JPH0920758A - New cyclic diamine derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new cyclic diamine derivative useful for treating a hypersensitive intestinal syndrome, etc., having selectivity in other smooth muscle muscarine higher than in cardiac muscarine and strong antagonism. SOLUTION: This compound is shown by formula I (R<1> and R<2> are each phenyl, pyridyl, etc.; R<3> is H or a lower alkyl; R<4> and R<5> are each independently H, a lower alkyl, etc.; R<6> and R<7> are each independently H, a lower alkyl, etc.; R<8> is H, halogen, etc.; Z is C or N; (m) is 1, 2, 3, or 4; (n) is 1, 2 or 3; (p) is 0, 1, 2 or 3) such as 2,2-diphenyl-4-[5-(4-fluorobenzyl)-2,5- diazabicyclo[2,2,2]octan-2-yl]butyronitrile. The compound of formula I is obtained by reacting a compound of formula II (X is an eliminable group) with a compound of formula III preferably at 60-150 deg.C.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel cyclic diamine derivative, and more specifically, the present invention relates to a cyclic diamine derivative as a selective muscarinic receptor antagonist.

[0002]

2. Description of the Related Art Anticholinergics have antispasmodic and antisecretory effects and are useful as therapeutic agents for functional disorders such as intestines and urinary bladder. Currently, as anticholinergics, alkaloids such as atropine, aminoalkanol esters such as oxybutynin and propantheline bromide, and their quaternary ammonium salts are known, and these are blockers of acetylcholine receptors. is there. However, the antagonism of these compounds is poor in organ selectivity, so that the occurrence of side effects is a problem, and development of highly selective anticholinergic drugs is desired in clinical practice.

Cyclic diamine derivatives having an anticholinergic effect are disclosed in JP-A-5-125068 and JP-A-5050.
-29578, Japanese Patent Publication No. 62-24428, etc., but they are structurally different from the novel compounds of the present invention and are not satisfactory in terms of efficacy.

[0004]

DISCLOSURE OF THE INVENTION The present invention is to provide a drug having a strong antagonistic action with a higher selectivity for muscarinic receptors of other smooth muscles than cardiac muscarinic receptors. is there.

[0005]

Means for Solving the Problems The present inventors have focused their attention on cyclic diamine derivatives for the above-mentioned purpose, and as a result of earnest studies, as a result, general formula (1) (In the formula, R ¹ and R ² each represent an unsubstituted or optionally substituted phenyl group, a pyridyl group, a cycloalkyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R 3
⁴ , R ⁵ are the same or different and each is a hydrogen atom,
It represents a lower alkyl group, and R ⁴ and R ⁵ may form an alkylene ring to form a bridge, and R ⁶ and R ⁷ are the same or different and each is a hydrogen atom, a lower alkyl group, an unsubstituted or substituted group. Represents a phenyl group which may have
⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, Z represents a carbon atom or a nitrogen atom, m represents 1 to 4, and n represents 1 to 3
And p represents 0 to 3. It was found that the cyclic diamine derivative represented by the formula (1) and its salt have a strong anticholinergic action and high selectivity, and have completed the present invention.

Therefore, the compound of the present invention is used for the treatment of gastrointestinal motility disorders such as irritable bowel syndrome, functional diarrhea, esophageal atlasia, cardia spasm, biliary tract, urethral spasm, urinary incontinence, etc., chronic airway. It is useful for medical use such as treatment of obstructive diseases.

Examples of the "substituent" of the phenyl group shown in the present invention include halogen, lower alkyl group, lower alkoxy group, hydroxyl group and the like. "Halogen" includes fluorine, chlorine, bromine and iodine. Examples of the "lower alkyl group" include linear or branched ones having 1 to 6 carbon atoms such as methyl, ethyl and isopropyl. Examples of the “cycloalkyl group” include cyclopentyl, cyclohexyl and other cyclic hydrocarbons having 5 to 7 carbon atoms. The "lower alkoxy group" is a methoxy group, an ethoxy group, an isopropoxy group or the like, which has a straight or branched carbon atom number of 1 to 6 at the oxygen atom.
And the alkyl group of is bonded. Examples of the "alkylenedioxy group" include methylenedioxy, ethylenedioxy and the like, which include a linear alkylene group having 1 to 3 carbon atoms between two oxygen atoms. Examples of the "hetero atom" include an oxygen atom, a sulfur atom and a nitrogen atom.

