WO1996039382A1 - Urea derivatives as 5-ht antagonists - Google Patents
Urea derivatives as 5-ht antagonists Download PDFInfo
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- WO1996039382A1 WO1996039382A1 PCT/JP1996/001500 JP9601500W WO9639382A1 WO 1996039382 A1 WO1996039382 A1 WO 1996039382A1 JP 9601500 W JP9601500 W JP 9601500W WO 9639382 A1 WO9639382 A1 WO 9639382A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/58—Derivatives of thiocarboxylic acids, the doubly-bound oxygen atoms being replaced by nitrogen atoms, e.g. imino-thio ethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- 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
Definitions
- the present invention relates to novel urea derivatives and a pharmaceutically acceptable salt thereof. More
- 5-hydroxytryptamine (5-HT) antagonism pharmacological activities such as 5-hydroxytryptamine (5-HT) antagonism and the like.
- Said urea derivatives or a pharmaceutically acceptable salt thereof are useful as a 5-HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders,
- CNS central nervous system
- migraine migraine, anorexia, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines,
- the urea derivatives of the present invention are novel and can be represented by the formula (I) :
- R 1 is cyano, thiocarbamoyl
- R 4 is hydrogen, lower alkyl which may have
- a 1 is lower alkylene
- n 0 or 1
- R 5 is morpholino, piperidino, 4-arylpiperazin-
- a 2 is lower alkylene, or a group of the formula in which R 6 and R 7 are each hydrogen, optionally
- alkylimino (optionally substituted aryl) methyl or lower alkyl which may have optionally substituted aryl, and
- a 3 is lower alkylene
- R 2 is hydrogen
- R 1 and R 2 are linked together to form
- R 8 is amino or acylamino
- R 9 is hydrogen, acyl or lower alkyl which may have optionally substituted aryl, and R 3 is 1-lower alkylindolyl, benzofuranyl,
- dihydrobenzofuranyl or optionally substituted aryl.
- the object compoundsan be prepared by the following main processes :
- R 1 , R 2 and R 3 are each as defined above.
- object compounds (I) prepared by the above Processes 1 to 4 can be achieved conversion of their side chain within the scope of the compounds of the present invention as shown in the Examples below.
- Suitable salt of the compounds (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) are conventional non-toxic pharmaceutically acceptable salt and may include 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.
- an alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
- an ammonium salt e.g. sodium salt, potassium salt, cesium salt, etc.
- 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.
- an organic carboxylic or sulfonic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
- a salt with a basic or acidic amino acid e.g.
- arginine aspartic acid, glutamic acid, etc.
- the preferable example thereof is an acid addition salt.
- lower is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
- pyridyl (lower) alkyl and “thienyl (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, preferably one having 1 to 4 carbon atoms, and the like, in which the most preferred one is methyl, ethyl, propyl or butyl.
- Suitable "lower alkylene” is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, hexamethylene, and the like, in which the preferred one is methylene or methylmethylene.
- Suitable "optionally substituted aryl” includes aryl (e.g. phenyl, naphthyl, etc.) which may have suitable substituent (s) such as lower alkyl as mentioned above, lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.), halogen (e.g. fluoro, chloro, bromo, etc.), trihalo (lower) alkoxy (e.g.
- N,N-di (lower alkyl) amino e.g. N,N- dimethylamino, etc.
- N,N-di (lower alkyl) amino e.g. N,N- dimethylamino, etc.
- lower alkyl which may have optionally substituted aryl means lower alkyl as mentioned above, which may have
- Suitable "4-arylpiperazin-1-yl” may include
- Suitable " (lower alkylimino) (optionally substituted aryl) methyl” may include (methylimino) (phenyl) methyl, and the like.
- acylamino may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
- acyl may be illustrated as follows : Carbamoyl; Thiocarbamoyl;
- Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,
- alkanoyl e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,
- tridecanoyl tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.
- lower or higher alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.
- alkylsulfonyl e.g., methylsulfonyl, ethylsulfonyl, etc.
- alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.
- cyclo (lower) alkylcarbonyl e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.; or the like;
- Aromatic acyl such as
- aroyl e.g., benzoyl, toluoyl, naphthoyl, etc.
- ar (lower) alkanoyl e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl,
- phenylisobutanoyl phenylpentanoyl, phenylhexanoyl, etc.
- naphthyl (lower) alkanoyl e.g., naphthylacetyl
- ar (lower) alkenoyl e.g., phenyl (lower) alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),
- naphthyl (lower) alkenoyl e.g., naphthylpropenoyl
- ar (lower) alkoxycarbonyl e.g., phenyl (lower) alkoxycarbonyl
- aryloxycarbonyl e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.
- aryloxy (lower) alkanoyl e.g., phenoxyacetyl
- arylglyoxyloyl e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.
- arylsulfonyl e.g., phenylsulfonyl, p-tolylsulfonyl, etc.; or the like;
- Heterocyclic acyl such as
- heterocyclic (lower) alkanoyl e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl,
- heterocyclic (lower) alkenoyl e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl,
- heterocyclichexenoyl etc.
- heterocyclicglyoxyloyl or the like
- heterocycliccarbonyl means, in more detail, saturated or
- heterocyclic group may be heterocyclic group such as
- unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl (e.g. 1H- benzimidazolyl, etc.), quinolyl, isoquinolyl,
- tetrahydroisoquinolyl e.g. 1,2,3,4-tetrahydroisoquinolyl, etc.
- indazolyl benzotriazolyl, quinazolinyl, quinoxalinyl, phthalazinyl, etc.
- benzotriazolyl quinazolinyl, quinoxalinyl, phthalazinyl, etc.
- acyl moiety as stated above may have one to ten, same or different, suitable substituent (s).
- R 1 , R 2 and R 3 are as follows.
- R 1 is cyano, thiocarbamoyl
- R 4 is hydrogen, lower alkyl, phenyl (lower) alkyl, di (lower alkoxy) phenyl (lower) alkyl, phenyl (lower) alkoxycarbonyl, phenyl, lower alkoxyphenyl, lower alkylthio or 1-lower alkylindolyl,
- a 1 is lower alkylene
- n 0 or 1
- R 5 is morpholino, piperidino, 4-phenylpiperazin-
- a 2 is lower alkylene, or
- R 6 and R 7 are each hydrogen, phenyl, lower
- alkanoyl phenyl (lower) alkoxycarbonyl, pyridyl (lower) alkyl, thienyl (lower) alkyl, 3,4-dihydroisoquinolinyl, (lower
- alkylimino (phenyl) methyl, lower alkyl, phenyl (lower) alkyl, naphthyl (lower) alkyl, (mono- or di- or trilower alkyl) phenyl- (lower) alkyl, (mono- or di- or trilower alkoxy) phenyl (lower) alkyl, (mono- or di- or trihalo) phenyl (lower) alkyl,
- a 3 is lower alkylene
- R 2 is hydrogen
- R 1 and R 2 are linked together to form
- R 8 is amino or lower alkanoylamino
- R 9 is hydrogen, phenyl (lower) alkoxycarbonyl or phenyl (lower) alkyl, and
- R 3 is 1-lower alkylindolyl, benzofuranyl,
- R 1 , R 2 and R 3 arellows.
- R 1 is cyano, thiocarbamoyl,
- R 4 is hydrogen or phenyl (lower) alkoxycarbonyl
- a 1 is lower alkylene
- R 4 is phenyl or 1-lower alkylindolyl
- a 1 is lower alkylene
- R 4 is hydrogen, lower alkyl, phenyl (lower) alkyl, di (lower alkoxy) phenyl (lower) alkyl, phenyl or lower alkoxyphenyl,
- R 5 is morpholino, piperidino, 4-phenylpiperazin-
- a 2 is lower alkylene, or
- R 6 and R 7 are each hydrogen, phenyl, lower
- alkanoyl phenyl (lower) alkoxycarbonyl, pyridyl (lower) alkyl, thienyl (lower) alkyl, 3,4-dihydroisoquinolinyl, (lower
- alkylimino (phenyl)methyl, lower alkyl, phenyl (lower) alkyl, naphthyl (lower) alkyl, (mono- or di- or trilower
- R 2 is hydrogen
- R 3 is 1-lower alkylindolyl, benzofuranyl, dihydrobenzofuranyl or N,N-di (lower alkyl) aminophenyl.
- the object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with 1,1'-carbonyldiimidazole and continuously by reacting the obtained compound (III) or a salt thereof with the compound (IV) or a salt thereof.
- the present reaction is usually carried out in a solvent such as dioxane, dimethylsulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, hexane,
- a solvent such as dioxane, dimethylsulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, hexane,
- the reaction temperature is not critical and the
- reaction is usually carried out under cooling, at ambient temperature or under heating.
- the object compound (I) or a salt thereof can be
- the reaction can be carried out in a similar manner to that of the aforementioned Process 1.
- the object compound (I) or a salt thereof can be
- Curtius Rearrangement reaction may be carried out by using a conventional reagent such as diphenylphosphoryl azide.
- the reaction may be also carried out in the presence of an organic or inorganic base such as an alkali metal
- N- (lower) alkylmorphorine N,N-di (lower) alkyIbenzylamine, or the like.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
- the object compound (I) or a salt thereof can be prepared by subjecting the compound (VIII) or a salt thereof to Curtius Rearrangement reaction and continuously by reacting the obtained compound (IX) or a salt thereof with the compound (II) or a salt thereof.
- the object compound (I) of the present invention can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
- the object compound (I) thus obtained can be converted to its salt by a conventional method.
- acceptable salt thereof may include a solvate [e.g.,
- enclosure compound e.g., hydrate, etc.
- the object compound (I) of the present invention are novel and exhibit pharmacological activities such as 5-HT antagonism, especially, 5-HT 2C antagonism, and the like and therefore are useful as 5-HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders,
- CNS central nervous system
- migraine migraine, anorexia, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines,
- the affinity of test drugs for the 5-HT 2C binding site can be determined by assessing their ability to displace
- [ 3 H]-mesulergine in the rat prefrontal cortex was similar to that of Pazos et al, 1984.
- the membrane suspension (500 ⁇ l) was incubated with
- Test drugs (10 -6 M) were added in a volume of 100 ⁇ l. The total assay volume was 1000 ⁇ l.
- IC 50 values were determined using a four parameter logistic program (DeLean 1978) and the pKi (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where :
- 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.
- 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 such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
- the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases or 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 single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the object compound (I) of the present invention may be used in treating diseases.
- the following Preparations and Examples are given for the purpose of illustrating the present invention.
- N-(Benzofuran-5-yl)-N'-(3-cyanophenyl)urea was prepared in a similar manner to that of Example 1. mp : 180-187°C
- N-(Benzofuran-5-yl)-N'-(3-thiocarbamoylphenyl)urea was prepared in a similar manner to that of Example 2.
- N-(1-Methylindol-5-yl)-N'-(3-piperidinomethylphenyl)urea was prepared in a similar manner to that of Example 13.
- Example 16 N-(1-Methylindol-5-yl)-N'-(3-morpholinomethylphenyl)urea was prepared in a similar manner to that of Example 13.
- N-(1-Methylindol-5-yl)-N'-(4-phthalimidomethylphenyl)- urea was prepared in a similar manner to that of Example 13.
- N-[3-(1-Formylaminoethyl)phenyl]-N'-[1-methylindol-5- yl]urea was prepared in a similar manner to that of Example 13.
- N-[3-(N-Methylanilino)methylphenyl]-N'-(1-methylindol-5- yl)urea was prepared in a similar manner to that of Example 13.
- N-(1-Methylindol-5-yl)-N'-[3-(1,2,3,4- tetrahydroquinolin-1-yl)methylphenyl]urea was prepared in a similar manner to that of Example 13.
- N-(1-Methylindol-5-yl)-N'-(3-anilinomethylphenyl]urea was prepared in a similar manner to that of Example 13.
- N-(1-Methylindol-5-yl)-N'-(3-phthalimidomethylphenyl)- urea was prepared in a similar manner to that of Example 13. mp : 222-226°C
- N-(1-Methylindol-5-yl)-N'-(3-diphenylaminomethylphenyl)- urea was prepared in a similar manner to that of Example 13. mp : 194-195°C
- N-[3-(1-Anilinoethyl)phenyl]-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
- N-(8-Formylamino-5,6,7,8-tetrahydro-2-naphthyl)-N'-(1- methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
- N-(2-Benzyloxycarbonyl-l,2,3,4-tetrahydroisoquinolin-5- yl)-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
- Example 32 N-(1-Benzyloxycarbonyl-1,2,3,4-tetrahydroquinolin-5-yl)- N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
- N-(1-Methylindol-5-yl)-N'-[3-[N-benzyloxycarbonyl-N-(4- methylbenzyl)aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 34.
- Example 37 N-(3-Cyanophenyl)-N'-(4-dimethylaminophenyl)urea was prepared in a similar manner to that of Example 36.
- N-(3-Cyanophenyl)-N'-(2,3-dihydrobenzo[b]furan-7-yl)urea was prepared in a similar manner to that of Example 36.
- N-(1-Methylindol-5-yl)-N'-(4-thiocarbamoylphenyl)urea was prepared in a similar manner to that of Example 2.
- N-(3-Thiocarbamoylphenyl)-N'-(4-dimethylaminophenyl)urea was prepared in a similar manner to that of Example 2.
- N-(4-Amidinophenyl)-N'-(1-methylindol-5-yl)urea hydroiodide was prepared in a similar manner to that of
- N-(1-Methylindol-5-yl)-N'-[4-(phenylamidino)phenyl]urea hydroiodide was prepared in a similar manner to that of Example 6.
- N-(1-Methylindol-5-yl)-N'-[3-(3-phenylpropyl)- amidinophenyl]urea hydroiodide was prepared in a similar manner to that of Example 6.
- N-(1-Methylindol-5-yl)-N'-[3-(2-phenylethyl)- amidinophenyl]urea hydroiodide was prepared in a similar manner to that of Example 6.
- N-(4-Aminomethylphenyl)-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 52.
- N-(2,3-Dihydrobenzo[b]furan-7-yl)-N'-(3- aminomethylphenyl)urea was prepared in a similar manner to that of Example 52.
- N-(1-Methylindol-5-yl)-N'-[3-[(4-methylbenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 57.
- N-(1-Methylindol-5-yl)-N'-[3-(methylaminomethyl)- phenyl]urea maleate was prepared in similar manners to those of Example 34, and then Example 57.
- N-(1-Methy ⁇ ndol-5-yl)-N'-(1,2,3,4- tetrahydroisoquinolin-7-yl)urea was prepared in a similar manner to that of Example 57.
- N-(1-Methylindol-5-yl)-N'-(1,2,3,4- tetrahydroisoquinolin-5-yl)urea was prepared in a similar manner to that of Example 57.
- N-(1-Methylindol-5-yl)-N'-(1,2,3,4-tetrahydroquinolin-5- yl)urea was prepared in a similar manner to that of Example 57.
- N-(1-Methylindol-5-yl)-N'-(1,2,3,4-tetrahydroquinolin-7- yl)urea was prepared in a similar manner to that of Example
- N-(8-Amino-5,6,7,8-tetrahydro-2-naphthyl)-N'-(1- methylindol-5-yl)urea was prepared in a similar manner to that of Example 64.
- N-(1-Methylindol-5-yl)-N'-[3-[[(imino)(phenyl)methyl]- aminomethyl]phenyl]urea hydroiodide was prepared in a similar manner to that of Example 66.
- N-(1-Methylindol-5-yl)-N'-[3-[[(1-methylindol-5- yl)(imino)methyl]aminomethyl]phenyl]urea hydroiodide was prepared in a similar manner to that of Example 66.
- Example 66 prepared in a similar manner to that of Example 66.
- N-(1-Methylindol-5-yl)-N'-[3-[(2-fluorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
- N-(1-Methylindol-5-yl)-N'-[3-[(3-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
- N-(1-Methylindol-5-yl)-N'-[3-[(2-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
- N-(1-Methylindol-5-yl)-N'-[3-[(4-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
- N-(1-Methylindol-5-yl)-N*-[3-[(4-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
- N-(1-Methylindol-5-yl)-N'-[3-[(3,5-dichlorobenzylamino) methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
- N-(1-Methylindol-5-yl)-N'-[3-[(N-methyl-N-benzylamino)- methyl]phenyl] urea was prepared in a similar manner to that of Example 73.
- N-(4-(Dibenzylaminomethyl)phenyl]-N'-[1-methylindol-5- yl]urea was prepared in a similar manner to that of Example 73.
- N-(1-Methylindol-5-yl)-N'-[3-[(2,6-dimethoxybenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
- N-(1-Methylindol-5-yl)-N'-[3-(3- pyridylmethylaminomethyl)phenyl]urea was prepared in a similar manner to that of Example 84.
- N-(1-Methylindol-5-yl)-N'-[3-[(2,5-difluorobenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
- N-(1-Methylindol-5-yl)-N'-[3-[(2-methoxybenzyl)- aminomethyl] phenyl] urea was prepared in a similar manner to that of Example 84.
- N-(1-Methylindol-5-yl)-N'-[3-[(1-naphthyl)- methylaminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
- N-(1-Methylindol-5-yl)-N'-[3-[(2,4,6-trimethoxybenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
- N-[3-(1-Benzylaminoethyl)phenyl]-N'-(1-methylindol-5- yl)urea was prepared in a similar manner to that of Example 84.
- N-(1-Methylindol-5-yl)-N'-[3-[(2,4,6-trimethylbenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
- N-(Benzo[b]furan-7-yl)-N'-(3-cyanophenyl)urea was prepared in a similar manner to that of Example 1.
- N-(Benzo[b]furan-7-yl)-N'-(3-thiocarbamoylphenyl)urea was prepared in a similar manner to that of Example 2.
- N-(1-Methylindol-5-yl)-N'-[3-[(2-thienylmethyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
- N-(1-Methylindol-5-yl)-N'-[3-[[(3- trifluoromethoxyphenyl)methyl]aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
- N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 84.
- N-(1-Methylindol-5-yl)-N'-[3-(phenethylammomethyl)- phenyl]urea was prepared in a similar manner to that of Example 84.
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Abstract
A compound of formula (I) wherein R1 is cyano, thiocarbamoyl, a group of formula (a) in which R4 is hydrogen, lower alkyl which may have optionally substituted aryl, acyl, optionally substituted aryl, lower alkylthio or 1-lower alkylindolyl, A1 is lower alkylene, and m and n are each 0 or 1, a group of the formula -A2-R5 in which R5 is morpholino, piperidino, 4-arylpiperazin-1-yl, phthalimido, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl or imidazol-1-yl, and A2 is lower alkylene, or a group of formula (b) in which R?6 and R7¿ are each hydrogen, optionally substituted aryl, acyl, pyridyl(lower)alkyl, thienyl(lower)alkyl, 3,4-dihydroisoquinolinyl, (lower alkylimino) (optionally substituted aryl) methyl or lower alkyl which may have optionally substituted aryl, and A3 is lower alkylene, and R2 is hydrogen; or R?1 and R2¿ are linked together to form (1), (2), or (3), in which R8 is amino or acylamino, and R9 is hydrogen, acyl or lower alkyl which may have optionally substituted aryl, and R3 is 1-lower alkylindolyl, benzofuranyl, dihydrobenzofuranyl, or optionally substituted aryl, and a pharmaceutically acceptable salt thereof, which is useful as a medicament for prophylactic and therapeutic treatment of 5-HT mediated diseases.
Description
DESCRIPTION
UREA DERIVATIVES AS 5-HT ANTAGONISTS TECHNICAL FIELD
The present invention relates to novel urea derivatives and a pharmaceutically acceptable salt thereof. More
particularly, it relates to novel urea derivatives and a pharmaceutically acceptable salt thereof which have
pharmacological activities such as 5-hydroxytryptamine (5-HT) antagonism and the like.
Said urea derivatives or a pharmaceutically acceptable salt thereof are useful as a 5-HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders,
migraine, anorexia, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines,
schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus, and the like in human being or animals.
BACKGROUND ART
With regard to the states of the arts in this field, for example, the following compound is known.
As a result of an extensive study, the inventors of the present invention could obtain the urea derivatives which have strong pharmacological activities.
The urea derivatives of the present invention are novel and can be represented by the formula (I) :
wherein R1 is cyano, thiocarbamoyl,
a group of the formula :
in which R4 is hydrogen, lower alkyl which may have
optionally substituted aryl, acyl, optionally substituted aryl, lower alkylthio or 1-lower alkylindolyl,
A1 is lower alkylene, and
m and n are each 0 or 1,
a group of the formula :
-A2-R5 in which R5 is morpholino, piperidino, 4-arylpiperazin-
1-yl, phthalimido, 1,2,3,4- tetrahydroquinolin-1-yl, 1,2,3,4- tetrahydroisoquinolin-2-yl or imidazol-1- yl, and
A2 is lower alkylene, or
a group of the formula
in which R6 and R7 are each hydrogen, optionally
substituted aryl, acyl,
pyridyl (lower) alkyl, thienyl (lower) alkyl, 3, 4-dihydroisoquinolinyl, (lower
alkylimino) (optionally substituted aryl) methyl or lower alkyl which may have optionally substituted aryl, and
A3 is lower alkylene, and
R2 is hydrogen; or
R1 and R2 are linked together to form
R9 is hydrogen, acyl or lower alkyl which may have optionally substituted aryl, and R3 is 1-lower alkylindolyl, benzofuranyl,
dihydrobenzofuranyl, or optionally substituted aryl.
According to the present invention, the object compoundsan be prepared by the following main processes :
wherein R1, R2 and R3 are each as defined above.
Further, the object compounds (I) prepared by the above Processes 1 to 4 can be achieved conversion of their side chain within the scope of the compounds of the present invention as shown in the Examples below.
Suitable salt of the compounds (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) are conventional non-toxic pharmaceutically acceptable salt and may include 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, cesium 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.), etc.; an inorganic acid addition salt (e.g.
hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g.
arginine, aspartic acid, glutamic acid, etc.); and the like, and the preferable example thereof is an acid addition salt.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.
The term "lower" is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
Suitable "lower alkyl" and lower alkyl moiety in the term "lower alkylthio", "1-lower alkylindolyl",
"pyridyl (lower) alkyl" and "thienyl (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, preferably one having 1 to 4 carbon atoms, and the like, in which the most preferred one is methyl, ethyl, propyl or butyl.
Suitable "lower alkylene" is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, hexamethylene, and the like, in which the preferred one is methylene or methylmethylene.
Suitable "optionally substituted aryl" includes aryl
(e.g. phenyl, naphthyl, etc.) which may have suitable substituent (s) such as lower alkyl as mentioned above, lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.), halogen (e.g. fluoro, chloro, bromo, etc.), trihalo (lower) alkoxy (e.g.
trifluoromethoxy, etc.), N,N-di (lower alkyl) amino (e.g. N,N- dimethylamino, etc.), and the like.
"lower alkyl which may have optionally substituted aryl" means lower alkyl as mentioned above, which may have
optionally substituted aryl as mentioned above.
Suitable "4-arylpiperazin-1-yl" may include
4-phenylpiperazin-1-yl, 4-naphthylpiperazin-1-yl, and the like.
Suitable " (lower alkylimino) (optionally substituted aryl) methyl" may include (methylimino) (phenyl) methyl, and the like.
Suitable "acyl" and "acyl moiety" in the terms
"acylamino" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable example of said acyl may be illustrated as follows : Carbamoyl; Thiocarbamoyl;
Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,
tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);
lower or higher alkylsulfonyl (e.g., methylsulfonyl,
ethylsulfonyl, etc.);
lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.);
cyclo (lower) alkylcarbonyl (e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); or the like;
Aromatic acyl such as
aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);
ar (lower) alkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl,
phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower) alkanoyl (e.g., naphthylacetyl,
naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];
ar (lower) alkenoyl [e.g., phenyl (lower) alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),
naphthyl (lower) alkenoyl (e.g., naphthylpropenoyl,
naphthylbutenoyl, etc.), etc.];
ar (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.);
arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);
arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like;
Heterocyclic acyl such as
heterocycliccarbonyl;
heterocyclic (lower) alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl,
heterocyclicpentanoyl, heterocyclichexanoyl, etc.);
heterocyclic (lower) alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl,
heterocyclichexenoyl, etc.);
heterocyclicglyoxyloyl; or the like;
in which suitable "heterocyclic moiety" in the terms
"heterocycliccarbonyl", "heterocyclic (lower) alkanoyl", heterocyclic (lower) alkenoyl" and "heterocyclicglyoxyloyl" as mentioned above means, in more detail, saturated or
unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
And, especially preferable heterocyclic group may be heterocyclic group such as
unsaturated 3 to 8-membered (more preferably 5 of 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,4- triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl,
piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl (e.g. 1H- benzimidazolyl, etc.), quinolyl, isoquinolyl,
tetrahydroisoquinolyl (e.g. 1,2,3,4-tetrahydroisoquinolyl, etc.) indazolyl, benzotriazolyl, quinazolinyl, quinoxalinyl, phthalazinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen
atom(s) and 1 to 3 nitrogen atom(s), for example,
morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
thiomorpholinyl, thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl,
dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example,
benzoxathiinyl, etc.; and the like.
The acyl moiety as stated above may have one to ten, same or different, suitable substituent (s).
The preferred embodiments of R1, R2 and R3 are as follows.
R1 is cyano, thiocarbamoyl,
a group of the formula :
wherein R4 is hydrogen, lower alkyl, phenyl (lower) alkyl, di (lower alkoxy) phenyl (lower) alkyl, phenyl (lower) alkoxycarbonyl, phenyl, lower alkoxyphenyl, lower alkylthio or 1-lower alkylindolyl,
A1 is lower alkylene, and
m and n are each 0 or 1,
a group of the formula :
-A2-R5 wherein R5 is morpholino, piperidino, 4-phenylpiperazin-
1-yl, phthalimido, 1,2,3,4- tetrahydroquinolin-1-yl, 1,2,3,4- tetrahydroisoquinolin-2-yl or imidazol-1- yl, and
A2 is lower alkylene, or
a group of the formula :
wherein R6 and R7 are each hydrogen, phenyl, lower
alkanoyl, phenyl (lower) alkoxycarbonyl,
pyridyl (lower) alkyl, thienyl (lower) alkyl, 3,4-dihydroisoquinolinyl, (lower
alkylimino) (phenyl) methyl, lower alkyl, phenyl (lower) alkyl, naphthyl (lower) alkyl, (mono- or di- or trilower alkyl) phenyl- (lower) alkyl, (mono- or di- or trilower alkoxy) phenyl (lower) alkyl, (mono- or di- or trihalo) phenyl (lower) alkyl,
[trihalo (lower) alkoxy] phenyl (lower) alkyl or [lower alkoxy] [trihalo (lower) alkoxy] - phenyl (lower) alkyl, and
A3 is lower alkylene, and
R2 is hydrogen; or
R1 and R2 are linked together to form
R9 is hydrogen, phenyl (lower) alkoxycarbonyl or phenyl (lower) alkyl, and
R3 is 1-lower alkylindolyl, benzofuranyl,
dihydrobenzofuranyl, or
N,N-di (lower alkyl) aminophenyl.
Further, the preferred embodiments of R1, R2 and R3 arellows.
R1 is cyano, thiocarbamoyl,
a group of the formula :
wherein R4 is hydrogen or phenyl (lower) alkoxycarbonyl, and
A1 is lower alkylene,
a group of the formula :
wherein R4 is phenyl or 1-lower alkylindolyl, and
A1 is lower alkylene,
a group of the formula :
wherein R4 is hydrogen, lower alkyl, phenyl (lower) alkyl, di (lower alkoxy) phenyl (lower) alkyl, phenyl or lower alkoxyphenyl,
a group of the formula :
wherein R4 is lower alkylthio,
a group of the formula :
-A2-R5
wherein R5 is morpholino, piperidino, 4-phenylpiperazin-
1-yl, phthalimido, 1,2,3,4- tetrahydroquinolin-1-yl, 1,2,3,4- tetrahydroisoquinolin-2-yl or imidazol-1- yl, and
A2 is lower alkylene, or
a group of the formula :
wherein R6 and R7 are each hydrogen, phenyl, lower
alkanoyl, phenyl (lower) alkoxycarbonyl, pyridyl (lower) alkyl, thienyl (lower) alkyl, 3,4-dihydroisoquinolinyl, (lower
alkylimino) (phenyl)methyl, lower alkyl, phenyl (lower) alkyl, naphthyl (lower) alkyl, (mono- or di- or trilower
alkyl) phenyl (lower) alkyl, (mono- or di- or trilower alkoxy) phenyl (lower) alkyl, (mono- or di- or trihalo) phenyl (lower) - alkyl, [trihalo (lower) alkoxy] phenyl- (lower) alkyl or [lower alkoxy] [trihalo- (lower) alkoxy]phenyl (lower) alkyl, and A3 is lower alkylene,
R2 is hydrogen and
R3 is 1-lower alkylindolyl, benzofuranyl, dihydrobenzofuranyl or N,N-di (lower alkyl) aminophenyl.
The processes 1 to 4 for preparing the object compounds (I) of the present invention are explained in detail in the following.
Process 1 :
The object compound (I) or a salt thereof can be
prepared by reacting the compound (II) or a salt thereof with 1,1'-carbonyldiimidazole and continuously by reacting the obtained compound (III) or a salt thereof with the compound (IV) or a salt thereof.
The present reaction is usually carried out in a solvent such as dioxane, dimethylsulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, hexane,
tetrahydrofuran, 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, at ambient temperature or under heating.
Process 2 :
The object compound (I) or a salt thereof can be
prepared by reacting the compound (IV) or a salt thereof with 1,1'-carbonyldiimidazole and continuously by reacting the obtained compound (V) or a salt thereof with the compound (II) or a salt thereof.
The reaction can be carried out in a similar manner to that of the aforementioned Process 1.
Process 3 :
The object compound (I) or a salt thereof can be
prepared by subjecting the compound (VI) or a salt thereof to Curtius Rearrangement reaction and continuously by reacting the obtained compound (VII) or a salt thereof with the compound (IV) or a salt thereof.
Curtius Rearrangement reaction may carried out by using a conventional reagent such as diphenylphosphoryl azide.
The reaction may be also carried out in the presence of an organic or inorganic base such as an alkali metal
bicarbonate, tri (lower) alkylamine, pyridine,
N- (lower) alkylmorphorine, N,N-di (lower) alkyIbenzylamine, or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
Process 4 :
The object compound (I) or a salt thereof can be prepared by subjecting the compound (VIII) or a salt thereof to Curtius Rearrangement reaction and continuously by reacting the obtained compound (IX) or a salt thereof with the compound (II) or a salt thereof.
This reaction can be carried out in a similar manner to that of the aforementioned Process 3.
The object compound (I) of the present invention can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
The object compound (I) thus obtained can be converted to its salt by a conventional method.
The object compound (I) and a pharmaceutically
acceptable salt thereof may include a solvate [e.g.,
enclosure compound (e.g., hydrate, etc.)].
The object compound (I) of the present invention are novel and exhibit pharmacological activities such as 5-HT antagonism, especially, 5-HT2C antagonism, and the like and therefore are useful as 5-HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders,
migraine, anorexia, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines,
schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus, and the like. In order to illustrate the usefulness of the object
compounds (I), pharmacological activity of representative compound of the present invention are shown below.
Test Method :
[3H] -mesulergine binding
The affinity of test drugs for the 5-HT2C binding site can be determined by assessing their ability to displace
[3H]-mesulergine in the rat prefrontal cortex. The method employed was similar to that of Pazos et al, 1984.
The membrane suspension (500 μl) was incubated with
[3H] -mesulergine (1 nM) in Tris HCl buffer containing CaCl2 4 mM and ascorbic acid 0.1% (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the presence of
mianserin (1 μM). 30 nM spiperone was used to prevent binding to 5-HT2A sites. Test drugs (10-6 M) were added in a volume of 100 μl. The total assay volume was 1000 μl.
