7.87(dd, J=8.22 and 1.96Hz, 1H), 7.76(dd, J=8.61 and 1.96 Hz, 1H), 7.27 (d, J=8.61 Hz, 1H), 6.82 (d, J=8.61 Hz, 1H).

[0278] B. According to general procedure C, using 2-amino-thiazol-4-one and 4-[2-chloro-4-(2,4-dioxo-thiazolidine-5-ylidenemethyl)-phenoxy ]-3-trifluoromethylbenzonitrile to prepare 4-[2-chloro-4-(2-imino-4-oxo-thiazolidine-5-ylidenemethyl)-phenoxy]-3-tri Fluoromethyl-benzonitrile. 1 HNMR (400MHz, DMSO-d6) δ 9.56 (br, 1H), 9.24 (br, 1H), 8.40 (d, J=1.56Hz, 1H), 8.08 (dd, J=8.6 and 1.95Hz, 1H), 7.90(d, J=1.96Hz, 1H), 7.65(d, J=2.35Hz, 1H), ...

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Abstract

The present invention relates to compounds of formula (I), methods for preparing these compounds, compositions, intermediates and derivatives thereof and for treating a condition including but not limited to ankylosing spondylitis, artherosclerosis, arthritis (such as rheumatoid arthritis, infectious arthritis, childhood arthritis, psoriatic arthritis, reactive arthritis), bone-related diseases (including those related to bone formation), breast cancer (including those unresponsive to anti-estrogen therapy), cardiovascular disorders, cartilage-related disease (such as cartilage injury / loss, cartilage degeneration, and those related to cartilage formation), chondrodysplasia, chondrosarcoma, chronic back injury, chronic bronchitis, chronic inflammatory airway disease, chronic obstructive pulmonary disease, diabetes, disorders of energy homeostasis, gout, pseudogout, lipid disorders, metabolic syndrome, multiple myeloma, obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis, Paget's disease, periodontal disease, polymyalgia rheumatica, Reiter's syndrome, repetitive stress injury, hyperglycemia, elevated blood glucose level, and insulin resistance.

Description

field of invention [0001] The present invention relates to certain novel compounds, methods of preparing compounds, compositions, intermediates and derivatives thereof, and methods of treating conditions such as cancer, arthritis, inflammatory respiratory diseases and metabolic disorders. More particularly, the compounds of the present invention are estrogen-related receptor alpha (ERR-alpha) modulators useful for treating, ameliorating, preventing or inhibiting the progression of disease states, disorders and conditions mediated by ERR-alpha activity. Background of the invention [0002] Nuclear receptors are members of the transcription factor superfamily. Each member of this family has a similar structure and regulates various biological effects (Olefsky, J.M.J. Biol. Chem. 2001, 276(40), 36863-36864). Ligands activate or repress these transcription factors that control genes involved in metabolism, differentiation and replication (Laudet, V. and H. Gronmeyer. The Nuclea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/34C07D417/04A61K31/427A61P19/00A61P35/00
CPCC07D277/34C07D417/04A61P1/02A61P11/00A61P19/00A61P19/02A61P19/06A61P19/10A61P29/00A61P3/00A61P3/10A61P35/00A61P3/04A61P3/06A61P35/04A61P43/00A61P5/50A61P9/00A61P9/10A61K31/427
Inventor M·高尔A·金L·L·西尔勒D·伦策佩里斯G·C·比南
Owner JANSSEN PHARMA NV
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