CS255880B2 - Process for preparing a quinaldine derivative - Google Patents

Abstract

The novel compound of the general formula I, where R1 and R2 independently of each other represent C1-C6alkyl or together with the adjacent nitrogen atom form a 5- to 7-membered ring and X represents hydrogen, C1-C6alkyl or C1-C6alkoxy, is prepared by reacting quinaldic acid of the formula II or a reactive derivative thereof selected from the group comprising quinaldic acid halide, mixed quinaldic acid and monocarboxylic acid anhydride, quinaldic acid anhydride and quinaldic acid p-nitrophenyl ester, with a compound of the general formula III, where R1, R2 and X have the above-mentioned meaning. The product is optionally converted into an acid addition salt. The novel compound has a central muscle relaxant effect, in particular a pronounced effect on the relaxation of stiffness induced by ischemic decerebration.

Description

The invention relates to a method for preparing a novel quinaldinamide derivative.

As a quinaldinamide derivative, N-(2-diethylaminoethyl)quinaldinamide is described in German Patent Application No. 2,099,894, in the article by M. Giannini, P. Boňi, M. Fedi, G. Bonacchi, Farmaco, Ed.

Sci., 28, 429-47 (1973) and the article by P. Boni, C. Bocciarelli, Farmaco, Ed. Sci,, 29, 923-35 (1974). In the said publications there is no mention that the described quinaldinamide compound has the ability to release stiffness. The authors of the present invention have experimentally proven that the said quinaldinamide derivative has a very weak effect on releasing stiffness.

The purpose of the invention is to provide a novel quinaldinamide derivative exhibiting a pronounced central muscle relaxant effect, in particular a pronounced effect on relieving stiffness induced by ischemic decerebration.

The subject of the invention is a method for preparing a novel quinaldine derivative of general formula I

12 where R and R independently represent an alkyl group with 1 to 6 carbon atoms or R and R together form a 5 to 7-membered ring in connection with the adjacent nitrogen atom and X represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms or an alkoxy group with 1 to 6 carbon atoms, and its addition salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, methanesulfonic acid or ρ-toluenesulfonic acid.

A quinaldinamide derivative of the general quinaldic acid of formula II of formula I can be prepared according to the invention by the reaction

COOH (II) or a reactive derivative thereof selected from the group consisting of quinaldic acid halide, mixed quinaldic acid and monoalkylcarboxylic acid anhydride, quinaldic acid anhydride and quinaldic acid p-nitrophenyl ester, and a compound of the general formula III h ₂ n . where R , R and X have the meanings given above.

A quinaldinamide derivative of general formula I for forming an amide bond by condensation reaction, (1) by a procedure starting from acid halides using a quinaldinoyl halide, e.g. quinaldinoyl chloride or quinaldinoyl bromide, (2) by a procedure inducing a reaction between the starting compounds in the presence of a condensing agent, e.g. N,N -dicyclohexylcarbodiimide, a combination of N,N'-dicyclohexylcarbodiimide and N-hydroxysuccinimide or a combination of N,N'-dicyclohexylcarbadiimide and 1-hydroxybenzotriazole,

(III) can therefore be prepared by any known method, for example:

(3) a process starting from a mixed acid anhydride, for example, from an anhydride derived from a combination of quinaldic acid and a monocarboxylic acid, (4) a process starting from an acid anhydride, for example, using quinaldic anhydride, (5) a process starting from a reactive ester, for example, using quinaldic acid p-nitrophenyl ester, and (6) a process in which the starting compounds are heated in the absence of a condensing agent.

The reaction between quinaldic acid or between a quinaldinoyl halide of general formula II and a compound of general formula III can be carried out according to the following reaction equation:

where Y represents a halogen atom or a hydroxyl group and

R and X have the meanings given above.

The above reactions can be carried out without the use of a solvent or in an organic solvent inert to these reactions, such as, for example, methylene chloride, chloroform, ether, tetrahydrofuran, benzene or ethyl acetate.

and

The quinaldinamide derivative obtained by the above reactions can be converted into an acid addition salt by a known method.

The starting compound of general formula III has the following equation:

O

NH ₂ OH . HCl

As examples:

compound 1: compound 2: compound 3: compound 4: compound 5: compound 6: compound 7: compound 8:

compounds of general formula I, produced by the method according to the invention

N-(3-dimethylamino-1-phenylpropyl)quinaldinamide,

N-(3-diethylamino-1-phenylpropyl)quinaldinamide,

N-(1-phenyl-3-dipropylaminopropyl)quinaldinamide,

N-(1-phenyl-3-pyrrolidinopropyl)quinaldinamide,

N-(1-phenyl-3-piperidinopropyl)quinaldinamide,

N-[3-(perhydroazepin-1-yl)-1-phenylpropyl]quinaldinamide,

N-[1-(2-methylphenyl)-3-piperidinopropyl]quinaldinamide,

N-[1-(3-methylphenyl)-3-piperidinopropyl] quinaldinamide.

compound 9: N-[1-(4-methylphenyl)-3-piperidinopropyl] quinaldiamide, compound 10: N-[1-(4-methoxyphenyl)-3-piperidinopropyl] quinaldiamide,

Experimental results regarding the central muscle relaxant effect (i.e. the effect on the release of rigidity induced by ischemic decerebration) and toxicity of compounds of general formula I are presented below.

