JPH03255068A - Novel quaternary indolium salt and its production method - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel quaternary indolium salt that is effective as a therapeutic agent for urinary disorders such as urinary incontinence and frequent urination.

[Prior Art and Problems to be Solved] Urinary incontinence and frequent urination cause mental pain to patients and significantly impede their social life. The essence of these pathologies is that the bladder is overstrained.

On the other hand, it was known that urination is caused by reflex bladder contraction.

Oxypudinine hydrochloride and telocillin hydrochloride are known as conventional drugs for treating urinary incontinence and frequent urination, and these drugs suppress bladder contraction by suppressing the micturition reflex based on their anticholinergic effect. Therefore, these drugs also reduce the ability to urinate and are likely to cause serious side effects such as urination and difficulty in urination, and are therefore not satisfactory as therapeutic agents. As a therapeutic drug for urinary incontinence and frequent urination, it is desirable to alleviate the hypertonic state of the bladder and increase bladder capacity without suppressing the micturition reflex. In the medical field, new types of urinary incontinence that do not cause the side effects mentioned above,
A drug to treat frequent urination is strongly desired.

In addition, as a quaternary indolium salt,
317 describes a 5-chlor derivative that exhibits a cholinergic effect, but the pharmacological action of this compound is a therapeutic effect on achlorhydria and gastric atony, which is completely different from the action of the compound of the present invention. It is something.

[Problems to be Solved by the Invention] The present invention provides a drug that can treat urinary incontinence and urinary frequency without causing the side effects of conventional drugs for treating urinary incontinence and urinary frequency. It is for the purpose of

[Means for Solving the Problems] For the above-mentioned purpose, the present inventors focused on quaternary indolium salts and, as a result of extensive research, found that - formula [D] [wherein R1 is a methyl group] or represents an ethyl group, R2 represents a lower alkyl group or an aralkyl group, R3 represents a hydrogen atom, a lower alkyl group, or a phenyl group, R4 represents a hydrogen atom or a lower alkyl group, or R2 and R3, R3 and R4 may form a ring via alkylene, R5 is a lower alkyl group, -0R6 (where 6 is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkylalkyl group, a substituent on the benzene ring) -Nll-R'
(Here, R7 represents a lower alkanoyl group or a benzoyl group) and X represents no anion] The quaternary indolium salt derivative shown in the following formula does not exhibit the side effects of existing drugs and increases bladder capacity. The present inventors have discovered that this can be done, and have completed the present invention.

In the present invention, "lower alkyl" refers to methyl,
Examples include linear or branched carbon atoms having 1 to 6 carbon atoms, such as ethyl, 0-propyl, and isopropyl. Examples of "lower alkenyl" include vinyl, aryl, and other straight or branched alkenyls having 2 to 6 carbon atoms and having at least one unsaturated bond. "Aralkyl" refers to a benzyl, phenethyl, or benzene ring having a lower alkyl substituted thereon, and examples of substituents that may be present include halogen, lower alkyl, and lower alkoxy. here"
Examples of the "halogen" include fluorine, chlorine, bromine, and iodine, and examples of the "lower alkoxy" include those having 1 to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy, and isopropoxy.

"Cycloalkyl" refers to alicyclic hydrocarbons having 3 to 6 carbon atoms, such as cyclopropyl and cyclohexyl.

"Cycloalkylalkyl" refers to cycloalkyl substituted with lower alkyl, such as cyclopropylmethyl and cyclohexylmethyl. The term "alkanoyl group" refers to an acyl group having a lower alkyl group having 1 to 6 carbon atoms, such as acedel, propionyl, and pivaloyl.

"Cycloalkylcarbonyl" refers to carbonyl substituted with an alicyclic hydrocarbon having 3 to 6 carbon atoms, such as cyclopropylcarbonyl and cyclohexylcarbonyl. Examples of "anion" include chlorine ion, bromide ion, methanesulfonate ion, p-toluenesulfonate ion, and the like.

In addition, in the quaternary indolium salt of the present invention, 1.2.
Regarding the substituents at the 3- and 5-positions, optical isomers and geometric isomers exist depending on the substituents, and the present invention includes both of these isomers and mixtures thereof.

In the present invention, the compound of general formula [I] can be produced by a method not shown below.

2 (1) - Formula [I (2) - Formula 1: I -a [In the formula, R1,
R2, R3, R4, Rli and X are as described above, and the compound represented by the formula [11] [wherein R2, R3, R4, R5 and
It can be produced by reacting a compound represented by -formula E m ] R1-X [II+ ] [wherein R1 and X are as described above]. This reaction is preferably carried out at 0 to 150° C. in a solvent such as dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, ether, tetrahydrofuran, benzene, toluene, acetone, ethanol, acetonitrile, or the like, or without a solvent.

[In the formula, R1, R2, R3, R4 and x are as described above, and R6° is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkylalkyl group, or a benzene ring having a substituent.] A compound represented by the formula [TV] [where R2, R3 and R4 are as described above] and a compound represented by the general formula [V]-y [V] [wherein,
R6p is as described above, and Y represents a leaving group.] It can be produced by reacting a compound represented by the following formula, and then converting it into a quaternary salt according to the method (1). Above Y
Examples of the "leaving group" represented by include halogen and substituted sulfonyloxy (eg, methanesulfonyloxy, p-toluenesulfonyloxy), and the like. The above condensation reaction is carried out in a solvent such as dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, ether, tetrahydrofuran, benzene, toluene, etc. in the presence of an alkali metal hydride, alkali metal hydroxide, alkali metal carbonate, etc. as a base. It is desirable to carry out at 0-100°C.

(3) General formula [T-b] [wherein, 111. R2, R3, R4 and x are as described above (DA
V) Tet.

The compound represented by -S
A compound represented by the formula [IV]2 [wherein R2, R3, and R4 are as described above] and a compound represented by the general formula [■con6'"-2[VT] [wherein R6° is as described above], Z can be produced by reacting a compound representing a halogen and then converting it into a quaternary salt according to the method (1).This condensation reaction can be carried out using dimethylformamide, dimethylsulfoxide, dichloromethane, In a solvent such as chloroform, ether, tetrahydrofuran, pyridine, benzene, toluene, etc., inorganic bases such as alkali metal oxides, alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal hydroxides, etc. or organic In the presence of a base, 0
It is preferable to carry out the test at ~100°C.

5 6 (4) General formula [I-c] [in the formula u1. R2, R3, n4 and x are as described above 0) a
') "II" ari, R7 represents a lower alkanoyl group or benzoyl group] The compound represented by -11R formula [■] 2 [wherein R2, R3 and R4 are as described above, the compound represented by A compound represented by the general formula [■] R'-2 [■] [In the formula, R7 is as described above and Z represents a halogen] is reacted, and then a quaternary chloride is prepared according to the method (1). It can be manufactured by

This condensation reaction is carried out in a solvent such as dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, ether, tetrahydrofuran, pyridine, benzene, toluene, etc., or in the absence of a solvent, using an alkali metal hydroxide, alkali metal carbonate, or alkali metal as a deoxidizing agent. It is preferable to carry out the reaction at 0 to 100° C. in the presence of an inorganic or organic base such as a bicarbonate or an alkaline earth metal hydroxide.

[Efficacy] The novel compound of the present invention, quaternary indolium salt, can treat urinary incontinence and frequent urination without causing the side effects of conventional drugs for treating urinary incontinence and frequent urination, such as pressure obstruction and difficulty in urination. There are benefits to be gained.

[Example] Hereinafter, the compounds of the present invention will be explained in detail with reference to Examples.

Example 1 2.3-dihydro-1,1,2-trimethyl-5-benzyloxy-Il+-indolium iodite a)
Mix anhydrous potassium carbonate (3.0 g) and dimethylformamide (DMF; 80 mfl) and add 2.3
-dihydro-5-hy[roxy1,2-dimethyl-I
H-indole (3.0 g) was added dropwise, heated to 70°C, and stirred for 30 minutes. Benzyl chloride (2.4 g) was added dropwise to the reaction solution, and the mixture was further stirred for 4 hours. The reaction solution was diluted with water and extracted with benzene. The organic layer was washed successively with water, saturated brine, and 5% aqueous sodium hydroxide solution, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform) to give 1,2,3-dihydro-1,2-dimethyl-5-benzyloxy-111-indole (3,
5g, 75.3%) was obtained.

b) The above compound (1, Og), methyl iodide (2,5m
1) and benzene (mix 10nl, 100ml in a sealed tube)
The reaction was carried out at ℃ for 15 hours. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from ethanol to obtain the desired product (800 mg: 51.3%) as colorless needle crystals. Melting point 1
94-196°C.

Elemental analysis value (%) Calculated value as C+aH22TNO, C: 54.77 H: 5.60 N:
3.54 actual value, C: 55.07 H: 5.6
1 N: 3.49 Examples 2 to 10 According to the method of Example 1, the compounds shown in Table 1 were synthesized.

9 JP-A-3-255068 (7) Example 11 5-cyclohexylmethyloxy-2,3-dihydro-
1,1,2-Trimethyl-111-indolium iodite a) After washing 60% sodium hydride (1.2 g) with n-hexane (10 m) three times, DMF (50 J)
added to. 2,3-dihydro-5-hydroxy-1,
After dropping 2-dimethyl-1H-indole (3.0 g), the mixture was stirred at room temperature for 30 minutes. Next, DMFI solution (10 mM) containing cyclohexyl bromide (2.3 g) was added dropwise to the above solution, and the mixture was stirred at 50° C. for 8 hours. After diluting the reaction solution with water, it was extracted with benzene. The organic layer is water,
After sequentially washing with saturated brine, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform) to give 5-cyclohexylmethyloxy-23
-dihydro-12-dimethyl-IH-indole (3,
2g: 68.1%) was obtained.

b) The above compound (2.0 g), methyl iodide (2.5
mu) and benzene (50 m9.) in a sealed tube.
The reaction was carried out at 0°C for 24 hours. After cooling to room temperature, n-hexane was added to the reaction solution, the precipitate was collected by filtration, and recrystallized from isopropyl ether-ethanol to obtain the desired product (1.37 g: 44.3%) as colorless needle crystals. Obtained. Melting point 18
5-186℃.

Elemental analysis value (%) Calculated value as C11lH28INO, C: 53.87 H: 7.03 N +
3.49 actual value, CI 53.84 H: 7.
07 N: 3.46 Examples 12 to 32 According to the method of Example 11, the compounds shown in Table 2 were synthesized.

1 2 JP-A-3 255068 (10) Example 33 2.3-dihydro-1,1,2-1-rimedyl-5-benzyloxy-111-indolium p4 luenesphone-+1 Compound of Example 1-a) ( 1,0g), p-)methyl luenesulfonate (0,Illg) and benzene (20
m) were mixed and reacted in a sealed tube at 80°C for 24 hours. After cooling to room temperature, n-hexane (50m9.
) was added and pressed for 30 minutes. The precipitate was collected by filtration and recrystallized from benzene-acetone to obtain the desired product (1.18 g: ea, s%) as colorless needle crystals.

Melting point 153-155℃ Elemental analysis value (%) Calculated value as C25H29NO4S, C: 68.32 H: Ii, 64 N
: 3.19 actual value, C: Ii8.26 H:
6.67 N: 3.20 Examples 34 to 37 According to the direction of Example 33, the compounds shown in Table 3 were synthesized.

545- JP-A-3 255068 (12) Example 38 6-acetylamino-2,3-dihydro-1,1-dimethyl-11(-indolium iodite a)[I-amino-2,3-dihydro-1- Methyl-111 indole (2.0 g) and acetic anhydride (50 mL) were mixed and refluxed for 1 hour. The reaction solution was diluted with water and then extracted with chloroform. The organic layer was washed successively with water, saturated brine, and 5% sodium hydroxide, and the solvent was distilled off under reduced pressure. n of leftovers
Recrystallization from -hexane-ethanol gave 6-acetylamino-2,3-dihydro-1-medy-IH-indole (2.0 g, 5.2%). Melting point 85-87℃
b) The above compound (1,0g>, methyl iodide (2mfl
) and ace]・n (30 mu) were mixed and heated at 80°C in a sealed tube.
The reaction was carried out for 24 hours. After cooling to room temperature, the precipitate was collected by filtration, washed with acetone, and recrystallized from ethanol to obtain the desired product (900 mg + 51.7%) as a colorless powder.
) was obtained. Melting point 201-202°C.

Elemental analysis value (%) Calculated value as C, 2H, 1N2O; C: 69.45 H: 7.41 N・1
4.73 actual value; C: 69.85 H: 7.1
4 N + 14.7! i Example 39 5-benzoyloxy-2,3-dihydro-l,1-dimethyl-IH-yne[.lium iodite a) 2
．． 3-dihydro-5-hydroxy-1-methyl-111
-Indole (1,, Og), benzoyl chloride (0,9
2g), anhydrous potassium carbonate (1.0g) and chloroform (20mU) were mixed and stirred at room temperature for 9 hours. The reaction solution was diluted with water and then extracted with chloroform. The organic layer was washed successively with water, saturated brine, and 5% sodium hydroxide, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform) to obtain 5-benzoyloxy-2,3-dihydro-1-methyl-IH-indole (13 g, 76.5%).

b) The above compound (1.3 g), methyl iodide (3 mN
) and benzene (20μ) were mixed and reacted in a sealed tube at 80°C for 24 hours. After cooling to room temperature, the precipitate was collected by filtration, washed with acetone, and recrystallized from ethanol to give a colorless The target product (1.4 g
0.0%) was obtained. Melting point 164-166°C.

Elemental analysis value (%) Calculated value; C: 51.66 Actual value, C: 51.76 H as CI7H181NO2: 4.59 N: 3.54H:
4.60 N: 3.50 Examples 40 to 50 According to the method of Example 39, the compounds shown in Table 4 were synthesized.

8 Example 51 1-ethyl-2,3-dihydro-1,2-dimethyl-5
benzyloxy-Il+-indolium iodite a
) 60% sodium hydride (8 g IC) was washed 3 times with n-hexane (50 mU), and then DMF (450 mU) was washed 3 times with n-hexane (50 mU).
sentence) was added. 1-ethyl-2,3-dihydro 1-methyl-5-hydroxy-IH-indole (40,0 g
) was added dropwise, and the mixture was stirred at room temperature for 30 minutes.

Then, after dropping 27.5 nl of benzyl bromide,
Stirred at 0°C for 16 hours. After diluting the reaction solution with water, it was extracted with pensene. The organic layer was washed successively with water and saturated brine, and then the solvent was distilled off under reduced pressure. The residue was distilled to obtain 7.1-ethyl-2,3-dihydro-1-methyl-5-benzyloxy-IH-indole (38.0 g + 62.9 g). Boiling point 225-230℃10. s Kawakawa 1-1g (
Kukerroll).

b) The above compound (7, Og), methyl iodide (11m
) and benzene (80m) were mixed and refluxed for 24B@. After cooling to room temperature, n-hexane (50 m, Q
) was added, the precipitate was collected by filtration, and the desired product (8.5g + 79.4g
g) was obtained.

The presence of geometric isomers was confirmed from the nuclear magnetic resonance spectrum of this product, and the production ratio was 1:4.5.

The above product was recrystallized three times from acetonitrile to obtain only one of the geometric isomers (3.0 g). Melting point 185-187°C Elemental analysis value (%) Calculated value as Cl9824 NO, C: 55.76 H: 5.
90 N: 3.42 actual value; C・55.51
H: 5.95 N + 3.46 Experiment 1: Bladder capacity R
IT4 High Effect Test A male rabbit (body weight 2.5-3 kg) anesthetized with urethane (1.5 g/kg, s, c,) was fixed in a dorsal position, and a midline incision was made in the lower abdomen. 5. Make an incision at the top of the bladder and insert a polyethylene crab. - Inserted. Physiological saline heated to 37° C. was injected from here at a rate of 2.5 mU/min, and the intravesical pressure was measured using a pressure transducer set midway through the cannula. After confirming that the bladder is filled with physiological saline and reflex urinary contractions occur, the test drug (Test 1 2 body dose: 1 mg/kg, i, v,) was administered, and the value obtained by dividing the micturition interval after administration by the micturition interval before administration was defined as the bladder capacity increase ratio (Rv). The results are shown in Table 5.

Experiment 2 - Acedercholine-induced ileal contraction inhibition test Guinea pigs were killed by exsanguination, and the ileum was removed to a length of 2.5 cm. Specimens were placed in an aerated Tyrode tube with a load of 1 g.
It was suspended in a liquid (37°C). Specimen responses were recorded on a recorder via an isotonic transducer. Acetylcholine was added to 1xlO in isolated guinea pig ileum specimens.
A dose-response curve was created by cumulatively adding the test drug until the maximum response was obtained, and the effect of pretreatment with the test drug for 5 minutes was examined. For drugs that translated the acetylcholine dose-response curve to the right, p8 values were determined.・Results are shown in Table 5
Shown below.

Acetylcholine-induced ileal contraction inhibition test The bladder capacity increasing effect of the compound of the present invention was superior to that of the control drug, and the anticholinergic effect, which is a side effect, was weaker than that of the control drug. In particular, the compound of Example 11 or Example 24 had a bladder capacity increasing effect 2 to 4 times that of the control drug, and the anticholinergic effect as a side effect was 172 to 1/300.

Claims (1)

[Claims] 1 General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R^1 represents a methyl group or an ethyl group, and R^2
represents a lower alkyl group or an aralkyl group, R^3 represents a hydrogen atom, a lower alkyl group, or a phenyl group, R^4
represents a hydrogen atom or a lower alkyl group, or R^2 and R
^3, R^3 and R^4 may form a ring via alkylene, R^5 is a lower alkyl group, -OR^6 (here, R^6 is a lower alkyl group, a lower alkenyl group, Cycloalkyl group, cycloalkylalkyl group, aralkyl group which may have a substituent on the benzene ring, lower alkanoyl group, diphenylacetyl group, cycloalkylcarbonyl group, benzoyl group, xanthene-9-carbonyl group, methane sulfonyl group, phenylsulfonyl group), -NH-R^7 (where R^7 represents a lower alkanoyl group or benzoyl group), and X represents an anion]. . 2 General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R^1, R^2, R^3, R^4, R^5 and X are as described above] In producing the quaternary indolium salt represented by the general formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] [In the formula, R^2, R^3, R^4, R^5 and X are as described above] is reacted with a compound represented by the general formula [III] Manufacturing method. 3 General formula [ I -a
] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[ I -a] [In the formula, R^1, R^2, R^3, R^4 and X are as described above, and R^6' is a lower grade In producing a quaternary indolium salt represented by an alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkylalkyl group, or an aralkyl group which may have a substituent on the benzene ring, general Formula [IV] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IV] Indoline derivative represented by [In the formula, R^2, R^3 and R^4 are as described above] and the general formula [V] R^ A compound represented by 6'-Y[V] [wherein R^6' is as described above and Y represents a leaving group] is reacted in the presence of an appropriate base, and the resulting compound is A production method characterized by reacting a product with a compound represented by the general formula [III] R^1-X[III] [wherein R^1 and X are as described above]. 4 General formula [ I -b] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I -b] [In the formula, R^1, R^2, R^3, R^4 and X are as mentioned above. , R^6'' represents a lower alkanoyl group, diphenylacetyl group, cycloalkylcarbonyl group, benzoyl group, xanthene-9-carbonyl group, methanesulfonyl group, phenylsulfonyl group]. In doing so, the general formula [IV] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IV] [In the formula, R^2, R^3 and R^4 are as described above] and the indoline derivative represented by the general formula [ VI] R^6"-Z[VI] [In the formula, R^6" is as described above and Z represents a halogen] is reacted in the presence of an appropriate base to obtain A manufacturing method characterized by reacting the obtained product with a compound represented by the general formula [III] R^1-X[III] [wherein R^1 and X are as described above].5 General formula [ I -c] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I -c] [In the formula, R^1, R^2, R^3, R^4 and X are as described above, R^7 represents a lower alkanoyl group or a benzoyl group] In producing a quaternary indolium salt represented by the general formula [VII] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [VII] [In the formula, R ^2, R^3 and R^4 are as described above] and an indoline derivative represented by the general formula [VIII] The compound is reacted in the presence or absence of an appropriate base, and the resulting product has the general formula R^1-X [III] [wherein R^1 and X are as described above] A manufacturing method characterized by reacting a compound represented by: 6 General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R^1 represents a methyl group or an ethyl group, and R^2
represents a lower alkyl group or an aralkyl group, R^3 represents a hydrogen atom, a lower alkyl group, or a phenyl group, R^4
represents a hydrogen atom or a lower alkyl group, or R^2 and R
^3, R^3 and R^4 may form a ring via alkylene, R^5 is a lower alkyl group, -OR^6 (here, R^6 is a lower alkyl group, a lower alkenyl group, Cycloalkyl group, cycloalkylalkyl group, aralkyl group which may have a substituent on the benzene ring, lower alkanoyl group, diphenylacetyl group, cycloalkylcarbonyl group, benzoyl group, xanthene-9-carbonyl group, methane sulfonyl group, phenylsulfonyl group), -NH-R^7 (where R^7 represents a lower alkanoyl group or benzoyl group), and X represents an anion]. A therapeutic agent for urinary dysfunction containing at least one or more of the following as an active ingredient.