US20040147598A1 - Nitric oxide donors and pharmaceutical compositions containing them - Google Patents

Nitric oxide donors and pharmaceutical compositions containing them Download PDF

Info

Publication number
US20040147598A1
US20040147598A1 US10/698,944 US69894403A US2004147598A1 US 20040147598 A1 US20040147598 A1 US 20040147598A1 US 69894403 A US69894403 A US 69894403A US 2004147598 A1 US2004147598 A1 US 2004147598A1
Authority
US
United States
Prior art keywords
group
compound
ring
sulfhydryl
ono
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.)
Abandoned
Application number
US10/698,944
Inventor
Abdullah Haj-Yehia
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.)
Yissum Research Development Co of Hebrew University of Jerusalem
Original Assignee
Yissum Research Development Co of Hebrew University of Jerusalem
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 Yissum Research Development Co of Hebrew University of Jerusalem filed Critical Yissum Research Development Co of Hebrew University of Jerusalem
Priority to US10/698,944 priority Critical patent/US20040147598A1/en
Assigned to YISSUM RESEARCH DEVELOPMENT COMPANY reassignment YISSUM RESEARCH DEVELOPMENT COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HAJ-YEHIA, ABDULLAH
Publication of US20040147598A1 publication Critical patent/US20040147598A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/19—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to nitric oxide donors containing at least one sulfhydryl group or a group capable of being converted in-vivo to a sulfhydryl group, and at least one nitric oxide donor group.
  • the novel compounds are effective substitutes for existing tolerance-inducing organic or inorganic nitric oxide donors.
  • GTN nitric oxide
  • GC guanylyl cyclase
  • GTN may directly interact with SH-group/s located on its target enzyme (GC) resulting in its S-nitrosylation and activation.
  • GC target enzyme
  • subsequent auto-oxidation (disulfide formation) of these SH-groups renders the enzyme inert towards further reaction with GTN, resulting in tolerance development.
  • Cysteine was found to be the specific sulfhydryl required for activation of soluble coronary arterial GC and to be the only one of several sulfhydryls to react non-enzymatically with GTN at physiologic pH resulting in formation of S-nitrosocysteine. Since S-nitrosothiols were shown to be potent activators of GC, S-nitrosocysteine/thiols were proposed as the intracellular mediators of organic nitrate-induced vasorelaxation. Additionally, N-acetylcysteine (NAC, an immediate donor of Cys thereby increasing GSH) was reported to potentiate GTN activity in vitro and in vivo.
  • Heart disease is the leading cause of death in Western society and is rapidly approaching this leading position worldwide.
  • Ischemic heart disease is the most common heart disease.
  • nitroglycerin and other organic nitrates have been used for the treatment of various types of myocardial ischemia, including acute myocardial infarction (AMI) and as adjuncts in the treatment of other heart diseases (congestive heart failure and resistant hypertension).
  • AMD acute myocardial infarction
  • Chronic prophylaxis and acute treatment are necessary to prevent complications of ischemic heart disease with potential fatal outcomes (25% death for AMI.
  • Tolerance to the anti-ischemic effect of these drugs is, by far, the most serious drawback of therapy with currently available organic nitrates.
  • the compounds proposed in this application constitute a novel approach to overcome tolerance.
  • the present invention provides a compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO 2 group.
  • the protected sulfhydryl group is an acetylated sulfhydryl group.
  • the compound is:
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising i) as an active ingredient at least one compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO 2 group; and ii) a pharmaceutically acceptable carrier.
  • the protected sulfhydryl group is an acetylated sulfhydryl group.
  • the active ingredient is:
  • the present invention provides a compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO 2 group.
  • the present invention further provides pharmaceutical compositions comprising one or more of said compounds as an active ingredient.
  • the protected sulfhydryl group is an acetylated sulfhydryl group.
  • the compound is:
  • the compounds are in vivo nitric oxide donors and they contain at least one sulfhydryl group.
  • a sulfhydryl group is either present in the reduced SH form, or is a group capable of being converted in-vivo to a sulfhydryl group.
  • the compounds contain a sulfhydryl group in the reduced —SH form.
  • the compounds contain a group capable of being converted in-vivo to a sulfhydryl group.
  • Suitable groups which are capable of being converted in-vivo to a sulfhydryl group are illustrated in the following embodiments:
  • the sulfhydryl group is in the oxidized —S—S disulfide form.
  • the sulfhydryl is present in a separately protected form (acetyl, carbamyl or other).
  • the sulfhydryl is present as an atom in a heterocyclic compound. In cases where the compound contains two sulfhydryl groups, these can exist in the reduced (SH) or the oxidized (disulfide) form or in a protected form.
  • each one of the compounds can also be regarded as a parent pro-drug which is assumed to undergo metabolic reduction or cleavage to provide the free SH groups in-vivo.
  • the present invention further provides a compound containing at least one nitric oxide (NO) donor group, and at least one sulfhydryl group as defined herein.
  • the compound is a compound containing one or more sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO 2 group.
  • the compound is a 5-membered ring heterocyclic compound containing a sulfur atom and a nitrogen atom, which ring is substituted by one or more substituents bearing a terminal —ONO 2 group.
  • the compound is a 5-membered ring compound containing two conjugate S-atoms, which ring is linked to one or more substituents bearing a terminal NO 2 group.
  • the compound is a compound containing an acyclic —S—S group, linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO 2 group.
  • the compound is a 6-membered ring compound containing two conjugate S-atoms which is substituted by one or more —ONO 2 groups or linked to one or more substituents bearing a terminal —ONO 2 group.
  • the compound is a 6-membered ring compound containing 2 conjugate S-atoms which is substituted by one or more —ONO 2 groups or linked to one or more substituents bearing a terminal —ONO 2 group, wherein said 6-membered ring is conjugated to at least one carbocyclic aromatic nucleus or at least one pyridine nucleus.
  • the compound is a compound having an S—S group in an open configuration linked to one or more —ONO 2 groups or linked to one or more substituents bearing a terminal —ONO 2 group.
  • the compound is:
  • the compound is:
  • the term “acid” should also be understood to include the corresponding acid halide, salts with pharmacologically acceptable alkali metal (including alkaline earth metal and ammonium bases), esters and amides.
  • the alcohol or the amines used to form the corresponding ester and amides of the acid can also bear a nitrate ester.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising i) as an active ingredient at least one compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO 2 group; and ii) a pharmaceutically acceptable carrier.
