EP1917008A2 - Utilisation d'activateurs de la guanylate cyclase soluble pour traiter les phenomenes de raynaud - Google Patents

Utilisation d'activateurs de la guanylate cyclase soluble pour traiter les phenomenes de raynaud

Info

Publication number
EP1917008A2
EP1917008A2 EP06762392A EP06762392A EP1917008A2 EP 1917008 A2 EP1917008 A2 EP 1917008A2 EP 06762392 A EP06762392 A EP 06762392A EP 06762392 A EP06762392 A EP 06762392A EP 1917008 A2 EP1917008 A2 EP 1917008A2
Authority
EP
European Patent Office
Prior art keywords
treatment
raynaud
phenomenon
medicament
guanylate cyclase
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.)
Withdrawn
Application number
EP06762392A
Other languages
German (de)
English (en)
Inventor
Thomas Krahn
Johannes-Peter Stasch
Gerrit Weimann
Wolfgang Thielemann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Healthcare AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1917008A2 publication Critical patent/EP1917008A2/fr
Withdrawn legal-status Critical Current

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
    • A61K31/33—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
    • 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
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic 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
    • A61K31/33—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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the use of compounds of formulas I-VI for the manufacture of a medicament for the treatment of primary and secondary Raynaud's phenomenon.
  • a distinction is a primary, uncomplicated Raynaud's phenomenon using an excessive physiological ⁇ reaction arteries of extremities to cold stimuli from a secondary Raynaud's phenomenon with systemic underlying disease from the rheumatic F ⁇ rmen Vietnamese or from the connective tissue disorders such as scleroderma, Sjogren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, polymyositis or dermatomyositis.
  • the secondary Raynaud phenomenon is also often associated with tissue necrosis of the fingers, ulcerations and gangrene.
  • vasodilators eg calcium channel blockers, cti-receptor blockers, nitro preparations and prostaglandin Often only cases and anecdotal reports on the different substances exist, with sometimes contradictory results.
  • the individual vasodilating principles show response rates of ' only about 50%.' Side effects are common Intravenous prostaglandins are not yet approved for the indication Raynaud and studies with various prostaglandin derivatives (iloprost, beraprost, cicaprost) have not been shown to confer clinical benefit on the calcium channel blockers and ⁇ i receptor blockers systemic hypotension show his illness.
  • cyclic guanosine monophosphate cGMP
  • NO nitric oxide
  • the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate
  • the particular features of the ligand and the nature of the ligands are divided into two groups: the particulate natriuretic peptides stimulable guanylate cyclases and the soluble NO-stimulable guanylate cyclases.
  • the soluble guanylate cyclases consist of two subunits and contain
  • NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme.
  • heme-free preparations can not be stimulated by NO.
  • CO is also capable of attacking the iron central atom of the heme, with stimulation by CO being significantly less than by NO.
  • the NO / cGMP system may be suppressed, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thrombosis, stroke , sexual dysfunction and mayocardial infarction.
  • a NO-independent treatment option for such diseases aimed at influencing the cGMP signaling pathway in organisms is a promising approach on account of the expected high efficiency and low side effects.
  • stimulators of soluble guanylate cyclase are particularly suitable for the therapy of microangiopathies.
  • the compounds according to the invention of formulas I to VI listed below have improved pharmacodynamic properties: they act vasodilating independently of the endogenously produced NO in the arterial end stream path even in the case of severe endothelial damage.
  • the stimulators of soluble guanylate cyclase enhance the effect of the endogenously produced NO.
  • Compound (I) corresponds to the following formula:
  • Connection (FVa) corresponds to the following formula: (IVa).
  • An additional embodiment of the present invention comprises the procedure for the prophylaxis and / or reduction of pulmonary hypertension 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.
  • pharmaceutical forms for inhalation include powder inhalers, nebulizers, nasal drops, solutions, sprays; tablets, wafers or capsules, suppositories paraben, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, powdered powders, implants or stents.
  • 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.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers for example, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and 7 odder odor correction for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbito
  • 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, according to the procedure, active substance between 0.1 and 99% active ingredient, suitably 25-95% for tablets and capsules and 1-50% for liquid formulations, i. the active substance should be present in sufficient quantities to reach the stated dose latitude.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de composés de formules (I-VI) pour produire un médicament destiné au traitement du phénomène de Raynaud primaire et secondaire.
EP06762392A 2005-07-16 2006-07-04 Utilisation d'activateurs de la guanylate cyclase soluble pour traiter les phenomenes de raynaud Withdrawn EP1917008A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102005033370 2005-07-16
DE102005047945A DE102005047945A1 (de) 2005-07-16 2005-10-06 Verwendung von Aktivatoren der löslichen Guanylatzyklase zur Behandlung von Raynaud Phänomenen
PCT/EP2006/006501 WO2007009589A2 (fr) 2005-07-16 2006-07-04 Utilisation d'activateurs de la guanylate cyclase soluble pour traiter les phenomenes de raynaud

Publications (1)

Publication Number Publication Date
EP1917008A2 true EP1917008A2 (fr) 2008-05-07

Family

ID=37563587

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06762392A Withdrawn EP1917008A2 (fr) 2005-07-16 2006-07-04 Utilisation d'activateurs de la guanylate cyclase soluble pour traiter les phenomenes de raynaud

Country Status (6)

Country Link
US (1) US20090215769A1 (fr)
EP (1) EP1917008A2 (fr)
JP (1) JP2009501737A (fr)
CA (1) CA2615051A1 (fr)
DE (1) DE102005047945A1 (fr)
WO (1) WO2007009589A2 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9260424B2 (en) * 2009-10-26 2016-02-16 Auspex Pharmaceuticals, Inc. 4,6-diaminopyrimidine stimulators of soluble guanylate cyclase
CA2800709C (fr) * 2010-05-26 2017-04-04 Claudia Hirth-Dietrich Utilisation de stimulateurs de la sgc, d'activateurs de la sgc, seuls et en association avec des inhibiteurs de la pde5 en vue du traitement de la sclerodermie systemique
DE102010021637A1 (de) 2010-05-26 2011-12-01 Bayer Schering Pharma Aktiengesellschaft Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung
EP2594270A3 (fr) * 2011-11-18 2013-07-31 BIP Patents Utilisation de stimulateurs de la sGC ou d'activateurs de la sGC, seuls et en combinaison avec des inhibiteurs de PDE5 pour le traitement de la sclérose systémique (Ssc)
EP3024455A1 (fr) 2013-07-25 2016-06-01 Bayer Pharma Aktiengesellschaft Stimulateurs de sgc ou activateurs de sgc et inhibiteurs de pde5 en combinaison avec un autre traitement pour la thérapie de la fibrose kystique
CN107580495A (zh) * 2015-05-06 2018-01-12 拜耳制药股份公司 单独和与PDE5抑制剂组合的sGC刺激剂、sGC活化剂用于治疗伴随系统性硬化症(SSc)的指溃疡(DU)的用途
WO2022032141A1 (fr) * 2020-08-07 2022-02-10 Eicos Sciences, Inc. Méthode de traitement de la sclérose systémique à phénomène de raynaud symptomatique par administration intraveineuse ou sous-cutanée d'iloprost

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69928260T2 (de) * 1998-07-08 2006-07-20 Sanofi-Aventis Deutschland Gmbh Schwefel-substituierte sulfonylaminocarbonsäure n-arylamide, ihre herstellung, ihre anwendung und diese enthaltende pharmazeutische zusammensetzungen
DE19834044A1 (de) * 1998-07-29 2000-02-03 Bayer Ag Neue substituierte Pyrazolderivate
GB9824310D0 (en) * 1998-11-05 1998-12-30 Univ London Activators of soluble guanylate cyclase
DE19943635A1 (de) * 1999-09-13 2001-03-15 Bayer Ag Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften
WO2001032604A1 (fr) * 1999-11-05 2001-05-10 University College London Activateurs de la guanylate cyclase soluble
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007009589A2 *

Also Published As

Publication number Publication date
CA2615051A1 (fr) 2007-01-25
JP2009501737A (ja) 2009-01-22
WO2007009589A2 (fr) 2007-01-25
WO2007009589A3 (fr) 2007-08-16
DE102005047945A1 (de) 2007-01-18
US20090215769A1 (en) 2009-08-27

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