JP2000351773A - Medicament consisting of furan derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new furan derivative having excellent maxi-K-channel opening action and useful as a high-conductance-type calcium-sensitive K-channel opening agent. SOLUTION: This new compound is a furan derivative of formula I (R1 is an aryl or heteroaryl; R2 is H, a lower alkyl, phenyl or the like; R3 is cyano or the like) (wherein excepting specific compounds such as 2-amino-5-phenyl-3- furannitrile), e.g. 2-amino-4-methyl-5-phenylfuran-3-carbonitrile. The compound of formula I is obtained, for example, by reacting a compound of formula II with an acetonitrile derivative of formula III to form a 4-oxobutyronitrile derivative of formula IV, which, in turn, is cyclized in the presence of an acid catalyst (pref. trifluoroacetic acid). This new compound thus obtained can exhibit high- conductance-type calcium-sensitive K-channel opening action, therefore being hopeful of its use in the therapies of pollakisuria, incontinence of urine and the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a medicament comprising a furan derivative or a salt thereof, or a novel furan derivative or a salt thereof.

[0002]

2. Description of the Related Art K channels play an important role in the generation of resting membrane potentials and action potentials in cells. The opening of K channels suppresses the excitability of cells by hyperpolarizing the cell membrane, thereby relaxing smooth muscle. It is known to exert an action (J. Urol., 154, 1914-20, 1995). High conductance calcium-sensitive K channel (maxi-K channel or B
K channel) is one of the calcium-sensitive K channels that opens by sensing an increase in intracellular Ca concentration and membrane depolarization, and is widely distributed in the body and is important as an excitatory negative feedback system. (Am.J.Physi
ol., 291, C9-C34, 1996). Therefore, drugs that open maxi-K channels exhibit various organ function-protecting and organ-improving effects by exerting a relaxing action on smooth muscle or an inhibitory action on excessive nerve excitation in nerve cells. It is expected. Especially, bladder smooth muscle
It is known that the sensitivity to the maxi-K channel inhibitor carybdotoxin is high (J. Pharmacol. Exp. Th.
er., 259 (1), 439-443, 1991), and drugs that open the maxi-K channel can be expected as therapeutic agents for pollakiuria and urinary incontinence, which exhibit high bladder selectivity. The compounds of the present invention have the action of opening maxi-K channels and hyperpolarize the membrane electrical potential of cells, for example, through the action of relaxing smooth muscles or suppressing nerve excitement, thereby increasing hypertension, asthma, premature birth, Irritable bowel syndrome,
Chronic heart failure, angina, myocardial infarction, cerebral infarction, subarachnoid hemorrhage, cerebral vascular spasm, cerebral hypoxia, peripheral vascular disorder, anxiety, male baldness, erectile dysfunction, diabetes, diabetic peripheral neuropathy, etc. It is useful for reducing diabetic complications, infertility, urolithiasis and associated pain, especially for the treatment of bladder instability, such as urinary frequency, urinary incontinence, and enuresis.

[0003] About the maxi-K channel opener. NS-8, a pyrrole derivative having the following structure, has a relaxing effect on the isolated bladder smooth muscle of the rat, and caribodotoxin exerts an inhibitory effect on the action, further abolishes the rhythmic bladder contraction of the anesthetized rat, and maximally contracts the bladder It has been reported that bladder capacity was increased without affecting pressure (Journal of the Japanese Urological Association, 89 (2), 138, 1998).

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[0004] In addition, maxi-K channel openers include
Benzimidazole derivatives of EP 478 819 and EP 617 023, WO 94/22807 and WO 96/0
Pyridine derivative of 6610, thiopyranopyridine derivative of WO96 / 2547, cyclohexadiene derivative of EP 696597, pyran derivative of EP758649, W
WO98 / 04135, nitrogen-containing 5-membered ring derivative, WO98 /
Indole derivative of 16222, WO 98/23273
And WO99 / 09983 quinoline derivatives, WO99
/ 07669 and WO99 / 07670 have been reported. However, there are no reports on furan derivatives.

