TR201809681T4 - N-[(r)-1-[(s)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamit hidroklorürün polimorfları. - Google Patents

N-[(r)-1-[(s)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamit hidroklorürün polimorfları. Download PDF

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Publication number
TR201809681T4
TR201809681T4 TR2018/09681T TR201809681T TR201809681T4 TR 201809681 T4 TR201809681 T4 TR 201809681T4 TR 2018/09681 T TR2018/09681 T TR 2018/09681T TR 201809681 T TR201809681 T TR 201809681T TR 201809681 T4 TR201809681 T4 TR 201809681T4
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Turkey
Prior art keywords
phenyl
ethoxy
solid form
ethyl
ethylcarbamoyl
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TR2018/09681T
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English (en)
Turkish (tr)
Inventor
Scott Northen Julian
Mykytiuk John
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Kalvista Pharmaceuticals Ltd
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Publication of TR201809681T4 publication Critical patent/TR201809681T4/tr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06078Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
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    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
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    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • A61P9/02Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00Preparation of carboxylic acid amides
    • C07C231/22Separation; Purification; Stabilisation; Use of additives
    • C07C231/24Separation; Purification
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

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TR2018/09681T 2012-07-06 2013-07-05 N-[(r)-1-[(s)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamit hidroklorürün polimorfları. TR201809681T4 (tr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261668543P 2012-07-06 2012-07-06
GB201212081A GB201212081D0 (en) 2012-07-06 2012-07-06 New polymorph

Publications (1)

Publication Number Publication Date
TR201809681T4 true TR201809681T4 (tr) 2018-07-23

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Family Applications (1)

Application Number Title Priority Date Filing Date
TR2018/09681T TR201809681T4 (tr) 2012-07-06 2013-07-05 N-[(r)-1-[(s)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamit hidroklorürün polimorfları.

Country Status (10)

Country Link
US (1) US9512065B2 (enExample)
EP (1) EP2870137B8 (enExample)
JP (1) JP6367187B2 (enExample)
CA (1) CA2878319C (enExample)
ES (1) ES2679370T3 (enExample)
GB (1) GB201212081D0 (enExample)
HU (1) HUE039775T2 (enExample)
PL (1) PL2870137T3 (enExample)
TR (1) TR201809681T4 (enExample)
WO (1) WO2014006414A1 (enExample)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2510407A (en) 2013-02-04 2014-08-06 Kalvista Pharmaceuticals Ltd Aqueous suspensions of kallikrein inhibitors for parenteral administration
TWI636047B (zh) 2013-08-14 2018-09-21 英商卡爾維斯塔製藥有限公司 雜環衍生物
GB201421083D0 (en) 2014-11-27 2015-01-14 Kalvista Pharmaceuticals Ltd Enzyme inhibitors
GB201421085D0 (en) 2014-11-27 2015-01-14 Kalvista Pharmaceuticals Ltd New enzyme inhibitors
WO2017153567A1 (en) 2016-03-10 2017-09-14 Thrombogenics Nv Posterior ocular fibrosis inhibition by antagonizing placental growth factor
HRP20201131T1 (hr) 2016-05-31 2020-10-30 Kalvista Pharmaceuticals Limited Derivati pirazola kao inhibitori kalikreina plazme
GB201609603D0 (en) * 2016-06-01 2016-07-13 Kalvista Pharmaceuticals Ltd Polymorphs of N-[(6-cyano-2-fluoro-3-methoxyphenyl)Methyl]-3-(methoxymethyl)-1-({4-[(2-ox opyridin-1-YL)Methyl]phenyl}methyl)pyrazole-4-carboxamide
GB201609607D0 (en) 2016-06-01 2016-07-13 Kalvista Pharmaceuticals Ltd Polymorphs of N-(3-Fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1-({4-((2-oxopy ridin-1-yl)methyl)phenyl}methyl)pyrazole-4-carboxamide and salts
ES2922379T3 (es) 2016-12-16 2022-09-14 Janssen Pharmaceutica Nv Compuestos de imidazo[4,5,D]pirrolo[2,3,B]piridina como inhibidores de Janus quinasas
JOP20190144A1 (ar) 2016-12-16 2019-06-16 Janssen Pharmaceutica Nv إيميدازو بيرولو بيريدين كمثبطات لعائلة jak الخاصة بإنزيمات الكيناز
IL268007B2 (en) 2017-01-30 2025-05-01 Janssen Biotech Inc Anti-tnf antibodies, compositions, and methods for the treatment of active psoriatic arthritis
AU2017398101B2 (en) 2017-02-07 2025-02-06 Janssen Biotech, Inc. Anti-TNF antibodies, compositions, and methods for the treatment of active Ankylosing Spondylitis
GB201719881D0 (en) 2017-11-29 2018-01-10 Kalvista Pharmaceuticals Ltd Solid forms of plasma kallikrein inhibitor and salts thereof
DK3716952T3 (da) 2017-11-29 2022-03-14 Kalvista Pharmaceuticals Ltd Doseringsformer omfattende en plasmakallikrein-inhibitor
TW202016110A (zh) 2018-06-15 2020-05-01 比利時商健生藥品公司 Jak激酶家族之小分子抑制劑
UY38438A (es) 2018-11-02 2020-05-29 Biocryst Pharm Inc Sales cristalinas de un inhibidor de calicreína plasmática
CA3138241A1 (en) 2019-05-23 2020-11-26 Janssen Biotech, Inc. Method of treating inflammatory bowel disease with a combination therapy of antibodies to il-23 and tnf alpha
WO2021028645A1 (en) 2019-08-09 2021-02-18 Kalvista Pharmaceuticals Limited Plasma kallikrein inhibitors
GB201918994D0 (en) * 2019-12-20 2020-02-05 Kalvista Pharmaceuticals Ltd Treatments of diabetic macular edema and impaired visual acuity
GB2591730A (en) 2019-12-09 2021-08-11 Kalvista Pharmaceuticals Ltd New polymorphs
EP4596046A3 (en) 2020-05-21 2025-10-22 Janssen Biotech, Inc. Method of treating inflammatory bowel disease with a combination therapy of antibodies to il-23 and tnf alpha
AU2022233254A1 (en) 2021-03-11 2023-10-26 Janssen Pharmaceutica Nv Lorpucitinib for use in the treatment of jak mediated disorders

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5187157A (en) 1987-06-05 1993-02-16 Du Pont Merck Pharmaceutical Company Peptide boronic acid inhibitors of trypsin-like proteases
IT1223401B (it) * 1987-12-02 1990-09-19 Montedison Spa Poliesteri aromatici liquido cristallini termotropici
GB9019558D0 (en) 1990-09-07 1990-10-24 Szelke Michael Enzyme inhibitors
SE9301911D0 (sv) 1993-06-03 1993-06-03 Ab Astra New peptide derivatives
US5589467A (en) 1993-09-17 1996-12-31 Novo Nordisk A/S 2,5',N6-trisubstituted adenosine derivatives
IL112795A (en) * 1994-03-04 2001-01-28 Astrazeneca Ab Peptide derivatives as antithrombic agents their preparation and pharmaceutical compositions containing them
US5914319A (en) * 1995-02-27 1999-06-22 Eli Lilly And Company Antithrombotic agents
US7001887B2 (en) * 2001-02-02 2006-02-21 Chugai Seiyaku Kabushiki Kaisha Peptide derivatives
GB0205527D0 (en) 2002-03-08 2002-04-24 Ferring Bv Inhibitors
DE10301300B4 (de) 2003-01-15 2009-07-16 Curacyte Chemistry Gmbh Verwendung von acylierten 4-Amidino- und 4-Guanidinobenzylaminen zur Inhibierung von Plasmakallikrein
PL1660057T3 (pl) 2003-08-27 2012-10-31 Ophthotech Corp Terapia łączona do leczenia zaburzeń związanych z neowaskularyzacją gałki ocznej
AU2005227733A1 (en) * 2004-04-02 2005-10-13 Glaxo Group Limited Chemical process and new crystalline form
US7453002B2 (en) * 2004-06-15 2008-11-18 Bristol-Myers Squibb Company Five-membered heterocycles useful as serine protease inhibitors
DE602005014138D1 (de) * 2004-11-30 2009-06-04 Mallinckrodt Inc Verfahren zur kristallisierung von benzphetamin
CA2633252A1 (en) * 2005-12-14 2007-06-21 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor xia inhibitors
US7625944B2 (en) 2006-07-31 2009-12-01 Activesite Pharmaceuticals, Inc. Inhibitors of plasma kallikrein
DE102006050672A1 (de) 2006-10-24 2008-04-30 Curacyte Discovery Gmbh Hemmstoffe des Plasmins und des Plasmakallikreins
CN102762203A (zh) 2009-12-18 2012-10-31 艾克提弗赛特制药股份有限公司 血浆激肽释放酶抑制剂的前药
NZ601521A (en) 2010-01-28 2014-09-26 Medicines Co Leipzig Gmbh Trypsin-like serine protease inhibitors, and their preparation and use
JP2013121919A (ja) 2010-03-25 2013-06-20 Astellas Pharma Inc 血漿カリクレイン阻害剤
EP2590945B1 (en) 2010-07-07 2014-04-30 The Medicines Company (Leipzig) GmbH Serine protease inhibitors
US9290485B2 (en) 2010-08-04 2016-03-22 Novartis Ag N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
WO2012142308A1 (en) 2011-04-13 2012-10-18 Activesite Pharmaceuticals, Inc. Prodrugs of inhibitors of plasma kallikrein
GB2494851A (en) * 2011-07-07 2013-03-27 Kalvista Pharmaceuticals Ltd Plasma kallikrein inhibitors

Also Published As

Publication number Publication date
US20150191421A1 (en) 2015-07-09
US9512065B2 (en) 2016-12-06
EP2870137A1 (en) 2015-05-13
HUE039775T2 (hu) 2019-02-28
CA2878319C (en) 2021-02-09
EP2870137B8 (en) 2018-07-18
PL2870137T3 (pl) 2018-12-31
GB201212081D0 (en) 2012-08-22
JP2015528798A (ja) 2015-10-01
WO2014006414A1 (en) 2014-01-09
JP6367187B2 (ja) 2018-08-01
CA2878319A1 (en) 2014-01-09
ES2679370T3 (es) 2018-08-24
EP2870137B1 (en) 2018-05-16

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