WO1994001422A1 - Compositions pharmaceutiques inhibant l'agregation et favorisant la vasodilatation - Google Patents

Compositions pharmaceutiques inhibant l'agregation et favorisant la vasodilatation Download PDF

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Publication number
WO1994001422A1
WO1994001422A1 PCT/EP1993/001559 EP9301559W WO9401422A1 WO 1994001422 A1 WO1994001422 A1 WO 1994001422A1 EP 9301559 W EP9301559 W EP 9301559W WO 9401422 A1 WO9401422 A1 WO 9401422A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
compounds
alkyl
formula
antiaggregant
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
Application number
PCT/EP1993/001559
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English (en)
Inventor
Paolo Chiesi
Stefano Bongrani
Maurizio Civelli
Giancarlo Folco
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Chiesi Farmaceutici SpA
Original Assignee
Chiesi Farmaceutici SpA
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 Chiesi Farmaceutici SpA filed Critical Chiesi Farmaceutici SpA
Priority to AU44192/93A priority Critical patent/AU4419293A/en
Publication of WO1994001422A1 publication Critical patent/WO1994001422A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • 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

Definitions

  • the present invention refers to pharmaceutical compositions having antiaggregant and vasodilating ac ⁇ tivities, containing as the active principle one or more furoxan or furazan derivatives of formula I
  • R. is C.-C.-alkyl; C.-C.-alkoxy; phenyl; an S(O) R graffiti group wherein R_ is C,-C 4 alkyl or phenyl op- tionally substituted by C,-C.-alkyl, or by halogen atoms;
  • Compounds of formula I have been prepared and te ⁇ sted as antibacterial, antiprotozoal and antimycotic agents in Eur. J. Med. Chem. 12(2) 157-159, 1977 and in Eur. J. Med. Chem. 15(5) 485-487, 1980 in view of the fact that nitro and sulphonyl groups often impart anti- microbial properties to a molecule.
  • furoxan and furazan derivatives of formula I have a remarkable vasodilating activity and, therefore, they may be conveniently used as cardiovascular drugs, particularly as vasodilator, antihypertensive, antianginal, cerebral and coronary vasodilating and antithrombotic agents.
  • Preferred compounds I are those wherein R,, is C,-C 4 -alkyl, C,-C.-alkoxy, phenyl or phenylsulphonyl and, R is phenyl.
  • the value of m is preferably 1.
  • PRP PRP (pH 7.6) was prepared by centrifugation at room temperature for 18 min at 160 g. Platelet poor plasma was prepared by subsequent centrifugation at 2000 g. Aggregation studies in PRP were performed according to the light transmission method of Born in a dual channel aggregometer (Elvi 840, Elvi Logos, Milan, Italy).
  • the tested compound dissolved in dimethyl sulfo- xide (DMSO) or the vehicle alone was added to PRP 1 min. prior to addition of one of the following aggrega ⁇ ting agents: collagen, ADP and PAF.
  • DMSO dimethyl sulfo- xide
  • the employed concentration of the ag ⁇ gregating agent was corresponding to the minimal con- centration producing the maximal aggregating response in 5 minutes.
  • Such concentration was defined as “threshold ag ⁇ gregating concentration” .
  • the induced aggregation was irreversible and was characterized by at least the 70-80% decrease in opti ⁇ cal density.
  • Transverse rings were obtained from the descending thoracic aorta of male New-Zealand white rabbits. Four rings were joined together with surgical silk (2.0) to form a chain and placed in a 10 ml glass organ bath containing Krebs 1 Henseleit bicarbonate solution at 37°C, aerated with a mixture of 95% 0-/5% C0 2 . Basal tension (2 g) was applied, followed by an equilibration period of 1 hour and the changes in isometric contrac ⁇ tion were monitored with a force transducer (Basile, mod. 7004) connected to a "Gemini 7070" Basile pen re ⁇ corder.
  • Basal tension (2 g) was applied, followed by an equilibration period of 1 hour and the changes in isometric contrac ⁇ tion were monitored with a force transducer (Basile, mod. 7004) connected to a "Gemini 7070" Basile pen re ⁇ corder.
  • Acetylcholine (Ach,l ⁇ M) was tested during the contraction evoked by NE, the bath rinsed and approx. 15 min. later the tone was again increased with NE.
  • Glycerine trinitrate (NTG, 1.3 ⁇ M) was then added and left in contact with the aortic rings in order to allow full development of its vasodilation. After extensive rinsing of the preparations, a third NE-induced con ⁇ traction was evoked; different drugs under investiga ⁇ tion were then added in a cumulative fashion starting from 10 nM.
  • DMSO dimethyl sulfoxide
  • the composition (mM) of the Krebs 1 buffer was: NaCl 118.9, KC1 4.66, KH 2 P0 4 1.18, MgS0 4 1.1, CaCl 2 2.52, Glucosio 5.55, NaHC0 3 25 (Merck; Darmstadt, Ger ⁇ many); pH was 7.4.
  • the following drugs were used: acetylcholine HC1 (Sigma Chemical Company; St. Louis, Missouri, USA), glycerine trinitrate (Trinitrina (R ') ;
  • Drug solutions were prepared on the day of the ex ⁇ periment, stored on ice, and added to the tissue bath in a volume not exceeding 50 ⁇ l.
  • Norepinephrine and ascorbic acid were added to the Krebs' reservoir.
  • Acetylcholine was added tot the tissue bath in a volume of 25 ⁇ l, from a solution 0.4 mM.
  • Glycerine trinitrate was added to the tissue bath, in a volume of 50 ⁇ l, from a solution 60 ⁇ /ml, obtained grinding a pill of Trinitrina (R) in a potter containing 5 ml of distilla- ted water.
  • Results are expressed as the concentration required to inhibit by 50% the threshold aggre ⁇ gating concentration of various agents.
  • Furazans are endowed with a potency distinctly lower than that found for furoxans.
  • the class of phenyl-sulfonyl substituted furoxans did show a marked vasodilating efficacy.
  • the vasodila ⁇ ting effect of furazans and furoxans was tested in va ⁇ scular preparations in which the endothelium had been completely removed through rubbing of the intima and verified by complete suppression of acetylcholine indu ⁇ ced relaxation.
  • the vasodilating capacity of the fura ⁇ zans and furoxans was fully independent of endothelial integrity.
  • Relative potency potency ratio in comparison with glyceryl trinitrate (NTG)
  • the present invention also relates to pharmaceuti ⁇ cal compositions containing as the active principle the compounds of formula I or the salts thereof, in combi ⁇ nation with pharmaceutically acceptable excipients, for use in cardiovascular therapy as vasodilators, antihy- pertensive, antianginal, cerebral and coronary vasodi ⁇ lators, antiaggregants and antithrombotics.
  • the daily dosage of the active principle can vary from 1 to 1,000 mg, preferably it will range from 5 to 500 mg.
  • the administration will be carried out through any routes, preferable by the oral or parenteral routes.
  • the compounds can be formulated in solid or liquid formulations and they can be in form of capsules, tablets, sugar-coated pills, coated tablets, granules, powders, solutions, suspen ⁇ sions or emulsions.
  • the oral solid forms can contain conventional ex ⁇ cipients, inert diluents, disgregation agents, binders and lubricants such as lactose, saccharose, sorbitol, mannitol; potato, cereal or maize starches, or amylo- pectin; cellulose and derivatives, gelatin, talc, ma ⁇ gnesium or calcium stearate, polyvinylpyrrolidone, cal ⁇ cium phosphate, calcium carbonate, polyethylene glycol or silica.
  • ex ⁇ cipients such as lactose, saccharose, sorbitol, mannitol; potato, cereal or maize starches, or amylo- pectin
  • cellulose and derivatives gelatin, talc, ma ⁇ gnesium or calcium stearate, polyvinylpyrrolidone, cal ⁇ cium phosphate, calcium carbonate, polyethylene glycol or silica.
  • Hard gelatin cap ⁇ sules can contain granulates of the active principle, together with solid, powdered excipients, such as lac- tose, saccharose, sorbitol, mannitol, starches (of the above indicated types), cellulose derivatives, gelatin, and they can also contain stearic acid or magnesium stearate or talc.
  • Liquid formulations can be prepared by dissolving or dispersing the active principle in a pharmaceuti- cally acceptable aqueous or non-aqueous solvent, which can also contain suspending agents, sweeteners, fla ⁇ vours or preservatives.
  • the excipients can be a pharmaceutically acceptable sterile liquid such as water, saline solu ⁇ tion, dextrose or fructose solutions, alcohol solu ⁇ tions, polyvinylpyrrolidone aqueous solutions optio ⁇ nally containing a stabilizing agent and/or a buffer, or oily carriers.
  • the active principle can either be dissolved in the liquid and sterilized before being distributed in vials, or it can suitably be freeze-dried, in which case vials containing injection liquid will be added to the package, to prepare the solution before use.
  • transdermal systems consisting of adhesive matri ⁇ ces which can be applied to the skin, in which the ac ⁇ tive principle is incorporated in a suitable concentra- tion and from which it is gradually released to the skin, to enter the blood stream.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivés de furoxane et de furazane répondant à la formule (I), dans laquelle R1, R et m ont les notations précisées dans la description, et étant uilisables comme agents cardio-vasculaires.
PCT/EP1993/001559 1992-07-03 1993-06-18 Compositions pharmaceutiques inhibant l'agregation et favorisant la vasodilatation Ceased WO1994001422A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44192/93A AU4419293A (en) 1992-07-03 1993-06-18 Pharmaceutical compositions having antiaggregant and vasodilating activities

