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WO1993013766A1 - Traitement des mouvements involontaires avec des agonistes recepteurs 5ht¿1a? - Google Patents

Traitement des mouvements involontaires avec des agonistes recepteurs 5ht¿1a? Download PDF

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Publication number
WO1993013766A1
WO1993013766A1 PCT/US1992/010514 US9210514W WO9313766A1 WO 1993013766 A1 WO1993013766 A1 WO 1993013766A1 US 9210514 W US9210514 W US 9210514W WO 9313766 A1 WO9313766 A1 WO 9313766A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
represented
ethyl
indol
amino
Prior art date
Application number
PCT/US1992/010514
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English (en)
Inventor
Martin Galvan
Original Assignee
Merrell Dow Pharmaceuticals 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.)
Filing date
Publication date
Application filed by Merrell Dow Pharmaceuticals Inc. filed Critical Merrell Dow Pharmaceuticals Inc.
Priority to JP51243592A priority Critical patent/JPH08503448A/ja
Publication of WO1993013766A1 publication Critical patent/WO1993013766A1/fr

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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • This invention relates to the new uses of a class of known 5HT 1A receptor agonists, and to the manufacture of these known compounds for their use as medicaments for their new uses.
  • this invention relates to the
  • B is represented by a C 1-4 alkylene bridging group
  • Alk is represented by a linear alkylene bridging group containing from 2-8 carbon atoms which may optionally be mono-substituted at one carbon atom with a C 1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted
  • D is represented by a bond or an ethenylene bridging group
  • X, Y, and Z are each independently represented by hydrogen, C 1-4 alkyl, phenyl, substituted phenyl or alkylphenyl in which the phenyl ring may be optionally substituted
  • R 1 is
  • R 2 and R 3 are each independently represented by H or a C 1-4 alkyl;
  • R 4 is
  • Het is represented by one of the following substituents:
  • R is represented by a substituent selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, O-CH 2 -C 5 H 5 , CF 3 , OCF 3, OH, NO 2 , CN, -CONR 5 R 6 ,
  • R 5 and R 6 are each independently represented by H or C 1-4 alkyl;
  • R 7 is represented by H, C 1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted;
  • A is represented by H, or C 1-4 alkyl; or a pharmaceutically acceptable salt thereof; with the proviso that when Het is an indolyl derivative, then R 1 is not a carbonyl derivative.
  • Another specific aspect of this invention is the use in the manufacture of a medicament for treating disease states characterized by unwanted and abnormal involuntary movements with a compound of Formula I, said disease states being those of the group comprised of epilepsy, parkinsonism, Huntington's chorea, tardive dyskinesia, Freidreich's ataxia, presenile dementia, and Gilles de la Tourette's syndrome.
  • the compounds encompassed by Formula I above may also be represented by the following subgeneric formulae:
  • R, A, B, Alk, D, X,Y, Z, and R 1 are as defined above.
  • halogen refers to a fluorine, chlorine, or bromine atom.
  • lower alkyl group and C 1-4 alkyl refer to a branched or straight chained alkyl group containing from 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, etc.
  • the terms "lower alkoxy group and C 1-4 alkoxy” refer to a straight or branched alkoxy group containing from 1-4 carbon atoms, such as methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, isobutoxy, etc.
  • the term "substituted phenyl ring” refers to a phenyl moiety (C 6 H 5 ) which is substituted with up to 3 substituents, each substituent is independently selected from the group consisting of halogens, C 1-4 alkyl, C 1-4 alkoxy, CF 3 , OCF 3 , OH, CN, and NO 2 . These substituents may be the same or different and may be located at any of the ortho, meta, or para positions.
  • the term "alkylphenyl substituent” refers to the
  • the term "pharmaceutically acceptable salt” refers to either a basic addition salt or an acid addition salt.
  • the phrase "C 1-4 alkylene bridging group” refers to a methylene, ethylene, propylene, butylene, 1-methyl-ethylene, 2-methyl-ethylene, 2-methyl-propylene, 2-ethyl-ethylene, 1-ethyl-ethylene, etc.
  • Alk refers to a linear alkylene group which may be represented by the following structure:
  • p and s are each independently represented by an integer from 0-7 and L is represented by H, C 1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted, with the proviso that the sum p and s is from 1-7.
  • linear alkylene groups include ethylene, propylene, butylene, hexylene, ⁇ -benzyl- pentylene, ⁇ -ethyl-heptylene, ⁇ -phenyl-propylene, ⁇ -benzyl- pentylene, ⁇ -methylpentylene, ⁇ -methylbutylene, etc.
