WO2002072099A1 - Agent therapeutique et / ou prophylactique pour la cardiopathie ischemique diabetique - Google Patents

Agent therapeutique et / ou prophylactique pour la cardiopathie ischemique diabetique Download PDF

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Publication number
WO2002072099A1
WO2002072099A1 PCT/JP2002/002286 JP0202286W WO02072099A1 WO 2002072099 A1 WO2002072099 A1 WO 2002072099A1 JP 0202286 W JP0202286 W JP 0202286W WO 02072099 A1 WO02072099 A1 WO 02072099A1
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WIPO (PCT)
Prior art keywords
group
heart disease
hydrogen atom
diabetes
agent
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Application number
PCT/JP2002/002286
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English (en)
Japanese (ja)
Inventor
Yoshimi Kitada
Original Assignee
Mitsubishi Pharma Corporation
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Publication of WO2002072099A1 publication Critical patent/WO2002072099A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D237/14—Oxygen atoms

Definitions

  • the present invention is based on the finding that the present invention relates to a specific phenylpyridazinone derivative or a salt thereof, or a hydrate or a solvate thereof.
  • SRJ sarcoplasmic reticulum
  • Ca calcium ion
  • JP-A-62-16282 and JP-A-61-289032 each disclose a specific phenylene pyridazinone derivative. It is described that these compounds are useful as cardiotonic agents, but these compounds are As far as the inventor knows, it has an effect on improving the uptake of Ca into the sarcoplasmic reticulum in ischemic heart disease due to diabetes. Not yet reported. In addition, as far as the present inventors know, the use of these compounds in combination with the ampicillin dipin, which is known as a Ca antagonist, is not limited. No reports have been reported so far.
  • the present invention aims to provide a drug that is effective in treating ischemic heart disease due to diabetes, and more particularly, to a specific phenylpyrene known as a cardiotonic. It is intended to provide a therapeutic and / or preventive drug for ischemic heart disease due to diabetes, which comprises a lidazinone derivative as an active ingredient. Disclosure of the invention
  • the inventors of the present invention have focused on a decrease in the ability of SR to take up Ca, which is said to be a cause of ischemic heart disease due to diabetes, and will improve the SR function.
  • a specific phenylene pyridazinone derivative which was previously only known as a cardiotonic agent, was used in the treatment of SR Ca in ischemic heart disease due to diabetes. It has been found that it has a function to improve the filling capacity.
  • simultaneous administration of Ca antagonists has been shown to reduce the cardioplegic effects often found in clinical use of Ca antagonists. Find out what can be reduced and thus provide new pharmacotherapy for the treatment and prevention or prevention of ischemic heart disease from diabetes This led to the completion of the present invention.
  • the gist of the present invention is as follows.
  • R 2 and R 2 are each independently a hydrogen atom, a hydrogen atom, a hydrogen atom, an alkyl group, an amino group, R, carboxyl, nitro, cyano, trifluoromethyl, acylamino, or alkoxy
  • R 3 represents a hydrogen atom, an acyl group or an alkynole group
  • R 4 is a 5- or 6-membered ring which may have a substituent on the ring. Represents a complex ring of.
  • a therapeutic and / or prophylactic agent for ischemic heart disease due to diabetes characterized by:
  • the effective component is represented by the following general formula (3) (
  • A represents a 5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms, and on the ring, an alkynole group, a cyano group, or a hydroxyl group , Alkoxy group, amino group, alkynole amino group, genolex amino group, ash ole amino group, carboxy linole group, annel oxy group It may have at least one substituent selected from the group consisting of a carbohydrate group and a carbamoinole group.
  • R t, R 2, and R 3 are each independently a hydrogen atom methyl group. Is a ethynole group, and is a compound represented by 2—pyridyl group 4—pyridyl group, 2_pyrimidyl group or 4-quinolinole group.
  • an agent for ameliorating cardiac function deterioration due to ischemic heart disease due to diabetes comprising a solvate thereof as an active ingredient.
  • the pheninolepyridazinone derivative represented by the general formula (1) or (2), a salt thereof, or a hydrate thereof is also included.
  • the active ingredient may be a phenylpyridazinone derivative represented by the general formula (3), a salt thereof, or a hydrate thereof. Is a solvate thereof, wherein the agent for reducing cardiac depression is described above.
  • R 2 and R 3 each independently represent a hydrogen atom methyl group or a hydrogen atom methyl group.
  • the agent of any one of the above which is characterized by being administered to a patient with ischemic heart disease due to diabetes.
  • a feninole pyridazinone derivative represented by the above general formula (1) or (2) or a salt or salt thereof.
  • a medicament containing such a hydrate or a solvate thereof, and (b) as an active ingredient, uptake of calcium ion of sarcoplasmic reticulum A method for treating ischemic heart disease due to diabetes and a method for preventing or treating ischemic heart disease using a medicine containing a Ca antagonist having an activity-improving action, and Use of the medicament (b) at the same time, separately or over time, for the treatment and / or the prophylactic Z or ischemic heart disease of diabetes due to diabetes.
  • the treatment and / or prevention of ischemic heart disease due to diabetes is based on the ability of sarcoplasmic reticulum to improve the uptake of canoledium ion.
  • a drug for treating and preventing or preventing ischemic heart disease due to diabetes using a drug containing a Ca antagonist having the formula (a) and the drug (b) ) Is used simultaneously or separately or with time, to improve cardiac function for ischemic heart disease due to diabetes.
  • a phenylpyridazinone derivative represented by the above general formula (1) or (2) or a salt or salt thereof A medicament containing these hydrates or solvates thereof, and (b) uptake of calcimion in the sarcoplasmic reticulum as an active ingredient.
  • Agent Best form to carry out the invention
  • Examples of the active ingredient of the drug of the present invention include compounds represented by the above general formula (1) or (2). That is, in the above general formulas (1) and (2), Ri and R 2 are each independently a hydrogen atom, a halogen atom, an alkyl group, and an amino group. , A carboxyl group, a nitro group, a cyano group, a trifluoromethyl group, an acylamino group or an alkoxy group;
  • R 3 represents a hydrogen atom, an acyl group or an alkyl group, and is a 5-membered or 6-membered ring which may have a substituent on the ring.
  • Compounds that represent complex rings are mentioned.
  • preferred compounds include the compound represented by the general formula (3), the general formula (1) or (2)
  • R 2 and R 3 are each independently represented by a hydrogen atom, a methylene group or an ethyl group, and R 4 is 2 — pyriyl. Examples include a lig compound represented by a jyl group, a 41-pyridinole group, a 2-pyrimidinole group or a 4-quinolinole group.
  • a particularly preferred compound is a compound represented by the general formula ('3), wherein the compound is an A 4 -pyridyl group. That is, 6_ [41- (4-pyridinoreamino) fuenoinore] _4,5—dinodidro_3 (2H) pyridazinon (below) Below, it may also be referred to as “MC 1—15 54.”) or its salts, or their hydrates or their solvates. Are listed.
  • these gazettes refer to the use as a cardiotonic agent for the fuirylpyridazinone derivative which is an effective component in the present invention.
  • the ability to incorporate Ca into this SR has been improved.
  • Pimonbendan is a drug that enhances the sensitivity to 'Ca' as well as the virubilidazinone derivative, which is an effective component of the present invention. Because of its unrecognized potential, all compounds known to be cardiotonic are adaptable to ischemic heart disease due to diabetes. Can be said to be unlimited.
  • the salt of the drug of the present invention is not particularly limited as long as it is a salt acceptable as a drug. Salts with mineral acids such as hydrochloric acid, phosphoric acid, and lactic acid, vinegar And salts with organic acids such as acids.
  • the compound in the present invention, can be used as a hydrate or a solvate of the above-listed compounds, and can be used as a solvate. In some cases, there are no particular restrictions on solvents that are acceptable as drugs.
  • MCI-154 or a salt acceptable as the drug may be used without any modification.
  • the above doses may be used as appropriate, depending on age, condition, gender, symptom, etc.
  • MCI-154 or as a drug Carriers for pharmaceutical preparations in which the acceptable salt thereof is usually used that is, carriers that can be used as a composition containing excipients and other additives are solid. It can be liquid or liquid.
  • a solid carrier When a solid carrier is used, it can take the form of tablets, powders, granules, hard gelatin capsules, suppositories, lozenges, etc. . At this time, the amount of the solid carrier is arbitrary.
  • Liquid carriers include syrups, emulsions, soft gelatin capsules, and sterile injectable solutions such as those containing a sample or aqueous or non-aqueous suspensions. Can be made into a liquid
  • the treatment and / or prophylactic agent of the present invention may be associated with SR C in diabetic ischemic heart disease, as shown in the Examples below.
  • a To improve uptake ability and improve cardiac function in diabetic ischemic heart disease it is recommended to improve ischemic heart disease due to diabetic, especially preferred for diabetic ischemic heart disease. It is used as a drug to treat and / or prevent cardiomyopathy.
  • the improvement of sarcoplasmic reticulum ion uptake ability refers to the sarcoplasmic reticulum ion uptake ability. Is to normalize
  • the above drug and a drug containing a Ca antagonist are simultaneously and separately administered for the treatment and / or prevention of ischemic heart disease due to diabetes.
  • a drug which can be used over time that is, a drug containing the compound represented by the above general formula (1) or (2) as an active ingredient; a.
  • the physician who contains the antagonist should be treated with one drug based on the dosage determined by increasing or decreasing the patient's age, condition, sex, symptoms, etc., as appropriate. It can be administered as a pharmaceutical composition, or can be administered as separate pharmaceutical compositions. It is also possible. When administered as separate pharmaceutical compositions, they can be administered in the same or different dosage forms at the same time, or they can be administered simultaneously. Each with the same or different dosage forms, with different times on the same day or depending on the patient's age, illness, gender, symptoms, etc. Can be given at regular intervals for days, weeks or months
  • a compound of the above formula (1) or (2) is used as an active ingredient in the treatment or Z or prophylaxis of ischemic heart disease due to diabetes.
  • the simultaneous use of a drug and a drug containing a Ca antagonist at the same time, separately or over time, can synergistically improve the SR function.
  • the problem of cardiac suppression often observed in the clinical use of Ca antagonists is also due to the above general formula (1) or ( It can be avoided by using a drug containing the compound described in 2) as an active ingredient. That is, the compound represented by the general formula (1) or (2) can be used as an agent for reducing the cardiac inhibitory effect of a Ca antagonist.
  • the antagonists used in the present invention are those that have the effect of improving the sarcoplasmic reticulum incorporation into the sarcoplasmic reticulum. There are no special restrictions. Specifically, there are those which have the function of improving the capability of retrieving the force as shown in the embodiment described later, and in particular, the one having the The use of pins is preferred. These Ca antagonists may be those that are commercially available as reagents, or if they are already marketed as pharmaceuticals, they may be used. You can use them. Example
  • Example 1 The MCI-154 used in the following examples was manufactured according to the method described in Example 1 described in Japanese Patent Application Publication No. 60-126282. I used what I did.
  • Example 1 The MCI-154 used in the following examples was manufactured according to the method described in Example 1 described in Japanese Patent Application Publication No. 60-126282. I used what I did.
  • Example 1 The MCI-154 used in the following examples was manufactured according to the method described in Example 1 described in Japanese Patent Application Publication No. 60-126282. I used what I did.
  • the diabetic cardiomyopathy model is an eight-week-old male male rat with striped zotocin (purchased from Sigma, hereinafter referred to as “STZ j”). This was caused by the administration of 40 mg Z kg in the tail vein (Am. J. Physiol. 1983; 244: E528-E535 J. Mo 1. Cell. 27: 169-179, Eur. Pharmacol. 1999; 374: 221-227). Rats seven months after the administration of STZ at which blood glucose levels are plotted. After anesthesia anesthesia, the heart was excised.The blood glucose level was 12.2 to 11.9 mg / d1 in a control rat, and 48 to 80 mg in a rat receiving STZ. 5 57.5 7 mg / d1.
  • a skid fiber sample that measures the ability of Ca to be taken into SR was used.
  • the SR functions reflect both expansion and contraction functions. Methods are described in Endo and li no J. Mus C 1 e Res. Cell. Moti 1.1980; 1: 89-100) and Kitada et al. (J. Pharmacol. Ep. Ther., 1987; 243: 633-638). That is, a fiber having a left ventricular papillary muscle strength of 2.5 to 3.0 mm and a thickness of 0.25 mm is prepared under a microscope. Next, the fin fin was soaked in 50 ⁇ g m1 saponin for 30 minutes to prepare a ski fin.
  • MCI-154 improves cardiac function by improving SR function, which is reduced in cardiomyopathy due to diabetes mellitus. It is. This effect is recognized in conventional cardiotonic drugs that have an effect of increasing cAMP and in Pimobendan, which enhances Ca sensitivity as well as in MCI-154. These powers have been created. In other words, in the diabetic cardiomyopathy model, MCI-154 was incorporated into SR, which was not recognized as a conventional ca-sensitive potentiator. It can be seen that it has an activity-promoting effect and that it has its effect at a concentration lower than the previously effective pharmacological concentration.
  • the combination of MCI-154 with amlodipine may represent a new drug therapy.
  • the cardioplegia problem that is often seen with the use of Ca antagonists in the clinical setting is also an issue with MCI-1.
  • the amount of Ca antagonist used can be reduced and the power S can be reduced, which also avoids side effects.

Abstract

Agent thérapeutique et / ou prophylactique pour la cardiopathie ischémique diabétique, caractérisé en ce qu'il contient, en tant que principe actif, un dérivé de phénylpyridazinone de formule générale (1) ou (2) dans lesquelles R1 et R2 représentent, par exemple, un atome d'hydrogène ou analogue, R3 représente, par exemple, un atome d'hydrogène ou analogue, et R4 représente, par exemple, un hétérocycle. Ledit principe actif peut être également un sel dudit dérivé de phénylpyridazinone, ou un hydrate ou solvate dudit dérivé.
PCT/JP2002/002286 2001-03-14 2002-03-12 Agent therapeutique et / ou prophylactique pour la cardiopathie ischemique diabetique WO2002072099A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2001071303 2001-03-14
JP2001071302 2001-03-14
JP2001-71303 2001-03-14
JP2001-71302 2001-03-14

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WO2002072099A1 true WO2002072099A1 (fr) 2002-09-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7071218B2 (en) 2001-11-15 2006-07-04 Incyte San Diego Incorporated N-substituted heterocycles for the treatment of hypercholesteremia, dyslipidemia and other metabolic disorders; cancer, and other diseases

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0145019A2 (fr) * 1983-12-14 1985-06-19 Mitsubishi Kasei Corporation Dérivés de pyridazinone et leurs sels
EP0197664A2 (fr) * 1985-03-12 1986-10-15 Smith Kline & French Laboratories Limited Dérivés de 2-aminopyrimidinones
EP0201988A2 (fr) * 1985-03-12 1986-11-20 Smith Kline & French Laboratories Limited Dérivés de dihydropyridazinone
JPS61289032A (ja) * 1985-06-14 1986-12-19 Mitsubishi Chem Ind Ltd 強心剤
JPH0240382A (ja) * 1988-07-28 1990-02-09 Nippon Soda Co Ltd ピリダジノン誘導体及びその製法
EP0383449A2 (fr) * 1989-02-11 1990-08-22 Orion-Yhtymà„ Oy Dérivés de pyridazinone et procédé de préparation
JPH11292852A (ja) * 1998-04-06 1999-10-26 Mitsui Chem Inc ジヒドロピリダジノン誘導体およびそれを有効成分として含有する腫瘍壊死因子産生抑制剤
JP2000290261A (ja) * 1999-04-01 2000-10-17 Mitsui Chemicals Inc ジヒドロピリダジノン誘導体およびそれを有効成分として含有する腫瘍壊死因子産生抑制剤

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0145019A2 (fr) * 1983-12-14 1985-06-19 Mitsubishi Kasei Corporation Dérivés de pyridazinone et leurs sels
EP0197664A2 (fr) * 1985-03-12 1986-10-15 Smith Kline & French Laboratories Limited Dérivés de 2-aminopyrimidinones
EP0201988A2 (fr) * 1985-03-12 1986-11-20 Smith Kline & French Laboratories Limited Dérivés de dihydropyridazinone
JPS61289032A (ja) * 1985-06-14 1986-12-19 Mitsubishi Chem Ind Ltd 強心剤
JPH0240382A (ja) * 1988-07-28 1990-02-09 Nippon Soda Co Ltd ピリダジノン誘導体及びその製法
EP0383449A2 (fr) * 1989-02-11 1990-08-22 Orion-Yhtymà„ Oy Dérivés de pyridazinone et procédé de préparation
JPH11292852A (ja) * 1998-04-06 1999-10-26 Mitsui Chem Inc ジヒドロピリダジノン誘導体およびそれを有効成分として含有する腫瘍壊死因子産生抑制剤
JP2000290261A (ja) * 1999-04-01 2000-10-17 Mitsui Chemicals Inc ジヒドロピリダジノン誘導体およびそれを有効成分として含有する腫瘍壊死因子産生抑制剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AM. J. PHYSIOL., vol. 276, no. 4, PT. 2, 1999, pages H1117 - H1123, XP002951865 *
CIRCULATION, vol. 95, no. 3, 1997, pages 732 - 739, XP002951866 *
J. PHARMACOL. EXP. THER., vol. 279, no. 1, 1996, pages 47 - 55, XP002951867 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7071218B2 (en) 2001-11-15 2006-07-04 Incyte San Diego Incorporated N-substituted heterocycles for the treatment of hypercholesteremia, dyslipidemia and other metabolic disorders; cancer, and other diseases

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