  • the protected sulfhydryl group is an acetylated sulfhydryl group.
  • the active ingredient is:
  • the present invention further provides a pharmaceutical composition for the treatment of disorders where nitric oxide donors are indicated, comprising a) as an active ingredient at least one compound containing at least one nitric oxide donor group, and at least one sulfhydryl group as defined herein; and b) a pharmaceutically acceptable carrier.
  • the active ingredient is a compound containing one or more sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO 2 group.
  • the active ingredient is a 5-membered ring heterocyclic compound containing a sulfur atom and a nitrogen atom, which ring is substituted by one or more substituents bearing a terminal —ONO 2 group.
  • the active ingredient is a 5-membered ring compound containing two conjugate S-atoms, which ring is linked to one or more substituents bearing a terminal —ONO 2 group.
  • the active ingredient is a compound containing an acyclic —S—S group, linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO 2 group.
  • the active ingredient is a 6-membered ring compound containing two conjugate S-atoms which is substituted by one or more —ONO 2 groups or linked to one or more substituents bearing a terminal —ONO 2 group.
  • the active ingredient is a 6-membered ring compound containing 2 conjugate S-atoms which is substituted by one or more —ONO 2 groups or linked to one or more substituents bearing a terminal —ON 2 group, wherein said 6-membered ring is conjugated to at least one carbocyclic aromatic nucleus or at least one pyridine nucleus.
  • the active ingredient is a compound having an S—S group in an open configuration linked to one or more —ONO 2 groups or linked to one or more substituents bearing a terminal —ONO 2 group.
  • the active ingredient is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl)-2-aminoethyl
  • the active ingredient is:
  • Atherosclerosis include (but are not limited to): atherosclerosis, pulmonary and systemic hypertension, asthma and other related respiratory diseases, trauma, shock, neurotoxicity, neurodegenerative and neurologic disorders, including those involving learning, memory, olfaction and nociception, Huntington, Alzheimer and Parkinson's diseases, multiple sclerosis and convulsive (seizure) disorders, AIDS-related disorders (i.e.
  • dementia disorders of gastric acid and other secretory and peristaltic functions of the alimentary system, drug and disease-induced neuropathy and nephropathy, pathological and premature uterine contractions, cellular defense impairment, and insulin-resistance in glucose intolerance and diabetes mellitus, pregnancy-induced hypertension, chemotaxis and phagocytic impairment in immunological disorders, cerebrovascular diseases, aggregation disorders, penile erection and treatment of male impotence.
  • the novel compounds are mixed in the usual way with appropriate pharmaceutical carrier substances, aroma, flavoring and coloring materials and formed, for example, into tablets or dragees of immediate or sustained release or, with additions of appropriate adjuvants, for example water or an oil such as olive or other oil, are suspended or dispersed or dissolved.
  • the compounds or the pharmaceutical composition thereof can be administered orally (including the sublingual and buccal routes) or via an injectable form (including the subcutaneous, intramuscular, intraperitoneal and the parenteral routes).
  • injectable form including the subcutaneous, intramuscular, intraperitoneal and the parenteral routes.
  • Other routes of administration such as aerosols and dermal preparations are also to be considered.
  • injection medium water is preferably used which contains the stabilizing agents, solubilizing agents and/or buffers usually utilized in the preparation of solutions for injection.
  • Such additives include, for example, tartarate and borate buffers, ethanol, ethylene and propylene glycols, glycerol, dimethyl sulphoxide, complex formers (i.e., ethylenediamine tetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation and polyethylene derivatives of sorbit anhydrides.
  • Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acid, high molecular weight polymers (i.e., polyethylene glycol).
  • Compositions suitable for oral administration can, if necessary, contain flavoring and sweetening agents.
  • the compound was easily synthesized utilizing the commercially available precursor trans-1,2-dihydroxy-4,5-dithiane.
  • 0.5 g of the precursor was added portionwise to chilled ( ⁇ 5° C.) 1:1 mixture of fuming nitric sulfuric acids.
  • the ice/salt bath was removed and the mixture brought to room temperature.
  • This mixture was added dropwise to a cooled mite of dry diethyl ether:acetonitrile:water (70:20:10) with vigorous stirring.
  • the lower aqueous phase was separated and extracted twice with diethyl ether.
  • the combined organic extracts were washed twice with water and once with cold 1% sodium carbonate solution.
  • the compound was synthesized in a similar fashion to compound 1 above using the commercially available precursor 2,2′-dithiodiethanol as the starting material.
  • the precursor was nitrated and separated as above yielding the tide compound 2,2′-dithiodiethanol-dinitrate.
  • This compound was synthesized by bishydroxymethylation of diethyl malonate followed by thiolation of the hydroxyl groups (via the halide intermediate).
  • the resulting 1,1-dicarboxy-3,4-dithiane was reduced by borane (catechol borane solution) to the corresponding 1,1-diemethanol-3,4-dithiane.
  • Direct nitration of this latter intermediate yielded the title compound 1,1-diemethanol dinitrate-3,4-dithiane.
  • This compound was synthesized by thiolation of the dichloride intermediate of the commercially available 1,1′-bishydroxymethyl-3-cyclohexene. Oxidation of the double bond either by hydrogen peroxide/asmium tetroxide to generate the cis-diol or by a peracid/formic acid mixture to generate the trans-diol followed by nitration of the diol will generate the corresponding (cis or trans) form of the title compound.
  • This compound was synthesized in a high yield process utilizing thioctic acid as the precursor. Following reduction of the acid (or its methyl or ethyl ester) by catechol borane solution, the resulting thioctyl alcohol was separated and mitrated as described above to yield the title compound.
  • vasorelaxant activities (measured as the ability of the tested drug to induce an increase in vascular cGMP) of the example compounds 1 to 6 were determined and compared to activity of nitroglycerin under the same experimental conditions following single and sustained exposure of rats to the compound.
  • the compound to be tested was administered, in each case, to 8 male Sprague-Dawley rats (300-400 g) before and after an 18 hr continuous intravenous infusion of the compound.
  • the 18 hr continuous infusion period was determined based on existing data demonstrating the development of tolerance to the drug effect in the case of nitroglycerin.
  • the existence of tolerance to the drug is demonstrated by the inability of the drug to attain 50% or more of the cGMP values measured in the vascular tissue after dosing of the drug to preciously treated animals as compared to controls (non-treated or vehicle-treated animals).
  • drug administration i.v.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

