WO2004103972A1 - 新規ピペリジン誘導体 - Google Patents
新規ピペリジン誘導体 Download PDFInfo
- Publication number
- WO2004103972A1 WO2004103972A1 PCT/JP2004/007132 JP2004007132W WO2004103972A1 WO 2004103972 A1 WO2004103972 A1 WO 2004103972A1 JP 2004007132 W JP2004007132 W JP 2004007132W WO 2004103972 A1 WO2004103972 A1 WO 2004103972A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- substituted
- lower alkyl
- alkyl group
- aryl
- Prior art date
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- 125000003118 aryl group Chemical group 0.000 claims description 50
- 125000003545 alkoxy group Chemical group 0.000 claims description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
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- 125000005842 heteroatom Chemical group 0.000 claims description 28
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- 125000001424 substituent group Chemical group 0.000 claims description 20
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940125722 laxative agent Drugs 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 210000003903 pelvic floor Anatomy 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 description 1
- KHFDEFLMWSUKAS-UHFFFAOYSA-N tert-butyl n-(2-bromopropyl)carbamate Chemical compound CC(Br)CNC(=O)OC(C)(C)C KHFDEFLMWSUKAS-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
-
- 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
-
- 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
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- 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
- A61P1/10—Laxatives
-
- 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
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to novel piperidine derivatives and the use of the piperidine derivatives as pharmaceuticals.
- Various abnormal diseases that can be caused by abnormal HT control function such as mental illness, circulatory system disease, gastrointestinal dysfunction, etc. It is suggested that the compound of the present invention has an affinity for 5-HT7 and acts as an agonist of 5-HT7, a partial agonist, or an engonist, whereby It is useful as a therapeutic or prophylactic agent for diseases.
- Visceral or abdominal pain is usually important biological information that informs the individual about the morbidity of the internal organs and abdomen, and is not only a symptom associated with bowel disease, i.e. There are also pains caused by sudden contraction and convulsions of tubular organs such as the stomach and gallbladder, and inflammation of the peritoneum and pleura. Antispasmodics and anti-inflammatory analgesics are used for these symptoms.
- Serotonin (5-hydroxytrymin, 5-HT) plays an important role in physiological or behavioral processes.
- 90% of intestinal chromophilic cells are present in vivo, and the physiological and pathophysiological significance in the intestinal tract is significant.
- 5-HT 7 receptor is the most recently identified 5-HT receptor and is expressed in peripheral tissues in coronary and intestinal tracts (See, for example, J. Biol. Chem., 268, pp234Z2 (1993)).
- the 5-HT 7 receptor is coupled to a G protein (Gs) that promotes the production of cyclic adenosine monophosphate (cAMP).
- Gs G protein
- cAMP cyclic adenosine monophosphate
- 5-HT 7 receptor antagonists are considered to be caused by various disorders of 5-HT central and peripheral 5-HT regulatory functions, such as mental disorders (manic depression, anxiety, anxiety, Possibility of being useful for treatment of schizophrenia, epilepsy, sleep disorder, biological rhythm disorder, migraine, etc., circulatory disease (such as hypertension), gastrointestinal dysfunction, etc.
- mental disorders manic depression, anxiety, anxiety, Possibility of being useful for treatment of schizophrenia, epilepsy, sleep disorder, biological rhythm disorder, migraine, etc.
- circulatory disease such as hypertension
- gastrointestinal dysfunction etc.
- the effect of treatment in a rat middle cerebral artery occlusion model is disclosed (see, for example, International Publication No. 2000037082 Pamphlet).
- compounds that have an affinity for 5-HT 7 may be associated with irritable bowel syndrome, abdominal pain or irritable bowel dysfunction induced by serotonin stimulation. It is expected to be effective for visceral pain.
- Another object of the present invention is to provide a novel conjugate having an affinity for 5-HT7. Another object of the present invention is to provide a pharmaceutical composition containing the novel compound.
- the present inventors have synthesized various piperidine derivatives to solve the above-mentioned problems.
- the present invention provides a piperidine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt.
- Sl, S2, and S3 may be the same or different, and each represents a hydrogen atom; a halogen atom; a hydroxyl group; a lower alkyl group; a lower alkenyl group; a lower alkynyl group; a cyclic alkyl group (including a hetero atom in the ring.
- Substituted lower alkylthio groups aryl A lower alkyl group substituted with an aryl group; a lower alkoxy group substituted with a heteroaryl group; a lower alkylthio group substituted with a heteroaryl group; A hetero atom may be contained in the ring) an oxy group; an aryloxy group; a heteroaryloxy group; a hydroxy lower alkyl group; a hydroxy lower alkenyl group; a hydroxy lower alkoxy group; a halogeno lower alkyl group; a halogeno lower alkoxy group; A lower alkylthio group; a halogeno lower alkenyl group; a nitro group; a cyano group; a substituted or unsubstituted amino group; a carbonyl group; a lower alkyloxycarbonyl group; a substituted or unsubstituted carbamoyl group; a lower alkanoyl group; A lower alkyl
- RNG is an optionally substituted aryl group; or an optionally substituted heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom;
- R1 is a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclic alkyl group (which may contain a hetero atom in the ring); an aryl group; a heteroaryl group; A lower alkyl group substituted with an aryl group; a lower alkenyl group substituted with an aryl group; a lower alkyl group substituted with a heteroaryl group; lower alkoxy.
- a lower alkyl group substituted with a heteroaryl group a lower alkenyl group substituted with an aryl group, a lower alkenyl group substituted with a heteroaryl group, a lower alkynyl group, a cyclic alkenyl group, or a piperonyl group
- a lower alkyl group substituted by an urea group which may be
- R2 is a lower alkyl group; a lower alkenyl group; a lower alkynyl group; a halogeno lower alkenyl group; a halogeno lower alkenyl group; a halogeno lower alkynyl group;
- ⁇ and ⁇ may be the same or different, and each represents a hydrogen atom; a halogen atom; or a lower alkyl group.
- the present invention also provides a compound having an affinity for 5-HT7, comprising the above-mentioned piperidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention also provides a therapeutic or preventive agent for irritable bowel syndrome, comprising the above-mentioned bidiziridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention also provides a therapeutic or preventive agent for visceral pain or abdominal pain, comprising the piperidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- FIG. 1 is a graph showing the measurement results of 5HT-7 agonist activity using 5HT-7 expressing cells.
- lower such as a lower alkyl group in the present specification means a group having 1 to 6 carbon atoms.
- the alkyl group, alkenyl group, and alkynyl group as components such as a kirthio group, an alkanoyl group, and an alkylamino group can be linear or branched.
- substituent is a component of another group, it is to be defined as the corresponding group.
- alkyl group examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a secondary butyl group, a butyl group, a pentyl group, and a hexyl group. 6 is preferred, and more preferably 1-4.
- the alkenyl group includes a vinyl group, a propenyl group, a butenyl group, a pentenyl group and the like, and preferably has 2 to 6 carbon atoms, and more preferably has 2 to 4 carbon atoms.
- alkynyl group examples include an ethynyl group, a propynyl group, a butynyl group, and the like, preferably having 2 to 6 carbon atoms, and more preferably having 2 to 4 carbon atoms.
- the cyclic alkyl group means a substituted or unsubstituted cyclic alkyl group.
- examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a norbornyl group, an adamantyl group, and a cyclohexenyl group.
- the alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group and a phenoxy group.
- the hetero atom include nitrogen, oxygen, zeolite, and the like.
- the hetero atom preferably has 1 to 6 carbon atoms, and more preferably has 1 to 4 carbon atoms.
- Halogen atoms indicate fluorine, chlorine, bromine and iodine.
- Examples of the neurogenoalkyl group include a chloromethyl group, a trichloromethyl group, a trifluoromethyl group, a trifluoroethyl group, and a penfluoromethyl group.
- Examples of the no and logenoalkoxy groups include a trichloromethoxy group and a trifluoromethoxy group.
- Examples of the hydroxyalkyl group include a hydroxymethyl group and a hydroxyethyl group. The bonding position of the hydroxyl group is not particularly limited.
- the cyclic alkyl group which may contain a hetero atom in the ring may be substituted or unsubstituted.
- examples include a cyclopentyl group, a cyclohexyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, and a lipolidinyl group.
- Tetrahydrofuranyl group, ⁇ A racyl group and the like are mentioned, and a 4- to 8-membered ring is preferable, and a 5- to 7-membered ring is more preferable.
- an aryl group represents a monocyclic to tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, and these may have a substituent.
- the aryl group include a phenyl group and 1 —Naphthyl group, 2-naphthyl group and the like, preferably phenyl group and substituted phenyl group, and halogen atom, alkoxy group, alkyl group, hydroxyl group, halogenoalkyl group, and halogenoalkoxy group are particularly preferable as substituents.
- a halogen atom and an alkyl group are particularly preferred as substituents, and among them, a chlorine atom and a methyl group are particularly preferred as substituents.
- the heteroaryl group is a 5- to 8-membered monocyclic to tricyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms. These may have a substituent.
- heteroaryl examples include a pyridyl group, a virazyl group, a pyrimidyl group, a pyrazolyl group, a pyrrolyl group, a triazinole group, a furyl group, a cyenyl group, an isoxazolyl group, an isothiazolyl group, and an indolyl group.
- Quinolyl group, isoquinolyl group, benzoimidazolyl group, etc. preferably pyridyl group, virazyl group, pyrimidyl group, furyl group, chenyl group and substituted pyridinole group, furyl group, chenyl group, etc.
- An alkoxy group, an alkyl group, a hydroxyl group, a halogenoalkyl group, and a halogenoalkoxy group Preferable as substituent.
- Examples of the lower alkyl group substituted with an aryl group include a substituted or unsubstituted benzyl group and a substituted or unsubstituted phenyl group.
- a halogen atom, an alkoxy group, an alkyl group, a hydroxyl group, a halogenoalkyl And halogenoalkoxy groups are particularly preferred as substituents.
- Examples of the lower alkyl group substituted with a heteroaryl group include, for example, a pyridylmethyl group, and a halogen atom, an alkoxy group, an alkyl group, a hydroxyl group, a halogenoalkyl group, and a halogenoalkoxy group are particularly preferable as the substituent.
- Examples of the alkanoyl group include formyl group, acetyl group, propanoyl group, butanoyl group, and vivaloyl group.
- Examples of the arylo group include a substituted or unsubstituted benzoyl group and a pyridylcarbonyl group.
- a halogen atom, an alkoxy group, an alkyl group, a hydroxyl group, a halogenoalkyl group, and a halogenoalkoxy group are particularly preferable as the substituent.
- the halogenoalkanoyl group include a trichloroacetyl group and a trifluoroacetyl group.
- the alkylsulfonyl group include a methanesulfonyl group and an ethanesulfonyl group.
- Examples of the arylsulfonyl group include a benzenesulfonyl group and a p-toluenesulfonyl group.
- heteroarylsulfonyl group examples include a pyridylsulfonyl group.
- halogenoalkylsulfonyl group examples include a trifluoromethanesulfonyl group.
- Alkyloxycarbonyl groups include methoxycarbonyl group, ethoxycarbonyl group, and butoxycarbonyl group, and aryl-substituted alkoxycarbonyl groups include benzyloxycarbonyl group and 9-fluorenylmethoxycarboxy group. And the like.
- substitution force rubamoyl group examples include a methylcarbamoyl group, a phenylcarbamoyl group, a substituted phenylcarbamoyl group, and the like.
- Halogen atoms, alkoxy groups, alkyl groups, hydroxyl groups, halogenoalkyl groups, and halogenoalkoxy groups are particularly preferred substituents. preferable.
- Examples of the substituted thiocarbamoyl group include a methylthiolrubamoyl group, a phenylthiolrubamoyl group, a substituted phenylthiolrubamoyl group, and the like, and include a halogen atom, an alkoxy group, an alkyl group, a hydroxyl group, a halogenoalkyl group, A alkoxy group is particularly preferred as a substituent.
- examples of the substituent in the substituted amino group include a lower alkyl group, a lower alkyl group substituted with an aryl group, a lower alkyl group substituted with a heteroaryl group, a lower alkanol group, an arylo group, and a halogeno lower group.
- Alkanoyl group lower alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, halogenoalkylsulfonyl group, lower alkyloxycarbonyl group, aryl substituted lower alkyloxycarbonyl group, substituted or unsubstituted rubamoyl Group, substituted or unsubstituted
- An alternative is the luminomoyl group.
- R2 is preferably a lower alkyl group, a halogeno lower alkyl group, more preferably a methyl group, an ethyl group and a propyl group, and particularly preferably a methyl group or a halogenomethyl group.
- Sl, S2, and S3 may be the same or different, and each may be a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, or a lower alkylthio group.
- Groups, hydroxy lower alkyl groups, hydroxy lower alkenyl groups, hydroxy lower alkoxy groups, halogeno lower alkyl groups, nodogeno lower alkoxy groups, halogeno lower alkylthio groups, halogeno lower alkenyl groups, and substituted or unsubstituted amino groups are particularly preferred.
- R2 is more preferably a lower alkyl group or a halogeno lower alkyl group, particularly preferably a methyl group or a halogenomethyl group.
- R1 represents an alkyl group substituted with a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cyclic alkyl group (which may contain a hetero atom in the ring), an aryl group, A lower alkyl group substituted with an aryl group, a lower alkenyl group substituted with an aryl group, a hydroxy lower argyl group, a hydroxy lower alkyl group substituted with an aryl group, a lower alkyl group substituted with a lower alkoxy group, lower A lower alkyl group substituted by a carbonyl group substituted by an alkyloxy group, an alkyl group substituted by a carboxyl group, an amino substituted lower alkyl group; a cyclic alkyl group (which may contain a hetero atom in the ring); a cyclic alkenyl group , Aryl, heteroaryl, lower alkyl, lower alkoxy, alkyl
- R1 is more preferably a lower alkyl group substituted by a sulfonamide group substituted by a lower alkyl group, a halogeno lower alkyl group, an aryl group or a heteroaryl group.
- RNG is preferably a substituted aryl group or a substituted or unsubstituted heteroaryl group in which a hetero atom is sulfur.
- a substituted aryl group a substituted phenyl group is more preferred.
- a substituted or unsubstituted phenyl group is more preferred.
- these substituents a halogen atom and a lower alkyl group are preferable, and a chlorine atom and a methyl group are particularly preferable.
- the number of substituents and the bonding position are not particularly limited. Of these, 3-chlorophenyl, 3,4-dichlorophenyl, 4-methylphenyl, 2-phenyl, 5-chloro-2-phenyl and 5-methyl-2-phenyl are preferred. .
- a and B may be the same or different, and each is preferably a hydrogen atom, a halogen atom, or a lower alkyl group, and particularly preferably a hydrogen atom.
- Sl, S2, and S3 may be the same or different, and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogeno lower alkyl group, or a halogeno lower alkoxy group.
- a halogeno lower alkylthio group, R2 represents a methyl group
- a and B preferably represent a hydrogen atom.
- the piperidine derivative (1) represented by the general formula (1) of the present invention can be produced by using the following method as an example of the production method.
- Arl and Ar2 represent an aryl group
- Arl and AQNIr2 or Ar2 and Ar1 each have a structure of RNG represented by the general formula (1) and a phenyl group having a substituent
- D and E each have the structure of A and B, or have a structure that can be converted to A and B respectively at any point in the synthesis process
- Q1 has the structure of R1 or a structure that can be converted at any point in the synthesis process.
- XI and X2 may be the same or different and represent a halogen atom.
- Grignard reagent of piperidine derivative (7) obtained by heating and refluxing a halogenated aromatic compound and magnesium in THF and an aromatic compound having a nitrile group (6) are heated at room temperature or refluxed in THF.
- the ketone (9) can be obtained by treating the imine (8) obtained by the reaction under an acidic condition under acidic conditions overnight.
- (11) can be obtained by reacting the halogenated aromatic compound with a Grignard reagent (10) obtained by reacting with magnesium in THF.
- a strong acid such as sulfuric acid and a mixed solvent such as methanol
- D, E, Ar Ar2 and Ql are the same as in Scheme 1.
- (14) is obtained by heating and refluxing (13) and ethyl chloroformate in a solvent such as toluene and the like, and then using potassium hydroxide or the like as a base in a solvent such as n-butyl alcohol. Hydrolysis by heating to reflux or the like gives (15). Furthermore, (16) can be obtained by performing alkylation using various alkyl halides and the like.
- T1 has the structure of S1 represented by the general formula (1) or at any time during the synthesis process
- T2 and ⁇ 3 each have a structure of S2 or S3 represented by the general formula (1), or a structure that can be converted to a structure of S2 or S3 represented by the general formula (1) at any point in the synthesis process Take.
- Q2 has a structure of R2 represented by the general formula (1) or a structure that can be converted to R2 represented by the general formula (1) at any point in the synthesis process.
- (18) is obtained by treating (17) with an acid such as BBr3 using a solvent such as dichloromethane.
- piperidine derivative of the present invention can be synthesized also by using the following method using the solid phase synthesis method.
- (24) is reacted with Grignard reagent to obtain (25), and then treated with acetic acid or the like to lead to (26).
- the Grignard reagent which may be different or the same, is reacted with (26) to form (27)
- (28) is obtained by reacting (27) with an alkyl halide or the like in a solvent such as concealment or DMF.
- (28) is treated with ammonia gas overnight under basic conditions, for example, by overnight treatment with ammonia gas.
- the compound is excised from the resin by Hofmann elimination, the compound is eluted with a solvent such as acetonitrile and dichloromethane. Can be obtained.
- (29) can also be obtained by reacting a solution of lithium hydroxide in a mixed solvent of THF and water with (28) overnight.
- the salt may be any pharmaceutically acceptable one.
- Salts with alkali metals such as ammonium salts, sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, pyridine and dicyclite Salts with organic amines such as oral hexylamine and salts with basic amino acids such as arginine and lysine can be mentioned.
- examples of the basic group include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, acetic acid, cunic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, and the like.
- examples thereof include salts with organic carboxylic acids such as succinic acid, and salts with organic sulfonic acids such as methanesulfonic acid and P-toluenesulfonic acid.
- a compound of the general formula (1) and a required acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or a cation exchange or a cation exchange is carried out from other salt forms. It can also be obtained by performing anion exchange.
- the compounds represented by the general formula (1) of the present invention also include solvates thereof, for example, hydrates and alcohol adducts.
- the compound represented by the general formula (1) or a salt thereof is administered as it is or as various pharmaceutical compositions.
- Examples of the dosage form of such a pharmaceutical composition include tablets, Powders, pills, granules, capsules, suppositories, solutions, dragees, depots, or capsules can be prepared according to the usual methods using ordinary formulation auxiliaries. You.
- tablets may contain the active ingredient of the present invention, a phenylalanine derivative, as a known auxiliary substance, for example, an inert diluent such as lactose, calcium carbonate or calcium phosphate, or a binder such as arabia gum, corn starch or gelatin.
- an inert diluent such as lactose, calcium carbonate or calcium phosphate
- a binder such as arabia gum, corn starch or gelatin.
- Swelling agents such as alginic acid, corn starch or pregelatinized starch, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, cocoa oil or cherry, magnesium stearate, talc or carboxymethylcellulose.
- Lubricants such as natural or hardened oils and excipients for suppositories, water, alcohol, glycerol, polyol, sucrose, invert sugar, glucose To be mixed with excipients for solutions such as vegetable oil Can be obtained.
- a piperidine derivative or a pharmaceutically acceptable salt containing the compound represented by the general formula (1) or a salt thereof as an active ingredient is also used for a disease state involving 5-HT7, for example, a gastrointestinal motility disorder.
- Functional gastrointestinal disorders including, for example, irritable bowel syndrome, ruminant syndrome, bulbar syndrome, functional heartburn, functional esophageal chest pain, functional gastrointestinal disorders, functional dysphagia, functional vomiting , Dysphagia, dysphagia, functional constipation, functional abdominal distension, functional abdominal pain syndrome, functional hypofunction, wedge sphincter dysfunction, gallbladder dysfunction, levator ani muscle syndrome, functional fecal incontinence, pelvic floor Emphasis movement disorder, dissipative anal pain, pediatric gastrointestinal dysfunction (pediatric reflux disease, childhood rumination syndrome, periodic vomiting syndrome, functional gastrointestinal disorders, irritable bowel syndrome, functional abdominal pain, paroxysmal abdominal pain, aspiration dysfunction, Functional diarrhea, pediatric dysfunction It can be used as a therapeutic
- the present invention also relates to a disease state involving 5-HT7, for example, a functional gastrointestinal disease.
- Diseases with similar pathology anxiety disorder (panic disorder and generalized anxiety disorder)
- somatoform disorder dissociative disorder, mood disorder, etc.
- bulimia bulimia
- anorexia nervosa sleep disorder, diabetic It can also be used as a therapeutic or prophylactic agent for gastrointestinal disorders or other digestive symptoms following abdominal surgery.
- the “irritable bowel syndrome” in the present invention is a disease in “functional intestinal gastrointestinal disease”, which is a disease showing chronic or repeated gastrointestinal dysfunction, which cannot be explained by organic or biochemical abnormalities, It is a condition in which bowel pain and abnormal bowel movements accompanied by abdominal discomfort persist for a certain period of time. This syndrome is "constipation type"
- visceral pain in the present invention refers to pain generated in the internal organs such as the stomach, intestinal tract, and heart, the peritoneum, and the pleura [Textbook of Pain, 4nd Ed, 603-709, CHURCHILL LIVINGSTON E, Hartcourt Publishers Limited (1999) ] 0
- “Abdominal pain” in the present invention is chronic or acute pain perceived in the abdominal region. [Textbook of Pain, 4nd Ed, 603-619, CHURCHILL LIVINGSTONE, Hartcourt Publishers Limited (1999)].
- the "agent for irritable bowel syndrome" in the present invention is useful not only for the treatment of irritable bowel syndrome but also for its improvement and prevention.
- the “agent for treating visceral pain” in the present invention is useful not only for treatment of visceral pain, but also for improvement and prevention.
- the “agent for treating abdominal pain” in the present invention is useful not only for treating abdominal pain, but also for improving and preventing abdominal pain.
- This compound can be used alone in the treatment of such diseases, but it can be used as an anticholinergic, laxative, antidiarrheal, intestinal, mucosal palsy, gastrointestinal motility regulator, autonomic nervous system It can also be used in conjunction with drugs such as modulators, herbal medicines, anxiolytics, antidepressants, sleeping pills, antipsychotics, serotonin antagonists, and serotonin agonists. Further, the compounds of the present invention are expected to be not only excellent in pharmacological action but also metabolically stable.
- the dosage used for the above purpose is determined by the target therapeutic effect, administration method, treatment period, age, body weight, etc., and is usually determined as a daily dose per adult by the oral or parenteral route. Use 1 g to 5 g for oral administration, and 0.0 l ⁇ g to: L g for parenteral administration.
- N-methyl-4-chloropiperidine 100 g
- magnesium 22
- ⁇ 500 mL
- benzonitrile 3-chloro 100 g was added, and the mixture was heated under reflux for 2 hours.
- 100 mL of water was gradually added, and then a 12N hydrochloric acid solution (1 L) was gradually added.
- reaction solvent was removed under reduced pressure, a solution prepared by mixing water (500 mL) and sodium hydroxide (500 g) was added, and the mixture was stirred well, and then the reaction solvent was removed again under reduced pressure.
- ethyl acetate 500 mL
- stirring well After adding ethyl acetate (500 mL) and stirring well, the operation of taking out the ethyl acetate solution by decantation was repeated 10 times, and then all the ethyl acetate solutions were concentrated to obtain the title compound.
- Example 1 The compound obtained in Step 2 was dissolved in a previously prepared mixed solution of concentrated sulfuric acid (24 mL) and methanol (60 mL), and heated at 50 ° C for 3 hours. Then, a solution prepared by mixing water (50 mL) and sodium hydroxide (40'g) was cooled in an ice bath, and then cooled to room temperature in concentrated sulfuric acid containing the target compound. The solution was added slowly. After the extraction procedure with the addition of ethyl acetate (300 mL) was repeated twice, the solution was concentrated to give the crude title compound. Further purification was performed by silica gel chromatography to obtain 17 g of the title compound.
- Example 2 Potassium hydroxide (6.75 g) and n-butanol (51 mL) were added to the entire amount of the compound obtained in Step 1, and the mixture was heated under reflux for 3 hours. After removing n-butanol by vacuum concentration, extraction was performed by adding ethyl acetate (100 mL) and water (50 mL), and the separated organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Thus, 10 g of the compound was obtained.
- Example 1 Grignard reagent obtained by vigorously stirring 2,5-dimethoxybromobenzene (4.5 g) and magnesium (0.5 g) with the compound (2 g) obtained in Step 1 was reacted at room temperature for 2 hours. I let it. After slowly adding water (100 mL), a 12N hydrochloric acid solution (150 mL) was gradually added. Next, the reaction solvent was removed under reduced pressure, a solution prepared by mixing water (150 mL) and sodium hydroxide (150 g) was added, and the mixture was stirred well, and then the reaction solvent was removed again under reduced pressure.
- Example 5 Potassium hydroxide (1.7 g) and n-butanol (10 mL) were added to the entire amount of the compound obtained in Step 1, and the mixture was heated under reflux for 3 hours. After removing n-butanol by vacuum concentration, extraction is performed by adding ethyl acetate (20 mL) and water (10 mL), and the separated organic phase is dried over magnesium sulfate and concentrated under reduced pressure. Thereby, 0.9 g of a representative compound was obtained.
- N-methyl-4-chloropiperidine (15 g), magnesium (3.3 g), and THF (50 mL) were added to a reaction vessel purged with argon, and the mixture was heated to reflux using an oil bath. When an exothermic reaction was observed, the oil bath was removed and vigorous stirring continued until the exotherm was complete. (About 1 hour) After the temperature of the reaction system was returned to room temperature, 2-methoxybenzonitrile (100 g) was added thereto, and the mixture was heated under reflux overnight. After the reaction system was cooled to 0 ° C. in an ice bath, 10 mL of water was gradually added, and then a 12N hydrochloric acid solution (100 mL) was gradually added.
- reaction solvent was removed under reduced pressure, a solution prepared by mixing water (50 mL) and sodium hydroxide (50 g) was added, and the mixture was stirred well, and then the reaction solvent was removed again under reduced pressure. After adding ethyl acetate (50 mL) and stirring well, decanting the target ethyl acetate solution was repeated 10 times, and then all the ethyl acetate solutions were concentrated. This gave the title compound as a cloud. Further purification by silica gel chromatography gave 4 g of the title compound.
- Example 4 The compound obtained in Step 2 was dissolved in a previously prepared mixed solution of concentrated sulfuric acid (8 mL) and methanol (20 mL), and heated at 50 ° C for 3 hours. After that, a solution prepared by mixing water (2 OmL) and sodium hydroxide (20 g) was cooled in an ice bath, and the concentrated sulfuric acid solution returned to room temperature was gradually added. After the extraction operation with ethyl acetate (150 mL) was repeated twice, the solution was concentrated to obtain the crude title compound. Furthermore, purification by silica gel chromatography was carried out to obtain the title compound lg.
- Example 4 Purification was performed in the same manner as in Step 2, to obtain the desired compound (70 mg).
- Example 2 The compound (4 g) obtained in Example 2 and (2-bromo-ethyl) -carbamic acid tert-butyl ester (5.7 g) were added at room temperature in acetonitrile (50 mL) in the presence of triethylamine (5.34 mL). The reaction was allowed to take place overnight.
- the target compound (4.13 g) was obtained by purifying in the same manner as in Step 2 of Example 4.
- Example 26 To the compound (4.0 g) obtained in Example 26 was added 4N HC1 / ethyl acetate (60 mL), and the mixture was stirred at room temperature for 40 minutes. The solvent was removed under reduced pressure to obtain the target compound (3.7g).
- the desired product can be obtained in the same manner as in Example 29 using the corresponding reaction reagents.
- Example 3 7 The desired product was obtained by using the compound obtained in Example 2 and (2-bromo-propyl) -carbamic acid tert-butyl ester in the same manner as in Example 26.
- Example 3 7 The desired product was obtained by using the compound obtained in Example 2 and (2-bromo-propyl) -carbamic acid tert-butyl ester in the same manner as in Example 26.
- Example 3 7
- Example 36 By subjecting the compound obtained in Example 36 to the treatment of Example 27, the intended product could be obtained.
- the target compound was obtained by subjecting the compound obtained in Example 37 to the same treatment as in Example 28.
- the target compound was obtained by subjecting the compound obtained in Example 27 to the same treatment as in Example 48.
- the desired product could be obtained in the same manner as in Example 1, Example 3, or Example 5.
- Example 6 Using the reaction reagents and reaction conditions of Example 6 or Example 7 or Example 8 or Example 9 or Example 11 or Example 23 with respect to the compound obtained in Example 4, could be obtained.
- the target compound was obtained by subjecting the compound obtained in Example 4 to the same treatment as in Example 26.
- Example 6 5
- the target compound was obtained by subjecting the compound obtained in Example 64 to the same treatment as in Example 27.
- Example 6 After mixing the compound obtained in Step 1 (100 mg), immobilized triphenylphosphine (1.6 t ol / lg resin, 600 mg), dichloromethane (10 mL), and ethanol (55 L), TMAD (165 mg) was added and reacted at room temperature for 3 days. After the solid phase resin was removed by filtration, the solvent was filtered under reduced pressure and purified using reverse-phase HPCL to obtain the desired product (40 mg).
- Example 66 The same procedure as in Step 6 of Example 66 was performed on the compound obtained in Step 1 using propanol to obtain the desired product. These examples are shown in Tables 1-8.
- Example 1 2 410. 411, 412
- Example S1 RNG ESI Example 5 3 W 308
- Example 5 1 ESI Example 5 8 372, 373, 374 Example 5 9 386. 387, 378
- Example 6 0 400, 401 r 402 Example 6 1 414, 415, 416 Example 6 2 4, 415, 416 Example 6 3 458, 459, 460
- Test Example 1 RBA (Receptor Binding Assay) using 5HT-7 expressing cells
- Human 5-HT 7 a receptor expressing CHO- K1 cells (EUROSCREEN; h5HT 7 -CI cells, No.ES-317-C -) of 400 g / ml G418 s 100 U / ml Penicillin ⁇ 100 / g / ml Streptomycin They were incubated at 37 ° C 5% C0 2 incubator at Ham's F12 medium containing ⁇ 10% ⁇ shea calf serum.
- Test Example 2 Measurement of 5HT-7 agonist activity using 5HT-7 expressing cells
- CH5-K1 cells expressing human 5HT-7 and h5HT7-C2 were purchased from Euroscreen. 100 ⁇ l of h5HT7-C2 cells suspended at 2 ⁇ 10 5 cells / ml were seeded on a 96-well plate in a medium (GIBCO CH0-SFM-II, Clontech) containing 1% fetal bovine serum. The cells were cultured overnight for 5 hours. After the medium was removed by suction, the wells were washed with 200 zl CHO-SFM-II medium per well, IOOI CHO-SFM-II medium was added per lwell, and the cells were cultured overnight at 37 ° C in a C02 incubator.
- a medium Gibco-SFM-II, Clontech
- the cAMP concentration obtained when 10 ⁇ M serotonin was used as the compound was 100 ° C.
- the cAMP concentration obtained when no compound was added was taken as 0%, and the cAMP concentration of the compound at each concentration was displayed in%.
- the maximum value of the sigmoid approximation curve of the relationship between the concentration and cAMP% was defined as the Emax value, and the concentration of the compound having cAMP of 1/2 of the Emax value was defined as the EC50 value.
- the compound of the present invention can exert an excellent effect as a 5-HT7 agonist.
- Test Example 3 Evaluation of test compound for action on in vivo mouse 5-hydroxytributophan (5-HTP) -induced defecation model ''
- Example 5 Using the compound obtained in Example 5 as a test compound for in vivo mouse 5-hydroxytributophan (5-HTP) -induced defecation model, the method of GJ Sanger et al. (British Journal of Pharmacology, 130: 706-712, 2000).
- 5-HTP 5-hydroxytributophan
- the condition of feces excreted for 30 minutes (0: normal stool and no feces, 1: scored as diarrhea or loose stool) was observed for each individual.
- the test compound inhibition rate (%) was calculated assuming that the score value obtained by connecting the vehicle (5-HTP) group to the vehicle (5-HTP non-) group was 100%.
- the inhibition rate of the test compound was 100%.
- the 5-HT7 receptor antagonist of the present invention can exert an excellent effect as a therapeutic agent for the diarrhea-type irritable bowel syndrome group.
- Test Example 4 Measurement of 5HT-7 gonist activity using 5HT-7 expressing cells
- CH5-K1 cells expressing human 5HT-7 and h5HT7-C2 were purchased from Euroscreen. 1% ⁇ sheet was 100 zl seeded medium (GIBCO CHO-SFM-I Is Clontech Co.) 2Xl0 5 cells / ml in suspension Nigoshi was H5HT7- C2 cells in 96-well plates containing calf serum, in 37 ° C C02 Inkyube The cells were cultured overnight for 5 hours. Aspirate the medium, wash with 200 zl CH0-SFM-II medium per well, add 100 ⁇ 1 CH0-SFM-II medium per lwell, and further overnight at 37 ° C C02 incube Cultured.
- Testi-Danigata 1 was examined using ICR male mice (4 weeks old). A 0.9% acetic acid solution (diluted with physiological saline) was intraperitoneally administered, and 5 minutes after that, the number of writhing for 15 minutes was measured. The test compound was suspended in a 0.5% tragacanth gum solution and orally administered at 5 mL / kg 90 minutes before administration of acetic acid. The inhibitory rate when the compound of Example 5 was administered at 10 mg / kg was 49%.
- the 5-HT 7 receptor antagonist of the present invention can exert an excellent effect as a therapeutic agent for visceral pain and abdominal pain.
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Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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JP2005506383A JP4730096B2 (ja) | 2003-05-20 | 2004-05-19 | 新規ピペリジン誘導体 |
US10/557,353 US7683077B2 (en) | 2003-05-20 | 2004-05-19 | Piperidine derivative |
EP04733967A EP1626044A4 (en) | 2003-05-20 | 2004-05-19 | NEW PIPERIDINE DERIVATIVE |
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JP2003142296 | 2003-05-20 | ||
JP2003-142296 | 2003-05-20 |
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WO2004103972A1 true WO2004103972A1 (ja) | 2004-12-02 |
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PCT/JP2004/007132 WO2004103972A1 (ja) | 2003-05-20 | 2004-05-19 | 新規ピペリジン誘導体 |
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US (1) | US7683077B2 (ja) |
EP (1) | EP1626044A4 (ja) |
JP (1) | JP4730096B2 (ja) |
WO (1) | WO2004103972A1 (ja) |
Cited By (1)
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US10622921B2 (en) | 2015-06-23 | 2020-04-14 | B&R Industrial Automation GmbH | Method and long stator linear motor for transferring a transport unit at a transfer position |
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JPS4932540B1 (ja) * | 1969-06-05 | 1974-08-31 | ||
JPS4932528B1 (ja) * | 1969-12-01 | 1974-08-31 | ||
JPS5387367A (en) * | 1977-01-11 | 1978-08-01 | Ucb Sa | Piperidine derivative |
JPS5782369A (en) * | 1980-09-18 | 1982-05-22 | Ucb Sa | 2-(4-(diphenylmethylene)-1-piperidinyl)-acetic acid and its amide, its nontoxic salt available as medicine and its manufacture |
JPS59104382A (ja) * | 1982-11-01 | 1984-06-16 | ジヤンセン・フア−マシユ−チカ・ナ−ムロ−ゼ・フエンノ−トシヤツプ | 新規〔〔ビス(アリ−ル)メチレン〕−1−ピペリジニル〕アルキル−ピリミジノン類、それを含む薬剤調整物およびその製法 |
JPH03157384A (ja) * | 1989-08-03 | 1991-07-05 | Dai Ichi Seiyaku Co Ltd | 二環性トリアゾール誘導体 |
WO1992018505A1 (en) * | 1991-04-23 | 1992-10-29 | Toray Industries, Inc. | Tricyclic triazole derivative, production thereof, and use thereof |
JP2001507350A (ja) * | 1996-12-20 | 2001-06-05 | アストラ・フアーマ・インコーポレイテツド | 鎮痛効果を有する新規な化合物 |
Family Cites Families (5)
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GB1242169A (en) * | 1969-04-09 | 1971-08-11 | Ucb Sa | Piperidine derivatives |
JPS4932528A (ja) | 1972-07-24 | 1974-03-25 | ||
JPH11189585A (ja) | 1997-12-25 | 1999-07-13 | Meiji Seika Kaisha Ltd | 5−ht7受容体結合能を有するテトラヒドロベンズインドール誘導体 |
GB9828004D0 (en) | 1998-12-18 | 1999-02-10 | Smithkline Beecham Plc | Use |
SE0301442D0 (sv) * | 2003-05-16 | 2003-05-16 | Astrazeneca Ab | Diarylmethylidene piperidine derivatives, preparations therof and uses thereof |
-
2004
- 2004-05-19 EP EP04733967A patent/EP1626044A4/en not_active Withdrawn
- 2004-05-19 US US10/557,353 patent/US7683077B2/en not_active Expired - Fee Related
- 2004-05-19 WO PCT/JP2004/007132 patent/WO2004103972A1/ja not_active Application Discontinuation
- 2004-05-19 JP JP2005506383A patent/JP4730096B2/ja not_active Expired - Fee Related
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS4932540B1 (ja) * | 1969-06-05 | 1974-08-31 | ||
JPS4932528B1 (ja) * | 1969-12-01 | 1974-08-31 | ||
JPS5387367A (en) * | 1977-01-11 | 1978-08-01 | Ucb Sa | Piperidine derivative |
JPS5782369A (en) * | 1980-09-18 | 1982-05-22 | Ucb Sa | 2-(4-(diphenylmethylene)-1-piperidinyl)-acetic acid and its amide, its nontoxic salt available as medicine and its manufacture |
JPS59104382A (ja) * | 1982-11-01 | 1984-06-16 | ジヤンセン・フア−マシユ−チカ・ナ−ムロ−ゼ・フエンノ−トシヤツプ | 新規〔〔ビス(アリ−ル)メチレン〕−1−ピペリジニル〕アルキル−ピリミジノン類、それを含む薬剤調整物およびその製法 |
JPH03157384A (ja) * | 1989-08-03 | 1991-07-05 | Dai Ichi Seiyaku Co Ltd | 二環性トリアゾール誘導体 |
WO1992018505A1 (en) * | 1991-04-23 | 1992-10-29 | Toray Industries, Inc. | Tricyclic triazole derivative, production thereof, and use thereof |
JP2001507350A (ja) * | 1996-12-20 | 2001-06-05 | アストラ・フアーマ・インコーポレイテツド | 鎮痛効果を有する新規な化合物 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10622921B2 (en) | 2015-06-23 | 2020-04-14 | B&R Industrial Automation GmbH | Method and long stator linear motor for transferring a transport unit at a transfer position |
US10917027B2 (en) | 2015-06-23 | 2021-02-09 | B&R Industrial Automation GmbH | Method and long stator linear motor for transferring a transport unit at a transfer position |
Also Published As
Publication number | Publication date |
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US20070021460A1 (en) | 2007-01-25 |
JPWO2004103972A1 (ja) | 2006-07-20 |
EP1626044A1 (en) | 2006-02-15 |
US7683077B2 (en) | 2010-03-23 |
JP4730096B2 (ja) | 2011-07-20 |
EP1626044A4 (en) | 2008-08-20 |
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