WO2007097276A1 - ピロール誘導体またはその塩 - Google Patents
ピロール誘導体またはその塩 Download PDFInfo
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- WO2007097276A1 WO2007097276A1 PCT/JP2007/052943 JP2007052943W WO2007097276A1 WO 2007097276 A1 WO2007097276 A1 WO 2007097276A1 JP 2007052943 W JP2007052943 W JP 2007052943W WO 2007097276 A1 WO2007097276 A1 WO 2007097276A1
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- lower alkylene
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- pyrrole
- lower alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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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
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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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
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Definitions
- Non-Patent Document 1 (Non-Patent Document 1).
- Non-Patent Document 12 1- ⁇ [1-benzyl-2-methyl-5- (4-nitrophenyl) -1H-pyrrol-3-yl] carbol ⁇ -4-methylbiperazine is antibacterial. It has been reported to be active and effective against Candida. 5-HT and 5-HT receptor antagonistic activity, and IBS
- Non-Patent Document 4 "The American n Journal of Gastroenterology” (USA), 2003, 98th, p.750-758
- Non-Patent Document 5 "Drugs” (New Zealand), 2001, 61st, No. 3, p.
- Non-Patent Document 6 "British Journal of Pharmacology", (UK), 1995, 114, p. 1525-1527
- Non-Patent Document 7 "British Journal of Pharmacology", (UK), 2002, No. 135, ⁇ .1144-1151
- Non-Patent Document 8 “European Journal of Pharmacology”, (Netherlands), 1995, No. 280, p.243-250
- Patent Document 1 International Publication No. 2006/085510 Pamphlet
- Patent Document 2 Pamphlet of International Publication No. 2005/79845
- Patent Document 3 International Publication No. 2005/80322 Pamphlet
- Patent Document 4 US Patent Application Publication No. 2005/0101657
- Patent Document 5 Pamphlet of International Publication No. 2004/60870
- Patent Document 6 International Publication No. 2005/108393 Pamphlet
- the present inventors have identified compounds having antagonistic activity at 5-HT and 5-HT receptors for the purpose of providing compounds useful as IBS therapeutic agents.
- the present invention was completed by finding out that it has an excellent therapeutic effect of IBS compared with the conventional compounds.
- the present invention relates to a pyrrole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
- R 11 -H, lower alkyl or lower alkylene aryl.
- R 12 nitrogen-containing saturated heterocyclic group (however, it has a bond at the carbon atom of the ring atom), lower alkylene-N (R 14 ), lower alkylene-nitrogen-containing saturated heterocyclic group, lower alkylene-C (O)
- the lower alkylene and nitrogen-containing saturated heterocyclic group in R 12 may each be substituted.
- R 13 substituted with a bond on the nitrogen atom of the ring atom, but a nitrogen-containing saturated hetero ring, provided that when the nitrogen atom contained in the nitrogen-containing saturated hetero ring in R 13 is 1, At least one of the nitrogen-saturated heterocycles is substituted with a group selected by the G group force.
- R 14 the same or different from each other, -H, lower alkyl, lower alkylene-OR °, lower alkylene-aryl or aryl.
- R ° each independently -H or lower alkyl.
- R 15 each substituted with a group selected from Group G, and further substituted, may be a cycloalkyl, aryl or hetero ring group.
- Group G -N (R 14 ), nitrogen-containing saturated heterocyclic group, -lower alkylene-N (R 14 ) and -lower alkyle
- R 3 lower alkyl, halogeno lower alkyl, cycloalkyl, heterocycle, aryl, lower alkylene-cycloalkyl, lower alkylene-aryl, lower alkylene-OR °, lower alkylene-N (R °), or -C (0 ) -R °.
- R 4 lower alkyl, cycloalkyl, aryl or heterocycle group.
- aryl and hetero ring groups in R 4 may be substituted! /.
- R 5 —H, lower alkyl, lower alkylene —OR °, —C (0) —R °, cycloalkyl, aryl or heterocycle.
