EP0946587A2 - Amindverbindungen und ihre verwendung als inhibitoren der bitric-oxid-synthase - Google Patents

Amindverbindungen und ihre verwendung als inhibitoren der bitric-oxid-synthase

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Publication number
EP0946587A2
EP0946587A2 EP97912529A EP97912529A EP0946587A2 EP 0946587 A2 EP0946587 A2 EP 0946587A2 EP 97912529 A EP97912529 A EP 97912529A EP 97912529 A EP97912529 A EP 97912529A EP 0946587 A2 EP0946587 A2 EP 0946587A2
Authority
EP
European Patent Office
Prior art keywords
preparation
group
phenyl
alkyl
nmr
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.)
Withdrawn
Application number
EP97912529A
Other languages
English (en)
French (fr)
Inventor
Takumi Yatabe
Yoshikuni Itoh
Takayuki Inoue
Hitoshi Hamashima
Ichiro Shima
Kazuhiko Ohne
Kousei Yoshihara
Teruo Oku
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.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
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
Priority claimed from AUPO4219A external-priority patent/AUPO421996A0/en
Priority claimed from AUPO5929A external-priority patent/AUPO592997A0/en
Priority claimed from AUPO9030A external-priority patent/AUPO903097A0/en
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP0946587A2 publication Critical patent/EP0946587A2/de
Withdrawn legal-status Critical Current

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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • TECHNICAL FIELD This invention relates to new amide compounds and pharmaceutically acceptable salts thereof which are useful as medicament.
  • This invention relates to new amide compounds.
  • One object of this invention is to provide the new and useful amide compounds and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on the production of nitric oxide (NO).
  • Another object of this invention is to provide a process for the preparation of the amide compounds and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising said amide compound or a pharmaceutically acceptable salt thereof.
  • Still further object of this invention is to provide a use of said amide compounds or pharmaceutically acceptable salts thereof as a medicament for prophylactic and therapeutic treatment of NO-mediated diseases such as adult respiratory distress syndrome, cardiovascular ischemia, myocarditis, heart failure, synovitis, shock (e.g., septic shock, etc.), diabetes (e.g., insulin-dependent diabetes mellitus, etc.), diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, glomerulonephritis, peptic ulcer, inflammatory bowel disease (e.g., ulcerative colitis, chronic colitis, etc.), cerebral infarction, cerebral ischemia, cerebral hemorrhage, migraine, rheumatoid arthritis, gout, neuritis, postherpetic neuralgia, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, derma
  • R 1 is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, benzofuranyl, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbaoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
  • R 2 is hydrogen or phenyl(lower)alkyl
  • R* is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halogen, trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy, quinolyl or 3,4-methylenedioxyphenyl;
  • R 5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
  • R 7 and R 8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
  • Y is a group of the formula
  • R 3 is hydrogen or a group of the formula -(CH 2 ) consult-R 6 in which R 6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
  • R 11 is phenyl, phenoxy or phenyl(lower)alkoxy; or R 2 and R 3 in combination form a group of the formula
  • R 1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof, provided that the compound shown below is excluded: a compound of the formula
  • R 1 ' is indolyl or benzofuranyl
  • R 2 ' is hydrogen, lower alkylthio(lower)alkyl or a group of the formula
  • R 5 ' is hydrogen, lower alkoxy or halogen
  • R 3 ' is hydrogen, quinolyl or phenyl which may have a suitable substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen
  • R*' is hydrogen or optionally esterified carboxy
  • X' is S or NR 6 ' in which R 6 ' is hydrogen, lower alkyl or a group of the formula - CH2 - ⁇ JT
  • R 7 ' is lower alkyl or lower alkoxy, and a pharmaceutically acceptable salt thereof.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an inorganic acid addition salt e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g., arginine, aspartic acid, gultamic acid, etc.
  • lower is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
  • Suitable "lower alkoxy” and “lower alkoxy moiety" in the terms “lower alkoxy(lower)alkoxy” and “phenyl(lower) lkoxy” include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy and hexyloxy, in which more preferred one is Ci-C* alkoxy.
  • Suitable "halogen” includes, for example, fluorine, bromine, chlorine and iodine.
  • Optionally esterified carboxy includes carboxy and esterified carboxy. Suitable examples of said ester include lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1 -methoxyethyl ester, 1 -ethoxyethyl ester, etc.); mono(or
  • Suitable "trihalomethyl” includes, for example, trifluoromethyl, trichloromethyl and tribromomethyl, in which preferred one is trifluoromethyl.