The present invention provides a compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO2 group. The present invention further provides pharmaceutical compositions comprising one or more of said compounds as an active ingredient.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a Continuation Application of U.S. application Ser. No. 10/041,680, filed Jan. 9, 2002, which is a Continuation Application of U.S. application Ser. No. 09/381,303, filed Dec. 30, 1999, which claims priority of PCT International Application No. PCT/IL98/00144, International Filing Date Mar. 26, 1998, which claims priority of Application IL 120,531, filed Mar. 26, 1997, which is hereby incorporated by reference[0001]
    • FIELD OF THE INVENTION
  • The present invention relates to nitric oxide donors containing at least one sulfhydryl group or a group capable of being converted in-vivo to a sulfhydryl group, and at least one nitric oxide donor group. The novel compounds are effective substitutes for existing tolerance-inducing organic or inorganic nitric oxide donors. [0002]
    • BACKGROUND OF THE INVENTION
  • For over a century, the nitric oxide (NO) donor nitroglycerin (GTN) has been the mainstay in the treatment of angina and related heart diseases. However, the existing mechanisms proposing the mediation of GTN action by free NO, intracellular or extracellular S-nitrosothiol formation and subsequent activation of guanylyl cyclase (GC), as well as those describing GTN tolerance, have become increasingly controversial. The phenomenon of tolerance to GTN, however, is of special clinical importance. In fact, early tolerance to the anti-anginal effects of the drug is the major drawback of nitrate therapy, especially during acute myocardial infarction. This is particularly important since alternative non-tolerance inducing agents have not yet been developed to successfully replace therapy with GTN. [0003]
  • Based on accumulating evidence, Applicant hypothesized that GTN may directly interact with SH-group/s located on its target enzyme (GC) resulting in its S-nitrosylation and activation. However, subsequent auto-oxidation (disulfide formation) of these SH-groups renders the enzyme inert towards further reaction with GTN, resulting in tolerance development. [0004]
  • Additionally, evidence has recently been provided to support an involvement of the superoxide anion in the mechanism/s underlying GTN tolerance and cross-tolerance. According to these reports, increased production of superoxide anion was found to accompany tolerance development to GTN in vascular tissue. Treatment with superoxide dismutase (SOD) significantly enhanced relaxation of control and tolerant vascular tissue to GIN and other exogenous and endogenous vasodilators. [0005]
  • While the precise mechanism for the vasorelaxant effect of GTN is unknown, a consensus exists regarding the primary involvement of cGMP in mediating the nitrate-induced relaxation. However, the roles of sulfhydryl groups [reduced glutathione (GSH) and cysteine (Cys)] and of various enzymes in the bioconversion of GIN and subsequent activation of guanylyl cyclase (GC) leading to relaxation have become increasingly controversial. Cysteine was found to be the specific sulfhydryl required for activation of soluble coronary arterial GC and to be the only one of several sulfhydryls to react non-enzymatically with GTN at physiologic pH resulting in formation of S-nitrosocysteine. Since S-nitrosothiols were shown to be potent activators of GC, S-nitrosocysteine/thiols were proposed as the intracellular mediators of organic nitrate-induced vasorelaxation. Additionally, N-acetylcysteine (NAC, an immediate donor of Cys thereby increasing GSH) was reported to potentiate GTN activity in vitro and in vivo. The enhanced reaction of thiols with GTN in plasma and blood versus buffer suggested that activation of GC by GTN may be mediated via extracellular formation of S-nitrosothiol/s. In either case (intra- or extracellular S-nitrosothiol formation), this association between sulfhydryls and GIN activity has long been recognized as evidence for the “thiol depletion hypothesis”. However, recent studies by the Applicant and those of Boesgard et al. revealed a dissociation between tissue thiol content (measured as Cys and GSH) and nitrate tolerance in vivo. [0006]
  • In vitro inhibitory studies provide indirect support for the involvement of enzymes in GTN bioactivation [glutathione 5-transferase (GST) and cytochrome P450 (P450)]. However, in view of several other reports suggesting the lack of any significant role of GST and P-450 in GTN bioactivation, the reduced bioactivation of GTN is unlikely to be the main factor underlying nitrate tolerance in vivo. In fact, reduced cGMP production was also shown to follow exposure of vascular preparation to direct NO-donors, for which no definitive metabolic pathway has been reported. [0007]
  • Furthermore, Applicant has recently presented in vivo evidence excluding the involvement of any particular metabolic pathway since reduced cGMP was also shown to follow treatment with S-alkylating agents in the absence of GTN. [0008]
  • Heart disease is the leading cause of death in Western society and is rapidly approaching this leading position worldwide. Ischemic heart disease is the most common heart disease. For over a century, nitroglycerin and other organic nitrates have been used for the treatment of various types of myocardial ischemia, including acute myocardial infarction (AMI) and as adjuncts in the treatment of other heart diseases (congestive heart failure and resistant hypertension). Chronic prophylaxis and acute treatment are necessary to prevent complications of ischemic heart disease with potential fatal outcomes (25% death for AMI. Tolerance to the anti-ischemic effect of these drugs is, by far, the most serious drawback of therapy with currently available organic nitrates. The compounds proposed in this application constitute a novel approach to overcome tolerance. [0009]
    • SUMMARY OF THE INVENTION
  • The present invention provides a compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO[0010] 2 group.
  • In one embodiment, the protected sulfhydryl group is an acetylated sulfhydryl group. [0011]
  • In one embodiment, the compound is: [0012]
    Figure US20040147598A1-20040729-C00001
  • The present invention further provides a pharmaceutical composition comprising i) as an active ingredient at least one compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO[0013] 2 group; and ii) a pharmaceutically acceptable carrier.
  • In one embodiment, the protected sulfhydryl group is an acetylated sulfhydryl group. [0014]
  • In one embodiment, the active ingredient is: [0015]
    Figure US20040147598A1-20040729-C00002
    • DETAILED DESCRIPTION OF THE PRESENT INVENTION
  • The present invention provides a compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO[0016] 2 group. The present invention further provides pharmaceutical compositions comprising one or more of said compounds as an active ingredient.
  • In one embodiment, the protected sulfhydryl group is an acetylated sulfhydryl group. [0017]
  • In one embodiment, the compound is: [0018]
    Figure US20040147598A1-20040729-C00003
  • The compounds are in vivo nitric oxide donors and they contain at least one sulfhydryl group. As defined herein, a sulfhydryl group is either present in the reduced SH form, or is a group capable of being converted in-vivo to a sulfhydryl group. In one embodiment, the compounds contain a sulfhydryl group in the reduced —SH form. In another embodiment, the compounds contain a group capable of being converted in-vivo to a sulfhydryl group. Suitable groups which are capable of being converted in-vivo to a sulfhydryl group are illustrated in the following embodiments: In one embodiment, the sulfhydryl group is in the oxidized —S—S disulfide form. In another embodiment, the sulfhydryl is present in a separately protected form (acetyl, carbamyl or other). In another embodiment, the sulfhydryl is present as an atom in a heterocyclic compound. In cases where the compound contains two sulfhydryl groups, these can exist in the reduced (SH) or the oxidized (disulfide) form or in a protected form. However, each one of the compounds can also be regarded as a parent pro-drug which is assumed to undergo metabolic reduction or cleavage to provide the free SH groups in-vivo. [0019]
