WO2002072580A1

WO2002072580A1 - Preventives and/or remedies for kidney diseases and kidney failure

Info

Publication number: WO2002072580A1
Application number: PCT/JP2002/001639
Authority: WO
Inventors: Chisei Ra; Toshio Kawashima
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2001-02-26
Filing date: 2002-02-25
Publication date: 2002-09-19
Also published as: KR100885007B1; JPWO2002072580A1; KR20030076710A; JP4171303B2

Abstract

Compounds represented by the following general formula: wherein R?1 and R3¿ independently represent each hydrogen or C¿1-6? alkyl; and R?2 and R4¿ independently represent each hydrogen, halogeno, C¿1-6? alkyl, C1-6 alkoxy or phenyl; or pharmacologically acceptable salts thereof which are efficacious in kidney disease models in association with the proliferation of mesangial cells and, therefore, useful as preventives and/or remedies for kidney diseases and/or kidney failure.

Description

Specification

Kidney diseaseProphylactic and / or therapeutic agent for renal failure

Technical field

The present invention provides a compound (I) represented by the following formula:

Wherein R ¹ and R ³ are independently hydrogen or an alkynole group having 1 to 6 carbon atoms, and R ² and R ⁴ are independently hydrogen, halogen, an alkyl group having 1 to 6 carbon atoms, It is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a phenyl group substituted by a hydroxyl group.)

Or a prophylactic and / or therapeutic agent for renal disease and / or renal failure containing a pharmacologically acceptable salt thereof as an active ingredient or a drug containing a pharmacologically acceptable salt thereof as an active ingredient. .

Background art

The mesangial region is one of the basic components of the glomerulus, and is composed of mesangial cells and mesangial matrix. Of these, mesangial cells are considered to be the supporting tissue of renal glomerular capillaries. In renal disease, this proliferation of mesangial cells and / or an increase in mesangial matrix is observed, eventually leading to glomerulosclerosis and renal failure. Therefore, suppressing the proliferation of mesangial cells is effective in preventing and / or treating various kidney diseases such as kidney disease and renal failure.

By the way, the potassium salt of 9-methyl-3_ (1H-tetrazol-5-yl) -14H-pyrido [1,2-a] pyrimidin-14_one (generic name: milolast) Below, ぺ called mirolast potassium. ) Is a drug widely used as a therapeutic drug for bronchial asthma, allergic rhinitis, etc., and is marketed in Japan as Aregizal (trade name) by the applicant, Mitsubishi Pharma Corporation. As far as the applicants are aware, there has been no report on the use of mirolast potassium alone in renal disease or failure associated with mesangial cell proliferation or in an animal model thereof.

At present, antihypertensive agents, antiplatelet agents, anticoagulants, corticosteroids, etc. are used for mesangial cell proliferative renal disease. Their effects are not sufficient. Accordingly, the present invention provides a novel agent for preventing and / or treating renal disease and renal failure, that is, a remedy for renal disease and renal failure comprising mirolast or a pharmacologically acceptable salt thereof as an active ingredient. And / or to provide a therapeutic agent. Disclosure of the invention

The present inventors have shown that compound (I) or a pharmacologically acceptable salt thereof is effective in a model of renal disease accompanied by mesangial cell proliferation, and is effective for prevention and / or treatment of renal disease and renal failure. The inventors have found that the present invention has been completed.

That is, the gist of the present invention is as follows.

1. Compound represented by the following formula

(Wherein R ¹ and R ³ are independently hydrogen or an alkyl group having 1 to 6 carbon atoms, and R ² and R ⁴ are independently substituted with hydrogen, halogen, an alkyl group having 1 to 6 carbon atoms, or a hydroxyl group. Or an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenyl group.) Or a pharmacologically acceptable salt thereof as an active ingredient. Prophylactic and / or therapeutic agent for failure. 2. R ¹ and R ³ are independently hydrogen or methyl, R ² is hydrogen, chlorine, methyl, ethyl, propyl, butyl or phenyl, and R ⁴ is hydrogen, chlorine, methyl 2. The prophylactic and / or therapeutic agent according to the above 1, which is a methyl group, an ethyl group, a propyl group, a butyl group, a hydroxymethyl group or a methyloxy group.

3. 9-Methyl-3- (1H-tetrazole-15-yl) -14H-pyrido [1,2-1a] pyrimidine-14-one or a pharmaceutically acceptable salt thereof as an active ingredient Prophylactic and / or therapeutic agent for renal disease and Z or renal failure.

4. The prophylactic agent according to paragraphs 1 to 3, wherein the renal disease is acute nephritis syndrome, rapidly progressive nephritis syndrome, recurrent or persistent hematuria, chronic (glomerular) nephritis syndrome and / or nephrotic syndrome. Or therapeutic agents.

5. The prophylactic and / or therapeutic agent according to any one of Items 1 to 4, wherein the renal disease is Ig A nephropathy.

6. The prophylactic and / or therapeutic agent according to Item 1 or 3, wherein the renal disease is a renal disease accompanied by mesangial cell proliferation.

7. 9-Methyl-1- (1-H-tetrazo-l-5-yl)-4H-pyrido [1,2-a] pyrimidine_4-one or a pharmaceutically acceptable salt thereof as an active ingredient A prophylactic and / or therapeutic agent for chronic nephritis syndrome and Z or nephrotic syndrome.

8. Contains 9-methyl-13_ (1H-tetrazole-15-yl) -14H-pyrido [1,2_a] pyrimidin_4_one or a pharmaceutically acceptable salt thereof as an active ingredient A preventive and / or therapeutic agent for Ig A nephropathy.

9. The prophylactic and / or therapeutic agent according to paragraphs 1 to 8, wherein the pharmacologically acceptable salt is potassium salt.

Hereinafter, the present invention will be described in detail.

In the present invention, glomerular disease and renal disease are treated as almost synonymous diseases because their boundaries are not clear.

When referring to renal disease, the WHO uses two types of clinical symptom classification and histological classification, which are classified into five categories according to the mode of onset, changes in renal function over time, and the degree of proteinuria. Honcho Reference to renal disease in the detailed description includes all renal diseases included in this clinical symptom classification and histological classification. Here, the clinical symptom classification will be described.

1. Acute nephritis syndrome

This syndrome is characterized by obvious onset, such as hematuria, proteinuria, hypertension, decreased glomerular filtration rate, and sudden appearance of Na and water retention. Examples of histological findings or diseases presenting this clinical picture include acute glomerulonephritis after streptococcal infection, crescentic glomerulonephritis, membranous proliferative glomerulonephritis, acute exacerbation of sclerosing glomerulonephritis, focal Proliferative glomerulonephritis, lupus nephritis, purpura nephritis, IgA nephropathy, hereditary nephritis (Alport syndrome), periarteritis nodosa, and Wegener granulomas.

2. Rapidly progressive nephritis syndrome

It is a syndrome in which hematuria, proteinuria, anemia, and rapidly developing renal failure develop rapidly or latently. Examples of histological findings or diseases presenting this clinical picture include crescent-forming glomerulonephritis, Goodpasture's syndrome (Goodpasture) syndrome, membranous proliferative glomerulonephritis, purpura nephritis, lupus nephritis, periarterial nodules Inflammation, Wegener's granulomas, infectious endocarditis, membranous nephropathy, cryoglobulinemia, hemolytic uremic syndrome.

3. Recurrent or persistent hematuria

Proteinuria with little or no proteinuria, but with gross or microscopic hematuria that appears latent or sudden and does not show any other signs of nephritis syndrome. Examples of histological findings or diseases presenting this clinical picture include focal proliferative glomerulonephritis, IgA nephropathy, IgM nephropathy, diffuse proliferative glomerulonephritis, membranous proliferative glomerulonephritis, focal filamentous nephritis Examples include globular sclerosis, sclerosing nephritis, Alport syndrome, lupus nephritis, basement membrane thinning syndrome, and no glomerular abnormalities.

4. Chronic (glomerular) nephritis syndrome

Sometimes called chronic nephritis syndrome. Those who have proteinuria, hematuria, and high blood pressure, and gradually fall into renal failure. Examples of histological findings or diseases that present this clinical picture include diffuse Reproductive glomerulonephritis, sclerosing nephritis, IgA nephropathy, membranous nephropathy, focal glomerulosclerosis, lupus nephritis, diabetic nephropathy, renal amyloidosis, Alport syndrome.

5. Nephrotic syndrome

'' A variety of glomerular lesions with massive proteinuria, edema, hypoalbuminemia, and syndromes often associated with hypercholesterolemia. Examples of histological findings or diseases presenting this clinical picture include minimal change nephrotic syndrome, focal glomerulosclerosis, membranous nephropathy, diffuse proliferative glomerulonephritis, and membranous proliferative glomerulonephritis , IgA nephropathy, IgM nephropathy, cryoglobulinemia, lupus nephritis, purpura nephritis, diabetic nephropathy, amyloidosis, Alport syndrome, congenital nephrotic syndrome.

In addition, the disease names shown above are given as examples, and as long as the disease meets the definition-a disease state; the renal disease in the present specification is not limited thereto.

In Japan, chronic nephritis includes "progressive cases in which proteinuria, hematuria, and hypertension are observed and gradually develops renal failure (advanced period), and non-advanced cases in which renal function is normal (fixed period). It is generally considered to be. Furthermore, Japan has its own criteria for nephrotic syndrome. The kidney disease herein includes these chronic nephritis and nephrotic syndrome.

In the present invention, the lip and the pharmacologically acceptable salt thereof used as the active ingredient are disclosed in Japanese Patent Application Laid-Open No. 54-36294, and Japanese Patent Application Laid-Open No. It can be easily manufactured according to the method described in Japanese Patent Application Laid-Open Publication No. H07-157, and a commercially available product can also be used. Pharmaceutically acceptable salts include inorganic acid salts such as hydrochloric acid, nitric acid, and sulfuric acid, organic acid salts such as acetic acid, citric acid, fumaric acid, and tartaric acid, and sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. Salts and amino acid salts such as alanine, leucine, glutamic acid, and glutamine; and organic salts such as ammonium salts, ethylamine and ethanolamine, and metal salts such as alkali metal and alkaline earth metal. Is particularly preferred. In addition, mirolast or a pharmacologically acceptable salt thereof May be isolated as hydrates or solvates or polymorphic substances, which are also included in the present invention.

In the compound (I), the alkyl group having 1 to 6 carbon atoms is a linear or branched saturated aliphatic hydrocarbon group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butynol group, and an isobutynol group. , Sec-petit / le, tert-butynole, pentynole, hexyl and the like.

Halogen is fluorine, chlorine, bromine and iodine.

The alkyl group having 1 to 6 carbon atoms substituted by a hydroxyl group is the above-mentioned alkyl group having 1 to 6 carbon atoms substituted by a hydroxyl group, for example, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl And hydroxybutyl groups.

The alkoxy group having 1 to 6 carbon atoms is the above-mentioned alkyloxy group having 1 to 6 carbon atoms, such as methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyl / Examples include a reoxy group, a tert-butyloxy group, a pentyloxy group, and a hexyloxy group.

In the compound (I), preferred examples of R ¹ include a hydrogen atom, a methyl group, an ethyl group, a propyl group and a butyl group, and more preferably a hydrogen or methyl group. Preferred hydrogen Examples R ^2, chlorine, methyl, Echiru group, propyl group, butyl group, Mechiruokishi group, Echiruokishi group, Puropiruokishi group, include Buchiruokishi group or phenylene group, more preferably hydrogen, chlorine, It is a methyl group, an ethyl group, a propyl group, a butyl group or a phenyl group. Preferred examples of R ³ include hydrogen, a methyl group, E Ji group, include propyl or butyl group, more preferably Ru hydrogen or methyl der. Preferred examples of R ⁴ include hydrogen, chlorine, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyxetyl, hydroxypropyl, methyloxy, ethyloxy, and propyloxy. Preferred are hydrogen, chlorine, methyl, ethyl, propyl, butyl, hydroxymethyl and methyloxy. Preferred examples of the compound (I) include 9-methyl-3- (1H-tetrazole-51-yl) -14H-pyrido [1,2-a] pyrimidine-14-one.

In the present invention, compound (I) or a pharmacologically acceptable salt thereof can be prepared by mixing a usual pharmaceutical carrier, such as tablets, hard or soft capsules, granules, powders, fine granules or suppositories. It is also possible to prepare and use solid preparations or liquid preparations such as injections, inhalants, syrups, 7Rs, suspensions or emulsions. Depending on the desired dosage form, the formulation carrier to be compounded includes, for example, excipients, binders, disintegrants, lubricants, coating agents, dissolution aids, emulsifiers, suspension agents, surfactants, absorption aids, A stabilizer or a solvent may be appropriately selected. The dosage varies depending on the age, symptoms and dosage form, but 0.1 to 100 mg per day for oral administration and 0.01 to 100 mg per day for parenteral administration divided into one or several doses. Used. The compound used in the present invention has high safety, and LD _{5 of} mirolast. The values were found to be 1317 mg / kg for oral administration of male rats and 533 mg / kg for intraperitoneal administration of male rats. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the ability to explain the present invention in more detail using examples The following examples do not limit the present invention. The milolast potassium used below was produced according to the method described in Japanese Patent Publication and Japanese Patent Application Laid-Open No. 2-289569. Example

Formulation example

Weigh 10 g of milolast potassium, and use gellan-forming polymer as pullulan, polyvinyl alcohol, Eudragit RS (trade name), Carbopol (trade name), sodium alginate Using a trim, 30 g of this and 59 g of lactose were added and mixed. Next, the mixture was kneaded and granulated using water as kneading water, dried with a hot-air blow dryer, and then sieved using a 16-mesh sieve. Predetermined amounts of the anhydrous kaic anhydride and magnesium stearate were weighed, mixed in a polyethylene bag, and compressed into tablets of 20 Omg per tablet using an 8 mm diameter punch.

Inhibitory effect of nephritis induced by mesangial cell proliferation

Intravenous administration of lmg / kg anti-Thy-1.1 antibody to male SD rats induced mesangial cell proliferative nephritis (Nephrol. Dial. Transplant (2000), 15, pp. 16-22). At 0, 3, 5, 7, and 10 days after the administration of the anti-Thy-1.1 antibody, urine was collected for 24 hours using a metapolic cage, and the amount of protein in the urine was measured.ロ Milorast potassium was orally administered once a day from '10 days before the administration of the anti-Thy-1.1 antibody. Table 1 shows the results. Table 1 Urine protein content Urine protein content (mg / day / animal)

Oral last potassium administration group

Later days Control group lmg / kg lOmg / kg

0 says 17.5 ± 2.7 12.6 ± 1.0 18.9 + 1.9

3 Says 41.8 ± 6.2 21.7 ± 4.3 42.8 ± 11.5

5 says 98.2 +17.4 26.9 ± 6.8 * 42.0 ± 14.3 *

7 says 93.2 ± 18.4 33.1 ± 7.4 * 38.6 ± 14.1 *

10 says 81.0 ± 9.8 39.4 ± 10.0 * 34.4 Sat 9.2 * The values are shown with the standard error of the mean (5 cases).

*: P 0.05

From the above results, it was confirmed that mimilast suppresses urinary protein, which is a parameter of nephritis progression, and suppresses nephritis induced by mesangial cell proliferation. From these results, it is expected that mirolast potassium will reduce glomerular sclerosis caused by the proliferation of mesangial cells and further reduce renal function decline. Industrial applicability

As is evident from the above results, a drug containing compound (I) containing mirolast or a pharmaceutically acceptable salt thereof as an active ingredient is a parameter of the progression of nephritis in a mesangial cell proliferative nephritis model. It suppresses urinary protein and can be used effectively as a preventive and / or therapeutic agent for renal failure caused by renal disease and exacerbation of renal disease. This application was filed with a priority claim based on Japanese Patent Application No. 2001-49778.

Claims

The scope of the claims

1. a compound represented by the following formula

(Wherein R ¹ and R ³ are independently hydrogen or an alkyl group having 1 to 6 carbon atoms, and R ² and R ⁴ are independently substituted with hydrogen, halogen, an alkyl group having 1 to 6 carbon atoms, or a hydroxyl group. Or an alkyl group having 1 to 6 carbon atoms, an alkoxy group or a phenyl group having 1 to 6 carbon atoms) or a pharmacologically acceptable salt thereof as an active ingredient. Prophylactic and Z or therapeutic agents.

2. R ¹ and R ³ are independently hydrogen or methyl, R ² is hydrogen, chlorine, methyl, ethyl, propyl, butyl or phenyl, and R ⁴ is hydrogen, chlorine, methyl 2. The prophylactic agent, the Z agent or the therapeutic agent according to claim 1, which is a methyl group, an ethyl group, a propyl group, a butyl group, a hydroxymethyl group or a methyloxy group.

3. 9-Methyl-3- (1H-tetrazole-15-yl) -14H-pyrido [1,2_a] pyrimidine_4-one or a pharmaceutically acceptable salt thereof as an active ingredient Prophylactic and / or therapeutic agents for renal disease and Z or renal failure.

4. The method according to claim 1, wherein the renal disease is acute nephritis syndrome, rapid progressive nephritis syndrome, recurrent or persistent hematuria, chronic (glomerular) nephritis syndrome and Z or nephrotic syndrome. Prophylactic and / or therapeutic agents.

5. The prophylactic and / or therapeutic agent according to claims 1 to 4, wherein the renal disease is Ig A nephropathy.

6. The preventive agent and the z or therapeutic agent according to claim 1 or 3, wherein the renal disease is a renal disease accompanied by mesangial cell proliferation.

7. 9-Methyl_3- (1H-tetrazole-5-yl) -14H-pyrido [1,2 — A] A prophylactic and / or therapeutic agent for chronic nephritis syndrome and / or nephrotic syndrome, comprising, as an active ingredient, pyrimidine-141one or a pharmacologically acceptable salt thereof.

8. Contains 9-methynole-1- (1H-tetrazole-51-yl) -14H-pyrido [1,2-1a] pyrimidine-14-one or a pharmaceutically acceptable salt thereof as an active ingredient A preventive and / or therapeutic agent for Ig A nephropathy.

9. The prophylactic agent, the Z agent or the therapeutic agent according to claim 1, wherein the pharmacologically acceptable salt is a potassium salt.