CA1306252C - Quinaldinamide derivatives and their preparations - Google Patents

Abstract

NOVEL QUINALDINAMIDE DERIVATIVES AND THEIR PREPARATIONS

ABSTRACT OF THE DISCLOSURE

A novel quinaldinamide derivative having the formula:

wherein each of R1 and R2 independently represents a lower alkyl group or R1 and R2 are combined together with the adjacent nitrogen atom to form a 5 - 7 membered ring;
and X represents the hydrogen atom, a lower alkyl group or a lower alkoxy group, and its acid-addition salt, which is prepared by a condensation reaction between quinaldinine or a quinaldinine derivative and a pertinent amine compound. This quinaldinamide derivative shows prominent central muscle relaxant effect, namely, rigidi-ty relieving effect on anemic decerebrated rigidity.

Description

` 1306X5'~

NOVEL QUINALDINAMIDE DERIVATIVES AND THEIR PREPARATIONS

BACKGROUND OF THE INVENTION

Field of the invention The present invention relates to a novel quinaldin-5 amide derivative and a process for the preparation of thesame.

Descri tion of rior arts P P

As a quinaldinamide derivative, N-(2-diethylamino-ethyl)quinaldinamide is described in Ger. Offen. No.
10 2,099,894; M. Giannini, P. Boni, M. Fedi, G. Bonacchi, Farmaco, Ed. Sci., 28, 429-47(1973); and P. Boni, C.
Bacciarelli, Farmaco, Ed. Sci., 29, 923-35(1974). These publications are silent with respect to rigidity reliev-ing effect of the described quinaldinamide compound. It 15 has been experimentally confirmed by the present inven-tors that this quinaldinamide derivative shows very weak rigidity relieving effect.
' SUMMARY OF THE INVENTION

It is an object of the present invention to provide 20 a novel quinaldinamide derivative showing a marked cen-tral muscle relaxant effect, namely, marked regidity relieving effect on anemic decerebrated rigidity.
It is another object of the invention to provide a novel quinaldinamide derivative of value as a pharmaceu-25 tical.
It is a further object of the invention to provide a .
i novel quinaldinamide derivative of value as an insecti-cide.
It is a further object of the invention to provide a process for the preparation of the novel quinaldinamide 5 derivative.
There is provided by the present invention a quinal-dinamide derivative having the formula (I):

~ /l ~ CO~H ~ `N \Rl (I) wherein each of Rl and R2 independently represents a lower alkyl group containing, for instance, 1 - 6 carbon atoms, or Rl and R2 are combined together with the adja-15 cent nitrogen atom to form a 5 - 7 membered ring; and X represents the hydrogen atom, a lower alkyl group containing, for instance, 1 - 6 carbon atoms or a lower alkoxy group containing, for instance, 1 - 6 carbon atoms, and its acid-addition salt.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 shows a figure to be employed for calculation o~ rigidity relieving effect of the compounds.

DETAILED DESCRIPTION OF THE INVENTION

The quinaldinamide derivative of the formula (I) shows a prominent central muscle relaxant effect, namely, marked rigidity relieving effect on anemic decerebrated rigidity.

, ' The quinaldinamide derivative of the formula (I) according to the present invention can be prepared by a reaction between quinaldinic acid of the formula (II):

~ ~ ~ COOH (II) or its reactive derivative and a compound of the formula (III):
~X

I Rl (III) whereln Rl, R2 and X have the samç meanings as men-tioned above.
Examples of the reactive derivatives of the quinal-15 dinic acids include acid halides such as acid chloride and acid bromide, mixed acid anhydrides such as that de-rived from a combination of quinaldinic acid and mono-alkylcarbonic acid, acid anhydrides of quinaldinic acid, : and active esters such as p-nitrophenylester of quinal-: 20 dinic acid.
Accordingly, the quinaldinamide derivative of the formula (I) can be prepared by any one of known processes for the formation of an amide-bonding through condensa-tion reaction, for instance:
(1) an acid halide process using a quinaldinoyl halide such as quinaldinoyl chloride or quinaldinoyl bromide;
(2) a process of causing reaction of the starting compounds in the presence of a condensation agent such as ~;~06252 N,N'-dicyclohexylcarbodiimide, a combination of N,N'-dicyclohexylcarbodiimide and N-hydroxysuccinimide or a combination of N,N'-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole;

(3) a mixed acid anhydride process using, for sxam-ple, an acid anhydride derived from a combination of quinaldinic acid and monoalkylcarbonic acid;

(4) an acid anhydride process using, for example, acid anhydride of quinaldinic acid;

(5) an active ester process using, for example, p-nitrophenylester of quinaldinic acid; and (6) a process of heating the starting compounds in the absence of a condensation agent.
The reaction between quinaldinic acid or quinal-15 dinoy' halide and a compound of the formula (II) can be performed according to the following reaction equation:
~X

~COY + H2N/~N
~R2 (II) ~ CONH ~ N
\R2 (I) wherein Y represents a halogen atom or a hydroxyl ., ~, .

--` 1306252 group, and Rl, R2 and X have the same meanings as men-tioned above.
The reactions can be performed with no solvent or in an organic solvent being inert to the reactions, such as 5 methylene chloride, chloroform, ether, tetrahydrofuran, benzene, or ethyl acetate.
The quinaldinamide derivative obtained in the above reactions can be converted to an acid-addition salt (i.e.
salt with an acid) by a known method. Examples of the 10 acids employable for the formation of the acid-addition salt include hydrochloric acid, hydrobromic acid, sulfur-ic acid, phosphoric acid, citric acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, methanesulfonic acid and p-toluenesulfonic acid.
The starting compound of the formula (II) can be prepared, for instance, by the process according to the following equation:

O O
zo ~ (IICUO)A ~A N~ HCI

HN ~HCQ X
X \R

NH20H-HCI ~ /~1 ~ed. i (II) Representative examples of the compounds of the for-mula (I) according to the invention include:

Compound 1: N-(3-dimethylamino-1-phenylpropyl)-quinaldinamide;
Compound 2: N-(3-diethylamino-1-phenylpropyl)-quinaldinamide;
Compound 3: N-(l-phenyl-3-dipropylaminopropyl)-quinaldinamide;
Compound 4: N-(l-phenyl-3-pyrrolidinopropyl)-quinaldinamide;
Compound 5: N-(l-phenyl-3-piperidinopropyl)-quinaldinamide;
Compound 6: N-~3-(perhydroazepin-1-yl)-1-phenyl-propyl~quinaldinamide;
- Compound 7: N-~1-(2-methylphenyl)-3-piperidino-propyl~quinaldinamide;
Compound 8: N-~1-(3-methylphenyl)-3-piperidino-propyl]quinaldinamide;
Compound 9: N-~1-(4~methylphenyl)-3-piperidino-propyl]quinaldinamide; and Compound 10: N-~1-(4-methoxyphenyl)-3-piperidino-propyl]quinaldinamide.
Experimental results of the central muscle relaxant effect (i.e., rigidity relieving ef~ect on anemic decere-- brated rigidity) and toxicity of the compounds of the formula (I) according to the invention are given below.
In the description of the experimental results, control compounds are as follows:
Control Compound 1: N-(2-diethylaminoethyl)quinal-dinamide fumarate; and Control Compound 2: tolperisone hydrochloride (2,4'-dimethyl-3-piperidinopro-piophenone hydrochloride, known ~; muscle relaxant) :
;

--`` 1306252 Experiment 1: Effect on Anemic Decerebrated Rigidity .
The experiment was performed using specimen of anemic decerebrated rigidity produced in rats according to the method of Fukuda, H., Ito, T., Hashimoto, S., and 5 Kudo, Y.; Japan. J. Pharmacol., 24, 810(1974).
Wister male rats (body weight: 270 to 350 g) were held on their backs and incised at their cervices under etherization. After the trachea and common carotid arteries were exposesd, the trachea was cannulated and 10 the bilateral common carotid arteri_s and esophagus were then double-litigated and cut. Subsequently, its occipi-tal bone was exposed through which a circular hole was bored to double-ligate the centrally extending basilar artery. As each rat started coming out of anesthetiza-15 tion, its front limbs became rigid.
Measurement was conducted by recording electromyo-graphlc (EMG) response from the muscle of the forelimb (M. triceps brachii) of the rat in the rigid state. The EMG pulses were converted to accumlated values every 10 20 seconds and recorded as a histogram on a recorder.
The effect of each test compound on the rigidity was evaluated in terms of the suppression rate. This rate was calculated first by determining the area (see Fig. 1) of a decreased EMG pulse part on the histrograpm upon pas-25 sage of 10 minutes after administration of a physicologi-cal saline solution of each test compound (3 mg/kg) through the femoral vein and then in accordance with the following equation:

; Suppression rate (%) = (a/A) x 100 whereln a means an EMG pulse area decreased as a result of the administration of the test compound; and A
means an EMG pulse area observed when no test compound : ' :

1306~S2 was administered (control).

The results are set forth in Table 1.

Table 1 Test Compound Relieving Rate (%) Compound 2* 24.6 Compound 4** 19.6 Compound 5* 18.8 Compound 6** 12.2 Compound 7* 11.2 Compound 8* 11.7 Control Compound 1 1.2 Control Compound 2 4.8 . .
Remarks. Compounds 2, 4, 5, 6, 7 and 8 are those identified hereinbefore.
"*" means that the compound is in the form of fumarate, and "**" means that the ~; compound is in the form of oxalate.

; Experiment 2: Accute Toxicity LD50 was determined by a known up-and-down method 20 using ddN male mouse. The test compound was dissolved in a physioIogical saline solution, and the resulting solu-tion was administered into the mouse through the tail vein.
The results are set forth in Table 2.

,- . . , - .

~ ~306252 g Table 2 (Accute Toxicity Value) Test Compound~D50 (mg/kg) tiV) .

Compound 2* 18.9 Compound 4** 17.2 5 Compound 5~ 24.8 Compound 6** 15.2 Compound 7* 23.5 Compound 8* 25.4 Remarks: Compounds 2, 4, 5, 6, 7 and 8 are those identified hereinbefore.
"~" means that the compound is in the form of fumarate, and "~*" means that the compound is in the form of oxalate.

The results given above indicate that the quinaldin-15 amide derivative of the formula (I) are useful for the therapy of a complaint which would have spastic paralysis ~ and rigidity and accordingly are useful for suppressing i-~ - or releasing dyskinasis, athetosis, myoclonus, tic, tre-~ mors, dystonia and ballismus of neuropathy.
" ~
~ 20 The quinaldinamide derivative of the ~ormula (I) ~ ~ :
according to the invention can be administered orally or parenterally, Examples of the preparation forms for oral administratiorl include tablets, capsules, powder, gra-nules and syrup. Examples of the preparation forms for 25 parenteral administration include an injectable prepara-tion. Fo~ the formulation of the preparations, known additlves such as excipients, disintegrants, binders, lublicants, pigments and diluents like can be employed.
' :

130625~:

Examples of the excipients include dextrose and lactose.
Examples of the disintegrants include starch and carboxy-methylcellulose. Examples of the lubricants include mag- -nesium stearate and talc. Examples of the binders 5 include hydroxypropylcellulose, gelatin and polyvinyl-pyrrolidone.
The dose generally is from about 1 mg/day to about 50 mg/day in the case of an injectable preparation and from about 10 mg/day to about 500 mg/day in the case of 10 oral administration, both ~or an adult. The dose may be either increased or decreased depending on the age and other conditions.
It has been further observed by the present inven-tors that the quinaldinamide derivative of the formula 15 (I) shows prominent glutamic acid(or glutamate)-blocking effect. As has been strongly suggested in the prior art, glutamic acid acts as an excitatory neurotransmitter at the central nervous systems of higher animals and at the neuromuscular ~unctions of lower animals ~Glutamate as a 20 Neuro-transmitterll edited by G.D. Chiara & G.L. Gessa:
Raven Press, New York, 1981 and H.M. Gerschenfeld:
Physiol. ~ev., 53, 1-119(1973)].
Therefore, the quinaldinamide derivative of the for-mula (I) capable of blocking glutamic acid is effective 25 in agricultural use to reduce and weaken activities of insects, and is of value as an insecticide.
~,:
Experiment 3: Blocking Effects on Glutamic Acid at Neuromuscular Junctions of Crayfish The method of Ishida et al. ~(J. Physiol., 298, 30 301-319 (1980)] and that of Shinoza~i et al. ~Comp. Bio-chem. Physiol., 70c, 49-58(1981)] were followed. The opener muscles of the first walking legs of crayfish were used as experimental materials. The neuromuscular sample was held in a bath in which a physiological solution ~NaCl(195 mM), CaCl2(18 mM), KC1(5.4 mM), tris-maleate buffer(pH 7.5, 10 mM), and glucose(11 mM)~ for use with the cray fish was perfused at room temperature and at a 5 constant flow rate. A glass micro-electrode filled with a 3M-KCl solution was inserted in a central part of the muscle fiber to intracellularly record the changes in the potential of the muscular cell membrane.
The blocking effect of each test compound on glu-10 tamic acid was evaluated in terms of the suppression rate to depolarization which was induced by bath-applying L-glutamic acid (10 4 M) in a 5-minute pretreatment with a solution of the test compound (2 x 10 4 M). The results are shown in Table 3.

Table 3 Test Compound Glutamic Acid-Blocking ~ate (%) Compound 5 (of the invention) 66 Control (N-(1-phenyl-3-piperidino- 30 ; 20 propyl)quinaldinamide) -~ Examples of the preparations of compounds according to the present invention are given below.

Example 1: Preparation of N-(1-phenyl-3-piperidinoprO-pyl)quinaldinamide by acid halide process To a solution of 655 mg (3.0 mmol.) of 1-(3-amino-3-phenylpropyl)piperidine and 334 mg (3.3 mmol.) of tri-ethyamine in 3 ml of dichloromethane was dropwise added .

-` 13062S2 over a period of 20 min. under chilling with ice a solu-tion of 575 mg (3.0 mmol.) of quinaldinoyl chloride in 6 ml of dichloromethane. After the addition was complete, the resulting mixture was stirred for 3 hours at room 5 temperature, and to the mixture was added 30 ml of ether.
The reaction mixture was washed twice with water and sub-sequently with a saturated aqueous sodium chloride solu-tion and then dried over sodium sulfate. Thus dried mix-ture was evaporated under reduced pressure to remove the 10 solvent. The residue was purified by silica gel column chromatography (silica gel: 6 g, CHCl3 and CHCl3/CH30H
(50:1 - 20:1)) to obtain 1.06 g (yield: 95 %) of the sub-ject compound as a pale yellow crystalline product.
M .p.: 88-90C (70 % ethanol) IR ~mBarX(cm 1): 3230, 2930, 2850, 2780, 1665, 1560, 1510, 1485, 1445, 1420, 1155, 1145, 1115, 1105, 845, 750, 695 NMR(CDC13) ~: CH2-CH2~
1.30-2.62(14H, m, CH2CH2-N CH2) 5.20-5.54(1H, m, CONHCH) 7.04-8.36(1lH, m, aromatic proton) 9.60(1H, broad d, CONH) Example 2: Preparation of N-(1-phenyl-3-piperidinopro-pyl)quinaldinamide using condensation agent To a solution of 1.73 g (10 mmol.) of quinaldinic acid and 1.53 g (10 mmol.) of 1-hydroxybenzotriazole monohydrate in 50 ml of ethyl acetate was dropwise added over a period of 20 min. under chilling with ice a solu-30 tion of 2.06 g (10 mmol.) of N,N'-dicyclohexylcarbodi-imide in 10 ml of ethyl acetate. After the addition was complete, the resulting mixture was stirred for 2 hours at room temperature and chilled with ice. To the chilled mixture was dropwise added over a period of 30 min. a solution of 2.18 g (10 mmol.) of î-(3-amino-3-phenylpro-pyl)piperidine in 8 ml of ethyl acetate. After the addi-tion was complete, the mixture was stirred overnight at room temperature. Precipitated insolubles were filtered 5 off and then the insolubles were washed with ethyl ace-tate. The filtrate and the washings were combined and washed twice with a saturated aqueous sodium hydrogencar-bonate solution and once with a saturated aqueous sodium chloride solution. The mixture was then dried over sodi-1~ um sulfate, and was evaporated under reduced pressure toremove the solvent. The residue was crystallized 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 15 overnight in a refrigerator. Precipitated insolubles were filtered off and the insolubles were washed with ethyl acetate. The flltrate and the washings wère com-bined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography 20 (silica gel: 40 g, CHC13 and CHC13/CH30H (30:1)) to obtain 3.07 g (yield: 82 %) of the subject compound as a pale yellow crystalline product.

Example 3: Preparation of N-(l-phenyl-3-piperidinopro-pyl)~uinaldinamide using condensation agent To a suspension of 866 mg (5.0 mmol.) of quinaldinic acid and 576 mg (5.0 mmol.) of l-hydroxysuccinimide in 20 ml of ethyl acetate was dropwise added over a period of 5-10 min. under chilling with ice a solution of 1.09 g (5.0 mmol.) of N,N'-dicyclohexylcarbodiimide. After the 30 addition was complete, the mixture was stirred for 2 - hours at room temperature. To this mixture was dropwise added 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 over-night at room temperature. Precipitated insolubles were filtered off and then the insolubles were washed with ethyl acetate. The filtrate and the washings were com-bined and washed twice with a saturated aqueous sodium 5 hydrogencarbonate solution and once with a saturated aqueous sodium chloride solution. The mixture was then dried over sodium sulfate, and was evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (silica gel:
10 20 g, CHCl3 and CHCl3/CH30H (30:1)) to obtain 1.72 g (yield: 92 %) of the subject compound as a pale yellow crystalline product.

Example 4: Preparation of N-(1-phenyl-3-piperidinopro-pyl)quinaldinamide by mixed acid anhydride process A solution of 520 mg (3.0 mmol.) of quinaldinic acid and 304 mg (3.0 mmol.) in dry tetra~nydrofuran was chilled to -10 - -5C. To the chilled solution (lower than -5C) was dropwise added 326 mg (3.0 mmol.) of ethyl chlorocar-20 bonate. After 5 min., to the resulting mixture was drop-wise added a solution of 655 mg (3.0 mmol.) of 1-(3-amino-3-phenylpropyl)piperidine in 6 ml of dry dichloro-methane. The mixture was stirred at 0C for 1 hour and then stirred overnight at room temperature. The reaction 25 mixture was concentrated under reduced pressure. The residue was violently shaken with a mixture of dichloro-methane and 5 % aqueous sodium hydroxide solution, and the organic layer was separated. The organic solution was washed successively with water and a saturated aque-30 ous sodium chloride solution and then dried over sodiumsulfate. Thus dried solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 15 g, CHC13 and CHC13/CH30H (30:1)) to obtain 1.10 g (yield: 98 %) of the ~30625~

subject compound as a pale yellow crystalline product.

Example 5: Preparation of N-(1-Phenyl-3-piperidinopro pyl)quinaldinamide fumarate To a solution of 3.02 g (8.1 mmol.) of N-(1-phenyl-5 3-piperidinopropyl)quinaldinamide in a mixture of 18 ml of ethanol and 8 ml of acetone was added a solution o~-0.939 g (8.1 mmol.) of fumaric acid in 20 ml of hot ethanol. The resulting mixture was stirred at room temperature and subsequently under chilling with ice.
10 Precipitated crystals were collected by filtration and washed with acetone. The washed crystals were suspended in 60 ml of n-hexane and the suspension was refluxed for 1.5 hours. The crystals were collected by ~iltration, washed with n-hexane and dried. Thus, 3.10 g (yield: 78 15 %) of the subject compound was obtained as a white crys-talline product, M.p.: 164-166C
IR~KmBarx(cm 1): 3400, 3250, 2950, 2870, 1710, 1670, 1590, 1515, 1490, 1445, 1420, 1350, 1300, 1250, 1190, 855, 780, 770, 700 NMR(CDC13/CD30D = 6/1) ~: r CH2 1.38-2.06(6H, m, N CH2) \--CH2 ,CH2~
2.24-3.24(8H, m, CH2CH2N / ) 5.02-5.32(1H, m, CONHCH) 6.77 (2H, s, CH=CH) 7.10-8.36(11H, m, aromatic proton) 30 Example 6: Preparation o~ N-(1-phenyl-3-pyrrolidinopro pyl)quinaldinamide The procedure o~ Example 1 was repeated using 613 mg ; (3.0 mmol.) of 1-(3-amino-3-phenylpropyl)pyrrolidine and 130625;~

575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 1.08 g (yield: 100 %) of the subject compound as a pale yellow crylstalline product.
M.p.: 98-99.5C (isopropyl alcohol) IR~KBr(cm 1): 3240, 2930, 2790, 1665, 1555, 1510, max 1485, 1450, 1420, 1205, 1160, 1140, 845, 750, 700 NMR(CDCl3) ~: CH2-CH2 1.60-2.77(12H, m, CH2CH2-N ¦ ) 5.22-5.57(lH, m, CONHCH) 7.14-8.39(1lH, m, aromatic proton) 9.55(1H, broad d, CONH) Example 7: Preparation of N-(1-phenyl-3-pyrrolidinopro-pyl)quinaldinamide oxalate In ethanol were dlsso~ved 259 mg (0.72 mmol.) of N-(1-phenyl-3-pyrrolidinopropyl)quinaldinamide and 91 mg of oxalic acid dihydrate. The resulting solution was eva-porated under reduced pressure to remove the solvent.
20 The residue was recrystall~zed from a mixture of acetone (6 ml) and diethyl ether (3 ml) to obtain 310 mg (yield:
96 %) of the subject compound as a white crystalline pro-duct.
M.p.: 138-140C
IR ~mBarX(cm 1): 3380, 3300, 3040, 1725, 1660, 1560, 1520, 1490, 1425, 1210, 840, 770, NMR ( CDC13 ) ~ CH2 ; 1.82-2.26(4H, m, N ¦ ) \- CH2 ,' '~
2.30-2.70(2H, m, CH2CH2-N ~ ) --~ 1306252 ~CH2 ~
2.81-3.73(6H, m, CH2-N ~ ) 5.00-5.39(1H, m, CONHCH) 7.11-8.38(1lH, m, aromatic proton) 8.67(1H, broad d, CONH) Example 8: Preparation of N-~3-(1-perhydroazepin-1-yl)-l-phenylpropyl]quinaldinamide The procedure of Example 1 was repeated using 697 mg 10 (3.0 mmol.) of 1-(3-amino-3-phenylpropyl)perhydroazePine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 921 mg (yield: 79 %) of the subject compound as a pale yellow oily product.
IR~nmeaaxt(cm 1): 3390, 3300, 2930, 2860, 2820, 1670, 1565, 1515, 1495, 1450, 1415, 1145, 845, 775, 750, 700 ~(CDC13) S : CH2-CH2-CH2 1.30-2.84(16H, m, CH2CH2-N ~ ) 5.17-5.50(1H, m, CONHCH) 7.02-8.38(11H, m, aromatic proton) , . . .
~ ~ 9.40(1H, broad d, CONH) , Example 9: Preparation of N-~3-(1-perhydroazepin-1-yl)-l-phenylpropyl]quinaldinamide oxalate In ethanol were dissolved 921 mg (2.38 mmol.) of N-[3-(perhydroazepin-1-yl)-1-phenyIpropyl]quinaldinamide and 300 mg (2.38 mmol.) of oxalic acid dihydrate. The ~, resulting solution was evaporated under reduced pressure to remove the solvent. The residue was recrystallized ., ~
30 from a mixture of ethanol (10 ml) and n-hexane (10 ml) to obtain 920 mg (yield: 81 %) of the subject compound as a ; white crystalline product.
M.p.: 149-151C
.,, ;

.
.. ., :.. .
' ~ :

.
~ ~ , . ~ ~ , . .

~306252 IR~KBr(cm 1): 3440, 3350, 2940, 2860, 1720, 1670, 1630, 1560, 1520, 1490, 1450, 1420, 1400, 1180, 845, 770, 690 MMR(CDC13) ~ : r CH2 CH2 1.44-2.05(8H, m, N ¦ ) ~CH2-CH2 \
2.30-2.70(2H, m, CH2CH2-~ J

~ CH2 2.90-3.46(6H, m, CH2-N ~ ) 4.99-5.34(lH, m, CONHCH) 7.10-8.34(11H, m, aromatic proton) 8.70(1H, broad d, CONH) Example 10: Preparation of N-(3-dlethylamino-1-phenyl _ propyl)quinaldinamide The procedure of Example 1 was repeated using 618 mg (3.0 mmol.) of N-(3-amino-3-phenylpropyl)-N,N-diethyl-20 amine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 1.08 g (yield: 100 %) of the subject compound as a pale yellow oily product.
IR~nmeaax~cm 1): 3380, 3220, 2970, 2810, 1670, 1565, 1510, I490, 1425, 1210, 1160, 1145, 1070, 845, 750, 695 MMR(CDC13) ~: 1.06(6H, t, J=7Hz, N(CH2CH3)2) 1.84-2.90(8H, m, CH2CH2N(CH2CH3)2 5.17-5.50(1H, m, CONHCH) 7.12-8.38(1lH, m, aromatic proton) ; 30 Example 11: Preparation of N-(3-diethylamino-1-phenyl - ~ propyl)quinaldinamide fumarate In ethanol were dissolved under heating 1.08 g (3.0 mmol.) of N-(3-diethylamino-1-phenylpropyl)quinaldinamide ~ 130625;~

and 313 mg (3.0 mmol.) of fumaric acid. 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 the subject 5 compound as a white crystalline product.
M.p.: 160-161C
IR~Ka8xr(cm 1): 3280, 2990, 2950, 1655, 1560, 1520, 1495, 1425, 1210, 1160, 980, 845, 775, 750, 695 10NMR(CDC13/CD30D = 6/1) ~ :
1.24(6H, t, J=7Hz, N(CH2CH3)2) 2.20-2.70(2H, m, CH2CH2N(CH2CH3)2 2.80-3.40(6H, m, CH2N(CH2CH3)2 5.06-5.34(1H, m, CONHCH) 6.76 (2H, s, CH=CH) 7.20-8.38(1lH, m, aromatic proton) Example 12: Preparation of N-[1-(2-methylphenyl)-3-_ piperidinopropyl]quinaldinamide The procedure of Example 4 was repeated using 465 mg 20 (2.0 mmol.) of 1-[3-amino-3-(2-methylphenyl)propyl]-piperidine and 347 mg (2.0 mmol.) of quinaldinic acid, to obtain 736 mg (yield: 95 %) of the subject compound as a pale yellow oily product.
IR~nmeaaxt(cm~l): 3260, 2930, 2850, 2800, 2770, 1665, 1515, 1495, 1425, 1160, 850, 755 NMR(CDCl3) ~ : r CH2 1.28-1.88(6H, m, N ~ /CH2) 1.88-2.60(8H, m, CH2CH2-N ~ ) 2.49 (3H, s, CH3) 5.36-5.68(lH, m, CO~HCH) 6.90-8.30(1OH, m, aromatic proton) ~ .

~306252 9.48(1H, broad d, CONH) Example 13: Preparation N-Cl-(2-methylphenyl)-3-piperi-dinopropyl]quinaldinamide fumarate The procedure of Example 11 was repeated using 736 5 mg (1.9 mmol.) of N-~1-(2-methylphenyl)-3-piperidinopro-pyl]quinaldinamide and 220 mg (1.9 mmol.) of fumaric acid, to obtain 708 mg (yield: 74 %) of the sub~ect compound.
IRVKmBarx(cm 1): 3420, 3320, 2950, 1670, 1625, 1510, 1490, 1440, 1300, 1280, 1200, 770, NMR(CDC13/CD30D = 2/1) ~ :
r CH2, 1.42-2.04(6H, m, N /CH2) ~ CH2 ~\
2.20-2.68(2H, m, CH2CH2-N

2.45 (3H, s, CH3) /CH2 ~
2.88-3.26(6H, m, CH2-N ~ ) 5.24-5.56(lH, m, CONHCH) 6.75 (2H, s, CH=CH) 7.04-8.40(1OH, m, aromatic proton) Example 14: Preparation of N-~1-(3-methylphenyl)-3-pipe-ridinopropyl]quinaldinamide The procedure of Example 1 was repeated using 697 mg (3.0 mmol.) of 1-~3-amino-3-(3-methylphenyl)propyl]pipe-30 ridine and 575 mg (3.0 mmol.) of quinaldinoyl chloride,to obtain 755 mg (yield: 65 %) of the subject compound as a pale yellow solid product.
IR~K~r(cm 1): 3250, 2930, 2850, 2790, 1665, 1560, max ~306~52 lS10, 1490, 1420, 1160, 1125, 845, 790, 750, 710 MMR(CDCl3) ~ : / H2-CH
1.35-2.60(17H. m, CH2CH2-\ /

CH3) 5.17-5.48(lH, m, CONHCH) 6.90-8.35(10H, m, aromatic proton) 9.50(lH, broad d, CONH) 10 Example lS: Preparation of N-~1-(3-methylphenyl)-3-pipe-ridinopropyl]quinaldinamide fumarate The procedure of Example 11 was repeated using 678 mg (1.75 mmol.) of N-[1-(3-methylphenyl)-3-piperidino-propyl]quinaldinamide and 203 mg (1.75 mmol.) of fumaric 15 acid, to obtain 620 mg (yield: 70 %) of the subject com-pound as a white crystalline product.
M,p.: 143-145C
IRUKmBarx(cm 1): 3460, 3340, 3020, 2950, ~860, 1670, : 1560, 1520, 1490, 1420, 12gO, 1165, ~ 20 980, 840, 770, 700 .~ NMR(CDCl3/CD30D = 6/1) Ç :
,- CH

1.40-2.00(BH, m, N /CH2) ~
`; 2.20-2.65(SH, m, CH2CH2-N ~ , CH3) , ~
CH2~
2.80-3.20(6H, m, CH2-N ~ ) ~: 30 CH2 5.00-5.27(1H, m, CONHCH) : 6.76 (2H, s, CH=CH) ~ : 6.94-8.37(10H, m, aromatic proton) : :

: ,.
. .. .. .
'' i~O625~

Example 16: Preparation of N-~l-(4-methylphenyl)-3-pipe _ ridinopropyl]quinaldinamide The procedure of Example 1 was repeated using 697 mg (3.0 mmol.) of 1-~3-amino-3-(4-methylphenyl)propyl]pipe-5 ridine and 575 mg (3.0 mmol.) of quinaldinoyl chloride,to obtain 1.09 g (yield: 94 %) of the subject compound as a pale yellow oily product.
IR~nmeaaxt(cm 1): 3390, 3280, 2940, 2870, 2810, 1670, 1565, 1510, 1490, 1425, 1160, 1125, 850, 815, 795, 760 NMR(CDCl3) ~ : /CH2 CH2 1.35-2.60(17H, m, CH2CH2-N\ /CH2, CH ) 5.16-5.45(lH, m, CONHCH) 6.95-8.34(1OH, m, aromatic proton) 9.50(1H, broad d, CONH) Example 17: Preparation of N-~1-(4-methylphenyl)-3-pipe-ridinopropyl]quinaldinamide oxalate The procedure of Example 7 was repeated using 917 mg (2.36 mmol.) of N-~1-(4-methylphenyl)-3-piperidinopro-pyl~quinaldinamide and 298 mg (2.36 mmol.3 of oxalic acid dihydrate, to obtain 901 mg (yield: 80 %) o~ the subject compound as a whilte crystalline product upon recrystal-25 lization from 8 ml of ethanol.
M.p.: 165-167C (decomp.) IR~KBr(cm 1): 3440, 3370, 3010, 2940, 2860, 1720, 1680, 1560, 1510, 1490, 1420, 1200, 1155, 835, 800, 790, 765 NMR(CDC13/CD30D = 6/1) ~ :
r CH2 1.40-2.05(6H, m, N CH2) ~0625;~

2.24-2.66(5H, m, CH2CH2-N ~ , CH3) ~CH2 ~
2.70-3.40(6H, m, CH2-N ~ ) 5.00-5.27(1H, m, CONHCH) 7.05-8.38(1OH, m, aromatic proton) Example 18: Preparation of N-~1-(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]pipe-ridine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 1.03 g (yield: 85 %) of the subject compound as a pale yellow oily product.
IR~neat(cm 1~ 3380, 3260, 3000, 2930, 2850, 2820, max 2800, 2760, 1665, 1610, 1560, 1510, 1490, 1420, 1245, 1175, 1155, 1120, 1030, 840, 820, 790, 750 NMR(CDC13) ~ : CH2-CH2 1.34-2.60(14H, m, CH2CH2-N~ CH

3.75 (3H, s, OCH3) 5.18-5.46(1H, m, CONHCH) 6.72-8.34(10H, m, aromatic proton) ~ ~ 25 9.50(1H, broad d, CONH) ,~ Example 19: Preparation of N-~1-(4-methoxyphenyl)-3-piperidinopropyl]auinaldinamide oxalate The procedure of Example 7 was repeated using 1.03 g (2.56 mmol.) of N-~1-(4-methoxyphenyl)-3-piperidinopro-30 pyl]quinaldinamLde and 323 mg (2.56 mmol.~ of oxalic acid dihydrate, to obtain 884 mg (yield: 70 %~ of the subject compound as a white powdery product upon recrystalliza-tion from 8 ml of ethanol.

.::

, 130625~

IR~KBr(cm~l): 3440, 3370, 2940, 1720, 1660, 1610, 1560, 1510, 1490, 1420, 1245, 1180, 1030, 845, 825, 775 NMR(CDC13)~ : r CH~
1.38-2.16(6H, m, N ~CH2) &H2~
2.16-3.8s(llH~ m, CH2CH2-N ~ .

OCH3) 4.92-5.26(1H, m, CONHCH) 6.68-8.26(1OH, m, aromatic proton) 8.50 (lH, broad d, CONH) Reference Example 1: Preparation of ~-piperidinopropio-_ phenone hydrochloride A mixture of 120 g of acetophenone, 133 g of piperi-dine hydrochloride and 50 g of paraformaldehyde in 120 ml of ethanol was refluxed for 6 hours. The mixture was then allowed to stand for cooling to solidify. The 20 resulting solid was crushed after addition of 400 ml of acetone, and then collected by filtration. The collected solid was washed successively with acetone and hexane and dried to obtain 191.6 g (yield: 75.4 %) of the subject compound as a white scaly product.
In the same manner as above, the following compounds were obtained.

:~ x Jl ~ - Z-HC~
~ A o 30X = H, Z = N ~ : m.p. 189-190 C

X = H, Z = N ~ : m.p. 160-162C

~306252 X = H, Z = N 3 : m.p. 160-161.5C

X = H, Z = N(C2H5)2 : m.p. 92- 93C

X = o-CH3~ Z = N ~ : m.p. 170-172C

X = m-CH3, Z = N ~ : m.p. 154-155C

X = p-CH3, Z = N 3 : m.p. 173-175C

X = p-OCH3, Z = N ~ : m.p. 205-207C(decomp.) Reference Example 2: Preparation of ~-piperidinopropio-phenone oxime In 470 ml of water were dissolved 60.2 g of ~-pipe-10 ridinopropiophenone hydrochloride and 18.1 g of hydroxyl-amine hydrochloride. To this solution was added portion-wise 21.9 g of sodium hydrogencarbonate. After the whole amount was added, the mixture was stirred overnight. To the stirred mixture was then added an aqueous solution of 15 14.2 g of sodium hydroxide in 47 ml of water. Thus obtained mixture was well stirred and allowed to stand for 2 hours to produce a white precipitate. The preci-pitate was collected by ~itration and washed successively with two portions of 200 ml of water and ethanol. The 20 washed precipitate was dried to obtain a white solid.
The solid was then recrystallized from methanol to obtain 41.2 g (yield: 74.8 %) of the subject compound as a silver-white scaly product.
In the same manner as above, the following compounds 25 were obtained.
.
NOH
~ \ Z

;
`

: .. . .. .

13()6252 X = H, Z = N ~ : m.p. 150.5-15~.5C

X = H, Z = N ~ : m.p. 154-156C

X = H, Z = N ~ : m.p. 141-142C

X = H, Z = N(C2H5)2 : m.p. 93.5-94.5C

X = o-CH3, Z = N ~ : m.p. 89-90.5C

m CH3, Z N ~ : m.p. 127-129C

p CH3, Z N 2 : m.p. 175-178C

X = p-OCH3, Z = N ~ : m.p. 132-134C

Reference Example 3: Preparation of 1-(3-amino-3-phenyl-propyl)piperidine dioxalate To a stirred solution of 23.2 g of ~-piperidinopro-piophénone oxime in 200 ml of formic acid was added por-tionwise 19.6 g of zinc powder. The resulting mixture generated heat to elevate its temperature. When the tem-15 perature of the mixture reached 65C, the addition wasinterrupted. Thereafter, the addition of zinc powder was continued intermittently to keep the mixture at a temper-ature within 60 to 65C. When it was observed that the addition of zinc powder caused no generation of heat, the 20 whole portion;of the remaining zinc powder was added to the reaction mixture. The mixture was subsequently stirred for 2 hours. The insolubles were filtered off and washed with 100 ml of formic acid. The filtrate and the washings were combined together and concentrated 25 under reduced pressure. To the residue was added 200 ml of water. The resulting aqueous solution was adjusted to pH 8 by addition of aqueous sodium hydroxide solution and ' ,~ , :: .......... ;, ;: .. ...
, ~, washed with chloroform. The aqueous solution was then made to pH 11 by addition of aqueous sodium hydroxide solution and extracted with chloroform. The extract was dried over sodium sulfate. The dried extract was evapo-5 rated under reduced pressure to remove the solvent.
Thus, a crude base product of the subject compound was obtained.
The crude product was dissolved in 200 ml of ethan-ol, and to this solution was added a solution of 25.2 g 10 of oxalic acid dihydrate in 200 ml of ethanol. The mix-ture was allowed to stand to produce white crystals. The crystals were collected by fitration, washed with ethanol and dried to obtain 27.9 g (yield: 70 %) of the subject compound .
In the same manner as above, the following compounds were obtained.
~\' H2N Z-2(COOH)2 X = H, Z = N ~ : m.p. 190-191C(decomp.) X = H, Z = N ~ : m.p. 178-180C(decomp.) X = H, Z = N ~ : m.p. 182-184C(decomp.) X = H, Z = N(C2H5)2 : m.p. 119-121C

X = m-CH3, Z = N~ : m.p. 178-180C(decomp.) X = p-CH3, Z = N ~ : m. p . 128-130C

The dioxalates can be converted to free acids by 130625~

treatment with an aqueous alkaline solution.

Example 20: Preparation in the form of pellet A pellet (220 mg) containing:
quinaldinamide compound (active component) 50 mg lactose 103 mg starch 50 mg magnesium stearate 2 mg hydroxypropylcellulose 15 mg was obtained.

10 Example 21: Preparation in the form of capsule A gelatin-shell hard capsule containing 350 mg of the core portion consisting of:
quinaldinamide compound (active component) 40 mg lactose 200 mg starch 70 mg polyvinylpyrrolidone 5 mg crystalline celllulose 35 mg was obtained.

Example 22: Preparation in the form of granules One gram of granules containing:
quinaldinamide compound (active component) 200 mg lactose 450 mg corn starch . 300 mg hydroxypropylcellulose 50 mg 25 was obtained.

Claims (8)

1. THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
   PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
   I. A quinaldinamide derivative having the formula (I) (I) wherein each of R1 and R2 independently represents a lower alkyl group or R1 and R2 are combined together with the adjacent nitrogen atom to form a 5 - 7 membered ring;
   and X represents the hydrogen atom, a lower alkyl group or a lower alkoxy group, and its acid-addition salt.
2. 2. The quinaldinamide derivative of the formula (I) and its acid addition salt as claimed in claim 1, wherein each of R1 and R2 independently represents an alkyl group containing 1 - 6 carbon atoms.
3. 3. The quinaldinamide derivative of the formula (I) and its acid addition salt as claimed in claim 1, wherein R1 and R2 are combined together with the adjacent nitrogen atom to form a 5 - 7 membered ring.
4. 4. The quinaldinamide derivative of the formula (I) and its acid addition salt as claimed in claim 1, wherein X
   represents the hydrogen atom.
5. 5. The quinaldinamide derivative of the formula (I) as its acid addition salt as claimed in claim 1, wherein X
   represents a lower alkyl group containing 1 - 6 carbon atoms.
6. 6. The quinaldinamide derivative of the formula (I) and its acid addition salt as claimed in claim 1, wherein X
   represents a lower alkyl group or a lower alkoxy group containing 1 - 6 carbon atoms.
7. 7. The quinaldinamide derivative of the formula (I) and its acid addition salt as claimed in claim 1, wherein the quinaldinamide derivative is N-(3-dimethyl-amino-1-phenylpropyl-quinaldinamide, N-3(-diethylamino-1-phenylpropyl)quinaldinamide, N-(1-phenyl-3-dipropyl-aminopropyl)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, N-[1-(4-methylphenyl)-3-piperidinopropyl]quinaldinamide or N-[1-(4-methoxy-phenyl)-3-piperidinopropyl]quinaldinamide.
8. 8. The acid addition salt of the quinaldinamide derivative of the formula (I) as claimed in claim 1, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, methane-sulfonic acid or p-toluenesulfonic acid.