  • The present invention further provides a compound containing at least one nitric oxide (NO) donor group, and at least one sulfhydryl group as defined herein. In one embodiment, the compound is a compound containing one or more sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO[0020] 2 group. In another embodiment, the compound is a 5-membered ring heterocyclic compound containing a sulfur atom and a nitrogen atom, which ring is substituted by one or more substituents bearing a terminal —ONO2 group. In another embodiment, the compound is a 5-membered ring compound containing two conjugate S-atoms, which ring is linked to one or more substituents bearing a terminal NO2 group. In another embodiment the compound is a compound containing an acyclic —S—S group, linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO2 group. In another embodiment, the compound is a 6-membered ring compound containing two conjugate S-atoms which is substituted by one or more —ONO2 groups or linked to one or more substituents bearing a terminal —ONO2 group. In another embodiment the compound is a 6-membered ring compound containing 2 conjugate S-atoms which is substituted by one or more —ONO2 groups or linked to one or more substituents bearing a terminal —ONO2 group, wherein said 6-membered ring is conjugated to at least one carbocyclic aromatic nucleus or at least one pyridine nucleus. In another embodiment, the compound is a compound having an S—S group in an open configuration linked to one or more —ONO2 groups or linked to one or more substituents bearing a terminal —ONO2 group.
  • In one embodiment, the compound is: [0021]
    Figure US20040147598A1-20040729-C00004
    Figure US20040147598A1-20040729-C00005
  • In another embodiment, the compound is: [0022]
    Figure US20040147598A1-20040729-C00006
    Figure US20040147598A1-20040729-C00007
    Figure US20040147598A1-20040729-C00008
    Figure US20040147598A1-20040729-C00009
  • All of the above compounds are such that they will undergo in vivo metabolic cleavage to provide free —SH groups. [0023]
  • According to this invention, whenever a compound exists in the acid form, the term “acid” should also be understood to include the corresponding acid halide, salts with pharmacologically acceptable alkali metal (including alkaline earth metal and ammonium bases), esters and amides. Moreover, the alcohol or the amines used to form the corresponding ester and amides of the acid can also bear a nitrate ester. [0024]
  • The present invention further provides a pharmaceutical composition comprising i) as an active ingredient at least one compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO[0025] 2 group; and ii) a pharmaceutically acceptable carrier.
  • In one embodiment, the protected sulfhydryl group is an acetylated sulfhydryl group. [0026]
  • In one embodiment, the active ingredient is: [0027]
    Figure US20040147598A1-20040729-C00010
  • The present invention further provides a pharmaceutical composition for the treatment of disorders where nitric oxide donors are indicated, comprising a) as an active ingredient at least one compound containing at least one nitric oxide donor group, and at least one sulfhydryl group as defined herein; and b) a pharmaceutically acceptable carrier. In one embodiment, the active ingredient is a compound containing one or more sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO[0028] 2 group. In another embodiment, the active ingredient is a 5-membered ring heterocyclic compound containing a sulfur atom and a nitrogen atom, which ring is substituted by one or more substituents bearing a terminal —ONO2 group. In another embodiment, the active ingredient is a 5-membered ring compound containing two conjugate S-atoms, which ring is linked to one or more substituents bearing a terminal —ONO2 group. In another embodiment the active ingredient is a compound containing an acyclic —S—S group, linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO2 group. In another embodiment, the active ingredient is a 6-membered ring compound containing two conjugate S-atoms which is substituted by one or more —ONO2 groups or linked to one or more substituents bearing a terminal —ONO2 group. In another embodiment the active ingredient is a 6-membered ring compound containing 2 conjugate S-atoms which is substituted by one or more —ONO2 groups or linked to one or more substituents bearing a terminal —ON2 group, wherein said 6-membered ring is conjugated to at least one carbocyclic aromatic nucleus or at least one pyridine nucleus. In another embodiment, the active ingredient is a compound having an S—S group in an open configuration linked to one or more —ONO2 groups or linked to one or more substituents bearing a terminal —ONO2 group.
  • In one embodiment, the active ingredient is [0029]
    Figure US20040147598A1-20040729-C00011
    Figure US20040147598A1-20040729-C00012
  • In another embodiment, the active ingredient is: [0030]
    Figure US20040147598A1-20040729-C00013
    Figure US20040147598A1-20040729-C00014
    Figure US20040147598A1-20040729-C00015
    Figure US20040147598A1-20040729-C00016
  • Because of their SH-content (radical scavenging and anti-oxidant properties), these compounds may also be applied for other pathologies. Thus, considering their promising chemical and pharmacological characteristics and the ever-increasing demand for better therapy for heart diseases, significant potential exists for compounds of this type to become the next generation of vasodilators. This is especially true concerning the considerable amount of recent evidence indicating the involvement of nitric oxide, reactive oxygen species and thiols in a variety of conditions, the pathogenesis of as well as the treatment for which have not been fully resolved. These include (but are not limited to): atherosclerosis, pulmonary and systemic hypertension, asthma and other related respiratory diseases, trauma, shock, neurotoxicity, neurodegenerative and neurologic disorders, including those involving learning, memory, olfaction and nociception, Huntington, Alzheimer and Parkinson's diseases, multiple sclerosis and convulsive (seizure) disorders, AIDS-related disorders (i.e. dementia), disorders of gastric acid and other secretory and peristaltic functions of the alimentary system, drug and disease-induced neuropathy and nephropathy, pathological and premature uterine contractions, cellular defense impairment, and insulin-resistance in glucose intolerance and diabetes mellitus, pregnancy-induced hypertension, chemotaxis and phagocytic impairment in immunological disorders, cerebrovascular diseases, aggregation disorders, penile erection and treatment of male impotence. [0031]
  • Although the exact mechanisms defining organic nitrates and other nitric oxide donors' action and tolerance are not completely elucidated, the primary roles of nitric oxide (being their first messenger) and cGMP (the second messenger) in mediating vasorelaxation are universally accepted. Applicant has demonstrated herein, utilizing example compounds 1 to 6 from pages 9-10, that, unlike currently available organic and inorganic nitrates, these compounds possess equipotent or ever superior vasorelaxant activity. Moreover, using cGMP measurements both in extended periods of exposure to the drug when used, for example, in nitroglycerin-equimolar dosing regimens for which tolerance to the cGMP-inducing activity of nitroglycerin has been documented under the same experimental conditions (see table on page 26). [0032]
