WO2012138945A1 - Procédés de traitement de la schizophrénie avec des inhibiteurs à base de dérivés du pyrazole de tgf-bêta - Google Patents

Procédés de traitement de la schizophrénie avec des inhibiteurs à base de dérivés du pyrazole de tgf-bêta Download PDF

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WO2012138945A1
WO2012138945A1 PCT/US2012/032446 US2012032446W WO2012138945A1 WO 2012138945 A1 WO2012138945 A1 WO 2012138945A1 US 2012032446 W US2012032446 W US 2012032446W WO 2012138945 A1 WO2012138945 A1 WO 2012138945A1
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alkyl
hydrogen
schizophrenia
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unsubstituted
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Meredith H. PRYSAK
Tage Honore
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Aestus Therapeutics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Embodiments of the invention relate to the treatment of schizophrenia in mammals.
  • Background Schizophrenia
  • Schizophrenia is a mental disorder marked by severe cognitive dysfunction and psychosis, estimated to affect greater than 1% of the population, with onset typically in late adolescence and early adulthood.
  • schizophrenia There are three main symptom categories of schizophrenia: positive symptoms, which include delusions, hallucinations, and movement and thought disorders, such as disorganized speech and/or grossly disorganized or catatonic behavior; negative symptoms comprised of social disturbances, flat affect and deficits in expressing emotion and experiencing pleasure such as alogia and/or avolition; and cognitive symptoms, which affect attention span, working memory and other intellectual functions and may include one or more of disorganized thinking, slow thinking, difficulty understanding, poor concentration, poor memory, difficulty expressing thoughts and difficulty integrating thoughts, feelings and behavior. Together, these symptoms have a severe impact on the quality of life for the schizophrenic patient, and contribute to a higher rate of substance abuse and suicide, factors contributing to a life expectancy of fifteen years less than the norm.
  • the positive symptoms of schizophrenia may also be present in other psychotic diseases, for example, bipolar disorder, delusional disorder, psychotic depression, Tourette syndrome, autism spectrum disorder, OCD, dementia and Alzheimer's disease.
  • Antipsychotics used to treat these symptoms of schizophrenia may also used to treat these symptoms in the other psychotic diseases.
  • Schizophrenia is a clear unmet medical need, of great import to general public health.
  • Eli Lilly & Co. is developing a series of TGF-beta inhibitors, including 4-[2-(6-Methyl- pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l ,2-b]pyrazol-3-yl]phenol and 4-[2-(6-Methyl-pyridin-2-yl)- 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl]-quinoline-6-carboxylic acid amide, also known as "LY- 2157299", for the potential treatment of inflammation, cancer and atherosclerosis. In January 2006, phase I trials had commenced for cancer indications with LY-2157299.
  • X is C, O or S:
  • Rl is unsubstituted or substituted phenyl; unsubstituted or substituted pyridine; unsubstituted or substituted pyridine N-oxide; unsubstituted or substituted quinoline; unsubstituted or substituted quinoline N-oxide; unsubstituted or substituted naphthyridine; unsubstituted or substituted pyrazine; furyl; unsubstituted or substituted thiazolyl; unsubstituted or substituted imidazolyl; unsubstituted or substituted pyrazolyl; or unsubstituted or substituted thiophenyl; wherein the substitution may be one or more of the following: (Cl-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (Cl-C6)alkoxy, (C2-C6)alkenyloxy, (C2- C6)alkynyloxy, (Cl-
  • R2 is unsubstituted or substituted quinoline; unsubstituted or substituted quinoline N-oxide; unsubstituted or substituted phenyl; unsubstituted or substituted naphthalene; unsubstituted or substituted pyridine; unsubstituted or substituted pyridine N-oxide; unsubstituted or substituted quinazoline; unsubstituted or substituted cinnoline; unsubstituted or substituted benzodioxole; unsubstituted or substituted benzodioxane; unsubstituted or substituted pyrimidine; unsubstituted or substituted benzothiophene; or unsubstituted or substituted phenanthrolene;
