AU2007257781B2 - Phenyl substituted pyrazinoylguanidine sodium channel blockers possessing beta agonist activity - Google Patents

Phenyl substituted pyrazinoylguanidine sodium channel blockers possessing beta agonist activity Download PDF

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Publication number
AU2007257781B2
AU2007257781B2 AU2007257781A AU2007257781A AU2007257781B2 AU 2007257781 B2 AU2007257781 B2 AU 2007257781B2 AU 2007257781 A AU2007257781 A AU 2007257781A AU 2007257781 A AU2007257781 A AU 2007257781A AU 2007257781 B2 AU2007257781 B2 AU 2007257781B2
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compound
independently
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AU2007257781A
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AU2007257781A1 (en
Inventor
Richard C. Boucher
Andrew J. Hirsh
Michael Ross Johnson
Jianzhong Zhang
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Parion Sciences Inc
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Parion Sciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
    • C07D241/30—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms in which said hetero-bound carbon atoms are part of a substructure —C(=X)—X—C(=X)—X— in which X is an oxygen or sulphur atom or an imino radical, e.g. imidoylguanidines
    • C07D241/32—(Amino-pyrazinoyl) guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Toxicology (AREA)
  • Nutrition Science (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Otolaryngology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
AU2007257781A 2006-06-09 2007-06-11 Phenyl substituted pyrazinoylguanidine sodium channel blockers possessing beta agonist activity Ceased AU2007257781B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US81207706P 2006-06-09 2006-06-09
US60/812,077 2006-06-09
PCT/US2007/070861 WO2007146869A1 (en) 2006-06-09 2007-06-11 Phenyl substituted pyrazinoylguanidine sodium channel blockers possessing beta agonist activity

Publications (2)

Publication Number Publication Date
AU2007257781A1 AU2007257781A1 (en) 2007-12-21
AU2007257781B2 true AU2007257781B2 (en) 2012-11-22

Family

ID=38832114

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2007257781A Ceased AU2007257781B2 (en) 2006-06-09 2007-06-11 Phenyl substituted pyrazinoylguanidine sodium channel blockers possessing beta agonist activity

Country Status (12)

Country Link
US (1) US8163758B2 (https=)
EP (1) EP2035004B1 (https=)
JP (1) JP5254961B2 (https=)
AU (1) AU2007257781B2 (https=)
CA (1) CA2654244A1 (https=)
DK (1) DK2035004T3 (https=)
ES (1) ES2392999T3 (https=)
NO (1) NO20085128L (https=)
PL (1) PL2035004T3 (https=)
PT (1) PT2035004E (https=)
SI (1) SI2035004T1 (https=)
WO (1) WO2007146869A1 (https=)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6858615B2 (en) * 2002-02-19 2005-02-22 Parion Sciences, Inc. Phenyl guanidine sodium channel blockers
AU2004266704B2 (en) 2003-08-18 2012-02-23 Parion Sciences, Inc. Capped pyrazinoylguanidine sodium channel blockers
US7807834B2 (en) 2005-08-03 2010-10-05 Parion Sciences, Inc. Capped pyrazinoylguanidine sodium channel blockers
KR100901664B1 (ko) 2007-08-06 2009-06-09 주식회사 오스코텍 β-아미노알콜 유도체, 이의 제조방법 및 이를유효성분으로 함유하는 ＴＮＦ-α 매개성 질환의 예방 및치료용 약학적 조성물
DE102007040615A1 (de) * 2007-08-27 2009-03-05 Bitop Ag Osmolyte zur Behandlung von allergisch oder viral bedingten Atemwegserkrankungen
US8551534B2 (en) 2007-10-10 2013-10-08 Parion Sciences, Inc. Inhaled hypertonic saline delivered by a heated nasal cannula
DE102007052380A1 (de) * 2007-10-31 2009-05-07 Bitop Ag Osmolythaltige Zubereitungen zur Anwendung bei trockenen Schleimhäuten
WO2009139948A1 (en) 2008-02-26 2009-11-19 Johnson Michael R Poly aromatic sodium channel blockers
UY33373A (es) 2010-05-10 2011-12-30 Gilead Sciences Inc ?Compuestos de pirazolopiridina bifuncionales, su uso en terapia y composiciones que los comprenden?.
CA2796826A1 (en) 2010-05-10 2011-11-17 Gilead Sciences, Inc. Bifunctional quinoline derivatives
WO2012032546A2 (en) * 2010-09-08 2012-03-15 Cadila Healthcare Limited Process for the preparation of salmeterol and its intermediates
DE102011103347B4 (de) * 2011-05-27 2014-10-30 Meda Pharma Gmbh & Co. Kg Nasale pharmazeutische Formulierung
US8778383B2 (en) 2011-06-07 2014-07-15 Parion Sciences, Inc. Methods of treatment
US8945605B2 (en) 2011-06-07 2015-02-03 Parion Sciences, Inc. Aerosol delivery systems, compositions and methods
AR086745A1 (es) * 2011-06-27 2014-01-22 Parion Sciences Inc 3,5-diamino-6-cloro-n-(n-(4-(4-(2-(hexil(2,3,4,5,6-pentahidroxihexil)amino)etoxi)fenil)butil)carbamimidoil)pirazina-2-carboxamida
HUE032851T2 (en) 2011-06-27 2017-11-28 Parion Sciences Inc A chemically and metabolically stable dipeptide having strong sodium channel blocking activity
MX2014014648A (es) 2012-05-29 2015-09-04 Parion Sciences Inc Aminoamidas tipo dendrimero que poseen actividad bloqueadora del canal de sodio para el tratamiento de ojo reseco y otras enfermedades mucosas.
RU2018138195A (ru) 2012-12-17 2018-12-18 Пэрион Сайенсиз, Инк. Соединения 3,5-диамино-6-хлор-n-(n-(4- фенилбутил)карбамимидоил)пиразин-2-карбоксамида
ES2674665T3 (es) * 2012-12-17 2018-07-03 Parion Sciences, Inc. Compuestos de 3,5-diamino-6-cloro-N-(N-(4-fenilbutilo)carbamimidoilo)-pirazina-2-carboxamida
SG10201708931XA (en) 2012-12-17 2017-12-28 Parion Sciences Inc Chloro-pyrazine carboxamide derivatives useful for the treatment of diseases favoured by insufficient mucosal hydration
SG11201601291QA (en) 2013-08-23 2016-03-30 Parion Sciences Inc Dithiol mucolytic agents
US9102633B2 (en) 2013-12-13 2015-08-11 Parion Sciences, Inc. Arylalkyl- and aryloxyalkyl-substituted epithelial sodium channel blocking compounds
GB201406225D0 (en) * 2014-04-07 2014-05-21 Hall Roderick L Treatment for respiratory disease
US20150376145A1 (en) 2014-06-30 2015-12-31 Parion Sciences, Inc. Stable sodium channel blockers
KR20170108088A (ko) 2015-01-30 2017-09-26 패리온 사이언스 인코퍼레이티드 신규 모노티올 점액용해제
JP2018520986A (ja) 2015-04-30 2018-08-02 パリオン・サイエンシィズ・インコーポレーテッド ジチオール粘液溶解剤の新規なプロドラッグ

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005018644A1 (en) * 2003-08-18 2005-03-03 Parion Sciences, Inc. Capped pyrazinoylguanidine sodium channel blockers

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPR034000A0 (en) * 2000-09-25 2000-10-19 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
US6858614B2 (en) * 2002-02-19 2005-02-22 Parion Sciences, Inc. Phenolic guanidine sodium channel blockers
US6858615B2 (en) * 2002-02-19 2005-02-22 Parion Sciences, Inc. Phenyl guanidine sodium channel blockers
US6903105B2 (en) * 2003-02-19 2005-06-07 Parion Sciences, Inc. Sodium channel blockers
US7268147B2 (en) * 2003-05-15 2007-09-11 Pfizer Inc Compounds useful for the treatment of diseases
GB0312832D0 (en) * 2003-06-04 2003-07-09 Pfizer Ltd 2-amino-pyridine derivatives useful for the treatment of diseases
US20050090505A1 (en) * 2003-08-18 2005-04-28 Johnson Michael R. Methods of reducing risk of infection from pathogens
US7375107B2 (en) * 2003-08-18 2008-05-20 Parion Sciences, Inc. Alaphatic pyrazinoylguanidine sodium channel blockers
JP2007502829A (ja) * 2003-08-18 2007-02-15 パリオン・サイエンシィズ・インコーポレーテッド 環状ピラジノイルグアニジンナトリウムチャネルブロッカー
US7745442B2 (en) * 2003-08-20 2010-06-29 Parion Sciences, Inc. Methods of reducing risk of infection from pathogens
US7399766B2 (en) * 2004-08-18 2008-07-15 Parion Sciences, Inc. Soluble amide & ester pyrazinoylguanidine sodium channel blockers
WO2006023617A2 (en) * 2004-08-18 2006-03-02 Johnson Michael R Cyclic amide & ester pyrazinoylguanidine sodium channel blockers
US20070021439A1 (en) * 2005-07-25 2007-01-25 Parion Sciences, Inc. Methods of reducing risk of infection from pathogens with soluble amide and ester pyrazinoylguanidine sodium channel blockers
US7807834B2 (en) * 2005-08-03 2010-10-05 Parion Sciences, Inc. Capped pyrazinoylguanidine sodium channel blockers
AU2007294547A1 (en) * 2006-09-07 2008-03-13 Parion Sciences, Inc. Methods of enhancing mucosal hydration and mucosal clearance by treatment with sodium channel blockers and osmolytes
US20080293740A1 (en) * 2007-04-03 2008-11-27 Parion Sciences, Inc. Method of treating acid-sensing ion channel mediated pain, cough suppression, and central nervous system disorders
US8288391B2 (en) * 2007-04-03 2012-10-16 Parion Sciences, Inc. Pyrazinoylguanidine compounds for use as taste modulators

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005018644A1 (en) * 2003-08-18 2005-03-03 Parion Sciences, Inc. Capped pyrazinoylguanidine sodium channel blockers

Also Published As

Publication number Publication date
PT2035004E (pt) 2012-11-21
WO2007146869A1 (en) 2007-12-21
JP2009539882A (ja) 2009-11-19
US8163758B2 (en) 2012-04-24
EP2035004B1 (en) 2012-08-08
ES2392999T3 (es) 2012-12-17
US20110008268A1 (en) 2011-01-13
DK2035004T3 (en) 2013-01-02
PL2035004T3 (pl) 2013-01-31
AU2007257781A1 (en) 2007-12-21
EP2035004A1 (en) 2009-03-18
EP2035004A4 (en) 2010-06-30
SI2035004T1 (sl) 2012-12-31
NO20085128L (no) 2009-02-18
JP5254961B2 (ja) 2013-08-07
CA2654244A1 (en) 2007-12-21

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