MXPA00006647A - Potassium channel activators - Google Patents

Abstract

Medicinal compositions comprising as the active ingredient pyrrole derivatives represented by general formula (1) or pharmaceutically acceptable salts thereof, wherein R1 represents hydrogen or alkoxycarbonylamino;R2 represents alkyl, optionally substituted aryl, optionally substituted heteroaryl, unsubstituted amino, monoalkylated amino, dialkylated amino or optionally substituted cyclic amino;R3 represents cyano or carbamoyl;R4 represents hydrogen or alkyl;E represents alkylene;q is 0 or 1;and A represents methyl, optionally substituted aryl or optionally substituted heteroaryl. These medicinal compositions are useful as potassium channel activators.

Description

POTASSIUM CHANNEL ACTIVATORS Field of Invention The present invention relates to a potassium channel activator (K + channel) comprising a pyrrole derivative or its pharmaceutically acceptable salt as an active ingredient. A potassium channel activator is useful for the prophylaxis or therapy of physiological disorders associated with the K + channel.

Background of the Invention The potassium channel exists in a variety of cells such as nerve cells and soft muscle cells and is involved in various physiological processes and controls the homeostasis of normal cell ions. Generally, potassium ions regulate the resting potential of the cell membrane, and a flow of potassium ions followed by a depolarization of the cell membrane results in repolarization of the membrane. The activator of the potassium channel causes hyperpolarization of the cells. Thus, Ref: 121365 in nerve cells, the suppression of cellular activity to reduce the transmitted release of the final nerves and, in soft muscle cells, suppress contractility.

Therefore, the activator of the potassium channel is considered to be of value in the therapy of nervous system disorders that induce spasmodic or ischemic responses through its action on nerve cells. In addition, through its action on soft muscle cells, the potassium channel activator is expected to be useful in the therapy of various diseases such as hypertension, angina pectoris, asthma and irritable bowel syndrome.

Compounds which are already known as compounds having activity in potassium channel activation are the benzopyran derivatives (Japanese Patent Expired S58-67683, Japanese Expired Patent H6-25233, WO 94/13297, etc.), thienopyran derivatives (WO 94/13297 etc.), benzoxazine derivatives (Japanese Expired Patent H5-70464, WO 94/13297, etc.), benzoxepin derivatives (WO 94/13297 etc.), quinoline derivatives (WO 94/13297 etc. .), indole derivatives (WO 94/13297 etc.), benzocycloheptane derivatives (WO 94/13297 etc.) and pyridine derivatives (The Merck Index, 11th edition, 7407), among others.

The compound according to the present invention (hereinafter referred to as the compound of the invention) is a pyrrole derivative that is structurally different from any of the aforementioned compounds having an activity that activates the potassium channel. It was not known until now that a pyrrole derivative ever had an activity that activates the potassium channel.

Description of the invention.

The object of the present invention is to provide a novel potassium channel activator.

By exploring several compounds with enthusiasm, the inventors of the present invention surprisingly found that a pyrrole derivative of the following general formula [1] has an activity that activates the potassium channel and has completed this invention.

