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Космические корабли и станции, автоматические КА и методы их проектирования, бортовые комплексы управления, системы и средства жизнеобеспечения, особенности технологии производства ракетно-космических систем

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Мониторинг СМИ и социальных сетей. Сканирование интернета, новостных сайтов, специализированных контентных площадок на базе мессенджеров. Гибкие настройки фильтров и первоначальных источников.

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Применить Всего найдено 256. Отображено 100.
09-01-2014 дата публикации

1,2-DISUBSTITUTED HETEROCYCLIC COMPOUNDS

Номер: US20140011808A1
Автор: Amy RIPKA, Gideon SHAPIRO, Richard CHESWORTH, RIPKA AMY, SHAPIRO GIDEON, CHESWORTH RICHARD
Принадлежит: Envivo Phamaceuticals Inc

1,2-disubstituted heterocyclic compounds which are inhibitors of phosphodiesterase 10 are described. Also described are processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. Among the disorders which may be treated are neurological, neurodegenerative and psychiatric disorders including, but not limited to, those associated with cognitive deficits or schizophrenic symptoms.

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Номер записи: 1
05-10-2017 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20170280720A1
Автор: Richard CHESWORTH, Lorna Helen MITCHELL, Gideon SHAPIRO, Oscar Miguel MORADEI, Kevin Wayne KUNTZ, Kenneth W. DUNCAN, Lei JIN, CHESWORTH RICHARD, MITCHELL LORNA HELEN, SHAPIRO GIDEON, MORADEI OSCAR MIGUEL, KUNTZ KEVIN WAYNE, DUNCAN KENNETH W, JIN LEI, CHESWORTH Richard, MITCHELL Lorna Helen, SHAPIRO Gideon, MORADEI Oscar Miguel, KUNTZ Kevin Wayne, DUNCAN Kenneth W., JIN Lei
Принадлежит: Epizyme, Inc.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 4. The compound of claim 3 , wherein Ris hydrogen.5. The compound of claim 3 , wherein Ris halogen.6. The compound of claim 3 , wherein Ris F.7. The compound of claim 3 , wherein Ris unsubstituted Calkyl.8. The compound of claim 3 , wherein Ris methyl.9. The compound of any one of - claim 3 , wherein Ris hydrogen.10. The compound of any one of - claim 3 , wherein Ris halogen.11. The compound of any one of claim 10 , wherein Ris F.12. The compound of any one of - claim 10 , wherein Ris unsubstituted Calkyl.13. The compound of claim 12 , wherein Ris methyl.15. The compound of claim 14 , wherein m is 0.16. The compound of claim 14 , wherein m is 1.17. The compound of or claim 14 , wherein Ris hydrogen.18. The compound of or claim 14 , wherein Ris unsubstituted Calkyl.19. The compound of claim 18 , wherein Ris methyl.20. The compound of any one of - claim 18 , wherein Ring A is an optionally substituted aryl.23. The compound of any one of - claim 18 , wherein Ris —N(R)or —C(═O)N(R).24. The compound of any one of - claim 18 , wherein Ris —N(R); and each instance of Ris independently hydrogen or optionally substituted alkyl.25. The compound of any one of - claim 18 , wherein Ris —N(CH)R claim 18 , wherein Ris hydrogen or optionally substituted alkyl.26. The compound of claim 25 , wherein Ris —CH-cyclopropyl.27. The compound of claim 23 , wherein Ris —C(═O)N(R) claim 23 , wherein each instance of Ris independently hydrogen claim 23 , optionally substituted alkyl claim 23 , or optionally substituted heterocyclyl.28. The compound of claim 27 , wherein Ris —C(═O)NHR.29. The compound of claim 28 , wherein Ris tetrahydropyranyl.30. The compound of claim ...

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Номер записи: 2
06-02-2014 дата публикации

5- AND 6-MEMBERED HETEROCYCLIC COMPOUNDS

Номер: US20140038965A1
Автор: Amy RIPKA, Gideon SHAPIRO, Richard CHESWORTH, RIPKA AMY, SHAPIRO GIDEON, CHESWORTH RICHARD
Принадлежит: EnVivo Pharmaceuticals, Inc.

5- and 6-membered heterocyclic compounds which are inhibitors of phosphodiesterase 10 are described as are processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. Also described is the treatment of neurological, neurodegenerative and psychiatric disorders including but not limited to those comparing cognitive deficits or schizophrenic symptoms. 1118-. (canceled)120. The compound claim 119 , wherein Y is —CHO— with the right most radical connected to the Z substituent; or a pharmaceutically acceptable salt thereof.121. The compound of claim 119 , wherein Y is —OCH— with the right most radical connected to the Z substituent; or a pharmaceutically acceptable salt thereof.122. The compound of claim 119 , wherein Z is an optionally substituted heteroaryl having only 6 ring atoms or an optionally substituted heterobicyclic ring system; or a pharmaceutically acceptable salt thereof.123. The compound of claim 119 , wherein Z is an optionally substituted heteroaryl having only 6 ring atoms selected from C and N provided the total number of ring nitrogens is less than or equal to two; said ring is optionally substituted with up to 2 substituents independently selected from the group consisting of C-Calkyl claim 119 , C-Calkoxy claim 119 , C-Ccycloalkyl claim 119 , C-Ccycloalkyloxy claim 119 , C-Ccycloalkylalkyl claim 119 , cycloalkylalkoxy claim 119 , halogen claim 119 , alkylsulfonyl claim 119 , cyano and nitro;or a pharmaceutically acceptable salt thereof.124. The compound of claim 119 , wherein Z is benzimidazolyl claim 119 , quinolinyl claim 119 , tetrahydroquinolyl claim 119 , imidazo[1 claim 119 ,2-a]pyridin-2-yl claim 119 , tetrahydroisoquinolyl claim 119 , 5-methylpyridin-2-yl claim 119 , 3 claim 119 ,5-dimethylpyridin-2-yl claim 119 , 6-fluoroquinolyl or isoquinolinyl ...

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Номер записи: 3
28-11-2013 дата публикации

PDE-10 INHIBITORS

Номер: US20130317025A1
Автор: Amy RIPKA, Gideon SHAPIRO, Richard CHESWORTH
Принадлежит:

Vicinal substituted cyclopropyl compounds which are inhibitors of phosphodiesterase 10 are described as are processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function, for example neurological, neurodegenerative and psychiatric disorders including, but not limited to, those comprising cognitive deficits or schizophrenic symptoms. 178-. (canceled)80. The pharmaceutical composition of claim 79 , wherein Ris hydrogen or C-C.81. The pharmaceutical composition of claim 79 , wherein Ris hydrogen or C-Calkyl.82. The pharmaceutical composition of claim 79 , wherein Ris hydrogen claim 79 , halogen claim 79 , C-Calkyl claim 79 , C-Ccycloalykl claim 79 , C-Calkoxy claim 79 , C-Ccycloalkyloxy claim 79 , cyano or alkylsulfonyl.83. The pharmaceutical composition of claim 79 , wherein Ris hydrogen claim 79 , halogen claim 79 , C-Calkyl claim 79 , C-Ccycloalykl claim 79 , C-Calkoxy claim 79 , C-Ccycloalkyloxy claim 79 , cyano or alkylsulfonyl.84. The pharmaceutical composition of claim 79 , wherein Y is C-Ccycloalykl claim 79 , C-Ccycloalkylalkyl claim 79 , C-Ccycloalkylalkoxy claim 79 , heterocycloalkyl claim 79 , or heterocycloalkyloxy.85. The pharmaceutical composition of claim 79 , wherein X is alkyl claim 79 , phenyl or heteroaryl.86. The pharmaceutical composition of claim 79 , wherein HET is a monocyclic heterocycloalkyl.87. The pharmaceutical composition of claim 86 , wherein HET is a monocyclic heterocycloalkyl having only 6 ring atoms.88. The pharmaceutical composition of claim 86 , wherein HET is a monocyclic heterocycloalkyl having only 5 ring atoms.89. The pharmaceutical composition of claim 79 , wherein HET is imidazolyl claim 79 , thiazolyl claim 79 , oxazolyl claim 79 , pyridinyl claim 79 , pyrmidinyl claim 79 , pyrazinyl claim 79 , triazolyl claim 79 , pyrazolyl claim 79 , ...

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Номер записи: 4
01-10-2015 дата публикации

1,2-DISUBSTITUTED HETEROCYCLIC COMPOUNDS

Номер: US20150274706A1
Автор: Richard CHESWORTH, Amy RIPKA, Gideon SHAPIRO
Принадлежит:

1,2-disubstituted heterocyclic compounds which are inhibitors of phosphodiesterase 10 are described. Also described are processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. Among the disorders which may be treated are neurological, neurodegenerative and psychiatric disorders including, but not limited to, those associated with cognitive deficits or schizophrenic symptoms. 1117-. (canceled)118. A method for making 4-bromo-2 ,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof , the method comprising contacting 2 ,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof with a brominating reagent to provide 4-bromo-2 ,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.119. The method of claim 118 , wherein the brominating reagent is N-bromosuccinimide.121. The method of claim 120 , wherein Z is quinolinyl.122. The method of claim 120 , wherein Z is imidazo[1 claim 120 ,2-b]pyridazine.123. The method of claim 120 , conducted in the presence of a catalyst.124. The method of claim 123 , wherein the catalyst is a palladium(0) or palladium(II) catalyst.125. The method of conducted in the presence of a base.126. The method of claim 125 , wherein the base is selected from the group consisting of potassium carbonate claim 125 , sodium carbonate and cesium carbonate. The disclosure relates to 1,2-disubstituted heterocyclic compounds which are inhibitors of phosphodiesterase 10. The disclosure further relates to processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. The disclosure also relates to methods for treating neurological, neurodegenerative and psychiatric ...

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Номер записи: 5
03-12-2015 дата публикации

5- AND 6-MEMBERED HETEROCYCLIC COMPOUNDS

Номер: US20150344467A1
Автор: Amy RIPKA, Gideon SHAPIRO, Richard CHESWORTH
Принадлежит:

5- and 6-membered heterocyclic compounds which are inhibitors of phosphodiesterase 10 are described as are processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. Also described is the treatment of neurological, neurodegenerative and psychiatric disorders including but not limited to those comparing cognitive deficits or schizophrenic symptoms. 2118-. (canceled) The disclosure relates to 5- and 6-membered heterocyclic compounds which are inhibitors of phosphodiesterase 10. The disclosure further relates to processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. The disclosure also relates to methods for treating neurological, neurodegenerative and psychiatric disorders including but not limited to those comprising cognitive deficits or schizophrenic symptoms.Cyclic phosphodiesterases are intracellular enzymes which, through the hydrolysis of cyclic nucleotides cAMP and cGMP, regulate the levels of these mono phosphate nucleotides which serve as second messengers in the signaling cascade of G-protein coupled receptors. In neurons, PDEs also play a role in the regulation of downstream cGMP and cAMP dependent kinases which phosphorylate proteins involved in the regulation of synaptic transmission and homeostasis. To date, eleven different PDE families have been identified which are encoded by 21 genes. The PDEs contain a variable N-terminal regulatory domain and a highly conserved C-terminal catalytic domain and differ in their substrate specificity, expression and localization in cellular and tissue compartments, including the CNS.The discovery of a new PDE family, PDE10, was reported ...

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Номер записи: 6
09-07-2015 дата публикации

Imidazotriazinone Compounds

Номер: US20150191476A1
Автор: Matthew Gregory BURSAVICH, Andrew J. MCRINER, Amy RIPKA, Gideon SHAPIRO
Принадлежит: Forum Pharmaceuticals Inc

The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9 and pharmaceutically acceptable salt thereof. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.

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Номер записи: 7
06-11-2014 дата публикации

IMIDAZOTRIAZINONE COMPOUNDS

Номер: US20140330014A1
Автор: Richard CHESWORTH, Gerhard KOENIG, Amy RIPKA, Gideon SHAPIRO, CHESWORTH RICHARD, KOENIG GERHARD, RIPKA AMY, SHAPIRO GIDEON
Принадлежит:

The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans. 1. (+)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one or a pharmaceutically acceptable salt thereof. This application is a continuation of U.S. patent application Ser. No. 13/237,795, filed Sep. 20, 2011 which claims the benefit of U.S. Provisional Application No. 61/384,694, filed Sep. 20, 2010, which are hereby expressly incorporated by reference in their entirety.The phosphodiesterases (PDEs) are a superfamily of enzymes with eleven members encoded by 21 genes that regulate intracellular cyclic nucleotide signaling (i.e., cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)). The PDEs contain a variable N-terminal regulatory domain and a highly conserved C-terminal catalytic domain and differ in their substrate specificity, expression and localization in cellular and tissue compartments, including the CNS. In neurons these cyclic nucleotides serve as second messengers in the signaling cascade of G-protein coupled receptors and lead to the activation of kinases which, in turn, will phosphorylate proteins involved in the regulation of synaptic transmission and homeostasis.The PDE9 enzyme selectively hydrolyzes cGMP over cAMP and has the highest affinity of any PDE for cGMP, K˜170 nM (Fisher et al., 1998, 273 (25), 15559-15564). PDE9 is found to be present in a variety of human tissues including prostate, colon, small intestine, spleen, kidney, brain and skeletal muscle. Specifically, PDE9 mRNA is found in the hippocampal formation further suggesting a role in learning and memory. Studies have also implicated cGMP pathways ...

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Номер записи: 8
11-12-2014 дата публикации

Tetrasubstituted Benzenes

Номер: US20140364641A1
Автор: Gideon SHAPIRO, Richard CHESWORTH, SHAPIRO GIDEON, CHESWORTH RICHARD
Принадлежит: ENVIVO PHARMACEUTICALS, INC.

Tetrasubstituted benzenes that act as modulators of gamma secretase and their use in the treatment of one or more symptoms of treating neurodegenerative disorders, e.g., Alzheimer's disease, are described. 162-. (canceled)64. The method of claim 63 , wherein the 4-trifluoromethylphenyl reagent is 4-trifluoromethylphenyl boronic acid.65. The method of claim 63 , wherein the reaction is conducted in the presence of a catalyst.66. The method of claim 65 , wherein the catalyst is a palladium(0) catalyst.67. The method of claim 63 , wherein the reaction is conducted in a presence of a base.68. The method of claim 67 , wherein the base is potassium carbonate.69. The method of claim 63 , further comprising isolating the product.71. The method of claim 70 , wherein the cyclobutylmethyl reagent is cyclobutylmethyl halide.72. The method of claim 71 , wherein cyclobutylmethyl halide is cyclobutylmethyl bromide.73. The method of claim 70 , wherein the reaction is conducted in the presence of a deprotonating base.74. The method of claim 73 , wherein the deprotonating base is sodium hydride.75. The method of claim 70 , further comprising isolating the product.77. The method of claim 76 , wherein the hydrolyzing reagent is a hydroxide reagent.78. The method of claim 77 , wherein the hydroxide reagent is lithium hydroxide.79. The method of claim 76 , wherein the reaction is conducted in the presence of methanol:tetrahydrofuran:water.80. The method of claim 76 , wherein acidification comprises addition of an inorganic acid.81. The method of claim 80 , wherein the inorganic acid is hydrochloric acid.82. The method of claim 76 , further comprising isolating the product or a salt thereof. This application claims priority to U.S. provisional application Ser. No. 61/015,605, filed Dec. 20, 2007, and to U.S. provisional application Ser. No. 61/109,665, filed Oct. 30, 2008, both of which are herein incorporated by reference.Alzheimer's disease (AD) is the most prevalent form of dementia. ...

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Номер записи: 9
11-02-2016 дата публикации

PYRAZOLE DERIVATIVES AS PRMT1 INHIBITORS AND USES THEREOF

Номер: US20160039767A1
Автор: Lorna Helen MITCHELL, Gideon SHAPIRO, Richard CHESWORTH, Paula Ann BORIACK-SJODIN, Oscar Miguel MORADEI
Принадлежит: Epizyme, Inc.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described. 1713. The compound of any one of - claims 1 , wherein Ris R claims 1 , wherein{'sup': y', 'B', 'A', 'B', 'A', 'z', 'z', 'B, 'sub': 2', 'n', '2, 'Ris —NRC(O)R, —NRSOR, or —(CRR)C(O)N(R);'}{'sup': 'z', 'each Ris independently hydrogen or fluoro; and'}n is 0, 1, 2, 3, or 4.1817. The compound of any one of - claims 1 , wherein Ris not hydrogen.19. The compound of claim 18 , wherein Ris —OR.20. The compound of claim 19 , wherein Ris —OR claim 19 , wherein Ris optionally substituted alkyl claim 19 , optionally substituted alkenyl claim 19 , optionally substituted alkynyl claim 19 , or optionally substituted carbocyclic.21. The compound of claim 20 , wherein Ris —OR claim 20 , wherein Ris optionally substituted Calkyl.22. The compound of claim 21 , wherein Ris —OR claim 21 , wherein Ris unsubstituted Calkyl.23. The compound of claim 22 , wherein Ris —O-propyl claim 22 , —O-isopropyl claim 22 , —O-isobutyl claim 22 , or —O-isoamyl.24. The compound of claim 22 , wherein Ris —OCH(CHCH)or —OCH(OH)CH(CH).25. The compound of claim 21 , wherein Ris —OR claim 21 , wherein Ris substituted Calkyl.26. The compound of claim 25 , wherein Ris —O—Calkyl-O—Calkyl.27. The compound of claim 26 , wherein Ris —OCHCHOCH claim 26 , —OCHCHCHOCH claim 26 , —OCHCHOH claim 26 , or —OCHCHOCHCHCH.28. The compound of claim 25 , wherein Ris —OCHCFor —OCHCHCHCF.29. The compound of claim 25 , wherein Ris —O—Calkyl-carbocyclyl.30. The compound of claim 29 , wherein Ris —O—CH-cyclobutyl claim 29 , —O—CH-cyclopropyl claim 29 , —O—CH-cyclopentyl claim 29 , or —O—CHCH-cyclohexyl.31. The compound of claim 25 , wherein Ris —O—Calkyl-heterocyclyl.32. The compound of claim 31 , wherein Ris —O—CH-tetrahydropyranyl or —O—CH- ...

