CH647497A5 - Process for the preparation of O-substituted hydroxylamines - Google Patents

Description

The invention thus relates to the method defined in the claims.

In the above definitions, the alkyl radicals R1 to R5 can each be straight-chain or branched and the aryl radicals R1, R2 and R3 and the aryl substituent on the second N atom in the saturated ring with a compound of the general formula Y-CH2-R6 (VIII) or

B) an O-alkylated hydroxylamine derivative of the formula

R4

R50

; C = N-O-CH, -Y

(IX)

with nucleophilic compounds of the formula HR6 (VI) to the common intermediates of the formula

R4

R30

: C = N-O-CH, -CH-CH, -R6

OH

(X)

- NO. 2

R3-

according to meaning f) one or more times, e.g. be substituted up to three times.

All of the aforementioned haloalkyl radicals preferably have 1 to 2 carbon atoms.

45 The synthesis of the compound according to formula (I), in which X represents the group -0-NH2, leads via the mutually protected intermediate of the formula

R4

R5> '

50 ^ C = N-O-CH2-CH-CH2-O-N = C;

implements the protective groups from these

R4

R5.

(XI)

OH

R4 RsO

hydrolytically cleaved as R4-COOR5 and the products of the formula (I) either isolated in the form of the free bases or converted into their physiologically tolerated acid addition salts using suitable acids, R4 in the above formulas being straight-chain or branched alkyl having 1 to 6 C-atoms or aryl and optionally substituted with alkyl or alkoxy each having up to 2 carbon atoms or halogen

R5 represent straight-chain or branched alkyl having 1 to 6 carbon atoms,

Re has the meanings given above for X or for in this special case, as starting materials (III) 55 or (VI), N-protected hydroxylamine derivatives of the group

—O — N = CR4

I.

R5 '

60

for R6.

Preferred compounds of the formula (II) are aldoximes and ketoximes, such as benzaldoxime or acetone oxime, which are readily accessible. 65 Suitable starting compounds of the formula (III), in which U is not hydrogen, are preferably 2,3-epoxypropyl derivatives, most of which are known from the literature or by processes known from the literature, e.g. made of epihalogen

647497

4th

hydrines, in particular epichlorohydrin, and the nucleophilic compounds of the formula (VI) can easily be prepared in the presence of basic agents. The 2-propanols Z-CH2-CH (OH) -CH2-R6, which are also suitable as starting compounds, can in principle be produced in the same way, but with the exclusion of basic condensing agents, from epoxides such as epichlorohydrin, epibromohydrin and 2,3-epoxypropylbenzene sulfonate, toluenesulfonate Prepare, -4-bromobenzenesulfonate or methanesulfonate.

Suitable compounds of the formula (II) in which T is not hydrogen are, in particular, the 0- (2,3-epoxypropyl) oximes known from the literature, such as 0- (2,3-epoxypropyl) acetaldoxime, benzaldoxime or acetone oxime which, according to process variant B, can be reacted with alcohols, thiols, phenols, thiophenols, amines or five-membered aromatic nitrogen heterocycles of the formula (VI).

Among the amines according to formula (VI) which can be used are preferably saturated cyclic compounds pyrrolidine, 2,5-dimethylpyrrolidine, piperidine, 2,6-dimethylpiperidine, 2,2,6,6-tetramethylipiperidine, hexamethyleneimine, morpholine, thiomorpholine and the piperazine which is optionally substituted in the 4-position. Suitable five-membered, aromatic, optionally fused nitrogen heterocycles are pyrrole, indole, pyrazole, indazole, imidazole. Benzimidazole, triazole, benzotriazole, tetrazole, carbazole and xanthines such as theophylline. "

The reactions according to claims 3 and 4 are expediently carried out in a solvent or distribution medium which is inert to the reactants at temperatures between 0 and 200 ° C, preferably between 50 ° C and the boiling point of the solvent used either in the presence of basic agents (for example alkali or Alkaline earth metal hydroxides, carbonates, hydrides and alcoholates or organic bases, such as triethylamine, pyridine, picoline and quino-lin) or using those from the oximes according to formula (V) or the alcohols, thiols, phenols, thipheno -len and nitrogen heteroaromatics corresponding to the formula (VI) separately prepared alkali or alkaline earth salts carried out, the reaction times can be from 1 hour to a few days.

For example, anhydrous alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol and ethers such as diethyl ether are used as solvents which are inert to the reactants. Diisopropyl ether, tetra-hydrofuran, dioxane or diethylene glycol dimethyl ether, hydrocarbons such as cyclohexane, petroleum ether. Benzene, toluene or Xvlol, halogenated hydrocarbons, such as di-chloromethane. Chloroform. Carbon tetrachloride or chlorobenzene, aprotic solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethylurea, hexamethylphosphoric trisamide, dimethyl sulfoxide or acetonitrile, and also mixtures of these solvents. Both in the reaction of the hydroxylamine derivatives (V) with epoxides of the formula (III) according to Claim 3 and in the addition of thiols and phenols. Thiophenols and nitrogen heteroaromatics of the formula (VI) to the oxiranes (II) according to claim 4, the work in dimethylformamide with the addition of triethylamine as a catalyst at temperatures between 50 and 100 ° C proves particularly good, the reactants in equimolar amounts or with a slight excess of the

CH2-CH-CH2 or Z-CH2-CH-CH2 group-bearing component of the alkylating agent are used.

In contrast, the condensation of (V) with the 2-propanols of the formula (III) is advantageously carried out using the alkali metal or alkaline earth metal oximes in alcoholic solution at boiling temperature.

5 The aminolysis of the oxiranes (II) with amines as representatives of compounds of the formula (VI) according to claim 4 is preferably carried out by boiling for 1 to 5 hours in higher-boiling alcohols such as n-propanol or isopropanol without further addition of base, especially in In the case of primary amines, their use in excess of up to 4 times the stoichiometric amount is recommended.

In general, pure isolation of the intermediate compound of the formula (IV) and (XI), which is obtained according to claim 3 or 4, is not necessary for the subsequent hydrolytic elimination of the respective protective group. If desired, however, it can be carried out by fractional vacuum distillation or, in isolated cases, also by crystallization.

The hydrolytic cleavage is preferably carried out under acidic conditions in aqueous, aqueous-alcoholic or aqueous-ethereal solution at reaction temperatures between 0 and 120 ° C., primarily from 60 to 110 ° C., the reaction time generally being between a few minutes and is a few hours. Diluted mineral acids such as hydrochloric acid and sulfuric acid are particularly suitable.

The new process products can be isolated either in the form of the stable free bases or preferably as non-toxic acid addition salts. Suitable acids for this are, for example, hydrohalic acids, in particular hydrochloric, sulfuric, phosphoric, vinegar, milk, maleic, fumaric, oxalic, wine, lemon, gluconic, p-toluene-sulfonic. , Methanesulfonic, benzenesulfonic and cyclohexylamidosulfonic acid.

35 Because of the propanol (2) structure, the compounds of the formula (I) according to the invention have a chiral center and can therefore be present in the optically active D or L form. The invention therefore relates to both the enantiomeric compounds and their racemic mixtures.

To display the pure antipodes, one can either start from the enantiomeric starting compounds of the formula (III) or (II) in the reactions according to claims 3 and 4, or the racemates obtained by one of the two process 45 variants using processes known per se , e.g. by fractional crystallization of the acid addition salts of an optically active acid into the enantiomers.

The new hydroxylamines of formula I and their physiologically compatible acid addition salts have valuable pharmacological properties.

Depending on the constitution of the substituent X, they show, in particular, hypotensive but also bronchospasmolytic, anticonvulsive, analgesic, anti-55 phlogistic, choleretic, uric acid-lowering (anthelmintic and antifungal effects. At the same time, they are important starting materials for the synthesis of other valuable drugs, for example for the production of substituted 0- (2-hydroxypropyl) aldoximes by reaction with 2- «-formyl-5-nitroimidazoles or 2-formyl-5-nitrofuran, as described in the unpublished German patent application 26 51 084, or for the production of products which are described in the unpublished German published documents 26 58 762 and 26 58 938 65.

The new compounds of formula (I) and their physiologically tolerable salts can, because of their pharmacological properties, in particular as pharmaceuticals

5

647497

as such for the treatment of hypertensive conditions, using them either alone or mixed with suitable carriers. The invention thus also relates to medicaments which contain at least one compound of the formula (I), optionally in the form of one of its physiologically tolerable acid addition salts, as active ingredient. The preparations can be administered orally and parenterally. Suitable solid or liquid pharmaceutical preparations are, for example, granules, powders, tablets, capsules, syrups, emulsions, suspensions, drops or injectable solutions and preparations with a released active ingredient. Commonly used carriers are e.g. Magnesium carbonate, various sugars, starches, cellulose derivatives, gelatin, animal and vegetable oils, poly-ethylene glycols and solvents.

A particular application of the compounds according to the invention corresponding to formula (I) and their salts is in the combination with other suitable active ingredients, for example diuretics, saluretics, <% - and in particular β-sympatholytics, tranquillizers, vasodilators and other antihypertensives.

Examples

The structure of the compounds described below has been demonstrated by elemental analysis and by IR and ^ i NMR spectra.

Analysis:

calc .: C 33.75% H 7.28% Cl 28.46% N 11.24% found: C 33.61% H 7.39% Cl 28.37% N 11.14%

5 The free base of dihydrochloride can also be isolated in crystalline form. After recrystallization from diisopropyl ether, it has a melting point of 80-81 ° C. C ,, H16N203 (MG = 176.2)

io analysis:

calc .: C 47.41% H 9.15% N 15.90%

found: C 47.95% H 9.24% N 15.98%

2) 0- [3- {4- (2-Methoxyphenyl) -l-piperazinyl} -2-hydroxy-15 propylj-hydroxylamine trihydrochloride monohydrate

According to the variant corresponding to claim 3, a solution of 7.3 g (0.1 mol) of acetone oxime and 24.8 g (0.1 mol) of l- (2,3-epoxypropylene) -4- (2-methoxy) is heated -phenyl) -piperazine in 150 ml of isopropanol and 2 ml of triethyl-20 amine under reflux for 8 hours, allowed to cool, the alcohol was distilled off under reduced pressure, 150 ml of 3N hydrochloric acid were added to the residue and the mixture was boiled vigorously for 15 minutes Stir. It is then evaporated under reduced pressure and the residue is recrystallized from methanol with the addition of diethyl ether at the boiling point until cloudy.

1) 0- [3- (4-Morpholinyl) -2-hydroxypropyl] hydroxylamine dihydrochloride

According to the variant corresponding to claim 4, a solution of 12.9 g (0.1 mol) of 0- (2,3-epoxypropyl) acetonoxime and 8.7 g (0.1 mol) of morpholine in 60 ml is heated Isopropanol under reflux for 4 hours, allowed to cool, the alcohol was distilled off under reduced pressure, 150 ml of 3N hydrochloric acid were added to the residue and the mixture was boiled for 15 minutes with vigorous stirring. It is then evaporated under reduced pressure and the residue is recrystallized from methanol with the addition of diethyl ether at the boiling point until cloudy.

Yield:

23.6 g (95% of theory)

Melting point 178-180 ° C (with decomposition)

A ~ \

-ÇH-CH2-N O • 2 HCl

OH ^ '

(MG = 249.1)

h2n-o-ch2

Yield:

29.4 g (72% of theory) i Melting point: 142 ° C (with decomposition)

35

H "M-0-CH" -CK 2 ■

C ^ I ^ gCljNsO,

x 3 HCl X

H O n2 <-

Analysis: calculated: i found:

C C

41.14% 40.91%

H H

6.90% 6.91%

Cl 26.02% Cl 26.04%

N N

10.28% 10.30%

C, H18C12N203

v

Claims (5)

647497 1 to 4 carbon atoms or halogen are substituted, d) aryl, which is optionally substituted once or up to three times with alkyl, alkoxy, haloalkyl, each having up to 4 carbon atoms or halogen, and which contains up to 10 carbon atoms in the aryl part, e) hydroxyl when the other radical is hydrogen, or both together with the nitrogen f) a 5- to 7-membered saturated ring which is optionally substituted up to four times with alkyl having 1 to 4 carbon atoms and whose CC sequence is optionally by a further heteroatom in the form of oxygen, sulfur or one ^ rN-R group is interrupted, where R is hydrogen or alkyl or hydroxyalkyl, each having up to 4 carbon atoms, aralkyl or diarylalkyl, each having up to 4 carbon atoms in the alkyl part, the mono- or dinuclear aryl radicals being mono- or triple may be substituted with halogen, or aryl, which is optionally mono- or up to triple substituted with alkyl, alkoxy, haloalkyl each having up to 4 carbon atoms, halogen or hydroxyl, or a 3-aminooxy-2-hydroxypropyl group , or g) a 5-membered heteroaromatic ring, optionally fused with a benzene or uracil ring, which in the case of fusing onto the benzene ring can contain up to 3, otherwise up to 4 nitrogen atoms, and their physiologically tolerated acid addition salts, characterized in that in the first stage a hydroxylamine derivative of the formula R4 ^ C = N — O — T (II) R5 ' with a compound of formula U-R6 (III) to the common intermediates of the formula R4 ^ C = N-O-CH2-CH-CH2-R6 (IV) R5> | OH implements the protective groups from these O II II R4-C-F5 'as R4-C-R5' hydrolytically cleaved and the products of the formula (I) either isolated in the form of the free bases or converted into their physiologically tolerable acid addition salts using suitable acids, R4 in the above formulas being alkyl having 1 to 6 carbon atoms or optionally up to three times with alkyl or Alkoxy each having up to 2 C atoms or halogen-substituted aryl and R5 'being hydrogen, alkyl having 1 to 6 C atoms or optionally up to triple aryl substituted by alkyl or alkoxy each having up to 2 C atoms or halogen, R6 has the meanings given above for X or for the rest R4 —O — N = CC stands, R5 ' T hydrogen if U has a meaning other than hydrogen, or the group CH2-CH-CH2- or Z-CH2-CH-CH2-, \ / I O OH U is hydrogen if T has a meaning other than hydrogen, or the group CH2-CH-CH2- or Z-CH2-CH-CH2-, \ '/ I O OH and Z is halogen or a reactive sulfonic acid ester grouping, in each case T or U being hydrogen. 1. Process for the preparation of O-substituted hydroxylamines of the general formula H2N-O-CH2-CH-CH2-X (I) OH wherein Margin X -OR1, SR1 or -NC R3 R1 a) hydrogen, b) in the rest OR1 an amino group, c) alkyl having 1 to 6 carbon atoms or d) a mono- or dinuclear aryl radical which may be mono- or up to triple with halogen, alkyl, alkoxy, haloalkyl each having up to 4 carbon atoms, cycloalkyl with 3 to 6 C atoms, nitro or cyano groups is substituted R2 and R3 are identical or different and a) hydrogen, b) alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 7 carbon atoms, which are optionally substituted by hydroxyl or alkoxycarbonyl having 1 to 4 carbon atoms, c) Aralkyl or diarylalkyl, the alkyl part of which has up to 4 carbon atoms and optionally with hydroxyl and the mono- or dinuclear aryl radicals, optionally up to three times with one of the alkoxy radicals 2. The method according to claim 1, characterized in that Z is chlorine or bromine. 2nd PATENT CLAIMS 3rd 647497 is reacted with nucleophilic compounds of the formula H-R6 (VI), where R4, R5 'and T have the meaning given above, but T is not hydrogen. 5. The method according to any one of claims 1, 2 and 4, characterized in that 0- (2,3-epoxypropyl) acetone oxime as a compound of the formula (II) is reacted with morpholine as a compound of the formula (VI). 6. Medicament, characterized by a compound produced by the process according to one of claims 1 to 5. 7 .. Medicament according to claim 6, characterized by a compound prepared by the method according to one of claims 1 to 5 in combination with other active ingredients. 8. Medicament according to claim 6 or 7 for the treatment of hypertensive conditions. In German Offenlegungsschrift 2,651,083 there are new O-substituted hydroxylamines of the formula H2N-O-CH2-CH-CH2-X OH (I) R4 -O — N = Cd, ORs 3. The method according to claim 1 or 2, characterized gekennr characterized in that in the first stage a hydroxylamine derivative of the general formula R4 ^; C = N — OH (V) R5>. is reacted with a compound of formula (III), where R4, RB 'and U have the meaning given above, but U is not hydrogen. 4. The method according to claim 1 or 2, characterized in that in the first stage an O-alkylated hydroxylamine derivative of the formula R4 ^ C = N — O — T (II) Rs> 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 5 Y the group CH2-CH- or Z-CH2-CH- and O / OH described, wherein X has the meaning defined in claim 1. These connections are made by going in the first stage A) a hydroxylamine derivative of the general formula R4 R50 ; C = N-OH (VII) Z is halogen, preferably chlorine or bromine, or a reactive sulfonic acid ester group. The synthesis of these pharmacologically active, multifunctional O-alkylhydroxylamines was thus achieved by linking the pharmacophoric 2-hydroxylpropyl group, which is functionally substituted in the 3-position, with the oxygen atom of the hydroxylamine molecule. In this case, alkyl hydroxymate or 0- (2,3-epoxypropyl) or 0- (3-halo-2-hydroxypropyl) hydroxymate alkyl ester 20 was used as the N-protected hydroxylamine derivative. This method has worked well. In a further embodiment of this method, it has now been found that aldoximes and ketoximes also ensure reversible protection of the amino function. This Ar-25 leads via compounds in which RsO is replaced by R5 'and a carbon atom of R5' is bonded directly to the carbon atom of the group R4-C = N-0-.