WO2008033932A2 - Acides carboxyliques de biarylthiazole - Google Patents

Acides carboxyliques de biarylthiazole Download PDF

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WO2008033932A2
WO2008033932A2 PCT/US2007/078283 US2007078283W WO2008033932A2 WO 2008033932 A2 WO2008033932 A2 WO 2008033932A2 US 2007078283 W US2007078283 W US 2007078283W WO 2008033932 A2 WO2008033932 A2 WO 2008033932A2
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alkyl
alkoxy
independently
alkenyl
alkynyl
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PCT/US2007/078283
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WO2008033932A3 (fr
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Michael C. Van Zandt
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The Institutes For Pharmaceutical Discovery, Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the invention relates to biarylthiazole carboxylic acids and more specifically to such compounds that are useful in the treatment of syndrome X (consisting of such abnormalities as obesity, dyslipidemia, hypercoagulation, hypertension, insulin resistance and leading to heart disease and diabetes) , obesity, diabetes, immunological disease, bleeding disorders, and/or cancer. More specifically, it relates to such compounds that are capable of inhibiting Protein tyrosine phosphatases (PTPs) , in particular Protein tyrosine phosphatase-lB (PTP-IB) which is a negative regulator of the insulin and leptin signaling pathway and improves insulin-sensitivity.
  • PTPs Protein tyrosine phosphatases
  • PTP-IB Protein tyrosine phosphatase-lB
  • This invention relates to a class of biarylthiazole carboxylic acids that are inhibitors of various PTPs, in particular PTP-IB.
  • Protein tyrosine phosphatases are a large family of transmembrane or intracellular enzymes that dephosphorylate substrates involved in a variety of regulatory processes (Fischer et al . , 1991, Science 253:401-406).
  • Protein tyrosine phosphatase-lB (PTP-IB) is an approximately 50 kd intracellular protein, which is present in abundant amounts in various human tissues (Charbonneau et al . , 1989, Proc. Natl. Acad. Sci. USA 86:5252-5256; Goldstein, 1993, Receptor 3:1-15). Determining which proteins are substrates of PTP-IB has been of considerable interest.
  • One substrate which has aroused especial interest is the insulin receptor.
  • insulin receptor tyrosine kinase The binding of insulin to its receptor results in autophosphorylation of the domain. This causes activation of the insulin receptor tyrosine kinase, which phosphorylates the various insulin receptor substrate (IRS) proteins that propagate the insulin signaling event further downstream to mediate insulin's various biological effects.
  • IRS insulin receptor substrate
  • GST glutathione S-transferase
  • Ahmad et al . , 1995, J. Biol. Chem. 270:20503-20508 used osmotic loading to introduce PTP-IB neutralizing antibodies into rat KRC-7 hepatoma cells.
  • the presence of the antibody in the cells resulted in an increase of 42% and 38%, respectively, in insulin stimulated DNA synthesis and phosphatidyinositol 3' kinase activity.
  • Insulin receptor autophosphorylation and insulin receptor substrate-1 tyrosine phosphorylation were increased 2.2 and 2.0-fold, respectively, in the antibody- loaded cells.
  • the antibody-loaded cells also showed a 57% increase in insulin stimulated insulin receptor kinase activity toward exogenous peptide substrates.
  • PTP-IB is a negative regulator of leptin signaling (Kaszua et al . MoI. Cell. Endocrinology, 195:109-118, 2002). PTP-IB deficient mice show enhanced potency for exogenous leptin to suppress food intake
  • inhibitors of PTP-IB augment the beneficial effects of leptin on food intake, body weight regulation and metabolism, in normal individuals and leptin resistant individuals.
  • inhibitors of PTPs are useful in controlling or treating obesity, syndrome X, Type 2 diabetes, in improving glucose tolerance, and in improving insulin sensitivity in patients in need thereof.
  • Such compounds are also useful in treating or controlling other PTP mediated diseases, such as the treatment of neurodegenerative diseases, cancer immunological disorders, bleeding and cardiovascular disorders, and the like.
  • the invention encompasses the compounds of formula (I) shown below, pharmaceutical compositions containing the compounds and methods employing such compounds or compositions in the treatment of diabetes and/or cancer.
  • the invention encompasses compounds of Formula (I) :
  • Li is -O- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -S- (Ci-C 6 ) alkyl-, -S (O) 2 - (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -S (O) 2 - (Ci-C 6 ) alkyl-, -N (R N2 ) - (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -N (R N2 ) - (Ci-C 6 ) alkyl-, -N (R 112 ) C (0) - (Ci-C 6 ) alkyl-,
  • each R A is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • n 0, 1, 2, 3, or 4 ;
  • L 2 is -N (R N8 )-, -0-, -S-, - (Ci-C 6 ) alkyl-N (R N8 ) -,
  • the invention also includes synthetic intermediates that are useful in making the compounds of the invention.
