US3804899A - 3-alkylamino-2-(3,4-dihydroxyphenyl)propanols and the salts thereof - Google Patents

3-alkylamino-2-(3,4-dihydroxyphenyl)propanols and the salts thereof Download PDF

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US3804899A
US3804899A US00183633A US18363371A US3804899A US 3804899 A US3804899 A US 3804899A US 00183633 A US00183633 A US 00183633A US 18363371 A US18363371 A US 18363371A US 3804899 A US3804899 A US 3804899A
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propanol
dihydroxyphenyl
hydrobromide
carbon atoms
accordance
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A Ebnother
K Hasspacher
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Sandoz AG
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton

Definitions

  • the compounds exhibit broncholytic properties.
  • the present invention relates to aminopropanol derivatives.
  • R is hydrogen, cycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to '8 carbon atoms, cycloalkylalkyl, in which the cycloalkyl ring is of 3 to 7 carbon atoms and the alkyl residue is of 1 to 6 carbon atoms, or phenylalkyl or diphenylalkyl, in which the phenyl radicals may be substituted in the 3, 4 or 5 position by 1 to 3 hydroxy or methoxy groups, or in the 3,4 position by a methylenedioxy group, and in which the alkyl residue is of 1 to 6 carbon atoms, a
  • a compound of Formula I may be obtained by a process comprising (2.) Converting the ether groups into hydroxy groups in a compound of Formula II,
  • R is methyl, ethyl or benzyl
  • R is hydrogen, cycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 8 carbon atoms, cycloalkylalkyl, in which the cycloalkyl ring is of 3 to 7 carbon atoms and the alkyl residue is of 1 to 6 carbon atoms, or phenylalkyl or diphenylalkyl, in which the phenyl radicals may be substituted in the 3, 4 or 5 postion by 1 to 3 hydroxy or methoxy groups, or in the 3,4 position by a methylenedioxy group, and are separated from the nitrogen atom by at least two carbon atoms, and in which the alkyl residue is of 2 to 6 carbon atoms,
  • R is hydrogen or benzyl
  • R is benzyl or, when R, is benzyl, is hydrogen or benzyl
  • R is as defined above, or
  • R is hydrogen, alkyl of 1 to 7- carbon atoms, or eycloalkyl or cycloalkylalkyl, in which the cycloalkyl ring is of 3 to 7 carbon atoms and the alkyl residue is of l to 5 carbon atoms, or phenylalkyl or diphenylalkyl, in which the phenyl radicals may be substituted in the 3, 4 or 5 position by 1 to 3 hydroxy or methoxy groups, or in the 3,4 position by a methylenedioxy group, and are separated from the oxygen atom by at least two carbon atoms, and in which the alkyl residue is of 1 to 5 carbon atoms, and
  • R is hydrogen or alkyl of 1 to 7 carbon atoms, or
  • R and R together with the carbon atom to which the oxygen atom is joined form a cycloalkyl group of 4 to 7 carbon atoms, provided that when R is alkyl, when R, is alkyl the total number of carbon atoms in R and R is not greater than 7, and when R, is cycloalkylalkyl, phenylalkyl or diphenylalkyl the total number of carbon atoms in R and in the alkyl residue of R is not greater than 5,
  • R is cycloalkyl of 4 to 7 carbon atoms, primary or secondary alkyl of l to 8 carbon atoms, cycloalkylalkyl, in which the cycloalkyl ring is of 3 to 7 carbon atoms and the alkyl residue is of 1 to 6 carbon atoms, or phenylalkyl or diphenylalkyl, in which the phenyl radicals may be substituted in the 3, 4 or 5 position by 1 to 3 hydroxy or methoxy groups, or in the 3,4 position by a methylenedioxy group, and are separated from the nitrogen atom by at least 2 carbon atoms, and in which the alkyl residue is of 2 to 6 carbon atoms, or
  • R is as defined above, and each of R and R is alkyl of 1 to 4 carbon atoms,
  • the alkyl groups represented by the symbols R may be straight-chained or branched and preferably contain 1 to 4 carbon atoms; the cycloalkyl groups preferably contain ring members.