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Номер записи: 10
09-11-2017 дата публикации

CARM1 INHIBITORS AND USES THEREOF

Номер: US20170320883A1
Автор: Richard CHESWORTH, Oscar Miguel MORADEI, Gideon SHAPIRO, Lei JIN, Robert E. BABINE
Принадлежит:

Provided herein are compounds of Formula (I): 135-. (canceled)38. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to and a pharmaceutically acceptable excipient.39. A pharmaceutical composition comprising the compound according to and a pharmaceutically acceptable excipient. This application claims priority under 35 U.S.C. §119(e) to U.S. provisional patent application Ser. No. 61/794,442, filed Mar. 15, 2013, and to U.S. provisional patent application Ser. No. 61/937,333, filed Feb. 7, 2014, the entire contents of which are incorporated herein by reference.Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases.Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., CARM1 (co-activator-associated arginine methyltransferase 1; PRMT4)), many of which are associated with specific genetic alterations that can cause human disease.Disease-associated chromatin-modifying enzymes play a role in diseases such as proliferative disorders, autoimmune disorders, muscular disorders, and neurological disorders. Thus, there is a need for the development of small molecules that are capable of inhibiting the activity of CARM1.CARM1 is an attractive target for modulation given its role in the regulation of diverse biological processes. It has now been found that compounds described herein, and pharmaceutically acceptable salts and compositions thereof, are effective as inhibitors of CARM1. Such ...

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Номер записи: 11
21-06-2018 дата публикации

3,3-DIFLUOROPIPERIDINE CARBAMATE HETEROCYCLIC COMPOUNDS AS NR2B NMDA RECEPTOR ANTAGONISTS

Номер: US20180170935A1
Автор: Gideon SHAPIRO
Принадлежит:

Disclosed are chemical entities of Formula (I), wherein Rand Z are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I). 2. The chemical entity of claim 1 , wherein Z is a 9-membered optionally substituted bicyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen heteroatoms.3. The chemical entity of claim 1 , wherein Z is a 9-membered optionally substituted bicyclic heteraromatic ring system having ring carbon atoms and 3 ring nitrogen heteroatoms.4. The chemical entity of claim 1 , wherein Z is a 9-membered optionally substituted bicyclic heteraromatic ring system having ring carbon atoms and 4 ring nitrogen heteroatoms.5. The chemical entity of claim 1 , wherein Z is a 6-membered optionally substituted monocyclic heteraromatic ring system having ring carbon atoms claim 1 , 1 ring nitrogen atom and 0 or 1 additional ring nitrogen atoms.6. The chemical entity of claim 5 , wherein Z is a 6-membered optionally substituted monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms.7. The chemical entity of claim 6 , wherein Z is a 6-membered monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms claim 6 , wherein Z is optionally substituted with 1 or 2 Rgroups.8. The chemical entity of claim 7 , wherein Z is a 6-membered monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms claim 7 , wherein Z is substituted with 1 or 2 Rgroups.9. The chemical entity of claim 8 , wherein Z is a 6-membered monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms claim 8 , wherein Z is substituted with 1 Rgroup.10. The chemical entity of any ...

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Номер записи: 12
12-11-2015 дата публикации

PHENOXYMETHYL HETEROCYCLIC COMPOUNDS

Номер: US20150322069A1
Автор: Amy RIPKA, Gideon SHAPIRO, Richard CHESWORTH
Принадлежит:

Phenoxymethyl compounds that inhibit at least one phosphodiesterase 10 are described as are pharmaceutical compositions containing such compounds an methods for treating various CNS disorders by administering such compounds to a patient in need thereof. 235-. (canceled)36. A method for making 4-(4-hydroxyphenyl)-2 ,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof , the method comprising using Suzuki coupling to obtain 4-(4-hydroxyphenyl)-2 ,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof from 4-bromo-2 ,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one.37. The method of claim 36 , conducted in a polar solvent mixture.38. The method of claim 37 , wherein the polar solvent mixture comprises water.39. The method of claim 36 , conducted in the presence of a catalyst.40. The method of claim 39 , wherein the catalyst is a palladium(0) or palladium(II) catalyst.41. The method of conducted in the presence of a base.42. The method of claim 41 , wherein the base is selected from the group consisting of potassium carbonate claim 41 , sodium carbonate and cesium carbonate.43. The method of claim 36 , further comprising isolating 4-(4-hydroxyphenyl)-2 claim 36 ,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.45. The method of claim 44 , conducted in a polar solvent.46. The method of claim 45 , wherein the polar solvent is CHCN or DMF.47. The method of conducted in the presence of a base.48. The method of claim 47 , wherein the base is selected from the group consisting of potassium carbonate claim 47 , sodium carbonate and cesium carbonate.49. The method of claim 44 , further comprising isolating 4-(4-((6-chloroimidazo[1 claim 44 ,2-b]pyridazin-2-yl)methoxy)phenyl)-2 claim 44 ,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.50. A method for making 4-(4-(imidazo[1 claim 44 ,2-b]pyridazin-2-ylmethoxy)phenyl)-2 claim 44 ,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof claim 44 ,the method comprising reducing 4-(4-((6- ...

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Номер записи: 13
27-06-2013 дата публикации

TETRASUBSTITUTED BENZENES

Номер: US20130165486A1
Автор: Gideon SHAPIRO, Richard CHESWORTH
Принадлежит: ENVIVO PHARMACEUTICALS, INC.

Tetrasubstituted benzenes that act as modulators of gamma secretase and their use in the treatment of one or more symptoms of treating neurodegenerative disorders, e.g., Alzheimer's disease, are described. 162.-. (canceled)64. The compound of claim 63 , wherein Rand Rare independently selected from the group consisting of (a) H claim 63 , (b) (C-C)alkyl and (c) (C-C)alkyl-(C-C)cycloalkyl provided that both Rand Rare not H claim 63 , wherein each alkyl or cycloalkyl of Rand Ris optionally independently substituted with one or more groups selected from the group consisting of halo claim 63 , hydroxy claim 63 , cyano claim 63 , CFand (C-C)alkyl claim 63 ,or{'sub': 1', '2', '1', '4', '3', '1', '4, 'Rand Rtaken together with the carbon to which they are attached form a 3-7 membered cycloalkyl or heterocycloalkyl ring which optionally bears a C-Calkyl substituent that can be optionally independently substituted with one or more groups selected from the group consisting of halo, hydroxy, oxo, cyano, CFand (C-C)alkyl,'}or{'sub': 1', '2', '20', '21', '20', '21', '3', '1', '4, 'Rand Rare taken together with the carbon to which they are attached form a 3-7 membered cycloalkyl ring substituted with Rand Rwherein Rand Rtaken together with the carbon or carbons to which they are attached form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently substituted with one or more groups selected from the group consisting of halo, hydroxy, cyano, CFand (C-C)alkyl;'}Y is —O—,{'sub': '4', 'claim-text': [{'sub': 0', '3', '3', '7, '(a) (C-C)alkyl(C-C)cycloalkyl,'}, '(b) trifluoroethyl and', '(c) trifluoropropyl;', {'sub': 6', '3', '2', '1', '4', '2', '2', '3', '6', '6', '2', '6, 'Z is a phenyl ring optionally bearing up to 3 substituents independently selected from the group consisting of halogen, R, CF, CN, NO, OH, (C-C)alkoxy, OCHCHOCH, SR, S(O)Rand S(O)R;'}], 'Ris selected from the group consisting of'}{'sub': 5', '3, 'claim-text': [{'sub': '6', 'Ris selected ...

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Номер записи: 14
22-11-2012 дата публикации

TETRASUBSTITUTED BENZENES

Номер: US20120295981A1
Автор: Gideon SHAPIRO, Richard CHESWORTH, SHAPIRO GIDEON, CHESWORTH RICHARD
Принадлежит: EnVivo PHARMACEUTICALS, INC.

Tetrasubstituted benzenes that act as modulators of gamma secretase and their use in the treatment of one or more symptoms of treating neurodegenerative disorders, e.g., Alzheimer's disease, are described. 162-. (canceled)63. A method for treating Alzheimer's disease comprising administering to a patient in need thereof an effective amount of (R)-2-(5-chloro-6-(2 ,2 ,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof.64. A method for treating Alzheimer's disease comprising administering to a patient in need thereof an effective amount of (S)-2-(5-chloro-6-(2 ,2 ,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof.65. A method for treating Alzheimer's disease comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising:(R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof; anda pharmaceutically acceptable carrier or excipient.66. The method of claim 65 , wherein the pharmaceutical composition is in a solid dosage form.67. The method of claim 65 , wherein the pharmaceutical composition is in an oral dosage form.68. The method of claim 67 , wherein the oral dosage form is a tablet or a capsule.69. The method of claim 68 , wherein the oral dosage form is a tablet.70. A method for treating Alzheimer's disease comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising:(S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof; anda pharmaceutically acceptable carrier or excipient.71. The method of claim 70 , wherein the pharmaceutical composition is in a solid dosage form.72. The method of claim 70 , wherein the pharmaceutical ...

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Номер записи: 15
06-06-2013 дата публикации

PHENOXYMETHYL HETEROCYCLIC COMPOUNDS

Номер: US20130143888A1
Автор: Amy RIPKA, Gideon SHAPIRO, Richard CHESWORTH
Принадлежит: ENVIVO PHAMACEUTICALS, INC.

Phenoxymethyl compounds that inhibit at least one phosphodiesterase 10 are described as are pharmaceutical compositions containing such compounds an methods for treating various CNS disorders by administering such compounds to a patient in need thereof. 135.-. (canceled)36. A method for treating a central nervous system (CNS) disorder comprising administering to a human in need thereof a therapeutically effective amount of 4-(4-(imidazo[1 ,2-b]pyridazin-2-ylmethoxy)phenyl)-2 ,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a pharmaceutically acceptable salt thereof.37. The method of claim 36 , wherein the CNS disorder is one or more of Huntington's disease claim 36 , schizophrenia claim 36 , schizo-affective condition claim 36 , delusional disorder claim 36 , drug-induced psychosis claim 36 , panic disorder claim 36 , obsessive compulsive disorder claim 36 , post-traumatic stress disorder claim 36 , age-related cognitive decline claim 36 , attention deficit/hyperactivity disorder claim 36 , bipolar disorder claim 36 , personality disorder of the paranoid type claim 36 , personality disorder of the schizoid type claim 36 , dyskinesia claim 36 , choreiform condition claim 36 , psychosis associated with Parkinson's disease claim 36 , psychotic symptoms associated with Alzheimer's disease claim 36 , dystonic condition claim 36 , mood disorder claim 36 , and dementia.38. The method of claim 36 , wherein the CNS disorder is schizophrenia claim 36 , schizo-affective condition claim 36 , Huntington's disease claim 36 , bipolar disorder claim 36 , obsessive compulsive disorder claim 36 , dystonic condition claim 36 , or tardive dyskinesia.39. The method of claim 37 , wherein the dementia is multi-infarct dementia claim 37 , AIDS-related dementia claim 37 , or neurodegenerative dementia.40. The method of claim 36 , wherein the CNS disorder is schizophrenia or schizo-affective condition.41. The method of claim 36 , wherein the CNS disorder is Huntington's disease.42. The method ...

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Номер записи: 16
21-06-2012 дата публикации

IMIDAZOTRIAZINONE COMPOUNDS

Номер: US20120157458A1
Автор: McRiner Andrew J., Ripka Amy, Shapiro Gideon
Принадлежит:

The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans. 2. The compound of claim 1 , wherein the substituents are selected from halogen claim 1 , —S(O)(C-C)alkyl claim 1 , OH claim 1 , —C(O)—(C-C)alkyl claim 1 , CN claim 1 , (C-C)alkyl claim 1 , and (C-C)alkoxy.3. The compound of claim 1 , wherein Ris selected from (C-C) alkyl.4. The compound of claim 1 , wherein Ris selected from the group consisting of heterocycloalkyl claim 1 , (C-C)cycloalkyl claim 1 , and restricted phenyl claim 1 , which may be optionally substituted with one or more substituents selected from the group consisting of halogen claim 1 , —S(O)(C-C)alkyl claim 1 , OH claim 1 , —C(O)—(C-C)alkyl claim 1 , CN claim 1 , (C-C)alkyl claim 1 , and (C-C)alkoxy.5. The compound of claim 1 , wherein Ris selected from the group consisting of a mono or bicyclic heteroaryl(C-C)alkyl and restricted phenyl(C-C)alkyl claim 1 , which may be optionally substituted with one or more substituents selected from the group consisting of halogen claim 1 , —S(O)(C-C)alkyl claim 1 , OH claim 1 , —C(O)—(C-C)alkyl claim 1 , CN claim 1 , (C-C)alkyl claim 1 , and (C-C)alkoxy.6. The compound of claim 1 , wherein X is a bond.8. The compound of claim 7 , where X is a bond.9. The compound of claim 1 , wherein Ris methyl.10. The compound of claim 1 , wherein said heterocycloalkyl is tetrahydropyranyl or piperidinyl claim 1 , which may be optionally substituted with one or more substituents selected from the group consisting of halogen claim 1 , —S(O)(C-C)alkyl claim 1 , OH claim 1 , —C(O)—(C-C)alkyl claim 1 , CN claim 1 , (C-C)alkyl claim 1 , and (C-C)alkoxy.11. The compound of claim 1 , wherein said halogen is F or Cl.13. The compound of claim 12 , where ...

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Номер записи: 17
13-09-2012 дата публикации

1,2-Disubstituted Heterocyclic Compounds

Номер: US20120232265A1
Автор: Chesworth Richard, Ripka Amy, Shapiro Gideon
Принадлежит:

1,2-disubstituted heterocyclic compounds which are inhibitors of phosphodiesterase 10 are described. Also described are processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. Among the disorders which may be treated are neurological, neurodegenerative and psychiatric disorders including, but not limited to, those associated with cognitive deficits or schizophrenic symptoms. 2117.-. (canceled) The disclosure relates to 1,2-disubstituted heterocyclic compounds which are inhibitors of phosphodiesterase 10. The disclosure further relates to processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. The disclosure also relates to methods for treating neurological, neurodegenerative and psychiatric disorders including but not limited to those comprising cognitive deficits or schizophrenic symptoms.Cyclic phosphodiesterases are intracellular enzymes which, through the hydrolysis of cyclic nucleotides cAMP and cGMP, regulate the levels of these mono phosphate nucleotides which serve as second messengers in the signaling cascade of G-protein coupled receptors. In neurons, PDEs also play a role in the regulation of downstream cGMP and cAMP dependent kinases which phosphorylate proteins involved in the regulation of synaptic transmission and homeostasis. To date, eleven different PDE families have been identified which are encoded by 21 genes. The PDEs contain a variable N-terminal regulatory domain and a highly conserved C-terminal catalytic domain and differ in their substrate specificity, expression and localization in cellular and tissue compartments, including the CNS.The discovery of a new ...

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Номер записи: 18
30-05-2013 дата публикации

Treatment of Cognitive Disorders with (R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-Carboxamide and Pharmaceutically Acceptable Salts Thereof

Номер: US20130137717A1
Автор: Chesworth Richard, Koenig Gerhard, Shapiro Gideon
Принадлежит: EnVivo Pharmaceuticals, Inc.

(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide has been found to have procognitive effects in humans at unexpectedly low doses. Thus, (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof can be used at unexpectedly low doses to improve cognition. 1. A method of improving cognition in a patient suffering from Schizophrenia or Alzheimer's disease , comprising:administering to said patient a daily dose of 3 mg, 2.70 mg, 2.50 mg, 2.25 mg, 2 mg, 1.75 mg, 1.50 mg, 1.25 mg, 1 mg, 0.7 mg, 0.5 mg, 0.3 mg, or 0.1 mg of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide, or a pharmaceutically acceptable salt thereof.2. The method of claim 1 , wherein the pharmaceutically acceptable salt of the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide is: (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride; (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate; or (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride solvate.3. The method of claim 2 , wherein the pharmaceutically acceptable salt of the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide is administered to said patient.4. The method of claim 3 , wherein the daily dose is 1 mg claim 3 , 2 mg claim 3 , or 3 mg.5. The method of claim 3 , wherein the pharmaceutically acceptable salt of the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide is (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride.6. The method of claim 3 , wherein the pharmaceutically acceptable salt of the (R)-7-chloro-N-(quinuclidin-3-yl]benzo[b]thiophene-2-carboxamide is (R)-7-chloro-N-(quinuclidin-3-yl]benzo[b]thiophene-2-carboxamide hydrochloride monohydrate.7. The method of claim 6 , wherein the daily dose is 1 mg.8. The method of claim 6 , wherein the daily dose is 2 mg.9. The method of claim 6 , wherein the ...

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Номер записи: 19
18-07-2013 дата публикации

Crystalline Form of (R)-7-Chloro-N-(Quinuclidin-3-yl)benzo[B]thiophene-2-Carboxamide Hydrochloride Monohydrate

Номер: US20130183380A1
Автор: Chesworth Richard, Ishige Takayuki, Kishida Muneki, Oliver-Shaffer Patricia, Shapiro Gideon
Принадлежит: EnVivo Pharmaceuticals, Inc.

Crystalline Forms I and II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate and compositions, methods of manufacture and therapeutic uses thereof are described. 1. A crystalline Form I of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate , characterized by an x-ray powder diffraction pattern having peaks expressed as 2⊖ at one or both of 17.48 and 20.58±0.20 degrees when measured against an internal silicon standard.2. The crystalline Form I of claim 1 , characterized by an x-ray powder diffraction pattern further having at least one peak expressed as 2⊖ at 4.50 claim 1 , 9.04 claim 1 , 14.60 claim 1 , 15.14 claim 1 , 15.80 claim 1 , 16.60 claim 1 , 18.16 claim 1 , 18.44 claim 1 , 19.48 claim 1 , 21.74 claim 1 , and 25.46±0.20 degrees when measured against an internal silicon standard.3. The crystalline Form I of claim 2 , characterized by an x-ray powder diffraction pattern further having at least two peaks expressed as 2⊖ at 4.50 claim 2 , 9.04 claim 2 , 14.60 claim 2 , 15.14 claim 2 , 15.80 claim 2 , 16.60 claim 2 , 18.16 claim 2 , 18.44 claim 2 , 19.48 claim 2 , 21.74 and 25.46±0.20 degrees when measured against an internal silicon standard.4. The crystalline Form I of claim 2 , characterized by an x-ray powder diffraction pattern further having at least four peaks expressed as 2⊖ at 4.50 claim 2 , 9.04 claim 2 , 14.60 claim 2 , 15.14 claim 2 , 15.80 claim 2 , 16.60 claim 2 , 18.16 claim 2 , 18.44 claim 2 , 19.48 claim 2 , 21.74 and 25.46±0.20 degrees when measured against an internal silicon standard.5. The crystalline Form I of claim 2 , characterized by an x-ray powder diffraction pattern further having at least six peaks expressed as 2⊖ at 4.50 claim 2 , 9.04 claim 2 , 14.60 claim 2 , 15.14 claim 2 , 15.80 claim 2 , 16.60 claim 2 , 18.16 claim 2 , 18.44 claim 2 , 19.48 claim 2 , 21.74 and 25.46±0.20 degrees when measured against an internal silicon standard.6. The ...

