Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • A61K31/275—Nitriles; Isonitriles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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
  • A61P9/06—Antiarrhythmics
• • 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
• • 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
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
• • E—FIXED CONSTRUCTIONS
  • E04—BUILDING
  • E04H—BUILDINGS OR LIKE STRUCTURES FOR PARTICULAR PURPOSES; SWIMMING OR SPLASH BATHS OR POOLS; MASTS; FENCING; TENTS OR CANOPIES, IN GENERAL
  • E04H13/00—Monuments; Tombs; Burial vaults; Columbaria
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• R is cyano, carboxyl, hydroxyl, amino, nitro, trifluoromethyl, alkyl of up to 5 carbon atoms, alkenyl of up to 5 carbon atoms, alkinyl of up to 5 carbon atoms, alkoxy of up to 5 carbon atoms, alkenyloxy of up to 5 carbon atoms, alkinyloxy of up to 5 carbon atoms, hydroxyalkyl of up to 5 carbon atoms, alkoxyalkyl of up to 5 carbon atoms, aminoalkyl of "up to 5 carbon atoms, alkylaminoalkyl of up.
• dialkylaminoalkyl of up to 5 carbon atoms dialkylaminoalkyl of up to 5 carbon atoms, alkylamino of up to 5 carbon atoms, cyano(alkyl of up to 5 carbon atoms), alkoxy of up to 5 carbon atoms)carbonyl, alkyl of up to 5 carbon atoms)amino-carbonyl, alkyltbio of up to 5 carbon atoms, acyloxy of up to 5 carbon atoms, acylamino of up to 5 carbon at0ms,'aryl of up to carbon atoms, aralkyl of up to 10 carbon atoms, aryloxy of up to 10 carbon atoms, aralkoxy-of up to 10 carbon atoms, arylamino of up to 10 carbon atoms or halogen,
• R is hydrogen, halogen, cyano, alkyl of up to 5 carbon atoms, alkoxy of up to 5 carbon atoms or alkenyl of up to 5 carbon atoms,
• R and R together with each other are 3,4-methyIenedioxy
• R is hydrogen, halogen, alkyl of up to 5 carbon atoms or alkoxy of up to 5 carbon atoms, and n is an integer from 2 to 7, inclusive,
• This invention relates to novel l-phenoxy-lZ-hydroxy- 3-(cycloalkyl-amino)-propanes and their non-toxic acid addition salts, as well as to various methods of preparing these compounds.
• R is alkyl of 1 to 5 carbon atoms
• R is cyano, carboxyl, hydroxyl, amino, nitro, trifluoromethyl, alkyl of up to 5 carbon atoms, alkenyl of up to 5 carbon atoms, alkinyl of up to 5 carbon atoms, alkoxy of up to 5 carbon atoms, alkenyloxy of up to 5 carbon atoms, alkinyloxy of up to 5 carbon atoms, hydroxyalkyl of up to 5 carbon atoms, alkoxyalkyl of up to 5 carbon atoms, aminoalkyl of up to 5 carbon atoms, alkylaminoalkyl of up to 5 carbon atoms, dialkylaminoalkyl of up to 5 carbon atoms, alkylamino of up to 5 carbon atoms, cyano(alkyl of up to 5 carbon atoms), (alkoxy of up to 5 carbon atoms) carbonyl, (alkyl of up to 5 carbon atoms)amino-carbonyl, alkylthio of up
• R is hydrogen, halogen, cyano, alkyl of up to 5 carbon atoms, alkoxy of up to 5 carbon atoms or alkenyl of up to 5 carbon atoms, 7
• R is hydrogen, halogen, alkyl of up to 5 carbon atoms or alkoxy of up to 5 carbon atoms
• n is an integer from 2 to 7, inclusive
• optically active components thereof or non-toxic, pharmacologically acceptable acid addition salts of said racemic or optically active compounds.
• the compounds according to the present invention may be prepared by a number of methods involving well known chemical principles, among which the following have proved to be particularly convenient and efiicient.
• Method B By reacting a compound of the Formula II with' an N,'N-dicycloalkylurea of the formula wherein R and n have the same meanings as in Formula I.
• the reaction is preferably performed in a water-immiscible, high-boiling-point solvent, such as Tetralin, Decalin, benzonitrile or the like, or without a solvent in the molten state, at temperatures between and 220 C., preferabl'y at 180200 C.
• this reaction is not practicable or can only be performed with difliculty, in those cases where heat-sensitive groups (such as unsaturated groups, hydroxyl or amino groups) are present in the starting material.
• Method C By splitting oif an easily removable protective group from a compound of the formula wherein R, R R R and n have the same meanings as in Formula I and G is a hydrolytically easily removable group (for instance, an acyl or an acetal group).
• Method D By splitting oif a protective group from a tertiary amine of the formula Sch / o om-onon-cmJr-oijonm wherein R, R R R and n have the same meanings as in Formula I and Sch represents a hydrogenolytically or hydrolytically easily removable protective group, such as benzyl or acetyl.
• R, R R R and n have the same meanings as in Formula I, for example with a strong alkali in an aqueous or aqueous/ alcoholic medium.
• Method F By hydrolysis or pyrolysis of a urea derivative of the formula wherein R, R R R and n have the same meanings as in Formula I, and R and R (which may be identical to or different from each other) are each hydrogen or alkyl (preferably lower alkyl), aralkyl (preferably benzyl), or aryl (preferably phenyl), in conventional fashion.
• the hydrolysis is carried out, for instance, with a strong base, such as aqueous KOH; on the other hand, the pyrolysis only be performed with good yields if there are no heatsensitive groups present in the starting material.
• R; R (IX) wherein R, R R and n have the same meanings as in Formula I and A is a group convertible by conventional methods into R such as the aldehyde-(CHO)-group (converts by reduction into -CH OH or CH the CONH or --CH NOH group (converts by dehydration into the cyano group), a halo-alkyl group (converts by reaction with ammonia or amines, water or aliphatic alcohols into an aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl or alkoxyaryl group), a hydroxyl group (converts by etherification into an alkoxy group), a halogen atom (converts by reaction with Cu(I)CN and pyridine at elevated temperatures into a cyano group), a nitro group (converts by reduction into the amino group), an alkoxycarbonyl group (converts by saponification into a carboxyl group
• R, R and R and n have the same meanings as in Formula I and B represents a group convertible into R; in conventional manner, such as the hydroxyl or aldehyde (CHO) group or an amino group, or compounds of the formula wherein R, R R and n have the same meanings as in Formula I and D represents a group convertible into R, in conventional manner (such as the aldehyde, hydroxyl or amino group), may be converted into compounds of the Formula I by using the conventional method required for each case (alkylation, reduction, diazotization and heating with a copper-I-salt, etc.).
• R and n have the same meanings as in Formula land Aris or Q where R, and R or R and R have the same meanings as in Formula I. his process may be carried out, for ex ample, by reaction with a mixture of concentrated bydrogen peroxide and the corresponding hydrohalic acid at elevated temperatures.
• the epoxides of the Formula II may easily be prepared by reacting a corresponding phenol or phenolate of the formula OKt (XIII) wherein R R and R have the same meaning as in Formula I and Kt represents hydrogen or a cation (for example, an alkali metal cation).
• the epoxides may be used for the preparation of further starting materials; for example, the halohydrins of the Formula 11 may be prepared by reaction of the epoxides with the corresponding hydrohalic acid.
• the ureas of the Formula IV may be prepared, for example, by reaction of phosgene with amines of the Formula III.
• the latter in turn, may be prepared starting from the corresponding carbinols according to the socalled Ritter reaction [see .I.A.C.S. 70 (1948), 4048] by reaction with KCN in glacial acetic acid and cleavage of the formamide thus formed with KOH.
• Compounds of the Formula V may be obtained by reacting a halohydrin of the Formula II with a compound which forms the protective group G, such as vinyl ether or dihydropyran, and subsequently reacting the obtained compound of the formula R3 (XIV) wherein R R R Hal and G have the meanings previously defined, with an amine of the Formula III.
• the tertiary amines of the Formula VI are obtained by reacting a compound of the Formula XIII with a compound of the formula Sch wherein R and n have the same meanings as in Formula I.
• a urea derivative of the Formula V may, for instance, be obtained according to the method described in Chem. Abstr.
• the compounds of the Formulas IX to XII already comprise the 1-phenoxy-2-hydroxy-3-cycloalkylaminopropane structure and may, therefore, be prepared analogous to method A described above, starting from the corresponding phenol, via the corresponding l-phenoxy2,3-epoxypropane (producible therefrom by reaction with epichlorohydrin) by reaction with a cycloalkylamine of the Formula III.
• the compounds according to the present invention comprise an asymmetric carbon atom in the CHOH-group and therefore occur as racemates as well as in the form of optical antipodes.
• the latter may be obtained not only by means of separation of racemates with the usual auxiliary acids, such as dibenzoyl-D-tartaric acid or D-3- bromocamphor-8-sulfouic acid, but also by using the corresponding optically active starting material.
• the 1-phenoxy-3-cycloalkylamino-propanols of the Formula I according to the invention may be converted into non-toxic pharmaceutically acceptable acid addition salts in conventional fashion.
• acid addition salts are, for instance, those formed with hydrochloric acid, hydro bromic acid, sulfuric acid, methane-sulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid, 8- chlorotheophylline or the like.
• the cooled aqueous phase was made alkaline with NaOH after extraction with ether, and the precipitated base was extracted with ether.
• the organic phase was Washed with water and dried over MgSO After distilling off the ether, the remaining crystalline base was recrystallized from ethylacetate by addition of petroleum ether.
• the dry substance was dissolved in a little acetonitrile, ethereal HCl was added, and the crystalline hydrochloride was collected by vacuum filtration. Yield: 5.8 gm., M.P. 163- 165 C.
• EXAMPLE 8 1- (2-ethinylphenoxy) -2-hydroxy-3-( 1"-methylcyclopentylamino) -propane hydro chloride 7.5 gm. (0.04 mol) of 1-(2'-ethinylphenoxy)-2,3- epoxypropane were dissolved in 80 ml. of ethanol, gm. (0.05 mol) of l-methylcyclopentylamine were added, and the mixture was refluxed for 2.5 hours. The residue remaining after distilling ofi the solvent was dissolved in ethanol, and ethereal HCl was added. The colorless crystalline precipitate was recrystallized from ethanol/ether. Yield: 6.7 gm., M.P. 171-173 C.
• EXAMPLE 16 Analogous to Example 1, 1 (2' methyl-4'-cyanophenoxy) 2 hydroxy 3 (1" methylcyclohexylamino)- propane hydrochloride was prepared from 1- (2'-methyl- 4' cyanophenoxy) 2,3 epoxypropane and l-methylgycllslgxylamine. M.P. of the HCl addition salt: 206- EXAMPLE 17 Analogous to Example 1, 1-(2-cyanophenoxy)-2-hydroxy 3 (1" isopropylcyclohexylamino)-propane hydrochloride was prepared by reacting 1-(2'-cyanophenoxy) -2,3-epoxypropane with 1-isopropylcyclohexylamine. The hydrochloride, obtained by dissolution of the base in ethanol and acidifying the solution with ethereal HCl, melted at ZOO-201 C.
• EXAMPLE 20 l (2' propargyloxyphenoxy) 2 hydroxy-3-(1"- methylcycloheptylamino)-propane hydrochloride was prepared from 1 (2' propargyloxyphenoxy):2,3-propaneepoxide and 1-methylcycloheptylamine. Dissolution of the base in ethanol and acidification of the solutlon with ethereal HCl yielded the HCl addition salt, M.P. 110- 111 C.
• EXAMPLE 21 1 (2' allylphenoxy) 2 hydroxy-3-(1"-methylcycloheptylamino)-propane hydrochloride was prepared from 1 (2 allylphenoxy) 2,3 epoxypropane and 1- methylcycloheptylamine, analogous to Example 7. The hydrochloride had a melting point of l24-126 C.
• EXAMPLE 27 1- (2'-aminophenoxy -2-hydroxy-3- I "-methylcyclohexylamino -prop ane 2 HCl
• EXAMPLE 28 1-(2'-bromophenoxy)-2-hydroxy-3-(1"-methylcyclohexylamino) -propane hydrochloride 1.16 gm. (0.00375 mol) of l-(2'-bromophenoxy)-2-hydroxy-3-bromopropane were heated in Tetralin with 1.8 gm. (0.0075 mol) of N,N'-bis-(1-methy1cyc1ohexyl)urea for two hours at l220 C. After cooling, 50 ml.
• EXAMPLE 29 1- (2'-bromophenoxy) -2-hydroxy-3-( 1"-methyl-cyclohexylamino)-propane hydrochloride
• the tetrahydropyranyl ether obtained from 7.25 gm. (0.025 mol) of 1-(2-bromophenoxy)-2-hydroxy-3- bromopropane, 2.52 gm. (0.03 mol) of dihydropyran and 10 gm. of p-toluenesulfonic acid at 50 C. was dissolved in50 ml. of ethanol, 8.5 gm. (0.075 mol) of l-methylcyclohexylamine were added to the solution, and the mixture was refluxed for six hours.
• the residue was dissolved in a little acetone, and upon addition of maleic acid to the solution, the maleate was obtained.
• 2 gm. of the maleate were heated in 25 ml. of 2 N HCl on a water bath for ten minutes. After cooling, the solution was extracted with ether. The aqueous phase was made alkaline with NaOH, and the precipitated base was taken up in ether. The ether solution was washed, dried, and the ether was distilled 01f.
• the hydrochloride was obtained by dissolving the residue in a little ethanol and adding ethereal HCl to the solution. Yield: mgm.; M.P.
• EXAMPLE 32 1- (2'-cyanophenoxy) -2-hydroxy-3 1 "-methylcyclohexylamino) -propane hydrochloride
• a diazonium salt solution prepared from 3.52 gm. (0.01 mol) of 1-(2'-aminophenoxy)-2-hydroxy-3-(1"- methylcyclohexylamino)-propane-2HCl, 4 ml. of concentrated HCl, 20 ml. of water and an aqueous solution of 1.4 gm. (0.02 mol) of NaNO was slowly added dropwise to a hot solution of gm. of copper sulfate, 5.8 gm. of copper cyanide in 30 ml. of water.
• EXAMPLE 33 Analogous to Example 1, l-(2'-cyano-5-methylphenoxy)-2-hydroxy 3 (l"-methylcyclohexylamino)-propane was prepared from 1-(2-cyano-5'-methylphenoxy)- 2,3-propaneepoxide and l-methylcyclohexylamine in ethanol. M.P. (hydrochloride): 173-476 C.
• EXAMPLE 36 1-(2'-chloro-5-methylphenoxy) -2-hydroxy-3- 1"- methylcyclopentyl amino) -propane hydrochloride 1.9 gm. (0.005 mol) of N-isopropyl-N-(1'-methylcyclopentyl)-N'- ⁇ 2-hydroxy-3"-(2.'-chloro 5" methylphenoxy)-propyl]-urea, 15 ml. of Tetralin and 100 mgm. of LiCl were combined, and the mixture was heated at 200 C. for one hour. Thereafter, the reaction mixture was diluted with ether and extracted twice with ml. of 1 N HCl each.
• EXAMPLE 37 1- (2'-cyanophenoxy) -2-hydroxy-3-( 1 "-methylcyclohexylamino)-propane hydrochloride 3.52 gm. (0.01 mol) of 1-(2'aminophenoxy) 2 hydroxy-3-(1" methylcyclohexylamino) propane hydrochloride were dissolved in a mixture of 20 ml. of water and 4 ml. of concentrated HCl, and then a solution of 1.4 gm. (0.02 mol) of NaNO in 5 ml. of water was slowly added dropwise to the solution. By exterior cooling with ice the temperature was kept between 9 and +5 C. After the addition was finished, the temperature of the combined solution was kept at about 0 C.
• EXAMPLE 3 8 1- (2'-cyano-5-methylphenoxy) -2-hydroxy-3-( 1"-methylcyclohexylamino) -propane hydrochloride 2.92 gm. (0.0111101) of 1-(2-amino-5'-methylphenoxy)- 2-hydroxy-3-(1"-methylcyclohexylamino) propane were dissolved in a mixture of 20 ml. of water and 6 ml. of HCl. Thereafter, a solution of 1.4 gm. (0.02 mol) of NaNO in 5 ml. of water was slowly added dropwise to the amine solution, while stirring. By exterior cooling with ice the temperature was kept between 0 and +5 C. After the addition was finished the mixed solution was kept at about 0 C. for 15 minutes more. 5 gm. of
• the compounds according to the present invention that is, those embraced by Formula I above and their nontoxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, the compounds of the instant invention exhibit very effective fi-adrenergic receptor blocking activities in warmblooded animals, such as guinea pigs, and are therefore useful therapeutics for the treatment and prophylaxis of diseases of the coronaries and for the treatment of cardiac arrythmia, especially tachycardia. The compounds also exhibit effective hypotensive activities.
• B-adrenergic receptor blocking agents are those compounds of the Formula I wherein R is methyl; R and R are hydrogen or also alkyl; R is an unsaturated group, such as ethinyl, cyano, allyl or allyloxy (especially in 2-position with respect to the proposed chain), or hydroxy-methyl; and n is 4, 5 or 6; and their non-toxic acid addition salts.
• compounds of the Formula I wherein R is methyl, R is halogen, R is hydrogen or methyl, R is hydrogen and n is 4, 5 or 6, and their non-toxic acid addition salts are also very strong B-adrenergic receptor blocking agents.
• the following specific compounds and their nontoxic acid addition salts are of special interest:
• the compounds according to the present invention are administered to warm-blooded animals perorally or parenterally as active ingredients in customary dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, Wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like.
• dosage unit compositions may, in addition to a compound of the present invention, also comprise an eifective dosage unit of one or more compounds having a diflerent pharmacodynamic property, such as a coronary dilator, a sympathomimetic, a cardiac glycoside and/or a tranquilizer.
• One effective dosage unit of the compounds according to the present invention is from 0.0166 to 5.0 mgm./ kg. body weight, preferably 0.083 to 1.67 mgm./kg. (perorally) and 0.0166 to 0.34 mgm./kg. (parenterally).
• Preparation The individual components were intimately admixed with each other, the mixture was granulated in customary fashion, and the granulate was compressed into 445 mgm.-tablets with a conventional tablet making machine. Each tablet contained 40 mgm. of the propanol salt and, when administered perorally to a warm-blooded animal of about 60 kg. body weight in need of such treat- 14 ment, produced a very effective fi-adrenergic receptor blocking action.
• EXAMPLE 40 Gelatin capsules The capsule filler composition was compounded from the following ingredients:
• Preparation The propanol salt, the CMC and the stearic acid were intimately admixed with each other, and the mixture was granulated in customary fashion, using a solution of the CAP in 200 ml. of a mixture of ethanol and ethylacetate as the moistening agent. The granulate was then compressed into 380 mgm.-cores, which were coated in the usual way with an aqueous 5% solution of polyvinylpyrrolidone containing sugar. Each coated tablet contained 25 mgm. of the propanol salt and, when administered perorally to a warm-blooded animal of about 60 kg. body weight in need of such treatment, produced a very etfective fi-adrenergic receptor blocking action over an extended period of time.
• a compound according to claim 1 which is 1-(2'- cyanophenoxy)-2-hydroxy 3 (1" methylcyclopentylamino)-propane or a non-toxic pharmaceutically acceptable acid addition salt thereof.
• a compound according to claim 1 which is 1-(2- cyanophenoxy)-2-hydroxy 3 (1" methylcyclohexylamino)-propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.
• a compound according to claim 1 which is 1-(2'- cyano-S'-methylphenoxy)-2-hydroxy-3-(1" methylcyc1o pentylamino)-propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.
• a compound according to claim 1 which is 1-(2'- cyano-5-methylphenoxy)-2-hydroxy-3-( 1" methylcyclohexylamino)-propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.
• a compound according to claim 1 which is 1-(2'- cyano-5-methylphenoxy)-2-hydroxy-3-(1" methylcycloheptylamino)-propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

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• 1969
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• 1970
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  • 1970-07-21 CS CS4506A patent/CS170529B2/cs unknown
  • 1970-07-22 JP JP45063634A patent/JPS5133106B1/ja active Pending
  • 1970-07-22 DK DK380170AA patent/DK140281B/da unknown
  • 1970-07-22 BG BG18645A patent/BG19132A3/xx unknown
  • 1970-07-22 BE BE753774D patent/BE753774A/xx not_active IP Right Cessation
  • 1970-07-22 BG BG17135A patent/BG17751A3/xx unknown
  • 1970-07-22 BG BG17137A patent/BG18852A3/xx not_active Expired
  • 1970-07-22 US US00057353A patent/US3755413A/en not_active Expired - Lifetime
  • 1970-07-22 BG BG17136A patent/BG17507A3/xx unknown
  • 1970-07-22 YU YU1860/70A patent/YU34395B/xx unknown
  • 1970-07-22 BG BG15254A patent/BG17749A3/xx unknown
  • 1970-07-23 NL NLAANVRAGE7010928,A patent/NL169874C/xx not_active IP Right Cessation
  • 1970-07-23 SE SE7010200A patent/SE370391B/xx unknown
  • 1970-07-23 AT AT118572A patent/AT304478B/de active
  • 1970-07-23 AT AT118072A patent/AT306703B/de not_active IP Right Cessation
  • 1970-07-23 FR FR7027291A patent/FR2059551B1/fr not_active Expired
  • 1970-07-23 AT AT117972A patent/AT306702B/de not_active IP Right Cessation
  • 1970-07-23 AT AT118672A patent/AT306704B/de not_active IP Right Cessation
  • 1970-07-23 AT AT118372A patent/AT304476B/de not_active IP Right Cessation
  • 1970-07-23 AT AT118472A patent/AT304477B/de not_active IP Right Cessation
  • 1970-07-23 AT AT118272A patent/AT304475B/de active
  • 1970-07-23 AT AT118172A patent/AT304474B/de active
  • 1970-07-23 AT AT674870A patent/AT303706B/de not_active IP Right Cessation
  • 1970-07-24 BG BG17133A patent/BG17506A3/xx unknown
  • 1970-07-24 BG BG17132A patent/BG17505A3/xx unknown
• 1971
  • 1971-09-09 ES ES394914A patent/ES394914A1/es not_active Expired
  • 1971-09-09 ES ES394919A patent/ES394919A1/es not_active Expired
  • 1971-09-09 ES ES394916A patent/ES394916A1/es not_active Expired
  • 1971-09-09 ES ES394913A patent/ES394913A1/es not_active Expired
  • 1971-09-09 ES ES394917A patent/ES394917A1/es not_active Expired
  • 1971-09-09 ES ES394915A patent/ES394915A1/es not_active Expired
  • 1971-09-09 ES ES394918A patent/ES394918A1/es not_active Expired
• 1973
  • 1973-06-06 JP JP48063727A patent/JPS5238556B1/ja active Pending
  • 1973-06-06 JP JP48063730A patent/JPS5210863B1/ja active Pending
  • 1973-06-06 JP JP48063729A patent/JPS5210862B1/ja active Pending
  • 1973-06-06 JP JP48063728A patent/JPS5210861B1/ja active Pending
• 1975
  • 1975-10-07 YU YU2546/75A patent/YU34663B/xx unknown
  • 1975-10-07 YU YU2544/75A patent/YU34396B/xx unknown
  • 1975-10-07 YU YU2551/75A patent/YU34113B/xx unknown
  • 1975-10-07 YU YU2545/75A patent/YU34662B/xx unknown

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