CA1119190A - 1-amino-3-aryloxy-2-propanols - Google Patents
1-amino-3-aryloxy-2-propanolsInfo
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- CA1119190A CA1119190A CA000299681A CA299681A CA1119190A CA 1119190 A CA1119190 A CA 1119190A CA 000299681 A CA000299681 A CA 000299681A CA 299681 A CA299681 A CA 299681A CA 1119190 A CA1119190 A CA 1119190A
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- 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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- C07C217/04—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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- C07C41/18—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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- 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
- 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
- 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
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- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
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Abstract
Abstract of the Disclosure 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, phenylthio-alkyl 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 alky-lene 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.
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, phenylthio-alkyl 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 alky-lene 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
l-AMINO-3-ARYLOXY-2-PROPANOLS
The present invention relates to l-amino-3-aryloxy-2-propanols.
The present invention provides compounds of formula I ~.
OH
OCH2CHCH2NH-Rl (CH2)n ~ .I
.0 wherein (i) m is 0, 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 Ot -~
Rl is (i) alkyl of 3 to 7 carbon atoms or (ii) phenylalkyl, phenoxyalkyl or phenylthio-alkyl 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 Rl is bound and wherein the phenyl ring is unsubstituted, or mono-substituted by,or inde~endently disubstituted by,a~yl or a~oxy or 1 to 4 carbon atoms, halogen of atomic number from 9 to 35, trifluoromethyl or cyano, R2 and R3 are either together straight chain alky-lene of 4 to 6 carbon atoms, - ;.,i 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 0 then at 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; and pharmaceutically acceptable acid addition salts thereof.
When m is 0, preferably n is 2 and p is 1. When m is 1, preferably n is 1. Alkyl and/or alkoxy con-- 10 tains preferably 1 or 2 carbon atoms, especially 1 carbon atom, except where otherwise stated herein- -after. Halogen is preferably chlorine or bromine, especially chlorine. Alkylene contains preferably 4 or 5 carbon atoms, especially 4 carbon atoms.
The alkylene moiety of the phenylalkyl, phenoxy-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 a-position to the nitrogen atom to which R1 is bound.when the phenyl ring is disubsti-tuted, the substituents are preferably in the 3 or 4 positions and are preferably identical.
When Rl is alkyl, this moiety preferably has 3 to 5 carbon atoms, especially 3 or 4 carbon atoms.
This is preferably branched, especially in the a-position.
,,,,;
~,, ..
Rl is preferably alkyl or phenylalkyl, especially alkyl. R2 and R3 are preferably either each alkyl or together alkylene. R4 and R5 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
OCH2-R ', ~ (CR4R f R3 II
O
wherein m, n, p and R2 to R5 are as defined above, and Rx is a group capable of reacting with an amine :to give a 2-amino-1-hydroxysthyl group, with a compound of formula III
Rl NH2 III
wherein Rl is defined above; and where necessary or desired, forming a pharmaceutically acceptable acid addition salt of the resulting compound of formula I.
The present process is an amination by a primary amlne. It may be effected in conventional manner for the production of analogous 3-amino-2-hydroxypropoxy-aryl compounds.FOr example R may be a group of formula -CH-CH2 or a reactive derivative of this group, e.g.
of formula -CH(OH)-CH2Y wherein Y is halogen, preferably chlorine or bromine/or a group Ry-SO2~O~ wherein Ry is phenyl, tolyl or lower alkyl. Y is especially chlorlne.
~*J' The reaction is effected preferably in an inert organic solvent/ e.g. in an appropriate ether such as dioxane- 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 tempera-ture 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 con-ventional 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 ra-cemic form or in individual optical isomer form. If either R2 and R3 or R4 and R5 are not identical, then the 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 ccmpounds are,however, the compounds wherein R2 and R3 are identical and R4 and R5 are identical.The ; preferred optical isomer has the S co~figuration at the asymmetrically substituted carbon atom of the hy-droxypropoxy side chain.
~J ~
~i 4 _ ~3. ~
Individual optical isomer forms and diastereo-isomeric 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. Indi-vidual 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
(CR4R5~ ~ IV
wherein m, n, p and R2 to R5 are as defined above, and R is methyl or benzyl, and replacing the hydroxy group by a group -O-CH2-R in the resulting phenol in kno~n manner.
-~
A compound of formula IV a RO
~ ~ ~ R2 I IVa wherein n is 1 or 2, R is as defined above, and either R2I and R3I together are straight chain alkylene of 4 to 6 carbon atoms, or R2 and R3 are, independently, hydrogen or alkyl (Cl 4) with the proviso that, when n is 2, R2 and R3 are not both hydrogen, may be obtained by a) reacting a compound of formula V
RO
~ (CH2)nI V
wherein n and R are as defined above, and Z is chlorine or bromine, with a compound of formula VI
The present invention relates to l-amino-3-aryloxy-2-propanols.
