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Dihydrobenzopyrans, dihydrobenzothiopyrans, and tetrahydroquinolines for the treatment of COX-2-mediated disorders

a technology of dihydrobenzopyrans and dihydrobenzothiopyrans, which is applied in the field of compounds, can solve the problems of limiting the therapeutic potential of compounds and more drastic side effects

Inactive Publication Date: 2005-01-13
GD SEARLE & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent describes a group of compounds that can be used to treat inflammation and other disorders caused by the action of cyclooxygenase-2. These compounds have various structures and can be used alone or in combination with other compounds to create pharmaceutical compositions. The compounds can be used to treat conditions such as arthritis, asthma, bronchitis, menstrual cramps, preterm labor, tendinitis, bursitis, allergic neuritis, cytomegalovirus infectivity, apoptosis, lumbago, liver disease, skin-related conditions, and post-operative inflammation. The compounds can also be used to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis."

Problems solved by technology

Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential.
An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.

Method used

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  • Dihydrobenzopyrans, dihydrobenzothiopyrans, and tetrahydroquinolines for the treatment of COX-2-mediated disorders
  • Dihydrobenzopyrans, dihydrobenzothiopyrans, and tetrahydroquinolines for the treatment of COX-2-mediated disorders
  • Dihydrobenzopyrans, dihydrobenzothiopyrans, and tetrahydroquinolines for the treatment of COX-2-mediated disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

rel-(2R,3S)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid

6,8-Dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid, prepared as described in WO98 / 47890, (0.32 g, 0.97 mmol) was placed in a Fisher & Porter™ tube with THF (30 mL), and platinium(IV) oxide (0.47 g). The tube was pressurized to 34 psi with hydrogen gas and the reaction mixture stirred at room temperature for about 23 hours. The reaction mixture was filtered through diatomaceous earth, concentrated in vacuo and passed through a column of silica gel with ethyl acetate-hexane-acetic acid (20:8.0:2) as the eluent, to give a white solid which was recrystallized from isooctane-hexane yielding a white crystalline solid (0.10 g, 31%): mp 165.0-170.2° C. 1H NMR (acetone-d6 / 300 MHz) 7.34 (s, 1H), 7.28 (s, 1H), 4.63-4.69 (m, 1H), 3.40 (d, 1H, J=13.5 Hz), 3.29 (d, 1H, J=18.1 Hz), 3.04-3.16 (m, 1H). 19F NMR (acetone-d6 / 282 MHz) −67.3 (d, J=8.7 Hz). FABLRMS m / z 329 (M−H). ESHRMS m / z 34...

example 2

(2S,3R)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

A 500 mL Parr™ shaker bottle was charged with platinum (IV) oxide (2.99 g) and acetic acid (120 mL) pressurized with hydrogen gas (50 psi) and shaken for 0.75 hours. The hydrogen was vented and the reactor was charged with (2S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (10.21 g, 32.62 mmol) and pressurized with hydrogen gas (25 psi). After 3 h, the reactor was vented, additional platinum (IV) oxide (1.59 g) was added, the reactor was pressurized with hydrogen gas (25 psi) and shaken for 2 h longer. The crude product mixture was filtered through diatomaceous earth and the filtrate concentrated in vacuo.

The resulting crude product was purified by flash silica chromatography (hexanes-ethyl acetate, 3:1) followed by reverse phase chromatography [C18 stationary phase, CH3CN—H2O with 0.1% TFA (gradient 15:85 to 50:50)] providing 5.02 g of a white, oily foam. This foam was fur...

example 3

rel-(2R,3S)-5,6-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Prepared by a procedure similar to that described in EXAMPLE 1. mp 173.0-174.4° C. 1H NMR (acetone-d6 / 300 MHz) 7.43 (d, 1H, J=8.9 Hz), 7.03 (d, 1H, J=8.9 Hz), 5.19-5.22 (m, 1H), 3.59-3.69 (m, 1H), 3.23 (dd, 1H, J=17.9 Hz, 6.2 Hz), 3.13 (dd, 1H, J=17.9 Hz, 7.5 Hz). 19F NMR (acetone-d6 / 282 MHz)-74.5 (d, J=7.2 Hz). FABLRMS m / z 313 (M−H). ESHRMS m / z 312.9635 (M−H, Calc'd 312.9646). Anal. Calc'd for C11H7Cl2F3O3: C, 41.93; H, 2.24. Found: C, 41.52; H, 2.53.

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Abstract

A class of dihydrobenzopyrans, dihydrobenzothiopyrans, tetrahydroquinolines, tetrahydronaphthalenes, and analogs thereof, is described for use in treating cyclooxygenase-2 mediated disorders. Compounds of particular interest are defined by Formula (I) wherein X, A1, A2, A3, A4, R, R″, R1 and R2 are as described in the specification.

Description

FIELD OF THE INVENTION This invention is in the field of anti-inflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating cyclooxygenase-2 mediated disorders, such as inflammation and inflammation-related disorders. BACKGROUND OF THE INVENTION Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2 has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of c...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/353A61K31/382A61K31/47A61P19/02A61P29/00A61P35/00A61P43/00C07D215/54C07D311/58C07D335/06
CPCC07D215/54C07D335/06C07D311/58A61P19/02A61P29/00A61P35/00A61P43/00
Inventor ROGIER, DONALD JR.CARTER, JEFFERYTALLEY, JOHN
Owner GD SEARLE & CO
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