WO1998035673A1 - Medicaments utilises dans la decongestion du flux sanguin peripherique - Google Patents

Medicaments utilises dans la decongestion du flux sanguin peripherique Download PDF

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Publication number
WO1998035673A1
WO1998035673A1 PCT/JP1998/000587 JP9800587W WO9835673A1 WO 1998035673 A1 WO1998035673 A1 WO 1998035673A1 JP 9800587 W JP9800587 W JP 9800587W WO 9835673 A1 WO9835673 A1 WO 9835673A1
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WO
WIPO (PCT)
Prior art keywords
compound
arterial occlusion
amino
cyano
chlorophenyl
Prior art date
Application number
PCT/JP1998/000587
Other languages
English (en)
Japanese (ja)
Inventor
Yuji Okada
Original Assignee
Kirin Beer Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kirin Beer Kabushiki Kaisha filed Critical Kirin Beer Kabushiki Kaisha
Priority to AU58801/98A priority Critical patent/AU5880198A/en
Publication of WO1998035673A1 publication Critical patent/WO1998035673A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to improvement of peripheral circulatory disorders, and more specifically, a peripheral circulatory disorder ameliorating agent, a pharmaceutical agent comprising a specific pyridinyl ruboximidamide compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to the use of the above-mentioned compound for the production of a compound, and a therapeutic method using the above-mentioned compound.
  • Peripheral circulatory disorders are caused by stenosis of the blood vessel lumen due to arteriosclerosis, embolism due to atherosclerotic tissue debris, or blood clot formation, vasculitis, contraction of blood vessels or increased blood viscosity, etc. It is a condition in which peripheral tissues fall into an ischemic state.
  • Disorders associated with peripheral circulatory disorders of the extremities include chronic arterial obstruction represented by obstructive arteriosclerosis and obstructive plug vasculitis (Buerger ⁇ ), progressive systemic sclerosis, systemic erythematosus, vibration disease, Reino's disease, aneurysm or various vasculitis are known.
  • limb peripheral circulatory disorders clinical symptoms include cold and numbness in the limbs, intermittent claudication, resting pain, ulcers and necrosis.
  • Surgical treatment, exercise therapy and drug therapy or a combination thereof are currently being used to improve these symptoms or prevent the symptoms from becoming worse.
  • the drugs used in pharmacotherapy are mainly antiplatelet drugs and vasodilators (pharmacotherapy for chronic arterial occlusive disease, medicine and drugs, Vol. 29, pp. 202-803, 199 3 Year) .
  • vasodilators can be expected to improve symptoms by increasing blood flow in the collateral circulation based on vasodilation and improving circulation by reducing spasm.
  • vasodilators are effective in treating peripheral circulatory disorders or chronic arterial occlusion, and drugs that increase blood flow at ischemic sites are suitable.
  • vasodilators have a considerable effect on lowering blood pressure, and the degree of blood pressure reduction may decrease the blood flow at the ischemic site. May not be used to treat
  • nifedipine a calcium antagonist
  • chronic arterial occlusion Effects of nifedipine in intermittent claudication, J Vase Med Biol, 2, 94-99, 1990; peripheral arterial occlusion
  • Effect of nifedipine on patients with sickness Angio 1 o gy. 34, 46-52, 1983).
  • vasodilators used in the treatment of chronic arterial occlusion are oral staglandin preparations.
  • prostaglandin preparations have an antiplatelet effect, and as a side effect, bleeding tendency is observed, and the combined use with other antiplatelet drugs ⁇ anticoagulants is considered difficult. Therefore, it is useful for chronic arterial occlusion, etc. If effective and pure vasodilators are provided to treatment sites, it will be easier to use them in combination with drugs such as antiplatelet drugs and anticoagulants, enabling more effective, less side effects, and pharmacotherapy. .
  • arteriosclerosis which is a cause of chronic arterial occlusion, is more likely to occur due to hyperlipidemia, hypertension, hyperinsulinemia, impaired glucose tolerance, insulin resistance, visceral fat accumulation, or a combination thereof.
  • W093Z15057 discloses that 5-amino-N-cyano-N '-[2- (2-chlorophenyl) ethyl] -3-pyridinecarboxyimidamide has a blood pressure lowering effect, Its action is based on the opening of the force channel (KRN4884 relaxation in the coronary vessels of the septum, Genera 1 Pharmaco 1 ogy, 27, 985-989, 1996).
  • Japanese Patent Application Laid-Open No. 08-165239 discloses 1) suppression of cultured vascular smooth muscle cell proliferation, 2) suppression of intimal hyperplasia after endothelial injury of rat carotid artery by balloon catheter, and 3) reduction of serum triglyceride. It is disclosed that it is effective in preventing or treating arterial sclerosis.
  • the present invention is intended to solve the above-mentioned problems, and an object of the present invention is to improve the symptoms of peripheral circulatory disorders of the limbs by vasodilating action, and to prevent and prevent the progression of peripheral circulatory disorders.
  • the goal is to provide a drug that is both therapeutic and prophylactic.
  • the present inventor has found that a specific pyridine-functional lipoxyimidamide derivative, that is, 5-amino-1-N-cyano— [2- (2-chlorophenyl) ethyl] _3—
  • pyridinecarboxyimidamide had an improving effect in arterial occlusion model rats, and also found an effect of increasing skeletal muscle blood. Therefore, this pyridinecarboximidamide derivative is a drug that improves the symptoms of limb peripheral circulation disorder by vasodilating action.
  • the pyridine carboximidamide derivative has also obtained new findings having an effect of improving hyperinsulinemia, impaired glucose tolerance, insulin resistance, and visceral fat accumulation.
  • the present invention has been completed based on the above findings. That is, the drug according to the present invention comprises the pyridinecarboximidamide compound described above.
  • the present invention also relates to the use of the above compound for producing an agent for improving peripheral circulatory disorders or treating arterial occlusion.
  • the pyridinecarboximidamide compound used in the present invention is represented by the following formula (I): 5-amino-N-cyano-l -'- [2- (2-chlorophenyl) ethyl] -3-1-pyridinecarboximidamide Or a salt thereof, which has an effect of improving peripheral circulatory disorder or hyperinsulinemia, impaired glucose tolerance, insulin resistance, and visceral fat accumulation, as confirmed in the Examples below. It can be used as a prophylactic, ameliorating or therapeutic agent for these disorders.