  • substitution may independently be one or more of the following:
  • X j is O, N, S, S0 2 , NR 13 , C(O), or bond
  • Q l is hydrogen, phenyl, 5- (2,2-difluoro-l,3-benzodioxolyl), C(0)Q 5 , or pyridyl when m and n are independently 0-2, except when one is 0 the other cannot be 0
  • Q l is OR n , NR n R 12 , halo, N-morpholino, N-piperazino-N'R 13 , N-imidazolyl, N- pyrazolyl, N-triazolyl, N-(4-piperidinylpiperidine), S0 2 R 14 , SOR 14 ,
  • R 13 is hydrogen, (Cl-C6)alkyl, 2-methoxyphenyl, 2-pyridimidinyl;
  • R 14 is 2-pyrimidinyl, N-methyl-2-imidazolyl, 4- chlorophenyl, 2-pyridylmethyl;
  • R 15 is (Cl-C6)alkyl, N-methyl-4-imidazolyl;
  • R 14 is 2-pyrimidin
  • R 3Q is hydrogen, or (Cl-C6)alkyl
  • R 31 is hydrogen, (Cl-C6)alkyl, 2- pyridyl, pyridylmethyl, amino, or hydroxy
  • R 32 and R 33 are each independently hydrogen, (Cl-C6)alkyl, acetyl, (Cl-C4)alkylsulphonyl, or R 32 and R 33 can be taken together to form a 4, 5, 6, or 7 membered ring,
  • X 2 is CH 2 , O, or N; q: is 2-3 except when Q 3 is a bond, q is 0-3; Q 3 is NR 36 R 37 , or OR 38 , and R 35 is hydrogen, or R 35 and Q 3 can be taken together to form a 5 membered ring; R 36 , R 3? , and R 38 are each independently hydrogen, or (Cl-C6)alkyl,
  • X 3 is cyano, carboxamide, ⁇ , ⁇ -dimethylcarboxamide, N,N- dimethylthiocarboxamide, ⁇ , ⁇ -dimethylaminomethyl, 4-methylpiperazi methyl or carboxylate,
  • Q 6 is N j R 41 R 42 ; r is 2-3; R 40 is hydrogen, or (Cl-C6)alkyl; R 41 , and R 42 are hydrogen, (Cl-C6)alkyl, or R 41 , and R 4Q can be taken together to form a 6 or 7 membered ring,
  • Q 7 is hydroxy, methoxy, dimethylamino, or N-piperidinyl; with the proviso that when one of Rl or R2 is unsubstituted or substituted phenyl, then the other cannot be unsubstituted or substituted phenyl or thiophen-2-yl; and with the proviso that when R2 is quinolin-4-yl, substitution at the quinoline 7-position cannot include an aryl, heteroaryl, fused aryl, or fused heteroaryl; k is 1-8; R 3 is one or more of the following: hydrogen; (Cl-C4)alkyl; (Cl-C4)alkylhydroxy; hydroxy; N,N-di(Cl-C4)alkylamino(Cl-C4)alkoxy; benzyl oxymethyl; phenyloxymethyl; oxo; carboxyl; (Cl-C4)alkylaryl; benzyloxy;
  • Rl is defined as in Formula I;
  • R2' is hydrogen; (Cl-C6)alkyl; (Cl-C6)alkylthio; (Cl-C6)alkoxy; halo; thiophenyl;
  • R6' and R7' are independently one or more of the following: hydrogen, (Cl-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cl-C6)alkylhalide, (Cl-C6)alkoxy, (C2- C6)alkenyloxy, (C2-C6)alkynyloxy, (Cl-C6)alkylthio, (Cl-C6)alkylsulphinyl, (Cl- C6)alkylsulphonyl, (Cl-C6)alkylamino, di-[(Cl-C6)alkyl]amino, (Cl- C6)alkoxycarbonyl, N— (C 1 -C6)alkylcarbamoyl, N,N-di-[(C 1 -C6)alkyl]carbamoyl, aminooxy, N— (Cl-C6)alkyl aminooxy, N,N-di-[(Cl-C6)
  • carboxamide ethylene, phenyl, thiophenyl, aminophenyl, phenylthio, halo, cyano, pyridinyl, arylalkyl, hydroxy, N-pyrrolidino, N-morpholino, carboxyl, [5-phenyl- 1,2,4- oxadiazole-3-yl]methoxy, 6-methyl-pyridazin-3-yloxy, (5-oxo-2-pyrrolidinyl)methoxy, 2-(4,5-dihydro-lH-imidazolyl), ⁇ , ⁇ -dialkylcarbamoyloxy, 1 -hydroxy- 1-methylethyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl, trifluoromethyl, trifluoromethoxy,
  • X j is O, N, S, S0 2 , NR 13 , C(O), or bond
  • Q j is hydrogen, phenyl, 5-(2,2- difluoro-l,3-benzodioxolyl), C(0)Q or pyridyl when m and n are independently 0-2, except when one is 0 the other cannot be 0;
  • Q j is OR j 1 ?
  • R j j and R 12 can be taken together to form a 3, 4, 5, 6, or 7 membered ring;
  • R 13 is hydrogen, (Cl-C6)alkyl, 2-methoxyphenyl;
  • R 14 is 2- pyrimidinyl, N-methyl-2-imidazolyl, 4-chlorophenyl, 2-pyridylmethyl;
  • R 15 is (C j - C6)alkyl, N-methyl-4-imidazolyl;
  • R 16 is hydrogen, halo, arylalkyl, aryl,
  • Q 2 is hydrogen, 4-imidazolyl, or C(0)NR 24 R 25 when o and p are independently 0-2;
  • Q 2 is OR 23 , NR 24 R 25 , or N-morpholino, when o and p are independently 0-2, but one or the other of o or p is not 0;
  • R 20 is hydrogen, or (Cl- C6)alkyl;
  • R 21 is hydrogen, (Cl-C6)alkyl, or R 21 and R 20 can be taken together to form a 4, 5, 6, or 7 membered ring;
  • R 22 is hydrogen, (Cl-C6)alkyl, arylalkyl, aryl, or R 21 and R 22 can be taken together to be a 3, 4, 5, 6, 7 membered ring;
  • R 23 is hydrogen or (Cl-C6)alkyl;
  • R ?4 is hydrogen, (Cl-C6)alkyl, or R ?4 and R ?