  • For the preparation of pharmaceutical compositions, the novel compounds are mixed in the usual way with appropriate pharmaceutical carrier substances, aroma, flavoring and coloring materials and formed, for example, into tablets or dragees of immediate or sustained release or, with additions of appropriate adjuvants, for example water or an oil such as olive or other oil, are suspended or dispersed or dissolved. [0033]
  • The compounds or the pharmaceutical composition thereof can be administered orally (including the sublingual and buccal routes) or via an injectable form (including the subcutaneous, intramuscular, intraperitoneal and the parenteral routes). Other routes of administration such as aerosols and dermal preparations are also to be considered. As injection medium, water is preferably used which contains the stabilizing agents, solubilizing agents and/or buffers usually utilized in the preparation of solutions for injection. Such additives include, for example, tartarate and borate buffers, ethanol, ethylene and propylene glycols, glycerol, dimethyl sulphoxide, complex formers (i.e., ethylenediamine tetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation and polyethylene derivatives of sorbit anhydrides. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acid, high molecular weight polymers (i.e., polyethylene glycol). Compositions suitable for oral administration (as defined above) can, if necessary, contain flavoring and sweetening agents. [0034]
  • The synthesis of the novel compounds was carried out utilizing conventional organic synthetic methods. The following examples are given for the purpose of illustrating the present invention: [0035]
    • EXAMPLE 1 trans-1,2-Dinitrato-4,5-dithiane (Compound 1, Page 9)
  • The compound was easily synthesized utilizing the commercially available precursor trans-1,2-dihydroxy-4,5-dithiane. 0.5 g of the precursor was added portionwise to chilled (−5° C.) 1:1 mixture of fuming nitric sulfuric acids. Upon completion of the addition, the ice/salt bath was removed and the mixture brought to room temperature. This mixture was added dropwise to a cooled mite of dry diethyl ether:acetonitrile:water (70:20:10) with vigorous stirring. The lower aqueous phase was separated and extracted twice with diethyl ether. The combined organic extracts were washed twice with water and once with cold 1% sodium carbonate solution. The organic layer was dried over magnesium sulfate and evaporated to near dryness under reduced pressure. The residual oil was loaded on a silica column and separated after elution with hexane. Evaporation under reduced pressure of the eluate yielded a yellowish oil (0.56 g) with analytical data consistent with the structure of trans-1,2-dinitrato-4,5-dithiane. [0036]
    • EXAMPLE 2 2,2′-Dithiodiethanol-dinitrate (Compound 2, Page 9)
  • The compound was synthesized in a similar fashion to compound 1 above using the commercially available precursor 2,2′-dithiodiethanol as the starting material. The precursor was nitrated and separated as above yielding the tide compound 2,2′-dithiodiethanol-dinitrate. [0037]
    • EXAMPLE 3 1,1-Diemethanol-dinitrate-3,4-dithiane (Compound 3, Page 10)
  • This compound was synthesized by bishydroxymethylation of diethyl malonate followed by thiolation of the hydroxyl groups (via the halide intermediate). The resulting 1,1-dicarboxy-3,4-dithiane was reduced by borane (catechol borane solution) to the corresponding 1,1-diemethanol-3,4-dithiane. Direct nitration of this latter intermediate yielded the title compound 1,1-diemethanol dinitrate-3,4-dithiane. [0038]
    • EXAMPLE 4 1,1′-Bisthiomethyl-3,4-dihydroxy-cyclohexane-dinitrate ester (Compound 4, Page 10)
  • This compound was synthesized by thiolation of the dichloride intermediate of the commercially available 1,1′-bishydroxymethyl-3-cyclohexene. Oxidation of the double bond either by hydrogen peroxide/asmium tetroxide to generate the cis-diol or by a peracid/formic acid mixture to generate the trans-diol followed by nitration of the diol will generate the corresponding (cis or trans) form of the title compound. [0039]
    • EXAMPLE 5 Thioctyl Alcohol Nitrate Ester (Compound 5, Page 10)
  • This compound was synthesized in a high yield process utilizing thioctic acid as the precursor. Following reduction of the acid (or its methyl or ethyl ester) by catechol borane solution, the resulting thioctyl alcohol was separated and mitrated as described above to yield the title compound. [0040]
    • EXAMPLE 6 1,2-Dihydroxy-dinitrate-6,8-dithiane (Compound 6, Page 10)
  • 2-Hydroxy lipoic (thioctic) acid was synthesized from thioctic acid via the 2-bromo derivative. This intermediate was reduced via borane to yield the direct precursor 1,2-dihydroxy-6,8-dithiane which, upon nitration as described above, yielded the title compound. [0041]
    • Experimental Report
  • Representative for the new compounds, the vasorelaxant activities (measured as the ability of the tested drug to induce an increase in vascular cGMP) of the example compounds 1 to 6 were determined and compared to activity of nitroglycerin under the same experimental conditions following single and sustained exposure of rats to the compound. [0042]
  • For this purpose the compound to be tested was administered, in each case, to 8 male Sprague-Dawley rats (300-400 g) before and after an 18 hr continuous intravenous infusion of the compound. The 18 hr continuous infusion period was determined based on existing data demonstrating the development of tolerance to the drug effect in the case of nitroglycerin. The existence of tolerance to the drug is demonstrated by the inability of the drug to attain 50% or more of the cGMP values measured in the vascular tissue after dosing of the drug to preciously treated animals as compared to controls (non-treated or vehicle-treated animals). After drug administration (i.v. push), the rat was sacrificed, the aorta immediately removed and processed for cGMP measurement as has been described in detail by us. All of the tested new compounds were utilized in nitroglycerin equimolar doses, either before of after the “tolerance” induction period. [0043]
  • The following table summarizes the results obtained following administration of either nitroglycerin or the tested compounds before and after an 18 hr continuous exposure to the same compound: [0044]
    cGMP (pmol/g tissue)
    Tested Compound Pre-infusion Post-infusion
    Nitroglycerin 153 ± 13  68 ± 9**
    Compound 1 196 ± 14 189 ± 13*
    Compound 2 169 ± 12 174 ± 13*
    Compound 3 171 ± 14 174 ± 16*
    Compound 4 149 ± 11 169 ± 13*
    Compound 5 123 ± 13 113 ± 11*
    Compound 6 193 ± 17 179 ± 12*
  • Besides their expected superior vasorelaxant activity, these results clearly demonstrate that whereas tolerance to the cGMP-inducing activity of nitroglycerin developed early (18 hr) following its continuous in vivo administration, no tolerance was observed to the cGMP-increasing effects of the novel compounds under the same experimental conditions used for the induction of in vivo tolerance. In fact, Applicant shows in preliminary results that no tolerance to this cGMP-inducing effect of these novel SH-containing-NO-donors develops even after exposure of the animals to the compounds for extended periods of time (i.e., not even after 168 hr of continuous intravenous infusions). [0045]
  • It will be understood that the compounds shown demonstrate the principle upon which this invention is based. Thus, the specification and examples given in this application are illustrative but not limitative of the present invention and embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art. Rather, the scope of this invention is defined by the claims which follow. [0046]

