WO2002002526A1 - Compositions pharmaceutiques servant a stabiliser la tension intraoculaire - Google Patents

Compositions pharmaceutiques servant a stabiliser la tension intraoculaire Download PDF

Info

Publication number
WO2002002526A1
WO2002002526A1 PCT/JP2001/005714 JP0105714W WO0202526A1 WO 2002002526 A1 WO2002002526 A1 WO 2002002526A1 JP 0105714 W JP0105714 W JP 0105714W WO 0202526 A1 WO0202526 A1 WO 0202526A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
dimethoxy
indanone
fluoro
hydrochloride
Prior art date
Application number
PCT/JP2001/005714
Other languages
English (en)
Japanese (ja)
Inventor
Yoichi Iimura
Takashi Kosasa
Akira Kato
Original Assignee
Eisai Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eisai Co., Ltd. filed Critical Eisai Co., Ltd.
Priority to AU2001267899A priority Critical patent/AU2001267899A1/en
Publication of WO2002002526A1 publication Critical patent/WO2002002526A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to a use of a pharmaceutical composition comprising a compound having acetylcholinesterase inhibitory activity or a salt thereof, and more particularly, to a use of the pharmaceutical composition for regulating intraocular pressure.
  • Conventional technology a pharmaceutical composition comprising a compound having acetylcholinesterase inhibitory activity or a salt thereof, and more particularly, to a use of the pharmaceutical composition for regulating intraocular pressure.
  • Elevated intraocular pressure results in various visual impairments.
  • glaucoma is a disease in which the eye pressure rises enough to impair normal eye function (visual field, visual acuity, etc.) due to impairment of the intraocular pressure regulation mechanism, causing abnormalities in visual function (primary glaucoma, secondary Glaucoma, congenital glaucoma, etc.), and particularly, visual field abnormalities are known to be serious.
  • Elevated intraocular pressure can also result in glaucomatous optic atrophy, resulting in impaired blood flow to the eye and compression of nerve tissue.
  • WO 95/334302 discloses a pharmaceutical composition comprising calcium chelate activity as an active ingredient.
  • Deme potassium a typical drug
  • cholinesterase inhibitors are already in clinical use, including (Demecarium) and Ecliothiophate.
  • side effects such as retinal detachment, miosis, cataract, and myopia are problematic. Therefore, there is a demand for a therapeutic agent that does not cause such side effects.
  • WO098 / 5 6379 discloses that ⁇ administration of donezil or an isomer thereof reduces intraocular pressure increased with glaucoma or ocular hypertension. There is a report on 'How to adjust'.
  • Donedil hydrochloride which is the hydrochloride salt of donezil (1-benzyl-4-([5,6-dimethoxy-11-indanone) —2-yl] methylpiperidine.hydrochloride
  • senile dementia For example, in the treatment of senile dementia of the Alzheimer type 1), cerebrovascular dementia, attention deficit hyperactivity disorder, etc., it is currently only useful in terms of pharmacological activity, side effects, number of administrations, dosage form, etc. Which is an acetylcholinesterase inhibitor.
  • the present inventors have searched for a compound having an even stronger acetylcholinesterase inhibitory activity than donezil hydrochloride,
  • R 1 is a substituent
  • R 3 are the same or different and a hydrogen atom, CI_ 6 alkoxy group, and the like;
  • R 4 represents a hydrogen atom or a C I 6 alkyl group;
  • m is shows the integer of 0 or 1 to 6
  • N represents an integer of 1 to 4;
  • p represents an integer of 1 or 2. It represents any one group selected from];
  • a pharmacologically acceptable salt thereof or a hydrate thereof JP-A-2000-319258
  • R 3 , R 4 , R 5 and R 6 are the same or different and are (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) nitrile group, (5) nitro Group, (6) — 7- acyl group, (7) ⁇ — 6-alkoxycarponyl group, (8) 0 ⁇ 6 alkylaminocarponyloxy group, (9) N, N—di-Ci-ealkylaminocarponylo group alkoxy group, (10) mercapto group, (l C ⁇ s thiophosphorous alkoxy group or (12), respectively which may have a substituent C _ 6 alkyl group, C 2 ⁇ 6 alkenyl group, C 2 _ 6 alkynyl group , C 3 - 8 cycloalkyl group, C 3 "8 a cycloalkyl Kenyir group, Ji Interview one 6 alkoxy group, an amino group or amide group; R 7 is a halogen
  • a 14-membered heterocyclic group and the substituents may be combined with each other to form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; halogen atom and a hydroxyl group, nitrile group, alkyl group, C 2 - 6 alkenyl group, C 2 - 6 alkynyl group, C 3 _ 8 cycloalkyl group, CI- 6 an alkoxy group, C ⁇ s alkoxyalkoxy group, Represents a group consisting of an aryloxy group and an aralkyloxy group]]; M represents a single bond or an alkylene group;
  • ⁇ represents a halide ion or an organic sulfonate ion.
  • R 1 is formula
  • the present invention provides (1) a pharmaceutical composition for adjusting intraocular pressure, comprising a compound represented by the formula (I) or a salt thereof,
  • M is a 6 alkylene group
  • M is CH 2: a is the (2)
  • R 3, R 4, R 5 and R 6 is the same or different and is a 6- alkoxy group which may have a hydrogen atom or a substituent;
  • composition according, (6) R 3 and R 6 are hydrogen atoms, R 4 and the R 5 is also may ⁇ 6 alkoxy group optionally having substituent (2)
  • the composition according (7) The composition according to the above (2), wherein R 7 is a halogen atom, (8) the composition according to the above (2), wherein R 7 is a fluorine atom, and (9) R 2 has a substituent.
  • R 4a and R 5a are the same or different and each represents a Cn alkoxy group which may have a substituent; and the G ring is any one of 1 to 4 selected from the substituent group a according to claim 1 above. Shows a benzene ring which may be substituted with 5 groups.
  • the composition according to the above (1) comprising a compound represented by the formula: or a salt thereof;
  • D-E represents the definition as defined above, respectively;
  • R 14 is a hydrogen atom, a halogen atom, CI_ 6 Al kill group, C 2 _ 6 alkenyl group or C 2 - 6 show an alkynyl group;
  • r is 0 to 5 Indicates an integer.
  • a composition according to the above (1) which comprises a 1-benzylpyridinium salt represented by the following formula: 1-Indanone) 12-yl] Methylbiperidine 'hydrochloride, 1-benzyl-4
  • the present invention provides a pharmacologically effective amount of the compound represented by the formula (I) or a salt thereof to a patient to treat or predict a disease in which adjustment of intraocular pressure is effective for treatment, prevention, and improvement. Provide a way to prevent and improve.
  • the present invention also provides a use of the compound represented by the formula (I) or a salt thereof for the manufacture of an agent for treating, preventing, or ameliorating a disease in which adjustment of intraocular pressure is effective for treatment, prevention, and improvement. Offer.
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmacologically effective amount of a compound represented by the formula (I) or a salt thereof and a carrier.
  • the structural formula of the compound may represent a certain isomer for convenience, but the compound represented by the formula (I) contained as an active ingredient in the pharmaceutical composition according to the present invention includes: All geometrically occurring isomers, optical isomers based on asymmetric carbon, It includes isomers such as rotamers, stereoisomers, and tautomers, and isomer mixtures, and is not limited to the description of the formula for convenience, and either one isomer or a mixture may be used.
  • an optically active compound and a racemic compound having an asymmetric carbon atom in the molecule may be present, but the present invention is not limited thereto.
  • a crystalline polymorph of the compound may exist, but is not similarly limited, and any one of the crystalline forms may be single or a mixture of crystalline forms.
  • the compound represented by the formula (I) or a salt thereof contained as an active ingredient in the pharmaceutical composition according to the present invention may be an anhydride or a hydrate.
  • Pharmaceutical compositions comprising a metabolite produced by decomposing them in a living body and a prodrug of the compound represented by the formula (I) or a salt thereof are also included in the claims of the present specification. Is done.
  • adjusting the intraocular pressure in the present specification refers to adjusting the intraocular pressure to a normal value, and includes, for example, suppressing a state where the intraocular pressure is increased (high intraocular pressure).
  • Diseases that can be treated or prevented by adjusting intraocular pressure with the pharmaceutical composition of the present invention include all diseases caused by an increase in intraocular pressure (high intraocular pressure), for example, glaucoma, glaucoma. Strabismus, mydriasis, glaucomatous mydriasis, etc.
  • halogen atom refers to an atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and is preferably a fluorine atom, a chlorine atom, or a bromine atom.
  • alkyl group refers to an alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, is 0-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2 —Methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl group, is 0-buty
  • C 2 _ 6 alkenyl group refers to 2 to 6 ⁇ Luque two Le group carbon atoms, preferred groups as for example, vinyl, Ariru group, 1 one propenyl group, 2 —Propenyl group, isopropyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group, 2-methyl-2-propyl group, 3-methyl-2-probenyl group Examples thereof include a benzyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1-pentenyl group, a 1-hexenyl group, a 1,3-hexanexenyl group, and a 1,6-hexanexenyl group.
  • C 2 6 alkynyl group has a carbon number shows a 2 to 6 alkynyl group, suitable groups as for example Echiniru group, 1 one-propynyl, 2-propynyl, 1 _ butynyl Group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynyl group, 1-hexynyl group, 1,3-hexanediynyl group; 1,6-hexanediynyl group, and the like.
  • Echiniru group 1 one-propynyl, 2-propynyl, 1 _ butynyl Group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2-propynyl group, 2-methyl-3-propy
  • Ji 3 _ 8 cycloalkyl group used herein, a cycloalkyl group composed of 3 to 8 carbon atoms, such as cyclopropyl group, Shikuropuchi group, cyclopentyl group, cyclohexyl group And a cycloheptyl group, a cyclooctyl group, and the like.
  • C 3 one 8 cycloalkenyl group refers to C 3 _ 8 Shikuroaruke two Le group composed of 3 to 8 carbon atom, for example, cyclopropene - 1 - I le, cyclo Propene-3-yl, cyclobutene-1f, cyclobutene-3-yl, 1,3-cyclobutadiene-1-yl, cyclopentene1-1-yl, cyclopentene-3-yl, cyclopentene-1 4 ⁇ , 1,3-cyclopentene 1-yl, 1,3-cyclopentene 2- ⁇ , 1,3-cyclopentene-5-yl, cyclohexene 11-yl, cyclohexene-3-yl, cyclohexene-41-yl, 1,3-cyclohexadiene-11-yl, 1,3-cyclohexadiene-2- ⁇ ⁇ 1,3-cyclohexadiene 5-yl, 1,4
  • Ji 6 alkoxy group represents a number from 1 to 6 ⁇ alkoxy group having a carbon, for example, methoxy, ethoxy, n- propoxy group, iso- propoxy group, sec- propoxy radical, n -Butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, iso-pentyloxy, sec-pentyloxy, n-hexoxy, iso-hexoxy, 1, 1-dimethylpropyloxy, 1,2-dimethylpropoxy, 2,2-dimethylpropyloxy, 21-ethylpropoxy, 1-methyl-2-ethyl Lepropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2 , 2-Dimethylbutoxy, 2,3-dimethylbutyloxy, 1,3-d
  • substituted in the "which may have a substituent” used herein, for example, a halogen atom, a hydroxyl group, nitrile group, alkyl group, C 3 - 8 cycloalkyl group, C - 6 alkoxy group, C - 6 alkoxyalkoxy group, ⁇ Li one Ruokishi group, Ararukiruokishi group, a halogenated C Bok 6 alkyl group, hydroxy Ji ⁇ - 6 alkyl group, Shiano C ⁇ s alkyl group, a halogenated C i _ 6 alkoxy group, Hydroxy C ⁇ 6 alkoxy group, cyano C-6 alkoxy group, C ⁇ eacyl group, -nitro group, '''' optionally substituted amino group, optionally substituted Examples include an amide group, a mercapto group, a C6 thioalkoxy group, and the like, and preferred are a halogen atom,
  • 7- acyl group refers to an atomic group obtained by removing an OH group from a carbonyl group of a fatty acid having 1 to 7 carbon atoms
  • preferable groups include, for example, a formyl group, an acetyl group, and a propionyl group.
  • C ⁇ 6 alkoxycarbonyl group used in the present specification include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, and an i-butoxy group.
  • a carbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, a hexyloxycarbonyl group and the like, preferably a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, and the like. can give.
  • Examples of the “substituent” in the “amino group optionally having substituent (s)” used in the specification of the present application include an alkyl group optionally having a substituent, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl group, CI- 6 alkylsulfonyl group, C 2 - 6 ⁇ Luque alkenyl-sulfonyl group, C 2 - 6 alkynylsulfonyl group, alkylcarbonyl group, C 2 _ 6 alkenyl Cal Poni Le group, C 2 _ 6 alkynyl Cal Poni group, one or two groups selected from such like, said. ⁇ 6 alkyl group, C 2 _ 6 alkenyl group,
  • the “substituent” for the group include a hydroxyl group, a halogen atom, a nitrile group, a 6 alkoxy group, a 6 alkylthio group, and the like.
  • amino group optionally having substituent (s) include a methylamino group, an ethylamino group, an n-propylamino group, an iso-propylamino group, an n-butylamino group, iso-butylamino, tert-butylamino, n-pentylamino, is ⁇ _ ⁇ > tylamino, neopentylamino, n-hexylamino, 1-methylpropylamino, 1,2-dimethylpropylamino Group, 2-ethylpropylamino group, 1-methyl-2-ethylpropylamino group, 1-ethyl-2-methylpropylamino group, 1,1,2-trimethylpropylamino group, 1-methylbutylamine Amino group, 2-methylbutylamino, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 2-ethy
  • the “amide group optionally having substituent (s)” used in the present specification means an amide group in which a nitrogen atom may be substituted with a group such as an alkyl group. Also includes an amide group of a cyclic amine.
  • the “optionally substituted amide group” includes, for example, an amide group, an N-methylamide group, a ⁇ , ⁇ -dimethylamide group, a ⁇ -ethylamide group, a ⁇ , ⁇ -getylamide group, a ⁇ -methyl- ⁇ - Examples include an ethylamide group, a pyrrolidinylcarbonyl group, a birazolinylcarbonyl group, a piperidylcarbonyl group, a piperazinylcarbonyl group, and the like.
  • Suitable groups in the “0 ⁇ 6 thioalkoxy group” used in the present specification include, for example, methylthio group, ethylthio group, n-propylthio group, i_propylthio group, n-butylthio group, i-butylthio group, tert-butylthio group Group, n-pentylthio group, i-pentylthio group, neopentylthio group, n-hexylthio group, and the like.
  • halogenated alkyl group used in the present specification include, for example, chloromethyl group, dichloromethyl group, trichloromethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, and difluoroethyl group.
  • Trifluoroethyl group, etc., and preferred groups in the "hydroxyalkyl group” used in the present specification include, for example, a hydroxymethyl group, a hydroxyethyl group, a 2,3-dihydroxypropyl group, and the like.
  • cyano C 6 alkyl group examples include, for example, a cyanomethyl group, a cyanoethyl group, a cyanopropyl group, and the like.
  • E alkylaminocarbonyloxy group or
  • Preferable groups in the “di (C i- 6 alkyl) aminocarbonyloxy group” include a methylaminocarbonyloxy group, an ethylaminocarponyloxy group, and an n-propylaminoamino group.
  • a preferable number of m is 0 or an integer of 1 to 5, more preferably 0 or an integer of 1 to 3, further preferably 0 or an integer of 1 to 2, Most preferably, it is 0 or 1.
  • the preferred number in n is 0, 2 or 4, and more preferably 0 or 2.
  • a preferred number for p is 1.
  • 2,2- (alkylenedioxy) ethyl group used in the present specification means a group (acetal group) in which the terminal carbon atom of the ethyl group is substituted by a cyclic alkylenedioxy group, and is a preferable group.
  • Alkoxy group means a group bonded thereto, and examples thereof include a methoxymethoxy group, a methoxyethoxy group, a methoxypropoxy group, an ethoxymethoxy group, an ethoxyethoxy group, an ethoxypropoxy group, and a propoxypropoxy group.
  • aryl group in the “aryloxy group” used in the present specification refers to an aromatic hydrocarbon cyclic group composed of 6 to 14 carbon atoms, and is a monocyclic group or a bicyclic group. Condensed rings such as formula groups and tricyclic groups are also included.
  • this group examples include phenyl, indenyl, 1-naphthyl, 2-naphthyl, azulenyl, heptenyl, biphenyl, indacenyl, acenaphthyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl And a cyclopentenyl group, a benzocyclooctenyl group, and the like.
  • Preferred examples of the “aryloxy group” include a phenoxy group and a naphthyloxy group.
  • aralkyloxy group refers to a group in which a group having the same meaning as the above aryl group is bonded to a Ci- 16 alkyl group, and the arylalkyl group is further bonded to an oxygen atom, preferably benzyloxy group.
  • an oxygen atom preferably benzyloxy group.
  • phenylethoxy group phenylpropoxy group, naphthylmethoxy group and the like.
  • Preferred examples of the "aliphatic ring" used in the specification of the present application include a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and the like.
  • Preferred examples of the "aromatic ring” include a benzene ring and the like.
  • Preferable examples of the "heterocyclic ring” include a furan ring, a thiophene ring, a pyrroyl ring, an imidazoyl ring, an oxazole ring, a thiazolyl ring, a triazole ring, a pyridine ring and a villa ring.
  • Gin ring pyrimidine ring, tetrahydrofuran ring, tetrahydropyran ring, dioxane ring, dioxolan ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring and the like.
  • Preferable examples in the above are methylenedioxy group, ethylenedioxy group, And lopylenedioxy groups.
  • the “5- to 14-membered heterocyclic group” represented by B is a cyclic group containing at least one atom selected from hetero atoms such as a nitrogen atom, a sulfur atom, and an oxygen atom. And includes "5- to 14-membered aromatic heterocycle” and "5- to 10-membered non-aromatic heterocycle”.
  • Preferred rings in the "heterocycle” include a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a tetrazolyl group, a benzotriazolyl group, a pyrazolyl group, an imidazolyl group, a benzimidazolyl group, Indolyl group, isoindolyl group, indolizinyl group, purinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolidyl group, phthalazyl group, naphthyridinyl group, quinoxalyl group, quinazolinyl group, cinnolinyl group, pteridini Group, imidazotriazinyl group, pyrazinopyridazinyl group, acridiny
  • halide ion used in the present specification, for example, a fluoride ion, a chloride ion, a bromide ion, an iodide ion and the like can be mentioned, and preferably a chloride ion, a bromide ion, and an iodide ion. Preferably, they are chloride ion and bromide ion, and most preferably, they are chloride ion.
  • Preferred ions in the “organic sulfonate ion” used in the present specification include methanesulfonic acid ion ′, trifluoromethanesulfonic acid ion, ethanesulfonic acid ion, benzenesulfonic acid ion, toluenesulfonic acid ion, camphorsulfonate and the like. Acid ions and the like.
  • a more preferred structure in the partial structure is a compound represented by the formula> CH—CH 2 —,> C (F) —CH 2 —,> C (C1) -CH 2 -or> C (Br) —CH 2 And most preferably a group of the formula> CH—CH 2 — or> C (F) —CH 2 —.
  • r is preferably 0, 2 or 4, and more preferably 0 or 2.
  • the pharmaceutical composition for adjusting intraocular pressure according to the present invention is a composition containing the compound represented by the above formula (I) or a salt thereof, and a preferred embodiment thereof is not particularly limited. In a more preferred embodiment, the formula
  • R 2 , RR 4 , R 5 , R 6 , R 7 and M each have the same meaning as defined above.
  • a pharmaceutical composition comprising the compound represented by the formula (I) or a salt thereof, and in a more preferred embodiment,
  • the most preferred example of the compound or a salt thereof contained in the pharmaceutical composition according to the present invention is 1-benzyl-41-((5,6-dimethoxy-2-fluoro--11-indanone) -12-y.
  • salt in the present specification is not particularly limited as long as it forms a pharmacologically acceptable salt with the compound represented by the formula (I) ′.
  • Hydrochloride eg hydrofluoride, hydrochloride, hydrobromide, hydrogen iodide
  • Inorganic salts eg, sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, etc.
  • organic carboxylates eg, acetates, oxalates, maleic acid
  • Salts eg, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate
  • Amino acid salts eg, aspartate, glutamate, etc.
  • quaternary amine salts alkali metal salts (eg, sodium salt
  • the compound represented by the formula (I) or a salt thereof, which is contained as an active ingredient in the pharmaceutical composition for adjusting intraocular pressure according to the present invention can be prepared by a known production method or a production method analogous thereto. Can be manufactured.
  • the known methods are described, for example, in Japanese Patent Application No. 2000-41005, Japanese Patent Application No. 2000-57016, Japanese Patent Application No. 11-247115, Japanese Patent Application No. 2000-186085, and Japanese Patent Application No. 2000-1 12627. Can be easily manufactured according to the manufacturing method.
  • other known methods for example, JP-A-64-79151 (EP-296560-A1), JP-A-55-140149 (EP-487071-A1), No.
  • 6-500794 Japanese Patent Application Laid-Open No. 6-510788, Japanese Patent Application No. 6-508904, Japanese Patent Application No. 5-279355, Japanese Patent Application Laid-Open No. 5-320160, Japanese Patent Application Laid-Open No. 6-116237, It can also be produced according to the method described in JP-A-6-41070, JP-A-11-263774 or JP-A-8-225527.
  • the above-mentioned production method is a typical example of the production method of the compound (I) or a salt thereof, and the starting compound in the production of the compound of the present invention may form a salt or a hydrate and inhibit the reaction. It is not particularly limited as long as it is not performed.
  • the compound (I) When the compound (I) is obtained as a free form, the compound (I) can be converted into a salt form which may be formed by the compound (I) according to a conventional method.
  • various isomers for example, geometric isomers, optical isomers based on asymmetric carbon, rotamers, stereoisomers, tautomers, etc.
  • Eg recrystallization, diastereomer salt It can be purified and isolated by using a method, enzymatic resolution, and various types of chromatography (eg, thin-layer chromatography, column chromatography, gas chromatography, etc.).
  • an optically active form When an optically active form is required, it can be obtained by, for example, a method of asymmetric reduction of an enone form, a method of optical resolution of a racemic form, or a method of using an optically active reagent (for example, a fluorinating agent).
  • an optically active reagent for example, a fluorinating agent
  • the pharmaceutical composition for adjusting intraocular pressure according to the present invention can be prepared by a commonly used method, and a preferred dosage form is an eye drop.
  • the pharmaceutical composition of the present invention can be made into a solid preparation that can be inserted into the eye or a liquid preparation other than eye drops, such as eye ointments, tablets, powders, fine granules, and granules.
  • eye ointments such as eye ointments, tablets, powders, fine granules, and granules.
  • Coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, ointments, nasal drops, ear drops, cataplasms, lotions and the like but more preferred dosage forms Are eye drops, eye ointments and the like.
  • excipients for formulation, commonly used excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH Modifiers, preservatives, antioxidants, etc. can be used, and components commonly used as raw materials for pharmaceutical preparations can be blended and formulated into pharmaceutical preparations by ordinary methods.
  • these components include, for example, (1) animal and plant oils such as soybean oil, tallow, synthetic glyceride; (2) hydrocarbons such as liquid paraffin, squalane, and solid paraffin; (3) octyldodecyl myristate, isopropyl myristate, and the like.
  • higher alcohols such as setostearyl alcohol and behenyl alcohol
  • silicone resin such as silicone resin
  • silicone oil such as silicone resin
  • Lower alcohols such as ethanol and isopropanol
  • Polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and solvyl
  • (11) Sugars such as glucose and sucrose
  • (12) inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate
  • (13) And purified water such as setostearyl alcohol and behenyl alcohol
  • silicone resin such as silicone
  • excipients such as lactose, corn starch, sucrose, glucose, mannitol, sorbit, crystalline cellulose, silicon dioxide, etc .
  • binders such as polyvinyl alcohol, polyvinyl ether, methyl cellulose, Til cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl virolidone, polypropylene glycol / polyoxyethylene / block polymer, medalmin, calcium citrate, dextrin, pectin, etc .
  • lozenges include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxy.
  • a lubricant for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc .
  • V As a coloring agent, it is permitted to be added to pharmaceuticals
  • Vi -Flavoring agents such as cocoa powder, heart-shaped brain, aromasan, heart-shaped oil, dragon brain, cinnamon powder, etc .;
  • antioxidant As the antioxidant, ascorbic acid, «-tocopherol, and the like, each of which is permitted to be added to pharmaceuticals, are used.
  • (1) eye drops can be produced by mixing components such as preservatives, viscosity enhancers, absorption enhancers, pH adjusters, sodium chloride, and sterile water.
  • the pH of the ophthalmic solution may be adjusted to an appropriate pH with an appropriate buffer, acid or base, and is not particularly limited as long as it is a normal buffer, acid or base used for adjusting the ophthalmic solution, but is preferably hydrochloric acid. And sodium hydroxide.
  • the pH to be adjusted is not particularly limited as long as it is a pH used in ordinary eye drops, but is preferably pH 4 to 8, and more preferably pH 6 to 7.
  • the concentration of the compound is not particularly limited as long as it is an appropriate concentration as an ophthalmic solution, but is preferably 0.00001 to 5 wt.%, More preferably 0.001 to 3 wt.%, Still more preferably 0.05 to lwt%, most preferably. Is 0.1 to 0.5 wt.%.
  • Oral preparations are prepared by adding an excipient to the compound of the present invention or a salt thereof, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc., and then using an ordinary method. Powders, fine granules, granules, tablets, coated tablets, capsules, etc.
  • Preferred examples of the suspending agent include methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, tragacanth powder, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate, etc .; Preferred examples include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate; preferred examples of the stabilizer include sodium sulfite, sodium metasulfite, ether etc; preferable examples in save agent, methyl Paraokishi benzoate, Paraokishi benzoic acid Echiru, Sorupin acid, phenol, cresol, chlorocresol and the like 3 ⁇ 4 b in the case of (5) external preparation, in particular production process Is not limited It can be manufactured by an ordinary method.
  • various raw materials usually used for pharmaceuticals, quasi-drugs, cosmetics, etc. can be used.
  • Agents, antioxidants, chelating agents, preservatives and fungicides, coloring agents, fragrances and the like can be added.
  • a component having a differentiation-inducing action, a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell activator, a vitamin, an amino acid, a humectant, a keratolytic agent, and the like can be added. .
  • the form thereof is not particularly limited and may be a systemic delivery method or a local administration method, and may be oral administration by a commonly used method. Parenteral administration may be used.
  • the administration timing and the administration interval are not particularly limited, and vary depending on the degree of symptoms and the like. Furthermore, it depends on the degree of symptoms, age, sex, weight, dosage form, type of salt, specific type of disease, etc.For example, in the case of eye drops, for adults, 1 or 2 per eye drop Drops are preferred and are applied 1 to 5 times per day, preferably 3 to 5 times per day. According to the present invention, a novel pharmaceutical composition useful in adjusting intraocular pressure can be provided.
  • the pharmaceutical composition according to the present invention is excellent in activity, side effects, number of administrations, administration form, and the like. Moreover, from the viewpoint of pharmacokinetics, an ophthalmic disease which is a peripheral disease compared to a conventional acetylcholinesterase inhibitor. Is highly useful for The pharmaceutical composition according to the present invention is useful for treating, preventing, and ameliorating a condition caused by an increased intraocular pressure (high intraocular pressure) or an increased intraocular pressure, particularly, glaucoma, strabismus associated with glaucoma, mydriasis, Excellent effect on glaucomatous mydriasis.
  • high intraocular pressure high intraocular pressure
  • an increased intraocular pressure particularly, glaucoma, strabismus associated with glaucoma, mydriasis, Excellent effect on glaucomatous mydriasis.
  • Tribenzyl-4-[(5,6-Jetoxy-1-indanone) -2-yl] methylbiperidine 0.20 g (0.49imol) was dissolved in 10 ml of tetrahydrofuran (THF), cooled to -78 ° C, and cooled to 1.0 M -0.59 ml of lithium bis (trimethylsilyl) amide / THF solution (0.59 band. 1) was injected. After raising the temperature from -78T: to -20 over 45 minutes, the mixture was cooled again to -78, and a solution of 0.23 g (0.73 bandol) of N-fluorene benzenesulfonimide in 2 ml of THF was injected.
  • Example 2 According to the production method of Example 2, the title compound was obtained as a pale yellow oil. (Yield; 84%) ⁇ -NMR ( 500MZ, CDC 1 3);.. ⁇ (ppm) 1. 14-1 30 (2H, m), 1. 50-1 63 (IH, m), 1. 89-
  • Example 2 According to the production method of Example 2, the title compound was obtained as a pale yellow oil. (Yield; 6) ⁇ -NMR (270MZ , CDC 1 3);.. 5 (ppm) 1. 14-1 48 (5H, m), 1. 55-2 12 (6H, ra), 2. 82 -
  • Example 2 According to the production method of Example 2, the title compound (free form) was obtained as a pale yellow oil (yield: 62%). This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol to obtain the title compound as pale yellow crystals.
  • Example 2 According to the production method of Example 2, a pale yellow oily title compound (free form) was obtained (yield: 67%). This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol-isopropyl ether to obtain the title compound as pale yellow crystals.
  • Example 2 According to the production method of Example 2, the title compound (free form) was obtained as a pale yellow oil (yield: 57%). This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol to obtain the title compound as pale yellow crystals.
  • Example 2 According to the production method of Example 2: The title compound (free form) was obtained as a pale yellow oil (yield: 80%). This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol to give a pale yellowish white color The title compound was obtained as crystals.
  • Example 2 A pale yellow oily title compound (free form) was obtained according to the production method of Example 2 (yield: 33%). This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol Zt-butylmethyl ether. This gave the title compound as pale yellow-white crystals.
  • Example 2 According to the production method of Example 2, the title compound (free form) was obtained as a pale yellow oil (yield: 57%). This was made into a salted salt by a conventional method and recrystallized from ethanol / tributyl methyl ether to obtain the title compound as pale yellowish white crystals.
  • Example 2 According to the production method of Example 2, a pale yellow oily title compound (free form) was obtained (yield: 18%). This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol / -butyl methyl ether to obtain the title compound as pale yellowish white crystals.
  • Example 2 According to the production method of Example 2, the title compound (free form) was obtained as a pale yellow oil (yield: 57%). This was converted into a hydrochloride in a conventional manner, and recrystallized from ethanol-butyl-methyl ether: to obtain the title compound as pale yellowish white crystals.
  • ⁇ -NM 400Mz: CDCl 3 ) ⁇ : 1.74-2.00 (3 ⁇ , m), 2.00-2.26 (4 ⁇ , m), 2.64-2.82 (2H, m), 3.15-3.25 (1H, m), 3.29 (1H , dd, M6.8Hz, 7-38.4Hz), 3.40-3.54 (2H, m), 3.90 (3H, s), 3.98 (3H, s), 4.22 (2H, s), 6.82 (1H, s), 7.12-7.18 (2H, m), 7.26-7.32 (1H, m), 7.46 (1H, bdd, .4Hz, Ml 6Hz), 7.92 (IH, bt, M.4Hz), 12.42 (IH, bs).
  • Example 2 According to the production method of Example 2, the title compound (free form) was obtained as a pale yellow oil (yield: 53). This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol Zt-butyl methyl ether to obtain the title compound as pale yellowish white crystals.
  • Example 23 the title compound (free form) was obtained as a pale yellow oil (yield: 40%). This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol // tert-butyl methyl ether to obtain the title compound as pale yellowish white crystals.
  • Acetonitrile 3 Om 1 was added to 53 mm o 1), and the mixture was dissolved by heating under reflux, and then benzyl bromide 0.5 Oml (4.2 lmmo 1) was added. After heating under reflux for an additional 2.5 hours, the mixture was allowed to cool to room temperature and concentrated under reduced pressure. N-Hexane 5 Om 1 was added to the residue. The precipitated crystals were separated by filtration and dried to obtain 1.60 g of the title compound as pale yellow crystals. Melting point: 173—177 ° C.
  • the intraocular pressure lowering effect of the pharmaceutical composition according to the present invention can be easily evaluated using a known in vitro assay, an in vivo assay, or a method analogous thereto.
  • the above-mentioned known methods include, for example, JP-A-2001-81048, JP-A-2001-48788, JP-2000-95691, JP-2000-95569, JP-A-2000-53 566, JP 2000-26297, JP-A-10-182845, JP-A-10-1775865, JP-A-10-167961, JP-A-10-1205572, JP-A-1
  • the pharmaceutical composition according to the present invention When the pharmaceutical composition according to the present invention was tested according to the above-mentioned known Atsey method, the pharmaceutical composition according to the present invention showed an excellent intraocular pressure lowering effect on the initial intraocular pressure.
  • the pharmaceutical composition according to the present invention is useful as a pharmaceutical composition for treating or preventing glaucoma.
  • the pharmaceutical composition according to the present invention is based on pharmacokinetic evaluation such as transfer into the brain. For example, it became clear that excellent effects could be exerted not only on central diseases but also on peripheral diseases.
  • acetylcholinesterase source using rat brain homogenates was measured esterase activity in compliance with Ellman's method upsilon.
  • acetylthiocholine, the analyte and DTNB [5,5'-dithiobis (2-nitrobenzoic acid)] are added as substrates, and after incubation, the produced thiocholine reacts with DT ⁇ to form The yellow product was measured as a change in absorbance at 412 nm to determine acetylcholinesterase activity.
  • the acetylcholinesterase inhibitory activity of each test compound was determined as a 50% inhibitory concentration (IC 50 ).
  • IC 50 50% inhibitory concentration
  • the compound represented by the formula (I), a salt thereof, or a hydrate thereof according to the present invention exhibited significant acetylcholinesterase inhibitory activity.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouvelles compositions pharmaceutiques servant à stabiliser la tension intraoculaire et conçues pour traiter, prévenir ou améliorer des maladies de l'oeil telles que le glaucome et la mydriase. Ces compositions contiennent des composés correspondant à la formule générale (I) dans laquelle R1 représente un groupe correspondant à la formule générale (II) (dans laquelle R?3, R4, R5 et R6¿ représentent chacun indépendamment hydrogène, alcoxy C¿1-6? éventuellement substitué, ou analogue; et R?7¿ représente halogéno); R2 représente hydrogène, alkyle C¿1-6? éventuellement substitué, un groupe -CH2-B (dans lequel B représente phényle éventuellement substitué ou analogue), ou analogue; M représente une liaison simple ou alkylène C1-6, et A représente (III) ou (IV) (où X?-¿ représente un ion halogène ou un ion sulfonate organique).
PCT/JP2001/005714 2000-07-03 2001-07-02 Compositions pharmaceutiques servant a stabiliser la tension intraoculaire WO2002002526A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001267899A AU2001267899A1 (en) 2000-07-03 2001-07-02 Pharmaceutical compositions for controlling intraocular pressure