  • R 24 and R 20 can be taken together to form a 6 or 7 membered ring
  • R 25 is hydrogen, (Cl-C6)alkyl, or acetyl, or a group of the formula
  • R 30 is hydrogen, or (Cl-C6)alkyl
  • R 31 is hydrogen, (Cl-C6)alkyl, 2-pyridyl, pyridylmethyl, amino, or hydroxy
  • R 32 and R 33 are each independently hydrogen, (Cl-C6)alkyl, acetyl, alkylsulphonyl, or R 32 and R 33 can be taken together to form a 4, 5, 6, or 7 membered ring,
  • X 2 is CH 2 , O, or N; q is 2-3 except when Q 3 is a bond, q is 0-3; Q 3 is NR 36 R 37 , OR 38 , or a bond; R 35 is hydrogen, or R 35 and Q 3 (when Q 3 is a bond) can be taken together to form a 5 membered ring; R 36 , R 37 , and R 38 are each
  • X 3 is cyano, carboxamide, ⁇ , ⁇ -dimethylcarboxamide, N,N- dimethylthiocarboxamide, ⁇ , ⁇ -dimethylaminomethyl, 4-methylpiperazin- lyl-methyl or carboxylate,
  • Q 6 is NR 41 R 42 ; r is 2-3; R 4Q is hydrogen, or (Cl-C6)alkyl; R 41 and R 42 are hydrogen, (Cl-C6)alkyl, or R 41 and R 40 can be taken together to form a 6 or 7 membered ring,
  • R 3 is one or more of the following: hydrogen; (Cl-C4)alkyl; (C1-C4) alkylhydroxy;
  • phenyl or an optionally substituted phenyl; wherein the substitution may be one or more of the following: (Cl-C6)alkoxy, halo, carboxy, or (Cl-C6)alkoxycarbonyl; with the proviso that R7' cannot be aryl; heteroaryl; fused aryl; or fused heteroaryl, and the pharmaceutically acceptable salts, esters and prodrugs thereof.
  • Rl is defined as in Formula I;
  • R3" is hydrogen, halo, thrifluoromethyl
  • R4" is hydrogen, halo, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, hydroxy, (Ci-C 6 )alkylsulphonyl; k and R3 are defined as in Formula I;
  • R6 may be one or more of the following: hydrogen, (Cl-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cl-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (Cl- C6)alkylthio, (Cl-C6)alkylsulphinyl, (Cl-C6)alkylsulphonyl, (Cl-C6)alkylamino, di- [(Cl-C6)alkyl]amino, (Cl-C6)alkoxycarbonyl, N— (C 1 -C6)alkylcarbamoyl, N,N-di- [(Cl-C6)alkyl]carbamoyl, (C2-C6)alkanoyl, (C2-C6)alkanoyloxy, (C2- C6)alkanoylamino, N— (C 1 -C6)alkyl-
  • R2" is unsubstituted or substituted quinoline-8-yl; unsubstituted or substituted quinoline-6-yl; unsubstituted or substituted 1-naphthyl; unsubstituted or substituted 2- naphthyl; unsubstituted or substituted 3,4-methylenedioxyphenyl; unsbustituted or substituted 3,4-ethylenedioxyphenyl; unsubstituted or substituted benzothiophen-2-yl; wherein the substitution may independently be one or more of the following: (Cl-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cl-C6)alkylhalide, (Cl- C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (Cl-C6)alkylthio, (Cl- C6)alkylsulphinyl, (Cl-C6)
  • X j is O, N, S, S0 2 , NR 13 , C(O), or bond
  • Q l is hydrogen, phenyl, 5- (2,2-difluoro-l,3-benzodioxolyl), C(0)Q 5 , or pyridyl when m and n are independently 0-2, except when one is 0 the other cannot be 0
  • Q l is OR n , NR n R 12 , halo, N-morpholino, N-piperazino-N'R 13 , N-imidazolyl, N- pyrazolyl, N-triazolyl, N-(4-piperidinylpiperidine), S0 2 R 14 , SOR 14 ,
  • Q 2 is hydrogen, 4-imidazolyl, or C(0)NR 24 R 25 when o and p are independently 0-2;
  • Q 2 is OR 23 , NR 24 R 25 , or N-morpholino, when o and p are independently 0-2, but one or the other of o or p is not 0;
  • R 20 is hydrogen, or (Cl-C6)alkyl;
  • R 21 is hydrogen, (Cl-C6)alkyl, or R 21 and R 2Q can be taken together to form a 4, 5, 6, or 7 membered ring;
  • R 22 is hydrogen, (Cl-C6)alkyl, arylalkyl, aryl, or R 21 and R 22 can be taken together to be a 3, 4, 5, 6, 7 membered ring;
  • R 23 is hydrogen or (C 1 -C6)alkyl;
  • R 24 is hydrogen, (Cl- C6)alkyl, or R 24 and R 25 can be taken together to form a 3, 4, 5, 6, or 7 membered
  • R 3Q is hydrogen, or (Cl-C6)alkyl
  • R 31 is hydrogen, (Cl-C6)alkyl, 2- pyridyl, pyridylmethyl, amino, or hydroxy
  • R 32 and R 33 are each independently hydrogen, (Cl-C6)alkyl, acetyl, alkylsulphonyl, or R 32 and R 33 can be taken together to form a 4, 5, 6, or 7 membered ring,
  • X 2 is CH 2 , O, or N
  • q is 2-3 except when Q 3 is a bond, q is 0-3
  • Q 3 is NR 36 R 37 , OR 38 , or a bond
  • R 35 is hydrogen, or R 35 and Q 3 (when Q 3 is a bond) can be taken together to form a 5 membered ring
  • R 36 , R 37 , and R 38 are each independently hydrogen, or (Cl-C6)alkyl
  • X 3 is cyano, carboxamide, ⁇ , ⁇ -dimethylcarboxamide, N,N- dimethylthiocarboxamide, ⁇ , ⁇ -dimethylaminomethyl, 4-methylpiperazi methyl or carboxylate,
  • Q 6 is NR 41 R 42 ; r is 2-3; R 40 is hydrogen, or (Cl-C6)alkyl; R 41 and R 42 are hydrogen, (Cl-C6)alkyl, or R 41 and R 4Q can be taken together to form a 6 or 7 membered ring,
  • Q 7 is hydroxy, methoxy, dimethylamino, or N-piperidinyl; k is 1-8;
  • R 3 is hydrogen; and the pharmaceutically acceptable salts, esters and prodrugs thereof.
  • US Patent 7,087,626 further discloses pharmaceutically acceptable salts, such as acid addition salts, solvates, hydrates and esters of such compounds, as well as pharmaceutical compositions of such compounds.
  • LY-2157299 possessed good activity and selectivity over p38 MAP kinase, with IC50 values of 0.047, 0.022, 0.105 and 4.3 microM against TGF-beta kinase domain, p3TP lux, NIH3T3 cell proliferation and p38 MAP kinase, respectively.
  • HUVEC cells were cultured in the presence or absence of TGF alpha, VEGF or bFGF, with varying concentrations of LY-2157299; TGF alpha signaling was found to be inhibited and
  • LY-2157299 was also found to stimulate VEGF or bFGF HUVEC migration.
  • TGF alpha inhibited cord formation in a dose- dependent fashion.
  • LY-2157299 potentiated angiogenesis.
  • the compound was also tested in vivo against a variety of cancer models, including the 3T1 breast cancer syngeneic model and the U87MG and A549 xenograft models. In all models, the tumor-bearing mice received LY-2157299 (75 mg/kg po bid) for 3 or 5 days.
  • LY-2157299 increased the vessel density in all tumor models and also inhibited tumor growth and prolonged survival in the syngeneic 4T1 breast cancer model.
  • schizophrenia and/or symptoms of schizophrenia and/or positive symptoms of schizophrenia in mammals is treated by the administration of a therapeutically effective amount of a TGF-beta antagonist of Formulas I, II, III or IV or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • An embodiment of the invention is a composition for the treatment of schizophrenia and/or symptoms of schizophrenia and/or positive symptoms of schizophrenia comprising at least one compound of Formulas I, II, III or IV or a salt, ester, hydrate, solvate, prodrug or polymorph thereof, incorporated in a pharmaceutically acceptable adjuvant, excipient, diluent or carrier composition.
  • An embodiment of the invention is a method of treating schizophrenia and/or symptoms of schizophrenia and/or positive symptoms of schizophrenia in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound selected from the group consisting of 4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl]phenol, 4-[2- (6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl]-quinoline-6-carboxylic acid amide and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and polymorphs thereof.
  • compositions used for treating schizophrenia and/or symptoms of schizophrenia and/or positive symptoms of schizophrenia comprising at least one compound selected from the group consisting of 4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[l,2-b]pyrazol-3-yl]phenol, 4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazol-3-yl]-quinoline-6-carboxylic acid amide and salts, esters, hydrates, solvates, prodrugs, and polymorphs thereof, incorporated in a pharmaceutically acceptable adjuvant, excipient, diluent, or carrier composition.
  • Figure 1 shows the reversal of PCP-induced pre -pulse-inhibition deficit in a rat model of schizophrenia by 100 mg/kg of 4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol- 3-yl]phenol (labeled as "Test Compound”), with a pre-pulse inhibition tone of 81 dB.
  • Figure 2 shows the reversal of PCP-induced pre -pulse-inhibition deficit in a rat model of schizophrenia by 20 mg/kg of 4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol- 3-yl]-quinoline-6-carboxylic acid amide (labeled as "LY-2157299”), with a pre-pulse inhibition tone of 69 dB.
  • Figure 3 shows the reversal of PCP-induced pre -pulse-inhibition deficit in a rat model of schizophrenia by 20 mg/kg of 4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol- 3-yl]-quinoline-6-carboxylic acid amide (labeled as "LY-2157299”), with a pre-pulse inhibition tone of 73 dB.
  • Embodiments of the invention provide methods for treating schizophrenia and/or symptoms of schizophrenia with compounds of Formula I, Formula II, Formula III or Formula IV.