Claims (6)

What is claimed is:
1. A compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO2 group.
2. A compound according to claim 1, wherein said protected sulfhydryl group is an acetylated sulfhydryl group.
3. A compound according to claim 1, wherein said compound is:
Figure US20040147598A1-20040729-C00017
4. A pharmaceutical composition comprising
i) as an active ingredient at least one compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing at least one terminal —ONO2 group; and
ii) a pharmaceutically acceptable carrier.
5. A composition according to claim 4, wherein said protected sulfhydryl group is an acetylated sulfhydryl group.
6. A composition according to claim 4 wherein the active ingredient is:
Figure US20040147598A1-20040729-C00018
US10/698,944 1997-03-26 2003-11-03 Nitric oxide donors and pharmaceutical compositions containing them Abandoned US20040147598A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US10/698,944 US20040147598A1 (en) 1997-03-26 2003-11-03 Nitric oxide donors and pharmaceutical compositions containing them

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
IL120531A IL120531A (en) 1997-03-26 1997-03-26 Nitric oxide donors and pharmaceutical compositions containing them
IL120531 1997-03-26
US09/381,303 US6369071B1 (en) 1997-03-26 1998-03-26 Nitric oxide donors and pharmaceutical compositions containing them
US10/041,680 US6642260B2 (en) 1997-03-26 2002-01-09 Nitric oxide donors and pharmaceutical compositions containing them
US10/698,944 US20040147598A1 (en) 1997-03-26 2003-11-03 Nitric oxide donors and pharmaceutical compositions containing them

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/041,680 Continuation US6642260B2 (en) 1997-03-26 2002-01-09 Nitric oxide donors and pharmaceutical compositions containing them

Publications (1)

Publication Number Publication Date
US20040147598A1 true US20040147598A1 (en) 2004-07-29

Family

ID=11069962

Family Applications (3)

Application Number Title Priority Date Filing Date
US09/381,303 Expired - Fee Related US6369071B1 (en) 1997-03-26 1998-03-26 Nitric oxide donors and pharmaceutical compositions containing them
US10/041,680 Expired - Fee Related US6642260B2 (en) 1997-03-26 2002-01-09 Nitric oxide donors and pharmaceutical compositions containing them
US10/698,944 Abandoned US20040147598A1 (en) 1997-03-26 2003-11-03 Nitric oxide donors and pharmaceutical compositions containing them

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US09/381,303 Expired - Fee Related US6369071B1 (en) 1997-03-26 1998-03-26 Nitric oxide donors and pharmaceutical compositions containing them
US10/041,680 Expired - Fee Related US6642260B2 (en) 1997-03-26 2002-01-09 Nitric oxide donors and pharmaceutical compositions containing them

Country Status (9)

Country Link
US (3) US6369071B1 (en)
EP (1) EP0984928B1 (en)
JP (1) JP4637304B2 (en)
AT (1) ATE393140T1 (en)
AU (1) AU742534B2 (en)
CA (1) CA2284620A1 (en)
DE (1) DE69839394T2 (en)
IL (1) IL120531A (en)
WO (1) WO1998042661A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050228184A1 (en) * 2002-04-19 2005-10-13 Haj-Yehia Abdullah I Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders
US20060046967A1 (en) * 2004-08-26 2006-03-02 Apparao Satyam Prodrugs containing novel bio-cleavable linkers
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same

Families Citing this family (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6310052B1 (en) 1996-06-04 2001-10-30 Queen's University At Kingston Nitrate esters and their use for neurological conditions
US20050137191A1 (en) * 1996-06-04 2005-06-23 Thatcher Gregory R. Nitrate esters and their use for mitigating cellular damage
US7115661B1 (en) 1999-12-29 2006-10-03 Queen's University At Kingston Methods and compositions for mitigating pain
US7914814B2 (en) 1997-09-17 2011-03-29 Strategic Science & Technologies, Llc Topical delivery of arginine of cause beneficial effects
US7629384B2 (en) * 1997-09-17 2009-12-08 Strategic Science & Technologies, Llc Topical delivery of L-arginine to cause beneficial effects
GB9801398D0 (en) 1998-01-22 1998-03-18 Anggard Erik E Chemical compounds
JPH11217330A (en) * 1998-01-30 1999-08-10 Sumitomo Pharmaceut Co Ltd Neurotrophic factor secretagogue
ES2142773B1 (en) 1998-10-07 2001-01-01 Lacer Sa ISOSORBIDA MONONITRATE DERIVATIVES AND THEIR EMPLOYMENT AS VASODILATATING AGENTS WITH DECREASED TOLERANCE.
JP2002530396A (en) 1998-11-25 2002-09-17 イッサム・リサーチ・ディベロップメント・カンパニー・オブ・ザ・ヘブルー・ユニバーシティ・オブ・エルサレム Scavenger compounds
AU4841700A (en) 1999-05-12 2000-11-21 Nitromed, Inc. Nitrosated and nitrosylated potassium channel activators, compositions and methods of use
KR20010038797A (en) * 1999-10-27 2001-05-15 김길환 Material for Nitric Oxide Doner using Fermented Rice with Monascus and Material for Medicine using it
DK1406867T3 (en) 2001-05-30 2009-04-06 Eisai Corp North America Thiolalkylbenzoic acid derivatives
ITMI20011307A1 (en) * 2001-06-21 2002-12-21 Nicox Sa DRUGS FOR EPILEPSY
US20030235609A1 (en) * 2002-01-25 2003-12-25 Lautt Wilfred Wayne Use of cholinesterase antagonists to treat insulin resistance
EP1336602A1 (en) * 2002-02-13 2003-08-20 Giovanni Scaramuzzino Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases
US20060247216A1 (en) * 2002-10-25 2006-11-02 Haj-Yehia Abdullah I Steroid compounds comprising superoxide dismutase mimic groups and nitric oxide donor groups, and their use in the preparation of medicaments
AU2003283789A1 (en) * 2002-11-22 2004-06-18 Yissum Research Development Company Of The Hebrew University Of Jerusalem Beta-blockers having antioxidant and nitric oxide-donor activity
EP1578413A2 (en) * 2002-11-29 2005-09-28 Yissum Research Development Company of The Hebrew University of Jerusalem Ace-inhibitors having antioxidant and no-donor activity
ES2258365B1 (en) * 2003-10-03 2007-12-01 Lacer, S.A. DERIVATIVES OF DISULFIDE, SULFIDE, SULFOXIDE AND SULFONE OF CYCLING SUGARS AND THEIR USES.
JP5376761B2 (en) * 2004-02-23 2013-12-25 ストラテジック サイエンス アンド テクノロジーズ， エルエルシー Topical delivery of nitric oxide to improve body and skin appearance
US9226909B2 (en) 2004-04-19 2016-01-05 Strategic Science & Technologies, Llc Beneficial effects of increasing local blood flow
JP2007532697A (en) * 2004-04-19 2007-11-15 ストラテジック サイエンス アンド テクノロジーズ， エルエルシー The beneficial effects of increased local blood flow
JP5198063B2 (en) 2004-08-26 2013-05-15 アッパラオ・サティアム Novel biocleavable linker
US7975699B2 (en) 2007-10-30 2011-07-12 The Invention Science Fund I, Llc Condoms configured to facilitate release of nitric oxide
US20110190604A1 (en) * 2006-12-22 2011-08-04 Hyde Roderick A Nitric oxide sensors and systems
US8642093B2 (en) * 2007-10-30 2014-02-04 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US7862598B2 (en) * 2007-10-30 2011-01-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
US8221690B2 (en) * 2007-10-30 2012-07-17 The Invention Science Fund I, Llc Systems and devices that utilize photolyzable nitric oxide donors
US7897399B2 (en) 2007-10-30 2011-03-01 The Invention Science Fund I, Llc Nitric oxide sensors and systems
US8980332B2 (en) 2007-10-30 2015-03-17 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US8877508B2 (en) * 2007-10-30 2014-11-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
US10080823B2 (en) 2007-10-30 2018-09-25 Gearbox Llc Substrates for nitric oxide releasing devices
US20090112055A1 (en) * 2007-10-30 2009-04-30 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Sleeves configured to facilitate release of nitric oxide
US8349262B2 (en) * 2007-10-30 2013-01-08 The Invention Science Fund I, Llc Nitric oxide permeable housings
EP3045171A1 (en) 2009-06-24 2016-07-20 Strategic Science & Technologies, LLC Topical composition
EP2445493A1 (en) 2009-06-24 2012-05-02 Strategic Science & Technologies, LLC Topical composition containing naproxen
US11684624B2 (en) 2009-06-24 2023-06-27 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
CN103429247A (en) 2010-12-29 2013-12-04 战略科学与技术有限责任公司 Treatment of erectile dysfunction and other indication
US9289495B2 (en) 2010-12-29 2016-03-22 Strategic Science & Technologies, Llc Systems and methods for treatment of allergies and other indications
US20130315891A1 (en) 2012-05-25 2013-11-28 Matthew Charles Formulations of human tissue kallikrein-1 for parenteral delivery and related methods
ES2625548T3 (en) 2012-06-04 2017-07-19 DiaMedica Therapeutics Inc. Glycosylation isoforms of human tissue calicrein-1
ES2774776T3 (en) * 2013-11-18 2020-07-22 Aurin Biotech Inc Acetylsalicylic acid dimers, synthesis thereof, and uses thereof to prevent and treat complement mediated disorders
JP2020510023A (en) 2017-03-09 2020-04-02 ダイアメディカ， インコーポレイテッド Tissue kallikrein 1 dosage form

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5862147A (en) * 1981-10-09 1983-04-13 Dai Ichi Seiyaku Co Ltd Nitric acid ester derivative
GB8717068D0 (en) 1987-07-20 1987-08-26 Fujisawa Pharmaceutical Co Nitric ester derivative
NL8802276A (en) * 1988-09-15 1990-04-02 Cedona Pharm Bv MEDICINAL PRODUCT WITH RELAXING EFFECT, CONTAINING A NITRATE ESTER AS ACTIVE SUBSTANCE.
DE4004841A1 (en) 1990-02-16 1991-08-22 Boehringer Mannheim Gmbh Nitric acid esters of cyclohexanol derivatives
US5298516A (en) 1991-03-27 1994-03-29 Sankyo Company, Limited Thiazolidone compounds and method of using the same as a vasodilator
JP3361836B2 (en) * 1991-07-04 2003-01-07 三共株式会社 Amino acid derivatives
JPH08507773A (en) * 1993-03-15 1996-08-20 ビイク ネダーラント ベスローテン フェンノートシャップ Use of substituted alkyl nitrates for the treatment of pathologically high intraocular pressure
HU218923B (en) * 1993-10-06 2000-12-28 Nicox S.A. Nitric esters having anti-inflammatory and/or analgesic activity, pharmaceutical compns. contg. them and process for their preparation
CA2190087C (en) * 1994-05-10 2005-08-02 Piero Del Soldato Nitro compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic activities
DE19515970A1 (en) * 1995-05-02 1996-11-07 Bayer Ag Acetylsalicylsäurenitrate
JPH09291075A (en) * 1996-03-01 1997-11-11 Sankyo Co Ltd Thiazolidine compounds
AU2230897A (en) * 1996-03-01 1997-09-16 Sankyo Company Limited Thiazolidine derivatives
US5807847A (en) * 1996-06-04 1998-09-15 Queen's University At Kingston Nitrate esters

