WO1995028377A1 - Composes de guanidine utilises comme regulateurs de la synthase de l'oxyde nitrique - Google Patents

Composes de guanidine utilises comme regulateurs de la synthase de l'oxyde nitrique Download PDF

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Publication number
WO1995028377A1
WO1995028377A1 PCT/US1994/004243 US9404243W WO9528377A1 WO 1995028377 A1 WO1995028377 A1 WO 1995028377A1 US 9404243 W US9404243 W US 9404243W WO 9528377 A1 WO9528377 A1 WO 9528377A1
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Prior art keywords
amino
pent
ene
oxazolidinecarboxylate
dimethyl
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PCT/US1994/004243
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English (en)
Inventor
Ferid Murad
James F. Kerwin
Lee D. Gorsky
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Abbott Laboratories
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Priority to PCT/US1994/004243 priority Critical patent/WO1995028377A1/fr
Publication of WO1995028377A1 publication Critical patent/WO1995028377A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/02—Guanidine; Salts, complexes or addition compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/30—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to nitro or nitroso groups
    • C07C279/32—N-nitroguanidines
    • C07C279/36—Substituted N-nitroguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine

Definitions

  • the present invention relates to novel unsaturated guanidino compounds, to compositions thereof useful in regulating the production of soluble guanylate cyclase or nitric oxide, to intermediates useful in the production thereof, and to a method of treating disorders of the vascular system or diseases of the cartilage, including hypotension, hypertension, coronary vasospasm, cerebral
  • vasoconstriction cardiomyopathy, atherogenesis, atherosclerosis, myocardial ischemia, cerebral ischemia, diabetes, endotoxemia, sepsis, asthma and rhinitis, synovitis, chondroarthritis and osteoarthritis.
  • endothelium-derived relaxing factor EDRF
  • endothelium-dependent receptor agonists including, for example, adenosine diphosphate (ADP), adenosine triphosphate (ATP), 5-hydroxytryptamine (5-HT), thrombin, acetylchoiine (ACh), vasoactive intestinal polypeptide (VIP), oxytocin,
  • cholecystokinin (CCK), calcitonin gene-related peptide, noradrenaline,
  • EDRF ethylene glycol
  • cGMP cyclic guanosine monophosphate
  • nitric oxide is the major endothelium-derived relaxing factor (R.M.J. Palmer et al., Nature, 1987, 327: 524-6; S. Moncada et al., Biochem.
  • nitric oxide was tested and found to elicit a potent and transient relaxation of bovine coronary artery accompanied by cGMP accumulation (CA. Guetter et al., J. Cyclic Nucleotide Res., 1979, 5: 211-24) and it was also shown to activate soluble guanylate cyclase and to elevate tissue cGMP levels.
  • L-arginine may be the endogenous source of EDRF (NO), and this hypothesis is further supported by the observation that EDRF (NO) production is inhibited by the simple arginine derivative, NG-methylarginine (R.M.J. Palmer et al., Biochem. Biophys. Res. Comm., 1988, 153: 1251-56; S. Moncada et al., Biochemical Pharmacology, 1988, 37: 2495-2501 ; and I. Sakuma et al., Proc. Natl. Acad. Sci. USA, 1988, 85: 8664-7).
  • NADPH represents reduced nicotinamide adenine dinucleotide phosphate
  • BH 4 represents
  • FAD represents flavin adenine dinucleotide
  • FMN represents flavin mononucleotide
  • Isoform I has been purified and characterized by Bredt and Snyder (Proc.
  • Isoform-specific agents may offer the advantage of selectivity, i.e., desired therapeutic effect with fewer or more tolerable side- effects.
  • hypotension S.
  • Examples of known compounds that act to regulate the production of cGMP by this method may be grouped into four categories: (1 ) those
  • those agents for example, hemoglobin, which directly bind either EDRF (NO) itself or one of its end products; (3) those agents which remove superoxide anion (O 2 )- and other oxidants, thereby enhancing the effect of EDRF (for example, the enzyme superoxide dismutase removes superoxide anion by converting it to molecular oxygen (O 2 ) and hydrogen peroxide); and (4) the nitrovasodilators, such as nitroglycerin, which provide nitrogen oxide to stimulate guanylate cyclase (F. Murad, J. Clin. Invest, 1986, 78: 1-5).
  • nitrovasodilators With the exception of the nitrovasodilators, none of these categories of compounds has provided a viable therapeutic agent for the regulation of cGMP production in disease states.
  • the nitrovasodilators because they provide nitrogenous oxides indiscriminately to numerous target tissues, and thus lead to such complications as tolerance (A. Mulsch et al., European J. Pharmacol., 1988, 158: 191-8), may not be the ultimate therapeutic agents of choice. More recently it has been reported that N-hydroxyarginine is a substrate for the NO synthase enzyme (Steuhr et al., J. Biol. Chem., 1991 , 266: 6259).
  • N G -acyl derivatives and N G -alkyl derivatives of arginine for use in oral hygiene compositions which were disclosed in Silbering et al., U.S. Patents 4,499,067 and 4,499,068, issued February 12, 1985, and cytoprotective guanidine derivatives useful in ischemic diseases, which were disclosed in Sportletti et al., U.S. Patent 4,789,681 , issued December 6, 1988.
  • Japanese Patent Application J67008012 published March 31 , 1967, disclosed a method for production of ⁇ -amino, ⁇ -guanidinocarboxylic acids, and Japanese Patent Application J55022601 , published February 18, 1980, disclosed ⁇ -protected aminoarginine esters that are useful in enzymatic activity determinations.
  • Japanese Patent Application J51075023 published June 29, 1976, disclosed the preparation of N G -alkyl arginines and Japanese Patent Application J72042823, published October 28, 1972, disclosed a method for the preparation of N-acetyl- ⁇ -hydroxyarginine.
  • the present invention is directed to regulators of nitric oxide synthase that indirectly modulate cyclic guanosine monophosphate (cGMP) production which have the formula:
  • the present invention is also directed to pharmaceutical compositions comprising a therapeutically-effective amount of a compound of formula (I) and a pharmaceutically-acceptable carrier or diluent, and to a method of treating disorders of vascular smooth muscles, macrophages, neurons, platelets, bronchial smooth muscles, optic muscles and gastrointestinal smooth muscles in humans and mammals, in addition to sickle cell anemia and diabetes, by administration of a compound of formula (I).