  • Symptoms of schizophrenia are well-documented by the literature and diagnostic authorities on schizophrenia and include delusions; hallucinations; movement and thought disorders, such as disorganized speech and/or grossly disorganized or catatonic behavior; social disturbances; flat affect; deficits in expressing emotion and experiencing pleasure such as alogia and/or avolition; disorganized thinking, slow thinking; difficulty understanding; poor concentration; poor memory; difficulty expressing thoughts; and difficulty integrating thoughts, feelings and behavior.
  • Embodiments of the invention also provide methods for treating positive symptoms of schizophrenia in other psychotic diseases, for example, bipolar disorder, delusional disorder, psychotic depression, Tourette syndrome, autism spectrum disorder, OCD, dementia and
  • Alzheimer's disease with one or more compounds of Formula I, Formula II, Formula III or Formula IV and pharmaceutically acceptable salts, esters and prodrugs thereof.
  • Embodiments of the invention provide methods for treating schizophrenia and/or symptoms of schizophrenia and/or positive symptoms of schizophrenia in other psychotic diseases, by administering to a subject in need of such treatment a therapeutically effective amount of a compound that modulates TGF-beta activity or expression.
  • a particular embodiment of the invention provides a method of treating schizophrenia and/or symptoms of schizophrenia and/or positive symptoms of schizophrenia in other psychotic diseases by administering to a mammal in need of such treatment a therapeutically effective amount of a TGF-beta antagonist.
  • a therapeutically effective amount of a compound of Formula I, Formula II, Formula III or Formula IV that modulates TGF-beta activity or expression is administered to a subject to treat schizophrenia and/or symptoms of schizophrenia and/or positive symptoms of schizophrenia in other psychotic diseases.
  • a compound useful in carrying out therapeutic method embodiments of the invention is advantageously formulated in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier. The amount of compound in the pharmaceutical composition depends on the desired dosage and route of administration.
  • suitable dose ranges of the active ingredient are from about 0.01 mg/kg to about 1500 mg/kg of body weight taken at necessary intervals (e.g., daily, every 12 hours, etc.), although it will, of course, readily be understood that the amount of the compound actually to be administered will be determined by a physician, in the light of all the relevant circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration.
  • a suitable dosage range of the active ingredient is from about 0.2 mg/kg to about 150 mg/kg of body weight taken at necessary intervals.
  • a suitable dosage range of the active ingredient is from about 3 mg/kg to about 15 mg/kg of body weight taken at necessary intervals.
  • the dosage and administration are such that TGF-beta activity or expression is only partially modulated so as to avoid any unacceptably deleterious effects.
  • compositions of the present invention are therapeutically effective amounts of the TGF- ⁇ antagonists noted above.
  • the composition may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions for convenient oral administration or administered by intramuscular or intravenous routes.
  • the compounds can be administered transdermally.
  • the method of treating a human patient according to the present invention includes administration of the TGF- ⁇ antagonists of Formula I.
  • the TGF- ⁇ antagonists of Formula I are formulated into formulations which may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection, by subcutaneous depot and by continuous or discontinuous intraarterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, gels, suspensions, aerosols, ointments, for example, containing from 1 to 10% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions.
  • compositions of Formula I may be provided in dosage unit form, preferably each dosage unit containing from about 5 to about 1000 mg (from about 5 to 100 mg in the case of parenteral or inhalation administration, and from about 25 to 1000 mg in the case of oral or rectal administration) the compounds.
  • the method of treating a human patient according to the present invention includes
  • TGF- ⁇ antagonists of Formula II are formulated into formulations which may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection, by subcutaneous depot and by continuous or discontinuous intraarterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, gels, suspensions, aerosols, ointments, for example, containing from 1 to 10%> by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions.
  • compositions of Formula II may be provided in dosage unit form, preferably each dosage unit containing from about 5 to about 1000 mg (from about 5 to 100 mg in the case of parenteral or inhalation administration, and from about 25 to 1000 mg in the case of oral or rectal administration) the compounds.
  • the method of treating a human patient according to the present invention includes
  • TGF- ⁇ antagonists of Formula III are formulated into formulations which may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection, by subcutaneous depot and by continuous or discontinuous intraarterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, gels, suspensions, aerosols, ointments, for example, containing from 1 to 10%> by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions.
  • formulations which may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection, by subcutaneous depot and by continuous or discontinuous intraarterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets,
  • compositions of Formula III may be provided in dosage unit form, preferably each dosage unit containing from about 5 to about 1000 mg (from about 5 to 100 mg in the case of parenteral or inhalation administration, and from about 25 to 1000 mg in the case of oral or rectal administration) the compounds.
  • the method of treating a human patient according to the present invention includes
  • TGF- ⁇ antagonists of Formula IV are formulated into formulations which may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection, by subcutaneous depot and by continuous or discontinuous intraarterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, gels, suspensions, aerosols, ointments, for example, containing from 1 to 10% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions.
  • formulations which may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection, by subcutaneous depot and by continuous or discontinuous intraarterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cache
  • compositions of Formula IV may be provided in dosage unit form, preferably each dosage unit containing from about 5 to about 1000 mg (from about 5 to 100 mg in the case of parenteral or inhalation administration, and from about 25 to 1000 mg in the case of oral or rectal administration) the compounds.
