WO1995024393A1 - Naphthalene derivatives as prostaglandin i2 agonists - Google Patents

Naphthalene derivatives as prostaglandin i2 agonists Download PDF

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Publication number
WO1995024393A1
WO1995024393A1 PCT/JP1995/000373 JP9500373W WO9524393A1 WO 1995024393 A1 WO1995024393 A1 WO 1995024393A1 JP 9500373 W JP9500373 W JP 9500373W WO 9524393 A1 WO9524393 A1 WO 9524393A1
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WIPO (PCT)
Prior art keywords
compound
salt
hydroxy
formula
hydrogen
Prior art date
Application number
PCT/JP1995/000373
Other languages
English (en)
French (fr)
Inventor
Kiyoshi Taniguchi
Masanobu Nagano
Kouji Hattori
Kazunori Tsubaki
Osamu Okitsu
Seiichiro Tabuchi
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 GB9404734A external-priority patent/GB9404734D0/en
Priority claimed from GB9407036A external-priority patent/GB9407036D0/en
Priority to AU18618/95A priority Critical patent/AU688871B2/en
Priority to AT95910763T priority patent/ATE205479T1/de
Priority to DK95910763T priority patent/DK0749424T3/da
Priority to HU9602466A priority patent/HU224822B1/hu
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP52335695A priority patent/JP3245864B2/ja
Priority to HK98114588.2A priority patent/HK1013289B/en
Priority to US08/702,546 priority patent/US5763489A/en
Priority to EP95910763A priority patent/EP0749424B1/en
Priority to DE69522676T priority patent/DE69522676T2/de
Priority to MX9603617A priority patent/MX9603617A/es
Publication of WO1995024393A1 publication Critical patent/WO1995024393A1/en
Priority to GR20010401952T priority patent/GR3037080T3/el

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • 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
    • C07C281/02—Compounds containing any of the groups, e.g. carbazates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • This invention relates to new naphthalene
  • naphthalene derivatives have been known as described, for example, in EP 0542203A2.
  • This invention relates to new naphthalene
  • this invention relates to new naphthalene derivatives and pharmaceutically
  • acceptable salts thereof which have pharmacological activities such as an inhibitory activity on platelet aggregation, vasodilating activity, antihypertensive activity or the like and are prostaglandin I 2 agonists, to processes for their production, to a pharmaceutical composition containing the same and to a use thereof for manufacture of medicaments.
  • one object of this invention is to provide new and useful naphthalene derivatives
  • Another object of this invention is to provide processes for production of the naphthalene derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, said naphthalene derivatives or
  • Still further object of this invention is to provide use of the naphthalene derivatives and pharmaceutically acceptable salts thereof for manufacture of medicaments for the therapeutic and/or prophylactic treatment of arterial obstruction, cerebrovascular disease, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis after percutaneous transluminal coronary angioplasty, hypertension or the like.
  • naphthalene derivatives of this invention can be represented by the following formula (I) :
  • R 1 is carboxy or protecred carboxy
  • R 2 is hydrogen, hydroxy or protected nydroxy
  • R 3 is hydrogen, hydroxy, protected hydroxy
  • R 4 is hydrogen or halogen
  • a 1 is lower alkylene
  • a 2 is bond or lower alkylene
  • -R 5 is (in which R 6 is mono (or di or
  • R 9 is hydrogen or lower alkyl
  • Q is N or CH
  • R 7 is aryl and R 8 is aryl
  • naphthalene derivatives (I) can be prepared by the processes which are illustrated in the following scheme.
  • R a 1 is protected carboxy
  • X 2 is halogen
  • X 3 is halogen
  • X 4 is halogen
  • R a 9 is lower alkyl.
  • R 10 is hydrogen or hydroxy protective group, R 11 is leaving group.