  • This invention relates to novel unsaturated guanidino compounds and pharmaceutical compositions thereof which regulate nitric oxide synthase and thereby indirectly modulate levels of cyclic guanosine monophosphate. These compounds may, therefore, be used in the treatment of disorders of vascular smooth musculature, macrophages or neurons, such as hypotension,
  • endotoxemia sepsis, hypertension, shock, cerebral vasoconstriction, cerebral vasodilation, or non-migraine headache
  • disease states involving platelet aggregation including preparation of platelets for transfusion or perfusion
  • ischemia thrombosis
  • coronary vasospasm cardiomyopathy
  • atherogenesis atherosclerosis
  • sickle cell anemia and diabetes in diseases involving the bronchial passages such as asthma; in diseases of the optic musculature; and in disorders of the gastrointestinal system, such as diarrhea, irritable bowel syndrome, spasm, and reflux esophagitis (GERD).
  • GERD reflux esophagitis
  • R 1 is selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 2 and R 3 are linked together by a single bond to form a nitrogen-containing ring of the formula:
  • R 1 and R 6 are as defined above, R 4 and W are as defined below, and R 2a is -CR 13 R 14 , wherein R 13 is selected from the group consisting of:
  • R 14 is hydrogen or C 1 -C 6 -alkyl
  • R 4 is hydrogen or C 1 -C 4 -alkyl
  • W is selected from the group consisting of:
  • R 8Z is hydrogen or C 1 -C 4 -alkyl
  • R 9Z is hydrogen, C 1 -C 4 -alkyl or halogen
  • R 10 is hydrogen or methyl
  • R 8E is hydrogen or C 1 -C 4 -alkyl
  • R 9E is selected from the group consisting of:
  • R 10 is hydrogen or methyl
  • R 5 is selected from the group consisting of:
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 8Z , R 9Z and R 10 are as defined above.
  • a preferred embodiment is the compound (1 a), wherein R 1 , R 2 , R 4 , R 6 , R 8Z , R 9Z and R 10 are hydrogen and R5 is nitro.
  • R 1 , R 2a , R 4 , R 5 , R 6 , R 8E , R 9E and R10 are as defined above.
  • a preferred embodiment is the compound (1 b) wherein R 5 and R 6 are hydrogen and the chiral center is S.
  • variable or substituent occurs more than once in any structure, it is understood to be independently selected at each occurrence.
  • C 2 -C 6 -Alkenyl refers to a straight-or branched-chain radical from 2-to-6 carbon atoms, which contains at least one carbon-carbon double bond.
  • C 1 -C 4 -alkoxy or C 1 -C 6 -alkoxy refers to the specified alkyl group, as defined below, attached to a linking oxygen atom.
  • C 1 -C 4 -alkoxycarbonyl refers to a C 1 -C 4 -alkoxy group attached to a linking carbonyl group, and includes, for example, methoxycarbonyl,
  • Alkyl refers to straight- or branched-chain alkyl radicals containing from 1 -to-3 carbon atoms (“C 1 -C 3 -alkyl”), 1 -to-4 carbon atoms (“C 1 -C 4 -alkyl”) or from 1-to-6 carbon atoms (C 1 -C 6 -alkyl) including, but not limited, to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-hexyl, and the like.
  • C 6 -C- 12 -Aryl or "C 6 -C 12 -aryl group”, as used herein, refers to carbocyclic aromatic isolated or fused rings of a total of from 6-to-12 carbon atoms, for example, phenyl, naphthyl, indanyl, fluorenyl, terahydronaphthyl, indenyl, or isoindenyl.
  • C 6 -C 12 -Aryl-C 1 -C 4 -alkyr refers to a C 6 -C 12 -aryl group, as defined above, appended to a C 1 -C 4 -alkyl radical, as defined above, including, but not limited to, benzyl, phenylethyl, naphthylmethyl, and the like.
  • C 6 -C 12 -Aryloxy refers to R 22 O-, wherein R 22 is a C 6 -C 12 -aryl group, as defined above.
  • Halogen refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).
  • Halo-C 1 -C 2 -alkyl refers to a C 1 -C 4 -alkyl radical, as defined above, in which one-to-three hydrogen atoms have been replaced by a halogen, including, but not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, and the like.
  • Haldroxy-protecting group refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures and includes, but is not limited to, substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and
  • benzylidene acetal cyclic ortho esters, for example, methoxymethylene; cyclic carbonates; and cyclic boronates.
  • N-Protecting group refers to those groups intended to protect an amino group or the N-terminus of an amino acid or peptide against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds, and includes, but is not limited to, sulfonyl; acyl, such as acetyl, pivaloyl and benzoyl; alkoxycarbonyl, such as t-butyloxycarbonyl (Boc) and carbobenzyloxy (Cbz); and ⁇ -aminoacyl residues, which may themselves be similarly N-protected.
  • Other intended groups may be found in Volume 3 of The Peptides. E. Gross and J. Meinhofer, editors, Academic Press, 1981.
  • “Pharmaceutically-acceptable amide” refers to the pharmaceutically-acceptable, nontoxic amides of the compounds of the present invention which include amides formed with suitable organic acids or with amino acids, including short peptides consisting of from 1-to-6 amino acids joined by amide linkages which may be branched or linear, wherein the amino acids are selected independently from naturally-occurring amino acids, such as for example, glycine, alanine, leucine, valine, phenylalanine, proline, methionine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine, lysine, arginine, tyrosine, histidine, ornithine, and the like.
  • “Pharmaceutically-acceptable ester” refers to the pharmaceutically- acceptable, nontoxic esters of the compounds of the present invention which include C 1 -C 6 -alkyl esters, wherein C 1 -C 6 -alkyl is as defined above, and C 5 -C 7 -cycloalkyl esters, wherein C 5 -C 7 -cycloalkyl refers to cyclic saturated hydrocarbon radicals, such as cyclopentyl, cyclohexyl, and the like. Also included are C 6 -C- 12 -aryl-C 1 -C 6 -alkyl esters, wherein C 6 -C 12 -aryl-C 1 -C 6 -alkyl are as defined above. Representative examples include benzyl, phenethyl, and the like.