In the present invention, the general formula (1) (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
R ⁸ , Z, m, n, and p are as described above), and the compound represented by the general formula (2) (In the formula, R ¹ , R ² , R ³ and m are as described above,
X represents an ejector. ) To the compound represented by the general formula (3) Manufactured by reacting a compound represented by the formula (wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z, n and p are as described above) in the presence or absence of a base. can do.

Examples of the "leaving group" include halogen, an aliphatic sulfonyloxy group such as methanesulfonyloxy group, and an arylsulfonyloxy group such as toluenesulfonyloxy group.

The reaction is carried out by using dimethylformamide, N-methylpyrrolidone, N, N'-dimethylimidazolidinone,
In an organic solvent such as dimethylsulfoxide, xylene or without solvent, in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, or an organic base such as triethylamine or pyridine as a base, or It can be carried out in the absence of 0 to 200 ° C., preferably 60 to 150 ° C.

In the present invention, the general formula (1) (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
R ⁸ , Z, m, n and p are as described above), and the compound represented by the general formula (4) (Wherein R ¹ and R ² are as described above), the compound represented by the general formula (5) (In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z, m,
It can be produced by reacting the compound represented by the formula (n, p and X are as described above) in the presence of a base.

The reaction is carried out in an inert organic solvent such as benzene, toluene or xylene, with sodium amide as a base,
From 0 in the presence of lithium amide, sodium hydride, etc.
It can be carried out at 200 ° C., preferably 100 to 150 ° C.

In the piperazine derivative of the present invention, there are optical isomers of compounds having an asymmetric carbon, and these isomers and mixtures are included in the present invention.

The novel compounds of the present invention are pharmaceutically acceptable inorganic salts such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, or organic acids such as maleic acid, fumaric acid, acetic acid, oxalic acid, tartaric acid, benzene. An acid addition salt can be obtained by reacting sulfonic acid or the like according to a conventional method.

Further, the administration form of the novel compound of the present invention includes oral administration by tablets, capsules, granules, powders, syrups and the like, or parenteral administration by injections, suppositories and the like.

[0016]

EXAMPLES The present invention will be described in detail below with reference to examples.

Example 1 4- (4-benzyl-1-piperazinyl) -2,2-diphenylbutyronitrile.2
Hydrochloride

4-Bromo-2,2-diphenylbutyronitor (3.00 g, 10.0 mmol), 1-benzylpiperazine (5.29 g, 30.0 mmol), triethylamine (1.40 ml, 1)
0.0mmol) and N, N-dimethylformamide (30ml)
Were mixed and heated and stirred at 150 ° C. for 20 hours. Then, the reaction solution was transferred into water, extracted with benzene, the extract was dried over anhydrous sodium sulfate and then concentrated, and the residue was subjected to silica gel chromatography (eluent; chloroform: ethanol = 1).
(1: 1), purified by hydrochloric acid ether solution and recrystallized from ethyl acetate-ethanol to give 3.01.
g of the title compound was obtained as a colorless powder. Yield 64%.

Melting point 220-223 ° C. Elemental analysis value (%) Calculated value as C ₂₇ H ₂₉ N ₃ .2HCl.1 / 10H ₂ O C: 68.96 H: 6.69 N: 8.94 Measured value C: 68.86 H: 6.73 N: 9.10

¹ H-NMR (400 MHz, CDCl ₃ ,
δ) 7.24 to 7.40 (15H, m), 3.49 (2H, s), 2.
58 ~ 2.62 (2H, m), 2.43 ~ 2.48 (8H, m), 1.68
(2H, s)

(Examples 2-35) According to the method of Example 1,
The following compounds were synthesized (Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8).

[0022]

[Table 1]

[0023]

[Table 2]

[0024]

[Table 3]

[0025]

[Table 4]

[0026]

[Table 5]

[0027]

[Table 6]

[0028]

[Table 7]

[0029]

[Table 8]

Reference Example 1 2-Tosyl-5- (4-fluorobenzyl) -2,5-
Diazabicyclo [2,2,1] heptane tritosylhydroxy-L-prolinol (10.67 g, 1
8.41 mmol), 4-fluorobenzylamine (6.91 g, 55.
A mixture of 21 mmol) and toluene (40 ml) was heated under reflux for 26 hours. After allowing to cool, the precipitated crystals were filtered, washed with toluene, combined with the filtrate, and evaporated under reduced pressure. Ethanol was added to the residue for crystallization, and the obtained crystals were collected by filtration and air-dried.5.
74 g (yield 86%) of the desired product was obtained as white prismatic crystals. Melting point 98-99 ° C

Reference Example 2 N- (4-Fluorobenzyl) -2,5-diazabicyclo [2,2,1] heptane dihydroiodide 2-tosyl-5- (4-fluorobenzyl) -2 , 5-
Diazabicyclo [2,2,1] heptane (5.74g, 15.9
2 mmol), red phosphorus (2.8 g, 90.41 mmol), hydroiodic acid (52
ml), acetic acid (62 ml) and water (12 ml) were heated to reflux for 4 hours. After cooling, the insoluble material was filtered off, washed with acetic acid and water, combined with the filtrate and evaporated under reduced pressure. The procedure of adding 50 ml of acetic acid to the residue and distilling it off under reduced pressure was repeated twice, and ethanol and ether were added for crystallization. The obtained crystals were collected by filtration and air-dried to obtain 5.18 g (yield 70%) of the desired product as a yellowish brown powder. Melting point 233-235 ° C

Example 36 2,2-Diphenyl-4- [5- (4-fluorobenzyl) -2,5-diazabicyclo [2,2,2] octane-2-yl] butyronitrile

(1) 2- (4-fluorobenzyl)-
2,5-diazabicyclo [2,2,2] octane-3,
6-dione Sodium hydride deoiled with n-hexane (1.7 g, 42.5
mmol) and DMF (20 ml) in a suspension of 2,5-diazabicyclo [2,2,2] octane-3,6-dione (3.0
g, 21.4 mmol) and a suspension of DMF (70 ml),
After heating to 50 ° C., the mixture was stirred at room temperature for 1 hour. Under ice cooling 4-
Fluorobenzyl chloride (3.1g, 21.4mmol) and D
A solution of MF (10 ml) was added dropwise and the temperature was kept for 30 minutes,
Then, the mixture was left to stir at room temperature for 3 days. 500 ml of ice water
The mixture was poured into the mixture, extracted with methylene chloride, the organic layers were combined, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give the desired product as colorless prism crystals 1.04.
g (yield 19.6%) was obtained. Melting point 165-169 ° C

(2) 2- (4-fluorobenzyl)-
2- (4-fluorobenzyl) -2, in a solution of 2,5-diazabicyclo [2,2,2] octane bitride (70% toluene solution, 5.6 ml) and toluene (14 ml)
5-diazabicyclo [2,2,2] octane-3,6-
Dione (1.04g, 4.2mmol) was added little by little, then 60 ℃
The mixture was heated and stirred for 2.5 hours. After allowing to cool, under ice cooling, a 2N sodium hydroxide solution was added to make it alkaline. The precipitate was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 830 mg of the desired product as a brown oily substance. This was used for the next reaction without further purification.

(3) 2,2-diphenyl-4- [5-
(4-Fluorobenzyl) -2,5-diazabicyclo [2,2,2] octane-2-yl] butyronitrile 2- (4-fluorobenzyl) -2,5-diazabicyclo [2,2,2] octane (710 mg , 32 mmol), triethylamine (0.89 ml, 6.4 mmol) and DMF (10 ml) were added to 4-bromo-2,2-diphenylbutyronitrile (9
(60 mg, 3.2 mmol) was added and the mixture was heated under reflux at 80 ° C for 4.5 hours. After allowing to cool, 50 ml of 1N hydrochloric acid was added and the mixture was washed with ether, and concentrated ammonia water was added under ice cooling to make it alkaline. The precipitate was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel chromatography, and the fractions containing the desired product were combined and the solvent was evaporated under reduced pressure. N-Hexane was added to the residue and pulverized, and the crystals were collected by filtration and air-dried to obtain 380 mg (yield 27%) of the target product as white prism crystals.

Melting point 122 to 123 ° C. Mass spectrometry M / Z 439 (M ⁺ ) Elemental analysis value (%) Calculated value as C ₂₉ H ₃₀ FN ₃ C: 79.24 H: 6.88 N: 9.56 Actual value C: 79.33 H: 6.94 N: 9.49

¹ H-NMR (400 MHz, CDCl ₃ ,
δ) 1.5 to 1.7 (2H, m), 1.8 to 2.0 (2H, m)
m), 2.5 to 2.7 (8H, m), 2.98 (2H, dd, J
1 = 36.6Hz, J2 = 10.3Hz), 3.62 (2H, s), 6.97
(2H, t, J = 8.8Hz), 7.2 to 7.5 (12H, m)

[0038]

【The invention's effect】

1: Anticholinergic action on the isolated guinea pig ileum and atrium After bruising the occipital region of a male Hartley guinea pig, blood was removed from the jugular vein and the ileum immediately adjacent to the heart and the cecum was extracted. The ileum was suspended as a small piece of 3 cm in length with a load of 1 g on the Magnus tube, and the response of the specimen was recorded isotonic.
The nutrient solution is Tyrode's solution, O ₂ : 95%, CO ₂ : 5
% Mixed gas was aerated, and the liquid temperature was 32 ° C. Acetylcholine (ACh) was administered cumulatively and test compounds were pretreated for 5 minutes. The affinity of the test compound was (pA2) Schild method (Arunlakshana, O. and Schild, HO (1959) Brit.
J. Pharmacol., 14 48-58). The isolated atrium was suspended in a Magnus tube with a load of 0.5 g and the response of the specimen was recorded isometrically. Tyrode's solution was used as the nutrient solution, a mixed gas of O ₂ : 95% and CO ₂ : 5% was aerated, and the solution temperature was 32 ° C. Acetylcholine was given cumulatively and test compounds were pretreated for 10 minutes. The affinity of the test compound was determined in the same manner as in the ileum. Table 9 shows the results.

[0039]

[Table 9]

2: Effect on Rhythmic Bladder Contraction Male Wistar rats were anesthetized with halothane, fixed in the back position, a catheter with a balloon was inserted from the apex of the bladder exposed by a midline abdominal incision, and purse string suture was performed. A catheter was pulled out from the sutured upper abdomen, and a three-way stopcock was connected, one side was connected with a syringe, and the other side was connected with a pressure transducer for measuring intravesical pressure. About 0.1-0.3m in the balloon
After injecting 1 l of distilled water and confirming that the induced rhythmic bladder contraction had a stable amplitude, the test compound was administered into the duodenum via a catheter previously placed. The inhibitory effect was evaluated from the decrease in the amplitude of rhythmic bladder contraction. The compound of the present invention showed an inhibitory action at 3 mg / kg.

3: Effect on diarrhea induced by besanecol The test compound was orally administered to male ICR mice, and 0.5 hours later, 20 mg / kg of besanecol was subcutaneously administered. The diarrhea manifested at this time was observed until 0.5 hours later. The compound of the present invention suppressed the expression of diarrhea at 30 mg / kg.

The compounds of the present invention were superior to the conventional anticholinergics in the selectivity of other smooth muscle muscarinic receptors for cardiac muscarinic receptors. Especially Example 2,
The compounds such as 4, 5, 6, and 7 showed 10 times or more selectivity.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/55 ACJ A61K 31/55 ACJ C07D 213/57 C07D 213/57 243/08 502 243/08 502 503 503 295/14 295/14 A 401/06 243 401/06 243 405/06 243 405 405 243 471/08 471/08 487/08 9271-4C 487/08 (72) Inventor Hiromi Kiyota Tochigi Prefecture 6096 Tomonuma, Nogi-cho, Shimotsuga-gun Dormitory of Minami-Tonuma (72) Inventor Mitsuru Segawa 594-5 Nakagawa, Omiya City, Saitama Prefecture

Claims (6)

[Claims] 1. General formula (1) (In the formula, R ¹ and R ² each represent an unsubstituted or optionally substituted phenyl group, a pyridyl group, a cycloalkyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R 3
⁴ , R ⁵ are the same or different and each is a hydrogen atom,
It represents a lower alkyl group, and R ⁴ and R ⁵ may form an alkylene ring to form a bridge, and R ⁶ and R ⁷ are the same or different and each is a hydrogen atom, a lower alkyl group, an unsubstituted or substituted group. Represents a phenyl group which may have
⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, Z represents a carbon atom or a nitrogen atom, m represents 1 to 4, and n represents 1 to 3
And p represents 0 to 3. ] The cyclic diamine derivative represented by these, and its pharmaceutically acceptable salt. 2. General formula (1) (In the formula, R ¹ and R ² each represent an unsubstituted or optionally substituted phenyl group, a pyridyl group, a cycloalkyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R 3
⁴ , R ⁵ are the same or different and each is a hydrogen atom,
It represents a lower alkyl group, and R ⁴ and R ⁵ may form an alkylene ring to form a bridge, and R ⁶ and R ⁷ are the same or different and each is a hydrogen atom, a lower alkyl group, an unsubstituted or substituted group. Represents a phenyl group which may have
⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, Z represents a carbon atom or a nitrogen atom, m represents 1 to 4, and n represents 1 to 3
And p represents 0 to 3. ) In producing the compound represented by the formula (1) and salts thereof, the compound represented by the general formula (2) (In the formula, R ¹ , R ² , R ³ and m are as described above, and X
Represents a leaving group) and a compound represented by the general formula (3) (Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z, n and p are as described above), and the reaction is carried out. 3. The general formula (1) (In the formula, R ¹ and R ² each represent an unsubstituted or optionally substituted phenyl group, a pyridyl group, a cycloalkyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R 3
⁴ , R ⁵ are the same or different and each is a hydrogen atom,
It represents a lower alkyl group, and R ⁴ and R ⁵ may form an alkylene ring to form a bridge, and R ⁶ and R ⁷ are the same or different and each is a hydrogen atom, a lower alkyl group, an unsubstituted or substituted group. Represents a phenyl group which may have
⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, Z represents a carbon atom or a nitrogen atom, m represents 1 to 4, and n represents 1 to 3
And p represents 0 to 3. ) In producing the compound represented by (Wherein R ¹ and R ² are as described above), the compound represented by the general formula (5) (In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z,
m, n and p are as described above, and X represents a leaving group.)
A method for producing a compound, which comprises reacting a compound represented by 4. The general formula (1) (In the formula, R ¹ and R ² each represent an unsubstituted or optionally substituted phenyl group, a pyridyl group, a cycloalkyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R 3
⁴ , R ⁵ are the same or different and each is a hydrogen atom,
It represents a lower alkyl group, and R ⁴ and R ⁵ may form an alkylene ring to form a bridge, and R ⁶ and R ⁷ are the same or different and each is a hydrogen atom, a lower alkyl group, an unsubstituted or substituted group. Represents a phenyl group which may have
⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, Z represents a carbon atom or a nitrogen atom, m represents 1 to 4, and n represents 1 to 3
And p represents 0 to 3. ) A pharmaceutical composition useful as a cholinergic receptor antagonist, which comprises a compound represented by the formula (4) and a pharmaceutically acceptable carrier. 5. The general formula (1) (In the formula, R ¹ and R ² each represent an unsubstituted or optionally substituted phenyl group, a pyridyl group, a cycloalkyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R 3
⁴ , R ⁵ are the same or different and each is a hydrogen atom,
It represents a lower alkyl group, and R ⁴ and R ⁵ may form an alkylene ring to form a bridge, and R ⁶ and R ⁷ are the same or different and each is a hydrogen atom, a lower alkyl group, an unsubstituted or substituted group. Represents a phenyl group which may have
⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, Z represents a carbon atom or a nitrogen atom, m represents 1 to 4, and n represents 1 to 3
And p represents 0 to 3. ) A pharmaceutical composition for treating dysuria, which comprises a compound represented by the formula (4) and a pharmaceutically acceptable carrier. 6. The general formula (1) (In the formula, R ¹ and R ² each represent an unsubstituted or optionally substituted phenyl group, a pyridyl group, a cycloalkyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R 3
⁴ , R ⁵ are the same or different and each is a hydrogen atom,
It represents a lower alkyl group, and R ⁴ and R ⁵ may form an alkylene ring to form a bridge, and R ⁶ and R ⁷ are the same or different and each is a hydrogen atom, a lower alkyl group, an unsubstituted or substituted group. Represents a phenyl group which may have
⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, Z represents a carbon atom or a nitrogen atom, m represents 1 to 4, and n represents 1 to 3
And p represents 0 to 3. ) A pharmaceutical composition for treating irritable bowel syndrome, which comprises a compound represented by the formula (4) and a pharmaceutically acceptable carrier.