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GB2067195A - 2-aminomethyl-6-halo-phenols their production and pharmaceutical composition containing them - Google Patents

2-aminomethyl-6-halo-phenols their production and pharmaceutical composition containing them Download PDF

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GB2067195A
GB2067195A GB8100803A GB8100803A GB2067195A GB 2067195 A GB2067195 A GB 2067195A GB 8100803 A GB8100803 A GB 8100803A GB 8100803 A GB8100803 A GB 8100803A GB 2067195 A GB2067195 A GB 2067195A
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methyl
dimethylindan
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/045—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of a group bound to the ring by nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/20—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms using aldehydes or ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/21—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing rings other than six-membered aromatic rings
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    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
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    • C07—ORGANIC CHEMISTRY
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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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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The new compounds are represented by the formula I: (FORMULA) wherein A or B represents X and the other: (FORMULA) formulas wherein: either X is bromine, n = 1 or 2, R<u1>u and R<u2>u both represent H or methyl or R<u1>u or R<u2>u represent H and the other one methyl, R<u3>u both represent either H or a linear alkyl group C<u1-4>u; or X represents iodine, n = 1, R<u1>u and R<u2>u both represent H and R<u3>u both represent an alkyl group C<u1-4>u or R<u1>u and R<u2>u both represent methyl or R<u1>u or R<u2>u represents H and the other methyl, R<u3>u both represent either H or an alkyl group C<u1-4>u; or n = 2, R<u1>u or R<u2>u represents H and the other one methyl or R<u1>u and R<u2>u represent methyl, R<u3>u both represent either H or an alkyl group C<u1-4>u. The compounds as well as the acid salts pharmaceutically acceptable are appropriate for use as salidiuretic and antihypertensive agents.

Description

SPECIFICATION New 2-aminomethyl-6-halo-phenols, their production and pharmaceutical compositions containing them This invention relates to 2-aminomethyl-6-halophenols, their productions and pharmaceutical compositions containing them.
U.K. Patent Application No. 201 3655A discloses a class of 2-aminoethyl-6-halo-phenols having an optionally alkyl substituted alkylene chain between the 3 and 4 ring positions or 4 and 5 ring positions, and optionally substituted by alkyl on the amino group. The compounds are said to be active as anti-inflammatory agents, analgesics, anti-pyretics, diuretics and hypotensive agents. We have now found that certain compounds of this class, in particular those having a 6-bromo group and/or having an a,-dialkyl-substituted trimethylene chain; and an unsubstituted amino group, which are nowhere specifically disclosed nor suggested by this patent application, as well as derivatives thereof, possess notable pharmacological activity, e.g. anti-hypertensive and salidiuretic activity.
The present invention provides a compound of formula I,
in which one of A and B is X and the other is
either X is Br, n is 1 or 2, both R, and R2 are either H or methyl, or one of R, and R2 is H and the other is methyl, and both R3 are either H or linear (C,~4) alkyl or X is I, n is 1, both R, and R2 are H and both R3 is (C,~4)alkyl or both R, and R2 are methyl or one of R, and R2 is H and the other is methyl and both R3 are either H or (C,~4)alkyl, n is 2, one or R, and R2 is H and the other is methyl, or both R, and R2 are methyl and both R3 are either H or (C14)alkyl.
The compounds of formula I are hereinafter referred to as compounds of the invention.
One group of compounds comprises the compounds of formula la,
in which R1, R2, X and n are as defined above and both R'3 are either H or methyl.
Another group of compounds comprises the compounds of formula I, in which A is
and B is X and R, R2, R3, X and n are as defined above.
A third group of compounds comprises the compounds of formula Ib,
in which both R', and R'2 are H or one of R', and R'2 is H and the other is methyl, both groups R'3 are either H or methyl, and X and n are as defined above.
A fourth group of compounds comprises the compounds of formula Ic,
in which R'" R'2 and X are as defined above.
A fifth group of compounds comprises the compounds of formula I, in which A, B, both R3and n are as defined above and both R, and R2 are methyl or one of R, and R2 is H and the other is methyl.
In formula I X is preferably Br; n is preferably 1; both R3 are preferably methyl and at least one of R, and R2 is preferably H. Most preferred compounds are those, in which these significances are combined.