  • R 12 is carboxy or protected carboxy,
  • a 4 is bond or C 1 -C 5 alkylene
  • R a 13 is halogen
  • R 13 is hydrogen or halogen
  • X 5 is halogen
  • R a 10 is hydroxy protective group
  • X 5 is acid residue
  • X 7 is halogen
  • R 14 is lower alkyl, or aryl which may have suitable substituent(s),
  • R 15 is lower alkyl
  • X 8 is halogen
  • R a 4 is halogen
  • R 16 is amino protective group.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, trierhylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, trierhylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzy
  • acetate maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g.
  • “mono (or di or tri)aryl(lower)alkyl” may include phenyl, naphthyl and the like.
  • Suitable "lower alkylene” may include straight or branched one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or the like, preferably one having 1 to 3 carbon atom(s).
  • Suitable "C 1 -C 5 alkylene” may include straight or branched one having 1 to 5 carbon atom(s), such as
  • Suitable "lower alkyl” and “lower alkyl moiety" in the term “mono (or di or tri)aryl(lower)alkyl may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl or the like, preferably one having 1 to 4 carbon atom(s).
  • Suitable "protected carboxy” may include esterified carboxy and the like.
  • ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s), for example, lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s), for example, lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobut
  • alkanoyloxy(lower)alkyl ester e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester,
  • alkylsulfonyl(lower)alkyl ester e.g. 2-mesylethyl ester, etc.
  • mono (or di or tri) -halo (lower) alkyl ester e.g. 2- iodoethyl ester, 2,2,2-trichloroethyl ester, etc.
  • lower alkoxycarbonyloxy(lower)alkyl ester e.g.
  • lower alkenyl ester e.g. vinyl ester, allyl ester, etc.
  • lower alkynyl ester e.g. ethynyl ester, propynyl ester, etc.
  • ar(lower)alkyl ester which may have at least one suitable substituent(s) such as mono (or di or tri)-phenyl(lower)alkyl ester which may have at least one suitable substituent(s) (e.g. benzyl ester,
  • substituent(s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • substituent(s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • Suitable "acid residue” may include halogen (e.g.
  • sulfonyloxy e.g. methylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, etc.
  • sulfonyloxy e.g. methylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, etc.
  • Suitable "protected hydroxy” may include acyloxy and the like.
  • acyl moiety in the term “acyloxy” may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring.
  • acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.);
  • lower alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.
  • lower alkoxycarbonyl e.g. methoxycarbonyl
  • alkanesulfonyl e.g. mesyl, ethanesulfonyl
  • arenesulfonyl e.g. benzenesulfonyl, tosyl, etc.
  • aroyl e.g. benzoyl, toluoyl, xyloyl, naphthoyl,
  • ar(lower)alkanoyl e.g. phenylacetyl, phenylpropionyl, etc.
  • ar(lower)alkoxycarbonyl e.g. benzyloxycarbonyl
  • Suitable "halogen” may include chlorine, bromine, iodine and fluorine.
  • Suitable “leaving group” may include lower alkoxy
  • Suitable "substituent” in the term “aryl which may have suitable substituent(s)” may include lower alkyl as exemplified above, and the like.
  • Suitable “amino protective group” may include acyl as exemplified above, mono (or di or tri) aryl (lower) alkyl and the like.
  • Suitable "hydroxy protective group” may include lower alkyl as exemplified above, silyl which may have one to three suitable substituent(s), and the like.
  • Suitable "substituent” in the term “silyl which may have one to three suitable substituent(s)” may include lower alkyl as exemplified above, aryl as exemplified above, and the like.
  • R 1 is carboxy, or protected carboxy (more preferably
  • esterified carboxy most preferably lower
  • R 2 is hydrogen, hydroxy, or protected hydroxy (more
  • R 3 is hydrogen, hydroxy, protected hydroxy (more
  • acyloxy preferably acyloxy), lower alkyl or halogen
  • R 4 is hydrogen or halogen
  • a 1 is lower alkylene (more preferably C 1 -C 3 alkylene,
  • a 2 is bond, or lower alkylene (more preferably C 1 -C 3
  • alkylene most preferably methylene or ethylene
  • Q is N or CH
  • R 7 is aryl (more preferably phenyl), and R 8 is aryl (more preferably phenyl)], and
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
  • This reaction is usually carried out in a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of a base.