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI92A001629 1992-07-03
ITMI921629A IT1255207B (it) 1992-07-03 1992-07-03 Composizioni farmaceutuche ad attivita' antiaggregante e vasodilatatrice

Publications (1)

Publication Number Publication Date
WO1994001422A1 true WO1994001422A1 (fr) 1994-01-20

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PCT/EP1993/001559 Ceased WO1994001422A1 (fr) 1992-07-03 1993-06-18 Compositions pharmaceutiques inhibant l'agregation et favorisant la vasodilatation

Country Status (3)

Country Link
AU (1) AU4419293A (fr)
IT (1) IT1255207B (fr)
WO (1) WO1994001422A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5424326A (en) * 1992-06-20 1995-06-13 Cassella Aktiengesellschaft Phenyl-1,2,5-oxadiazolecarboxamide-2-oxides, their preparation and their use
EP0683159A1 (fr) * 1994-05-20 1995-11-22 Hoechst Aktiengesellschaft Furoxanes substitués
DE19624990A1 (de) * 1996-06-22 1998-01-08 Gluesenkamp Karl Heinz Dr Verfahren zur chemischen kontrollierten Modifizierung von Oberflächen sowie von Acyl- und/oder Hydroxyl-Gruppen tragenden Polymeren
WO2007016677A2 (fr) 2005-08-02 2007-02-08 Nitromed, Inc. Composes antimicrobiens promoteurs d'oxyde nitrique, compositions et procedes d'utilisation
WO2006138428A3 (fr) * 2005-06-15 2007-05-10 Hydra Biosciences Inc Modulateurs d'hypermotilite de sperme et utilisations de ceux-ci
US8067414B2 (en) 2006-03-29 2011-11-29 Nicox S.A. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
WO2016113802A1 (fr) * 2015-01-14 2016-07-21 国立大学法人神戸大学 Composé furoxane et son procédé de production

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0038438A2 (fr) * 1980-04-02 1981-10-28 CASSELLA Aktiengesellschaft Composants pharmaceutiques constitués de 1,2,5 oxadiazol-2-oxydes substitués pour utilisation comme médicaments et médicaments les contenant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0038438A2 (fr) * 1980-04-02 1981-10-28 CASSELLA Aktiengesellschaft Composants pharmaceutiques constitués de 1,2,5 oxadiazol-2-oxydes substitués pour utilisation comme médicaments et médicaments les contenant