  • the formulations useful for separate administration of the TGF- ⁇ antagonists will normally consist of at least one compound selected from the compounds specified herein mixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by an ingestible carrier in the form of a capsule, sachet, cachet, paper or other container or by a disposable container such as an ampoule.
  • a carrier or diluent may be a solid, semi-solid or liquid material which serves as a vehicle, excipient or medium for the active therapeutic substance.
  • diluents or carrier which may be employed in the pharmaceutical compositions of the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis oil, alginates, tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane,
  • a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tableting machine.
  • a lubricant there may be employed for instance aluminum, magnesium or calcium stearates, talc or mineral oil.
  • compositions of the present invention include capsules, tablets, suppositories, injectable solutions, creams and ointments. Additional forms are formulations for inhalation application, such as an aerosol, for injection, and for oral ingestion.
  • the therapeutic agent is delivered in a controlled release manner.
  • a therapeutic agent can be administered using intravenous infusion with a continuous pump, or in a polymer matrix such as poly-lactic/glutamic acid (PLGA), or in a pellet containing a mixture of cholesterol and the active ingredient, or by subcutaneous implantation, or by transdermal patch.
  • PLGA poly-lactic/glutamic acid
  • Embodiments of the invention provide methods for treating schizophrenia and/or symptoms of schizophrenia and/or positive symptoms of schizophrenia in other psychotic diseases in a subject in need of such treatment by antagonizing TGF-beta by administering a therapeutically effective amount of at least one compound selected from the group consisting of:
  • nnnnn 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)-7-(3-pyrrolidin-l-yl-propoxy)- quinoline,
  • nnnnnn N,N-Dimethyl-N'-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)-pyridin-2- yl]-ethane- 1 ,2-diamine
  • nnnnnnnn (1 - ⁇ 3-[7-(2-Chloro-ethoxy)-quinolin-4-yl]-5,6-dihydro-4H-pyrrolo[ 1 ,2-b]pyrazol-2-yl ⁇ - propenyl)-methylene-amine
  • Iddddddckk 7-[2-(l-Methyl-pyrrolidin-2-yl)-ethoxy]-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazol-3-yl)-quinoline hydrochloride
  • nnnnnnnnn 4-[2-(6-Methyl-l-oxy-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl]- quinoline,
  • nnnnnnnnnnn 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)-quinoline-7-carboxylic acid [2-(lH-imidazol-4-yl)-ethyl] -amide,
  • nnnnnnnnnnnn 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)-quinoline-7-carboxylic acid amide
  • nnnnnnnnnnnnnnn 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)-quinoline-7-carboxylic acid hydroxyamide
  • nnnnnnnnnnnnnnnn 7-Bromo-2-isopropyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3- yl)-quinoline,
  • nnnnnnnnnnnnnnnnnnnn 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)-7-[4-(4-pyrimidin- 2-yl-piperazin- 1 -yl)-butoxy] -quinoline,
  • sssssssssssssssssssssssssssssssssssssssss) 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)-quinoline-7-carboxylic acid(3-dimethylamino-propyl)-amide, tttttttttttttt) 4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl]-quinoline-7- carboxylic acid(2-dimethylamino-ethyl)-methyl-amide,
  • zzzzzzzzzzzzzzzz 4-(7-Chloroquinolin-4-yl)-3-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2Db]pyrazole, aaaaaaaaaaaaaaaaa) 4-(2-Furan-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)-quinoline, bbbbbbbbbbbbbbbb) 3- ⁇ 4 2 6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl]- quinolin-6-yl ⁇ -acrylic acid methyl ester,
  • compositions used for treating schizophrenia and/or symptoms of schizophrenia and/or positive symptoms of schizophrenia in other psychotic diseases comprising at least one compound selected from the group consisting of 4-[2-(6-Methyl- pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl]phenol; 4-[2-(6-Methylpyridin-2-yl)-5,6- dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl]-quinoline-6-carboxylic acid amide; and salts, esters, hydrates, solvates, prodrugs, and polymorphs thereof incorporated in a pharmaceutically acceptable adjuvant, diluent, or carrier composition.
  • Prepulse inhibition of the acoustic startle response is the reduction of the startle response to a sudden pulse of noise when it is preceded by a weak prepulse stimulus.
  • the effect of the prepulse is considered as a form of sensorimotor gating and is common to many species, from mice to humans.
  • PPI Deficits in PPI are commonly associated with schizophrenia, or positive symptoms of schizophrenia in other psychotic diseases, and can be reproducibly induced in laboratory animals by administration of psychotropic agents such as dopamine agonists (apomorphine), NMDA antagonists (phencyclidine) or even serotonin agonists. These deficits can be partially reversed by antipsychotic agents such as Clozapine and Risperidone.
  • antipsychotic agents such as Clozapine and Risperidone.
  • the effectiveness of a number of putative antipsychotic agents in animal models of PPI has been shown to correlate closely to their clinical effectiveness. Given their predictive value, animal models of PPI are now one of the most widely-used preclinical models for evaluating novel antipsychotic drugs.