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Номер записи: 20
09-01-2014 дата публикации

Dibenzo[B,F][1,4]Oxazepin-11-yl-N-Hydroxybenzamides as HDAC Inhibitors

Номер: US20140011988A1
Автор: BEAULIEU Patrick, Chantigny Yves Andre, Chesworth Richard, Deziel Robert, Leit Silvana, Mancuso John, Shapiro Gideon, Smil David, Tessier Pierre
Принадлежит:

This invention relates to compounds for the inhibition of histone deacetylase. More particularly, the invention provides for compounds of formula (I) 225.-. (canceled) This application claims the benefit of U.S. application Ser. No. 11/925,151, filed Oct. 26, 2007, which claims the benefit of U.S. provisional application 60/884,287, filed Jan. 10, 2007, and U.S. provisional application 60/863,347, filed Oct. 28, 2006.1. Field of the InventionThis invention relates to compounds for the inhibition of histone deacetylase.2. Description of Related ArtIn eukaryotic cells, nuclear DNA associates with histones to form a compact complex called chromatin. The histones constitute a family of basic proteins which are generally highly conserved across eukaryotic species. The core histones, termed H2A, H2B, H3, and H4, associate to form a protein core. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. Approximately 146 base pairs of DNA wrap around a histone core to make up a nucleosome particle, the repeating structural motif of chromatin.Csordas, 286: 23-38 (1990) teaches that histones are subject to posttranslational acetylation of the N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HAT1). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure. Indeed, Taunton et al., 272: 408-411 (1996), teaches that access of transcription factors to chromatin templates is enhanced by histone hyperacetylation. Taunton et al. further teaches that an enrichment in underacetylated histone H4 has been found in transcriptionally silent regions of the genome.Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed histone deacetylases (HDACs). The molecular cloning of gene sequences encoding proteins with HDAC activity has established the ...

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Номер записи: 21
27-02-2014 дата публикации

Materials and Methods for Detection of Nucleic Acids

Номер: US20140057269A1
Автор: Christopher B. Sherrill, Craig S. Richmond, David J. Marshall, Gideon Shapiro, James R. Prudent, Jennifer K. Grenier, Jerod L. Ptacin, Simona Jurczyk
Принадлежит: Luminex Corp

Assays using non-natural bases are described. In one embodiment, the method involves contacting a sample suspected of containing the target nucleic acid with a polymerase and first and second primers; amplifying the target nucleic acid by PCR using the first and second primers to generate an amplification product having a double-stranded region and a single-stranded region that comprises the non-natural base; contacting the sample with a reporter comprising a label and a non-natural base that is complementary to the non-natural base of the single-stranded region; annealing at least a portion of the reporter to the single-stranded region of the amplification product; and correlating a signal of the label with the presence of the target nucleic acid in the sample. The invention also provides corresponding kits for use in detecting target nucleic acids in a sample.

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Номер записи: 22
20-03-2014 дата публикации

CAI-BASED SYSTEMS AND METHODS FOR THE LOCALIZED TREATMENT OF OCULAR AND OTHER DISEASES

Номер: US20140079694A1
Автор: Franklin Alan J., Jurczyk Simona, Robinson Gary, Shapiro Gideon
Принадлежит: RFE Pharma LLC

The subject invention provides CAI compounds and formulations thereof, and methods for their use in the localized treatment of non-life threatening diseases. Formulations of CAI compounds of the subject invention include CAI free base and CAI prodrug microcrystallines, microparticles, emulsions, and the like. The subject invention further provides methods for treating non-life threatening diseases using the CAI compounds of the invention (i.e., novel delivery systems and combination therapies), that are effective and are associated with little or no adverse side effects. 1. A method for treating a patient suffering from age-related macular degeneration or diabetic retinopathy comprising:(a) diagnosing age-related macular degeneration, diabetic retinopathy- or symptom thereof in a patient; and(b) ocularly administering to said patient a sterile, aqueous suspension formulation free of organic solvents comprising a therapeutically effective amount of suspended solid microparticulates of CAI (5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide) free base form, wherein the effective amount comprises a dose of 0.1 to 30 mg/ml of CAI in formulation with hydroxypropyl β-cyclodextrin.2. A method for treating a patient suffering from age-related macular degeneration or diabetic retinopathy comprising:(a) diagnosing age-related macular degeneration, diabetic retinopathy- or symptom thereof in a patient; and(b) ocularly administering to said patient a sterile, aqueous suspension formulation free of organic solvents comprising a therapeutically effective amount of suspended solid microparticulates of CAI (5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide) free base form, wherein the effective amount comprises a dose of 0.1 to 30 mg/ml of CAI in formulation.3. The method of claim 1 , wherein the local ocular administration is assisted by sonophoresis or iontophoresis.4. The method of claim 1 , wherein the effective amount of ...

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Номер записи: 23
12-01-2017 дата публикации

Cai-based systems and methods for the localized treatment of ocular and other diseases

Номер: US20170007581A1
Автор: Alan J. Franklin, Gary Robinson, Gideon Shapiro, Simona Jurczyk
Принадлежит: RFE Pharma LLC

The subject invention provides CAI compounds and formulations thereof, and methods for their use in the localized treatment of non-life threatening diseases. Formulations of CAI compounds of the subject invention include CAI free base and CAI prodrug microcrystallines, microparticles, emulsions, and the like. The subject invention further provides methods for treating non-life threatening diseases using the CAI compounds of the invention (i.e., novel delivery systems and combination therapies), that are effective and are associated with little or no adverse side effects.

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Номер записи: 24
14-01-2016 дата публикации

CRYSTALLINE FORM OF (R)-7-CHLORO-N-(QUINUCLIDIN-3-YL)BENZO[B]THIOPHENE-2-CARBOXAMIDE HYDROCHLORIDE MONOHYDRATE

Номер: US20160009707A1
Автор: Chesworth Richard, Ishige Takayuki, Kishida Muneki, Oliver-Shaffer Patricia, Shapiro Gideon
Принадлежит:

Crystalline Forms I and II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate and compositions, methods of manufacture and therapeutic uses thereof are described. 1. A crystalline Form II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate , characterized by an x-ray powder diffraction pattern having peaks expressed as 2Θ at:i) one or both of 21.16 and 21.38±0.20 degrees when measured against an internal silicon standard; andii) at least four peaks selected from a group of peaks consisting of: 4.48, 9.00, 13.58, 15.62, 16.48, 19.02, 19.44, 22.46, and 25.00±0.20 degrees when measured against an internal silicon standard.2. The crystalline Form II of claim 1 , characterized by an x-ray powder diffraction pattern claim 1 , wherein at least six peaks are selected from the group of peaks.3. The crystalline Form II of claim 1 , characterized by an x-ray powder diffraction pattern claim 1 , wherein at least eight peaks are selected from the group of peaks.4. The crystalline Form II of claim 1 , characterized by an x-ray powder diffraction pattern claim 1 , wherein all of the peaks are selected from the group of peaks.5. A pharmaceutical composition comprising the crystalline Form II of .6. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Alzheimer's disease.7. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Schizophrenia.8. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Alzheimer's disease.9. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Schizophrenia.10. A pharmaceutical composition ...

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Номер записи: 25
28-01-2016 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20160024016A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Shapiro Gideon, Swinger Karren Kalai
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 65. The compound of any one of - claims 1 , wherein -L-Ris optionally substituted carbocyclyl.7. The compound of claim 6 , wherein -L-Ris optionally substituted cyclohexyl.85. The compound of any one of - claims 1 , wherein -L-Ris optionally substituted heterocyclyl.9. The compound of claim 8 , wherein -L-Ris optionally substituted piperidine.105. The compound of any one of - claims 1 , wherein -L-Ris optionally substituted alkyl.11. The compound of claim 10 , wherein Lis Calkylene and Ris optionally substituted aryl or optionally substituted heteroaryl.2524. The compound of any one of - claims 12 , wherein Ring A is optionally substituted phenyl.2624. The compound of any one of - claims 12 , wherein Ring A is optionally substituted heteroaryl.2724. The compound of any one of - claims 12 , wherein Ring A is optionally substituted carbocyclyl.2824. The compound of any one of - claims 12 , wherein Ring A is optionally substituted heterocyclyl.2924. The compound of any one of - claims 12 , wherein Ring A is optionally substituted bicyclic carbocyclyl.3024. The compound of any one of - claims 12 , wherein Ring A is optionally substituted bicyclic heterocyclyl.3130. The compound of any one of - claims 1 , wherein Ris hydrogen.3230. The compound of any one of - claims 1 , wherein Ris Calkyl.33. The compound of claim 32 , wherein Ris methyl.3430. The compound of any one of - claims 1 , wherein Ris cyclopropyl or cyclobutyl.3534. The compound of any one of - claims 1 , wherein Ris hydrogen.3634. The compound of any one of - claims 1 , wherein Ris optionally substituted Calkyl.37. The compound of claim 36 , wherein Ris unsubstituted Calkyl.38. The ...

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Номер записи: 26
28-01-2016 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20160024017A1
Автор: Chesworth Richard, Kuntz Kevin Wayne, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 5. The compound of claim 3 , wherein Ris branched Calkyl.2625. The compound of any one of - claims 1 , wherein X is NRand Y is N.2725. The compound of any one of - claims 1 , wherein X is N and Y is NR.2928. A pharmaceutical composition comprising a compound of any one of - claims 1 , or a pharmaceutically acceptable salt thereof claims 1 , and optionally a pharmaceutically acceptable excipient.30. The pharmaceutical composition of claim 29 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound.3128. A kit or packaged pharmaceutical comprising a compound of any one of - or a pharmaceutically acceptable salt thereof claims 1 , and instructions for use thereof.3228. A method of inhibiting an arginine methyl tranferase (RMT) comprising contacting a cell with an effective amount of a compound of any one of - or a pharmaceutically acceptable salt thereof.33. The method of claim 32 , wherein the arginine methyl transferase is PRMT1.34. The method of claim 32 , wherein the arginine methyl transferase is PRMT3.35. The method of claim 32 , wherein the arginine methyl transferase is PRMT4.36. The method of claim 32 , wherein the arginine methyl transferase is PRMT6.37. The method of claim 32 , wherein the arginine methyl transferase is PRMT8.3828. A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of any one of - or a pharmaceutically acceptable salt thereof.3928. A method of modulating transcription comprising contacting a cell with an effective amount of a compound of any one of - or a pharmaceutically acceptable salt thereof.4039. The ...

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Номер записи: 27
24-01-2019 дата публикации

PRMT1 Inhibitors and Uses Thereof

Номер: US20190022064A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, Kuntz Kevin Wayne, MITCHELL Lorna Helen, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит:

Described herein are compounds of Formula (I-a) and (I-b), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described. 39.-. (canceled)10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris R claim 1 , wherein{'sup': y', 'B', 'A', 'B', 'A', 'z', 'z', 'B, 'sub': 2', 'n', '2, 'Ris —NRC(O)R, —NRSOR, or —(CRR)C(O)N(R);'}{'sup': 'z', 'each Ris independently hydrogen or fluoro; and'}n is 0, 1, 2, 3, or 4.1116.-. (canceled)17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , halo claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , optionally substituted carbocyclic claim 1 , or —CN.1847.-. (canceled)48. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , halo claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , optionally substituted carbocyclic claim 1 , or —CN.4987.-. (canceled)88. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , halo claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , optionally substituted carbocyclic claim 1 , or —CN.89128.-. (canceled)129. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris hydrogen or halo.130. (canceled)131. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris hydrogen or halo.132. (canceled)133. The compound of claim 1 , or a pharmaceutically acceptable salt ...

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Номер записи: 28
04-02-2016 дата публикации

Arginine methyltransferase inhibitors and uses thereof

Номер: US20160031839A1
Автор: Gideon Shapiro, Lorna Helen Mitchell, Richard Chesworth
Принадлежит: Epizyme Inc

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

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Номер записи: 29
01-02-2018 дата публикации

3,3-DIFLUORO-PIPERIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS

Номер: US20180030055A1
Автор: Shapiro Gideon
Принадлежит:

Disclosed are chemical entities of Formula (I): wherein X, Y, Z, R, R, Rand Rare defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I). 2. The chemical entity of claim 1 , wherein:{'sub': 1', '4', '1', '3', '1', '4', '1', '2', '2', '2, 'sup': 2', '8', '7', '6, 'X is —H; —F; —Cl; C-Calkyl; C-Calkyl substituted with 1 to 6 fluoro; cyclopropyl; C-Calkoxy; C-Calkoxy substituted with 1 to 3 fluoro; —CN; —NO; —N(R)(R); —SR; or —S(O)R;'}{'sup': '2', 'Y is C(R) or N;'}Z is C(H) or N;{'sup': 1', '7', '8', '7', '7', '8, 'sub': 1', '4', '1', '2', '1', '4', '1', '2', '2', '2, 'Ris —H; —F; —Cl; C-Calkyl; C-Calkyl substituted with 1 to 3 fluoro; cyclopropyl; C-Calkoxy; C-Calkoxy substituted with 1 to 3 fluoro; —CN; —NO; —N(R)(R); —COR; or —C(O)N(R)(R);'}{'sup': '2', 'sub': 1', '4', '1', '2', '1', '4', '1', '2, 'Ris —H; —F; —Cl; C-Calkyl; C-Calkyl substituted with 1 to 3 fluoro; cyclopropyl; C-Calkoxy; C-Calkoxy substituted with 1 to 3 fluoro;'}{'sup': '3', 'sub': 3', '3', '3, 'Ris —H, —F, —Cl, —CH, —CFor —OCH;'}{'sup': '4', 'sub': 3', '3, 'Ris —H, —F, —Cl, —CH, —CF, or cyclopropyl;'}{'sup': '5', 'sub': '3', 'Ris —H or —CH;'}{'sup': '6', 'sub': 1', '2, 'each instance of Rindependently is C-Calkyl optionally substituted with 1 to 3 fluoro;'}{'sup': '7', 'sub': 1', '2, 'each instance of Rindependently is C-Calkyl; and'}{'sup': '8', 'sub': 1', '2, 'each instance of Rindependently is —H or C-Calkyl.'}3. The chemical entity of claim 1 , wherein:{'sub': 1', '2', '1', '2, 'X is —H; —F; —Cl; C-Calkyl optionally substituted with 1 to 3 fluoro; or C-Calkoxy optionally substituted with 1 to 3 fluoro;'}{'sup': '2', 'Y is C(R) or N;'}Z is C(H) or N;{'sup': '1', 'sub': '3', 'Ris —H, halo or —CH;'}{' ...

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Номер записи: 30
11-02-2016 дата публикации

CARM1 INHIBITORS AND USES THEREOF

Номер: US20160039834A1
Автор: Babine Robert E., Chesworth Richard, Jin Lei, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Provided herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X, R, R, R, R, R, R, are as defined herein, and Ring HET is a 6-membered monocyclic heteroaryl ring system of Formula (II) wherein L, R, G, G, G, and Gare as defined herein. Compounds of the present invention are useful for inhibiting CARM1 activity. Methods of using the compounds for treating CARM1-mediated disorders are also described. 43. The compound of any one of - claims 1 , wherein X is —O—.53. The compound of any one of - claims 1 , wherein X is —S—.63. The compound of any one of - claims 1 , wherein X is —CH—.1514. The compound of any one of - claims 1 , wherein Ris hydrogen claims 1 , methyl claims 1 , ethyl claims 1 , n-propyl claims 1 , isopropyl claims 1 , or cyclopropyl.1615. The compound of any one of - claims 1 , wherein R claims 1 , R claims 1 , and Rare hydrogen.1716. The compound of any one of - claims 1 , wherein Ris halogen or —OR.1817. The compound of any one of - claims 1 , wherein Lis a bond claims 1 , —N(R)— claims 1 , —NRC(O)O— claims 1 , —NRC(O)N(R)— claims 1 , —N(R)— claims 1 , —N(R)SON(R)— claims 1 , —NR—(CH)—C(O)O— claims 1 , —NR—(CH)—O— claims 1 , —NRC(O)N(R)— claims 1 , —NR—(CH)— claims 1 , —(CH)—NR— claims 1 , —NRC(O)O(CH)— claims 1 , —NRC(O)NR(CH)— claims 1 , or —NR(CH)NRC(O)—.2019. The compound of any one of - claims 1 , wherein Ring HET comprises a group -L-Ris attached thereto.21. The compound of claim 20 , wherein Lis a bond claim 20 , —N(R)— claim 20 , —NRC(O)O— claim 20 , —NRC(O)N(R)— claim 20 , —N(R)— claim 20 , —N(R)SON(R)— claim 20 , —NR—(CH)—C(O)O— claim 20 , —NR—(CH)—O— claim 20 , —NRC(O)N(R) claim 20 , —NR—(CH)— claim 20 , —(CH)—NR— claim 20 , —NRC(O)O(CH)— claim 20 , —NRC(O)NR(CH)— claim 20 , or —NR(CH)NRC(O)—.23. The compound of claim 1 , wherein the compound is selected from the group consisting of compounds depicted in Tables 1A and 2 claim 1 , or a pharmaceutically acceptable ...