  • Suitable base may include the inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium
  • alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium hydroxide, etc.
  • alkali metal carbonate e.g. sodium carbonate, potassium
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium
  • organic base such as tri(lower)alkylamine (e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.), di(lower)alkylaniline (e.g. dimethylaniline, etc.), pyridine or the like.
  • tri(lower)alkylamine e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.
  • di(lower)alkylaniline e.g. dimethylaniline, etc.
  • pyridine e.g., pyridine
  • the compound (lb) or a salt thereof can be prepared by subjecting the compound (la) or a salt thereof to elimination reaction of the carboxy protective group.
  • Suitable method of this reaction may include
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium,
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline 1,5-diazabicyclo[4.3.0]-non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
  • Suitable acid may include 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.
  • trichloroacetic acid e.g. trichloroacetic acid, trifluoroacetic acid, etc.
  • cation trapping agents e.g. anisole, phenol, etc.
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid,
  • a metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic 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
  • colloidal palladium palladium on barium sulfate
  • 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, etc.
  • copper catalysts e.g. reduced copper, Raney copper, Ullman copper, etc.
  • the reduction is usually carried out in a
  • N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof are in liquid, they can also be used as a solvent.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (Ic) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
  • This reaction is usually carried out in a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of a base.
  • Suitable base can be referred to that of Process 1.
  • a liquid base can be also used as the solvent.
  • the compound (Id) or a salt thereof can be prepared by reactin ⁇ the compound (VI) or a salt thereof with the compound (VII) or a salt thereof. This reaction is usually carried out in a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of a base.
  • Suitable base can be referred to that of Process 1.
  • the compound (Ie) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX) or its reactive derivative at the carboxy group or a salt thereof.
  • Suitable reactive derivative at the carboxy group of the compound (IX) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • 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 dibenzylphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorous acid dialkylphosphorous acid
  • sulfurous acid dialkylphosphorous acid
  • methanesulfonic acid ethanesulfonic acid, etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g. pivalic acid, pentanoic acid, isopentanoic acid
  • aromatic carboxylic acid e.g. benzoic acid, etc.
  • aromatic carboxylic acid e.g. benzoic acid, etc.
  • a symmetrical acid anhydride an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole
  • an activated ester e.g.
  • thioester p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine,
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride,
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
  • N-cyclohexyl-N'-morpholinoethylcarbodiimide or the like.
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.
  • an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, 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 (Ig) or a salt thereof can be prepared by reacting the compound (If) or a salt thereof with the compound (X) or a salt thereof.
  • This reaction can be carried out in accordance with the method disclosed in the Example 20 described later or similar manners thereto.
  • the compound (XIII) or a salt thereof can be prepared by reacting the compound (XI) or a salt thereof with the compound (XII) or a salt thereof.
  • the compound (XV) or a salt thereof can be prepared by subjecting the compound (XIV) or a salt thereof to reduction reaction.
  • This reaction can be carried out in accordance with the method disclosed in the Preparation 32 described later or similar manners thereto.
  • the compound (XVII) or a salt thereof can be prepared by subjecting the compound (XVI) or a salt thereof to dehydration reaction.
  • This reaction can be carried out in accordance with the method disclosed in the Preparation 33 described later or similar manners thereto.
  • the compound (XIX) or a salt thereof can be prepared by subjecting the compound (XVIII) or a salt thereof to oxidation reaction.
  • This reaction can be carried out in accordance with the methods disclosed in the Preparations 34 and 35 described later or similar manners thereto.
  • the compound (XX) or a salt thereof can be prepared by subjecting the compound (XV) or a salt thereof to halogenation reaction.