The present invention, therefore, is directed to a potassium channel activator composition comprising a pyrrole derivative of the following general formula [1] or a pharmaceutically acceptable salt thereof as an active ingredient: wherein Ri represents hydrogen or alkoxycarbonylamino; R represents (i) alkyl, (ii) aryl that can be substituted, (iii) aromatic heterocyclyl which can be substituted, (iv) a group of the following formula [2] 6 / [wherein R6 and R7 can be the same or different and each represents (1) hydrogen or (2) alkyl (said alkyl can be substituted by (1) aryl which can be substituted by alkoxy, (2) aromatic heterocyclyl, or ( 3) hydroxy)], or (v) a group of the following formula [3] Z1 and Z2 can be the same or different and each represents -CH2- or > C = 0; with the proviso that Z1 and Z2 do not currently represent > C = 0; Y represents -CH2-, -O-, -S-, or > NR9; R9 represents hydrogen, alkyl, acyl, aryl, or aromatic heterocyclyl; m represents an integer of 1-3; n represents an integer of 0-2; p represents 0 or 1; in case R represents substituted aryl or aromatic heteroaryl which is substituted, the particular aryl or aromatic heterocyclyl can be substituted by 1-3 same or different members selected from the group consisting of (1) halogen, (2) alkyl which can be to be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (said alkoxy can be substituted by (1) halogen, (2) aryl which can be substituted by alkoxy, or (3) alkoxy), (8) -NHS02R82, and (9) NR83R84; or two adjacent substituent groups can represent united • 0- (CH2) t-0- (t represents 1 or 2); R 82 represents (1) alkyl (2) aryl which can be substituted by alkyl; R83 and R84 may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R 83 and R 84 joined together and taken together with the adjacent N atom represent a cyclic amino of 5 to 7 members; R represents cyano or carbamoyl; R represents hydrogen or alkyl; E represents alkylene; q represents 0 or 1; A represents (1) methyl, (2) aryl that can be substituted, or (3) aromatic heterocyclyl which can be substituted; in case A represents aryl that is substituted or aromatic heterocyclyl being substituted, the particular aryl or aromatic heterocyclyl can be substituted by 1-3 same or different members selected from the group consisting of (1) halogen, (2) alkyl which can be to be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (said alkoxy can be substituted by (1) halogen, (2) aryl which can be substituted by alkoxy, or (3) alkoxy), (8) -NHS02R92, and (9) NR93R94; or two adjacent substituent groups can together represent -O- (CH2) u-0- u represents 1 or 2); represents (1) alkyl or (2) aryl which can be substituted by alkyl; R93 and R94 may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R93 and R94 attached and taken together with the adjacent N atom represent a cyclic amino of 5 to 7 members; A- (E) q, R, and the double bond of the pyrrole ring can come together, this is how X represents -O-, -S-, or > NR 90 where R 90 represents alkyl; R, 95, R, 96 and R, 97 may be the same or different and each is selected from the group consisting of (1) hydrogen, (2) halogen, (3) alkyl which can be substituted by halogen, (4) cyano, (5) nitro, (6) alkoxycarbonyl, (7) hydroxy, (8) alkoxy (said alkoxy can be substituted by halogen or alkoxy), (9) -NHS02R92 (R92 is as defined above), and (10) -NR93R94 (R93 and R94 are as defined above); any of two adjacent groups of between R95, R96, and R97 can together represent -0- (CH2) u-0- (u is as defined above).

In the context of the present invention, "alkyl" includes straight chain or branched chain alkyl groups containing from 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl and tert-butyl.

The "aryl" includes aryl groups of 6-12 carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 3-biphenyl and 4-biphenyl.

The "aromatic heterocyclyl" includes ring groups of 5 or 6 aromatic members containing 1-4 nitrogen, oxygen or sulfur atoms as ring members and the corresponding ring systems fused with benzene (however, 2-pyrrolyl and 3-pyrrolyl). -pyrrolyl are excluded), thus including 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 1-indolyl, 2-indolyl, 3-indolyl, 1-tetrazolyl, 2-furyl, 3-furyl, 2-benzofuranyl, 3-benzofuranyl, 2-thienyl, and 3-thienyl, among others.

The "alkylene" includes straight chain or branched chain groups of 1-4 carbon atoms, such as the following.

-CH-CH -CU, 2 CH2-CH- - (CH2) 2- ÍH - (CH2) 3-, CH3 CH, CH, 1 H3 -c | - ~ (CH2) 4- -CH- (CH2) 2- -CH2-CH-CH2 CH,. . CH3 CH, CH 3 CH 3 - (CH 2) 2-CH- -CH-CH-1 -C-CH 2 - -CH 2 -C-CH 3 CH CH 3 CH 3 CH, The alkyl portion of said "alkoxy", "alkoxycarbonyl" or "alkoxycarbonylamino" include the alkyl groups mentioned above.

"Halogen" includes fluoride, chlorine, bromine and iodine The "acyl" includes groups of 1-7 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, isohexanoyl and benzoyl.

The 5-7 membered cyclic amino represented by NR83R84 NR93R94 includes, but is not limited to l-pyrrolidinyl, 1-pyridinyl and 1-hexamethyleneimino.

The preferred species of the compound [1] of the invention includes the compound in which R1 is hydrogen, R2 is NH2, pyrrolidino or methyl, R3 is cyano, R4 is hydrogen or methyl, q is 0, and A is aryl that can be substituted or an aromatic heterocyclyl which can be substituted.

Particularly preferred examples of the compound [1] of the invention, include the following compounds. (1) 2 -Amino-3-cyano-5- (2-fluorophenyl) -4-methylpyrrole (hereinafter referred to as compound 1) (2) 2-Amino-3-cyano-4-methyl-5-phenylpyrrole (hereinafter referred to as compound 2) (3) 2-amino-5- (3-chlorophenyl) -3-cyano-4- met i Ipirrol (Hereinafter referred to as compound 3) (4) 2-Amino-3-cyano-5- (2-furyl) -4-met i Ipirrol (hereinafter referred to as compound 4) (5) 2-Amino-3-cyano-5- (3,4-metylenedioxyphenyl) pyrrole (hereinafter referred to as compound 5) (6) 2-amino-3-cyano-5- (2,4-difluorophenyl) pyrrole (hereinafter referred to as compound 6) (7) 5- (3-chlorophenyl) -3-cyano-2-met ilpyrrole (hereafter referred to as compound 7) (8) 2-amino-3-cyano-4-methyl-5- (3-nitrophenyl) pyrrole (hereinafter referred to as compound 8) (9) 3-Cyano-2,4-dimethyl-5-phenylpyrrole (hereinafter referred to as compound 9) ) 3-Cyano-5- (3-ethoxy phenyl) -2-pyrrolidinopyrrole Hereinafter referred to as compound 10) (11) 3-Cyano-5- (3,4-methylenedioxyphenyl) -2-pyrrolidinopyrrole (From hereinafter referred to as compound 11).

The compound of the invention, represented by the general formula [1] above, can be produced by any of the processes described in WO 96/40634.

Among the species of the compound of the invention, any compound that is basic can be administered for medication in a free base form but optionally can be converted to a pharmaceutically acceptable salt by the known method and administered. The salt includes salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and salts with organic acids, such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-acid. -toluenesulfonic, benzenesulfonic acid, methanesulonic acid.

The compound of the invention has an activity that activates the potassium channel potency and therefore is only slightly toxic as shown in the experimental examples that will appear below, so it is useful as a prophylactic or therapeutic medicine for diseases cardiovascular diseases such as hypertension, ischemic diseases (such as angina pectoris and myocardial infion), atherosclerosis, hyperlipidemia, congestive heart failure, arrhythmia and peripheral vascular disorders.

In addition, the compound of the invention is useful as a therapeutic drug for various disorders associated with mild muscle contraction, such as cerebrovascular disorders (e.g. cerebrovascular spasm), peripheral vascular disorders (e.g., rheogenetic failure, psilosis, coldness of the members, etc.), respiratory disorders (reversible airway obstruction, hyper-sensitive airway obstruction, asthma), gastrointestinal disorders (ulcer, irritable bowel syndrome, obliteration of the bile duct, etc.), visual disturbances- auditory (for example, glaucoma, ocular hypertension, etc.), disorders of the urinary system (renal failure, disorders accompanied by the passage of kidney stones, etc.), and disorders of the genital organs (erectile dysfunction, premature birth, etc.). ).

In addition, the compound of the invention is useful as a therapeutic medicine for blood sugar abnormalities (hypoglycemia, etc.) and as a prophylactic or therapeutic drug for disorders due to abstinence in cases of abuse of such substances as cocaine, nicotine , alcohol, and benzodiazepine, disorders that can be prevented or cured with an anticonvulsant, such as epilepsy, neuropathies as a result of cerebrovascular disorders, and various nervous system disorders such as schizophrenia.

For the use of the compound of the invention as a medicine, the compound can be administered, either as such or in the form of a pharmaceutical composition containing it in a concentration of, for example, 0.1-99.5%, preferably 0.5-90%, in a pharmaceutically acceptable carrier, non-toxic and inert, to mammals including humans.

As the carrier, at least one member selected from solid, semi-solid or liquid diluents, fillers and other auxiliary formulation agents are employed. The pharmaceutical composition is preferably administered in a unit dosage form. The pharmaceutical composition of the present invention can be administered intravenously, orally, in the target tissue, locally (for example transdermally) or rectally. The appropriate dosage forms for the respective routes of administration must, of course, be selected. Oral administration is particularly preferred.

Oral administration can be done using a solid or liquid unit dose, such as pure powders, powders, tablets, sugar-coated tablets, capsules, granules, suspensions, solutions, thick mixtures, drops, sublingual tablets and the like.

The pure powders can be prepared by grinding the active substance to an appropriate particle size. The powders can be produced by grinding the active substance to an appropriate starting size and mixing the resulting particles with a similarly ground pharmaceutical carrier, such as fine particles of, for example, an edible carbohydrate such as starch or mannitol. Where necessary, flavoring agents, preservatives, dispersants, coloring agents, perfumes, etc. may also be added and mixed.

Capsules can be produced by filling molded pieces for capsules, such as molded pieces for gelatin capsules, with such pure ground powders or powders or granules prepared therefrom as described below for the manufacture of tablets. Prior to filling, a lubricant or fluidizing agent, such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, etc., can be added to the powder material. In addition, the biological availability of the medicament after introducing it into the capsule can be improved by adding a disintegrator or solubilizer, such as carboxymethylcellulose, calcium carboxymethylcellulose, low-substitution hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate, carbonate sodium and others.

The finely divided powder mentioned above can be dispersed in a vegetable oil, polyethylene glycol, glycerin or a surfactant and the resulting suspension is wrapped in gelatin sheets to provide soft capsules. The tablets can be produced by preparing a powder mixture using an excipient, granulated or chopped, adding a disintegrator or a lubricant, and compressing the mixture. The powder mixture can be prepared by mixing a suitable ground powder of the active substance with said diluent or base and, where necessary, adding a binder (for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc. .), a retarder of the dissolved (for example paraffin), a reabsorption agent (for example, a quaternary salt) and an absorbent (for example bentonite, kaolin, bicalcium phosphate). The powder mixture can be processed into granules by moistening with a binder, such as a syrup, starch paste, gum arabic, cellulose solution or polymer solution, first, by stirring the mixture, drying it, and spraying it. Instead of granulating the powder, it can be compressed with a tablet machine first and the pieces crushed crudely into granules.

The granules thus obtained can be protected against int eradhes ion by adding a lubricant such as stearic acid, a stearate, talc, mineral oil or the like. The lubricant mixture is then compressed. The smooth tablets thus obtained can be coated with a film or coated with sugar.

The medicament can be administered with a free-flowing inert carrier and compressed directly into tablets without such granulation or slicing operation. A transparent or translucent protective film comprising a hermetic lacquer coating, a sugar or polymer coating film, or an upper polishing wax coating, can also be used.

Other forms of oral doses, such as a solution, a syrup and an elixir, can also be provided as a unit dosage form containing a predetermined amount of the medicament in a given amount. The syrups can be produced by dissolving the compound in aqueous solution of suitable flavor, while the elixirs can be produced using non-toxic alcoholic vehicles. The suspensions can be formulated by dispersing the compound in non-toxic vehicles, where necessary, solubilizers and emulsifiers (for example ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester), preservatives and flavoring agents (for example peppermint oil, saccharin) can be added, others.

If necessary, the unit dose formulations for oral administration can be microencapsulated. Such formulations can be coated or incorporated in a high polymer or wax to prolong the duration of action or ensure a sustained release.

Administration to the target tissue can be done using a liquid unit dosage form suitable for subcutaneous, intramuscular or intravenous administration, for example a solution or suspension. Such dosage forms may be produced by suspending or dissolving a predetermined amount of the compound in an injectable non-toxic liquid carrier such as an aqueous medium or an oily medium and, then, sterilizing the suspension or solution. For the isotization of such parenteral products, solutions of non-toxic salts or salts may be added. A stabilizer, a preservative and / or an emulsifier can also be incorporated.

