EP1901730A1 - Verwendung von aktivatoren der löslichen guanylatzyklase zur behandlung von reperfusionsschäden - Google Patents
Verwendung von aktivatoren der löslichen guanylatzyklase zur behandlung von reperfusionsschädenInfo
- Publication number
- EP1901730A1 EP1901730A1 EP06818217A EP06818217A EP1901730A1 EP 1901730 A1 EP1901730 A1 EP 1901730A1 EP 06818217 A EP06818217 A EP 06818217A EP 06818217 A EP06818217 A EP 06818217A EP 1901730 A1 EP1901730 A1 EP 1901730A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- medicament
- treatment
- reperfusion damage
- guanylate cyclase
- soluble guanylate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs 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
Definitions
- the present invention relates to the use of compounds for the manufacture of a pharmaceutical product / medicament for the prophylaxis and / or treatment of reperfusion injury.
- Reperfusion damage generally occurs after the cessation of a prolonged ischemic period, e.g. as a result of invading accumulating toxic metabolites after restoration of blood flow and / or massive release of calcium ions in excitable cells. These damages often occur after vascular occlusions, especially after acute arterial occlusions, when a compensating collateral circulation is absent (so-called infarcts).
- the best known forms are the heart attack and the cerebral infarction (stroke). While early restoration of blood flow by thrombolysis following transient ischemia may prevent or reduce the extent of cell damage (infarct size), reperfusion may still be to some extent dysfunctional, e.g. of the heart or cause cell death. Therefore, it is of great clinical value to find medicines which inhibit normal function, e.g. of the heart during reperfusion and at various forms of cardiac surgery.
- ischemic reperfusion injury and associated cellular damage e.g. occur in: Myocardial infarction, replacement of arterial coronary vessels, in particular cardiac surgery on the open chest, angina, peripheral vascular occlusive diseases, stroke, tissue and organ transplants (eg, heart, liver, kidney, lung), general surgery, - acute renal failure and reduced perfusion of Organs (eg lung, heart, liver, intestine, pancreas, kidney, extremities or brain).
- Elevated cGMP levels may protect cells, tissues, and organs from reperfusion damage.
- the activation (agonists) of soluble guanylate cyclase leads to an increase of the intracellular messenger cGMP.
- the compounds of the invention activators of soluble guanylate cyclase are particularly suitable for the preparation of pharmaceutical substances / medicaments for the prophylaxis and / or treatment and the limitation of reperfusion injury in mammals, especially humans.
- Connection (FVa) corresponds to the following formula: - A -
- An additional embodiment of the present invention comprises the procedure for the prophylaxis and / or treatment of reperfusion injury using at least one of the compounds of formulas (I-VI).
- Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention and at least one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
- the compounds according to the invention can act systemically and / or locally.
- they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
- the compounds according to the invention can be administered in suitable administration forms.
- Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
- a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
- absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
- parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
- inhalant medicines including powder inhalers, nebulizers
- nasal drops solutions, sprays
- lingual sublingual or buccal.
- the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
- These adjuvants include, among others. Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example Antioxi - Dantien such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.
- Carriers for example microcrystalline cellulose, lactose, mannitol
- solvents eg liquid polyethylene glycols
- emulsifiers and dispersing or wetting agents for example sodium
- compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
- the formulations may contain from 0.1 to 99% active ingredient according to the procedure, suitably 25-95% for tablets and capsules and 1-50% for liquid formulations, ie the active ingredient should be present in sufficient amounts reach specified dosage latitude. - 1 -
- An additional exemplary embodiment of the present invention is the use of a combination of one or more of the compounds according to the invention with one or more other substances.
- Suitable combinations of substances are, for example, substances which are used for the prophylaxis and / or treatment of infarcts and reperfusion damage.
- exemplary and preferred in this context are cGMP-increasing substances such as NO-releasing substances, inhibitors of phosphodiesterases, thrombolytics and adenosine agonists.
- Infarct size was determined at the end of the experiment by quickly removing the isolated heart from the Langendorff setup. After a wash in physiological saline, the coronary artery was resealed and fluorescent microspheres infused into the heart to represent the risk zone or ischemic area as non-fluorescent tissue. After the heart was weighed and deep frozen, it could be sliced into 2mm thick slices. These disks were incubated in 1% triphenyltetrazolium chloride (TTC) in sodium phosphate buffer at 37 ° C for 20 minutes. The viable tissue is dyed dark red whereas the necrotic tissue does not stain and appear brownish.
