WO2004111000A2 - Derives de piperidyle - Google Patents

Derives de piperidyle Download PDF

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Publication number
WO2004111000A2
WO2004111000A2 PCT/JP2004/008371 JP2004008371W WO2004111000A2 WO 2004111000 A2 WO2004111000 A2 WO 2004111000A2 JP 2004008371 W JP2004008371 W JP 2004008371W WO 2004111000 A2 WO2004111000 A2 WO 2004111000A2
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WO
WIPO (PCT)
Prior art keywords
compound
phenyl
methoxy
salt
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2004/008371
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English (en)
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WO2004111000A3 (fr
Inventor
Kazuhiko Take
Takashi Tojo
Hidenori Azami
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Astellas Pharma Inc
Original Assignee
Fujisawa Pharmaceutical Co Ltd
Astellas Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd, Astellas Pharma Inc filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of WO2004111000A2 publication Critical patent/WO2004111000A2/fr
Publication of WO2004111000A3 publication Critical patent/WO2004111000A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 no 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
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new piperidyl derivatives and a salt thereof.
  • one object of the present invention is to provide new and useful piperidyl derivatives and a salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like.
  • Another object of the present invention is to provide a process for the preparation of said piperidyl derivatives and a salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said piperidyl derivatives and a pharmaceutically acceptable salt thereof.
  • Still further object of the present invention is to provide a use of said piperidyl derivatives or a pharmaceutically acceptable salt thereof as Tachykinin antagonist, especially Substance P antagonist, Neurokinin A antagonist or Neurokinin B antagonist, useful for treating or preventing Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g., migraine, headache, toothache, cancerous pain, back pain, etc.); and the like in human being or animals.
  • respiratory diseases such as asthma, bronchitis, rhinitis, cough, expect
  • the object compound of the present invention can be represented by the following general formula (I) :
  • -X- is -NH or -0-;
  • R ⁇ , R ⁇ and R ⁇ are independently hydrogen, lower alkyl, mono (or di or tri) halo (lower) alkyl, cyclo (lower) alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkoxy, cyclo (lower) alkyloxy or ⁇ tetrahydrofranyloxy;
  • R 6 , R 7 and R 17 are independently hydrogen or lower alkoxy;
  • R xz is lower alkoxy;
  • R ⁇ is hydrogen or lower alkoxy
  • R- 1 - ⁇ is hydrogen or lower alkoxy (lower) alkoxy or carbamoyl (lower) alkoxy;
  • R-*- ⁇ is hydrogen or isopropoxy;
  • R ⁇ " is hydrogen or mono (or di or tri) halo (lower) alkyl;
  • R 1 x R o is hydrogen or oxo) ;
  • RlI -Z- is bond or I ⁇ CH ⁇
  • R- ⁇ is hydrogen or lower alkyl
  • R and R are independently hydrogen or lower alkyl, or join together to form oxo
  • R 8 is hydrogen, (5-oxo ⁇ 4, 5-dihydro-lH-l, 2, 4-triazol-3- yl)methyl or an amino protective group
  • R" and R ⁇ - 0 are independently hydrogen, halogen, lower alkyl or lower alkoxy, and
  • R 1 ⁇ , R 14 and R 1 ⁇ are each as defined above, then
  • -Z- is ⁇ 11 (in which R- ⁇ is as defined / CH ⁇ above) , and a salt thereof.
  • the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention.
  • isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the • present invention.
  • the object compound (I) or a salt thereof can be prepared by processes which are illustrated in the following schemes.
  • X, Y, Z, R 1 , R 2 , R 8 , R 9 and R 10 are each as defined above, R
  • Suitable salts of the starting and object compounds are conventional non-toxic and pharmaceutically acceptable salt and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g.
  • an amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g
  • lower is intended to mean 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise indicated.
  • Suitable “halogen” may include fluorine, chlorine, bromine and iodine.
  • Suitable “lower alkyl” and “lower alkyl” moiety in the term of "mono (or di or tri) halo (lower) alkyl” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl/ hexyl and the like, in which the preferred one is C- ⁇ -C ⁇ alkyl and the most preferred one is methyl, ethyl, propyl or tert-butyl.
  • Suitable "mono (or di or tri) halo (lower) alkyl” may be fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, -1, 1-difluoroethyl, 2, 2-difluoroethyl, 2,2,2- trifluoroethyl, and the like, in which the preferred one may be trifluromethyl .
  • Suitable "cyclo (lower) alkyl” and “cyclo (lower) alkyl” moiety in the term of "cyclo (lower) alkyloxy” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, in which the preferred One is cyclo (C3 ⁇ Cg) alkyl and the most preferred one is cyclopropyl or cyclobutyl.
  • Suitable "lower alkoxy” and “lower alkoxy” moiety in the term of "mono (or di or tri) halo (lower) alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like, in which the preferred one is C ⁇ -C ⁇ alkoxy and the most preferred one is methoxy, ethoxy, isopropoxy or tert-butoxy.
  • Suitable "mono (or di or tri) halo (lower) alkoxy” may include chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, tribromomethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1 or 2-chloroethoxy, 1 or 2-bromoethoxy, 1 or 2-fluoroethoxy, 1, 1-difluoroethoxy, .2,2- difluoroethoxy, 2, 2, 2-trifluoroethoxy, and the like, in which the preferred one may be 2, 2, 2-trifluoroethoxy.
  • Suitable "leaving group” may include lower alkoxy (e.g.
  • Suitable "acid residue” may be halogen (e.g., chlorine, bromine, iodine, etc.), sulfonyloxy (e.g., methanesulfonyloxy, phenylsulfonyloxy, mesitylenesulfonyloxy, toluenesulfonyloxy, etc.) or the like.
  • halogen e.g., chlorine, bromine, iodine, etc.
  • sulfonyloxy e.g., methanesulfonyloxy, phenylsulfonyloxy, mesitylenesulfonyloxy, toluenesulfonyloxy, etc.
  • amino protective group may be common amino protective group such as acyl, for example, substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxy- carbonyl, etc.], substituted or unsubstituted aralkyloxy- carbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g.
  • benzenesulfonyl, tosyl, etc. ] , nitrophenylsulfenyl, ar (lower) alkyl [e.g. trityl, benzyl, etc.], and the like, in which preferable one is tert-butoxycarbonyl.
  • Preferred embodiments of the object compound (I) are as follows:
  • -X- is -NH or -0-;
  • R , R ⁇ and R ⁇ are independently hydrogen, lower alkyl, cyclo (lower) alkyl, lower alkoxy or cyclo (lower) alkoxy;
  • R" and R' are independently hydrogen or lower alkoxy; R 1 ⁇ is lower alkoxy; and
  • R- ⁇ is hydrogen or lower alkoxy
  • R-"- and R ⁇ are independently hydrogen or lower alkyl; R° is hydrogen; and
  • R° and R ⁇ are each hydrogen.
  • the object compound (Ia) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) .
  • Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea or the like; a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene and the like.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction, or the mixture thereof.
  • a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction, or the mixture thereof.
  • the reaction may also be carried out in the presence of a reductive regent such as hydrides (e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.), or the like.
  • a reductive regent such as hydrides (e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.), or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the object compound (Ib) or a salt thereof can be prepared by reacting the- compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (IV) .
  • the object compound (Ic) or a salt thereof can be prepared by reacting the compound (Id) or its reactive derivative at the amino group or a salt thereof with the compound (VI) . This reaction can be carried out in substantially the same manner as in Example 4.
  • the object compound (Ie) or a salt thereof can be prepared by elimination of the amino protective group of the compound (Id) or a salt thereof.
  • the object compound (I) and a pharmaceutically acceptable salt thereof have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism or Neurokinin B antagonism, and therefore are useful for treating or preventing Tachykinin- mediated diseases, particularly Substance P-mediated diseases, for example, respiratory diseases such as asthma, bronchitis (e.g.
  • ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like
  • cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like
  • inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like
  • pains or aches e.g. migraine, headache, cluster headache, toothache, cancerous pain, back pain, neuralgia, etc.
  • the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing ophthalmic diseases such as glaucoma, uveitis, and the like; gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like; inflammatory diseases such as nephritis, and the like; circulatory diseases such as hypertension, angina pectoris, cardiac failure, thrombosis, Raynaud's disease, and the like; epilepsy; ' spastic paralysis; overactive bladder such as nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystiris (e.g.
  • ophthalmic diseases such as glaucoma, uveitis, and the like
  • gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like
  • inflammatory diseases such as nephritis, and the like
  • circulatory diseases such as hypertension
  • interstitial ⁇ cystitis chronic prostatitis, prostatic hypertrophy, and the like
  • micturiation disorder such as stress incontinence, urge incontinence, mixed incontinence, functional incontinence, overflow incontinence, and the like
  • Parkinson diseases dimentia; AIDS related dementia; Alzheimer's diseases; Down's syndrome; Huntington's chorea; carcinoid syndrome; disorders related to immune enhancement or suppression; disorders caused by Helicobacter pylori or another spiral urease-positive gram-negative bacterium; sunburn; angiogenesis or diseases caused by angiogenesis; and the like.
  • the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing chronic obstructive pulmonary diseases, particularly chronic pulmonary emphysema; blinkis; proliferative vitreoretinopathy; psoriasis; inflammatory intestinal diseases, particularly Crohn's diseases; hepatitis; superficial pain on congelation, burn, herpes zoster or diabetic neuropathy; telalgia attended to hyperlipidemia; postoperative neuroma, particularly of mastectomy; vulvar vestibulitis; hemodialysis-associated itching; lichen planus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough; pulmonary tuberculosis; cystic fibrosis; emesis (e.g., nausea, retching, vomiting, acute emesis, delayed emesis, anticipatory emesis, past operative nausea and vomiting (PONV)
  • emesis
  • the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are Central Nervous System '(CNS) penetrant.
  • the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, internal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, internal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration.
  • the pharmaceutical preparations may be solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, or the like.
  • auxiliary substances stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
  • an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating Tachykinin-mediated diseases such as asthma and the like.
  • amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
  • Test compound showed 100% inhibition rate of emesis in the dog at the dose of 1.0 mg/kg.
  • Test compound The object compound of the
  • Test Method Male Hartley guinea pigs (3-4 weeks old) were anesthetized with urethane (1.2 g/kg body weight, s.c), and the lower abdomen was opened along the midline to expose the urinary bladder. After performing a small dissection at the apex of the bladder, a catheter was inserted into the bladder. The catheter was connected through a three-way stopcock attached to a pressure transducer for measurement of intravesical pressure. A tube for drug administration was inserted into the jugular vein.
  • Acetic acid (0.1%) was infused at a rate of 0.3 ml/min for over 30 minutes.
  • the micturition pressure, threshold pressure and time to the micturition (bladder capacity) were measured.
  • the mean value from the three trials was taken as the value before drug administration.
  • the mean value from the three trials for 30 minutes was taken as the value after administration.
  • a test compound was administered intravenously at a dose of 0.1 mg/kg.
  • the data were analyzed by Dunnett's multiple comparison test following randomized block designed analysis of variance compared with the value before drug administration.
  • test compound significantly increased bladder capacity, but did not significantly change micturition pressure and threshold pressure.
  • Test compound The object compound of Example 9- (24)
  • Some of the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are less subject to metabolism in human being or animals.
  • This compound was obtained as a mixture of reactant and dehydroxylated compound and was used to the next reaction without purification.
  • the pH of the extract was made acidic with IN hydrochloric acid, and was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give the, title compound (96.8mg) as solid.
  • butyllithium (1.58M solution in hexane) (1.57ml) was dropwise added to 5-bromo-2-cyclopropyl- 4, 6-bis (2,2, 2-trifluoroethoxy) pyrimidine (888.7mg) in a mixture of ether (20ml) and tetrahydrofuran (4ml), and stirred for lhr at the same temperature.
  • isopropyl formate (1.13ml) was added at one portion at -70°C.
  • Example 5 The following compound was obtained in substantially the same manner as that of Example 4.
  • Trifluoroacetic acid (2.2ml) was added to tert-butyl (2S, 3S) -3- [ (2-cyclopropyl-4-isopropoxy-6-methoxy-5- pyrimidinyl) methoxy] -2-pheny1-1-piperidinecarboxylate (143mg) and the resulting solution was stirred at 5O 0 C bath for 2h. After cooling, saturated sodium hydrogen carbonate solution and ethyl acetate were added to the mixture. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo.
  • Example 9 The following compounds were obtained in substantially the same manner as that of Example 8.
  • Example 11 To a solution of cis-2-phenyl-3-piperidinamine (30 mg) in dichloromethane (0.7 ml) were added 2-cyclopropyl-4- isopropoxy-6-methoxy-5-pyrimidinecarbaldehyde (40 mg) and sodium triacetoxyborohydride (55 mg) , and the whole was stirred at room temperature overnight. To the mixture were added saturated sodium bicarbonate solution and ethyl acetate, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over potassium carbonate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography
  • reaction mixture was added with 2 ml of saturated sodium bicarbonate aqueous solution, then extracted with dichloromethane (5 ml x 3), dried over diatomaceous earth. The organic layer was evaporated under reduced pressure to give the title compound as a crude white foam (10.9 mg) , that was used crude in the next reaction.