The present invention in another respect provides a process for the production of a compound of the invention, characterized in that a) a compound of the formula I, wherein B is
and A is X and R" R2, both3, n and X are as defined above, is prepared by brominating or iodinating a corresponding compound of formula II,
in which R1, R2, both R3 and n are as defined above, b) a compound of the formula I, wherein B is X and A is
and R, and R2 are H, both R3, n and X are as defined above, is prepared by hydrolysing a corresponding compound of formula Ill,
in which both R3,X and n are as defined above, c) a compound of the formula I, wherein B is X and A is
and one of R, and R2 is hydrogen and the other is methyl, both Ra and n are as defined above, is prepared by reducing a corresponding compound of formula IV,
in which both R3,X and n are as defined above, or d) a compound of the formula 1, in which B is X and A is
and R, and R2 both are methyl and both R3 and n are as defined above, is prepared by catalytically hydrogenating a compound of formula V,
in which R3, n and X are as defined above and reintroducing a substituent X, if removed by the hydrogenation, by bromination or ordination.
Process a) may be effected in conventional manner for the production of analogous halo-phenols.
The process may be effected at temperatures of between approximately -10 and +500 C, preferably between approximately OOC and room temperature. The bromination or iodination may be effected by direct reaction with Br2 or ICI respectively. The bromination process is preferably effected in a solvent which is inert under the reaction conditions, such as methylene chloride, chloroform, carbon tetrachloride or glacial acetic acid.
The iodination is preferably effected with iodine chloride. The reaction may be effected in glacial acetic acid or in water, optionally in the presence of a water-miscible solvent which is inert under the reaction conditions, such as dioxane. The process is suitably effected under acidic conditions.
Process b) may be effected in conventional manner for the hydrolysis of analogous acylamino compounds, preferably by acid hydrolysis with a strong acid, such as concentrated hydrochloric acid or sulphuric acid. The reaction is preferably effected in a lower alcohol, such as ethanol, or in a water miscible solvent, e.g. dioxane, at the reflux temperature.
Process c) may be effected in conventional manner for the reduction of analogous imino compounds e.g. with complex metal hydrides, such as NaBH4, LiAIH4, diborane or borane-dimethyl sulphide complex and may be effected in a solvent suitable for the chosen reducing agent, such as tetrahydrofuran, methanol, ethanol or ether, at approximately 0 to 700 C, e.g. as described in Example 2c.
Process d) may be effected in conventional manner for the catalytic hydrogenation of analogous azido compounds e.g. with palladium or platinum and is preferably effected in an alcohol as a solvent at approximately 20 to 600C and 5 to 20 atmospheres, e.g. as described in Example 6c. Any radical X removed by the hydrogenation may be reintroduced by a haiogenating agent having a brominating or iodinating effect, in analogous manner to process a). The isolation and purification of the reaction products may take place by known methods.
The starting compounds used in the processes of the invention may be produced in several steps, which can be illustrated by the following two reaction schemes I and II, from an indanol or 5,6,7,8tetrahydronaphthol of formula IX.
The first substitution of compound IX, whether by acylaminomethylation, acetylation or halogenation, takes place mainly in position 6, if it is an indanol, or in position 3, if it is a tetrahydronaphthol and to a minor extent in indanol position 4 or in tetrahydronaphthol position 1. The second substitution is then effected in the remaining second ortho position of the phenol ring. In schemes I and II the main substitution is indicated. The starting products used in the processes of the invention may be obtained by using three different processes depending on whether the aminomethylene group in the ortho-position of the phenol ring is unsubstituted or is substituted by one or two methyl groups.
Reaction scheme I
(CH )R3 (CU ) 3 X 9 d-Acyl R3 x Hydrolysis Ila OH OH R3 /ýlamlnomethyl ation (CH2)nR3 R3 R3 R3 9 e. (C}t2)n+ R3 CH ) CU -3 C/C113 NH 013 Reduction C H x t11110n XI Ol! ' .1lI CU3Li xii lIb NH2 or R3 R3 R3 ( d2)nlR3 tCH2)ntR3 tCSi2)n+R3 ) oC 3 bide > / CH3 C:t.- CH3 -l A:ide / 3 Cat. - /3 XIV rC; c08i3 XII Cj N3 Hydrogenation C N1z 1! \ OH CU3 CR3 lIc OR cji3 Reaction scheme II R3 (CH;!) 1zR3 Acpl-HN h III H2 '41cyiarninomtyiation R3 (cg2)n R3 aiogenati1 ) SH1logenatictx t tCEitR3 IX OH VIDII C X c OH VI CH3Li O (IV) tNH or CN3MgHat R3 (3R3 ( > 12 > ss3 ss (vII) A::jde H3C Y;j3 (VrI) HO OH N3)C OH H3C V 113C The compounds of formula IX are known or may be produced by known processes, e.g. as described in the Examples hereinafter. Insofar as the preparation of any particular starting material is not particularly described, this is known or may be made in known manner or in a manner analogous to the processes mentioned herein. Free base forms of the compounds of the invention and of basic starting materials and of intermediate products may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation include hydrochloric acid, fumaric acid, oxalic acid, and hydrobromic acid.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
EXAMPLE 1 6-aminomethyl-4-bromo-1 ,1 -dimethlindan-5-ol (I) [process a)] a) 1, 1-dimethyllndan-5-oI (IX) A solution of 10.3 g of sodium nitrite in 80 ml of water is added dropwise at 0--50 while stirring to 20 g of 6-amino-1 ,1 -dimethylindan in 100 ml of water and 25 ml of concentrated sulphuric acid. The resulting reaction solution is then added dropwise to a boiling solution of 40 ml of concentrated sulphuric acid in 1 50 ml of water. The title compound is separated from the reaction mixture by water vapor distillation and is obtained by recrystallization from petroleum ether as white crystals. M.p.
9698 .
b) 6-chloroacetylaminomethyl- 1,1 -dimethylindan-5-ol (X) 8.1 g of 1,1 -dimethylindan-5-ol are dissolved in a mixture of 60 ml of glacial acetic acid and 6 ml of concentrated sulphuric acid and a total of 6.2 g of 2-chloro-N-hydroxymethylacetamide are added portionwise at 100. The reaction mixture is stirred for 2 hours at 1520 and is then poured on to icewater. The heading compound is extracted from the aqueous solution with ethyl acetate. This crude product is used without further purification in the next step c).
c) 6-aminomethyl- 1,1-dimethylindan-5-ol (via) The crude produce described in b) is boiled under reflux in a mixture of 80 ml of ethanol and 80 ml of concentrated hydrochloric acid for 4.5 hours. Upon removal of the ethanol in a vacuum, dilute ammonia is poured on to the residue. The mixture is extracted with methylene chloride. The organic phase is dried and evaporated and the resultant crude base may be converted into the crystalline hydrobromide with HBr in ethanol for the purpose of purification. M.p. 220--2240.
d) 6-aminomethyl-4-bromo- 1, -dimethylindan-5-ol (I) 1.0 g of 6-aminomethyl-1 ,1-dimethylindan-5-oI is dissolved in 10 ml of glacial acetic acid and a solution of 1.1 g of bromine in 2 ml of glacial acetic acid is added dropwise while stirring at room temperature. Upon careful concentration by evaporation of the volatile components in a vacuum the heading compound remains as a crystalline crude product which may be purified by recrystallization from ethanol/ether. M.p. 197--1980 (hydrobromide). EXAMPLE 2 6-(1-aminoethyl)-4-bromindan-5-ol (I) [process a)] a) 6-acetylindan-5-ol (XIIIJ 100 mg of 5-indanol are heated to 600 for 4 hours in a mixture of 200 ml of acetic anhydride and 200 ml of pyridine.The volatile components are completely removed by evaporation in a vacuum.
Subsequently 113 g of aluminium chloride are added portionwise. The reaction mixture is heated to 1400 for 2 hours. Upon decomposing the mixture with ice-water, extracting it with methylene chloride and concentrating the organic phase by evaporation, 6-acetylindan-5-ol remains as a slowly crystallizing mass which is further used in the next step b) without further purification.
b) 6-f l -iminoethyl)indan-5-ol (XI) 20 g of the crude ketone described in a) are allowed to stand overnight at room temperature in 1 50 ml of methanol saturated with ammonia whereupon the imine crystallizes in yellow crystals and may be filtered off. M.p. 229--2300.
c) 6-(1-aminoethyl)indan-5-ol (rib) 3.5 g of the 6-(1 -iminoethyl)indan-5-ol are dissolved in 30 ml of methanol. 2.0 g of NaBH4 are added portionwise at room temperature and the mixture is allowed to stand for one hour. Subsequently the excess NaBH4 is decomposed with a small amount of dilute hydrochloric acid. The mixture is concentrated by evaporation in a vacuum and diluted with water. The alkaline reaction mixture is extracted with methylene chloride, the organic phase is dried and concentrated by evaporation and the remaining yellow oil is crystallized from ether. M.p. 1 14--1 1 50.
d) 6-(1 -aminoethyl)-4-bromindan-5-oI {l) The bromination is effected in analogous manner as described in Example 1. The 6-( 1 - aminoethyl)-4-bromindan-5-ol is crystallized from ethanol. M.p. 1 53-1 540 (free base).
EXAMPLE 3 6-(1 -aminoethyl)-4-bromo-1 ,1 -dimethylindan-5-ol (I) [process a)] In analogous manner as described in Example 2 the following compounds are produced successively: a) 6-acetyl-1 ,1 -dimethylindan-5-ol (from 14.0 g of 1,1 -dimethylindan-5-ol (XIII), yellow oil.
b) 6-( 1 -iminoethyl)- 1 , 1 -dimethylindan-5-ol (Xl) M.p. 1 72-1 740 (from methanol).
c) 6-(1 -aminoethyl)-1 1 -dimethylindan-5-ol (llb), M.p. 1341360.
d) 6-(1 -aminoethyl)-4-bromo-1 ,1 -dimethylindan-5-ol (I), M.p. 120--1210 (from ether) (free base).
This is converted into the hydrobromide.
EXAMPLE 4 6-(l-aminoethyl)-4-iodoindan-5-ol (I) [process a)] To a solution of 1.8 g of 6-( 1 -am inoethyl)inda n-5-ol in 20 ml of glacial acetic acid there are added within 10 minutes 1.9 g of ICI and the reaction mixture is stirred for 3 hours at room temperature. Upon removal of the volatile components in a vacuum the mixture is made alkaline with aqueous dilute ammonia and is extracted with methylene chloride. Upon drying and concentration of the organic phase by evaporation, a brown oil remains from which the heading compound is obtained in pure form by crystallization from ethanol. M.p. 119-121 0 (free base).
EXAMPLE 5 4-aminomethyl-6-brnmo-1 , 1 -dimethylindan-5-ol (I) [process b)] a) 4-(3-methoxyphen yl)-2-m ethylbutan-2-ol To a solution of 25.8 g of 3-(3-methoxyphenyl)-propionic acid methyl ester in 300 ml of absolute ether there are added dropwise under stirring and cooling with ice 200 ml of a 1.5-molar solution of methyl magnesium bromide in ether. The mixture is allowed to stand at room temperature for one hour and is poured on to ice-water and acidified with dilute hydrochloric acid. The organic phase is separated, dried over sodium sulphate and concentrated by evaporation. The heading compound is obtained by distillation in a high vacuum at approximately 1000 (bulb tube distillation) as a colourless liquid.
b) 5-methoxy-1, 1-dimethyllndan 29.0 g of 4-(3-methoxyphenyl)-2-methylbutan-2-ol are added dropwise within 30 minutes at 1000 to 45 ml of 85% phosphoric acid while stirring. The mixture is then further stirred for one hour at this temperature and is poured onto ice-water and extracted with ethyl acetate. Upon drying and concentration by evaporation of the organic phase, the heading compound is obtained by high vacuum distillation at 8090 as a colourless oil.
c) 1,1 -dimethyllndan-5-oI (IX) A mixture of 8.5 g of 5-methoxy-1 ,1 -dimethylindan and 80 ml of 63% hydrobromic acid is boiled under reflux for 2 hours, is poured onto ice-water and is extracted with methylene chloride. Upon drying and concentration by evaporation of the organic phase the crude heading compound remains as a crystalline residue and may be purified by crystallization from hexane. M.p. 980.
d) 6-bromo- 1,1 -dimethylindan-5-ol (VIII) To an ice-cooled solution of 40 g of 1,1-dimethylindan-5-ol in 400 ml of carbon tetrachloride there are added dropwise 1 5 ml of bromine in 70 ml of CCI4 while stirring well within one hour. The reaction mixture is then evaporated to dryness in a vacuum and the product is distilled in a high vacuum at 1100.
e) 6-bromo-4-chloroacetylaminomethyl-1,1-dimethylindan-5-ol (III) 55.8 gof6-bromo-1,1-dimethylindan-5-oI are dissolved in a mixture of 60 ml of concentrated sulphuric acid and 560 ml of glacial acetic acid. 35 g of 2-chloro-N-hydroxymethyl-acetamide are added portionwise while stirring and cooling with ice. The mixture is allowed to stand for 2 hours at room temperature, is poured onto 2 litres of ice/water and is allowed to crystallize overnight. Upon filtration and drying the crude heading compound is obtained which is used in the next step without further purification.
f) 4-aminomethyl-6-bromo- 1,1 -dimethylindan-5-oI (I) 78 g of crude 6-bromo-4-chloroacetylaminomethyl-1 ,1 -dimethylindan-5-ol are boiled at reflux during the course of 3 hours in a mixture of 400 ml of ethanol and 300 ml of concentrated hydrochloric acid. The clear solution is thoroughly concentrated by evaporation in a vacuum in order to remove the alcohol. The title compound crystallizes in the form of beautiful, white crystals upon cooling and allowing to stand. M.p. 204--2070. The free base of the title compound is obtained as a crystalline compound upon adding dilute ammonia to the aqueous solution of the hydrochloride. M.p. 1 67-1 680 (hydrochloride).
EXAMPLE 6 6-( 1-amino- 1 -methylethyl)-4-bromo- , 1 -dimethylindan-5-ol [process a)] a) 6-( 1 -hydroxy- 1 -methylethyl)- 1,1 1-dimethylindan-5-ol (XIVJ To a solution of 12.9 g of 6-acetyl-1 ,1 -dimethylindan-5-ol in 150 ml of absolute ether there are added dropwise at room temperature in a nitrogen-atmosphere 90 ml of a 1.6 molar solution of methyllithium in ether. The reaction mixture is stirred for one hour and is poured onto a mixture of ice and diluted hydrochloric acid. The organic phase is separated, dried and concentrated. The title compound is obtained by recrystallisation of the residue in hexane. M.p. 94--950.
b) 6-(1-azido-1-methylethyl)-1, 1-dimethylindan-5-ol FXIIJ To a solutiuon of 8.5 g of 6-( 1 -hydroxy-1 -methylethyl)-1 ,1 -dimethylindan-5-ol in 100 ml of chloroform are added 5.0 g of sodium azide. The suspension is cooled to 80. 1 5 ml of trifluoroacetic acid are added dropwise within 30 minutes while stirring well. The reaction mixture is stirred for 2 hours at room temperature and is made alkaline with concentrated ammonia. Upon separating the organic phase, washing it with water, drying and concentrating it to dryness, the heading compound remains as a yellow oil.
c) 6-( 1-amino- 1 -methylethyl)- 1,1 -dimethylindan-5-ol (IlcJ 8.9 g of 6-(1-azido-1-methylethyl)-1,1-dimethylindan-5-oI are hydrogenated at 500 in 220 ml of ethanol at an overpressure of 5 atm. in the presence of a Pt-catalyst. The catalyst is removed by filtration and the reaction solvent evaporated to dryness. The heading compound is recrystallized from hexane. M.p. 115--117 (free base). M.p. 180--1850 (hydrochloride).
d) 6-( 1-amino- 1 -methylethyl)-4-bromo- 1,1 -dimethylindan-5-ol (I) The bromination is effected in analogous manner as described in the foregoing Example 1. M.p.
219220 (hydrobromide). M.p. 109-111 (free base).
EXAMPLE 7 4-aminomethyl-6-bromo-1 ,1-dimethylindan-5-ol [process b)] In analogous manner as described in the foregoing Example 5 the following compounds are produced successively a) 1,1-diethylindan-5-ol (IX) colourless viscous oil.
b) 6-bromo-1 ,1-diethylindan-5-ol B.p. 120--130 (at 0.1 mm Hg).
c) 6-bromo-4-chloroacetylaminomethyl-1 ,1 -diethylindan-5-ol yellowish oil.
d) 4-aminomethyl-6-bromo-1 ,1 -diethylindan-5-ol M.p. 165--166 .
In an analogous manner to that described in the foregoing Examples the following compounds are prepared: Compounds of formula I
Example r A 1 B n Ra M.p. i) I Process 8 I -CH(CH3)NH2 1 CH3 132-133 a 9 1 -CH2-NH2 1 CH3 137-138 0 a 10 i -C(CH3)2-NH2 1 i CH3 141-142 a 1) free base form.
The compounds of the invention exhibit pharmacological activity and are therefore indicated for use as pharmaceuticals, i.e. for therapy. In particular, the compounds of the invention exhibit salidiuretic activity as indicated in the standard test in the rat described in Schweiz. Med. Wochenschrift, 93, (1963), 1232-1237. After oral administration of 1 to 100 mg/kg of animal body weight of the compounds, a salidiuretic activity is observed.
The compounds are therefore indicated for use as salidiuretics.
Additionally the compounds are indicated for use as anti-hypertensives, as indicated in the standard test in the spontaneously hypertensive rat, described in Proc. Soc. Exptl. Biol. and Med. 57, (1944), 102. After oral administration of 1 to 100 mg/kg of body weight a blood-pressure lowering activity is observed. The compounds are therefore furthermore indicated for use as anti-hypertensives.
An indicated daily dosage is in the range of from about 1 to about 150 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 75 mg of the compounds, or in sustained release form.
The compounds of formula I, in which one of A and B is X and the other is
X is Br or I, n is 1 or 2, both R, and R2 are H and both R3 are either H or methyl, possess more beneficial pharmacological activity than would be expected for such compounds. In particular they are well tolerated, well absorbed on p.o. administration and exhibit little potassium ion excretion and/or exhibit a potent long-lasting anti-hypertensive effect. The compounds of the invention may be administered in pharmaceutically acceptable addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms. The present invention also provides a pharmaceutical composition comprising a compound of the invention, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositioins may be in the form of, for example, a solution or a tablet.
The preferred compounds are the compounds of Examples 3 and 5.

Claims (33)

1. A process for the production of a compound of formula I,
in which one of A and B is X and the other is
either X is Br, n is 1 or 2, both R1 and R2 are either H or methyl, or one of R1 and R2 is H and the other is methyl, and both R3 are either H or linear (C,~4) alkyl or X is l, n is 1, both R, and R2 are H and both R3 is (C,~4)aíkyl or both R, and R2 are methyl or one of R, and R2 is H and the other is methyl and both R3 are either H or (C14)alkyI, n is 2, one or R, and R2 is H and the other is methyl, or both R, and R2 are methyl and both R3 are either H or (C14)aIkyl.
n is 2, one of R, and R2 is H and the other is methyl and both R3 are either H or (C,~4)alkyl or both R, and R2 are methyl and both R3 and either H or (C,~4)alkyl characterized in that a) a compound of the formula I, wherein B is
and A is X and Rr, R2, both3, n and X are as defined above is prepared by brominating or iodinating a corresponding compound of formula II,
in which R1, R2, both R3 and n are as defined above.
b) a compound of the formula I, wherein B is X and A is
and R, and R2 are H, both R3, n and X are as defined above, is prepared by hydrolysing a corresponding compound of formula Ill,
in which both R3, X and n are as defined above, c) a compound of the formula I, wherein B is X and A is
and one of R, and R2 is hydrogen and the other is methyl, both R3 and n are as defined above, is prepared by reducing a corresponding compound of formula IV,
in which both R3,X and n are as defined above, or d) a compound of the formula I, in which B is X and A is
and R, and R2 both are methyl and both R3 and n are as defined above, is prepared by catalytically hydrogenating a compound of formula V,
in which both R3, n and X are as defined above and re-introducing a substituent X, if removed by the hydrogenation, by bromination or iodination.
2. A process for the production of a compound of formula I as defined in claim 1, as hereinbefore described with reference to any one of the examples.
3. A compound of formula I as defined in claim 1, whenever produced by a process of claim 1 or 2.
4. A compound of formula I as defined in claim 1.
5. A compound of claim 4 of formula la,
in which R1, R2, X and n are as defined in claim 1 and both R'3 are either H or methyl.
6. A compound of claim 4 of formula I, in which A is
and B is X and R1, R2, R3, X and n are as defined in claim 1.
7. A compound of claim 4 of formula Ib
in which both R', and R'2 are H or one of R', and R'2 is H and the other is methyl, both groups R'3 are either H or methyl, and X and n are as defined in claim 1.
8. A compound of claim 4 of formula Ic,
in which R'" R'2 and X are as defined in claim 1.
9. A compound of claim 4, in which A, B, both R3 and n are as defined in claim 1 and both R, and R2 are methyl or one of R, and R2 is H and the other is methyl.
10. A compound of claim 4, in which X is Br.
11. A compound of claim 4, in which n is 1.
12. A compound of claim 4, in which both R3 are methyl.
13. A compound of claim 4, in which at least one of R, and R2 is H.
14. A compound of claim 4, which is 6-(1 -aminoethyl)-4-bromo-1 ,1 -dimethylindan-5-ol.
15. A compound of claim 4 which is 4-aminomethyi-6-bromo-1 1 -dimethylindan-5-ol.
16. A compound of claim 4, which is 6-aminomethyl-4-bromo-1 ,1 -dimethylindan-5-ol.
17. A compound of claim 4, which is 6-(1 -aminoethyl)-4-bromindan-5-ol.
18. A compound of claim 4, which is 6-(1 -aminoethyl)-4-iodiondan-5-ol.
19. A compound of claim 4, which is 6-(l-amino-l -methylethyl )4-bromo-l,l -dimethylindan-5- ol.
20. A compound of claim 4, which is 4-aminomethyl-6-bromo-1,1 -dimethylindan-5-ol.
21. A compound of claim 4, which is 6-(l-aminoethyl )4-iodo-l,l -dimethylindan-5-ol.
22. A compound of claim 4, which is 6-aminomethyl-4-iodo-1 ,1 -dimethylindan-5-ol.
23. A compound of claim 4, which is 6-(1 -amino-1-methylethyl)-4-iodo-1 ,1 -dimethylindan-5-ol.
24. A compound of formula XIII,
in which both groups Ra and n are as defined in claim 1.
25. A compound of formula IX,
in which both R"3 are methyl or ethyl.
26. A compound of formula VI,
in which both groups R3, X and n are as defined in claim 1.
27. A compound of formula VIII,
in which both R3 are either H or linear (C14)alkyl and X is Br or I.
28. A compound according to any one of claims 3 to 23 in free base form.
29. A compound according to any one of claims 3 to 23, in acid addition salt form.
30. A compound according to any one of claims 3 to 23 for use as a pharmaceutical.
31. A compound according to any one of claims 3 to 23 for use against edemas or hypertension.
32. A pharmaceutical composition comprising a compound of any one of claims 3 to 23 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier.
33. A method of treating edemas or hypertension, which comprises administering a compound of any one of claims 3 to 23 to a subject in need of such treatment.
GB8100803A 1980-01-14 1981-01-12 2-aminomethyl-6-halo-phenols their production and pharmaceutical composition containing them Withdrawn GB2067195A (en)

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US4980352A (en) * 1988-05-25 1990-12-25 Ici Americas Inc. Gem-dimethyl substituted bicyclic compounds useful as eukalemic diuretics

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JPS6049183B2 (en) * 1977-12-29 1985-10-31 小野薬品工業株式会社 2-Aminomethylphenol derivative
DE2934508A1 (en) * 1978-09-06 1980-03-20 Sandoz Ag ALPHA -ALKYL-O-OXYBENZYLAMINE DERIVATIVES, THEIR PRODUCTION AND REMEDIES CONTAINING THEM
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4980352A (en) * 1988-05-25 1990-12-25 Ici Americas Inc. Gem-dimethyl substituted bicyclic compounds useful as eukalemic diuretics

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FR2473512A1 (en) 1981-07-17

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