IE46590B1 - Propanolamine derivatives - Google Patents

Propanolamine derivatives

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Publication number
IE46590B1
IE46590B1 IE577/78A IE57778A IE46590B1 IE 46590 B1 IE46590 B1 IE 46590B1 IE 577/78 A IE577/78 A IE 577/78A IE 57778 A IE57778 A IE 57778A IE 46590 B1 IE46590 B1 IE 46590B1
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compound
chg
carbon atoms
alkyl
formula
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IE577/78A
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IE780577L (en
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Sandoz Ltd
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Priority claimed from CH375377A external-priority patent/CH628021A5/en
Priority claimed from CH375177A external-priority patent/CH633521A5/en
Application filed by Sandoz Ltd filed Critical Sandoz Ltd
Publication of IE780577L publication Critical patent/IE780577L/en
Publication of IE46590B1 publication Critical patent/IE46590B1/en

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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/38—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system containing rings other than six-membered aromatic rings
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    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
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    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
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Abstract

Compounds of formula I wherein (i) m is o, n is 2 and p is 1 or (ii) m is o or 1, n is 1, and p is 1 or (iii) m is 1, n is 1 or 2 and p is o, R1 is (i) alkyl of 3 to 7 carbon atoms or (ii) phenylalkyl, phenoxyalkyl, phenylthioalkyl of 8 to 11 carbon atoms in the aggregate thereof and wherein the phenyl ring is separated by at least 2 carbon atoms from the nitrogen atoms to which R1 is bound and wherein the phenyl ring is unsubstituted, or mono-substituted by, or independently disubstituted by, alkyl or alkoxy of 1 to 4 carbon atoms, halogen of atomic number from 9 to 35. trifluoromethyl or cyano, R2 and R3 are either together straight chain alkylene of 4 to 6 carbon atoms. or, independently, hydrogen or alkyl of 1 to 4 carbon atoms, with the proviso that when m is 1, n is 1 and p is O then least one of R2 and R3 is other than hydrogen, and R4 and R5 are, independently, hydrogen or alkyl of 1 to 4 carbon atoms, are useful in the treatment of coronary disorders.

Description

IMPROVEMENTS IN OR RELATING TO' ORGANIC’ COMPOUNDS The present invention relates to l-amino-3aryloxy-2-propanols.
The present Invention provides compounds of formula I wherein (i) m is 0, n is 2 and p is 1 or (ii) m is 0 or 1, n is 1, and p is 1 or (iii) m is 1, n is 1 or 2 and p is 0f R^ is (i) alkyl of 3 to 7 carbon atoms or (ii) phenylalkyl, phenoxyalkyl or phenylthioalkyl of 8 to 11 carbon atoms in the aggregate thereof and wherein the phenyl ring is separated by at least 2 carbon atoms from the nitrogen atom to which R^ is bound and wherein the phenyl ring is unsubstituted, or mono-substituted by, or independently disubstituted by,alkyl or alkoxy of 1 to 4 carbon atoms, halogen of atomic number from 9 to 35, trifluoromethyl or cyano, an4 Kg are either together straight chain alkylene of 4 to 6 carbon atoms, or, independently, hydrogen or alkyl of 1 to 4 carbon atoms, with the proviso that when m is 1, nisi and p is 0 then at least one of Rj and R, is other than hydrogen, and R^ and Rg are, independently, hydrogen or alkyl of 1 to 4 carbon atoms.
When m is 0, preferably n is 2 and p is 1. When m is 1, preferably n is 1. Alkyl and/or alkoxy contains preferably 1 or 2 carbon atoms, especially 1 carbon atom, except where otherwise stated hereinafter. Halogen is preferably chlorine or bromine, especially chlorine. Alkylene contains preferably 4 or 5 carbon atoms, especially carbon atoms.
The alkylene moiety of the phenylalkyl, pbenoxy15 alkyl or phenylthioalkyl radical has preferably 2 to 4 carbon atoms. When the alkylene moiety,·contains more than 2 carbon atoms it is preferably branched, preferably in the α-position to the nitrogen atom to which R^ is bound. When the phenyl ring is mono-substituted, the sub20 stitutent is preferably in the 3 or 4 position. When the phenyl ring is disubstituted, the substituents are preferably in the 3 and 4 positions and are preferably identical.
When is alkyl, this moiety preferably has 3 to carbon atoms, especially 3 or 4 carbon atoms. This is preferably branched, especially in the a-position. is preferably alkyl or phenylalkyl, especially alkyl. Rj and R^ are preferably either each alkyl or together alkylene. R^ and R^ are preferably each hydrogen The present invention provides a process for the production of a compound of formula I as defined above which comprises reacting a compound of formula II 00ΙΙΛ wherein m, η, p and Rj to R^ are as defined above, and R^ is a group capable of reacting with an amine •.to give a 2-amino-l-hydroxyethyl group, with a compound of formula III Rj. NHj III wherein R^ ip defined above.
The present process is an amination by a primary amine. It may be effected in conventional manner for the production of analogous 3-amino-2-hydroxypropoxyaryl compounds.por example R .may be a group of formula -CH-CH^ or a reactive derivative of this group, e.g. of formula -CH(OH)-CH2Y wherein Y is halogen, preferably chlorine or bromineyor a group R^-SOj-O- wherein R^ is phenyl, tolyl or lower alkyl, Y is especially chlorine.
The reaction is effected preferably in an inert organic solvent, e.g. in an appropriate ether such as diaxane. Optionally an excess of a compound of formula III may be used as solvent. Alternatively the reaction may be effected in a fusion melt.
Suitable reaction temperatures may be from about 20 to about 200° C, conveniently the reflux temperature of the reaction mixture when a solvent is present.
Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation include maleic acid and fumaric acid.
In the compounds of formula I, the carbon atom to which the hydroxy group is bound is asymmetrically substituted. The compounds may thus exist in the racemic form or in individual optical isomer form. If either R2 and R3 or R^ and R$ are not identical, then the 10 compounds may exist in individual diastereoisomeric forms. In certain conditions these diastereoisomeric forms may be interconverted,e.g. when there is a hydrogen atom attached to a carbon atom adjacent to a carbonyl group,epimerisation may occur in the presence of a base.
Preferred compounds are, however, the compounds wherein P and R., are identical and R. and Rc are identical .The preferred optical isomer has the S cofifiguration at the asymmetrically substituted carbon atom of the hydroxypropoxy side chain. - 4 _ Individual optical isomer forms and diastereoisomeric forms may be obtained in conventional manner. For example the S isomers may be produced by using optically active starting materials or by fractional crystallisation using optically active acids. Individual diastereoisomeric forms may be similarly obtained using fractional crystallisation, or chromatography, of a mixture of salt forms or using optically active starting materials.
The starting materials may be obtained as follows: Compounds of formula II may be obtained by demethylating or debenzylating a compound of formula IV wherein m, η, p and R2 to Rg are as defined above, and R is methyl or benzyl, and replacing the hydroxy group by a group -O-CH--R in u X the resulting phenol in known manner. - 5 46580 A compound of formula IV a wherein n is 1 or 2, R is as defined above, and I I either and R^ together are straight chain alkylene I I of 4 to 6 carbon atoms, or R2 and R^ are, independently, hydrogen or alkyl (C^_^) with the I II proviso that, when n is 2, Rg and R_ are not both hydrogen, may be obtained by a) reacting a compound of formula V Z is chlorine or bromine, with a compound of formula VI VI wherein Rg1 and Rg1 are as defined above and Rg is,alkyl (C1_4>, to produce a compound of formula VII b) hydrolysing the compound of formula VII and splitting off carbon dioxide from the reaction product to produce a compound of formula VIII RO and, c) cyclizing the resulting compound of formula VIII with e.g. poly-phosphoric acid.
For the production of a compound of formula VIII when n1 is 1 and Rg and Rg are both hydrogen, it is preferred to react oyanoethylene with a compound of formula V and to hydrolyse the resulting compound.
Compounds of formula IVaa RO IVaa 746590 may be produced by oxidizing the corresponding benzo5-suberol with, for example, chromium dioxide or manganese dioxide.
Compounds of formula IVb I II or m is 0 and n is 2, R is as defined above, and either 311 a t03ether are straight-chain alkylene (C^_g), II II or R2 and R3 are, independently, hydrogen or alkyl (C , R^ and Rj.·1 are, independently, alkyl (Cl-4}' may be obtained by alkylating the corresponding 5-nonalkylated compounds.
Compounds of formula IVc I IX II II wherein m , h , R^, R2 , Rg and R^ are as defined above, may be obtained by a) effecting a wittig reaction between a compound of formula IVd to obtain a compound of formula X and, b) reacting the resultaiit compound of formula X with thallium trinitrate in the presence of a lower alkanol. - 9 46590 I II II When m is 0 and R_ and R, are both other 3 than hydrogen in the compound of formula X, this may alternatively be produced by (a) reacting the appropriate compound of formula IVd with a Grignard reagent of an alkyl bromide to produce a carbinol arid (b) splitting off water from the resulting carbinol.
Compounds of formula IVda , · HI , ι -, wherein n is 1 or 2., R is defined above, and either Rg111 and Rg111 together are straight chain alkylene (C4_g) , or R2Ii:r is hydrogen or alkyl > and R/11 is alkyl (C^) , may be produced by mono-or di-alkylating the corresponding compound wherein the 6 position is unsubstituted.
In so far the preparation of any particular starting material is not particularly described, this may be effected in conventional manner.
In the following examples all temperatures are in degrees Centigrade and are uncorrected. 4659 EXAMPLE 1 1- (3-tert~butylamino-2-frydroxypropoxy)-6 ,7 , ' 8., 9-tet'rahydro-7,'.7-dintethyl-5H-benzocyclo' hepten-6-one 2,2 g crude 1-(3-chloro-2-hydroxypropoxy)-6,7, 8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-6-one in 20 ml dioxane and 10 ml tert-butylamine are heated at 130° for 20 hours in an autoclave. The reaction mixture is divided between 10¾ (w/w) aqueous tartaric acid solution and ether. The aqueous phase is made alkaline and extracted with ether. Evaporation of the ether phase yields the title compound (M.pt of hydrogen maleate 186-188°after crystallization from ethanol).
The starting material may be obtained as follows: a) 44.0 g 5-methoxy-l-tetralone in tetrahydrofuran are added dropwise to a suspension of 21 g sodium hydride in tetrahydrofuran. 142 g methyl iodide in tetrahydrofuran is added to the resulting mixture. 5-methoxy-2,2dimethyl-l-tetralone (M.pt 162-170°/12 mm) is obtained after working up. b) A solution of methyl magnesium iodide (produced from 69.7 g methyl iodide and 11.9 g magnesium turnings in ether) is treated with a solution of 66.5 g 5-methoxy2,2-dimethyl-l-tetralone in ether. The reaction mixture is treated with a solution of 62 g ammonium chloride in water. The resultant carbinol is extracted with ether and is treated, dissolved in benzene, with 0.5 g para-toluene-sulphonic acid. After chromatographic purification on basic aluminium oxide using petroleum ether as eluant, methyl 1-(5,6,7,8~tetrahydro-6,6dimethyl-5-methylene-naphthyl) ether is obtained as an oil which is worked up further directly, c) 125 g thallium trinitrate trihydrate in methanol are treated with 55 g methyl 1-(5,6,7,8-tetrahydro-6,6-dime10 thyl-5-methylene-naphthyl) ether in benzene.The precipitated thallium nitrate is filtered off and the solution is extracted with methylene chloride. The resultant 6,7,8,9-tetrahydro~l-methoxy-7,7-dimethy1-5Hbenzocyclohepten-6-one melts at 58-59° (from hexane). d) 4.0 g 6,7,8,9-tetrahydro-l-methoxy-7,7-dimethyl-5Hbenzocyclohepten-6-one are refluxed with 45 ml acetic acid aiid 5 ml 4 8¾ hydrobromic acid for 20 hours. The solution is concentrated, diluted with water and extracted with ether. After removal of the ether, 6,7,8,9-tetra20 hydro-7,7-dimethyl-6-oxo-5H-benzocyclohepten-l-ol melts at 152-154° (from toluene). e) Two drops of piperidine are added to 1.8 g 6,7,8,9tetrahydro-7,7-dimethyl-6-oxo-5H-benzocyclohepten-l-ol in 8 ml epichlorhydrin. The mixture is stirred at 100° for 4 hours. The solution is evaporated, taken up in ether, filtered and concentrated.to 12 give crude 1-(3-chloro-2-hydroxypropoxy)-6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-6-one.
EXAMPLE 2 81 -(3-tert-butylamino-2-hydroxypropoxy)spiro [cyclopentane-l, 2''(1'H)'-naphthalen]-4 1 (3'H)-one The title compound is obtained in analogous manner to Example 1 starting from 8'-(3-chloro-2hydroxypropoxy)spiro[cyclopentane-l,2'(1' H) -naphthalen] -4’(3'H)-one. M.pt.(hydrogen maleate) 188-190° (from ethanol).
The starting material may be obtained as 10 follows: a) A solution of 39.9 g cyclopentylidene cyanoacetic acid ethyl ester In 350 ml tetrahydrofuran is added dropwise to a solution of 2-methoxybenzyl magnesium chloride (produced from 5.3 g magnesium and 31.2 g 2-methoxybenzyl chloride in 400 ml ether). The mixture is stirred for 2 hours at room temperature. The mixture is treated with a 300 ml 15¾ ammonium chloride solution.
The product is extracted with ether and the ethereal solution concentrated to yield:crude α-cyano-[1-(220 methoxybenzyl)cyclopentane]-acetic acid ethyl ester which distilled at 14O-18O°/O.OO2 mm Hg. b) 33.6 g potassium hydroxide are added to a solution of 32.4 g a-cyano-[l-(2-methoxybenzyl)cyclopentanc]acetic acid ethyl ester in 300 ml ethylene glycol. - 13 46590 The mixture is stirred at 180° for 40 hours. The solution is cooled, poured onto ice/water and the neutral side products removed by extraction with ether. The aqueous phase is made acid with hydrochloric acid and extracted with ether. After removal of the solvent 1-(2-methoxybenzyl)cyclopentane acetic acid (M.pt 85-87° from hexane) is obtained. c) 5.7 g 1-(2-methoxybenzyl)cyclopentane-acetic acid is added with stirring to 30 g polyphosphoric acid at 110°. The mixture is cooled and treated with 250 ml water. After extraction with ether and concentration of the ether extract 8'-methoxy-spiro[cyclopentare-l,2' (1' H)-naphthalen}-4 ' (3 Ή) -one (M.pt 62-66°/- is obtained. d) In analogous manner to Example 1 step d)^ 8'-hydroxyspiro[cyclopentane-1,2' (l'H)-naphthalen]-4'(3'H)-one (M.pt 163-165° from toluene) is obtained from the 8-methoxy derivative, and is converted into crude 8'- (3-chloro-2-hydroxypropoxy)-spiro [cyclopentane-1,2' (1'H)-naphtalen]-4'(3'H)-one in analogous manner to Example 1 step e).
From the appropriate compound of formula II wherein R is CH (OH) .CII..C1 and thi.· appropriate compound X of formula III the following compounds of formula I may be obtained in analogous manner to Examples 1 and 2: 14 46S90 0 0 o o o 0 O 0 •Ή «3« IO 0 o. M3 CO co CM in cn CM rH rH [s. rH O rH ι-1 r-H t i—< rH m rH CM CM rH CM | CM CM | +J Ολ rH CM in 1 M* cn o CO O CM rH CO fs. tn «—I in O r-i rH r-Ι H H in CM CM rH CM CM CM S' ? CM co ro co a o O ' o o o o o O rH • rH (J r-i CM rH rH rH CM rH rH f—| rH E rH rH rH rH rH rH rH rH O r-H ro co e e u u ι I in E CM U I E u to to _ Ε E Ε o a ί I I CM Ε u ro ro Ε E α u i I tn E CM u w I I ro E Pi (O E U ffi U I ro E U I ro co ro I CO to i υ CO CO CO ,_ o <—» o ^-s *-s <-> to co co to co co CM co to co E E E E BJ K BJ E E E BJ E w o u O U u u U a rn U o U u s^ S«X V s' * *** W 1 W *-<* u 1 o 1 u 1 1 υ o I y—O~U u 1 u u 1 0 Z tf fs. o rH CM w co m • ID co rH rH H Hj Ο •u Φ w φ w Ή Φ Λ 4J Ο « Φ r-i C α φ 4J (ΰ Μ Φ Φ ω ιΰ Λ w ♦Η Λ iw Ο +J G Ή Ο ο tn d •Η •μ rH Φ Ε β μ Ο in φ ti Λ Φ Φ ιη Φ •Ρ Φ Φ γ—ι Φ d Φ tn Ο ΓΟ >1 Λ diastereoisomeric mixture Η (Ν 6 5 9 0 The compound; of formula I exhibit pharmacological activity in animals. In particular, the compounds of formula I inhibit glycerol release stimulated by isoproterenol in standard tests, e.g. as follows; i) Injvltro_ Isolated fat cells are obtained from dog subcutaneous tisue, and from rat and quinea pig epididymal fat pads, in accordance with the method of M.Rodbell [J. Biol. Chem. 239, 375-380 (1964)]. Cells from one of the animals are dispersed in Krebs phosphate buffer containing 4% bovine serum albumin. 1 ml aliquots of the cell suspension in plastic incubation, flasks are treated with the test substance at from about 0.01 to about -7 mg/litre and isoproterenol at 10 Molar. The glycerol release is determined in conventional manner, e.g. according to the method of S. Laurell et al, Helv. Chim. Acta 13, 317-322 (1966). ii) In_vivo Rats are fasted for 16 hours. A sub-cutaneous injection of 400 /ig/kg of isoproterenol results in a glycerol concentration in the blood plasma of 400¾ the original value. This increased glycerol concentration remains constant for ca. 60 minutes and acts as a control value. The test substance is administered s.c. at a dose of from about 0.01 to about 0.5 mg/kg 10 minutes before the isoproterenol--;-------------------injection, and the animals are decapitated 40 minutes after the isoproterenol injection. The glycerol concentration in the blood is calculated in conventional manner, e.g. using the conventional glycero-3-phosphatedehydrogenase method [according S. Laurell et al} reference as mentioned above].
The compounds are therefore indicated for use in 10 the treatment of the increase of free fatty acid concentration in the blood induced by emotional stress, and also inhibit lipolysis induced by emotional stress, and myocardial infarction induced by emotional stress.
The compounds of formula I additionally inhibit 15 hyperglycemia induced by emotional stress, as indicated by an inhibition of glycogenolysis in standard tests, as follows:In the above-mentioned rat in vivo test the glucose concentration in the blood is determined in 2q conventional manner, e.g. using the ferricyanide method.
In the control animals the glucose concentration doubles after 40 minutes after isoproterenol administration. The compounds are administered parenterally at a dose of from about 0.01 to about 5 mg/kg animal body vzeight. 46S&0 The compounds are therefore indicated for use in the treatment of hyperglycemia induced by emotional stress, e.g. for suppressing of appetite induced by emotional stress .
Additionally, the compounds exhibit a cardiovascular adrenergic Q-blocking effect as indicated in standard tests, e.g. by an inhibition of the positive inotropic adrenaline effect in the spontaneously beating quinea pig atrium at bath concentrations of from 0.005 to 2.5 mg/litre in accordance with the method of K.Sammeli, Helv. Physiol.Acta 25, CR 215-221 (1967)·, and in the infusion test in narcotized cats at doses of approximately 0.02 to 0.6 mg/kg i.v., where they induce a strong, long lasting inhibition of the tachycardia and blood pressure lowering caused by isoproterenol.
The compounds are therefore indicated for use as cardio-vascular adrenergic β-blocking agents, e.g. for the prophylaxis and therapy of Angina pectoris, and also as arrhythmics.
In general, the 2(S) optical isomers are more active than the 2(R) optical isomers in the cardiovascular β-blocking tests.
For all these indications an indicated daily dose is from about 1 to about 200 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 100 mg o the compound or in sustained release form.
The compounds of formula I also exhibit a sali5 diuretic effect as indicated in standard tests, e.g. in the diuretic rat test in accordance with the principles of E. Fliickiger et al, Schweiz.med. Wschr. 1963 , 93 , 1232, on administration p.o. of from about 0.1 to about mg/kg animal body weight of the compounds.
O The compounds are therefore indicated for use as salidiuretic agents, e.g. for the treatment of odema and hypertension.
An indicated daily dose is from about 1 to about 100 mg, conveniently administered in divided do5 ses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 50 mg of the compounds, or in sustained release form.
The example 1 and 2 compounds exhibit particularly interesting properties.
The compounds may be administered in pharmaceutically acceptable acid addition salt form. Such forms exhibit the same order of activity as the free base forms. The present invention also provides a pharmaceutical composition comprising a compound of formula I in free base form or in pharmaceutically acceptable acid addition g salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be, for example, a solution or tablet.
In a group of compounds p is 0, m is 1 and 10 n is 1 or 2. Preferably is alkyl and Rg and Rg are each alkyl or together alkylene of 4 or 5 carbon atoms. In a sub-group Rg and Rg are together alkylene.
In another sub-group Rg is alkyl of 3 or 4 carbon atoms.
In another group of compounds p is 1, m is 1 and n is isl.In another group p is 1, m is 0 and n is 1.
In another group p is 1, m is 0 and n is 2.

Claims (30)

1. A process for the production of a compound of formula I wherein (i) m is 0, n is
2. And p is 1 or (ii) in is O or 1, n is 1, and p is 1 or (iii) in is 1, n Is 1 or 2 and p is 0, Rg is (i) alkyl of 3 to 7 carbon atoms or (ii) phenylalkyl, phenoxyalkyl or phenylthioalkyl of 8 to 11 carbon atoms in the aggregate thereof and wherein the phenyl ring is separated by at least 2 carbon atoms from the nitrogen atom to which Rg is bound and v/herein the phenyl ring is unsubstituted, or mono-substituted by, or independently disubstituted by, alkyl or alkoxy of 1 to 4 carbon atoms, halogen of atomic number from 9 to 35, trifluoromethyl or cyano, Rg and Rg are either together straight chain alky lene of 4 to 6 carbon atoms, or, independently hydrogen or alkyl ofj.to 4 car bon atoms,with the proviso that when m is 1, n is 1 and p is 0 then at least one of Rg and Rg is other than hydrogen, and R^ and Rg are, independently, hydrogen or alkyl of 1 to 4 carbon atoms, which comprises reacting a compound of formula XI wherein m, η, p and R 2 to Rg are as defined above, and 3 R x is a 9 rou P capable of reacting with an amine .to give a 2-amino-l-hydroxysthyl group, with a compound of formula III R x nh 2 III wherein R^ is defined above. 10. 2A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to any one of the Examples
3. A compound of formula I, whenever produced by a process according to claim 1 or 2.
4. 4. A compound of formula I, as defined in claim 1.
5. A compound Of claim 4 wherein m is 1, n is 1 and p is 0.
6. A compound of cl aim 4 wherein m is 1, n is 2 and p is 0.
7. A compound of claim 5 or 6 wherein R 1 is alkyl ( C 3-7 ,).
8. A compound of claim 7 wherein and R 3 are, inde- pendently, alkyl or together alkylene (C^_ g ).
9. A compound of claim 4 wherein m is 1, n is 1 and lo p is 1.
10. A compound of claim 4 wherein p is 1, m is 0 and n is 1.
11. A compound of claim 4 wherein m is 0, n is 2 and p is 1.
12. 12. 1-(3-tert-butylamino-2-hydroxypropoxy)-6,7,8,9-tetrahydro~7,7-dimethyl-51J-benzoeyclohepten-C~one.
13. 8’- (3-tert-but.ylamino-2-hydroxypropoxy)spiro{cyclo pentane-1,2'(l'H)-naphthalen]-4'(3'H)-one.
14. A compound of claim 5 wherein is -and 20. and R^ together are
15. A compound of claim 6 wherein R^, and R 3 respec tively are -C(CH ) , -CH 3 ,and CH^.
16. A compound of claim 5 wherein R^, R 2 and R 3 respectively are -C(CH 3 ) 3 , “CHg, and -CH 3 · 4659. ο
17. A compound of claim 5 wherein R^, Rg and Rg respectively are CH , CHg, and -CHg. -C-CH-O- -CN \ CH 3.
18. A compound of claim 5 wherein R^, Rg and Rg tively are -C(CHg)g, -CgHg, and -CgHg.
19. A compound of claim 6 wherein R^, Rg and Rg tively are -C(CHg)g, -H, and -H.
20. A compound of claim 5 wherein R^, Rg and Rg tively are pH, /-\ , -CHg, and CHg.
21. respecrespecrespec21. A compound of claim 5 wherein R^, Rg and Rg respectively are -C(CHg)g, -CH(CHg)g, and -H.
22. A compound of claim 10 wherein R^, Rg and Rg, R^ and Rg are respectively -C(CHg)g, -CHg and CHg, -H, and -H.
23. A compound of claim 9 wherein R^, Rg, Rg, R^, and Rg are respectively--C(CHg)g, CHg, and CHg, -H, and -H.
24. A compound of claim 9 wherein R^, Rg, Rg, R^, and Rg are respectively -C(CHg)g, -H, and -H, -CHg, and -CHg.
25. A compound of claim 9 wherein R^, Rg, Rg, R^ and Rg are respectively -C(CHg)g, -H, and -H, -h, and -H.
26. A compound of claim 10 wherein R^, Rg, Rg, R^ and Rg are respectively -C(CHg)g, -H, and -H, -CHg, and CHg.
27. Λ compound of claim 11 wherein R^, Rg, and Rg are respectively -C(CHg)g, -CH_, and -CHg, -CHg, and -CHg
28. A compound according to any one of claims 3 to 27 in free base form.
29. A compound itccording to any one of claims 3 to 27 in acid addition salt form.
30. A pharmaceutical composition comprising a compound according to any one of claims 3 to 27 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent. Dated this 22nd day of March, 1978. BY: TOMKINS & CO., Applicants' Agents,
IE577/78A 1977-03-24 1978-03-22 Propanolamine derivatives IE46590B1 (en)

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CH375377A CH628021A5 (en) 1977-03-24 1977-03-24 Process for the preparation of 3-amino-2-hydroxypropoxy derivatives
CH375177A CH633521A5 (en) 1977-03-24 1977-03-24 Process for preparing novel 3-amino-2-hydroxypropoxy derivatives

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IE46590B1 true IE46590B1 (en) 1983-07-27

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CA1119190A (en) 1982-03-02
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NZ186758A (en) 1980-10-24
SU959622A3 (en) 1982-09-15
ES468132A1 (en) 1979-07-01
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IL54327A0 (en) 1978-06-15
IL54327A (en) 1982-09-30
AU3442678A (en) 1979-09-27
AT370720B (en) 1983-04-25
JPS53149960A (en) 1978-12-27
AU521709B2 (en) 1982-04-29
FR2384740B1 (en) 1980-06-20
DE2810869A1 (en) 1978-09-28
PT67807A (en) 1978-04-01
ATA207178A (en) 1982-09-15
IE780577L (en) 1978-09-24
SE7802972L (en) 1978-09-25
IT7848558A0 (en) 1978-03-23
FI780820A7 (en) 1978-09-25

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