WO1994001422A1 - Pharmaceutical compositions having antiaggregant and vasodilating activities - Google Patents
Pharmaceutical compositions having antiaggregant and vasodilating activities Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- compounds
- alkyl
- formula
- antiaggregant
- Prior art date
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Classifications
-
- 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.
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- 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)
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 (en) | 1994-01-20 |
Family
ID=11363616
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1993/001559 WO1994001422A1 (en) | 1992-07-03 | 1993-06-18 | Pharmaceutical compositions having antiaggregant and vasodilating activities |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU4419293A (it) |
IT (1) | IT1255207B (it) |
WO (1) | WO1994001422A1 (it) |
Cited By (7)
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 (de) * | 1994-05-20 | 1995-11-22 | Hoechst Aktiengesellschaft | Substituierte Furoxane |
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 |
WO2006138428A2 (en) * | 2005-06-15 | 2006-12-28 | Hydra Biosciences, Inc. | Modulators of sperm hypermotility and uses thereof |
WO2007016677A2 (en) | 2005-08-02 | 2007-02-08 | Nitromed, Inc. | Nitric oxide enhancing antimicrobial 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 (ja) * | 2015-01-14 | 2016-07-21 | 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 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0038438A2 (de) * | 1980-04-02 | 1981-10-28 | CASSELLA Aktiengesellschaft | Substituierte 1,2,5-Oxadiazol-2-oxide zur Anwendung als Arzneimittel und sie enthaltende Arzneimittel |
-
1992
- 1992-07-03 IT ITMI921629A patent/IT1255207B/it active IP Right Grant
-
1993
- 1993-06-18 AU AU44192/93A patent/AU4419293A/en not_active Abandoned
- 1993-06-18 WO PCT/EP1993/001559 patent/WO1994001422A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0038438A2 (de) * | 1980-04-02 | 1981-10-28 | CASSELLA Aktiengesellschaft | Substituierte 1,2,5-Oxadiazol-2-oxide zur Anwendung als Arzneimittel und sie enthaltende Arzneimittel |
Non-Patent Citations (15)
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 (17)
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 (de) * | 1994-05-20 | 1995-11-22 | Hoechst Aktiengesellschaft | Substituierte Furoxane |
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 |
US9732050B2 (en) | 2005-06-15 | 2017-08-15 | Hydra Biosciences, Inc. | Modulators of sperm hypermotility and uses thereof |
US8952041B2 (en) | 2005-06-15 | 2015-02-10 | Hydra Biosciences, Inc. | Modulators of sperm hypermobility and uses thereof |
WO2006138428A3 (en) * | 2005-06-15 | 2007-05-10 | 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 |
WO2006138428A2 (en) * | 2005-06-15 | 2006-12-28 | Hydra Biosciences, Inc. | Modulators of sperm hypermotility and uses thereof |
WO2007016677A3 (en) * | 2005-08-02 | 2007-11-22 | Nitromed Inc | Nitric oxide enhancing antimicrobial compounds, compositions and methods of use |
WO2007016677A2 (en) | 2005-08-02 | 2007-02-08 | Nitromed, Inc. | Nitric oxide enhancing antimicrobial 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 |
US8846674B2 (en) | 2006-03-29 | 2014-09-30 | Nicox, S.A. | Nitric oxide enhancing prostaglandin compounds, compositions and methods of use |
WO2016113802A1 (ja) * | 2015-01-14 | 2016-07-21 | 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 |
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 |
---|---|
ITMI921629A0 (it) | 1992-07-03 |
ITMI921629A1 (it) | 1994-01-03 |
IT1255207B (it) | 1995-10-20 |
AU4419293A (en) | 1994-01-31 |
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