  • the invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods .
  • the invention also provides pharmaceutical compositions comprising a compound or salt of formula (I) and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent .
  • the compounds of formula (I) bind to PTPs, and in particular to PTP-IB.
  • the invention provides a method for inhibiting protein tyrosine phosphatases, preferably PTP-IB, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound or salt of formula (I) .
  • the invention further provides methods of treating diseases such as Type I and Type II diabetes, syndrome X, obesity, cancer, neurodegenerative disease, immunological disease, bleeding disorders, and cardiovascular disease in a patient in need of such treatment, comprising administering to the patient a compound or pharmaceutically acceptable salt of formula (I), or a pharmaceutical composition comprising a compound or salt of formula (I) .
  • the invention provides a method for treating metabolic disorders related to insulin resistance or hyperglycemia, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound or salt of formula (I) .
  • the invention provides formulations and pharmaceutical compositions, as well as methods for combination therapy for treating Type I diabetes, Type II diabetes, and Syndrome X with the compounds of formula (I) plus therapeutically-effective amounts additional compounds and medicaments.
  • Treatment methods of the invention for Type I diabetes, Type II diabetes, and Syndrome X comprise administration of the inventive compounds of formula (I) as disclosed herein concomitantly, simultaneously or together with a therapeutically-effective amount of said additional compounds and medicaments.
  • the invention also provides the use of a compound or salt according to formula (I) for the manufacture of a medicament for use in treating diabetes or cancer or other diseases related to PTPs.
  • the invention provides compounds of the formula (I) ,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl
  • B L 1 , L 2 , R A , RB, RI, XI, X2, n, and p are as defined in formula (I) .
  • the invention provides compounds of formula (I), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl; and Li, L 2 , RA, RB, RI, Xi, X2, n, and p are as defined in formula (I) .
  • the invention provides compounds of formula (I), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • L 2 is -N(R N8 )-, -0-, -S-, - (C 1 -C 6 ) alkyl-N(R N8 ) -, -N (R 118 )- (Ci-C 6 ) alkyl-,
  • R N8 is -H, - (C 1 -C 6 ) alkyl, -allyl, -propargyl, -C (0) (C 1 -C 6 ) alkoxy, -C (0) (C 1 -C 6 ) alkyl, or -C (0) (C 1 -C 6 ) alkyl- (C 3 -C 8 ) cycloalkyl; and L 1 , R A , R B/ Ri/ Xi/ n, and p are as defined in formula (D .
  • the invention provides compounds of formula (I), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • L 2 is -N(R N8 )-, -0-, -S-, -(Ci-C 6 ) alkyl-N(R N8 )-,
  • R N8 is -H, - (C 1 -C 6 ) alkyl, -allyl, -propargyl, -C(O) (Ci-C 6 ) alkoxy, -C (O) (Ci-C 6 ) alkyl, or -C (O) (Ci-C 6 ) alkyl- (C 3 -C 8 ) cycloalkyl;
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (Ci-C 6 ) alkyl-,
  • the invention provides compounds of formula (I), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • L 2 is -N(R N8 )-, -O-, -S-, - (Ci-C 6 ) alkyl -N (R N8 ) -, -N
  • R N8 is -H, - (Ci-C 6 ) alkyl, -allyl, -propargyl, -C(O) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C (0) (Ci-C 6 ) alkyl- (C 3 -C 8 ) cycloalkyl;
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -S- (Ci-C 6 ) alkyl-, -N(R N2 )- (C I -C 6 ) alkyl-,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , RB, XI, X2, n, and p are as defined in formula (I) .
  • the invention provides compounds of the formula (II) ,
  • Li is -O- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -O- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -S- (Ci-C 6 ) alkyl-, -S (O) 2 - (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -S (O) 2 - (Ci-C 6 ) alkyl-, -N (R N2 ) - (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -N (R N2 ) - (Ci-C 6 ) alkyl-, -N (R N2 ) C (0) - (Ci-C 6 ) alkyl-,
  • each R A is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • n 0, 1, 2, 3, or 4;
  • R 3 is -H, - (Ci-C 6 ) alkyl, -allyl, -propargyl, -C(O) (Ci-C 6 ) alkoxy,
  • each R B is aryl- or heteroaryl-; each R B is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention provides compounds of formula (II) , wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl
  • B Li, R A , R B , Ri, R3, Xi, X 2 , n, and p are as defined in formula (II) .
  • the invention provides compounds of formula (II), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl; and Li, R A , R B , Ri, R3, Xi, X2, n, and p are as defined in formula (II) .
  • the invention provides compounds of formula (II), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (Ci-C 6 ) alkyl-,
  • the invention provides compounds of formula (II), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • B is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -S- (Ci-C 6 ) alkyl-, -N(R N2 )- (C I -C 6 ) alkyl-,
  • R N2 is -H or - (Ci-C 6 ) alkyl, wherein R N4 and R N5 are each independently -H,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , R B , R3, Xi, X 2 , n, and p are as defined in formula (II) .
  • the invention provides compounds of the formula (III) ,
  • R N1 is -H or - (Ci-C 6 ) alkyl
  • X 2 is CH or N
  • Ri is -H, - (Ci-C 6 ) alkyl, - (Ci-C 6 ) alkyl-phenyl, or
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -S- (Ci-C 6 ) alkyl-, -S (O) 2 - (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -S (O) 2 - (Ci-C 6 ) alkyl-, -N (R N2 ) - (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -N (R N2 ) - (Ci-C 6 ) alkyl-, -N (R N2 ) C (0) - (Ci-C 6 ) alkyl-,
  • each R A is independently - (C 1 -C 6 ) alkoxy, - (C 1 -C 6 ) alkyl,
  • R N6 and R N7 are each independently -H,
  • R 3 is -H, - (Ci-C 6 ) alkyl, -allyl, -propargyl, -C (O) (C 1 -C 6 ) alkoxy, -C(O) (Ci-C 6 ) alkyl, or -C(O) (C 1 -C 6 )BIkYl-(C 3 -C 8 )CyClOaIkYl; and R B is - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention provides compounds of formula (III), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, and Li, R A , and n are as defined in formula (III) •
  • the invention provides compounds of formula (III), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -S- (Ci-C 6 ) alkyl-, -N(R N2 )- (Ci-C 6 ) alkyl-,
  • the invention provides compounds of formula (III), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -S- (Ci-C 6 ) alkyl-, -N(RN 2 )- (C I -C 6 ) alkyl-,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , RB, R3, Xi, X2, and n are as defined in formula (III) .
  • the invention provides compounds of formula (III), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; Li is - (CH 2 ) i-e-0- (Ci-C 6 ) alkyl- or
  • R A , RB, R3, Xi, X 2 , and n are as defined in formula (III) .
  • the invention provides compounds of the formula (IV) ,
  • R 1 is -H, - (C 1 -C 6 ) alkyl, - (C 1 -C 6 ) alkyl-phenyl, or
  • L 1 is -0- (C 1 -C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (C 1 -C 6 ) alkyl-, -S- (C 1 -C 6 ) alkyl-, - (CH 2 ) ⁇ 6 -S- (C 1 -C 6 ) alkyl-, -S (O) 2 - (C 1 -C 6 ) alkyl-, - (CH 2 ) i- 6 -S (O) 2 - (C 1 -C 6 ) alkyl-, -N (R N2 ) - (C 1 -C 6 ) alkyl-, - (CH 2 ) ⁇ 6 -N (R N2 ) - (C 1 -C 6 ) alkyl-, -N (R N2 ) C (0) - (C 1 -C 6 ) alkyl-,
  • each R A is independently - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • n 0, 1, 2, 3, or 4;
  • R 3 is -H, - (Ci-C 6 ) alkyl, -allyl, -propargyl, -C (0) (Ci-C 6 ) alkoxy, -C (0) (Ci-C 6 ) alkyl, or -C (0) (Ci-C 6 ) alkyl- (C 3 -C 8 ) cycloalkyl; and R B is - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl,
  • the invention provides compounds of formula (IV) , wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, and Li, R A , R B , RI, R3, and n are as defined in formula (IV) .
  • the invention provides compounds of formula (IV), wherein, A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -S- (Ci-C 6 ) alkyl-, -N(R N2 )- (Ci-C 6 ) alkyl-,
  • the invention provides compounds of formula (IV) , wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -S- (Ci-C 6 ) alkyl-, -N (R N2 ) -(Ci-C 6 ) alkyl-, - (CH 2 ) 1-6-N (R N2 ) - (Ci-C 6 ) alkyl - , wherein the alkyl portion of each of the above is substituted with 1, 2, 3, or 4 substituents that are independently - (Ci-C 6 ) alkyl, - (Ci-C 6 ) alkoxy,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , RB, R3, and n are as defined in formula (IV) .
  • the invention provides compounds of formula (IV), wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl;
  • L 1 is - (CH 2 ) 1- 6 -0- (Ci-C 6 ) alkyl- or
  • the invention provides compounds of formula (IV), wherein, A is phenyl, and L 1 , R A , R B , R 1 , R 3 , and n are as defined in formula (IV) .
  • the invention provides compounds of formula (IV), wherein, A is phenyl
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -S- (Ci-C 6 ) alkyl-, -N (R N2 ) -(Ci-C 6 ) alkyl-,
  • R A , RB, R I , R3, and n are as defined in formula (IV) .
  • the invention provides compounds of formula (IV), wherein, A is phenyl
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i- 6 -S- (Ci-C 6 ) alkyl-, -N (R N2 ) - (C 1 -C 6 ) alkyl-,
  • R 1 is -H, - (C 1 -C 6 ) alkyl, benzyl, or allyl; and R A , R B , R3, and n are as defined in formula (IV) .
  • the invention provides compounds of formula (IV), wherein, A is phenyl
  • R 1 is -H, - (C 1 -C 6 ) alkyl, benzyl, or allyl;
  • L 1 is - (CH 2 ) 1-6-0- (Ci-C 6 ) alkyl- or
  • R A , RB, Ra, and n are as defined in formula (IV) .
  • the invention provides compounds of the formula (V) or (VI),
  • Li is -0- (Ci-C b ) alkyl-, - (CH 2 ) i- b -0- (C 1 -C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -S- (Ci-C 6 ) alkyl-, -S (O) 2 - (Ci-C 6 ) alkyl-, - (CH 2 )i_ 6 -S (O) 2 - (Ci-C 6 ) alkyl-, -N (R N2 ) - (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -N (R N2 ) - (Ci-C 6 ) alkyl-, -N (R N2 ) C (0) - (Ci-C 6 ) alkyl-,
  • each R A is independently - (C 1 -C 6 ) alkoxy, - (C 1 -C 6 ) alkyl,
  • R N6 and R N7 are each independently -H,
  • n 0, 1, 2, 3, or 4;
  • R 3 is -H, - (C 1 -C 6 ) alkyl, -allyl, -propargyl, -C (0) (C 1 -C 6 ) alkoxy,
  • R B is - (Ci-C 6 ) alkoxy, - (Ci-C 6 ) alkyl
  • the invention provides compounds of formula (V) or (VI), wherein, Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -0- (Ci-C 6 ) alkyl-,
  • the invention provides compounds of formula (V) or (VI), wherein,
  • Li is -0- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -0- (Ci-C 6 ) alkyl-, -S- (Ci-C 6 ) alkyl-, - (CH 2 ) i_ 6 -S- (Ci-C 6 ) alkyl-, -N (R N2 ) -(Ci-C 6 ) alkyl-, - (CH 2 ) 1-6-N (R N2 ) - (Ci-C 6 ) alkyl - , wherein the alkyl portion of each of the above is substituted with 1, 2, 3, or 4 substituents that are independently - (Ci-C 6 ) alkyl, - (Ci-C 6 ) alkoxy,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; and R A , RB, R3, and n are as defined in formula (VI) .
  • the invention provides compounds of formula (V) or (VI), wherein,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl; Li is - (CH 2 )i- 6 -O- (Ci-C 6 ) alkyl- or
  • the invention provides compounds of formula (V) or (VI), wherein,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl;
  • Li is - (CH 2 ) 1-6-S- (Ci-C 6 ) alkyl-, wherein the alkyl portion of each of the above is substituted with 1, 2, 3, or 4 substituents that are independently - (Ci-C 6 ) alkyl, - (Ci-C 6 ) alkoxy, allyl, propargyl, -C(O) (Ci-C 6 ) alkoxy, acetyl, -halogen, or -N(R N4 R N5 ), wherein R N4 and R N5 are each independently -H,
  • the invention provides compounds of formula (V) or (VI), wherein,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl;
  • Li is - (CH 2 ) 1-6-S- (Ci-C 6 ) alkyl-, wherein the alkyl portion of each of the above is substituted with 1, 2, 3, or 4 substituents that are independently - (Ci-C 6 ) alkyl, - (Ci-C 6 ) alkoxy, allyl, propargyl, -C(O) (Ci-C 6 ) alkoxy, acetyl, -halogen, or -N(R N4 R N5 ), wherein R N4 and R N5 are each independently -H,
  • R 3 is -H or - (Ci-C 6 ) alkyl; and R A , R B , and n are as defined in formula (VI) .
  • the invention provides compounds of formula (V) or (VI), wherein,
  • Ri is -H, - (Ci-C 6 ) alkyl, benzyl, or allyl;
  • Li is - (CH 2 ) 1-6-S- (Ci-C 6 ) alkyl-, wherein the alkyl portion of each of the above is substituted with 1, 2, 3, or 4 substituents that are independently - (Ci-C 6 ) alkyl, - (Ci-C 6 ) alkoxy, allyl, propargyl, -C(O) (Ci-C 6 ) alkoxy, acetyl, -halogen, or -N(R N4 R N5 ), wherein R N4 and R N5 are each independently -H,
  • R 3 is -H or - (Ci-C 6 ) alkyl; RB is - (Ci-C 6 ) alkyl; and R A and n are as defined in formula (VI) .
  • the invention provides compounds of formula (V) or (VI), wherein,
  • Li is - (CH 2 ) 1-6-S- (Ci-C 6 ) alkyl-, wherein the alkyl portion of each of the above is substituted with 1, 2, 3, or 4 substituents that are independently - (Ci-C 6 ) alkyl, - (Ci-C 6 ) alkoxy, allyl, propargyl, -C(O) (Ci-C 6 ) alkoxy, acetyl, -halogen, or -N(R N4 R N5 ), wherein R N4 and R N5 are each independently -H,
  • R 3 is -H or - (Ci-C 6 ) alkyl
  • RB is - (Ci-C 6 ) alkyl
  • Ri is H; and R A and n are as defined in formula (VI) .
  • the invention includes synthetic intermediates that are useful in making the compounds of the invention .
  • the invention provides methods of preparing the compounds of the invention and the intermediates used in those methods.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable solvent, carrier, adjuvant, or excipient .
  • the invention provides a methods of treating Type I diabetes, Type II diabetes, and Syndrome X
  • the compounds of the invention inhibit PTP-IB, and therefore, are useful in the treating or controlling other PTP- IB mediated diseases, including controlling or treating Type 2 diabetes, improving glucose tolerance, and in improving insulin sensitivity in patients in need thereof.
  • the invention encompasses a method of inhibiting PTP-IB comprising administering to a patient in need thereof, either a pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention encompasses a method of treating cancer comprising administering to a patient in need thereof, either a pharmaceutically acceptable amount of a compound or salt of formula (I), or a pharmaceutical composition comprising a compound or salt of formula (I) .
  • the invention encompasses a method of treating neurodegenerative diseases comprising administering to a patient in need thereof, either a pharmaceutically acceptable amount of a compound or salt of formula (I), or a pharmaceutical composition comprising a compound or salt of formula (I) .
  • the invention provides a method of treating immunological disease comprising administering either a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
  • the invention provides a method of treating bleeding disorders comprising administering either a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
  • the invention also provides methods of using PTP-IB inhibitors of formula (I) for improving the cardiovascular or cerebrovascular risk profile in patients experiencing or subject to type II diabetes (non-insulin-dependent diabetes mellitus) or Syndrome X, preferably in patients experiencing or subject to human type II diabetes. These methods may also be characterized as the reduction of risk factors for heart disease, stroke, or heart attack in patients experiencing or subject to type II diabetes or Syndrome X.
  • the invention also provides methods and compositions for combination therapy of Type I diabetes, Type II diabetes, and Syndrome X.
  • Table 1 methods for using a pharmacological combination of one or more PTP-IB inhibitor and one or more combination agent are described for the treatment of Type II diabetes or Syndrome X in a patient in need of such treatment.
  • such treatments comprise administration of the inventive compounds of formula (I) as disclosed herein either concomitantly, simultaneously, or together with a therapeutically-effective amount of said additional compounds and medicaments.
  • combination therapy methods involving insulins as the associated agent the methods are for the treatment of Type I or Type II diabetes in a patient in need of such treatment.
  • Insulins useful with the methods and combinations of this invention include rapid acting insulins, intermediate acting insulins, long acting insulins and combinations of intermediate and rapid acting insulins.
  • Rapid acting commercially available insulin products include HUMALOG ® Brand Lispro Injection (rDNA origin); HUMULIN ® Regular Human Injection, USP [rDNA origin]; HUMULIN ® Regular U- 500 Concentrated Human Injection, USP [rDNA origin]; REGULAR ILETIN ® II (insulin injection, USP, purified pork) available from Eli Lilly and Co.; and the NOVALIN ® Human Insulin Injection and VENOSULIN ® BR Buffered Regular Human Injection, each available from Novo Nordisk Pharmaceuticals.
  • intermediate acting insulins useful with this invention include, but are not limited to, the HUMULIN ® L brand LENTE ® human insulin [rDNA origin] zinc suspension, HUMULIN ® N NPH human insulin [rDNA origin] isophane suspension, LENTE ® ILETIN. RTM.
  • Also useful with the methods and formulations of this invention are intermediate and rapid acting insulin combinations, such as the HUMALOG ® Mix 75/25 (75% Insulin Lispro Protamine Suspension and 25% Insulin Lispro Injection), HUMULIN ® 50/50 (50% Human Insulin Isophane Suspension and 50% Human Insulin Injection) and HUMULIN ® 70/30 (70% Human Insulin Isophane Suspension and 30% Human Insulin Injection), each available from Eli Lilly and Company. Also useful are the NOVALIN ® 70/30 (70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin Injection) line of combination products available from Novo Nordisk Pharmaceuticals.
  • a commercially available long acting insulin for use with this invention is the HUMULIN ® U Ultralente ® human insulin [rDNA origin] extended zinc suspension, available from Eli Lilly and Company.
  • inhaled insulin products such as the EXUBERA ® inhaled insulin product developed by Pfizer Inc. and Aventis SA.
  • Each of these insulin products can be administered as directed by a medical professional using administrations, dosages and regimens known in the art, such as those published for each product in the Physicians' Desk Reference, 55 Edition, 2001, published by Medical Economics Company, Inc. at Montvale, N.J., the relevant sections of which are incorporated herein by reference .
  • the compounds of general Formula (I) may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.
  • a pharmaceutical formulation comprising a compound of general Formula (I) and a pharmaceutically acceptable carrier.
  • One or more compounds of general Formula (I) may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients.
  • compositions containing compounds of general Formula (I) may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques. In some cases such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Formulations for oral use may also be presented as lozenges .
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil or a mineral oil or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring, and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the invention may also be administered in the form of suppositories, e.g., for rectal administration of the drug.
  • suppositories e.g., for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • Compounds of the invention may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w.
  • the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof.
  • the topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
  • the encapsulating agent may also function as the membrane.
  • the transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner.
  • the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier (s) with or without stabilizer (s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients.
  • suitable carrier especially an aqueous solvent for the active ingredients.
  • the antiinflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.
  • the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) .
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the composition may also be added to the animal feed or drinking water. It may be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to the feed or drinking water.
  • Preferred non- human animals include domesticated animals.
  • alkoxy represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge.
  • alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl .
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing the designated number of carbon atoms and containing at least one carbon-carbon double bond.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l- heptenyl, and 3-decenyl.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing the designated number of carbon atoms and containing at least one carbon- carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3- butynyl, 2-pentynyl, and 1-butynyl.
  • aryl refers to an aromatic hydrocarbon ring system containing at least one aromatic ring.
  • the aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings.
  • aryl groups include, for example, phenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthalene and biphenyl .
  • Preferred examples of aryl groups include phenyl, naphthyl, and anthracenyl . More preferred aryl groups are phenyl and naphthyl. Most preferred is phenyl .
  • cycloalkyl refers to a cyclic hydrocarbon, containing no heteroatoms .
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • halogen or halo indicate fluorine, chlorine, bromine, and iodine.
  • haloalkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy .
  • haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl .
  • heterocycloalkyl refers to a ring or ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein said heteroatom is in a non-aromatic ring.
  • the heterocycloalkyl ring is optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/or phenyl rings.
  • Preferred heterocycloalkyl groups have from 3 to 7 members.
  • heterocycloalkyl groups include, for example, 1 , 2 , 3, 4-tetrahydroisoquinolinyl, piperazinyl, morpholinyl, piperidinyl, tetrahydrofuranyl, pyrrolidinyl, pyridinonyl, and pyrazolidinyl .
  • Preferred heterocycloalkyl groups include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyridinonyl, dihydropyrrolidinyl, and pyrrolidinonyl .
  • heteroaryl refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings.
  • heteroaryl groups include, for example, pyridine, furan, thienyl, 5, 6, 7, 8-tetrahydroisoquinoline and pyrimidine.
  • heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl .
  • the compounds of this invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, chiral non-racemic or diastereomers . In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates.
  • Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound.
  • variable R B is as defined in formula (I) and Ra is as defined in formula (II) .
  • X represents halogens or leaving groups such as tosylate, triflate, mesylate, and the like, which are familiar to those skilled in the art.
  • Protecting groups are designated by P, and linkers are noted by L.
  • Z may consist of S, 0, or NR, where R is H or any substitution with does not interfere with an alkylation reaction .
  • brominating agents include elemental bromine, N- bromosuccinimide, DBU complex with hydrogen tribromide, or 2,4,4, 6-tetrabromo-2, 5-cyclohexadienone .
  • Amination of A2 with a primary amine to yield the secondary amine, A3, may be performed under palladium-catalyzed conditions according to Buchwald-Hartwig methodology, with Pd2(dba)3, a ligand, and a base.
  • Representative primary amines include, but are not limited to, alkyl and cyclic amines such as, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isoamylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, and aniline, any of which are readily commercially available or prepared by those skilled in the art.
  • the primary amine may be functionalized with any group which does not interfere with the catalytic amination reaction.
  • the palladium source may be, for example, Pd (PPh 3 ) 4 , Pd 2 (dba) 3 , Pd(OAc) 2 , PdCl 2 (PPh 3 ) 2, PdCl 2 (MeCN) 2, PdCl 2 (PhCN) 2 , PdCl 2 (dppf), PdCl 2 (dppp), PdCl 2 (dppe) , PdCl 2 (COD), Pd (PCy 3 ) 2 , or Pd(tBu 3 P) 2 , all of which are available commercially from either Aldrich Chemical (Milwaukee, WI) or Strem Chemical (Newburyport, MA) .
  • Appropriate ligands include t-Bu 3 P, BINAP, P (tBu 3 ) 2 (biphenyl) , P(2-furyl) 3 , dppe, dppp, dppf, and N- heterocyclic carbenes, such as Arduengo's carbene, N, N' - bis (2, 6-diisopropylphenyl) imidazol-2-ylidene, or N, N' - bis (2, 4, 6-trimethylphenyl) imidazolidin-2-ylidene, and the like.
  • Bases that may be utilized include NaOtBu, K 3 PO 4 , Cs 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , NaOAc, CsOAc, NaOMe, KOMe, KOH, NaOH, and the like.
  • amination of a haloarene, such as A2 with a primary amine may be achieved through copper catalysis, utilizing a copper (I) source, such as CuI or CuOAc, in the presence of K 3 PO 4 and a ligand.
  • a copper (I) source such as CuI or CuOAc
  • K 3 PO 4 K 3 PO 4
  • ligands include, for example, N,N-diethylsalicylamide or ethylene glycol.
  • A3 may be alkylated, in the presence of a base, with compounds of structure A4 or A4', where R' is any group which will not interfere with the subsequently required reactivity, such as phenyl, n-alkyl, s-alkyl, t-alkyl, and the like, to yield tertiary amines of structure A5.
  • bases include, but are not limited to, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , triethylamine, diethylisopropylamine, NaOH, and KOH.
  • Catalysts may be added to facilitate the reaction, including KI, n-Bu 4 NI, and the like. The preparation of A4 will be discussed below with respect to Scheme B.
  • Ester hydrolysis to the 2-hydroxymethyl thiazole derivative and subsequent conversion to the 2- halomethyl thiazole derivative yields compounds of structure A6.
  • Use of a nucleophilic activation and reaction agent such as PPh 3 Br 2 , PBr 3 , POBr 3 , or PPh 3 and CBr 4 yields the 2-bromomethyl thiazole derivative of structure A6;
  • the 2-chloromethyl thiazole derivative of structure A6 may be prepared analogously with PPh 3 Cl 2 , POCl 5 , PCl 5 , or PPh 3 and CCl 4 .
  • the 2- iodomethyl thiazole derivative of structure A6 may be prepared using PPh 3 I 2 .
  • the 2-halomethyl thiazole derivative, A6 may alkylate a thiol, alcohol, or amine under Williamson ether synthesis conditions, involving an appropriate base.
  • the thiol, alcohol, or amine necessarily includes an appropriately protected carboxylic acid.
  • bases include, but are not limited to, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , triethylamine, diethylisopropylamine, NaOH, and KOH.
  • deprotection of the carboxylic acid reveals compounds of structure A7, wherein Z may consist of S, 0, or NR, where R is H or any substitution with does not interfere with the preceding alkylation reaction.
  • an ester protecting group may be hydrolyzed under basic conditions to yield the carboxylic acid.
  • Appropriate thiols, alcohols, and amines for preparation of compounds of the present invention include, but are not limited to, N-BOC-protected amino acid esters, such as, alkyl N-BOC-Cys, alkyl N-BOC-Ser, alkyl N-BOC- Thr, alkyl N-BOC-His, alkyl N-BOC-Lys, alkyl N-BOC-Tyr, alkyl N-BOC homoserine, alkyl N-BOC homocysteine, and the like.
  • N-BOC-protected amino acid esters such as, alkyl N-BOC-Cys, alkyl N-BOC-Ser, alkyl N-BOC- Thr, alkyl N-BOC-His, alkyl N-BOC-Lys, alkyl N-BOC-T
  • Compounds of structure A4 may be prepared according to the conditions outlined in Scheme B. For example, condensation of 4- (bromoacetyl) benzoic acid with 2, 2-dimethylpropionic acid thiocarbamoylmethyl ester yields a thiazole of structure Bl, where R' is t-butyl .
  • the carboxylic acid may be reduced to the alcohol, by activation with benzotriazol-1- yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) in the presence of diisopropylamine (DIPA) followed by treatment with sodium borohydride.
  • methods for the reduction of the carboxylic acid in the presence of an ester include addition of 1, 1' -carbonyldiimidazole or a dicarbonate, such as di-t-butyl dicarbonate, diallyl dicarbonate, di-t-amyl dicarbonate, diethyl dicarbonate, dibenzyl dicarbonate, or dimethyl dicarbonate, followed by treatment with sodium borohydride; preparation of the N- succinimidyl ester, with N-hydroxysuccinimide and a coupling agent such as dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC), N- (3-dimethylaminopro ⁇ yl) -N' - ethylcarbodiimide (EDC) , diethylazodicarboxylate (DEAD) and triphenylphosphine, or the like, followed by reduction with sodium borohydride; and reduction with borane .
  • test compounds are evaluated for their in vitro inhibitory activity against recombinant human PTP-IB with phosphotyrosyl dodecapeptide TRDI(P)YETD(P)Y(P)YRK.
  • TRDI(P)YETD(P)Y(P)YRK phosphotyrosyl dodecapeptide
  • This corresponds to the 1142-1153 insulin receptor kinase regulatory domain, phosphorylated on the 1146, 1150 and 1151 tyrosine residues; IR-triphosphopeptide as a source of substrate.
  • Enzyme reaction progression is monitored via the release of inorganic phosphate as detected by the malachite green ammonium molybdate method for the phosphopeptide .
  • Preferred compounds of the invention exhibit IC 50 values of less than 10 ⁇ M; more preferred compounds of the invention exhibit IC 5 O values of less than 1 ⁇ M. Particularly preferred compounds exhibit IC 50 values of less than 300 nM.

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Abstract

L'invention concerne des composés et des sels pharmaceutiquement acceptables de formule (I) et qui sont utiles dans le traitement de troubles métaboliques liés à l'insulinorésistance, à la résistance à la leptine ou à l'hyperglycémie. Les composés de l'invention comprennent des inhibiteurs des protéines tyrosines phosphatases, notamment la protéine tyrosine phosphatase-1B (PTB-1B), qui sont utiles dans le traitement du diabète et autres maladies induites par PTP telles que le cancer, les maladies neurodégénératives et analogues. L'invention concerne également des compositions pharmaceutiques comprenant ces composés et des méthodes de traitement des états précités au moyen de ces composés.
PCT/US2007/078283 2006-09-13 2007-09-12 Acides carboxyliques de biarylthiazole WO2008033932A2 (fr)

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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
US8106209B2 (en) 2008-06-06 2012-01-31 Achillion Pharmaceuticals, Inc. Substituted aminothiazole prodrugs of compounds with anti-HCV activity
US8183263B2 (en) 2007-05-22 2012-05-22 Achillion Pharmaceuticals, Inc. Heteroaryl substituted thiazoles
US8216582B2 (en) 2006-06-23 2012-07-10 Alethia Biotherapeutics Inc. Polynucleotides and polypeptide sequences involved in cancer
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US8580257B2 (en) 2008-11-03 2013-11-12 Alethia Biotherapeutics Inc. Antibodies that specifically block the biological activity of kidney associated antigen 1 (KAAG1)
US8937163B2 (en) 2011-03-31 2015-01-20 Alethia Biotherapeutics Inc. Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
US11084872B2 (en) 2012-01-09 2021-08-10 Adc Therapeutics Sa Method for treating breast cancer

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Cited By (19)

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Publication number Priority date Publication date Assignee Title
US8216582B2 (en) 2006-06-23 2012-07-10 Alethia Biotherapeutics Inc. Polynucleotides and polypeptide sequences involved in cancer
US8183263B2 (en) 2007-05-22 2012-05-22 Achillion Pharmaceuticals, Inc. Heteroaryl substituted thiazoles
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
US8106209B2 (en) 2008-06-06 2012-01-31 Achillion Pharmaceuticals, Inc. Substituted aminothiazole prodrugs of compounds with anti-HCV activity
US8580257B2 (en) 2008-11-03 2013-11-12 Alethia Biotherapeutics Inc. Antibodies that specifically block the biological activity of kidney associated antigen 1 (KAAG1)
US9855291B2 (en) 2008-11-03 2018-01-02 Adc Therapeutics Sa Anti-kidney associated antigen 1 (KAAG1) antibodies
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
US9393302B2 (en) 2011-03-31 2016-07-19 Alethia Biotherapeutics Inc. Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
US8937163B2 (en) 2011-03-31 2015-01-20 Alethia Biotherapeutics Inc. Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
US9828426B2 (en) 2011-03-31 2017-11-28 Adc Therapeutics Sa Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
US10597450B2 (en) 2011-03-31 2020-03-24 Adc Therapeutics Sa Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US11084872B2 (en) 2012-01-09 2021-08-10 Adc Therapeutics Sa Method for treating breast cancer

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