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7378438B2 (en) 2002-04-19 2008-05-27 Yissum Research Development Company Of The Hebrew University Of Jerusalem Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders
US20050228184A1 (en) * 2002-04-19 2005-10-13 Haj-Yehia Abdullah I Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders
US8357723B2 (en) 2004-08-26 2013-01-22 Piramal Enterprises Limited and Apparao Satyam Prodrugs containing novel bio-cleavable linkers
US20060046967A1 (en) * 2004-08-26 2006-03-02 Apparao Satyam Prodrugs containing novel bio-cleavable linkers
US20060205674A2 (en) * 2004-08-26 2006-09-14 Nicholas Piramal India Ltd. Prodrugs containing novel bio-cleavable linkers
US7932294B2 (en) 2004-08-26 2011-04-26 Apparao Satyam Prodrugs containing novel bio-cleavable linkers
US8349901B2 (en) 2004-08-26 2013-01-08 Piramal Enterprises Limited and Apparao Satyam Prodrugs containing novel bio-cleavable linkers
US8354455B2 (en) 2004-08-26 2013-01-15 Piramal Enterprises Limited and Apparao Satyam Prodrugs containing novel bio-cleavable linkers
US8956658B2 (en) 2005-05-27 2015-02-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403851B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8962029B2 (en) 2005-05-27 2015-02-24 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US11691995B2 (en) 2005-05-27 2023-07-04 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403852B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9737561B2 (en) 2009-08-21 2017-08-22 Novan, Inc. Topical gels and methods of using the same
US10376538B2 (en) 2009-08-21 2019-08-13 Novan, Inc. Topical gels and methods of using the same
US11583608B2 (en) 2009-08-21 2023-02-21 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
US9713652B2 (en) 2011-02-28 2017-07-25 The University Of North Carolina At Chapel Hill Nitric oxide-releasing S-nitrosothiol-modified silica particles and methods of making the same
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same

Also Published As

Publication number Publication date
EP0984928B1 (en) 2008-04-23
US6369071B1 (en) 2002-04-09
WO1998042661A1 (en) 1998-10-01
IL120531A0 (en) 1997-07-13
JP4637304B2 (en) 2011-02-23
AU6516098A (en) 1998-10-20
ATE393140T1 (en) 2008-05-15
EP0984928A1 (en) 2000-03-15
US20020143187A1 (en) 2002-10-03
JP2001520670A (en) 2001-10-30
AU742534B2 (en) 2002-01-03
DE69839394T2 (en) 2009-05-07
US6642260B2 (en) 2003-11-04
DE69839394D1 (en) 2008-06-05
EP0984928A4 (en) 2004-08-18
IL120531A (en) 2006-12-31
CA2284620A1 (en) 1998-10-01

Similar Documents

Publication Publication Date Title
US6642260B2 (en) Nitric oxide donors and pharmaceutical compositions containing them
US6492405B2 (en) Nitric oxide donors and pharmaceutical compositions containing them
EP3489220B1 (en) Lipids for therapeutic agent delivery formulations
US6369098B1 (en) Dithiolane derivatives
EP1133487B1 (en) Antioxidants
CA2369071A1 (en) Novel lipoic acid derivatives, their preparation, pharmaceutical use and pharmaceutical compositions cantaining them
PL206245B1 (en) Ortho-substituted and meta-substituted bis-aryl compounds, method for the production thereof, their use as a medicament, and pharmaceutical preparations containing these compounds
CA2627211C (en) Aminoacid derivatives containing a disulfanyl group in the form of mixed disulfanyl and aminopeptidase n inhibitors
WO1999045922A1 (en) Lipoic acid analogs
Perrino et al. New prostaglandin derivative for glaucoma treatment
US8648111B2 (en) N1-2-thiophene-2-ylethyl-N2-substituted biguanide derivate, preparation method thereof, and pharmaceutical composition containing the same as active ingredients
AU2004229015A1 (en) Nitric oxide donors and pharmaceutical compositions containing them
CZ290989B6 (en) Optically active thiazolidinone derivative, pharmaceutical preparation containing thereof and use of such derivative as well as process of its preparation
KR890004664B1 (en) 2-(2-pyridyl)methyl suefinyl thieno imidazols and related compounds
CA2441534C (en) Benzoaxathiepin derivatives and their use as medicines
CA2515680A1 (en) Acylated aminopropanediols and analogues and therapeutic uses thereof
NZ208027A (en) Thiazoles and pharmaceutical compositions
KR820000179B1 (en) Process for preparation of polyene compounds
FR2517202A1 (en) PHARMACEUTICAL COMPOSITIONS HAVING NORMOLIPEMIANT PROPERTIES AND CONTAINING COMPOUNDS HAVING AN N-SUBSTITUTED BENZENESULFONAMIDE STRUCTURE
CA2171756A1 (en) Succinamic acid compound, production method thereof and use thereof
KR840002159B1 (en) Process for preparing tetrahydrothiopyrano(3,2-b)indole derivatives
JPS649981B2 (en)
JPH0358950A (en) Phermaceutically-active 3-aryl and 3-heteroaryl-2-fluoro-1- olefin
IL143332A (en) Scavenger compounds
WO2000063202A2 (en) BENZO[b] THIOPHENE SULFONAMIDE-1, 1-DIOXIDE DERIVATIVES AND THEIR USE AS ANTINEOPLASTIC AGENTS

Legal Events

Date Code Title Description
AS Assignment

Owner name: YISSUM RESEARCH DEVELOPMENT COMPANY, ISRAEL

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:HAJ-YEHIA, ABDULLAH;REEL/FRAME:015228/0968

Effective date: 20040321

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION