WO2011059080A1 - Dérivé de diamine substitué par un isotope - Google Patents

Dérivé de diamine substitué par un isotope Download PDF

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Publication number
WO2011059080A1
WO2011059080A1 PCT/JP2010/070261 JP2010070261W WO2011059080A1 WO 2011059080 A1 WO2011059080 A1 WO 2011059080A1 JP 2010070261 W JP2010070261 W JP 2010070261W WO 2011059080 A1 WO2011059080 A1 WO 2011059080A1
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compound
pharmaceutically acceptable
substituted
amino
acceptable salt
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PCT/JP2010/070261
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English (en)
Japanese (ja)
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勉 永田
利治 吉野
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第一三共株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to an isotope-substituted diamine derivative that exhibits an inhibitory action on activated blood coagulation factor X and is useful as a preventive and / or therapeutic agent for thrombotic diseases.
  • activated blood coagulation factor X (sometimes referred to as activated factor X or FXa) and is useful as a prophylactic and / or therapeutic agent for thrombotic diseases, the following formula (II-A)
  • R 1 to R 30 each represent 1 H, D, or T, and Q 1 to Q 24 each represent 12 C or 14 C, provided that at least one of R 1 to R 30 is A compound represented by D or T and / or at least one of Q 1 to Q 24 is 14 C.
  • a pharmaceutically acceptable salt thereof, or a solvate thereof [10] The compound according to [9], a pharmaceutically acceptable salt thereof or a salt thereof, wherein at least 1 to 3 of R 1 to R 6 , R 16 or R 28 to R 30 are D or T Solvates; [11] The compound according to [9] or [10], a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein at least one of Q 8 , Q 9 , Q 17 or Q 24 is 14 C object; [12] The following general formula (IV)
  • each carbon atom represents 12 C, R 1 to R 30 each represents 1 H or D, provided that at least one of R 1 to R 30 is D).
  • An isotope-substituted compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is also useful as a test substance in a test for examining the pharmacokinetics of a pharmaceutical product containing a solvate, is provided.
  • the present invention comprises the following formula (II)
  • each hydrogen atom represents a 1 H, each carbon atom indicates the 12 C.
  • solvate is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include hydrates and ethanol solvates.
  • isotope includes both radioactive isotopes and non-radioactive isotopes unless otherwise specified.
  • a deuterium atom (Deuterium, which may be referred to as D or 2 H in this specification) may be referred to as a non-radioactive isotope.
  • a tritium atom (Tritium; sometimes referred to as T or 3 H in the specification) and 14 C may be collectively referred to as a radioisotope.
  • isotopic substituted compounds II of the 1 H and 24 is 12 C in 30 in the compound II, any one or more compounds II substitutions at each isotope That means.
  • isotopically substituted compound II refers to a compound in which one or more 1 H of compound II is substituted with D or T and / or one or more 12 C is substituted with 14 C I mean II.
  • isotope-substituted compound II means that when the isotope-substituted compound II is viewed in molecular units, it is not necessary that all the molecules are substituted with isotopes, It suffices if the isotope substitution is carried out at a higher ratio than that existing.
  • the isotope substitution position is not particularly limited and may be appropriately selected according to the purpose of use.
  • the introduction of the isotope in the second half is less than the introduction of the isotope from the first half of the production process, and the operation is reduced.
  • a position that can be introduced in the latter half of the manufacturing process is preferable.
  • the number of 1 H and / or 12 C substituted with an isotope is not particularly limited and may be appropriately selected depending on the purpose of use.
  • the number of 1 H substituted with D or T is 1 to 30 1 to 15 is more preferable, and 1 to 9 is even more preferable.
  • the number of 12 C substituted with 14 C is preferably 1 to 24, more preferably 1 to 10, and even more preferably 1 or 2.
  • Compound II substituted with an isotope of the present invention has an optical isomer based on an asymmetric center in the molecule.
  • the compound of the present invention includes all of these isomers and a mixture of these isomers in any proportion.
  • Some of the compounds of the present invention exhibit an inhibitory action on activated blood coagulation factor X, and are useful as preventive and / or therapeutic agents for thrombotic diseases.
  • deuterium is heavier than hydrogen, it is known that a deuterium-substituted CD bond binds more strongly than a non-deuterium-substituted CH bond.
  • the metabolic rate can be delayed by substituting the hydrogen atom of the C—H bond with deuterium.
  • Drugs with a slow metabolic rate have a longer retention time in the body, resulting in an increase in the amount of drugs that are effectively used. By delaying the metabolic rate of the drug and increasing the amount of the drug that is effectively used, the number of administrations of the drug can be reduced.
  • the compound of the present invention should be used as a test substance in a test (for example, LC / MS / MS) for examining the pharmacokinetics of a drug containing Compound II, a pharmaceutically acceptable salt thereof or a solvate thereof. Can do.
  • a test for example, LC / MS / MS
  • the type of isotope can be selected according to the purpose.
  • the isotope is selected from non-radioactive isotopes.
  • an isotope May be a radioactive isotope or a non-radioactive isotope.
  • each hydrogen atom represents 1 H and each carbon atom represents 12 C.
  • At least one 1 H of the compound represented by (Compound II-A) is substituted with D and / or T.
  • WHO World Health Organization
  • IPN International Nonproprietary Names
  • the compound of the present invention has the following general formula (III)
  • R 1 to R 30 each represent 1 H, D, or T, and Q 1 to Q 24 each represent 12 C or 14 C, provided that at least one of R 1 to R 30 is And / or at least one of Q 1 to Q 24 is 14 C.
  • at least one or more D or T at positions R 1 to R 30 And / or those having at least one or more 14 C at positions Q 1 to Q 24 are preferred.
  • preferred positions where 1 H can be substituted with D or T include R 1 to R 6 , R 16 and R 28 to R 30 , and more preferred positions are R 1 to R 6 and R 28 to R 30 .
  • the number of 1 H substituted with D or T is preferably 1 to 9, and more preferably 1 to 6.
  • a compound substituted with D is preferred.
  • the compound of the present invention is used as a test substance in a test for examining the pharmacokinetics of a drug containing Compound II, a pharmaceutically acceptable salt thereof or a solvate thereof, the compound substituted with D is also Any of the compounds substituted with T is also preferred.
  • preferable positions that can be substituted with 14 C include Q 8 , Q 9 , Q 17, and Q 24 , and more preferable positions include Q 8 , Q 9, and Q 17.
  • the number of 12 C substituted with 14 C is preferably 1 to 5, more preferably 1 to 3.
  • the compound of the present invention substituted with 14 C can be preferably used as a test substance in a test for examining the pharmacokinetics of a drug containing Compound II, a pharmaceutically acceptable salt thereof or a solvate thereof. .
  • a compound in which Q 8 and Q 9 are 14 C is, for example, (1S, 3R, 4S) -4- ⁇ [[(5-chloropyridin-2-yl) amino] (oxo) acetyl] amino ⁇ -3- ⁇ [(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ cyclohexanecarboxylic acid is reacted with a salt of ( 14 C) dimethylamine Can be obtained.
  • the compound of the present invention is preferably the following general formula (IV)
  • R 1 to R 30 each represents 1 H or D, provided that at least one of R 1 to R 30 is D).
  • those having at least one or more D at positions R 1 to R 30 are preferable.
  • preferred positions where 1 H can be substituted with D include R 1 to R 6 , R 16 and R 28 to R 30 , and more preferred positions include R 1 to R 6 and R 28 to R 30 may be mentioned.
  • the number of 1 H substituted with D is preferably 1-6.
  • the compound represented by the general formula (IV) also exhibits the pharmacokinetics of a pharmaceutical agent containing Compound II, a pharmaceutically acceptable salt thereof or a solvate thereof as a preventive and / or therapeutic agent for thrombotic diseases. It may also be useful as a test substance in a test to be examined.
  • the present invention also includes the following general formula (V)
  • X 1 represents a dimethylcarbamoyl group, a methylcarbamoyl group or a carboxy group
  • X 2 represents an optionally substituted hydroxyl group or a 5-chloro-2-pyridylamino group
  • X 3 represents a substituted group.
  • each hydrogen atom represents 1 H and each carbon atom represents 12 C.
  • at least one 1 H of the compound represented by is substituted with D and / or T and / or at least one 12 C is substituted with 14 C, its pharmaceutically acceptable Or a solvate thereof.
  • X 2 is an “optionally substituted hydroxyl group”
  • substituents that can be substituted on the hydroxyl group include an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms. However, it is not limited to these.
  • X 3 is “optionally substituted 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group”, 4,5,6,7-tetrahydrothiazolo [
  • substituent on the 5,4-c] pyridin-2-yl group one or several, for example, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (for example, a methyl group or an ethyl group) , An alkoxy group having 1 to 6 carbon atoms, or a lower alkoxycarbonyl group having 2 to 8 carbon atoms, but is not limited thereto.
  • the isotope-substituted compound of the present invention is synthesized according to the method described in the examples, or relates to the method described in any one of Patent Documents 1 to 8 and isotope substitution usually performed by those skilled in the art. It can be synthesized by combining organic chemical methods.
  • the solvent used in each reaction step for synthesizing the compound of the present invention is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • the solvent include: hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin and cyclohexane; amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide; diethyl ether, Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-1-propanol; dimethyl sulfoxide Sulfoxides such as sulfolane; Sulfones such as sulfolane; Nitriles such as acet
  • the base used in each reaction step for synthesizing the compound of the present invention is not particularly limited, and examples thereof include alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium bicarbonate, potassium bicarbonate and lithium bicarbonate.
  • nona-5-ene DBN
  • organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); n-butyllithium, lithium diisopropylamide, lithium bis Organometallic bases such as (trimethylsilyl) amide; or amino acids such as proline.
  • the condensing agent used in each reaction step for synthesizing the compound of the present invention is not particularly limited.
  • reaction temperature varies depending on the solvent, starting material, reagent and the like
  • reaction time varies depending on the solvent, starting material, reagent, reaction temperature and the like.
  • each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc., filtering, and then distilling off the solvent.
  • an immiscible organic solvent such as ethyl acetate
  • the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.
  • a target compound insoluble in a solvent the obtained solid crude product can be purified by washing with a solvent.
  • the target compound in each step can be directly used in the next reaction without purification.
  • the compound labeled with a non-radioactive isotope of the present invention is useful as a blood coagulation inhibitor, a prophylactic and / or therapeutic agent for thrombus or embolism.
  • the compound of the present invention is a medicament for mammals including humans, an activated blood coagulation factor X inhibitor, a blood coagulation inhibitor, a prophylactic and / or therapeutic agent for thrombosis and / or embolism, prevention and / or treatment of thrombotic diseases.
  • thrombus and / or associated with cerebral infarction cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris, acute coronary syndrome, non-valvular atrial fibrillation (NVAF) Embolism, deep vein thrombosis, deep vein thrombosis after surgery, thrombus formation after prosthetic valve / joint replacement, thromboembolism after total hip replacement (THR), total knee replacement (Total Knee Replacement, TKR) Thromboembolism, Hip Fracture Surgery (Hip Fracture) Thromboembolism after surgery, HFS), thrombus formation and / or reocclusion after revascularization, Buerger's disease, generalized intravascular coagulation syndrome, systemic inflammatory response syndrome (SIRS), multiple organs Prophylactic agent (in this specification, prevention includes secondary prevention) and / or therapeutic agent for insufficiency (Multiple Organ Function Syndrome, MODS),
  • NVAF non-
  • the compound of the present invention is also useful as a blood coagulation inhibitor, a prophylactic and / or therapeutic agent for thrombus or embolism.
  • the medicament containing the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient is preferably a compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • Provided in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers.
  • the dosage form of the medicament of the present invention is not particularly limited and can be administered orally or parenterally, but is preferably administered orally.
  • Examples of the pharmaceutically acceptable carrier used in the manufacture of a pharmaceutical composition containing the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient include, for example, excipients, disintegrants or Disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants or adhesives However, it is not limited to these.
  • Examples of formulations suitable for oral administration of a pharmaceutical composition comprising the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient include, for example, tablets, powders, granules, capsules, Examples include solutions, syrups, elixirs, oily or aqueous suspensions, and the like.
  • Examples of preparations suitable for parenteral administration include injections, drops, suppositories, inhalants, and patches.
  • the dosage of the pharmaceutical composition containing the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient is not particularly limited, and depends on various conditions such as the age, weight, and symptoms of the patient.
  • the active ingredient is preferably 1 mg to 1000 mg, preferably 5 mg to 500 mg, more preferably 5 mg to 300 mg, still more preferably 5 mg to 100 mg per day for adults once to several times per day. Is preferably administered once or twice daily depending on the symptoms.
  • each hydrogen atom in the chemical formula represents 1 H
  • each carbon atom represents 12 C
  • Boc represents a tert-butoxycarbonyl group.
  • the solvent was distilled off under reduced pressure, and 10% aqueous citric acid solution (100 ml) and ethyl acetate (150 ml) were added to the residue for liquid separation.
  • the organic layer was washed with saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine (100 ml each), and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and diisopropyl ether (100 ml) was added to the resulting residue.
  • the precipitated solid was collected by filtration to give the title compound (2.98 g, 7.61 mmol, 52%) as a pale yellow solid.
  • the solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution (100 ml) and methylene chloride (150 ml) were added to the residue to carry out a liquid separation operation.
  • the obtained solid was washed with diethyl ether to give the title compound (4.47 g, 9.48 mmol, 56%) as a colorless solid.
  • the obtained washing solution was evaporated under reduced pressure, and methylene chloride and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue for separation.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (SI-40W-2L, 3% methanol-methylene chloride). Paratoluenesulfonic acid monohydrate was added to the obtained free form (1 g), and the solvent was distilled off to obtain the title compound (1.23 g, 2.16 mmol, 6.4%) as a yellow powder.
  • the solvent was distilled off under reduced pressure, and methylene chloride (250 ml) and saturated aqueous sodium hydrogen carbonate solution (200 ml) were added to the residue for liquid separation, and the aqueous layer was extracted with methylene chloride (2 ⁇ 250 ml). The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid was washed with diethyl ether to give the title compound (3.26 g, 5.61 mmol, 94%) as a tan foamy solid.
  • the mixture was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate (200 ml).
  • the obtained solid (1.81 g, 3.02 mmol) was purified by silica gel chromatography (Yamazen SI-40W-L, 8 ⁇ 20% methanol-methylene chloride). Distilled water (10 ml) and 1N aqueous hydrochloric acid (2.84 ml, 2.84 mmol) were added to the resulting free form and concentrated.
  • the obtained pale yellow powder was washed with ethyl acetate (2 ⁇ 10 ml) to obtain the title compound (1.73 g, 2.73 mmol, 90%, pale yellow powder).
  • Methyl-d 3 -amine hydrochloride (328 mg, 4.65 mmol), 1-hydroxybenzotriazole (314 mg, 2.32 mmol), 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (668 mg, 3.49 mmol) and triethylamine (972 ⁇ l, 6.97 mmol) were added and stirred at room temperature overnight.
  • the reaction solution was concentrated under reduced pressure, and methylene chloride (150 ml) and a saturated aqueous sodium hydrogen carbonate solution (100 ml) were added to separate the layers.
  • the aqueous layer was extracted with methylene chloride (2 ⁇ 150 ml), the organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel chromatography (Yamazen SI-40W-2L, 8% methanol-methylene chloride). 1N Hydrochloric acid ethanol solution (3 ml) was added to the resulting free form and concentrated. Ethyl acetate (50 ml) was added and the precipitated pale yellow solid was collected by filtration to give the title compound (950 mg, 1.55 mmol, 67%, pale yellow powder).

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Abstract

La présente invention a pour objet un composé substitué par un isotope qui possède une activité inhibitrice sur le facteur de coagulation sanguine activé X, est utile en tant qu'agent prophylactique et/ou thérapeutique pour les maladies thrombotiques ou en tant que substance d'essai destinée à être utilisée dans un essai pour examiner la pharmacocinétique in vivo d'un composé représenté par la formule (II) ou analogue, un sel pharmaceutiquement acceptable du composé, ou un solvate du composé ou du sel pharmaceutiquement acceptable. La présente invention concerne spécifiquement le N1-(5-chloropyridin-2-yle)-N2-(4- [(diméthylamino) carbonyle]-2-{[(5-méthyl-4,5,6,7- tétrahydrothiazolo [5,4-c] pyridin-2-yle) carbonyle] amino}- cyclohexyle) éthane diamide substitué par un isotope.
PCT/JP2010/070261 2009-11-16 2010-11-15 Dérivé de diamine substitué par un isotope WO2011059080A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014520140A (ja) * 2011-06-20 2014-08-21 ハー・ルンドベック・アクチエゼルスカベット 統合失調症の治療のための重水素化１−ピペラジノ−３−フェニルインダン
US11535600B2 (en) 2018-12-03 2022-12-27 H. Lundbeck A/S Prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003016302A1 (fr) * 2001-08-09 2003-02-27 Daiichi Pharmaceutical Co., Ltd. Derives de diamine
JP2006521345A (ja) * 2003-03-28 2006-09-21 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー ニコチン性アセチルコリン受容体の正のアロステリック調節剤
WO2007143468A2 (fr) * 2006-06-05 2007-12-13 Auspex Pharmaceuticals, Inc. Préparation et utilité de composés d'imidazopyridine substitués ayant des effets hypnotiques
WO2008049116A2 (fr) * 2006-10-19 2008-04-24 Auspex Pharmaceuticals, Inc. Indoles substitués
WO2008108730A1 (fr) * 2007-03-06 2008-09-12 Astrazeneca Ab Nouveaux benzothiophènes et benzofuranes 709 à substitution 2-hétéroaryle

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003016302A1 (fr) * 2001-08-09 2003-02-27 Daiichi Pharmaceutical Co., Ltd. Derives de diamine
JP2006521345A (ja) * 2003-03-28 2006-09-21 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー ニコチン性アセチルコリン受容体の正のアロステリック調節剤
WO2007143468A2 (fr) * 2006-06-05 2007-12-13 Auspex Pharmaceuticals, Inc. Préparation et utilité de composés d'imidazopyridine substitués ayant des effets hypnotiques
WO2008049116A2 (fr) * 2006-10-19 2008-04-24 Auspex Pharmaceuticals, Inc. Indoles substitués
WO2008108730A1 (fr) * 2007-03-06 2008-09-12 Astrazeneca Ab Nouveaux benzothiophènes et benzofuranes 709 à substitution 2-hétéroaryle

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014520140A (ja) * 2011-06-20 2014-08-21 ハー・ルンドベック・アクチエゼルスカベット 統合失調症の治療のための重水素化１−ピペラジノ−３−フェニルインダン
US9012453B2 (en) 2011-06-20 2015-04-21 H. Lundbeck A/S Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia
US9216961B2 (en) 2011-06-20 2015-12-22 H. Lundbeck A/S Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia
US9617231B2 (en) 2011-06-20 2017-04-11 H. Lundbeck A/S Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia
US10118907B2 (en) 2011-06-20 2018-11-06 H. Lundbeck A/S Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia
US10501427B2 (en) 2011-06-20 2019-12-10 H. Lundbeck A/S Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia
US11059798B2 (en) 2011-06-20 2021-07-13 H. Lundbeck A/S Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia
US11535600B2 (en) 2018-12-03 2022-12-27 H. Lundbeck A/S Prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine

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