On the other hand, there have been reports on the synthesis of the following compounds for 2-aminofuran derivatives, but none of them suggests or discloses any action as a drug (Zh. Org. Khim., 2 (1)
1), 2018-20,1966 / Zh.Org.Khim., 3 (4), 681-4,1967 / Zh.Or
g.Khim., 5 (12), 2161-4,1969 / J.Chem.Soc., Perkin Tran
s., 1 (9), 2009-11,1984 / Chem.Pharm.Bull., 33 (3), 937-4
3,1985 / Egypt.J.Pharm.Sci., 30 (1-4), 103-10,1989 / J.Pr
akt.Chem., 331 (1), 31-6,1989 / Khim.Geterotsikl.Soedi
n., 2,173-8,1994 / Tetrahedron Lett., 35 (33), 5989-92,1
994 / J.Org.Chem., 60 (21), 6684-7,1995 / Bull.Korean Cha
m. Soc., 17 (8), 676-678, 1996 / Liebigs Ann.Recl., 2,435
-439,1997 / Egypt.J.Pharm.Sci., 40 (2), 105-116,1997 / J.
Heterocycl.Chem., 35 (6), 1313-1316,1998, / Monatsh.Che
m.126 (3), 333-40,1995 / Zh.Org.Khim., 3 (3), 596-7,196
7 / Indian J. Heterocycl. Chem., 4 (3), 191-4,1995 / JH
eterocycl.Chem., 33 (6), 2007-11, 1996 / J. Heterocyc
l. Chem., 33 (3), 689-664, 1996 / J. Prakt. Chem./Chem.
-ztg., 338 (3), 206-13.). 2-amino-5-phenyl-3-furannitrile, 2-amino-5-p-tosyl-
3-furannitrile, 2-amino-5- (p-methoxyphenyl) -3-furannitrile, 2-amino-5-
(P-chlorophenyl) -3-furannitrile, 2-amino-5- (p-bromophenyl) -3-furannitrile, 2-amino-4-methyl-5-phenyl-3-furannitrile, 2-amino- 4,5-diphenyl-3-furannitrile, 2-amino-5-p-tolyl-4-phenyl-3-furannitrile, 2-amino-5- (4-biphenylyl) -4-phenyl-3-furan Nitrile,
2-amino-5- (p-methoxyphenyl) -4-phenyl-3-furannitrile, 2-amino-5- (p-ethoxyphenyl) -4-phenyl-3-furannitrile, 5-amino-4- Cyano-2-phenyl-3-furonic acid ethyl ester, 2-amino-4-benzoyl-5
-Phenyl-3-furannitrile, 2-amino-4-acetyl-5-phenyl-3-furannitrile.

[0006]

The compounds described in the above publications are known as maxi-K channel openers. However, more excellent maxi-K channel openers, and frequent urination and urinary incontinence based on this action are disclosed. Is an important medical issue.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies in order to achieve the above object, and found that a newly synthesized furan derivative has an excellent maxi-K channel opening action. Was completed. That is, the present invention relates to a medicament comprising a furan derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof, particularly a high conductance calcium-sensitive K channel (maxi-K channel) opener.

Embedded image(The groups in the formula have the following meanings: R¹: An aryl or a substituent which may have a substituent
Optionally a heteroaryl group R²: H, lower alkyl, phenyl, R⁴-CO-, R
⁴-O-lower alkyl-, R⁴-O-CO-, R⁴-O
-CO-lower alkyl-, R⁴− (R⁵−) N-CO−
Or R⁴− (R⁵-) N-CO-lower alkyl group R³： Cyano or R⁶-SO₂-Group R⁴, R⁵: Same or different, H, lower alkyl or
A phenyl group or R ⁴And R⁵Is one with the adjacent N atom
3 to 8 membered nitrogen-containing nitrogen atom which may have O atom
R may form an unsaturated ring;⁶: Lower alkyl or phenyl group. )

[0008] The present invention also relates to a furan derivative represented by the following general formula (I ') or a pharmaceutically acceptable salt thereof.

Embedded image(The groups in the formula have the following meanings: R¹: An aryl or a substituent which may have a substituent
Optionally a heteroaryl group R²: H, lower alkyl, phenyl, R⁴-CO-, R
⁴-O-lower alkyl-, R⁴-O-CO-, R⁴-O
-CO-lower alkyl-, R⁴− (R⁵−) N-CO−
Or R⁴− (R⁵-) N-CO-lower alkyl group R³： Cyano or R⁶-SO₂-Group R⁴, R⁵: Same or different, H, lower alkyl or
A phenyl group or R ⁴And R⁵Is one with the adjacent N atom
3 to 8 membered nitrogen-containing nitrogen atom which may have O atom
R may form an unsaturated ring;⁶: Lower alkyl or phenyl group. However, the following compounds are excluded. 2-amino-5-phenyl
-3-furannitrile, 2-amino-5-p-tosyl-
3-furannitrile, 2-amino-5- (p-methoxy
Phenyl) -3-furannitrile, 2-amino-5-
(P-chlorophenyl) -3-furannitrile, 2-a
Mino-5- (p-bromophenyl) -3-furannitrile
2-amino-4-methyl-5-phenyl-3-fura
Ninitrile, 2-amino-4,5-diphenyl-3-f
Lannitrile, 2-amino-5-p-tosyl-4-fe
Nyl-3-furannitrile, 2-amino-5- (4-bi
Phenylyl) -4-phenyl-3-furannitrile,
2-amino-5- (p-methoxyphenyl) -4-fe
Nyl-3-furannitrile, 2-amino-5- (p-e
Toxiphenyl) -4-phenyl-3-furannitrile
5-amino-4-cyano-2-phenyl-3-fura
Acid ethyl ester, 2-amino-4-benzoyl-5
-Phenyl-3-furannitrile, 2-amino-4-a
Cetyl-5-phenyl-3-furannitrile. The furan derivative of the present invention has an amino group at the 2-position of the furan ring.
Is replaced by a cyano or sulfonyl group at position 3.
Has a structural characteristic and a strong opening to the maxi-K channel.
It has pharmacological characteristics in that it has an oral action. One of the present invention
The compound contained in the furan derivative represented by the general formula (I) is
Although some reports have been made as mentioned above,
There is no suggestion or disclosure.

