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Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor

a technology of cyclooxygenase and leukotriene, applied in the field of immunology, can solve the problems of increased malignancy, hair loss, hair loss, and hair loss, and increase the incidence of malignancy, and achieve the effects of suppressing the growth of normal cells, and reducing the number of patients

Inactive Publication Date: 2005-02-24
PHARMACIA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs which abrogate mitosis and cell division have severe cytotoxic side effects on normal cell populations which have a high turn-over rate, such as bone marrow cells and cells of the gastrointestinal (GI) tract lining.
Accordingly, such drugs often have severe side effects, particularly, lymphopenia, neutropenia, bone marrow depression, hemorrhagic cystitis, liver damage, increased incidence of malignancy, hair loss, GI tract disturbances, and infertility.
But the adrenal corticosteroids lack specificity of effect and can exert a broad range of metabolic, antiinflammatory and immune effects.
Typical side effects of this class include increased organ-recipient infections and interference with wound healing, as well as disturbing hemodynamic balance, carbohydrate and bone metabolism and mineral regulation.
While cyclosporins have provided significant benefits in organ transplantation, cyclosporins are non-specific immunosuppressives.
Tolerated dosages do not provide complete suppression of rejection response.
Cyclosporins can produce severe side effects in many organ recipients, and show host-variable effects on the liver, kidney, the CNS and GI tract.
Significant among the adverse side effects are damage to the kidney and liver, hyperplasia of gum tissue, refractory hypertension and increased incidence of infections and malignancy.
However, little research has been directed at determining direct effects of eicosanoids on tissue rejection.
(Clin. Pharmacol. Ther., 47, 540 (1990)) describe the combination of naproxen and methotrexate as safe, although concurrent administrations of methotrexate with other NSAIDs have been reported to be toxic and sometimes fatal.
However, combinations of naproxen with indomethacin or ibuprofen offer no advantage in the treatment of arthritis (M. Seifert and C. Engler, Curr. Med. Res. Opin., 7, 38 (1980)).

Method used

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  • Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
  • Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
  • Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 4,4,4-trifluoro-1-[4-(chloro)phenyl]-butane-1,3-dione

Ethyl trifluoroacetate (23.52 g, 166 mmol) was dissolved in methyl tert-butyl ether (75 mL). To the stirred solution was added 25 weight % sodium methoxide (40 mL, 177 mmol). 4′-Chloroacetophenone (23.21 g, 150 mmol) was dissolved in methyl tert-butyl ether (20 mL) and added to the reaction dropwise. After stirring overnight (15.75 hours), 3N HCl (70 mL) was added. The organic layer was collected, washed with brine (75 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a yellow-orange solid. The solid was recrystallized from isooctane to give the dione (31.96 g, 85%): mp 66-67° C.

Step 2: Preparation of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

4-Sulphonamidophenyl hydrazine hydrochloride (982 mg, 4.4 mmol, 1.1 equiv.) was added to a stirred solution of 4,4,4-trifluoro-1-[4-(c...

example 2

4-[5-(3-Fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 3′-fluoro-4′-methoxy-acetophenone.

Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL), maintaining the temperature between 5-10° C. The mixture was stirred for 10 minutes at 5° C. before the dropwise addition of 2-fluoroanisole (62.6 g, 0.5 mol). The mixture was stirred at 0-10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL) The combined organic layers were washed with water (2×150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford material suitable for use in the next step ...

example 3

3-[Methyl(3-[4-phenylmethyl)phenoxy]propyl]-amino]propanoic acid

3-[Methyl[3-[4-phenylmethyl)phenoxy]propyl]-amino]propanoic acid is prepared by a four step method. 4-Hydroxydiphenylmethane is alkylated with 3-chlorobromopropane at 70° C. in the presence of potassium carbonate for 16 hours to form the 1-chloro-3-[4-phenylmethyl)phenoxy]propane. The chloropropane is condensed with methylamine at 60° C. in a Parr bomb at 200 psi for 20 hours. The secondary amine is isolated as the hydrochloride salt. Condensation of the secondary amine ith benzyl acetate in ethanol at room temperature for 3 ours affords the β-amino acid derivative. The derivative is directly hydrogenated (Pd / C, H2, ethanol, 2 psi) to afford 3-[methyl[3-[4-phenylmethyl)phenoxy]propyl]-amino]propanoic acid.

Biological Evaluation

A combination of a cyclooxygenase-2 inhibitor and a LTA4 hydrolase inhibitor is evaluated as described in the following tests.

Transplantation and Evaluation of Graft Rejection

The method of...

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PUM

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Abstract

Treatment with a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor is described as being useful in reducing recipient rejection of transplanted organs and for treatment of autoimmune diseases.

Description

FIELD OF THE INVENTION This invention is in the field of clinical immunology and relates to compositions having immunosuppressive properties. Of particular interest is a method of reducing recipient acute or chronic rejection of transplanted cells or organs, and for treatment of autoimmune diseases, hypersensitivity reactions of the acute or delayed type, allergic disorders, granulomas, meningitis, and septic shock by administering a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase (LTA4 hydrolase) inhibitor. BACKGROUND OF THE INVENTION Successful organ transplantation requires effective physiological and pharmacological intervention of the immune system of an organ recipient. Immunologic mechanisms are universal within the human species, but histocompatibility variations between organ donor and recipient may lead to rejection of donor tissue by stimulation of the recipient's immune system, except perhaps, in donor-recipient pairing of the monozygotic type. One approach t...

Claims

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Application Information

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IPC IPC(8): A61K31/10A61K31/18A61K31/415A61K31/4164A61K31/42A61K45/00A61K31/422A61K31/454A61K45/06A61P7/00A61P25/00A61P35/00A61P37/06A61P37/08
CPCA61K45/06A61P25/00A61P29/00A61P35/00A61P37/00A61P37/06A61P37/08A61P7/00
Inventor GREGORY, SUSAN A.ISAKSON, PETER C.ANDERSON, GARY
Owner PHARMACIA CORP
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