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WO1993006108A1 - Derives de pyrrolobenzoxazine utilises comme agents agonistes et antagonistes de la 5-ht - Google Patents

Derives de pyrrolobenzoxazine utilises comme agents agonistes et antagonistes de la 5-ht Download PDF

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Publication number
WO1993006108A1
WO1993006108A1 PCT/JP1992/001220 JP9201220W WO9306108A1 WO 1993006108 A1 WO1993006108 A1 WO 1993006108A1 JP 9201220 W JP9201220 W JP 9201220W WO 9306108 A1 WO9306108 A1 WO 9306108A1
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WIPO (PCT)
Prior art keywords
compound
salt
acid
ester
halogen
Prior art date
Application number
PCT/JP1992/001220
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English (en)
Inventor
Masayuki Kato
Shigetaka Nishino
Hisashi Takasugi
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
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP5505964A priority Critical patent/JPH06510782A/ja
Publication of WO1993006108A1 publication Critical patent/WO1993006108A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the present invention relates to novel
  • pyrrolobenzoxazine derivatives and a pharmaceutically acceptable salt thereof. More particularly, it relates to novel pyrrolobenzoxazine derivatives and a
  • 5-hydroxytryptamine (5-HT) antagonism and agonism to processes for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a
  • one object of the present invention is to provide novel pyrrolobenzoxazine derivatives and a pharmaceutically acceptable salt thereof, which are useful as a potent and selective antagonist and agonist of 5-HT receptor.
  • Another object of the present invention is to provide processes for preparation of said pyrrolobenzoxazine derivatives or a salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said pyrrolobenzoxazine derivatives or a pharmaceutically acceptable salt thereof.
  • Still further object of the present invention is to provide a use of said pyrrolobenzoxazine derivatives or a pharmaceutically acceptable salt thereof as a 5-HT
  • central nervous system e.g. schizophrenia, mania, etc.
  • anxiety e.g.
  • depression e.g., anxiety, and depression
  • pains or aches e.g. migraine, cluster headaches, vascular headaches, etc.
  • neuralgia e.g.
  • gastrointestinal disorders such as symptoms of gastrointestinal dysfunction such as occur with, for example, dyspepsia, peptic ulcer, reflux oesophagitis and flatulence, and irritable bowel syndrome (IBS); nausea or vomiting, each of which may be associated with cancer therapy; motion sickness; and the like in human being or animals, particularly nausea and vomiting, and as a 5-HT agonist useful for treating or preventing gastrointestinal disorders such as constipation (irritable bowel syndrome, etc.), dyspepsia, reflux oesophagitis, nausea or vomiting and the like in human being or animals.
  • IBS irritable bowel syndrome
  • the pyrrolobenzoxazine derivatives of the present invention are novel and can be represented by the formula [I] :
  • R 1 is hydrogen or halogen
  • R 2 and R 3 are each hydrogen or lower alkyl, R 4 is lower alkylamino;
  • R 5 is hydrogen, halogen, lower alkyl, acyl or
  • X is CONH- or NHCONH-
  • A is lower alkylene
  • n is an integer of 0 or 1.
  • inventions may adopt an endo or exo configuration, and in such a case, the endo configuration is preferred.
  • optical and geometrical isomers may be separated one from the other by the usual manners.
  • the object compound [I] can be prepared by the following processes.
  • Process 1 Process 1 :
  • R 1 , R 2 , R 3 , R 4 , R 5 , A and n are each as defined above.
  • R 6 is protected carboxy
  • R 7 is protected hydroxy
  • Suitable “lower alkyl” may include straight or branched one, having 1 to 6 carbon atom(s), such as methyl ethyl,, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like.
  • Suitable "lower alkylamino" may include
  • di(lower) alkylamino [e.g. dimethylamino, diethylamino, dipropylamino, methylethylamino, etc.] and the like.
  • Suitable "lower alkylene” is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene,
  • Suitable "halogen” may include chlorine, bromine, iodine and fluorine.
  • Suitable "ar( lower) alkyl” may include benzyl
  • Suitable "azabicyclo(C 5 -C 12 )alkyl may include azabicyclo[3,2,1]octyl, azabicyclo[2,2,2]octyl,
  • lower alkyl as stated above (e.g. methyl, ethyl, etc.) preferably azabicyclo(C 7 -C 10 ) alkyl which may be substituted with lower alkyl, more preferably
  • Suitable "protected carboxy” may include carbamoyl; acylcarbamoyl such as lower alkylsulfonylcarbamoyl (e.g., methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl,
  • propylsulfonylcarbamoyl isopropylsulfonylcarbamoyl, butylsulfonylcarbamoyl, t-butylsulfonylcarbamoyl,
  • esterified carboxy in which said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.), lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.), lower alkynyl ester (e.g.
  • lower alkyl ester e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.
  • lower alkenyl ester e.g., vinyl ester
  • ethynyl ester ethynyl ester, propynyl ester, etc.
  • mono(or di or tri)-halo(lower)alkyl ester e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.
  • alkanoyloxy(lower)alkyl ester e.g., acetoxymethyl ester, propionyloxymethyl ester, 1-acetoxypropyl ester,
  • 2-propionyloxyethyl ester 1-isobutyryloxyethyl ester, etc.
  • lower alkanesulfonyl( lower) alkyl ester e.g., mesylmethyl ester, 2-mesylethyl ester, etc.
  • ar( lower) alkyl ester for example, phenyl( lower) alkyl ester which may be substituted with one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiarybutyl- benzyl ester, etc.), lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester,
  • ethoxycarbonyloxymethyl ester ethoxycarbonyloxyethyl ester, etc.
  • aroyloxy( lower)alkyl ester e.g.,
  • aryl ester which may have one or more suitable substituent(s) (e.g, phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); and the like.
  • suitable substituent(s) e.g, phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • Suitable "protected hydroxy” may include acyloxy such as lower alkanoyloxy having 1 to 6 carbon atoms (e.g.
  • Suitable "N-containing heterocyclic group” may include unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 nitrogen atom(s), for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 1,2,3,6-tetrahydropyridyl, etc.;
  • Suitable acyl may include an aliphatic acyl, an aromatic acyl and an aliphatic acyl substituted with aromatic group(s).
  • the aliphatic acyl may include saturated or
  • unsaturated, acyclic or cyclic ones such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl,
  • lower alkanesulfonyl e.g. methanesulfonyl, ethanesulfonyl, propanesulfonyl,
  • butanesulfonyl pentanesulfonyl, hexanesulfonyl, etc.] lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), carbamoyl and the like.
  • the aromatic acyl may include aroyl (e.g. benzoyl, toluoyl, xyloyl, etc.) and the like.
  • aroyl e.g. benzoyl, toluoyl, xyloyl, etc.
  • the aliphatic acyl substituted with aromatic group(s) may include ar(lower)alkanoyl such as
  • phenyl(lower)alkanoyl e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.
  • ar(lower)alkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), phenoxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, etc.), and the like.
  • acyl moiety in the term of “acylamino” can be referred to the ones as exemplified above.
  • Suitable “acylamino” may include lower
  • alkanoylamino e.g. formylamino, acetylamino, etc.
  • alkanoylamino e.g. formylamino, acetylamino, etc.
  • Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts and include an organic acid salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate etc.], a salt with an amino acid [e.g. arginine salt, ornithine salt, etc.], or the like, and the like.
  • organic acid salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, sulfate, phosphate etc.
  • Suitable pharmaceutically acceptable salts of the starting compound [II] are conventional non-toxic salts and include a salt with base such as alkali metal salt
  • an alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
  • an alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
  • the object compound [la] or its salt can be prepared by reacting the compound [II] or its reactive derivative at the carboxy group or its salt with the compound [III] or its reactive derivative at the amino group or its salt.
  • Suitable reactive derivative at the carboxy group of the compound [II] may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g.
  • halogenated phosphoric acid, etc. dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole,
  • dimethylpyrazole, triazole or tetrazole or an activated ester
  • N-hydroxy compound e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
  • N-hydroxyphthalimide 1-hydroxy-1H-benzotriazole, etc.]
  • These reactive derivatives can optionally be selected from them according to the kind of the
  • Suitable salt of the reactive derivative of the compound [II] can be referred to the salt as exemplified for the compound [I].
  • Suitable reactive derivative at the amino group of the compound [III] may include Schiff 's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound [III] with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound [III] with a silyl compound such as bis(trimethylsilyl)acetamide,
  • Suitable salts of the compound [III] and its reactive derivative can be referred to the salt as exemplified for the compound [I].
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • reaction when the compound [II] is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
  • N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;
  • oxychloride phosphoryl chloride
  • phosphorus trichloride diphenyl phosphorylazide
  • diphenylphosphoinic chloride thionyl chloride
  • oxalyl chloride lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;
  • reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarboante, 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, at ambient temperature or under warming.
  • the intermediate compound [XII] can be prepared by subjecting a compound [II] or its reactive derivative at the carboxy group or its salt to rearrangement reaction.
  • Suitable reactive derivative at the carboxy group of the compound [II] can be referred to those as exemplified in Process 1.
  • Suitable rearrangement reaction can include Curtius rearrangement, Lossen rearrangement, Hofmann
  • the intermediate compound [XII] can be prepared by reacting a compound [II] or its reactive derivative at the carboxy group or its salt with an azide derivative.
  • Suitable azide derivative may include diphenyl phosphoroazidate, sodium azide, etc..
  • This reaction is usually carried out in a
  • the reaction temperature is not critical, and the reaction is usually carried out under warming or heating.
  • the intermediate compound [XII] may be used without isolation for the next reaction.
  • the object compound [lb] or its salt can be prepared by reacting the compound [XII] with the compound [III] or its reactive derivative at the amino group or its salt.
  • Suitable reactive derivative at the amino group of the compound [III] can be referred to those as exemplified in Process 1.
  • reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. base, condensing agent, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
  • reaction mode and reaction conditions e.g. base, condensing agent, solvent, reaction temperature, etc.
  • the compound [VI] can be prepared by reacting the compound [IV] with the compound [V].
  • the reaction is usually carried out in a conventional solvent such as dichloromethane, benzene or any other solvent which does not adversely influence the reaction.
  • a conventional solvent such as dichloromethane, benzene or any other solvent which does not adversely influence the reaction.
  • the reaction is preferably carried out in the
  • Suitable acid may include an organic acid (e.g.
  • acetic acid formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc.
  • inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • the compound [Ila] or its salt can be prepared by subjecting the compound [VI] to elimination reaction of the carboxy protective group.
  • the present reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
  • the protective group is an ester
  • the protective group can be eliminated by hydrolysis.
  • Suitable base may include 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 bicarboante thereof, trialkylamine (e.g. trimethylamine, triethylamine, etc.), 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.
  • Suitable acid may include an 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, etc.
  • Reduction can be applied preferably for elimination of the protective group such as 4-nitrobenzyl,
  • the reduction method applicable for the elimination reaction may include, for example reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst (e.g. palladium-carbon, etc.).
  • a metal e.g. zinc, zinc amalgam, etc.
  • a salt of chrome compound e.g. chromous chloride, chromous acetate, etc.
  • an organic or inorganic acid e.g. acetic acid, propionic acid, hydrochloric acid, etc.
  • conventional catalytic reduction in the presence of a conventional metallic catalyst e.g. palladium-carbon, etc.
  • the reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, 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.
  • the compound [lIc] or its salt can be prepared by halogenating the compound [lIb] or its salt.
  • Suitable halogenating agent of this reaction may include conventional ones for example, halogen [e.g.
  • N-halosuccinimide e.g. N-chlorosuccinimide
  • pyridinium hydrohalide perhalide e.g. pyridinium hydrobromide perbromide, pyridinium hydrochloride perchloride, etc.
  • guarternary ammonium perhalide e.g. phenyltrimethylammonium
  • halogenating agents may be selected according to the kind of the starting compound [lIb] to be used.
  • This reaction is usually carried out in a
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming or heating.
  • the compound [VII] can be prepared by subjecting the compound [IVa] to introduction reaction of the hydroxy protective group.
  • the agents used in this reaction may be one which is capable of introducing the hydroxy protective group as exemplified before such as a conventional acylating agent, or the like.
  • Suitable acylating agent may include an organic acid as exemplified in the explanation of the above Process A - or its reactive derivative.
  • the suitable reactive derivative of the organic acid may be a conventional one such as an acid halide (e.g.
  • the acylation reaction may preferably be conducted in the presence of a conventional condensing agent such as
  • This reaction is usually carried out in a solvent which does not adversely influence the reaction such as methanol, ethanol, propanol, dichloromethane, pyridine, tetrahydrofuran, chloroform and the like.
  • reaction temperature is not critical and the reaction can be carried out under cooling to under
  • the compound [VIII] can be prepared by subjecting the compound [VII] to Vilsmeier reaction.
  • the reaction is usually carried out in a conventional solvent such as, water, acetone, dioxane, acetonitrile, ethylene chloride, tetrahydrofuran, diethyl ether or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as, water, acetone, dioxane, acetonitrile, ethylene chloride, tetrahydrofuran, diethyl ether or any other organic solvent which does not adversely influence the reaction.
  • the N,N-dimethylformamide can also be used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound [IX] can be prepared by subjecting the compound [VIII] to elimination reaction of the hydroxy protective group.
  • the present elimination reaction is carried out in accordance with a conventional method such as hydrolysis; reduction; or the like as explained in Process A - .
  • reaction mode and reaction conditions e.g. acid, base, reducing agent, solvent, reaction temperature, etc.
  • this reaction are to be referred to those as explained in Process A - 2 Process C - 4
  • the compound [X] can be prepared by reducing the compound [IX].
  • the reaction including chemical reduction and
  • catalytic reduction may be carried out in a conventional manner.
  • Suitable reducing agents to be used in chemical reduction are a metal [e.g. tin, zinc, iron, etc.], a combination of such metal and/or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid,
  • a metal hydride compound such as aluminum hydride compound [e.g. lithium aluminum hydride, sodium aluminum hydride, aluminum hydride, lithium trimethoxyaluminum hydride, lithium tri-t-butoxyaluminum hydride, etc.], borohydride compound [e.g. sodium borohydride, lithium borohydride, sodium cyanoborohydride, tetramethylammonium borohydride, borane, diborane, etc.], a phosphorus compound [e.g.
  • triphenylphosphine triethylphosphine, etc.
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst [e.g.
  • platinum plate spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalyst e.g. spongy palladium, palladium black
  • palladium oxide palladium on carbon
  • colloidal palladium palladium on barium sulfate
  • nickel catalyst e.g. reduced nickel, nickel oxide, Raney nickel, etc.
  • cobalt catalyst e.g. reduced cobalt, Raney cobalt, etc.
  • iron catalyst e.g. reduced iron, Raney iron, etc.
  • copper catalyst e.g. reduced copper, Raney copper, Ullman copper, etc.
  • a suitable solvent to be used may be water, alcohol [e.g. methanol, ethanol, propanol, etc.], acetonitrile or any other conventional organic solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • acetonitrile or any other conventional organic solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.
  • liquid acids to be used in chemical reduction can also be used as a solvent.
  • the compound [XI] can be prepared by subjecting the compound [X] to cyclization reaction.
  • This cyclization reaction is carried out in the presence of a dehydrating agent.
  • Suitable dehydrating agents used of this reaction may include conventional organic or inorganic ones such as an inorganic halogen compound [e.g. thionyl chloride,
  • carbodiimide compound e.g. N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide,
  • phosphorus compound e.g. phosphorus pentoxide, polyphosphate ester, etc.
  • a combination of phosphine compound e.g. triethylphosphine, triphenylphosphine, etc.
  • azodicarboxylate ester compound e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.]; and the like or an optional mixture thereof.
  • This reaction is usually carried out in a
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under cooling to under heating.
  • the compound [lId] or its salt can be prepared by subjecting the compound [XI] to elimination reaction of the carboxy protective group.
  • the reaction can be carried out in substantially the same manner as Process A - and therefore the reaction mode and reaction conditions [e.g. acid, base reducing agent, solvent, reaction
  • the object compound [I] of the present invention can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional
  • the object compound [I] of the present invention are novel and exhibit pharmacological activities such as 5-HT antagonism, especially, 5-HT 3 antagonism, and 5-HT
  • agonism especially, 5-HT 4 agonism and the like and therefore are useful as 5-HT antagonist and agonist for treating or preventing central nervous system (CNS) disorders such as psychosis (e.g. schizophrenia, mania, etc.), anxiety, and depression; pains or aches such as headaches (e.g. migraine, cluster headaches, vascular headaches, etc.), and neuralgia (e.g. trigeminal
  • CNS central nervous system
  • psychosis e.g. schizophrenia, mania, etc.
  • anxiety e.g.
  • depression e.g. migraine, cluster headaches, vascular headaches, etc.
  • neuralgia e.g. trigeminal
  • gastrointestinal disorders such as symptoms of gastrointestinal dysfunction such as occur with, for example, dyspepsia, peptic ulcer, reflux
  • oesophagitis and flatulence, and irritable bowel syndrome IBS
  • nausea or vomiting each of which may be associated with cancer therapy
  • motion sickness constipation and the like.
  • object compound [I] of the present invention are useful as therapeutical and/or preventive agents for obesity; lung embolism;
  • arrhythmia withdrawal syndrome resulting from addition to a drug or substance of abuse
  • stress-related psychiatric disorders stress-related psychiatric disorders
  • rhinitis and serotonin-induced nasal
  • Rats were given a rapid bolus injection of
  • Nonfasted female beagles weighing about 10 kg were administered test compound or saline intravenously twice 10 minutes prior to and 90 minutes after Cisplatin dosing (3.2 mg/kg, iv).
  • Cisplatin was dissolved in 0.9% warm saline with a final concentration of 3 mg/ml and used immediately. The beagles were observed for vomiting for up to 5 hours following Cisplatin administration. Test Result :
  • Isolated strips of guinea pig ileum were set up in chambers containing Tyrode solution (37°C) with a resting tension of 0.3-0.6 g.
  • the object compound [I] of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • the pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.
  • auxiliary substances stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid
  • magnesium stearate magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
  • While the dosage of the compound [I] may vary from and also depend upon the age, conditions of the patient, a kind of diseases of conditions, a kind of the compound [I] to be applied, etc. In general amounts between 0.01 mg and about 500 mg or even more per day may be administered to a patient.
  • An average singele dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 10 mg, 20 mg, 50 mg, 100 mg of the object compound [I] or the present invention may be used ih treating diseases.
  • Phosphorus oxychloride (0.42 ml) was added dropwise to N,N-dimethylformamide (0.357 g) cooled to 0°C. The mixture was stirred at 0°C for 10 minutes and then at room temperature for 15 minutes. To this mixture cooled to 0°C, were added 1,2-dichloroethane (5 ml) and a solution of ethyl 2-acetoxy-5-chloro-3-(pyrrol-1-yl)benzoate (1.1 g) in 1,2-dichloroethane (9 ml). The mixture was stirred at room temperature for 20 minutes and at 70°C for 1 hour.
  • reaction mixture was treated with a solution of sodium acetate trihydrate (4.3 g) in water (20 ml) and stirred at 60°C for 20 minutes. After cooling, the reaction mixture was extracted twice with dichloromethane. The organic layer was washed with water and brine, dried over
  • N-chlorosuccinimide (1.44 g) in N,N-dimethylformamide (30 ml) was stirred at 0°C for 4 hours and then at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with dichloromethane.