Rectal administration can be done using elaborate suppositories by dissolving or suspending the compound in a low boiling or water insoluble solid, such as polyethylene glycol, cocoa butter, a semi-synthetic oil (eg Witepsol ™), a higher ester ( for example myristyl palmitate) or a mixture thereof.

The dose as a potassium channel activator is preferably established with reference to the nature and severity of the disease, the patient's factors such as age and body weight, the route of administration, etc., but the usual daily dose is 0.1 -1000 mg / adult patient, preferably 1-500 mg / adult patient, in terms of the compound of the invention.

The reduction of the dose can be guaranteed in some cases, while the dose scale may be necessary in others. Moreover, the previous dose can be administered in 2-3 divided doses per day.

Best Way to Carry Out the Invention The following experimental examples and formulation example illustrate the present invention in further detail without defining the scope of the invention.

EXPERIMENTAL EXAMPLE 1. KCl-induced contraction effect of the isolated rat aortic specimen.

It has been generally demonstrated that the relaxant effect of a potassium channel activator in an induced contraction of KCl in isolated preparations is attenuated to the extent that the KCl concentration is increased (Br. J. Pharmacol., 8_8, 103-111 (1986)). In the present experiment, the activity that activates the potassium channel is evaluated by comparing the pIC50 values representing the relaxant effects of the test drug on the induced contraction of KCl of 20 mM and the induced contraction of KCl of 100 mM. According to Br. J. Pharmacol., 88, 103-111 (1986) referred above, potassium channel activators produce greater relaxation effects in the induced contraction of KCl of 20 mM than in the induced contraction of KCl of 100. mM.

Male SD rats of 7-13 weeks of age (body weights of 240-480 g) were used in groups of 4-6. After the animal bled to death under ether anesthesia, the thoracic aorta was isolated and dissected in a spiral specimen about 2 mm wide by about 20 mm long. Each specimen was suspended in a 10 ml Magnus bath containing Krebs-Henseleit solution (KH solution) aerated with 95% 02 + 5% C02 at 37 ° C. A filling tension of 1 g was applied and with the KH solution exchanging every 20 minutes, the specimen equilibrated for about 90 minutes. Then, the experiment began. The change in specimen tension was recorded in a straight recorder through an isometric voltage converter. The specimen was caused to contract by replacing the KH solution in the Magnus bath with a KH solution containing 20 mM or 100 mM KCl (NaCl in KH solution was replaced with an equimolar amount of KCl) and when the shrinkage response reached the silver, the test drug was applied cumulatively to evaluate the relaxation effect.

The results are shown in Table 1. Each result is expressed in the average of the relaxation ratio obtained in the presence of the test drug, with the maximum relaxation found with papaverine (100 μM) being taken as the 100% response of Specimen relaxation Table 1 Effect on the KCl induced contraction of the isolated rat aortic specimen.

In the isolated rat aortic specimen, the compound of the invention showed a greater relaxation effect in the induced contraction of KCl of 20 mM than in the induced contraction of KCl of 100 mM. It is, therefore, clear that the compound of the invention has a potent activity to activate the potassium channel.

EXPERIMENTAL EXAMPLE 2 Effect of KCl-induced contraction of the trachea specimen of guinea pigs.

As in Experimental Example 1, the activity that activates the potassium channel was evaluated by comparing the relaxing effects of the test drug on the induced contraction of KCl of 20 mM and on the induced contraction of KCl of 100 mM.

Hartiey guinea pigs males 5-13 weeks of age (body weights of 400-730 g) were used in groups of 2-4. After the animals were bled to death under ether anesthesia, the trachea was isolated and the 4 tapes of the trachea were connected to prepare a specimen in accordance with the method of Takagi et al. (Chem. Pharm. Bull., 6, 716-720 (1958)). The experiment was carried out in the same manner as described in Experimental Example 1.

Results are shown in table 2 Table 2 Effect on the KCl induced contraction of the isolated guinea pig trachea specimen.