  • This reaction can be carried out in accordance with the method disclosed in the Preparation 40-(1) described later or similar manners thereto.
  • the compound (XXII) or a salt thereof can be prepared by subjecting the compound (XXI) or a salt thereof to reduction reaction.
  • the compound (XXV) or a salt thereof can be prepared by reacting the compound (XXIII) or a salt thereof with the compound (XXIV) or a salt thereof.
  • the compound (II) or a salt thereof can be prepared by subjecting the compound (XXXXIV) or a salt thereof to elimination reaction of the hydroxy protective group.
  • the reagent to be used in this reaction may include halotrialkylsilane (e.g., iodotrimethylsilane, etc.), alkali metal thioalkoxide (e.g., sodium thioethoxide, etc.), alkali metal sulfide (e.g., sodium sulfide, etc.), alkali metal diphenylphosphide (e.g., lithium
  • diphenylphosphide, etc. diphenylphosphide, etc.
  • aluminum halide e.g., aluminum chloride, aluminum bromide, etc.
  • boron trihalide e.g., boron trichloride, boron tribromide, etc.
  • pyridine hydrochloride alkylmagnesium halide (e.g.,
  • lithium halide e.g., lithium chloride, etc.
  • tetraalkylammonium halide e.g., tetrabutylammonium fluoride, etc.
  • methionine and sulfonic acid e.g., methanesulfonic acid, etc.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol, (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N,N-dimethylforamamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction.
  • a conventional solvent such as water, alcohol, (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N,N-dimethylforamamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (XXVIII) or a salt thereof can be prepared by reacting the compound (XXVI) or a salt thereof with the compound (XXVII) or a salt thereof.
  • This reaction can be carried out in accordance with the method disclosed in the Preparations 8, 17 and 19 described later or similar manners thereto.
  • the compound (XXX) or a salt thereof can be prepared from the compound (XXIX) or a salt thereof in accordance with the method disclosed in the Preparation 54 described later or similar manners thereto.
  • the compound (XXXI) or a salt thereof can be prepared by subjecting the compound (XV) or a salt thereof to reduction reaction.
  • the compound (XXXIII) or a salt thereof can be prepared by reacting the compound (XXIII) or a salt thereof with the compound (XXXII) or a salt thereof.
  • This reaction is usually carried out in a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, pyridine, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, pyridine, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the reaction is usually carried out in the presence of a base.
  • Suitable base can be referred to that of Process 1.
  • the compound (XXXXV) or a salt thereof can be prepared by subjecting the compound (XXIII) or a salt thereof to halogenation reaction.
  • This reaction can be carried out in accordance with the methods disclosed in the Preparations 14 and 15 described later or similar manners thereto.
  • the compound (XXXVIII) or a salt thereof can be prepared by subjecting the compound (XXXVII) or a salt thereof to halogenation reaction.
  • This reaction can be carried out in accordance with the method disclosed in the Preparation 21 described later or similar manners thereto.
  • the compound (XXXX) or a salt thereof can be prepared by reacting the compound (XXXIX) or a salt thereof with the compound (IX) or its reactive derivative at the carboxy group or a salt thereof.
  • This reaction can be carried out in a similar manner to that of the aforementioned Process 5, and therefore the reagents to be used and the reaction conditions (e.g.
  • the compound (IV) or a salt thereof can be prepared by reacting the compound (XXXXI) or a salt thereof with the compound (III) or a salt thereof.
  • This reaction can be carried out in a similar manner to that of 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 1.
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (VI) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (XXXXII).
  • This reaction is usually carried out in a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of a base.
  • Suitable base can be referred to that of Process 1.
  • the compound (VIII) or a salt thereof can be prepared by subjecting the compound (XXXXIII) or a salt thereof to elimination reaction of the amino protective group.
  • This reaction can be carried out in a similar manner to that of the aforementioned Process 2 , 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 2.
