JPH11100366A - Novel N-substituted cyclic amine derivative and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel N-substituted cyclic amine derivative having high selective and potent muscarinic receptor antagonistic activity on smooth muscle muscarinic receptors and effective for treating irritable bowel syndrome and the like. SOLUTION: General formula (1) [Wherein R represents a hydrogen atom, a lower alkoxy group or a halogen atom, and X represents OCH ₂ , SCH ₂ , SOCH ₂ , SO ₂
A CH ₂ , NHCO group or NR ¹ CH ₂ (where R ¹ represents a hydrogen atom or a lower acyl group), m represents an integer of 2 or 3, and n represents an integer of 1 or 2. The present invention relates to a novel N-substituted cyclic amine derivative and a method for producing the same.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a highly selective and potent muscarinic receptor antagonizing effect on smooth muscle muscarinic sites rather than cardiac muscarinic sites, irritable bowel syndrome, diverticulosis, urinary incontinence, esophageal relaxation The present invention relates to a novel N-substituted cyclic amine derivative useful as a therapeutic agent for a disease associated with altered automotility and / or tone of smooth muscle such as impotence and chronic obstructive airway disease, and a method for producing the same.

[0002]

2. Description of the Related Art Anticholinergic drugs have been used as one of the drugs for irritable bowel syndrome, but have not shown sufficient therapeutic effects due to lack of organ selectivity. Also, compounds known to have a selective antagonism to smooth muscle muscarinic receptors (JP-A-2-282360 and JP-A-7-149640) are known. Side effects have not been fully resolved. Further, these compounds have a structure different from that of the compound of the present invention in which a diphenylalkyl site is bonded at a carbon site of a cyclic amine and is bonded at a nitrogen site.

[0003]

DISCLOSURE OF THE INVENTION The present invention has a highly selective and potent antagonism to smooth muscle muscarinic receptors,
An object of the present invention is to provide a novel N-substituted cyclic amine derivative effective for treating irritable bowel syndrome and the like.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies on drugs having a high selective and strong antagonism to smooth muscle muscarinic receptors and having few side effects of mydriasis. The present inventors have found that the novel N-substituted cyclic amine derivative represented by the formula (1) has high safety and is effective for treating irritable bowel syndrome and the like, and completed the present invention.

That is, the present invention provides a compound represented by the general formula (1) [Wherein R represents a hydrogen atom, a lower alkoxy group or a halogen atom, and X represents OCH ₂ , SCH ₂ , SOCH ₂ , SO ₂
A CH ₂ , NHCO group or NR ¹ CH ₂ (where R ¹ represents a hydrogen atom or a lower acyl group), m represents an integer of 2 or 3, and n represents an integer of 1 or 2. An N-substituted cyclic amine derivative and a pharmaceutically acceptable salt,
And a therapeutic agent for irritable bowel syndrome or the like containing at least one of them as an active ingredient.

The pharmacologically acceptable salts of the compound represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, benzenesulfonate, citrate, fumarate, gluconate Acid addition salts such as acid, lactate, maleate, methanesulphonate, succinate and tartrate. Further, a hydrate of the compound represented by the general formula (1) is also included.

In the present invention, the "lower alkoxy group" includes straight or branched ones having 1 to 3 carbon atoms such as methoxy, ethoxy and propoxy. The “lower acyl group” includes straight or branched ones having 2 to 4 carbon atoms, such as acetyl, propionyl and butyryl. "Halogen atoms" include chlorine, bromine and iodine atoms.

According to the present invention, the compound represented by the general formula (1) can be produced by the following method. [Where R, X, m, and n are as described above]

The compound represented by the general formula (1) can be produced by hydrolyzing the compound represented by the general formula (4). [Where R, X, m, and n are as described above]

In the case of an acid catalyst, the hydrolysis is preferably carried out under heating, preferably at 70 to 110 ° C., using an inorganic acid such as concentrated sulfuric acid. On the other hand, in the case of an alkali catalyst, for example, the reaction can be carried out using an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in alcohol, and it is preferable to carry out the reaction using potassium hydroxide in tertiary butanol while heating under reflux.

The compound represented by the general formula (4) can be obtained by adding the compound represented by the general formula (3) to the compound represented by the general formula (2) when R ² is a hydrogen atom. In the case of the above, the compound can be produced by reacting after deprotection. [Wherein Y represents a halogen atom, and m represents the same as described above] [Wherein R, X, and n are as described above, and R ² represents a hydrogen atom or a tert-butoxycarbonyl group.]

The reaction is carried out according to a conventional method in the presence of an inorganic salt or an organic salt, by adding a compound represented by the general formula (2)
The reaction can be carried out by reacting the compound represented by the formula as it is, or by deprotecting the compound by treating the protecting group with trifluoroacetic acid or the like and then reacting the compound. Upon deprotection, it can be used for the next reaction without isolation after the reaction. At this time, the base is preferably an organic base such as triethylamine. As the reaction solvent, N, N
Inert solvents such as dimethylformamide, dimethylsulfoxide or N-methyl-2-pyrrolidone can be used, but N-methyl-2-pyrrolidone is preferred and the reaction temperature is between room temperature and 200 ° C, preferably between 100 ° C and 150 ° C. It is preferred to stir.

The general formula (4) which is a part of the general formula (4)
-B) (4-c) can be produced from the general formulas (4-a) and (5) and (6), respectively. [Where R, m, and n are as described above] Wherein R, m, and n are as described above, and p is an integer of 1 or 2. [Wherein m and n are as described above, and Boc represents a tertiary butoxycarbonyl group] [Wherein R is as described above, and Y ¹ is a halogen atom] [Where R, m, and n are as described above]

In the case of the general formula (4-b), the compound represented by the general formula (4-a) is reacted with an oxidizing agent, aqueous hydrogen peroxide,
The reaction can be carried out by stirring under ice-cooling to room temperature in the presence of m-chloroperbenzoic acid (preferably the latter). The general formula (4-
In the case of c), the compound represented by the general formula (5) is treated with trifluoroacetic acid under ice cooling and deprotected, and then in the presence of an inorganic base, potassium carbonate, sodium carbonate, and sodium hydrogen carbonate (preferably, carbonic acid). Potassium) The reaction can be carried out by reacting the compound of the general formula (6) with N, N-dimethylformamide or the like as a solvent at room temperature.

[0015]

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples. The compounds of the present invention include optical isomers based on asymmetric carbons at the 2- and 3-positions of pyrrolidine and piperidine and a sulfinyl group, and all of them are included. The compounds of the present invention also include hydrates, all of which are included in the scope of the present invention. The abbreviations used in the present invention have the following meanings. MS mass spectrum NMP N-methyl-2-pyrrolidone FAB MS fast atom bombardment mass spectrum DMF N, N-dimethylformamide

Example 1 4- [3- (4-chlorobenzylthio) pyrrolidine-1
-Yl] -2,2-diphenylbutyronitrile

1-tert-butoxycarbonyl-3
20 ml of trifluoroacetic acid was added to 7.25 g of-(4-chlorobenzylthio) pyrrolidine under ice-cooling and stirring, and the mixture was stirred at 0 ° C for 30 minutes, and excess trifluoroacetic acid was distilled off under reduced pressure. 4 for residue
-Bromo-2,2-diphenylbutyronitrile 6.63 g,
3.36 g of triethylamine and 20 ml of NMP were added and 140 ° C.
For 1.5 hours. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1).
Purification in 1) gave 6.30 g of the desired product as a brown oil. FAB MS: 447 [M + H] ⁺

Examples 2 and 3 The following compounds were obtained in the same manner as in Example 1.

[0019]

[Table 1]

Example 4 5- [3- (3-chlorobenzyloxy) pyrrolidine-
Production of 1-yl] -2,2-diphenylpentanonitrile

318 mg of 5-bromo-2,2-diphenylpentanonitrile was dissolved in 10 ml of DMF, and potassium carbonate 1
69 mg was added, and 225 mg of 3- (3-chlorobenzyloxy) pyrrolidine was added dropwise. After stirring at room temperature for 8 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 10: 1) to obtain 331 mg of the desired product as a yellow oil. MS: 444 M ⁺

Example 5 Preparation of 4- [3- [N- (4-fluorobenzyl) -N-acetylamino] pyrrolidin-1-yl] -2,2-diphenylbutyronitrile

1-tert-butoxycarbonyl-3
Dissolve 3.20 g of-[N- (4-fluorobenzyl) -N-acetylamino] pyrrolidine in 20 ml of ethyl acetate and add 3N
9.51 ml of hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour, and excess hydrochloric acid-ethyl acetate was distilled off under reduced pressure. Residue is DMF15
dissolved in potassium hydroxide, 6.58 g of potassium carbonate and 4-bromo-2,
After adding 2.85 g of 2-diphenylbutyronitrile and stirring with heating at 100 ° C. for 6 hours, the reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 580 mg of the desired product as a yellow oil. FAB MS: 456 [M + H] ⁺

Example 6 Preparation of 4- [3- (4-chlorobenzylsulfinyl) pyrrolidin-1-yl] -2,2-diphenylbutyronitrile

The 4- [3- (4-chlorobenzylthio) pyrrolidin-1-yl] -2,2-diphenylbutyronitrile obtained in Example 1 is dissolved in 10 ml of dichloromethane, and m-chloroform is stirred under ice-cooling. 771 mg of perbenzoic acid in dichloromethane
A 20 ml solution was slowly added dropwise. The mixture was stirred at 0 ° C. for 30 minutes, added with 50 ml of dichloromethane, washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane: methanol = 40: 1 → 20:
Purification in 1) gave 800 mg of the desired product as a yellow oil. MS: 462 M ⁺

Example 7 Preparation of 4- [3- (N-tert-butoxycarbonylamino) pyrrolidin-1-yl] -2,2-diphenylbutyronitrile

4.00 g of 3- (N-tert-butoxycarbonylamino) pyrrolidine, 6.45 g of 4-bromo-2,2-diphenylbutyronitrile and 4.45 g of triethylamine.
50 ml was dissolved in 20 ml of NMP, and the mixture was heated and stirred at 140 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue,
Extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 3.70 g of the desired product as a yellow oil. FAB MS: 406 [M + H] ⁺

Example 8 Preparation of 4- [3- (4-fluorobenzylamino) pyrrolidin-1-yl] -2,2-diphenylbutyronitrile

10 ml of trifluoroacetic acid was added to 3.00 g of 4- [3- (N-tert-butoxycarbonylamino) pyrrolidin-1-yl] -2,2-diphenylbutyronitrile obtained in Example 7 while stirring under ice-cooling. In addition, the mixture was stirred at 0 ° C. for 30 minutes, and excess trifluoroacetic acid was distilled off under reduced pressure. Residue D
Dissolved in 10 ml of MF, added 5.11 g of potassium carbonate, and stirred at room temperature with 10 ml of 4-fluorobenzyl chloride in 1.07 g of DMF.
The solution was added dropwise and stirred at room temperature for 20 hours. The reaction mixture was poured into ice water, extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1 → 10: 1) to obtain 1.25 g of the desired product as a yellow oil. FAB MS: 414 [M + H] ⁺

Example 9 4- [3- (4-chlorobenzylthio) pyrrolidine-1
-Yl] -2,2-diphenylbutanamide

To 1.00 g of 4- [3- (4-chlorobenzylthio) pyrrolidin-1-yl] -2,2-diphenylbutyronitrile obtained in Example 1, 628 mg of potassium hydroxide and 20 ml of tert-butanol were added. And refluxed for 48 hours. The reaction mixture was poured into ice water, extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (dichloromethane: methanol = 2
0: 1) purification, yellow amorphous 630m
g was obtained. FAB MS: 465 [M + H] ⁺

Elemental analysis value: C ₂₇ H ₂₉ ClN ₂ OS · １ ／ H ₂ O; calculated value of CH N 69.06 6.33 5.97 found value 69.14 6.36 5.94

Examples 10 to 13 The following compounds were obtained in the same manner as in Example 9.

[0034]

[Table 2]

Example 14 Preparation of 4- [3- (4-fluorobenzoylamino) pyrrolidin-1-yl] -2,2-diphenylbutanamide

The following compounds were obtained in the same manner as in Example 9.