Incubation was stopped by rapid filtration using a Brandel cell harvester and radioactivity measured by scintillation counting.
The IC50 values were determined using a four parameter logistic program (DeLean 1978) and the pKi (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where :
Ki = inhibition constant
C = concentration of [ 3H]-mesulergine
Kd = affinity of mesulergine for 5-HT2C binding sites.
Test Compounds
(1) N-(1-Methyl-1H-indol-5-yl)-N'-(3-pyridyl)urea
(Reference compound (A))
(2) N-[3-(Butylamidino)phenyl]-N'-[1-methyl-1H-indol-5- yl]urea hydroiodide
(3) N-[3-(Benzylamidino)phenyl]-N'-[1-methyl-1H-indol-5- yl]urea hydroiodide
(4) N-[3-[2-(3,4-Dimethoxyphenyl)ethyl]amidinophenyl]-N'-[1- methyl-1H-indol-5-yl]urea hydroiodide
Test Result :
For therapeutic or preventive administration, 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. 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.
If needed, there may be included in the above
preparations auxiliary substances, stabilizing agents,
wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, 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 or 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 single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the object compound (I) of the present invention may be used in treating diseases. The following Preparations and Examples are given for the purpose of illustrating the present invention.
Preparation 1
A mixture of 3-nitrobenzyl bromide (1 g) and 4- methoxybenzylamine (2.26 g) in chloroform (20 ml) was
refluxed for 3 hours. This solution was washed with IN aqueous sodium hydroxide solution twice, dried over magnesium sulfate, filtered, and evaporated. The residue was
chromatographed on silica gel (hexene: chloroform = 1:1) to give N-(4-methoxybenzyl)-3-nitrobenzylamine.
IR (Film) : 3300, 1600, 1580 cm-1
NMR (DMSO-d6, δ) : 2.80 (1H, s), 3.62 (2H, s), 3.79
(3H, s), 3.87 (2H, s), 6.85-6.88 (2H, m), 7.23-7.27 (2H, m), 7.60 (1H, t, J=7.9Hz), 7.78 (1H, d,
J=7.6Hz), 8.09 (1H, d, J=8.1Hz), 8.38 (1H, s)
Preparation 2
A mixture of 3-nitrobenzyl chloride (1.01 g),
diphenylamine (500 mg), potassium hydroxide (993 mg),
potassium carbonate (652 mg) and tetra-n-butylammonium
sulfate (79 mg) in toluene (30 ml) was stirred at 72°C for 3 hours. The mixture was washed with water, dried over
magnesium sulfate, filtered, and evaporated. This oil was chromatographed on silica gel (hexane: ethyl acetate = 8:1) to give N-(3-nitrobenzyl)diphenylamine.
IR (Nujol) : 1580, 1520 cm-1
NMR (DMSO-d6, δ) : 5.16 (2H, s), 6.90-7.31 (12H, m),
7.62 (1H, t, J=7.8Hz), 7.80 (1H, d, J=7.7Hz), 8.08 (1H, d, J=8.1Hz), 8.19 (1H, s)
MASS : 305 (M+1)
Preparation 3
A mixture of N-(4-methoxybenzyl)-3-nitrobenzylamine (1.8 g), benzyloxycarbonyl chloride (1 ml) and triethylamine (1 ml) in toluene (15 ml) was stirred at ambient temperature for 3 hours. This solution was washed with water twice, dried over magnesium sulfate, filtered, and evaporated. The residue was chromatographed on silica gel (chloroform) to give N-(benzyloxycarbonyl)-N-(4-methoxybenzyl)-3- nitrobenzylamine.
IR (Film) : 3450, 1690, 1600 cm-1
NMR (DMS0-d6, δ) : 3.72 (3H, s), 4.45 (2H, s), 4.54
(2H, s), 5.16 (2H, s), 6.84-6.88 (2H, m), 7.11-8.11 (11H, m)
Preparation 4
The following compound was obtained according to a similar manner to that of Preparation 3. N-(Benzyloxycarbonyl)-N-(4-methylbenzyl)-3- nitrobenzylamine
IR (Film) : 3000, 2900, 1680 cm-1
NMR (DMSO-d6, δ) : 2.27 (3H, s), 4.47 (2H, s), 4.54
(2H, s), 5.16 (2H, s), 7.12-7.4 (9H, m), 7.5-7.8 (2H, m), 7.90-8.12 (2H, m)
Preparation 5
A mixture of N-(3-nitrobenzyl)diphenylamine (400 mg), ferric chloride (150 mg), active carbon (700 mg) and
hydrazine monohydrate (260 mg) in ethanol (15 ml) was stirred at 70°C for 2 hours. The mixture was filtered, evaporated. The residue was dissolved in chloroform, washed with water, dried over sodium sulfate, filtered, and evaporated to give 3-(N,N-diphenylaminomethyl)aniline.
IR (Nujol) : 1575, 1520 cm-1
NMR (DMSO-d6, δ) : 4.83 (2H, s), 5.01 (2H, s), 6.36-
6.47 (2H, m), 6.56 (1H, s), 6.86-7.28 (11H, m) MASS : 275 (M+1)
Example 1
A solution of m-aminobenzonitrile (3.01 g) and 1,1'- carbonyldiimidazole (4.14 g) in tetrahydrofuran (30 ml) was stirred at room temperature for 5 hours. A solution of 5- amino-1-methylindole (2.48 g) in tetrahydrofuran (20 ml) was added to the solution. The solution was stirred at room temperature for 48 hours. After evaporation of the solvent, the residue was dissolved in chloroform-methanol (7:3, V/V). The solution was evaporated in vacuo to the volume of 15 ml. The solution was diluted with methanol and allowed to stand at room temperature overnight. The crystals formed was collected and washed with methanol to give N-(3-cyanophenyl)- N'-(1-methyl-1H-indol-5-yl)urea (2.48 g). From the filtrate, another crop of the product (0.82 g) was obtained in a similar manner to that described above,
mp : 203-208°C
IR (Nujol) : 3280, 2220, 1630, 1555 cm-1
NMR (DMSO-d6, δ) : 3.76 (3H, s), 6.35 (1H, d, J=3Hz),
7.14-7.75 (7H, m), 8.00 (1H, s), 8.60 (1H, s), 8.93 (1H, s) Example 2
To a solution of N-(3-cyanophenyl)-N'-(1-methyl-1H- indol-5-yl)urea (2.99 g) in pyridine (30 ml) and
triethylamine (10 ml) was passed through slowly hydrogen sulfide gas for 8 hours at room temperature. After 12 hours the solution was diluted with water and stirred for 2 hours. The precipitate formed was collected and washed with water to give N-(1-methyl-1H-indol-5-yl)-N'-(3-thiocarbamoylphenyl)- urea (3.19 g).
mp : 211-214°C
IR (Nujol) : 3290, 3180, 1625, 1604, 1568 cm-1
NMR (DMSO-d6, δ) : 3.76 (3H, s), 6.34 (1H, d, J=3Hz),
7.12-7.70 (7H, m), 7.95 (1H, s), 8.42 (1H, s), 8.76 (1H, s), 9.46 (1H, s), 9.84 (1H, s) Example 3
To a solution of N-(1-methyl-1H-indol-5-yl)-N'-(3- thiocarbamoylphenyl) urea (1.87 g) in a mixture of
acetonitrile (8 ml) and N,N-dimethylformamide (15 ml) was added methyliodide (2 ml). After 24 hours, the solution was diluted with ether. The precipitate formed was collected and washed with ether to give N-(1-methyl-1H-indol-5-yl)-N'-[3- [methylthio(imino)methyl]phenyl]urea hydroiodide (2.60 g). mp : 187-196°C
IR (Nujol) : 3270, 3150, 1675, 1590, 1555 cm-1
NMR (DMSO-d6, δ) : 2.85 (3H, s), 3.77 (3H, s), 6.36
(1H, d, J=3Hz), 7.15-7.70 (8H, m), 8.22 (1H, s), 8.60 (1H, s), 9.03 (1H, s)
Example 4
A mixture of N-(1-methyl-1H-indol-5-yl)-N'-[3-
[methylthio(imino)methyl]phenyl]urea (0.51 g) and aniline (0.20 g) in N,N-dimethylformamide (3 ml) was stirred at 70°C for 8 hours. After evaporation of the solvent, the residue was neutralized with IN aqueous sodium hydroxide, solution and extracted twice with butanol. The butanol layer was
evaporated in vacuo. The residue was purified by column chromatography on silica gel (15% methanol in chloroform) to give N-[1-methyl-1H-indol-5-yl]-N'-[3-(phenylamidino)- phenyl]urea (80 mg) as an amorphous powder.
IR (Nujol) : 3430, 3300, 1690, 1630, 1570 cm-1
NMR (DMSO-d6, δ) : 3.75 (3H, s), 6.22 (1H, br s), 6.34 (1H, d, J=3Hz), 6.80-7.60 (13H, m), 7.70 (1H, d, J=2Hz), 8.03 (1H, s), 8.42 (1H, s), 8.70 (1H, s) Example 5
A mixture of N-(1-methyl-1H-indol-5-yl)-N'-[3- [methylthio(imino)methyl]phenyl]urea (0.60 g) and ammonium acetate (0.30 g) in methanol (6 ml) was heated at 65°C for 7 hours. After cooling, the precipitate formed was collected and washed with methanol to give N-(3-amidinophenyl)-N'-(1- methyl-1H-indol-5-yl)urea hydroiodide (75 mg).
mp : 214-218°C
IR (Nujol) : 3340, 3260, 1690, 1640, 1560, 1525 cm-1 NMR (DMSO-d6, δ) : 3.75 (3H, s), 6.32 (1H, d, J=3Hz), 7.20-7.80 (9H, m), 7.97 (1H, s), 9.60-10.40 (4H, m)
Example 6
A mixture of N-(1-methyl-1H-indol-5-yl)-N'-[3- [methylthio(imino)methyl]phenyl]urea (300 mg), butylamine (188 mg), and acetic acid (154 mg) in methanol (3 ml) was stirred at 60°C for 6 hours. After evaporation of the solvent, the residue was washed once with ether and twice with water. The oil was dissolved in methanol and the solution was evaporated in vacuo. The residue was triturated with ether and the powder obtained was collected and washed with ether to give N-[3-(butylamidino)phenyl]-N'-[1-methyl- 1H-indol-5-yl]urea hydroiodide (274 mg) as an amorphous powder.
IR (Nujol) : 3250, 1660, 1590, 1540 cm-1
NMR (DMSO-d6, δ) : 0.93 (3H, t, J=7Hz), 1.39 (2H, m),
1.61 (2H, m), 3.36 (2H, t, J=7Hz), 3.75 (3H, s), 6.33 (1H, d, J=3Hz), 7.10-6.80 (7H, m), 8.00 (1H, s), 9.66 (1H, s), 10.10 (1H, s) Example 7
N-[3-(Benzylamidino)phenyl]-N'-[l-methyl-1H-indol-5- yl]urea hydroiodide was prepared in a similar manner to that of Example 6.
IR (Nujol) : 3250, 1660, 1620, 1580, 1540 cm-1
NMR (DMSO-d6, δ) : 3.76 (3H, s), 4.66 (2H, s), 6.35
(1H, d, J=3Hz), 7.10-7.70 (12H, m), 7.99 (1H, s), 8.59 (1H, s), 8.96 (1H, s), 8.60-9.60 (3H, br s)
Example 8
N-[3-[2-(3,4-Dimethoxyphenyl)ethyl]amidinophenyl]-N'-[1- methyl-1H-indol-5-yl]urea hydroiodide was prepared in a similar manner to that of Example 6.
IR (Nujol) : 3250, 1665, 1585, 1560 cm-1
NMR (DMSO-d6, δ) : 2.90 (2H, br t, J=7Hz), 3.62 (2H, br t, J=7Hz), 3.72 (3H, s), 3.76 (6H, s), 6.34 (1H, d, J=3Hz), 6.70-7.80 (9H, m), 8.0.0 (1H, s), 9.03 (1H, s), 9.41 (1H, s)
Example 9
N-[3-(4-Methoxyphenylamidino)phenyl]-N'-[1-methyl-1H- indol-5-yl]urea hydroiodide was prepared in a similar manner to that of Example 6.
IR (Nujol) : 3250, 1660, 1600, 1550, 1510 cm-1
NMR (DMSO-d6, δ) : 3.76 (3H, s), 3.82 (3H, s), 6.35
(1H, d, J=3Hz), 7.10-7.75 (12H, m), 8.12 (1H, s),
8.61 (1H, s), 8.97 (1H, s)
Example 10
N-(Benzofuran-5-yl)-N'-(3-cyanophenyl)urea was prepared in a similar manner to that of Example 1.
mp : 180-187°C
IR (Nujol) : 3270, 2230, 1630, 1600, 1560 cm-1
NMR (DMSO-d6, δ) : 6.93 (1H, m), 7.25-8.00 (8H, m),
8.83 (1H, s), 9.00 (1H, s)
Example 11
N-(Benzofuran-5-yl)-N'-(3-thiocarbamoylphenyl)urea was prepared in a similar manner to that of Example 2.
mp : 188-194°C
IR (Nujol) : 3280, 3170, 1625, 1600, 1565 cm-1
NMR (DMSO-d6, δ) : 6.92 (1H, m), 7.25-8.00 (8H, m),
8.66 (1H, s), 8.84 (1H, s), 9.46 (1H, s), 9.84 (1H, s) Example 12
N-(Benzofuran-5-yl)-N'-[3-[methylthio(imino)methyl]- phenyl] urea hydroiodide was prepared in a similar manner to that of Example 3.
mp : 190-196°C
IR (Nujol) : 3180, 1675, 1590, 1550 cm-1
NMR (DMSO-d6, δ) : 2.86 (3H, s), 6.94 (1H, m),
7.30-8.20 (8H, m), 8.84 (1H, s), 9.12 (1H, s)
Example 13
10% Pd-C (100 mg) was added to a solution of 1-methyl-5- nitroindole (500 mg) in ethanol (20 ml). This mixture was hydrogenated at 1 atm at ambient temperature for 2 hours.
The mixture was filtered through celite and evaporated. The resulting oil was coevaporated with toluene. To the
resulting mass, 1,1'-carbonyldiimidazole (460 mg) was added. This mixture was stirred at ambient temperature for 4 hours. To this solution, 3-(dimethylaminomethyl)aniline (341 mg) was added. This mixture was stirred at ambient temperature overnight, evaporated, and partitioned between chloroform (50 ml) and water (20 ml). The organic layer was washed with
water (2 x 20 ml), dried with magnesium sulfate, filtered, and evaporated. The residue was chromtographed over silica gel (chloroform) and recrystallized from methanol - ethyl acetate to give N-(3-dimethylaminomethylphenyl)-N'-(1- methylindol-5-yl)urea.
mp : 128-133°C
IR (Nujol) : 1630 cm-1
NMR (DMSO-d6, δ) : 2.16 (6H, s), 2.96 (1H, d,
J=3.0Hz), 3.75 (3H, s), 6.86 (1H, d, J=6.9H2), 7.12-7.35 (5H, m), 7.45 (1H, s), 7.69 (1H, d,
J=1.7Hz), 8.42 (1H, s), 8.59 (1H, s)
Example 14
N-(1-Methylindol-5-yl)-N'-[3-[(4-phenylpiperazin-1- yl)methyl]phenyl]urea was prepared in a similar manner to that of Example 13.
mp : 183-185°C
IR (Nujol) : 1610 cm-1
NMR (DMSO-d6, δ) : 2.4-2.6 (4H, m), 3.08-3.23 (4H, m), 3.49 (2H, s), 3.75 (3H, s), 6.34 (1H, d, J=3.0Hz),
6.76 (1H, t, J=7.3Hz), 6.89-6.94 (3H, m), 7.11-7.38 (7H, m), 7.47 (1H, s), 7.68 (1H, s), 8.39 (1H, s), 8.59 (1H, s) Example 15
N-(1-Methylindol-5-yl)-N'-(3-piperidinomethylphenyl)urea was prepared in a similar manner to that of Example 13.
mp : 172-173°C
IR (Nujol) : 1625 cm-1
NMR (DMSO-d6, δ) : 1.3-1.6 (6H, m), 2.25-2.45 (4H, m),
3.37 (2H, s), 3.75 (3H, s), 6.34 (1H, d, J=3.0Hz), 6.85 (1H, d, J=7.4Hz), 7.11-7.40 (6H, m), 7.68 (1H, d, J=1.8Hz), 8.36 (1H, s), 8.56 (1H, s) Example 16
N-(1-Methylindol-5-yl)-N'-(3-morpholinomethylphenyl)urea was prepared in a similar manner to that of Example 13.
mp : 174-175°C
IR (Nujol) : 1650, 1615 cm-1
NMR (DMSO-d6, δ) : 2.36 (4H, t, J=4.4Hz), 3.42 (2H, s), 3.58 (4H, t, J=4.4Hz), 3.75 (3H, s), 6.34 (1H, d, J=2.7Hz), 6.88 (1H, d, J=7.4Hz), 7.11-7.36 (5H, m), 7.44 (1H, s), 7.69 (1H, d, J=1.8Hz), 8.38 (1H, s), 8.57 (1H, s)
Example 17
N-(1-Methylindol-5-yl)-N'-(4-phthalimidomethylphenyl)- urea was prepared in a similar manner to that of Example 13.