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • pharmacological activities such as an inhibitory activity on platelet aggregation, vasodilating activity,
  • prostaglandin I 2 agonists can be used for treating and/or preventing arterial obstruction (e.g., chronic arterial obstruction, etc.), cerebrovascular disease, gastric ulcer, hepatitis, hepatic insufficiency, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis after percutaneous transluminal coronary angioplasty, hypertension, inflammation, heart failure, renal disease (e.g., renal failure, nephritis, etc.), diabetic complication (e.g., diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, etc.), peripheral circulatory disturbance, and the like, and can be also used for protecting organs after transplantation.
  • arterial obstruction e.g., chronic arterial obstruction, etc.
  • cerebrovascular disease gastric ulcer
  • hepatitis hepatic insufficiency
  • hepatic cirrhosis CAD
  • arteriosclerosis ischemic heart disease
  • Test Compound (1) Sodium salt of [5-(carboxymethoxy)-2-hydroxy-1,2,3,4- tetrahydro-2-naphthyl]methyl N,N-diphenylcarbamate
  • composition of assay buffer was as follows : 20 mM MES (pH 6.0), 10 mM MgCl 2 , 1 mM EDTA, and 0.1 mM PMSF. Frozen cells were thawed and aliquots (4.5 ⁇ 10 5 cells) were incubated for 60 minutes under shaking at 30°C in plastic tubes in 100 ⁇ l of assay buffer with 10 nM of
  • a pharmaceutical preparation for example, in solid, semisolid or liquid form (e.g. tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, solution, emulsion, suspension etc.), which contains the object compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient, suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
  • solid, semisolid or liquid form e.g. tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, solution, emulsion, suspension etc.
  • object compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient
  • the pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose, such as excipient (e.g. sucrose, starch, mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binding agent (e.g. cellulose. methyl cellulose, hydroxypropylcellulose,
  • excipient e.g. sucrose, starch, mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.
  • binding agent e.g. cellulose. methyl cellulose, hydroxypropylcellulose
  • disintegrator e.g. starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycol-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.
  • lubricant e.g. magnesium
  • stearate stearate, talc, sodium laurylsulfate, etc.
  • flavoring agent e.g. citric acid, mentol, glycine, orange powders, etc.
  • preservative e.g. sodium benzoate, sodium
  • bisulfite methylparaben, propylparaben, etc.
  • stabilizer e.g. citric acid, sodium citrate, acetic acid, etc.
  • suspending agent e.g. methyl cellulose
  • polyvinylpyrrolidone aluminum stearate, etc.
  • dispersing agent e.g. water
  • aqueous diluting agent e.g. water
  • base wax e.g. cacao butter, polyethyleneglycol, white petrolatum, etc.
  • the effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.
  • 6-diphenylmethyl-3(2H)-pyridazinone (6.26 g) as a white powder.
  • Carbontetrabromide (1.00 g ⁇ 4) was added portionwise to a solution of 3,4-dihydro-5-methoxy-2-naphthyl)methanol (2.00 g) and triphenylphosphine (4.14 g) in
  • N,N-dimethylformamide (2 ml) was added a solution of 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl bromide (0.18 g) in N,N-dimethylformamide ( 3 ml ) at room temperature.
  • the reaction mixture was stirred for 2 hours at the same temperature and partitioned between water and ethyl acetate.
  • the organic layer was washed with water (3 times) and brine, dried over sodium sulfate, and
  • Ethyl [(6RS)-5,6,7,8-tetrahydro-6-[((1S)-1-phenylethyl)amino]-1-naphthyloxy]acetate (185 mg) was converted to the hydrochloride using 4N hydrogen chloride in ethyl acetate in a usual manner.
  • a mixture of the hydrochloride, 10% palladium on carbon (50% wet, 100 mg), and ammonium formate (330 mg) in ethanol (40 ml) was stirred under reflux for 30 minutes and the hot reaction mixture was filtered. The filtrate was evaporated in vacuo and the residue was partitioned between ethyl acetate and sodium bicarbonate aqueous solution.
