FI57945B - ANALOGIFOHER PHARMACEUTICAL FRAMEWORK FOR THERAPEUTIC ACTIVITY 1- (1- (2-HYDROXIPROPYL) -PIPERIDYL- (4)) - IMIDAZOLIDINONE- (2) - OCH -HEXAHYDRO-PYRIMIDINONE- (2) -DERIV - Google Patents

Description

IvSaFI [B] (11) classified ad 1: 7945 L J '' UTLÄGGN I NGSSKRIFT ^ '2¾¾¾ (45) n, M- 1J / / / · wa f * // u.

^ --- ^ (51) Kv.ik.Vc.3 c 07 D 4-01 / 04 // C 07 D 233/36, 239/10 FINLAND —FINLAND (21) PKunttlhukumu · - PMuntamBknlng 2257/73 (22) ) 17 * 07.73 * * (23) Alkuptivi — Glklghutsdag 17 · 07> 73 (41) Tullut lulklMk »- Bllvlt offantllg 25-02.74

Patent-registered (44) N «h« vtt, .p «o« j. date | - 0, n7

Patent- OCh reglsterstyrelsen 'Ainekin utlagd och utUkriftin publlcurtd 31 · u f. Ου ^ (32) (33) (31) Requested «uolkMM — Begirt prlorltit 24.08.72 03.07.73 Switzerland-Switzerland (CH) 12539/72 9670/73 (71) Ciba-Geigy AG, 4002 Basel, Switzerland-Switzerland (CH) (72) Max Wilhelm, Watchung, NJ, USA, Kurt Eichenberger, Therwil,

Herbert Schröter, Fiillinsdorf, Franz Ostermayer, Riehen, Switzerland-Schweiz (CH) (74) Oy Jalo Ant-Wuorinen Ab (54) Analogue method for new, therapeutically active 1- [1- (2-hydroxypropyl) -piperidyl- (4) ) For the preparation of N-imidazolidinone (2) and hexahydro-pyrimidinone (2) derivatives - Analogifarfarande för fram-ställning avrya, therapeutiskttiva 1- (1- (2-hydroxypropyl) -piperidyl- (4) y -imidazolidinone- (2) -oche-hexahydro-pyrimidinone- (2) -derivatives

The invention relates to an analogous process for the preparation of new piperidine derivatives and their salts of the formula (V n rva, alk? H / ΤΛ / \

R.-O-CH 2 -CH-CH 2 -N y N N - I

\ _ / Y

wherein R 1 optionally represents lower alkyl radicals, lower alkenyl radicals, lower alkoxy lower alkyl groups, acetamide, acetyl, lower alkoxy groups, lower alkenyloxy groups, lower alkynyloxy groups, n-aryloxy groups, lower alkylthio-lower alkoxy groups, benzyloxy, benzyl or a doubly substituted phenyl residue, R 2 is hydrogen or a lower alkyl residue, an alk lower alkylene residue which separates both nitrogen atoms by two or three carbon atoms, R 1 is hydrogen or lower alkyl and n is from 1 to 4.

2 57945

Lower residues above and below are in particular those residues / which contain up to 7 carbon atoms, in particular up to 4 carbon atoms.

Lower alkyl radicals are, for example, methyl, ethyl, n-propyl or isopropyl, or straight-chain or branched butyl, pentyl or hexyl, which may be bonded in any position.

Lower alkoxy radicals are in particular those radicals in which the lower alkyl moiety preferably has at most 7 carbon atoms, in particular at most 4 carbon atoms, in which case lower alkyl has the same meaning as above. Examples of such lower alkoxy radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-amyloxy.

Lower alkenyl residues are, for example, vinyl, propenyl, allyl or methallyl. Lower alkenyloxy radicals are, for example, allyloxy, methallyloxy or propenyloxy.

Lower alkoxy lower alkyl radicals are, for example, radicals in which the lower alkyl moiety in each case has up to 7 carbon atoms, preferably up to 4 carbon atoms, for example methoxymethyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl, 2- (n-butoxy) ethyl, 3- (n -propoxy) -propyl or especially 2-methoxyethyl.

Suitable halogen atoms are, in particular, fluorine or bromine atoms, in particular chlorine; halo-lower alkyl groups include, for example, groups in which the lower alkyl moiety has the same meaning as above, for example chloromethyl, 2-chloroethyl, dichloromethyl and especially trifluoromethyl.

The lower alkyl groups R4 are in particular the abovementioned radicals, for example ethyl, n-propyl, isopropyl and especially methyl.

The lower alkylene residue alk is in particular a straight or branched lower alkylene residue having 2 or 3 chain carbon atoms, but which may nevertheless contain a total of e.g. up to 7, in particular up to 4 carbon atoms, alk preferably an optionally lower alkylated dimethylene or trimethylene residue, in particular - or a trimethylene residue and in particular an unsubstituted dimethylene or trimethylene residue.

The new compounds have valuable pharmacological properties. Thus, they have an antihypertensive effect which can be demonstrated in animal experiments, e.g. by administering doses of about 1-100 mg / kg intravenously to anesthetized cats. In addition, the new compounds resist dysentery in the heart and affect α-sympatholysis, which can also be demonstrated in animal experiments, e.g. in in vitro experiments using doses of 3-100 γ / ml in guinea pigs (Langendorff preparation) versus in vitro experiments using 0 , Concentrations of 1-100 y / ml in the rat (isolated perfused mesenteric artery). The novel compounds can thus be used as antihypertensive agents, antiarrhythmics and α-sympatholytic agents. In addition, the new piperidines can be used as starting or intermediate products for the preparation of other compounds, in particular therapeutically active compounds.

Of particular note are compounds of formula I wherein phenyl is preferably substituted in the ortho position by lower alkyl, lower alkoxy, lower alkenyl, lower alkynyloxy, halogen or hydroxy, R 2 is hydrogen or lower alkyl, R 1 is hydrogen or methyl, wherein n is 1 and alkyl is n and 1 is alkyl; a ni or trimethylene residue.

Particular mention may be made of compounds of the formula I in which R 1 is a phenyl radical simply substituted by lower alkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, hydroxy or halogen (preferably in the ortho position), R 2 is hydrogen or lower alkyl, R 1 is hydrogen and alk is ethylene.

Particular mention should be made of the piperidines of the formula I in which R 1 is phenyl, R 2 is hydrogen or methyl, R 2 is hydrogen and alk is simply substituted by methyl, niethoxy, allyl, allyloxy, hydroxy or chloro (preferably in the ortho position).

Particular mention should be made of 1- {1- (3- (p-acetamido-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) {1- {1- (3- (o allyylifenoksi) -2-hydroxy-l-propyl) -piperidyyli- (4)} - imidazolide noni- (2); 1- {1- (3- (o-chlorophenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2); 1- (1- (3- (o-methoxyphenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} - 3-methylimidazolidinone (2); 1- {1- (3- (o -methyl-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} - imidazolidinone- (2) and especially 1- {1- (3- (o-methoxyphenoxy) -2-hydroxy-1 propyl) -piperidyyli- (4)} - imidazolidinone (2).

The new compounds are prepared by reacting a compound of formula

Rl - ° - γΐ II

reacting with a compound of formula • 1 '4 57945 (R4> n, alk ΛΓΛ / \ γ2 - y ΝγΝ - r2 111 0 in which one of the residues Y1 and Y2 represents the residue -CH2- £ h-CH2 ~ Z, where X represents OH and Z represents a reactive esterified hydroxyl group, or X and Z together form an epoxy group, and one of the residues Y 1, R 2 and Y 2 is hydrogen, and R 1, R 2, R 4, n and alk have the same meaning as above.

Thus, for example, a compound of the formula may be used

X

Rx - O - CH2 - CH - CH2 - Z II 'is reacted with a compound of formula 7 "alk aK / \ HN ^ J- N ^^ N ~ R2 1111

O

wherein R 1, R 2, R 2, n and alk are as defined above and X is OH and Z is a reactive esterified hydroxyl group, or X and Z together form an epoxy group.

The reactive esterified hydroxyl group is in particular a strong, inorganic or organic acid, in particular a hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydrobromic acid, but also a sulfuric acid or an organic sulfonic acid toluene sulfonic acid p-sulfonic acid, Thus, Z in particular means chlorine, bromine or iodine.

This reaction is carried out in a conventional manner. When a reactive ester is used as starting material, it is preferred to work in the presence of a basic condensing agent and / or using an excess of a compound of formula III '.

In addition, a compound of formula 5,57945 may be used

Rx - OH II ”where the same is as defined above, reacts with a compound of formula <R4>„ v, alk? / Z-CH ~ -CH-CHO-N VNN - R ~ III "2 2 \ _ / ν '0 wherein X represents OH and Z is a reactive esterified hydroxyl group or X and Z form an epoxy group and R2, R1, n and alk have the same meaning as above.

This reaction is carried out in a conventional manner. If reactive esters are used as starting material, the compound of formula II "may preferably be used in the form of a metal phenolate such as alkali phenolate, for example sodium phenolate, or in the presence of an acid scavenger, especially a condensing agent which may form a salt with a compound of formula II" such as alkali alcoholate. .

The resulting compounds can be cleaved, attached or modified within the final products.

In addition, in the obtained compounds of formula I in which R 2 / R 4, n and alk have the same meaning as above and R 1 is a hydroxyl-substituted phenyl residue, this residue R 1 can be converted into a lower alkoxy-substituted phenyl residue, e.g. by reaction with a lower alkyl-Z 1 compound of formula , wherein there is a reactive esterified hydroxyl group. In particular, the reaction component can be used in the form of a salt.

In the obtained compounds having a benzyloxy group, this can be replaced with hydrogen in a conventional manner.

The above reactions are carried out in a conventional manner using, with or without diluents, condensation and / or catalytic agents, at reduced, ordinary or elevated temperature, optionally in a closed vessel.

Depending on the process conditions and starting materials, the final products are obtained in free form or as their acid addition salts within the scope of the invention. Thus, for example, basic, neutral or mixed salts can be obtained, possibly also hemi-, '* 6 57945 mono-, sesquis or polyhydrates. The acid addition salts of the novel compounds can be converted into the free compound in a manner known per se, e.g. with basic substances such as alkalis or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. In particular, acids suitable for the formation of therapeutically useful salts are used to form acid addition salts. Examples of such acids are: hydrohalic acids, e.g. hydrochloric acid, sulfuric acids, e.g. sulfuric acid, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, acetic, acetic, , lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid, fumaric, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic acid, salicylic or p-aminosalicylic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid; halogenobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid; methionine, tryptophan, lysine or arginine.

These and other salts of the novel compounds, such as picrates, can also be used to purify the resulting free bases, converting the free bases to salts, separating these, and releasing the free bases from the salts. Since the new compounds in free form and in the form of their salts are very similar, in the above and below the free compounds at the same time and expediently may be understood to mean also the corresponding salts.

The invention also relates to those embodiments of the process in which the starting material is used as a reaction mixture obtainable under the process conditions.

The starting materials, if they form salts, can be used in the form of their salts. Starting materials with an asymmetric center can be used in the form of their racemates or optical antipodes.

Depending on the starting materials and the working method, the new compounds can always be in the form of optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, also as racemic mixtures and / or pure geometric isomers or mixtures thereof (isomeric mixtures).

The resulting mixtures of isomers can be separated into the pure geometric isomers in a known manner on the basis of the physicochemical differences of the constituents, for example by chromatography on a suitable stationary phase such as a complexing heavy metal compound, e.g. -metal addition compound, e.g. a silver nitrate complex, by separating these into addition compounds of pure isomers, e.g. by fractional crystallization and subsequent release of the pure isomers.

The pure isomers obtained, e.g. trans isomers, can be converted in a conventional manner, e.g. photochemically, for example by irradiation with light of a suitable wavelength, preferably in a suitable solvent such as an aliphatic hydrocarbon, or in the presence of a suitable catalyst to the opposite isomer. cis-isomer.

The racemic mixtures can be separated into both stereoisomers (diastereomers) into pure racemates on the basis of the physicochemical differences of the components in a known manner, for example by chromatography and / or fractional crystallization.

The racemates obtained can be separated according to known methods, for example by recrystallization from an optically active solvent, by microorganisms or by reaction with a racemic compound with an optically active acid which forms salts, and by separation of the salts thus obtained, e.g. based on their different solubilities, into diastereomers. may be released from suitable substances. Particularly useful optically active acids are, for example, the D and L forms of tartaric acid, di-o-toluene tartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. Preferably, more potent L antipodes are isolated.

In order to carry out the reaction according to the invention, it is expedient to use such starting materials from which the groups of end products specifically mentioned at the outset and, in particular, the end products described or preferred in particular, are obtained.

A compound of formula III 'may be prepared by hydrogenation of compounds of formula (84> n 6alk / \

N N - R, VI

Y

o preferably catalytically, as explained above.

8 57945

The compounds of formula III 'are novel and are used as intermediates in the preparation of compounds of formula I.

The starting materials are known or, if they are new, can be prepared according to methods known per se.

The novel compounds can be used as medicaments, for example in the form of pharmaceutical preparations containing these and their salts in admixture with, for example, a pharmaceutical, organic or inorganic solid or liquid carrier suitable for enteral or parenteral administration. To form these, substances which do not react with the new compounds are suitable, such as, for example, water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gum, polyalkylene glycols, petrolatum, cholesterol or other known drug carriers. The pharmaceutical preparations can be in the form of tablets, granules, capsules, suppositories, ointments, creams or in liquid form as solutions (e.g. elixirs or syrups), suspensions or emulsions. They may optionally be sterilized and may contain adjuvants such as preservatives, stabilizers, wetting agents, or emulsifiers, salts for varying the osmotic pressure, or buffers. They may contain other therapeutically valuable substances. Preparations which can also be used in veterinary medicine are prepared according to conventional methods.

The novel compounds can also advantageously be used in combination with other antihypertensive and / or diuretic agents in pharmaceutical preparations.

The following examples illustrate the invention. Temperatures are given in degrees Celsius.

Example 1:

A solution of 10 g of 1- (o-methoxy-phenoxy) -2,3-epoxy-propane and 10 g of 1- (piperidyl- (4)) -imidazolidinone- (2) in 50 ml of ethanol is heated 4 hours at 80 ° and then evaporated in vacuo. The residue is dissolved in 100 ml of 2N hydrochloric acid, extracted with ether and the aqueous phase is made alkaline by adding 10 [mu] l of sodium hydroxide. This gives 1- {1- (3- (p-methoxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), which melts 138 ° after recrystallization from ethanol. :in. The hydrochloride melts at 158-160 °.

The starting 1- (piperidyl- (4)] - imidazolidinone- (2) can be prepared as follows: 9,57945

To a solution of 47 g of 4-aminopiperidine in 200 ml of dimethylformamide is added dropwise 55 g of β-chloroethyl isocyanate and stirred for 1 hour. 400 ml of water are added to precipitate N- (4-piperidyl) -N'-β-chloroethyl urea, which, after recrystallization from alcohol-water, melts at 120-122 °.

66 g of N- (4-piperidyl) -N1-β-chloroethyl urea are heated with a solution of 12 g of sodium ethylate in 400 ml of ethanol under reflux for 2 hours. This precipitates 1- (4-pyridyl) imidazolidinone (2), which melts at 205-206 °.

15 g of 1- (4-pyridyl) -imidazolidinone- (2) are hydrogenated in 150 ml of alcohol using 1.5 g of ruthenium carbon (10%) at 150 ° and 150 mm / kg. When the absorption of hydrogen is complete, the catalyst is filtered off, evaporated and recrystallized from methylene chloride-petroleum ether. Obtained as 1- (piperidyl- (4)) - imidazolidinone- (2) crystals, m.p. 154-158 °.

Example 2: 15 g of 1- (m-methoxy-phenoxy) -2,3-epoxy-propane and 15 g of 1- (piperidyl- (4)) -imidazolidinone- (2) are heated for 4 hours in 30 ml of ethanol At 80 ° and then evaporated in vacuo. The residue is then saponified with 100 ml of 2N hydrochloric acid and extracted with ether. The aqueous layer is then made alkaline by adding 10 μl of sodium hydroxide and extracted with methylene chloride. After evaporation of the solvent, 1- {1- (3- (m-methoxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) is obtained as a viscous oil, the fumarate of which melts 192-193 ° C.

Example 3:

A solution of 15 g of 1- (p-allyloxy-phenoxy) -2,3-epoxy-propane and 15 g of 1- (piperidyl- (4)) - imidazolidinone- (2) in 30 ml of alcohol is heated to 4 hours to 90 ° and then evaporated in vacuo. The residue is dissolved in 2N hydrochloric acid, extracted with ether and 10 [mu] l of sodium hydroxide are added to the aqueous phase until the alkaline reaction. After extraction with methylene chloride and evaporation of the solvent, 1- {1- (3- (p-allyloxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) remains, which is recrystallized. after which the ethanol melts at 132-133 °. The methanesulfonate melts at 154-157 °.

Example 4: 10 g of 1- {1- (3- (p-benzyloxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) are hydrogenated in 200 ml of methanol ίο 5 7 9 4 5 using 1 g of palladium-on-carbon (5%) at room temperature under normal pressure. When the absorption of hydrogen has ceased, the catalyst is filtered off and the solvent is evaporated. There remains 1- (1- (3- (p-hydroxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), the hydrochloride of which melts at 238 °.

Similarly, 1- {1- (3- (o-benzyloxyphenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) can be prepared by catalytic hydrogenation of 1- {1- (3- ( o-hydroxyphenoxy) -2-hydroxy-cipropyl) -piperidyl- (4)} -imidazolidinone- (2), melting at 183-185 °.

Example 5: By heating 15 g of 1- (p-benzyloxy-phenoxy) -2,3-epoxy-propane and 15 g of 1- (4-piperidyl) -2-imidazolidinone in 30 ml of ethanol to 80 ° and its after evaporation of the solvent, 1- (1- (3- (p-benzyloxyphenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) is obtained, melting at 166 °.

In a similar manner, 1- {1- (3- (o-benzyloxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- can be prepared. (2).

Example 6:

A mixture of 15 g of 1- (p-acetamido-phenoxy) -2,3-epoxy-propane, 15 g of 1- (4-piperidyl) -2-imidazolidinone and 30 ml of alcohol is heated at 80 ° for 3 hours: and then evaporated in vacuo. The residue is dissolved in 2N hydrochloric acid, extracted with ether, after which the aqueous phase is made alkaline by adding 10% sodium hydroxide. This precipitates 1- {1- (3- (p-acetamido-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), which, after recrystallization from ethanol, melts 162- 165 ° C. The hydrochloride melts at 257-259 °.

Example 7:

A mixture of 15 g of 1- (o-allyl-phenoxy) -2,3-epoxy-propane, 15 g of 1- (4-piperidyl) -2-imidazolidinone and 30 ml of alcohol is heated at 80 ° for 4 hours: then evaporated. The residue is dissolved in 200 ml of 2N hydrochloric acid, extracted with ether, after which the aqueous phase is made alkaline by adding 10 [mu] l of sodium hydroxide. 1- {1- (3- (o-allyl-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) separates as an oil. The hydrochloride melts at 186-189 °.

,,, VI; 11 57945

Example 8:

A mixture of 15 g of 1- (o-allyloxy-phenoxy) -2,3-epoxy-propane, 15 g of 1- (4-piperidyl) -2-imidazolidinone and 45 ml of ethanol is heated at 90 ° for 4 hours: and then evaporated in vacuo. The residue is dissolved in 200 ml of 2N hydrochloric acid, extracted with ether and the aqueous phase is made alkaline by adding concentrated sodium hydroxide. The precipitated 1- {1- (3- (o-allyloxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) is shaken with methylene chloride. After drying and evaporating the ether, the residual oil is dissolved in 44 ml of ethanol. Upon addition of 10.5 g of cyclohexylsulfamic acid, cyclohexylsulfamate crystals are separated which, after recrystallization from ethanol, melt at 128-130 °.

Example 9:

A solution of 30 g of 1- (o-methoxy-phenoxy) -2,3-epoxy-propane and 30 g of 1- (piperidyl- (4)) - 3-methylimidazolidinone in 100 ml of ethanol is heated 3 hours at 90 ° and evaporated in vacuo. The residue is dissolved in 100 ml of 2N hydrochloric acid, extracted with ether and the aqueous phase is made alkaline by adding 10 [mu] l of sodium hydroxide. After extraction with methylene chloride and evaporation of the solvent, 1- {1- (3- (o-methoxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} - 3-methyl-imidazolidinone- (2) as an oil. After recrystallization, the hydrochloride melts from ethanol-ether at 172 °.

The required 1- (piperidyl- (4)) - 3-methylimidazolidinone can be prepared by hydrogenation of 1- (4-pyridyl) -3-methylimidazolidinone (2), using ruthenium as a catalyst. The compound melts at 60-64 °.

Example 10:

In a manner similar to that described in Example 1, 1- {1- (pN-methylcarbamoyl-phenoxy) -2,3-epoxy-propane and 1- (piperidyl- (4)) -imidazolidinone- (2) give 1- {1- ( 3- (pN-methylcarbamoyl-1-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} - imidazolidinone- (2), which, after recrystallization from ethyl acetate, melts at 180-182 ° and whose nautal fumarate is methanol recrystallized from ether, melting at 194-196 °.

12,57945

Example 11:

In a manner similar to that described in Example 1, 1- (o-methyl-phenoxy) -2,3-epoxy-propane and 1- (piperidyl- (4)) -imidazolidinone- (2) 1- {1- (3- ( o-methyl-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), m.p. 114-116 °. Example 12:

In a manner similar to that described in Example 1, 1- (1- (3-chlorophenoxy) -2,3-epoxypropane and 1- (piperidyl- (4)) -imidazolidinone- (2) give 1- (1- (3) - (o-chloro-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} - imidazolidinone- (2), mp 150-151 °, the neutral fumarate of which, recrystallized from methanol-ether, melts 172- At 173 ° (sintered from 170 °).

Example 13:

In a manner similar to that described in Example 1, 1- (2-methoxy-4-N-methylcarbamoyl-phenoxy) -2,3-epoxy-propane and 1- (piperidyl- (4)) - imidazolidinone- (2) 1- ( 1- (3- (2-Methoxy-4-N-methylcarbamoyl-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), which, after recrystallization from isopropanol, melts 104 -107 ° C.

Example 14:

A solution of 6.56 g of 1- (o-tolyloxy) -2,3-epoxypropane and 7.7 g of 1- (piperidyl- (4)) - 2-oxo-hexahydro-pyrimidine in 5 ml of ethanol , is heated for 3 1/2 hours at a bath temperature of 95 ° and then evaporated in vacuo. Upon trituration with ethyl acetate, crystallization begins. The crystals thus obtained are stirred with water, filtered off and recrystallized from ethyl acetate-petroleum ether. There is thus obtained 1- (3- (o-tolyloxy) -2-hydroxypropyl) -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine, m.p. 145-147 °.

The starting 1- (piperidyl- (4)] - 2-oxo-hexahydro-pyrimidine can be prepared as follows:

To a solution of 18.8 g of 4-aminopyridine in 80 ml of dimethylformamide is added dropwise within 2 hours at room temperature 30 g of γ-chloropropyl isocyanate and then stirred for a further 24 hours. After evaporation of the dimethylformamide at 80 [deg.] C. in a water-jet vacuum, 4.27 g of the residue are dissolved in 25 ml of methanol and then a solution of 1.19 g of sodium methylate in 25 ml of methanol is added at reflux for 20 minutes with stirring. It is then boiled for a further hour under reflux. The separated sodium chloride is filtered off, evaporated in vacuo and the residue is crystallized from chloroform-petroleum ether. There is thus obtained 1- (pyridyl- (4)) - 2-oxo-hexahydro-pyrimidine, m.p. 180-182 °.

17.7 g of 1- (pyridyl- (4)) - 2-oxo-hexahydro-pyrimidine Hydrate in 180 ml of water using 2.5 g of ruthenium carbon (10%) at 120 ° and 120 ° C: n pressure. After uptake of hydrogen, the catalyst is filtered off, evaporated to dryness and crystallized from chloroform-petroleum ether. 1- (Piperidyl- (4)) - 2-oxo-hexahydro-pyrimidine is obtained, m.p. 207-210 °.

Example 15;

A solution of 9 g of 1- (o-methoxy-phenoxy) -2,3-epoxy-propane and 9.15 g of 1- (4-piperidyl) -2-oxo-hexahydro-pyrimidine in 7 ml absolute ethanol, heated at 95 ° for 5 hours and then evaporated in vacuo. The residue is crystallized from ethyl acetate-petroleum ether. There is thus obtained 1- (3- (o-methoxyphenoxy) -2-hydroxypropyl) -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine, m.p. 130-133 °.

17.1 g of the above base are dissolved in 100 ml of absolute ethanol and added to a solution of 5.5 g of fumaric acid in 105 ml of absolute ethanol. Upon addition of ether, 1- (3- (o-methoxyphenoxy) -2-hydroxypropyl) -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine fumarate (1: 1) precipitates, m.p. 149-151 °. Example 16:

A solution of 10.4 g of 1- (p- (2-methoxyethyl) phenoxy) -2,3-epoxypropane and 9.15 g of 1- (4-piperidyl) -2-oxyhexahydro-pyridine mididine in 7 ml of absolute ethanol, heated at 95 ° for 5 hours and then evaporated in vacuo. The residue is crystallized from ethyl acetate-petroleum ether. 1- (3- (p- (2-methoxyethyl) -phenoxy) -2-hydroxypropyl) -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine is obtained, m.p. 113-115 °.

18.5 g of the above base are dissolved in 30 ml of absolute ethanol and added to a solution of 5.5 g of fumaric acid in 105 ml of absolute ethanol. Upon addition of ether, 1- (3- (p- (2-methoxyethyl) phenoxy) -2-hydroxypropyl) -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine fumarate (2: 1), m.p. p. 157-159 °.

Example 17:

A solution of 10.35 g of 1- (p-acetamido-phenoxy) -2,3-epoxy-propane and 9.15 g of 1- (4-piperidyl) -2-oxo-hexahydro-pyrimidine in 10 ml of absolute the ethanol is heated to 95 °. After about 5 minutes, the reaction product crystallizes at boiling temperature. The crystal porridge is diluted with 10 ml of absolute ethanol and heated for a further 5 hours. After completion of the reaction, it is evaporated in vacuo and the residue is crystallized from abosute ethanol-ether. There is obtained 1- (3- (p-acetamido-phenoxy) -2-hydroxypropyl) -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine, m.p. 218-221 °.

The above-mentioned base prepared in a conventional manner melts after recrystallization from methanol-ether at 260-263 °. Example 18:

A solution of 9.2 g of 1- (o-chlorophenoxy) -2,3-epoxypropane and 9.15 g of 1- (4-piperidyl) -2-oxo-hexahydropyrimidine in 7 ml of absolute ethanol, heated for 5 hours at S5 ° and then evaporated in vacuo. The residue is crystallized from chloroform-petroleum ether. There is thus obtained 1- (3- (o-chlorophenoxy) -2-hydroxypropyl-1 H) -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine, m.p. 150-153 °.

12.7 g of the above base are dissolved in 60 ml of absolute ethanol and added to a solution of 4.05 g of fumaric acid in 77 ml of absolute ethanol. Addition of ethyl acetate and ether precipitates 1- (3- (o-chlorophenoxy) -2-hydroxypropyl) -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine fumarate (2: 1), m.p. 169-171 °.

Example 19:

A solution of 10.3 g of 1- (o-allyloxy-phenoxy) -2,3-epoxy-propane and 9.15 g of 1- (4-piperidyl) -2-oxo-hexahydro-pyrimidine in 7 ml of absolute ethanol is heated 5 hours at 95 ° and then evaporated in vacuo. The residue is crystallized from isopropanol.

There is thus obtained 1- (3- (o-allyloxy-phenoxy) -2-hydroxypropyl) -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine, m.p. 122-125 °.

8.45 g of the above base are dissolved in 50 ml of absolute ethanol and added to a solution of 2.52 g of fumaric acid in 50 ml of absolute ethanol. Upon addition of ether, 1- (3- (o-allyloxy-phenoxy) -2-hydroxypropyl) -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine fumarate (1: 1) precipitates, m.p. 154-156 °. Example 20:

A solution of 10.8 g of 1- (p-methoxy-phenoxy) -2,3-epoxy-propane and 10.15 g of 1- (4-piperidyl) -imidazolidinone- (2) in 10 ml of absolute ethanol, heated at 95 ° for 5 hours and then evaporated in vacuo. The residue is dissolved in 80 ml of 2N hydrochloric acid, extracted with methylene chloride and the aqueous phase is made alkaline by adding concentrated sodium hydroxide. Extract with methylene chloride and evaporate the solvent to give 1- (3- (p-methoxy-phenoxy) -2-hydroxy-propyl) -4- (2-oxo-1-imidazolidinyl) -piperidine, which, after recrystallization, melts from isopropanol 148 -150 ° C.

13.7 g of the above base are dissolved in 40 ml of absolute ethanol at heat and 20.7 ml of 1.9N ethanolic hydrochloric acid are added. After cooling, 1- (3- (p-methoxyphenoxy) -2-hydroxypropyl) -4- (2-oxo-1-imidazolidinyl) -piperidine hydrochloride precipitates, m.p. 209-211 °.

Example 21: To 0.50 g of 1- (3- (o-hydroxy-phenoxy) -2-hydroxypropyl) -4- (2-oxo-1-imidazolidinyl) -piperidine in 20 ml of dimethylformamide is added 65 mg of sodium hydride suspension (55% in paraffin oil) and stirred for 1 hour at 20-30 °. 0.23 g of methyl iodide are then added and the reaction mixture is stirred for 18 hours at 20-30 °. After evaporation of the solvent in vacuo, the residue is washed with 5 ml of pentane. The insoluble matter is partitioned between 30 ml of ethyl acetate and 3 ml of 6 N sodium hydroxide. The organic phase is extracted once more with 3 ml of 6N sodium hydroxide, dried over magnesium sulphate and evaporated in vacuo. 0.45 g of a yellow oil is thus obtained, from which recrystallization from ethanol gives pure 1- (3- (o-methoxy-phenoxy) -2-hydroxypropyl) -4- (2-oxo-1-imidazolidinyl) -piperidine, m.p. 138 °, the hydrochloride of which melts at 158-160 °. The product is identical to the product described in Example 1 by thin layer chromatography.

Example 22:

A mixture of 10.1 g of 1- (o-methoxy-phenoxy) -2,3-epoxy-propane and 11.25 g of 1- (2,2,6,6-tetramethyl-4-piperidyl) - imidazole-dinone- (2) in 20 ml of absolute ethanol, reflux for 10 hours. After completion of the reaction, the precipitated product is triturated with ether, filtered and washed with ether. There is thus obtained 1- (1- (3- (o-methoxy-phenoxy) -2-hydroxy-1-propyl) -2,2,6,6-tetramethyl-4-piperidyl} -imidazolidinone- (2), which after abs. ethanol melts at 197-198 °.

17 g of this base are suspended in 100 ml of abs. ethanol and 21 ml of 2.4 N ethanolic hydrochloric acid are added. Ether and ethyl acetate are added to the resulting solution to give 1- {1- (3- (o-methoxy-phenoxy) -2-hydroxy-1-propyl) -2,2,6,6-tetramethyl-4-piperidyl} -imide. '' * '- 16 57945 Dazolidinone (2) hydrochloride precipitates which, after recrystallization from isopropanol, melts at 211-213 °.

The starting 1- (2,2,6,6-tetramethyl-4-piperidyl) -imidazolidinone (2) is prepared as follows:

A solution of 26 g of 2,2,6,6-tetramethyl-4-piperidone hydrate, 27 g of ethylenediamine and 3 drops of conc. sulfuric acid in 400 ml of methanol, hydrogenated using 1.5 g of 5% platinum on carbon at room temperature and normal pressure. At the end of the absorption of hydrogen, the catalyst is filtered off and the methanol is evaporated off under vacuum. The residue is dissolved in methylene chloride and dried over sodium sulfate. After evaporation of the methylene chloride, the residue is fractionated under high vacuum. There is thus obtained N- (2,2,6,6-tetramethyl-4-piperidyl) -ethylenediamine as an oil, b.p. q / 78-80 °.

To 19.7 g of the diamine prepared above are added 230 ml of toluene and 150 ml of 3N potassium hydroxide. 230 ml of a 20% toluene solution of phosgene and 135 ml of 6 N potassium hydroxide are added dropwise at the same time, stirring carefully at 0 °, for 45 minutes. After the addition is complete, stir for an additional 1/2 hour at 0 ° and 20 hours at room temperature.

Water is then added, the aqueous phase is separated from the toluene layer, the conc. with sodium hydroxide to pH 11-12 and repeatedly extracted with methylene chloride.

After drying and evaporation of the methylene chloride solution, 1- (2,2,6,6-tetramethyl-4-piperidyl) -imidazolidinone- (2) is obtained, which, after recrystallization from methylene chloride / petroleum ether, melts at 176-178.5 °.

Example 23: 12.4 g of guaiacol, 84 ml of 2N sodium hydroxide and 11.3 g of 1- (1- (2,3-epoxypropyl) -piperidyl- (4)) - imidazolidinone- (2) are refluxed for 20 hours. After cooling, methylene chloride is added and the aqueous phase is separated. The methylene chloride solution is washed several more times with sodium hydroxide and water. After drying over magnesium sulphate, it is evaporated to dryness. The crystalline residue thus obtained is dissolved in absolute ethanol and an excess of ethanolic hydrochloric acid. Upon addition of ether, 1- (1- (3- (o-methoxyphenoxy) -2-hydroxypropyl) -piperidyl- (4)} -imidazolidinonine- (2) hydrochloride crystallizes, mp 158-160 °. the base melts at 138 ° (from ethanol).

Example 24: 12.4 g of guaiacol and 31 g of 1- (1- (3-bromo-2-hydroxy-1-propyl) -17,57945 piperidyl- (4)) - imidazolidinone- (2) are boiled with 14 g of potassium carbonate for 24 hours under reflux and stirring. The reaction mixture is then filtered. The filtrate is evaporated to dryness, aqueous hydrochloric acid is added to the residue and extracted with ether. The aqueous acid phase is made alkaline and shaken twice with methylene chloride. After drying and evaporating the methylene chloride solution, the residue is dissolved in alcohol and a calculated amount of alcoholic hydrochloric acid is added. Upon addition of ether, 1- {1- (3- (o-methoxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) hydrochloride, m.p. 148-160 °.

Example 25;

In a manner similar to that described in Example 1 or 2, the following compounds can be prepared by reacting the corresponding phenol with the corresponding 1- (1- (2,3-epoxypropyl) -4-piperidyl) -imidazolidinone- (2) or -2-hexahydropyrimidinone. : a) 1- {1- (3- (m-methoxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) (oil); fumarate sul.p. 192-193 °; b) 1- {1- (3- (p-allyloxyphenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), m.p. 132-133 ° (ethanol); methane sulfonate m.p. 154-157 °; c) 1- {1- (3- (p-hydroxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), m.p. 238 °; d) 1- {1- (3- (p-benzyloxyphenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), m.p. 166 °; e) 1- {1- (3- (p-acetamido-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), m.p. 162-165 ° (from ethanol); hydrochloride sul.p. 257-259 °; f) 1- {1- (3- (o-allyl-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) (oil); hydrochloride m.p. 186-189 °; g) 1- {1- (3- (o-allyloxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2) (oil); cyclohexyl sulfamate m.p. 128-130 ° (ethanol); h) 1- {1- (3- (o-methoxy-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} - 3-methyl-imidazolidinone- (2) (oil); hydrochloride m.p.

172 ° (from ethanol / ether); i) 1- {1- (3- (p-N-methylcarbamoyl-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), m.p. 180-182 ° (from ethyl acetate); neutral fumarate sul.p. 194-196 ° (from methanol / ether); j) 1- (1- [3- (o-methyl-phenoxy) -2-hydroxy-1-propyl) -piperidyl-18,57,94 5 (4)} -imidazolidinone- (2), m.p. 114-116 °; k) 1- {1- (3- (o-chloro-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), m.p. 150-151 °; neutral fumarate sul.p. 172-173 ° (sintered from 170 °) (from methanol / ether); l) 1- (1- (3- (2-methoxy-4-N-methylcarbamoyl-phenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), m.p. 104-107 ° (from isopropanol); m) 1- (1- (3- (o-hydroxyphenoxy) -2-hydroxypropyl) -piperidyl- (4)} -imidazolidinone- (2), mp 183-185 ° n) 1- (1- (3- (o-tolyloxy) -2-hydroxypropyl) -piperidyl- (4)} - hexahydro-1-pyrimidinone- (2), mp 145-147 O) 1- (1- (3- (o-methoxyphenoxy) -2-hydroxypropyl) -piperidyl- (4)} - hexahydro-1-pyrimidinone- (2), mp 130-133 °; (1: 1) mp 149-151 ° (from ethanol / ether) p) 1- (1- (3- (p- (2-methoxyethyl) phenoxy) -2-hydroxypropyl) -piperidyl- (4 )} -hexahydro-1-pyrimidinone- (2), mp 113-115 °, fumarate (2: 1) mp 157-159 ° (ethanol / ether) q) 1- (1- ( 3- (p-acetamido-phenoxy) -2-hydroxypropyl) -piperidyl- (4)} - imidazolidinone- (2), mp 218-221 °, hydrochloride mp 260-263 ° (from methanol / ether) r) 1- (1- (3- (o-chloro-phenoxy) -2-hydroxypropyl) -piperidyl- (4)} -imidazolidinone- (2), mp 150-153 °; fumarate (2: 1) m.p. 169-171 ° (ethanol / ethyl acetate / ether); s) 1- (1- (3- (o-allyloxy-phenoxy) -2-hydroxypropyl) -piperidyl- (4)} -imidazolidinone- (2), mp 122-125 °; fumarate (1: 1 ) mp 154-156 ° (from ethanol / ether); t) 1- (1- (3- (p-methoxy-phenoxy) -2-hydroxypropyl) -piperidyl- (4)} - imidazolidinone- (2) mp 148-150 ° (from isopropanol); m.p. 209-211 ° (from ethanol); u) 1- (1- (3- (o-methoxy-phenoxy) -2-hydroxy-1- propyl) -2,2,6,6-tetramethyl-4-piperidyl} imidazolidinone- (2), mp 197-198 ° (from ethanol), m.p. 211-213 ° (from isopropanol) v) 1- (1- (3- (o-benzyloxyphenoxy) -2-hydroxy-1-propyl) -piperidyl- (4)} -imidazolidinone- (2), mp 145-147 ° (from isopropanol) (w) 1- (1- (3- (o-acetyl-phenoxy) -2-hydroxy-1-propyl) -piperidinyl- (4)} -imidazolidinone- (2), mp 147-148 ° ( neutral fumarate mp 184-185 ° (from isopropanol) x) 1- (1- (3- (o-cyanophenoxy) -2-hydroxy-1-propyl) -piperidinyl- (4)} -imidazolidinone- (2), neutral fumarate mp 181-183 ° (isopropyl -methanol);

Claims (1)

19 57945 y) 1- {1- (2-hydroxy-3- (o-nitro-phenoxy) -1-propyl) -piperidinyl- (4)} -imidazolidinone- (2), neutral fumarate m.p. 166-168 ° (isopropanol); z) 1- {1- (3- (p- (2-methyl-thioethoxy) -phenoxy) -2-hydroxy-1-propyl) -piperidinyl- (4)} -imidazolidinone- (2), fumarate m.p. . 165-167 ° (from isopropanol) and 1- {1- (2-hydroxy-3- (o-propargyloxy-phenoxy) -propyl) -piperidyl- (4)} -imidazolidinone- (2) -hydrochloride, mp 193-195 ° (from isopropanol). ✓ Patent claim; Analogue procedure for new therapeutically active 1- (1- (2-hydroxypropyl) -piperidyl- (4)) -imidazolidinone- (2) - and hexahydro-pyrimidinone- (2)-derivatives of the formula (R4> n | alk? H Α + Λ / \ R, -O-CHo-CH-CHo-N VN N - Rn I 1 2 2 w γ 2 o where R 1 represents optionally lower alkyl radicals, lower alkenyl radicals, lower alkoxy lower alkyl groups, acetamide, acetyl , lower alkoxy groups, lower alkenyloxy groups, lower alkynyloxy groups, lower alkylthio-lower alkoxy groups, benzyloxy groups, hydroxy groups, haloethyl groups, alkyl groups, substituents nitrogen atoms with two or three carbon atoms, R 1 represents hydrogen or lower alkyl and n represents a number from 1 to 4, and for the preparation of their salts, characterized in that y a compound of the formula R1 "0 'Y1 11 20 5794 5 is reacted with a compound of the formula" Vn I alk rr \ / \ Y0 - NVNN - R ~ III 2 w Ύ 2 o in which formulas one of the residues and Y2 represents a residue -CH 2 -CH-XH 2 -Z, wherein X is OH and Z is a reactive esterified hydroxyl group, or X and Z together form an epoxy group, and one of Y 1 and Y 2 is hydrogen, and R 1, R 2, R 4, n and alk are as defined above, and if desired in the obtained compounds having a benzyloxy group, this is cleaved, and / or in the obtained compounds in which R 1 represents a phenyl residue substituted by a hydroxyl group, the hydroxyl group is lower alkylated and / or the salts obtained are converted into free compounds or other salts or the resulting free compounds . claim; Analogs for the preparation of therapeutically active 1- (1- (2-hydroxypropyl) -piperidyl- (4)) - imidazolidinone- (2) - and -hexa-hydro-pyrimidinone- (2) -derivatives with the formula <Vn alk ° H rr \ / \ R, -O-CHo-CH-CH, -N VN N - R-, I 1 2 2 vV γ 2 o color R ,, acetyl, lgrealkoxigrup-per, legrealkenyloxigrupper, legrealkinyloxygrupper, lgrealkylthiolgreakoxi-groupper, benzyloxylgroup, hydroxylgroup, halogen atomer, skiljer de bäda kväveatomerna frän varandra genom tvä eller tre kolatomer, R ^ betecknar väte eller lägre-