- aryl and heterocyclic groups in R 5 may be substituted.
- R 2 may be substituted.
- R 21 aryl, -0-aryl, -0-lower alkylene-aryl, cycloalkyl, heterocyclic group, -CN, -S-lower alkyl, -S (O) -lower alkyl, -S (O) -lower Alkyl, -C (O)
- aryl and heterocyclic groups in R 21 may be substituted.
- R 2 lower alkylene-aryl, lower alkylene-heterocyclic group or -0-lower alkylene-aryl.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising the pyrrole derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, particularly a 5-HT receptor and a 5-HT receptor.
- a pharmaceutically acceptable carrier particularly a 5-HT receptor and a 5-HT receptor.
- composition that is a 2B 7 heavy antagonist or a remedy for irritable bowel syndrome.
- a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- the compound of the present invention is only one of the existing 5-HT or 5-HT receptor.
- the compound of the present invention is useful as a therapeutic agent for IBS.
- FIG. 1 is a graph showing the results of measuring the number of defecations during RS-127445 administration in the rat restraint stress stool excretion model of test method (4).
- FIG. 2 is a graph showing the results of measuring the number of defecations at the time of SB-269970 administration in the rat restraint stress stool excretion model of test method (4).
- FIG. 4 is a graph showing the results of measuring the number of stools at the time of administration of Example Compound 161 in the rat restraint stress stool excretion model of test method (4).
- lower alkyl and “lower alkylene” are each linear or branched having 1 to 6 carbon atoms (hereinafter sometimes referred to as C) unless otherwise specified.
- lower alkyl means alkyl of C, specifically, for example, methyl
- Ethynole propyl, butynole, pentyl or hexyl, or structural isomers thereof such as isopropyl, isobutyl or tert-butyl, preferably alkyl.
- Alkylene means a divalent group formed by removing one hydrogen from any position of alkyl.
- Lower alkylene means C alkylene. Specifically, methylene,
- Tylene methylmethylene, dimethylmethylene, propylene, butylene, pentylene, hexylene and the like.
- Preferred is C alkylene, and more preferred is methylene, ethylene,
- Tinolemethylene dimethylmethylene and propylene.
- Cycloalkyl means a non-aromatic hydrocarbon ring of C, and a bridged ring spiro ring.
- the benzene ring which may have a partially unsaturated bond may be condensed.
- the bond is on the non-aromatic ring.
- Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclohexenyl, cyclooctane genyl, adamantyl, norbornyl, and indanyl having a bond at the 1 to 3 position.
- Halogen means a halogen atom, specifically, for example, fluoro, black mouth, bromine, iodine, etc., preferably fluoro or black mouth.
- aryl means a monocyclic to tricyclic C aromatic hydrocarbon ring, specifically
- the chloroalkyl ring may be condensed. However, when the cycloalkyl ring is fused, the bond is on the aromatic ring. For example, indanyl having a bond at positions 4 to 7 and tetrahydronaphthyl having a bond at positions 5 to 8 may be formed.
- Heterocycle is a monocyclic ring containing 1 to 4 heteroatoms selected from 0, S and N.
- a monocyclic ring having 3 to 12 members saturated, partially unsaturated or aromatic A heterocycle, a bicyclic heterocycle in which the monocyclic heterocycles are condensed with a cycloalkyl ring or a benzene ring, the bicyclic heterocycle is a monocyclic heterocycle, It means a tricyclic heterocycle condensed with a cycloalkyl ring or a benzene ring.
- the ring atom S or N may be oxidized to form an oxide or a dioxide, or a bridged ring or a spiro ring may be formed.
- Monocyclic heterocycles include, for example, pyrrolyl, furyl, chael, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, azolidinyl, azetidyl, oxetidyl, Examples include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, homopiperidinyl, homomorpholinyl, tetrahydrofuran, tetrahydrobiral, tetrahydrothiobiral and the like.
- Bicyclic heterocycles include, for example, indolyl, benzofuryl, benzochel, benzogenous xazolinole, benzisoxazolinole, benzoimidazolinole, benzothiazolinole, benzothiadiazolyl, quinolyl, isoquinolyl, quinazolinyl Quinoxalinyl, cinnolyl, indolyl, tetrahydroquinolinyl, tetrahydroisoquinolyl, octahydropyrrolo [1,2-a] pyrazur, octahydro-2H-pyrido [1,2-a] pyrazur, and the like.
- tero ring examples include carbazolyl, phenoxazyl, fluorenyl and the like.
- bridged ring examples include quinuclidyl and 3,8-diazabicyclo [3.2.1] octal.
- Preferred examples of the heterocycle include furyl, chael, pyridyl, azetidyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrobilanyl and quinutalidinyl.
- the “nitrogen-containing saturated heterocycle” means a saturated heterocycle containing one or more nitrogen atoms among the “heterocycle”.
- Preferred are azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl and quinutalidinyl.
- R 11 'Ariru which may be substituted in R"" ⁇ reel"
- nitrogen-containing heterocyclic group saturated which may be substituted in the group G
- R in each of “aryl” and “heterocyclic group” which may be substituted in each of 4 and in each of “aryl” and “heterocyclic group” which may be substituted in R 5 Preferred examples of the permissible substituent include groups selected from the following G 1 group.
- Group G 1 Nono androgenic, lower alkyl, -OR 0, -0- halogeno-lower alkyl and Okiso.
- Substituents which may be substituted in R 12 but are preferably allowed to be “lower alkylene” include groups selected from halogen and aryl.
- Substituents that may be substituted in R 12 are preferably selected from the following group G 2 as an acceptable substituent in the “nitrogen-containing saturated heterocyclic group”. More preferably, it is halogen, lower alkyl, halogeno lower alkyl, -OR ° or -0-halogeno lower alkyl. More preferably lower alkyl.
- G 2 group Nono androgenic, lower alkyl, halogeno-lower alkyl, -OR 0, -0- halogeno lower alk kill, lower alkylene - OR °, lower alkylene - N (R °), lower alkylene - cycloalkyl
- the aryl and heterocyclic groups in the G 2 group may be substituted with a group selected from the G 1 group.
- the aryl and heterocyclic groups in the G 3 group may be substituted with a group selected from the G 1 group.
- the substituted group in R 2 may preferably be a group selected from the following G 4 group as an acceptable substituent in “cycloalkyl”.
- Group G 4 Nordogen, lower alkyl, halogeno lower alkyl, -OR 0 , -0-halogeno lower alkyl, -N (R °), -S-lower alkyl, -S (0) -lower alkyl and -S (0) -Lower alkyl.
- Substituents which may be substituted in R 2 and are allowed in “lower alkylene” are preferably groups selected from halogen and —OR Q.
- R 3 is lower alkyl (the compound described in 3 ⁇ 4).
- binding affinity means the ability of a test compound to bind to a part of a receptor, and this evaluation is performed in vitro as described in the test method. This is done by comparing the Ki value calculated by the receptor binding test, and optionally the IC value in the receptor binding test performed under the same conditions. In the receptor binding test,
- the compound If the IC value cannot be calculated without sufficient inhibitory action at a certain concentration, the compound The value of may be considered above the concentration.
- the binding affinity of the compound of the present invention to 5-HT and 5-HT receptors is higher than that of other receptors.
- “Selective” means that the binding affinity for the receptor is higher than the binding affinity for the other receptor. In the present invention, “selective” means that the Ki value or IC value indicating the binding affinity for the receptor is 10 minutes compared with the value for “other receptors”.
- this value is 1/50 or less, more preferably 1/100 or less, even more preferably 1/500 or less, and particularly preferably 1/1000 or less.
- the binding affinity to the receptor is a selective compound compared to the a, M and D receptors.
- the binding affinity to 5-HT and 5-HT receptors is M, D, 5-HT, 5-
- the compound (I) of the present invention may have geometric isomers and tautomers.
- the following tautomers exist. Even if it describes with one form in this specification, this invention is not limited to one form.
- the present invention includes one or a mixture of such tautomers.
- the compound of the present invention may have an isomer based on an asymmetric carbon atom.
- the present invention includes a mixture or an isolated form of these optical isomers.
- the compound (I) of the present invention includes all compounds that are metabolized in vivo and converted into the compound (I) or a salt thereof, so-called prodrugs.
- the group that forms this prodrug includes “Progress in Medicine”, Lifecycle
- the bases described in Ens' Medica, 1985, May 5, p.2157-2161 include the bases described in Yodogawa Shoten 1990, “Development of Drugs”, VII Molecular Design 163-198.
- Examples of the pharmaceutically acceptable salt of the compound (I) of the present invention include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and formic acid. , Acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid and other organic acids Examples include acid addition salts. Depending on the type of substituent, a salt with a base may be formed.
- inorganic bases containing metals such as sodium, potassium, magnesium, calcium, and aluminum, or methylamine, ethylamine, ethanolamine, lysine, Examples thereof include salts with organic bases such as ortin and ammonium salts.
- the present invention also includes various hydrates, solvates and crystal polymorphs of Compound (I) and salts thereof.
- HBTU HBTU
- DPPA Diphlo-Lulin Acid azide
- phosphorous oxychloride PS-Carbodiimide (Argonaut Technology, USA), etc.
- additives eg, N-hydroxysuccinimide (HONSu) or It is preferable to use 1-hydroxybenzotriazole (HOBt) etc.!
- the reaction is carried out using the compound (1) and the amine derivative (2) in an equal amount or one of them in an excess amount, and using a condensing agent in an equivalent amount or an excess amount with respect to the carboxylic acid.
- Aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, jetyl ether, tetrahydrofuran (THF), dioxane or dimethoxyethane (DME), ethers such as ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, acetonitrile, water, etc. Under heating, it can be carried out preferably at -20 ° C to 60 ° C.
- the compound represented by the general formula (Ib) is represented by the general formula (Ia). It can manufacture by attaching
- the compound represented by the general formula (I-f) can be produced by subjecting the compound of the present invention represented by the general formula (I-e) to an acid-acid reaction.
- the reaction is carried out by treating compound (Ie) with an equal or excess amount of an oxidizing agent.
- an oxidizing agent for example, hydrogen peroxide, metachlorinated perbenzoic acid, sodium metaperiodate, acid osmium (VII), ruthenium oxide (VII) are used.
- oxidizing agent for example, hydrogen peroxide, metachlorinated perbenzoic acid, sodium metaperiodate, acid osmium (VII), ruthenium oxide (VII) are used.
- the compound of the present invention having various functional groups such as amino group, carboxyl group, amide group, hydroxyl group, alkylamino group, alkoxy and the like has a corresponding -tro group, ester group, carboxyl group, amino group, hydroxyl group and the like.
- the compound of the present invention as a raw material, it can be easily synthesized by using a method obvious to those skilled in the art or a modified method thereof. For example, it can be produced by the following reaction.
- a compound having a hydroxyalkyl group can be produced by reducing a compound having an ester group.
- the reaction can be carried out using lithium aluminum hydride, sodium borohydride or the like as a reducing agent.
- a compound having a carboxyl group By hydrolyzing the compound having an ester group, a compound having a carboxyl group can be produced. For example, it can be carried out according to the deprotection reaction described in the above-mentioned “Protective 'Groups' In'Gaak Synthesis”.
- a compound having an amide group can be produced by amidating a compound having a carboxyl group or an amino group. It can carry out according to said 1st manufacturing method. 4-e: N-alkylation
- a compound having an alkylamino group can be produced by alkylating a compound having an amino group.
- various alkylating agents for example, alkyl halides, alkylsulfonic acid esters, etc.
- a compound having an amino group can be produced by reductive alkylation with a carbo-louie compound.
- the method described in “Chemical Experiment Course (20) Organic Synthesis 2” edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, P.300, etc. can be applied to the alkyl group of the amino group. 4-f: O-alkylation
- a compound having an alkoxy group can be produced by alkylating a compound having a hydroxyl group.
- alkylation reaction various alkylating agents (for example, alkyl halides, alkylsulfonic acid esters, etc.) can be used and reacted in a conventional manner. For example, it can be carried out by the method described in the Chemical Society of Japan “Experimental Chemistry Course (Maruzen)” (4th edition, 20 ⁇ , 1992, pl87).
- the starting compound used for the production of the compound (I) of the present invention can be produced, for example, using the following method, a known method, or a modified method thereof.
- the halogeni reaction in step A should be carried out by the method described in, for example, “Experimental Chemistry Course (Maruzen)” (4th edition, 19 ⁇ , 1992, p430) Can do.
- the alkylation reaction of step B can be carried out, for example, by the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, 21st year, 1991, p298).
- the formation reaction of the pyrrole ring in step C can be carried out, for example, by the method described in “New edition of heterocyclic compounds (Kodansha Scientific)” (2004, pl34).
- L 2 represents a leaving group such as —OH or halogen, —0-methanesulfone, or —Op-toluenesulfonyl; the same shall apply hereinafter.
- the formation reaction of the pyrrole ring in Step D can be carried out, for example, by the method described in “New edition of heterocyclic compound basics (Kodansha Scientific)” (2004, pl34). .
- the N-alkyli reaction in step E can be carried out, for example, by the method described in “The Laboratory of Experimental Chemistry (Maruzen)” (4th edition, 20 ⁇ , 1992, p284), edited by the Japan Society for Chemical Research.
- L 2 is —OH
- L 3 represents a leaving group such as halogen, -0-methanesulfol, -Op-toluenesulfol,
- step J The reductive alkylation reaction in step J can be carried out in the same manner as in raw material synthesis 3B (raw material synthesis 5).
- the o-alkyl ⁇ reaction of process ⁇ can be carried out, for example, by the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, 20 ⁇ , 1992, pl87). it can.
- step L can be carried out, for example, by the method described in the Chemical Society of Japan, “Experimental Chemistry Course (Maruzen)” (4th edition, 21 ⁇ , 1991, pl06).
- step M can be performed, for example, according to the method described in “Protective Groups” in Organic ”Synthesis.
- Compound (I) produced in this way is free compound, its salt or hydrate. It can be isolated and purified as a seed solvate.
- the salt can be produced by subjecting it to normal salt formation treatment. Isolation / purification is carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatographic techniques.
- optical isomers can be isolated by conventional methods using the difference in physicochemical properties between isomers.
- optical isomers can be obtained by introducing a racemate into a diastereomeric salt with an optically active organic acid (such as tartaric acid), followed by fractional recrystallization, or column chromatography using a chiral packing material. , Each can be separated and purified.
- the optically active compound can also be produced by using an appropriate optically active compound as a raw material.
- a diastereomer mixture can also be separated by fractional crystallization or chromatography.
- Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- aqueous solvent include distilled water for injection and physiological saline.
- Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (Pharmacopeia name), and the like.
- Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can be prepared by preparing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.
- the dry powder inhaler or the like can use a dry powder or a capsule containing a powder, which can be used for single or multiple administrations.
- a dry powder or a capsule containing a powder which can be used for single or multiple administrations.
- it may be in the form of an appropriate propellant such as a caloric aerosol spray using a suitable gas such as black mouth fluoroalkane, hydrofluoroalkane or carbon dioxide.
- the cells were detached with a scraper in the presence of PBS ( ⁇ ), and the cells were collected by centrifugation (1,000 rpm, 10 minutes, 4 ° C.). Homogenize with a homogenizer (registered trademark: Polytron (PTA 10-TS)) in the presence of 5 mM Tris-HCl (pH 7.4) buffer, and centrifuge (40,000 X g, 10 minutes, 4 ° C) did. The suspension was suspended in a glass Teflon (registered trademark) homogenizer in the presence of 50 mM Tris-HCl (pH 7.4) buffer. Centrifugation (40,000 X g, 10 minutes, 4 ° C) was carried out, suspended in 50 mM Tris-HCl (pH 7.4), and stored at -80 ° C.