In the isolated guinea pig trachea, the compound of the invention showed a greater relaxation effect in the induced contraction of KCl of 20 mM than in the induced contraction of KCl of 100 mM. It is, therefore, clear that the compound of the invention has a potent activity to activate the potassium channel.

Experimental Example 3 Effect on blood pressure in anesthetized rats.

Female SD rats 10-13 weeks of age (body weights of 180-300 g) were fasted from the day before to be used in groups of 2-4. The animal was placed in an upright position under urethane anesthesia and the femoral artery was cannulated to measure the bleeding pressure. The bleeding pressure was recorded on a recorder through the cannula and a pressure converter. When the bleeding pressure stabilized, the test drug was administered intoduodenally and the effect on blood pressure was observed for 3 hours after administration.

The results are shown in Table 3. Each value is expressed as the% change average at the time of the maximum action.

Table 3 Effect on blood pressure in anesthetized rats When administered intododenally, the compound of the invention showed blood pressure lowering effects apparently ascribed to its activity to activate the io potassium channel.

Experimental Example 4. Acute toxicity test Male ddY mice 6-7 weeks old (body weights of 20-40 g) were used in groups of 4. The animal was fasted from the previous day (for 16-18 hours), and using a gastric tube, was administered the test drug in a dose of 1000 mg / kg orally. The mortality of the animals was observed for 2 weeks. As test drugs, compound 1, compound 2 and compound 4 were respectively administered. As a result, no death was found in any of the compound groups.

Formulation Example 1. Tablets (oral tablets).

Recipe, in 200 mg per tablet Compound 1 20 mg Corn starch 88 mg Crystalline cellulose 80 mg Carboxymethylcellulose Ca 10 mg Light silicon anhydride 1 mg Magnesium stearate 1 mg Industrial Application As shown above, the compound of the invention is a compound having potent activity to activate the potassium channel and of low toxic potential and, therefore, a pharmaceutical composition comprising the compound of the invention as an active ingredient that It is useful as an activator of the potassium channel in mammals including humans.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (5)

Claims

1. A composition that activates the potassium channel, characterized in that it comprises a pyrrole derivative of the following general formula [1] or a pharmaceutically acceptable salt thereof as an active ingredient: wherein Ri represents hydrogen alkoxycarbonylamino; R represents (i) alkyl, (ii) aryl that can be substituted, (iii) aromatic heterocyclyl which can be substituted, (iv) a group of the following formula [2] 6 / R [wherein R6 and R7 can be the same or different and each represents (1) hydrogen or (2) alkyl (the alkyl can be substituted by (1) aryl which can be substituted by alkoxy, (2) aromatic heterocyclyl, or ( 3) hydroxy)], or (v) a group of the following formula [3] Z1 and Z2 can be the same or different and each represents -CH2- or > C = 0; with the proviso that Z1 and Z2 do not currently represent > C = 0; Y represents -CH2-, -0-, -S-, or > NR " R- represents hydrogen, alkyl, acyl, aryl, or aromatic heterocyclyl; m represents an integer of 1-3; n represents an integer of 0-2; p represents 0 or 1; in case R represents substituted aryl or aromatic heteroaryl which is substituted, the particular aryl or aromatic heterocyclyl can be substituted by 1-3 same or different members selected from the group consisting of (1) halogen, (2) alkyl which can be to be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (the alkoxy can be substituted by (1) halogen, (2) aryl which can be substituted by alkoxy, (3-alkoxy) NHS02R, 82, and (9) NR 3pR84; or two adjacent substituent groups can represent attached -0- (CH2) t-0-represents 1 or 2); Rc represents (1) alkyl (2) aryl which can be substituted by alkyl; R83 and R84 may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R 83 and R 84 joined together and taken together with the adjacent N atom represent a cyclic amino of 5 to 7 members; R represents cyano or carbamoyl; R represents hydrogen or alkyl; E represents alkylene; q represents 0 or 1; A represents (1) methyl, (2) aryl that can be substituted, or (3) aromatic heterocyclyl which can be substituted; in case A represents aryl being substituted or aromatic heterocyclyl being substituted, the particular aryl or aromatic heterocyclyl can be substituted by 1-3 same or different members selected from the group consisting of (1) halogen, (2) alkyl which can be to be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (the alkoxy can be substituted by (1) halogen, (2) aryl which can be substituted by alkoxy ( 3) alkoxy) -NHS02R, 9"2 (9) NR93R9 two adjacent substituent groups can together represent -O- (CH2) u-0- (or represents 1 or 2); R, 92 represents (1) alkyl or (2) aryl which can be substituted by alkyl; R93 and R94 may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R93 and R94 attached and taken together with the adjacent N atom represent a cyclic amino of 5 to 7 members; A- (E) q, R, and the double bond of the pyrrole ring can come together, this is A as X represents -O-, -S-, > NR 90 where R 90 represents alkyl; R95, R96 and R97 may be the same or different and each is selected from the group consisting of (1) hydrogen, (2) halogen, (3) alkyl which can be substituted by halogen, (4) cyano, (5) nitro, (6) alkoxycarbonyl, (7) hydroxy, (8) alkoxy (the alkoxy can be substituted by halogen or alkoxy), (9) -NHS02R92 (R92 is as defined above), and (10) -NR93R94 (R93 and R94 are as defined above); any of two adjacent groups of between R95, R96, and R97 can together represent -0- (CH2) u-0- (u is as defined above).