  • N-methylmorpholine 600 mg
  • N,N-dimethylformamide (2 ml) were added and the mixture was stirred at 0°C for 2 hours and then at room temperature for 14 hours.
  • the reaction mixture was diluted with water, made basic with 3N aqueous sodium hydroxide solution, and extracted three times with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. Column chromatography on silica gel (15% methanol-chloroform) of the residue gave an oil (0.72. g), which was treated with hydrogen chloride in dioxane and crystallized from methanol-ether to give
  • N,N-dimethylformamide (20 ml) was stirred at ambient temperature for one hour.
  • a mixture of endo-8-methyl-8-azabicyclo[3.2.1]octyl- 3-amine dihydrochloride (0.54 g)
  • triethylamine (0.91 g)
  • N,N-dimethylformamide 10 ml
  • the mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water.
  • the separated organic layer was washed with brine and dried over magnesium sulfate, and evaporated in vacuo.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention se rapporte à des dérivés de pyrrolobenzoxazine, representés par la formule (I) où R1 représente hydrogène, etc., R2 et R3 représentent chacun alkyle inférieur etc., R4 représente azabicyclo(C¿5?-C12)alkyle, qui peut être substitué par alkyle inférieur, etc., R?5¿ représente halogène etc., X représente α, etc., A représente alkylène inférieur et n représente un nombre entier égal à 0 ou à 1. Ces composés et leur sel pharmaceutiquement acceptable possèdent des propriétes pharmacologiques notamment comme agents antagonistes et agonistes de la 5-HT (5-hydroxytryptamine).
PCT/JP1992/001220 1991-09-27 1992-09-25 Derives de pyrrolobenzoxazine utilises comme agents agonistes et antagonistes de la 5-ht WO1993006108A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP5505964A JPH06510782A (ja) 1991-09-27 1992-09-25 ５−ｈｔ作動薬および拮抗薬としてのピロロベンズオキサジン誘導体

Applications Claiming Priority (2)

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GB919120628A GB9120628D0 (en) 1991-09-27 1991-09-27 Pyrrolobenzoxazine derivatives and process for preparation thereof
GB9120628.4 1991-09-27

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AU (1) AU2654692A (fr)
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014348A1 (fr) * 1999-08-20 2001-03-01 The Scripps Research Institute Formation d'heterocycles
US6586446B1 (en) 1999-10-15 2003-07-01 Bristol-Myers Squibb Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US6608227B1 (en) 1999-10-15 2003-08-19 Bristol-Myers Squibb Pharma Benzylcycloalkyl amines as modulators of chemokine receptor activity
US6638950B2 (en) 2000-06-21 2003-10-28 Bristol-Myers Squibb Pharma Company Piperidine amides as modulators of chemokine receptor activity
US6784200B2 (en) 2000-10-13 2004-08-31 Bristol-Myers Squibb Pharma Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
WO2005014001A1 (fr) * 2003-07-18 2005-02-17 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Utilisation de derives de 2h-1',3-ixazino-3',2-a-indole pour le traitement de la douleur neuropathique
US6858613B2 (en) 2002-02-19 2005-02-22 Pfizer Inc. Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease
US6951868B2 (en) 2001-11-09 2005-10-04 Pfizer Inc. Azabicyclic-phenyl-fused-heterocyclic compounds for treatment of disease
US6974869B2 (en) 2001-09-18 2005-12-13 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
US6992091B2 (en) 2002-09-12 2006-01-31 Bristol-Myers Squibb Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US7067515B2 (en) 2001-06-12 2006-06-27 Pfizer Inc. Quinuclidines-substituted-multi-cyclic-heteroaryls for the treatment of disease
US7638534B2 (en) 2003-07-18 2009-12-29 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Use of indazole derivatives for the treatment of neuropathic pain

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4035495A (en) * 1975-02-10 1977-07-12 Ayerst Mckenna And Harrison Ltd. Pyrrolobenzoxazines, pyrrolobenzothiazines and process therefor
EP0313393A2 (fr) * 1987-10-22 1989-04-26 Yoshitomi Pharmaceutical Industries, Ltd. Composés benzoxazines et leur utilisation pharmaceutique
EP0407137A2 (fr) * 1989-07-03 1991-01-09 Yoshitomi Pharmaceutical Industries, Ltd. Dérivés de benzazine et leurs applications pharmaceutiques
EP0419397A1 (fr) * 1989-09-08 1991-03-27 Novo Nordisk A/S Dérivés de l'urée, leur préparation et leur utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4035495A (en) * 1975-02-10 1977-07-12 Ayerst Mckenna And Harrison Ltd. Pyrrolobenzoxazines, pyrrolobenzothiazines and process therefor
EP0313393A2 (fr) * 1987-10-22 1989-04-26 Yoshitomi Pharmaceutical Industries, Ltd. Composés benzoxazines et leur utilisation pharmaceutique
EP0407137A2 (fr) * 1989-07-03 1991-01-09 Yoshitomi Pharmaceutical Industries, Ltd. Dérivés de benzazine et leurs applications pharmaceutiques
EP0419397A1 (fr) * 1989-09-08 1991-03-27 Novo Nordisk A/S Dérivés de l'urée, leur préparation et leur utilisation

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014348A1 (fr) * 1999-08-20 2001-03-01 The Scripps Research Institute Formation d'heterocycles
US6864380B2 (en) 1999-10-15 2005-03-08 Bristol-Myers Squibb Pharma Company Benzylcycloalkyl amines as modulators of chemokine receptor activity
US6586446B1 (en) 1999-10-15 2003-07-01 Bristol-Myers Squibb Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US6608227B1 (en) 1999-10-15 2003-08-19 Bristol-Myers Squibb Pharma Benzylcycloalkyl amines as modulators of chemokine receptor activity
US7126010B2 (en) 1999-10-15 2006-10-24 Bristol-Myers Squibb Pharma Company Benzylcycloalkyl amines as modulators of chemokine receptor activity
US6960666B2 (en) 1999-10-15 2005-11-01 Bristol-Myers Squibb Pharma Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US7550500B2 (en) 1999-10-15 2009-06-23 Bristol-Myers Squibb Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US6638950B2 (en) 2000-06-21 2003-10-28 Bristol-Myers Squibb Pharma Company Piperidine amides as modulators of chemokine receptor activity
US6984651B2 (en) 2000-06-21 2006-01-10 Bristol-Myers Squibb Pharma, Company Piperidine amides as modulators of chemokine receptor activity
US6784200B2 (en) 2000-10-13 2004-08-31 Bristol-Myers Squibb Pharma Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US7067515B2 (en) 2001-06-12 2006-06-27 Pfizer Inc. Quinuclidines-substituted-multi-cyclic-heteroaryls for the treatment of disease
US7514430B2 (en) 2001-09-18 2009-04-07 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
US6974869B2 (en) 2001-09-18 2005-12-13 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
US6951868B2 (en) 2001-11-09 2005-10-04 Pfizer Inc. Azabicyclic-phenyl-fused-heterocyclic compounds for treatment of disease
US6858613B2 (en) 2002-02-19 2005-02-22 Pfizer Inc. Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease
US6992091B2 (en) 2002-09-12 2006-01-31 Bristol-Myers Squibb Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
EA008927B1 (ru) * 2003-07-18 2007-08-31 Ацьенде Кимике Рьюните Анджелини Франческо A.K.P.A.Ф. С.П.А. Применение производных 2h-[1,3]оксазино[3,2-a]индола для лечения невропатической боли
WO2005014001A1 (fr) * 2003-07-18 2005-02-17 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Utilisation de derives de 2h-1',3-ixazino-3',2-a-indole pour le traitement de la douleur neuropathique
US7638534B2 (en) 2003-07-18 2009-12-29 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Use of indazole derivatives for the treatment of neuropathic pain

Also Published As

Publication number Publication date
AU2654692A (en) 1993-04-27
GB9120628D0 (en) 1991-11-06
JPH06510782A (ja) 1994-12-01

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