Elemental analysis value: C ₂₇ H ₂₈ FN ₃ O ₂ .4 / 5H ₂ O; calculated value of CH N 70.51 6.49 9.14 found value 70.70 6.70 8.86

Example 15 Preparation of 4- [3- (4-chlorobenzylsulfonyl) pyrrolidin-1-yl] -2,2-diphenylbutanamide

4- [3- (4-Chlorobenzylsulfonyl) pyrrolidin-1-yl] -2,2- obtained in Example 2
To 1.10 g of diphenylbutyronitrile was added 5 ml of 70% sulfuric acid, and the mixture was heated and stirred at 120 ° C. for 30 minutes. The reaction solution was poured into ice water, neutralized with a 5N aqueous sodium hydroxide solution, and extracted with dichloromethane. After drying over sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give the target compound as pale yellow crystals.
600 mg were obtained. Recrystallization from ethyl acetate gave 315 mg as colorless crystals. FAB MS: 497 [M + H] ⁺

Elemental analysis value: C ₂₇ H ₂₉ ClN ₂ O ₃ S · １ ／ H ₂ O: CH N Calculated: 64.66 5.93 5.59 Found: 64.44 6.01 5.43

Example 16 4- [3- (3-chlorobenzyloxy) piperidine-
Production of 1-yl] -2,2-diphenylbutyronitrile

1.76 g of 4-bromo-2,2-diphenylbutyronitrile, 1.32 g of 3- (3-chlorobenzyloxy) piperidine and 0.89 g of triethylamine were dissolved in 20 ml of NMP and heated and stirred at 140 ° C. for a total of 24 hours. . After cooling, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain 1.54 g of the desired product as a brown oil. FAB MS: 445 [M + H] ⁺

Example 17 4- [4- (3-chlorobenzyloxy) piperidine-
Production of 1-yl] -2,2-diphenylbutyronitrile

In the same manner as in Example 16, the desired product was obtained as a brown oily substance in a yield of 77%. FAB MS: 445 [M + H] ⁺

Example 18 4- [3- (3-chlorobenzyloxy) piperidine-
Production of 1-yl] -2,2-diphenylbutanamide

1.54 g of 4- [3- (3-chlorobenzyloxy) piperidin-1-yl] -2,2-diphenylbutyronitrile obtained in Example 16, 1.17 g of potassium hydroxide,
A mixture of 15 ml of tertiary butanol was heated to reflux for 48 hours. The reaction mixture was poured into ice water (100 ml), extracted with methylene chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give the desired product as a brown oil. This was further subjected to Kugelrohr distillation (290 ° C., 0.1 mmHg) to obtain 0.68 g of the desired product as a yellow oil.

[0047]

Example 19 4- [4- (3-chlorobenzyloxy) piperidine-
Production of 1-yl] -2,2-diphenylbutanamide

The 4- [4- (3-chlorobenzyloxy) piperidin-1-yl] -2,2-diphenylbutyronitrile obtained in Example 17 was treated again with acetonitrile in the same manner as in Example 18. By crystallization, the target product was obtained as colorless needles in a yield of 61%. mp 130-133 ° C

[0050]

Experimental Example 1 1. Antagonistic action on ileal acetylcholine contraction After killing male Hartley guinea pigs, the ileum was excised and 1.5-2 cm specimens were prepared. Specimen is 95% O ₂ , 5
10 ml filled with Tyrode's solution at 28 ° C ventilated with ₂ % CO ₂
Suspended in a Magnus tube. The tension was 1 g and the contraction was recorded isotonic. The effect of the test drug is acetylcholine 10 ^-9 M
It was determined pA ₂ by Schild plots from the right degree of movement of the concentration-response curve of ~3 × 10 ^-6 M.

2. Antagonistic action of pupil on acetylcholine contraction A Japanese white male rabbit was sacrificed, the eyeball was excised, and a pupil sphincter specimen was prepared. The sample is 95% O ₂ , 5% CO ₂
Was suspended in a 10 ml Magnus tube filled with aerated Krebs solution at 30 ° C. The initial tension was 0.2 g and the tension was recorded isometric. The effect of the test drug is acetylcholine 10 ^-6 M to 10
PA ₂ was determined by Schild plot from the degree of rightward shift of the ⁻² M concentration-response curve.

3. Antagonism of Acetylcholine Inhibition of Atrial Contraction After killing male Hartley guinea pigs, the heart was excised and an atrial specimen was prepared. The sample is 95% O ₂ , 5% CO ₂
Was filled with aerated Krebs-Henseleit solution at 32 ° C.
Suspended in a 10 ml Magnus tube. The initial tension was 0.5 g and the tension was recorded isometric. The action of the test drug was determined from the degree of rightward shift of the concentration-response curve of acetylcholine 10 ⁻⁹ M to 3 × 10 ⁻⁶ M, and pA ₂ was determined by Schild plot.

According to the above method, a novel N-substituted cyclic amine having high selectivity and potent muscarinic receptor antagonism for smooth muscle muscarinic sites rather than cardiac muscarinic sites and useful as a therapeutic agent for irritable bowel syndrome and the like Derivatives have been found.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Yukie Takahashi 5982-1 Tomonuma, Nogi-machi, Shimotsuga-gun, Tochigi Prefecture (72) Inventor Katsuya Awano 352-22 Kizawa, Oyama City, Tochigi Prefecture Otome 3-18-6

Claims (6)

[Claims] 1. General formula (1) [Wherein R represents a hydrogen atom, a lower alkoxy group or a halogen atom, and X represents OCH ₂ , SCH ₂ , SOCH ₂ , SO ₂
A CH ₂ , NHCO group or NR ¹ CH ₂ (where R ¹ represents a hydrogen atom or a lower acyl group), m represents an integer of 2 or 3, and n represents an integer of 1 or 2. N-substituted cyclic amine derivatives and pharmacologically acceptable salts. 2. General formula (1) [Wherein R represents a hydrogen atom, a lower alkoxy group or a halogen atom, and X represents OCH ₂ , SCH ₂ , SOCH ₂ , SO ₂
A CH ₂ , NHCO group or NR ¹ CH ₂ (where R ¹ represents a hydrogen atom or a lower acyl group), m represents an integer of 2 or 3, and n represents an integer of 1 or 2. A therapeutic agent for irritable bowel syndrome comprising as an active ingredient at least one of an N-substituted cyclic amine derivative and a pharmacologically acceptable salt. 3. General formula (2) [Wherein Y represents a halogen atom and m represents an integer of 2 or 3]. [Wherein R represents a hydrogen atom, a lower alkoxy group or a halogen atom, and X represents OCH ₂ , SCH ₂ , SOCH ₂ , SO ₂
CH ₂ , NHCO or NR ¹ CH ₂ (where R ¹ represents a hydrogen atom or a lower acyl group), R ² represents a hydrogen atom or a tert-butoxycarbonyl group, and n represents 1
Or a compound represented by the general formula (4), which is reacted as it is or after deprotection. [Wherein R, X, m, and n are as described above]. 4. Formula (4-a) Wherein R represents a hydrogen atom, a lower alkoxy group or a halogen atom, m represents an integer of 2 or 3, and n represents an integer of 1 or 2. (4-b) [Wherein R, m and n are as described above, and p is an integer of 1 or 2]. 5. General formula (5) Wherein Boc represents a tertiary butoxy group, m represents an integer of 2 or 3, and n represents an integer of 1 or 2. After deprotection, the compound represented by the general formula (6) Wherein R represents a hydrogen atom, a lower alkoxy group or a halogen atom, and Y ¹ represents a halogen atom. The compound represented by the general formula (4-c): [Wherein R, m and n are as described above]. 6. The general formula (4) [Wherein R represents a hydrogen atom, a lower alkoxy group or a halogen atom, and X represents OCH ₂ , SCH ₂ , SOCH ₂ , SO ₂
A CH ₂ , NHCO group or NR ¹ CH ₂ (where R ¹ represents a hydrogen atom or a lower acyl group), m represents an integer of 2 or 3, and n represents an integer of 1 or 2. General formula (1) characterized in that the compound is hydrolyzed [Wherein R, X, m, and n are as described above].