  • ⁇ -carbon should be
  • indolyl derivative refers to a compound in which Het is represented by:
  • benzodioxan refers to a compound in which Het is represented by:
  • C 1-5 alkoxy refers to:
  • a straight or branched alkoxy group containing from 1-5 carbon atoms such as methoxy, ethoxy, n-propoxy,
  • pharmaceutically acceptable acid addition salts is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates.
  • inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
  • organic acids which form suitable salts include the mono-, di-, and tri- carboxylic acids.
  • Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic,
  • succinic glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as
  • methanesulfonic acid and 2-hydroxyethane sulfonic acid can exist in either a hydrated or substantially anhydrous form.
  • acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
  • Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides;
  • All of the compounds of Formula la contain an indole. This indole may be optionally substituted as is indicated by the presence of the R substituent. When R is represented by a substituent other than hydrogen, there can be up to 3 such non-hydrogen substituents occurring on the indole ring. These substituents may appear at any of positions 2, 4, 5, 6, or 7. The 1-position of the indole may also be optionally substituted as indicated by the A substituent. All of the compounds represented by Formula lb contain a benzodioxan. This benzodioxan may be optionally substituted as indicated by the R substituent. When R is represented by a substituent other than hydrogen, there can be up to 3 such non-hydrogen substituents occurring on the benzodioxan.
  • All of the compounds of Formula I contain a phenyl ring adjacent to the amide substituent. This phenyl ring may also be substituted as is indicated by the R 1 substituent.
  • R 1 is represented by a substituent other than hydrogen, there can be up to 3 such non-hydrogen substituents occurring on the phenyl ring. These substituents can be the same or different and can be located at any of the ortho, meta, or para positions. As noted above, if Het is represented by an indolyl derivative, then R 1 should not be represented by a carbonyl derivative.
  • amino-alkylene chain connecting the benzodioxan or indole with the terminal phenyl ring may be further
  • X, Y, and Z may be represented by the same substituents or differing substituents.
  • Alk is represented by a linear alkylene group. This alkylene group may be further substituted with only one alkyl, phenyl or alkylphenyl substituent. This one substituent may occur on any one carbon atom of the alkylene chain.
  • Examples of compounds encompassed by the present invention include: a) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-heptanamide; b) 7-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4- methoxyphenyl)-octanamide; c) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-phenyl- heptanamide; d) 5-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-hexanamide; e) 6-[[2-(5-Hydroxy-1H-
  • 5HT 1A receptor agonists include: a) 5-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4- (trifluoromethyl)phenyl]-pentanamide; b) 6-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[2- (trifluoromethyl)phenyl]-hexanamide; c) 6-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-heptanamide; d) 7-[[2-(5-Hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4- (trifluoromethyl)phenyl]-heptanamide; d) 7-[[2-(5-Hyd
  • Preferred 5HT 1D Agonists include: a) 5-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4- ( trifluoromethyl)phenyl]-pentanamide; b) 5-[(2,3-Dihydro-1,4-benzodioxin-2(S)-yl)methylamino]-N- (4-chlorophenyl)-pentanamide; c) 5-[(2,3-Dihydro-1,4-benzod ⁇ oxin-2(S)-yl)methyl amino]-
  • the initial step in the reaction is to carry out an amidation reaction between the acid derivative of structure 1 and N,O-dimethylhydroxylamine, thereby producing the amido-derivative depicted by structure 3.
  • This amido-derivative is subjected to a Grignard reaction thereby producing the compound of structure 5.
  • the desired product of Formula la is then produced by carrying out a reductive animation between the compound of structure 5 and the indole derivative of structure 6.
  • the appropriate acid derivative to utilize as a starting material is one in which Alk, D, R 1 , and Z are represented by the same substituents as is desired in the final product of Formula la.
  • Methods for producing these acid derivatives are known in the art. For example, see Leznoff, C.C. and Goldwasser, J.M. Tetrahedron Letters, 1875-1878 (1977) and Leznoff C.C. and Goldwasser, J.M., Can. J. Chem., 56, 1562- 1568 (1978).
  • the amidation reaction of Step A can be carried out using techniques known in the art.
