FI62054C - PROCEDURE FOR THE PHARMACOLOGICAL PROPERTIES OF VAERDEFULLA 1-ARYLOXI-2-HYDROXI-3-ALKINYLAMINOPROPANER - Google Patents

Description

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Patent and registration authorities AiwMcm uttafd och utl.tkrtft * n pubtlcorad (32) (33) (31) Request for utuellwu · —a «fM priorHut 28.02.73 26.01.7! + Federal Republic of Germany-Förbunds-republics , p 21 + 03809.3 (71) CH Boehringer Sohn, D-6507 Ingelheim am Rhein, Federal Republic of Germany- Förbundsrepubliken Tyskland (DE) (72) Herbert Köppe, Ingelheim / Rhein, Werner Kummer, Ingelheim / Rhein,

Helmut Stähle, Ingelheim / Rhein, Gojko Muacevic, Ingelheim / Rhein,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (71+) Leitzinger Oy (5I +) Method for the preparation of pharmacologically valuable 1-aryloxy-2-hydroxy-3-alkynylaminopropanes - Förfarande för framställning av pharmacologi skt värdefulla 1-arlo 3 ~ alkinylaminopropaner

The invention relates to a process for the preparation of new pharmacologically valuable substituted racemic or optically active 1-aryloxy-2-hydroxy-3-alkynylaminopropanes and their acid addition salts.

The general formula of the new compounds is R1 A \ f4 <L ') -OCH, -CHO-CH, -NH-C-CeCH

* ΓΎ I

R 3 R 5 In this formula is a hydrogen or halogen atom, a nitro group, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkenyl or alkynyl group having 2 to 5 carbon atoms, a lower alkyl (or dialkyl) amino group, a lower alkoxyalkyl group or lower alkyl (or dialkyl) aminoalkyl. ? ·. j.

2 62CS4, a group of the formula - (CH2) x-CN, ”(CH2) X-NH2 or - <ΟΗ2) χ-ΟΗ, where x is zero or an integer from 1 to 3, -COOH, -COORg, where Rg is an alkyl group having 1 to 1 carbon atoms, an alkenyloxy or alkynyloxy group having 3 to 6 carbon atoms, a lower aliphatic, araliphatic or aromatic acyl, acyloxy or acylamino group, a cycloalkyl group having 3 to 7 carbon atoms, a group -Q-CO -NHR7R8, wherein Q is a single bond, an oxygen atom, an NH, CH2- or CH2-NH group, and R? and R 9 is hydrogen, lower alkyl or together with the nitrogen atom a heterocycle such as a pyrrolidino, piperidino or morpholino group, or an aryl or aryloxy (preferably phenyl or phenoxy) group optionally substituted by halogen, alkyl, alkoxy, nitro, cyano or carboxyl group , R 2 is a hydrogen or halogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms, an acyl or alkenyl group having 2 to 4 carbon atoms, a cyano, amino or nitro group or, together with the group R 1, a 3,4-methylenedioxy group ,

Rg is a hydrogen or halogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms or, together with the group R2, a group -CH = CH-CH = CH- or “(CH2) - (n = integer 3-5), where the bond of the free valences is in the o-position relative to each other, R4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R8 is an alkyl group having 1 to 3 carbon atoms, or together with the group R1 is a group - (CH2) p-, where p is an integer 4-6.

When R 1 is a lower aliphatic acyl group, there is, for example, an acetyl, propionyl or butyryl or isobutyryl group. As the araliphatic acyl group, R 1 may denote, for example, a phenacetyl group optionally substituted on phenyl by one or more halogen atoms, alkyl groups, nitro-r, cyano or carboxyl groups. When denoting an aromatic acyl, R 1 may be, for example, a benzoyl group which is optionally substituted one or more times by halogen, lower alkyl, nitro, cyano or carboxyl.

If R1 represents an acyloxy or acylamino group, then the acyl group may optionally be an acyl group separately attached in the above step.

The new compounds can be prepared in the following ways: 3 62054 a) A compound of general formula II

L

() -OCH 2 -Z II

* 3 wherein R2. "R3 'is exactly the same as in formula I, and Z is a group -CH-CH2 or -CHOH-CH2-HalI (Hal = halogen), is reacted with an amine represented by the general formula is

NH2-CRi + R5-CsCH III

wherein R 1 and R 2 have the same meaning as in formula I.

b) The easily removable protecting group is cleaved from the compound of general formula IV fl IR, r Λ -och2-ch-ch2-nh-cc c iv 0G R5 R3 wherein R1 -R2 have the same meaning as in formula I and G is readily hydrolytically a cleavable group, for example an acyl or acetal group.

c) The protecting group is cleaved off from the compound of general formula V R1 fl \\ -OCH2-CH-CH2-N-C-C ch v R OH SchRg> 2 R3 ·. 62054 wherein R1-R8 have the same meaning as in formula I, and Sch is an easily cleavable protecting group, for example an acyl group or a carbobenzoxy group.

d) Hydrolysis of the oxazolidine derivative of the general formula VI R0 0 N - C-C

2 1 \ / I

x R 3 R 5 wherein R 1 -R 8 have the same meaning as in formula I, and X is a -CO-, -CH 2 - or -CH-lower alkyl group, for example with sodium or potassium hydroxide in water or an alcohol-water mixture.

There are other possibilities for the preparation of the compounds of the general formula I, since in compounds which already have a 3-alkynylaminopropanol-2-chain, however, no substituent R1, R2 or R8 already exists in the phenyl nucleus but represents a group which can be converted into this group, this the group is converted to the group R1 or R2 or Rg by conventional methods. Thus, for example, it is possible that e) Compounds of formula Vila

A

rh fT \ -OCHo-CH-CHo-NH-C-CfCH Vila w · ;, 'i, R2 R3 wherein R2 * R8 have the same meaning as in formula I, and A is a group which can be converted to the group R1 by conventional methods, such as -CONHj - or -COORg group (wherein Rg is as defined in formula I), an alkoxy, Oacyl or NOj group, or compounds of the general formula VIIb 5 62054

B

A

r N 1 -OCH 0 -CH-CH 0 -NH-CC 2 CH V 11b 2 OH 2 is R 3 wherein and R 9 -R 8 are as defined in formula I, and B is a group which can be converted into R 2 by conventional methods, such as -CO-NH 2 or NO 2 as an example. group, is converted into the compounds of the general formula I using the procedure required in each case (cleavage of water, reduction, saponification, ether cleavage, alkylation).

For the preparation of compounds of general formula I in which R 2 or R 3 represents a halogen atom, it is further suitable that f) a halogen atom is attached to the compounds of formula VIII in%

Ar-O-CHo-CHO-CHo »* NH-C-C" CH VIII

1 1 1 R 5 in which R 1 and R 4 have the same meaning as in formula I and Ar represents a group of the sub formula I 1 and V '2 · R 3 (in which R 1, R 2 and R 8 have the same meaning as above), for example halogenated hydrochloric acid / hydrogen peroxide mixture at an elevated temperature.

To prepare compounds of general formula I in which R1 and R2 represent a CN group, it is further possible to g) attach a CN group to compounds of general formula IXa

S

> v 'M-O-CHo-CHOH-CHo-NH-C-CsCH IXa * * 1 R5 6 62054 wherein and have the same meaning as in formula I, and M is a group of the formula C Rx R, R3 (where R , R 2 and R 8 have the same meaning as in formula I) and C is an amino group or halogen. In the case where C represents an amino group, this can be done by diazotization and boiling in the presence of a cyanide such as potassium cyanide, and in the case where C represents halogen, by reaction with Cu (I) CN in a high boiling solvent.

The starting material required for carrying out methods a) to g) is already known in part, for example it can be obtained by conventional methods. Thus, epoxides of formula II are readily prepared by reaction with the corresponding phenol or phenolate of formula R1

(f -OKt X

R 3 wherein R 1 -R 2 are as defined above and Kt is hydrogen or a cation (e.g. an alkali metal cation). The epoxide, on the other hand, can be used to prepare other starting materials, for example, the halohydrins of formula II can be prepared by reacting the epoxide with the corresponding hydrohalic acid.

The amines of formula III are known and are numerous commercial products. Compounds of formula IV may be obtained by reacting a halohydrin of formula II with a protecting group. Gr, with a forming compound (such as vinyl ether or dihydropyran) followed by a compound of formula i 62054

Ri / ~ h \

() -OCHo-CH-CHo-Hal XI

, -V to R 3 are reacted with a compound of general formula III.

Tertiary amines of formula V are obtained by reacting a compound of general formula X with a compound of general formula

Sch Ru i r

Z-CH.-N C-CsCH XII

and I

R 5 where R 1, R 5 and Sch are as defined above. Oxazolidinones of formula VII (i.e. compounds where X = CO) can be obtained, for example, by starting from epoxides of formula II by reacting the latter with urethane (can be prepared from ethyl chloroformate and an amine of formula II) of formula HC CC-HN-C -OC2H5 xiii R5 0 where and R & have the same meaning as above.

The compounds of formula VIIa, VIIIb, VIII, IXa and IXb already have a 1-phenoxy-2-hydroxy-3-alkynylaminopropane backbone and can be prepared analogously to method a) described above starting from the corresponding phenol and the corresponding 1-phenoxy-2,3- via epoxypropane (can be prepared by reacting epichlorohydrin with the people) by reacting with an alkynylamine of formula III.

The compounds of the invention have an asymmetric carbon atom in the CHOH group and therefore exist as a racemate as well as an optical antipyretic. The latter can be obtained not only by separating the racemate with common auxiliary acids such as dibenzoyl (or di-p-toluyl) -D-tartaric acid or With D-3-bromocamphor-8-sulfonic acid, also using optically active starting materials.

The 1-phenoxy-2-hydroxy-3-alkynylaminopropanes of the general formula I according to the invention can be converted into their physiologically acceptable acid addition salts in the customary manner. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid or 8-chlorotheophylline.

The compounds of the general formula I or their physiologically acceptable acid addition salts have been shown to have valuable therapeutic properties, in particular β-adrenolytic properties, in animal experiments on guinea pigs. They can therefore be used, for example, for the treatment or prophylaxis of cardiovascular diseases and for the treatment of irregular cardiac function, in particular tachycardia, in humans. The antihypertensive properties of the compounds are also of therapeutic interest. Compared to known β-receptor blocking compounds, for example the commercial product 1- (1-naphthyloxy) -2-hydroxy-3-isopropylaminopropane (Propranolol), the compounds have the advantage of significantly lower toxicity and better effect.

Compounds of the general formula I in which and in each case denote a methyl group (substituted 1-phenoxy-3- (2-methylbutinyl-3-amino-2 -) - 2-propanols) have proved to be particularly valuable.

The group R 1 is particularly preferably an unsaturated substituent, such as alkenyl (e.g. allyl), alkynyl (e.g. ethynyl, propynyl), alkenyloxy (e.g. allyloxy), alkynyloxy (e.g. propargyloxy) or cyano, especially when they are 2- to the propanolamine side chain. position. In this case, R 1 may preferably represent hydrogen, further also lower alkyl (e.g. methyl) - preferably in the 5-position relative to the propanolamine side chain, while R 3 generally represents hydrogen. Another preferred subgroup consists of compounds of general formula I wherein R 1 is hydroxyalkyl, in particular a hydroxymethyl group; further an amino or acylamino group, in particular an acetylamino group, in which case R 2 and R 2 may in the first case denote hydrogen, in the second case hydrogen or also halogen or lower alkyl. Important individual compounds are, in particular, 1- (2-cyanophenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol and 1- (2-ethynylphenoxy) -3- (2-methylbutoxy) - 9 62054 methylbutinyl-3-amino-2) -2-propanol, 1- (2-allylphenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol, further 1- (3,5- dibromo-4-aminophenoxy) -2- (2-methylbutinyl-3-amino-2 -) - 2-propanol, 1- (2-hydroxymethylphenoxy) -3- (2-methylbutynyl-3-amino-2) -2- propanol, 1- (3-chlorophenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol and 1- (4-acetamidophenoxy) -3- (2-methylbutynyl-3-amino-2) - propanol or their physiologically acceptable acid addition salts.

The unit dose of the substances according to the invention is 1-300 mg, preferably 4-100 mg (orally) or 1-20 mg (parenterally).

comparison Tests

The compounds prepared according to the invention were compared with the compounds known from the prior art, i.e. NO-132 835, NO-131 984 and NO-115 028. The experiments investigated the aludrin-antagonist effect of the compounds. As can be seen from the experimental results shown in the table, the compounds according to the invention are many times more potent than the known compounds.

Compound aludrin antagonistic activity on dichloroisoprotermol_ A. Invention a) Example 4 170 b) List on page 13, compound 9 107 c) List on page 13, compound 17 62 d) List on page 18, compound 18_78_ B. Reference compounds a) NO-132 835

Example 1 19

Example 4 4

Example 32 19

Example 28 5 62054 ίο

Compound aludrin antagonistic activity dichloroisoprotermol in_ b) NO-131 984 1- (4-acetylaminomethylphenoxy) -3-isopropylaminopropanol (2) 3-7 1-4 (acetylaminomethylphenoxy} -3-isopropylaminopropanol (2) 4.6 c) NO-115 028 1- (4-methoxynaphthoxy) -3-isopropylaminopropanol (2) 0.2 1-4 (hydroxynaphthoxy) -3-isopropylaminopropanol (2) 2.5

The following examples illustrate the invention without limiting it:

Example 1 lc <-naphthoxy-3- (3-ethylpentynyl-4-amino) -2-propanol · HCl (method a) 10 g (0.05 mol) of 1 - (- naphthoxy-2,3-epoxypropane) dissolved in 80 ml of ethanol, 5.55 g (0.05 mol) of 3-ethylpentin-4-amine-3 are added and the mixture is refluxed for 2 hours, after cooling, the solvent is distilled off, the residue is dissolved in ether and acidified with alcoholic hydrochloric acid. isolated and recrystallized from a mixture of acetonitrile and ethanol Yield: 9.5 g, melting point: 195-196 ° C.

. · V '' * i 11 62054

Example 2 1-m-Tolyloxy-3- (2-methylbutynyl-3-amino-2) -propanol · HCl (Method a) 8.2 g (0.05 mol) of 1m-tolyloxy-2,3-epoxypropane is dissolved in 90 ml of ethanol and 6.25 g (0.075 mol) of 2-methylbutin-3-amine-2 are added. It is then heated at reflux for 2 hours. The solvent is distilled off and the residue is recrystallized from ethyl acetate by adding petroleum ether. The crystalline base is dissolved in acetonitrile, alcoholic hydrochloric acid is added and crystallization is started by adding ether. Chromatographically pure colorless crystals give 6.5 g.

Melting point: 139-141 ° C.

Example 3 1- (2-Allylphenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol oxalate (Method a) 9.5 g (0.05 mol) 1- (2-allylphenoxy) -2 The 3-epoxypropane is dissolved in 60 ml of methanol, 8.3 g (0.1 mol) of 2-methylbutyn-3-amine-2i are added and the mixture is refluxed for 3 hours. After distilling off the solvent, the basic residue is dissolved in acetone and a solution of 6 g of oxalic acid in acetone is added. The crystalline separable oxalate is crystallized once more from acetone.

Yield: 4.7 g, melting point: 114-146 ° C.

Example 4 1- (2-Cyanophenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol · HCl (Method a) 17.5 g (0.1 mol) 1- (2-cyanophenoxy) -2 The 3-epoxypropane is dissolved in 130 ml of ethanol. 16.6 g (0.2 mol) of 2-methylbutyn-3-amine-2 are added and the mixture is refluxed for 2 hours. The solvent is distilled off, and the remaining residue is acidified with hydrochloric acid and shaken. The insolubles are then removed by suction, the filtrate is made alkaline with sodium hydroxide, the precipitated base is dissolved in chloroform and, after separation, the organic phase is dried over sodium sulfate. After filtration, the chloroform is distilled off and the residue is recrystallized from ethyl acetate by adding petroleum ether. The base is dissolved in acetonitrile and acidified with 12,62054 alcoholic hydrochloric acid. The hydrochloride crystallizes colorless. Yield: 13.9 g (thin layer chromatography uniform), melting point: 169-171 ° C.

Example 5 1- (2-Cyanophenoxy) -3- (1-ethynylcyclohexylamino) -2-propanol · HCl (Method a) 9 g (0.05 mol) of 1-ethynylcyclohexylamine and 8.7 g (0.05 mol) of 1 - (2-Cyanophenoxy) -2,3-epoxypropane is dissolved in 100 ml of ethanol and heated at reflux for two hours. The solvent is distilled off and the residue is dissolved in ethyl acetate and shaken with dilute hydrochloric acid. The aqueous phase is made alkaline with sodium hydroxide, the precipitated base is extracted with ethyl acetate. The organic phase is washed, dried over magnesium sulfate, filtered and the solvent is distilled off. The remaining residue is recrystallized from ethyl acetate by adding nitroin. The colorless crystalline base is dissolved in alcohol, alcoholic hydrochloric acid is added and the hydrochloride is crystallized by dropwise addition of ether. The salt is separated and crystallized once more from ethanol by adding ether.

Yield 6, Ug, m.p .: 176-177 ° C.

The following compounds of general formula I are prepared by method a) analogously to Examples 1-5, i. by reacting a correspondingly substituted 1-phenoxy-2,3-epoxypropane of formula II with a corresponding amine of formula III in ethanol: mp 62054 13 R2 R3 R4 R5 HCl salt m.p.

unless otherwise stated 2- CN CN HH C2H5 C2H5 170-171 ° 3- CH3 HH C2H5 C2H5 143-145 ° 2-O-CH2-CH = CH2 HH C2H5 C2H5 112-113 ° 2-CH2-CH = CH2 HH C2H5 C2H5 128 -129 ° 2,3-CH = CH-CH = CH-H CH3 CH3 159-161 ° 2-O-CH2-CH = CH2 HH CH3 CH3 100-103 ° 3- CH3 HH - (CH2) 5-159- 160 ° 2- CH2-CH = CH2 HH - (CH2) 5- 120-122 ° 2-Br HH CH3 CH3 138-139 ° 4- CN HH CH3 CH3 194-196 ° 4-NO2 HH CH3 CH3 183-184 ° 4-CH2OH HH CH3 CH3 108-110 ° (base) 2-OCH3 HH CH3 CH3 161-163 ° 4-COOCH3 HH CH3 CH3 127-129 ° 3,4- (CH2) 3- H CH3 CH3 139-140 ° 4 -tert.C4H9 HH CH3 CH3 146-147 ° 2-isoC3H7 HH CH3 CH3 157-158 ° 2-C = CH HH CH3 CH3 165-167 ° 4-NH-CO-NHCH 3 HH CH3 CH3 107-109 ° (base ) 4-O-CO-N (C2H5) 2HH CH3 CH3 125-127 ° 4-NH-CO-NHC2H5 2-CN H CH3 CH3 161-164 ° (base s) 4-NH-CO-NHCH3 2-CN H CH3 CH3 155-157 ° (base s) 4-NH-CO-NH-i-C3Hη 2-CN H CH3 CH3 127-130 ° (base) 4-CH2-CO-NH2 HH CH3 CH3 107-110 ° ( base) 3- (C2H5) -HH CH3 CH3 134-137 ° (dihydrochloride) 146204 R2 R3 R4 R5 HCl salt m.p.

unless otherwise stated 4-COOH HH CH3 CH3 159-162 ° 4-NH-COCH3 HH CH3 CH3 137-138 ° (base) 2-CH2-OH HH CH3 CH3 150-152 ° (oxalate) 2 "c6H11 H h Ch3 CH3 150-152 ° 2- Cl4-C1H CH3 CH3 170-171 ° 3- C1HH CH3 CH3 142-144 ° 2-CONH2 HH CH3 CH3 230-233 ° 2- CN 4-C1H CH3 CH3 176-177 ° 3- Br 4 -NH 2 5-Br CH 3 CH 3 183-185 ° (dihydrochloride) 2-CC-CH 3 H h CH 3 CH 3 164-166 ° 3,4-0- (CH 2) -O- H CH 3 CH 3 175-176 ° 4-CO-C2H5 HH CH3 CH3 149-151 ° 4- OH HH CH3 CH3 136-137.5 ° (base) 2-C6H5 HH CH3 CH3 157-158 ° 2-Cl HH CH3 CH3 150-151 ° 4-NH -COC3H7 HH CH3 CH3 129-130 ° (base) 4-NH-COC3H7 6-COCH3 H CH3 CH3 175-177 ° 2-coCH3 4-NH2 H CH3 CH3 118-119 ° (base) 2-C3H7 hh CH3 CH3 140 -141 ° 2-C2H5 HH CH3 CH3 149-151 ° 4-NH-CO-C3H η 6-CN H CH3 CH3 137-138 ° (base) 2-CN 4-NH2 H CH3 CH3 56-59 ° (base) ) 15 62054

Example 6 1- (2-Allyloxyphenoxy) -3- (2-methylbutynyl-3-amino-2 -) - 2-propanol in THCl (Method b)

To a mixture of 6.42 g (0.025 moles) of 1- (2-allyloxyphenoxy) -3-bromo-2-propanol and a catalytic amount of p-toluenesulfonic acid is slowly added dropwise at 20-25 ° C 2.4 g (0.025 moles) of ) tetrahydropyran. It is then heated for 30 minutes at 40 [deg.] C., dissolved in 40 ml of benzene and 5 g (0.06 mol) of 2-methylbutyn-3-amine-2 are added. The mixture is heated at reflux for 2 hours, then the solvent is distilled off and the residue and dilute hydrochloric acid are heated at 80 ° C for 15 minutes. Cool and extract with ether, make the alkaline phase alkaline with sodium hydroxide. The precipitated basic portion is taken up in ether, the organic phase is dried over magnesium sulphate and, after filtration, the ether is distilled off. The residue is dissolved in a small amount of ethanol, ethereal hydrochloric acid is added, and the crystalline hydrochloride is crystallized twice more.

Melting point: 99-102 ° C.

Example 7 1- (4-Nitrophenoxy) -3- (2-methylbutynyl-3-amino-2) -propanol * HCl (Method c) 2.7 g (about 0.008 moles) of 1- (4-nitrophenoxy) -3- (N-Acetyl-2-methyl-butynyl-3-amino-2) -2-propanol in 25 ml of ethanol and 1 g of potassium hydroxide are heated at reflux for two hours. After distilling off the solvent, a viscous residue remains, which is triturated with dilute hydrochloric acid. Shake with ether and adjust the aqueous phase alkaline with sodium hydroxide. The precipitated amine is taken up in chloroform. Dry over sodium sulfate and distill off the solvent, and the residue is recrystallized from ethyl acetate by adding petroleum ether.

Yield: 1.5 g, melting point: 125-127 ° (base). Melting point with the material obtained according to method a: 126-127 ° C.

Example 8 1- (2-cyanophenoxy) -3- (2-methylbutyn-3-amine-2) -2-propanol * HCl (m / d) 16 62054 2.8 * + g (0.01 mol) 3- ( 2-Methylbutin-3-yl-2--5- (2-cyanophenoxymethyl) -oyl · azolidolid-2-one in 20 ml of ethanol is heated at reflux for three hours after the addition of 3 g of potassium hydroxide. In 6 ml of water. The solvent is distilled off, the residue is triturated with water and extracted with chloroform. The chloroform solution is shaken with dilute hydrochloric acid and the separated aqueous phase is made alkaline with sodium hydroxide. The precipitated base is taken up in chloroform, the organic phase is washed with water and dried over sodium sulfate. After filtration, the chloroform is distilled off and the residue is recrystallized from ethyl acetate by adding petroleum ether.

Yield: 1.3 g, melting point: 84-86 ° C (base). Melting point with identical substance: 83-85 ° C.

Example 9 1- (* + - Aminophenoxy) -3- (2-methylbutinyl-3-amino-2) -2-propanol · HCl (Method e)

A mixture of 8.1 g of zinc II chloride in 20 ml of concentrated hydrochloric acid is heated at 60 [deg.] C. and 2.62 g (0.01 mol) of 1- (* + - nitrophenoxy) -3- (2-methylbutynyl-3-amino-2--2-propanol so that the temperature does not rise above 65 ° C. After the addition, stir for a further 30 minutes and, after cooling, make alkaline with sodium hydroxide. The precipitated basic portion is shaken with chloroform, the chloroform solution is washed After distilling off the chloroform, a solid residue remains which is recrystallized from ethyl acetate by adding petroleum ether Yield: 1, * + g, melting point: 122-123 ° (base).

According to method e) it is also possible to obtain 1- (4-hydroxyphenoxy) -3- (2-methylbutynyl-2-amino-2-) -2-propanol 1- (* + - diethylaminocarbonyloxyphenoxy) -3- (2 -methylbutynyl-3-amino-2) -2-propanol (melting point of hydrochloride: 126 ° C) by heating with concentrated hydrochloric acid. Melting point: 136-137.5 ° (base).

Example 10 1- (2-Cyano - * + - chlorophenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol * HCl (Method f) 3.87 g (0.015 mol) 1- (2 -cyanophenoxy) -3- (2-methylbutynyl-3-17,62054 -amino-2) -2-propanol is added to 25 ml of concentrated hydrochloric acid and heated at 45 ° C. Under cooling, 1.7 g (0.015 mol) of 30% hydrogen peroxide are added so that the temperature does not rise above 65 ° C. After the addition, a further 30 minutes are added, the porridge crystalline mass is separated by suction and washed with water. The hydrochloride is recrystallized from ethanol.

Yield: 1.95 g, melting point: 176-177 ° C.

Example 11 1- (2-Cyanophenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol · HCl (Method g) 0.697 g (0.002 moles) 1- (2-bromophenoxy) -3- ( 2-Methylbutynyl-3-amino-2) -2-propanol hydrochloride and 0.376 g (0.0042 mol) of Cu (I) CN and 0.4 g of dimethylformamide are stirred and heated at 190 [deg.] C. for 2 hours. After cooling, it is triturated with water and made alkaline with sodium hydroxide. The basic portion is taken up in chloroform and washed with water. The chloroform is distilled off and the residue is purified on a silica gel column. The pure base thus obtained is dissolved in acetonitrile and acidified with alcoholic hydrochloric acid. The hydrochloride crystallizes colorless.

Melting point: 168-171 ° C.

Example 12 1- (4-Hydroxycarbonylphenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol · HCl (Method e) 5 g of 1- (4-ethoxycarbonylphenoxy) -3- (2-methylbutynyl) -3-Amino-2) -2-propanol hydrochloride is boiled in 30 ml of concentrated hydrochloric acid for 2 hours at reflux. After cooling, the crystalline mass formed in the hydrolysis is filtered off with suction and recrystallized a second time from ethanol by adding ether.

Yield: 3.1 g; melting point: 159-162 ° C.

Example 13 1- (3,5-Dibromo-4-aminophenoxy) -3- (2-methylbutynyl-3-amino-2-) -2-propanol · HCl (Method f)

Claims (2)

• ie 62054 4.96 g (0.02 mol) of 1- (4-aminophenoxy) -3- (2-methylbutinyl-3-amino-2) -propanol are added to a mixture of 30 ml of hydrogen bromide (65% strength by weight). ) and 10 ml of water, and heated to 45 ° C. With stirring and cooling, 4.54 g (0.04 mol) of hydrogen peroxide are then added dropwise at 30% so that the temperature does not rise above 65 ° C. Hold for a further 30 minutes at about 6 ° C and the crystalline material is filtered off with suction after cooling. Recrystallize from ethanol by adding to ether. The hydrochloride is dissolved in water, sodium hydroxide is added, the base is extracted with chloroform and, after evaporation of the solvent, recrystallized from ethyl acetate by adding petroleum ether. The chromatographically pure base is dissolved in ethanol, alcoholic hydrochloric acid is added and the dihydrochloride is crystallized by adding ether. Yield: 3.8 g, melting point: 183-185 ° C. The process for the preparation of pharmacologically valuable 1-aryloxy-2-hydroxy-3-alkynylaminopropanes of the general formula R, I lp A 1 | 4 K. y-OCH, -CHOH-CH, -NH-C-CSCH R 1 R 3 R 5 wherein R 1 is a hydrogen or halogen tower, a nitro group, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, or an alkyl group. 19 62054 alkynyl group, lower alkyl (or dialkyl) amino group, lower alkoxyalkyl group or lower alkyl (or dialkyl) aminoalkyl group, group having the sub-formula - (CH2) X-CN, - (CH2> x-NH2 or - ( CH 2> x -OH, where x is zero or an integer from 1 to 3, -COOH, -COOR 8, wherein R 8 is an alkyl group having 1 to 4 carbon atoms, an alkenyloxy or alkynyloxy group having 3 to 6 carbon atoms, a lower aliphatic, araliphatic or aromatic acyl group. , an acyloxy or acylamino group, a cycloalkyl group having 3 to 7 carbon atoms, a group -Q-CO-NHR hydrogen, lower alkyl or together with the nitrogen atom a heterocycle such as a pyrrolidino, piperidino or morpholino group, or an aryl or aryloxy group optionally substituted by a halogen, alkyl, alkoxy, nitro, cyano or carboxyl group, preferably a phenyl or phenoxy group, R2 is hydrogen - or a halogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms, 2 to 4 carbon a liatomic acyl or alkenyl group, a cyano, amino or nitro group or, together with the group R 1, a 3,4-methylenedioxy group, R 8 is a hydrogen or halogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms, or together with R 2 a group - CH = CH-CH = CH- or - (CH2) J1 (n = integer 3-5) with free valences attached to the phenyl in the o-position relative to each other, R4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R8 is 1 to 3 a carbon-alkyl group or, together with R4, a group - (CH2) p-, in which p is an integer from 4 to 6, or their physiologically acceptable acid addition salts, characterized in that a) a compound of the general formula R3 in which R1-R8 have the same meaning as in formula I, and Z is a group -CH-CH 2 or -CHOH-CH 2 -Hal (Hal = halogen), is reacted with an amine of general formula NH 2 -CR 4 R 5 -ClCH III wherein R 1 and R 8 are as defined in formula I, or that in a compound of formula R 3 wherein R 1 -R 8 have the same meaning as in formula I and G is readily hydrolytically cleavable group, group G is replaced by hydrogen, or that c) in a compound of general formula RU <> -OCHo-CH-CHo-N-C-C = CH „X-1 · / 2 i 2 II v R 2 '-H 7 OH Sch Rg R 3 wherein R 1 -R 2 have the same meaning as in formula I and Sch is an easily cleavable protecting group, the group Sch is replaced by hydrogen, or that d) the oxazolidine derivative of the general formula R 1 (' -OCH, -CH-CH2RX * / i 1 i R0 0 N - CC2 CH VI 2 'x' R3 R5 where R1 -R8 have the same meaning as in formula I and X is -CO-, -CH2 ~ or -CH-lower alkyl group, or that e) a compound of formula A Λ r * V / -OCHo-CH-CHo-NH-C-CHCH Vila κ2 \ φ / 2 i5 R3 21 62054 where ^ 2 -55 is the same as in formula I and A is a group which can be converted into a group, or a compound of the general formula Ϊ1 / r \ <> -OCH2-CH-CH2-NH-C-CaCH VIIb B Vzr / OH R & R3 wherein R1 "R3 Da R5 have the same meaning as in formula I and B is a group convertible into R2, are converted to a compound of general formula I by converting A to R1 or B to R2, or that f) to a compound of general formula h Ar -O-CHo-CHOH-CHo-NH-CC-CH VIII 1 Cl R5 if and R 1 and R 2 are as defined in formula I and Ar is a group of the sub-formula - A R 3 wherein R 1, R 2 and R 3 are as defined above, a halogen atom is attached, or that g) in a compound of general formula% M- O-CH2-CHO-CH2-NH-C-CsCH IXa R5 wherein R1 and have the same meaning as in formula I and M is a group of the sub-formula 22 62054, 4> - R3 3 where R1, 1 * 2 3a r3 mean the same as in formula I and C is an amino group or a halogen, the group C is replaced by a cyano group, and that the optically active compounds of the general formula I are prepared from optically active starting materials, or the racemic compounds of the general formula I are converted into diastereomeric salts by reaction with appropriate auxiliary acids the salts are separated by fractional crystallization. 23 6 2 0 5 4 For the preparation of pharmacologically active compounds 1-aryloxy-2-hydroxy-3-alkynylaminopropane with the formula (\ '4-OCHCH-CHOH-CH2-NH-C-C2CH) ) »» -amino group, with a lower alkoxyalkyl group or a lower alkyl- (or dialkyl) aminoalkyl group, without a residue - (CH2) X-CN, - (CH2) x-NH2 or - (CH2) x-OH, and then x zero or a total number from 1 to 3, -COOH, -COORg, and Rg is an alkyl group having 1-4 cholaters, an alkenyloxy or an alkyloxy group having 3 to 6 cholaters, an aliphatic, araliphatic or aromatic acyl, acyloxy - or acylamino, and cycloalkyl having 3-7 cholaters, groups -Q-CO-NHR7Rq, and in which Q is used for the preparation of cyanogen, en NH2, CH2 ~ or CH2-NH groups and R7 and Rg, nedre al in the case of columns with the N-atom and the heterocyclic lixome pyrrolidino, piperidino or morpholino or halogen, halogen, alkyl, alkoxy, nitro, cyano or carboxyl substituents aryl or aryloxy, radical phenyl, phenyl betyder is a halogen atom, an alkyl or an alkoxy group having 1 to 4 cholatomers, an acyl or an alkenyl group having 2 to 4 cholatomers, a cyano, amino or a nitro group or a tulyl group with R, 3,4-methylenedioxy groups, Rg Vä- or halogen, alkyl- or alkoxy with 1-4 cholaters or tills with R2 group -CH = CH-CH = CH- or - (CH2) n (n = total number 3-5) at the bond valenterna for phenyl and o-bonding for varandra, R4 is a substituent or an alkyl group having 1-3 chapters and, R5 is an alkylrest with 1-3 cholera or an alkyl group having R4 groups -CH2) p-, i is selected from the group consisting of of the total number 4-6, and the total physiological value of the syringes, nnnetecknat därav, att a) förbindelse med den allmänna formuleln 62054 24 Ri (/ VS-OCH.-Z II ,, ν R3 i vilken R ^ -Rg betyder liksom definierats i formuleln I and Z betyder Gruppen -CH-CH2 © Her - CHOH-CH 2 -Hal (Hal = halogen) is selected from the group consisting of NH2-CR14R5-C = CH III and the same R1 and Rg as defined in formula I or (b) in the form of a compound of formula R1 (/'--CHCH-CH-CH9-NH-CC = CH IV, 2V and R3 i flashes - r5 is a formula I and a group of G hydrolytic spaltbar groups, Group G is a genomic group, or ) and the first of these formulas R1 // -OCH.-CH-CH.-NC-CsCH V Λφ / 2 Äh 2 U5 Rj Sch R3 i vilken R ^ -Rg betyder liksom definierats i formuleln I and Sch betyder en lätt spaltbar skyddgrupp, Gruppen Sch ersätts genom väte, eller att d) en oxazolidine derivatives with all the formulas 62054 25 Ri (/ \ S-OCH9-CH-CH, Rk VI x = t / I ΓΓ R0 I qn - cc = ch R3 X \ 5 and then R ^ -R5 betyder liksom definition of formulas I and X in which -C0-, -CH2- or -CH-nederalkyl group, hydrolysis, or e) en derivative of formula A </ \> - OCH0-CH-CH0-NH-CC = CH Vila SV ”R3 is defined as R2 ~ R5 is defined by formula I and A is defined as R1 in the form of a group or a preferred group of all formulas Ä * · //. \\ - 0CHo-CH-CHo-NH-CC = CH Vllb X ^ J 2 in 2 i, R3 i vilken R ^ -Rg och Rg betys derivative as defined in formula I, and B is en and R2 is an equivalent group, genome omvandling a A to R 1 or B to R 2 is a compound of formula I, or f) and a compound of formula N Ar-O-CH 2 -CHOH-CH 2 -NH-CC = CH VIII K i vilken R4 och R5 betyder liksom definierats i formuleln i och Ar Betyder en rest med delformeln .. * · *