The present invention further provides a novel process for producing a furan derivative of the general formula (I) or a salt thereof,
Is reacted with an acetonitrile derivative represented by the general formula (III) to give a 4-oxobutyronitrile derivative represented by the general formula (IV) under an acid catalyst (particularly, trifluoroacetic acid). To produce a furan derivative of the general formula (I) or a pharmaceutically acceptable salt thereof.

Embedded image

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The compounds represented by the general formulas (I) and (I ') are further described below. In the definition of the general formula in this specification, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. Therefore, "lower alkyl group"
Is an alkyl group having 1 to 6 carbon atoms, specifically, these structural isomers such as methyl, ethyl, propyl, butyl, pentyl (amyl), hexyl and isopropyl, and preferably 1 to 3 alkyl groups.

The "3- to 8-membered nitrogen-containing saturated ring optionally having an O atom" is specifically exemplified by, for example, aziridine, azetidine, pyrrolidine, piperidine, hexahydroazepine, octahydroazocine, morpholine and piperazine. No. “Aryl” is an aromatic ring group which may have a substituent, and specific examples include a phenyl, biphenyl, naphthyl, anthryl, phenanthryl group and the like, and a phenyl group is preferred. "Heteroaryl" means monocyclic heteroaryl such as furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazyl, triazolyl, tetrazolyl, naphthyridinyl, 1,3-benzodioxyl And a bicyclic heteroaryl such as a group, preferably a thienyl group. The substituent of the aryl or heteroaryl group, a halogen atom, -OH, -COOH, nitro, cyano, mercapto, lower alkyl, -SO ₂ - lower alkyl, -O- lower alkyl, halogeno-lower alkyl, -CO-O —Lower alkyl, CO—N (—R ⁶ ) —
R ⁷ , —N (—R ⁶ ) —R ⁷ , —N—R ⁶ —SO ₂ —R
⁷ , —N—R ⁶ —CO—R ⁷ and a phenyl group, which may be substituted by 1 to 3 groups (here,
R ⁶ and R ⁷ are the same or different and are H, a lower alkyl or a phenyl group, or R ⁶ and R ⁷ may be a 3- to 8-membered member which may have an O atom together with an adjacent N atom. A nitrogen-containing saturated ring may be formed). “Halogen atom” includes fluorine atom, chlorine atom, bromine atom or iodine atom.

The compound of the present invention depends on the type of the group.
There are optical isomers (optically active substances, diastereomers, etc.). Further, some of the compounds of the present invention have an amide bond, and tautomers based on the amide bond also exist. The present invention includes a separated form or a mixture of these isomers. The compounds of the present invention form salts with acids or bases. Examples of salts with acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and mineral acids with phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, and fumaric acid. Acid addition salts with organic acids such as acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid can be mentioned. Examples of salts with bases include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; organic bases such as methylamine, ethylamine, meglumine, and ethanolamine; salts with basic amino acids such as lysine, arginine, and ornithine; and ammonium salts. Is mentioned. Further, the compound of the present invention can form hydrates, solvates with ethanol and the like, and polymorphs.

Manufacturing method (first manufacturing method)

Embedded image (Wherein, R ¹ , R ² and R ³ have the same meanings as described above, and X represents a halogen atom.) The compound (I) of the present invention is obtained by converting a compound represented by the general formula (II) into a compound represented by the general formula (III) )) In the presence of a base to carry out a ring-closing reaction, and then, if desired, convert R ¹ , R ² or R ³ . Here, the halogen atom represented by X includes iodine, bromine, chlorine and the like. The reaction is performed by reacting corresponding amounts of compound (II) and acetonitrile derivative (III),
Alternatively, one of them is used as an excess mole, and no solvent or dimethylformamide (DMF), dimethylsulfoxide (DMSO), ether, tetrahydrofuran (TH
F), dioxane, acetone, methyl ethyl ketone, methanol, ethanol, methylene chloride, dichloroethane, chloroform in a solvent inert to the reaction, sodium alkoxide such as sodium methoxide, sodium ethoxide, diethylamine, dimethylaniline, N
It is advantageously carried out in the presence of a base such as methylmorpholine, trimethylamine, triethylamine, sodium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide and the like, at room temperature or under heating.

The conversion of R ¹ , R ² or R ³ depends on the type of the substituent, but all are carried out by applying a conventional method. For example, the conversion of the hydrogen atom of R ² into an alkyl group or the like is performed after converting the compound (I) into a halogen derivative such as bromine.
The reaction is carried out in an inert solvent for the reaction of an alkylating agent such as an alkyl halide with hexamethylphosphoramide (HMPA) or THF in the presence of a base such as n-butyllithium (Tetrahedron, 46 (4), 1199). -1210, 1990). Furthermore, a general reductive methylation reaction using formalin and acetic acid-hydrogen bromide can be performed (J. Org. Chem., 21, 297, 1956).
etc). The conversion of the hydrogen atom of R ² into an alkyl group or the like can be carried out by using tin tetrachloride or the like in a solvent inert to the reaction of acid chloride or acid anhydride with benzene (J. Am. Chem. Soc., 82, 4883, 1990).

R ⁴ —O—CO— or R ⁴ —O— of R ²
The conversion of CO-lower alkyl- to HO-lower alkyl- is carried out by reduction with a suitable reducing agent such as diisobutylaluminum hydride in a solvent inert to a reaction such as THF. In addition, R ⁴ —O—CO— or R ⁴ —O—
CO-lower alkyl- is hydrolyzed with a base such as aqueous sodium hydroxide solution in a solvent inert to a reaction such as THF to obtain HO-CO- or HO-CO-lower alkyl-.
Can be obtained. Further, by using a condensing agent such as water-soluble carbodiimide (WCS) and an amine in a solvent inert to a reaction such as THF, the R ^4- (R ⁵
-) N-CO- or ^{R 4 - (R 5 -)} N-CO- lower Alkyl can be obtained.

(Second production method)

Embedded image (Wherein, R ¹ , R ² , and R ³ have the same meanings as described above, and X represents a halogen atom.) The compound (I) of the present invention is obtained by converting the compound (II) to a methyl cyanide derivative (II) under basic conditions Can be produced by subjecting a 4-oxobutyronitrile derivative represented by the general formula (IV) obtained by reacting to a ring closure reaction in the presence of an acid catalyst. Here, the halogen atom represented by X includes iodine, bromine, chlorine and the like. The reaction is carried out using a reaction-corresponding amount of compound (II) and acetonitrile derivative (III) or an excess mole, without solvent or with DMF, DMS
O, ether, THF, dioxane, acetone, methyl ethyl ketone, methanol, ethanol, methylene chloride, dichloroethane, chloroform, etc., in a solvent inert to the reaction, sodium t-butoxide, potassium t-butoxide, sodium ethoxide, pyridine, picoline,
The reaction was carried out at room temperature or under heating in the presence of a base such as dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine, sodium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, and potassium hydroxide. The 4-oxobutyronitrile derivative of the general formula (IV) can be prepared by using an acid catalyst as a solvent or acetic acid, water, ether, toluene in the presence of an acid catalyst such as hydrogen bromide, acetic acid or trifluoroacetic acid (TFA). The reaction can be carried out by performing a ring-closure reaction in a solvent inert to the reaction under ice-cooling or at room temperature to under heating. The solvent is particularly preferably an acid catalyst. TFA is particularly preferred as the acid catalyst.

The compound of the present invention thus produced is isolated and purified as it is or as a salt thereof. Isolation and purification include extraction, concentration, distillation, crystallization, filtration,
It is performed by applying ordinary chemical operations such as recrystallization and various types of chromatography. Various isomers can be isolated by a conventional method utilizing the difference in physical properties between the isomers. For example, a racemic compound can be converted to a stereoisomerically pure isomer by a racemic resolution method (for example, a diastereomer salt with a general optically active acid (tartaric acid, etc.) and an optical resolution method). . The mixture of diastereomers can be obtained by a conventional method.
For example, they can be separated by fractional crystallization or chromatography. The optically active compound can also be produced by using an appropriate optically active starting compound.

[0018]

The compound of the present invention has a high conductance type calcium-sensitive K channel (maxi-K channel) opening action and is useful in the treatment of pollakiuria and urinary incontinence.

The pharmacological action of the compound of the present invention was confirmed by the following method. The compound of the present invention has an inhibitory effect on spontaneous contraction of an isolated rat bladder specimen. Since the inhibitory effect was blocked by a caliboxin known as a maxi-K channel blocker, it was confirmed that the effect of the compound of the present invention was based on the maxi-K channel opening effect.

<Inhibition of contraction of rat bladder specimen contraction> Male SD rats (9 to 13 weeks of age) were used in the experiment. After exsanguination and death under ether anesthesia, the bladder was removed. The excised bladder was immediately maintained at 37 ° C. in Krebs-Henseleit solution (Na
Cl 118.4, KCl 4.7, KH ₂ PO ₄ 1.2, MgSO ₄ 1.2, CaCl ₂ 2.5,
NaHCO ₃ 25.0, containing glucose 11.1 [mM], 95% O ₂ , 5% CO ₂
After washing in a mixed gas), a vertical strip specimen about 10 mm long and about 2 mm wide was prepared on a Petri dish filled with Krebs Henseleit solution. Both ends of the specimen were ligated with cotton thread via a cell fin, one side was fixed to the lower part of the bath, the other was fixed to the FD pickup, and suspended vertically in an organ bath filled with Krebs-Henseleit solution. After the operation was completed, a static tension of 1.0 g was applied to each strip, and the strips were left for 1.5 to 2 hours to stabilize the specimen. Next, contraction was induced by adding a KCl solution so that the final K ⁺ ion concentration in the organ bath became 15 mM. The experiment was then started after the sample was left to stabilize for about 1 to 2 hours. The contraction of the smooth muscle was measured isometrically via an FD pickup, the output signal was amplified via a strain stress amplifier, and the chart was continuously recorded with a pen recorder. Simultaneously, a contraction waveform to be analyzed was obtained as magnetic data by a personal computer via an analog / digital signal converter, and the area under contraction was calculated by analysis software. 5 immediately after the start of the experiment
The minute contraction was defined as the value before administration of the test drug (100% control value).
Next, the test drug was administered to the bath at 30 minute intervals, and each was administered
The 5-minute contraction after 25 minutes was subjected to analysis. Study drugs were administered cumulatively from low doses at a common ratio of 3 or 10. The effect of the test drug was expressed as a dose that inhibited 50% of the value before administration (100% control value). After the acquisition of the contraction waveform at the highest dose of the test drug was completed, calibdotoxin, a selective blocker of the maxi-K channel, was administered so that the final concentration in the organ bath became 100 nM, and the effect of the test drug was blocked. It was observed whether it was possible or not. As a result, the compound of the present invention strongly suppressed contraction of the isolated rat bladder specimen, and its effect was blocked by the administration of carybdotoxin. This confirmed that the compound of the present invention inhibits bladder smooth muscle contraction through maxi-K channel opening.