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Номер записи: 31
25-02-2016 дата публикации

1-phenoxy-3-(alkylamino)-propan-2-ol derivatives as carm1 inhibitors and uses thereof

Номер: US20160052922A1
Автор: Gideon Shapiro, Kenneth W. Duncan, LEI Jin, Loma Helen Mitchell, Oscar Miguel Moradei, Richard Chesworth, Robert E. Babine
Принадлежит: Epizyme Inc

Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X, R 1 , R 2a , R 2b , R 2c , R 2d , are as defined herein, and Ring HET is an optionally substituted 6,5-bicyclic heteroaryl ring system comprising 2 to 5 nitrogen atoms, inclusive, wherein the point of attachment is provided on the 6-membered ring of the 6,5-bicyclic heteroaryl ring system, and wherein the 6-membered ring is further substituted with a group of formula -L 1 -R 3 , wherein L 1 and R 3 are as defined herein. Compounds of the present invention are useful for inhibiting CARM1 activity. Methods of using the compounds for treating CARM1-mediated disorders are also described.

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Номер записи: 32
02-03-2017 дата публикации

CARM1 INHIBITORS AND USES THEREOF

Номер: US20170056409A1
Автор: Babine Robert E., Chesworth Richard, Jin Lei, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Provided herein are compounds of Formula (I): 125-. (canceled)27. The method of claim 26 , wherein the disorder is a proliferative disorder.28. The method of claim 26 , wherein the disorder is cancer.29. The method of claim 28 , wherein the cancer is associated with E2F1 upregulation.30. The method of claim 28 , wherein the cancer is associated with aberrant CARM1 activity.31. The method of claim 28 , wherein the cancer is breast cancer claim 28 , prostate cancer claim 28 , or colorectal cancer.32. The method of claim 28 , wherein the cancer is ERα-dependent breast cancer.33. The method of claim 28 , wherein the cancer is castration-resistant prostate cancer.34. The method of claim 28 , wherein the cancer is colorectal cancer associated with dysregulated WNT/β-catenin signaling.35. The method of claim 26 , wherein the disorder is a metabolic disorder.36. The method of claim 28 , wherein the cancer is leukemia claim 28 , lymphoma claim 28 , or multiple myeloma.37. The method of claim 36 , wherein the cancer is leukemia.38. The method of claim 36 , wherein the cancer is lymphoma.39. The method of claim 36 , wherein the cancer is multiple myeloma.41. The method of claim 40 , wherein the disorder is a metabolic disorder.42. The method of claim 40 , wherein the disorder is a proliferative disorder.43. The method of claim 40 , wherein the disorder is cancer.44. The method of claim 43 , wherein the cancer is associated with E2F1 upregulation.45. The method of claim 43 , wherein the cancer is associated with aberrant CARM1 activity.46. The method of claim 43 , wherein the cancer is breast cancer claim 43 , prostate cancer claim 43 , or colorectal cancer.47. The method of claim 43 , wherein the cancer is ERα-dependent breast cancer.48. The method of claim 43 , wherein the cancer is castration-resistant prostate cancer.49. The method of claim 43 , wherein the cancer is colorectal cancer associated with dysregulated WNT/β-catenin signaling.50. The method of claim 43 , wherein ...

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Номер записи: 33
02-03-2017 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20170057926A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, Duncan Kenneth W., Jin Lei, MITCHELL Lorna Helen, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 1174-. (canceled)176. A pharmaceutical composition comprising a compound of claim 175 , or a pharmaceutically acceptable salt thereof claim 175 , and a pharmaceutically acceptable excipient.177. A kit or packaged pharmaceutical comprising a compound of claim 175 , or a pharmaceutically acceptable salt thereof claim 175 , and instructions for use thereof.178. A method of inhibiting an arginine methyltransferase (RMT) comprising contacting a cell with an effective amount of a compound of claim 175 , or a pharmaceutically acceptable salt thereof.179. A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of claim 175 , or a pharmaceutically acceptable salt thereof.180. A method of modulating transcription comprising contacting a cell with an effective amount of a compound of claim 175 , or a pharmaceutically acceptable salt thereof.181. A method of treating an RMT-mediated disorder claim 175 , comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 175 , or a pharmaceutically acceptable salt thereof.182. The method of claim 181 , wherein the disorder is a proliferative disorder claim 181 , a neurological disorder claim 181 , a muscular dystrophy claim 181 , an autoimmune disorder claim 181 , or a vascular disorder.183. The method of claim 182 , wherein the proliferative disorder is cancer.184. The method of claim 182 , wherein the neurological disorder is amyotrophic lateral sclerosis. The present application claims priority under 35 U.S.C §119(e) to U.S. Provisional Patent Application Ser. No. 61/781,054, filed Mar. 14, 2013, the entire ...

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Номер записи: 34
29-05-2014 дата публикации

Treatment of Cognitive Disorders with (R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-Carboxamide and Pharmaceutically Acceptable Salts Thereof

Номер: US20140148479A1
Автор: Chesworth Richard, Koenig Gerhard, Shapiro Gideon
Принадлежит: EnVivo Pharmaceuticals, Inc.

(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide has been found to have procognitive effects in humans at unexpectedly low doses. Thus, (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof can be used at unexpectedly low doses to improve cognition. 1. A method for improving cognition comprising administering to a subject (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof at a daily dose of less than 3 mg.2. The method of wherein the daily dose is 1 mg or less.3. The method of wherein the daily dose is 0.3 mg or less.4. (canceled)5. The method of wherein the daily dose is 1 mg or less.6. The method of wherein the daily dose is 0.3 mg or less.7. (canceled)8. The method of wherein the daily dose is 1 mg or less.9. The method of wherein the daily dose is 0.3 mg or less10. (canceled)11. The method of wherein the daily dose is 1 mg or less.12. The method of wherein the daily dose is 0.3 mg or less.13. (canceled)14. The method of wherein the daily dose is 1 mg or less.15. The method of wherein the daily dose is 0.3 mg or less.16. (canceled)17. The method of wherein the daily dose is 1 mg or less.18. The method of wherein the daily dose is 0.3 mg or less.19. (canceled)20. The method of wherein the daily dose is 1 mg or less.21. The method of wherein the daily dose is 0.3 mg or less.22. (canceled)23. The method of wherein the daily dose is 1 mg or less.24. The method of wherein the daily dose is 0.3 mg or less.25. The method of claim 1 , wherein the subject is suffering from anxiety or agitation.2628-. (canceled) This application is a continuation of U.S. application Ser. No. 13/129,782, filed Aug. 9, 2011, now U.S. Pat. No. 8,642,638 granted Feb. 4, 2014, which is a National Phase application of International Application No. PCT/US2009/065173, filed Nov. 19, 2009, which designated the United States and was published in English, and which ...

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Номер записи: 35
17-03-2016 дата публикации

Pyrrolopyrimidine derivatives as nr2b nmda receptor antagonists

Номер: US20160075713A1
Автор: Gideon Shapiro
Принадлежит: Rugen Holdings (Cayman) Ltd

Disclosed are chemical entities of formula I: wherein X, Y, Z, R 1 , R 3 , R 4 , R 5 and R 6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula I, and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.

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Номер записи: 36
05-06-2014 дата публикации

CAI-BASED SYSTEMS AND METHODS FOR THE LOCALIZED TREATMENT OF OCULAR AND OTHER DISEASES

Номер: US20140154246A1
Автор: Franklin Alan J., Jurczyk Simona, Robinson Gary, Shapiro Gideon
Принадлежит: RFE Pharma LLC

The subject invention provides CAI compounds and formulations thereof, and methods for their use in the localized treatment of non-life threatening diseases. Formulations of CAI compounds of the subject invention include CAI free base and CAI prodrug microcrystallines, microparticles, emulsions, and the like. The subject invention further provides methods for treating non-life threatening diseases using the CAI compounds of the invention (i.e., novel delivery systems and combination therapies), that are effective and are associated with little or no adverse side effects. 1. A method for treating a patient suffering from age-related macular degeneration or diabetic retinopathy comprising:(a) diagnosing age-related macular degeneration, diabetic retinopathy- or symptom thereof in a patient; and(b) ocularly administering to said patient a sterile, aqueous suspension formulation free of organic solvents comprising a therapeutically effective amount of suspended solid microparticulates of CAI (5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide) free base form, wherein the effective amount comprises a dose of 0.1 to 30 mg/ml of CAI in formulation with hydroxypropyl β-cyclodextrin.2. A method for treating a patient suffering from age-related macular degeneration or diabetic retinopathy comprising:(a) diagnosing age-related macular degeneration, diabetic retinopathy- or symptom thereof in a patient; and(b) ocularly administering to said patient a sterile, aqueous suspension formulation free of organic solvents comprising a therapeutically effective amount of suspended solid microparticulates of CAI (5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide) free base form, wherein the effective amount comprises a dose of 0.1 to 30 mg/ml of CAI in formulation.3. The method of claim 1 , wherein the local ocular administration is assisted by sonophoresis or iontophoresis.4. The method of claim 1 , wherein the effective amount of ...

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Номер записи: 37
05-06-2014 дата публикации

TREATMENT OF COGNITIVE DISORDERS WITH (R)-7-CHLORO-N-(QUINUCLIDIN-3-YL)BENZO[B]THIOPHENE-2-CARBOXAMIDE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

Номер: US20140155430A1
Автор: Chesworth Richard, Koenig Gerhard, Shapiro Gideon
Принадлежит:

(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide has been found to have procognitive effects in humans at unexpectedly low doses. Thus, (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof can be used at unexpectedly low doses to improve cognition. 1. A method of treating negative symptoms associated with Schizophrenia in a patient in need thereof , comprising:administering to said patient a daily dose in the range of between 0.1 mg to 3.0 mg of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide, or a pharmaceutically acceptable salt thereof.2. The method of claim 1 , wherein the pharmaceutically acceptable salt of the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide is: (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride; (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate; or (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride solvate.3. The method of claim 2 , wherein the pharmaceutically acceptable salt of the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide is administered to the patient.4. The method of claim 3 , wherein the pharmaceutically acceptable salt of the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide is (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride.5. The method of claim 3 , wherein the pharmaceutically acceptable salt of the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide is (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate.6. The method of claim 5 , wherein the daily dose is in the range of between 0.3 mg to 1.5 mg.7. The method of claim 5 , wherein the daily dose is in the range of between 0.7 mg to 1.25 mg.8. The method of claim 5 , wherein the daily dose is in the range of between 1.0 mg to 3.0 mg.9. The method of claim 5 , ...

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Номер записи: 38
18-03-2021 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20210078951A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Shapiro Gideon, Swinger Kerren Kalai
Принадлежит:

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 178.-. (canceled)812. The compound or pharmaceutically acceptable salt of claim , wherein V , V , V , and Vare each —CH—.822. The compound or pharmaceutically acceptable salt of claim , wherein each Ris independently optionally substituted alkyl , or optionally substituted alkoxyalkyl.834. The compound or pharmaceutically acceptable salt of claim , wherein each Ris independently optionally substituted alkoxyalkyl.845. The compound or pharmaceutically acceptable salt of claim , wherein each alkoxyalkyl is independently —CHOR , —CHCHOR , or —CHCHCHOR ,{'sup': 'A', 'wherein each Ris independently optionally substituted alkyl.'}852. The compound or pharmaceutically acceptable salt of claim , wherein two Rgroups are joined to form an optionally substituted carbocyclic ring.867. The compound or pharmaceutically acceptable salt of claim , wherein the carbocyclic ring is optionally substituted cyclopentane and optionally substituted cyclohexane.872. The compound or pharmaceutically acceptable salt of claim , wherein two Rgroups are joined to form an optionally substituted heterocyclic ring.889. The compound or pharmaceutically acceptable salt of claim , wherein the heterocyclic ring is optionally substituted furan or optionally substituted pyran.891. A pharmaceutical composition comprising a compound of claim , or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable excipient.901. A kit or packaged pharmaceutical comprising a compound of claim , or a pharmaceutically acceptable salt thereof , and instructions for use thereof.911. A method of inhibiting an arginine methyl transferase (RMT) comprising contacting a cell with ...

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Номер записи: 39
14-03-2019 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20190077795A1
Автор: Boriack-Sjodin Paula Ann, MITCHELL Lorna Helen, Shapiro Gideon, Swinger Kerren Kalai
Принадлежит: EPIZYME, INC.

Provided herein are various compounds, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 2. A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable excipient.3. A kit or packaged pharmaceutical comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and instructions for use thereof.4. A method of inhibiting an arginine methyl transferase (RMT) comprising contacting a cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.5. The method of claim 4 , wherein the arginine methyl transferase is PRMT1.6. The method of claim 4 , wherein the arginine methyl transferase is PRMT6.7. The method of claim 4 , wherein the arginine methyl transferase is PRMT8.8. A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.9. A method of modulating transcription comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.10. The method of claim 4 , wherein the cell is in vitro.11. The method of claim 4 , wherein the cell is in a subject.12. A method of treating a RMT-mediated disorder claim 1 , comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.13. The method of claim 12 , wherein the RMT-mediated disorder is a PRMT1-mediated disorder.14. The method of claim 12 , wherein the RMT-mediated disorder is a PRMT6-mediated disorder.15. The method of claim 12 , wherein the RMT-mediated disorder is a PRMT8-mediated disorder.16. The method of claim 12 , wherein the ...

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Номер записи: 40
30-03-2017 дата публикации

Arginine methyltransferase inhibitors and uses thereof

Номер: US20170088529A1
Автор: Gideon Shapiro, Lorna Helen Mitchell, Richard Chesworth
Принадлежит: Epizyme Inc

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

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Номер записи: 41
13-04-2017 дата публикации

DIFLUOROETHYLPYRIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS

Номер: US20170101412A1
Автор: Shapiro Gideon
Принадлежит:

Disclosed are chemical entities of formula (I) wherein X, Y, Z, R, R, R, Rand Rare defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I. 3. The chemical entity of claim 2 , wherein:{'sub': 3', '2', '3', '2', '3', '2', '3', '2', '3', '2', '3', '3', '2', '3', '2', '2', '2', '3', '3', '2', '2', '2', '3', '3', '3', '2', '2, 'X is hydrogen, —CN, —SCH, —SOCH, —SOCF, —NO, —N(CH), —F, —Cl, —CH, —CHCH, —CH(CH), —CF, —CHF, —CHF, —CFCF, —CH(CF), —CHCFCF, —OCH, —OCF, —OCHF, —OCFHor cyclopropyl;'}{'sup': '1', 'sub': 3', '2', '3', '3', '2', '3', '3', '3', '2', '2', '2', '2', '3', '2', '2', '3', '3', '2', '3, 'Ris hydrogen, —F, —Cl, —CH, —CHCH, —CH(CH), —CF, —OCH, —OCF, —OCHF, —OCFH, —CN, —NO, —COCH, —COCHCH, —C(O)N(CH), —C(O)NH(CH) or cyclopropyl;'}{'sup': '2', 'sub': 3', '2', '3', '3', '2', '3', '3', '3', '2', '2, 'Ris hydrogen, —F, —Cl, —CH, —CHCH, —CH(CH), —CF, cyclopropyl, —OCH, —OCF, —OCHFor —OCFH; and'}{'sup': '3', 'sub': 3', '3', '3, 'Ris hydrogen —F, —Cl, —CH, —CFor —OCH.'}5. The chemical entity of claim 4 , wherein:{'sub': 3', '2', '3', '2', '3', '2', '3', '2', '3', '2', '3', '3', '2', '3', '2', '2', '2', '3', '3', '2', '2', '2', '3', '3', '3', '2', '2, 'X is hydrogen, —CN, —SCH, —SOCH, —SOCF, —NO, —N(CH), —F, —Cl, —CH, —CHCH, —CH(CH), —CF, —CHF, —CHF, —CFCF, —CH(CF), —CHCFCF, —OCH, —OCF, —OCHF, —OCFHor cyclopropyl; and'}{'sup': '1', 'sub': 3', '2', '3', '3', '2', '3', '3', '3', '2', '2', '2', '2', '3', '2', '2', '3', '3', '2', '3, 'Ris hydrogen, —F, —Cl, —CH, —CHCH, —CH(CH), —CF, —OCH, —OCF, —OCHF, —OCFH, —CN, —NO, —COCH, —COCHCH, —C(O)N(CH), —C(O)NH(CH) or cyclopropyl.'}7. The chemical entity of claim 6 , wherein:{'sub': 3', '2', '3', '2', '3', '2', '3', '2', '3', '2', '3', ...

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Номер записи: 42
04-04-2019 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20190100496A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Shapiro Gideon, Swinger Kerren Kalai
Принадлежит:

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 111.-. (canceled)1434.-. (canceled)35. The compound of claim 12 , or a pharmaceutically acceptable salt thereof claim 12 , wherein Ris hydrogen or optionally substituted Calkyl.3638.-. (canceled)39. The compound of claim 12 , or a pharmaceutically acceptable salt thereof claim 12 , wherein Ris hydrogen or optionally substituted Calkyl.4051.-. (canceled)53. A pharmaceutical composition comprising a compound of claim 12 , or a pharmaceutically acceptable salt thereof claim 12 , and a pharmaceutically acceptable excipient.54. A kit or packaged pharmaceutical comprising a compound of claim 12 , or a pharmaceutically acceptable salt thereof claim 12 , and instructions for use thereof.55. A method of inhibiting an arginine methyl-tranfserase (RMT) comprising contacting a cell with an effective amount of a compound of claim 12 , or a pharmaceutically acceptable salt thereof.5660.-. (canceled)61. A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of claim 12 , or a pharmaceutically acceptable salt thereof.62. A method of modulating transcription comprising contacting a cell with an effective amount of a compound of claim 12 , or a pharmaceutically acceptable salt thereof.63. (canceled)64. (canceled)65. A method of treating a RMT-mediated disorder claim 12 , comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 12 , or a pharmaceutically acceptable salt thereof claim 12 , or a pharmaceutical composition of .6670.-. (canceled)71. The method of claim 65 , wherein the disorder is a proliferative disorder claim 65 , a neurological disorder ...

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Номер записи: 43
21-04-2016 дата публикации

Arginine methyltransferase inhibitors and uses thereof

Номер: US20160108018A1
Автор: Gideon Shapiro, Lorna Helen Mitchell, Oscar Miguel Moradei, Richard Chesworth
Принадлежит: Epizyme Inc

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

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Номер записи: 44
19-04-2018 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20180105497A1
Автор: Chesworth Richard, Kuntz Kevin Wayne, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 5. (canceled)9. (canceled)11. (canceled)12. (canceled)13. (canceled)14. (canceled)15. (canceled)17. (canceled)18. (canceled)20. (canceled)22. (canceled)23. (canceled)25. (canceled)26. (canceled)27. (canceled)29. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and optionally a pharmaceutically acceptable excipient.30. (canceled)31. A kit or packaged pharmaceutical comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and instructions for use thereof.32. A method of inhibiting an arginine methyl tranferase (RMT) comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.33. (canceled)34. (canceled)35. (canceled)36. (canceled)37. (canceled)38. A method of modulating gene expression comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof.39. A method of modulating transcription comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.40. (canceled)41. (canceled)42. A method of treating a RMT-mediated disorder claim 1 , comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , or a pharmaceutical composition of .43. (canceled)44. (canceled)45. (canceled)46. (canceled)47. (canceled)48. The method of claim 42 , wherein the disorder is a proliferative disorder.49. The method of claim 42 , wherein the disorder is cancer.50. The method of claim 42 , wherein the ...

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Номер записи: 45
03-07-2014 дата публикации

1,3,4-TRISUBSTITUTED BENZENES

Номер: US20140187786A1
Автор: Chesworth Richard, Shapiro Gideon
Принадлежит: EnVivo Pharmaceuticals, Inc.

Compounds that are 1,3,4-trisubstituted benzenes which modulate (e.g., inhibit) the activity of γ-secretase. The compounds are expected to reduce the level of Aβ42 in patients and be useful in the treatment of diseases (e.g., Alzheimer's disease) characterized by elevated levels of Aβ42 and/or the formation of Aβ plaques. 294-. (canceled) This application is a continuation of U.S. application Ser. No. 12/678,175, filed on Oct. 29, 2010, which is the National Stage of International Application No. PCT/US2008/076408, filed Sep. 15, 2008, which claims priority to and U.S. Provisional Patent Application Ser. No. 60/972,299, filed on Sep. 14, 2007. The contents of these applications are hereby incorporated by reference in their entireties.Alzheimer's disease (AD) is the most prevalent form of dementia. It is a neurodegenerative disorder that is associated (though not exclusively) with aging. The disorder is clinically characterized by a progressive loss of memory, cognition, reasoning and judgment that leads to an extreme mental deterioration and ultimately death. The disorder is pathologically characterized by the deposition of extracellular plaques and the presence of neurofibrillary tangles. These plaques are considered to play an important role in the pathogenesis of the disease.These plaques mainly comprise of fibrillar aggregates of (β-amyloid peptide (Aβ), which are products of the amyloid precursor protein (APP), a 695 amino-acid protein. APP is initially processed by β-secretase forming a secreted peptide and a membrane bound C99 fragment. The C99 fragment is subsequently processed by the proteolytic activity of γ-secretase. Multiple sites of proteolysis on the C99 fragment lead to the production of a range of smaller peptides (Aβ 37-42 amino acids). N-terminal truncations can also be found e.g. Aβ (4-42) for convenience Aβ40 and Aβ42 as used herein incorporates these N-terminal truncated peptides. Upon secretion, the Aβ peptides initially form soluble ...

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Номер записи: 46
04-05-2017 дата публикации

Arginine methyltransferase inhibitors and uses thereof

Номер: US20170119735A1
Автор: Gideon Shapiro, Kevin Wayne Kuntz, Lorna Helen Mitchell, Richard Chesworth
Принадлежит: Epizyme Inc

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

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Номер записи: 47
27-05-2021 дата публикации

CARM1 INHIBITORS AND USES THEREOF

Номер: US20210155631A1
Автор: Babine Robert E., Chesworth Richard, Jin Lei, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит:

Provided herein are compounds of Formula (I): 135-. (canceled)37. The compound or pharmaceutically acceptable salt of claim 36 , wherein:X is O;{'sup': '1', 'sub': '1-4', 'Ris optionally substituted Caliphatic;'}{'sup': '1a', 'Ris hydrogen;'}{'sub': '10', 'sup': '10', 'Gis C—R; and'}{'sub': '11', 'sup': '11', 'Gis C—R.'}39. The compound or pharmaceutically acceptable salt of claim 38 , wherein:{'sup': '2c', 'Ris halogen;'}{'sup': 1', 'L, 'Lis a bond or —N(R)—;'}Q is N; Y is O; and{'sup': '13A', 'W is CH or CR.'}40. The compound or pharmaceutically acceptable salt of claim 39 , wherein:{'sup': '1', 'Ris methyl;'}{'sup': '2c', 'Ris chloro;'}{'sup': '1', 'Lis a bond;'}{'sup': '3', 'Ris a cyclic moiety;'}{'sup': '10', 'Ris methyl;'}{'sup': '13A', 'W is CR; and'}{'sup': '13A', 'each Ris methyl.'}42. The compound or pharmaceutically acceptable salt of claim 41 , wherein:{'sup': '1', 'Ris methyl;'}{'sup': '2c', 'Ris chloro;'}{'sup': '13A', 'W is CR;'}Y is O;{'sup': '10', 'Ris methyl; and'}{'sup': '13A', 'each Ris methyl.'}44. The compound or pharmaceutically acceptable salt of claim 43 , wherein:each n is 0;{'sup': '1', 'Ris methyl;'}{'sup': '2c', 'Ris chloro;'}{'sup': '3B', 'sub': '2', 'Ris —COMe;'}{'sup': '13A', 'W is CR;'}Y is O;{'sup': '10', 'Ris methyl; and'}{'sup': '13A', 'each Ris methyl.'}46. The compound or pharmaceutically acceptable salt of claim 45 , wherein:n is 0;{'sup': '1', 'Ris methyl;'}{'sup': '2c', 'Ris chloro;'}{'sup': '13A', 'W is CR;'}Y is O;{'sup': '10', 'Ris methyl; and'}{'sup': '13A', 'each Ris methyl.'}47. A pharmaceutical composition comprising a compound of claim 36 , or a pharmaceutically acceptable salt thereof claim 36 , and a pharmaceutically acceptable excipient.48. A method of treating a CARM1-mediated disorder claim 36 , comprising administering to a subject in need thereof an effective amount of a compound of claim 36 , or a pharmaceutically acceptable salt thereof.49. The method of claim 48 , wherein the disorder is a proliferative ...

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Номер записи: 48
19-05-2016 дата публикации

PYRAZOLE DERIVATIVES AS ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20160137609A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, Duncan Kenneth W., Jin Lei, MITCHELL Lorna Helen, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. Formula (I). 35-. (canceled)812-. (canceled)13. The compound of claim 1 , wherein Ris not hydrogen.14. The compound of claim 13 , wherein Ris —OR.15. The compound of claim 14 , wherein Ris —OR claim 14 , wherein Ris optionally substituted alkyl claim 14 , optionally substituted alkenyl claim 14 , optionally substituted alkynyl claim 14 , or optionally substituted carbocyclic.16. The compound of claim 15 , wherein Ris —OR claim 15 , wherein Ris optionally substituted Calkyl.17. (canceled)18. The compound of claim 16 , wherein Ris —O-propyl claim 16 , —O-isopropyl claim 16 , —O-isobutyl claim 16 , or —O-isoamyl.19. The compound of claim 16 , wherein Ris —OR claim 16 , wherein Ris substituted Calkyl.2021-. (canceled)22. The compound of claim 19 , wherein Ris —O—Calkyl-carbocyclyl or —O—Calkyl-heterocyclyl.2342-. (canceled)43. The compound of claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , halo claim 1 , —CN claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , or optionally substituted carbocyclic.4467-. (canceled)68. The compound of claim 43 , wherein Ris halo.69. The compound of claim 68 , wherein Ris fluoro or chloro.70117-. (canceled)118. The compound of claim 1 , wherein Ris hydrogen.119. The compound of claim 1 , wherein Rand Rare hydrogen.120127-. (canceled)128. The compound of claim 1 , wherein Ris Calkyl.129. The compound of claim 128 , wherein Ris methyl.130. The compound of claim 1 , wherein Ris hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.131. The compound of claim 1 , ...

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Номер записи: 49
19-05-2016 дата публикации

Crystalline Form of (R)-7-Chloro-N-(Quinuclidin-3-YL)benzo[B]thiophene-2-Carboxamide Hydrochloride Monohydrate

Номер: US20160137638A1
Автор: Gideon Shapiro, Muneki Kishida, Patricia Oliver-Shaffer, Richard Chesworth, Takayuki Ishige
Принадлежит: Forum Pharmaceuticals Inc, Mitsubishi Tanabe Pharma Corp

Crystalline Forms I and II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate and compositions, methods of manufacture and therapeutic uses thereof are described.

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Номер записи: 50
09-05-2019 дата публикации

Carm1 inhibitors and uses thereof

Номер: US20190135819A1
Автор: Gideon Shapiro, LEI Jin, Oscar Miguel Moradei, Richard Chesworth, Robert E. Babine
Принадлежит: Epizyme Inc

Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein X, R 1 , R 1a , R 2a , R 2b , R 2c , R 2d , are as defined herein, and Ring HET is a 6-membered monocyclic heteroaryl ring system of Formula: wherein L 2 , R 13 , G 8 , G 10 , G 11 , and G 12 are as defined herein. Compounds of the present invention are useful for inhibiting CARM1 activity. Methods of using the compounds for treating CARM1-mediated disorders are also described.

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Номер записи: 51
01-06-2017 дата публикации

Imidazotriazinone compounds

Номер: US20170152265A1
Автор: Amy Ripka, Gerhard Koenig, Gideon Shapiro, Richard Chesworth
Принадлежит: Ironwood Pharmaceuticals Inc

The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.

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Номер записи: 52
04-09-2014 дата публикации

Crystalline Form of (R)-7-Chloro-N-(Quinuclidin-3-YL)benzo[B]thiophene-2-Carboxamide Hydrochloride Monohydrate

Номер: US20140249179A1
Автор: Gideon Shapiro, Muneki Kishida, Patricia Oliver-Shaffer, Richard Chesworth, Takayuki Ishige
Принадлежит: Envivo Phamaceuticals Inc

Crystalline Forms I and II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate and compositions, methods of manufacture and therapeutic uses thereof are described.

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Номер записи: 53
30-06-2016 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20160184267A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит:

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 175-. (canceled)77. The method of claim 76 , wherein the cancer is leukemia.78. The method of claim 77 , wherein the leukemia is acute lymphocytic leukemia.79. The method of claim 77 , wherein the leukemia is acute myelocytic leukemia.80. The method of claim 77 , wherein the leukemia is chronic myelocytic leukemia.81. The method of claim 77 , wherein the leukemia is chronic lymphocytic leukemia.82. The method of claim 76 , wherein the compound inhibits PRMT1 at an ICless than or equal to 10 μM.83. The method of claim 76 , wherein the compound inhibits PRMT1 at an ICless than or equal to 1 μM.84. The method of claim 76 , wherein the compound inhibits PRMT1 at an ICless than or equal to 0.1 μM.87. The method of claim 76 , wherein Lis a bond claim 76 , and Ris optionally substituted carbocyclyl.88. The method of claim 76 , wherein Lis a bond claim 76 , and Ris optionally substituted cyclohexyl.89. The method of claim 76 , wherein Lis a bond claim 76 , and Ris optionally substituted heterocyclyl.90. The method of claim 76 , wherein Ris Calkyl.91. The method of claim 90 , wherein Ris methyl.92. The method of claim 76 , wherein Rand Rare hydrogen.93. The method of claim 76 , wherein Ris optionally substituted Calkyl.94. The method of claim 93 , wherein Ris methyl.97. The method of claim 96 , wherein the cancer is selected from the group consisting of breast cancer claim 96 , prostate cancer claim 96 , lung cancer claim 96 , colorectal cancer claim 96 , bladder cancer claim 96 , and leukemia.98. The method of claim 97 , wherein the cancer is leukemia.99. The method of claim 98 , wherein the leukemia is acute lymphocytic leukemia.100. The method of ...

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Номер записи: 54
30-06-2016 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20160185772A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит:

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 147-. (canceled)53. The compound of claim 48 , wherein Q is an optionally substituted 8- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen claim 48 , oxygen claim 48 , and sulfur.54. The compound of claim 53 , wherein Q is an optionally substituted 9-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen claim 53 , oxygen claim 53 , and sulfur.55. The compound of claim 48 , wherein Q is an optionally substituted 5- to 6-membered. heteroaryl having 1-3 heteroatoms independently selected from nitrogen claim 48 , oxygen claim 48 , and sulfur.56. The compound of claim 55 , wherein Q is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen claim 55 , oxygen claim 55 , and sulfur.57. The compound of claim 48 , wherein Q is an unsubstituted claim 48 , monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen claim 48 , oxygen claim 48 , and sulfur.58. The compound of claim 48 , wherein Q is substituted claim 48 , monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen claim 48 , oxygen claim 48 , and sulfur.59. The compound of claim 48 , wherein Q is substituted or unsubstituted pyrrolyl claim 48 , substituted or unsubstituted furanyl claim 48 , substituted or unsubstituted thienyl claim 48 , substituted or unsubstituted imidazolyl claim 48 , substituted or unsubstituted pyrazolyl claim 48 , substituted or unsubstituted oxazolyl claim 48 , substituted or unsubstituted thiazolyl claim 48 , substituted or unsubstituted isothiazolyl claim 48 , substituted or ...

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Номер записи: 55
29-06-2017 дата публикации

PRMT1 INHIBITORS AND USES THEREOF

Номер: US20170182005A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, Kuntz Kevin Wayne, MITCHELL Lorna Helen, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I-a) and (I-b), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described. 216-. (canceled)17. The method of claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , —CN claim 1 , halo claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , or optionally substituted carbocyclic.18124-. (canceled)125. The method of claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , —CN claim 1 , halo claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , or optionally substituted carbocyclic.126. The method of claim 1 , wherein Ris hydrogen and Ris not hydrogen or wherein Ris not hydrogen and Ris hydrogen.127132-. (canceled)133. The method of claim 1 , wherein Ris hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.134136-. (canceled)137. The method of claim 1 , wherein Ris hydrogen or optionally substituted Calkyl.138140-. (canceled)141. The method of claim 1 , wherein Ris hydrogen or optionally substituted Calkyl.142146-. (canceled)147. The method of claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , isopropyl claim 1 , hydroxyethyl claim 1 , methoxyethyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.148153-. (canceled)155162-. (canceled)163. The method of claim 1 , wherein the disorder is a proliferative disorder claim 1 , a neurological disorder claim 1 , a muscular dystrophy claim 1 , an autoimmune disorder claim 1 , a vascular disorder claim 1 , or a metabolic disorder.164. The method of claim 163 , wherein the proliferative disorder is cancer.165. (canceled)166. The method of claim 163 , ...

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Номер записи: 56
22-07-2021 дата публикации

TREATMENT OF AUTISM SPECTRUM DISORDERS, OBSESSIVE-COMPULSIVE DISORDER AND ANXIETY DISORDERS

Номер: US20210220365A1
Автор: Flood Dorothy G., Shapiro Gideon
Принадлежит:

Disclosed are methods for treating NMDA receptor-mediated disorders by administering certain NR2B subunit-selective NMDA (N methyl-D aspartate) antagonists. NMDA receptor-mediated disorders include autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders. 148-. (canceled)50. A pharmaceutical composition comprising the chemical entity of and a pharmaceutically acceptable carrier.51. A method of treating an NMDA receptor-mediated disorder in a subject in need thereof claim 50 , comprising administering to the subject an effective amount of the pharmaceutical composition of claim 50 , wherein the NMDA-receptor mediated disorder is selected from (i) an obsessive-compulsive disorder (OCD) and/or related disorder claim 50 , (ii) an autism spectrum disorder (ASD) claim 50 , or (iii) an anxiety disorder.52. The method according to claim 51 , wherein the NMDA receptor-mediated disorder is an obsessive-compulsive disorder (OCD) and/or related disorder.53. The method according to claim 51 , wherein the NMDA receptor-mediated disorder is an autism spectrum disorder (ASD).54. The method according to claim 51 , wherein the NMDA receptor-mediated disorder is an anxiety disorder.55. The method according to claim 52 , wherein the OCD and/or related disorder is selected from body dysmorphic disorder (e.g. claim 52 , anorexia nervosa) claim 52 , hoarding disorder claim 52 , trichotillomania and excoriation disorder.56. The method according to claim 53 , wherein the ASD is characterized by one or more of repetitive or ritualistic behaviors claim 53 , behavioral rigidity claim 53 , constant movements claim 53 , lack of social interaction claim 53 , restricted patterns of interest that are abnormal in intensity or focus claim 53 , or sensory abnormalities.57. The method of claim 53 , wherein the autism spectrum disorder is autism claim 53 , Asperger's syndrome claim 53 , or pervasive developmental disorder not otherwise specified (PDD-NOS).58. The method of claim 54 ...

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Номер записи: 57
13-07-2017 дата публикации

PRMT5 INHIBITORS AND USES THEREOF

Номер: US20170198006A1
Автор: Chesworth Richard, Duncan Kenneth W., Jin Lei, Kuntz Kevin Wayne, Munchhof Michael John, Olhava Edward James, Patane Michael A., Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I)-(XIII), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described. 48. The compound of or , wherein one Ris —CHor —CH.49. The compound of or , wherein both instances of Rare hydrogen.50. The compound of or , wherein one instance of Ris —COH.56. The compound of any of - , wherein Q is O.57. The compound of any of - , wherein Ris —NH.58. The compound of any of - , wherein Z is N.59. The compound of claim 16 , wherein n is 0.60. The compound of claim 16 , wherein Ris hydrogen.61. The compound of claim 16 , wherein Ris —CHCHNHC(═O)R; and Ris unsubstituted phenyl.64. The compound of any of - claim 16 , wherein Ris —NMe.65. The compound of any of - claim 16 , wherein Ris hydrogen claim 16 , -Me claim 16 , —F claim 16 , or —NH.67. The compound of claim 23 , wherein M is a bond; and Ris —OR.68. The compound of claim 23 , wherein M is NH; and Ris a halogen.69. The compound of any of - claim 23 , wherein Ris —NMe.70. The compound of any of - claim 23 , wherein Ris unsubstituted phenyl.71. The compound of any of - claim 23 , wherein Ris unsubstituted Calkyl.72. The compound of any of - claim 23 , wherein Lis a bond.73. The compound of any of - claim 23 , wherein Lis NH.78. A compound selected from the group consisting of the compounds listed in Table 1A-Table 1O claim 23 , and pharmaceutically acceptable salts thereof.79. A pharmaceutical composition comprising a compound of any one of - claim 23 , or a pharmaceutically acceptable salt thereof claim 23 , and a pharmaceutically acceptable excipient.80. A kit or packaged pharmaceutical comprising a compound of any one of - and instructions for use thereof.81. A method of inhibiting PRMT5 comprising contacting a cell with an effective amount of a compound of any one of - or a pharmaceutically ...

