| Anilinopyrazole derivatives useful for the treatment of diabetes -> Monitor Keywords |
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Anilinopyrazole derivatives useful for the treatment of diabetesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Five-membered Hetero Ring Containing At Least One Nitrogen Ring Atom (e.g., 1,2,3-triazoles, Etc.), Tetrazoles (including Hydrogenated), PyrazolesAnilinopyrazole derivatives useful for the treatment of diabetes description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080064734, Anilinopyrazole derivatives useful for the treatment of diabetes. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims benefit of U.S. Provisional Application Ser. No. 60/429,917, filed Nov. 27, 2002, and U.S. Provisional Application Ser. No. 60/498,214, filed on Aug. 27, 2003, the contents of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION [0002] The present invention relates to anilinopyrazole compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders. BACKGROUND OF THE INVENTION [0003] Diabetes is characterized by impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patient. Underlying defects lead to a classification of diabetes into two major groups. Type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), arises when patients lack insulin-producing beta-cells in their pancreatic glands. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), occurs in patients with impaired beta-cell function and alterations in insulin action. [0004] The current treatment for type 1 diabetic patients is injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin. The drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, and metformin. [0005] Over time, almost one-half of type 2 diabetic subjects lose their response to these agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain. [0006] Because of the problems with current treatments, new therapies to treat type 2 diabetes are needed. In particular, new treatments to retain normal (glucose-dependent) insulin secretion are needed. Such new drugs should have the following characteristics: dependency on glucose for promoting insulin secretion (i.e., compounds that stimulate insulin secretion only in the presence of elevated blood glucose); low primary and secondary failure rates; and preservation of islet cell function. [0007] INS-1 cells are a model for islet beta-cell insulin secretion. When maintained in the presence of beta-mercaptoethanol, these cells retain many of the characteristics of islet beta-cells in situ. The cells secrete insulin in response to physiologically relevant glucose concentrations with an EC.sub.50 of 6 mM glucose (Hohmeier, et al., Diabetes 49:424, 2002). These cells also secrete insulin in response to multiple known secretagogues, including agents that elevate intracellular cyclic AMP, nutrients other than glucose, and potassium chloride. This characteristic of INS-1 cells further demonstrates that the cells retain many of the signaling pathways that are involved in the insulin secretory response, and as such are suitable for identifying compounds that affect these pathways. INS-1 cells are therefore useful tools for identifying compounds that stimulate insulin secretion in the presence of glucose and thus useful in the treatment of diabetes and related disorders. DETAILED DESCRIPTION OF THE INVENTION [0008] The invention provides anilinopyrazole derivatives of Formula (I) wherein [0009] R is H or (C.sub.1-C.sub.6)alkyl; [0010] R.sup.1 is H, [0011] (C.sub.1-C.sub.6)alkyl optionally substituted with one substituent selected from the group consisting of (C.sub.1-C.sub.4)alkoxy, phenyl optionally substituted with halo, and [tri(C.sub.1-C.sub.4)alkyl]silyl, [0012] (C.sub.3-C.sub.6)alkenyl, [0013] (C.sub.3-C.sub.6)alkynyl, [0014] (C.sub.3-C.sub.6)cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C.sub.1-C.sub.3)alkyl, CF.sub.3, and halo, [0015] (C.sub.1-C.sub.3)haloalkyl, or [0016] phenyl optionally substituted with up to four substituents selected from the group consisting of [0017] halo, [0018] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0019] (C.sub.1-C.sub.6)alkoxy, [0020] (C.sub.1-C.sub.3)haloalkyl, [0021] (C.sub.1-C.sub.3)haloalkoxy, [0022] NR.sup.8R.sup.8, [0023] cyano, and [0024] (C.sub.1-C.sub.6)alkylthio; [0025] R.sup.2 is H, [0026] halo, [0027] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0028] (C.sub.3-C.sub.6)cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C.sub.1-C.sub.3)alkyl and halo, [0029] (C.sub.1-C.sub.3)haloalkyl, [0030] pyridyl optionally substituted with up to two substituents selected from the group consisting of (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkythio, halo, and (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0031] pyrimidyl, [0032] phenyl optionally substituted with up to four substituents selected from the group consisting of [0033] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0034] (C.sub.1-C.sub.6)alkoxy, [0035] hydroxy, [0036] NR.sup.8R.sup.8, [0037] cyano, [0038] (C.sub.1-C.sub.6)alkylthio, [0039] halo, [0040] CO.sub.2R.sup.8, [0041] (C.sub.1-C.sub.3)haloalkoxy, [0042] (C.sub.1-C.sub.4)acyl, and [0043] benzoyl, [0044] or [0045] tetrahydronaphthyl, indanyl, benzodioxolyl, or benzodioxanyl, each of which may be optionally substituted with up to two substituents selected from the group consisting of (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkythio, halo, and (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0046] or [0047] when R.sup.1 and R.sup.2 are (C.sub.1-C.sub.6)alkyl, they may, together with C atoms to which they are attached, form a 5- or 6-membered carbocyclic ring, [0048] or [0049] R.sup.1 and R.sup.2 may, together with the C atoms to which they are attached form a 6-membered heterocyclic ring containing a N atom and optionally substituted on N with (C.sub.1-C.sub.3)alkyl; [0050] R.sup.3 is (C.sub.1-C.sub.6)alkyl, [0051] (C.sub.3-C.sub.6)cycloalkyl, [0052] benzyl optionally substituted on the aryl ring with up to four substituents selected from the group consisting of [0053] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0054] halo, [0055] (C.sub.1-C.sub.3)haloalkyl, [0056] (C.sub.1-C.sub.6)alkoxy, [0057] (C.sub.1-C.sub.3)haloalkoxy, [0058] NR.sup.8R.sup.8, [0059] cyano, [0060] (C.sub.1-C.sub.6)alkylthio, and [0061] SO.sub.2(C.sub.1-C.sub.3)alkyl, [0062] (C.sub.2-C.sub.3)haloalkyl, or [0063] phenyl optionally substituted with up to four substituents selected from the group consisting of [0064] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0065] halo, [0066] (C.sub.1-C.sub.3)haloalkyl, [0067] (C.sub.1-C.sub.6)alkoxy, [0068] (C.sub.1-C.sub.3)haloalkoxy [0069] NR.sup.8R.sup.8, [0070] cyano, [0071] (C.sub.1-C.sub.6)alkylthio, and [0072] SO.sub.2(C.sub.1-C.sub.3)alkyl; [0073] R.sup.4 is (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0074] (C.sub.1-C.sub.6)alkoxy, [0075] (C.sub.1-C.sub.6)alkylthio, [0076] (C.sub.1-C.sub.3)haloalkyl, [0077] (C.sub.1-C.sub.3)haloalkoxy, [0078] halo, [0079] NR.sup.8R.sup.8, [0080] pyrimidyl, [0081] pyridyl, [0082] imidazolyl, or [0083] phenyl optionally substituted with up to four substituents selected from the group consisting of [0084] halo, [0085] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0086] (C.sub.1-C.sub.6)alkoxy, [0087] (C.sub.1-C.sub.3)haloalkyl, [0088] (C.sub.1-C.sub.3)haloalkoxy, [0089] NR.sup.8R.sup.8, [0090] cyano, and [0091] (C.sub.1-C.sub.6)alkylthio; [0092] n=0, 1, 2, or 3; [0093] X is CO.sub.2R.sup.8, CONR.sup.5R.sup.6, SO.sub.2NHR.sup.7, or oxadiazolyl optionally substituted with (C.sub.1-C.sub.6)alkyl; [0094] R.sup.5is H, [0095] (C.sub.1-C.sub.6)alkyl, [0096] (C.sub.2-C.sub.6)alkyl substituted with OR.sup.6, [0097] benzyl optionally substituted on the aryl ring with up to four substituents selected from the group consisting of [0098] halo, [0099] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0100] (C.sub.1-C.sub.6)alkoxy, [0101] (C.sub.1-C.sub.3)haloalkyl, [0102] (C.sub.1-C.sub.3)haloalkoxy, [0103] NR.sup.8R.sup.8, [0104] cyano, and [0105] (C.sub.1-C.sub.6)alkylthio, [0106] phenyl optionally substituted with up to four substituents selected from the group consisting of [0107] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0108] halo, [0109] (C.sub.1-C.sub.6)alkoxy, [0110] (C.sub.1-C.sub.3)haloalkyl, [0111] (C.sub.1-C.sub.3)haloalkoxy, [0112] NR.sup.8R.sup.8, [0113] cyano, and [0114] (C.sub.1-C.sub.6)alkylthio, [0115] pyridyl optionally substituted with up to two substituents selected from the group consisting of [0116] halo, [0117] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0118] (C.sub.1-C.sub.6)alkoxy, [0119] (C.sub.1-C.sub.3)haloalkoxy, [0120] NR.sup.8R.sup.8, [0121] cyano, and [0122] (C.sub.1-C.sub.6)alkylthio, [0123] SO.sub.2-phenyl said phenyl optionally substituted with up to four substituents selected from the group consisting of [0124] halo [0125] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0126] (C.sub.1-C.sub.6)alkoxy, [0127] (C.sub.1-C.sub.3)haloalkyl, [0128] (C.sub.1-C.sub.3)haloalkoxy, [0129] NR.sup.8R.sup.8, [0130] cyano, and [0131] (C.sub.1-C.sub.6)alkylthio; [0132] R.sup.6 is H or (C.sub.1-C.sub.6)alkyl; [0133] or [0134] R.sup.5 and R.sup.6 together with N atom to which they are attached, may form a piperidine, morpholine, thiomorpholine, or piperazine ring said piperazine optionally substituted on N