  • AD-mix- ⁇ (trade name, Aldrich) (9.2 g) in a mixture of t-butyl alcohol (30 ml) and water (30 ml) was stirred for 1 hour and then methanesulfonamide (0.62 g) and 2-ethoxycarbonyl-5-t-butyldiphenylsilyloxy-3,4-dihydronaphthalene (3.0 g) were added to the solution at room temperature. After being stirred for 20 hours at the same temperature, sodium sulfite (9.0 g) was added, and the mixture was stirred for 30 minutes. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat.
  • HPLC chiralcel AD, 5% isopropanol/hexane
  • HPLC chiralcel AD, 5% isopropanol/hexane
  • 2-(N,N-Diphenylcarbamoyloxymethyl)-5-t-butyldiphenylsilyloxy-3,4-dihydronaphthalene was prepared from 2-ethoxycarbonyl-5-t-butyldiphenylsilyloxy-3,4-dihydronaphthalene in similar manners to those of
  • 2-(N,N-Diphenylcarbamoyloxymethyl)-2-methyl-5-methoxy-1,2,3,4-tetrahydronaphthalene was prepared from 2-methoxycarbonyl-2-methyl-5-merhoxy-1,2,3,4-tetrahydronaphthalene in similar manners to those of Preparations 1 and 46.
  • 5-t-Butyldiphenylsilyloxy-1,2-dihydroxy-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene was prepared from 5-t-butyldiphenylsilyloxy-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-3,4-dihydronaphthalene in a similar manner to that of Example 21.
  • N,N-diphenylcarbamoyl chloride 50 mg
  • pyridine 32 mg
  • the ethyl acetate layer was washed successively with water, aqueous sodium

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PCT/JP1995/000373 1994-03-10 1995-03-08 Naphthalene derivatives as prostaglandin i2 agonists WO1995024393A1 (en)

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MX9603617A MX9603617A (es) 1994-04-08 1995-03-08 Derivados de naftaleno.
DE69522676T DE69522676T2 (de) 1994-03-10 1995-03-08 Naphtalen-derivate als prostaglandin i2 agonisten
AT95910763T ATE205479T1 (de) 1994-03-10 1995-03-08 Naphtalen-derivate als prostaglandin i2 agonisten
DK95910763T DK0749424T3 (da) 1994-03-10 1995-03-08 Naphthalenderivater som prostaglandin-I2-agonister
HU9602466A HU224822B1 (en) 1994-03-10 1995-03-08 Naphthalene derivatives as prostaglandin i2 agonists, pharmaceutical compns. contg. them and process for preparing them
AU18618/95A AU688871B2 (en) 1994-03-10 1995-03-08 Naphthalene derivatives as prostaglandin I2 agonists
JP52335695A JP3245864B2 (ja) 1994-03-10 1995-03-08 プロスタグランジンｉ２アゴニストとしてのナフタレン誘導体
HK98114588.2A HK1013289B (en) 1994-03-10 1995-03-08 Naphthalene derivatives as prostaglandin 12 agonists
US08/702,546 US5763489A (en) 1994-03-10 1995-03-08 Naphthalene derivatives as prostaglandin I2 agonsists
EP95910763A EP0749424B1 (en) 1994-03-10 1995-03-08 Naphthalene derivatives as prostaglandin i2 agonists
GR20010401952T GR3037080T3 (en) 1994-03-10 2001-10-31 Naphthalene derivatives as prostaglandin i2 agonists

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WO1997029095A1 (de) * 1996-02-06 1997-08-14 Hoechst Schering Agrevo Gmbh 2,4-diamino-1,3,5-triazine, verfahren zu deren herstellung und deren verwendung als herbizide und pflanzenwachstumsregulatoren
