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WO1993023385A1 - Amines actives sur le plan biologique - Google Patents

Amines actives sur le plan biologique Download PDF

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Publication number
WO1993023385A1
WO1993023385A1 PCT/GB1993/001015 GB9301015W WO9323385A1 WO 1993023385 A1 WO1993023385 A1 WO 1993023385A1 GB 9301015 W GB9301015 W GB 9301015W WO 9323385 A1 WO9323385 A1 WO 9323385A1
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Prior art keywords
formula
compound
group
pharmaceutically acceptable
terminated
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PCT/GB1993/001015
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English (en)
Inventor
Roger Victor Bonnert
Roger Charles Brown
David Ranulf Cheshire
Francis Ince
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Fisons Plc
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Publication of WO1993023385A1 publication Critical patent/WO1993023385A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms

Definitions

  • X represents a C 2 alkyiene chain interrupted or terminated by one or more groups selected from -CR''R 7 -, -C(Z)- or -NR 8 -; the chain being further optionally interrupted or terminated by one or more groups selected from -S(0) n -, -O-, CR 9 R 10 , phenyl ethine, -NH-, -CONH-, -NHCO- and -NHCONH-, 5 Y represents an optionally substituted aryl or cycloalkyl group,
  • Z represents O or S
  • R 1 , R 2 , R 5 , R", R'° and R" each independently represent hydrogen or alkyl C,. 6 ,
  • R 3 and R 4 represent hydrogen, or R 3 and R 4 together form a group -S-, -NR 11 - or -CH 2 -, 0 R" and R 7 independently represent hydrogen, fluoro, cyano or CF 3 ; provided that at least one of R 6 and R 7 is other than hydrogen,
  • R s represents alkyl C, .6 or when X is interrupted or terminated by more than one -NR 8 - group may together with another R s group form the chain -CH 2 -CH 2 -, and n represents 0, I or 2, and pharmaceutically acceptable derivatives thereof.
  • leaving groups which L may represent include halide, such as chloride, bromide and iodide, and alkyl or arylsulphonyloxy groups such as methanesulphonyloxy or p-toluenesulphonyloxy.
  • the reaction is preferably carried out in the presence of a base, e.g. an inorganic base such as sodium or potassium carbonate, or an organic base such as triethylamine, N,N-diisopropylethylamine or pyridine.
  • a solvent such as an ether, e.g. tetrahydrofuran or dioxan, a ketone, e.g.
  • the alkylating agent of formula III may be prepared from the corresponding alcohol (i.e. the compound in which L represents OH) by known methods.
  • the alcohol may be reacted with a halogenating agent to yield the compound of formula III in which L represents a halogen atom.
  • Suitable halogenating agents include, for example, triphenylphosphine-tetrahalogenomethane adduct (conveniently formed in situ, e.g.
  • triphenylphosphine and carbontetrabromide by the reaction of triphenylphosphine and carbontetrabromide).
  • the reaction may take place in the presence of a solvent such as acetonitrile, or a chlorinated hydrocarbon, e.g. dichloromethane, at a temperature in the range of 0-30°C.
  • suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium, on a support such as charcoal, using an alcohol, e.g. ethanol, or an ester, e.g. ethyl acetate, or an ether, e.g. tetrahydrofuran, or water, as reaction solvent, or a mixture of solvents, at normal or elevated temperature and pressure.
  • a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium
  • a support such as charcoal
  • an alcohol e.g. ethanol
  • an ester e.g. ethyl acetate
  • an ether e.g. tetrahydrofuran
  • water e.g. tetrahydrofuran
  • Suitable solvents for the reaction with these reducing agents will depend on the particular hydride used, but will include alcohols, such as methanol or ethanol, or ethers, such as diethyl ether or t-butyl methyl ether, or tetrahydrofuran.
  • Alkylation using the compound of formula IV may give rise to an intermediate imine, reduction of which under the conditions described yields the compound of formula I.
  • the compounds of formulae II and IV and the alcohols corresponding to formula III are either known or may be prepared by known techniques.
  • the reaction may be carried out using conventional reduction techniques.
  • the reducing agent may be electrophilic, e.g. diborane, or nucleophilic, e.g. a complex metal hydride such as lithium aluminium hydride or sodium bis(2-methoxyethoxy)aluminium hydride.