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Номер записи: 58
25-09-2014 дата публикации

Carm1 inhibitors and uses thereof

Номер: US20140288067A1
Автор: Gideon Shapiro, LEI Jin, Oscar Miguel Moradei, Richard Chesworth, Robert E. Babine
Принадлежит: Epizyme Inc

Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X, R 1 , R 2a , R 2b , R 2c , R 2d , are as defined herein, and Ring HET is a 6-membered monocyclic heteroaryl ring system of formula: wherein L 2 , R 13 , G 8 , G 10 , G 11 , and G 12 are as defined herein. Compounds of the present invention are useful for inhibiting CARM1 activity. Methods of using the compounds for treating CARM1-mediated disorders are also described.

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Номер записи: 59
25-09-2014 дата публикации

Arginine methyltransferase inhibitors and uses thereof

Номер: US20140288105A1
Автор: Gideon Shapiro, Lorna Helen Mitchell, Oscar Miguel Moradei, Richard Chesworth
Принадлежит: Epizyme Inc

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

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Номер записи: 60
25-09-2014 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20140288124A1
Автор: Chesworth Richard, Kuntz Kevin Wayne, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 34-. (canceled)5. The compound of claim 2 , wherein Ris optionally substituted alkyl claim 2 , optionally substituted carbocyclyl claim 2 , optionally substituted aryl claim 2 , optionally substituted five- to six-membered heteroaryl claim 2 , or —OR.68-. (canceled)1013-. (canceled)1525-. (canceled)26. The compound of claim 1 , wherein X is NRand Y is N.27. The compound of claim 1 , wherein X is N and Y is NR.29. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and optionally a pharmaceutically acceptable excipient.30. (canceled)31. A kit or packaged pharmaceutical comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and instructions for use thereof.32. A method of inhibiting an arginine methyl tranferase (RMT) comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.33. The method of claim 32 , wherein the arginine methyl transferase is PRMT1 claim 32 , PRMT3 claim 32 , PRMT4 claim 32 , PRMT6 claim 32 , or PRMT8.3437-. (canceled)38. A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.39. A method of modulating transcription comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.4041-. (canceled)42. A method of treating a RMT-mediated disorder claim 1 , comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.43 ...

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Номер записи: 61
25-09-2014 дата публикации

Arginine methyltransferase inhibitors and uses thereof

Номер: US20140288128A1
Автор: Gideon Shapiro, Lorna Helen Mitchell, Oscar Miguel Moradei, Richard Chesworth
Принадлежит: Epizyme Inc

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

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Номер записи: 62
25-09-2014 дата публикации

PRMT1 INHIBITORS AND USES THEREOF

Номер: US20140288129A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, Kuntz Kevin Wayne, MITCHELL Lorna Helen, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I-a) and (I-b), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described. 39-. (canceled)10. The compound of claim 1 , wherein:{'sup': 1', 'B', 'A', 'B', 'A', 'z', 'z', 'B, 'sub': 2', 'n', '2, 'Ris —NRC(O)R, —NRSOR, or —(CRR)C(O)N(R);'}{'sup': 'z', 'each Ris independently hydrogen or fluoro; and'}n is 0, 1, 2, 3, or 4.1116-. (canceled)17. The compound of claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , —CN claim 1 , halo claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , or optionally substituted carbocyclic.18124-. (canceled)125. The compound of claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , —CN claim 1 , halo claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , or optionally substituted carbocyclic.126. The compound of claim 1 , wherein Ris hydrogen and Ris not hydrogen or wherein Ris not hydrogen and Ris hydrogen.127132-. (canceled)133. The compound of claim 1 , wherein Ris hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.134136-. (canceled)137. The compound of claim 1 , wherein Ris hydrogen or optionally substituted Calkyl.138140-. (canceled)141. The compound of claim 1 , wherein Ris hydrogen or optionally substituted Calkyl.142146-. (canceled)147. The compound of claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , isopropyl claim 1 , hydroxyethyl claim 1 , methoxyethyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.148153-. (canceled)155. A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and a ...

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Номер записи: 63
25-09-2014 дата публикации

PRMT1 INHIBITORS AND USES THEREOF

Номер: US20140288140A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, MITCHELL Lorna Helen, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described. 37-. (canceled)916-. (canceled)17. The compound of claim 1 , wherein:{'sup': 1', 'B', 'A', 'B', 'A', 'z', 'z', 'B, 'sub': 2', 'n', '2, 'Ris —NRC(O)R, —NRSOR, or —(CRR)C(O)N(R);'}{'sup': 'z', 'each Ris independently hydrogen or fluoro; and'}n is 0, 1, 2, 3, or 4.18. (canceled)19. The compound of claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , halo claim 1 , —CN claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , or optionally substituted carbocyclic.2056-. (canceled)57. The compound of claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , halo claim 1 , —CN claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , or optionally substituted carbocyclic.5887-. (canceled)88. The compound of claim 1 , wherein Ris hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.8991-. (canceled)92. The compound of claim 1 , wherein Ris hydrogen or optionally substituted Calkyl.9395-. (canceled)96. The compound of claim 1 , wherein Ris hydrogen or optionally substituted Calkyl.97101-. (canceled)102. The compound of claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , isopropyl claim 1 , hydroxyethyl claim 1 , methoxyethyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.103108-. (canceled)110. A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable excipient.111. A kit or packaged pharmaceutical comprising a compound of or a pharmaceutically acceptable salt ...

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Номер записи: 64
25-09-2014 дата публикации

PRMT1 INHIBITORS AND USES THEREOF

Номер: US20140288141A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, Kuntz Kevin Wayne, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described. 2. (canceled)3. The compound of claim 1 , wherein Ris —NHC(O)R claim 1 , —NHSORor —CHC(O)N(R).47-. (canceled)915-. (canceled)1724-. (canceled)25. The compound of claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , halo claim 1 , —CN claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , or optionally substituted carbocyclic.2664-. (canceled)65. The compound of claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , halo claim 1 , —CN claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , or optionally substituted carbocyclic.66103-. (canceled)104. The compound of claim 1 , wherein Ris hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.105107-. (canceled)108. The compound of claim 1 , wherein Ris hydrogen or optionally substituted Calkyl.109111-. (canceled)112. The compound of claim 1 , wherein Ris hydrogen or optionally substituted Calkyl.113117-. (canceled)118. The compound of claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , isopropyl claim 1 , hydroxyethyl claim 1 , methoxyethyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.119124-. (canceled)126. A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable excipient.127. A kit or packaged pharmaceutical comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and instructions for use thereof.128. A method of inhibiting protein arginine methyl tranferase 1 (PRMT1) ...

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Номер записи: 65
27-07-2017 дата публикации

Pyrrolopyrimidine derivatives as nr2b nmda receptor antagonists

Номер: US20170209449A1
Автор: Gideon Shapiro
Принадлежит: Rugen Holdings (Cayman) Ltd

Disclosed are chemical entities of formula I: wherein X, Y, Z, R 1 , R 3 , R 4 , R 5 and R 6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula I, and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.

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Номер записи: 66
27-07-2017 дата публикации

PRMT5 INHIBITORS AND USES THEREOF

Номер: US20170210751A1
Автор: Chesworth Richard, Duncan Kenneth W., Munchhol Michael John, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof: wherein Y1 is of formula (x) or formula (y):Ring Y is a 5- to 6-membered heteroaryl ring; and V, V, R, x, y, and n are as defined herein. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described. 20. The compound of any one of - , wherein Lis a linker L , wherein Lis —N(R)C(O)— , —C(O)N(R)— , —N(R)C(O)N(R)— , —N(R)C(O)O— , or —OC(O)N(R)— , and each R is independently hydrogen or optionally substituted Caliphatic.21. The compound of any one of - , wherein Lis a linker L , wherein:{'sub': D', 'B', 'B', '1-6, 'Lis the linker Lwherein Lis —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)O—, or —OC(O)N(R)— and each R is independently hydrogen or optionally substituted Caliphatic; or'}{'sub': 'D', 'sup': 2A', '3A', '2A', '3A', '2A', '3A', '2A', '3A', '2A', '3A', '2A', '3A', '2A', '3A', '2A', '3A', '2A', '3A', '2A', '3A', '9', '10', '2A', '3A', '9', '10', '2A', '3A', '9', '10', '2A', '3A', '9', '2A', '3A', '9', '10, 'Lis a linker selected from the group consisting of —O—, —N(R)—, —C(R)(R)—, —O—CRR, —N(R)—CRR—, —O—CRR—O—, —N(R)—CRR—O, —N(R)—CRR—N(R)—, —O—CRR—N(R)_, —CRR—O—, —CRR—N(R), —O—CRR—CRR—, —N(R)—CRRCRR—, —CRR—CRR—O—, —CRR—CRR—N(R)—, or —CRR—CRR—;'}{'sub': '1-6', 'each R is independently hydrogen or optionally substituted Caliphatic;'}{'sup': 2A', '3A', 'A', 'B', 'A', 'A', 'A', 'A', 'B', 'B', 'B', 'A', 'B', 'B', 'A', 'B', 'B', 'B', 'B', 'B', 'B', 'A', 'A', 'B', 'A', 'B', 'A', 'A', 'A', 'B', 'B', 'B', 'B', 'B', 'A', 'B', 'B', 'A', 'A', 'A', 'A', 'B', 'A', 'B', '2A', '3A, 'sub': 2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2, 'Rand Rare independently selected from the group consisting of hydrogen, halo, —CN, —NO, optionally substituted aliphatic, optionally substituted carbocyclyl; optionally substituted phenyl, ...

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Номер записи: 67
04-08-2016 дата публикации

Dibenzo[B,F][1,4]oxazepin-11-yl-N-Hydroxybenzamides as HDAC Inhibitors

Номер: US20160222026A1
Автор: BEAULIEU Patrick, Chantigny Yves Andre, Chesworth Richard, Deziel Robert, Leit Silvana, Mancuso John, Shapiro Gideon, Smil David, Tessier Pierre
Принадлежит:

This invention relates to compounds for the inhibition of histone deacetylase. More particularly, the invention provides for compounds of formula (I) 6. The compound according to claim 5 , wherein J is selected from the group consisting of a —C-Calkyl-C-Cheteroalkyl-C-Calkyl- claim 5 , —C-Calkyl-aryl-C-Calkyl- claim 5 , —C-Calkyl-aryl-C-Cheteroalkyl- claim 5 , —C-Calkyl-cycloalkyl-C-Calkyl- claim 5 , —C-Cheterocyclyl-aryl-C-Calkyl- claim 5 , —C-Cheterocyclyl-aryl-C-Cheteroalkyl- claim 5 , —C-Calkyl-C-Cheterocyclyl-C-Calkyl- claim 5 , —C-Calkyl-heteroaryl-C-Calkyl- claim 5 , —C-Calkyl-heteroaryl-C-Cheteroalkyl- claim 5 , —C-Cheterocyclyl-heteroaryl-C-Calkyl- claim 5 , —C-Calkyl-aryl-C-Calkynyl- claim 5 , —C-Calkyl-heteroaryl-C-Calkynyl- claim 5 , —C-Calkyl-aryl-C-Calkynyl-C-Calkenyl- claim 5 , —C-Calkyl-aryl-C-Calkenyl- claim 5 , —C-Calkyl-heteroaryl-C-Calkenyl- claim 5 , —C-Calkenyl-aryl-C-Calkyl- claim 5 , —C-Calkenyl-heteroaryl-C-Calkyl- claim 5 , —C-Calkylaryl-aryl-C-Calkyl- claim 5 , —C-Calkylaryl-heteroaryl-C-Calkyl- and —C-Calkyl-C-Ccycloalkyl-C-Calkyl- claim 5 , wherein each alkyl claim 5 , alkenyl claim 5 , alkynyl claim 5 , heteroalkyl claim 5 , aryl claim 5 , heteroaryl claim 5 , heterocyclyl claim 5 , and cycloalkyl moiety is optionally substituted.23. A composition comprising a compound according to and a pharmaceutically acceptable carrier.24. A method of inhibiting histone deacetylase claim 1 , the method comprising contacting the histone deacetylase with a compound according to or a composition thereof.25. A method of treating a polyglutamine (polyQ) expansion disease claim 1 , comprising administering to an individual in need of treatment a therapeutically effective amount of a compound according to claim 1 , or a composition thereof. This application claims the benefit of U.S. application Ser. No. 11/925,151, filed Oct. 26, 2007, which claims the benefit of U.S. provisional application 60/884,287, filed Jan. 10, 2007, and U.S. provisional ...

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Номер записи: 68
23-10-2014 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20140315904A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 3. (canceled)5. (canceled)6. The compound of claim 1 , wherein Lis a bond and Ris optionally substituted carbocyclyl.7. The compound of claim 6 , wherein Lis a bond and Ris optionally substituted cyclohexyl.8. The compound of claim 1 , wherein Lis a bond and Ris optionally substituted heterocyclyl.9. The compound of claim 8 , wherein Lis a bond and Ris optionally substituted piperidine.1028-. (canceled)29. The compound of claim 1 , wherein Ris Calkyl.30. The compound of claim 29 , wherein Ris methyl.31. The compound of claim 1 , wherein Ris hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.32. The compound of claim 1 , wherein Ris hydrogen.33. The compound of claim 1 , wherein Ris optionally substituted Calkyl.34. The compound of claim 33 , wherein Ris unsubstituted Calkyl.35. The compound of claim 34 , wherein Ris methyl.36. The compound of claim 1 , wherein Ris hydrogen.37. The compound of claim 1 , wherein Ris optionally substituted Calkyl.38. The compound of claim 37 , wherein Ris unsubstituted Calkyl.39. The compound of claim 38 , wherein Ris methyl.40. The compound of claim 1 , wherein Ris optionally substituted Calkyl.41. The compound of claim 40 , wherein Ris unsubstituted Calkyl.42. The compound of claim 41 , wherein Ris methyl.43. The compound of claim 40 , wherein Ris ethyl claim 40 , isopropyl claim 40 , propyl claim 40 , butyl claim 40 , hydroxyethyl claim 40 , methoxyethyl claim 40 , cyclopropyl claim 40 , or cyclobutyl.4448-. (canceled)50. A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and a ...

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Номер записи: 69
23-10-2014 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20140315961A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 3. (canceled)531-. (canceled)32. The compound of claim 4 , wherein L is selected from the group consisting of —O— claim 4 , —NR— claim 4 , —NRC(═O)— claim 4 , —C(═O)NR— claim 4 , —(CH)—O— claim 4 , —(CH)— claim 4 , —C≡C— claim 4 , trans-CR═CR— claim 4 , cis-CR═CR— claim 4 , —S(═O)NR— claim 4 , and —NRS(═O)— claim 4 , wherein s is 1 claim 4 , 2 claim 4 , 3 claim 4 , 4 claim 4 , 5 claim 4 , or 6.33. The compound of claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , isopropyl claim 1 , propyl claim 1 , butyl claim 1 , hydroxyethyl claim 1 , methoxyethyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.34. The compound of claim 1 , wherein Ris hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.35. The compound of claim 4 , wherein E is hydrogen.39. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and optionally a pharmaceutically acceptable excipient.40. (canceled)41. A kit or packaged pharmaceutical comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and instructions for use thereof.42. A method of inhibiting an arginine methyl tranferase (RMT) comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.43. The method of claim 42 , wherein the arginine methyl transferase is PRMT1 claim 42 , PRMT3 claim 42 , PRMT6 claim 42 , PRMT8 claim 42 , or CARM1.44. The method of claim 43 , wherein the arginine methyl transferase is PRMT1.4547-. (canceled)48. A method of modulating gene expression comprising contacting a cell ...

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Номер записи: 70
18-07-2019 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20190218194A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит:

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 259.-. (canceled)60. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , provided that only one of X claim 1 , Y claim 1 , Z and V is O claim 1 , S claim 1 , or NR.61. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , provided that only one of X claim 1 , Y claim 1 , Z and V is NR.64. The compound of claim 63 , or a pharmaceutically acceptable salt thereof claim 63 , wherein each instance of L is independently selected from the group consisting of a bond claim 63 , —O— claim 63 , —NR— claim 63 , —NRC(═O)— claim 63 , —C(═O)NR— claim 63 , —(CH)—O— claim 63 , —(CH)— claim 63 , —C≡C— claim 63 , trans-CR=CR— claim 63 , cis-CR=CR— claim 63 , —S(═O)NR— claim 63 , and —NRS(═O)—;wherein s is 1, 2, 3, 4, or 5.65. The compound of claim 63 , or a pharmaceutically acceptable salt thereof claim 63 , wherein each instance of L is a bond.66. The compound of claim 63 , or a pharmaceutically acceptable salt thereof claim 63 , wherein each instance of E is independently optionally substituted aryl.67. The compound of claim 63 , or a pharmaceutically acceptable salt thereof claim 63 , wherein each instance of Ris hydrogen.68. The compound of claim 63 , or a pharmaceutically acceptable salt thereof claim 63 , wherein each instance of E is independently optionally substituted aryl and each instance of L is a bond.69. The compound of claim 63 , or a pharmaceutically acceptable salt thereof claim 63 , wherein each instance of E is independently optionally substituted aryl claim 63 , each instance of L is a bond claim 63 , and each instance of Ris hydrogen.70. The compound of claim 63 , or a ...

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Номер записи: 71
30-10-2014 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20140323537A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, Duncan Kenneth W., Jin Lei, MITCHELL Lorna Helen, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 35-. (canceled)812-. (canceled)13. The compound of claim 1 , wherein Ris not hydrogen.14. The compound of claim 13 , wherein Ris —OR.15. The compound of claim 14 , wherein Ris —OR claim 14 , wherein Ris optionally substituted alkyl claim 14 , optionally substituted alkenyl claim 14 , optionally substituted alkynyl claim 14 , or optionally substituted carbocyclic.16. The compound of claim 15 , wherein Ris —OR claim 15 , wherein Ris optionally substituted Calkyl.17. (canceled)18. The compound of claim 16 , wherein Ris —O-propyl claim 16 , —O-isopropyl claim 16 , —O-isobutyl claim 16 , or —O-isoamyl.19. The compound of claim 16 , wherein Ris —OR claim 16 , wherein Ris substituted Calkyl.2021-. (canceled)22. The compound of claim 19 , wherein Ris —O—Calkyl-carbocyclyl or —O—Calkyl-heterocyclyl.2342-. (canceled)43. The compound of claim 1 , wherein Ris hydrogen claim 1 , —OR claim 1 , halo claim 1 , —CN claim 1 , optionally substituted alkyl claim 1 , optionally substituted alkenyl claim 1 , optionally substituted alkynyl claim 1 , or optionally substituted carbocyclic.4467-. (canceled)68. The compound of claim 43 , wherein Ris halo.69. The compound of claim 68 , wherein Ris fluoro or chloro.70117-. (canceled)118. The compound of claim 1 , wherein Ris hydrogen.119. The compound of claim 1 , wherein Rand Rare hydrogen.120127-. (canceled)128. The compound of claim 1 , wherein Ris Calkyl.129. The compound of claim 128 , wherein Ris methyl.130. The compound of claim 1 , wherein Ris hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , butyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.131. The compound of claim 1 , wherein Ris ...

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Номер записи: 72
17-08-2017 дата публикации

PRMT1 INHIBITORS AND USES THEREOF

Номер: US20170233347A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, Kuntz Kevin Wayne, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described. 141.-. (canceled)143. A pharmaceutical composition comprising a compound of claim 142 , or salt thereof claim 142 , and a pharmaceutically acceptable carrier.144. A compound that is N-(4-(4-((methyl(2-(methylamino)ethyl)amino)methyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)phenyl)isobutyramide claim 142 , or salt thereof.145. A pharmaceutical composition comprising a compound of claim 144 , or salt thereof claim 144 , and a pharmaceutically acceptable carrier. The present application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application, U.S. Ser. No. 61/781,052, filed Mar. 14, 2013, the entire contents of which is incorporated herein by reference.Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases.Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., PRMT1), many of which are associated with specific genetic alterations that can cause human disease.Disease-associated chromatin-modifying enzymes (e.g., PRMT1) play a role in diseases such as proliferative disorders, autoimmune disorders, muscular disorders, vascular disorders, metabolic disorders, and neurological disorders. Thus, there is a need for the development ...

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Номер записи: 73
23-08-2018 дата публикации

PYRAZOLE DERIVATIVES AS ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20180237397A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, Duncan Kenneth W., Jin Lei, MITCHELL Lorna Helen, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит:

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. Formula (I). 1150.-. (canceled)152. The method of claim 151 , wherein the RMT is PRMT1 claim 151 , PRMT6 claim 151 , PRMT3 claim 151 , PRMT8 claim 151 , or CARM1.153156.-. (canceled)159. The method of claim 151 , wherein the cell is in vitro.160. The method of claim 151 , wherein the cell is in a subject.162. The method of claim 161 , wherein the RMT-mediated disorder is a PRMT1-mediated disorder claim 161 , a PRMT6-mediated disorder claim 161 , a PRMT3-mediated disorder claim 161 , a PRMT8-mediated disorder claim 161 , or a CARM1-mediated disorder.163166.-. (canceled)167. The method of claim 161 , wherein the disorder is a proliferative disorder claim 161 , a neurological disorder claim 161 , amyotrophic lateral sclerosis claim 161 , a muscular dystrophy claim 161 , an autoimmune disorder claim 161 , or a metabolic disorder.168. The method of claim 167 , wherein the disorder is cancer.169174.-. (canceled)178. The method of claim 161 , wherein Ris not hydrogen.179. The method of claim 161 , wherein Ris —OR.180. The method of claim 161 , wherein Ris —OR claim 161 , wherein Ris optionally substituted alkyl claim 161 , optionally substituted alkenyl claim 161 , optionally substituted alkynyl claim 161 , or optionally substituted carbocyclic.181. The method of claim 161 , wherein Ris —OR claim 161 , wherein Ris optionally substituted Calkyl.182. The method of claim 161 , wherein Ris —O-propyl claim 161 , —O-isopropyl claim 161 , —O-isobutyl claim 161 , or —O-isoamyl.183. The method of claim 161 , wherein Ris —OR claim 161 , wherein Ris substituted Calkyl.184. The method of claim 161 , wherein Ris —O—Calkyl-O—Calkyl or —O—Calkyl-carbocyclyl.185. ...

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Номер записи: 74
24-09-2015 дата публикации

Treatment of Cognitive Disorders with (R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-Carboxamide and Pharmaceutically Acceptable Salts Thereof

Номер: US20150265583A1
Автор: Chesworth Richard, Koenig Gerhard, Shapiro Gideon
Принадлежит:

(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide has been found to have procognitive effects in humans at unexpectedly low doses. Thus, (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof can be used at unexpectedly low doses to improve cognition. 1. A method for improving cognition comprising administering to a subject (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof at a daily dose of less than 3 mg.2. The method of wherein the daily dose is 1 mg or less.3. The method of wherein the daily dose is 0.3 mg or less.4. A method for treating a cognitive disorder comprising administering to a subject (R)-7-chloro-N-(quinuclidin-3-yObenzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof at a daily dose of less than 3 mg.5. The method of wherein the daily dose is 1 mg or less.6. The method of wherein the daily dose is 0.3 mg or less.7. A method for treating a disorder selected from schizophrenia claim 5 , schizophreniform disorder claim 5 , schizoaffective disorder claim 5 , and delusional disorder comprising administering to a subject (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof at a daily dose of less than 3 mg.8. The method of wherein the daily dose is 1 mg or less.9. The method of wherein the daily dose is 0.3 mg or less10. A method for improving one or more of: learning claim 8 , delayed memory claim 8 , working memory claim 8 , visual learning claim 8 , speed of processing claim 8 , vigilance claim 8 , verbal learning claim 8 , visual motor function claim 8 , social cognition claim 8 , long term memory or executive function comprising administering to a subject (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof at a daily dose of less than 3 mg.11. The method of wherein the daily dose ...

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Номер записи: 75
21-09-2017 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20170267642A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Shapiro Gideon, Swinger Kerren Kalai
Принадлежит: EPIZYME, INC.

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

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Номер записи: 76
20-09-2018 дата публикации

PRMT1 INHIBITORS AND USES THEREOF

Номер: US20180265478A1
Автор: Boriack-Sjodin Paula Ann, Chesworth Richard, Kuntz Kevin Wayne, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит:

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described. 1125.-. (canceled)128132.-. (canceled)134. The method of claim 133 , wherein the disorder is a proliferative disorder claim 133 , a neurological disorder claim 133 , a muscular dystrophy claim 133 , an autoimmune disorder claim 133 , a vascular disorder claim 133 , or a metabolic disorder.135. The method of claim 134 , wherein the disorder is cancer.136. (canceled)137. The method of claim 134 , wherein the disorder is amyotrophic lateral sclerosis.138141.-. (canceled)142. The method of claim 133 , wherein Ris —NHC(O)R claim 133 , —NHSOR claim 133 , or —CHC(O)N(R).145. The method of claim 133 , wherein Ris hydrogen claim 133 , —OR claim 133 , halo claim 133 , optionally substituted alkyl claim 133 , optionally substituted alkenyl claim 133 , optionally substituted alkynyl claim 133 , optionally substituted carbocyclic claim 133 , or —CN.146. The method of claim 133 , wherein Ris hydrogen claim 133 , —OR claim 133 , halo claim 133 , optionally substituted alkyl claim 133 , optionally substituted alkenyl claim 133 , optionally substituted alkynyl claim 133 , optionally substituted carbocyclic claim 133 , or —CN.147. The method of claim 133 , wherein Ris hydrogen or Calkyl.148. The method of claim 133 , wherein Ris hydrogen claim 133 , methyl claim 133 , ethyl claim 133 , propyl claim 133 , butyl claim 133 , cyclopropyl claim 133 , or cyclobutyl.149. The method of claim 133 , wherein Ris hydrogen or optionally substituted Calkyl.150. The method of claim 133 , wherein Ris hydrogen or optionally substituted Calkyl.151. The method of claim 133 , wherein Ris optionally substituted Calkyl.152. The method of claim 133 , wherein Ris methyl claim 133 , ethyl claim 133 , propyl claim 133 , butyl ...

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Номер записи: 77
08-10-2015 дата публикации

Prmt1 inhibitors and uses thereof

Номер: US20150284334A1
Автор: Gideon Shapiro, Kevin Wayne Kuntz, Lorna Helen Mitchell, Paula Ann Boriack-Sjodin, Richard Chesworth
Принадлежит: Epizyme Inc

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described.

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Номер записи: 78
27-09-2018 дата публикации

Treatment of Cognitive Disorders with (R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-Carboxamide and Pharmaceutically Acceptable Salts Thereof

Номер: US20180271844A1
Автор: Chesworth Richard, Koenig Gerhard, Shapiro Gideon
Принадлежит:

(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide has been found to have procognitive effects in humans at unexpectedly low doses. Thus, (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof can be used at unexpectedly low doses to improve cognition. 1. A method for improving cognition comprising administering to a subject (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide , or a pharmaceutically acceptable salt thereof , at a daily dose of less than 3 mg.2. The method of wherein the daily dose is 1 mg or less.3. The method of wherein the daily dose is 0.3 mg or less.4. A method for treating a cognitive disorder comprising administering to a subject (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , at a daily dose of less than 3 mg.5. The method of wherein the daily dose is 1 mg or less.6. The method of wherein the daily dose is 0.3 mg or less.7. A method for treating a disorder selected from schizophrenia claim 5 , schizophreniform disorder claim 5 , schizoaffective disorder claim 5 , and delusional disorder claim 5 , comprising administering to a subject (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , at a daily dose of less than 3 mg.8. The method of wherein the daily dose is 1 mg or less.9. The method of wherein the daily dose is 0.3 mg or less10. A method for improving one or more of: learning claim 8 , delayed memory claim 8 , working memory claim 8 , visual learning claim 8 , speed of processing claim 8 , vigilance claim 8 , verbal learning claim 8 , visual motor function claim 8 , social cognition claim 8 , long term memory or executive function claim 8 , comprising administering to a subject (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide claim 8 , or a pharmaceutically acceptable salt thereof ...

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Номер записи: 79
27-09-2018 дата публикации

TREATMENT OF ANXIETY DISORDERS AND AUTISM SPECTRUM DISORDERS

Номер: US20180271869A1
Автор: Chen Gang, Liu Jie, Shapiro Gideon, Verdoorn Todd A.
Принадлежит:

Disclosed are methods for treating autism spectrum disorders and/or anxiety disorders by administering certain NR2B subunit-selective NMDA (N methyl-D aspartate) antagonists. Anxiety disorders include agoraphobia (with or without panic disorder), generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD). 1. A method for treating an anxiety disorder in an individual in need thereof , comprising administering to the individual an effective amount of an NR2B subunit-selective NMDA antagonist , wherein the antagonist is (+)-(1S ,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenyl-piperidino)-1-propanol , cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate , or N-(1-(2 ,2-difluoro-2-(4-trifluoromethyl)phenyl-ethyl)piperidin-4-yl)-1H-pyrazolo-[3 ,4-d]pyrimidin-4-amine , or a pharmaceutically acceptable salt thereof.2. The method of claim 1 , wherein the anxiety disorder is obsessive compulsive disorder.3. The method of claim 1 , wherein the anxiety disorder is generalized anxiety disorder.4. The method of claim 1 , wherein the anxiety disorder is agoraphobia with panic disorder.5. The method of claim 1 , wherein the anxiety disorder is agoraphobia without panic disorder.6. The method of claim 1 , wherein the anxiety disorder is panic disorder.7. The method of claim 1 , wherein the anxiety disorder is post-traumatic stress disorder.8. The method of claim 1 , wherein the anxiety disorder is social anxiety disorder.10. The method of claim 9 , wherein the anxiety disorder is obsessive compulsive disorder or generalized anxiety disorder.11. The method of any of - claim 9 , wherein the NR2B subunit-selective NMDA antagonist is cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate claim 9 , or a pharmaceutically acceptable salt thereof.12. The method of claim 11 , wherein the NR2B subunit-selective NMDA antagonist is ...

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Номер записи: 80
05-10-2017 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20170283400A1
Автор: Boriack-Sjodin Paula Ann, MITCHELL Lorna Helen, Shapiro Gideon, Swinger Kerren Kalai
Принадлежит: EPIZYME, INC.

Provided herein are various compounds, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 1. A compound of Table 1 , or a pharmaceutically acceptable salt thereof.2. A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable excipient.3. A kit or packaged pharmaceutical comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and instructions for use thereof.4. A method of inhibiting an arginine methyl tranferase (RMT) comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.5. The method of claim 4 , wherein the arginine methyl transferase is PRMT1.6. The method of claim 4 , wherein the arginine methyl transferase is PRMT6.7. The method of claim 4 , wherein the arginine methyl transferase is PRMT8.8. A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.9. A method of modulating transcription comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.10. The method of any one of - claim 1 , wherein the cell is in vitro.11. The method of any one of - claim 1 , wherein the cell is in a subject.12. A method of treating a RMT-mediated disorder claim 1 , comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , or a pharmaceutical composition of .13. The method of claim 12 , wherein the RMT-mediated disorder is a PRMT1-mediated disorder.14. The method of claim 12 , wherein the RMT-mediated disorder is a PRMT6-mediated disorder.15. ...

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Номер записи: 81
05-10-2017 дата публикации

CARM1 INHIBITORS AND USES THEREOF

Номер: US20170283440A1
Автор: Babine Robert E., Chesworth Richard, Duncan Kenneth W., Jin Lei, MITCHELL Lorna Helen, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Provided herein are compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X, R, R, R, R, R, are as defined herein, and Ring HET is an optionally substituted 6,5-bicyclic heteroaryl ring system comprising 2 to 5 nitrogen atoms, inclusive, wherein the point of attachment is provided on the 6-membered ring of the 6,5-bicyclic heteroaryl ring system, and wherein the 6-membered ring is further substituted with a group of formula -L-R, wherein Land Rare as defined herein. Compounds of the present invention are useful for inhibiting CARM1 activity. Methods of using the compounds for treating CARM1-mediated disorders are also described. 4. The compound of any one of - , wherein X is —O—.5. The compound of any one of - , wherein X is —S—.6. The compound of any one of - , wherein X is —CH—.23. The compound of or , at least one instance of R , R , and Ris optionally substituted Ccarbocyclyl or optionally substituted Calkyl.24. The compound of or , at least one instance of R , R , R , and Ris hydrogen , optionally substituted C-alkyl , optionally substituted Ccarbocyclyl , —CN , —C(═O)R′ , —C(═O)OR′ , or —C(═O)N(R′).25. The compound of any one of - , wherein Lis a bond , —N(R)— , —NRC(O)O— , —NRC(O)N(R)— , —N(R)— , —N(R)SON(R)— , —NR—(CH)—C(O)O— , —NR—(CH)—O— , —NRC(O)N(R)— , —NR—(CH)— , —(CH)—NR—NR— , —NRC(O)O(CH)— , —NRC(O)NR(CH)— , or —NR(CH)NRC(O)—.26. The compound of any one of - , wherein Ris an optionally substituted monocyclic or bicyclic heterocyclyl , or an optionally substituted monocyclic or bicyclic heteroaryl.28. The compound of any one of - , wherein Ris hydrogen , methyl , ethyl , n-propyl , isopropyl , or cyclopropyl.29. The compound of any one - , wherein each of R , R , and Ris hydrogen.30. The compound of any one - , wherein Ris —F , —Cl , —Br , —I , —CN , optionally substituted Calkyl , optionally substituted Ccarbocyclyl , or —OR , wherein Ris optionally substituted Calkyl , or ...

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Номер записи: 82
04-10-2018 дата публикации

CARM1 INHIBITORS AND USES THEREOF

Номер: US20180282343A1
Автор: Babine Robert E., Chesworth Richard, Jin Lei, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит:

Provided herein are compounds of Formula (I): 135.-. (canceled)38. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to claim 36 , and a pharmaceutically acceptable excipient.39. A pharmaceutical composition comprising the compound according to claim 37 , and a pharmaceutically acceptable excipient. This application claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application, U.S. Ser. No. 61/794,442, filed Mar. 15, 2013, and to U.S. provisional patent application, U.S. Ser. No. 61/937,333, filed Feb. 7, 2014, the entire contents of which are incorporated herein by reference.Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases.Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., CARM1 (co-activator-associated arginine methyltransferase 1; PRMT4)), many of which are associated with specific genetic alterations that can cause human disease.Disease-associated chromatin-modifying enzymes play a role in diseases such as proliferative disorders, autoimmune disorders, muscular disorders, and neurological disorders. Thus, there is a need for the development of small molecules that are capable of inhibiting the activity of CARM1.CARM1 is an attractive target for modulation given its role in the regulation of diverse biological processes. It has now been found that compounds described herein, and pharmaceutically acceptable salts and compositions thereof, are ...

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Номер записи: 83
11-10-2018 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20180289671A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит:

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 39.-. (canceled)10. The compound of claim 1 , wherein -L-Ris optionally substituted alkyl.1127.-. (canceled)28. The compound of claim 1 , wherein Ris hydrogen claim 1 , Calkyl claim 1 , cyclopropyl claim 1 , or cyclobutyl.2931.-. (canceled)32. The compound of claim 1 , wherein Ris hydrogen or optionally substituted Calkyl.3335.-. (canceled)36. The compound of claim 1 , wherein Ris hydrogen or optionally substituted Calkyl.3739.-. (canceled)40. The compound of claim 1 , wherein Ris optionally substituted Calkyl or optionally substituted Ccycloalkyl.4148.-. (canceled)50. A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable excipient.51. A kit or packaged pharmaceutical comprising a compound of or a pharmaceutically acceptable salt thereof claim 1 , and instructions for use thereof.52. A method of inhibiting an arginine methyl tranferase (RMT) comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.53. The method of claim 52 , wherein the arginine methyl transferase is PRMT1 claim 52 , PRMT6 claim 52 , PRMT3 claim 52 , PRMT8 claim 52 , or CARM1.5457.-. (canceled)58. A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.59. A method of modulating transcription comprising contacting a cell with an effective amount of a compound of or a pharmaceutically acceptable salt thereof.60. (canceled)61. (canceled)62. A method of treating a RMT-mediated disorder claim 1 , comprising administering to a ...

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Номер записи: 84
11-10-2018 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20180290982A1
Автор: Chesworth Richard, Kuntz Kevin Wayne, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит:

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. 130.-. (canceled)33. The method of claim 32 , wherein the arginine methyl transferase is PRMT1 claim 32 , PRMT3 claim 32 , PRMT4 claim 32 , PRMT6 claim 32 , or PRMT8.3437.-. (canceled)40. (canceled)41. (canceled)43. The method of claim 42 , wherein the RMT-mediated disorder is a PRMT1-mediated disorder claim 42 , a PRMT3-mediated disorder claim 42 , a PRMT4-mediated disorder claim 42 , a PRMT6-mediated disorder claim 42 , or a PRMT8-mediated disorder.4447.-. (canceled)48. The method of claim 42 , wherein the disorder is a proliferative disorder claim 42 , a neurological disorder claim 42 , a muscular dystrophy claim 42 , an autoimmune disorder claim 42 , a vascular disorder claim 42 , or a metabolic disorder.49. The method of claim 42 , wherein the disorder is cancer.50. The method of claim 42 , wherein the disorder is selected from the group consisting of breast cancer claim 42 , prostate cancer claim 42 , lung cancer claim 42 , colon cancer claim 42 , bladder cancer claim 42 , lymphoma claim 42 , leukemia claim 42 , diabetes mellitus claim 42 , kidney failure claim 42 , coronary heart disease claim 42 , oculopharyngeal muscular dystrophy claim 42 , and amyotrophic lateral sclerosis.52. The method of claim 51 , wherein Ris optionally substituted Calkyl claim 51 , optionally substituted Ccarbocyclyl claim 51 , optionally substituted phenyl claim 51 , optionally substituted 5- to 6-membered heteroaryl or optionally substituted Calkyl-Cy claim 51 , wherein Cy is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl.55. The method of claim 42 , wherein X is NRand Y is N.56. The method of claim 42 , wherein ...

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Номер записи: 85
19-10-2017 дата публикации

SALTS, CO-CRYSTALS, AMORPHOUS FORMS, AND CRYSTALLINE FORMS OF A CO-ACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1) INHIBITOR

Номер: US20170298073A1
Автор: Babine Robert E., Chesworth Richard, Jin Lei, Moradei Oscar Miguel, Olhava Edward James, Shapiro Gideon
Принадлежит: Epizyme, Inc

Provided herein are solid forms (e.g., salts, co-crystals, amorphous forms, and crystalline forms) of methyl (R)-2-(2-(2-chloro-5-(2-hydroxy-3-(methylamino)propoxy)phenyl)-6-(3,5-dimethylisoxazol-4-yl)-5-methylpyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (compound 109-3). Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve the solid forms for inhibiting the activity of co-activator-associated arginine methyltransferase 1 (CARM1) and for treating CARM1-mediated disorders (e.g., proliferative disorders and metabolic disorders). 2. The amorphous form A of claim 1 , wherein the amorphous form A is substantially free of impurities.3. The amorphous form A of any one of - claim 1 , wherein the amorphous form A is substantially free of crystalline forms of compound 109-3.4. The amorphous form A of any one of - claim 1 , wherein the amorphous form A is characterized by an X-ray powder diffraction (XRPD) pattern substantially similar to the one depicted in .5. The amorphous form A of any one of - claim 1 , wherein the amorphous form A is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to the one depicted in .6. The amorphous form A of any one of - claim 1 , wherein the amorphous form A is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising a glass-transition temperature (T) of 65.1±2° C.7. The amorphous form A of any one of - claim 1 , wherein the amorphous form A is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising a midpoint temperature of 68.1±2° C.8. The amorphous form A of any one of - claim 1 , wherein the amorphous form A is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising a peak temperature (T) of 70.8±2° C.9. The amorphous form A of any one of - claim 1 , wherein the amorphous form A is characterized by a ...

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Номер записи: 86
17-09-2020 дата публикации

ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

Номер: US20200289469A1
Автор: Chesworth Richard, MITCHELL Lorna Helen, Shapiro Gideon
Принадлежит:

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

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Номер записи: 87
26-10-2017 дата публикации

CARM1 INHIBITORS AND USES THEREOF

Номер: US20170305922A1
Автор: Babine Robert E., Chesworth Richard, Jin Lei, Moradei Oscar Miguel, Shapiro Gideon
Принадлежит: EPIZYME, INC.

Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein R1, R2a, R2b, R3 and Ring B are as defined herein, and Ring A is a group of Formula (A-i), (A-ii), or (A-iii): wherein R, R, R, R, and R are as defined herein. Compounds of the present invention are useful for inhibiting CARM1 activity. Methods of using the compounds for treating CARM1-mediated disorders are also described. 218-. (canceled)2021-. (canceled)2395-. (canceled)104142-. (canceled)145147-. (canceled)148. A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable excipient.149159-. (canceled)164. A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof claim 162 , and a pharmaceutically acceptable excipient.165. A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof claim 163 , and a pharmaceutically acceptable excipient. The present application claims priority under 35 U.S.C. §119(e) to U.S. provisional patent application, U.S. Ser. No. 62/051,872, filed Sep. 17, 2014, the entire contents of which is incorporated herein by reference.Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases.Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., CARM1 (co-activator-associated arginine methyltransferase 1 ...

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Номер записи: 88
25-10-2018 дата публикации

PYRROLOPYRIMIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS

Номер: US20180303834A1
Автор: Shapiro Gideon
Принадлежит:

Disclosed are chemical entities of formula I: 120-. (canceled)23. A pharmaceutical composition comprising the chemical entity of and a pharmaceutically acceptable carrier.24. The pharmaceutical composition of claim 23 , which is suitable for oral administration.25. A method of treating a disease or disorder responsive to NR2B antagonism in a subject in need of such treatment claim 21 , comprising administering an effective amount of the chemical entity of .26. The method of claim 25 , wherein the disease or disorder is depression claim 25 , a seizure disorder claim 25 , pain claim 25 , a movement disorder claim 25 , Huntington's disease claim 25 , cognitive dysfunction claim 25 , cerebral ischaemia claim 25 , traumatic brain injury claim 25 , or a substance abuse disorder.27. The method of claim 26 , wherein the disease or disorder is depression.28. A pharmaceutical composition comprising the chemical entity of and a pharmaceutically acceptable carrier.29. The pharmaceutical composition of claim 28 , which is suitable for oral administration.30. A method of treating a disease or disorder responsive to NR2B antagonism in a subject in need of such treatment claim 22 , comprising administering an effective amount of the chemical entity of .31. The method of claim 30 , wherein the disease or disorder is depression claim 30 , a seizure disorder claim 30 , pain claim 30 , migraine claim 30 , a movement disorder claim 30 , tardive dyskinesia claim 30 , Huntington's disease claim 30 , cognitive dysfunction claim 30 , cerebral ischaemia claim 30 , traumatic brain injury claim 30 , or a substance abuse disorder.32. The method of claim 31 , wherein the disease or disorder is depression. Non-selective NMDA receptor antagonists, originally developed in stroke and head trauma, have more recently shown clinical efficacy in treating depression. The non-selective NMDA receptor antagonist, ketamine, has been shown to have rapid onset and efficacy in depression resistant to standard ...

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Номер записи: 89
03-10-2019 дата публикации

TREATMENT OF AUTISM SPECTRUM DISORDERS, OBSESSIVE-COMPULSIVE DISORDER AND ANXIETY DISORDERS

Номер: US20190298725A1
Автор: Flood Dorothy G., Shapiro Gideon
Принадлежит:

Disclosed are methods for treating NMDA receptor-mediated disorders by administering certain NR2B subunit-selective NMDA (N methyl-D aspartate) antagonists. NMDA receptor-mediated disorders include autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders.

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Номер записи: 90
24-09-2020 дата публикации

3,3-difluoropiperidine carbamate heterocyclic compounds as nr2b nmda receptor antagonists

Номер: US20200299300A1
Автор: Gideon Shapiro
Принадлежит: Rugen Holdings (Cayman) Ltd

Disclosed are chemical entities of Formula (I), wherein R 1 and Z are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I).

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Номер записи: 91
02-11-2017 дата публикации

Crystalline Form of (R)-7-Chloro-N-(Quinuclidin-3-YL)benzo[B]thiophene-2-Carboxamide Hydrochloride Monohydrate

Номер: US20170313694A1
Автор: Chesworth Richard, Ishige Takayuki, Kishida Muneki, Oliver-Shaffer Patricia, Shapiro Gideon
Принадлежит:

Crystalline Forms I and II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate and compositions, methods of manufacture and therapeutic uses thereof are described. 1. A crystalline Form II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate , characterized by an x-ray powder diffraction pattern having peaks expressed as 2Θ at:i) one or both of 21.16 and 21.38±0.20 degrees when measured against an internal silicon standard; andii) at least four peaks selected from a group of peaks consisting of: 4.48, 9.00, 13.58, 15.62, 16.48, 19.02, 19.44, 22.46, and 25.00±0.20 degrees when measured against an internal silicon standard.2. The crystalline Form II of claim 1 , characterized by an x-ray powder diffraction pattern claim 1 , wherein at least six peaks are selected from the group of peaks.3. The crystalline Form II of claim 1 , characterized by an x-ray powder diffraction pattern claim 1 , wherein at least eight peaks are selected from the group of peaks.4. The crystalline Form II of claim 1 , characterized by an x-ray powder diffraction pattern claim 1 , wherein all of the peaks are selected from the group of peaks.5. A pharmaceutical composition comprising the crystalline Form II of .6. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Alzheimer's disease.7. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Schizophrenia.8. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Alzheimer's disease.9. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Schizophrenia.10. A pharmaceutical composition ...

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Номер записи: 92
16-11-2017 дата публикации

IMIDAZOTRIAZINONE COMPOUNDS

Номер: US20170327502A1
Автор: Bursavich Matthew Gregory, McRiner Andrew J., Ripka Amy, Shapiro Gideon
Принадлежит:

The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9 and pharmaceutically acceptable salt thereof. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.

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Номер записи: 93
17-10-2019 дата публикации

Crystalline Form of (R)-7-Chloro-N-(Quinuclidin-3-YL)benzo[B]thiophene-2-Carboxamide Hydrochloride Monohydrate

Номер: US20190315736A1
Автор: Chesworth Richard, Ishige Takayuki, Kishida Muneki, Oliver-Shaffer Patricia, Shapiro Gideon
Принадлежит:

Crystalline Forms I and II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate and compositions, methods of manufacture and therapeutic uses thereof are described. 1. A crystalline Form II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate , characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at:i) one or both of 21.16 and 21.38±0.20 degrees when measured against an internal silicon standard; andii) at least four peaks selected from a group of peaks consisting of: 4.48, 9.00, 13.58, 15.62, 16.48, 19.02, 19.44, 22.46, and 25.00±0.20 degrees when measured against an internal silicon standard.2. The crystalline Form II of claim 1 , characterized by an x-ray powder diffraction pattern claim 1 , wherein at least six peaks are selected from the group of peaks.3. The crystalline Form II of claim 1 , characterized by an x-ray powder diffraction pattern claim 1 , wherein at least eight peaks are selected from the group of peaks.4. The crystalline Form II of claim 1 , characterized by an x-ray powder diffraction pattern claim 1 , wherein all of the peaks are selected from the group of peaks.5. A pharmaceutical composition comprising the crystalline Form II of .6. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Alzheimer's disease.7. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Schizophrenia.8. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Alzheimer's disease.9. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Schizophrenia.10. A pharmaceutical composition ...

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Номер записи: 94
06-12-2018 дата публикации

3,3-DIFLUOROPIPERIDINE CARBAMATE HETEROCYCLIC COMPOUNDS AS NR2B NMDA RECEPTOR ANTAGONISTS

Номер: US20180346476A1
Автор: Shapiro Gideon
Принадлежит:

Disclosed are chemical entities of Formula (I): 24-. (canceled)5. The chemical entity of claim 1 , wherein Z is a 6-membered optionally substituted monocyclic heteraromatic ring system having ring carbon atoms claim 1 , 1 ring nitrogen atom and 0 or 1 additional ring nitrogen atoms.6. The chemical entity of claim 5 , wherein Z is a 6-membered optionally substituted monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms.7. The chemical entity of claim 6 , wherein Z is a 6-membered monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms claim 6 , wherein Z is optionally substituted with 1 or 2 Rgroups.8. The chemical entity of claim 7 , wherein Z is a 6-membered monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms claim 7 , wherein Z is substituted with 1 or 2 Rgroups.9. The chemical entity of claim 8 , wherein Z is a 6-membered monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms claim 8 , wherein Z is substituted with 1 Rgroup.10. The chemical entity of claim 7 , wherein Ris selected from —CH claim 7 , —CFH claim 7 , —CFH claim 7 , or —CF.1113-. (canceled)14. The chemical entity of claim 1 , wherein each of R claim 1 , Rand Rindependently is —H claim 1 , —F claim 1 , —Cl claim 1 , —CH claim 1 , —CFH claim 1 , —CFH claim 1 , —CF claim 1 , —CHCH claim 1 , —CFCH claim 1 , —CHCF claim 1 , isopropyl claim 1 , tert-butyl claim 1 , cyclopropyl claim 1 , —OCF claim 1 , —OCFH claim 1 , —SCH claim 1 , —SCHCH claim 1 , —S(O)CH claim 1 , —S(O)CHCH claim 1 , —S(O)CFor —C≡CH.15. The chemical entity of claim 14 , wherein each of R claim 14 , Rand Rindependently is —H claim 14 , —F claim 14 , —Cl claim 14 , —CH claim 14 , —CFH claim 14 , —CFH claim 14 , —CF claim 14 , —CHCH claim 14 , —CFCH claim 14 , —CHCF claim 14 , cyclopropyl claim 14 , —OCF claim 14 , —OCFH claim 14 , —SCH claim 14 , —S(O)CHor —C≡CH.16. The chemical entity of claim 15 , wherein ...

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Номер записи: 95
28-05-2009 дата публикации

1,3,5 tri-subtituted benzenes for treatment of alzheimer's disease and other disorders

Номер: WO2009067493A2
Автор: Gideon Shapiro, Richard Chesworth
Принадлежит: EnVivo Pharmaceuticals, Inc.

The present disclosure relates to novel 1,3,5 tri-substituted benzenes of general formula (I), (II) or (III) and the use of such compounds in the treatment of diseases associated with the deposition of -amyloid in the brain.

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Номер записи: 96
14-04-2009 дата публикации

Materials and methods for detection of nucleic acids

Номер: US7517651B2
Автор: Christopher B. Sherrill, David J. Marshall, Gideon Shapiro, James R. Prudent, Jerod L. Ptacin, Simon Jurczyk
Принадлежит: Eragen Biosciences Inc

Assays using non-natural bases are described. In one embodiment, the method involves contacting a sample suspected of containing the target nucleic acid with a polymerase and first and second primers; amplifying the target nucleic acid, if present in the sample, by PCR using the first and second primers to generate an amplification product having a double-stranded region and a single-stranded region that comprises the non-natural base; contacting the sample with a reporter comprising a label and a non-natural base that is complementary to the non-natural base of the single-stranded region; annealing at least a portion of the reporter to the single-stranded region of the amplification product; and correlating a signal of the label with the presence of the target nucleic acid in the sample. The invention also provides corresponding kits for use in detecting target nucleic acids in a sample.

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Номер записи: 97
04-04-2017 дата публикации

Materials and methods for detection of nucleic acids

Номер: US9611509B2
Автор: Christopher B. Sherrill, Craig S. Richmond, David J. Marshall, Gideon Shapiro, James R. Prudent, Jennifer K. Grenier, Jerod L. Ptacin, Simona Jurczyk
Принадлежит: Luminex Corp

Assays using non-natural bases are described. In one embodiment, the method involves contacting a sample suspected of containing the target nucleic acid with a polymerase and first and second primers; amplifying the target nucleic acid by PCR using the first and second primers to generate an amplification product having a double-stranded region and a single-stranded region that comprises the non-natural base; contacting the sample with a reporter comprising a label and a non-natural base that is complementary to the non-natural base of the single-stranded region; annealing at least a portion of the reporter to the single-stranded region of the amplification product; and correlating a signal of the label with the presence of the target nucleic acid in the sample. The invention also provides corresponding kits for use in detecting target nucleic acids in a sample.

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Номер записи: 98
02-06-2009 дата публикации

Materials and methods for detection of nucleic acids

Номер: US7541147B2
Автор: Christopher B. Sherrill, David J. Marshall, Gideon Shapiro, James R. Prudent, Jerod L. Ptacin, Simona Jurczyk
Принадлежит: Eragen Biosciences Inc

Assays using non-natural bases are described. In one embodiment, the method involves contacting a sample suspected of containing the target nucleic acid with a polymerase and first and second primers; amplifying the target nucleic acid, if present in the sample, by PCR using the first and second primers to generate an amplification product having a double-stranded region and a single-stranded region that comprises the non-natural base; contacting the sample with a reporter comprising a label and a non-natural base that is complementary to the non-natural base of the single-stranded region; annealing at least a portion of the reporter to the single-stranded region of the amplification product; and correlating a signal of the label with the presence of the target nucleic acid in the sample. The invention also provides corresponding kits for use in detecting target nucleic acids in a sample.

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Номер записи: 99
27-08-2013 дата публикации

Materials and methods for detection of nucleic acids

Номер: US8519117B2
Автор: Christopher B. Sherrill, Craig S. Richmond, David J. Marshall, Gideon Shapiro, James R. Prudent, Jennifer K. Grenier, Jerod L. Ptacin, Simona Jurczyk
Принадлежит: Luminex Corp

Assays using non-natural bases are described. In one embodiment, the method involves contacting a sample suspected of containing the target nucleic acid with a polymerase and first and second primers; amplifying the target nucleic acid by PCR using the first and second primers to generate an amplification product having a double-stranded region and a single-stranded region that comprises the non-natural base; contacting the sample with a reporter comprising a label and a non-natural base that is complementary to the non-natural base of the single-stranded region; annealing at least a portion of the reporter to the single-stranded region of the amplification product; and correlating a signal of the label with the presence of the target nucleic acid in the sample. The invention also provides corresponding kits for use in detecting target nucleic acids in a sample.

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Номер записи: 100