WO2008033931A1 - Acides carboxyliques de para-xylylène et isothiazolones utiles comme protéines tyrosine phosphatases (ptps) en particulier ptp-ib - Google Patents

Acides carboxyliques de para-xylylène et isothiazolones utiles comme protéines tyrosine phosphatases (ptps) en particulier ptp-ib Download PDF

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WO2008033931A1
WO2008033931A1 PCT/US2007/078282 US2007078282W WO2008033931A1 WO 2008033931 A1 WO2008033931 A1 WO 2008033931A1 US 2007078282 W US2007078282 W US 2007078282W WO 2008033931 A1 WO2008033931 A1 WO 2008033931A1
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alkyl
alkoxy
compound according
independently
alkenyl
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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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the invention relates to para-xylylene 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 ignaling pathway and improves insulin-sensitivity.
  • PTPs Protein tyrosine phosphatases
  • PTP-IB Protein tyrosine phosphatase-lB
  • This invention relates to a class of para-xylylene 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 ubstrates 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 ntracellular protein, which is present in abundant amounts in various human tissues (Charbonneau et al . , 1989, Proc. Natl.
  • GST glutathione S-transferase
  • 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, n the antibody-loaded cells.
  • the antibody-loaded cells also howed a 57% increase in insulin stimulated insulin receptor kinase activity toward exogenous peptide substrates.
  • a drug that mproved insulin sensitivity would have several advantages over traditional therapy of NIDDM using sulfonylureas, which do not alleviate insulin resistance but instead compensate by ncreasing insulin secretion.
  • Ragab et al (2003, J. Biol. Chem 278(42), 40923-32) howed that PTP-IB is involved in regulating platelet aggregation. Hence, inhibition of PTP-IB can be predicted to have an effect on bleeding disorder, and cardiovascular disease .
  • PTP-IB deficient mice show enhanced potency for exogenous leptin to suppress food intake Cheng, et al . Developmental Cell 2:497-503, 2002).
  • nhibitors of PTP-IB augment the beneficial effects of leptin on food intake, body weight regulation and metabolism, in normal individuals and leptin resistant individuals. Therefore, inhibitors of PTPs, and inhibitors of PTP-IB in particular, 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 cancer, neurodegenerative diseases, immunological disorders, bleeding and cardiovascular disorders, and the ike.
  • the invention provides compounds of formula (I) shown below, pharmaceutically acceptable salts of the compounds pharmaceutical compositions containing the compounds or salts, and methods employing such compounds or compositions in the treatment of diabetes and/or cancer.
  • the invention provides compounds of Formula (I) :
  • R is -H, -OH, - (C 1 -C 6 ) alkyl, - (C 1 -C 6 ) alkoxy, -aryl, - heteroaryl, - (C3-C8) cycloalkyl, heterocycloalkyl, -C (0) (C 1 -C 6 ) alkoxy, -C (0) (C 1 -C 6 ) alkyl, or -C(O) aryl;
  • R 3 is -H, -halo, -amino, -NO 2 , -CN, -COOH, -C (0) (C 1 -C 6 ) alkoxy, - (C 1 -C 6 ) alkyl, -aryl, -heteroaryl, (C3-C8) cycloalkyl, -heterocycloalkyl;
  • q is 0 1 X 1 is 0, S, or N(R) ;
  • X 2 is S
  • R 1 is -H, - (C 1 -C 6 ) alkyl, - (C 1 -C 6 ) alkyl-phenyl, or
  • L 1 is a bond, - (C3-C8) cycloalkyl-, -heterocycloalkyl-,
  • Y is -O-, -S-, -S(O) 2 -, -N(R N1 )-, -N (R N1 ) C (0) -, -C (0) N (R N1 ) -, -S(O) 2 N(R N1 )-, -N(R N1 )S(O) 2 -, - (C 1 -C 6 ) alkyl-O-, -0- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-,
  • R N1 and R N2 are independently -H or -(C 1 -C 6 ) alkyl, wherein R N3 and R N4 are each independently -H,
  • each R 2 is independently - (C 1 -C 6 ) alkoxy, - (C 1 -C 6 ) alkyl,
  • R N5 and R N6 are each independently -H, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl,
  • R N7 is -H, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • n 0, 1, 2, 3, or 4.
  • Another aspect of the invention provides synthetic ntermediates that are useful in making the compounds of the nvention .
  • Another aspect of the invention provides methods of preparing the compounds of the invention and the intermediates used in those methods.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof 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
  • Another aspect of 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 pharmaceutically acceptable alt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof .
  • Another aspect of the invention provides methods of treating diseases such as Type I and Type II diabetes, yndrome X, obesity, cancer, neurodegenerative disease, mmunological disease, bleeding disorders, and cardiovascular disease in a patient in need of such treatment, comprising administering to the patient 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.
  • Another aspect of 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Another aspect of 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 diabetes, Type II diabetes, and Syndrome X comprise administration ormula (I) as disclosed herein concomitantly, simultaneously or together with a therapeutically-effective amount of said additional compounds and medicaments.
  • Another aspect of the invention provides the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in treating diabetes or cancer or other diseases related to PTPs.
  • Another aspect of the invention provides compounds of formula (I) and the pharmaceutically acceptable salts thereof, wherein A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, and D, L 1 , L2, RA, Ri/ R2/ in, and n are as defined in formula I) .
  • Another aspect of the invention provides compounds of formula (I) and the pharmaceutically acceptable salts thereof, wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • L 1 is -O-, -S-, -N(R N1 )-, - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-,
  • Li is -0-, -S-, -S(O) 2 -, -N(R N i)-, -N (R N i) C (0) -, -C (0) N (R N1 ) -, -S(O) 2 N(R N i)-, -N(R N i)S(O) 2 -, - (C 1 -C 6 ) alkyl-O-, -0- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-S-, -S- (C 1 -C 6 ) alkyl-,
  • each R 2 is independently - (C 1 -C 6 ) alkoxy, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (C 1 -C 6 ) alkoxy, -C (0) (C 1 -C 6 ) alkyl, or -C(O)H; each R 2 is independently - (C 1 -C 6 ) alkoxy, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C (0) (C 1 -C 6 ) alkoxy, -C(O) (C 1 -C 6 ) alkyl, -C(O)OH, -CN, - (C 1 -C 6 ) haloalkoxy,
  • -C (0) C 1 -C 6 ) alkyl- (C 3 -C 8 ) cycloalkyl, or -C(O)H
  • A is -aryl- or -heteroaryl-; each R A is independently - (C 1 -C 6 ) alkoxy, - (C 1 -C 6 ) alkyl,
  • n 0, 1, 2, 3, or 4.
  • Another aspect of the invention provides compounds of formula (II) and the pharmaceutically acceptable salts thereof, wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl, and L 1 , R A , R 1 , R 2 , R 3 , m, and n are as defined in formula (II) .
  • Another aspect of the invention provides compounds of formula (II) and the pharmaceutically acceptable salts thereof, wherein,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, or pyrazolyl;
  • L 1 is -0-, -S-, -N(R N1 )-, - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-,
  • R A , R 1 , R 2 , R 3 , m, and n are as defined in formula (II) .
  • Another aspect of the invention provides compounds of formula (II) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is -0-, -S-, -N(R N i)-, - (C 1 -C 6 ) alkyl-0- (C 1 -C 6 ) alkyl-,
  • Another aspect of the invention provides compounds of formula (III),
  • R 1 is -H, - (C 1 -C 6 ) alkyl, - (C 1 -C 6 ) alkyl-phenyl, or - (C 3 -C 6 ) alkenyl;
  • L 1 is -0-, -S-, -S(O) 2 -, -N(R N1 )-, -N (R N1 ) C (0) -, -C (0) N (R N1 ) -, -S(O) 2 N(RN 1 )-, -N(RN 1 )S(O) 2 -, - (C 1 -C 6 ) alkyl-0-, -0- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-0- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl- (C 1 -C 6 ) alkyl-S- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-S (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-S (C 1 -C
  • R N1 and R N2 are independently -H or
  • each R 2 is inde kyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C(O) (C 1 -C 6 ) alkoxy, -C (0) (C 1 -C 6 ) alkyl, or -C(O)H; each R 2 is inde kyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C (0) (C 1 -C 6 ) alkoxy, -C (0) (C 1 -C 6 ) alkyl, -C(O)OH, -CN, - (C 1 -C 6 ) haloalkoxy,
  • R A is - (C 1 -C 6 ) alkoxy, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, - (C 2 -C 6 ) alkynyl, -C (0) (C 1 -C 6 ) alkoxy, -C (0) (C 1 -C 6 ) alkyl, -C(O)OH, -CN, - (C 1 -C 6 ) haloalkoxy,
  • Another aspect of the invention provides compounds of formula (III) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is -0-, -S-, -N(R N i)-, - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-,
  • R A , R 1 , R 2 , R 3 , and m are as defined in formula (III) .
  • Another aspect of the invention provides compounds of formula (IV) ,
  • R 1 is -H, - (C 1 -C 6 ) alkyl, - (C 1 -C 6 ) alkyl-phenyl, or
  • L 1 is -0-, -S-, -S(O) 2 -, -N(R N1 )-, -N (R N1 ) C (0) -, -C (0) N (R N1 ) -, -S(O) 2 N(R N1 )-, -N(R N1 )S(O) 2 -, - (C 1 -C 6 ) alkyl-0-, -0- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-0- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-0- (C 1 -C 6 ) alkyl-,
  • each R 2 is independently -(C 1 -C 6 JaIkOXy, - (C 1 -C 6 ) alkyl,
  • Another aspect of the invention provides compounds of formula (IV) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is -0-, -S-, -N(R N1 )-, - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-S-, -S- (C 1 -C 6 ) alkyl-,
  • R N1 is -H or - (C 1 -C 6 ) alkyl
  • R N3 and R N 4 are each independently -H, - (C 1 -C 6 ) alkyl
  • R A , R 1 , R 2 , R3, and m are as defined in formula (IV) .
  • Another aspect of the invention provides compounds of formula (IV) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is - (C 1 -C 6 ) alkyl-0- (C 1 -C 6 ) alkyl- or
  • R N3 and R N 4 are each - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, -(C 2 - C 6 ) alkynyl,
  • L 1 is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl- or
  • R 3 is -H, - (C 1 -C 6 ) alkyl, -C (0) (C 1 -C 6 ) alkyl, or
  • Another aspect of the invention provides compounds of formula (IV) and the pharmaceutically acceptable salts thereof, wherei L 1 is - (C 1 -C 6 ) alkyl-0- (C 1 -C 6 ) alkyl- or
  • R 3 is -H, - (C 1 -C 6 ) alkyl, -C (0) (C 1 -C 6 ) alkyl, or
  • L 1 is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl- or
  • R 3 is -H, - (C 1 -C 6 ) alkyl, -C (0) (C 1 -C 6 ) alkyl, or
  • Another aspect of the invention provides compounds of formula (IV) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is - (C 1 -C 6 ) alkyl-0- (C 1 -C 6 ) alkyl- or - (C 1 -C 6 ) alkyl-S- (C 1 -C 6 ) alkyl-, wherein, the alkyl portion of each of the above is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R 3 is -H, - (C 1 -C 6 ) alkyl, -C (0) (C 1 -C 6 ) alkyl, or
  • Another aspect of the invention provides compounds of formula (V) ,
  • R 1 is -H, - (C 1 -C 6 ) alkyl, - (C 1 -C 6 ) alkyl-phenyl, or
  • L 1 is -0-, -S-, -S(O) 2 -, -N(R N i)-, -N (R N1 ) C (0) -, -C(O)N(R N1 )- -S(O) 2 N(R N1 )-, -N(R 111 )S(O) 2 -, - (C 1 -C 6 ) alkyl-O-,
  • each R 2 is independently -(C 1 -C 6 JaIkOXy, - (C 1 -C 6 ) alkyl,
  • Another aspect of the invention provides compounds of formula (V) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is -0-, -S-, -N(R N1 )-, - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-S-, -S- (C 1 -C 6 ) alkyl-,
  • R N1 is -H or - (C 1 -C 6 ) alkyl
  • R N3 and R N 4 are each independently -H, - (C 1 -C 6 ) alkyl
  • R A , R 1 , R 2 , R3, and m are as defined in formula (V) .
  • Another aspect of the invention provides compounds of formula (V) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is - (C 1 -C 6 ) alkyl-0- (C 1 -C 6 ) alkyl- or
  • R N3 and R N 4 are each - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, -(C 2 - C 6 ) alkynyl,
  • R A , R 1 , R 2 , R 3 , and m are as defined in formula (V) .
  • Another aspect of the invention provides compounds of formula (V) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl- or - (C 1 -C 6 ) alkyl-S- (C 1 -C 6 ) alkyl-, wherein, the alkyl portion of each of the above is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R 3 is -H, - (C 1 -C 6 ) alkyl, -C (0) (C 1 -C 6 ) alkyl, or -C(O) (C 1 -C 6 ) alkyl- (C 3 -C 8 ) cycloalkyl; and R A , R 1 , R 2 , and m are as defined in formula (V) .
  • Another aspect of the invention provides compounds of formula (V) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl- or - (C 1 -C 6 ) alkyl-S- (C 1 -C 6 ) alkyl-, wherein, the alkyl portion of each of the above is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R 3 is -H, - (C 1 -C 6 ) alkyl, -C (0) (C 1 -C 6 ) alkyl, or -C(O) (C 1 -C 6 ) alkyl- (C 3 -C 8 ) cycloalkyl;
  • R A is - (C 1 -C 6 ) alkyl or benzyl; and R 1 , R 2 , and m are as defined in formula (V) .
  • Another aspect of the invention provides compounds of formula (V) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl- or - (C 1 -C 6 ) alkyl-S- (C 1 -C 6 ) alkyl-, wherein, the alkyl portion of each of the above is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R 3 is -H, - (C 1 -C 6 ) alkyl, -C (0) (C 1 -C 6 ) alkyl, or -C(O) (C 1 -C 6 ) alkyl- (C 3 -C 8 ) cycloalkyl;
  • R A is - (C 1 -C 6 ) alkyl or benzyl; R 1 is H; and R 2 and m are as defined in formula (V) .
  • Another aspect of the invention provides compounds of formula (V) and the pharmaceutically acceptable salts thereof, wherein,
  • L 1 is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl- or - (C 1 -C 6 ) alkyl-S- (C 1 -C 6 ) alkyl-, wherein, the alkyl portion of each of the above is optionally substituted with 1, 2, 3, or 4 substituents that are independently
  • R N3 and R N4 are each independently -H, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl, -(C 2 -
  • R 3 is -H, - (C 1 -C 6 ) alkyl, -C (0) (C 1 -C 6 ) alkyl, or -C(O) (C 1 -C 6 ) alkyl- (C 3 -C 8 ) cycloalkyl;
  • R A is - (C 1 -C 6 ) alkyl or benzyl; R 1 is H; R 2 is H; and m is as defined in formula (V) .
  • Another aspect of the invention provides compounds of formula (I) and the pharmaceutically acceptable salts thereof, wherein
  • L 2 is - (C 1 -C 6 ) alkyl-N (R N7 ) - (C 1 -C 6 ) alkyl-, wherein the alkyl portions are each optionally substituted with one group which is - (C 1 -C 6 ) alkyl, -aryl, -(C 3 - C 8 ) cycloalkyl, -heterocycloalkyl, -heteroaryl, -COOH, or -C (0) (C 1 -C 6 ) alkoxy; and R N7 is -H or - (C 1 -C 6 ) alkyl; and A, D, R A , R 1 , R 2 , m and n are as defined in Formula (I) .
  • Another aspect of the invention provides compounds of Formula (VI) , O N ⁇ Y ⁇ O° Ri
  • Another aspect of the invention provides compounds of Formula (VI) and the pharmaceutically acceptable salts thereof, wherein
  • Y is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-,
  • R N3 and R N4 are each independently -H,
  • Another aspect of the invention provides compounds of Formula (VI) and the pharmaceutically acceptable salts thereof, wherei A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, or dibenzofuryl; and wherein L 2 , R A , R I , R2, Y, m and n are as defined in Formula D •
  • Another aspect of the invention provides compounds of Formula (VII),
  • Another aspect of the invention provides compounds of Formula (VII) and the pharmaceutically acceptable salts thereof, wherein
  • Y is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-,
  • R A , R I , R2, m and n are as defined in Formula (I) .
  • Another aspect of the invention provides compounds of Formula (VII) and the pharmaceutically acceptable salts thereof, wherein
  • R 1 is H ;
  • Y is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-,
  • R N3 and R N4 are each independently -H, - (C 1 -C 6 ) alkyl, -C (0) (C 1 -C 6 ) alkoxy, or
  • R A , R2, m and n are as defined in Formula (I) .
  • Another aspect of the invention provides compounds of Formula (VII) and the pharmaceutically acceptable salts thereof,
  • L 2 is - (C 1 -C 6 ) alkyl-N (R N7 ) -, -N (R N7 ) - (C 1 -C 6 ) alkyl-, or - (C 1 -C 6 ) alkyl-N (R N7 ) - (C 1 -C 6 ) alkyl-, wherein each carbon is independently, and optionally substituted with one group which is - (C 1 -C 6 ) alkyl, - aryl, - (C 3 -C 8 ) cycloalkyl, -heterocycloalkyl, heteroaryl, -COOH, or -C (0) (C 1 -C 6 ) alkoxy; and R N 7 is -H, - (C 1 -C 6 ) alkyl, - (C 2 -C 6 ) alkenyl,
  • R A , R 1 , R 2 , Y, in and n are as defined in Formula (I) .
  • Another aspect of the invention provides compounds of Formula (VIII),
  • Another aspect of the invention provides compounds of Formula (VIII) and the pharmaceutically acceptable salts thereof, wherein
  • Y is - (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) alkyl-, - (C 1 -C 6 ) alkyl-S- (C 1 -C 6 ) alkyl- or
  • R N3 and R N4 are each independently -H, - (C 1 -C 6 ) alkyl, -C (0) (C 1 -C 6 ) alkoxy, or -C(O) (C 1 -C 6 ) alkyl; and R N7 , R A , R 1 , R 2 , m and n are as defined in Formula (I) .
  • Another aspect of the invention provides compounds of Formula (VIII) and the pharmaceutically acceptable salts thereof, wherein
  • R N7 and one of R A taken together are - (CH 2 ) q - and connect the nitrogen to which R N7 is attached to A, wherein q is 2, 3 or 4; and R A , R 1 , R 2 , Y, m and n are as defined in Formula (I) .
  • Another aspect of the invention provides compounds of Formula (VIII) and the pharmaceutically acceptable salts thereof, wherein R 1 is H; and R N7 , R A , R 2 , Y, m and n are as defined in Formula (I) .
  • Another aspect of the invention provides compounds of Formula (I) and the pharmaceutically acceptable salts thereof, wherein
  • R is -H, -OH, - (C 1 -C 6 ) alkyl, - (C 1 -C 6 ) alkoxy, aryl, - heteroaryl, - (C 3 -C 8 ) cycloalkyl, heterocycloalkyl,
  • R 3 is -H, -halo, -amino, -NO 2 , -CN, -COOH, -C (0) (C 1 -C 6 ) alkoxy, - (C 1 -C 6 ) alkyl, -aryl, -heteroaryl, -
  • X 1 is 0, S, or N(R) ;
  • X 2 is S(0) p , wherein p is 0, 1, or 2; bond a is a single or double bond, provided that if a is a double bond, then q is 0 or 1; and A, L 2 , R A , R 1 , R 2 , m and n are as defined in Formula (I) . uch compounds are refered to herein as compounds of Formula IX) .
  • Another aspect of the invention provides compounds of Formula (IX) and the pharmaceutically acceptable salts thereof, wherein
  • L 2 is a bond; and A, L 2 , R A , R 1 , R 2 , m and n are as defined in Formula (I) .
  • Another aspect of the invention provides compounds of Formula (X) ,
  • A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, or dibenzofuryl; and R, Ri, R2, Xi, X2, in and n are as defined in Formula (I) .
  • Another aspect of the invention provides compounds of
  • Xi is O or S; R is -H or - (C 1 -C 6 ) alkyl; A is phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazolyl, pyrimidyl, imidazolyl, furanyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, or dibenzofuryl ; and Ri, R2, X2, m and n are as defined in Formula (I) .
  • Another aspect of the invention provides synthetic ntermediates that are useful in making the compounds of the nvention .
  • Another aspect of the invention provides methods of preparing the compounds of the invention and the intermediates used in those methods.
  • Another aspect of 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 .
  • Another aspect of the invention provides methods of treating T d Syndrome X (consisting of such abnormalities as obesity, dyslipidemia, hypercoagulation, hypertension, insulin resistance and leading to heart disease and diabetes) , comprising administering 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 to a patient n need of such treatment.
  • the compounds of the present 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 nsulin sensitivity in patients in need thereof.
  • Another aspect of the invention provides a method of nhibiting 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.
  • Another aspect of the invention provides a method of treating cancer 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.
  • Another aspect of the invention provides a method of treating neurodegenerative diseases 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.
  • Another aspect of the invention provides a method of treating immunological disease comprising administering 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 to a patient n need of such treatment.
  • Another aspect of the invention provides a method of treating bleeding disorders comprising administering 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 to a patient n need of such treatment.
  • the invention also provides methods of using PTP-IB nhibitors of formula (I) for improving the cardiovascular or cerebrovascular risk profile in patients experiencing or ubject 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 ubject 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 yndrome X in a patient in need of such treatment.
  • such treatments comprise administration of the inventive compounds of formula (I) as disclosed her aneously, 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 nsulins, long acting insulins and combinations of ntermediate and rapid acting insulins.
  • Rapid acting commercially available insulin products nclude HUMALOG ® Brand Lispro Injection (rDNA origin); HUMULIN ® Regular Human Injection, USP [rDNA origin]; HUMULIN ® Regular U- 00 Concentrated Human Injection, USP [rDNA origin]; REGULAR LETIN ® II (insulin injection, USP, purified pork) available from Eli Lilly and Co.; and the NOVALIN ® Human Insulin njection 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 uspension, HUMULIN ® N NPH human insulin [rDNA origin] isophane uspension, LENTE ® ILETIN. RTM.
  • Also useful with the methods and formulations of this nvention are intermediate and rapid acting insulin combinations, such as the HUMALOG ® Mix 75/25 (75% Insulin Lispro Protamin ro 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 0% 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 nsulin products such as the EXUBERA ® inhaled insulin product developed by Pfizer Inc. and Aventis SA.
  • 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), ntramuscular, or intrathecal injection or infusion techniques and the like.
  • a pharmaceutical formulation com ula (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, uch 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 ca 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.
  • Formulations for oral use may also be presented as ozenges .
  • 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, uch 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 uch 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 uch as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Swee 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 for example sweetening, flavoring and coloring agents, may also be present.
  • compositions of the invention may also be n 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 terile injectable aqueous or oleaginous suspension. This uspension 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 uspension in e 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 present 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 present 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 ocal 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 n a cream with an oil-in-water cream base
  • the topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the kin 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.
  • 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
  • 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.
  • 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 uch 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 nvention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with actose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium tearate, mag um 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 non-aqueous isotonic sterile injection solutions or uspensions. 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 40 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 ngredient 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 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. t 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. Examples of 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.
  • alkyl include, but are not imited 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.
  • alkenyl include, but are not imited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pe 2-methyl-1- heptenyl, a
  • 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.
  • 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 ystem 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.
  • 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 imited 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 imited 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.
  • 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. Examples of heterocycloalkyl groups include, for example, , 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, midazolyl, 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 f 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.
  • brominating agents include elemental bromine, N- bromosuccinimide, DBU complex with hydrogen tribromide, or ,4,4, 6-tetrabromo-2, 5-cyclohexadienone .
  • Amination of A2 with a primary amine to yield the econdary 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 n ic amination reaction.
  • the palladium source may be, for example, Pd (PPh 3 ) 4 ,
  • PdCl 2 (dppf), PdCl 2 (dppp), PdCl 2 (dppe) , PdCl 2 (COD), Pd (PCy 3 ) 2 , or
  • Ligands can include tBu 3 P, BINAP,
  • Bases that may be utilized include NaOtBu, K 3 PO 4 , Cs 2 CO 3 ,
  • 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 with a p- (bis (halomethyl) benzene) under Williamson ether synthesis conditions, involving an appropriate base to give the tertiary amine, A4.
  • bases nclude, 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.
  • this reaction may produce a mixture of the desired product, A4, with a dimeric compound consisting of the addition of two equivalents of A3 to the p- bis (halomethyl) benzene) .
  • A4 may be alkylated with a thiol, alcohol, or amine under conditions similar to conversion of A3 to A4 discussed previously.
  • the thiol, alcohol, or amine necessarily includes an appropriately protected carboxylic acid. Those skilled in the art will recognize that any of a number of protecting groups may be used for protection of the carboxylic acid.
  • Appropriate groups include, but are not limited to, benzylic (CBZ) , trityl, 2-nitrobenzyl, t-butyl, tetrahydropyranyl (THP) , trimethylsilyl (TMS), triisopropylsilyl (TIPS), t- butyldimethylsilane (TBDMS), and the like.
  • THP trimethylsilyl
  • TIPS triisopropylsilyl
  • TDMS t- butyldimethylsilane
  • bases include, but are not limited to, Na2CO3, K2CO3, CS2CO3, triethylamine, diethylisopropylamine, NaOH, and KOH.
  • deprotection of the carboxylic acid reveals compounds of structure A5, wherein Z may consist of S, 0, or NR, where R is H or any ubstitution with does not interfere with the preceding alkylation reaction.
  • R is H or any ubstitution with does not interfere with the preceding alkylation reaction.
  • an ester protecting group may be hydrolyzed under basic conditions to yield the carboxylic acid.
  • thiols, alcohols, and amines for preparation of compounds of the present invention include, but are not limited to, 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; straight and branched alkyl thiols, alcohols, and amines such as alkyl mercaptoacetates, alkyl 2-mercaptopropanoates, alkyl 3- mercaptopropanoates, alkyl hydroxyacetates, alkyl 2- hydroxypropanoates, alkyl 3-hydroxypropanoates, alkyl glycinates, alkyl beta-alaninates, alkyl alinates
  • Example 1 The following compounds are prepared essentially as outlined above in Schemes A-C:
  • test compounds are evaluated for their in vitro nhibitory 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 ubstrate.
  • 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 IC50 values of less than 10 ⁇ M; more preferred compounds of the invention exhibit IC50 values of less than 1 ⁇ M. Particularly preferred compounds exhibit IC50 values of less than 300 nM.

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Abstract

L'invention concerne des composés et des sels pharmaceutiquement acceptables de formule (I) dans laquelle A, D, L2, RA, R1, R2, m et n sont tels que définis dans le descriptif 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/US2007/078282 2006-09-13 2007-09-12 Acides carboxyliques de para-xylylène et isothiazolones utiles comme protéines tyrosine phosphatases (ptps) en particulier ptp-ib WO2008033931A1 (fr)

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Cited By (14)

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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
WO2012046869A1 (fr) 2010-10-08 2012-04-12 持田製薬株式会社 Dérivé d'amide cyclique
WO2012147516A1 (fr) 2011-04-28 2012-11-01 持田製薬株式会社 Dérivé d'amide cyclique
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
US8455500B2 (en) 2009-10-30 2013-06-04 Mochida Pharmaceutical Co., Ltd. 3-hydroxy-5-arylisoxazole derivative
US8476287B2 (en) 2009-12-25 2013-07-02 Mochida Pharmaceutical Co., Ltd. 3-hydroxy-5-arylisothiazole derivative
US8557766B2 (en) 2011-04-27 2013-10-15 Mochida Pharmaceutical Co., Ltd. 3-hydroxyisothiazole 1-oxide derivatives

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
US8455500B2 (en) 2009-10-30 2013-06-04 Mochida Pharmaceutical Co., Ltd. 3-hydroxy-5-arylisoxazole derivative
US8476287B2 (en) 2009-12-25 2013-07-02 Mochida Pharmaceutical Co., Ltd. 3-hydroxy-5-arylisothiazole derivative
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
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation 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
WO2012046869A1 (fr) 2010-10-08 2012-04-12 持田製薬株式会社 Dérivé d'amide cyclique
JP2016028072A (ja) * 2010-10-08 2016-02-25 持田製薬株式会社 環状アミド誘導体
JP5809157B2 (ja) * 2010-10-08 2015-11-10 持田製薬株式会社 環状アミド誘導体
US9040525B2 (en) 2010-10-08 2015-05-26 Mochida Pharmaceutical Co., Ltd. Cyclic amide derivative
US8765752B2 (en) 2011-04-27 2014-07-01 Mochida Pharmaceutical Co., Ltd. 3-hydroxyisothiazole 1-oxide derivatives
US8629102B2 (en) 2011-04-27 2014-01-14 Mochida Pharmaceutical Co., Ltd. 3-hydroxyisothiazole 1-oxide derivatives
US8557766B2 (en) 2011-04-27 2013-10-15 Mochida Pharmaceutical Co., Ltd. 3-hydroxyisothiazole 1-oxide derivatives
JPWO2012147516A1 (ja) * 2011-04-28 2014-07-28 持田製薬株式会社 環状アミド誘導体
US9072758B2 (en) 2011-04-28 2015-07-07 Mochida Pharmaceutical Co., Ltd. Cyclic amide derivative
WO2012147516A1 (fr) 2011-04-28 2012-11-01 持田製薬株式会社 Dérivé d'amide cyclique
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

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