KR820000384B1 - Process for preparing 1-aryloxy-2-hydroxy-3-alkylene-aminopropanes - Google Patents

Abstract

Title compds. (I; R1 = H, halogen, nitro, C1-8 straight or side chain alkyl; X = 1-3; R2 = H, halogen, C7-14 aralkoxy; R3 = H, halogen, C1-4 alkyl or alkoxy; R4 = H, C1-5 alkyl, C7-14 aralkyl; R5 = II or III; R10,R11=H, halogen, C1-4 straight or side alkyl; B = -OCH2; A = H or acyl) useful as sympatholytics, antiarrhythmics and antidepressives(no data). Thus, 1-(3-amino-3,3-dimethylpropyl)-benzimidazolidinone-(2) was refluxed with 1-(naphtyl-(1)-oxypropylene-(2,3)-oxide in 98 % alc., then treated with HCl and AcOH in MeOH to give IHCl(R1 = CL; R2 = H; R3 = H; R4 = H; R5 = III).

Description

Method for producing 1-aryloxy-2-hydroxy-3-alkyleneaminopropane

The present invention relates to a racemate or optically active 1-aryloxy-2-hydroxy-3-alkyleneaminopropane of the following general formula (I) useful as an arrhythmia therapeutic agent and a process for preparing acid addition salts thereof.

Wherein R ₁ is hydrogen, halogen, trifluoromethyl, nitro, straight or branched chain alkyl having 1 to 8 carbon atoms, straight or branched chain alkoxy having 1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, and 2 to 5 carbon atoms Phosphorus alkenyl or alkynyl, alkenyloxy or alkynyloxy having 3 to 6 carbon atoms, (optionally) bridged and / or unsaturated cycloalkoxy having 3 to 12 carbon atoms, partial general formula (CH ₂ ) _X -A ＇ Group, —COOR ₆ group, lower aliphatic, araliphatic or aromatic acyl, acyloxy or acylamino group, partial general formula —NH—CO—NR ₇ R ₈ or —O—CO—NR ₇ R ₈ group, halogen , alkyl, nitro, cyano and carboxyl groups or a once or several times, optionally substituted lower arylalkyl, allyloxy or aralkoxy group (phenyl, phenoxy or benzyloxy the desirability) partial formula NH-R _9, or N- Is an alkylene-R ₉ group

X is an integer from 1 to 3

A is a cyano, amino, carboxamido or hydroxy group

R ₆ is hydrogen or an alkyl group having 1 to 4 carbon atoms

R ₇ and R ₈ are hydrogen, alkyl or a heterocycle such as a pyrrolidino, piperidino or morpholino group with a nitrogen atom,

R ₉ is lower alkyl or an acyl group such as CH ₃ SO _2- , (CH ₃ ) ₂ SO _2- , alkyl-O-CO- group or -CONH-alkyl, -CONH-NH ₂ , -CH ₂ SO ₂ and -CO-NH-OH group

R ₂ is hydrogen, halogen, straight or branched alkyl having 1 to 4 carbon atoms, aralkyl group having 7 to 14 carbon atoms (preferably benzyloxy group), alkenyl group having 2 to 4 carbon atoms, cyano, nitro, hydr or hydroxy or amino group, or with _{R 3 -O-CH 2 O-,} -O- (CH 2) 2 -O, -CH = CH-CH = CH-, -OCH 2 -CONH-, - (CH 2 ) _2- CONH-, -CH = CH-NH-, -O-CO-NH, -CH ₂ -CH = CH-CH _2- , -O-CH = CH-, -O- (CH ₂ ) _3- , A divalent group such as —S (CH ₂ ) ₃ — or —CO (CH ₂ ) ₃ , wherein preferably the two free valences are bonded to each other in an ortho-position;

R ₃ is hydrogen, halogen, straight or branched chain alkyl or alkoxy having 1 to 4 carbon atoms, araloxy having 7 to 14 carbon atoms (preferably benzyloxy group) or hydroxy group

R ₄ is hydrogen, alkyl having 1 to 5 carbon atoms or an optionally substituted aralkyl group having 7 to 14 carbon atoms

R ₅ is the following heterocycle group

R ₁₀ and R ₁₁ are hydrogen, -O- (CH wherein halogen or straight or branched alkyl or alkoxy group having 1 to 4 carbon atoms, trifluoromethyl or carbox amido group or two free atoms are bonded to each other in ortho-position; ₂ ) a divalent group of a partial general formula of y-O- (y being 1 or 2)

B is a> NR ₁₂ group, a -OCH ₂ -group (which becomes a condensed phenyl ring in combination with oxygen) or a _divalent group-(CH ₂ ) ₂ -group

R ₁₂ is hydrogen, lower alkyl, alkenyl, alkynyl, cycloalkyl or optionally substituted aryl and alkylene is a straight or branched alkylene group having 1 to 12 carbon atoms

A is preferably hydrogen or an acyl group, in particular the particular acyl group described in R ₁ .

If R _1, R ₂ or R ₃ is an alkyl or alkoxy group, here it first means methyl or methoxy, ethyl or ethoxy, or isopropyl or isopropoxy group, respectively, alkenyl or alkynyl, alkenyloxy or R _{1 which} is an alkynyloxy group is preferably a vinyl, allyl, ethynyl, allyloxy or propargyloxy group. R _{1, which} is a cycloalkyl or cycloalkoxy group, is preferably a cyclopropyl, cyclopentyl, cyclopentyloxy or adamantyl group.

As halogen, R ₁ , R ₂ or R ₃ , fluorine, chlorine, bromine or iodine are suitable.

When R ₁ is an acyl group, it is meant a benzoyl or naphthoyl group in which an acetyl, propionyl, butyryl or isobutyryl group, phenacetyl, phenyl is substituted with halogen, lower alkyl, nitro, cyano and or carboxyl groups. The same group can be used for the 2-hydroxyl group esterification in the propane side chain, meaning A.

When R ₁ is an acyloxy or acylamino group, the acyl group is the same as the acyl group described above.

When R ₂ is a group -OCH ₂ -O- with R _3, the group is a 3,4-OCH ₂ -O- group is preferable.

Examples of the alkylene group linked to R ₅ include ethylene, triethylene, terramethylene, hexamethylene, dodecamethylene, 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene, 1,1-dimethylpropylene, 1,1-dimethylbutylene or a 1,1,4,4 or tedlamethylbutylene group is suitable.

The 1-aryloxy-2-hydroxyalkyleneamino-propane has at least one subtitle carbon, ie one of the groups of the propane side chain is the subtitle carbon. It may therefore be in racemate or optically active form. Ordinary optically active auxiliary acids such as dibenzoyl or di-P-toluyl-D-tartaric acid, D-3-bromo-camphorsulfonic acid or (-)-2, 3, by racemate-based methods 4,5-di-0-isopropylidene-2-keto-L-gulonic acid can be used to separate optically active isomers, which are then crystallized and stabilizers (e.g. allylamine in petroleum ether) are added. Can be. However, optically active starting materials can be used to obtain optically active compounds. In addition, the pharmacological activity (β-sympathetic block) is stronger in the optically active form with the "S" configuration.

Suitable acid addition salts of the compounds according to the invention include, for example, salts of inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid or sulfuric acid with methanesulfonic acid, maleic acid, acetic acid, acetic acid, oxalic acid, lactic acid, tartaric acid, 8-chloro- Salts with organic acids such as theophytic acid, salicylic acid, citric acid, β-naphtheic acid, adipic acid-1,1, -methylene-bis- (2-hydroxy-3-naphthoic acid), for example Sulfonated polystyrenes have salts derived from acid synthetic resins such as resins.

The compound of general formula (I) or a pharmaceutically toxic acid addition salt thereof has an α and β-sympathetic nerve block as tested by an animal test. Therefore, it can be used in various therapeutic fields. Therefore, it can be used, for example, in the treatment or prevention of coronary artery disease and in the treatment of deep veins, especially palpitations. This action is much stronger than known commercially available drugs such as propranolol or triprolol. The possibility of high pressure therapy is particularly important in the therapeutic sense. Compared with known α-blockers such as phentolamine, the compounds in particular have the advantage of having no or much less heart palpitations. The third field of use can be used as an antidepressant, ie in the treatment of diseases caused by depression.

An extremely effective substance as an antihypertensive agent having an α and β blocking action is 1- (α-naphthoxy) -3-[(1,1-dimethyl-3-benzamidazoleidedi in the form of an acid addition salt such as hydrochloride). Monopropyl) amino] -propanol-2. When tested in genetically hypertensive rats, the substance maintains blood pressure lowering and bradycardia for 24 hours (dose to 10 to 30 mg / kg) once and orally, as well as several times orally. Intravenous injection of 3mg / kg into anesthetized rabbits and cats results in hypotensive and bradycardial effects. α-sympathetic blockade is 10 times weaker than phentolamine (isolated from the semen bag of rats). However, β-sympathetic nerve blocking action is three to four times stronger than propranolol.

It is a β-sympathetic nerve-blocking cold substance with oral administration and has a distinct bradycardia effect (about 10 to 12 times stronger than propranolol), which is 1- (2-brophenoxy) -3-N-benzimidazolyl In the form of acid addition salts, such as hydrochloride of -3-propylamino) -propane- (2) -ol (this test was conducted by anesthesia with mortar).

Listed compounds having surprising pharmacological action as mentioned above are as follows.

a) excellent β-sympathetic blocker

1- [3,3-Dimethyl-3- (3-0-chlorophenoxy-2-hydroxypropyl) -propylamino] -3-phenylimidazolidi is-2-

1- (2-chlorophenoxy) -3- [1,1-dimethyl-3-benzimidazole lidinone-2 propyl) amino] -propanol (2)

1- [1,1-dimethyl-3- (3-phenylimidazolidinone-2-yl) propyl-amino} -3- (2-methylphenoxy) cy-propanol- (2)

1- (2-allylphenoxy) -3- (N-benzimidazoloyl)-(3-propylamino) -propanol- (2)

1- (3-methylphenoxy) -3- (N-benzimidazoloyl-3-propylamino) -propanol- (2)

1- (3-methoxyphenoxy) -3-[-1,1-dimethyl-3- (3-phenylimidazolidinonyl) -propyl amino-1] -propanol- (2)

1- (2-propargyloxyphenoxy) -3- [1,1-dimethyl-3- (3-phenylimidazolidinyl) propyl amino-1] -propanol- (2)

1- (2-acetyl-4-aminobutyrylphenoxy) -3- (3-N-benzimidazole ronyl-1,1-dimethyl-1-propylamino) propanol (2)

1- (2-chloro-5-methylphenoxy) -3- (3-N-benzimidazoloyl-1,1-dimethyl-1-propylamino) propanol (2)

(b) substances with excellent blood pressure drop and / or bradycardia

1- (2-chlorophenoxy) -3- [1,1-dimethyl-3-benzimidazolidinone-2-ylpropyl) amino] -propanol (2)

1- [1,1-dimethyl-3- (3,4-dihydro-1,4-2H-benz oxaz-3-onyl) -propyl amino] -propanol (2)

1- [1,1-dimethyl-3- (3-phenylimidazolidinone-2-yl) propyl amino-]-3- (3-methylphenoxy) -propanol (2)

1- (3-methylphenoxy) -3- [3N-1,2,3,4, -tetrahytroquinonolone (2) -1,1-dimethylpropylamino] -propanol (2)

1- (2-n-propylphenoxy) -3- [1,1-dimethyl-3- (3-phenylimidazolidinonyl) -propylamino] -propanol (2)

1- (4-methoxyphenoxy) -3- [1,1-dimethyl-3- (3-phenylimidazolonyl) -propylamino-1] -propanol (2)

1- (2-allylphenoxy) -3-[(1,1-dimethyl) -2- (3-phenylimidazolidinonyl) -ethylamino-1] propanol (2)

1- (3-trifluoromethylphenoxy) -3-[(1,1-dimethyl) -2- (3-phenyl-amidazole lidinyl) ethylamino-1] -propanol (2)

1- (Indanyloxy) -3-[(1,1-dimethyl) -3- (3-phenylimidazole lidinyl) -propylamino-1] -propanol (2)

1- (3,5-dimethylphenoxy) -3- [1,1-dimethyl-3- (3-phenylimidazole-ridinonyl-propylamino-1] -propanol (2)

1- (2-propargyloxyphenoxy) -3- [1,1-dimethyl-3- (3-phenylimidazole-ridinyl) propylamino-1] propanol (2)

1- (3-methoxyphenoxy) -3- [1,1-dimethyl-3- (3phenylimidazole lidinyl) propylamino-1] propanol (2)

1- (3,5-dimethylphenoxy) -3- [2- (3-phenylimidazole lidinonyl) -ethylamino-1] propanol (2)

1- (3-methylphenoxy) -3- [2- (3-phenylimidazole lidinonyl) -ethylamino-1] propanol (2)

1- (3,5-dimethylphenoxy) -3-[(3-phenylimidazole lidinonyl) -propyl-amino-1] -propanol (2)

1- (2,6-dimethylphenoxy) -3-([1,1-dimethyl-3-N-benzimidazolonyl) propylamino-1] propanol (2)

1- (3,5-dimethylphenoxy) -3-[(1,1-dimethyl-3-N-benzimidazoloyl) -propylamino-1] -propanol (2)

1- (2-bromophenoxy) -3-[(1-methyl-2-N-benzimidazoloyl) -ethyl-amino-1] -propanol (2)

1- (3-methylphenoxy) -3-[(1-methyl-2-N-benzimidazolonyl) -ethyl-amino-1] -propanol (2)

1- (2,4-Dichlorophenoxy) -3-[(1-dimethyl-2-N-benzimidazoloyl) -ethylamino-1] -propanol (2)

1- (4-chlorophenoxy-3- [1,1-dimethyl-3-N- (1,2,3,4, -tetrahydroquinolyl-propylamino)] propanol (2)

Substances having antidepressant action include, for example, 1- (2,6-dichlorophenoxy-3- (N-benzimidazoloyl-3-propylamino-1) propanol (2).

The single dose of the compound according to the invention is 1 to 500 mg, preferably 2 to 200 mg for oral administration and 1 to 20 mg for parenteral administration.

The active substance according to the present invention can be mixed with conventional weakly suitable excipients and prepared in conventional formulations such as tablets, dragees, solutions, emulsions, powders, capsules or sustained release formulations by conventional methods. Corresponding tablets contain the actives inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or carboxytolymethylene carboxy Prepared by mixing additives for sustained release formulations such as methylcellulose, cellulose acetate phthalate or polyvinyl acetate.

Purification can also be made into a multilayer. In addition, it is possible to prepare a coated tablet coated with a coating material such as polyvinyl pyrrolidone or shellac, gum arabic, talc, titanium dioxide or sucrose. In order to obtain a sustained release form or to make incompatible drugs compatible, the heart can be multi-layered. Using the above-mentioned excipients, the coated tablet can be made into a multilayer release as well as a sustained release formulation.

Juices of the active substances or mixtures of the active substances according to the invention may contain substances which can improve the taste by adding flavoring agents such as saccharin, cyclate, glycerin, or sucrose, as well as perfumes such as vinyline or orange essential oil. Can be.

Suspending agents may contain additives or weighting agents such as sodium carboxy methyl cellulose, wetting agents such as condensation products of aliphatic alcohols with ethylene oxide or preservatives such as P-hydroxybenzoates.

Injectables are prepared by conventional methods, including preservatives such as P-hydroxy-benzoate or stabilizers such as complexes, and are filled in vials or ampoules for injection.

Capsules containing the active substance or mixtures with the active substance are prepared by mixing the active substance with an inert carrier such as lactose or sorbitol and filling it into gelatin capsules.

Suitable suppositories are prepared by mixing the active substance or mixture of active substances with natural carriers or conventional carriers such as polyethylene glycol or derivatives thereof.

The compounds according to the present invention are suitable for use in coronary artery dilators such as dipyridamole, sympathetic stimulants such as isoprenaline or orsiprenarin, cardiac glycosides or neurostabilizers such as chlorodiazepoxides, diazepam or oxazpam, glyceryl trinatate Or vasodilators such as isosorbite dinitrate, diuretics such as chlorothiazide, blood pressure lowering agents such as cronidine, reserpin or guanetidine, and α-blockers such as Parkinson's disease medication pentleamine such as benzohexole; It is also suitable to mix with other pharmacologically active substances.

The novel compounds are synthesized by linking the following four classes of groups.

1. An aryloxy group of the following general formula.

Wherein R ₁ , R ₂ , and R ₃ are as described above.

2. 2-hydroxypropylene side chain groups of the following general formula (optionally esterified)

3. Amino group of the following general formula.

Wherein R ₄ is as described.

4. Heterocyclic group of the next pair.

Alkylene and R ₅ in the formula are as described above.

The various intermediate steps can, in principle, proceed in the order required.

The present invention relates to a method for producing the compound of formula (I) produced by the following production method.

a) reacting the following general formula (II) compound with an amine of the following general formula (III), or

b) reductively aminating the following compound of formula (V) with a primary amine of the general formula (IV), wherein the 2-OH group of the propane side chain is optionally esterified, or

c) reacting phenol of the following general formula (IV) with acetodinol of the following general formula (VIII), or

d) condensing the amine of the following general formula (IX) with a compound of the following general formula (X), or

e) hydrolyzing the compound of formula (XI) to hydrolyze the oxazolidine, or

f) decomposing the protecting group of the compound of the general formula (XII) to obtain a compound of the general formula (I) wherein A is hydrogen; or

g) catalytically hydrogenating the compound of formula (I) wherein R ₄ is an arylmethyl group to obtain a compound wherein R ₄ is hydrogen; or

h) catalytically hydrogenating or ether-decomposing a compound of formula (I) wherein at least one of R ₁ to R ₃ is a benzyloxy group to obtain a compound wherein at least one of R ₁ to R ₃ is an OH-group, or

i) Ammonia decomposition of the general formula (I) compound wherein R ₁ is -COO-alkyl, wherein R ₁ is -CHNH ₂ , -CONH-alkyl, -CON (alkyl) ₂ , -CO-NH NH ₂ or -CONHOH To obtain a compound of formula (I), or

k) halogenating a compound of formula (I) wherein at least one of R ₁ , R ₂ or R ₃ , R ₁₀ or R ₁₁ is hydrogen, with hydrogen halide in the presence of hydrogen peroxide, or

l) Compounds of general formula (I) wherein R ₄ is hydrogen are alkylated using conventional alkylating agents such as alkyl halides, -mesylates or tosylates, or with formaldehyde formic acid (when introducing methyl groups) to form R ₄ Obtaining a compound of formula (I) which is alkyl, or

m) A general formula (I) in which R ₁ is a primary amino group, wherein the sandmer reaction (diazotised and treated with either first copper halide or first copper cyanide) yields a general formula wherein R ₁ is a halogen or cyano group.

(I) converting to a compound, or

n) R ₁ is reduced to the general formula (I) compound which can be converted to a convertible group such as the nitro or -COO-alkyl group mentioned in R ₁ above by reducing, so that R ₁ is amino or -CH ₂ Obtaining a compound of formula (I) which is a group which may be produced by reduction such as an OH group, or

o) at least one of R ₁ , R ₂ or R ₃ is a lower alkoxy (preferably methoxy) group ether-decomposed by concentrated halogenated hydrochloric acid to at least one of R _1, R ₂ or R ₃ Compound (I) is prepared by producing compound (I), wherein one is a hydroxy group.

이고Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A and alkylene are as described above and Z is

ego

Hal is halogen, M is hydrogen or methyl, X is an ester group that can be easily removed with an anion, halogen, mesyl or tosyl groups are preferred, Q is —CH ₂ — or —CO— and Sch is a common protecting group. _One of the acyl groups mentioned in ₁ is a benzyl or acetal group.

과 반응시켜 제조할 수 있다.Formula (II) compound in the reaction a) is epichlorohydrin phenol of the general formula (IV)

It can be prepared by reaction with.

All other methods of preparation described below are possible by the four-step reaction sequence, but are not mentioned individually individually.

In the reaction b), a conventional hydrogenating agent such as LiAlH ₄ , SDMA is used or catalytically hydrogenated. It can also be synthesized starting from Schiffbase, the following general formula (VII) produced in the middle stage. The preparation is not suitable for preparing compounds of formula (I) wherein R ₁ , R ₂ and or R ₃ are unstable to the reducing agent, ie unsaturated carbon double bonds—C═N or C═O bonds.

Wherein R ₁ to R ₃ , M and R ₅ are as described above.

The decomposition of the protecting group in the reaction f) can be hydrolytically (for example in alkaline or acid aqueous solution or hydrogenolytically (by catalytically activated hydrogen).

In the latter case it is not possible to prepare compounds which are unstable to reduction.

One or several of the substituents R _4, R _10, R _11, R ₁ , R ₂ or R ₃ of the compounds according to the invention can also be converted to other substituents according to the invention. The reactions belonging to this reaction are reactions g) to o).

Reaction g) is only suitable for the preparation of compounds of formula (I) in which R _1, R _2, and or R ₃ are not changed by catalytically activated hydrogen.

The ether decomposition reaction in the reaction h) can be carried out using, for example, hydrochloric acid or borotrihalide. Catalytic hydrogenation can be used only for compounds of the general formula (I) which are stable upon reduction of the compounds of the general formula (I) _, i.e. the R _1, R _2, R _3, or R ₅ groups cannot be changed by the catalytically activated hydrogen. Can be.

When only one equivalent of hydrogen halide / H ₂ O ₂ is used in the reaction k), the halogen substitution reaction may be limited only to the aryl group.

The reaction n) is also suitable for preparing a compound of general formula (I) that is stable to a reducing agent, that is, a compound of general formula (I) wherein R ₂ and or R ₃ is stable to reduction can be used as a starting material.

Compounds of the general formulas (II), (V)-(VII), (IX) and (XII) used as intermediate products are already known compounds.

When it is not a known compound, it can obtain from general formula (III) and (IV) by a well-known method. In general formula (IV), phenol is usually easily obtained by a known method. Intermediates of the general formula (III), (VIII) and (X) are still described in the literature. Therefore, the preparation of these compounds is as follows, and in particular, since they are starting materials of reactions a), c) and d), the most attention is paid from an economic point of view for the preparation of the final product according to the present invention.

General formula (III) compound can be manufactured as follows.

a ₁ ) reducing the nitro compound of formula (XIII)

b ₁ ) prepared by decomposing one or two protecting groups of the compound of the following general formula (XIV).

Alkylene and R ₅ in the formula is as described above

Sch ₁ is acyl, —COO—DCD is a common protecting group such as alkyl, arylmethyl, aryl) or arylmethyl group

Sch ₂ is Sch ₁ or together with hydrogen or Sch ₁ a = CH-D or a dicarboxylic acid group (e.g. a 'cinyl or phthalyl group).

The a ₁ ) reaction produces a compound of formula (III) wherein R ₄ is hydrogen.

In some cases, an alkyl group having 1 to 5 carbon atoms or an aralkyl group having 7 to 14 carbon atoms can be introduced into the amino group of the compound obtained in a ₁ ) or b ₁₎ by a conventional method.

Starting materials of formula (X) corresponding to formula (XV) can be prepared by reacting with isocyanate of formula (XVII) followed by oxazolidinone of formula (XVI).

Wherein alkylene, R _10, R _11, and X are as described above

Compounds of formula (VII) (A = hydrogen) can be prepared by reacting an amino compound of formula (III) with epichlorohydrin.

Wherein R ₄ and R ₅ are as described above.

The starting material of general formula (X) corresponding to the following general formula (XVIII) may be prepared by converting a compound of general formula (XIX) (typically prepared by ring closing a compound of general formula (XX)) to a conventional halogenating agent (e.g., SOCl ₂ or POCl ₃ ). In addition, the side chain X-alkylene is activated differently to the following formula (XXI) compound, and then the dihalogen-alkylene (ex: a-bromo-W-chloro-alkylene) of general formula (XXII) is used. It may also be introduced by.

Wherein X, alkylene, B, R ₁₀ and R ₁₁ are as described above and X ₁ and X ₂ are halogen wherein X ₂ is of greater atomic weight than X ₁ .

The following examples illustrate the invention but do not limit it.

Example 1

1- (α-naphthoxy) -3- [1,1-dimethyl-3- (N-benzimidazolone- (2) -yl) -propyl amino (1)]-propanol (2) hydrochloride-mono Hitrate (Reaction a)

3 g of 1- (3-amino-3,3-dimethylpropyl) -benz imidazolidinone (2) in 12 ml of 98% alcohol for 3,3 g of 1- (naphthyl-(1)- Reflux with oxypropylene— (2,3) —oxide The alcohol is distilled off, the residue is treated with methanol, acidified with hydrochloric acid and shaken with ethyl acetate After the ethyl acetate is distilled off, the hydrochloride is added with ether and water Crystallize with monohydrate The yield is 60% and the melting point is 161 ° C. after recrystallization with alcohol.

According to Example 1 the following general formula (Ia) compounds are synthesized by reacting the corresponding epoxides of general formula (II) with the corresponding aminoalkyl compounds of general formula (III) in reflux at 98% ethanol.

The corresponding epoxide of formula (II) in 98% ethanol according to Example 1 is reacted with the corresponding (optionally substituted) aminoalkyl-N-phenylimidazolidinone- (2) of formula (III) The compound of the following general formula (Ib) is obtained.

Example 2

1-0-tolyloxy-3-[(1-methyl-2-benzimidazolone- (2) -yl) -ethylamino] -propanol- (2) (reaction b)

1 equivalent of 5.8 g of 3-acetonyl-benzimidazolone- (2) and 5.06 g of 1- (2-methylphenoxy) -3-aminopropanol- (2) -solution dissolved in 120 ml of methanol 750 ml of platinum oxide is added to hydrogenate until hydrogen is absorbed. The melting point of the title compound is 160 ° C.

Example 3

1- (2,4-Dichlorophenoxy) -3- [1,1-dimethyl-2- (3-phenylimidazolidinonyl) -ethyl amino-1] -propanol-2, hydrochloride (reaction a) 4.25 g (0.015 mole) of 1,1-dimethyl-2- (3-phenylimidazolidinonyl) -ethyl amine was dissolved in 30 ml of ethanol and 3.3 g (0.015 mole) of 1- (2,5- Dichlorophenoxy) -2,3-oxypropane solution. The mixture is refluxed for 1 hour, and then the solvent is distilled off in vacuo. The residue is purified by silica gel column chromatography. Constant fractions are evaporated to give an oily residue that is dissolved in ethyl acetate, washed with water and dehydrated with magnesium sulfate. 3.2 g base is obtained after evaporation of ethyl acetate. The base is dissolved in ether and the solution is crystallized by filtration and cooling. The colorless crystalline material is suction filtered and dried. Yield: 1.7 g, melting point 106 to 109 ° C

Run the remaining fractions to obtain 1.9 g more pure material.

Reflux with the corresponding general formula (II) phenoxy-2,3-epoxypropanol 1,1-dimethyl-2- (3-phenylimidazolinonyl) -ethylamine in ethanol according to the method described in Example 3 Reaction at temperature gives a compound of the following general formula (IC).

Example 4

1- (2-propargyloxyphenoxy) -3- [1,1-dimethyl-3- (3-phenylimidazolidinooxyl) -propylamino-1] propanol-2-oxylate (reaction a) 4.8 g (0.017 mol) of 1,1-dimethyl-3- (3-phenylamidazolidinonyl) -propyl-amine hydrochloride was dissolved in 20 ml of methanol and 8.5 g (0.017 mol) of 2N sodium hydroxide was dissolved. It is added and combined with 3.46 g (0.017 mol) of 1- (2-propargyloxyphenoxy) -2,3-epoxypropane solution in 20 ml methanol. The mixture is refluxed for 1 hour and then distilled off. The residue is treated with ether and the solution is washed with water, separated and dehydrated with sodium sulfate. After distilling off the ether, the residue was purified by a silica gel column. Evaporate the combined fractions of the ingredients. The residue dissolved in ethyl acetate is washed with water, dehydrated, and the ethyl acetate is evaporated. The remaining basic residue is dissolved in acetone and 3 g of acetone is added to an aqueous solution.

Ether is added to crystallize the colorless oxalate. Recrystallize again with a mixture of acetonitrile, ethanol and methanol with ether added. The melting point of the isolated colorless crystalline material (1.6 g) is 207 to 209 ℃. The mother liquor is evaporated to give a further solid material and the melting point after recrystallization from methanol / ether is 205 to 207 캜. Yield: 1.5 g: TLC The two fractions are the same substance.

As described in Example 4, 1-phenoxy-2,3-epoxypropane and 1,1-dimethyl-3 (3-phenylimidazolidinonyl) -propylamine hydrochloride of general formula (II) are alkaline. Synthesis in methanol yields the following general formula (Id) compound.

Example 5

1- (4-hydroxyphenoxy) -3- [1,1-dimethyl-3- (3-phenylimidazolidinonyl) -propylamino-1] -propanol-2-oxalate (reaction o) 2.5 15 ml of g 1- (4-methoxyphenoxy) -3- [1,1-dimethyl-3- (3-phenylimidazolidinonyl) -propylamino-1] propanol-2 at 100 ° C Heated in hydrogen sulfide for 100 hours. Hydrogen embrittlement is then distilled under vacuum and the residue is treated with water. After distilling off the water, the mixture was alkaline with ammonium hydroxide, extracted with ethyl acetate, the organic layer was dehydrated, and the solvent was evaporated in vacuo. The residue is dissolved in acetone and added to 3 g of aquatic solution dissolved in acetone. Ether is added to precipitate oxalate into crystals. Separate, dry and recrystallize with ethanol. Melting point 198 ° to 200 ° C. yield 200 mg.

Example 6

1- (4-methoxyphenoxy) -3- [2- (3-phenylamidazolidinonyl) ethylamino-1] -propanol-2- (reaction d)

2.8 g (0.0122 mol) of 1- (2-chloroethyl) -3-phenyl-imidazolidinone-2, 2.4 g (0.0122 mol) of 1- (4-methoxyphenoxy) -3-amino-2 -A mixture of propanol, 15 ml of diglyme (= diethylene glycol dimethyl ether) and 1.3 g (0.0122 mol) of sodium hydroxide solution is stirred and heated at 150 ° C to 160 ° C for 2 hours. After distilling off the solvent, the residue was treated with ethyl acetate, washed with sodium hydroxide and water, and left overnight.

The separated crystalline material is recrystallized from ethyl acetate. Melting point of the colorless, crystalline compound is 104 to 110 ° C. Yield: 500 mg

The mother liquor is treated to give more 200 mg of pure material with a melting point of 107 to 110 ° C. TLC is a two-piece equivalent.

1- (2-Chloroethyl-3-phenylimidazolidinone (2) in the corresponding (Phenyl 3-phenoxy-3-aminopropanol- (2) -alkaline diglyme solution as IX1) according to the method of Example 6 To a compound of formula (Ie):

According to Example 5, the corresponding 4- (or 3-)-methoxy compound was saponified at 100 ° C. with hydrogen embrittlement to prepare the next compound of general formula (Ie).

Example 7

1- (2-cyanophenoxy)-[3- (3-phenylimidazolidinonyl) -propylamino-]-propanol-2 (reaction a)

0.875 g (0.005 mol) of 1- (2-cyanophenoxy) -2,3-epoxypropane and 1.3 g (0.005 mol) of N-aminopropyl- (3) -3-phenylimidazolidinone -2 is dissolved in 10 ml of ethanol and 0.75 triethylamine are added and refluxed for 1 hour. Then 2.5 ml of N-sodium hydroxide are added. The solvent is distilled under vacuum and the residue is mixed with water and shaken with ethyl acetate.

The organic layer is washed, dehydrated and evaporated. Cinnabar is dissolved in ethyl acetate and cooled to crystallize. The melting point of the colorless crystalline material is 105 ° to 108 ° C. Yield: 800 kg

Thin layer chromatography results in a certain component.

According to Example 7, the corresponding epoxide of the general formula (II) is refluxed and reacted in the ethanol with the corresponding aminoalkyl-N-phenylimidazolidinone (2) of the general formula (III). To form a compound.

Example 8

1- (2-Cyanophenoxy) -3- (1,1-dimethyl-4-N-benzimidazoloyl-butylamino-1) -propanol-2 (reaction a)

1.75 g (0.0 moles) of 1- (2-cyanophenoxy) -2,3-epoxypropane and 2.16 g (0.008 moles) of N- (1,1-dimethyl-1 aminobutyl 1-benzimida Solon (2) is dissolved in 80 ml of ethanol, 8 ml of 1N-sodium hydroxide is added and the mixture is boiled and heated for 1 hour with stirring The ethanol is distilled off and the residue is stirred with water and shaken with ethyl acetate The organic layer is dehydrated and the ethyl acetate is evaporated The remaining basic residue is purified by silica gel column to give 2.5 g of pure material.

TLC results in a certain component. The oily residue does not crystallize even with bases or salts.

1- (2-Bromophenoxy) -3- (1,1-dimethyl-4-N-benzimidazoloyl-butylamino-1-)-propanol-2 to 1- (2-bromophenoxy -2-2,3-epoxypropane and N- (1,1dimethyl-1-aminobutyl) -benzimidazolone- (2)-are prepared by reacting in the same manner while refluxing in ethanol-sodium hydroxide solution.

Example 9

1- (3-methoxyphenoxy) -3- (1,1-dimethyl-3- (N-benzimidazoloyl-propylamino-1) -propanol-2-maleinate (reaction a)

4 g (0.022 moles of 1- (3-methoxyphenoxy) -2,3-epoxypropane are dissolved in 50 mL of methanol and 4.4 g (0.02 moles) of N- (1,1 in 50 mL of methanol). -Dimethyl-1-aminopropyl) -benzimidazolone is added and the mixture is refluxed for 1.5-hours, then the solvent is distilled off and the residue is purified by silica gel column A portion of the solvent mixture is evaporated to give 7 g of residue. This is dissolved in acetone and added to a solution of maleic acid in acetone, followed by stirring, ether is added followed by crystallization of the maleate, separation and crystallization with methanol in ether.

Yield: 6 g, Melting point: 167 to 169 ° C

The result of TLC is a certain component.

The corresponding 1-phenoxy-2,3-epoxypropane according to Example 9 was refluxed with N- (1,1-dimethyl-1-aminopropyl) -benzimidazolone-2 in methanol to yield the following general Obtain a compound of formula (Ig).

According to Example 5 the corresponding 4- (or 3) -methoxy compound is specifically saponified in hydrogen embrittlement to produce the next compound of general formula (Ig).

Example 10

1- (2-propargyloxyphenoxy) -3- (1,1-dimethyl-2-N-benzimidazoloyl-ethylamino-1) -propanol-2 hydrochloride (reaction a)

2.25 g (0.011 mol) of 1- (2-propargyloxyphenoxy) -2,3-epoxypropane was dissolved in 50 mL of methanol and 2 g (0.01 mol) of N- (1,1-dimethyl-1) Aminoethyl)-add methanolic solution of benzimidazolone. After refluxing for 1-hour, the solvent is removed and the residue is dissolved in ethanol and ether is added. Hydrochloride is separated into colorless crystalline material. It is separated and recrystallized once more by adding ether.

Yield: 2.3 g, Melting point: 203 ° to 20 ° C

Try TLC to get certain ingredients.

The corresponding 1-phenoxy-2,3-epoxypropane of general formula (II) according to Example 10 was reacted with N- (1,1-dimethyl-1-aminoethyl) benzimidazolone- (2) in methanol. Reaction was carried out under reflux to prepare the following general formula (Ih) compound.

Formula (Ib) Compound

Similarly to Example 4, the corresponding 4- (or 3) -methoxy compounds are saponified with hydrogen bromide at 100 ° C. to prepare compounds of the above table of formula (Ih).

The compound of formula (Ih) according to Example 10 was prepared with the corresponding 1-phenoxy-2,3-epoxypropane N- (1,1-dimethyl-1-aminoethyl) -benzimi It is prepared by reacting dazolone- (2) with reflux.

Example 11

1-3- (m-tolyloxy) -3- (N-benzimidazoloyl-3-propylamino-1) -propanol-2 (reaction a)

Dissolve 3.28 g (0.02 mole) of 1- (m-tolyloxy) -2,3-epoxypropane and 3.8 g (0.02 mole) of 3-benzimidazoloylpropylamine- (1) in 100 ml of ethanol And reflux for 30 minutes. The solvent is distilled off and the residue is chromatographed on a silica gel column. The remaining portion of the solvent mixture is recrystallized from ethyl acetate with petroleum ether. Isolate and dry to yield 2.8 g of base. Melting Point: 133 ° C to 135 ° C

TLC is a constant component.

According to Example 11, 3-benzamidazoloylpropylamine (1) was refluxed in the ethanol to the corresponding 1-phenoxy-2,3-epoxypropane of general formula (II) And react to prepare.

Example 12

1- (2-cyanophenoxy) -3- (1,1,4-tetramethyl-4-N-benzimidazoloyl-butylamino-1) -propanol-2-oxalate (reaction a)

2.61 g (0.01 mol) of N-1-amino 1,1,4,4, -tetramethylbutyl-benzimidazolone and 3.5 g (0.02 mol) of 1- (2-cyanophenoxy) -2, 3-Epoxypropane is dissolved in 100 ml of ethanol and refluxed for 1 hour. Ethanol is distilled off and the residue is mixed with water, sodium hydroxide is added, shaken with ethyl acetate, the organic layer is washed with water and dehydrated with sodium sulfate. Ethyl acetate is evaporated and the base is purified by silica gel. A portion of the fractions are combined and evaporated to dissolve the residue in acetonitrile and add 1.5 g of an aqueous solution of acetonitrile. Ether is added to crystallize the colorless oxalate. Recrystallize from acetonitrile in ether.

Yield: 1.7 g, Melting point: 107 to 109 ° C.

The result by TLC is a constant component.

According to Example 12, a compound of the following general formula (I1) was prepared with 1-phenoxy-2,3-epoxypropane and N-1-amino-1,1,4,4,-( Tetramethylbutyl) -benzimidazolone- (2) is prepared by reacting with reflux in ethanol.

Example 13

1- (2,4-dichlorophenoxy) -3- [1,1-dimethyl-3-N- (1,2,3,4-tetrahydroquironyl-propylamino-propanol ox-2-salate (Reaction a)

4.6 g of N-1-amino-1,1-dimethylpropyl-1,2,3,4-tetrahydroquinone- (2) and 6 g of 1- (2,4-dichlorophenoxy) -2,3 -Dissolve in 100 ml of epoxypropanol ethanol and mix and reflux for 1 hour before evaporating. The residue is mixed with water, acidified with hydrochloric acid and shaken with ether. The aqueous layer is alkaline with ashed sodium hydroxide and the precipitated base is treated with ether. After washing with water the solution is dehydrated with sodium sulfate, separated and evaporated. The residue is purified by silica gel. Combine the fractions and evaporate. The basic residue is dissolved in acetonitrile, added to an aqueous solution of acetone nitrile, and ether is added to precipitate a fine crystalline hydroxide. Recrystallization from ethanol / ether gives a colorless crystalline material of 3.1.

Melting point is 144 ° to 145 ° C

As a result of TLC, it is a constant component.

According to Example 13, the following compound of general formula (Im) was prepared with 1-phenoxy-2,3-epoxypropane and N-1-amino-1,1-dimethylpropyl-1,2,3 as general formula (II). It is prepared by refluxing the 4-tetrahydroquinoneron (2) in ethanol.

In a similar manner to Example 5, the compound, which is General Time (Im), is prepared by saponifying the corresponding 4- (or 2-) methoxy compound at 100 ° C with hydrogen embrittlement.

According to Example 13, the following general formula (In) compound was prepared with the corresponding 1-phenoxy-2,3 epoxypropane N-1-aminopropyl-1,2,3,4-tetrahydroqui Norron- (2) or N-1-benzylaminopropyl-1,2,3,4-tetrahydroquinonolone- (2) is prepared by refluxing in ethanol.

Example 14

1- (3-methoxyphenoxy) -3- (3-N-1,2,3,4-tetrahydroquinonolone-2-yl-propylamino) -propanol-2-hydrochloride (manufacturing a)

50 ml of 6.1 g of 1- (3-methoxyphenoxy) -3- (3-N-1,2,3,4-tetrahydroquinonolone-2-yl-benzylpropylamino) -propanol-2 It is dissolved in methanol and hydrogenated to palladium / charcoal at 6 atm and 60 ° C. After hydrogen absorption, the catalyst is suction filtered, the solvent is evaporated and the residue is purified by silica gel. After evaporation of the solvent mixture, a residue is obtained from a predetermined fraction, which is dissolved in alcoholic hydrochloric acid. Add ether and recrystallize once again with methanol.

Yield: 2.7 g, Melting point: 122 to 123 ° C

Thin layer chromatography shows that it is a constant component.

A solution is prepared according to the reaction from 0.5 g (0.00105 mol) of the following general formula, 5 ml of 20 ml of ethanol and 1.5 g of potassium hydroxide.

The solution is refluxed for 1 hour and evaporated. The residue is mixed with 40 ml of water, acidified with 10% hydrochloric acid and shaken twice with methylene chloride (40 ml). The aqueous layer was alkalinized with ice with sodium hydroxide and shaken twice with 50 ml of methylene chloride, then the methylene chloride layer was washed with 50 ml of water, dehydrated with sodium sulfate and evaporated. The residue is recrystallized from isopropanol. Melting Point: 147 ° to 149 ° C

Example 16

A mixture is prepared according to the reaction from 1.1 g (0.0024 mol) of a compound of the following general formula, 3 ml of formic acid and 6 ml of a 30% formalin solution.

This solution is refluxed on the water bath for 1 hour. CO ₂ is developed. The batch is cooled, diluted with 30 ml of water and shaken twice with 50 ml of ether. The aqueous layer was made alkaline with 10% sodium hydroxide, extracted three times with 30 ml of ethyl acetate, the ethyl acetate layer was washed with 20 ml of water, dehydrated with sodium sulfate and evaporated. The residue is purified by silica gel column using 70 ml of ethyl acetate, 30 ml of isopropanol and 2.5 ml of 25% ammonia solution as eluent. Pure compounds are dissolved in acetonitrile, acidified with alcoholic hydrochloric acid, precipitated with ether, suction filtered and recrystallized from acetonitrile and ether.

Melting point: 191-195 ° C

Thin layer chromatography Result: Pure material.

Example 17

Next, 880 mg (0.002 mol) of the compound of the general formula was dissolved in 15 cm ³ of ethanol, 1 g of potassium hydroxide dissolved in 3 ml of water was added, and the mixture was refluxed for one hour.

The solvent is evaporated in vacuo. The residue is mixed with water and shaken twice with ethyl acetate. The ethyl acetate layer is washed with water, dehydrated with sodium sulfate, filtered and dried. Hydrochloride is recrystallized from acetonitrile after the addition of ether. Melting Point: 135 ° -137 ° C

Example 18

0.7 g (0.0025 mol) of the following general formula are dissolved in 20 cm ³ of benzyl alcohol, and 0.4 g (0.003 mol) of 3-methoxyphenol and 0.1 g of potassium hydroxide are added thereto.

Thereafter, the reaction is carried out for 5 hours on an oil bath at 140 ° C. The solvent is evaporated in vacuo. The residue is acidified with 1N hydrochloric acid and shaken twice with ethyl acetate. The aqueous layer is alkaline with 1 N sodium hydroxide and shaken twice with a small amount of ethyl acetate. The ethyl acetate layer was dehydrated with sodium sulfate and evaporated to give a residue, which was purified by silica gel column.

Example 16

1- (2-aminophenoxy) -3- [3-phenylimidazolidinonyl-propylamino-1] -propanol-2 (reaction n)

Dissolve in 3 g of 1- (2-nitrophenoxy) -3- [3- (3- (3- (phenylimidazolidinonyl) -propylamino-1] -propanol-2-ol in 100 ml of methanol and at room temperature and atmospheric pressure. Hydrogenate with Raney-Ni, absorb the theoretical amount of hydrogen, filter the catalyst by suction, evaporate the solvent in vacuo, dissolve the residue in acetonitrile and acidify methane with hydrochloric acid. Suction filtered and dried.

Yield: 1.9 g, Melting point: 190-192 ° C

Check for certain components by DC.

Example 20

1- (2-cyanophenoxy) -3- [3- (3-phenylimidazolidinonyl) -propylamino-1] -propanol-2 (reaction l)

876 mg (0.0015 mole) of 1- (2-aminophenoxy) -3- [3- (3-phenylimidazolidinonyl) -propylamino-1] -propanol-2 is dissolved in 5 ml of water.

1 ml of concentrated hydrochloric acid is added and then added dropwise to a solution of 207 mg of sodium nitrite in 25 ml of water at 3-5 ° C. The homogeneous solution is stirred at 20 ° C. for 60 minutes. The solution is then added to a hot mixture of 800 mg of CuSO ₄ H ₂ O, 850 mg of potassium cyanide and 5 ml of water at 80-90 ° C. with stirring. After the addition, adjust to alkali with sodium hydroxide. The resinous material is separated off and the aqueous layer is extracted with acetylacetate. The organic layer is washed with water, dehydrated with sodium sulfate and evaporated in vacuo.

The viscous residue is separated by silica gel. Fractions of certain components are combined, evaporated in vacuo with solvent and the residue is recrystallized from ethyl acetate. The melting point of the colorless crystalline material is 103 to 107 캜. As a result of thin layer chromatography, the Rf value is the same as the material mentioned in Example 7.

The preparation of the novel intermediate product of general formula (III) is described in the following examples:

Example 21

From 69.6 g of the following compound of formula (B) and 55.6 g of chloroacetone, potassium carbonate and potassium iodide in acetone are added, followed by acid catalytic hydrolysis to obtain 32 g of the following compound of formula (C). Melting Point: 182 ℃

19 g of the compound is mixed with 300 ml of methanol and 25 ml of ammonia for reductive amination and hydrogenated using Raney-Nickel as catalyst at 40-60 ° C., 6 atmospheres. 15.6 g of an amino compound, which is a compound of the above formula, is separated with hydrochloride. Melting Point: 267 ° to 270 ° C

Example 22

To a 0.42 mole sodium solution in 200 ml of anhydrous alcohol is added 69.6 g of the following general formula (B) compound followed by 0.44 moles of 3- (dibenzylamino) propyl chloride in 300 ml of anhydrous alcohol. The reaction mixture was refluxed for 6 hours, the resulting sodium chloride was separated by cooling with stirring, and 45 ml of concentrated sulfuric acid was mixed. After 3 hours, 700 ml of water is added, the alcohol is evaporated, ammonia is added, and then the following general formula (C) compound is separated. (Melting point 146 ℃, crystallized with acetonitrile)

60 g of this compound in a mixture of 499 mL methanol and 200 mL water in the presence of 16 mL concentrated hydrochloric acid and palladium / charcoal are hydrogenated at 60 ° C. and 6 atmospheres until one equivalent of hydrogen is absorbed. The yield was 88% with the general formula compound isolated.

(Melting point 60 ° C)

Example 23

53.4 g of the following general formula (B) compound dissolved in 420 ml of methanol and 80 ml of water is hydrogenated until 20 equivalents of hydrogen are absorbed at 60 ° C. and 6 atm in the presence of 20 ml of concentrated hydrochloric acid and palladium / charcoal. .

The compound of the general formula titled above is isolated in hydrochloride state in 91% yield.

(Melting point 315 ° C)

10.1 g of sodium hydride and 45 g of N- (3-chloropropyl) -phthalimide were added to a solution of 31.1 g of the following general formula (B) compound dissolved in 150 ml of hexametaful in a nitrogen stream, followed by 100 DEG C. Stir for 5 hours at.

The crude isolated compound (C) was then refluxed in 13 g of 85% hydrazine hydrate and 1 liter of alcohol for 90 minutes, mixed with 21 ml of concentrated hydrochloric acid and 100 ml of water and heated again for 20 minutes. The precipitated phthalic acid hydrazide is filtered off with suction and the compound of the title is separated in the hydrochloride state.

Melting point 915 ° C., alcohol crystallized.

Example 25

To a solution of 9.2 g of the following general formula (B) compound in 40 ml of anhydrous hexametapol, 3.3 g of sodium hydride (55%) was added in a nitrogen stream, and a calculated amount of hydrogen was imported, followed by 3 in 13 ml of hexametapol. A solution of benzylamino-propylchloride (bd ₁₂ 140 ° C.) is added. After stirring at 100 ° C. for 5 hours, the solution is added to ice, and then the compound of formula (C) is shaken off with ether, separated and hydrolyzed with 2N hydrochloric acid without stagnation. Isolate the compound of the above formula in hydrochloride state in 67% yield.

Melting Point: 152-155 ° C

According to Examples 21-25, the following intermediate product was prepared.

Example 26

174 g of the following general formula (B) compound solution dissolved in 700 ml of anhydrous hexametapol was mixed with 48 g of 55% suspension sodium hydride, and after hydrogenation, 341 g of the following general formula in 450 ml of hexametapol ( C) It is mixed with a compound (melting point 76 degreeC). The solution is stirred at 100 ° C. for 5 hours, added to ice, treated with ether and evaporated, then the residue is dissolved in 3 L of alcohol and mixed with 300 ml of 5N sulfuric acid. The next day the next compound of formula (D) is isolated in 61% yield.

(Melting point 198 ° C)

58.75 g of the compound is dissolved in 1700 ml of methanol and hydrogenated by adding Ranickel at 40 to 60 ° C. and 6 atm. The compound of the general formula entitled above is isolated in 92% yield.

(Melting point 135 ° C)

The formulation of the novel intermediate product of formula (VIII) is described in the following examples:

Example 27

1.4 g of N-1. 1-Dimethyl-2-benzimidazoloylethyl-azetidinol

3, 1 g of N-1-amino-2 and 2-dimethylbenzimidazolone are dissolved in 30 ml of acetonitrile and epichlorohydrin is added to 1.4 g. The mixture is refluxed for 6 hours. After cooling, the solvent is evaporated in vacuo. The residue is treated with water and shaken with ethyl acetate. The aqueous layer is made alkaline with sodium hydroxide and extracted with ethyl acetate. The organic layer is dehydrated and the ethyl acetate is evaporated. 1.4 g of N-1,1-dimethyl-2-benzimidazoloylethyl-azetidinol is obtained.

The preparation of the novel intermediate product of formula (X) is described in the following examples:

Example 28

1- (2-chloroethyl) -2- (4-chlorophenyl) -imidazolidinone

22.4 g (0.15 mol) of N-2-chloroethyloxazolidinone-2 is added with 23 g (0.15 mol) of 4-chlorophenylisoanate and lithium chloride and heated at 160 to 180 ° C. for 5 hours. The crystalline material produced by cooling is recrystallized from ethanol.

Yield: 26 g

Melting Point: 015-107 ℃

Example 29

N-2-chlorophenyl-benzimidazolone

13. g of N-2-hydroxypropylbenzimidazole is dissolved in 150 ml of dioxane and 8 ml of SOCl ₂ is added and refluxed for 1 hour. After evaporation in vacuo, the residue was dissolved in ethyl acetate, washed with bicarbonate solution and water and dehydrated with sodium sulfate. After evaporating the solvent, 13.4 g of N-2-chloropropylbenzimidazolone is obtained.

[Example]

1. Refining

1- (2-cyanophenoxy) -3- (1,1-dimethyl-4-N-benzimidazolone (2) -yl) -butylamino-1) propanol- (2) 40.0 mg

Corn Starch 164.0mg

Calcium Dihydrogen Phosphate 240.0mg

Magnesium Stearate 1.0mg

445.0mg

Preparation: The individual ingredients are mixed intimately and the mixture is granulated according to conventional methods. The granules are compressed into 445 weight tablets containing 40 mg of active ingredient.

The same amount of 1- (α-naphthoxy) -3- [1,1-dimethyl-3- (N-benzimidazolone- (2) -yl) -propylamino ( 1)]-propanol- (2) hydrochloride monohydrate and 1-0-tolyloxy-3-[(1-methyl-2-benzimidazolone- (2) -yl) -ethylamino] -propanol- ( 2) can be used.

2. Gelatin Capsule

The capsule content is as follows.

1- (4-hydroxyphenoxy) -3- [1,1-dimethyl-3- (3-phenylimidazolidinone- (2) -yl) -propylamino-1] -2-propanol (2) -Oxalate 25.0 mg

Corn Starch 175.0mg

200.0

Recipe: Mix each ingredient of the capsules well and fill 200mg of the mixture into the appropriate size gelatin capsules. Each capsule contains 25 mg of active ingredient.

3. Tablets coated with sustained release material

Shim Jung

25.0 g of 1- (α-naphthoxy) -3- [1,1-dimethyl-3- (N-benzimidazolone- (2) -yl) -propylamino- (1)]-propanol- (2)

Carboxymethyl Cellulose (CMC) 295.0 g

20.0 g of stearic acid

Cellulose acetate phthalate (CAP) 40.0 g

380.0g

Preparation: The active ingredient, CMC and stearic acid are mixed intimately and the mixture is granulated in a conventional manner using a CAP solution dissolved in a mixture of 200 ml of ethanol / etheracetate. The granules are then coated by conventional methods with 5% polyvinylpyrrolidone sucrose, which is tableted into 380 mg weight tablets and dissolved in water. Each coated tablet contains 25 mg of active ingredient.

4. Refining

(-)-1-alpha-naphthoxy-3- [1.1-dimethyl-3- (N) -benzimidazolone- (2) -yl) -propylamino- (1)]-propanol- (2) 35.0 g

2, 6-bis- (diethanolamino) -4, 8-dipiperidino pyrimido- [5, 4-d] -pyrimidine 75.0 g

Lactose 164.0 g

Corn Starch 194.0g

14.0 g of clad silicate

6.0 g of polyvinylpyrrolidone

Magnesium Stearate 2.0g

10.0 g soluble starch

500.0 g

Equivalent amount of 1- (2,4-dichlorophenoxy) -3-1,1-dimethyl-2- (3-phenylimidazolidone- (2) instead of the β-adrenergic active substance mentioned in this example. ) -Yl) -ethylamino-1] -propanol-2- and 1- (2-propargyloxyphenoxy (-3- (1,1-dimethyl-N-benzimidazolone- (2) -yl)) -Ethylamino-1) -propanol- (2) .HCl can be used.

Preparation: The active ingredient is thoroughly mixed with lactose, corn, starch clathic silicic acid and polyvinylpyrrolidone and then the mixture is granulated by conventional methods using an aqueous solution of soluble starch. The granules were mixed with magnesium stearate and tableted with 1000 tablets of 500 mg weight, this tablet containing 35 mg of the first active ingredient and 75 mg of the second active ingredient.

Claims (1)

A process for preparing the following compound of formula (I) or a salt thereof, characterized by amination of the compound of formula (II) with the following compound of formula (III) under reducing conditions.

Wherein R ₁ is hydrogen, halogen, trifluoromethyl, nitro, straight or branched alkyl having 1 to 8 carbon atoms, straight or branched chain alkoxy having 1 to 4 carbon atoms, alkoxy alkyl having 2 to 8 carbon atoms, and 2 to 5 carbon atoms Phosphorus alkenyl or alkynyl, alkenyloxy or alkynyloxy with 3 to 6 carbon atoms, cycloalkyl or cycloalkoxy, optionally bridged or unsaturated, having 3 to 12 carbon atoms, partial formula (CH ₂ ) x -A Group, —COOR ₆ group, lower aliphatic, araliphatic or aromatic acyl, acyloxy or acylamino group, partially general formula —NH—CO—NR ₇ R ₈ group, halogen, alkyl, nitro, cyano and / or A lower aryl, aryloxy or aralkoxy group (preferably phenyl, phenoxy or benzyloxy) optionally substituted one or several times with a carboxyl group, a partial general NH-R ₉ or N-alkylene-R ₉ group X is an integer from 1 to 3 A 'is a cyano, amino carboxamido or hydroxy group R ₆ is hydrogen or an alkyl group having 1 to 4 carbon atoms R ₇ and R ₈ are hydrogen, alkyl or a heterocycle such as a pyrrolidino, piperidino or morpholino group with a nitrogen atom, R ₉ is lower alkyl or an acyl group such as CH ₃ SO _2- , (CH ₃ ) ₂ N-SO _2- , alkyl-O-CO- group or -CONH-alkyl, -CONH-NH ₂ , -CH ₂ SO ₂ and -CO-NH-OH group R ₂ is hydrogen, halogen or straight or branched chain alkyl having 1 to 4 carbon atoms, preferably alkoxy group 9 benzyloxy group having 7 to 14 carbon atoms), alkenyl group having 2 to 4 carbon atoms, cyano, nitro, hydroxy Or an amino group or together with R ₃ , —O—CH ₂ O—, —O (CH ₂ ) ₂ —O—, —CH═CH—CH═CH—, —OCH ₂ —CONH—, — (CH ₂ ) | ₂ -CONH-, -CH = CH-NH, -O-CO-NH, -CH ₂ -CH = CH-CH _2- , -O-CH = CH-, -O- (CH ₂ ) | _A divalent group such as _3- , -S (CH ₂ ) ₃ -or -CO (CH ₂ ) ₃ , wherein preferably two free atoms are bonded to each other in an ortho-position; R ₃ is hydrogen, halogen, mono- or branched alkyl or alkoxy having 1 to 4 carbon atoms, aralkoxy having 7 to 14 carbon atoms (preferably benzyloxy group) or hydroxy group R ₄ is hydrogen, alkyl having 1 to 5 carbon atoms or an optionally substituted aralkyl group having 7 to 14 carbon atoms R ₅ is the following heterocycle group

R ₁₀ and R ₁₁ are hydrogen, halogen, a linear or branched alkyl or alkoxy group having 1 to 4 carbon atoms, a trifluoromethyl or a carboxamido group or a -O- (where two free atoms are bonded to each other in an ortho-position; CH ₂ ) a partial general formula divalent group of y-O- (y is 1 or 2) B is a> NR ₁₂ group, -OCH ₂ -group (which becomes a condensed phenyl ring in combination with oxygen) or a _divalent group which is-(CH ₂ ) ₂ -group R ₁₂ is hydrogen, lower alkyl, alkenyl, alkynyl, cycloalkyl or optionally substituted aryl and alkylene is a straight or branched alkylene group having 1 to 12 carbon atoms A is preferably hydrogen or an asir group, in particular the particular acyl group described in R ₁ Z is

Hal is halogen.