- TTC triphenyltetrazolium chloride
- soluble guanylate cyclase activators are useful in reducing infarct size and reducing reperfusion injury.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102005031576A DE102005031576A1 (de) | 2005-07-06 | 2005-07-06 | Verwendung von Aktivatoren der löslichen Guanylatzyklase zur Behandlung von Reperfusionsschäden |
PCT/EP2006/006600 WO2007025595A1 (de) | 2005-07-06 | 2006-07-06 | Verwendung von aktivatoren der löslichen guanylatzyklase zur behandlung von reperfusionsschäden |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1901730A1 true EP1901730A1 (de) | 2008-03-26 |
Family
ID=37433912
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06818217A Ceased EP1901730A1 (de) | 2005-07-06 | 2006-07-06 | Verwendung von aktivatoren der löslichen guanylatzyklase zur behandlung von reperfusionsschäden |
Country Status (14)
Country | Link |
---|---|
US (1) | US20090298822A1 (de) |
EP (1) | EP1901730A1 (de) |
JP (1) | JP2009500365A (de) |
KR (1) | KR20080033238A (de) |
CN (1) | CN101257901A (de) |
AU (1) | AU2006286896A1 (de) |
BR (1) | BRPI0612685A2 (de) |
CA (1) | CA2614088A1 (de) |
DE (1) | DE102005031576A1 (de) |
IL (1) | IL188584A0 (de) |
MX (1) | MX2008000276A (de) |
RU (1) | RU2432948C2 (de) |
WO (1) | WO2007025595A1 (de) |
ZA (1) | ZA200800025B (de) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102007026392A1 (de) | 2007-06-06 | 2008-12-11 | Bayer Healthcare Ag | Lösungen für die Perfusion und Konservierung von Organen und Geweben |
JP5940062B2 (ja) * | 2010-07-09 | 2016-06-29 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングBayer Intellectual Property GmbH | 環縮合4−アミノピリミジンおよび可溶性グアニル酸シクラーゼの刺激剤としてのその使用 |
AU2012280246A1 (en) * | 2011-07-06 | 2014-01-23 | Bayer Intellectual Property Gmbh | Heteroaryl-substituted pyrazolopyridines and use thereof as soluble guanylate cyclase stimulators |
US10531655B2 (en) | 2011-12-02 | 2020-01-14 | The Regents Of The University Of California | Reperfusion protection solution and uses thereof |
EP2961754B1 (de) * | 2013-03-01 | 2016-11-16 | Bayer Pharma Aktiengesellschaft | Benzyl-substituierte pyrazolopyridine und ihre verwendung |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003040332A2 (en) * | 2001-11-06 | 2003-05-15 | Buck Institute | Neuroglobin is up-regulated by and protects neuronsfrom hypoxic-ischemic injury |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US173514A (en) * | 1876-02-15 | Improvement in call-bells | ||
CZ302691B6 (cs) * | 1998-07-08 | 2011-09-07 | Sanofi - Aventis Deutschland GmbH | N-Arylamidová sloucenina, zpusob její prípravy, farmaceutický prostredek tuto slouceninu obsahující, tato sloucenina pro použití jako aktivátor a pro použití k terapii nebo profylaxi |
DE19834044A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | Neue substituierte Pyrazolderivate |
DE19943635A1 (de) * | 1999-09-13 | 2001-03-15 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
AR031176A1 (es) * | 2000-11-22 | 2003-09-10 | Bayer Ag | Nuevos derivados de pirazolpiridina sustituidos con piridina |
DE10220570A1 (de) * | 2002-05-08 | 2003-11-20 | Bayer Ag | Carbamat-substituierte Pyrazolopyridine |
DE10351903A1 (de) * | 2003-11-06 | 2005-06-09 | Bayer Healthcare Ag | Neue Kombination |
WO2005077005A2 (en) * | 2004-02-04 | 2005-08-25 | The General Hospital Corporation | Enhancing the effectiveness of an inhaled therapeutic gas |
CA2583073A1 (en) * | 2004-10-05 | 2006-04-13 | Bayer Healthcare Ag | A guanylane cyclase stimulator and nitric oxide for treating bronchoconstriction and pulmonary vasoconstriction |
-
2005
- 2005-07-06 DE DE102005031576A patent/DE102005031576A1/de not_active Withdrawn
-
2006
- 2006-07-06 US US11/922,838 patent/US20090298822A1/en not_active Abandoned
- 2006-07-06 CN CNA200680024418XA patent/CN101257901A/zh active Pending
- 2006-07-06 MX MX2008000276A patent/MX2008000276A/es not_active Application Discontinuation
- 2006-07-06 JP JP2008519861A patent/JP2009500365A/ja active Pending
- 2006-07-06 AU AU2006286896A patent/AU2006286896A1/en not_active Abandoned
- 2006-07-06 RU RU2008103549/15A patent/RU2432948C2/ru not_active IP Right Cessation
- 2006-07-06 CA CA002614088A patent/CA2614088A1/en not_active Abandoned
- 2006-07-06 BR BRPI0612685-5A patent/BRPI0612685A2/pt not_active IP Right Cessation
- 2006-07-06 EP EP06818217A patent/EP1901730A1/de not_active Ceased
- 2006-07-06 WO PCT/EP2006/006600 patent/WO2007025595A1/de active Application Filing
- 2006-07-06 KR KR1020087000280A patent/KR20080033238A/ko not_active Application Discontinuation
-
2008
- 2008-01-02 ZA ZA200800025A patent/ZA200800025B/xx unknown
- 2008-01-03 IL IL188584A patent/IL188584A0/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003040332A2 (en) * | 2001-11-06 | 2003-05-15 | Buck Institute | Neuroglobin is up-regulated by and protects neuronsfrom hypoxic-ischemic injury |
Non-Patent Citations (2)
Title |
---|
See also references of WO2007025595A1 * |
YANG XI-MING ET AL: "Postconditioning's protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activation.", BASIC RESEARCH IN CARDIOLOGY JAN 2005 LNKD- PUBMED:15614590, vol. 100, no. 1, January 2005 (2005-01-01), pages 57 - 63, ISSN: 0300-8428 * |
Also Published As
Publication number | Publication date |
---|---|
ZA200800025B (en) | 2009-09-30 |
US20090298822A1 (en) | 2009-12-03 |
CN101257901A (zh) | 2008-09-03 |
DE102005031576A1 (de) | 2007-01-25 |
CA2614088A1 (en) | 2007-03-08 |
AU2006286896A1 (en) | 2007-03-08 |
WO2007025595A1 (de) | 2007-03-08 |
RU2432948C2 (ru) | 2011-11-10 |
MX2008000276A (es) | 2008-03-19 |
BRPI0612685A2 (pt) | 2010-11-30 |
KR20080033238A (ko) | 2008-04-16 |
IL188584A0 (en) | 2008-06-05 |
JP2009500365A (ja) | 2009-01-08 |
RU2008103549A (ru) | 2009-08-20 |
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