JPH07291944A - Novel cyclic diamine derivative and production thereof - Google Patents

Abstract

PURPOSE:To obtain the novel compound high in the selectivity to the muscarine receptors for other smooth muscles compared to cardiac muscarine receptors, having potent antagonistic activity, useful as, e.g. a medicine for dysuria, irritable intestine syndrome, etc. CONSTITUTION:The cyclic diamine derivative of formula I [R<1> and R<2> each is (substituted) phenyl or pyridyl; R<3> is H or a lower alkyl; R<4> and R<5> each is H or a lower alkyl, or are combined into an alkylene ring which may be crosslinked; R<6> and R<7> each H, a lower alkyl or (substituted) phenyl; R<8> is H, a halogen, etc.; (m) is 1-4; (n) is 1-3; (p) is 0-3] or a pharmaceutically permissible salt, e.g. 4-(4-benzyl-1-piperazinyl)-2,2-diphenylbutylonitrile dihydrochloride. The compound of the formula I is obtained, for example, by reaction of a compound of the formula II (X is an eliminable group) with a compound of the formula III.

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 quaternary ammonium salts thereof are known, and these are acetylcholine receptor blockers. 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 or pyridyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ are the same. or different and each represents a hydrogen atom, a lower alkyl group, further R ^4, R ⁵ may be crosslinked to form an alkylene ring, R ^6, R ⁷ are the same or different and each represents a hydrogen atom, a lower It represents an alkyl group, an unsubstituted or optionally substituted phenyl group, R ⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, and m represents 1 to 4. , N is 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. 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) (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
R ⁸ , 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) (Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , n and p are as described above) to produce a compound by reacting in the presence or absence of a base. You can

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) (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
R ⁸ , 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) (Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , m, n,
p and X can be produced by reacting the compound represented by the 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 dihydrochloride

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 to 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 to 21) According to the method of Example 1,
The following compounds were synthesized (Table 1, Table 2, Table 3, Table 4)

[0022]

[Table 1]

[0023]

[Table 2]

[0024]

[Table 3]

[0025]

[Table 4]

[0026]

【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. The results are shown in Table 5.

[0027]

[Table 5]

2: Effect on rhythmic bladder contraction Male Wistar rats were fixed in the back position under halothane anesthesia, 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 ICR male mice were orally administered with a test compound, 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 in selectivity to other smooth muscle muscarinic receptors to cardiac muscarinic receptors as compared with conventional anticholinergics. 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 number Reference number within the agency FI Technical indication C07D 317/58 471/08 // C07D 213/57 (72) Inventor Hiromi Kiyota Nogi, Shimotsuga-gun, Tochigi Prefecture 6096 Machitomonuma Dormitory, Minamitonuma (72) Inventor Mitsuru Segawa 594-5 Nakagawa, Omiya City, Saitama Prefecture

Claims (6)

[Claims] 1. The general formula (1) (In the formula, R ¹ and R ² each represent an unsubstituted or optionally substituted phenyl group or pyridyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ are the same. Alternatively, they may each independently represent a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ may be crosslinked to form an alkylene ring, and R ⁶ and R ⁷ are the same or different and each represent a hydrogen atom or a lower alkyl group. It represents an alkyl group, an unsubstituted or optionally substituted phenyl group, R ⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, and m represents 1 to 4. , N is 1 to 3
And p represents 0 to 3. ] The cyclic diamine derivative represented by these, and its pharmaceutically acceptable salt. 2. The general formula (1) (In the formula, R ¹ and R ² each represent an unsubstituted or optionally substituted phenyl group or pyridyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ are the same. Alternatively, they may each independently represent a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ may be crosslinked to form an alkylene ring, and R ⁶ and R ⁷ are the same or different and each represent a hydrogen atom or a lower alkyl group. It represents an alkyl group, an unsubstituted or optionally substituted phenyl group, R ⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, and m represents 1 to 4. , N is 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) (Wherein R ¹ , R ² , R ³ and m are as described above and X represents a leaving group), and the compound represented by the general formula (3) (Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , 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 or pyridyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ are the same. Alternatively, they may each independently represent a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ may be crosslinked to form an alkylene ring, and R ⁶ and R ⁷ are the same or different and each represent a hydrogen atom or a lower alkyl group. It represents an alkyl group, an unsubstituted or optionally substituted phenyl group, R ⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, and m represents 1 to 4. , N is 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 , m, n
And p are as described above, and X represents a leaving group). 4. The general formula (1) (In the formula, R ¹ and R ² each represent an unsubstituted or optionally substituted phenyl group or pyridyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ are the same. Alternatively, they may each independently represent a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ may be crosslinked to form an alkylene ring, and R ⁶ and R ⁷ are the same or different and each represent a hydrogen atom or a lower alkyl group. It represents an alkyl group, an unsubstituted or optionally substituted phenyl group, R ⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, and m represents 1 to 4. , N is 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 or pyridyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ are the same. Alternatively, they may each independently represent a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ may be crosslinked to form an alkylene ring, and R ⁶ and R ⁷ are the same or different and each represent a hydrogen atom or a lower alkyl group. It represents an alkyl group, an unsubstituted or optionally substituted phenyl group, R ⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, and m represents 1 to 4. , N is 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 or pyridyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ are the same. or different and each represents a hydrogen atom, a lower alkyl group, further R ^4, R ⁵ may be crosslinked to form an alkylene ring, R ^6, R ⁷ are the same or different and each represents a hydrogen atom, a lower It represents an alkyl group, an unsubstituted or optionally substituted phenyl group, R ⁸ represents a hydrogen atom, a halogen, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group, and m represents 1 to 4. , N is 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.