  • Suitable “amino protective group” includes, for example, acyl and conventional protective group such as mono(or di or tri)aryl(lower)- alkyl, for example, mono(or di or tri)phenyl(lower)alkyl (e.g., benzyl, trityl, etc.).
  • acyl and “acyl moiety” in the terms “acylamino”, “diacylamino” and “acylamino(lower)alkyl” include, for example, carbamoyl which may be substituted by suitable substituent(s), aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or a heterocyclic ring, which is referred to as heterocyclic acyl.
  • acyl which may be substituted by suitable substituent(s)
  • substituent(s) includes a group of the formula
  • R 12 and R 13 are the same or different and each is hydrogen, lower alkyl, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, phenyl(lower)- alkyl, pyridyl, pyridyl(lower)alkyl or 3,4-methylenedioxyphenyl; aliphatic acyl such as lower alkanoyl which may be substituted by one to three halogen atoms (e.g., formyl, acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, trichloroacetyl, trifluoroacetyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert- pentyl
  • naphthyl(lower)alkanoyl e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.
  • aryl(lower)alkoxycarbonyl e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.
  • aryloxycarbonyl e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.
  • aryloxy(lower)alkanoyl e.g., phenoxyacetyl, phenoxypropionyl, etc.
  • arylsulfonyl e.g., phenylsulfonyl, p-tolylsufonyl, etc.
  • heterocyclic acyl such as indolylcarbonyl (e.g., indolylcarbon
  • Optionally protected hydroxy includes hydroxy and protected hydroxy.
  • Suitable examples of "hydroxy protective group" in the term “protected hydroxy” include acyl (e.g., acetyl, trichloroacetyl, etc.), mono(or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
  • acyl e.g., acetyl, trichloroacetyl, etc.
  • mono(or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) (
  • Suitable "protected carboxy” is carboxy group protected by conventional protective group such as lower alkoxycarbonyl [e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.], optionally substituted phenyl(lower)- alkoxycarbonyl for example, mono- or di- or triphenyl(lower)- alkoxycarbonyl which may be substituted by nitro [e.g., benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, etc.] and the like.
  • lower alkoxycarbonyl e.g., methoxycarbonyl,
  • Suitable "cyclo(lower)alkyl” includes cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in which more preferred ones are cyclopropyl and cyclobutyl.
  • morpholinyl includes 2-morpholinyl, 3-morpholinyl and 4-morpholinyl (i.e. morpholino).
  • piperidyl includes 1 -piperidyl (i.e. piperidino), 2- piperidyl, 3-piperidyl and 4-piperidyl.
  • the object compound (I) of the present invention can be prepared by the following processes.
  • R 1 , R 2 , R ft , R 5 , R 7 , R 8 , R 9 , X, Y, m and n are each as l 7 defined above,
  • R 1 * is amino protective group
  • R 15 is hydrogen or lower alkyl
  • R 16 is acyl
  • R 1 is acylamino or diacylamino
  • R 18 is carboxy or lower alkoxycarbonyl
  • R 19 is esterified carboxy
  • R 20 is acylamino or diacylamino
  • R 21 is carbamoyl which may be substituted by suitable substituent(s)
  • R 22 is hydroxy protective group
  • R 23 is acyl
  • R 2 * is lower alkyl
  • R 25 is protected carboxy
  • R 26 is esterified carboxy
  • R 27 is carbamoyl which may be substituted by suitable substituent(s)
  • R 28 is acylamino or diacylamino
  • R 29 is acyl
  • R 30 is esterified carboxy.
  • the starting compounds can be prepared by the method of Preparation mentioned below or by a process known in the art for preparing their structually analogous compounds.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group, or a salt thereof with the compound (III) or its reactive derivative at the
  • Suitable reactive derivative of the compound (II) includes Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as N,0- bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene.
  • Suitable reactive derivative of the compound (III) includes an acid halide, an acid anhydride and an activated ester.
  • the suitable example may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'- dicyclohexylcarbodiimide; N-cyclohexyl-N' -morpholinoethylcarbodiimide; N-cyclohexyl-N' -(4-diethylaminocyclohexyl)carbodiimide; N,N' - diisopropylcarbodiimide; N-ethyl-N' -(3-dimethylaminopropyl)- carbodiimide; N,N-carbonyl-bis-(2-methylimidazole) ; pentamethylene- ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1 -alkoxy-1 -chloroethylene; trialkyl pho
  • the reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N- di(lower)alkylbenzylamine, or the like.
  • an organic or inorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N- di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound (I)-1 or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (IV).
  • the reaction can be carried out in the same manner as in or a manner similar to Example 27.