with (C.sub.1-C.sub.3)alkyl; [0135] R.sup.7 is H or methyl; [0136] R.sup.8 is H, [0137] (C.sub.1-C.sub.6)alkyl, [0138] benzyl optionally substituted on the aryl ring with up to four substituents selected from the group consisting of [0139] halo, [0140] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0141] (C.sub.1-C.sub.3)alkoxy, [0142] (C.sub.1-C.sub.3)haloalkyl, [0143] (C.sub.1-C.sub.3)haloalkoxy, [0144] cyano, and [0145] (C.sub.1-C.sub.6)alkylthio, [0146] or [0147] phenyl optionally substituted with up to four substituents selected from the group consisting of [0148] (C.sub.1-C.sub.6)alkyl optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0149] halo, [0150] (C.sub.1-C.sub.6)alkoxy, [0151] (C.sub.1-C.sub.3)haloalkyl, [0152] (C.sub.1-C.sub.3)haloalkoxy, [0153] cyano, and [0154] (C.sub.1-C.sub.6)alkylthio; [0155] and the pharmaceutically acceptable salts thereof; [0156] provided that when R and R.sup.2 are H and X is CO.sub.2H, then R.sub.1 is not H, methyl, or ethyl, and further provided that the Formula (I) compound is not [0157] The terms identified above have the following meaning throughout: [0158] The term "halo" means F, Br, Cl, and I. [0159] The terms "(C.sub.1-C.sub.3)alkyl," "(C.sub.1-C.sub.6)alkyl," and "(C.sub.2-C.sub.6)alkyl" mean a linear or branched saturated hydrocarbon radical having from about 1 to about 3 C atoms, about 1 to about 6 C atoms, about 2 to about 6 C atoms, respectively. Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like. [0160] The term "(C.sub.3-C.sub.6)alkenyl" means a linear or branched unsaturated hydrocarbon radical containing a double bond and from about 3 to about 6 carbon atoms. The double bond may be between any two available carbon atoms in the chain. Such groups include, allyl, isopropenyl, 2-butenyl, 2-ethyl-2-butenyl, 1-hexenyl, and the like. [0161] The term "(C.sub.3-C.sub.6)alkynyl" means a linear or branched unsaturated hydrocarbon radical containing a triple bond and from about 3 to about 6 carbon atoms. The triple bond may be between any two available carbon atoms in the chain. Such groups include, propargyl, 2-butynyl, 1-methyl-2-butynyl, 3-hexynyl, and the like. [0162] The term "(C.sub.3-C.sub.6)cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. [0163] The terms "(C.sub.1-C.sub.3)alkoxy," "(C.sub.1-C.sub.4)alkoxy," and "(C.sub.1-C.sub.6)alkoxy" mean a linear or branched saturated hydrocarbon radical having from about 1 to about 3 C atoms, about 1 to about 4 C atoms, or about 1 to about 6 C atoms, respectively, said radical being attached to an O atom. The O atom is the atom through which the alkoxy substituent is attached to the rest of the molecule. Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like. [0164] The terms "(C.sub.1-C.sub.3)haloalkoxy" and "(C.sub.2-C.sub.3)haloalkoxy" mean a (C.sub.1-C.sub.3)alkoxy group or a (C.sub.2-C.sub.3)alkoxy group, respectively, substituted on C with a halogen atom. Such groups include trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloroethoxy, 3-chloropropoxy, 1-fluoro-2,2,-dichloroethoxy, and the like. [0165] The terms "(C.sub.1-C.sub.3)haloalkyl" and "(C.sub.2-C.sub.3)haloalkyl" mean a (C.sub.1-C.sub.3)alkyl group or (C.sub.2-C.sub.3)alkyl group substituted on C with a halogen atom. Such groups include trifluoromethyl, difluoroethyl, 1-fluoro-2,2-dichloroethyl, 3-chloropropyl, 4-bromohexyl, and the like. [0166] The term "[tri(C.sub.1-C.sub.4)alkylsilyl]" means a Si radical bearing three (C.sub.1-C.sub.4)alkyl substituents, each substituent being independently selected. The Si atom is the atom through which the radical is attached to the rest of the molecule. Such groups include, but are not limited to, trimethylsilyl, tert-butyl-dimethylsilyl, and the like. [0167] The formula C(O) means a radical in which the C atom bears a doubly bonded oxygen, (an oxo substituent) and in which there remains two additional binding sites, that is, represents a radical of the formula: [0168] The term "(C.sub.1-C.sub.4)acyl" means a (C.sub.1-C.sub.4)alkyl radical substituted on the C of a C(O) group. The C of the C(O) is the group is also the atom through which the substituent is attached to the rest of the molecule. Such groups include, but are not limited to, acetyl(CH.sub.3C(O)--), n-propanoyl(CH.sub.3CH.sub.2C(O)--), isobutanoyl[(CH.sub.3).sub.2CHC(O)--], and the like. [0169] The formula "NR.sup.8R.sup.8" means that each of the two possible R.sup.8 groups attached to the N atom are selected independently from the other so that they may be the same or they may be different. Continue reading about Anilinopyrazole derivatives useful for the treatment of diabetes... 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