PL93998B1 - Alkanolamine derivatives[ca945172a] - Google Patents

Abstract

1-(Substd.-phenoxy)-3-isopropylamino-2-propanols as beta-adrenergic blocking agents Cpds. of gen. formula (I): (where R1 is alkyl or hydroxyalkyl; R2 is an electronegative residue esp. MeCO, EtCO, CN, MeOCO, EtOCO, NH2CO, MeNHCO, isoPr-NHCO, BuNHCO, AllylNHCO or carbazoyl; A is alkylene or alkenylene; n is 1 or 2; and R3 is H, Hal, alkyl, cycloalkyl, alkenyl, NO2, OH, alkylthio, alkoxy, alkenyloxy, aryl, aryloxy, aralkyl, aralkoxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, acyl, alkoxycarbonyl, or CN and when n = 2 R3 groups may be the same or different) and the esters, condensation products with aldehydes and salts of (I). [FR2034561A1]

Description

The subject of the invention is a process for the preparation of alkanolamine derivatives of the general formula I, in which R1 is an alkyl or hydroxyalkyl radical, each with no more than 6 carbon atoms, R2 is an acyl radical with no more than 6 carbon atoms, a carbamyl radical, alkylcarbamyl or alkenylcarbamyl in which the alkyl or alkenyl moiety contains no more than 6 carbon atoms, or a carbazoyl radical, A is an alkylene radical with 1-5 carbon atoms, n is a numerical value of 1 or 2, and R8 - optionally different, if n = 2, represents a hydrogen or halogen atom, a nitro, hydroxy or cyan radical, an alkyl, alkenyl, acyl or alkoxycarbonyl radical, each with no more than 6 carbon atoms, a cycloalkyl radical with no more than S atoms carbon, thioalkyl, alkoxy or alkenyloxy radical, each with no more than 5 carbon atoms, aryl, aryloxy, aralkyl or aralkoxy radical, each with no more than 10 carbon atoms, or rhodium an alkyl group of no more than 5 carbon atoms substituted with one or more hydroxyl radicals, alkoxy radicals of no more than 4 carbon atoms or halogen atoms, and acid addition salts of these compounds, of course. Certain alkanolamine derivatives also apply to all possible stereoisomers and mixtures of these compounds. A suitable radical R1 is an alkyl or hydroxyalkyl radical, each with no more than 6 carbon atoms, in particular 3-5 carbon atoms, preferably branched on carbon in the α-position, for example isopropyl radical, 2nd order. butyl, 3rd order butyl, 2-hydroxy-1,1-dimethylethyl or 2-hydroxy-1-methylethyl. A suitable acyl radical having the symbol R2 is an alkanoyl radical with no more than 6 carbon atoms, such as acetyl or propionyl. .; r A suitable alkylcarbamyl or alkenylcarbamyl radical denoted by the symbol R2 is one in which the alkyl or alkenyl moiety contains no more than 6 carbon atoms, for example, a methylcarbamyl, isopropylcarbamyl, n-butylcarbamyl or allylcarbamyl radical. A is an alkylene radical having 1-5 carbon atoms, such as methylene, ethylene, ethylide, and trimethylene. A suitable halogen R8 is fluorine, chlorine, bromine or iodine. 93 99 893 998 3 4 A suitable alkyl radical R8 is an alkyl radical of no more than 6 carbon atoms, e.g. a methyl, n-propyl or II-tert-butyl radical. A suitable cycloalkyl radical of the symbol H3 is a cycloalkyl radical of No more than 8 carbon atoms, e.g. a cyclopropyl, cyclobutyl or cyclopentyl radical, and an alkenyl radical with the symbol R8 is suitable an alkenyl radical with no more than 6 carbon atoms, e.g. an allyl radical. A suitable thioalkyl, alkoxy or alkenoxy radical is suitable. R8 is a thioalkyl, alkoxy or alkenyloxy radical, each with no more than 5 carbon atoms, e.g. a thiomethyl, methoxy, isopropoxy or allyloxy radical. A suitable aryl or aryloxy radical with the symbol R8 is an aryl or aryloxy radical , each with no more than 10 carbon atoms, e.g. phenyl or phenoxy. A suitable aralkyl or aralkoxy radical with the symbol R8 is aralkyl or b aralkoxy of no more than 10 carbon atoms, e.g. a benzyl, α-phenylethyl or benzyloxy radical. A suitable hydroxyalkyl, alkoxyalkyl or haloalkyl radical with the symbol R 3 is, for example, an alkyl radical with no more than 5 carbon atoms, one or more hydroxyl groups or alkoxy radicals with no more than 4 carbon atoms or halogen atoms, for example, hydroxymethyl, methoxymethyl or trifluoromethyl radicals. A suitable acyl or alkoxycarbonyl radical with the symbol H * is an acyl or alkoxycarbonyl radical each with no more than 6 carbon atoms, eg acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl radicals. The free base form of alkanolamine derivatives according to the invention can be converted into acid addition salts in a known manner. Suitable acid addition salts of alkanolamine derivatives are those with inorganic acids, e.g., hydrochlorides, bromhydrides, phosphates, sulfates or salts with organic acids, e.g. oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, P-naphthoates, adipates or 1,1-methylene-di- (2-hydroxy-3-naphthoates) and salts of acidic synthetic resins, for example sulphonated polystyrene resins such as Zeocarb 225. of the alkanolamine derivatives obtained by the process of the invention are compounds of the general formula II in which R 1, R 2, A and R * have the meaning given above and acid addition salts of these compounds. The 2 groups of these compounds are particularly distinguished by the compounds of formula II in which R 1 is an isopropyl or T1-tert-butyl radical, R 2 is a carbamyl or alkylcarbamyl radical in which the alkyl radical contains no more than 3 carbon atoms , A represents a methylene radical, Rs represents a hydrogen atom, a halogen atom, an alkyl, alkenyl or alkoxy radical, each with no more than 4 carbon atoms, or the compounds of the general formula (II) in which R1 is as defined above, R2 is the radical acetyl or carbamyl, A represents an ethylene radical, R8 represents an alkoxy radical with no more than 4 carbon atoms, and acid addition salts of these compounds. Specific alkanolamine derivatives prepared according to the invention are described in the following examples, particularly active ¬nymi sa: lp-carbamylmethylphenoxy-3-isopropylamino-2-propanol, lp- (N-isopropylcarbamylmethyl) -phenoxy-3-isopropylamino-2-propanol, 1- <2-bromo-4-carbamylmethylphenoxy) - 3 - isopropyl - Amino-2-propanol, 1β-carbamylmethylphenoxy-3-III-order-butylamino-2-propanol, 1-m-carbamylmethylphenoxy-3-isopropylamino-2-propanol, 1- (2-allyl-4 -carbamylmethylphenoxy) -3-isopropylamino-2-propanol, 1- (4-carbamylmethyl-2-methoxyphenoxy) -3-isopropylamino-2-propanol, lp- (N-methylcarbamylmethyl) - phenoxy- 3 - isopropylamino-2-propanol, 1- (4-carbamylmethyl-2-iodophenoxy) -3-isopropylamino-2-propanol, 1- (4-carbamylmethyl-z-methylphenoxy) -3-isopropylamino-2-propanol, 1- (4-carbamylmethyl-2-n-propylphenoxy) - 3-isopropylamino-2-propanol, 1- (4-carbamylmethyl-2-tert-butylphenoxy) - 3-isopropylamino-2-propanol panol, 1- (4-carbamylmethyl-2-methoxyphenoxy) -3- -III-tert-butylamino-2-propanol, 1- (4-N-methyl-carbamylmethyl- (2-n-propylphenoxy) -3-isopropyl - lamino-2-propanol, 1- (2-allyl-4-N-methylcarbamylmethylphenoxy) -3-isopropylamino-2-propanol, 1- - (2-allyl-4 - N-methoxycarbamylmethylphenoxy) -3- -III -butylamino-2-propanol, l - (4-carbamylmethyl-2,5-dimethylphenoxy) -3-isopropylamino-2-propanol, 1- (4-p-carbamylethyl-2-methoxyphenoxy) -3-isopropylamino-2-propanol, 1- (4- | 3-carbamylethyl-2-methoxyphenoxy) - 3-tertiary-butylamino--2-propanol, 1- [2-methoxy-4- (3-ketobutyl) -phenoxy] - -3- isopropylamino-2-propanol, 1- [4-p-cyanomethyl-2-methoxyphenoxy) -3-isopropylamino-2-propanol, 1- (2-methoxy-4-p-methoxycarbonylvinylphenoxy) - -3-isopropylamino-2 -propanol, 1- (4- (5-cyanovinyl-2-methoxyphenoxy) -3-isopropylamino-2-propanol and acid addition salts of these compounds. The method according to the invention for the preparation of alkanolamine derivatives of the above-mentioned formula 1, in in which all the symbols have the meaning given above, it consists in the fact that a compound of the general formula III, in which R2, R8, A and n are as defined above, or a salt of this compound with an alkali metal, is reacted with a compound of the general formula YCl.CHOHCHgNHR1 or of the general formula IV, in which the formulas R1 has the meaning given above no, and Y is halogen, preferably chlorine or bromine, and then the free base alkanolamine derivative is optionally reacted with an acid to form its acid addition salt. The reactions are preferably carried out in a solvent or diluent environment, e.g. methanol or ethanol, in the presence of an acid-binding agent that forms during the reaction, for example sodium hydroxide, and the reactions can be accelerated and terminated by heating. The phenol used as the starting material may be used in the form of its sodium or potassium salt. A preferred group of alkanolamine derivatives prepared according to the invention are compounds of general formula 5 or 6, in which In the formulas, R1 represents an isopropyl or tertiary-butyl radical, R3 represents a hydrogen atom or a halogen or an alkyl, alkenyl or alkoxy radical with no more than 4 carbon atoms, R10 represents a hydrogen atom or an alkyl radical with no more than 3 carbon atoms, and A is a methylene group. The above compounds are prepared so that the compound of general formula 8; in which R * and R1§ have the above meaning, or an alkali metal salt of this compound, is reacted with a compound of the general formula YCHjjCHOHCHaNHR1 or of the general formula IV, in which formulas R1 is isopropyl or III-order. -butyl and Y is chlorine or bromine. A particularly preferred compound is 1-p-carbamylmethylphenoxy-3-isopropylamino-2-propanol and the acid addition salts of this compound, these compounds being prepared by - carbamylmethylphenol or an alkali metal salt thereof is reacted with a compound of formula YCH2CHOHCCH2NHCH (CH3) 2, wherein Y is chlorine or bromine, or with a compound of formula 9, and the resulting free base compound is then optionally subjected to By reacting with an acid to form its acid addition salt. Alkanolamine derivatives and their acid addition salts have shown great activity in the treatment and prevention of heart disease. Some of these compounds have the ability to selectively block adrenergic β-receptors, the degree of selective blocking being greater for the β-receptors of the heart than for peripheral blood vessels and bronchial muscle. Thus, a dose of the compound can be selected that will block the effects of catecholamines, e.g. isoprenaline, on the inotropic and cryotropic heart function, but will not block the relaxing effect of isoprenaline on the smooth, mucous membrane of the trachea or peripheral vasculature induced by vasculature. . Due to the above selective properties, the compounds of the invention can be used in conjunction with known sympathomimetics that dilate the tracheal smooth muscles, such as isoprenaline, orci-prenalin, adrenaline or ephedrine in the treatment of asthma or other respiratory disorders. While selective compounds inhibit the undesirable inducing effect of bronchodilators on the heart, they do not counteract the desired therapeutic effects of the bronchodilators. Numerous compounds are known to have the ability to block adrenergic 3-receptors; many of which represent 1-aryloxy-3-amino-2-propanol derivatives, in particular those containing the - 1-aryloxy radical with an acylamino substituent. It is desirable, but not; It is essential that a compound showing the ability to block O-adrenergic receptors in clinical use does not have any sympathomimetic activity. One of the compounds best known in clinical trials is propanol- (1-isopropylamino-3 -) - naphthyloxy- 1 (2-pilopanol, mentioned in British Patent No. 994,918; this compound does not exhibit any sympathomimetic activity. However, apart from the above-mentioned compound, and there are no known compounds yet known to block adrenergic receptors, which would not show internal sympathomimetic activity. Prastolol 1- (4-acetamidophenoxy) -3-isopropylamino-2-propanol, mentioned in British Patent No. 1078852, is characterized by significant sympathomimetic activity, with simultaneous selective blocking action of O-adrenergic receptors. It has now been found that the selective ability to block the beta-adrenergic receptor This isoprenaline, marked by the inhibition of cat's tachycardia induced in cats, devoid of antagonistic activity against the vasodilating effect of isoprenaline, or elimination of the effect of isoprenaline on histamine bronchoconstriction in marine chicks, shows some compounds according to the invention, in particular lphenoxy-3-caramoyl isopropylamino-2-propanol and 1- (4-P-carbamoylethyl-2-methoxyphenoxy) -3-isopropylamino-2-propanol. The compounds according to the invention, however, do not have a sympathomimetic effect, as demonstrated by their ineffectiveness in increasing the heart rate of rats previously treated with a roserpine derivative, such as syrosingopine, in which catecholamines are devastated under these conditions; The alkanolamine derivatives are preferably used in humans orally in daily doses of 20-600 mg, in daily doses of 6-8 hours or intravenously in a dose of 1-201 mg. In oral preparations, tablets or capsules are preferred in the form of tablets or capsules containing -100 mg, preferably 10-40 mg of active ingredient. The intravenous injections are preferably administered in sterile aqueous solutions at a concentration of 0.05 to 1%, in particular 0.1%, of the active ingredient. The following examples illustrate the invention without limiting its scope. Example I. To a solution of 3 g of 4-hydroxy-phenylacetamide 1.6 g of sodium hydroxide in 40 ml of water, 3.8 g of 1-chloro-3-isopropylaminopropanol-2-hydrochloride are added and the resulting solution is heated at 90-95 ° C for 18 hours. The reaction mixture is made alkaline to a pH value of 10 and extracted three times with 50 ml of chloroform. The combined chloroform extracts are dried and; evaporates to dryness, then the residue becomes * three times extracted with cyclohexane in 60 portions of 50 ml. The cyclohexanone extracts are evaporated to dryness, the residue dissolved in 10 ml of ethyl acetate and then the acetate solution. ethyl ether is diluted with 15 ml of petroleum ether, boiling point 60-80 ° C, by adding petroleum ether in portions over several hours. The mixture is kept at 0 ° C for 17 hours, then filtered. and the semi-solid residue is crystallized from ethyl acetate to give 1-p-carbamylmethylphenoxy-3-isopropylaminopropanol-2, mp 146-148 ° C. Example II. In the manner described in Example I, starting from the appropriate phenol derivatives and the corresponding 4-chloro-3-aminopropanol-2-hydrochloride derivatives, the compounds are obtained: in general formulas 5, 6 and 7, which are The symbols R10, Rs, R2, R1 and A as well as the melting point of the compounds obtained are given in Tables I, II, III and IV. continued Table I 1 methyl amine HHHH 2 n-propyl H fluorine fluorine chlorine chlorine 3 isopropyl isopropyl isopropyl tertiary-butyl isopropyl tertiary-butyl 4 125-127 92 - 93 97-100 92- 95 101-102 100-101 • 'R10.; ¦¦ 1 HHHHH ¦;, A- h HHH n-butyl n-butyl allyl methyl 1 methyl allyl isopropyl isopropyl methyl, H Table ¦ R3 2 methoxy methoxy iodine methyl H bromo allyl II-order -butyl n-propyl HHH allyl allyl allyl H nitro: HH ica I R1 3 isopropyl III-order, .- - butyl isopropyl isopropyl 1-methyl -2-hydroxyethyl isopropyl isopropyl isopropyl isopropyl isopropyl and tertiary-1-butyl isopropyl isopropyl III -butyl isopropyl isopropyl tert-butyl isopropyl tert-butyl Melting point ° C 4 118-120 87-89 126-128 126-127 134 R-136, 105-107 hydrooxalate and 101-102 Hydroxalate 124-1330 116-117 115-117 oxalate 211-213 112-114 106-108 oxalate 187-189 94-96 132-134 117-119 87- 89 119-120-butyl Table II RW HHHHHH isoprops | Iowa 1 HHHA —OH2CH2— ¦ — CH2CH2CH2— —CH2CH2— —CH (CH3) - '—CH2CH2— —OH2OH2CH2— —CH ^ CHg-— —CH2CH2CH2—' —CH2CH2— * —CH2CH2— R * bromo-bromo Nitrous H allyl allyl nitro HH methoxyl Melting point ° C 102-104 69-71 130-132 101-104 93-95 78-80 108-110 85-87 102-104 108-109 Table III R »CH3CO H2NCO R1 isopropyl tert-butyl Melting point ° C 71— 72 hydrogen oxalate 148—149 Table IV ftPL Substituent position H2NCOCH2— 2— 3— 4 ^ - 4 ^ - 4— Other basics Petrol rings in a gasoline ring - -. 3-methyl 2,3-dimethyl 2,5-dimethyl Melting point ° C hydrogen oxalate] 146-148 82- 84 132-134 hydrogen oxalate 213-215 111-113 40 45 50 55 methyl amino HHHH n-propyl H-fluoro fluorinated chloro isopropyl isopropyl isopropyl isopropyl tertiary-butyl isopropyl tert-butyl 125-127 92- 93 97-100 92-95 101-102 100-1019 93 998 PL

Claims (3)

Claims 1., 1. A process for the preparation of alkanolamine derivatives of the general formula I, wherein R1 is an alkyl or hydroxyalkyl radical, each with no more than 6 carbon atoms, R2 is an acyl radical with no more than 6 carbon atoms, a carbamyl, alkylcarbamyl or alkenylcarbamyl radical in which the alkyl or alkenyl moiety contains no more than 6 carbon atoms, or a carbazoyl radical, A is an alkylene radical of 1-5 carbon atoms, and n is the numerical value of 1 or 2, and R8 are optionally different, if n = 2, and is a hydrogen or halogen atom, a nitro, hydroxyl or cyano radical, an alkyl, alkenyl, acyl or alkoxycarbonyl radical, each with no more than 6 carbon atoms, a cycloalkyl radical of no more than 8 carbon atoms, a thioalkyl, alkoxy or alkenyloxy radical, each with no more than 5 carbon atoms, an aryl, aryloxy, aralkyl or aralkoxy radical, each with no more than 10 carbon atoms, oran alkyl radical of no more than 5 carbon atoms, substituted with one or more hydroxyl radicals, alkoxy radicals of no more than 4 carbon atoms or halogen atoms, and acid addition salts of these compounds, characterized by the compound of general formula III wherein R2, R8, A and n are as defined above, or a salt of this compound with an alkali metal, is reacted with a compound of the general formula YCH2CHOHCH2NHR1 or of the general formula IV, in which the formulas R1 is as above and Y is a halogen atom, preferably chlorine or bromine, and the free base form of the alkanolamine derivative is optionally reacted with an acid to form its acid addition salt. 2. The method according to claim The process of claim 1, characterized in that the compound of general formula 8, in which R * is a hydrogen or halogen atom, or an alkyl, alkenyl or alkoxy radical, each with no more than 10 carbon atoms, and R10 is a hydrogen atom or an alkyl radical of no more than More than 3 carbon atoms, or an alkali metal salt of this compound, is reacted with a compound of the general formula YCHjjCHOHCHzNHR1 or of the general formula 4, in which formulas R1 is an isopropyl or tertiary butyl radical. and Y is chlorine or bromine and the resulting compound of general formula 5 or 6, wherein R1, R3 and R10 are as defined above and A is a methylene group, optionally converted from the free base into an acid addition salt. 3. The method according to p. 2. The process of claim 2, characterized in that for the preparation of 1-p-carbamylornethylphenoxy-3-isopropylamino-2-propanol and its acid addition salts, p-carbamylmethylphenol or its alkali metal salt is reacted with a compound of formula YCH2CHOHCH2NHCH (CH3) 2, wherein Y is chlorine or bromine, or with a compound of formula 9 and the compound formed is optionally converted from the free base to an acid addition salt. 30 * A OCHgCHOHCHgNHR FORMULA 4 R2A ^ <OCKLCH OHCHoNHR .—, 2 2 ^ R3 FORMULA 2 ARA FORMULA 3 CHg -— CHCHgNHR FORMULA A93 998 R10NHCOCH2- ^ V-OCH2CH2CHOHCH2NOH ^ \ ^ NCH-5R * CHj? PATTERN 6 R2CHgCH2 \\ CHP CHP OCH3 PATTERN 7 R1 ° NHCOCM f y_0H 2 PATTERN 8 CH2 CHP_CKNHCH (CH) 0 PATTERN 9 DESIGN ORDER 1679 (110 + 25 copies) Price PLN 10 PL