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2000-200899 2000-07-03
JP2000200899 2000-07-03
JP2000-230319 2000-07-31
JP2000230319 2000-07-31

Publications (1)

Publication Number Publication Date
WO2002002526A1 true WO2002002526A1 (fr) 2002-01-10

Family

ID=26595256

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/005714 WO2002002526A1 (fr) 2000-07-03 2001-07-02 Compositions pharmaceutiques servant a stabiliser la tension intraoculaire

Country Status (2)

Country Link
AU (1) AU2001267899A1 (fr)
WO (1) WO2002002526A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1300395A1 (fr) * 2000-06-21 2003-04-09 Eisai Co., Ltd. Compose piperidine 4-substitue
JP2005154320A (ja) * 2003-11-25 2005-06-16 Ss Pharmaceut Co Ltd 眼疾患治療薬
WO2005076749A2 (fr) * 2004-02-11 2005-08-25 Jubilant Organosys Limited Nouveau procede de preparation de 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine
US7091218B1 (en) 1999-09-01 2006-08-15 Eisai Co., Ltd. 4-substituted piperidine compound
US8346956B2 (en) 2004-10-29 2013-01-01 Akamai Technologies, Inc. Dynamic image delivery system
KR101714575B1 (ko) 2015-10-15 2017-03-09 국방과학연구소 피리디니움 옥심 유도체 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 포함하는 약학적 조성물

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0296560A2 (fr) * 1987-06-22 1988-12-28 Eisai Co., Ltd. Pipéridines 1,4-substituées comme inhibiteurs de l'acétylcholinestérase et leur utilisation dans le traitement de la maladie d'Alzheimer
WO1998056379A1 (fr) * 1997-06-11 1998-12-17 Alcon Laboratories, Inc. Compositions et procedes de traitement des glaucomes
WO1998056380A1 (fr) * 1997-06-11 1998-12-17 Alcon Laboratories, Inc. Procede faisant retroceder la mydriase
WO2000051985A1 (fr) * 1999-03-03 2000-09-08 Eisai Co., Ltd. Fluorures de derives de piperidine substitues en position 4
WO2001016105A1 (fr) * 1999-09-01 2001-03-08 Eisai Co., Ltd. Derives de piperidine 4-substituee

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0296560A2 (fr) * 1987-06-22 1988-12-28 Eisai Co., Ltd. Pipéridines 1,4-substituées comme inhibiteurs de l'acétylcholinestérase et leur utilisation dans le traitement de la maladie d'Alzheimer
WO1998056379A1 (fr) * 1997-06-11 1998-12-17 Alcon Laboratories, Inc. Compositions et procedes de traitement des glaucomes
WO1998056380A1 (fr) * 1997-06-11 1998-12-17 Alcon Laboratories, Inc. Procede faisant retroceder la mydriase
WO2000051985A1 (fr) * 1999-03-03 2000-09-08 Eisai Co., Ltd. Fluorures de derives de piperidine substitues en position 4
WO2001016105A1 (fr) * 1999-09-01 2001-03-08 Eisai Co., Ltd. Derives de piperidine 4-substituee

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7091218B1 (en) 1999-09-01 2006-08-15 Eisai Co., Ltd. 4-substituted piperidine compound
EP1300395A1 (fr) * 2000-06-21 2003-04-09 Eisai Co., Ltd. Compose piperidine 4-substitue
EP1300395A4 (fr) * 2000-06-21 2003-05-28 Eisai Co Ltd Compose piperidine 4-substitue
US6906083B2 (en) 2000-06-21 2005-06-14 Eisai Co., Ltd. 4-substituted piperidine compound
JP2005154320A (ja) * 2003-11-25 2005-06-16 Ss Pharmaceut Co Ltd 眼疾患治療薬
WO2005076749A2 (fr) * 2004-02-11 2005-08-25 Jubilant Organosys Limited Nouveau procede de preparation de 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine
WO2005076749A3 (fr) * 2004-02-11 2006-06-08 Jubilant Organosys Ltd Nouveau procede de preparation de 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine
US8346956B2 (en) 2004-10-29 2013-01-01 Akamai Technologies, Inc. Dynamic image delivery system
KR101714575B1 (ko) 2015-10-15 2017-03-09 국방과학연구소 피리디니움 옥심 유도체 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 포함하는 약학적 조성물

Also Published As

Publication number Publication date
AU2001267899A1 (en) 2002-01-14

Similar Documents

Publication Publication Date Title
CN105745206B (zh) 用于治疗疾病的葡萄糖神经酰胺合成酶抑制剂
TWI592400B (zh) 犬尿胺酸－３－單氧化酶抑制劑、其醫藥組成物及其使用方法
WO2001053258A1 (fr) Composes azotes cycliques et compositions pharmaceutiques les contenant
DE60014043T2 (de) Flouride von 4-substituierten piperidin-derivaten
JPH05279357A (ja) アザヘテロサイクリルメチル−クロマン類
UA72611C2 (uk) Похідні заміщеного піролопіридинону, корисні як інгібітори фосфодіестерази
US11498896B2 (en) Dopamine D2 receptor ligands
KR19990067377A (ko) 치환비닐피리딘유도체및이를함유하는의약
TW201514136A (zh) 組蛋白去乙醯酶抑制劑及組成物，暨其使用之方法
WO1996038415A1 (fr) Nouveaux derives de l'acide 2-amino-3-phenylpropionique
KR100710596B1 (ko) 항균제
EP1847535A1 (fr) Dérivé de 1-(pipéridin-4-yl)-1h-indole
WO1992002501A1 (fr) Derives de piperidine substitues en position 3
KR20240019063A (ko) 펜알킬아민 및 이의 제조 및 사용 방법
DE60034577T2 (de) In 4-stellung substituierte piperidinderivate
WO2002002526A1 (fr) Compositions pharmaceutiques servant a stabiliser la tension intraoculaire
EP0508334B1 (fr) Nouveaux dérivés d'aminophénol et compositions pharmaceutiques qui les contiennent
EP3233799B1 (fr) Ligands du récepteur d2 de la dopamine
CA2084541A1 (fr) Derives chromane a substituant piperidylmethyle
US6060485A (en) Arylacetic amide derivative or salt thereof, and pharmaceutical comprising it
RU2729074C2 (ru) Способ очистки производного бензопирана, его кристаллическая форма и способ получения кристаллической формы
JP4242032B2 (ja) ４−置換ピペリジン誘導体フッ化物
CZ20012591A3 (cs) Reverzní hydroxamátové inhibitory matricových metalloproteinas
EP0502031B1 (fr) Acides carboxyliques azaheterocycliques a substitution n et preparation pharmaceutique
JP4630555B2 (ja) アミン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref country code: JP

Ref document number: 2002 507783

Kind code of ref document: A

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase