JPH02218651A - Butynylamine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> and R<2> are cycloalkyl, phenyl or 2-thienyl; R<3> and R<4> are H, alkyl or linked and, together with N, form cycloalkyl; R<5> and R<6> are H, alkyl or linked and, together with N, form cyclic amino group; A is O or NR (R is H or alkyl), etc.] and salts thereof. EXAMPLE:4-Diethylamino-2-butynyl alpha,alpha-(2,2'-dithienyl)glycolate.hydrochloride. USE:With anticholine and calcium antagonistic action and useful for treating urinary bladder abnormality, such as pollakiuria or incontinentia urinae. PREPARATION:An ester or amide expressed by formula II (R<7> is lower alkyl) is reacted with a 2-butyne compound expressed by formula III (R<8> is H or lower alkanoyl) in the presence of a base (e.g. potassium alkoxide) in a solvent, such as benzene, at 50-200 deg.C to afford the compound expressed by formula I.

Description

[Detailed description of the invention] [Industrial application field]

The present invention exhibits anticholinergic effect and calcium antagonistic effect,
The present invention relates to a butynylamine derivative represented by the following general formula CI) and a pharmacologically acceptable salt thereof useful as a therapeutic agent for bladder abnormalities including frequent urination and various other urinary incontinence. Here, R' and R' are the same or different and represent cycloalkyl, phenyl or 2-thienyl. R' and R' are the same or different and represent hydrogen or alkyl, or R3 and R4 combine to form cycloalkyl together with adjacent carbon atoms. R1 and Ra are the same or different and represent hydrogen or alkyl, or R5 and R6 are combined to form a grooved amino group together with the adjacent nitrogen atom. A represents oxygen or NR (R represents hydrogen or alkyl).

[Conventional technology]

Conventionally, as a treatment for frequent urination, flavoxate (flav
The number of pharmaceuticals in this field is extremely small, as only oxate) is used. Telocilin and oxybutynin have only recently been introduced as successors to flavoxate. A compound similar to the compound of the present invention is oxybutynin, but oxybutynin has a strong anticholinergic effect and causes side effects such as dry mouth, making it a major obstacle in treatment.

Problems to be Solved by the Invention [] The present inventors have conducted research with the aim of obtaining a compound that fully compensates for the above-mentioned drawbacks and has an effect superior to that of conventionally known agents for treating frequent urination. Layered. [Measures to Solve Problem 1111 &] The gist of the present invention lies in the structure itself of the compound represented by the general formula CI). The compound according to the present invention is a novel compound that has not been described in any literature, has excellent medicinal efficacy as described below, and has low toxicity. The compounds according to the present invention will be explained in detail. In the general formula (1), the cycloalkyl represented by R' and R'' preferably has 5 to 7 carbon atoms,
Examples include cyclopentyl, cyclohexyl, cycloheptyl and the like. The alkyl represented by R' and R' is preferably a straight or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl. , tert-butyl and the like. When R3 and R4 combine to form cycloalkyl with adjacent carbon atoms, a 5- to 6-membered ring is preferred. The alkyl represented by Ra or Ra is preferably a straight or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ec-phthyl, Examples include tert-butyl. When R' and R6 combine to represent a cyclic amino together with the adjacent nitrogen atom, oxygen, sulfur, nitrogen atoms, etc. may be included as constituent atoms of the ring. Examples of such a cyclic amino group include pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, and homopiperazino. These cyclic amino groups may be substituted with alkoxy-substituted phenyl. The alkoxy preferably has 1 to 4 carbon atoms, such as methoxy, ethoxy, O-propoxy, impropoxy, n-butoxy, imbutoxy,
Examples include 8eC-butoxy and tart-butoxy. Examples of the salts of the compounds of the present invention include salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and salts of organic acids such as sychoic acid, tartaric acid, maleic acid, and benzenesulfonic acid. The compound of the present invention can be produced, for example, by the following method. Method A [■] (III) → [I] (In the formula, ASR'%R', R', R' and R6 are the same as above. R7 is lower alkyl, and Ra is hydrogen or lower alkanoyl. [13] can be produced by reacting the ester or amide represented by ) [■] with the 2-butyne compound of CI [I] by a known method. For example, in this reaction, In an inert solvent, use a base catalyst (potassium alkoxide, sodium alkoxide, etc.) to remove the alcohol produced in a dehydration tube, or if [■] is a methyl ester, preferably use molecular sieves. [I] can be obtained in high yield by selectively adsorbing methanol produced by coexistence.As the reaction solvent, those commonly used in this type of reaction can be used.For example, benzene ,toluene,
Hydrocarbon solvents such as n-pentane, n-hexane, petroleum ether, anhydrous ether, ether solvents such as tetrahydrofuran, isopropyl ether, dioxane, dimethoxyethane, diethylene glycol, dimethyl ether, acetonitrile, N,N-dimethylformamide, sulfolane Aprotic solvents such as, etc. can be used. The reaction temperature is 50 to 200°C, preferably 90°C.
~120°C. The amount of [■] to be used is 1 to 2 times the mole of [■], preferably 1 to 1.2 times the mole of [■]. Also, acid catalysts (sulfuric acid, fl-)luenesulfonic acid, etc.)
By using [III] in large excess, or by removing low-boiling methanol when [■] is a methyl ester, (II) can be produced in high yield. Method B ( Grignard method) (IV) R"-Li (■) → (I) (wherein ASR', R', R', R', R', R and R6
is the same as above. ) CI) can be produced by reacting a compound represented by (rV] with a Grignard reagent [v] or a lithium compound [VI). The reaction is carried out in a reaction-inert solvent between -78°C and 100°C, preferably between -20°C and 50°C. As the reaction solvent, ether solvents such as anhydrous ether, tetrahydrofuran, isopropyl ether, dioxane, dimethoxyethane, diethylene glycol, and dimethyl ether are most preferred. In addition, benzene, toluene,
Hydrocarbon solvents such as n-pentane, n-hexane, petroleum ether, and optionally amines can also be used. CrV) is usually used in an amount of 1.0 to 0.8 equivalents relative to the Grignard reagent or lithium compound, and preferably is dissolved in a small amount of the same solvent, and the Grignard reagent or lithium compound is added thereto. Method C (Mannich reaction) → [I] (In the formula, A, R', R', R'', R', R' and R6 are the same as above,...) [■] and secondary amine [■] The compound of the present invention (13) is produced by reacting with
The reaction is carried out without a solvent or in a solvent inert to the reaction in the presence of an aldehyde. As the reaction solvent, those commonly used in this type of reaction can be used. For example, alcohols such as methanol, ethanol, propatool, and butanol, ethers such as tetrahydrofuran and dioxane, aprotic solvents such as acetonitrile, N, todimethylformamide, dimethyl sulfoxide, and sulfolane, water, or mixtures thereof may be used. Can be done. As the aldehyde, there can be used a reagent having an effect equivalent to that of formaldehyde during the Mannich reaction, such as paraformaldehyde, formalin, methitool, ethyral, piperidinomethylphthalimide, hexamethylenetetramine, and the like. The amount of aldehyde and secondary amine to be used is approximately 1 to 10 times mole relative to [■]. In addition, secondary amines are
Can be used in salt form. In order to accelerate the reaction, a catalytic amount (0.01 to 0.1 molar equivalent) of a copper salt such as cupric chloride or copper acetate, or zinc chloride may be added to carry out the reaction. The reaction temperature is usually 0 to 100°C. Although the reaction time varies depending on the raw materials, the type of aldehyde, the reaction temperature, etc., 20 minutes to 40 hours is usually sufficient. D method → (Il (wherein, A, R', R", R', R', R'R and R"
is the same as before. X represents halogen. ) The compound represented by the general formula [IX] is reacted with the amine represented by the general formula [■] to produce the compound CI) of the present invention. The reaction is usually carried out at -20 to 100°C in a solvent inert to the reaction. As the reaction solvent, those commonly used in this type of reaction can be used. For example, tetrahydrofuran,
Examples include ethers such as dioxane and ether, and aromatic hydrocarbons such as benzene and toluene. The amine is preferably used in large excess, preferably 5 to 10 times the mole of [■]. The starting materials [III], CIV) and [■] contain new compounds, and these new compounds can be prepared using known methods (J, Org, Chew, 27.290
5 (1962); J, ^Machi Chant, Sac,
, 71.3772 (1949); J, Ma
d, Chewl, 13.1249 (1970)^ct
a, Phara+, 5uecica 6.349 (1
969);Brlt, 1051723;US 32
02655) or can be produced in the same manner as the method of Reference Example described below. The target compound [I] thus produced can be prepared in the form of a free base or in the form of an acid addition salt by means known per se.
For example, it can be isolated and purified by concentration, liquid conversion, dissolution, solvent extraction, crystallization, fractional distillation, chromatography, etc. When the compound of the present invention is administered as a medicament, the compound of the present invention may be administered as is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, from 0.1 to 99.5%, preferably from 0.5 to 99.5%. It is administered to animals, including humans, as a pharmaceutical composition containing 90%. As carriers, one or more solid, semisolid, or liquid diluents, fillers, and other formulation auxiliaries are used. Preferably, the pharmaceutical composition is administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intracellularly, locally (transdermally, etc.), or rectally. Of course, it is administered in a dosage form suitable for these administration methods. For example, oral administration is particularly preferred. It is desirable to adjust the dose of the agent for treating frequent urination, taking into consideration the patient's condition such as age and weight, the route of administration, the nature and severity of the disease, etc. The amount of active ingredient is generally in the range of 1 to 100 mg/person, preferably 1 to 10 mg/person per day. In some cases, a lower dose than this may be sufficient, and in other cases, a higher dose may be required. Also 2-3 a day
It can be administered in divided doses. [Example] The present invention will be explained in more detail by referring to Reference Examples, Examples, and Test Examples below. Reference Example 1 α,α-(2,2′-sichenyl)glycolic acid methyl ester 0.73 g of magnesium and 4.9 g of 2-bromothiophene in anhydrous tetrahydrofuran (THF) under a nitrogen atmosphere
A Grignard reagent prepared by a conventional method is added dropwise to a solution of 4.25 g of α-oxo-2-thiophene acetic acid methyl ester in anhydrous THF under ice cooling. After completion of the dropwise addition, after stirring for 2 hours at water temperature, an aqueous ammonium chloride solution (ammonium chloride 1.5g/15nlH3
Add 0) under water cooling and separate. The THF layer is dried over magnesium sulfate and then concentrated under reduced pressure to obtain crystals of the target product. Recrystallized from n-hexane-ether to give 3.5
Crystals of g were obtained. Melting point 92-93°C Reference example 2 α-cyclohexyl-α-phenyl glycolic acid 1.1
-dimethyl-2-provinyl ester Under a nitrogen atmosphere, in anhydrous THF, 1.1-dimethyl-2-provinyl ester was prepared by a conventional method from 3.38 g of magnesium and 2.27 g of cyclohexyl bromide, and Grignard reagent was added under ice cooling. Add dropwise to a solution of vinyl benzoyl formate in anhydrous THF. After the dropwise addition was completed, the mixture was stirred at water temperature for 18 hours, and then an aqueous ammonium chloride solution (ammonium chloride 7, 5 g/3
0 ml HJ) and separate. The organic layer is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography (Wakogel C-200, ethyl acetate/n-hexane 1:15) to obtain 17.6 g of the desired oily substance. IR(fila+cm-') 3500.3300
．． 2920.2110.1725° The following compound was obtained in the same manner. α-Cyclobenyl α-phenylglycolic acid 1.1
-dimethyl-2-propynyl ester I R (fila
+c+s-') 3500.2950.1725.
1250° 1130, 695 α-Funidyl-α-(2-thienyl)glycolic acid 1.
1-dimethyl-2-propynyl ester IR (film cIll-') 3480. 1
73G, 1255.1125°α,α-diphenylglycolic acid 1,1-dimethyl-2-propynyl ester IR (fila+ cm-') 3500.3295
．． 2110.1725゜α-cyclohexyl-α-(2
-thienyl)glycolic acid 1-methyl-2-propynyl ester I R (film cm-') 3500
．． 3300.2940. H.I.G. α-Cyclobenyl α-(2-thienyl)glycolic acid 1-methyl-2-propynyl ester elemental analysis value (
CtsH+aOaS ” 1/10)!J) Calculated value (%
) (l: 64.30 H6,54 actual value (%)
C64,03) 16.63α-cyclohexyl-α-(
2-thienyl) glycol w11.1-dimethyl-2-
Propynyl ester (film cr') 3500
．． 3300.2910.2100.1725゜α-cyclopentyl-α-(2-thienyl)glycolic acid 111
-dimethyl-2-propynyl ester (filrncm
-') 3500.3300.2950.2110.
1725゜α-cyclohexyl-α-7enylglycolic acid 1-ethynyl-1-cyclopentyl ester α-
cyclopentyl-α-phenylglycolic acid l-ethynyl-1-cyclopentyl ester α-cyclohexyl-
α-Phenylglycol a t-ethynyl-1-cyclohexyl ester α-cyclobenthyl-α-phenylglycolic acid 1-ethynyl-1-cyclohexyl ester α-phenyl-α-2-thienyl) glycolic acid 1
-ethynyl-1-cyclopentyl ester α-phenyl-α-(2-thienyl)glycolic acid l-
Ethynyl-1-cyclohexyl ester N-(2-propynyl)-2-hydroxy-2,2-(
2,2'-dithenyl)acetamide Melting point 128.0
°C To(2-propynyl)-2-cyclobenthyl-2-hydroxy-2-(2-thienyl)acetamide I R(
film cm-') 3390.3300.23
00.1665.1515(2-propynyl)-2-
Cyclohexyl-2-hydroxy-2-(2-thienyl)acetamide Melting point 134-135°C N-(2-propynyl)-2-cyclohexyl-2-hydroxy-2-7enylacetamide Melting point L42.
5-143℃ Reference Example 3 α-oxo-2-thiopheneacetic acid 4-diethylamino-1-methyl-2-butynyl ester α-oxo-2-thiopheneacetic acid 4.3g was dissolved in methylene chloride, and 0.5ml of Pyridine was added, and 6.75 g of thionyl chloride was added dropwise while cooling with water. After heating under reflux for 7 hours, the mixture is concentrated under reduced pressure. Ether is added to the residue to remove insoluble matter, and then concentrated under reduced pressure. Obtained oil jt4.1
g under water cooling, 5-diethylamino-3-pentyne-2-
Add dropwise to a solution of 4.5 g of ol in ether. 18 hours,
After stirring under water temperature, the mixture is made alkaline with an aqueous potassium carbonate solution and separated. The ether layer is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography (Wakogel C-200 ethyl acetate) to obtain 2.48g of the target product as an oily substance.
Obtained. I R (film co+-') 1735.166
The following compound was obtained in the same manner as 5.14i0.1195. α-oxo-2-thiopheneacetic acid 4-diethylamino-2-butynyl ester I R (film co+-') 1735.1660
．． 1410.1185 Reference Example 4 (4-diethylamino-2-butynyl)benzoylformamide N-(2-propynyl)benzoylformamide 0,3
6 g, 80% paraformaldehyde 90 mg and diethylamine 162 mg are added to anhydrous dioxane, 4+ ng of dichloride is added, and the mixture is heated and stirred at 70-80°C. After 1.5 hours, the mixture was cooled to room temperature, acidified with a 5% aqueous hydrochloric acid solution, and the aqueous layer was separated. The aqueous layer is washed with ether, made weakly alkaline with a 5% aqueous solution of caustic soda under water cooling, and extracted with ether. The ether layer is washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained oily residue was subjected to silica gel column chromatography (Wakogel C-200 chloroform) to obtain 0.39 g of the desired product. I R3300, 1690, 1665, 1215 Reference Example 5 α-Cyclohexyl-α-7enylglycolic acid 4-bromo 1,1-dimethyl-2-butynyl ester 4-diethylamino-1,1-dimethyl-2-butynyl α- An ether solution of 3.2 g of bromcyan was added dropwise to an ether solution of 9.5 g of cyclohexyl-α-7enyl glycolate under water cooling, and the mixture was stirred at the same temperature for 1 hour and then at water temperature for 18 hours. After completion of the reaction, 14% of 2N-hydrochloric acid aqueous solution was added under ice-cooling.
Add a+1 and separate the ether layer. The ether layer is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuko-gel C-200 ethyl acetate/n-hexane = 1:15)
The mixture was developed to obtain 6.0 g of the desired product as a colorless oily substance. I RCf1lωcm-') 3500.2920.1
? 25.1270゜I250.1235.1120 Example 1 4-diethylamino-2-butynyl α,α-(2,2'
-dichenyl)glycolate 37 mg of sodium methoxide hydrochloride was prepared and suspended in n-hebutane. 1.09 g of 4-diethylamino-2-butynol and 1.78 g of α,α-(2,2'-dichenyl)glycolic acid methyl ester were added, and the mixture was refluxed for 6 hours while removing methanol using a dehydration tube. Thereafter, ice is added to the reaction mixture, diluted with ethyl acetate, and the organic layer is separated, washed three times with water, and then dried over sodium sulfate. After distilling off the solvent, 2.6 g of a dark red oil was obtained. This was purified by column chromatography (30 g of silica gel, 1 chloroform:methanol 100:1 - Loll). 1.6 g of red oily substance was obtained. This was dissolved in ether and salted with ether/hydrochloric acid. Recrystallization from ethanol/ether yielded 1.18 g of the target compound as a pale yellow powder. Melting point 138.5-140℃ Elemental analysis value (C,, H□N0-5t・HCI) Calculated value (
%) C54,05I5.54 N3.50 Actual value (%") C53,97I5.53 N3.37 Example 2 4- [4-(2-methoxyphenyl)-1-piperazinyl-2-butynyl α, α-( 22 mg of sodium 2,2'-dichenyl)glycolate and 54 mg of sodium methoxide prepared from anhydrous methanol and 1.6 g of α,α-(2,2'-dichenyl)glycolic acid methyl ester and 4-
Add 2.18 g of [4-<2-methoxyphenyl)-1-piperazinyl-2-butynyl acetate to rhohebutane, attach a dehydration tube, and heat to reflux while distilling off the formed methyl acetate. After 18 hours, ice water was added to the reaction solution, the mixture was separated and extracted with a 10% aqueous hydrochloric acid solution. The acidic layer is washed with ether, made weakly alkaline with a 10% aqueous sodium hydroxide solution under water cooling, and extracted with ether. The ether layer is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue is isolated and purified using flash column chromatography (Kiesel Gel 60H). The resulting oil crystallizes on standing. Recrystallization from ethyl acetate/n-hexane yielded a white powder of 0.4
Obtain 9g. Melting point 113-114°C Elemental analysis value (C□H□Nip-5t) Calculated value (%) C62,2285,43N5.80 Actual value (%) C62,271 (5,55N5.71 Example 3 4-diethylamino- 1-methyl-2-butynyl α,
α-(2,2'-dithenyl)glycolate 2-bromothiophene 1.58 and magnesium 223 under nitrogen flow
An anhydrous ether solution of Grignard reagent prepared from B by a conventional method is added dropwise to an anhydrous ether solution of 4-diethylaminol l-methyl-2-butynyl α-oxo-2-thiophene acetate at -10 to -15°C. After the dropwise addition was completed, the mixture was stirred at the same temperature for 3 hours, and then an aqueous ammonium chloride solution (492ff1g/6ml LD) was added at the same temperature. After separating the ether layer, the aqueous layer is extracted with ether. The ether layers were combined, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oily residue is subjected to flash column chromatography (Kiesselgel 60H1 chloroform:methanol=20:1) and developed with chloroform:methanol (100:1) to obtain the desired product. Recrystallization from petroleum ether/ether gives 47 g of white powder 1. Melting point 65.5-66℃ Elemental analysis value (C4H-NO-
St) Calculated value (%) C60,45H6,14N3.71 Actual value (%') C6G,20)16.10 N
3.98 Example 4 4-Diethylamino-1,1-dimethyl-2-butynyl α-cyclohexyl-α-phenyl glycolate hydrochloride 1.1-dimethyl-2-propynyl α-cyclohexyl-α-phenyl glycolate 9.4g, 2.1g of 90% paraformaldehyde, 1162ωg of first chloride in 40ml of anhydrous dioxane! and stir on a 60°C oil bath. Next, add 2.5g of diethylamine to 1011LI! The solution in anhydrous dioxane is added dropwise over 45 minutes. After the addition was completed, the mixture was stirred at the same temperature for 4 hours. Cool to room temperature;
After removing insoluble matter, it is concentrated under reduced pressure. The obtained residue was dissolved in isopropyl ether, and 18% of 2N-hydrochloric acid was added under water cooling.
- and wash the obtained crystals thoroughly with isopropyl ether. Dissolve the hydrochloride in chloroform, wash with ice water, make alkaline with saturated aqueous sodium bicarbonate solution,
Wash with water and dry with magnesium sulfate. Concentrate under reduced pressure,
The obtained oily substance was purified by flash column chromatography (Kieselgel 60H ethyl acetate/n-hexane=
4:6) to obtain the desired product. This was dissolved in ether, and 15% hydrochloric acid/ether was added under water cooling to obtain the hydrochloride. Recrystallization from ethyl acetate gave 9.0 g of colorless prism crystals. Melting point 158-160℃ Elemental analysis value (C24H□NO,・HCI) Calculated value (%)
C68,3L H8,60N 3.32 Actual value (%
) C6B, 19 88.78 N 3.31 Example 5 4-diethylamino-2-butynyl α-cyclohexyl-α・-(2-thienyl)glycolate Hydrochloride 2-
84hg of propynyl α-cyclohexyl-α-(2-thienyl)cricholate, 136mg of 80% paraformaldehyde, 265mg of diethylamine and dichloride@
Add 17 mg to dry dioxane and stir at 80° C. for 1 hour. Cool to room temperature and evaporate dioxane under reduced pressure. Add water to the residue and extract with chloroform. The chloroform layer is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wafugel C-200, chloroform:methanol 15
0:1) to obtain the desired product as an oily substance. Hydrochloride was added with ether/hydrochloric acid and recrystallized with ethanol/ether/n-hexane to obtain 0.443 g of a colorless powder. Melting point i19.5℃ (decomposition) Elemental analysis value (Ci. HasNOsS ”) IcI) Calculated value (%> c6o:oe H7,56N3.5
0 Actual value (%”) C59,76) 17.76
N3.67 Example 6 N-(4-N', N'-diethylamino-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide Magnesium in anhydrous tetrahydrofuran (THF) under a nitrogen stream 510 ■ and cyclohexyl chloride 2.5
Grignard reagent prepared from g by a conventional method was mixed with N-(4
-N',N'-diethylamino-2-butynyl)benzoylformamide (2.5 g) was added dropwise to an anhydrous THF solution under ice cooling. After the dropwise addition was completed, the mixture was stirred at room temperature for 18 hours, and an aqueous ammonium chloride solution (1.12 g/15 m1) was added.
) under water cooling. After separating the aqueous layer, the THF layer was washed with water.
After drying over magnesium sulfate, concentrate under reduced pressure. The obtained residue is isolated and purified using flash column chromatography (Kiesel Gel 60H). The resulting oily substance crystallizes on standing. Recrystallization was performed from ether/petroleum ether to obtain 0.74 g of white powder. Melting point 1
05-105.5℃ Elemental analysis value (CiJsJ*Oa) Calculated value (%') C74,1289,05N7.86
Actual value (%) C74,1889,12N7.75 Example 7 1,1-dimethyl-4-(1-pyrrolidinyl)-2-butynyl α-cyclobenthyl α-phenyl glycolate hydrochloride 1,1-dimethyl- 1.6 g of 2-propynyl α-cyclopentyl-α-phenyl glycolate is added to a homogeneous solution of an anhydrous dioxane solution of 243 mg of 90% paraformaldehyde and 440 a+g of pyrrolidine heated and stirred at 80° C. for 1 hour. Next, the temperature is raised to 100°C, and after 18 hours, it is concentrated under reduced pressure. The obtained residue is dissolved in isopropyl ether, washed with water, and then extracted with a 5% aqueous hydrochloric acid solution. The acidic layer is washed with ether and then extracted with chloroform. The chloroform layer is washed with ice-water. Next, a saturated aqueous sodium bicarbonate solution was added to the chloroform extract, and the chloroform layer was separated, washed with water, and dried (MgSO, ).
, concentrate under reduced pressure. The obtained oily substance was subjected to flash column chromatography (Kiesel Gel 60) 1.4
0% ethyl acetate/n-hexane) to obtain the desired product as an oily substance. Hydrochloride with 20% IIcI/ether and ethyl acetate/
Recrystallization from acetone yields 1.37 g of colorless columnar crystals. Melting point 167-168℃ Elemental analysis value (C*Js+NOs・)IcI) Calculated value (%
) C68,05H7,95N3.45 Actual value (%
) C67,8487,93N3.36 Example 8 4-ethylamino-1,1-dimethyl-2-butynyl
α-Cyclohexyl-α-phenyl glycolate Hydrochloride 4-bromo-1,1-dimethyl-2-butynyl α-Cyclohexyl-α-phenyl glycolate 6.0 g Dissolved in 0 g of benzene and cooled with water, 8.2 g of ethylamine was added to benzene. The solution is added dropwise over a period of 1 hour. After stirring as it is for 18 hours, the mixture is washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is subjected to column chromatography (Wako Gel C-200 ethyl acetate/n-hexane=2:1) to obtain the desired product as an oily substance. Dissolve this in isopropyl ether and
% salt R/ether to make hydrochloride. Recrystallization from ethanol-ethyl acetate gave 3.6 g of colorless prism crystals.
Melting point 158-160℃ Elemental analysis value (CsJs+NOs・
HCI) Calculated value (i%) C67,0788,19N
3.56 Actual value (%) C66,7588,25N 3
．． 75 The following compounds were obtained in the same manner. Example 9 4-(1-pyrrolidinyl)-2-butynyl α, α-(
2,2'-dithenyl)glycolate Melting point: 128-129°C Elemental analysis value (C, @) 1. lN0sS2) Calculated value (%)
C59,81N5JON3.87 Actual value (%)
C59,84) 15.41 N3.94 Example 10 4-morpholino-2-butynyl α,α-(2,2'-
dichenyl) glycolate Melting point 113-115℃ Elemental analysis value (C+-HIJO-Ss) Calculated value (%) C57,2785,07N 3.71
Actual value (%) C57,07N5.29 N3.7
1 Example 11 4-piperidino-2-butynyl α,α-(2,2'-
Dichenyl) glycolate Melting point 140-141℃ Elemental analysis value (C+J*, NOsSi) Calculated value (%) C60,77) 15.64 N 3
．． 73 Actual value (%) C61,O? B5,96
N3. TO Example 12 1-Methyl-4-(1-pyrrolidinyl)-2-butynyl α. α-(2,2'-dithenyl)glycolate Melting point 106
~107℃ Elemental analysis value (CIJ2+NO-35) Calculated value (%”) C60,77B5.64 N3
．． 73 Actual value (%) C60, To B5.78
N3.75 Example 13 4-diethylamino-1-methyl-2-butynyl α-
Cyclohexyl-α-(2-thienyl)glycolate
Hydrochloride. Melting point 156-159℃ (decomposition) Elemental analysis value (C*+H*+N0sS-) 1cI・3/4
H Yukiguchi) Calculated value (%) C58,99B7.89 1
13.28 Actual value (%) C59,17B7. B15
N3.44 Example 14 4-diethylamino-1,1-dimethyl-2-butynyl α-cyclohexyl ~ α-(2-thienyl) glycolate hydrochloride Melting point 191-192°C Elemental analysis value (C2JssNOaS”) ICI) calculated value (%) C61,731 (8,01N3.27 Actual value (%) C61,51) 17.99 N3.33
Example 15 1.1-dimethyl-4-(1-pyrrolidinyl)-2-butynyl α-cyclohexyl-α-(2-thienyl) glycolate hydrochloride Melting point 164-165°C Elemental analysis value (CzJstNOsS-HCI) Total X value (!II)
CB2.03 ) 17.57 N3.29 Actual value (
%) C61,92B7.56 N3.29Example 16 4-diethylamino-2-butynyl α-cyclopentyl-α-(2-thienyl)glycolate Melting point 55-57
°C Elemental analysis value (C1stltJO*S) Calculated value (%) C65,30) 17.79 N4.
01 Actual value (%) C65,2088,07N4.1
2 Example 17 4-diethylamino-1,1-dimethyl-2-butynyl α-cyclopentyl-α-(2-thienyl)glycolate hydrochloride Melting point 155-156°C Elemental analysis value (CiJsJ mouth as −) 1c+・1/ 4H
20) Calculated value (%) C60,26B7.82 N
3.34 Actual value (%”) C60,38B7.86
N3.60 Example 18 N-(4-N', N'-diethylamino-2-butynyl)-2-hydroxy-2,2-(2,2'-dithenyl)acetamide Melting point 98-100°C. Elemental analysis value (C+JttN*02St) calculated value (%)
C59,64H6,12N 7.73 Actual value (%) C
59,58H6,14N 7.59 Example 19 N-(4-N', N'-diethylamino-2-butynyl)-2-cyclohexyl-2-hydroxy-2-(2
-thienyl)acetamide Melting point 77-78℃ Elemental analysis value (C,.B5゜NiO*S) calculated value (%)
C66,2688,34N 7.73 Actual value (%) C
66,12H8,59N 7.65 Example 2O N-(4-N', N'-diethylamino-2-butynyl)-2-cyclopentyl-2-hydroxy-2-(2
-thienyl)acetamide hydrochloride Melting point 131-132
°C elemental analysis value (C+5HisN Snow 0□S -HCI) Calculated value (%) C59,28H7,59N 7.28 Actual value (%) C59,03H7,74N 7.33 Example 21 N-(4-pyrrolidino-2 -Butynyl)-2-hydroxy-2,2-(2,21-dithenyl)acetamide Melting point: 164-166°C Elemental analysis (C1,) 1. . NiOsS*) calculated value (%
) C59,9785,59N 7.77 Actual value (%)
C59,7285,87N 7.70 Example 22 N-(4-pyrrolidino-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide Melting point 112-114°C Elemental analysis value (C* JsoNsOz) Calculated value (%) C74,5488,53N? , 90 actual value (%') C74,1688,68N 7.84 Example 23 4-diethylamino-1-methyl-2-butynyl α-
Cyclohexyl-α-phenyl glycolate Hydrochloride Melting point 80-82℃ Elemental analysis value (CsJ3sNO*・oci・1/4LO)
Calculated value (%) C64,17H8,54N 3.25 Actual value (%') C64,3988,46N 3.31 Example 24 1.1-Dimethyl-4-(1-pyrrolidinyl)-2-butynyl α-cyclohexyl -α-phenyl glycolate hydrochloride Melting point 174-175℃ Elemental analysis value (C,,H,,NO,・HCI) Calculated value (%
”) C68,64) 18°16N3.33 Actual measurement value (%
) C68,40) 18.04 N 3.26 Example 25 1.1-dimethyl-4-dimethylamino-2-butynyl α-cyclohexyl-α-phenyl glycolate hydrochloride Melting point 155-159°C Elemental analysis value (C -J31NO-・)IC'l・1/2L
D) Calculated value (%) C65,57) 18.25 N
3.48 Actual value (%) C65,4488,32N 3
．． 50 Example 26 1.1-dimethyl-4-morpholino-2-butynyl α
-Cyclohexyl-α-phenylglycolate Hydrochloride Melting point 186-190℃ Elemental analysis value (CsJ-NO-・HCI) calculation value (%)
C66,12H7,86N 3.21 Actual value (%) C
65,91H7,94N 3.22 Example 27 1.1-dimethyl-4-piperidino-2-butynyl α
-Cyclohexyl-α-phenyl glycolate Hydrochloride Melting point 207-208°C Elemental analysis value (CssHssNOs ・flcl) Calculated value (%) C68,79it 8.44 N 3.31
Actual measurement value (%) C69, 18ft 8.36N 3.
23 Example 28 4-diethylamino-1,1-dimethyl-2-butynyl α-cyclobenthyl α-phenyl glycolate hydrochloride Melting point 120-121°C Elemental analysis value (C2sHsaNOs ・) HCI ・1/
4HJ) Calculated value (%) C66,97H8,43N 3
．． 40 Actual value (%'I C67,08) 18.39
N 3.40 Example 29 1.1-dimethyl-4-piperidino-2-butynyl α
-Cyclobenyl α-phenyl glycolate Hydrochloride Melting point 157-158℃ Elemental analysis value (C2sHssNOs・HCI・1/4tl
J) Calculated value (%) C67,91It 8.19 N
3.30 Actual value (%) C67,90) 18.38
N 3.21 Example 30 1.1-dimethyl-4-dimethylamino-2-butynyl α-cyclopentyl-α-phenyl glycolate hydrochloride Melting point 125-127°C Elemental analysis value (Cz+H2JOs・)ICI・1/2H2
0) Calculated value (%”) C64,85) 18.03 N
3.60 Actual value (%) C65,01H8,20N
3.62 Example 31 1.1-dimethyl-4-morpholino-2-butynyl α-
Cyclobenyl α-phenyl glycolate Hydrochloride Melting point 150-151℃ Elemental analysis value (CssLl) JO4・HCI・1/4H,
0) Calculated value (%) C64,78H7,68N 3.2
8 Actual value (%”) C65,07H7,75N 3.2
7 Example 32 1-(3-diethylamino-1-propynyl)cyclopentyl α-cyclobenthyl α-phenyl glycolate hydrochloride Melting point 132-133°C Elemental analysis value (C
2sHssNOs・HCI・1/4H,0) Calculated value (%
) C68,47) 18.39 N 3.19 Actual value (%) C68,56H8,42N 3.27 Example 3
3 1-(3-diethylamino-1-propynyl)cyclohexyl α-cyclobenti-α-phenyl glycolate hydrochloride Melting point 113-115℃ Elemental analysis value (Cs
5) IsJOs 'HCI' 1/4HJ) Calculated value (%) C69,0088,57N 3.10 Actual value (
%) C69,14H8,65N 3.14 Example 34 4-diethylamino-1,1-dimethyl-2-butynyl α-phenyl-α-(2-thienyl) glycolate
Hydrochloride Melting point 155-156℃ Elemental analysis value (C22H2JO3S -HCI) calculation value (
%) C62,62H6,89N 3°32 actual measurement value (%
') C62,4186,78N 3.37 Example 35 1.1-dimethyl-4-(1-pyrrolidinyl)-2-butynyl α-phenyl-α-(2-thienyl) glycolate hydrochloride Melting point 129-130°C Elemental analysis value (C2) l*5NOss-HCI・115
H20) Calculated value (%) C62,38) 16.04
N 3.30 Actual value (%) C62,4886,12N
3.35 Example 36 1-(3-diethylamino-1-propynyl)cyclopentyl α-7enyl-α-(2-thienyl)glycolate Hydrochloride Melting point 149-151°C Elemental analysis value (C24HzsNOsS -) ICI) Calculated value ( %') C64,34N 6.75 N 3.1
3 Actual measurement value (%) C, 64,09H6,81N 3.1
5 Example 37 1-[3-<1-pyrrolidinyl)-1-propynylcocyclopentyl α-phenyl-α-(2-thienyl)
Cricolate hydrochloride Melting point 133-135℃ Elemental analysis value (Cm,) 12ffNOIS -HCI) Calculated value (
%) C64,63H6,33N 3.14 Actual value (%
) C64,35H6,57N 3.18 Example 38 1-(3-diethylamino-1-propynyl)cyclohexyl α-phenyl-α-(2-enyl)glycolate hydrochloride Melting point 120-121°C Elemental analysis value (CsJslNOsS'HCI>Calculated value (%) C64,99H6,98N 3.03 Actual value (
%) C64,9986,93N 3.00 Example 39 4-diethylamino-1,1-dimethyl-2-butynyl α. α-Diphenyl glycolate Hydrochloride Melting point 176-177℃ Elemental analysis value (CiJssNOs・HCI) Calculated value (%'
I C69,3087,27N 3.37 Actual value (%'
) C69,09N 7.43 N 3.44 Example 40 1.1-dimethyl-4-(1-pyrrolidinyl)-2-butynyl α,α-diphenyl glycolate Hydrochloride Melting point 1
44-146℃ Elemental analysis value (C241btNOs・)IcI・1/10
) 120) Calculated value (%) C69,34) 16.84
N 3.37 Actual value (%) C69,07ft 6.
81 N 3.42 Example 41 1-(3-diethylamino-1-propynyl)cyclohexyl α-cyclohexyl-α-phenyl glycolate hydrochloride Melting point 132-134°C Elemental analysis value (Ca
, HssNOs・)ICI・1/4LO) Calculated value (%'
) C69,5088,75N 3.00 Actual value (%)
C69,47H8,69N 3.13 Example 42 1-(3-diethylamino-1-propynyl)cyclohexyl α-cyclohexyl-α-phenyl glycolate hydrochloride Melting point 172-173℃ Elemental analysis value (C,
, H, JO3・HCI) Calculated value (%) C69,70N
8.55 N 3.13 Actual value (%”) C69,
56H8,62N 3.09 Test Examples The results of pharmacological tests showing the usefulness of representative examples of the compounds of the present invention are shown below. Test method 1, Effect on rabbit isolated bladder detrusor muscle fy + ki (
Jll/NIBUS/RABITON d' 2-3k
g) (D After removing the bladder, the bladder body was incised along the longitudinal muscle to prepare a specimen with a width of 2 to 3 cm and a length of 10 cm. The specimen was diluted with Modified Krebs solution (37 ± 0.1
A load of 1 g was applied to the tube and the tube was suspended in a Magnus tank filled with a mixed gas (aeration). (1) Anticholinergic effect Carbachol was accumulated, the specimen was contracted, and a concentration response curve for carbachol was determined. A concentration-response curve was obtained in the same manner under investigational drug treatment, and aranrakshana (^run
The pA2 value was calculated according to the method of M. lakshana and Shild. (2) Ca"+ antagonistic effect Magnus tank liquid is changed to Ca"free high to C1-ma
dif 1ed Krebs solution, calcium chloride was accumulated, the specimen was contracted, and a concentration response curve for calcium chloride was determined. Concentration-response curves were determined in the same manner under test drug treatment, and pAw values were calculated according to the method of Alanrakshana and Shields. The results are shown in Table 1. The anticholinergic effect of the compound of Example 4 is greater than that of oxybutynin.
The C,+4 antagonism is 717 times weaker, and on the contrary, it is 8.3 times stronger.
It became twice as strong. 2. Effect on rat bladder rhythmic contraction Rat (SD
After anesthetizing ♂ 280-360g with urethane,
A small incision was made at the top of the bladder, a balloon was inserted, warm water at about 37° C. was injected into the balloon, the pressure inside the balloon was kept constant, and the rhythmic amplitude of urinary contractions was recorded. When the frequency of contractions becomes constant, the test drug is cumulatively administered i, v,
The effect on the frequency of contractions was investigated. The results are shown in Table 2. The compound of Example 4 suppressed contractions in a dose-dependent manner by more than 0.1 ωg/kg i,v, but oxybutynin
No such effect was observed. 3. Four acutely toxic mice (ddY male, 6-7 weeks old) were used in the − group. After fasting from the previous day (16-18 hours),
The drug was forcibly administered orally using a sonde, and the LD50 value was calculated from the mortality rate over a period of one week using the Mail Civil Code. The LD value of the compound of Example 4 is 841+++g/k
g p, o. The Ds0 value of oxybutynin was 354 mg/kg.
P.o. It was much weaker than. 4. Plasma concentration of unchanged drug: 3 doses of test drug to rats (SO type ♂ 280-360 g)
After administration of ωg/kg/v, blood was collected over time and the plasma unchanged drug concentration was measured. The elimination half-life (t 1/2) of the compound of Example 4 was much longer lasting than oxybutynin's t 1/2 (0.28 hours) at 0.85 hours. Table 2 Effect on rat bladder rhythmic contractions The compound of the present invention has excellent effects not found in existing pharmaceuticals, is long-lasting, and has low toxicity. It can be safely used as a therapeutic agent for frequent urination or various types of urinary incontinence due to neurogenic cystitis and enuresis.

Claims (1)

[Claims] (1) A butynylamine derivative represented by the following general formula [I] and a pharmacologically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] Here, R^1 and R^2 are the same or different and represent cycloalkyl, phenyl, or 2-thienyl. R^3 and R^4 are the same or different and represent hydrogen or alkyl, or R^3 and R^4 are bonded together to form cycloalkyl with adjacent carbon atoms. R^5 and R^6 are the same or different and are hydrogen or
It represents alkyl, or represents that R^5 and R^6 are bonded together to form a cyclic amino group with adjacent nitrogen atoms. A represents oxygen or NR (R represents hydrogen or alkyl). However, this excludes the case where both R^3 and R^4 are hydrogen, A is oxygen, and either R^1 or R^2 is phenyl.