The present invention provides compounds of formula I ~.
OH
OCH2CHCH2NH-Rl (CH2)n ~ .I
.0 wherein (i) m is 0, 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 Ot -~
Rl is (i) alkyl of 3 to 7 carbon atoms or (ii) phenylalkyl, phenoxyalkyl or phenylthio-alkyl 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 Rl is bound and wherein the phenyl ring is unsubstituted, or mono-substituted by,or inde~endently disubstituted by,a~yl or a~oxy or 1 to 4 carbon atoms, halogen of atomic number from 9 to 35, trifluoromethyl or cyano, R2 and R3 are either together straight chain alky-lene of 4 to 6 carbon atoms, - ;.,i 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 0 then at 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; and pharmaceutically acceptable acid addition salts thereof.
When m is 0, preferably n is 2 and p is 1. When m is 1, preferably n is 1. Alkyl and/or alkoxy con-- 10 tains preferably 1 or 2 carbon atoms, especially 1 carbon atom, except where otherwise stated herein- -after. Halogen is preferably chlorine or bromine, especially chlorine. Alkylene contains preferably 4 or 5 carbon atoms, especially 4 carbon atoms.
The alkylene moiety of the phenylalkyl, phenoxy-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 a-position to the nitrogen atom to which R1 is bound.when the phenyl ring is disubsti-tuted, the substituents are preferably in the 3 or 4 positions and are preferably identical.
When Rl is alkyl, this moiety preferably has 3 to 5 carbon atoms, especially 3 or 4 carbon atoms.
This is preferably branched, especially in the a-position.
,,,,;
~,, ..
Rl is preferably alkyl or phenylalkyl, especially alkyl. R2 and R3 are preferably either each alkyl or together alkylene. R4 and R5 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
OCH2-R ', ~ (CR4R f R3 II
O
wherein m, n, p and R2 to R5 are as defined above, and Rx is a group capable of reacting with an amine :to give a 2-amino-1-hydroxysthyl group, with a compound of formula III
Rl NH2 III
wherein Rl is defined above; and where necessary or desired, forming a pharmaceutically acceptable acid addition salt of the resulting compound of formula I.
The present process is an amination by a primary amlne. It may be effected in conventional manner for the production of analogous 3-amino-2-hydroxypropoxy-aryl compounds.FOr example R may be a group of formula -CH-CH2 or a reactive derivative of this group, e.g.
of formula -CH(OH)-CH2Y wherein Y is halogen, preferably chlorine or bromine/or a group Ry-SO2~O~ wherein Ry is phenyl, tolyl or lower alkyl. Y is especially chlorlne.
~*J' The reaction is effected preferably in an inert organic solvent/ e.g. in an appropriate ether such as dioxane- 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 tempera-ture 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 con-ventional 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 ra-cemic form or in individual optical isomer form. If either R2 and R3 or R4 and R5 are not identical, then the 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 ccmpounds are,however, the compounds wherein R2 and R3 are identical and R4 and R5 are identical.The ; preferred optical isomer has the S co~figuration at the asymmetrically substituted carbon atom of the hy-droxypropoxy side chain.
~J ~
~i 4 _ ~3. ~
Individual optical isomer forms and diastereo-isomeric 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. Indi-vidual 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
(CR4R5~ ~ IV
wherein m, n, p and R2 to R5 are as defined above, and R is methyl or benzyl, and replacing the hydroxy group by a group -O-CH2-R in the resulting phenol in kno~n manner.
-~
A compound of formula IV a RO
~ ~ ~ R2 I IVa wherein n is 1 or 2, R is as defined above, and either R2I and R3I together are straight chain alkylene of 4 to 6 carbon atoms, or R2 and R3 are, independently, hydrogen or alkyl (Cl 4) with the proviso that, when n is 2, R2 and R3 are not both hydrogen, may be obtained by a) reacting a compound of formula V
RO
~ (CH2)nI V
wherein n and R are as defined above, and Z is chlorine or bromine, with a compound of formula VI
2 ~_ " ,R
1 . VI
R~OOC CN
wherein R2I and R3I are as defined above and R6 is alkyl (Cl_43, to produce a compound of formula VII
R~ I
( 2)n ~ I VII
R OOC ~
6 ~N
b) hydrolysing the compound of formula VII and splitting off carbon dioxide from the reaction product to pro-duce a compound of formula VIII
( 2) ~ 2 VIII
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 n is 1 and R2 and R3 are both hydrogen, it is preferred to react cyanoethylene with a compound of formula V and to hydrolyse the resulting compound~
Compounds of formula IVaa ~, IVaa - ~.9 ~
may be produced by oxidizing the corresponding benzo-5-suberol with, for example, chromium dioxide or manganese dioxide.
Compounds of formula IVb wherein either m is 0 or 1 and n is 1, or m is 0 and n is 2, R is as defined above, and either R2 I and R3 I together are straight-chain alkylene (C4_6)~
or R2 and R3 are, independently, hydrogen or alkyl (Cl_4), R4I and R5I are, independently, alkyl (Cl_4 ), may be obtained by alkylating the corresponding 5-non-alkylated compounds.
Compounds of formula IVc R,0 II
II IVc wherein m , n I, Rl, R2 I, R3 and R4 are as defined above, may be obtained by a) effecting a wittig reaction between a compound of formula IVd ~ ( ~)mI Vd with a compound of formula IX
~ f - CH - R4 IX
~ ' ' .~ ~
to obtain a compound of formula X
2)nII R~
~ 2 ~nI
and, b) reacting the resulta~t compound of formula X with thallium trinitrate in the presence of a lower alkanol.
~ hen m is 0 and R2 and R3 are both other 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 and (b) splitting off water from the resulting carbinol.
Compounds of formula IVda 1 o ~ lII IV da h i III is 1 or 2 R is defined above, and either R2 and R3 together are straight chain alkylene (C4_6), or R2 is hydrogen or alkyl (Cl 4), and R3 is alkyl (Cl_4), may be produced by mono-or di-alkylating 'the corresponding compound wnerein the 6 position is un-substituted.
Insofar as 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.
~ - 10 -~ 100-4767 EXAMPLE 1 1-(3-tert-butYlamlno-2-hydroxypropoxy)-6,7, '8,9- rahy'dro'-'7','7-dimethYl-5H-benzocYclo-'hepten-6-one 2,2 g crude 1~(3-chloro-2-hydroxypropoxy)-6,7, 8,9-tetrahydro-7,7-dimethyl-5~-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 10~ (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 186-188after crystallization from ethanol).
The starting material may be obtained as follows: -a) 44.0 g 5-methoxy-1-tetralone in tetrahydrofuran are added dropwise to a suspension of 21 g sodium hydride in tetrahydrofuran. 142 g methyl iodide in tetrahydro-furan is added to the resulting mixture. 5-methoxy-2,2-dimethyl-l-tetralone ~M.pt 162-170/12 mm) is obtained ater working up.
b) A solution of methyl magnesium iodide ~producea from 69.7 g methyl iodide and 11.9 g magnesium turnings in ether) is treated with a solution of 66.5 g 5-methoxy-2,2-dimethyl-1-tetralor.e in ether~The reaction mixture is treated with a solution of 62 g ammonium chloride -.
- . . ~
1~0-4767 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 usin~ petroleum ether as eluant, methyl 1-(5,6,7,8-tetrahydro-6,6-dimethyl-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-tetrahy~ro-6,6-dime-thyl-5-methylene-naphthyl~ ether in benzene-.~he--precipi-tated thallium nitrate is filtered off and the solution is extracted with methylene chloride. The resultant 6,7,8,9-tetrahydro-1-methoxy-7,7-dimethyl-5H-~
benzocyclohepten-6-one melts at 58-59 (from hexane).
d) 4.0 g 6,7,8,9-tetrahydro-1-methoxy-7,7-dimethyl-5H-benzocyclohepten-6-one are refluxed with 45 ml aeetic acid and 5 ml 48% hydrobromic acid for 20 hours. The solutlon is concentrated, diluted with water and extracted with ether. After removal of the e~her~6,7,8,9-tetra-hydro-7,7-dimethyl-6-oxo-5~-benzocyclohepten-1-ol melts at 152-154 (from toluene).
e) Two drops of piperidine are added to 1.8 ~ 6,7,8,9-tetrahydro-7,7-dimethyl-6-oxo-5H-benzocycloheptQn-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 -give crude 1-(3-ChlOrO-2-hydroxypropoxy)-6~7~8~9~tetra-hydro-7,7-dimethyl-5H-benzocyclohepten-6-one.
EXAMP~E 2 8'-(3-tert-butYlamino-2-hydroxy~ropoxy)sPiro [cyclopentane-1,2'(1~ na~hthalen]-4'~3'H)-one The title compound is obtained in analogous manner to Example 1 starting from 8'-(3-chloro-2-hydroxypropoxy)spiro[cyclopentane-1,2'(1'H)~naphthalen]
-4'(3'E~)-one. M.pt.(hydrogen maleate) 18a-190 (from ethanol).
The starting material may be obtained as 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 15% ammonium chloride solution.
The product is extracted with ether and the ethereal solution concentrated to yield~crude a-cyano-tl-~2-methoxybenzyl)cyclopentane]-acetic acid ethyl ester which distilled at 140-180/0.002 mm Hg.
b) 33.6 g potassium hydroxide are added to a solution of 32.4 g a-cyano-[1-(2-methoxybenzyl)cyclopentane)-acetlc acid ethyl ester in 300 ml ethylene glycol.
The mlxt~re is stirred at 180 for 40 hours. The solution is cooled,poured onto ioehYater and the neutral side products removed by extraction with ether. The aqueous phase is made acid with hydrochlor' 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[cyclopentane-1,2' (l'~)-naphthalen}4'(3'H)-one (M.pt 62-66~- is ob-tained, d) In analogous manner to Example 1 step d)/ 8'-hydroxy-spiro[cyclopentane-1,2'(1'H)-naphthalenl-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' (llH)-naphthalen]-4l ~3'H)-one in analogous manner to Example 1 step e).
From the appropriate compound of formula II
wherein Rx is CH(OH).CH2Cl and the appropriate compound of formula III the following compounds of formula I may be obtained in analogous manner to Examples 1 and 2: -j~ i ~i - 14 -, rY T~
r~ ~ ~ N N ,_~ ~N N
,_ ~
~ ~ ~ ,~
.
. O 0'0 o O O o O ~ ~ , ~ -1 N ~ 1 N ,~ I
E~ ~
p~m I I I r ~ m m P~ I, I , ,m m ........ -- ..
. In' ' ' p~ m~ mN ~ ~ m :~:
~n m~ m~ :~
-- 1 - .
z I ,,,,,,. .~
': ~ . ~ '`
~ _ _ o -- -- o ~ --~ ~ ~ ~ ~ N ~) ~ ~ ~ ~ ~7 P; m ~ m - ~ ~ - -- -:
.` ` - ~ ` .
- ~ o ~ ~ .
CO Ln ~ ~
O O ~ ~t ~ o o O O
I I N
~ r~ 1 .
,, ~J ~ O O
. ,~
U ~D
) O
. ~1 ~ 51 ~;~ m ~ m ~ .
.' ~ . h~
~ ~ ~ ~a 0 ~ ,_ ~ ~ ~ d K m m :~ m o ~_ _ _ _ .
l l l l ~ ~ ~ rl _ I ' ,~
~' , .
The compoun~sof formula I exhibit pharma-cological activity in animals. In particular, the com-pounds of formula I inhibit glycerol release stimulated by isoproterenol in standard tests, e.g. as follows: -i) In vitro Isolated fat cells are obtained from dog sub-cutaneous tisue, and from rat and guinea 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 10 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).
~1) In vivo _______ :
Rats are fasted for 16 hours. A sub-cutaneous injection of 400 ~g/kg of isoproterenol results in a glycerol concentration in the blood plasma of 400~ 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 do~e of ~ - 17 -. 'l' . ~ ~
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 ca~culated in conventional manner, e.g. using the~ conventional glycero-3-phosphate-dehydrogenase method ~according S. Laurell et al;
reference as mentioned above].
The compounds are therefore indicated for use in 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 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 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 weiqht.
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 cardio-vascular adrenergic ~-blocking effect as indicated in standard tests, e.g. by an inhibition of the positive inotropic adrenaline effect in the spontaneously beating guinea pig atrium at bath concentrations of from 0.005 to 2.5 mg/litre in accordance with the method of K.Sam~eli, Helv. Physiol.Acta 25, CR 215-221 tl967); 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 ~-blockina asents, 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 cardiovas-cular ~-blocking tests.
For all these indications an indicated daily dose is from about 1 to about 200 mg, conveniently - lg -s~
administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 100 mg of the compound or in sustained release form.
The compounds of formula I also exhibit a sali-diuretic effect ~s indicated in standard tests, e.g. in the diuretic rat test in accordance with the principles of E. Fluckiger et al, Schweiz.med. Wschr. 1963, 93, 1232, on administration p.o. of from about 0.1 to about - ~0 mg/kg animal body weight of the comPounds.
The compoundsare therefore indicated for use as salidiuretic agents, e.g. for thP treatment of odema and hypertension.
An indicated daily dose is from abol~t 1 to about 100 mg, conveniently administered in divided do-ses 2 to 4 times a day in unit dosage form con-taining from abQut 0.25 to about 50 mg of the compaunds, or in sustained release form.
The example 1 and 2 compounds exhibit particu-larly interesting properties.
The compounds may be administered in pharmaceuti-cally acceptable acid addition salt form. Such forms exhiblt 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 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 f ablet.
,, In a group of compounds p is 0, m is 1 and n is 1 or 2. Preferably Rl is alkyl and R2 and R3 are each alkyl or together alkylene of 4 or 5 carbon atoms. In a sub-group R2 and R3 are together alkylene.
In another s,ub-group R2 is a]kyl 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 l, m is 0 and n is 2.
- 21 ~
1 . VI
R~OOC CN
wherein R2I and R3I are as defined above and R6 is alkyl (Cl_43, to produce a compound of formula VII
R~ I
( 2)n ~ I VII
R OOC ~
6 ~N
b) hydrolysing the compound of formula VII and splitting off carbon dioxide from the reaction product to pro-duce a compound of formula VIII
( 2) ~ 2 VIII
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 n is 1 and R2 and R3 are both hydrogen, it is preferred to react cyanoethylene with a compound of formula V and to hydrolyse the resulting compound~
Compounds of formula IVaa ~, IVaa - ~.9 ~
may be produced by oxidizing the corresponding benzo-5-suberol with, for example, chromium dioxide or manganese dioxide.
Compounds of formula IVb wherein either m is 0 or 1 and n is 1, or m is 0 and n is 2, R is as defined above, and either R2 I and R3 I together are straight-chain alkylene (C4_6)~
or R2 and R3 are, independently, hydrogen or alkyl (Cl_4), R4I and R5I are, independently, alkyl (Cl_4 ), may be obtained by alkylating the corresponding 5-non-alkylated compounds.
Compounds of formula IVc R,0 II
II IVc wherein m , n I, Rl, R2 I, R3 and R4 are as defined above, may be obtained by a) effecting a wittig reaction between a compound of formula IVd ~ ( ~)mI Vd with a compound of formula IX
~ f - CH - R4 IX
~ ' ' .~ ~
to obtain a compound of formula X
2)nII R~
~ 2 ~nI
and, b) reacting the resulta~t compound of formula X with thallium trinitrate in the presence of a lower alkanol.
~ hen m is 0 and R2 and R3 are both other 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 and (b) splitting off water from the resulting carbinol.
Compounds of formula IVda 1 o ~ lII IV da h i III is 1 or 2 R is defined above, and either R2 and R3 together are straight chain alkylene (C4_6), or R2 is hydrogen or alkyl (Cl 4), and R3 is alkyl (Cl_4), may be produced by mono-or di-alkylating 'the corresponding compound wnerein the 6 position is un-substituted.
Insofar as 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.
~ - 10 -~ 100-4767 EXAMPLE 1 1-(3-tert-butYlamlno-2-hydroxypropoxy)-6,7, '8,9- rahy'dro'-'7','7-dimethYl-5H-benzocYclo-'hepten-6-one 2,2 g crude 1~(3-chloro-2-hydroxypropoxy)-6,7, 8,9-tetrahydro-7,7-dimethyl-5~-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 10~ (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 186-188after crystallization from ethanol).
The starting material may be obtained as follows: -a) 44.0 g 5-methoxy-1-tetralone in tetrahydrofuran are added dropwise to a suspension of 21 g sodium hydride in tetrahydrofuran. 142 g methyl iodide in tetrahydro-furan is added to the resulting mixture. 5-methoxy-2,2-dimethyl-l-tetralone ~M.pt 162-170/12 mm) is obtained ater working up.
b) A solution of methyl magnesium iodide ~producea from 69.7 g methyl iodide and 11.9 g magnesium turnings in ether) is treated with a solution of 66.5 g 5-methoxy-2,2-dimethyl-1-tetralor.e in ether~The reaction mixture is treated with a solution of 62 g ammonium chloride -.
- . . ~
1~0-4767 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 usin~ petroleum ether as eluant, methyl 1-(5,6,7,8-tetrahydro-6,6-dimethyl-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-tetrahy~ro-6,6-dime-thyl-5-methylene-naphthyl~ ether in benzene-.~he--precipi-tated thallium nitrate is filtered off and the solution is extracted with methylene chloride. The resultant 6,7,8,9-tetrahydro-1-methoxy-7,7-dimethyl-5H-~
benzocyclohepten-6-one melts at 58-59 (from hexane).
d) 4.0 g 6,7,8,9-tetrahydro-1-methoxy-7,7-dimethyl-5H-benzocyclohepten-6-one are refluxed with 45 ml aeetic acid and 5 ml 48% hydrobromic acid for 20 hours. The solutlon is concentrated, diluted with water and extracted with ether. After removal of the e~her~6,7,8,9-tetra-hydro-7,7-dimethyl-6-oxo-5~-benzocyclohepten-1-ol melts at 152-154 (from toluene).
e) Two drops of piperidine are added to 1.8 ~ 6,7,8,9-tetrahydro-7,7-dimethyl-6-oxo-5H-benzocycloheptQn-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 -give crude 1-(3-ChlOrO-2-hydroxypropoxy)-6~7~8~9~tetra-hydro-7,7-dimethyl-5H-benzocyclohepten-6-one.
EXAMP~E 2 8'-(3-tert-butYlamino-2-hydroxy~ropoxy)sPiro [cyclopentane-1,2'(1~ na~hthalen]-4'~3'H)-one The title compound is obtained in analogous manner to Example 1 starting from 8'-(3-chloro-2-hydroxypropoxy)spiro[cyclopentane-1,2'(1'H)~naphthalen]
-4'(3'E~)-one. M.pt.(hydrogen maleate) 18a-190 (from ethanol).
The starting material may be obtained as 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 15% ammonium chloride solution.
The product is extracted with ether and the ethereal solution concentrated to yield~crude a-cyano-tl-~2-methoxybenzyl)cyclopentane]-acetic acid ethyl ester which distilled at 140-180/0.002 mm Hg.
b) 33.6 g potassium hydroxide are added to a solution of 32.4 g a-cyano-[1-(2-methoxybenzyl)cyclopentane)-acetlc acid ethyl ester in 300 ml ethylene glycol.
The mlxt~re is stirred at 180 for 40 hours. The solution is cooled,poured onto ioehYater and the neutral side products removed by extraction with ether. The aqueous phase is made acid with hydrochlor' 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[cyclopentane-1,2' (l'~)-naphthalen}4'(3'H)-one (M.pt 62-66~- is ob-tained, d) In analogous manner to Example 1 step d)/ 8'-hydroxy-spiro[cyclopentane-1,2'(1'H)-naphthalenl-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' (llH)-naphthalen]-4l ~3'H)-one in analogous manner to Example 1 step e).
From the appropriate compound of formula II
wherein Rx is CH(OH).CH2Cl and the appropriate compound of formula III the following compounds of formula I may be obtained in analogous manner to Examples 1 and 2: -j~ i ~i - 14 -, rY T~
r~ ~ ~ N N ,_~ ~N N
,_ ~
~ ~ ~ ,~
.
. O 0'0 o O O o O ~ ~ , ~ -1 N ~ 1 N ,~ I
E~ ~
p~m I I I r ~ m m P~ I, I , ,m m ........ -- ..
. In' ' ' p~ m~ mN ~ ~ m :~:
~n m~ m~ :~
-- 1 - .
z I ,,,,,,. .~
': ~ . ~ '`
~ _ _ o -- -- o ~ --~ ~ ~ ~ ~ N ~) ~ ~ ~ ~ ~7 P; m ~ m - ~ ~ - -- -:
.` ` - ~ ` .
- ~ o ~ ~ .
CO Ln ~ ~
O O ~ ~t ~ o o O O
I I N
~ r~ 1 .
,, ~J ~ O O
. ,~
U ~D
) O
. ~1 ~ 51 ~;~ m ~ m ~ .
.' ~ . h~
~ ~ ~ ~a 0 ~ ,_ ~ ~ ~ d K m m :~ m o ~_ _ _ _ .
l l l l ~ ~ ~ rl _ I ' ,~
~' , .
The compoun~sof formula I exhibit pharma-cological activity in animals. In particular, the com-pounds of formula I inhibit glycerol release stimulated by isoproterenol in standard tests, e.g. as follows: -i) In vitro Isolated fat cells are obtained from dog sub-cutaneous tisue, and from rat and guinea 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 10 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).
~1) In vivo _______ :
Rats are fasted for 16 hours. A sub-cutaneous injection of 400 ~g/kg of isoproterenol results in a glycerol concentration in the blood plasma of 400~ 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 do~e of ~ - 17 -. 'l' . ~ ~
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 ca~culated in conventional manner, e.g. using the~ conventional glycero-3-phosphate-dehydrogenase method ~according S. Laurell et al;
reference as mentioned above].
The compounds are therefore indicated for use in 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 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 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 weiqht.
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 cardio-vascular adrenergic ~-blocking effect as indicated in standard tests, e.g. by an inhibition of the positive inotropic adrenaline effect in the spontaneously beating guinea pig atrium at bath concentrations of from 0.005 to 2.5 mg/litre in accordance with the method of K.Sam~eli, Helv. Physiol.Acta 25, CR 215-221 tl967); 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 ~-blockina asents, 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 cardiovas-cular ~-blocking tests.
For all these indications an indicated daily dose is from about 1 to about 200 mg, conveniently - lg -s~
administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 100 mg of the compound or in sustained release form.
The compounds of formula I also exhibit a sali-diuretic effect ~s indicated in standard tests, e.g. in the diuretic rat test in accordance with the principles of E. Fluckiger et al, Schweiz.med. Wschr. 1963, 93, 1232, on administration p.o. of from about 0.1 to about - ~0 mg/kg animal body weight of the comPounds.
The compoundsare therefore indicated for use as salidiuretic agents, e.g. for thP treatment of odema and hypertension.
An indicated daily dose is from abol~t 1 to about 100 mg, conveniently administered in divided do-ses 2 to 4 times a day in unit dosage form con-taining from abQut 0.25 to about 50 mg of the compaunds, or in sustained release form.
The example 1 and 2 compounds exhibit particu-larly interesting properties.
The compounds may be administered in pharmaceuti-cally acceptable acid addition salt form. Such forms exhiblt 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 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 f ablet.
,, In a group of compounds p is 0, m is 1 and n is 1 or 2. Preferably Rl is alkyl and R2 and R3 are each alkyl or together alkylene of 4 or 5 carbon atoms. In a sub-group R2 and R3 are together alkylene.
In another s,ub-group R2 is a]kyl 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 l, m is 0 and n is 2.
- 21 ~
Claims (6)
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) 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 0, R1 is (i) alkyl of 3 to 7 carbon atoms or (ii) phenylalkyl, phenoxyalkyl or phenylthio-alkyl of 8 to 11 carbon atoms in the aggregate thereof and wherein the phenyl ring is separa-ted by at least 2 carbon atoms from the nitro-gen atom to which R1 is bound and wherein the phenyl ring is unsubstituted, or mono-substi-tuted by, or independently disubstituted by, alkyl or alkoxy of 1 to 4 carbon atoms, halo-gen of atomic number from 9 to 35, trifluoro-methyl or cyano, R2 and R3 are either toge-ther 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 at 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, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound of formula II
II
wherein m, n, p and R2 to R5 are as defined above, and Rx is a group capable of reacting with an amine to give a 2-amino-1-hydroxyethyl group, with a compound of formula III
wherein R1 is defined above, and where necessary or desired, converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof, or an obvious chemical equi-valent thereof.
wherein (i) m is 0, 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 0, R1 is (i) alkyl of 3 to 7 carbon atoms or (ii) phenylalkyl, phenoxyalkyl or phenylthio-alkyl of 8 to 11 carbon atoms in the aggregate thereof and wherein the phenyl ring is separa-ted by at least 2 carbon atoms from the nitro-gen atom to which R1 is bound and wherein the phenyl ring is unsubstituted, or mono-substi-tuted by, or independently disubstituted by, alkyl or alkoxy of 1 to 4 carbon atoms, halo-gen of atomic number from 9 to 35, trifluoro-methyl or cyano, R2 and R3 are either toge-ther 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 at 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, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound of formula II
II
wherein m, n, p and R2 to R5 are as defined above, and Rx is a group capable of reacting with an amine to give a 2-amino-1-hydroxyethyl group, with a compound of formula III
wherein R1 is defined above, and where necessary or desired, converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof, or an obvious chemical equi-valent thereof.
2. A compound of formula I, as stated in claim 1, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by a process according to claim 1 or by an obvious chemical equivalent thereof.
3. A process according to claim 1 for the produc-tion of 8 -(3-tert-butylamino-2-hydroxypropoxy)spiro [cyclopentane-1,2'(1'H)-naphthalen]-4'(3'H)-one, which comprises reacting a compound of formula II, wherein m and n are 1, p is 0, R2 and R2 together are tetramethylene and Rx is as defined in claim 1, with tert-butylamine, or an obvious chemical equi-valent thereof.
4. A process according to claim 1 for the production of 8'-(3-tert-butylamino-2-hydroxypropoxy)spiro [cyclopentane-1,2'(1'H)-naphthalen]-4'(3'H)-one, which comprises reacting 8'-(3-chloro-2-hydroxypro-poxy)spiro[cyclopentane-1,2'(1'H)-naphthalen]-4'(3'H)-one in dioxane with tert-butylamine, or an obvious chemical equivalent thereof.
5. A process according to claim 1 for the production of a compound of formula I, as stated in claim 1, having the S configuration at the asymmetrically substituted carbon atom of the hydroxy propoxy side chain, which comprises reacting a compound of formula II, as stated in claim 1, having the S configuration at the asymmetrically substituted carbon atom of the hydroxy propoxy side chain, with a compound of formula III, as stated in claim 1, or an obvious chemical equivalent thereof.
6. The compound 8'-(3-tert-butylamino-2-hydroxy-propoxy)spiro[cyclopentane-1,2'(1'H)-naphthalen]-4'(3'H)-one, whenever produced by a process according to claim 3,4 or 5, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| CH3753/77 | 1977-03-24 | ||
| CH3751/77 | 1977-03-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1119190A true CA1119190A (en) | 1982-03-02 |
Family
ID=25693765
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000299681A Expired CA1119190A (en) | 1977-03-24 | 1978-03-23 | 1-amino-3-aryloxy-2-propanols |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS53149960A (en) |
| AT (1) | AT370720B (en) |
| AU (1) | AU521709B2 (en) |
| CA (1) | CA1119190A (en) |
| DE (1) | DE2810869A1 (en) |
| DK (1) | DK117578A (en) |
| ES (1) | ES468132A1 (en) |
| FI (1) | FI780820A (en) |
| FR (1) | FR2384740A1 (en) |
| GB (1) | GB1597886A (en) |
| IE (1) | IE46590B1 (en) |
| IL (1) | IL54327A (en) |
| IT (1) | IT1104178B (en) |
| NL (1) | NL7802975A (en) |
| NZ (1) | NZ186758A (en) |
| PH (1) | PH13897A (en) |
| PT (1) | PT67807A (en) |
| SE (1) | SE7802972L (en) |
| SU (1) | SU959622A3 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU516491B2 (en) * | 1978-11-06 | 1981-06-04 | Nippon Steel Corporation | Continuous casting |
| FR2507181A1 (en) * | 1981-06-05 | 1982-12-10 | Sanofi Sa | NOVEL ETHERS OF PHENOL ACTIVE ON THE CARDIOVASCULAR SYSTEM, PROCESS FOR PREPARING THEM AND USE THEREOF IN MEDICAMENTS |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3641152A (en) * | 1968-09-23 | 1972-02-08 | Warner Lambert Pharmaceutical | 3 4-dihydronaphthalenoneoxy-2-hydroxy-propylamines |
| CH621330A5 (en) * | 1976-05-14 | 1981-01-30 | Sandoz Ag |
-
1978
- 1978-03-13 DE DE19782810869 patent/DE2810869A1/en not_active Ceased
- 1978-03-15 SE SE7802972A patent/SE7802972L/en unknown
- 1978-03-15 FI FI780820A patent/FI780820A/en not_active Application Discontinuation
- 1978-03-15 DK DK117578A patent/DK117578A/en not_active Application Discontinuation
- 1978-03-20 NL NL7802975A patent/NL7802975A/en unknown
- 1978-03-21 GB GB1110/78A patent/GB1597886A/en not_active Expired
- 1978-03-21 FR FR7808108A patent/FR2384740A1/en active Granted
- 1978-03-22 ES ES468132A patent/ES468132A1/en not_active Expired
- 1978-03-22 PT PT67807A patent/PT67807A/en unknown
- 1978-03-22 NZ NZ186758A patent/NZ186758A/en unknown
- 1978-03-22 IE IE577/78A patent/IE46590B1/en unknown
- 1978-03-22 AU AU34426/78A patent/AU521709B2/en not_active Expired
- 1978-03-22 IL IL54327A patent/IL54327A/en unknown
- 1978-03-22 PH PH20916A patent/PH13897A/en unknown
- 1978-03-23 JP JP3246278A patent/JPS53149960A/en active Pending
- 1978-03-23 SU SU782594304A patent/SU959622A3/en active
- 1978-03-23 IT IT48558/78A patent/IT1104178B/en active
- 1978-03-23 CA CA000299681A patent/CA1119190A/en not_active Expired
- 1978-03-23 AT AT0207178A patent/AT370720B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NZ186758A (en) | 1980-10-24 |
| FR2384740A1 (en) | 1978-10-20 |
| ATA207178A (en) | 1982-09-15 |
| IT7848558A0 (en) | 1978-03-23 |
| DE2810869A1 (en) | 1978-09-28 |
| IL54327A0 (en) | 1978-06-15 |
| PT67807A (en) | 1978-04-01 |
| JPS53149960A (en) | 1978-12-27 |
| AU3442678A (en) | 1979-09-27 |
| FR2384740B1 (en) | 1980-06-20 |
| FI780820A (en) | 1978-09-25 |
| SU959622A3 (en) | 1982-09-15 |
| GB1597886A (en) | 1981-09-16 |
| PH13897A (en) | 1980-10-27 |
| IE780577L (en) | 1978-09-24 |
| SE7802972L (en) | 1978-09-25 |
| DK117578A (en) | 1978-09-25 |
| IE46590B1 (en) | 1983-07-27 |
| AT370720B (en) | 1983-04-25 |
| ES468132A1 (en) | 1979-07-01 |
| NL7802975A (en) | 1978-09-26 |
| IL54327A (en) | 1982-09-30 |
| AU521709B2 (en) | 1982-04-29 |
| IT1104178B (en) | 1985-10-21 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |