Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems
• • 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
  • A61P9/08—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
  • A61P9/10—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 novel derivatives of isosorbide mononitrate which have a potent vasodilating activity and which, at the same time, have a significantly reduced tolerance.
• nitric acid esters of organic compounds common known as nitrated organic compounds, are known and have been used as vasodilating agents.
• nitrated organic compounds are known and have been used as vasodilating agents.
• the usefulness of mono and di-nitrated isosorbide is well known, and further there have been described compounds with vascular and coronary activities based on substitution reactions of the free hydroxyl group of isosorbide mononitrate.
• the U.S. Pat. No. 4,891,373 patent describes derivatives of aminepropanol corresponding to the formulas
• R 5 represents a hydrogen atom, a C 1 -C 6 alkyl group, a phenyl, etc.
• nitrated organic compounds described in the documents mentioned above do not in itself solve the problems originating from the tolerance of the nitrated organic compounds, since these still have problems in relation to low vasodilating activity, high tolerance, etc.. Accordingly, it is still necessary to develop novel nitrated organic compounds which have a high vasodilating activity combined with a more decreased level of tolerance being maintained persistently.
• An object of the invention is a novel type of compounds, derivatives of isosorbide mononitrate, which are capable of providing a potent vasodilating effect and which at the same time show a small or null tolerance effect.
• a further object of the present invention relates to the use of the novel derivatives of isosorbide mononitrate for the manufacture of a medicament for the treatment of disorders related to dysfunctions of the circulatory system, in particular at the level of the coronary system.
• Z is an oxygen atom or sulphur atom
• R is an alkyl C 1 -C 4 group, an aryl group or an aralkyl group, eventually substituted, or the group
• R 1 is hydrogen or an alkyl C 1 -C 4 group, an aryl group or an aralkyl group, eventually substituted.
• R is an alkyl C 1 -C 4 group, an aryl group or an aralkyl group, eventually substituted
• R 1 represents the groups indicated above.
• R when Z is a sulphur atom, R is a short chain C 1 -C 4 alkyl group, and when Z is an oxygen atom, R 1 is a hydrogen atom or a short chain C 1 -C 4 alkyl group. More preferably, within above mentioned criteria, B is the —ONO 2 group, i.e. the compounds wherein the nitrate ester is at position 5 in the ring-shaped system of the isosorbide.
• the compounds of the present invention can be obtained by techniques of esterification using known or accessible starting products described in the basic organic chemical literature known to the skilled person, for example the publications of Chemical Abstracts Service, the Beilstein Encyclopedia of organic products, or in any other appropriate publication available at university libraries.
• the compounds when Z is an oxygen atom the compounds may be obtained from isosorbide or the corresponding isosorbide mononitrate through a reaction of esterification of these with the corresponding carboxylic acid or an activated derivative of this, for example an acid chloride, an anhydride, an active ester, etc. If the starting product is isosorbide, it will be necessary finishing with a further step consisting of nitrating the free hydroxyl group of the isosorbide, a thing which is not necessary if there is started from any of the isosorbide mononitrates in position 5 or in position 2 of the ring-shaped structure of said compound.
• R 1 is hydrogen
• these compounds have a thiol group which can be unintentionally oxidized producing disulphur dimers.
• the dimers can be reverted to the corresponding monomers by reaction with triphenylphosphine in water, as described in R. Humphrey (1964), Analytical Chem,36,1812 y L. E. Overman (1974), Synthesis, 59.
• the compounds of the invention may very efficiently be used for the manufacture of a medicament with vasodilating effect for the treatment of dysfunctions of the circulatory system, in particular at the cardiovascular and coronary level.
• the compounds of the general formula (I), as well as their pharmaceutically acceptable salts may be used, via the use of conventional pharmaceutical techniques, in the manufacture of medicaments which may be administrated by different routes.
• compositions such as tablets, capsules, syrups and suspensions.
• parenterally in form of solutions or emulsions, etc. may also be administrated topically in form of creams, pomades, balsams, etc., and transdermically for example through the use of patches or bandages. They may also be applied directly in the rectum as suppositories.
• the preparations may comprise physiologically acceptable carriers, excipients, activators, chelating agents, stabilisators, etc. In case of injections there may be incorporated physiologically acceptable buffers, solubilizing agents or isotonics.
• the daily dose may be varied depending on the specific symptoms, the age, the body weight of the patients, the specific mode of administration, etc., and a daily normal dose for an adult person could be between 1 to 500 mg, and could be administrated as one dose only or divided into several doses during the day.
• Step 1 In a 50 mL glass flask, provided with a reflux refrigerator, closed with a CaCl 2 tube, and magnetic agitation, 4.25 g (23.2 mmol) 2-ethylthionicotinate acid are dissolved in 20 mL of thionyl chloride (1.64 g/ml; 275.6 mmol). The reaction mixture is refluxed for 3.5 h. After this period, the mixture is cooled down and excess thionyl chloride is eliminated under reduced pressure while adding portions of toluene. After drying at reduced pressure, 4.67 g of a solid yellowish product corresponding to the acid chloride of interest are obtained. Yield: 100%.
• Step 2 In a 50 ml glass flask, provided with magnetic agitation and reflux refrigerator, 4.67 g (23.2 mmol) of the acid chloride obtained in the step above are dissolved, under Ar atmosphere, in 25 ml pyridine. The solution is cooled down in a ice bath and 4.44 g (23.2 mmol) of isosorbide 5-mononitrate are added. The reaction mixture is agitated at room temperature under Ar atmosphere for 19 h. After this period the solvent is eliminated at reduced pressure. The residue is dissolved in 50 mL of CHCl 3 and washed: first with 50 mL of water, secondly with 50 mL aqueous solution of 5% HCl and once more with 50 mL water. The organic phase is dried over anhydrous MgSO 4 , filtered, and the solvent is eliminated at reduced pressure. After drying at reduced pressure, 7.25 g of the product of interest are obtained. Yield: 88%.
• Step 3 In a 250 ml three neck glass flask, provided with a reflux refrigerator closed with a CaCl 2 tube, magnetic agitation, and an addition funnel with a compensated pressure, 6.0 g (16.85 mmol) of the product obtained in the previous step are dissolved in 150 mL of EtOEt. The solution is agitated at room temperature and added, drop by drop, 30 mL of EtOEt solution saturated with HCl (solution prior prepared bubbling HCl gas directly into the EtOEt until saturation), producing a white solid precipitate. The solid is filtered and washed with an excess of EtOEt and dried at reduced pressure. 6.55 g of the product of interest are obtained. Yield: 99%.
• Step 1 The same method as in step 2 of example 1 is used, applying as starting product the isosorbide 2-mononitrate.
• the product of interest is obtained at a chemical yield of 88%.
• Step 2 In a 500 ml three neck glass flask provided with a reflux refrigerator closed with a CaCl 2 tube, magnetic agitation, and a addition funnel with a compensated pressure, 7.0 g (19.66 mmol) of the product obtained in the former step are dissolved in a mixture of 200 mL of EtOEt+100 mL de CH 2 Cl 2 . The solution is agitated at room temperature and added, drop by drop, 30 mL of EtOEt solution saturated with HCl (solution prior prepared bubbling HCl gas directly into the EtOEt until saturatio), producing a white solid precipitate. The solid is filtered and washed with an excess of EtOEt and dried at reduced pressure. 7.05 g of the product of interest are obtained. Yield: 91%.
• Step 1 In a 100 mL glass flask, provided with a reflux refrigerator closed with a CaCl 2 tube and magnetic agitation, 3.0 g (19.35 mmol) of 2-mercaptonicotinic acid are suspended in 30 mL of thionyl chloride (1.64 g/ml; 431.4 mmol). The mixture is left to reflux for 2 h, observing the dissolution of the solid during this period. The mixture is cooled down and excess thionyl chloride is eliminated under reduced pressure while adding portions of toluene. After drying at reduced pressure, 3.35 g of a solid yellow-orange corresponding to the acid chloride of interest are obtained. Yield, 100%.
• Step 2 In a 250 mL glass flask, provided with a reflux refrigerator and magnetic agitation, 3.0 g (17.29 mmol) of the acid chloride obtained in the former step are suspended, under Ar atmosphere, in 75 mL of pyridine. The suspension is cooled down in an ice bath and 3.30 g (17.29 mmol) of isosorbide 5-mononitrate are added. The reaction mixture is left agitating at room temperature under Ar atmosphere for 19 h, a period of time wherein the mixture is getting dark. Once the reaction finished, the solvent is eliminated at reduced pressure.
• the residue is dissolved in 250 mL of CHCl 3 and washed: first with 250 mL of water, secondly with 250 mL aqueous solution of 5% HCl and once more with 250 mL water.
• the organic phase is dried over anhydrous MgSO 4 , filtered, and the solvent is eliminated at reduced pressure. After drying at reduced pressure, 5.45 g of a yellow solid are obtained, which are recrystallized in isopropanol to obtain 4.83 g of a white solid which is reacted in acid medium for 20 min. with triphenylphosphine (1:1.25 mol/mol) in methanol, with a 10% of water.
• the solvent is eliminated at reduced presureand the residue is disolved in AcOEt, washing the solution with some water.
• the organic phase is dried and the solvent is eliminated at reduced presure, recovering the product of interest by preparative chromatography. Yield: 35.7%.
• the residue is dissolved in 300 mL of CHCl 3 and washed: first with 300 mL of water, secondly with 300 mL aqueous solution of 5% HCl and once more with 300 mL water.
• the organic phase is dried over anhydrous MgSO 4 , filtered, and the solvent is eliminated at reduced pressure. After drying at reduced temperature, 5.10 g of a white-yellowish solid are obtained, which are re-crystallized in isopropanol to obtain 4.55 g of a white solid which is reacted in acid medium for 20 min. with triphenylphosphine (1:1.25 mol/mol) in methanol, with a 10% of water.
• the solvent is eliminated at reduced presure and the residue is disolved in AcOEt, washing the solution with some water.
• the organic phase is dried and the solvent is eliminated at reduced presure, recovering the product of interest by preparative chromatography. Yield: 37.6%.
• Step 1 In a 1 L glass flask provided with a reflux refrigerator, an addition funnel with a compensated pressure, and magnetic agitation, 60 g (411 mmol) of isomanide, 88 g (461 mmol) of paratoluenesulfonyl chlorine, 296 mL of CCl 4 , 33 mL of CH 2 Cl 2 and 247 mL of H 2 O are mixed. An Ar atmosphere is made and a solution of 29.9 g (453 mmol) of 85% KOH is added, drop by drop, while maintaining the reaction temperature at 5° C. The period of time of the addition is 1 h 20 min. The resulting mixture is agitated at 50 C for 7 h. The solid is filtered and with 2 ⁇ 125 mL portions of H 2 O and dried at reduced pressure.
• the obtained solid is re-crystallized in 1200 mL of CCl 4 , hot filtered and the filtrate is left to cool down.
• the obtained crystals are filtered and washed yielding 54.5 g of a fraction A of the product of interest, monotosilate of isomanide.
• Step 2 In a 500 mL glass flask provided with a reflux refrigerator and magnetic agitation, 22.7 g (76 mmol) of monotosilate of isomanide and 13.0 g (113 mmol) of potassium thioacetate are mixed in 113 mL of n-butanol. An Ar atmosphere is made and the reaction mixture is let to reflux for 1 h. The mixture is cooled down, filtered and washed with 200 mL ethanol and the solvents are eliminated at reduced pressure. 20 g of a solid are obtained.
• a thin layer chromatographic analysis with independent sample shows that the product of interest is not a major part of the crude.
• Step 3 A nitrating mixture is prepared by addiing, slowly and carefully, 2.4 ml of 60% HNO 3 into a mixture of 10 mL of acetic anhydride and 10 mL of acetic acid. The mixture is prepared at 0° C.
• the two compounds tested have a potent vasodilating activity, at least similar to that of the reference, and the compound 1 has a vasodilating activity superior to that of the reference product.
• the different compounds rested are subcutaneously administrated to rats at a dose of 10 mg/Kg for three days, each eight hours, and the assay is then done ex vivo to test the capacity to vasodilate the arterial segments of the rats after the subcutaneous administration of the compound.
• the different compounds are tested at 5 different concentrations, at a concentration range from 0.001 to 10 mM, using from 6 to 9 arterial rings for each compound.
• the obtained results are compared to those from the isosorbide 5-mononitrate, which is used as reference product, and with those obtained from the animals wherein there have not been administrated any compound.
• CE 50 of isosorbide 5-mononitrate in the group of animals wherein said compound was administrated was seven times superior as compared to that of the not treated animals.

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• 1998
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