  • the compound (I)-2 or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to elimination reaction of the amino protective group.
  • Suitable method of this elimination reaction includes conventional one such as hydrolysis, reduction and the like, (i) For hydrolysis :
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base includes an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline, 1 ,5-diazabicyclo[ .3.0]non-5-one, or the like.
  • an alkali metal e.g., sodium, potassium, etc.
  • an alkaline earth metal e.g., magnesium, calcium, etc.
  • trialkylamine e.g., trimethylamine, triethylamine, etc.
  • picoline 1 ,5-diazabicyclo[ .3.0]non-5-one, or the like.
  • Suitable acid includes an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], and an inorganic acid [e.g. , hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].
  • organic acid e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g. , hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.
  • Lewis acid such as trihaloacetic acid [e.g., trichloroacetic acid, trifluoroacetic acid, etc.], or the like is preferably carried out in the presence of cation trapping agents [e.g., anisole, phenol, etc.]. This reaction is usually carried out without solvent.
  • the reaction may be carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • reaction temperature is not critical and the reaction is usually carried out under cooling to warming, (ii) For reduction :
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing reagent to be used in chemical reduction are hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.), or a combination of a metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
  • a metal e.g., tin, zinc, iron, etc.
  • metallic compound e.g., chromium chloride, chromium acetate, etc.
  • organic acid or inorganic acid e.g., formic acid, acetic acid, propionic acid,
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.
  • platinum catalysts e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.
  • nickel catalysts e.g., reduced nickel, nickel oxide, Raney nickel, etc.
  • cobalt catalysts e.g., reduced cobalt, Raney cobalt, etc.
  • iron catalysts e.g., reduced iron, Raney iron, Ullman iron, etc.
  • the reduction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • alcohol e.g., methanol, ethanol, isopropyl alcohol, etc.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (I)-4 or a salt thereof can be prepared by reacting the compound (I) ⁇ 3 or its reactive derivative at the amino group, or a salt thereof with the compound (VI) or its reactive derivative at the carboxy group, or a salt thereof.
  • This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (1 ) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process ⁇ .
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (I)-6 or a salt thereof can be prepared by subjecting the compound (I)-5 or a salt thereof to reduction.
  • the reduction can be carried out in the same manner as in or a manner similar to Example 60.
  • the compound (I)-7 or a salt thereof can be prepared by subjecting the compound (I)-6 or a salt thereof to acylation.
  • the acylation can be carried out in the same manner as in or a manner similar to Example 61.
  • the compound (I)-9 or a salt thereof can be prepared by subjecting the compound (I)-8 or a salt thereof to reduction.
  • the reduction can be carried out in the same manner as in or a manner similar to Example 111.
  • the compound (I)-10 or a salt thereof can be prepared by subjecting the compound (I)-9 or a salt thereof to oxidation.
  • the oxidation can be carried out in the same manner as in or a manner similar to Example 112.
  • the compound (I)-12 or a salt thereof can be prepared by subjecting the compound (I)-11 or a salt thereof to hydrolysis.
  • the hydrolysis can be carried out in the same manner as in or a manner similar to Example 113.
  • the compound (I)-14 or a salt thereof can be prepared by subjecting the compound (I)-13 or a salt thereof to reduction.
  • the reduction can be carried out in the same manner as in or a manner similar to Example 123.
  • the compound (I)-15 or a salt thereof can be prepared by subjecting the compound (I)-14 or a salt thereof to acylation.
  • the acylation can be carried out in the same manner as in or a manner similar to Example 124.
  • the compound (I)-16 or a salt thereof can be prepared by subjecting the compound (I)-12 or a salt thereof to amidation.
  • the compound (I)-18 or a salt thereof can be prepared by subjecting the compound (I)-17 or a salt thereof to elimination reaction of the hydroxy protective group.
  • This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (3) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc. ) can be referred to those of the Process (3).
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (I)-19 or a salt thereof can be prepared by subjecting the compound (I)-18 or a salt thereof to esterification.
  • the esterification can be carried out in the same manner as in or a manner similar to Example 133.
  • the compound (I)-20 or a salt thereof can be prepared by subjecting the compound (I)-18 or a salt thereof to 0-alkylation.
  • the 0-alkylation can be carried out in the same manner as in or a manner similar to Example 135.
  • the compound (I)-22 or a salt thereof can be prepared by subjecting the compound (I)-21 or a salt thereof to elimination reaction of the carboxy protective group.
  • This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (3) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (3).
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (I)-23 or a salt thereof can be prepared by subjecting the compound (I)-22 or a salt thereof to esterification.