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH vol. 42, no. 7, 1992, AULENDORF DE pages 921 - 925 A. M. GASCO ET. AL. 'Synthesis and Cardiovascular Properties of Furazanyl-1,4-dihydropyridines and of Furoxanyl Analogues.' *
BIOCHEMICAL PHARMACOLOGY vol. 43, no. 6, 17 March 1992, pages 1281 - 1288 A. GASCO ET. AL. 'Characterization of a New Class Compound, S35b, as a Guanylate Cyclase Activator in Human Platelets.' cited in the application *
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY.CHIMICA THERAPEUTICA vol. 12, no. 2, 1977, PARIS FR pages 157 - 159 CALVINO ET. AL. 'Furazan and Furoxan Sulfones: Synthesis and Antimicrobal activity.' cited in the application *
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY.CHIMICA THERAPEUTICA vol. 15, no. 5, 1980, PARIS FR pages 485 - 487 CALVINO ET. AL. 'Antimicrobial Properties of Some Furazan and Furoxan Derivatives.' cited in the application *
HETEROCYCLES vol. 24, no. 4, 1986, pages 889 - 892 T. SHIMIZU ET. AL. 'Reactions of Sulfonyl substituted Furoxans with Olefins.' *
IL FARMACO vol. 48, no. 2, May 1992, pages 321 - 334 R. CALVINO ET. AL 'Pharmacochemistry of the Furoxan Ring: Recent Developments. Presented at the 5th Meeting on Heterocyclic Structures in Medicinal Chemistry, Palermo May 17-20, 1992.' *
J. HETEROCYCLIC CHEMISTRY vol. 10, 1973, pages 587 - 590 A. GASCO ET. AL. 'Unsymmetrically Substituted Furoxans. III. Methylnitrofuroxan: Its Structure and Behaviour Toward Nucleophilic Substitution.' cited in the application *
J. HETEROCYCLIC CHEMISTRY vol. 14, 1977, pages 1415 - 1416 J. L. KELLEY ET. AL. 'Synthesis of Bis(Arylsulfonyl)furoxans from Aryl Nitromethyl Sulfones.' cited in the application *
J. HETEROCYCLIC CHEMISTRY vol. 19, 1982, pages 427 - 430 R. CALVINO, R. FRUTTERO, A. GASCO, V. MORTARINI 'Unsymmetrically Substituted Furoxans.' *
JOURNAL OF MEDICINAL CHEMISTRY. vol. 35, no. 17, 1992, WASHINGTON US pages 3296 - 3300 A. GASCO ET. AL. '4-Methyl-3-(arylsulfonyl)furoxans: A new Class of Potent Inhibitors of Platelet Aggregation.' cited in the application *
JOURNAL OF THE CHEMICAL SOCIETY March 1964, LETCHWORTH GB pages 904 - 906 W. V. FARRAR 'The 3,4-Bisarenesulphonylfuroxans.' cited in the application compounds of formula I *
JOURNAL OF THE CHEMICAL SOCIETY PERKIN TRANSACTIONS 2 1992, LETCHWORTH GB pages 1643 - 1646 R. CALVINO, A. GASCO, A. LEO 'An Analysis of the Lipophilicity of Furazan and Furoxan Derivatives Using the CLOGP Algorithm' *
SYNTHETIC COMMUNICATIONS vol. 1, no. 2, 1971, NEW YORK pages 121 - 124 J. B. F. N. ENGBERTS ET. AL. 'Reaction of Aliphatic Diazo Compounds with Dinitrogen Trioxide. A Facile Route to 3,4-Disubstituted 1,2,5-Oxadiazole-2-oxides (Furoxans).' cited in the application *
SYNTHETIC COMMUNICATIONS vol. 4, no. 5, 1974, NEW YORK pages 311 - 316 A. M. VAN LEUSEN ET. AL. 'Synthesis of C-Sulfonylcarbohydroximoyl Chlorides from .alpha.Diazosulfones and Nitrosyl Chloride.' cited in the application compounds of formula 5 *
TETRAHEDRON, (INCL. TETRAHEDRON REPORTS) vol. 41, no. 4, 1985, OXFORD GB pages 727 - 738 T. SHIMIZU ET. AL. 'Reaction of 3,4-Disubstituted 1,2,5-Oxadiazole-2-oxides with Dipolarophiles.' *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5424326A (en) * 1992-06-20 1995-06-13 Cassella Aktiengesellschaft Phenyl-1,2,5-oxadiazolecarboxamide-2-oxides, their preparation and their use
EP0683159A1 (fr) * 1994-05-20 1995-11-22 Hoechst Aktiengesellschaft Furoxanes substitués
DE19624990A1 (de) * 1996-06-22 1998-01-08 Gluesenkamp Karl Heinz Dr Verfahren zur chemischen kontrollierten Modifizierung von Oberflächen sowie von Acyl- und/oder Hydroxyl-Gruppen tragenden Polymeren
US8952041B2 (en) 2005-06-15 2015-02-10 Hydra Biosciences, Inc. Modulators of sperm hypermobility and uses thereof
WO2006138428A3 (fr) * 2005-06-15 2007-05-10 Hydra Biosciences Inc Modulateurs d'hypermotilite de sperme et utilisations de ceux-ci
US9732050B2 (en) 2005-06-15 2017-08-15 Hydra Biosciences, Inc. Modulators of sperm hypermotility and uses thereof
US8394840B2 (en) 2005-06-15 2013-03-12 Hydra Biosciences, Inc. Modulators of sperm hypermotility and uses thereof
WO2007016677A2 (fr) 2005-08-02 2007-02-08 Nitromed, Inc. Composes antimicrobiens promoteurs d'oxyde nitrique, compositions et procedes d'utilisation
WO2007016677A3 (fr) * 2005-08-02 2007-11-22 Nitromed Inc Composes antimicrobiens promoteurs d'oxyde nitrique, compositions et procedes d'utilisation
US8846674B2 (en) 2006-03-29 2014-09-30 Nicox, S.A. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
US8067414B2 (en) 2006-03-29 2011-11-29 Nicox S.A. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
WO2016113802A1 (fr) * 2015-01-14 2016-07-21 国立大学法人神戸大学 Composé furoxane et son procédé de production
CN107108533A (zh) * 2015-01-14 2017-08-29 国立大学法人神户大学 氧化呋咱化合物及其制造方法
JPWO2016113802A1 (ja) * 2015-01-14 2017-10-26 国立大学法人神戸大学 フロキサン化合物及びその製造方法
US10053435B2 (en) 2015-01-14 2018-08-21 National University Corporation Kobe University Furoxan compound, and manufacturing method for same
CN107108533B (zh) * 2015-01-14 2020-09-18 国立大学法人神户大学 氧化呋咱化合物及其制造方法

Also Published As

Publication number Publication date
ITMI921629A1 (it) 1994-01-03
AU4419293A (en) 1994-01-31
ITMI921629A0 (it) 1992-07-03
IT1255207B (it) 1995-10-20

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