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Abstract

Composé de formule (I) dans laquelle R1, R2, R8, R9 et R10 sont chacun tels que définis dans le descriptif, et -X- représente -NH ou -O-, Y représente les formules (II), (III), (IV), etc., et -Z- représente une liaison ou (V) dans laquelle R3, R4, R5, R6, R7 et R11 sont chacun tels que définis dans le descriptif, ou sel dudit composé. Le composé selon la présente invention possède des activités pharmacologiques telles que l'antagonisme de la tachykinine et est utile pour la fabrication d'un médicament destiné à traiter ou à prévenir les maladies médiées par la tachykinine.
PCT/JP2004/008371 2003-06-10 2004-06-09 Derives de piperidyle Ceased WO2004111000A2 (fr)

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AU2003902882 2003-06-10
AU2003902882A AU2003902882A0 (en) 2003-06-10 2003-06-10 Piperidyl derivatives

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WO2004111000A2 true WO2004111000A2 (fr) 2004-12-23
WO2004111000A3 WO2004111000A3 (fr) 2005-05-26

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WO2009072643A1 (fr) * 2007-12-03 2009-06-11 Takeda Pharmaceutical Company Limited Composé hétérocyclique contenant de l'azote et son utilisation
WO2010032856A1 (fr) 2008-09-19 2010-03-25 武田薬品工業株式会社 Composé hétérocyclique contenant de l'azote et son utilisation
JP2012505173A (ja) * 2008-10-09 2012-03-01 エフ．ホフマン−ラ ロシュ アーゲー ピロリジンｎ−ベンジル誘導体
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WO2005113503A3 (fr) * 2004-05-21 2006-03-16 Pfizer Prod Inc Metabolites de (+)-(2s, 3s)-3-(2-methoxy-5-trifluoromethoxybenzylamino)-2-phenyl-piperidine
US8470816B2 (en) 2007-12-03 2013-06-25 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound and use thereof
WO2009072643A1 (fr) * 2007-12-03 2009-06-11 Takeda Pharmaceutical Company Limited Composé hétérocyclique contenant de l'azote et son utilisation
JP5580741B2 (ja) * 2008-09-19 2014-08-27 武田薬品工業株式会社 含窒素複素環化合物およびその用途
EP2336105A4 (fr) * 2008-09-19 2012-03-28 Takeda Pharmaceutical Composé hétérocyclique contenant de l'azote et son utilisation
US8592454B2 (en) 2008-09-19 2013-11-26 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound and use of same
WO2010032856A1 (fr) 2008-09-19 2010-03-25 武田薬品工業株式会社 Composé hétérocyclique contenant de l'azote et son utilisation
USRE48334E1 (en) 2008-09-19 2020-12-01 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound and use of same
USRE49686E1 (en) 2008-09-19 2023-10-10 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound and use of same
JP2012505173A (ja) * 2008-10-09 2012-03-01 エフ．ホフマン−ラ ロシュ アーゲー ピロリジンｎ−ベンジル誘導体
JP2012507485A (ja) * 2008-11-03 2012-03-29 エフ．ホフマン−ラ ロシュ アーゲー ３−（ベンジルアミノ）−ピロリジン誘導体及びｎｋ−３受容体アンタゴニストとしてのその使用
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US12156866B2 (en) 2018-06-06 2024-12-03 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor

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