2. A composition that activates the potassium channel, characterized in that it comprises, as the active ingredient, the pyrrole derivative or the pharmaceutically acceptable salt described in claim 1, wherein R1 is hydrogen, R2 is NH2, R3 is cyano, R4 is hydrogen or methyl, q is 0, and A is aryl that can be substituted or an aromatic heterocyclic that can be substituted.

3. A composition that activates the potassium channel, characterized in that it comprises, as an active ingredient, the pyrrole derivative or the pharmaceutically acceptable salt described in claim 1 which is selected from the following compounds: (1) 2 -Amino-3-cyano-5- (2-fluorophenyl) -4-met ilpyrrole (2) 2-Amino-3-cyano-4-met il-5-phenylpyrrole 3) 2-amino-5- (3-chlorophenyl) -3-cyano-4-methylpyrrole 4) 2 -Amino-3-cyano-5- (2-furyl) -4 -met i Ipyrrole (5) 2-Amino-3-cyano-5- (3, -methylenedioxyphenyl) pyrrole (6) 2 -Amino-3-cyano-5- (2,4-difluorophenyl) pyrrole (7) 5- (3-chlorophenyl) -3-cyano-2-methylpyrrole (8) 2 -Amino-3-cyano-4-methyl-5- (3-nitrophenyl) pyrrole (9) 3-Cyano-2, 4 -dimet il-5-phenylpipe (10) 3-Cyano-5- (3-ethoxyphenyl) -2-pyrrolidinopyrrole (11) 3-Cyano-5- (3,4-methylenedioxyphenyl) -2-pyrrole idinopyrrole.

4. A therapeutic composition for hypertension, characterized in that they comprise, as the active ingredient, the pyrrole derivative or the pharmaceutically acceptable salt described in claims 1-3.

5. A bronchodilator composition, characterized in that it comprises, as the active ingredient, the pyrrole derivative or the pharmaceutically acceptable salt described in claims 1-3. POTASSIUM CHANNEL ACTIVATORS Summary of the invention. The invention is directed to a pharmaceutical composition comprising a pyrrole derivative of the following formula [1] or its pharmaceutically acceptable salt as the active ingredient: (wherein R: represents hydrogen or alkoxycarbonylamino; R 2 represents alkyl, aryl that can be substituted, an aromatic heterocyclyl which can be substituted, unsubstituted amino, substituted monoalkyl amino, substituted amino dialkyl, or cyclic amino which can be substituted; R 3 represents cyano or carbamoyl R 4 represents hydrogen or alkyl, E represents alkylene, q represents 0 or 1, A represents methyl, aryl that can be substituted, or an aromatic heterocyclyl which can be substituted). This pharmaceutical composition is useful as an activator of the potassium channel.