  • the alkyl residue of the aralkyl group may be straight-chained or branched and is preferably of 2 to 5 carbon atoms.
  • Process variants (a) may be effected in accordance with conventional methods for ether splitting.
  • a compound of Formula II may be allowed to react with a Lewis acid, e.g. boron tribromide or aluminium chloride, in an inert organic solvent, e.g. a halogenated hydrocarbon such as methylenechloride or carbon tetrachloride, or an aromatic hydrocarbon such as toluene or benzene, at --80 to -+70 C.
  • a compound of Formula II may be treated for a short period with a strong mineral acid, e.g. hydrobromic or hydriodic acid, optionally at an elevated temperature, e.g.
  • the debenzylation in accordance with process variant (b) may, for example, be effected by catalytic hydrogenation in an inert solvent, e.g. ethyl acetate, or a lower alkanol such as methanol or ethanol. Hydrogenation is preferably effected at a temperature from 20 to 100 C., at a hydrogen pressure of 1 to 100 atmospheres.
  • a palladium catalyst may, for example, be used as hydrogenation catalyst.
  • Process variant (c) may, for example, be efiected by catalytic reduction with a platinum, palladium or nickel catalyst, at l to 100 atmospheres hydrogen pressure and at 20 to 80 C., in an inert solvent such as ethanol.
  • the metal hydrides suitable for the reaction are, for example, optionally complex aluminium metal hydrides, such as lithium aluminium hydried, aluminium hydride, diisobutyl aluminium hydride, trialkoxy lithium aluminium hydrides, sodium dihydro-bis- (2 methoxyethoxy)aluminate, or dibroane or lithium borohydride, and the reaction is preferably effected at room temperature. Reaction times under preferred conditions are from approximately /2 to several hours.
  • the compounds of Formula I may be isolated from the reaction mixture in conventional manner.
  • the processes of the invention yield optically active compounds of Formula I.
  • racemic compounds are used as starting materials, the processes of the invention yield racemates of the compounds of Formula I, which, if desired, may be separated into the optical antipodes in conventional manner, e.g. by converting the racemates with optically active acids into a mixture of their diastereoisomeric salts, and isolating the optical antipodes of the compounds of Formula I therefrom.
  • the compounds of Formula II may be obtained by a process comprising (on) Reducing the ester group in a compound of Formula VIa,
  • R is as defined above, or
  • R is methyl or ethyl
  • Process variants (oz) and 8) may, for example, be effected in an inert solvent, e.g. an ether such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, with lithium aluminium hydride or aluminium hydride.
  • an inert solvent e.g. an ether such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, with lithium aluminium hydride or aluminium hydride.
  • Process variants (a) and (7) yield optically active compounds of Formula II when optically active compounds are used as starting materials.
  • racemic compounds are used as starting materials in both processes, as well as in process variants (p)
  • racemates of compounds of Formula II are obtained, which may be separated into their optical antipodes in conventional manner, e.g. by converting racemates with optically active acids into a mixture of their diastereoisomeric salts, and isolating the optical antipodes of the compounds of Formula II therefrom.
  • R R and R are as defined above,
  • the reaction may, for example, be effected at 20 to C., using equimolar amounts of both compounds, and optionally in an inert solvent, e.g. a lower alcohol.
  • an inert solvent e.g. a lower alcohol.
  • Compounds of Formula VId may, for example, be obtained by reacting a compound of Formula IXa,
  • the compounds of Formula I are useful because they possess pharmacological activity in animals.
  • the compounds are useful in the treatment of bronchospasms, such as in bronchial asthma, as indicated by their exhibition of generalized sympathomimetic, especially broncholytic, properties, as illustrated by their effect in vagally induced bronchospasms, and bronchospasms produced by histamine and acetylcholine in cats and guinea pigs.
  • the dosage administered will, of course, vary depending on the compound employed, mode of administration and treatment desired. However, in general satisfactory results are obtained when administered at a daily dosage of from about 0.005 to 5 mg./kg. animal body weight, conveniently given in divided doses 2 to 3 times a day, or in sustained release form.
  • the total daily dosage is in the range of from about 10 to 20 mg.