<Effect of Cultured Cells from Human Bladder on 86 Rubidium Outflow> This experiment was performed by Daniel et al. (Journal of Pharm
acological Methods 25, 185-193 (1991)) with minor modifications. Cultured cells from human bladder (HTB-9) were used for the experiment. This cell is Monen
Have confirmed that the maxi-K channel is abundant (J. Membrane Biol. 161,247-256 (1998)).
The cells were cultured in a 96-well culture dish containing RPMI-1640 medium containing 10% fetal bovine serum so that the cells became dense. Next, the medium was aspirated and removed.
RPMI-1640 medium containing rubidium (86Rb) at 1 μCi / ml was added at 100 μl / well. After 18 to 24 hours, the cells are incubated with an incubation solution (HEPES-buffered salt solution: HBS, HEPES 20, NaCl 137, KCl 4.7, CaCl ₂ 1.8, Mg
Washed well with Cl ₂ 0.6 and glucose 7.7 [mM]. Next, in the presence or absence of the test substance, an incubation solution containing 0.3 μM of calcimycin (A23187) and DMSO was added at 200 μl / well. Thirty minutes later, the incubation solution was collected with a pipette, a new incubation solution was added at 150 μl / well, mixed with the washed one, and 86Rb that had flowed out of the cells into the supernatant was completely recovered (solution 1). Next, 86Rb remaining in the cells was recovered. That is, 0.175 μl / wel of NaOH aqueous solution (0.1N)
Then, the mixture was mixed well with a mixer for 15 minutes to destroy the cells, and then neutralized by adding 0.175 μl / well of an aqueous HCl solution (0.1N), and all were collected with a pipette (solution 2). 96-well culture dish (white) for solution recovery
This was used as a counting vessel. 86 included in the counting vessel
The amount of Rb was measured with a liquid scintillation counter.
The increase of 86Rb effluxed from the cells was calculated as [radioactive cpm in solution 1] / ([radioactive cpm in solution 1] + [radioactive cpm in solution 2]) × 100 (%). The dose at which the above-mentioned 86Rb efflux increased by the test drug was 60% was calculated and defined as the test drug activity. As a result, the compound of the present invention potently increased the outflow of 86 rubidium from cultured cells derived from human bladder. The above results indicate that the compound of the present invention has a maxi-K channel opening effect on human bladder cells.

<Effects on Rhythmic Bladder Contraction of Urethane-Anesthetized Rats> SD female rats (about 300 g) were used.
A catheter was inserted into the bladder through the external urethra under urethane anesthesia (1.2 g / kg, intraperitoneal administration) and spontaneous breathing. The other end was connected to a pressure transducer and an infusion pump via a three-way cock. A blood pressure measurement catheter was inserted into the right common carotid artery. 4.2 ml / hr of saline heated to about 38 ° C until rhythmic bladder contraction is induced
Was injected into the bladder. Changes in intravesical pressure were continuously recorded on the recorder. After the rhythmic bladder contraction becomes stable,
The test compound suspended in a 0.5% methylcellulose aqueous solution was administered via a catheter previously attached to the duodenum. Evaluation items were bladder contraction frequency (every 10 minutes), bladder contractility, and mean blood pressure, which were observed up to 2 hours after administration of the test compound. As a result, the compound of the present invention has a potent inhibitory effect on the frequency of bladder contraction without changing the mean blood pressure and bladder contractility of urethane-anesthetized rats, and is expected as a therapeutic agent for pollakiuria and / or urinary incontinence. Is done. The above results indicate that the compound of the present invention has a maxi-K channel opening action on bladder smooth muscle and is useful as a therapeutic agent for pollakiuria and urinary incontinence.

A preparation containing one or more of the compound of the present invention or a salt thereof as an active ingredient is prepared using carriers, excipients and other additives usually used in the preparation of preparations. Pharmaceutical carriers and excipients may be solid or liquid, such as lactose, magnesium stearate,
Examples include starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used ones. The drug may be administered orally in the form of tablets, pills, capsules, granules, powders, liquids, etc., or parenteral infusions such as intravenous and intramuscular injections, suppositories, and transdermals. Good. The dose is determined as appropriate depending on the individual case, taking into account the symptoms, age, sex, etc. of the administration subject.
1 to 1,000 mg, preferably 50 to 20 per day
It is orally administered once to several times a day in the range of 0 mg, or is administered intravenously once to several times a day in the range of 1 to 500 mg per adult per day, or Intravenous administration for 1 hour to 24 hours per day. Of course, as mentioned above, the dosage varies under various conditions, so that an amount smaller than the above dosage range may be sufficient.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. It is mixed with magnesium aluminate. The composition may contain, in a conventional manner, additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or with a film of gastric or enteric substance. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water. , Ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use.

[0025]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. In addition, room temperature usually shows about 10-30 degreeC. REFERENCE EXAMPLE 1 3.4 g of malononitrile in 50 ml of THF was added to a solution of 2.0 g of 60% sodium hydride in 20 ml of THF under ice cooling.
1 solution was added dropwise. After stirring for 10 minutes, 10 g at -78 ° C
TH of 2-bromo-1-phenylpropan-1-one of
The F solution was added dropwise. After stirring at room temperature for 2 hours, the mixture was poured into a mixture of ice and 1N hydrochloric acid, and extracted with ethyl acetate. Water the organic layer,
After washing with saturated saline, it was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 8.06 g of 2- (1-methyl-2-oxo-2-phenylethyl) malononitrile. In the same manner as in Reference Example 1, the compound of Reference Example 8 was obtained.

Reference Example 2 One drop of DMF and 7.7 ml of thionyl chloride were added to a solution of 10 g of 4-trifluoromethylbenzoic acid in 100 ml of THF, and the mixture was heated and stirred at 60 ° C. for 4 hours. Further, 7.7 ml of thionyl chloride was added, and the mixture was heated and stirred at 60 ° C. for 1 hour, and then the reaction solution was concentrated under reduced pressure. To the residue, 100 ml of dichloromethane, 5.39 g of N, O-dimethylhydroxyamine hydrochloride, 16.1 ml of triethylamine,
10 mg of N, N-dimethylaminopyridine was added, and the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 8.72 g of N-methoxy-.
N-methyl-4-trifluoromethylbenzamide was obtained. THF1 of 6.49 g of N-methoxy-N-methyl-4-trifluoromethylbenzamide under a stream of argon
26 ml of a 2 M ethylmagnesium chloride ether solution was added dropwise to the 00 ml solution at -78 ° C. The reaction solution was stirred at room temperature for 1 hour, poured into a mixture of ice and saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration,
The filtrate was concentrated to give 6.49 g of 1- (4-trifluoromethylphenyl) -propan-1-one.

To a solution of 6.49 g of 1- (4-trifluoromethylphenyl) -propan-1-one in 70 ml of diethyl ether was added dropwise 1.98 ml of bromine under ice cooling. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed with saturated saline,
After washing with a saturated aqueous solution of sodium hydrogen carbonate, the solution was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to 8.71 g.
Of 2-bromo-1- (4-trifluoromethylphenyl) propan-1-one. To a solution of 1.03 g of malononitrile in 20 ml of THF was added 1.76 g of potassium t-butoxide under ice cooling. After stirring for 10 minutes,
At −78 ° C., a THF solution of 10 g of 2-bromo-1- (4-trifluoromethylphenyl) propan-1-one was added dropwise. After stirring at room temperature for 2 hours, the mixture was poured into a mixture of ice and 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3.4.
2 g of 2- [1-methyl-2-oxo-2- (4-trifluoromethylphenyl)] ethylmalononitrile were obtained. As in Reference Example 2, Reference Examples 3 to 7 and Reference Example 9
~ The compound of Reference Example 35 was obtained.

Example 1-a To 4.00 g of 2- (1-methyl-2-oxo-2-phenylethyl) malononitrile was added 40 ml of TFA, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the resulting crystals were washed with hexane-ethyl acetate, collected by filtration, and 2.98 g of 2-
Amino-4-methyl-5-phenylfuran-3-carbonitrile was obtained. Example 4 was performed in the same manner as in Example 1-a.
-7, 9-23, 30-32 and 43 were obtained. Example 1-b 22.6 g of 2- (1-methyl-2-oxo-2-phenylethyl) malononitrile was dissolved in 100 ml of acetic acid, and 37 ml of a 25% hydrogen bromide acetic acid solution was added dropwise under ice-cooling.
Stirred at room temperature for 30 minutes. The reaction mixture was added to ice water, stirred, and the precipitated powdery substance was collected by filtration.The filtrate was extracted with ethyl acetate and washed with a saturated sodium chloride aqueous solution.
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 633 mg of 2-amino-4-methyl-5-phenylfuran-3-carbonitrile. Examples 8, 25, 26, 28, 29, 33 in the same manner as in Example 1-b.
And 34 compounds were obtained.

Example 2 1.00 g of 2- [1-methyl-2-oxo-2- (4
[Trifluoromethylphenyl) ethyl] malononitrile, 10 ml of TFA was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the obtained crystals were recrystallized from toluene.
mg of 2-amino-4-methyl-5- (4-trifluoromethylphenyl) furan-3-carbonitrile was obtained. Example 3 1.00 g of 2- [2- (2-methoxyphenyl) -1
-Methyl-2-oxoethyl] malononitrile acetic acid 1
1.0 ml of concentrated hydrochloric acid was added dropwise to the 0 ml solution under ice cooling. After stirring at room temperature for 3.5 hours, 0.5 ml of concentrated hydrochloric acid was further added under ice cooling.
Was added dropwise. After stirring at room temperature for 20 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate-hexane) to obtain crystals. The obtained crystals are
After washing with -hexane, 233 mg of 2-amino-5- (2
-Methoxyphenyl) -4-methylfuran-3-carbonitrile was obtained.

Example 24 1.00 g of 2- (2-oxo-2-phenylethyl)
Hydrochloric acid gas was introduced into a solution of malononitrile in 3.0 ml of benzyl alcohol under ice cooling for 45 minutes. After stirring at room temperature for 16 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate-hexane) to obtain crystals. The obtained crystals were washed with ethanol-hexane to give 23
3 mg of 2-amino-5-phenylfuran-3-carbonitrile were obtained. Example 27 1.00 g of 2- [2-oxo-2- (2-methoxyphenyl) ethyl] malononitrile in 10 ml of ethanol
1 ml of piperazine was added to the solution, and the mixture was heated under reflux for 2 hours.
After concentrating the reaction solution, it was purified by silica gel column chromatography (chloroform) to obtain crystals. The obtained crystals were recrystallized from methanol to give 122 mg of 2-amino-5
(2-Methoxyphenyl) furan-3-carbonitrile was obtained.

Example 35 To a solution of 1.5 g of ethyl 2- (5-amino-4-cyano-2-phenylfuran-3-yl) acetate in THF-methanol was added 7.0 m of a 1N aqueous sodium hydroxide solution.
and stirred at 50 ° C. for 2 hours. After concentrating the reaction solution,
The mixture was acidified with N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and 1.30 g of 2- (5-
Amino-4-cyano-2-phenylfuran-3-yl)
Acetic acid was obtained. 470 mg of 2- (5-amino-4-cyano-2-phenylfuran-3-yl) acetic acid in THF10
To the ml solution, 558 mg of water-soluble carbodiimide (WSC), 475 mg of dimethylamine hydrochloride, and 1.2 ml of triethylamine were added, and the mixture was stirred at room temperature overnight. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 84 mg of 2- (5-amino-4).
-Cyano-2-phenylfuran-3-yl) -N, N-
Dimethylacetamide was obtained. As in Example 35,
The compounds of Examples 36 and 37 were obtained.

Example 38 2.51 g of malononitrile in 20 ml of THF was
Under ice cooling, 4.26 g of potassium t-butoxide was added. After stirring for 10 minutes, a THF solution of 4.30 g of 2-chloro-3-oxo-3-phenylpropanoic acid ethyl ester was added dropwise at -78 ° C. After stirring at room temperature for 3 hours, the mixture was poured into a mixture of ice and 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was recrystallized from ethanol to give 3.71 g of 5-amino-4.
-Cyano-2-phenylfuran-3-carboxylic acid ethyl ester was obtained. As in the case of the embodiment 38, the embodiment 4
Compound 2 was obtained.

Example 39 305 mg of a 1M diisobutylaluminum hydride solution in 4.2 ml of toluene and 3 ml of THF at -78 ° C.
A solution of 2- (5-amino-4-cyano-2-phenylfuran-3-yl) acetic acid ethyl ester in THF (3 ml) was added dropwise. After stirring at −20 ° C. for 1 hour, methanol, 1
N hydrochloric acid and ethyl acetate were added. After concentrating the organic layer under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate) and crystallized from hexane-ethyl acetate to give 85 mg of 2-amino-4- (2-hydroxyethyl) -5. -Phenylfuran-3-carbonitrile was obtained. Example 40 500 mg of 2-amino-5- (2-benzyloxy-
5-chlorophenyl) -4-methylfuran-3-carbonitrile in a 20 ml dichloromethane solution at -78 ° C.
5.2 ml of M tribromoboron was added dropwise. -78 ° C
After stirring for 1 hour, methanol and water were added. After concentrating the organic layer under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate) and crystallized from ether to give 80 mg of 2-amino 5- (5-chloro-2-hydroxyphenyl) -4. -Methyl-furan-3
-Carbonitrile was obtained.

Example 41 500 mg of 5-amino-4-cyano-2-phenylfuran-3-carboxylic acid ethyl ester in methanol 10
To the resulting solution was added 105 mg of sodium methoxide, and the mixture was stirred at room temperature for 1 hour. Further sodium methoxide 21
After adding 0 mg and stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-
(Ethyl acetate) and crystallized from ether to give 170
mg of 5-amino-4-cyano-2-phenylfuran-
3-Carboxylic acid methyl ester was obtained.

Table 1 shows the structure and physical properties of the compounds of the Examples.
3 is shown. The symbols in the table have the following meanings. REF: Reference example number, EX: Example number, DATA: Physical properties, mp: Melting point, NMR: Nuclear magnetic resonance spectrum (DMSO is used as an internal standard, unless otherwise specified.
-d6 was used as a measuring solvent), FAB-MS: mass spectrometry (fast atom bombardment), Me: methyl, Et: ethyl, Ph: phenyl, Bn: benzyl, The: thienyl, Nap: naphthyl, iPr: isopropyl , BiPh: biphenyl, 1,3-Bndio
x: 1,3-benzodioxazole, Mor: 4-morpholinyl,

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/381 A61K 31/38 601 C07D 409/04 C07D 409/04 (72) Inventor Takahiro Kuramochi Tsukuba, Ibaraki Inside Miyukigaoka 21 Yamanouchi Pharmaceutical Company Limited (72) Inventor Kenichi Kawaguchi Inside Miyukigaoka 21 Tsukuba City, Ibaraki Prefecture Inside Yamanouchi Pharmaceutical Company Limited (72) Inventor Kazumi Kikuchi 21 Miyukigaoka Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical Company Limited (72) Inventor Toshio Okazaki 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Company Limited (72) Inventor Yusuke Hirano 21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical Company Limited (72) Chief Saito 21 Miyukigaoka, Tsukuba, Ibaraki F-term (reference) in Yamanouchi Pharmaceutical Company 4C037 MA01 MA10 4C063 AA01 BB01 CC75 CC92 DD52 DD75 EE01 4C 086 AA01 AA02 AA03 AA04 BA03 BB02 BC70 GA02 GA04 GA09 MA01 MA04 NA14 ZA05 ZA08 ZA15 ZA20 ZA36 ZA40 ZA42 ZA59 ZA66 ZA81 ZA92 ZC35 ZC41

Claims (5)

[Claims] 1. A furan derivative represented by the general formula (I) or
A medicament comprising a pharmaceutically acceptable salt thereof. Embedded image(The groups in the formula have the following meanings: R¹: An aryl or a substituent which may have a substituent
Optionally a heteroaryl group R²: H, lower alkyl, phenyl, R⁴-CO-, R
⁴-O-lower alkyl-, R⁴-O-CO-, R⁴-O
-CO-lower alkyl-, R⁴− (R⁵−) N-CO−
Or R⁴− (R⁵-) N-CO-lower alkyl group R³： Cyano or R⁶-SO₂-Group R⁴, R⁵: Same or different, H, lower alkyl or
A phenyl group or R ⁴And R⁵Is one with the adjacent N atom
3 to 8 membered nitrogen-containing nitrogen atom which may have O atom
R may form an unsaturated ring;⁶: Lower alkyl or phenyl group. ) 2. The medicament according to claim 1, which is a high conductance calcium-sensitive K channel opener. 3. A furan derivative represented by the general formula (I '):
Is a pharmaceutically acceptable salt thereof. Embedded image(The groups in the formula have the following meanings: R¹: An aryl or a substituent which may have a substituent
Optionally a heteroaryl group R²: H, lower alkyl, phenyl, R⁴-CO-, R
⁴-O-lower alkyl-, R⁴-O-CO-, R⁴-O
-CO-lower alkyl-, R⁴− (R⁵−) N-CO−
Or R⁴− (R⁵-) N-CO-lower alkyl group R³： Cyano or R⁶-SO₂-Group R⁴, R⁵: Same or different, H, lower alkyl or
A phenyl group or R ⁴And R⁵Is one with the adjacent N atom
3 to 8 membered nitrogen-containing nitrogen atom which may have O atom
R may form an unsaturated ring;⁶: Lower alkyl or phenyl group. However, the following compounds are excluded. 2-amino-5-phenyl
-3-furannitrile, 2-amino-5-p-tosyl-
3-furannitrile, 2-amino-5- (p-methoxy
Phenyl) -3-furannitrile, 2-amino-5-
(P-chlorophenyl) -3-furannitrile, 2-a
Mino-5- (p-bromophenyl) -3-furannitrile
2-amino-4-methyl-5-phenyl-3-fura
Ninitrile, 2-amino-4,5-diphenyl-3-f
Lannitrile, 2-amino-5-p-tosyl-4-fe
Nyl-3-furannitrile, 2-amino-5- (4-bi
Phenylyl) -4-phenyl-3-furannitrile,
2-amino-5- (p-methoxyphenyl) -4-fe
Nyl-3-furannitrile, 2-amino-5- (p-e
Toxiphenyl) -4-phenyl-3-furannitrile
5-amino-4-cyano-2-phenyl-3-fura
Acid ethyl ester, 2-amino-4-benzoyl-5
-Phenyl-3-furannitrile, 2-amino-4-a
Cetyl-5-phenyl-3-furannitrile. ) 4. A 4-oxobutyronitrile derivative represented by the general formula (IV) obtained by reacting a compound represented by the general formula (II) with an acetonitrile derivative represented by the general formula (III) A method of producing a furan derivative of the general formula (I) or a pharmaceutically acceptable salt thereof by ring closure in the presence of an acid catalyst. Embedded image 5. The method according to claim 4, wherein the acid catalyst is trifluoroacetic acid.
A method for producing a furan derivative of the above general formula (I) or a pharmaceutically acceptable salt thereof.