  • “Pharmaceutically-acceptable salts” refers to the pharmaceutically-acceptable, nontoxic, inorganic or organic acid addition salts of the compounds of the present invention, as described in greater detail below.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compounds of Formula (I), as for example, by hydrolysis in blood.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
  • esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of Bioreversible Carriers in Drug Design: Theory and Application, edited by E.B. Roche, Pergamon Press (1987).
  • prodrug ester group refers to any of several ester-forming groups that are hydrolyzed under physiological conditions.
  • Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art.
  • Substituted C 1 -C 6 -alkyl refers to a C 1 -C 6 -alkyl group, as defined above, substituted with one substituent selected from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, carboxy, carbo-C 1 -C 4 -alkoxy, nitro, halo-C 1 -C 4 -alkyl, hydroxy, amino, and C 1 -C 4 -alkylamino.
  • Substituted C 6 -C 12 -aryl refers to a substituted C 6 -C 12 -aryl group, as defined above, substituted with one, two, or three substituents independently selected from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, carboxy, carbo-C 1 -C 4 -alkoxy, nitro, halo-C 1 -C 4 -alkyl, hydroxy, amino, and C 1 -C 4 -alkylamino.
  • Substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl refers to a C 6 -C 12 -aryl group, as defined above, appended to a C 1 -C 4 -alkyl radical, as defined above.
  • Substituted C 6 -C 12 -aryloxy refers to a substituted C 6 -C 12 -aryl group, as defined above, attached to a linking oxygen atom.
  • a “therapeutically-effective amount” of the compound of the invention is meant a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is to be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts and well within the capabilities of attending physicians.
  • Thioalkoxy refers to R 19 S-, wherein R 19 is either a C 1 - C 4 -alkyl group or a C 1 -C 6 -alkyl group, as specified.
  • potassium carbonate KOH for potassium hydroxide, LAH for lithium aluminum hydride, Ms for methanesulfonyl, MsCl for methanesulfonyl chloride, NaHCO 3 for sodium hydrogen carbonate or sodium bicarbonate, NaOH for sodium hydroxide, NH 3 for ammonia, N 2 H 4 for hydrazine, NH4OH for ammonium hydroxide, NH 4 OAC for ammonium acetate, NMM for N-methylmorpholine, PAW for pyridine/acetic acid/water (20:6:11 ), p-TsOH for p-toluene sulfonic acid, rt for room temperature, TBAF for tetrabutylammonium fluoride, TBDMS-Cl for t-butyldimethylsilyl chloride, TEA for triethylamine, TFA for trifluoroacetate, THF for tetrahydrofuran, TMSi for trimethyl
  • Amino acids are herein designated as the natural L-isomer or as the D- isomer in accordance with convention, or chiral compounds, including amino acids, are assigned the R, S, or (R,S) configuration at the chiral center.
  • Preferred compounds of the present invention are those which have the S configuration at the alpha-carbon atom, i.e., the carbon atom in the formula (I) designated by an *.
  • the terms "R" and "S” configuration used herein are as defined by IUPAC (IUPAC 1974 Recommendations for Section E. Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.)
  • the compounds of the present invention can be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids.
  • salts include, but are not limited to, the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, flavianate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, succinate,
  • cationic salts are also readily prepared by conventional procedures such as treating an acid of formula (I) with an appropriate amount of base, such as an alkali or alkaline earth metal hydroxide, e.g., sodium,
  • potassium, lithium, calcium, or magnesium or an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine,
  • the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • the salts of the present invention can be synthesized from the compounds of formula I which contain a basic or acidic moiety by conventional methods, such as by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • the total daily dose administered in single or divided doses may be in amounts, for example, from about 0.01 to about 50 mg/kg body weight, or more usually, from about 0.2 to about 30 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administering to a patient in need of such treatment from about 20 mg to about 2000 mg of the
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular treatment and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender and diet of the patient, the time of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles as desired.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • Liquid dosage forms for oral administration may include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; and sweetening, flavoring and perfuming agents.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butandiol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as a solvent or
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the injectable formulation may be sterilized, as for example by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • the most common way to accomplish this is to inject a suspension of crystalline or amorphous material with poor water solubility.
  • the rate of absorption of the drug becomes dependent on the rate of dissolution of the drug which is, in turn, dependent on the physical state of the drug, for example, the crystal size and the crystalline form.
  • Another approach to delaying absorption of a drug is to administer the drug as a solution or suspension in oil.
  • Injectable depot forms may also be made by forming microcapsule matrices of drugs and biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly-orthoesters and polyanhydrides.
  • the depot injectables may also be made by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • Suppositories for rectal administration of the drug may be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills may additionally be prepared with enteric coatings.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically-acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the present agents may also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic physiologically acceptable and metabolizable lipid capable of forming liposomes may be used.
  • the present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art.
  • the compounds of this invention may be administered alone or in combination or in concurrent therapy with other agents.
  • Compound 2 is reacted under mild acid conditions (e.g., with p-TsOH) with an appropriate aldehyde, ketone, or acetal/ketal equivalent thereof ((R 1 3 (CO)R 14 ) e.g., dimethoxypropane, benzaldehyde, cyclohexanone, etc.) to provide ester 3.
  • Ester 3 is converted to the aldehyde 4 either by direct reduction with DIBAL or via the fully reduced alcohol form (e.g., further reaction with DIBAL, LAH, etc.) followed by oxidation (Swern conditions, pyridine sulfur trioxide complex, etc.).
  • the aldehyde 4 can serve as a precursor to the secondary alcohol 5 via reaction with an appropriate nucleophile (e.g., alkylmagnesium halides, alkenylmagnesium halides, alkynyllithium reagents, alkyllithium reagents, etc.).
  • an appropriate nucleophile e.g., alkylmagnesium halides, alkenylmagnesium halides, alkynyllithium reagents, alkyllithium reagents, etc.
  • the alcohol 5 may be oxidized to the ketone 6 (e.g., Swern oxidation, pyridine sulfur trioxide complex, pyridinium chlorochromate, etc.).
  • Either the aldehyde 4 or the ketone 6 can then be converted to enoate 7 via the appropriate Wittig, Homer Emmons reagent or their synthetic equivalents (e.g., alkyl (triphenylphosphoranylidene)acetate, etc.).
  • R 8 H.
  • the enoate 7 can be reduced to the allylic alcohol 8 or to the intermediate reduction product aldehyde 9.
  • Aldehyde 9 can also be obtained more directly via the oxidation of alcohol 8 under a number of conditions (vide supra).
  • the aldehyde 9 can be converted to the alcohol 10 via reaction with organometallic nucleophiles (e.g., methylmagnesium bromide, etc.).
  • organometallic nucleophiles e.g., methylmagnesium bromide, etc.
  • An alternative procedure to provide 10 wherein R 10 is methyl is reaction of the aldehyde derived from ester 7 with a nucleophilic reagent (e.g.,
  • Compound 10 is equivalent to the alcohol 8 when R 10 is hydrogen.
  • the alcohol 10 is reacted with MsCl under basic conditions (TEA, etc.) to provide the mesylate 11.
  • the mesylate 11 is reacted with sodium azide to provide the azide 12a or with phthalimide anion to provide the phthalimide 12b.
  • Azide 12a can be reduced under a number of conditions (e.g., sodium borohydride, palladium catalyzed hydrogenation, triphenylphosphine followed by acid hydrolysis, etc.) to provide the amine 13.
  • the phthalimide 12b is reacted with N 2 H 4 to provide the amine 13.
  • the amine 13 is guanylated with a variety of guanylation reagents (e.g., S-methyl N-nitrothiopseudothiourea, etc.) to provide the desired compound 14.
  • guanylation reagents e.g., S-methyl N-nitrothiopseudothiourea, etc.
  • the amine nitrogen can be protected with the N-protecting group (P) to provide the intermediate 15.
  • Compound 15 is reacted with acid under hydrolytic conditions to remove the aldehydic/ketonic group (R 1 3 (CO)R 1 5 ) (Scheme 1 , continued) and provide the compound 16.
  • the N-protecting group (P) is labile and a second step of N-protection with (P) is required to provide 16.
  • the alcohol 16 can be oxidized to the compound 17.
  • the protecting group (P') of compound 17 is removed in a standard fashion to provide compound 18.
  • the amine 18 can be guanylated using various guanylation reagents to the provide the compound 19.
  • the protecting group (P) of compound 19 is removed to provide the desired
  • compounds of the type 14 can be reacted under acidic hydrolytic conditions when (P) is an acid labile N-protecting group to provide the desired aminoalcohol 21.
  • compound 23 can be transformed to compound 24.
  • compounds such as 18 can be reacted with cyanogen bromide (alternatively via the sequence involving the intermediate urea form) to produce the cyanamide 25.
  • Compound 25 is converted to the guanidino compound 26 which in turn can be deprotected (loss of (P)) to produce the guanidino compound 27.
  • Compound 13 is reacted with diarylcyanocarbonimidate to provide compound 28 where in the ⁇ symbol represents the aryl group.
  • Compound 28 can be reacted with a nucleophile Y' to provide compound 29 where in R 5 may represent cyano or hydrogen.
  • compound 18 can be reacted with diarylcyanocarbonimidate to yield 30, and compound 30 can be reacted with the nucleophile Y' to produce compound 31.
  • the approach outlined in Scheme 4 begins with readily available ⁇ -amino acids of either D, L, D or L configuration.
  • the ⁇ -amino acids 32 are converted through a number of methods to the corresponding ⁇ -amino acid aldehyde 33.
  • the dimethylpyrazolide of 32 is prepared and then reduced with LAH to provide 33, or the ester of 32 can be reduced to the aldehyde directly via DIBAL reduction or the ester can be reduced fully to the alcohol state and the alcohol oxidized to the aldehyde 33.
  • the aldehyde 33 is reacted with alkenyl lithium reagents to provide the allylic alcohol 34.
  • an alkenyl lithium reagents to provide the allylic alcohol 34.
  • alkynylorganometallic reagent may be added and this intermediate reduced to the corresponding allylic alcohol 34.
  • the alcohol is protected with an O-protecting group (e.g., Cbz, trialkylsilylgroups, etc.) to provide compound 35.
  • Compound 35 is oxidatively degraded to compound 36 via the action of ozone or as an alternative via the action of osmium tetroxide and sodium periodate.
  • the compound 36 is condensed with a Wittig reagent (or Horner-Emmons reagent or their equivalents) to provide the enoate 37.
  • a preferred reagent when R 8 is hydrogen is an alkyl (triphenylphosphoranylidene)acetate or an alkyl (triphenylphosphoranylidene)-propionate.
  • the enoate 37 is reduced via the action of DIBAL (or other reductants) to the allylic alcohol 38.
  • the allylic alcohol 38 is oxygen protected with a different protecting group (P") (eg. t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylacetyl, etc.) to provide compound
  • P protecting group
  • the first O-protecting group (P ') is selectively removed to provide compound
  • Compound 40 is reacted under basic conditions with trichloroacetonitrile to provide an intermediate imidate which upon heating in xylene results in the formation of compound 41.
  • the amide 41 is converted to the guanidine 42 via a sequence of N-deprotection (removal of (P)) and guanylation.
  • the trichloroacetamide can be replaced with alternate N-protecting groups prior to or subsequent to the guanylation step to provide compound 42.
  • compound 42 is fully deprotected via removal of both (P) and (P") to provide compound 43.
  • Compound 41 may also be oxidized to ⁇ -aminoacid 44.
  • O-protecting group (P) is removed and the resulting alcohol treated with Jones reagent (or similar oxidant) to provide 44.
  • Compound 44 may then be transformed to the guanidine 45 in a similar fashion to the transformation of 41 to 42.
  • the guanidine 45 can be converted to the the ⁇ -aminoacid 46 via base treatment to remove the trichloroacetamide group.
  • Scheme 5 illustrates the general synthetic paths that may be used to achieve guanylation of compounds; some of these methods have been illustrated in the previous schemes.
  • An amine of general formula 47 (examples from previous schemes include, but are not limited to, compounds 13, 18 and the N- deprotected forms of compounds 41 and 44) is reacted directly with S-methyl alkylthiopseudouronium salts, N-substituted aminoiminomethanesulfonic acids or the like (for example S-methyl N-methylthiopseudothiourea, S-methyl N-nitrothiopseudothiourea, N-ethyl aminoiminomethanesulfonic acid, etc.) to provide the product 48 directly.
  • S-methyl alkylthiopseudouronium salts for example S-methyl N-methylthiopseudothiourea, S-methyl N-nitrothiopseudothiourea, N-ethyl aminoiminomethanesulf
  • R 3 is equivalent to a carboxylic acid and NR 1 R 2 is equivalent to a simple unprotected amine form
  • cupric salt complex can then be reacted with the guanylating agent and subsequently the copper removed via the action of hydrogen sulfide (or its synthetic equivalents) to provide compound 48.
  • Guanylating reagents such as thiopseudouronium salts, aminoiminosulfonic acids, etc. can generally be prepared from literature sources via the intermediating corresponding urea or thiourea.
  • Compound 47 can also be reacted with isocyanates or isothiocyanates to provide the compound 49.
  • An alternative approach to compound 49 is to first react the amine 47 with phosgene, thiophosgene, or their synthetic equivalents followed by reaction with the amine H 2 NR 5 providing compound 49 in two sequential steps.
  • the parent urea or thiourea produced may be alkylated to provide an intermediate isourea or isothiourea form, which when reacted with the nucleophile NH 2 R5, provides the compound 48.
  • R5 may represent a protecting groups (e.g., Cbz, benzoyl, etc.) which can be removed subsequent to the reaction with NH 2 R 5 to provide the product 48.
  • Cyanamide 50 can also be produced via dehydration of the urea form of 49 in the particular case when R 5 is hydrogen. The cyanamide 50 is reacted with the nucleophile H 2 NR 5 to provide the desired 48.
  • Another specific synthetic transformation outlined in Scheme 6 is the conversion of nitroguanidino compounds to their corresponding aminoguanidino and guanidino derivatives. For example compounds containing the substructure nitroguanidine represented by 51 are reduced in the presence of zinc and acetic acid to provide the aminoguanidine compounds represented by substructure 52. Full reduction of the nitroguanidine 51 provides the guanidine compound represented by substructure 53.
  • NO synthase utilizes L-arginine to produce NO and the by-product citrulline.
  • the enzyme activity can be monitored.
  • an inhibitor would lower the conversion rate, and a substrate would compete with L-arginine and likewise lower the conversion rate.
  • Compounds which reduce citrulline production in this assay are therefore modulators of NO synthase activity.
  • the reaction was stopped by adding 1 mL of stop buffer (2 mM EGTA, 2 mM EDTA, 20 mM Hepes, pH 5.5). The total volume was then applied to a 1 mL Dowex AG 50WX-8 column (Na + form, Bio-Rad) that had been pre-equilibrated with the stop buffer. L-[2,3- 3 H]Citrulline was eluted (2x) with 0.5 mL of stop buffer and radioactivity was determined by liquid scintillation counting.
  • cGMP Assay - Rat Fetal Lung Fibroblast (RFL-6) cells as detectors of EDRF/NO
  • bovine aortic endothelial (BAE) cells cultured in tissue culture plates (alternatively cytosolic preparations from a murine macrophase cell line--RAW cells--induced for 16 hours with 10 ⁇ g/mL medium of LPS, or partially purified (phosphocellulose column) type I isozyme from rat brain cerebellum, or partially purified isozyme III from BAE cells) was quickly transferred to RFL-6 incubations in order to determine NO.
  • RFL cells are incubated directly with the preparation.
  • RFL-6 cells cultured in 6-well tissue culture plates exhibited very high sensitivities to both NO and EDRF: e.g., they
  • Rat fetal lung fibroblast cells (RFL-6, Stanford University, CA) were grown in 6-, 12-, 24- or 48-well tissue culture plates containing F-12 Ham's nutrient mixture supplemented with 15% uninactivated fetal bovine serum.
  • Bovine aortic endothelial (BAE) cells (NIGMS, Human Genetic Mutant Cell Repository,
  • Camden, NJ were cultured in the 6-well plates containing Eagle's Minimum Essential Medium (MEM) supplemented with 20% fetal bovine serum and MEM nonessential amino acids (0.1 mM each). Both culture media contained 2 mM L-glutamate, 100 U/mL penicillin and 0.1 mg/mL streptomycin. Cells were maintained at 37°C under an atmosphere of 95% air: 5% CO 2 .
  • MEM Eagle's Minimum Essential Medium
  • BAE cells (RAW cells [induced with LPS], N1 E-115 cells, rat brain homogenate passed through a phosphocellulose column, etc.) grown to confluence in 6-well plates were used as the source of EDRF/NO. After removing the culture medium, cells were washed twice with 2 mL of Lockes solution
  • RFL-6 cells cultured to confluence were washed twice with a Ca- and Mg-free PBS then equilibrated in Locke's buffer (with 0.3 mM IBMX, 20U/mL of SOD). The volume for preincubation was 500 ⁇ L - 1000 ⁇ L. After incubating RFL-6 cells with conditioned medium from BAE cells (or other EDRF/NO producing systems) for the indicated time periods ( ⁇ 3 minutes), the medium was removed and ice-cold 50 mM sodium acetate buffer (pH 4.0) was added to each well to stop the reaction followed by liquid nitrogen. Cyclic GMP levels in RFL-6 cells were determined by RIA (radioimmunoassay) or samples could be stored at -70°C until radioimmunoassay.
  • inhibitors of NO synthase compounds that reduce the amount of cyclic GMP are termed inhibitors of NO synthase and those that increase cyclic GMP in the absence of exogenous L-arginine are termed substrates or stimulators of NO synthase.
  • substrates or stimulators of NO synthase compounds that reduce the amount of cyclic GMP are termed substrates or stimulators of NO synthase.
  • Table III presents data illustrating that compounds of the invention are effective inhibitors of NO synthase activity, and not competitive substrates of the enzyme.
  • Step 1b 3-(1, 1-Dimethylethyl ) 4-methyl-(R)-2,2-dimethyl-3,4-oxazolidinecarboxylate
  • Example 1 a To a solution of the methyl ester of Example 1 a (1.05 g, 4.8 mmol) in benzene was added 2-methoxypropane (1.0 g, 2 eq) and p-TsOH (0.914 g, 0.1 eq), and the reaction mixture was heated to reflux for 48 hr. The reaction mixture was extracted with EtOAc and the combined organic extracts were washed with brine and H 2 O, dried over MgSO 4 , and concentrated in vacuo.
  • 2-methoxypropane 1.0 g, 2 eq
  • p-TsOH 0.914 g, 0.1 eq
  • Step 1c 1 ,1-Dimethylethyl (R)-4-formyl-2, 2-dimethyl-3-oxazolidinecarboxylate
  • a solution of the methyl ester of Example 1 b (4.61 g, 17.8 mmol) in ⁇ CH 3 cooled to -78°C was added 1 M DIBAL (2.2 mL, 2.2 eq) over a 15-20 minute period.
  • the reaction was stirred for 3-4 hr at -78°C and then quenched with MeOH at -78°C.
  • Step 1d 3-(1 ,1-Dimethylethyl)-(S)-4-(3-(ethoxypropen-2E-oyl))-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 1 e. 3-(1 ,1 -Dimethylethyl)-(S)-4-(3-hydroxypropen-1 ,E-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 1f 3- (1 ,1-Dimethylethyl)-(S)-4-(3-mesyloxypropen-1,E-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 1 g 3-(1,1 -Dimethylethyl )-(S)-4-(3-azidopropen-1.E-yl)-2,2-dimethyl-3- oxazolidinecarboxylate
  • Step 1 h 3-(1,1-Dimethylethyl)-(S)-4-(3-aminopropen-1 ,E-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 1i 3-(1 ,1-Dimethylethyl)-(S)-4-(3-N G -nitroguanidinopropen-1 ,E-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Example 1 h (3-(1 ,1-dimethylethyl)-(S)-4-(3-aminopropen-1 ,E- yl)-2,2-dimethy!-3-oxazolidinecarboxylate) (512 mg, 2 mmol) was dissolved in 20 mL of Et 2 O and treated with CNBr (732 ⁇ L, 2.2 mmol, 3 M in CH 2 Cl 2 ), followed by TEA (613 ⁇ L, 4.4 mmol). After 10 minutes, EtOH (20 mL) and NH 2 OH ⁇ Cl (306 mg, 4.4 mmol) were added and the reaction was stirred overnight at rt (cf. Wagenaar and Kerwin, J. Org.
  • Example 7 The product of Example 7 (19.6 mg, 0.062 mmol) was treated with 5 mL of 4N HCl in dioxane at 4°C and allowed to reach rt. After 1 hr, the reaction: mixture was filtered and the resulting solid was rinsed with Et 2 O.
  • CD 3 OD CD 3 OD
  • ⁇ : 1.47 (s, 9H), 1.51 (s, 3H), 1.60 (s, 3H), 2.83 (s, 3H), 3.57 (m, 2H), 3.60 (m, 1 H), 3.82 (d, J 3.5 Hz, 1 H), 4.08 (m, 1 H), 5.70 (m, 2H); 13 C NMR (500 MHz, D 2 O) ⁇ : 161.5, 134.3, 126.8, 64.2, 56.7, 44.7, 44.5.
  • Step 14b 3-( 1,1-Dimethylethyl)-(S)-4-(3-hydroxy-2-methylpropen-1 ,E-yl)-2,2- dimethyl-3-oxazolidinecarboxylate.
  • Step 14c 3-(1 ,1-Dimethylethyl)-(S)-4-(3-phthalimido-2-methyl-propen-1 ,E-yl)-
  • Step 14d 3- (1 ,1-Dimethylethyl)-(S) -(3-amino-2-methyl-propen-1 ,E-yl)-2,2-dimethyl-3-oxazolidinecarboxylate.
  • MeOH 4.0 mL
  • N 2 H 4 85% N 2 H 4
  • the reaction was then poured into brine and washed (3x) with 25 mL of CH 2 Cl 2 , dried over Na 2 SO 4 , and concentrated in vacuo.
  • Step 14e 3-(1 ,1-Dimethylethyl)-(S)-4-(3-nitroauanidino-2-methyl-propen-1 ,E-yl)-
  • Step 16a 3-(1,1-Dimethylethyl)-(S)-4-(3-(2-benzyl-benzyloxypropen-2E-oyl))-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 16b 3-(1 ,1-Dimethylethyl)-(S)-4-(3-hydroxy-2-benzyl-propen-1 ,E-yl)-2,2-dimethyl-3-oxazolidinecarboxylate.
  • Step 16c 3-(1, 1-Dimethylethyl)- (S)-4-(3-phthalimido-2-benzyl-propen-1 ,E-yl)-2,2-dimethyl-3-oxazolidinecarboxylate.
  • Step 16d 3-(1, 1-Dimethylethyl)- (S)-4-(3-amino-2-benzyl-propen-1 ,E-yl)-2,2-dimethyl-3-oxazolidinecarboxylate.
  • Step 16e 3-(1, 1-Dimethylethyl)- (S)-4-(3-nitroguanidino-2-benzyl-propen-1,E-yl)- 2,2-dimethyl-3-oxazolidinecarboxylate.
  • N4-Boc-N G Methylguanidinyl-4(S)-amino-pent-2.E-ene-5-ol
  • 3-(1 ,1-dimethylethyl)-(S)-4-(3-aminopropen-1 ,E-yl)-2,2-dimethyl- 3-oxazolidinecarboxylate from Example 1 h (0.257 g, 1.0 mmol) in EtOH/H 2 O 1/1 (9.0 mL) was added N-methyl-S-methylthiopseudouronium sulfate (0.5560 g, 2.0 eq) and TEA (0.142 mmol, 1.0 eq) and the reaction mixture was stirred at rt for 24 hr.
  • Example 24 Utilizing the material from example 22 and the procedure of example 4 the product is prepared.
  • Example 24
  • Step 30a N-[(1,1-Dimethylethoxy)carbonyl]-D-serine methyl ester
  • Step 30b 3-(1 ,1-Dimethylethyn 4-methyl-(R)-2,2-dimethyl-3,4-oxazolidinecarboxylate
  • Example 30a To a solution of the methyl ester of Example 30a (1.05 g, 4.8 mmol) in benzene was added 2-methoxypropane (1.0 g, 2 eq) and p-TsOH (0.0914 g, 0.1 eq), and the reaction mixture was heated to reflux for 48 hr. The reaction mixture was extracted with EtOAc and the combined organic extracts were washed with brine and H 2 O, dried over MgSO 4 and concentrated in vacuo.
  • 2-methoxypropane 1.0 g, 2 eq
  • p-TsOH p-TsOH
  • Step 30c 1 ,1-Dimethylethyl (R)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate
  • a solution of the methyl ester of Example 30b (4.61 g, 17.8 mmol) in ⁇ CH 3 cooled to -78°C was added 1 M DIBAL (2.2 mL, 2.2 eq) over a 15-20 minute period.
  • the reaction mixture was stirred for 3-4 hr at -78°C and then quenched with CH 3 OH at -78°C.
  • Step 30d 3-(1 ,1-Dimethylethyl )-(S)-4-(3-(methoxypropen-2 ,Z-oyl))-2,2-dimethyl- 3-oxazolidinecarboxylate
  • Step 30e 3-( 1,1-Dimethylethyl )-(S)-4-(3-hydroxypropen-1 ,Z-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 30f 3-(1 ,1-Dimethylethyl)-(S)-4-(3-mesyloxypropen-1 ,Z-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 30g 3-(1 ,1-Dimethylethyl)-(S)-4-(3-phthalimidopropen-1 ,Z-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 30h 3-(1,1 -Dimethylethyl)-(S)-4-(3-aminopropen-1 ,Z-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 30 i 3-(1 ,1 -Dimethylethyl)-(S)-4-(3-N G -nitroguanidinopropen-1 ,Z-yl )-2,2-dimethyl-3-oxazolidinecarboxylate
  • Example 30g To the product of Example 30g (1.50 g, 3.88 mmol) was added 7.5 mL HOAc, 2.5 mL H 2 O, and 0.5 mL 12M HCl. The mixture was allowed to stir at ambient temperature for approximately 3 hr, whereupon the volatile components were removed in vacuo to give the title compound as a white solid (1.10 g, 3.88 mmol) in quantitative yield.
  • Step 32b N 2 -t-Butyloxycarbonyl-2-amino-5-phthalimido-(2,S,-3, Z-penten-1-ol
  • the product from Example 32a (501 mg, 1.77 mmol) was dissolved in 10 mL of anhydrous DMF.
  • Di-t-butyl dicarbonate (464 mg, 2.12 mmol) and NMM (214 mg, 2.12 mmol) were added, and the reaction was allowed to stir at rt overnight whereupon the reaction was diluted with EtOAc and saturated aqueous KHSO 4 .
  • Step 32c N 4 -t-Butyloxycarbonyl-4-amino-5-methoxy-1-phthalimido-(4,S)-2, Z-pentene
  • Example 32b The product of Example 32b (330 mg, 0.95 mmol) was dissolved in 4.75 mL of anhydrous DMF. Calcium sulfate (CaSO 4 ) (646 mg, 4.75 mmol), CH 3 I (649 mg, 4.75 mmol), and freshly prepared silver (I) oxide (220mg, 0.95 mmol) were added, and the reaction was heated at 40-45°C for 72 h whereupon EtOAc was added. The organic layer was then washed twice with saturated aqueous
  • Partial Data- minor component 1.5 (s, 9H), 2.82 (s, 3H), 3.39 (s, 3H), 5.55 (m, 1 H); MS (Cl) major: m/e 378 (m+NH 4 ) + , 361 (m+H) + ; minor: 392 (m+NH 4 ) + , 375 (m+H) + .
  • Step 32d N 4 -t-Butyloxycarbonyl -amino- 1-N G -nitroguanidino-5-methoxy-(4 ,S)- 2, Z-pentene
  • Example 32c The products from Example 32c (290 mg, 0.80 mmol) were dissolved in 4 mL of anhydrous CH 3 OH and N 2 H4 hydrate (77 mg, 2.40 mmol) was added. The mixture was stirred at ambient temperature under nitrogen atmosphere overnight whereupon it was refluxed for 2 hr to effect phthaloyi deprotection. The volatile components were removed in vacuo and the resulting tan solids (190 mg) were dissolved in 2 mL of CH 3 OH.
  • Example 32d The product of Example 32d was deprotected as in example 31.
  • Example 34 Example 34
  • Example 32b To the product of Example 32b (200 mg, 0.58 mmol) and freshly recrystallized imidazole (chloroform / hexane) dissolved in DMF (1 mL) was added t-butyldimethylsilyl chloride (105 mg, 0.70 mmol). The mixture was heated under a N 2 atmosphere at 35°C overnight whereupon the mixture was diluted with EtOAc and subjected to aqueous washes and extractive work-up in a manner similar to that described for Example 32c giving the title compound (228 mg, 0.49 mmol) as a clear oil which was carried on without further purification.
  • imidazole chloroform / hexane
  • Step 34b N 2 -Methyl-N 2 -t-butyloxycarbonyl-2, 5-diamino-1-t-butyldimethylsilyloxy-(2,S)-3,Z-pentene
  • Step 36a N-[(1 ,1-Dimethylethoxy)carbonyl]-S-serine methyl ester
  • Step 36b 3-(1,1-Dimethylethyl) 4-methyl-(S)-2,2-dimethyl-3,4-oxazolidinecarboxylate
  • Step 36c 1 ,1-Dimethylethyl (S)-4-formyl-2, 2-dimethyl-3-oxazolidinecarboxylate
  • a solution of the methyl ester of Example 36b (37 mmol) in 200 mL ⁇ CH 3 cooled to -78°C was added 1 M DIBAL (65 mmol, in ⁇ CH 3 ) over a 15-20 minute period.
  • the reaction was stirred for 3-4 hr at -78°C and then quenched with CH 3 OH (12 mL) at -78°C.
  • Step 36d 3-(1 ,1-Dimethylethyl)-(R)-4-(3-(methoxypropen-2,Z-oyl))-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 36f 3-(1 ,1-Dimethylethyl)-(R)-4-(3-mesyloxypropen-1 ,Z-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 36g 3-(1 ,1-Dimethylethyl)-(R)-4-(3-phthalamidopropen-1 ,Z-yl -2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 36h 3-(1 ,1-Dimethylethyl)-(R)-4-(3-aminopropen-1 ,Z-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Step 36i 3-(1 ,1-Dimethylethyl)-(R)-4-(3-N G -nitroguanidinopropen-1 ,Z-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Example 31 Enantiomeric purity determinations for proucts from Example 31 and Example 37 were performed by chiral HPLC using a Daicel Crownpak CR(+) 4.6 ⁇ 150 mm column and 0.01 M perchloric acid mobile phase at 5°C with the results: Example 31 , 95.6 % ee; Example 38, 93.6 % ee.
  • Step 38a 3-(1 ,1 -Dimethylethyl)-(S)-4-.3-N G -aminoguanidinopropen-1 .Z-yl)-2,2-dimethyl-3-oxazolidinecarboxylate
  • Example 30h The product of Example 30h (163 mg, 0.64 mmol) was dissolved in 20 mL Et 2 O and treated with TEA (178 ⁇ L, 1.28) followed by cyanogen bromide (200 ⁇ L, 0.60 mmol, 3M in CH 2 Cl 2 ) added dropwise over 2 min. After 1 hr, the crude reaction mixture was chromatographed on silica gel eluted with 2:1 hexane-EtOAc to provide 150 mg, 0.53 mmol, 83 % yield of the intermediate cyanamide material. The cyanamide (145 mg, 0.52 mmol) was dissolved in 20 mL EtOH and treated with N 2 H 4 monohydrochloride (110 mg, 1.7 mmol) at reflux temperature overnight.
  • reaction mixture was cooled and the residue from solvent evaporation was chromatographed on silica gel and eluted with 20:1 :1 CH 3 CN-HOAC-H 2 O to provide product 147 mg, 0.42 mmol, 70%.
  • Example 38a The protected product of Example 38a (75 mg, 0.21 mmol) was treated with 1 mL 6N HCl for 3 hr at rt. The crude reaction was diluted with H 2 O and lyophilized to provide 58.6 mg, 0.20 mmol, 95% yield (as 5.75 HCl salt); HPLC: 99.1% pure (YMC-ODS-AQ column, elution with H 2 O). RF 0.2 (1 :2 EtOAc-PAW); 1 H NMR
  • Step 41 a N,N-Di-t-butyloxycarbonyl-3-Hydroxymethyl-6-methyl-[1 ,6][2,3]-tetrahydropyridazine.
  • Step 41 b N 2 ,5 -Di-t-Butyloxycarbonyl-2,5-diaminohex-3,Z-en-1 -ol.
  • Example 41a Into a solution of the product of Example 41a (1.54 g, 4.7 mmoles) in 20 mL of THF was distilled 60 mL of NH 3 with vigorous stirring. Sodium metal was added until the solution remained blue, and the reaction mixture was stirred for 90 min, then quenched with anhydrous NH 4 Cl. The NH 3 was allowed to evaporate, and the residue was poured into 50 mL of H 2 O. The mixture was extracted with 150 mL of 70% EtOAc/hexane. The organic phase was washed with 150 mL of H 2 O, then 100 mL of saturated NaHCO 3 . The organic phase was dried over MgSO4, and concentrated in vacuo to give a thick syrup.
  • Step 41 c.3-(t-butyloxycarbonylamino-3.Z-butenyl)-2-oxazolidinone
  • Step 41 e.3-(N-nitroguanidinoamino-3,Z-butenyl )-2-oxazolidinone

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Abstract

L'invention se rapporte à des composés de guanidine de la formule (I) ou à un sel pharmaceutiquement acceptable de ceux-ci, un ester, un amide ou un promédicament de ceux-ci, qui sont des régulateurs de la synthase de l'oxyde nitrique et qui sont utilisés dans le traitement de troubles du système vasculaire, tels que l'hypotension, l'hypertension, le choc d'origine vasculaire, l'athérosclérose, la migraine ou l'ischémie; ainsi que dans le traitement de troubles du système gastro-intestinal, tels que le reflux ÷sophagien, la diarrhée, ou le côlon irritable, et des états pathologiques associés aux muscles lisses bronchiques, tels que l'asthme. L'invention se rapporte en outre à l'inhibition de l'agrégation et du traitement des plaquettes utilisées dans les transfusions et perfusions, et au traitement des diabètes.
PCT/US1994/004243 1994-04-18 1994-04-18 Composes de guanidine utilises comme regulateurs de la synthase de l'oxyde nitrique WO1995028377A1 (fr)

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US6034137A (en) * 1996-10-22 2000-03-07 Syntex (U.S.A.) Inc. Cationic lipids for gene therapy
WO2000076451A2 (fr) * 1999-06-11 2000-12-21 Centre National De La Recherche Scientifique - Cnrs Composition pharmaceutique comprenant du no un compose donneur de no, ou inducteur de la formation de no et son utilisation en therapie
WO2007009462A2 (fr) * 2005-07-15 2007-01-25 Region Hovedstaden V/Glostrup Hospital Traitement de la migraine et des cephalees
US9216178B2 (en) 2011-11-02 2015-12-22 Biomarin Pharmaceutical Inc. Dry blend formulation of tetrahydrobiopterin
US9433624B2 (en) 2003-11-17 2016-09-06 Biomarin Pharmaceutical Inc. Methods and compositions for the treatment of metabolic disorders

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WO2000076451A2 (fr) * 1999-06-11 2000-12-21 Centre National De La Recherche Scientifique - Cnrs Composition pharmaceutique comprenant du no un compose donneur de no, ou inducteur de la formation de no et son utilisation en therapie
WO2000076451A3 (fr) * 1999-06-11 2002-06-20 Centre Nat Rech Scient Composition pharmaceutique comprenant du no un compose donneur de no, ou inducteur de la formation de no et son utilisation en therapie
JP2003506320A (ja) * 1999-06-11 2003-02-18 センター ナショナル デ ラ レシェルルシェ サイエンティフィック−シーエヌアールエス Ｎｏもしくは少なくとも１つのｎｏ供与化合物または細胞においてｎｏを放出するかもしくはｎｏの形成を誘導することが可能な他の化合物を含む薬学的組成物
US6872751B2 (en) 1999-06-11 2005-03-29 Centre National De La Recherche Scientifique - Cnrs Composition and method for augmenting or restoring the production of fetal protein in patient in need thereof
US9433624B2 (en) 2003-11-17 2016-09-06 Biomarin Pharmaceutical Inc. Methods and compositions for the treatment of metabolic disorders
US9993481B2 (en) 2003-11-17 2018-06-12 Biomarin Pharmaceutical Inc. Methods and compositions for the treatment of metabolic disorders
WO2007009462A2 (fr) * 2005-07-15 2007-01-25 Region Hovedstaden V/Glostrup Hospital Traitement de la migraine et des cephalees
WO2007009462A3 (fr) * 2005-07-15 2007-05-03 Koebenhavns Amt Traitement de la migraine et des cephalees
US9216178B2 (en) 2011-11-02 2015-12-22 Biomarin Pharmaceutical Inc. Dry blend formulation of tetrahydrobiopterin

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