In the description of the experimental results, the following compounds are meant as control compounds:

control compound 1: N-(diethylaminoethyl)quinaldinamide fumarate and control compound 2: tolperisone hydrochloride (2,4'-dimethyl-3-piperidinopropiophenone hydrochloride used as a muscle relaxant)

Experiment 1: A remedy for stiffness caused by ischemic decerebration

The experiment was conducted on a case of rigidity caused by ischemic decerebration, which was induced in rats by the method of Fukuda H., Ito T., Hashimoto S. and Kudo Y., Japan. J. Pharmacol., 24, 810 (1974).

Male Wistar rats (body weight: 270 to 350 g) were placed in the supine position under ether anesthesia with an incision made in the neck. After exposing the trachea and common carotid arteries, a cannula was inserted into the trachea and both common carotid arteries and the esophagus were double ligated and transected. The occipital bone was then exposed and a circular hole was drilled in it to allow double ligation of the centrally located basilar artery. When the rats began to emerge from anesthesia, their forelimbs were stiff.

Measurements were made by recording the electromyographic response of the forelimb muscle (M. triceps brachii) of a rat in a rigid state. The amplitudes of the EMG curve were converted every 10 seconds into accumulated values and recorded on a recording device.

The effect of each test compound on stiffness was evaluated as a suppression ratio. This value was calculated by first determining the area (see attached drawing) of the reduced part of the EMG amplitude curve on the histogram after 10 minutes of administration of each of the test compounds (3 mg/kg), dissolved in physiological saline, to the femoral artery and then according to the following equation:

suppression ratio (%) = (a/A) x 100, where a denotes the area of the EMG waveform amplitudes decreased due to administration of the test compound and A denotes the area of the EMG waveform amplitudes recorded when no test compound was administered (control).

The results are shown in Table 1.

Table 1

Test compound Relaxation (%) Compound ^2X 24.6 Compound 4 ^XX 19.6 Compound ^5X 18.8 Compound 6 ^XX 12.2 Compound ^7X 11.2 Compound ^8X 11.7 Control compound 1 1.2 Control compound 2 4.8

Notes: Compounds 2, 4, 5, 6, 7 and 8 are the compounds identified above.

x indicates that the compound is in the fumarate form, and xx indicates that the compound is in the oxalate form.

As can be seen from the above results, the quinaldinamide derivative of general formula I, prepared by the method according to the invention, is very effective as a central muscle relaxant, i.e. it is very effective for relieving stiffness induced by ischemic decerebration.

Experiment 2: Acute toxicity

The LD50 was determined by a known method using male ddN mice. The test compound was dissolved in saline and the resulting solution was administered to the mouse via the tail vein.

The results of the experiment are shown in Table 2.

Table 2 (Acute toxicity value)

Test compound _LD50 (mg/kg) (iv) Compound ^2X 18.9 Compound 4 ^XX 17.2 Compound ^5X 24.8 Compound 6 ^XX .15.2 Compound ^7X 23.5 Compound ^8X 25.4

Notes: Compounds 2, 4, 5, 6 _{, 7} , and 8 are the compounds identified above.

"x" means that the compound is in the fumarate form, and "xx" means that the compound is in the oxalate form.

The above results demonstrate that quinaldinamide derivatives of general formula I are useful for treating a condition in which spastic paralysis and rigidity would occur, and are therefore useful for suppressing or relieving dyskinesia, athetosis, myoclonus, tics, tremor, dystonia and ballismus neuropathy.

The quinaldinamide derivative of general formula 1 can be administered orally or parenterally. Examples of the forms of preparations for oral administration include tablets, capsules, powder, granules and syrup. Examples of the forms of preparations for parenteral administration include an injection preparation.

For the processing of these preparations, known additives such as inert carriers, disaggregating agents, binders, lubricants, pigments and diluents can be used. Examples of inert carriers include dextrose and alactose. Examples of disaggregating agents include starch and carboxymethylcellulose.

F

Examples of lubricants include magnesium stearate and talc. Examples of binders include hydroxypropylcellulose, gelatin and polyvinylpyrrolidone.

For the injectable preparation, the dosage is usually 1 mg/day to 50 mg/day, and for oral administration, the dosage is approximately 10 mg/day to 500 mg/day. These values apply to adults. Depending on age and other conditions, the dosage can be either increased or decreased.

The present inventors have further found that the quinaldinamide derivative of general formula 1 exhibits a remarkable effect on blocking glutamic acid (or glutamate).

As is strongly stated in the literature, glutamic acid acts as an excitatory neurotransmitter in the central nervous systems of higher animals and at the neuromuscular junctions of lower animals. ^Glutamate as a Neuro-transmitter, edited by G. D.

Chiara adn G.L. Gessa: Raven Press, New York, 1981 and Η. M. Gerschenfeld: Physiol. Rev., _5_3, 1-119 (1973)J.

For this reason, the quinaldinamide derivative of the general formula I, which is capable of blocking glutamic acid, is useful in agriculture to reduce or weaken the action of insects and is a valuable insecticide.

Experiment 3: Effects on blocking glutamic acid and neuromuscular junctions in rats

The opening muscles of the first limbs of crayfish used for walking were used as experimental material. The neuromuscular sample was maintained in a bath through which a physiological solution of NaCl (195 mM), CaCl ₂ (18 mM), KCl (5.4 mM), trismaleate buffer (pH 7.5, 10 mM) and glucose (11 mM) was allowed to flow at a constant rate at room temperature. A glass microelectrode filled with 3M KCl solution was inserted into the middle part of the muscle fiber for intracellular recording of changes in the potential of the muscle cell membrane.

The blocking effect of each test compound on glutamic acid was evaluated as the -4 suppression ratio to the depolarization that was induced by the application of L-glutamic acid (10 M).

-4 , from the bath after a 5-minute pretreatment with a solution of the test compound (2 x 10 M). Results

i summarized in Table 3. bulk 3 Test compound Blocking acid glutamic (%) Compound 5 (according to the invention) 66 Control (N-(1-phenyl-3-piperidinopropyl)quinaldinamide) 30

The following text provides examples of the preparation of compounds of general formula I by the process according to the invention.

Example

Preparation of N-(1-phenyl-3-piperidinopropyl)quinaldinamide by a procedure starting from an acid halide

To a solution of 655 mg (3.0 mmol) of 1-(3-amino-3-phenylpropyl)piperidine and 334 mg (3.3 mmol) of triethylamine in 3 ml of dichloromethane was added dropwise a solution of 575 mg (3.0 mmol) of quinaldinoyl chloride in 6 ml of dichloromethane over 20 minutes under ice-cooling. After the addition was complete, the resulting solution was stirred at room temperature for 3 hours, and 30 ml of ether was added to the mixture. The reaction mixture was washed twice with water and then with saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The dried mixture was evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (silica gel: 6 g, CHCl3 and CHCl3/CH3OH (50:1 to 20:1)) to give 1.06 g (yield: 95% of theory) of N-(1-phenyl-3-piperidinopropyl)quinaldinamide as a light yellow crystalline product.

Melting point: 88 to 90 °C (70% ethanol) _lC y tartan' ¹ ): 3 230, 2 930, 2 850, 2 780, 1 665, 1 560, 1 510, 1 485, 1 445, 1 420, ^raax 1 155, 1 145, 1 115, 1 105, 845, 750, 695

I

CH.

•2

NMR(CDC1 ₃ )0 : 1.30-2.62 (14Η, m, (¾

5.20-5.54 (1H, m, CONHCH)

7.04-8.36 (11H, m, aromatic proton) 9.60 (1H, broad d, CONH)

Example 2

Preparation of N-(1-phenyl-3-piperidinopropyl)quinaldinamide by a condensation agent procedure

To a solution of 1.73 g (10 mmol) quinaldic acid and 1.53 g (10 mmol) 1-hydroxybenzotriazole monohydrate in 50 ml ethyl acetate was added dropwise a solution of 2.06 g (10 mmol) N,N^-dicyclohexylcarbodiimide in 10 ml ethyl acetate over 20 minutes under ice cooling.

After the addition was complete, the resulting mixture was stirred at room temperature for 2 hours under ice cooling. A solution of 2.18 g (10 mmol) of 1-(3-amino-3-phenylpropyl)piperidine in 8 ml of ethyl acetate was added dropwise to the cooled mixture over a period of 30 minutes. After the addition was complete, the mixture was stirred overnight at room temperature.

The precipitated insolubles were filtered off, and then the insolubles were washed with ethyl acetate. The filtrate and washings were combined and washed twice with a saturated aqueous sodium bicarbonate solution and once with a saturated aqueous sodium chloride solution.

The mixture was then dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue was allowed to crystallize after addition of n-hexane. The resulting crystals were washed three times with n-hexane and dissolved in 35 ml of ethyl acetate. The resulting solution was allowed to stand overnight in a refrigerator. The precipitated insolubles were filtered off and washed with ethyl acetate.

The filtrate and washings were combined and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 40 g, CHCl ₃ and CHCl 3 /CH 2 OH (30:1)) to obtain 3.07 g (yield: 82% of theory) of N-(1-phenyl-3-piperidinopropyl)quinaldinamide as a light yellow crystalline product.

Example 1 and 3 «

Preparation of N-(1-phenyl-3-piperidinopropyl)quinaldinamide by a condensation agent procedure

To a suspension of 866 mg (5.0 mmol) of quinaldic acid and 576 mg (5.0 mmol) of 1-hydroxysuccinimide in 20 ml of ethyl acetate was added dropwise a solution of 1.09 g (5.0 mmol) of N,N-dicyclohexylcarbodiimide over 5 to 10 minutes under ice-cooling. After the addition was complete, the mixture was stirred for 2 hours at room temperature. To this mixture was added dropwise a solution of 1.09 g (5.0 mmol) of 1-(3-amino-3-phenylpropyl)piperidine in 5 ml of ethyl acetate. After the addition was complete, the mixture was stirred at room temperature overnight. The precipitated insolubles were filtered off, and then the insolubles were washed with ethyl acetate. The filtrate and the washings were combined and washed twice with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. The mixture was then dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (silica gel: 20 g, CHCl ₃ and CHCl ₃ /CH ₃ OH (30:1)) to give 1.72 g of N-(1-phenyl-3-piperidinopropyl)quinoline diamide as a light yellow crystalline product.

Example4

Preparation of N-(1-phenyl-3-piperidinopropyl)quinaldinamide by a procedure starting from a mixed acid anhydride

A solution of 520 mg (3.0 mmol) of quinald.ic acid in dry tetrahydrofuran was cooled to -10 to -5 °C. To the cooled solution (below -5 °C) was added dropwise 326 mg (3.0 mmol) of ethyl chlorocarbonate. After 5 minutes, a solution of 655 mg (3.0 mmol) of

1-(3-amino-3-phenylpropyl)piperidine in 6 ml of dry dichloromethane. The mixture was stirred at 0 °C for 1 hour and then stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure. The residue was shaken vigorously with a mixture of dichloromethane and 5% aqueous sodium hydroxide solution and the organic layer was separated. The organic solution was washed successively with water and saturated aqueous sodium chloride solution and then dried over sodium sulfate. The thus dried solution was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (silica gel: 15 g, CHCl3 and CHCl3/CH2OH 30:1)) to obtain 1.10 g (yield: 98% of the title) of N-(1-phenyl-3-piperidinopropyl)quinaldinamine as a light yellow crystalline product.

Example 5

Preparation of N-(1-phenyl-3-piperidinopropyl)quinaldinamide fumarate

To a solution of 3.02 g (8.1 mmol) of N-(1-phenyl-3-piperidinopropyl)quinaldinamide in a mixture of 18 ml of ethanol and 8 ml of acetone was added a solution of 0.939 g (8.1 mmol) of fumaric acid in 20 ml of hot ethanol. The resulting mixture was mixed at room temperature and then cooled with ice. The precipitated crystals were filtered off and washed with acetone. The washed crystals were suspended in 60 ml of n-hexane and the suspension was heated under reflux for 1.5 hours. The crystals were filtered off, washed with n-hexane and dried. Thus, 3.10 g (yield: 78% of theory) of N-(1-phenyl-3-piperidinopropyl)quinaldinamide fumarate was obtained as a white crystalline product.

Melting point: 164 to 166 °C

ID J( ^KBr (cra ^-1 : 3,400, 3,250, 2,950, 2,870, 1,710, 1,670, 1,590, 1,515, 1,490, 1,445, max

420, 1,350, 1,300, 1,250, 1,190, 855, 780, 770, 700

NMR (CDC1 ₃ /CD ₃ OD = 6/1) 4 :

/” ^C —2

1.38-2.06(6H, ra, NCH,)

2.24-3.24 (811, m

CH _n

CH.

5.02-5.32(1H, ra, CONHCH)

6.77 (2H, s, CH=CH)

7.10-8.36(1111, m, aromatic proton)

Example 6

Preparation of N-(1-phenyl-3-pyrrolidinopropyl)quinaldinamide

613 mg (3.0 mmol) of 1-(3-amino-3-phenylpropyl)pyrrolidone and 575 mg (3.0 mmol) of quinaldinoyl chloride were used and the procedure was as in Example 1. 1.08 g/yield was thus obtained:

100% of theory/ N-(1-phenyl-3-pyrrolidinopropyl)quinaldinamide in the form of a light yellow crystalline product.

Melting point: 98 to 99.5 C (isopropyl alcohol)

KBr , -1. icy „ (cm ) : 3,240, 2,930, 2,790, 1,665, 1,555, 1,510 mass 1,160, 1,140, 845, 750, 700 CH.-CH. —2 -2 NMR(CDCl ₃ )J : 1.60-2.77{12H, m, _CH2CH2 - _N ^ 1 > ch ₂ ~ch ₂ 5.22-5.57(1H, m, CONHCH) 7.14-8.39(11H , m, aromatic proton) 9.55(1H, m, w wide d, CONH)

420, 1,205,

Example 7

Preparation of N-(1-phenyl-3-pyrrolidinopropyl)quinaldinamidoxalate

259 mg (0.72 mmol) of N-(1-phenyl-3-pyrrolidinopropyl)quinaldinamide and 91 mg of oxalic acid dihydrate were dissolved in ethanol. The resulting solution was evaporated under reduced pressure to remove the solvent. The residue was recrystallized from a mixture of acetone (6 ml) and diethyl ether (3 ml) to give 310 mg (yield: 96% of theory) of N-(1-phenyl-3-pyrrolidinopropyl)quinaldinamide oxalate as a white crystalline product.

melting point: 138 to 140 °C

IR> max ^{(cm )Σ 3 3θ0/ 3 300} ' ³ ° ⁴⁰ ' ^{1 725} ' ^{1 660} ' ^{1 560} ' ^{1 520} ' ^{1 490} ' ^{1 425} ' ^{1 210} '

840, 770, 695 • CH.

Γ --2

NMR (CDCl ₃ ) : 1.82-2.26 (4H, m, N | ) [-CH., /'

2.81-3.73(6H, m, C12-N2)

- CH.

5.00-5.39(1H, m, CONHCH)

7.11-8.38(11H, m, aromatic proton) 8.67(1H, broad d, CONH)

Example8

Preparation of N-p-(1-perhydroazepin-1-yl)-1-phenylpropylquinaldinamide

The procedure of Example 1 was repeated using 697 mg (3.0 mmol) of 1-(3-amino-3-phenylpropyl)perhydroazepine and 575 mg (3.0 mmol) of quinaldinoyl chloride, thereby obtaining 921 mg (yield 79% of theory) of N-p-(1-perhydroazepin-1-yl)-1-phenylpropyl]quinaldinamide in the form of a light yellow oily product.

JJV substance^ . . _{3 390} , _{3 300} , _{2 930) 2} 860, 2 820 , 1 670, 1 565, 1 515, 1 495, max ' -1

450, 1415, 1145, 845, 775, 750, 700 ch ₂ -ch ₂ ~ch ₂

NMR(CDCl ₃ ) cT: 1.30-2.84(16H, m, /ch ₂ CH ₂ -N | ) ^ch ₂ -ch ₂ -ch ₂

5.17-5.50(1H, m, CONHCH)

7.02-8.38(11H, m, aromatic ;-otone)

9.40(1H, broad d, CONH)

Example 9

Preparation of N-p-(1-perhydroazepin-1-yl)-1-phenylpropyl quinaldinamidoxalate

921 mg (2.38 mmol) of N-[3-(perhydroazepin-1-yl)-1-phenylpropyl]quinaldinamide and 300 mg (2.38 mmol) of oxalic acid dihydrate were dissolved in ethanol. The resulting solution was evaporated under reduced pressure to remove the solvent. The residue was recrystallized from a mixture of ethanol (10 ml) and n-hexane (10 ml) to obtain 920 mg (yield: 81% of theory)

N-[3-(1-perhydroazepin-1-yl)-1-phenylpropyl]quinaldinamidoxalate in the form of a white crystalline product.

Melting point: 149 to 151 °C

IR Pmax ^{(cra-1): 3} ' ⁴⁴⁰ ' ^{3 350} ' ^{2 940} ' ^{2 860} ' ^{1 72} °- ¹ 670, ^{1 630} ' ^{1 560} ' ^{1 52} °- ¹ 490,

450, 1420, 1400, 1180, 845, 770, 690 /~ch ₂ -ch ₂

NMR(CDCl ₃ ) δ: 1.44-2.05 (8H, m, N

2.30-2.70(2H, m, _CH2CH2 - _N )

2.90-3.46 (6H, m, CH-N).

from \

4.99-5.34(1H, m, CONHCH)

7.10-8.34(11H, m, aromatic proton) 8.7O(1H, broad d, CONH)

Example

Preparation of N-(3-diethylamino-1-phenylpropyl)quinaldinamide

The procedure of Example 1 was repeated using 618 mg (3.0 mmol) of N-(3-amino-3-phenylpropyl)-Ν,Ν-diethylamine and 575 mg (3.0 mmol) of quinaldinoyl chloride, thereby obtaining 1.08 g (yield: 100% of theory) of N-(3-diethylamino-1-phenylpropyl) quinaldinamide in the form of a light yellow oily product.

_Ich in substance, _{3,380 3,220 2,970 2,810} χ ₆₇₀₎ χ _{565 (} χ ₅₁₀ χ ₄₉₀ , _{x 425} , ' max

210, 1160, 1145, 1070, 845, 750, 695 nmr(cdci ₃ ) <fl.06(6H, t, J=7Hz, N(CH ₂ CH ₃ ) ₂ )

1.84-2.90 (8H, m, CH ₂ CH.,N (CH ₂ CH ₃ ) ₂

5.17-5.50(1H, m, CONHCH)

7.12-8.38(11H, m, aromatic proton)

Example

Preparation of N-(3-diethylamino-1-phenylpropyl)quinaldinamide fumarate

1.08 g (3.0 mmol) of N-(3-diethylamino-1-phenylpropyl)quinaldinamide and 313 mg (3.0 mmol) of fumaric acid were dissolved in ethanol with heating. The resulting solution was evaporated under reduced pressure to remove the solvent. The residue was recrystallized from 8 ml of ethanol to obtain 1.14 g (yield: 88% of theory) of N-(3-diethylamino-1-phenylpropyl)quinaldinamide fumarate as a white crystalline product.

Melting point: 160 to 161 °C ^{IR >} 'max ^(cm ” ^{1) : 3 28} °' ^{2 990} ' ^{2 950} ' ^{1 655} ' ^{1 560} ' ^{1 52} °- ^{1 495} ' ^{1 425} ' ^{1 210} ' ^{1 160} ' 980, 845, 775, 750, 695

NMR(CDC1 ₃ /CD ₃ OD = 6/1)/: 1.24(6H, t, J=7Hz, N(CH ₂ CH ₃ ) ₂ ) f

2.20-2.70 (2H, m, CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ 2.80-3.40(6H, m, CH ₂ N(CH ₂ CH ₃ ) ₂ 5.06-5.34(1H, m, CONHCH)

6.76 (2H, s, CH=CH)

7.20- 8.38 (11H, m, aromatic proton)

Example 12

Preparation of N-[1-(2-methylphenyl)-3-piperidinopropyl]quinaldinamide

The procedure of Example 4 was repeated using 465.g (2.0 mmol) of 1-p-amino-3-(2-methylphenyl-propyl)piperidine and 347 mg (2.0 mmol) of quinaldic acid, thereby obtaining 736 mg (yield: 95% of theory) of N-[1,(2-methylphenyl-3-piperidinopropyl]quinaldinamide as a light yellow oily product.

lC1' _and ® ^UbStanC1 (cm ^-1 ): 3 260, 2 930, 2 850, 2 800, 2 770, 1 665, 1 515, 1 495, 1 425, 1,160, 850, 755

NMR( _CDCl3 ) 1.28-1.88(6H, m.

1.88-2.60(811, m, C12CH2-1

2.49 (2H, s, CH,)

5.36-5.68(1H, m, CONHCH)

6.90-8.30(1 OH, m, aromatic proton) 9.48(1H, broad d, CONH) example 13

Preparation of N-1-(2-methylphenyl)-3-piperidinopropyl quinaldinamide fumarate

The procedure of Example 11 was repeated using 736 mg (1.9 mmol) of N-[1-(2-methylphenyl)-3-piperidinopropyl]quinaldinamide and 220 mg (1.9 mmol) of fumaric acid, thereby obtaining 708 mg (yield: 74% of theory) of N-[1-(2-methylphenyl)-3-piperidinopropyl]quinaldinamide fumarate.

ieyKBr _(cm 1 _{); 3 42θ} , _{3 320} , _{2 950( 3 670} , _{3 625} , _{3 510} , _{3 490} , _{3 440} , _{3 300} , _{3 280} ,

200, 770, 750

Z" ² ,

NMR (CDCl, /CD, OD = 2/1): 1, 4 2-2.04 (6H, m, N CH„),

J J K ✓ from

TARGET·

2.20-2.68(2H, m, CH ₂ CH ₂ -N ?)

2.45 (3H, s, CH)

2.88-3.26 (6Η, m, CH,-N·.>) ^ch ₂ 5.24-5.56(1H, m, CONHCH)

6.75 (2H, s, CH=CH)

7.04-8.40(10H, m, aromatic proton)

Example 14

Preparation of N-p-(3-methylphenyl)-3-piperidinopropylquinaldinamide

The procedure of Example 1 was repeated using 697 mg (3.0 mmol) of 1-p-amino-3-(3-methylphenyl)propyl]piperidine and 575 mg (3.0 mmol) of quinaldinoyl chloride, thereby obtaining 755 mg (yield: 65% of theory) of N-[1-(3-methylphenyl-3-piperinopropyl]quinaldinamide as a light yellow solid.

ID P

KBr max , “li (cm )

250, 2,930, 2,850, 2,790, 1,665, 1,560, 1,510, 1,490, 1,420, 1,160, 1,125, 845, 790, 750, 710 ·

NMR(CDCl ₃ ) i" :

1.35-2.60(17H, m, CH,CH,-N' _C h ₃ )

5.17-5.48(1H, m, CONHCH)

6.90-8.35(10H, ra, aromatic proton) 9.50(1H, broad d, CONH)

Example 15

Preparation of N- [1-(3-methylphenyl)-3-piperidinopropyl] quinaldinamide fumarate

The procedure of Example 11 was repeated using 678 mg (1.75 mmol) of N-[1-(3-methylphenyl)-3-piperidinopropyl] quinaldinamide and 203 mg (1.75 mmol) of fumaric acid, thereby obtaining 620 mg (yield: 70% of theory) of N-[1-(3-methylphenyl)-3-piperidinopropyl] quinaldinamide furamarate as a white crystalline product.

Melting point: 143 to 145 °C

IR ^KBr (cm ^-1 ): 3,460, 3,340, 3,020, 2,950, 2,860, 1,670, 1,560, 1,520, 1,490, 1,420, ' max

290, 1,165, 980, 840, 770, 700

NMR(CDCl ₃ /CD ₃ OD = 6/1)/ : 1.40-2.00 (6H, m,

2.20-2.65(5H, m,

2.80-3.20 (6H, m,

5.00-5.27(1H, m,

CONHCH)

6.76 (2H, s, CH=CH)

6.94-8.37(10H, m, aromatic proton)

Example 16

Preparation of N-[1-(4-methylphenyl)-3-piperidinopropyl]quinaldinamide

The procedure of Example 1 was repeated using 697 mg (3.0 mmol) of 1-[3-amino-3-(4-methylphenyl)propyl]piperidine and 575 mg (3.0 mmol) of quinaldinoyl chloride, thereby obtaining 1.09 g (yield: 94% of theory) of N-[1-(4-methylphenyl)-3-piperidinopropyl]quinaldinamide as a light yellow oily product.

_c subst.j -1 _{): 3 3go 3 280} roax

160, 1,125,

NMR(CDCl ₃ ) / : 1.35-2.60 (17H, m,

940, 2,870, 2,810, 1,670, 1,565, 1,510, 1,490, 1,425, 850, 815, 795, 760 —2\ ch _o ch _o -nc;

_{CH2 -} ^CH2

CH

2'

5.16-5.45(1H, m, CONHCH)

6.95-8.34(10H, m, aromatic proton)

9.50 (10H, wide d, CONH)

Example 17

Preparation of N-[1-(4-methylphenyl)-3-piperidinopropyl]quinaldinamidoxalate

The procedure of Example 7 was repeated using 917 mg (2.36 mmol) of N-[1-(4-methylphenyl)-3-piperidinopropyl]quinaldinamide and 298 mg (2.36 mmol) of oxalic acid dihydrate, thereby obtaining 901 mg (yield: 80% of theory) of N-[1-(4-methylphenyl-3-piperidinopropyl]quinaldinamide oxalate as a white crystalline product after recrystallization from 8 ml of ethanol.

Melting point: 165 to 167 C (decomposition)

ID ))™^(cra ^-1 ) : 3 440, 3 370, 3 010, 2 940, 2 860, 1 720, 1 680, 1 560, 1 510, 1 490 ,

NMR (CDCl ₃ /CD ₃ OD = 6/1) (T: 1.40-2.05 ( 6H, m,

420, 1200, 1155, 835, 800, 790, 765 /— CH N

2\

CH ₀

FROM

2.24-2.66(5H, m, _CH2CH2 - _N )

2.70-3.40(6H, m, CH,-N\

5.00-5.27 (1H, m, CONHCH)

7.05-8.38 (1.0H, m, aromatic proton)

Example 18

Preparation of N™ Jl-(4-methoxyphenyl)-3-piperidinopropyl ·,' quinaldinamide

The procedure of Example 1 was repeated using 745 mg (3.0 mmol) of 1-[3-amino-3-(4-methoxyphenyl)propyl]piperidine and 575 mg (3.0 mmol) of quinaldinoyl chloride to give 1.03 g (yield: 85% of theory) of N-[1-(4-methoxyphenyl)-3-piperidinopropyl]quinaldinamide as a light yellow oily product.

Icl> ^{in substance} (cm ^-1 ): 3,380, 3,260, 3,000, 2,930, 2,850, 2,820, 2,800, 2,760, 1,665, IttclX

610, 1,560, 1,510, 1,490, 1,420, 1,245, 1,175, 1,155, 1,120,

030, 840, 820, 790, 750

CH ₀ -CH. z* “2 —2 \

NMR(CDC1 ₃ ) d: 1.34-2.60(14H, m, CH ₂ CH ₂ -N CH,, ^2 ^- ¾^

3.75 (3H, s, OCH ₃ )

5.18-5.46(1H, m, CONHCH)

6.72-8.34 (10H, m, aromatic proton)

9.50(10H, wide d, CONH)

Example 19

Preparation of N-[1-(4-methoxyphenyl)-3-piperidinopropyl]quinaldinamidoxalate

The procedure of Example 7 was repeated using 1.03 g (2.56 mmol) of N-[1-(4-methoxyphenyl)-3-piperidinopropyl]quinaldinamide and 323 mg (2.56 mmol) of oxalic acid dihydrate, thereby obtaining 884 mg (yield 70% of theory) of N-[1-(4-methoxyphenyl)-3-piperidinopropyl]quinaldinamide oxalate as a white powder product after recrystallization from 8 ml of ethanol.

IC>

KBr max . -li (cm )

NMR(CDCl ₃ ) χf :

440, 3 370, 2 1 245, 1 180, 1

1.38-2.16(6H, m,

940, 1,720, 1,660, 1,610, 1,560, 1,510, 1,490, 030, 845, 825, 775

420,

CH.

2.16-3.85(11H, m, CH ₂ CH ₂ -N och ₃ )

4.92-5.26(1H, m, CONHCH)

6.68-8.26 (10H, m, aromatic proton)

8.50 (1H, broad d, CONH)

Example

Reference

Preparation of beta-piperidinopropiophenone hydrochloride

A mixture of 120 mg of acetophenone, 133 g of piperidine hydrochloride and 50 g of paraformaldehyde in 120 ml of ethanol was heated under reflux for 6 hours. The resulting solid was triturated with 400 ml of acetone and then filtered off. The filtered solid was washed successively with acetone and hexane and dried. 191.6 g (yield: 75.4% of theory) of beta-piperidinopropiophenone hydrochloride was obtained as a white flaky product.

In the same manner as above, the following compounds were obtained.

melting point ,160 to 162 °C melting point

160 to 161.5°C

X = H, z = N(C ₂ H ₅ ) ₂ melting point up to 93 °C

1'

X = O“CH ₃

FROM

melting point

170 to 172°C

S = m-CH ₃ melting point 154 to

X ~ p-CH ₃

X = p-OCH ₃ ,

melting point 173 to temperature

Example

Reference

155°C

175 °C melting 205 to 207 °C decomposition)

Preparation of beta-piperidinopropiophenone oxime

60.2 g of beta-piperidinopropiophenone hydrochloride and 18.1 g of hydroxylamine hydrochloride were dissolved in 470 ml of water. To this solution was added 21.9 g of sodium bicarbonate in portions. After the entire amount was added, the mixture was stirred overnight. An aqueous solution of 14.2 g of sodium hydroxide in 47 ml of water was then added to the mixture while stirring.

The mixture thus obtained was thoroughly stirred and allowed to stand for 2 hours to separate a white precipitate. The precipitate was filtered off and washed successively with two 200 ml portions of water and ethanol. The precipitate was dried to give a white solid. This solid was then recrystallized from methanol to give 41.2 g (yield: 74.8% of theory) of beta-piperidinopropiophenone as a gray-white flaky product.

In the same manner as described above, the following compounds were obtained:

Olympic Games

X = H, =o: melting point 150.5 to 151.5 C

,.Q melting point 154 to 156 °C

X = H, Z = nJ : melting point 141 to 142 °C X = H, z = N(C ₂ H ₅ ) ₂ : melting point 93.5 to 94.5 °C X = p-CH ₃ , ^! 'Oh : melting point 89 to 90.5 °C X = m-CH ₃ , z. O : melting point 127 to 129 °C X “ p-CH ₃ , -O : melting point 175 to 178 °C X = p-OCH ₃ , -o : melting point 132 to 134 °C

Example 3 Reference

Preparation of 1-(3-amino-3-phenylpropyl)piperidinedioxalate

To a solution of 23.2 g of beta-piperidinopropiophenone oxime in 200 ml of formic acid, 19.6 g of zinc dust were added portionwise while stirring, the resulting mixture evolved heat, thereby increasing its temperature. When the temperature of the mixture reached -65 °C, the addition of zinc dust was discontinued. Then, the addition of zinc dust was continued with breaks to maintain the temperature of the mixture in the range of 60 to 65 °C. When it was found that the addition of zinc dust no longer caused the evolution of heat, the entire remaining portion of zinc dust was added at once to the reaction mixture. The mixture was then stirred for another 2 hours. Insoluble substances were filtered off and washed with 100 ml of formic acid. The filtrate and washings were combined and evaporated under reduced pressure. ,

200 ml of water was added to the residue. The resulting aqueous solution was adjusted to pH 8 by adding aqueous sodium hydroxide solution and washed with chloroform. The aqueous solution was then adjusted to pH 11 by adding aqueous sodium hydroxide solution and extracted with chloroform. The extract was dried over sodium sulfate. The dried extract was evaporated under reduced pressure to remove the solvent. This gave the crude base of the product being prepared.

The crude product was dissolved in 200 ml of ethanol and a solution of 25.2 g of oxalic acid dihydrate in 200 ml of ethanol was added to this solution. The mixture was allowed to stand to precipitate white crystals.

The crystals were filtered off, washed with ethanol and dried, thereby obtaining 27.9 g (yield; 70% of theory) of 1-(3-amino-3-phenylpropyl)piperidinedioxalate.

by the method described above, the following compounds were obtained:

The same

melting point 190 to 191 °C (decomposition) melting point

178 to 180 °C (decomposition) melting point 182 to 184 °C (decomposition)

X = Η, Z = N(C ₂ H ₅ ) ₂ melting point 119 to 121 °C melting point 178 to 180 °C

X = p-CtL· melting point 128 to 130 °C

Dioxalates can be converted to free acids by the action of an aqueous alkaline solution.

Example 20

Preparation in the form of pellets

Pellets were prepared (20 mg each) contains who: quinaldine compounds (active ingredients) 50 mg lactose 103 mg starch 50 mg magnesium stearate 2 mg hydroxypropylcellulose 15 mg

Example 21

Capsule preparation

Hard gelatin-shelled capsules were prepared containing 350 mg of a filling consisting of

quinaldine compounds (active ingredients) 40 mg lactose 200 mg starch 70 mg polyvinylpyrrolidone 5 mg crystalline cellulose 35 mg

Example 22

Preparation in the form

One gram granules were prepared containing:

quinaldine compounds (active ingredients) 200 mg lactose 450 mg cornstarch 300 mg hydroxypropylcellulose 50 mg

Claims (2)

A process for the preparation of a quinaldinamide derivative of the formula I SUBJECT OF THE INVENTION (I) Wherein R and R are independently C 1 -C 6 alkyl or R and R are taken together with the adjacent nitrogen atom to form a 5-7 membered ring and X is hydrogen, C 1 -C 6 alkyl or alkoxy having 1 to 6 carbon atoms, and addition salts thereof with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, methanesulfonic acid or p-toluenesulfonic acid, characterized by by reacting the quinaldic acid of formula II COOH (II) or a reactive derivative thereof selected from the group consisting of quinaldic acid halide, mixed quinaldic anhydride and monoalkylcarboxylic acid, quinaldic anhydride and quinaldic acid p-nitrp.phenyl ester with a compound of formula III to R, R and X are as defined above, and the compound of formula I is optionally converted to the above salt. 2. A process according to claim 1, wherein the reaction between the quinaldinic acid of the formula II and the compound of the formula III is carried out in the presence of a condensing agent selected from the group consisting of Ν, Ν'-dicyclohexylcarbodiimide. with N-hydroxysuccinimide and a combination of N, N- ^A dicyclohexylcarbodiimide with 1-hydroxybenzotriazole.