  • mice Male Sprague-Dawley rats weighing 210-250 g at time of experiment were used. Animals were housed in a temperature and humidity controlled environment and allowed free access to food and water prior to use.
  • the amplitude of the inherent startle response varies considerably from animal to animal.
  • the gain of the platforms must be calibrated to ensure that the average startle waveform falls within the desired range.
  • baseline studies were conducted before the full PPI protocol to allow the calibration of the platforms to be fine-tuned to the startle waveform amplitude. This also allows the animals to become acclimatised to the testing equipment prior to drug administration.
  • Acclimation Period Animals were exposed to 5 minutes of 65 decibel (dB) background noise (white noise).
  • Block 1 10 x startle stimulus alone (white noise, 120 dB, 40 ms)
  • Block 2 6 x startle stimulus alone
  • the study compounds were suspended from dry powder stocks in Vehicle (5% Tween 80/5% PEG/saline) and sonicated for 60 minutes at 37°C to generate suspensions suitable for oral dosing.
  • Control rats received Vehicle by oral gavage.
  • PCP was dissolved in sterile saline (0.9% NaCl).
  • Rats were dosed with either saline (0.9% NaCl) or 2.5 mg/kg PCP by intraperitoneal injection 15 minutes prior to PPI testing.
  • Block 1 6 x startle stimulus alone (white noise, 120 dB, 40 ms)
  • Block 2 14 x startle stimulus
  • Block 3 6 x startle stimulus alone
  • %PPI (100 x [ (pulse alone score) - (prepulse + pulse score) ] / pulse alone
  • a therapeutically effective amount refers to an amount of a compound of the present invention that is capable of measurably alleviating, partially or completely, one or more symptoms of schizophrenia in that subject.
  • C 1 -C4 alkyl denotes a straight-chain or branched-chain
  • C J-C alkyl group consisting of carbon and hydrogen atoms, examples of which are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and the like.
  • C C ⁇ cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • C 1 -C4 alkoxy denotes an alkyl group as defined earlier, which is attached via an oxygen atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and the like.
  • CJ-C4 alkylthio denotes an alkyl group as defined earlier and is attached via a sulfur atom, and includes methylthio, ethylthio, isobutylthio, and the like.
  • halo or halogen represents fluorine, chlorine, bromine, or iodine.
  • hydroxy alone or in combination, represents an— OH moiety.
  • Carboxy or “carboxyl” refers to a carboxylic acid.
  • carboxylic acid refers to a carbonyl substituted with an— NH2 moiety.
  • oxo refers to a carbonyl group.
  • aryl represents a substituted or unsubstituted phenyl or naphthyl.
  • Aryl may be optionally substituted with one or more groups independently selected from hydroxy, carboxy, C j -Cg alkoxy, C j -Cg alkyl, halogen, carboxamide, trifluoromethyl, hydroxymethyl, and hydroxy(C ⁇ -C ⁇ alkyl.
  • C3-Cg cycloalkyl refers to a C3-Cg cycloalkyl as defined herein unsubstituted or substituted with one or more groups independently selected from hydroxy, carboxy, C alkoxy, C j _g alkyl, halogen, carboxamide, trifluoromethyl, hydroxymethyl, and hydroxy(C j -C ⁇ alkyl.
  • C 1 -Cg alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • C j -Cg alkyl includes within its definition the terms “C C 4 alkyl” and "C j ⁇ alkyl.”
  • C 1 -Cg alkenyl refers to a straight or branched, divalent, unsaturated aliphatic chain of 1 to
  • 6 carbon atoms and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, 1-butylenyl, pentylenyl, isopentylenyl, hexylenyl.
  • C 1 -Cg alkoxycarbonyl represents a straight or branched C 1 -Cg alkoxy chain, as defined above, that is attached via the oxygen atom to a carbonyl moiety.
  • Typical C 1 -Cg alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, 1-butoxycarbonyl and the like.
  • di(C 1 -Cg alkyl)amino refers to a group of the formula: R
  • each R group independently represents a "C j -Cg alkyl” group, as defined above.
  • An “optionally substituted phenyl” is a phenyl ring that is unsubstituted or substituted with 1 to 5 substituents, or 1 to 3 substituents, for example: halo, C ⁇ - ⁇ alkyl, C ⁇ - ⁇ alkoxy, C ⁇ - ⁇ alkylamino, trifluoromethyl, nitro, and cyano.
  • An “optionally substituted benzyl” is a benzyl ring that is unsubstituted or substituted with 1 to 5 substituents, or 1 to 3 substituents, for example: halo, C ⁇ - ⁇ alkyl, C ⁇ - ⁇ alkoxy,
  • Phenoxycarbonyl refers to the group: phenyl-0— C(O)— .
  • Aryl refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthracenyl).
  • such aryl groups can optionally be substituted with 1 to 5 substituents, more preferably 1 to 3 substituents, selected from the group consisting of halo, hydroxy, acetyl, nitro, cyano, C ⁇ - ⁇ alkyl, Cj-Cg alkoxy, phenyl, di(C j-Cg alkyl)amino, trifluoromethyl, trifluoromethoxy,— S(0) m — (Cj-Cg alkyl), and— S(0) m - (phenyl), wherein m can be 0, 1 , or 2.
  • Arylalkyl refers to aryl groups attached to alkyl groups, preferably having 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atoms in the aryl moiety. Such arylalkyl groups are exemplified by benzyl, phenethyl, and the like.
  • arylalkyl groups can be optionally substituted with 1 to 5 substituents, more preferably 1 to 3 substituents, selected from the group consisting of halo, hydroxy, nitro, cyano, C j-Cg alkyl, Cj-Cg alkoxy, di(C j-Cg alkyl)amino, trifluoromethyl, trifluoromethoxy, carbamoyl, pyrrolidinyl,— S(0) m — (C j-Cg alkyl), and—
  • arylalkyl groups may be optionally substituted on the aryl moiety, the alkyl moiety, or both the aryl moiety and the alkyl moiety.
  • heterocycle represents an unsubstituted or substituted 5- to 7-membered monocyclic, or 7- to 1 1-membered bicyclic heterocyclic ring that is saturated or unsaturated and that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring to another heterocycle as defined above.
  • heteroaryls represents the above-defined heterocylic rings that are fused to a benzene ring to another heterocycle as defined above.
  • heterocycles can be optionally substituted with 1 to 8 substituents selected from the group consisting of halo, nitro, cyano, hydroxy, acetyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, optionally substituted phenyl, phenethyl, phenoxy, phenoxycarbonyl, optionally substituted benzyl, 1,1- diphenylmethyl, oxo, C1-C6 alkoxycarbonyl, (C1-C6 alkoxy)Cl-C6 alkyl-, trifluoromethyl, pyridyl, (pyrrolidinyl)Cl-C6 alkyl-, and (pyridyl)Cl-C6 alkyl-, di(Cl-C6 alkyl)amino, trifluoromethyl, trif uoromethoxy,— S(0)m
  • heterocycles examples include azepinyl, azetidinyl, benzazepinyl, benzimidazolyl, benzoazolyl, benzodioxolyl, benzodioxanyl, benzopyranyl, benzothiazolyl, benzothienyl, dihydropyrazolooxazinyl, dihydropyrazolooxazolyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, napthyridinyl, oxadiazolyl, oxazolyl, oxazolidinyl, phthalimidyl, piperazinyl, piperidinyl, pyr
  • Preferred heterocycles include: benzodioxolyl, dihydropyrrolopyrazolyl, pyridyl and quinolinyl.

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Abstract

Conformément à des modes de réalisation, l'invention concerne le traitement de la schizophrénie chez des mammifères. Des modes de réalisation de l'invention portent sur des procédés pour traiter la schizophrénie et/ou des symptômes de la schizophrénie et/ou des symptômes positifs de la schizophrénie dans une maladie psychotique, ainsi que sur des procédés pour préparer des médicaments utilisés dans le traitement de la schizophrénie chez des mammifères. Dans un mode de réalisation, des procédés de l'invention comprennent l'inhibition de TGF-bêta pour le traitement de la schizophrénie chez des mammifères.
PCT/US2012/032446 2011-04-08 2012-04-06 Procédés de traitement de la schizophrénie avec des inhibiteurs à base de dérivés du pyrazole de tgf-bêta WO2012138945A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094833A1 (fr) 2001-05-24 2002-11-28 Eli Lilly And Company Derives de pyrrole utilises comme agents pharmaceutiques
WO2004069837A1 (fr) * 2003-02-06 2004-08-19 Pfizer Products Inc. Derives de pyrazolo[1,5-a][1,3,5]triazine en tant que ligands de recepteur cannabinoide
WO2004069838A1 (fr) * 2003-02-10 2004-08-19 Pfizer Products Inc. Ligands du recepteur cannabinoide et leurs utilisations
WO2005049034A2 (fr) * 2003-11-19 2005-06-02 Glaxo Group Limited Utilisation d'inhibiteurs selectifs de cyclooxygenase-2 pour le traitement de troubles schizophreniques

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Publication number Priority date Publication date Assignee Title
WO2002094833A1 (fr) 2001-05-24 2002-11-28 Eli Lilly And Company Derives de pyrrole utilises comme agents pharmaceutiques
US7087626B2 (en) 2001-05-24 2006-08-08 Eli Lilly And Company Pyrrole derivatives as pharmaceutical agents
WO2004069837A1 (fr) * 2003-02-06 2004-08-19 Pfizer Products Inc. Derives de pyrazolo[1,5-a][1,3,5]triazine en tant que ligands de recepteur cannabinoide
WO2004069838A1 (fr) * 2003-02-10 2004-08-19 Pfizer Products Inc. Ligands du recepteur cannabinoide et leurs utilisations
WO2005049034A2 (fr) * 2003-11-19 2005-06-02 Glaxo Group Limited Utilisation d'inhibiteurs selectifs de cyclooxygenase-2 pour le traitement de troubles schizophreniques

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SAWYER, J. SCOTT ET AL.: "Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-b type I receptor kinase domain", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, no. 13, 2004, pages 3581 - 3584

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