IR (Nujol) : 1760, 1700, 1665 cm-1
NMR (DMS0-d6, δ) : 3.75 (3H, s), 4.41 (2H, s), 6.33
(1H, d, J=3Hz), 7.12 (1H, dd, J=9Hz, 2Hz), 7.20- 7.45 (6H, m), 7.67 (1H, d, J=2Hz), 7.80-7.95 (4H, m), 8.40 (1H, s), 8.59 (1H, s) Example 18
N-[3-(1-Formylaminoethyl)phenyl]-N'-[1-methylindol-5- yl]urea was prepared in a similar manner to that of Example 13.
mp : 165-168°C
IR (Nujol) : 1650, 1635 crn-1
NMR (DMSO-d6, δ) : 1.36 (3H, d, J=7Hz), 3.75 (3H, s), 4.80-5.10 (1H, m), 6.34 (1H, d, J=3Hz), 6.80-6.95 (1H, m), 7.10-7.50 (6H, m), 7.69 (1H, d, J=2Hz), 8.03 (1H, s), 8.40 (1H, s), 8.50-8.60 (2H, m)
MASS : 337 (M+1⊕)
Example 19
N-[3-(N-Methylanilino)methylphenyl]-N'-(1-methylindol-5- yl)urea was prepared in a similar manner to that of Example 13.
mp : 143-144°C
IR (Nujol) : 1610 cm-1
NMR (DMSO-d6, δ) : 3.02 (3H, s), 3.75 (3H, s), 4.52
(2H, s), 7.33 (1H, d, J=3.0Hz), 6.60-6.81 (4H, m), 7.09-7.40 (8H, m), 7.67 (1H, d, J=1.7Hz), 8.35 (1H, s), 8.54 (1H, s)
MASS : 385 (M+1)
Example 20
N-(1-Methylindol-5-yl)-N'-[3-(1,2,3,4- tetrahydroquinolin-1-yl)methylphenyl]urea was prepared in a similar manner to that of Example 13.
mp : 181-184°C
IR (Nujol) : 1610 cm-1
NMR (DMSO-d6, δ) : 1.19-1.99 (2H, m), 2.74 (2H, t,
J=6.1Hz), 3.38 (2H, t, J=5.4Hz), 3.75 (3H, s), 4.43
(2H, s), 6.33-6.34 (1H, m), 6.42-6.49 (2H, m), 6.82-6.91 (3H, m), 7.10-7.40 (6H, m), 7.66 (1H, s), 8.33 (1H, s), 8.53 (1H, s)
MASS : 411 (M+1)
Example 21
N-(1-Methylindol-5-yl)-N'-(3-anilinomethylphenyl]urea was prepared in a similar manner to that of Example 13.
mp : 129-131°C
IR (Nujol) : 1610 cm-1
NMR (DMSO-d6, δ) : 3.75 (3H, s), 4.22 (2H, d,
J=5.9Hz), 6.19 (1H, t, J=5.8Hz), 6.33 (1H, d,
J=2.9Hz), 6.47-6.59 (2H, m), 6.92-7.40 (9H, m), 7.67 (1H, s), 8.35 (1H, s), 8.52 (1H, s) MASS : 371 (M+1)
Example 22
N-(1-Methylindol-5-yl)-N'-[3-(1,2,3,4- tetrahydroisoquinolin-2-yl)methylphenyl]urea was prepared in a similar manner to that of Example 13.
mp : 189-190°C
IR (Nujol) : 1620, 1540 cm-1
NMR (DMSO-d6, δ) : 2.70 (2H, d, J=5.2Hz), 2.81 (2H, d, J=5.2Hz), 3.54 (2H, s), 3.61 (2H, s), 3.75 (3H, s), 6.33 (1H, d, J=3.0Hz), 6.91-7.50 (10H, m), 7.68
(1H, s), 7.69 (1H, s), 8.37 (1H, s), 8.56 (1H, s) MASS : 411 (M+1)
Example 23
N-(1-Methylindol-5-yl)-N'-(3-phthalimidomethylphenyl)- urea was prepared in a similar manner to that of Example 13. mp : 222-226°C
IR (Nujol) : 1700, 1610 cm-1
NMR (DMSO-d6, δ) : 3.75 (3H, s), 4.74 (2H, s), 6.33
(1H, d, J=3.0Hz), 6.87-7.44 (8H, m), 7.84-7.95 (4H, m), 8.56 (1H, s), 8.80 (1H, s)
MASS : 425 (M+1)
Example 24
N-(1-Methylindol-5-yl)-N'-(3-diphenylaminomethylphenyl)- urea was prepared in a similar manner to that of Example 13. mp : 194-195°C
IR (Nujol) : 1610 cm-1
NMR (DMSO-d6, δ) : 3.75 (3H, s), 4.97 (2H, s), 6.33
(1H, d, J=3.0Hz), 6.88-7.40 (17H, m), 7.66 (1H, d,
J=1.8Hz), 8.35 (1H, s), 8.57 (1H, s)
MASS : 447 (M+1)
Example 25
N-[3-(1-Anilinoethyl)phenyl]-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
mp : 158-162°C
IR (Nujol) : 1650, 1600 cm-1
NMR (DMSO-d6, δ) : 1.42 (3H, d, J=7Hz), 3.-75 (3H, s), 4.38 (1H, quint., J=7Hz), 6.14 (1H, d, J=6Hz), 6.33
(1H, d, J=3Hz), 6.40-6.55 (3H, m), 6.90-7.45 (9H, m), 7.68 (1H, s), 8.36 (1H, s), 8.52 (1H, s)
MASS : 385 (M+1⊕)
Example 26
N-[3-(Imidazol-1-ylmethyl)phenyl]-N'-(1-methylindol-5- yl)urea was prepared in a similar manner to that of Example
13.
mp : 170-175°C
IR (Nujol) : 1630 cm-1
NMR (DMSO-d6, δ) : 3.75 (3H, s), 5.17 (2H, s), 6.34
(1H, d, J=3Hz), 6.82 (1H, d, J=8Hz), 6.92 (1H, s),
7.05-7.45 (7H, m), 7.68 (1H, d, J=2Hz), 7.75 (1H, s), 8.40 (1H, s), 8.61 (1H, s)
MASS : 346 (M+1⊕)
Example 27
N-(8-Formylamino-5,6,7,8-tetrahydro-2-naphthyl)-N'-(1- methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
IR (Nujol) : 1630 cm-1
NMR (DMSO-d6, δ) : 1.60-2.00 (4H, m), 2.66 (2H, br s),
3.75 (3H, s), 5.00-5.10 (1H, m), 6.33 (1H, d,
J=3Hz), 6.99 (1H, d, J=8Hz), 7.11 (1H, dd, J=9Hz,
2Hz), 7.20-7.40 (4H, m), 7.67 (1H, d, J=2Hz),
8.12 (1H, s), 8.30 (1H, s), 8.40-8.60 (2H, m)
Example 28
N-(2-Benzyloxycarbonyl-l,2,3,4-tetrahydroisoquinolin-7- yl)-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
mp : 218-222°C
IR (Nujol) : 1700, 1660, 1615 cm-1
NMR (DMSO-d6, δ) : 2.73 (2H, br t, J=6Hz), 3.62 (2H, br t, J=6Hz), 3.75 (3H, s), 4.55 (2H, br s), 5.13 (2H, s), 6.33 (1H, d, J=3Hz), 7.03-7.40 ( 6H, m), 7.68 (1H, d, J=2Hz), 8.43 (1H, br s), 8.49 (1H, br s)
MASS : 455 (M+1⊕)
Example 29
N-(2-Benzyloxycarbonyl-l,2,3,4-tetrahydroisoquinolin-5- yl)-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
mp : 153-156°C
IR (Nujol) : 1690, 1630 cm-1
NMR (DMSO-d6, δ) : 2.71 (2H, br t, J=6Hz), 3.69 (2H, br t, J=6Hz), 3.75 (3H, s), 4.59 (2H, br s), 5.13 (2H, s), 6.33 (1H, d, J=3Hz), 6.88 (1H, d, J=8Hz),
7.10-7.40 (9H, m), 7.60-7.80 (2H, m), 7.88 (1H, br s), 8.76 (1H, br s)
MASS : 455 (M+1⊕)
Example 30
N-(2-Benzyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(1- methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
mp : 165-167°C
IR (Nujol) : 1635 cm-1
NMR (DMSO-d6, δ) : 2.55-2.80 (4H, m), 3.50 (2H, s),
3.64 (2H, s), 3.75 (3H, s), 6.32 (1H, d, J=3Hz), 6.90-7.40 (11H, m), 7.66 (1H, s), 8.37 (2H, br s) MASS : 411 (M+1⊕)
Example 31
N-(1-Benzyloxycarbonyl-l,2,3,4-tetrahydroquinolin-7-yl)- N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
IR (Nujol) : 1680, 1640, 1610 cm-1
NMR (DMSO-d6, δ) : 1.84 (2H, quar., J=6Hz), 2.67 (2H, t, J=6Hz), 3.60-3.76 (5H, m), 5.20 (2H, s), 6.33
(1H, d, J=3Hz), 7.00 (1H, d, J=8Hz), 7.10-7.50 (9H, m), 7.69 (1H, s), 7.84 (1H, s), 8.32 (1H, s), 8.52 (1H, s) Example 32
N-(1-Benzyloxycarbonyl-1,2,3,4-tetrahydroquinolin-5-yl)- N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
mp : 147-152°C
IR (Nujol) : 1700, 1630 cm-1
NMR (DMSO-d6, δ) : 1.80-2.00 (2H, m), 2.65 (2H, t,
J=7Hz), 3.60-3.80 (5H, m), 5.19 (2H, s), 6.33 (1H, d, J=3Hz), 6.90-7.50 (10H, m), 7.60 (1H, d, J=7Hz), 7.71 (1H, d, J=2Hz), 7.84 (1H, s), 8.83 (1H, s)
Example 33
N-(2,3-Dihydrobenzo[b]furan-7-yl)-N'-(3- phthalimidomethylphenyDurea was prepared in a similar manner to that of Example 13.
IR (Nujol) : 3260, 1740, 1700, 1640 cm-1
NMR (DMSO-d6, δ) : 3.21 (2H, t, J=8.6Hz), 4.60 (2H, t, J=8.7Hz), 4.74 (2H, s), 6.71-7.03 (3H, m), 7.19- 7.42 (3H, m), 7.66-8.10 (5H, m), 8.67 (1H, s), 9.13 (1H, s)
MASS : 414 (M+1)
Example 34
To a solution of N-(benzyloxycarbonyl)-N-(4- methoxybenzyl)-3-nitrobenzylamine (1.5 g) in ethanol (20 ml), were added ferric chloride (50 mg), active carbon (500 mg), and hydrazine monohydrate (2 ml). This mixture was stirred at 70ºC for 2 hours, filtered, and evaporated. The residue was dissolved in chloroform and washed with water, dried over magnesium sulfate, filtered, and evaporated. By using this amine, the following compound was obtained according to a similar manner to that of Example 13. N-(1-Methylindol-5- yl)-N'-[3-[N-benzyloxycarbonyl-N-(4-methoxybenzyl)- aminomethyl]phenyl]urea.
IR (Nujol) : 3300, 1700, 1610, 1560 cm-1
NMR (DMSO-d6, δ) : 3.74 (3H, s), 3.76 (3H, s), 4.36
(4H, s), 5.18 (2H, s), 6.34 (1H, d, J=2.9Hz), 6.80-
6.96 (3H, m), 7.13-7.36 (13H, m), 7.70 (1H, s),
8.41 (1H, s), 8.61 (1H, s)
MASS : 549 (M+1)
Example 35
N-(1-Methylindol-5-yl)-N'-[3-[N-benzyloxycarbonyl-N-(4- methylbenzyl)aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 34.
IR (Nujol) : 3260, 1690, 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 2..29 (3H, s), 3.76 (3H, s), 4.37
(4H, s), 5.18 (2H, s), 6.34 (1H, s, J=2.9Hz), 6.79
(1H, s), 7.13-7.36 (15H, m), 7.70 (1H, s), 8.42
(1H, s), 8.63 (1H, s)
Example 36
To a suspension of 1-methylindole-5-carboxylic acid (1.0 g) in benzene were added triethylamine (0.80 ml) and
diphenylphosphoryl azide (1.23 ml). The mixture was refluxed for 3 hours. After being cooled, 4-cyanoaniline (1.35 g) was added and refluxed for 7 hours. The reaction mixture was partitioned between water and ethyl acetate. Precipitates were collected, washed with water, and dried to give N-(4- cyanophenyl)-N'-(1-methylindol-5-yl)urea (1.11 g). From the ethyl acetate layer, another 0.41 g of N-(4-cyanophenyl)-N'-
(1-methylindol-5-yl)urea was obtained.
mp : 238-240°C
IR (Nujol) : 2315, 1695, 1640 cm-1
NMR (DMSO-d6, δ) : 3.76 (3H, s), 6.36 (1H, d, J=3Hz), 7.15 (1H, dd, J=8Hz, 2Hz), 7.28 (1H, d, J=3Hz),
7.35 (1H, d, J=9Hz), 7.60-7.80 (5H, m), 8.63 (1H, s), 9.11 (1H, s)
MASS : 291 (M+1⊕) Example 37
N-(3-Cyanophenyl)-N'-(4-dimethylaminophenyl)urea was prepared in a similar manner to that of Example 36.
IR (Nujol) : 3310, 2200, 1640, 1600 cm-1
NMR (DMSO-d6, δ) : 2.84 (6H, s), 6.68 (1H, s), 6.73 (1H, s), 7.25 (1H, s), 7.29 (1H, s), 7.37-7.67 (3H, m), 8.32 (1H, s), 8.47 (1H, s), 8.89 (1H, s)
MASS : 281 (M+1)
Example 38
N-(3-Cyanophenyl)-N'-(2,3-dihydrobenzo[b]furan-7-yl)urea was prepared in a similar manner to that of Example 36.
IR (Nujol) : 2200, 1650, 1600 cm-1
NMR (DMSO-d6, δ) : 3.23 (2H, t, J=8.8Hz), 4.62 (2H, t, J=8.7Hz), 6.74-6.92 (2H, m), 7.40-7.64 (3H, m), 7.80 (1H, d, J=7.3Hz), 7.98 (1H, s), 8.30 (1H, s),
9.41 (1H, s)
MASS : 280 (M+1)
Example 39
N-(1-Methylindol-5-yl)-N'-(4-thiocarbamoylphenyl)urea was prepared in a similar manner to that of Example 2.
IR (Nujol) : 1650, 1620, 1590 cm-1
NMR (DMSO-d6, δ) : 3.76 (3H, s), 6.35 (1H, d, J=3Hz), 7.15 (1H, dd, J=7Hz, 2Hz), 7.27 (1H, d, J=3Hz), 7.35 (1H, d, J=9Hz), 7.44 (2H, d, J=12Hz), 7.70
(1H, d, J=2Hz), 7.80-8.00 (3H, m), 8.55 (1H, s), 8.91 (1H, s), 9.30 (1H, br s), 9.61 (1H, br s)
Example 40
N-(1-Methylindol-5-yl)-N'-[4-[methylthio(imino)methyl]- phenyl]urea hydroiodide was prepared in a similar manner to that of Example 3.
mp : 95-105°C
IR (Nujol) : 1645 cm-1
NMR (DMSO-d6, δ) : 2.83 (3H, s), 3.77 (3H, s),, 6.36
(1H, d, J=3Hz), 7.17 (1H, dd, J=9Hz, 2Hz), 7.30
(1H, d, J=3Hz), 7.37 (1H, d, J=9Hz), 7.70-7.80 (3H, m), 7.80-8.10 (2H, m), 8.73 (1H, s), 9.34 (1H, s) MASS : 339 (M+1⊕), 291 (M-48 (CH3SH)+1)⊕ Example 41
N-(3-Thiocarbamoylphenyl)-N'-(4-dimethylaminophenyl)urea was prepared in a similar manner to that of Example 2.
IR (Nujol) : 3280, 1620 cm-1
NMR (DMSO-d6, δ) : 2.83 (6H, s), 6.67 (1H, s), 6.72
(1H, s), 7.24-7.39 (4H, m), 7.61-7.66 (1H, m), 7.91
(1H, s), 8.28 (1H, s), 8.71 (1H, s), 9.46 (1H, s), 9.84 (1H, s)
MASS : 315 (M+1) Example 42
N-[3-[Methylthio(imino)methyl]phenyl]-N'-(4- dimethylaminophenyl)urea hydroiodide was prepared in a similar manner to that of Example 3.
IR (Nujol) : 1670 cm-1
NMR (DMSO-d6, δ) : 2.86 (3H, s), 3.61 (3H, s), 7.25-
7.76 (5H, m), 7.89 (1H, s), 8.16 (1H, s), 9.25 (1H, s), 9.29 (1H, s)
MASS : 329 (M+1) Example 43
N-[3-[Methylthio(imino)methyl]phenyl]-N'-(2,3- dihydrobenzo[b]furan-7-yl)urea hydroiodide was prepared in similar manners to those of Example 2, and then Example 3.
IR (Nujol) : 1690, 1600 cm-1
NMR (DMSO-d6, δ) : 2.41 (3H, s), 3.23 (2H, t,
J=8.8Hz), 4.62 (2H, t, J=8.7Hz), 6.73-6.90 (2H, m), 7.25-7.51 (3H, m), 7.82-7.86 (1H, s), 8.16-8.20 (1H, m), 9.28 (1H, s), 10.19 (1H, s), 10.36 (1H, s) MASS : 328 (M+1)
Example 44
N-(4-Amidinophenyl)-N'-(1-methylindol-5-yl)urea hydroiodide was prepared in a similar manner to that of
Example 5.
mp : 167-172°C
IR (Nujol) : 1650, 1630 cm-1
NMR (DMSO-d6, δ) : 3.77 (3H, s), 6.35 (1H, d, J=3Hz),
7.17 (1H, dd, J=9Hz, 2Hz), 7.28 (1H, d, J=3Hz),
7.34 (1H, d, J=9Hz), 7.60-7.90 (5H, m), 8.60-9.40 (6H, m)
MASS : 308 (M+1⊕)
Example 45
N-(1-Methylindol-5-yl)-N'-[4-(phenylamidino)phenyl]urea hydroiodide was prepared in a similar manner to that of Example 6.
mp : >280°C
IR (Nujol) : 1685, 1650 cm-1
NMR (DMSO-d6, δ) : 3.77 (3H, s), 6.36 (1H, d, J=3Hz),
7.15 (1H, dd, J=9Hz, 2Hz), 7.29 (1H, d, J=3Hz), 7.30-7.65 (6H, m), 7.70-7.75 (3H, m), 7.86 (2H, d,
J=9Hz), 8.66 (1H, s), 9.14 (1H, s)
MASS : 384 (M+1⊕)
Example 46
N-[4-(Benzylamidino)phenyl]-N'-(1-methylindol-5-yl)urea hydroiodide was prepared in a similar manner to that of Example 6.
mp : 155-165°C
IR (Nujol) : 1650 cm-1
NMR (DMSO-d6, δ) : 3.76 (3H, s), 4.65 (2H, s), 6.35 (1H, d, J=3Hz), 7.10-8.10 (16H, m), 9.34 (1H, s),
9.86 (1H, s)
MASS : 398 (M+1⊕)
Example 47
N-(1-Methylindol-5-yl)-N'-[3-(3-phenylpropyl)- amidinophenyl]urea hydroiodide was prepared in a similar
manner to that of Example 6.
IR (Nujol) : 3250, 1650, 1580 cm-1
NMR (DMSO-d6, δ) : 1.70-2.00 (4H, m), 2.70 (2H, m), 3.40 (2H, t, J=7Hz), 3.75 (3H, s), 6.32 (1H, d, J=3Hz), 7.15-7.40 (11H, m), 7.47 (1H, t, J=9Hz), 7.75 (2H, m), 8.06 (1H, s), 9.94 (1H, s), 10.40 (1H, s) MASS : 426 (M++1)
Example 48
N-(1-Methylindol-5-yl)-N'-[3-(2-phenylethyl)- amidinophenyl]urea hydroiodide was prepared in a similar manner to that of Example 6.
IR (Nujol) : 3250, 1655, 1580, 1540 cm-1
NMR (DMSO-d6, δ) : 2.97 (2H, t, J=8Hz), 3.36 (2H, t, J=8Hz), 3.76 (3H, s), 6.35 (1H, d, J=3Hz), 7.10-
7.40 (12H, m), 7.48 (1H, t, J=8Hz), 7.64 (1H, d, J=9Hz), 7.77 (1H, s), 7.85 (1H, s), 8.92 (1H, s) , 9.28 (1H, s)
MASS : 412 (M++1)
Example 49
N-(Benzo[b]furan-5-yl)-N'-[3-(pheriylamidino)phenyl]urea hydroiodide was prepared in a similar manner to that of Example 6.
IR (Nujol) : 3500-3000, 1650, 1590, 1540 cm-1
NMR (DMSO-d6, δ) : 6.60 (1H, m), 6.90-7.00 (1H, m), 7.20-7.60 (10H, m), 7.70 (1H, m), 7.85 (1H, d, J=2Hz), 7.95 (1H, d, J=2Hz), 8.13 (1H, m), 8.83 (1H, s), 9.04 (1H, s)
MASS : 371 (M++1)
Example 50
N-[3-(Phenylamidino)phenyl]-N'-(4-dimethylaminophenyl)- urea hydroiodide was prepared in a similar manner to that of Example 6.
mp : 166-172°C
IR (Nujol) : 1650 cm-1
NMR (DMSO-d6, δ) : 3.59 (6H, s), 7.36-7.77 (10H, m), 7.88-7.92 (2H, m), 8.10 (1H, s), 9.06 (1H, s), 9.22-9.24 (2H, m), 9.85 (1H, s), 11.43 (1H, s)
MASS : 374 (M+1)
Example 51
N-[3-(Phenylamidino)phenyl]-N'-(2,3-dihydrobenzo[b]- furan-7-yl)urea hydroiodide was prepared in a similar manner to that of Example 6.
mp : 97-105°C
IR (Nujol) : 1660 cm-1
NMR (DMSO-d6, δ) : 3.23 (2H, t, J=8.6Hz), 4.61 (2H, t, J=8.6Hz), 6.73-7.06 (5H, m), 7.30-7.62 (5H, m),
7.85 (1H, d, J=7.8Hz), 7,99 (1H, s), 8.21 (1H, s), 9.28 (1H, s)
MASS : 373 (M+1) Example 52
A mixture of N-(1-methylindol-5-yl)-N'-(3- phthalimidomethylphenyl)urea (420 mg) and hydrazine
monohydrate (150 mg) in ethanol (100 ml) was stirred at 70°C for 5 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate and IN aqueous sodium hydroxide. The organic layer was washed with water, dried over magnesium sulfate, filtered, and evaporated. This residue was recrystallized from chloroform-hexane to give N-(1-methylindol-5-yl)-N'-(3-aminomethylphenyl)urea.
mp : 123-126°C
IR (Nujol) : 1610 cm-1
NMR (DMSO-d6, δ) : 1.81 (2H, s), 3.75 (3H, s), 6.32
(1H, d, J=2.9Hz), 6.90 (1H, d, J=7.5Hz), 7.14-7.48 (8H, m), 7.74 (1H, s), 9.39 (1H, s), 9.51 (1H, s) MASS : 295 (M+1)
Example 53
N-(4-Aminomethylphenyl)-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 52.
mp : 173-175°C
IR (Nujol) : 1635 cm-1
NMR (DMSO-d6, δ) : 3.65 (2H, s), 3.75 (3H, s), 6.33
(1H, d, J=3Hz), 7.10-7.45 (7H, m), 7.68 (1H, d,
J=2Hz), 8.44 (1H, s), 8.54 (1H, s)
MASS (FAB) : 295 (M+1⊕)
Example 54
N-(2,3-Dihydrobenzo[b]furan-7-yl)-N'-(3- aminomethylphenyl)urea was prepared in a similar manner to that of Example 52.
mp : 151-153°C
IR (Nujol) : 3240, 1650, 1590 cm-1
NMR (DMSO-d6, δ) : 3.22 (2H, t, J=8.6Hz), 4.02 (2H, s), 4.61 (2H, t, J=8.7Hz), 6.72-6.95 (3H, m), 7.16- 7.37 (3H, m), 7.86 (1H, d, J=7.1Hz), 8.17 (1H, s), 9.07 (1H, s)
MASS : 284 (M+1)
Example 55
To a solution of 7-nitrobenzo [b] furan (1.23 g) in ethanol (100 ml) were added hydrazine hydrate (660 μl), ferric chloride (20 mg) and active carbon (200 mg). The mixture was stirred at 70°C for 2 hours, filtered, and evaporated. The residue was dissolved in ethyl acetate, and washed with water. The organic layer was dried over
magnesium sulfate, filtered, and evaporated to give 7- aminobenzo[b]furan. By using this, the following compound was obtained according to similar manners to those of Example 13, and then Example 52.
N-(3-Aminomethylphenyl)-N'-(benzo[b]furan-7-yl)urea IR (Nujol) : 1680 cm-1
NMR (DMSO-d6, δ) : 3.71 (2H, s), 6.95-6.98 (2H, m),
7.13-7.43 (5H, m), 7.98-8.06 (2H, m), 8.87 (1H, s), 9.15 (1H, s)
MASS : 282 (M+1) Example 56
To a mixture of N-(1-methylindol-5-yl)-N'-[3-[(3- benzyloxycarbonylguanidino)methyl]phenyl]urea (100 mg), tetrahydrofuran (10 ml) and methanol (10 ml), 10% palladium on carbon (30 mg) was added. This mixture was hydrogenated at 1 atm at ambient temperature for 1 hour. The mixture was filtered through celite and evaporated. The resulting oil was triturated with diisopropyl ether to give N-(1- methylindol-5-yl)-N'-[3-(guanidinomethyl)phenyl]urea.
IR (Nujol) : 1650, 1540 cm-1
NMR (DMSO-d6, δ) : 3.75 (3H, s), 4.33 (2H, s), 6.33
(1H, d, J=2.9Hz), 6.86 (1H, d, J=7.4Hz), 7.14-7.73 (9H, m)
MASS : 337 (M+1) Example 57
To a mixture of N-(1-methylindol-5-yl)-N'-[3-[N- benzyloxycarbonyl-N-(4-methoxybenzyl)aminomethyl]phenyl]urea (1 g) in methanol (15 ml) and tetrahydrofuran (15 ml) were added 10% palladium on carbon. This mixture was hydrogenated at 1 atm at ambient temperature for 1 hour, filtered and evaporated. The resulting oil was triturated with
diisopropyl ether to give N-(1-methylindol-5-yl)-N'-[3-[(4- methoxybenzyl)aminomethyl]phenyl]urea.
mp : 78-80°C
IR (Nujol) : 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 2.80-3.00 (1H, m), 3.63 (4H, s),
3.73 (3H, s), 3.75 (3H, s), 6.34 (1H, s), 6.86-6.90 (3H, m), 7.10-7.50 (6H, m), 7.69 (1H, s), 8.41 (1H, s), 8.55 (1H, s)
MASS : 415 (M+1)
Example 58
N-(1-Methylindol-5-yl)-N'-[3-[(4-methylbenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 57.
mp : 92-94°C
IR (Nujol) : 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 2.28 (3H, s), 3.64-3.65 (4H, m),
3.75 (3H, s), 6.34 (1H, d, J=2.9Hz), 6.91 (1H, d, J=6.9Hz), 7.10-7.43 (11H, m), 7.69 (1H, d,
J=1.5Hz), 8.41 (1H, s), 8.56 (1H, s)
MASS : 533 (M+1)
Example 59
N-(1-Methylindol-5-yl)-N'-[3-(methylaminomethyl)- phenyl]urea maleate was prepared in similar manners to those of Example 34, and then Example 57.
mp : 172-175°C
IR (Nujol) : 3300, 1630, 1610 cm-1
NMR (DMSO-d6, δ) : 2.56 (3H, s), 3.76 (3H, s), 4.10 (2H, s), 6.04 (2H, s), 6.34 (1H, d, J=2.6Hz), 7.05
(1H, d, J=6.7Hz), 7.15 (1H, dd, J=8.7Hz, 1.9Hz),
7.27-7.42 (4H, m), 7.70-7.71 (2H, m), 8.57 (1H, s),
8.6-8.9 (3H, m)
MASS : 309 (M+1)
Example 60
N-(1-Methyϋndol-5-yl)-N'-(1,2,3,4- tetrahydroisoquinolin-7-yl)urea was prepared in a similar manner to that of Example 57.
mp : 174-177°C
IR (Nujol) : 1600, 1640 cm-1
NMR (DMSO-d6, δ) : 2.63 (2H, t, J=6Hz), 2.96 (2H, t,
J=6Hz), 3.75 (3H, s), 3.84 (2H, s), 6.33 (1H, d,
J=3Hz), 6.95 (1H, d, J=8Hz), 7.10-7.40 (5H, m), - 7.68 (1H, d, J=2Hz), 8.45 (1H, s), 8.48 (1H, s)
MASS : 321 (M+1⊕)
Example 61
N-(1-Methylindol-5-yl)-N'-(1,2,3,4- tetrahydroisoquinolin-5-yl)urea was prepared in a similar manner to that of Example 57.
mp : 167-169°C
IR (Nujol) : 1625 cm-1
NMR (DMSO-d6, δ) : 2.55 (2H, t, J=6Hz), 3.03 (2H, t,
J=6Hz), 3.76 (3H, s), 3.84 (2H, s), 6.34 (1H, d, J=3Hz), 6.70 (1H, d, J=7Hz), 7.00-7.20 (2H, m),
7.26 (1H, d, J=3Hz), 7.34 (1H, d, J=9Hz), 7.70-7.80
(3H, m), 8.86 (1H, s)
MASS : 321 (M+1⊕)
Example 62
N-(1-Methylindol-5-yl)-N'-(1,2,3,4-tetrahydroquinolin-5- yl)urea was prepared in a similar manner to that of Example 57.
mp : 180-185°C
IR (Nujol) : 1620, 1600 cm-1
NMR (DMSO-d6, δ) : 1.83 (2H, br s), 2.51 (2H, br s),
3.12 (2H, br s), 3.75 (3H, s), 5.59 (1H, br s), 6.17 (1H, d, J=8Hz), 6.33 (1H, d, J=3Hz), 6.70-7.40 (5H, m), 7.57 (1H, s), 7.69 (1H, s), 8.70 (1H, s) MASS : 321 (M+1⊕)
Example 63
N-(1-Methylindol-5-yl)-N'-(1,2,3,4-tetrahydroquinolin-7- yl)urea was prepared in a similar manner to that of Example
57.
mp : 225-230°C
IR (Nujol) : 1640, 1620 cm-1
NMR (DMSO-d6, δ) : 1.60-1.90 (2H, m), 2.40-2.65 (2H, m), 3.10-3.20 (2H, m), 3.75 (3H, s), 5.60 (1H, br s), 6.32 (1H, d, J=3Hz), 6.45 (1H, dd, J=8Hz, 2Hz), 6.60-6.75 (2H, m), 7.11 (1H, dd, J=9Hz-, 2Hz), 7.25 (1H, d, J=3Hz), 7.31 (1H, d, J=9Hz), 7.66 (1H, d,
J=2Hz), 8.16 (1H, s), 8.26 (1H, s)
MASS : 321 (M+1⊕)
Example 64
To a solution of N-[3-(1-formylaminoethyl)phenyl]-N'-(1- methylindol-5-yl)urea (0.30 g) in ethanol (10 ml) was added lN-aqueous sodium hydroxide (2.7 ml). The mixture was refluxed for 9 hours. After evaporation, resulting mass was partitioned between water and ethyl acetate. Organic layer was dried over sodium sulfate, and chromatographed on silica gel eluted by chloroform-methanol-aqueous ammonia (10:1:0 to 10:1:0.05) to give N-[3-(1-aminoethyl)phenyl]-N'-[1- methylindol-5-yl]urea (0.19 g).
mp : 90-110°C (amorphous)
IR (Nujol) : 1650 cm-1
NMR (DMSO-d6, δ) : 1.29 (3H, d, J=6Hz), 3.75 (3H, s),
4.03 (1H, q, J=6Hz), 6.33 (1H, d, J=3Hz), 7.10-7.40 (5H, m), 7.47 (1H, s), 7.70 (1H, s), 8.56 (1H, s),
8.70 (1H, s)
MASS : 309 (M+1⊕), 617 (2M+1⊕)
Example 65
N-(8-Amino-5,6,7,8-tetrahydro-2-naphthyl)-N'-(1- methylindol-5-yl)urea was prepared in a similar manner to that of Example 64.
mp : 175-180°C
IR (Nujol) : 1665, 1595 cm-1
NMR (DMSO-d6, δ) : 1.50-2.10 (4H, m), 2.45-2.70 (2H, m), 3.75 (3H, s), 4.00 (1H, br s), 6.32 (1H, d,
J=3Hz), 6.98 (1H, d, J=8Hz), 7.14 (1H, dd, J=9Hz,
2Hz), 7.20-7.35 (3H, m), 7.52 (1H, d, J=2Hz), 7.70 (1H, d, J=2Hz), 8.69 (2H, s)
MASS : 318 (M-NH2)⊕
Example 66
To a solution of N-[4-(aminomethyl)phenyl]-N'-(1- methylindol-5-yl)urea (0.10 g) in N,N-dimethylformamide (5 ml) was added [(methylthio)(imino)methyl]benzene hydroiodide
(95 mg). The mixture was stirred at 100°C for 5 hours.
After being cooled, the mixture was poured into water, alkalized by aqueous sodium hydroxide to pH=12, and extracted with ethyl acetate. The extract was dried over sodium sulfate, evaporated, and chromatographed on silica gel eluted by chloroform-methanol-aqueous ammonia (9:1:0.1, V/V), to give N-[4-[[(imino)(phenyl)methyl]aminomethyl]phenyl]-N'-(1- methylindol-5-yl)urea (0.08 g) .
mp : 120-130°C
IR (Nujol) : 1650, 1590 cm-1
NMR (DMSO-d6, δ) : 3.75 (3H, s), 4.36 (2H, s), 6.33
(1H, d, J=3Hz), 7.14 (1H, dd, J=9Hz, 2Hz), 7.20-
7.50 (10H, m), 7.69 (1H, d, J=2Hz), 7.75-7.85 (2H, m), 8.53 (1H, br s), 8.67 (1H, br s)
MASS : 398 (M+1⊕)
Example 67
N-(1-Methylindol-5-yl)-N'-[3-[[(imino)(phenyl)methyl]- aminomethyl]phenyl]urea hydroiodide was prepared in a similar manner to that of Example 66.
mp : 144-147°C
IR (Nujol) : 1650 cm-1
NMR (DMSO-d6, δ) : 3.76 (3H, s), 4.67 (2H, s), 6.34
(1H, d, J=2.9Hz), 7.01 (1H, d, J=6.8Hz), 7.15 (1H, dd, J=8.7Hz, 1.9Hz), 7.2-7.4 (5H, m), 7.6-7.9 (9H, m), 8.55 (1H, s), 8.76 (1H, s), 9.1-9.7 (1H, m),
10-10.4 (1H, m)
MASS : 398 (M+1)
Example 68
N-[3-[1-[[(Imino)(phenyl)methyl]amino]ethyl]phenyl]-N'- [1-methylindol-5-yl]urea was prepared in a similar manner to that of Example 66.
mp : 110-125°C
IR (Nujol) : 1650, 1590 cm-1
NMR (DMSO-d6, δ) : 1.40 (3H, d, J=7Hz), 3.75 (3H, s),
4.70-4.80 (1H, m), 6.33 (1H, d, J=3Hz), 6.90 (2H, br s), 7.00-7.50 (10H, m), 7.69 (1H, d, J=2Hz),
7.75-7.85 (2H, m), 8.44 (1H, s), 8.61 (1H, s) MASS : 412 (M+1⊕)
Example 69
N-(1-Methylindol-5-yl)-N'-[3-[[(1-methylindol-5- yl)(imino)methyl]aminomethyl]phenyl]urea hydroiodide was prepared in a similar manner to that of Example 66.
mp : 164-172°C
IR (Nujol) : 1640, 1580 cm-1
NMR (DMSO-d6, δ) : 3..76 (3H, s), 3.88 (3H, s), 4.69 (2H, s), 6.34 (1H, d, J=2.9Hz), 6.67 (1H, d,
J=3.1Hz), 7.02 (1H, d, J=6.5Hz), 7.15 (1H, dd, J=8.8Hz, 1.9Hz), 7.27-7.36 (4H, m), 7.56-7.72 (5H, m), 8.15 (1H, s), 8.51 (1H, s), 8.73 (1H, s), 9.00
(1H, s), 9.41 (1H, s), 10.08 (1H, s)
MASS : 451 (M+1)
Example 70
N-[3-[[(Imino)(phenyl)methyl]aminomethyl]phenyl]-N'- (benzo[b]furan-7-yl)urea hydrochloride was prepared in a similar manner to that of Example 66.
mp : 132-165°C
IR (Nujol) : 1680, 1600 cm-1
NMR (DMSO-d6, δ) : 4.71 (2H, d, J=5.9Hz), 6.98-7.48
(6H, m), 7.60-8.05 (8H, m), 9.12 (1H, s), 9.36 (1H, s), 9.66 (1H, s), 9.80 (1H, s), 10.39 (1H, s) MASS : 385 (M+1) Example 71
N-[3-[[(Imino)(phenyl)methyl]aminomethyl]phenyl]-N'- (2,3-dihydrobenzo[b]furan-7-yl)urea hydrochloride was
prepared in a similar manner to that of Example 66.
mp : 132-165°C
IR (Nujol) : 1660, 1590 cm-1
NMR (DMSO-d6, δ) : 3.22 (2H, t, J=8.7Hz), 4.59 (2H, t, J=8.7Hz), 4.71 (2K, s), 6.72-6.89 (2H, m), 7.03 (1H, d, J=7.4Hz), 7.27-7.43 (2H, m), 7.59-7.86 (7H, m), 8.33 (1H, d, J=6.3Hz), 9.39 (1H, s), 9.58 (1H, s), 9.67 (1H, s), 10.40 (1H, s)
MASS : 387 (M+1)
Example 72
A mixture of N-(1-methylindol-5-yl)-N'-[3- (aminomethyl)phenyl]urea (280 mg) and N-benzyloxycarbonyl-S- methylisothiourea (230 mg) in isopropyl alcohol (15 ml) was heated at 80°C overnight. After evaporation of the solvent, the residue was dissolved in chloroform, washed with 1N aqueous sodium hydroxide solution twice, dried over magnesium sulfate, filtered, and evaporated. The residue was
chromatographed on silica gel (2% methanol in chloroform) to give N-(1-methylindol-5-yl)-N'-[3-[(3-benzyloxycarbonyl- guanidino)methyl]phenyl]urea.
IR (Nujol) : 3410, 1650, 1610 cm-1
NMR (DMSO-d6, δ) : 3.75 (3H, s), 4.3-4.4 (2H, m), 4.97
(2H, s), 6.33-6.34 (1H, m), 6.83-6.87 (1H, m), 7.11-7.68 (14H, m), 8.38 (1H, s), 8.59 (1H, s)
Example 73
A mixture of N-(1-methylindol-5-yl)-N'-[3-
(aminomethyl)phenyl]urea (500 mg), benzyl bromide (318 mg) and potassium carbonate (257 mg) in N,N-dimethylformamide (15 ml) was stirred at 100°C for 3 hours. This solution was partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate, filtered, and evaporated. The residue was chromatographed on silica gel (chloroform), triturated with ether to give N-(1- methylindol-5-yl)-N'-[3-(benzylaminomethyl)phenyl]urea,
mp : 119-123°C
IR (Nujol) : 1610 cm-1
NMR (DMSO-d6, δ) : 3.66 (2H, s), 3.71 (2H, s), 3.75 (3H, s), 6.34 (1H, d, J=2.9Hz), 6.93 (1H, d,
J=7.3Hz), 7.13-7.44 (12H, m), 7.70 (1H, s), 8.44 (1H, s), 8.59 (1H, s)
MASS : 385 (M+1)
Example 74
N-[3-(Benzylammomethyl)phenyl]-N'-(benzo[b]furan-7-yl)- urea was prepared in a similar manner to that of Example 73. mp : 78-82°C
IR (Nujol) : 1620 cm-1
NMR (DMSO-d6, δ) : 3.70 (2H, s), 3.73 (2H, s), 6.99- 7.47 (12H, m), 7.96-8.05 (2H, m), 8.83 (1H, s), 9.15 (1H, s)
MASS : 372 (M+1)
Example 75
N-[3-(Benzylammomethyl)phenyl]-N'-(2,3- dihydrobenzo[b]furan-7-yl)urea hydrochloride was prepared in a similar manner to that of Example 73.
mp : 106-112°C
NMR (DMSO-d6, δ) : 3.22 (2H, t, J=8.6Hz), 4.09-4.15
(4H, m), 4.59 (2H, t, J=8.6Hz), 6.72-6.89 (2H, m), 7.17 (1H, d, J=7.4Hz), 7.29-7.64 (8H, m), 7.82 (1H, d, J=7.7Hz), 8.37 (1H, s), 9.54 (1H, s), 9.75 (2H, s)
MASS : 387 (M+1)
Example 76
N-(1-Methylindol-5-yl)-N'-[3-[(2-fluorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
mp : 109-112°C
IR (Nujol) : 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 3.69 (4H, s), 3.75 (3H, s), 6.34
(1H, d, J=2.9Hz), 6.93 (1H, d, J=7.4Hz), 7.11-7.55 (11H, m), 7.68 (1H, s), 8.41 (1H, s), 8.55 (1H, s) MASS : 403 (M+1) Example 77
N-(1-Methylindol-5-yl)-N'-[3-[(3-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
mp : 124-125°C
IR (Nujol) : 1610, 1540 cm-1 .
NMR (DMSO-d6, δ) : 2.75 (1H, s), 3.65 (2H, s), 3.70
(2H, s), 3.75 (3H, s), 6.34 (1H, d, J=2.8Hz), 6.92 (1H, d, J=7.4Hz), 7.12-7.45 (11H, m), 7.70 (1H, d, J=1.7Hz), 8.40 (1H, s), 8.55 (1H, s)
MASS : 419 (M+1)
Example 78
N-(1-Methylindol-5-yl)-N'-[3-[(2-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
mp : 126-136°C
IR (Nujol) : 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 2.69 (1H, s), 3.71 (2H, s), 3.75
(3H, s), 3.78 (2H, s), 6.34 (1H, d, J=2.8Hz), 6.95 (1H, d, J=7.3Hz), 7.12-7.44 (9H, m), 7.59 (1H, d,
J=6.2Hz), 7.69 (1H, s), 8.40 (1H, s), 8.54 (1H, s) MASS : 419 (M+1)
Example 79
N-(1-Methylindol-5-yl)-N'-[3-[(4-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
mp : 114-119°C
IR (Nujol) : 1610 cm-1
NMR (DMSO-d6, δ) : 3.64 (2H, s), 3.68 (2H, s), 3.75
(3H, s), 6.34 (1H, d, J=2.9Hz), 7.34 (1H, d, J=7.3Hz), 7.12-7.43 (11H, m), 7.68 (1H, s), 8.40 (1H, s), 8.54 (1H, s)
MASS : 419 (M+1)
Example 80
N-(1-Methylindol-5-yl)-N*-[3-[(4-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
mp : 141-144°C
IR (Nujol) : 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 3.66 (2H, s), 3.69 (2H, s), 3.75 (3H, s), 6.34 (1H, d, J=2.6Hz), 6.93 (1H, d, J=7.6Hz), 7.10-7.44 (11H, m), 7.69 (1H, s), 8.44 (1H, s), 8.58 (1H, s)
MASS : 403 (M+1)
Example 81
N-(1-Methylindol-5-yl)-N'-[3-[(3,5-dichlorobenzylamino) methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
mp : 155-159°C
IR (Nujol) : 1610, 1570 cm-1
NMR (DMSO-d6, δ) : 2.87 (1H, s), 3.64 (2H, s), 3.70 (2H, s), 3.75 (3H, s), 6.33 (1H, d, J=2.8Hz), 6.97
(1H, d, J=7.3Hz), 7.13-7.44 (9H, m), 7.71 (1H, s), 8.41 (1H, s), 8.55 (1H, s)
MASS : 453 (M) Example 82
N-(1-Methylindol-5-yl)-N'-[3-[(N-methyl-N-benzylamino)- methyl]phenyl] urea was prepared in a similar manner to that of Example 73.
mp : 78-80°C
IR (Nujol) : 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 2.10 (3H, s), 3.46 (2H, s), 3.50
(2H, s), 3.76 (3H, s), 6.34 (1H, d, J=2.9Hz), 6.92 (1H, d, J=7.4Hz), 7.13-7.70 (12H, m), 8.61 (1H, s), 8.77 (1H, s)
MASS : 399 (M+1)
Example 83
N-(4-(Dibenzylaminomethyl)phenyl]-N'-[1-methylindol-5- yl]urea was prepared in a similar manner to that of Example 73.
mp : 181-183°C
IR (Nujol) : 1640 cm-1
NMR (DMSO-d6, δ) : 3.44 (2H, s), 3.49 (4H, s), 3.75
(3H, s), 6.33 (2H, d, J=3Hz), 7.13 (1H, dd, J=9Hz, 2Hz), 7.20-7.50 (16H, m), 7.68 (1H, d, J=2Hz), 8.41
(1H, br s), 8.54 (1H, br s)
MASS : 475 (M+1⊕)
Example 84
To a suspension of N-[4-(aminomethyl)phenyl]-N'-[1- methylindol-5-yl]urea (0.15 g) in toluene (5 ml) was added benzaldehyde (0.052 ml). The mixture was refluxed under nitrogen atmosphere for 4 hours. After evaporation, the residue was suspended in ethanol (15 ml), and sodium
borohydride (57.9 mg) was added. The mixture was stirred at 50°C for 2 hours. After evaporation, the residue was
partitioned between water and chloroform. The chloroform layer was dried over sodium sulfate, and chromatographed on silica gel eluted by chloroform-methanol (0-5%, V/V) to give N-[4-(benzylaminomethyl)phenyl]-N'-[1-methylindol-5-yl]urea (0.11 g) .
mp : 125-130°C
IR (Nujol) : 1640 cm-1
NMR (DMSO-d6, δ) : 3.62 (2H, s), 3.68 (2H, s), 3.75
(3H, s), 6.33 (1H, d, J=3Hz), 7.10-7.45 (12H, m), 7.68 (1H, d, J=2Hz), 8.40 (1H, br s), 8.51 (1H,
br s)
MASS : 385 (M+1®), 278 (M-phCH2NH⊕)
Example 85
N-(1-Methylindol-5-yl)-N'-[3-[(2,6-dimethoxybenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
mp : 168-171°C
IR (Nujol) : 1610, 1590, 1540 cm-1
NMR (DMSO-d6, δ) : 3.34 (4H, s), 3.75 (3H, s), 3.77 (7H, s), 6.34 (1H, d, J=2.9Hz), 6.64 (1H, s), 6.68
(1H, s), 6.87 (1H, d, J=7.4Hz), 7.12-7.31 (6H, m), 7.47 (1H, s), 7.69 (1H, d, J=1.7Hz), 8.50 (1H, s), 8.64 (1H, s)
MASS : 445 (M+1)
Example 86
N-(1-Methylindol-5-yl)-N'-[3-(3- pyridylmethylaminomethyl)phenyl]urea was prepared in a similar manner to that of Example 84.
mp : 115-122°C
IR (Nujol) : 1650, 1600, 1540 cm-1
NMR (DMSO-d6, δ) : 2.84 (1H, s), 3.66 (2H, s), 3.71
(2H, s), 3.75 (3H, s), 6.34 (1H, d, J=2.9Hz), 6.93 (1H, d, J=7.3Hz), 7.13-7.44 (7H, m), 7.70-7.80 (2H, m), 8.41-8.55 (4H, m)
MASS : 386 (M+1)
Example 87
N-(1-Methylindol-5-yl)-N'-[3-[(2,5-difluorobenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
mp : 121-130°C
IR (Nujol) : 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 2.72 (1H, s), 3.68 (2H, s), 3.72
(2H, s), 3.75 (3H, s), 6.34 (1H, d, J=2.9Hz), 6.93
(1H, d, J=7.4Hz), 7.12-7.44 (9H, m), 7.69 (1H, s), 8.40 (1H, s), 8.55 (1H, s)
MASS : 421 (M+1) Example 88
N-(1-Methylindol-5-yl)-N'-[3-[(2-methoxybenzyl)- aminomethyl] phenyl] urea was prepared in a similar manner to that of Example 84.
mp : 124-140°C
IR (Nujol) : 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 3.68-3.69 (4H, m), 3.75 (3H, s),
3.77 (3H, s), 6.33 (1H, d, J=2.9Hz), 6.89-6.98 (3H, m), 7.12-7.45 (8H, m), 7.69 (1H, d, J=1.7Hz), 8.42 (1H, s), 8.57 (1H, s)
MASS : 415 (M+1)
Example 89
N-(1-Methylindol-5-yl)-N'-[3-[(1-naphthyl)- methylaminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
mp : 74-78°C
IR (Nujol) : 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 3.75 (3H, s), 3.79 (2H, s), 4.14
(2H, s), 6.34 (1H, d, J=2.8Hz), 6.98 (1H, d,
J=7.3Hz), 7.13-7.94 (14H, m), 8.10-8.20 (1H, m),
8.41 (1H, s), 8.56 (1H, s)
MASS : 435 (M+1)
Example 90
N-(1-Methylindol-5-yl)-N'-[3-[(2,4,6-trimethoxybenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
mp : 144-152°C
IR (Nujol) : 1700, 1610, 1540 cm-1
NMR (DMSO-d6, δ) : 3.76 (3H, s), 3.79 (9H, s), 3.88
(2H, s), 3.96 (2H, s), 6.28 (2H, s), 6.33 (1H, d,
J=2.8Hz), 7.05 (1H, d, J=7.7Hz), 7.16 (1H, d, J=8.6Hz), 7.28-7.40 (4H, m), 7.65 (1H, s), 7.71
(1H, s), 8.83 (1H, s), 8.99 (1H, s)
MASS : 475 (M+1)
Example 91
N-(1-Methylindol-5-yl)-N'-[3-[(2,4-dimethoxybenzyl)- aminomethyl]phenyl]urya was prepared in a similar manner to that of Example 84.
mp : 108-111°C
IR (Nujol) : 1610, 1600, 1580, 1540 cm-1
NMR (DMSO-d6, δ) : 3.66 (2H, s), 3.72 (2H, s), 3.75-
3.77 (9H, m), 6.34 (1H, d, J=3.0Hz), 6.47-6.55 (2H, m), 6.94 (1H, d, J=7.4Hz), 7.12-7.38 (7H, m), 7.45
(1H, s), 7.70 (1H, d, J=1.6Hz), 8.52 (1H, s), 8.67 (1H, s)
MASS : 445 (M+1) Example 92
N-[3-(1-Benzylaminoethyl)phenyl]-N'-(1-methylindol-5- yl)urea was prepared in a similar manner to that of Example 84.
mp : 75-90°C
IR (Nujol) : 1640 cm-1
NMR (DMSO-d6, δ) : 1.27 (3H, d, J=7Hz), 3.40-3.80 (3H, m), 3.76 (3H, s), 6.34 (1H, d, J=3Hz), 6.95 (1H, d, J=7Hz), 7.10-7.50 (12H), 7.69 (1H, d, J=2Hz), 8.39 (1H, s), 8.55 (1H, s)
Example 93
N-(Benzo[b]furan-5-yl)-N'-[3-(benzylaminomethyl)- phenyl]urea was prepared in a similar manner to that of
Example 84.
mp : 130-131°C
IR (Nujol) : 1620, 3260 cm-1
NMR (DMSO-d6, δ) : 3.68 (2H, s), 3.72 (2H, s), 6.90- 6.97 (2H, m), 7.18-7.51 (10H, m), 7.84 (1H, d, J=2.0Hz), 7.93 (1H, d, J=2.2Hz), 8.64-8.65 (2H, m) MASS : 372 (M+1)
Example 94
N-(Benzo[b]furan-5-yl)-N'-[3-[(2,4,6-trimethoxybenzyl)- aminomethyl]phenyl]urea acetate was prepared in a similar manner to that of Example 84.
mp : 95-110°C
IR (Nujol) : 1660 cm-1
NMR (DMSO-d6, δ) : 3.78-3.89 (13H, m), 6.27 (1H, s),
6.90 (1H, s), 7.03 (1H, d, J=8.0Hz), 7.26-7.60 (5H, m), 7.84 (1H, s), 7.93 (1H, d, J=2.1Hz), 8.98 (1H, d, J=6.3Hz)
MASS : 462 (M+1)
Example 95
N-[3-[(3,4-Dimethoxybenzyl)aminomethyl]phenyl]-N'-(1- methylindol-5-yl)urea was prepared in a similar manner to that of Example 84.
mp : 100-110°C
IR (Nujol) : 1640 cm-1
NMR (DMSO-d6, δ) : 3.67 (3H, s), 3.73 (4H, s), 3.75
(6H, s), 6.33 (1H, d, J=2.9Hz), 6.88-7.00 (4H, m), 7.11-7.50 (6H, m), 7.68 (1H, s), 7.69 (1H, s), 8.45 (1H, s), 8.59 (1H, s)
MASS : 445 (M+1)
Example 96
N-(1-Methylindol-5-yl)-N'-[3-[(2,4,6-trimethylbenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
mo : 178-179°C
IR (Nujol) : 1635 cm-1
NMR (DMSO-d6, δ) : 2.18 (3H, s), 2.26 (6H, s), 3.58
(2H, s), 3.73 (2H, s), 3.75 (3H, s), 6.33 (1H, d, J=3.0Hz), 6.78 (2H, s), 6.96 (1H, d, J=7.4Hz), 7.11-7.45 (7H, m), 7.68 (1H, d, J=1.7Hz), 8.52 (1H, s), 8.58 (1H, s)
MASS : 427 (M+1)
Example 97
N-(Benzo[b]furan-5-yl)-N'-[3-[(2,4,6-trimethylbenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
mp : 183-185°C
IR (Nujol) : 1635 cm-1
NMR (DMSO-d6, δ) : 2.18 (3H, s), 2.26 (6H, s), 3.59
(2H, s), 3.75 (2H, s), 6.78 (2H, s), 6.90 (1H, t, J=0.86Hz), 6.99 (1H, d, J=7.5Hz), 7.18-7.52 (5H, m), 7.83 (1H, d, J=2.0Hz), 7.93 (1H, d, J=2.2Hz), 8.60 (1H, s), 8.63 (1H, s)
MASS : 414 (M+1)
Example 98
N-[3-[(3,4-Dihydroisoquinolin-1-yl)aminomethyl]phenyl]- N'-(1-methylindol-5-yl)urea hydroiodide was prepared in a similar manner to that of Example 66.
mp : 224-228°C
IR (Nujol) : 1600, 1630, 1675 cm-1
NMR (DMSO-d6, δ) : 3.03 (2H, t, J=6.4Hz), 3.54 (2H, t, J=6.7Hz), 3.75 (3H, s), 4.66 (2H, s), 6.33 (1H, d, J=2.9Hz), 6.97 (1H, d, J=7.1Hz), 7.13 (1H, dd,
J=8.7Hz, 1.9Hz), 7.26-7.74 (9H, m), 8.06 (1H, d, J=7.7Hz), 8.46 (1H, s), 8.68 (1H, s), 9.90 (2H, s) MASS : 424 (M+1) Example 99
N-[3-[[(Methylimino)(phenyl)methyl]aminomethyl]phenyl]- N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 66.
mp : 138-152°C
IR (Nujol) : 1640 cm-1
NMR (DMSO-d6, δ) : mixture of tautomers, [major, 3.07 (3H, s), 4.36 (2H, s)], [minor, 2.82 (2H, s), 4.62 (2H, s)], [both, 3.76 (3H, s), 6.34-6.35 (1H, m), 6.75-6.79 (1H, m), 7.00-7.68 (14H, m), 8.48-8.51 (1H, m), 8.64-8.71 (1H, m), 9.6-9.8 (1H, m)]
MASS : 412 (M+1)
Example 100
N-(Benzo[b]furan-7-yl)-N'-(3-cyanophenyl)urea was prepared in a similar manner to that of Example 1.
mp : 208-215°C (MeOH)
IR (Nujol) : 3300, 2240, 1640, 1610, 1560 cm-1
NMR (DMSO-d6, δ) : 7.00 (1H, d, J=2Hz), 7.19 (1H, t, J=8Hz), 7.31 (1H, d, J=7Hz), 7.48 (2H, m), 7.68 (1H, d, J=9Hz), 7.94 (1H, d, J=7Hz), 8.04 (2H, m),
8.99 (1H, s), 9.46 (1H, s)
Example 101
N-(Benzo[b]furan-7-yl)-N'-(3-thiocarbamoylphenyl)urea was prepared in a similar manner to that of Example 2.
mp : 155-164°C
IR (Nujol) : 3270, 1630, 1600, 1555 cm-1
NMR (DMSO-d6, δ) : 7.00 (1H, d, J=2Hz), 7.14-7.46 (4H, m), 7.75 (1H, m), 7.98-8.08 (2H, m), 8.60 (1H, s), 9.35 (1H, s), 9.51 (1H, s), 9.89 (1H, s)
Example 102
N-(Benzo[b]furan-7-yl)-N'-[3-[methylthio(imino)methyl]- phenyl]urea hydroiodide was prepared in a similar manner to that of Example 3.
mp : 180-182°C
IR (Nujol) : 3400, 3170, 1680, 1625, 1550 cm-1
NMR (DMSO-d6, δ) : 2.86 (3H, s), 7.00 (1H, d, J=2Hz),
7.20 (1H, t, J=8Hz), 7.32 (1H, d, J=7Hz), 7.46 (1H, d, J=8Hz), 7.60 (1H, t, J=8Hz), 7.70 (1H, d,
J=8Hz), 7.94 (1H, d, J=8Hz), 8.08 (1H, d, J=2Hz), 8.20 (1H, m), 8.94 (2H, s), 9.56 (1H, s)
Example 103
N-(Benzo[b]furan-7-yl)-N'-[3-(phenylamidino)phenyl]urea was prepared in a similar manner to that of Example 6.
mp : 190-200°C
IR (Nujol) : 3200, 1675, 1650, 1625, 1590, 1540 cm-1 NMR (DMSO-d6, δ) : 7.01 (1H, d, J=2Hz), 7.19 (1H, t, J=8Hz), 7.32 (1H, d, J=7Hz), 7.40-7.80 (8H, m),
7.96 (1H, d, J=7Hz), 8.08 (1H, d, J=2Hz), 8.14 (2H, m), 9.00 (2H, m), 9.51 (1H, s)
Example 104
N-(1-Methylindol-5-yl)-N'-[3-[(2-thienylmethyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
Example 105
N-(1-Methylindol-5-yl)-N'-[3-[[(3- trifluoromethoxyphenyl)methyl]aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
Example 106
N-[3-[[(3-Methoxyphenyl)methyl]aminomethyl]phenyl]-
N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 84.
Example 107
N-[3-[[(2-Methoxy-5-trifluoromethoxyphenyl)methyl]-
aminomethyl]phenyl]-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 84.
Example 108
N-(1-Methylindol-5-yl)-N'-[3-(phenethylammomethyl)- phenyl]urea was prepared in a similar manner to that of Example 84.
Claims
1. A compound of the formula :
wherein R1 is cyano, thiocarbamoyl,
a group of the formula : 
in which R4 is hydrogen, lower alkyl which may have optionally substituted aryl, acyl, optionally substituted aryl, lower alkylthio or 1-lower alkylindolyl, A1 is lower alkylene, and
m and n are each 0 or 1,
a group of the formula :
-A2-R5 in which R5 is morpholino, piperidino,
4-arylpiperazin-1-yl, phthalimido, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl or imidazol-1-yl, and
A2 is lower alkylene, or
a group of the formula : 
in which R6 and R7 are each hydrogen, optionally substituted aryl, acyl,
pyridyl (lower) alkyl,
thienyl (lower) alkyl,
3,4-dihydroisoquinolinyl, (lower alkylimino) (optionally substituted aryl) methyl or lower alkyl which may have optionally substituted aryl, and
A3 is lower alkylene, and
R2 is hydrogen; or
R1 and R2 are linked together to form
in which R8 is amino or acylamino, and
R9 is hydrogen, acyl or lower alkyl which may have optionally substituted aryl, and
R3 is 1-lower alkylindolyl, benzofuranyl,
dihydrobenzofuranyl or optionally substituted aryl,
and a pharmaceutically acceptable salt thereof.
2. A compound of claim 1, wherein
R1 is cyano, thiocarbamoyl,
a group of the formula : 
wherein R4 is hydrogen, lower alkyl,
phenyl (lower) alkyl, di (lower
alkoxy) phenyl (lower) alkyl,
phenyl (lower) alkoxycarbonyl, phenyl, lower alkoxyphenyl, lower alkylthio or 1-lower alkylindolyl,
A1 is lower alkylene, and
m and n are each 0 or 1,
a group of the formula : -A2-R5 wherein R5 is morpholino, piperidino,
4-phenylpiperazin-1-yl, phthalimido, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl or imidazol-1-yl, and
A2 is lower alkylene, or
a group of the formula : 
wherein R6 and R are each hydrogen, phenyl,
lower alkanoyl,
phenyl (lower) alkoxycarbonyl,
pyridyl (lower) alkyl,
thienyl (lower) alkyl, 3,4- dihydroisoquinolinyl, (lower
alkylimino) (phenyl) methyl, lower alkyl, phenyl (lower) al.kyl,
naphthyl (lower) alkyl, (mono- or di- or trilower alkyl) phenyl (lower) - alkyl, (mono- or di- or trilower alkoxy) phenyl (lower) alkyl, (mono- or di- or trihalo) phenyl (lower) alkyl, [trihalo (lower) alkoxy] phenyl (lower) - alkyl or [lower alkoxy] [trihalo- (lower) alkoxy] phenyl (lower) alkyl, and
A3 is lower alkylene, and
R2 is hydrogen; or
R1 and R2 are linked together to form
R9 is hydrogen, phenyl (lower) alkoxycarbonyl or phenyl (lower) alkyl, and
R3 is 1-lower alkylindolyl, benzofuranyl,
dihydrobenzofuranyl or
N,N-di (lower alkyl) aminophenyl.
3. A compound of claim 2, wherein
R1 is cyano, thiocarbamoyl,
a group of the formula : 
wherein R4 is hydrogen or
phenyl (lower) alkoxycarbonyl, and A1 is lower alkylene,
a group of the formula : 
wherein R4 is phenyl or 1-lower alkylindolyl, and
A1 is lower alkylene,
a group of the formula : 
wherein R4 is hydrogen, lower alkyl.
phenyl (lower) alkyl, di (lower alkoxy) phenyl (lower) alkyl, phenyl or lower alkoxyphenyl,
a group of the formula : 
wherein R4 is lower alkylthio,
a group of the formula :
-A2-R5 wherein R5 is morpholino, piperidino, 4-phenylpiperazin-1-yl, phthalimido,
1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl or imidazol-1-yl, and
A2 is lower alkylene, or
a group of the formula : 
wherein R6 and R7 are each hydrogen, phenyl, lower alkanoyl, phenyl (lower) - alkoxycarbonyl, pyridyl (lower) alkyl, thienyl (lower) alkyl, 3,4- dihydroisoquinolinyl, (lower
alkylimino) (phenyl) methyl, lower alkyl, phenyl (lower) alkyl,
naphthyl (lower) alkyl, (mono- or di- or trilower alkyl) phenyl (lower) - alkyl, (mono- or di- or trilower alkoxy) phenyl (lower) alkyl, (mono- or di- or trihalo) phenyl (lower) alkyl, [trihalo (lower) alkoxy] phenyl (lower) - alkyl or [lower alkoxy] [trihalo- (lower) alkoxy] phenyl (lower) alkyl, and
A3 is lower alkylene, and
R2 is hydrogen.
4. A process for preparing a compound of the formula 
wherein R1 is cyano, thiocarbamoyl,
a group of the formula : 
in which R4 is hydrogen, lower alkyl which may have optionally substituted aryl, acyl, optionally substituted aryl, lower alkylthio or 1-lower alkylindolyl, A1 is lower alkylene, and
m and n are each 0 or 1,
a group of the formula :
-A2-R5 in which R5 is morpholino, piperidino,
4-arylpiperazin-1-yl, phthalimido, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl or imidazol-1-yl, and
A2 is lower alkylene, or
a group of the formula : 
in which R6 and R7 are each hydrogen, optionally substituted aryl, acyl,
pyridyl (lower) alkyl,
thienyl (lower) alkyl, 3,4-dihydroisoquinolinyl, (lower alkylimino) (optionally substituted aryl) methyl or lower alkyl which may have optionally substituted aryl, and
A3 is lower alkylene, and
R2 is hydrogen; or
R1 and R2 are linked together to form
R9 is hydrogen, acyl or lower alkyl which may have optionally substituted aryl, and
R3 is 1-lower alkylindolyl, benzofuranyl,
dihydrobenzofuranyl, or optionally substituted aryl,
or a pharmaceutically acceptable salt thereof,
which comprises
(1) reacting a compound of the formula :
or a salt thereof,
with 1,1'-carbonyldiimidazole,
to give a compound of the formula :
wherein R1 and R2 are each as defined above,
or a salt thereof, and continuously reacting the obtained compound or a salt thereof, with a compound of the formula :
H2N-R3 wherein R3 is as defined above,
or a salt thereof,
to give a compound of the formula
wherein R1, R2 and R3 are each as defined above, or a salt thereof, or
(2) reacting a compound of the formula :
H2N-R3 wherein R3 is as defined above,
or a salt thereof,
with 1,1'-carbonyldiimidazole,
to give a compound of the formula
or a salt thereof, and continuously reacting the obtained compound or a salt thereof, with a compound of the formula :
wherein R1 and R2 are each as defined above,
or a salt thereof,
to give a compound of the formula :
wherein R1, R2 and R3 are each as defined above, or a salt thereof, or
(3) subjecting a compound of the formula 
wherein R1 and R2 are each as defined above,
or a salt thereof,
to Curtius Rearrangement reaction,
to give a compound of the formula :
wherein R1 and R2 are each as defined above,
or a salt thereof, and continuously reacting the obtained compound or a salt thereof, with a compound of the formula :
H2N-R3 wherein R3 is as defined above,
or a salt thereof,
to give a compound of the formula
(4) subjecting a compound of the formula :
HOOC-R3 wherein R3 is as defined above,
or a salt thereof,
to Curtius Rearrangement reaction,
to give a compound of the formula :
OCN-R3 wherein R3 is as defined above,
or a salt thereof, and continuously reacting the obtained compound or a salt thereof, with a compound of the formula :
wherein R1 and R2 are each as defined above,
or a salt thereof,
to give a compound of the formula :
5. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
6. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 with a pharmaceutically acceptable carrier or excipient.
7. A compound of claim 1 for use as a medicament.
8. A compound of claim 1 for use as a 5-HT antagonist.
9. A compound of claim 1 for use as a 5-HT2C antagonist.
10. A use of a compound of claim 1 for manufacturing a
medicament for treating 5-HT mediated diseases.
11. A method for treating 5-HT mediated diseases which
comprises administering a compound of claim 1 to human or animals.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9500302A JPH11506468A (en) | 1995-06-06 | 1996-06-04 | Urea derivatives as 5-HT antagonists |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9511355.1A GB9511355D0 (en) | 1995-06-06 | 1995-06-06 | Urea derivatives |
| GB9511355.1 | 1995-06-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996039382A1 true WO1996039382A1 (en) | 1996-12-12 |
Family
ID=10775534
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1996/001500 Ceased WO1996039382A1 (en) | 1995-06-06 | 1996-06-04 | Urea derivatives as 5-ht antagonists |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPH11506468A (en) |
| GB (1) | GB9511355D0 (en) |
| TW (1) | TW325462B (en) |
| WO (1) | WO1996039382A1 (en) |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998024785A1 (en) * | 1996-12-02 | 1998-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Indole-urea derivatives with 5-ht antagonist properties |
| WO1999014197A1 (en) * | 1997-09-12 | 1999-03-25 | Smithkline Beecham Plc | Substituted isoquinolines as anticonvulsivants |
| WO1999015526A3 (en) * | 1997-09-19 | 1999-05-20 | Smithkline Beecham Plc | N-5,6,7,8-tetrahydro(1,6)naphthyridine-n'-phenylurea derivatives |
| WO1999025709A1 (en) * | 1997-11-18 | 1999-05-27 | Smithkline Beecham P.L.C. | Isoquinoline derivatives and their therapeutical use |
| WO1999067204A1 (en) * | 1998-06-22 | 1999-12-29 | Astrazeneca Ab | Novel compounds |
| WO2000008022A1 (en) * | 1998-08-05 | 2000-02-17 | Smithkline Beecham Plc | Urea derivatives |
| WO2001087834A1 (en) * | 2000-05-16 | 2001-11-22 | Takeda Chemical Industries, Ltd. | Melanin-concentrating hormone antagonist |
| US6335445B1 (en) * | 1997-03-24 | 2002-01-01 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them |
| WO2002070467A1 (en) * | 2001-02-26 | 2002-09-12 | 4Sc Ag | Derivatives of diphenylurea, diphenyloxalic acid diamide and diphenylsulfuric acid diamide and their use as medicaments |
| WO2003087087A3 (en) * | 2002-04-09 | 2003-12-18 | Astex Technology Ltd | Heterocyclic compounds and their use as modulators of p38 map kinase |
| US7241758B2 (en) | 1999-11-16 | 2007-07-10 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
| EP2036564A1 (en) | 1999-12-06 | 2009-03-18 | H.Lundbeck A/S | The combination of a serotonin reuptake inhibitor and a 5-HT2C antagonist, inverse agonist or partial agonist |
| US7579352B2 (en) | 1997-12-11 | 2009-08-25 | Janssen Pharmaceutica N.V. | Retinoic acid mimetic anilides |
| US7777040B2 (en) | 2005-05-03 | 2010-08-17 | Cgi Pharmaceuticals, Inc. | Certain substituted ureas, as modulators of kinase activity |
| US8076348B2 (en) | 2005-08-08 | 2011-12-13 | Astellas Pharma Inc. | Acylguanidine derivative or salt thereof |
| AU2011253934B2 (en) * | 2004-06-17 | 2012-11-22 | Cytokinetics, Inc. | Substituted urea derivatives for treating cardiac diseases |
| US8445495B2 (en) | 2005-12-15 | 2013-05-21 | Cytokinetics, Inc. | Certain Chemical entities, compositions and methods |
| US8513257B2 (en) | 2004-06-17 | 2013-08-20 | Cytokinetics, Incorporated | Ureas and their use in the treatment of heart failure |
| WO2024178127A1 (en) * | 2023-02-21 | 2024-08-29 | 1Cbio, Inc. | Heterocyclic compounds and methods of use thereof |
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|---|---|---|---|---|
| CA2557158A1 (en) * | 2004-02-20 | 2005-09-01 | Astellas Pharma Inc. | Prophylactic antimigraine agents |
| CA3166358A1 (en) * | 2020-02-12 | 2021-08-19 | Monali BANERJEE | Small molecule sting antagonists |
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| WO1992005170A1 (en) * | 1990-09-13 | 1992-04-02 | Beecham Group Plc | Indole ureas as 5 ht receptor antagonist |
| WO1993018028A1 (en) * | 1992-03-12 | 1993-09-16 | Smithkline Beecham Plc | Indole derivatives as 5ht1c antagonists |
| WO1994014801A1 (en) * | 1992-12-29 | 1994-07-07 | Smithkline Beecham Plc | Heterocyclic urea derivatives as 5ht2c and 5ht2b antagonists |
| WO1995006044A1 (en) * | 1993-08-20 | 1995-03-02 | Smithkline Beecham Plc | Amide and urea derivatives as 5ht1d receptor antagonists |
-
1995
- 1995-06-06 GB GBGB9511355.1A patent/GB9511355D0/en active Pending
-
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- 1996-06-04 WO PCT/JP1996/001500 patent/WO1996039382A1/en not_active Ceased
- 1996-06-04 JP JP9500302A patent/JPH11506468A/en active Pending
- 1996-06-05 TW TW085106706A patent/TW325462B/en active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992005170A1 (en) * | 1990-09-13 | 1992-04-02 | Beecham Group Plc | Indole ureas as 5 ht receptor antagonist |
| WO1993018028A1 (en) * | 1992-03-12 | 1993-09-16 | Smithkline Beecham Plc | Indole derivatives as 5ht1c antagonists |
| WO1994014801A1 (en) * | 1992-12-29 | 1994-07-07 | Smithkline Beecham Plc | Heterocyclic urea derivatives as 5ht2c and 5ht2b antagonists |
| WO1995006044A1 (en) * | 1993-08-20 | 1995-03-02 | Smithkline Beecham Plc | Amide and urea derivatives as 5ht1d receptor antagonists |
Cited By (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998024785A1 (en) * | 1996-12-02 | 1998-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Indole-urea derivatives with 5-ht antagonist properties |
| US6335445B1 (en) * | 1997-03-24 | 2002-01-01 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them |
| WO1999014197A1 (en) * | 1997-09-12 | 1999-03-25 | Smithkline Beecham Plc | Substituted isoquinolines as anticonvulsivants |
| WO1999015526A3 (en) * | 1997-09-19 | 1999-05-20 | Smithkline Beecham Plc | N-5,6,7,8-tetrahydro(1,6)naphthyridine-n'-phenylurea derivatives |
| WO1999025709A1 (en) * | 1997-11-18 | 1999-05-27 | Smithkline Beecham P.L.C. | Isoquinoline derivatives and their therapeutical use |
| US6274594B1 (en) | 1997-11-18 | 2001-08-14 | Smithkline Beecham P.L.C. | Isoquinoline derivatives and their therapeutical use |
| US7579352B2 (en) | 1997-12-11 | 2009-08-25 | Janssen Pharmaceutica N.V. | Retinoic acid mimetic anilides |
| WO1999067204A1 (en) * | 1998-06-22 | 1999-12-29 | Astrazeneca Ab | Novel compounds |
| US6777561B1 (en) | 1998-06-22 | 2004-08-17 | Astrazeneca Canada Inc. | Compounds |
| WO2000008022A1 (en) * | 1998-08-05 | 2000-02-17 | Smithkline Beecham Plc | Urea derivatives |
| US7241758B2 (en) | 1999-11-16 | 2007-07-10 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
| EP1232150B1 (en) * | 1999-11-16 | 2007-10-10 | Boehringer Ingelheim Pharmaceuticals Inc. | Urea derivatives as anti-inflammatory agents |
| EP2036564A1 (en) | 1999-12-06 | 2009-03-18 | H.Lundbeck A/S | The combination of a serotonin reuptake inhibitor and a 5-HT2C antagonist, inverse agonist or partial agonist |
| US7229986B2 (en) | 2000-05-16 | 2007-06-12 | Takeda Pharmaceutical Company Ltd. | Melanin-concentrating hormone antagonist |
| WO2001087834A1 (en) * | 2000-05-16 | 2001-11-22 | Takeda Chemical Industries, Ltd. | Melanin-concentrating hormone antagonist |
| US6949567B2 (en) | 2001-02-26 | 2005-09-27 | 4Sc Ag | Compounds for the treatment of protozoal diseases |
| WO2002070467A1 (en) * | 2001-02-26 | 2002-09-12 | 4Sc Ag | Derivatives of diphenylurea, diphenyloxalic acid diamide and diphenylsulfuric acid diamide and their use as medicaments |
| WO2003087087A3 (en) * | 2002-04-09 | 2003-12-18 | Astex Technology Ltd | Heterocyclic compounds and their use as modulators of p38 map kinase |
| US10035770B2 (en) | 2004-06-17 | 2018-07-31 | Cytokinetics, Incorporated | Compounds, compositions and methods |
| US8871769B2 (en) | 2004-06-17 | 2014-10-28 | Cytokinetics, Inc. | Ureas and their use in the treatment of heart failure |
| AU2011253934B2 (en) * | 2004-06-17 | 2012-11-22 | Cytokinetics, Inc. | Substituted urea derivatives for treating cardiac diseases |
| US12264133B2 (en) | 2004-06-17 | 2025-04-01 | Cytokinetics, Incorporated | Compounds, compositions and methods |
| US8513257B2 (en) | 2004-06-17 | 2013-08-20 | Cytokinetics, Incorporated | Ureas and their use in the treatment of heart failure |
| AU2011253934C1 (en) * | 2004-06-17 | 2013-08-22 | Cytokinetics, Inc. | Substituted urea derivatives for treating cardiac diseases |
| US10975034B2 (en) | 2004-06-17 | 2021-04-13 | Cytokinetics, Inc. | Compounds, compositions and methods |
| US10385023B2 (en) | 2004-06-17 | 2019-08-20 | Cytokinetics, Inc. | Compounds, compositions and methods |
| US9150564B2 (en) | 2004-06-17 | 2015-10-06 | Cytokinetics, Inc. | Compounds, compositions and methods |
| US9643925B2 (en) | 2004-06-17 | 2017-05-09 | Cytokinetics, Incorporated | Compounds, compositions and methods |
| US7777040B2 (en) | 2005-05-03 | 2010-08-17 | Cgi Pharmaceuticals, Inc. | Certain substituted ureas, as modulators of kinase activity |
| US8076348B2 (en) | 2005-08-08 | 2011-12-13 | Astellas Pharma Inc. | Acylguanidine derivative or salt thereof |
| US8871768B2 (en) | 2005-12-15 | 2014-10-28 | Cytokinetics, Inc. | Certain chemical entities, compositions and methods |
| US8445495B2 (en) | 2005-12-15 | 2013-05-21 | Cytokinetics, Inc. | Certain Chemical entities, compositions and methods |
| WO2024178127A1 (en) * | 2023-02-21 | 2024-08-29 | 1Cbio, Inc. | Heterocyclic compounds and methods of use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH11506468A (en) | 1999-06-08 |
| TW325462B (en) | 1998-01-21 |
| GB9511355D0 (en) | 1995-08-02 |
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