  • the solvent is preferably inert to the reaction conditions. Aprotic solvents are preferred, e.g. tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane.
  • the reaction may be carried out at a temperature of from about 0 to 100°C.
  • the compounds of formulae V and Va may be prepared by coupling of an amine and an acid or acid chloride by conventional means.
  • the coupling may be performed in the presence of dicyciohexylcarbodiimide using the method of Sheehan and s Hess, J. Am. Cliem. Soc, 1955, 77, 1067; or 1,1-dicarbonyldiimidazole as described by Staab,Angew. Cliem. Int. Ed. Engl., 1962, 1, 351.
  • the amines required for the coupling reaction are either known or may be prepared by conventional methods, for example, compounds in which R 3 and R 4 together represent -S- may be prepared as described in J. Med. Cliem., 1987, 30, 1166. o
  • the intermediates of formula Va are novel, thus according to a further aspect of the invention there are provided compounds of formula Va,
  • process d) may involve the removal of one or more protecting groups.
  • Suitable protecting groups and methods for their removal are, for example, those described in "Protective Groups in
  • Hydroxy groups may, for example, be protected by arylmethyl groups such as phenylmethyl, diphenylmethyl or triphenyimethyl, or as tetrahydropyranyl derivatives.
  • Suitable amino protecting groups include arylmethyl groups such as benzyl, (R,S)- ⁇ -phenylethyl, diphenylmethyl or triphenyimethyl, and acyl groups such as acetyl, 5 trichloroacetyl or trifluoroacetyl. Conventional methods of deprotection may be used.
  • Arylmethyl groups may, for example, be removed by hydrogenolysis in the presence of a metal catalyst e.g. palladium on charcoal. Tetrahydropyranyl groups may be cleaved by hydrolysis under acidic conditions.
  • Acyl groups may be removed by hydrolysis with a base such as sodium hydroxide or potassium carbonate, or a group such as ID trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid.
  • compositions of the compound of formula I include pharmaceutically acceptable salts, esters and amides thereof.
  • Suitable pharmaceutically acceptable salts of the compounds of formula I include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, is hydrobromides, sulphates, phosphates, maleates, tartrates, citrates, benzoates,
  • the compounds may also form salts with suitable bases.
  • suitable bases examples include alkali metal, e.g. sodium and potassium, and alkaline earth metal, e.g. calcium and magnesium, salts.
  • alkali metal e.g. sodium and potassium
  • alkaline earth metal e.g. calcium and magnesium
  • compositions of formula I may be prepared by reacting the compound of formula I with an appropriate acid or base in the presence of a suitable solvent.
  • Suitable pharmaceutically acceptable esters of the compounds of formula I include alkyl C,. 6 esters, e.g. ethyl ester.
  • the esters may be made by conventional so techniques, e.g. esterification or transesterification.
  • Suitable amides include unsubstituted or mono- or di-substituted alkyl C 1-6 or phenyl amides, and may be made by conventional techniques, e.g. reaction of an ester of the corresponding acid with ammonia or an appropriate amine.
  • the compounds of formula I may exhibit tautomerism, they may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Dlastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation.
  • alkyl we mean straight, branched or cyclic saturated or unsaturated alkyl groups.
  • cycloalkyl includes C 3 . 12 cyclic groups.
  • the cycloalkyl group may contain from 1 to 3 heteroatoms selected from N, O and S,
  • Particular cycloalkyl groups which may be mentioned include C 5 and C 6 cycloalkyl groups, e.g. cyclohexane.
  • aryl includes aromatic radicals having five or six atoms in a single ring system, such groups may contain from 1 to 3 heteroatoms selected from N, O and S.
  • the single ring system may be substituted to form a multiple fused ring system containing up to 10 atoms, for example, naphthyl, indenyl or benzothiazolyl.
  • aryl groups which may be mentioned include 5- and 6-membered carbocyclic and heterocyciic aryl groups, for example, furanyl, pyridinyl and thienyl.
  • Y represents phenyl.
  • X represents a C 3 ⁇ , more preferably a C 4 . 7 , and especially a C ⁇ alkylene chain.
  • compounds of fomula I in which X is interrupted or terminated by one or two groups selected from -CR 6 R 7 -, -C(Z)- and -NR 8 -.
  • the chain to be further interrupted or terminated by one group selected from -S(0) ⁇ -, -O- and -NH-.
  • SUBSTITUTE SHEET ISA/EP which -CR 6 R 7 - may represent include -CF 2 - and -C(CN) 2 -.
  • R 8 may represent included alkyl C,. 3 , e.g. methyl.
  • those groups may be the same or different.
  • X may represent include the following:
  • the compounds of formula I are useful in that they exhibit pharmacological activity in animals.
  • the compounds are 3 2 -adrenoreceptor agonists.
  • the activity may be demonstrated in the isolated trachea of the guinea pig, as described by I.G. Dougall, D. Harpar, D.M. Jackson, and P. Leff, Br. J. Pharmacol., 1991, 104, 1057.
  • the compounds are also dopamine DA 2 -agonists.
  • the binding affinities of the test compounds for the DA 2 binding sites in bovine pituitary membranes may be determined from the displacement of [ 3 H]-N-n-propylnorapomorphine and of [ 3 H]-spiperone in the absence or presence of nonhydrolysable GTP analogue respectively, D.R. Sibley, A. DeLean and I. Creese, Anterior Pituitary Dopamine Receptors, Demonstration of Interconvertible High and Low Affinity States of the D-2 Dopamine Receptor, J. Biol. Cliem., 1982, 257(11), 6351-6361.
  • the DA 2 activity may also be demonstrated in a functional screen, the rabbit isolated ear artery, as described by Brown and O'Connor, Br. J. Pharmacol, 1981, 73, 189P.
  • the compounds also show advantageous DA 2 : 3 2 activity ratios.
  • the compounds of formula I are indicated for use in the treatment of the range of conditions known as reversible obstructive airways disease.
  • the term "reversible obstructive airways disease" will be well understood by those skilled in the art to include conditions such as asthma, including bronchial asthma, allergic asthma, intrinsic asthma,
  • SUBSTITUTE SHEET extrinsic asthma and dust asthma particularly chronic or inveterate asthma (for example late asthma and airway hyper-responsiveness); bronchitis and the like (see, for example, UK Patent No. 2022078 and Br. J. Pharmacol., 1987, 24, 4983).
  • treatment includes prophylaxis as well as relieving the symptoms of disease.
  • a method of treatment or prophylaxis of reversible obstructive airways disease comprises administering a therapeutically effective quantity of a compound of o formula I, or a pharmaceutically acceptable derivative thereof, to a patient suffering from or susceptible to such a condition.
  • the compounds of formula I are also indicated for use in the treatment of various other conditions, e.g. inflammatory and allergic skin disorders, congestive heart failure and glaucoma.
  • doses administered will, of course, vary with compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compound of formula I is administered at a daily dosage of from about 1 ⁇ g to about 20 mg per kg of animal body weight, preferably given in divided doses 1 to 4 times a day or in sustained release form.
  • the total daily dose is in the range of from 70 ⁇ g to 1,400 mg and unit dosage forms suitable for administration comprise from 20 ⁇ g to 1,400 mg of the compound admixed with a solid or liquid pharmaceutical diluent or carrier.
  • the compounds of formula I may be used on their own or in the form of appropriate pharmaceutical compositions for topical, enteral or parenteral s administration.
  • compositions in a form suitable for topical administration to the lung include aerosols, e.g. pressurised or non-pressurised powder compositions; compositions in a form suitable for oesophageal administration include tablets, capsules and dragees; o compositions in a form suitable for administration to the skin include creams, e.g. oil-in-water emulsions or water-in-oil emulsions; compositions in a form suitable for administration intravenously include injections and infusions; and
  • SUBSTITUTE SHEET ISA/EP compositions in a form suitable for administration to the eye include drops and ointments.
  • a pharmaceutical composition comprising, preferably less than 80% and more preferably less than 50% by weight of, 5 a compound of formula I, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
  • diluents and carriers are: for tablets and dragees - lactose, starch, talc, stearic acid; for capsules - tartaric acid or lactose; and i ⁇ for injectable solutions - water, alcohols, glycerin, vegetable oils.
  • the compound of formula I When the compound of formula I is to be administered to the lung it may be inhaled as a powder which may be pressurised or non-pressurised.
  • Pressurised powder compositions of the compounds of formula I may contain a liquified gas propellant or a compressed gas.
  • non-pressurised powder compositions the active ingredient in is finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable carrier comprising particles of up to, for example, 100 ⁇ in diameter.
  • Suitable inert carriers include, e.g. crystalline lactose.
  • the compounds of formula I have the advantage that they are less toxic, more efficacious, are longer acting, have a broader range of activity, are more potent, produce o fewer side effects, are more easily absorbed or have other useful pharmacological properties, than compounds of a similar structure.
  • the sub-titled compound was prepared by the method outlined in step a) using the material from step b) and 7-[2-aminoethyl]-4-hydroxy-l,3-benzothiazoI-2(3H)-one 5 hydrobromide. mp 187-188°;
  • the sub-titled compound was prepared according to the procedure outlined in ⁇ o J. Cliem. Soc. Cliem. Comm., 1992, 233 using the compound from step a) (0.422 g), ethyl difluoroiodoacetate (0.3 g), zinc (0.157 g) and NiCI 2 .6H,0 (0.029 g) to yield the sub ⁇ titled compound (0.16 g, 22%).
  • step b) The product from step b) was hydrolysed according to the method outlined in Example lb), to yield the sub-titled compound as a yellow oil (0.18 g) which was used without further purification, a) Mass Spectrum: El TMS derivative 344 (M) + ;
  • step a) The material from step a) (2.978 g) was dissolved in concentrated hydrobromic acid (48% aqueous, 60 ml) to which hypophosphorous acid was added (2 drops). The whole was refluxed and the course of the reaction followed by reverse phase HPLC.
  • 6-[2-phenyIethoxy]-l-hexen-3-one prepared by the oxidation of the alcohol formed by s reaction between 4-[2-phenylethoxy]butanal and vinyl magnesium bromide, 1.0 g
  • phthalimide 0.674 g
  • DMSO DMSO
  • the mixture was stirred overnight, diluted with water and extracted with ether. The combined organic extracts were washed with water and brine and then dried (MgS0 4 ).
  • step c) The material from step c) (0.500 g) was dissolved in 80% formic acid (5 ml) and left to stand at room temperature until TLC analysis indicated that the reaction had gone to completion (17 hours). The reaction mixture was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The combined organic extracts were washed with aqueous sodium bicarbonate solution and brine, dried and evaporated to yield the sub-titled compound as a colourless oil (0.349g, 70%). This was used without further purification.
  • step d) To a solution of the material from step d) (0.35 g) in methanol (10 ml) was added 7-[2-aminoethyl]-4-hydroxy-l,3-benzthiazol-2(3H)-one hydrobromide (0.271 g) followed by sodium cyanoborohydride (0.044 g) and 15 drops of 6% aqueous acetic acid.
  • the sub-titled compound was prepared by the method outlined in Example la) using the material from step a) (1 g), 1-hydroxybenzotriazole hydrate (0.696 g) and N-methyl-2,2-dimethoxyethylamine (0.661 ml) except that no triethylamine was employed. This yielded the sub-titled compound (0.9 g). lo Mass Spectrum: FAB (+ve) 296 [(M+H) + ];
  • step b) The material from step b) (1.4 g) was mixed with acetic acid (20 ml) and heated at 100° for 1 hour under nitrogen. The acetic acid was removed under reduced pressure and the residue (1.38 g) was dissolved in methanol (50 ml). To this solution was added sodium cyanoborohydride (0.224 g), 7-[2-aminoethyl]-4-hydroxy-l,3- 20 benzthiazol-2(3H)-one hydrobromide (1.4 g) and 6% aqueous acetic acid (1 ml). The whole was stirred overnight at room temperature. The mixture was made basic by the addition of concentrated aqueous ammonium hydroxide solution.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des composés de la formule (I): Ar-CH2CH2-NH-CR1R2-X-Y. Dans cette formule Ar représente un groupe (α), X représente une chaîne (C¿1?-C12)alkylène interrompue ou se terminant par un ou plusieurs groupes choisis parmi -CR?6R7¿-, -C(Z)- ou -NR8-; le cas échéant, la chaîne est en outre interrompue ou se termine par un plusieurs groupes choisis parmi -S(O)¿n?-, -O-, CR?9R10¿, phénylméthine, -NH-, -CONH-, -NHCO- et -NHCONH-, Y représente une groupe aryle ou cycloalkyle, le cas échéant substitué, Z représente O ou S, R?1, R2, R5, R10 et R11¿ représentent chacun indépendamment hydrogène ou (C¿1?-C6)alkyle, R?3 et R4¿ représentent hydrogène ou R3 et R4 forment ensemble un groupe -S-, -NR11- ou -CH¿2?-, R?6 et R7¿ représentent d'une manière indépendante hydrogène, fluoro, cyano ou CF¿3?, une condition à satisfaire étant qu'au moins un parmi R?6 et R7¿ ne soit pas hydrogène, R8 représente un groupe (C¿1?-C6)alkyle ou lorsque X est interrompu ou se termine par plus d'un groupe -NR?8¿- il peut former ensemble avec un autre groupe R8 la chaîne -CH¿2?-CH2- et n représente 0, 1 ou 2. On décrit également des dérivés de ces composés acceptables sur le plan pharmaceutique, ainsi que des procédés permettant de les préparer, des compositions pharmaceutiques les contenant et des thérapies les utilisant.
PCT/GB1993/001015 1992-05-19 1993-05-18 Amines actives sur le plan biologique WO1993023385A1 (fr)

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GB929210632A GB9210632D0 (en) 1992-05-19 1992-05-19 Compounds

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010227A1 (fr) * 1995-09-15 1997-03-20 Astra Pharmaceuticals Limited Derives de la benzothiazolone
WO1997023470A1 (fr) * 1995-12-23 1997-07-03 Astra Pharmaceuticals Ltd. Ethanamines de benzothiazolone biologiquement actives
WO1998035946A1 (fr) * 1997-02-18 1998-08-20 American Home Products Corporation Derives 4-aminoalcoxy-1,3-dihydrobenzoimidazol-2-ones, leur preparation et leur utilisation comme agonistes de l'autorecepteur de la dopamine (d2)
US5990144A (en) * 1997-02-18 1999-11-23 American Home Products Corporation 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one dopamine autoreceptor agonists
WO2000003702A1 (fr) * 1998-07-16 2000-01-27 A+ Science Invest Ab Preparation pharmaceutique et procede correspondant
WO2007018461A1 (fr) 2005-08-09 2007-02-15 Astrazeneca Ab Dérivés innovants de benzothiazolone
WO2007071609A1 (fr) * 2005-12-22 2007-06-28 Basf Se Composés de malononitrile
US7345060B2 (en) 2003-11-21 2008-03-18 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
WO2008075025A1 (fr) * 2006-12-20 2008-06-26 Astrazeneca Ab Dérivés aminés et leur utilisation pour les maladies induites par le récepteur bêta-2 adrénergique
US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
US7951954B2 (en) 2006-03-14 2011-05-31 Astrazeneca Ab Bezothiazol derivatives as Beta2 adrenoreceptor agonists
US8017602B2 (en) 2008-06-18 2011-09-13 Astrazeneca Ab N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(phenethoxy)propanamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide
CN101282950B (zh) * 2005-08-09 2012-09-12 阿斯利康(瑞典)有限公司 新颖的苯并噻唑酮衍生物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0046666A1 (fr) * 1980-08-22 1982-03-03 Smithkline Beckman Corporation 2(3H)-Indolones, procédé de préparation et compositions les contenant
EP0174811A2 (fr) * 1984-09-12 1986-03-19 Smithkline Beckman Corporation 7-(2-Aminoéthyl)-1,3-benzothia ou oxazol-2(3H)-ones
EP0175525A1 (fr) * 1984-09-12 1986-03-26 Smithkline Beecham Corporation 7-[2-(dialcoylamino)éthyl]-4-hydroxy-1,3-benzimidazol-2-ones
EP0180944A2 (fr) * 1984-11-05 1986-05-14 V M E I "Lenin" Dispositif pour la mesure du débit d'un fluide
WO1992008708A1 (fr) * 1990-11-20 1992-05-29 Fisons Plc Amines biologiquement actives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0046666A1 (fr) * 1980-08-22 1982-03-03 Smithkline Beckman Corporation 2(3H)-Indolones, procédé de préparation et compositions les contenant
EP0174811A2 (fr) * 1984-09-12 1986-03-19 Smithkline Beckman Corporation 7-(2-Aminoéthyl)-1,3-benzothia ou oxazol-2(3H)-ones
EP0175525A1 (fr) * 1984-09-12 1986-03-26 Smithkline Beecham Corporation 7-[2-(dialcoylamino)éthyl]-4-hydroxy-1,3-benzimidazol-2-ones
EP0180944A2 (fr) * 1984-11-05 1986-05-14 V M E I "Lenin" Dispositif pour la mesure du débit d'un fluide
WO1992008708A1 (fr) * 1990-11-20 1992-05-29 Fisons Plc Amines biologiquement actives

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5977384A (en) * 1995-09-15 1999-11-02 Astra Pharmaceuticals Ltd. Benzothiazolone derivatives
US5846989A (en) * 1995-09-15 1998-12-08 Astra Pharmaceuticals Limited Benzothiazolone derivatives
US5973167A (en) * 1995-09-15 1999-10-26 Astra Pharmaceuticals Ltd. Intermediates for making benzothiazolone derivatives
WO1997010227A1 (fr) * 1995-09-15 1997-03-20 Astra Pharmaceuticals Limited Derives de la benzothiazolone
US6008365A (en) * 1995-09-15 1999-12-28 Astra Pharmaceuticals Ltd. Benzothiazolone derivatives
US6080869A (en) * 1995-09-15 2000-06-27 Astra Pharmaceuticals Limited Benzothiazolone derivatives
CN1073098C (zh) * 1995-09-15 2001-10-17 阿斯特拉曾尼卡有限公司 苯并噻唑酮衍生物
WO1997023470A1 (fr) * 1995-12-23 1997-07-03 Astra Pharmaceuticals Ltd. Ethanamines de benzothiazolone biologiquement actives
US5929100A (en) * 1995-12-23 1999-07-27 Astra Pharmaceuticals Limited Biologically active benzothiazolone ethanamines
RU2177476C2 (ru) * 1995-12-23 2001-12-27 Астра Фармасьютикалз Лтд. Биологически активные этанамины бензотиазолона
WO1998035946A1 (fr) * 1997-02-18 1998-08-20 American Home Products Corporation Derives 4-aminoalcoxy-1,3-dihydrobenzoimidazol-2-ones, leur preparation et leur utilisation comme agonistes de l'autorecepteur de la dopamine (d2)
US5990144A (en) * 1997-02-18 1999-11-23 American Home Products Corporation 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one dopamine autoreceptor agonists
WO2000003702A1 (fr) * 1998-07-16 2000-01-27 A+ Science Invest Ab Preparation pharmaceutique et procede correspondant
US7838535B2 (en) 2003-11-21 2010-11-23 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US8247564B2 (en) 2003-11-21 2012-08-21 Theravance, Inc. Compounds having BETA2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7345060B2 (en) 2003-11-21 2008-03-18 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7842704B2 (en) 2003-11-21 2010-11-30 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
WO2007018461A1 (fr) 2005-08-09 2007-02-15 Astrazeneca Ab Dérivés innovants de benzothiazolone
CN101282950B (zh) * 2005-08-09 2012-09-12 阿斯利康(瑞典)有限公司 新颖的苯并噻唑酮衍生物
US7709511B2 (en) 2005-08-09 2010-05-04 Astrazeneca Ab Benzothiazolone derivatives
US20100210688A1 (en) * 2005-08-09 2010-08-19 Roger Bonnert Novel Benzothiazolone Derivatives
WO2007071609A1 (fr) * 2005-12-22 2007-06-28 Basf Se Composés de malononitrile
JP2009520755A (ja) * 2005-12-22 2009-05-28 ビーエーエスエフ ソシエタス・ヨーロピア マロノニトリル化合物
US8916592B2 (en) 2005-12-22 2014-12-23 Merial Limited Malononitrile compounds
US7951954B2 (en) 2006-03-14 2011-05-31 Astrazeneca Ab Bezothiazol derivatives as Beta2 adrenoreceptor agonists
WO2008075025A1 (fr) * 2006-12-20 2008-06-26 Astrazeneca Ab Dérivés aminés et leur utilisation pour les maladies induites par le récepteur bêta-2 adrénergique
US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
RU2472783C2 (ru) * 2006-12-20 2013-01-20 Астразенека Аб Аминные производные и их применение в бета-2-адренорецептор-опосредованных заболеваниях
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide
US8017602B2 (en) 2008-06-18 2011-09-13 Astrazeneca Ab N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(phenethoxy)propanamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy

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