- a homogenizer registered trademark: Polytron (PTA 10-TS)
- PTA 10-TS Polytron
- the suspension was suspended in a glass Teflon (registered trademark) homogenizer in the presence of 50
- Ki IC / (l + [L] / [Kd]) ([L]: Ligand concentration, [Kd]: Dissociation
- a total amount of 500 / zl containing a membrane sample and radioligand [ 3 H] 5-HT (3.40 TBq / mmol) was incubated at 25 ° C. for 1 hour.
- the compound was dissolved in 100% DMSO and diluted to various concentrations.
- Nonspecific binding was defined as the binding amount in the presence of 10 / z M metergoline, and the specific binding amount was obtained by subtracting the nonspecific binding amount from the total binding amount.
- 4 mL of 50 mM Tris-HCl buffer (pH 7.4) was added, filtered under reduced pressure through a GF / B glass filter, and the filter was washed with the same buffer (4 mL ⁇ 3).
- RS-127445 (2-amino-4- (4-fluoronaphtho-1-yl) -6-isopropylpyrimidine; see W097 / 44326 for the production method) described in the following test method (4) and SB -269970 ((R) -3- (2- (2- (4-Methylbiperidine-1-yl) ethyl) pyrrolidine-1-sulfol) phenol; see WO 97/48681 for production method)
- R S-127445 for example, “British Jouurnal of Pharmacology” (UK), 1999, No. 127 From p.1075-1082, the pKi to the 5-HT receptor of the compound is 9.5, 5-HT, 5-HT, 5-HT, 5-HT, 5
- the IBS therapeutic effect of the compound (I) of the present invention was evaluated using a test method in which restraint stress was applied to rats and the amount of defecation was measured (“Journal of pharmacology experimental” cefpi 1 ⁇ (The Journal of Pharmacology Experimental rherapeutics), uncountry), 1992, 261, p.297-303).
- 5-HT receptor antagonist a diarrhea-type IBS treatment
- IBS can be expected to show an excellent IBS-improving effect compared to one selective receptor antagonist.
- Example Compound 161 when Example Compound 161 was administered, it showed a significant inhibitory effect from a dose of lmg / kg (p.o.).
- Example Compound 153 when Example Compound 153 was administered, it showed a significant inhibitory effect from a dose of lmg / kg (p.o.).
- the compound of the present invention is 5-HT HT
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
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- Veterinary Medicine (AREA)
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- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT07714469T ATE542794T1 (de) | 2006-02-20 | 2007-02-19 | Pyrrolderivat oder salz davon |
EP07714469A EP1988075B1 (en) | 2006-02-20 | 2007-02-19 | Pyrrole derivative or salt thereof |
MX2008010644A MX2008010644A (es) | 2006-02-20 | 2007-02-19 | Derivado de pirrol o sal del mismo. |
CA002642619A CA2642619A1 (en) | 2006-02-20 | 2007-02-19 | Pyrrole derivative or salt thereof |
CN2007800059535A CN101384549B (zh) | 2006-02-20 | 2007-02-19 | 吡咯衍生物或其盐 |
US12/278,609 US8222274B2 (en) | 2006-02-20 | 2007-02-19 | Pyrrole derivative or salt thereof |
ES07714469T ES2379734T3 (es) | 2006-02-20 | 2007-02-19 | Derivado de pirrol o sal del mismo |
JP2008501700A JP5157893B2 (ja) | 2006-02-20 | 2007-02-19 | ピロール誘導体またはその塩 |
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JP2006041830 | 2006-02-20 | ||
JP2006-041830 | 2006-02-20 |
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WO2007097276A1 true WO2007097276A1 (ja) | 2007-08-30 |
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ID=38437316
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PCT/JP2007/052943 WO2007097276A1 (ja) | 2006-02-20 | 2007-02-19 | ピロール誘導体またはその塩 |
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Country | Link |
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US (1) | US8222274B2 (ja) |
EP (1) | EP1988075B1 (ja) |
JP (1) | JP5157893B2 (ja) |
KR (1) | KR20080105092A (ja) |
CN (1) | CN101384549B (ja) |
AT (1) | ATE542794T1 (ja) |
CA (1) | CA2642619A1 (ja) |
ES (1) | ES2379734T3 (ja) |
MX (1) | MX2008010644A (ja) |
WO (1) | WO2007097276A1 (ja) |
Cited By (5)
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---|---|---|---|---|
WO2009026407A1 (en) * | 2007-08-22 | 2009-02-26 | Allergan, Inc. | Pyrrole compounds having sphingosine-1-phosphate receptor agonist or antagonist biological activity |
CN102224142A (zh) * | 2008-11-21 | 2011-10-19 | 拉夸里亚创药株式会社 | 具有5-ht2b受体拮抗活性的新型吡唑-3-羧酰胺衍生物 |
WO2013079223A1 (en) | 2011-12-02 | 2013-06-06 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
JP2014504632A (ja) * | 2011-02-03 | 2014-02-24 | ルピン・リミテッド | α7nAChRのモジュレータとして使用されるピロール誘導体 |
US10344002B2 (en) | 2016-09-26 | 2019-07-09 | Nusirt Sciences, Inc. | Compositions and methods for treating metabolic disorders |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200638926A (en) * | 2005-02-08 | 2006-11-16 | Astellas Pharma Inc | A therapeutic agent for irritable bowel disease |
WO2007018168A1 (ja) * | 2005-08-08 | 2007-02-15 | Astellas Pharma Inc. | アシルグアニジン誘導体またはその塩 |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2009026407A1 (en) * | 2007-08-22 | 2009-02-26 | Allergan, Inc. | Pyrrole compounds having sphingosine-1-phosphate receptor agonist or antagonist biological activity |
JP2010536871A (ja) * | 2007-08-22 | 2010-12-02 | アラーガン、インコーポレイテッド | スフィンゴシン−1−リン酸受容体アゴニストまたはアンタゴニスト生物学的活性を有するピロール化合物 |
CN102224142A (zh) * | 2008-11-21 | 2011-10-19 | 拉夸里亚创药株式会社 | 具有5-ht2b受体拮抗活性的新型吡唑-3-羧酰胺衍生物 |
JP2014504632A (ja) * | 2011-02-03 | 2014-02-24 | ルピン・リミテッド | α7nAChRのモジュレータとして使用されるピロール誘導体 |
WO2013079223A1 (en) | 2011-12-02 | 2013-06-06 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
US9815851B2 (en) | 2011-12-02 | 2017-11-14 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor RAR-related orphan receptor-gamma (RORγ, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
US10344002B2 (en) | 2016-09-26 | 2019-07-09 | Nusirt Sciences, Inc. | Compositions and methods for treating metabolic disorders |
Also Published As
Publication number | Publication date |
---|---|
MX2008010644A (es) | 2008-10-28 |
CA2642619A1 (en) | 2007-08-30 |
US20090036421A1 (en) | 2009-02-05 |
JP5157893B2 (ja) | 2013-03-06 |
JPWO2007097276A1 (ja) | 2009-07-16 |
CN101384549B (zh) | 2011-04-13 |
US8222274B2 (en) | 2012-07-17 |
EP1988075B1 (en) | 2012-01-25 |
ATE542794T1 (de) | 2012-02-15 |
EP1988075A1 (en) | 2008-11-05 |
CN101384549A (zh) | 2009-03-11 |
EP1988075A4 (en) | 2010-03-03 |
KR20080105092A (ko) | 2008-12-03 |
ES2379734T3 (es) | 2012-05-03 |
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