WO1999024397A1 (en) * 1997-11-10 1999-05-20 Fujisawa Pharmaceutical Co., Ltd. Benzocycloheptene derivatives
WO1999032435A1 (en) * 1997-12-22 1999-07-01 Fujisawa Pharmaceutical Co., Ltd. Naphthalene derivatives
WO2000078350A1 (fr) * 1999-06-21 2000-12-28 Fujisawa Pharmaceutical Co., Ltd. Medicaments destines a un ulcere cutane
US6245790B1 (en) * 1997-06-02 2001-06-12 Fujisawa Pharmaceutical Co., Ltd. Oxazole compounds useful as PGE2 agonists and antagonists
WO2002042243A1 (fr) * 2000-11-21 2002-05-30 Fujisawa Pharmaceutical Co., Ltd Processus de preparation de derives de tetrahydronaphtalene
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WO1997013758A1 (de) * 1995-10-09 1997-04-17 MERCK Patent Gesellschaft mit beschränkter Haftung Pyridazinone als endothelin-rezeptor-antagonisten
US6071860A (en) * 1996-02-06 2000-06-06 Hoechst Schering Agrevo Gmbh 2,4-Diamino-1, 3,5-triazines, their preparation, and their use as herbicides and plant growth regulators
WO1997029095A1 (de) * 1996-02-06 1997-08-14 Hoechst Schering Agrevo Gmbh 2,4-diamino-1,3,5-triazine, verfahren zu deren herstellung und deren verwendung als herbizide und pflanzenwachstumsregulatoren
US6245790B1 (en) * 1997-06-02 2001-06-12 Fujisawa Pharmaceutical Co., Ltd. Oxazole compounds useful as PGE2 agonists and antagonists
US8513027B2 (en) 1997-09-25 2013-08-20 Asterand Uk Acquisition Limited Method of identifying an inhibitor of the prostanoid EP4 receptor
WO1999024397A1 (en) * 1997-11-10 1999-05-20 Fujisawa Pharmaceutical Co., Ltd. Benzocycloheptene derivatives
US6384072B1 (en) * 1997-11-10 2002-05-07 Fujisawa Pharmaceutical Co., Ltd. Benzocycloheptene derivatives
WO1999032435A1 (en) * 1997-12-22 1999-07-01 Fujisawa Pharmaceutical Co., Ltd. Naphthalene derivatives
US6303649B1 (en) 1997-12-22 2001-10-16 Fujisawa Pharmaceutical Co., Ltd. Naphthalene derivatives
WO2000078350A1 (fr) * 1999-06-21 2000-12-28 Fujisawa Pharmaceutical Co., Ltd. Medicaments destines a un ulcere cutane
WO2002042243A1 (fr) * 2000-11-21 2002-05-30 Fujisawa Pharmaceutical Co., Ltd Processus de preparation de derives de tetrahydronaphtalene
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HU9602466D0 (en) 1996-11-28
DK0749424T3 (da) 2001-11-26
ATE205479T1 (de) 2001-09-15
CN1057522C (zh) 2000-10-18
PT749424E (pt) 2002-03-28
CN1147250A (zh) 1997-04-09
JP3245864B2 (ja) 2002-01-15
AU1861895A (en) 1995-09-25
KR100383305B1 (ko) 2003-11-01
DE69522676T2 (de) 2002-04-18
TW282456B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1996-08-01
US5863918A (en) 1999-01-26
HK1013289A1 (en) 1999-08-20
ES2160156T3 (es) 2001-11-01
JPH09509958A (ja) 1997-10-07
EP0749424B1 (en) 2001-09-12
DE69522676D1 (de) 2001-10-18
AU688871B2 (en) 1998-03-19
KR970701698A (ko) 1997-04-12
EP0749424A1 (en) 1996-12-27
RU2155188C2 (ru) 2000-08-27
GR3037080T3 (en) 2002-01-31
HU224822B1 (en) 2006-02-28
US5763489A (en) 1998-06-09
HUT75226A (en) 1997-04-28
CA2185104A1 (en) 1995-09-14

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