  • the esterification can be carried out in the same manner as in or a manner similar to Example 74.
  • the compound (I)-24 or a salt thereof can be prepared by subjecting the compound (I)-22 or a salt thereof to amidation.
  • the amidation can be carried out in the same manner as in or a manner similar to Example 95.
  • the compound (I)-26 or a salt thereof can be prepared by subjecting the compound (I)-25 or a salt thereof to reduction.
  • the reduction can be carried out in the same manner as in or a manner similar to Example 119.
  • the compound (I)-27 or a salt thereof can be prepared by subjecting the compound (I)-26 or a salt thereof to acylation.
  • the acylation can be carried out in the same manner as in or a manner similar to Example 120.
  • the compound (I)-29 or a salt thereof can be prepared by subjecting the compound (I)-28 or a salt thereof to esterification.
  • the esterification can be carried out in the same manner as in or a manner similar to Example 138.
  • the compound (I)-31 or a salt thereof can be prepared by subjecting the compound (I)-30 or a salt thereof to hydrolysis.
  • the hydrolysis can be carried out in the same manner as in or a manner similar to Example 168.
  • the compound (I)-32 or a salt thereof can be prepared by reacting the compound (I)-31 or its reactive derivative at the carboxy group, or a salt thereof with the compound (VII) or its reactive derivative at the amino group, or a salt thereof.
  • This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (1 ) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process
  • the compound (I)-33 can be prepared by reacting the compound (VIII) with the compound (IX) in the presence of an acid.
  • This reaction can be carried out in the same manner as in or a manner similar to Example 178.
  • Suitable salts of the starting compounds and their reactive derivatives in Process (1) can be referred to the ones as exemplified for the compound (I).
  • the compounds obtained by the above process can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
  • the compound (I) and the other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixtures thereof are included within the scope of this invention.
  • the object compounds (I) and pharmaceutically acceptable salts thereof include solvates [e.g., enclosure compounds (e.g., hydrate, etc.)].
  • the object compounds (I) and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO).
  • the object compounds (I) and pharmaceutically acceptable salts thereof are expected to possess a nitric oxide synthase (NOS)-inhibitory activity or a NOS-production inhibitory activity.
  • NOS nitric oxide synthase
  • NO-mediated diseases such as adult respiratory distress syndrome, cardiovascular ischemia, myocarditis, heart failure, synovitis, shock (e.g., septic shock, etc.), diabetes (e.g., insulin-dependent diabetes mellitus, etc.), diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, glomerulonephritis, peptic ulcer, inflammatory bowel disease (e.g., ulcerative colitis, chronic colitis, etc.), cerebral infarction, cerebral ischemia, cerebral hemorrhage, migraine, rheumatoid arthritis, gout, neuritis, postherpetic neuralgia, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, dermatitis, hepatitis, liver cirrhosis, multiple sclerosis, pancrea
  • test Compounds In order to illustrate the usefulness of the object compound (I) , the pharmacological test result of the representative compound of the compound (I) is shown in the following. Test Compounds :
  • RAW264.7 American Type Culture Collection, No. TTB71
  • DMEM Dulbecco's modified Eagle's medium
  • penicillin, streptomycin and 10$ heat-inactivated fetal bovine serum were removed from culture flasks by rubber cell scraper and were centrifuged and resuspended in DMEM without phenol red. They were plated in 96-well microtiter plates (10 5 cells per well) and allowed to adhere over 2 hours.
  • test samples were added and the cells were preincubated for 1 hour. Thereafter the cells were activated with both of lipopolysaccharide (LPS) (1/zg/ml) and interferon ⁇ (INF ) (3 u/ml) for 18-24 hours.
  • LPS lipopolysaccharide
  • INF interferon ⁇
  • An equal volume of Griess reagent ( ] % sulfanilamide/0.1/ ⁇ N-naphthylethylenediamine dihydrochloride/2.5% H3PO1*) was added and the cells were incubated at room temperature for 10 minutes. The absorbance was read at 570 nm using microplate reader and NO ⁇ " was measured using NaNO ⁇ as a standard.
  • the object compound (I) of the present invention and pharmaceutically acceptable salts thereof are used in the form of a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • the pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee, suppository or ointment, or in a liquid form such as solution, suspension or emulsion for injection, intravenous drip, ingestion, eye drop, etc.
  • auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
  • the effective ingredient may usually be administered in a unit dose of 0.001 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, body weight and conditions of the patient or administering method.