  • peptide coupling reagent such as isobutylchloroformate.
  • the amidation is also typically carried out in the presence of an approximately equivalent amount of a base such as triethylamine, 4-ethylmorpholine, or 4-methylmorpholine.
  • the reaction is typically carried out in an aprotic solvent such as tetrahydrofuran or dichloro- methane for a period of time ranging from 1 to 24 hours.
  • the reaction is typically carried out at a temperature range of from -20° to 20°C.
  • the resulting amide derivative of structure 3 can be recovered from the reaction zone by extraction with
  • the Grignard reaction in which the Grignard reagent is as described by structure 4 in which Y is as in Formula la and is represented by the same substituent as is desired in the final product.
  • the amide of structure 3 is contacted with an excess of the Grignard reagent (2.0 to 3.0 equivalents) in an ethereal solvent such as ether or
  • Step C a reductive amination is carried out between the ketone or aldehyde derivative of structure 5 and the indole derivative of structure 6 in which R, A, X, and B are as in Formula la and are represented by the same
  • the reductive amination is carried out in the presence of an excess of sodium cyanoborohydride (about 1.5 equivalents).
  • the reaction is typically carried out in an alcoholic solvent such as methanol at a concentration of 0.1 molar.
  • the reaction is carried out at room temperature for a period of time ranging from 1 to 7 days.
  • the resulting product of Formula la can be recovered by the addition of sodium bicarbonate and water followed by
  • the compounds of structure 5 can also be prepared according to the procedures described in Journal of Medicinal Chemistry, 26(4), 494 (1983) and in Int. J. Pept. Protein Res., 22, 284 (1983).
  • benzodioxan derivatives of Formula lb can also be prepared by techniques known in the art. One suitable method is disclosed below in Reaction Scheme II:
  • the compounds of Formula lb are prepared by carrying out an N-alkylation between a
  • benzodioxan derivative as described by structure 8 in which Alk, D, R 1 , Y and Z are as in Formula lb and Hal is a halogen.
  • the appropriate benzodioxan derivative to use is one in which R, X and B are represented by the same substituents as is desired in the final product.
  • Methods for producing these benzodioxans are known in the art. For example, see Dewar, G.H. et al., Eur. J. Med. Chem. Chim. Ther. 18, 286-289 (1983); Shapero, M., et al., J. Med. Chem. 12, 326-329.
  • the appropriate alkylhalide derivative of structure 8 to use is one in which Y, Z, Alk, D and Ri are represented by the same substituents as is desired in the final product.
  • Methods for producing the alkylhalide derivatives are known in the art. For example, see Stirling, C.J.M., Journal of the Chemical Society, 4531-4536 (1958), and Stirling, C.J.M., Journal of the Chemical Society, 255-262 (1960).
  • the N-alkylation reaction is carried out using
  • the compounds of Formula lb can be prepared by the procedure outlined above in Reaction Scheme I. The only modification is that the benzodioxan derivative of structure 7 is utilized rather than the indole derivative of structure 6. Likewise, the compounds of Formula la in which R is H can be prepared by the method disclosed in Reaction Scheme II, but substituting the appropriate indole starting material for the benzodioxan of structure 7.
  • the compounds of Formula I are serotonin 5HT 1A receptor agonists and it is now discovered that they will be useful in the treatment of unwanted and abnormal involuntary movements such as those found in epilepsy, parkinsonism, Huntington's chorea, tardive dyskinesia, Freidreich's ataxia, presenile dementia, and Gilles de la Tourette's syndrome.
  • Serotonin 5HT 1A receptors are present on many different types of neurones in the mammalian brain. Activation of these receptors with serotonin or novel synthetic agonists has inhibitory actions on neuronal function. Thus, it has been shown that agonists at 5HT 1A receptors increase the membrane permeability for potassium ions leading to a hyperpolarization of the neuronal membrane potential and a decrease in membrane resistance. Such a hyperpolarization reduces the probability of the cell membrane potential reaching the threshold for action potential discharge and is thus intrinsically inhibitory in nature. In cells which are spontaneously discharging, activation of 5HT 1A receptors leads to a decrease in discharge rate; in quiescent cells, the membrane potential is moved to more negative levels.
  • Electrophysiological experiments on single neurones in the rat hippocampus, dorsolateral septal nucleus and raphe nucleus show that the these compounds hyperpolarize the neuronal membrane potential and inhibit neuronal activity.
  • 5HT 1A receptors as observed in autoradiographical experiments on mammalian brain, are located in many parts of the mammalian brain, including the cortex and the limbic system. Abnormal neuronal function in such brain areas is thought to underlie many types of seizure discharges and so inhibition of these neurons can be of use in the treatment of seizure discharge. These would include Grand Mal and Petit Mal epilepsy, partial and complex seizures of known and unknown origin. The anti-seizure activity of these compounds has been shown by their ability to antagonize pentylenetetrazole-induced seizures in mice, a standard method for the evaluation of antiepileptic drugs (Krall, et al., 1978).
  • 5HT 1A receptor agonists can inhibit neuronal activity, these compounds are to be found as being useful in the treatment of Parkinson's disease, Huntington's chorea, and such other diseases where tremor and/or involuntary
  • Parkinson's disease A beneficial effect in Parkinson's disease could be
  • MPTP neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • the compounds be administered to the patient in an effective amount.
  • the dosage range at which these compounds exhibit this effect can vary widely depending upon the severity of the patient's condition, the particular compound being administered, the route of administration, the co-administration of other therapeutic agents, and the presence of other underlying disease states.
  • the compounds will be administered at a dosage range of from 0.01 mg/kg/day to about 100 mg/kg/day. Repetitive daily administration may be desirable and will vary with the conditions described above. However, the compounds are typically administered from 1 to 4 times daily or as a continuous intravenous infusion.
  • compositions can be manufactured
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or
  • Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.
  • the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.
  • Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.
  • the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a
  • suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin.
  • the pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art.
  • the compounds of this invention can also be administered topically. This can be accomplished by simply preparing a solution of the compound to be administered, preferably using a solvent known to promote transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • a solvent known to promote transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO)
  • topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • Some suitable transdermal devices are described in U.S. Pat. Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,894. These devices generally contain a backing member which defines one of its face surfaces, an active agent permeable adhesive layer defining the other face surface and at least one reservoir containing the active agent interposed between the face surfaces.
  • the active agent may be contained in a plurality of microcapsules distributed throughout the permeable adhesive layer.
  • the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
  • the encapsulating agent may also function as the membrane.
  • the pharmaceutically active compound is contained in a matrix from which it is delivered in the desired gradual, constant and controlled rate. The matrix is permeable to the release of the compound through diffusion or microporous flow.
  • the release is rate controlling. Such a system, which requires no membrane is described in U.S. Pat. No. 3,921,636. At least two types of release are possible in these systems. Release by diffusion occurs when the matrix is non-porous. The pharmaceutically effective compound dissolves in and diffuses through the matrix itself. Release by microporous flow occurs when the pharmaceutically effective compound is transported through a liquid phase in the pores of the matrix.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation d'agonistes récepteurs 5HT1A de formule (I), où Het représente: (a) ou (b), B est un groupe C1-4 alkylène, D est une liaison ou un groupe de liaison éthylène, X, Y, Z, A, R, R1 ont des significations qui leur sont données dans la description, pour le traitement des mouvements involontaires dans les maladies suivantes: épilepsie, maladies de Parkinson, chorée de Huntington, diskinésies tardives, maladie de Freidreich, démence présénile et maladie de Gilles de la Tourette.
PCT/US1992/010514 1992-01-07 1992-12-07 Traitement des mouvements involontaires avec des agonistes recepteurs 5ht¿1a? WO1993013766A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP51243592A JPH08503448A (ja) 1992-12-07 1992-12-07 ５ｈｔ▲下１▼▲ａ▼受容体アゴニストによる不随意運動の処置

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP92400032.6 1992-01-07
EP92400032 1992-01-07

Publications (1)

Publication Number Publication Date
WO1993013766A1 true WO1993013766A1 (fr) 1993-07-22

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PCT/US1992/010514 WO1993013766A1 (fr) 1992-01-07 1992-12-07 Traitement des mouvements involontaires avec des agonistes recepteurs 5ht¿1a?

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AU (1) AU3241093A (fr)
CA (1) CA2126554A1 (fr)
MX (1) MX9300035A (fr)
WO (1) WO1993013766A1 (fr)
ZA (1) ZA9312B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999029323A1 (fr) * 1997-12-05 1999-06-17 Princeton University Utilisation d'antagonistes du recepteur 5ht1a pour prevenir et/ou traiter l'epilepsie temporale
WO2002036107A3 (fr) * 2000-11-03 2003-01-16 Univ Manchester Traitement de fluctuations motrices
WO2005092339A1 (fr) * 2004-03-25 2005-10-06 Solvay Pharmaceuticals B.V. Derives de 1-[2h-1-benzopyran-2-one-8-yl]-piperazine utilises dans le traitement des troubles du mouvement
US7776860B2 (en) 2004-03-25 2010-08-17 Solvay Pharmaceuticals B.V. Process for the preparation of 3-amino-8-(1-piperazinyl)-2H-1-benzopyran-2-one and salts and solvates thereof
US9066903B2 (en) 2006-02-28 2015-06-30 The United States Of America As Represented By The Department Of Veterans Affairs Pharmacological treatment of Parkinson's disease
US20170128446A1 (en) * 2014-06-26 2017-05-11 Contera Pharma Aps Use of buspirone metabolites
CN111116451A (zh) * 2020-01-16 2020-05-08 宁波大学 一种多取代色胺基苯甲酰胺类化合物及其制备方法和用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0271099A2 (fr) * 1986-12-12 1988-06-15 Hoechst Aktiengesellschaft Amides d'acide aminopropionique substitués, leur procédé de préparation, agents les contenant et leur utilisation, ainsi que les produits intermédiaires formés pendant la préparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0271099A2 (fr) * 1986-12-12 1988-06-15 Hoechst Aktiengesellschaft Amides d'acide aminopropionique substitués, leur procédé de préparation, agents les contenant et leur utilisation, ainsi que les produits intermédiaires formés pendant la préparation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 12, no. 446 (C-546)(3293) 24 November 1988 *
PATENT ABSTRACTS OF JAPAN vol. 15, no. 48 (C-802)(4576) 5 February 1991 *
Section Ch, Week 8133, 23 September 1981 Derwent Publications Ltd., London, GB; Class B0, Page 2, AN 08384 B/05 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999029323A1 (fr) * 1997-12-05 1999-06-17 Princeton University Utilisation d'antagonistes du recepteur 5ht1a pour prevenir et/ou traiter l'epilepsie temporale
US5919802A (en) * 1997-12-05 1999-07-06 Princeton University Methods of preventing and/or treating temporal lobe epilepsy
AU738121B2 (en) * 1997-12-05 2001-09-06 Princeton University Use of 5HT1A receptor antagonists for preventing and/or treating temporal lobe epilepsy
WO2002036107A3 (fr) * 2000-11-03 2003-01-16 Univ Manchester Traitement de fluctuations motrices
US9668995B2 (en) 2000-11-03 2017-06-06 Motac Neuroscience Limited Treatment of motor fluctuations
US8173660B2 (en) 2004-03-25 2012-05-08 Solvay Pharmaceuticals B.V. Process for the preparation of 3-amino-8-(1-piperazinyl)-2H-1-benzopyran-2-one and salts and solvates thereof
US7776860B2 (en) 2004-03-25 2010-08-17 Solvay Pharmaceuticals B.V. Process for the preparation of 3-amino-8-(1-piperazinyl)-2H-1-benzopyran-2-one and salts and solvates thereof
WO2005092339A1 (fr) * 2004-03-25 2005-10-06 Solvay Pharmaceuticals B.V. Derives de 1-[2h-1-benzopyran-2-one-8-yl]-piperazine utilises dans le traitement des troubles du mouvement
US9066903B2 (en) 2006-02-28 2015-06-30 The United States Of America As Represented By The Department Of Veterans Affairs Pharmacological treatment of Parkinson's disease
US9226904B2 (en) 2006-02-28 2016-01-05 The United States Of America As Represented By The Department Of Veterans Affairs Pharmacological treatment of Parkinson's disease
US20170128446A1 (en) * 2014-06-26 2017-05-11 Contera Pharma Aps Use of buspirone metabolites
US11478476B2 (en) * 2014-06-26 2022-10-25 Contera Pharma Aps Use of buspirone metabolites
CN111116451A (zh) * 2020-01-16 2020-05-08 宁波大学 一种多取代色胺基苯甲酰胺类化合物及其制备方法和用途

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MX9300035A (es) 1994-05-31
ZA9312B (en) 1993-08-05
CA2126554A1 (fr) 1993-07-22
AU3241093A (en) 1993-08-03

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