KR790001870B1 - Process for preparing piperidine derivatives - Google Patents

Abstract

Piperidine derivs. (I ; R = H, lower alkyl, R' = H, lower alkyl, C5-C7 cycloalkyl, etc., Ar = substituted or non-substituted phenyl, x = O,S), their acid salts, and quaternary ammonium salts useful as antihypertensive, were prepd. by treating ArCO(CH2)3Y (Y = halogen, equivalent to substitutable elements or groups) with III, hydrolyzing I(R' = aroyl) to give I (R' = H), or dehydrating I (Ar= one lower alkoxy, alkyloxysubstitutes) to give I contg. one hydroxy group.

Description

Process for preparing piperidine derivative

The present invention relates to a novel piperidine derivative of formula (I) and acid addition salts or quaternary ammonium salts thereof, which exert pharmacological effects on the cardiovascular system such as blood pressure strengthening and / or antihypertensive action in warm blooded animals.

In the above structural formula

R is hydrogen or lower alkyl:

R ¹ is hydrogen, lower alkyl, cycloalkyl having 5 to 7 dehydration, substituted or unsubstituted aryl lower alkyl, substituted or unsubstituted aryl lower alkyl, substituted or unsubstituted aryl (including heterocyclic aryl), Or unsubstituted aroyl:

Ar represents a substituted or unsubstituted phenyl group:

X represents oxygen or sulfur.

The phenyl group represented by Ar is halogen such as fluorine or chlorine, lower alkoxy such as methoxy, aryl lower alkoxy such as benzyloxy, hydroxy, lower alkyl such as methyl, alkylenedioxy such as methylenedioxy, trifluoromethyl and The same trohal may be substituted with lower alkyl or the like.

As used herein, the term "lower" used in alkyl and alkoxy groups means a group containing 1 to 6 carbon atoms. Usually such groups contain 1 to 4 carbon atoms. Examples of lower alkyl groups in the substituents on R, R ¹ and phenyl group Ar include those such as methyl, ethyl, n-propyl, iso-propyl, n-butyl and isobutyl. Examples of the aryl group in the group represented by R ¹ include phenyl and substituted phenyl.

Lower alkoxy groups include methoxy, ethoxy, propoxy and butoxy.

Examples when R ¹ is a heteroaryl group include indolyl (eg 3-ynyldol), thienyl (eg 2-thienyl), furyl (eg 2-furyl) and pyridyl (eg 2-pyridyl and 3-pyridyl).

A phenyl group or an aryl group substituted with a phenyl group as part of the R ¹ substitution at R ¹ include chlorine, alkyl, methylene dioxy, and ethylene, such as alkoxy, methyl or ethyl, such as halogen, ethoxy-methoxy, or, such as fluorine or bromine-deoxy , Nitro, amino, alkylamino, dialkylamino, acylamino (eg alkanoylamino), hydroxy, lower-alkoxycarbonyl, trihalo loweralkyl (eg trifluoromethyl), mercapto, methylthio Also included are methanesulfonyl, alkylsulfonamido (e.g. methane sulfonamido), phenyl substituted by one or more substituents selected from phenyl and phenyl substituted by substituents mentioned in substituted phenyl groups.

Preferred when R ¹ is an aroyl group include benzoyl or substituted benzoyl (eg halobenzoyl such as P-chlorobenzoyl).

Examples when R ¹ is a cycloalkyl group include cyclopentyl, cyclohexyl and cyclohexyl.

Substituent-NRCXNHR ¹ in the compound of formula (I) is preferably present at the 4-position.

Acid addition salts of the compounds of formula (I) include salts of inorganic and organic acids, in particular sulfates, hydrochlorides, hydrobromide, hydroiodide, nitrates, phosphates, sulfonates (e.g. methanesulfonate and P-toluenesulfonate) And acetate, maleate, fumarate, tartrate and formate and pharmaceutically toxic acid addition salts.

Quaternary ammonium salts of compounds of formula (I) also include salts formed with alkyl halides (eg methylbromide or chloride) and aralkyl halides (eg benzylbromide or chloride).

As a test for the anti-hypertensive action of the compound of formula (I) according to the present invention, oral administration of the compound of formula (I) to rats suffering from hypertension and measurement of cardiac contractility of the rat resulted in 1-phenyl-3- [1- (4-phenyl-4-oxobutyl) -piperid-4-yl) urea hydrochloride of I) showed significant anti-hypertensive action at a dose of 40 mpk.

In addition, the hypotensive action of the compound of formula (I) was tested by intravenously administering the compound to rats of normal blood pressure. In this test, 1-phenyl-3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] thiourea hydrochloride and 1-benzoyl-3- [1- ( 4-phenyl-4-oxobutyl) piperid-4-yl] both urea hydrochloride showed good hypotension.

Any of the compounds of formula (I) according to the invention may also be used as intermediates for the preparation of other compounds of formula (I).

According to the present invention, a compound of formula (II) is reacted with a compound of formula (III) to give a compound of formula (I).

In the above structural formula

Ar is as defined above,

Y is halogen or an equivalent substitutable atom or group (eg an organicsulfonyl group such as a tosyl group);

R, R ¹ and X are as defined above.

Starting material (II) can be prepared according to the methods described in British Patent No. 1,345,782. Compounds of formula (III) can be prepared according to known methods.

The compound of formula (I) prepared in this way can convert one or more substituents in the molecule to other substituents specified in the structure, if necessary. For example,

Compounds of formula (I) wherein R ¹ is hydrogen can be aroylated, e.g., using a reactive derivative of R ¹ COOH (where R ¹ is aroyl) acid, where R ¹ is aroyl ( Compounds of I) are obtained. Examples of reactive derivatives of the above formula R ¹ COOH acid include halide (eg chloride and anhydride) derivatives.

When Ar is produced a compound of formula (I) containing lower alkoxy or aryl lower alkoxy substituents, hydrolysis or dealkylation to a compatible hydroxyl compound can be carried out according to known methods.

If desired, reactive substitution groups in the reactions described above can be protected during the reaction and removed in the final reaction process.

The present invention also includes a pharmaceutical composition containing, as an active ingredient, the compound of formula (I) obtained according to the preparation method of the present invention as described above. To prepare a pharmaceutical composition, a nontoxic carrier substance in the form of a solid, a liquid, or a solid and a liquid mixture is added and prepared according to known methods. The solid compositions are powders, tablets and capsules, and the solid carrier may be used as a capsule material as one or more substances capable of functioning as fragrances, lubricants, solubilizers, suspending agents, binders or tablet disintegrating agents. The carrier used in powder is a finely divided solid material mixed with finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having a binding capacity in suitable proportions and tableted in a desired shape and size. Powders and tablets contain 5 to 99% of the compound of formula (I) as an active ingredient, preferably 10 to 80%. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragagant, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes and cocoa butter. Liquid compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient is dissolved or suspended in a pharmaceutically sterile, sterile liquid carrier such as sterile water, sterile organic solvent or a mixture thereof. Liquid carriers are suitable for parenteral injection, and when the active ingredient is sufficiently dissolved, conventional saline may be used as a carrier, but if not dissolved, water-soluble propylene glycol or polyethylene glycol is suitable. The composition may also be prepared by dispersing the finely divided active ingredient in a suitable oil such as a water-soluble starch or CMC solution, or arachid oil. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be used for intramuscular, intraperitoneal or subcutaneous injection. In most cases, oral administration of the compound is effective and is administered as a composition in solid or liquid form.

The pharmaceutical composition is preferably in unit dosage form. In this form, the composition is subdivided into unit doses containing an effective amount of the active ingredient, and the packaged form contains a specific amount of the composition, such as capsules, cachets or tablets.

The amount of active ingredient in a unit dose of the composition may vary from 5 mg or less to 500 mg or more, depending on the particular needs and actions of the active ingredient. The present invention may also be in unit dosage form without the carrier.

The following examples illustrate the invention.

Example 1

1-phenyl-3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

A solution of 1.23 g of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine added to 125 ml of benzene was stirred at room temperature, followed by 0.63 g of phenyl isocyanate (about 5%) in 25 ml of benzene. The solution precipitates soon after adding the dissolved solution. After stirring the reaction mixture for 18 hours, the target product was filtered off as a white solid (1.55 g), dried and treated with ethanolic hydrogen chloride to convert into hydrochloride (1.57 g).

Yield: 78%

Melting Point: 190 ℃ or higher (decomposition)

Elemental Analysis: C ₂₂ H ₂₇ N ₃ O ₂ HCl

Calc .: C 67.53; H 7.02; N 10.45%

Found: C 65.58; H 7.07; N 10.31%

Example 2

1- (4-methoxyphenyl) -3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

1.23 g of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine and 0.82 g of 4-methoxyphenyl isocyanate were added to 125 ml of benzene and condensed in the same manner as in Example 1 to obtain the target compound 1.3. g is obtained. It is crystallized from ethanol / hydrochloric acid to give 1.26 g of hydrochloride with a melting point of 199.2 ° C.

Elemental Analysis: C ₂₃ H ₂₉ N ₃ O ₃ HCl

Calc .: C 63.89; H 6.94; N 9.72

Found: C 64.52; H 6.85; N 9.71%

Example 3

1- (3-toluyl) -3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

By the method of Example 1, 1.23 g of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine and 0.73 g of 3-toluylisocyanate were condensed in 125 ml of benzene to give 1.1 g of the target product. To obtain. Crystallization with ethanol / hydrochloric acid gives 0.7 g of hydrochloride with a melting point of 181.6 ° C.

Elemental Analysis: C ₂₃ H ₂₉ N ₃ O ₂ HCl

Calculated: C 63.60; H 7.37; N 9.68

Found: C 64.07; H 7.34; N 9.77%

Example 4

1- (2, 6-dimethylphenyl) -3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

1.23 g of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine and 0.81 g of 2,6-dimethylphenyl isocyanate were condensed in 125 ml of benzene by the method of Example 1 to obtain the target 1.1. g is obtained. Crystallization with ethanol / hydrochloric acid gives 0.85 g of hydrochloride with a melting point of 214.2 ° C.

Elemental Analysis: C ₂₄ H ₃₁ N ₃ O ₂ HCl

Calc .: C 67.06; H 7.45; N 9.78

Found: C 67.44; H 7.55; N 9.54

Example 5

1- (2-trifluoromethylphenyl) -3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

1.23 g of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine and 1.03 g of 2-trifluoro methylphenyl isocyanate are condensed in 125 ml of benzene in the same manner as in Example 1 to give 1.01 of the target compound. g is obtained. This was crystallized with ethanol / hydrochloric acid to give 0.67 g of hydrochloride having a melting point of 193.7 ° C.

Elemental analysis: C ₂₃ H ₂₆ F ₃ N ₃ O ₂ HCl

Calc .: C 58.73; H 5.75; N 8.94

Found: C 58.88; H 5.93; N 8.79

Example 6

1- (4-chlorophenyl) -3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

1.23 g of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine and 0.85 g of 4-chlorophenyl isocyanate are condensed in 125 ml of benzene in the same manner as in Example 1 to obtain 1.5 g of the target substance. To obtain. This was crystallized with ethanol / hydrochloric acid to give 1.12 g of hydrochloride with a melting point of 245.0 ° C.

Elemental Analysis: C ₂₂ H ₂₆ ClN ₃ O ₂ HCl

Calculated: C 60.50; H 6.19; N 9.63%

Found: C 60.75; H 6.40; N 9.59%

Example 7

1- (3,4-dichlorophenyl) -3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

1.23 g of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine and 1.03 g of 3,4-dichlorophenyl isocyanate are condensed in 125 ml of benzene as in Example 1 to give 1.2 g of the target substance. To obtain. This was crystallized with ethanol / hydrochloric acid to give 1.12 g of hydrochloride with a melting point of 217.9 ° C.

Elemental analysis: C ₂₂ H ₂₅ Cl ₂ N ₃ O ₂ HCl

Calculated: C, 56.07; H, 5.52; N, 8.82%

Found: C, 56.00; H, 5. 66; N, 8.81%

Example 8

1-phenyl-3- [1- (3-benzoylpropyl) piperid-4-yl] thiourea

A solution of 1.23 g (0.005 mol) of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine dissolved in 125 ml of benzene was treated with 0.74 g of phenyl isothiocyanate (0.0055 mol). The reaction mixture is stirred at room temperature for 24 hours. The precipitated target is filtered off, washed with a small amount of benzene, dried (1.17 g) and dissolved in ethanol and then converted to hydrochloride by addition of an ethanol solution saturated with hydrochloric acid. Filtration of the obtained hydrochloride of the target product yielded 1.17 g of a colorless needle with a melting point of 221.3 占 폚.

Elemental Analysis: C ₂₂ H ₂₇ N ₃ OSHCl

Calc .: C 63.21; H 6.75; N 10.05

Found: C 62.87; H 7.07; N 9,94%

Example 9

1-cyclohexyl-3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

1.23 g of 4-amino-1 (4-phenyl-4-oxobutyl) piperidine (0.005 mol) is dissolved in 50 ml of benzene and the mixture is treated with 0.685 g (0.0055 mol) of cyclohexyl isocyanate. After stirring for 18 hours, the filtrate was obtained as a colorless crystal (melting point: 178.6 DEG C) of the target product (0.952 g).

Elemental Analysis:

Calc .: C 69.44; H 9.01; N 11.04%

Found: C 69.20; H 9.00; N 10.79%

Example 10

1- (3-trifluoromethylphenyl) -3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

1.232 g of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine and 1.03 g (5% excess) of 3-trifluoromethylphenyl isocyanate are condensed in 150 ml of ben as in Example 1 1.28 g of the target product was obtained as a white solid. This was crystallized with ethanol hydrochloric acid to obtain 1.006 g of hydrochloride having a melting point of 192.5 占 폚.

Elemental analysis: C ₂₃ H ₃₆ F ₃ N ₃ O ₂ ClH ₂ O

Calc .: C 56.56; H 5.53; N 8.60%

Found: C 56.60; H 5.79; N 8.53%

Example 11

1-benzoyl-3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

1.232 g of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine are treated as 0.81 g (5% excess) of benzoyl isocyanate as in Example 1. The reaction mixture is evaporated to afford the desired product as a white solid (1.81), which is crystallized with ethanol hydrochloric acid to give 1,200 g of hydrochloride having a melting point of 201.6 ° C.

Elemental analysis: C ₂₃ H ₂₇ N ₃ O ₃ HCl ₂ H ₂ O

Calculated: C 59.28; H 6.92; N 9.02%

Found: C 59.43; H 6.97; N 8.84%

Example 12

1-benzoyl-3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] thiourea

0.71 g of benzoyl chloride was added to a solution of 0.42 g of ammonium isothiocyanide in 7 ml of anhydrous acetone and refluxed for 5 minutes. To this solution was added 10 ml of anhydrous acetone and a solution of 1.23 g of 4-amino-1- (4-phenyl-4-oxobutyl) piperidine was refluxed for 10 minutes, and the solution was added to 100 ml of water and chloroform. Extract. The chloroform extract is evaporated to afford the desired product as a pale yellow solid. It is crystallized with ethanol hydrochloric acid to give 0.580 g of hydrochloride having a melting point of 187.0 ° C.

Elemental analysis: C ₂₃ H ₂₇ N ₃ O ₂ HCl 1/4 H ₂ O

Calc .: C 61.27; H 6,33; N 9.32%

Found: C 61.17; H 6,64; N 9.17%

Example 13

3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

Hydrolysis of 1-benzoyl-3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea prepared according to Example 11 yields the above target.

Example 14 (a)-(9)]

The method of Example 1 was repeated to produce the urea of formula (I) according to the following scheme.

In the above structural formula A, R, R ¹ and X are as follows.

Ar RR ¹ X

(a) p-hydroxyphenyl H phenyl O

(b) p-methoxyphenyl H phenyl O

(c) p-fluorophenyl H phenyl O

(d) Phenyl Methyl Phenyl O

(e) 2, 5-dimethylphenyl H phenyl O

(f) p-chlorophenyl H phenyl S

(g) p-benzyloxyphenyl H phenyl S

(h) m-trifluoromethylphenyl H phenyl S

(i) Phenyl H 2-thienyl O

(j) Phenyl H 2-furyl O

(k) Phenyl H 2-pyridyl O

(l) Phenyl H Methyl O

(m) Phenyl H Benzyl O

(n) Phenyl H p-chlorobenzoyl O

(o) Phenyl H p-methylbenzoyl O

(p) phenyl H p-methoxybenzoyl O

Example 15

1-phenyl-3- [1- (4-phenyl-4-oxobutyl) piperid-3-yl] urea

The 3-amino-1- (4-phenyl-4-oxobutyl) piperidine is reacted with phenyl isocyanate according to a method analogous to that of Example 1 to obtain the above target.

Example 16

1-benzoyl-3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea

3- [1- (4-phenyl-4-oxobutyl) piperid-4-yl] urea is reacted with benzoyl chloride in the presence of anhydrous benzene solvent and anhydrous pyridine to obtain the hydrochloride dihydrate salt of this purpose. .

Example 17

1-benzoyl-3- ｛1- (4- [4-fluorophenyl] -4-oxobutyl) piperid-4-yl｝ urea

4.70 g (0.015 mole) of 4-benzoylureidopiperidine and 2.07 g (0.05 mole) of potassium carbonate were triturated in mortar and then the mixture was poured into 3.01 g (0.015 mole) of 4-chloro-4'-fluorobutyrophenone. After the addition, the mixture was stirred at 100 DEG C for 1 hour, then DMF was added and heated with stirring for 3 hours. Water is added to separate the reddish brown oil. After decanting off the water, the oil is dissolved in chloroform and the chloroform layer is washed with water. The chloroform extract is dehydrated with magnesium sulfate and evaporated to give a solid material. In order to remove impurities, the solid material is dissolved in chloroform and the organic layer is extracted with 1N hydrochloric acid. The chloroform extract is dehydrated with magnesium sulfate and then evaporated to dissolve the green solid material in ethanol and treated with activated carbon. The solution is filtered and treated with ethanolic hydrochloric acid to give the hydrochloride of the title compound. Melting Point: 207 ~ 208 ℃

Elemental analysis: C ₂₃ H ₂₆ N ₃ O ₃ FH ・ ClH ₂ O

Calculated: C 59.16; H6.26; N9.00%

Found: C 58.91; H6.21; N9.06%

Example 18

The title compound of Examples 1-12 is prepared using 4-chloro-butyrophenone and suitable ureido-piperidine as starting materials according to similar methods described in Example 17.

Claims (1)

Following structural formula the following structural formula to the compound of (Ⅱ) characterized by the following Sikkim compound and the reaction of formula (Ⅲ), as the case may be by R ¹ hydrolyzing a compound of the studded yl formula (I) corresponding to the R ¹ is hydrogen ( Structural formula (I) containing one or more hydroxyls, either by obtaining a compound of I) or by hydrolysis or dealkylation of a compound of formula (I) wherein Ar contains one or more lower alkoxy or aryl lower alkoxy substituents Process for preparing compounds and acid addition salts or quaternary ammonium salts thereof.

In the above structural formula R is hydrogen or lower alkyl R ¹ is hydrogen, lower alkyl, cycloalkyl having 5 to 7 carbon atoms, substituted or unsubstituted aryl lower alkyl, substituted or unsubstituted aryl (including heterocyclic aryl) or substituted or unsubstituted aroyl Ar is substituted or unsubstituted phenyl X is oxygen or sulfur Y is a halogen or equivalent substitutable atom or group.