  • R 1 is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, benzofuranyl, phenyl which may have one or two
  • R 2 is hydrogen or phenyl(lower)alkyl
  • R* is phenyl or pyridyl, each of which has suitable substituent(s) selected from the group consisting of trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazoly1, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy, or 3, -methylenedioxyphenyl;
  • R 5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
  • R 7 and R 8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
  • Y is a group of the formula
  • R 6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower) lkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
  • R 1 ' is phenyl, phenoxy or phenyl(lower)alkoxy; or R 2 and R 3 in combination form a group of the formula
  • R 1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
  • R 1 is indolyl which has a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbamoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
  • R 2 is hydrogen or phenyl(lower)alkyl
  • R ft is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen or quinolyl;
  • R 5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
  • R 7 and R 8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
  • Y is a group of the formula
  • R 6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
  • R 1 ' is phenyl, phenoxy or phenyl(lower)alkoxy; or R 2 and R 3 in combination form a group of the formula
  • R 1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
  • R 1 is indolyl or benzofuranyl
  • R 2 is hydrogen or phenyl(lower) lkyl
  • R* is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen or quinolyl;
  • R 5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
  • R 7 and R 8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
  • Y is a group of the formula
  • R 3 is a group of the formula in which R 6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, phenyl which has a suitable substituent selected from the group consisting of amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
  • R 11 is phenyl, phenoxy or phenyl(lower)alkoxy; or R 2 and R 3 in combination form a group of the formula
  • R 1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
  • R 1 is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro or benzofuranyl;
  • R 2 is hydrogen
  • R" is phenyl which may have suitable substituent(s) selected from the group consisting of trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy;
  • R 5 is hydrogen
  • Y is a group of the formula
  • R 6 is pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, and n is an integer of 0 to 3; m is 0 or 1 ; and X is NR 9 in which R 9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
  • R 1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
  • the starting compound (430 mg) was dissolved in trifluoroacetic acid (1.5 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, made basic with 1N sodium hydroxide solution and extracted three times with chloroform. The organic layer was dried over magnesium sulfate and filtered. Evaporation of the solvent gave the object compound as an oil (314 mg).
  • the starting compound (600 mg) was heated at 40°C for 2 hours in methyl iodide (10 ml). The reaction mixture was evaporated, and the residue was suspended in an aqueous sodium carbonate solution. The mixture was extracted with chloroform. The organic layer was washed successively with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a chloroform-methanol (20:1) as eluent to give the object compound as a pale yellow oily solid (376.5 mg). mp : 116-119°C MASS (ESI) (m/z) : 302 (M+H) +
  • the object compound was obtained according to a similar manner to that of Preparation 3 except that a mixutre of trifluoroacetic acid and dichloromethane was used instead of trifluoroacetic acid.
  • MASS 322 (M+1)
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • a solution of potassium tert-butoxide (4.2 g) in anhydrous tetrahydrofuran (70 ml) was cooled under nitrogen atmosphere to -70°C, and a solution of the starting compound (10 g) in anhydrous tetrahydrofuran (35 ml) was added while maintaining the reaction temperature at -70°C. After 30 minutes, this solution was added dropwise to a solution of 4-bromobenzoyl chloride (8.21 g) in anhydrous tetrahydrofuran (24 ml) with stirring while cooling at -70°C on a cooling bath. The reaction mixture was stirred at -70°C for 1 hour and quenched with 3N-hydrochloric acid (100 ml).
  • the cooling bath was removed and the reaction mixture was concentrated to dryness under reduced pressure.
  • the residue was dissolved in water (15 ml) and extracted with diethyl ether (twice).
  • the aqueous layer was concentrated in vaciio , and the residue was dissolved in anhydrous methanol.
  • the precipitated white solid (KCl) was removed by filtration.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 91.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5 except that a mixture of dichloromethane and dimethylformamide was used instead of dichloromethane.

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EP97912529A 1996-12-16 1997-11-20 Amindverbindungen und ihre verwendung als inhibitoren der bitric-oxid-synthase Withdrawn EP0946587A2 (de)

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AUPO4219A AUPO421996A0 (en) 1996-12-16 1996-12-16 New amide compounds
AUPO421996 1996-12-16
AUPO5929A AUPO592997A0 (en) 1997-04-01 1997-04-01 New amide compounds
AUPO592997 1997-04-01
AUPO903097 1997-09-09
AUPO9030A AUPO903097A0 (en) 1997-09-09 1997-09-09 New amide compounds
PCT/JP1997/004243 WO1998027108A2 (en) 1996-12-16 1997-11-20 New amide compounds and their use as nitric oxide synthase inhibitors

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USD928751S1 (en) 2008-02-29 2021-08-24 Antennas Direct, Inc. Antenna

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