  • dosage forms suitable for oral administration comprise from about 3 to 10 mg. of the compound admixed with a solid or liquid pharmaceutical carrier or diluent.
  • 3-tert.butylamino-2-(3,4-dihydroxyphenyl)propanol has particularly interesting properties.
  • the compounds of Formula I may be administered in pharmaceutically acceptable acid addition salt form.
  • Such salts possess the same order of activity as the free bases and are readily prepared in conventional manner.
  • Suitable such salt forms include organic acid salts such as the fumarate, maleate, tartrate, methane-, ethaneand benzenesulphonate, citrate and malate, and mineral acid 7 salts such as the hydrochloride, hydrobromide and sulphate.
  • the compounds of Formula I or their pharmaceutically acceptable acid addition salts may be used as medicaments on their own or in the form of appropriate medicinal preparations, e.g. tablets, drages, capsules, granules, suppositories or injectable solutions or suspensions, for enteral or parenteral administration.
  • appropriate medicinal preparations e.g. tablets, drages, capsules, granules, suppositories or injectable solutions or suspensions, for enteral or parenteral administration.
  • these preparations may also contain suitable preserving stabilizing or wetting agents, solubilizers, sweetening or coloring substances and flavorings.
  • the invention accordingly also provides a pharmaceutical composition
  • a pharmaceutical composition comprising as active agent a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or diluent.
  • the 2 (3,4-dimethoxyphenyD-3-(isopropylamino)propanol, required as starting material, may be produced as follows:
  • the hydrochloric acid solution is rendered alkaline with concentrated ammonia while cooling, whereby crude 2-(3,4-dimethoxyphenyl)-3-(isopropylamino)propionic acid ethyl ester separates as a yellow oil, and this is taken up in chloroform.
  • the solution is dried over sodium sulphate and concentrated by evaporation; the residue is converted into the hydrochloride with hydrochloric acid in ethanol.
  • M.P. 159-162 The hydrochloric acid solution is rendered alkaline with concentrated ammonia while cooling, whereby crude 2-(3,4-dimethoxyphenyl)-3-(isopropylamino)propionic acid ethyl ester separates as a yellow oil, and this is taken up in chloroform.
  • the solution is dried over sodium sulphate and concentrated by evaporation; the residue is converted into the hydrochloride with hydrochloric acid in ethanol.
  • M.P. 159-162 M.
  • EXAMPLE 6 3-cyclopentylamino-2- 3,4-dihydroxyphenyl propanol 3-cyclopentylamino-2-(3,4 dimethoxyphenyl)propanol (obtained in a manner analogous to Example 1, M.P. of the bis-naphthalene 1,5-disulphonate 231-235) is reacted in accordance with the process described in Example l.
  • the hydrobromide of the title compound has a M.P.
  • EXAMPLE 10 9 EXAMPLE 11 20 g. of 3-amino 2 (3,4 dimethoxyphenyl)propanol are dissolved in 250 cc. of methylene chloride and 52.5 g. of boron tribromide in the form of a 1 molar solution in methylene chloride are slowly added at --75 while stirring. After hours the solvent is distilled off in a vacuum, the residue is heated under reflux with 100 cc. of ethanol for 1 hour, the reaction solution is concentrated by evaporation and the residue is recrystallized from ethanol/ ether. The hydrobromide of the title compound has a M.P. of 87-91".
  • the 3-amino 2 (3,4-dimethoxyphenyl)propanol, required as starting material, may be obtained as follows:
  • EXAMPLE 16 3- (n-hexylamino) -2- (3,4-dihydroxyphenyl propanol 3-(n-hexylamino) 2 (3,4-dimethoxyphenyl)propanol (obtained in a manner analogous to Example 1, M.P. of the hydrochloride 94-97") is reacted in accordance with the process described in Example 1.
  • the hydrobromide of the title compound has a M.P. of 92-95.
  • EXAMPLE 22 3-ethylamino-2-(3,4-dihydroxyphenyl)propanol 3'ethylamino-2-(3,4 dimethoxyphenyl)propanol (obtained in a manner analogous to Example 1, M.P. 67- 69") is reacted in accordance with the process described in Example 1.
  • the hydrobromide of the title compound has a M.P.
  • EXAMPLE 27 -3 -tert.butylamino-2- (3 ,4-dihydroxyphenyl propanol hydrobromide ()-3-tert.butylamino 2 (3,4 dimethoxyphenyl) propanol is reacted in accordance with the process described in Example 1.
  • (+)- or ()-3-tert.butyl-amino 2 (3,4 dimethoxyphenyl)propanol are obtained as follows:
  • racemic 3-tert.butylamino-2-(3,4-dimethoxyphenyl)propanol are dissolved in 4 liters of ethanol and a solution of 60 g. of ()di-O (p toluoyl) L- tartaric acid in 4 liters of ethanol is added.
  • (+)-3-tert. butylamino-Z-(3,4-dimethoxyphenyl) propanol hydrogen- (-)di-O-(p-toluoyl)-L-tartrate crystallizes. M.P. after recrystallization from methanol l91-192.
  • the salt of the optically active base is decomposed with 2 N caustic soda solution/ chloroform.
  • the base resulting from the chloroform phase is recrystallized from cyclohexane. )-3-tert.butylamino-2-( 3,4 dimethoxyphenyl)propanol is obtained.
  • M.P. 77-79 [a] 32.5 in ethanol.
  • EXAMPLE 28 3-tert.butylamino-2-(3,4-dihydroxyphenyl)propanol 10.0 g. of racemic 3-tert.butylamino 2-(3,4-dimethoxyphenyl)propanol (prepared as described in Example 27) are heated under refiux in 100 cc. of 48% hydrobromic acid for 15 minutes. The reaction solution is subsequently evaporated to dryness and the residue is recrystallized from ethanol/ether.
  • the hydrobromide of the title compound has a M.P. of 113-1 15.
  • EXAMPLE 29 2(3,4-dihydroxyphenyl)-3-(p-methoxyphenethylamino) propanol
  • process variant (b) 11.0 g. of 2-(3,4-dibenzyloxyphenyl) 3 (p-methoxyphenethylamino)propanol are dissolved in 200 cc. of ethanol, 1.0 g. of palladium on charcoal (10%) is added and hydrogenation is efiected at room temperature for 30 minutes. The catalyst is then filtered 01f, the solution is concentrated by evaporation and the residue is converted into the hydrochloride of the title compound. M.P. 198-200.
  • the starting material is obtained as follows:
  • reaction mixture is stirred at room temperature over night, is then diluted with 250 cc. of water and the toluene phase is separated. After drying over sodium sulphate the solvent is distilled off, and the resulting a-(3,4-dibenzyloxyphenyl)acrylic acid ethyl ester is used for the next reaction without previous purification.
  • EXAMPLE 33 3-cyclohexylamino-2-(3,4-dihydroxyphenyl)propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with cyclohexanone in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of 95-97".
  • EXAMPLE 34 3-cyclopentylamino-2-(3,4-dihydroxyphenyl)propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with cyclopentanone in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of 92-95.
  • EXAMPLE 36 2- (3 ,4-dihydroxyphenyl) -3 1-phenyl-2-propylamino) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with benzyl methyl ketone in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of 109-110".
  • EXAMPLE 38 2- (3,4-dihydroxyphenyl)-3-(n-propylamino) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with propionaldehyde in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of 84-85.
  • the hydrobromide of the title compound has a M.P. of 65-70.
  • EXAMPLE 42 3- n-hexylamino -2- 3 ,4-dihydroxyphenyl propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with hexanal in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of 92-95
  • EXAMPLE 43 3-(n-heptylamino -2- (3,4-dihydroxyphenyl) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with n-heptanal in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of 128-13l.
  • EXAMPLE 45 3- (p-hydroxyphenethylamino -2- 3 ,4-dihydroxypheny1) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with p-hydroxy-phenylacetaldehyde in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of 65-70".
  • EXAMPLE 46 2.- 3,4-dihydroxyphen'yl) -3- 3- (p-hydroxyphenyl) propylamino1propanol 3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with 3-(p-hydroxyphenyl)propionaldehyde in accordance with the process described in Example 30.
  • EXAMPLE 49 3-(3,4-dihydroxyphenethylamino)-2-(3,4-dihydroxyphenyl propanol S-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with 3,4-dihydroxy-phenylacetaldehyde in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of 77-80.
  • EXAMPLE 50 2-(3,4-dihydroxyphenyl)-3-(2,2-diphenylethylamino) propanol 3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with diphenylacetaldehyde in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of (HS-117.
  • the starting material is obtained as follows:
  • EXAMPLE 55 3- (cyclopentylmethyl)amino] -2-(3,4- dihydroxyphenyl propanol 3 amino 2-(3,4-dihydroxyphenyl)propanol is reacted with cyclopentylformaldehyde in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of 87-91 (decomp.).
  • EXAMPLE 5 3- 3-cyclopentylpropylamino) -2- 3,4-dihydroxyphenyl) propanol 3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with 3 cyclopentylpropanone in accordance with the process described in Example 30.
  • the hydrobromide of the title compound has a M.P. of 164-167.
  • R is alkyl of l to 8 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US00183633A 1970-09-30 1971-09-24 3-alkylamino-2-(3,4-dihydroxyphenyl)propanols and the salts thereof Expired - Lifetime US3804899A (en)

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CH1446170A CH534658A (de) 1970-09-30 1970-09-30 Verfahren zur Herstellung neuer Dihydroxyphenylverbindungen
CH1445970A CH535739A (de) 1970-09-30 1970-09-30 Verfahren zur Herstellung neuer Dihydroxyphenylverbindungen

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AU (1) AU3403671A (enrdf_load_stackoverflow)
BE (1) BE773204A (enrdf_load_stackoverflow)
DD (1) DD99159A5 (enrdf_load_stackoverflow)
DE (1) DE2148551A1 (enrdf_load_stackoverflow)
ES (1) ES395494A1 (enrdf_load_stackoverflow)
FR (1) FR2108100B1 (enrdf_load_stackoverflow)
GB (1) GB1359871A (enrdf_load_stackoverflow)
HU (1) HU162651B (enrdf_load_stackoverflow)
NL (1) NL7112938A (enrdf_load_stackoverflow)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888829A (en) * 1971-06-25 1975-06-10 Sandoz Ag N,n'-bis(3-hydroxy-2-(3,4-dihydroxy-phenyl)-1-propyl)-aliphatic-diamines
US3952021A (en) * 1973-04-28 1976-04-20 Tanabe Seiyaku Co., Ltd. α-(3,4-Dimethoxyphenethylaminomethyl)-3,4 or 3,5-dihydroxybenzylalcohols and salts thereof
US4058642A (en) * 1973-10-11 1977-11-15 Boehringer Ingelheim Gmbh 2-Amino-3-(3'-hydroxy-phenyl)-propanols and salts thereof
US4252824A (en) * 1975-11-12 1981-02-24 Valeas S.R.L., Industria Chimica E Farmaceutica Amino-ethanol derivatives
US4309350A (en) * 1975-11-26 1982-01-05 Commonwealth Scientific And Industrial Research Organization Process of making phenylacrylic esters
US4396517A (en) * 1981-08-10 1983-08-02 Mobil Oil Corporation Phenolic-containing mannich bases and lubricants containing same
US4536601A (en) * 1982-09-28 1985-08-20 Dainippon Pharmaceutical Co., Ltd. Optically active N-substituted phenylalaninols and use thereof
US4788010A (en) * 1985-04-24 1988-11-29 E. R. Squibb & Sons, Inc. Amino substituted benzenepropanols
EP0345591A1 (de) * 1988-06-10 1989-12-13 F. Hoffmann-La Roche Ag Propanolaminderivate
US4994617A (en) * 1986-01-30 1991-02-19 Jouveinal S.A. Aminoalcohols, their preparation process and their applications, particularly in therapeutics
EP0329464A3 (en) * 1988-02-19 1991-07-17 Gensia, Inc. System for the closed-loop administration of an exercise simulating agent
US5770615A (en) * 1996-04-04 1998-06-23 Bristol-Myers Squibb Company Catecholamine surrogates useful as β3 agonists
US5776983A (en) * 1993-12-21 1998-07-07 Bristol-Myers Squibb Company Catecholamine surrogates useful as β3 agonists
JP2013177470A (ja) * 2006-07-06 2013-09-09 Array Biopharma Inc Ａｋｔプロテインキナーゼ阻害剤としてのヒドロキシル化およびメトキシル化されたシクロペンタ［ｄ］ピリミジン
US9359340B2 (en) 2006-07-06 2016-06-07 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as Akt protein kinase inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3163871D1 (en) 1980-07-09 1984-07-05 Draco Ab 1-(dihydroxyphenyl)-2-amino-ethanol derivatives; preparation, compositions and intermediates
IE903957A1 (en) * 1989-11-06 1991-05-08 Sanofi Sa Aromatic amine compounds, their method of preparation and¹pharmaceutical compositions in which they are present

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888829A (en) * 1971-06-25 1975-06-10 Sandoz Ag N,n'-bis(3-hydroxy-2-(3,4-dihydroxy-phenyl)-1-propyl)-aliphatic-diamines
US3952021A (en) * 1973-04-28 1976-04-20 Tanabe Seiyaku Co., Ltd. α-(3,4-Dimethoxyphenethylaminomethyl)-3,4 or 3,5-dihydroxybenzylalcohols and salts thereof
US4058642A (en) * 1973-10-11 1977-11-15 Boehringer Ingelheim Gmbh 2-Amino-3-(3'-hydroxy-phenyl)-propanols and salts thereof
US4252824A (en) * 1975-11-12 1981-02-24 Valeas S.R.L., Industria Chimica E Farmaceutica Amino-ethanol derivatives
US4309350A (en) * 1975-11-26 1982-01-05 Commonwealth Scientific And Industrial Research Organization Process of making phenylacrylic esters
US4396517A (en) * 1981-08-10 1983-08-02 Mobil Oil Corporation Phenolic-containing mannich bases and lubricants containing same
US4536601A (en) * 1982-09-28 1985-08-20 Dainippon Pharmaceutical Co., Ltd. Optically active N-substituted phenylalaninols and use thereof
US4788010A (en) * 1985-04-24 1988-11-29 E. R. Squibb & Sons, Inc. Amino substituted benzenepropanols
US4994617A (en) * 1986-01-30 1991-02-19 Jouveinal S.A. Aminoalcohols, their preparation process and their applications, particularly in therapeutics
US5460605A (en) * 1988-02-19 1995-10-24 Gensia, Inc. Diagnosis, evaluation and treatment of coronary artery disease by exercise simulation using closed loop drug delivery of an exercise simulating agent beta agonist
EP0329464A3 (en) * 1988-02-19 1991-07-17 Gensia, Inc. System for the closed-loop administration of an exercise simulating agent
US5045567A (en) * 1988-06-10 1991-09-03 Hoffmann-La Roche Inc. Propanolamine derivatives having anti-diabetic effects
EP0345591A1 (de) * 1988-06-10 1989-12-13 F. Hoffmann-La Roche Ag Propanolaminderivate
US5776983A (en) * 1993-12-21 1998-07-07 Bristol-Myers Squibb Company Catecholamine surrogates useful as β3 agonists
US5770615A (en) * 1996-04-04 1998-06-23 Bristol-Myers Squibb Company Catecholamine surrogates useful as β3 agonists
JP2013177470A (ja) * 2006-07-06 2013-09-09 Array Biopharma Inc Ａｋｔプロテインキナーゼ阻害剤としてのヒドロキシル化およびメトキシル化されたシクロペンタ［ｄ］ピリミジン
US9359340B2 (en) 2006-07-06 2016-06-07 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as Akt protein kinase inhibitors

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ES395494A1 (es) 1974-11-01
FR2108100A1 (enrdf_load_stackoverflow) 1972-05-12
NL7112938A (enrdf_load_stackoverflow) 1972-04-05
BE773204A (fr) 1972-03-28
DE2148551A1 (de) 1972-05-10
DD99159A5 (enrdf_load_stackoverflow) 1973-07-20
AU3403671A (en) 1973-04-05
GB1359871A (en) 1974-07-10
HU162651B (enrdf_load_stackoverflow) 1973-03-28
FR2108100B1 (enrdf_load_stackoverflow) 1975-04-18

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