Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same

a technology of interleukin-12 signaling and therapeutic compounds, which is applied in the field of therapeutic compounds, can solve the problems of affecting the immune system affecting the survival rate of subjects, etc., and achieves the effect of limiting the inflammatory response of subjects

Inactive Publication Date: 2005-03-03
CELL THERAPUETICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017] It is another object of the present invention to provide novel therapeutic compounds, pharmaceutical compositions thereof and methods that are capable of limiting the inflammatory response of a subject without adversely affecting the specificity of the immune system deemed necessary for protecting the subject.

Problems solved by technology

In severe cases, shock and death may occur.
Diseases involving inflammation are particularly harmful when they afflict the respiratory system, resulting in obstructed breathing, hypoxemia, hypercapnia and lung tissue damage.
Furthermore, steroid treatment broadly attenuates cytokine production, but it cannot modulate it selectively, e.g., just the Th0, the Th1 or the Th2 pathways.
Although their effect in reversing some of the acute symptoms of autoimmune disease, such as MS, are well known, their side effects have precluded long-term use.
These drugs act like “sledgehammers” in that they suppress the entire immune system and raise problems that attend broad-spectrum immunosuppression therapies.
The same problems also are likely with newer therapies such as cyclosporine, anti-CD4 monoclonal antibodies, and others.
However, antibody based immunotherapy may result in immune complex formation and deposition, thus leading to glomerulonephritis, vasculitis and arthritis.
The use of anti-inflammatory and symptomatic relief reagents is a serious problem because of their side effects or their failure to attack the underlying cause of an inflammatory response.
These agents, however, have serious side effect potential, including, but not limited to, increased susceptibility to infection, liver toxicity, drug-induced lung disease, and bone marrow suppression.
Thus, such drugs have found limited clinical use, for example, in the treatment of most airway hyperresponsiveness lung diseases.

Method used

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  • Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same
  • Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same
  • Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 1-(5-(N-Hydroxy)aminohexyl)-3,7-dimethylxanthine (CT7549)

[0160] Sodium cyanoborohydride (62.84 mg, 1 mmol) was added to a solution of 1-(5-oximinohexyl)-3,7-dimethylxanthine (Klein, J. P.; Leigh, A. Oxime Substituted Therapeutic Compounds, U.S. Pat. No. 5,770,595 (Jun. 23, 1998)) (293 mg, 1 mmol) in methanol (10 ml). 1 M hydrogen chloride in ether was added to pH 4-5. After stirring for 3 hours, the mixture was concentrated under reduced pressure. 1 N aqueous sodium hydroxide solution to pH 9-10 (10 ml). The mixture was extracted with 10% methanol-dichloromethane (3×50 ml). The combined extracts were washed with water (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-dichloromethane to provide 1-(5-(N-hydroxy)aminohexyl)-3,7-dimethylxanthine (180 mg).

example 2

Synthesis of (R)-3-(5-Hydroxyhexyl)-1,7-dimethylxanthine (CT11495)

[0161] To a stirring solution of 1,7-dimethylxanthine (0.30 g, 1.67 mmol) in dimethylsulfoxide (20 ml) was added sodium hydride (42 mmg, 1.75 mmol) in one portion. After stirring for 30 minutes, (R)-5-acetoxy-1-bromohexane (0.31 g, 1.75 mmol) was added neat. (R)-5-Acetoxy-1-bromohexane was prepared according to methods described in U.S. patent application Ser. No. 09 / 002,345, which is incorporated herein by reference. After heating at 80° C. for 18 hours, water (25 ml) was added and the aqueous solution was extracted with dichloromethane (3×20 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate to give (R)-3-(5-acetoxyhexyl)-1,7-dimethylxanthine (0.34 g, 64% yield) as a colorless oil.

[0162] To a stirring solution of (R)-3-...

example 3

Synthesis of (R)-1-(5-Hydroxyhexyl)-3,7-dimethyluric acid (CT11499)

[0163] To a stirring solution of 3,7-dimethyluric acid (0.40 g, 2.04 mmol) in dimethylsulfoxide (20 ml) was added sodium hydride (49 mg, 2.04 mmol) in one portion. After stirring for 45 minutes, a solution of chloromethyl pivalate (0.29 g, 2.04 mmol) in dimethylsulfoxide (1 ml). After stirring for 24 hours, water (50 ml) was added. After cooling to room temperature, the solid was filtered, rinsed with water (4×20 ml), with ether (20 ml) and dried under vacuum to give 9-pivaloyloxymethyl-3,7-dimethyluric acid (0.18 g, 28% yield) as a white solid.

[0164] To a stirring solution of 9-pivaloyloxymethyl-3,7-dimethyluric acid (0.14 g, 0.45 mmol) in dimethylsulfoxide (10 ml) was added sodium hydride (12 mg, 0.47 mmol) in one portion. The solution was stirred for 15 minutes. (R)-5-Acetoxy-1-iodohexane (0.13 g, 0.47 mmol) in dimethylsulfoxide (1 ml) was added. The solution of (R)-5-acetoxy-1-iodohexane was prepared according ...

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Abstract

Novel heterocyclic compounds having a six membered ring structure fused to a five membered ring structure are found to be useful for the treatment and prevention of symptoms or manifestations associated with disorders affected by lnterleukin-12 (“IL-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. The therapeutic compounds, pharmaceutically acceptable derivatives (e.g., resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, have the following general formula: Each X, Y and Z are independently selected from a member of the group consisting of C(R3), N, N(R3) and S. Each R1, R2 and R3 is substituted or unsubstituted and is independently selected from a member of the group consisting of hydrogen, halo, oxo, C(1-20)alkyl, C(1-20)hydroxyalkyl, C(1-20)thioalkyl, C(1-20)alkylamino, C(1-20)alkylaminoalkyl, C(1-20)aminoalkyl, C(1-20)aminoalkoxyalkenyl, C(1-20)aminoalkoxyalkynyl, C(1-20)diaminoalkyl, C(1-20)triaminoalkyl, C(1-20)tetraaminoalkyl, C(5-15)aminotrialkoxyamino, C(1-20)alkylamido, C(1-20)alkylamidoalkyl, C(1-20)amidoalkyl, C(1-20)acetamidoalkyl, C(1-20)alkenyl, C(1-20)alkynyl, C(3-8)alkoxyl, C(1-11)alkoxyalkyl, and C(1-20)dialkoxyalkyl.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This patent application is a (1) continuation-in-part of U.S. application Ser. No. 09 / 288,556, which was filed Apr. 9, 1999, which in turn is a continuation-in-part of U.S. application Ser. No. 09 / 008,020, which was filed Jan. 16, 1998; (2) continuation-in-part of allowed U.S. application Ser. No. 08 / 486,264, which was filed Jun. 7, 1995, which in turn is a continuation-in-part of abandoned U.S. application Ser. No. 08 / 217,051, which was filed Mar. 24, 1994; and (3) continuation-in-part of allowed U.S. application Ser. No. 08 / 483,871, which was filed Jun. 7, 1995, which in turn is a continuation-in-part of abandoned U.S. application Ser. No. 08 / 199,368, which was filed Feb. 18, 1994. The entire disclosures of the above-identified patent applications are incorporated herein by reference and the benefit of each is hereby claimed.FIELD OF THE INVENTION [0002] The present invention generally relates to novel therapeutic compounds, pharmaceu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/00C07D239/54C07D473/04C07D473/06C07D473/10C07D487/04C07D495/04C07D513/04
CPCA61K31/00C07D239/54C07D473/04C07D473/06C07D473/10C07D487/04C07D495/04C07D513/04
Inventor KLEIN, J.KLAUS, STEPHENKUMAR, ANILGONG, BAOQING
Owner CELL THERAPUETICS INC
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