  • the compound represented by the formula (I) as described above can be produced by any suitable method, for example, by the method described in the above-mentioned WO93-15757. Can be manufactured. This method can be summarized as follows.
  • an alkoxydionion is allowed to act on a cyanopyridine compound to produce an imidate compound, which is reacted with cyanamide to convert it into ⁇ -cyano-pyridine carboximide, which is then converted into various amines.
  • This is a method for obtaining the desired ( ⁇ -cyano-N′-substituted) pyridinecarboximimidamide compound by reacting with a compound. The specific method is also described for reference in the preparation examples of Examples below.
  • the compound represented by the general formula (I) used as an active ingredient in the present invention is a basic compound It has a nitrogen atom and can form acid addition salts.
  • the acid to form an acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, or acetic acid, propionic acid, maleic acid, and oleic acid.
  • Organic acids such as lumitic acid, citric acid, succinic acid, tartaric acid, fumaric acid, glutamic acid, tontoic acid, methanesulfonic acid, toluenesulfonic acid, and radialsulfonic acid can be given.
  • the acid addition salt is used as a medicine, it goes without saying that the acid must be pharmaceutically acceptable.
  • the pharmaceutical agent according to the present invention contains 5-amino-N-cyano-N '-[2- (2-chlorophenyl) ethyl]-3-pyridinecarboxyimidamide or a salt thereof as an active ingredient.
  • peripheral circulatory circulatory disease reduces peripheral tissue obstruction by reducing tissue damage around the occluded site, and improves these disorders by increasing blood flow at the ischemic site. It can be used as a disorder ameliorating drug or as a cure for arterial obstruction.
  • the pharmaceutical agent according to the present invention suppresses the increase in insulin without increasing the blood glucose level and prevents the decrease in insulin sensitivity in hyperinsulinemia and insulin resistance as shown in the Examples below.
  • hyperinsulinemia improves glucose intolerance by suppressing excessive rise in blood glucose level during Darcos challenge and reducing visceral fat accumulation by lowering fat tissue weight.
  • the term “ameliorating agent” or “therapeutic agent” includes any of a preventive agent (agent), an improving agent (agent) and a therapeutic agent (agent).
  • the improvement of peripheral circulation increases the blood flow power of skeletal muscle, and increases glucose and triglyceride intake to skeletal muscle. Increase in the amount of cerebral hypertension, impaired glucose tolerance, insulin resistance, and improvement of visceral fat accumulation.
  • it can be said to be a drug for improving, preventing or treating hyperinsulinemia, impaired glucose tolerance, insulin resistance and visceral fat accumulation.
  • the above-mentioned agent for improving peripheral circulation or therapeutic agent for arterial obstruction according to the present invention also includes an agent for improving, preventing or treating hyperinsulinemia, impaired glucose tolerance, insulin resistance and visceral fat accumulation.
  • the pharmaceutical agent of the present invention can be administered orally or parenterally (intramuscularly, subcutaneously, intravenously, transdermally).
  • the pharmaceutical agent of the present invention When the pharmaceutical agent of the present invention is administered orally, it is administered as a tablet, granule, powder, capsule or the like, and when administered parenterally, it is injected, suspension, sublingual tablet, suppository, patch , Lotions or ointments. To prepare these preparations, excipients, binders, disintegrants, lubricants, stabilizers and the like can be added.
  • lactose for example, lactose, starch, crystalline cellulose, mannitol, maltose, calcium hydrogen phosphate, light gay anhydride, calcium carbonate, etc.
  • a binder for example, starch, polyvinylpyrrolidone, hydroxypropyl cellulose , Ethyl cellulose, carboxymethyl cellulose, gum arabic, etc., as disintegrants, for example, starch, carboxymethyl cellulose, etc., as lubricants, for example, magnesium stearate, talc, hardened oils, etc., as stabilizers, for example, lactose, Mannitol, maltose, polysorbates, polyoxyethylene hard castor oil and the like.
  • These components can be used to produce tablets, granules, capsules, injections and the like.
  • the method of administration and the dosage or therapeutically effective amount of the agent of the present invention will vary depending on the circumstances of the individual patient to be treated, for example, body weight, sex, susceptibility, time of administration, concomitant agent, patient or degree of the disease. Needless to say, the appropriate dose and the number of doses under certain conditions must be determined by a dosage determination test by a specialist based on the above guidelines, but it is usually oral administration per adult per day The amount is about 0.001 to 1.0 mg mg as an active ingredient, and the intravenous dose is about 0.1 to 100 gZ as an active ingredient.
  • Compound 2 can be synthesized by the method described in the above-mentioned JP-B-6-62567 according to the method for synthesizing compound 1 described above.
  • the condition of the hind paws was observed 10 days later, and the degree of lesion of the paws was classified into the following 0 to 5 to determine the effect. The judgment was based on the following evaluation. Score 0: no change, 1: edema or redness of the foot, 2: mummification or necrosis of the nail, 3: mummification or necrosis of the finger, 4: mummification or necrosis up to half of the instep, 5: whole of the instep Mummification or necrosis. The significance test was performed by the U test of Mann-Whitney.
  • Test Example 4 Effect on lactate-induced arterial occlusion rat
  • the high fructose diet was started immediately after administration. Serum glucose and insulin levels and adipose tissue weight around epididymis were measured 4 hours after the last administration of compound 1. The significance test was performed by Dunnett's multiple comparison test or Student's t test.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des médicaments ayant un effet vasodilatateur et qui sont efficaces pour prévenir et traiter les troubles du flux sanguin périphérique. Ces médicaments contiennent, comme ingrédient actif, 5-amino-N-cyano-N'-[2-(2-chlorophényl)éthyl]-3-pyridinecarboximidamide ou des sels de celui-ci, et sont utilisés comme médicaments ayant, en plus des effets précités, des effets réduisant l'hyperinsulinémie, l'intolérance au glucose, la résistance insulinique et l'accumulation des graisses viscérales.
PCT/JP1998/000587 1997-02-14 1998-02-13 Medicaments utilises dans la decongestion du flux sanguin peripherique WO1998035673A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58801/98A AU5880198A (en) 1997-02-14 1998-02-13 Drugs for relieving peripheral circulation disorder

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP3063897 1997-02-14
JP9/30638 1997-02-14

Publications (1)

Publication Number Publication Date
WO1998035673A1 true WO1998035673A1 (fr) 1998-08-20

Family

ID=12309389

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/000587 WO1998035673A1 (fr) 1997-02-14 1998-02-13 Medicaments utilises dans la decongestion du flux sanguin peripherique

Country Status (2)

Country Link
AU (1) AU5880198A (fr)
WO (1) WO1998035673A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993015057A1 (fr) * 1992-01-28 1993-08-05 Kirin Beer Kabushiki Kaisha Compose de pyridinecarboximidamide et son utilisation
JPH0733729A (ja) * 1993-07-26 1995-02-03 Kirin Brewery Co Ltd Ｎ−シアノ−ｎ′−置換−アリールカルボキシイミダミド化合物の製造法
JPH08165239A (ja) * 1994-12-09 1996-06-25 Kirin Brewery Co Ltd 抗動脈硬化剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993015057A1 (fr) * 1992-01-28 1993-08-05 Kirin Beer Kabushiki Kaisha Compose de pyridinecarboximidamide et son utilisation
JPH0733729A (ja) * 1993-07-26 1995-02-03 Kirin Brewery Co Ltd Ｎ−シアノ−ｎ′−置換−アリールカルボキシイミダミド化合物の製造法
JPH08165239A (ja) * 1994-12-09 1996-06-25 Kirin Brewery Co Ltd 抗動脈硬化剤

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BRITISH JOURNAL OF PHARMACOLOGY, No. 120, (Apr. 1997), p. 1471-1476. *
CHEM. PHARM. BULL., Vol. 42, No. 12, (1994), p. 2483-2490. *
MEDICAL DICTIONARY, 17th Edition, NANZANDO, (1990), p. 1395. *
NAUNYN-SCHMIEDEBERG'S ARCH. PHARMACOL., No. 337, (1988), p. 341-346. *

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AU5880198A (en) 1998-09-08

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