NL7906557A - ALPHA-ALKYL-O-OXYBENZYLAMINE DERIVATIVES, AND METHODS FOR PREPARING THESE DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING THESE DERIVATIVES. - Google Patents

Description

* ** A

SANDOZ AG, in Basel, Switzerland.

α-alkyl-o-oxybenzylamine derivatives, as well as methods for preparing these derivatives and drugs containing these derivatives.

The invention relates to α-alkyl-o-oxybenzylamine derivatives, as well as to methods of preparing these derivatives and of drugs containing these derivatives.

These are new α-alkyl-o-oxybenzylami-5 derivatives, the phenyl nucleus of which are substituted by one or at most two halogen atoms with a sequence number of 17 to 53, the dehalogen atoms being placed meta with respect to the aminoalkyl group, respectively. compounds hereinafter referred to as compounds of the invention.

The definition above also includes derivatives of which the amino group is substituted. The oxy group can represent, for example, hydroxyl and acyloxy.

The invention particularly relates to new compounds of the formula I, wherein R 1 represents an alkyl group with at most 4 carbon atoms and R 2 - R 4, independently of one another, a hydrogen atom or also an alkyl group with up to 4 carbon atoms and either Z represents a hydrogen atom or an alkyl group with up to 7 carbon atoms and W represents a halogen atom with a sequence number from 17 to 53, or Z represents a halogen atom with a sequence number from 17 to 53 and W 20 represents a hydrogen atom or an alkyl group with up to 7 carbon atoms, or Z and W represent a halogen atom with a sequence number from 9 to 53, wherein both substituents do not represent both fluorine and its o and / or N-acyl derivatives.

N-acyl derivatives only occur if in formula 1 at least one of the substituents R 2 and R 2 represents a hydrogen atom. O and / or N-acyl derivatives of compounds of formula 1 are those derivatives in which the hydroxyl and / or amino group is present in acylated form. Compounds of formula 1 are preferred over 30 79 0 6 5 5 7 **? "2 of their derivatives. Of these derivatives, those which are acylated only on the nitrogen atom deserve recommendations.

When R 1, R 2, R 3 and / or R 4 represent an alkyl group, they preferably contain 1 or 2, in particular 1, carbon atom.

5 It is recommended that they have a straight chain. Z or W represent an alkyl group, it preferably contains 3-5, especially 3 or 4, carbon atoms. It is preferably branched α-to the carbon atom of the phenyl ring, such as in isopropyl and t-butyl. It is recommended that halogen be bromine or iodine, especially bromine.

R 1 preferably represents a hydrogen atom.

If this substituent is an alkyl group, it is preferably equal to Rj. R2 and / or R1 preferably represent a hydrogen atom. When R2 and R4 represent an alkyl group, it is recommended that they be equal. R 2 and / or R 4 represent an alkyl group, then R 3 is preferably a hydrogen atom.

It is recommended that Z be an alkyl group or a halogen atom, especially an alkyl group. Preferably W represents a halogen atom or an alkyl group, in particular a halogen atom.

A group of compounds of formula 1 are formed by compounds of formula Ipa, wherein R 1 and R 2 have the meanings indicated above and Z 2 a are an alkyl group with up to 7 carbon atoms and a halogen atom with a sequence number from 17 to 53.

Another group of compounds of formula 1 is formed by compounds of formula Ipb, in which R 1 and R 1 have the meanings indicated above nh * 7 and 7r a halogen atom with a sequence number of 17 to 53 and Wr an alkyl group with up to 7 carbon atoms introduce.

Yet another group of compounds of formula 1 are compounds of formula 1pc, wherein R 1 and R 2 have the meanings indicated above and 7pc represent a halogen atom with a sequence number from 9 to 53 and Wpc represent a halogen atom with a sequence number from 17 to 53 .

Finally, yet another group of compounds 7906557 3 of the formula 1 is formed by compounds of the formula lpd, in which R 1 and the meanings indicated above represent an alkyl group with up to 4 carbon atoms and either Z 1 represents an alkyl group with up to 7 carbon atoms and a halogen atom with a sequence number pd 5 from 17 to 53, or Z represent a halogen atom with a sequence number from 17 to 53 and an alkyl group with up to 7 carbon atoms, or Z * represents a halogen atom with a sequence number from 9 to 53 and Η13 a halogen atom with a sequence number from 17 to 53.

The compounds of the invention can be prepared in a manner conventional for analogous compounds, for example, by chlorination, bromination or iodination of a corresponding alkyl-o-oxybenzylamine derivative, the phenyl ring of which is substituted by at most 1 halogen atom. The compounds of formula I and the O and / or N-acyl derivatives can be prepared in particular by a corresponding compound of formula 2, wherein R 1 -R 2 have the meanings indicated above and either Z is a hydrogen atom or a alkyl group with up to 7 carbon atoms and W 'represent a hydrogen atom, or Z' represent a hydrogen atom and W * represent an alkyl group with up to 7 carbon atoms, or Z 'represent a halogen atom with a sequence number of 9 to 53 and 20 W' represent a hydrogen atom, or Z a hydrogen atom and W * represent a halogen atom with a sequence number from 9 to 53, wherein A) if Z and W represent a halogen atom with a sequence number from 17 to 53 and are different, one of the Z 'and W' substituents represents a halogen atom with a sequence number is from 17 to 53 and 25 is B) if Z or W represents a fluorine atom,. Z 'or W' is a fluorine atom, or the G and / or N acyl derivatives thereof, to be chlorinated, brominated or iodinated.

These halogenation processes can be carried out analogously to known methods for preparing corresponding o-oxy-halobenzyl-30 amines by mono- or di-halogenation. The reaction temperature will be between about -10 and about +50 ° C, preferably between 0 ° C and room temperature.

Chlorination or bromination can be carried out, for example, by direct reaction with chlorine gas or bromine. A catalyst, such as iron or iron (III) chloride, is suitably used. The reaction is preferably carried out in an inert solvent such as methylene chloride, chloroform, carbon tetrachloride or acetic acid. The iodination can, for example, take place with iodine chloride. For example, the reaction is carried out in water, preferably using an additional hydrophilic solvent, such as dioxane. Acidic conditions are suitably used.

When Z 'and W' represent a hydrogen atom, a mixture of compounds can be formed, which can be separated in a known manner, for example by chromatography or fractional crystallization.

The compounds of the invention can be separated from the reaction mixture in a known manner and purified.

The compounds according to the invention can be present both in free form and in the form of a salt. Salts of the compounds in free form can be prepared in a known manner and vice versa. Acid addition salts can be obtained with acids such as, for example, maleic, fumaric, tartaric and hydrochloric acids. If the oxy group represents a hydroxy group, salts with strong bases, such as, for example, sodium hydroxide, can be obtained.

Different R 1 and R 2, then the carbon atom containing these substituents is asymmetrically substituted. Therefore, such compounds can exist in a racemic or optically active form. The compounds in optically active form can be recovered in a known manner, for example starting from the corresponding racemates, by known splitting methods, such as fractional crystallization of the corresponding diastereoisomeric salts with optically active acids, for example tartaric, malic or mandelic acid.

The starting materials can be obtained analogously to known methods.

The O- and / or N-acyl derivatives of the compounds of formula II are obtained, for example, by 0- and / or N-acylation of corresponding compounds of formula II, optionally selectively. For example, compounds of formulas 2a, 2b or 2c can be prepared using the methods indicated in Reaction Scheme A, where 7906557 * R 1 -R 1 have the meanings indicated above, R 1 is an alkyl group having up to 4 carbon atoms and either Z "a hydrogen or fluorine atom or an alkyl group with up to 7 carbon atoms and W" represents a hydrogen atom, or Z ". hydrogen and W" represent an alkyl group with 5 up to 7 carbon atoms or a fluorine atom.

Insofar as the preparation of the necessary starting materials is not described herein, these materials are known or can be prepared by methods known per se or analogous to the methods described herein or analogous to known methods.

Temperatures given in ° C in the following examples are uncorrected.

Example I

2- (1-aminoethyl) -6-bromo-4-tert-butylphenol.

5.0 g of 2- (1-aminoethyl) -4-tert-butylphenol were dissolved in 100 ml of acetic acid. 5.8 g of bromine was added dropwise to this solution with stirring and at room temperature, and the reaction mixture was allowed to stir for an additional hour. The reaction mixture was then evaporated to dryness under reduced pressure, the resulting residue was dissolved in water and diluted ammonia was added dropwise to this solution.

As a result, the title compound, melting point: 92-94 ° C, precipitated from a mixture of hexane and petroleum ether. Melting point of the hydrochloride: 196-198 ° C from a mixture of ethanol and diethyl ether.

The starting material can be obtained as follows; a) To 40 g of aluminum chloride in 350 ml of sulfur carbon at 10 ° C was added slowly with stirring 40 g of acetyl chloride. After rental, 30 g of 4-t-butylanisole were added thereto within 15 minutes and the resulting reaction mixture was stirred for an additional 15 hours at room temperature. After working up in a usual manner, 5-tert-butyl-2-hydroxy-acetophenone, boiling point at 0.01 mm Hg: 130 ° C was obtained.

22 g of 5-tert-butyl-2-hydroxyacetophenone in 70 ml of ethanol saturated with ammonia were left overnight at room temperature.

7906557 £ 6

There was thus obtained 5-tert-butyl-2-hydroxyacetophenonimine (melting point: 121-122 ° C, from hexane).

c) To a solution of 44 g of 5-tert-butyl-2-hydroxyaceto-5-phenonimine in 250 ml of methanol in portions and at room temperature was added 10 g of sodium borohydride. After 45 minutes, the reaction mixture was evaporated to dryness, dilute hydrochloric acid was added to the residue obtained and extracted with diethyl ether. The acidic solution was then made with concentrated ammonium alkalis and extracted with diethyl ether. There was thus obtained 2- (1-aminoethyl) -4-tert, butylphenol, m.p .: 78-79 ° C, from a mixture of hexane and petroleum ether; melting point of the hydrogen maleinate: 164-165 ° C.

example n 2- (1-aminoethyl) -4,6-dibromophenol.

a) In racemic form.

4.7 g of 2r (1-aminoethyl) -phenol were dissolved in 100 ml of glacial acetic acid and added dropwise, with stirring and at room temperature within 30 minutes, a total of 11.0 g of bromine. The reaction mixture was then stirred for an additional 1 hour. The colorless solution was then evaporated to dryness under reduced pressure, the resulting residue was dissolved in water and the title compound was precipitated in crystalline form by dripping with dilute ammonia, mp: 187-188 ° C.

B) The starting material used can be obtained as follows: 22.4 g of 2-hydroxyacetophenonimine are partially dissolved in 300 ml of absolute tetrahydrofuran and 24 ml of boran-dimethyl sulfide are slowly added in an argon atmosphere. When the first reaction had ended, the reaction mixture was refluxed for an additional 2 hours. The resulting colorless solution was then evaporated to dryness under reduced pressure and the residue obtained by evaporation was partitioned between diethyl ether and dilute hydrochloric acid. The acidic aqueous phase was then made alkaline with ammonia and extracted with diethyl ether. After drying and evaporation of the organic phase 7906557 7, 2- (1-aminoethyl) phenol as beige-colored, crystalline residue, with a melting point of the hydrochloride of 176-177 ° C, remained from a solution of hydrogen chloride in isopropanol, behind ..

5 b) In optically active form

30 g of racemic 2- (1-aminoethyl) -4,6-dibromophenol and 17 g of L (+) tartaric acid are dissolved together in 300 ml of hot water. Upon cooling to room temperature, a tartrate first crystallized, of which the base is a rotation of 6%. This salt was recrystallized a number of times until the base liberated therefrom with ammonia had a fixed rotation. There was thus obtained the (-) - antipode of 2- (1-aminoethyl) -4,6-dibromophenol: α 7-1-12 ° (c-1: 0.1 N HCl); mp 165-166 ° C (from ethanol).

The procedure described above was repeated starting from D - (-) - tartaric acid. The (+) - antipode of 2- (1-aminoethyl) -4,6-dibromophenol: / α7Q + 11.8 ° (c = 1; 0.1 N HCl) mp 166-167 ° C was thus obtained. ethanol).

Example III

2- (1-amino-1-methylethyl) -4-tert-butyl-6-iodine phenyl

1.6 g of 2- (1-amino-1-methylethyl) -4-tert-butylphenol hydrochloride were dissolved in 15 ml of water and 5 ml of dilute hydrochloric acid and dripped thereto, while stirring and cooling with ice, 1.3 g of chloriodide to. After the reaction mixture was stirred for an additional 1 hour at room temperature, it was made alkaline with dilute ammonia and extracted with methylene chloride. After drying and distilling off the solvent under reduced pressure, the title compound remained. Melt-30 point: 136-137 ° C from hexane.

The starting material used can be prepared as follows; a) 30 g of 2-acetyl-4-tert-butylphenol were dissolved in 250 ml of dry diethyl-35 ether and added to this with stirring and at room temperature within 7906557 φ-τ 8 within 30 min. 300 ml of a 1-mole solution of methyl lithium in diethyl ether (/ After stirring the reaction mixture for an additional 2 hours at room temperature, it was worked up in a customary manner to give 4-tert-butyl-2- (1-hydroxy-1-methyl-ethyl) phenol, melting point: 5 66-67 ° C, obtained, b) A mixture of 23 g of 4-tert-butyl-2- (1-hydroxy-1-methyl-ethyl) -phenol and 14.4 g of sodium azide in 250 ml of chloroform was cooled to -10 ° C, dropping a mixture of 45 ml of tri fluoroacetic acid and 100 of 10 ml of chloroform. The reaction mixture was then stirred for an additional 3 hours at room temperature. After working up in a customary manner, 2- (1-azido-1-methylethyl) -4-tert-butylphenol (light brown oil) was obtained.

c) A solution of 26 g of 2- (1-azido-1-methylethyl) -4-tert-butylphenol (crude product from b) in 250 ml of alcohol in the presence of 900 ml of PtOj at 6 atmosphere and 50 ° C was hydrogenated . The catalyst was then filtered off and the filtrate was evaporated to dryness under reduced pressure.

After working up in a usual manner, 2- (1-amino-1-methyl-ethyl) 4-t-butylphenol (m.p .: 89-90 ° C from hexane) was obtained.

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Both the compounds of the invention in free form and in the form of their. physiologically tolerated salts are distinguished by interesting pharmacodynamic properties, which make them useful as medicines. For example, they have a salidiuretic effect, so that they can be used as salidiuretics, for example for the treatment of edema and hypertonia. In addition, they have anti-hypertensive properties, which means that they can be used as anti-hypertensives, for example to combat high blood pressure, because of their antihypertensive effect.

Doses to be administered for the aforementioned conditions vary depending on the particular compound, the mode of administration and the condition to be treated. In general, however, satisfactory results are obtained with a daily dose of about 1 to about 50 mg, which dose can be administered in two to four partial doses if necessary and also in a slow-release form. For oral applications, the partial doses contain about 0.25 to about 20 mg of the compounds of the invention, optionally with solid and / or liquid carriers.

Preferred are the compounds of Examples I, II, III and XII, in particular of I, II.

The compounds of the invention can be used both in free form and in their form. administer physiologically tolerated salts alone or in a suitable form of administration. These drug forms, for example a solution or a tablet, can be prepared or manufactured by known methods. The invention therefore also relates to a method for the preparation of a medicament by bringing one or a number of compounds according to the invention and / or the salts thereof into a dosage form suitable for such use, as well as to the method using this method. formed drugs. If desired, the auxiliaries and / or carriers customary in pharmacy can be used in the manufacture of these medicaments.

7906557

Claims (19)

2. Compounds of formula 1, wherein R 1 represents an alkyl group with up to 4 carbon atoms, R 2 ~ R 10 'from each other, a hydrogen atom or an alkyl group with up to 4 carbon atoms and either Z represents a hydrogen atom or an alkyl group with up to 4 7 carbon atoms and W represent a halogen atom with a sequence number of 17 to 53, or Z represents a halogen atom with a sequence number of 17 to 53 and W represents a hydrogen atom or an alkyl group with up to 15 7 carbon atoms, or Z and W represent a halogen atom with a sequence number of 9 to 53, wherein these substituents are not both fluorine, as are the o- and / or N-acyl derivatives and their salts. Compounds according to claim 2, said formula Ipa, wherein and R2 have the meanings set forth in claim 2, Z ^ a represents an alkyl group having up to 7 carbon atoms and W ^ a represents a halogen atom having a sequence number of 17 to 53, as well as the salts thereof. Compounds according to claim 2, having formula 25 lpb, wherein R 1 and R 2 have the meanings given in claim 2 and Zpb represents a halogen atom with a sequence number of 17 to 53 and Vr an alkyl group with up to 7 carbon atoms, and the salts thereof . Compounds according to claim 2, having formula 30 lpc, wherein R 1 and R 2 have the meanings given in claim 2 and Z 2 C is a halogen atom with a sequence number from 9 to 35 and W 2 C is a halogen atom with a sequence number from 17 to 35 53 and the salts thereof. Compounds according to claim 2, which have formula 35pd, wherein R 1 and R 2 have the meanings indicated in claim 2 7906557 Τ * ΐΛ have an alkyl group with at most 4 carbon atoms and either Zed represents an alkyl group with at most 7 carbon atoms and W 2 a pel halogen atom with a sequence number from 17 to 53, or Z represents a halogen atom with a sequence number from 17 to 53 and W ^ d represent an alkyl group pd 5 with up to 7 carbon atoms, or Z represents a halogen atom 13cl with a sequence number from 9; to 53 and W represent a halogen atom with a sequence number from 17 to 53, and the salts thereof. 7. 2- (1-aminoethyl) -4,6-dibromophenol and its salts. Process for the preparation of a benzyl amine derivative, characterized in that a g-alkyl-o-oxybenzylamine derivative as defined in claim 1 is prepared by a corresponding α-alkyl-o-oxybenzylamine derivative whose phenyl ring is at most 1 halogen is substituted, to be chlorinated, brominated or iodinated and the compounds in free form or in salt form recover. Process for the preparation of a benzyl amine derivative, characterized in that a compound of formula 1, wherein the substituents and symbols have the meanings indicated in claim 2, a 0- and / or N-acyl derivative or a salt thereof , prepared by a corresponding compound of formula 2, wherein R 1 -R 2 represents the meanings indicated above and either Z 'represents a hydrogen atom or an alkyl group having up to 7 carbon atoms and W' represents a hydrogen atom, or Z 'represents a hydrogen atom and W' represents a alkyl group with up to 7 carbon atoms, either Z 'represents a halogen atom with a sequence number from 9 to 53 and W' represents a hydrogen atom, or Z 'represents a hydrogen atom and W' represents a halogen atom with a sequence number from 9 to 53, where A) if Z and W represent a halogen atom with a sequence number from 17 to 53 and different from each other, one of the substituents Z 'or W' 30 is a halogen atom with a sequence number from 17 to 53, and B) if Z or W is a fluorine atom, accordingly Z 'or W' is also a fluorine atom, as well as to chlorinate, bromine or iodine its O-eri / or N-acyl derivatives and to recover the compounds thus obtained in free form or in the form of a salt . 35 7906557 5 » Process according to claim 9, characterized in that a compound of formula Ipa, in which the substituents and symbols have the meanings indicated in claim 3, is prepared. Process according to claim 9, characterized in that a compound of formula Ipb, in which the substituents and symbols have the meanings indicated in claim 4, is prepared. Process according to claim 9, 10, characterized in that a compound of formula 1pc, in which the substituents and symbols have the meanings indicated in claim 5, is prepared. 13. Process according to claim 9, characterized in that a compound of formula lpd, in which the substituents and symbols have the meanings indicated in claim 6, is prepared. Process according to claim 9, characterized in that 2- (1-aminoethyl) -4,6-dibromophenol is prepared. 15. A method of preparing a medicament, characterized in that one or more compounds according to claim 1 and / or their physiologically tolerable salts are introduced into a dosage form suitable for such use. 16. Process according to claim 15, characterized in that one or more compounds according to claims 2-7 and / or a physiologically tolerated salt thereof are used. Process according to claim 15 or 16, characterized in that a compound described in examples I, II, III and / or XII is used. 18. Process according to claim 17, 30, characterized in that a compound described in example I and / or II is used. 19. Method as described in the description and / or examples. 20. Shaped drugs, obtained using a method according to claims 15-19. , 7906557 V ~ VZ Zpa Zpb A <wPa '^ V ^ CH-NH.R1 R OH IN, OH OH'] Rs V Ipa 1 pb Zpc zpd OH OH I nHH “Rl Rpd lPc Ipd 3 z *, jèic.R . «Ίο 2 SANDOZ AG, Basel, Switzerland 7906557 V * -ί * - A- 2" Ζ ”Ζ” ΓΟμ r,, r, JO] .r, W-'Vc '' RRW ^ V ^ CH R OH | V 1 OH I n ^ Ri OH 'h "" 1 k Nr * k 2a 2b "2c,' I ~ I> I -: - 1 reaction with catalytic hydro. R generation and if desired - HN ^ * - then wishes mono. N or dialkylation wc; 'OH I Cl ° H' Λ, __ / 3 * imme-reduction _1 --- Π and optionally J> reaction with reaction with subsequent mono-or thionyl chloride | 1 NaN, dia. ** z, -jèl Λ wA'Y'XH-0H w OH r OH R * W in reduction ---: - ï- ί-1 reaction with Rl MgBr introduction of COR, - or R1 Li on the 2- place by - - »» Friedel Crafts acylation and at the same time z "time ether cleavage | Z" I reaction with IZ "- LigJ. WAV ^ COR, wV1c * Q O.alkyl. OH OH NRi. 6 _, 7 Z introduction of - COR ^ pde 2-place by O-acylation and then rearrange. Fress ring according to Friess in the presence of a Lewis acid W ..... - M .... 1 nun 70065 5 7