WO1996020920A1

WO1996020920A1 - Amidinonaphthyl ester derivative

Info

Publication number: WO1996020920A1
Application number: PCT/JP1995/000002
Authority: WO
Inventors: Hiroyuki Uchiyama; Toyoo Nakayama; Hiroyuki Kawamura
Original assignee: Torii Pharmaceutical Co., Ltd.
Priority date: 1995-01-05
Filing date: 1995-01-05
Publication date: 1996-07-11
Also published as: AU1391795A

Abstract

An amidinonaphthyl ester derivative efficacious in treating thrombosis.

Description

Description Amidino naphthyl ester derivative Technical field

The present invention relates to a novel amidino naphthyl ester derivative and a medicament containing the same as an active ingredient. Background art

A clot formed by coagulation of blood in the heart or blood vessels is called a thrombus, and the pathological phenomenon associated with the formation of this thrombus is called thrombosis. There are various types of thrombosis, including cerebral infarction, myocardial infarction, and pulmonary infarction.

Treatment methods for thrombosis can be broadly classified into two types according to their mechanism of action. Antithrombotic therapy to prevent thrombus formation, and thrombolytic therapy to dissolve the formed thrombus.

Of these, thrombolytic therapy uses a thrombolytic agent to activate plasminogen, a precursor of the regulator of the blood fibrinolysis system, into plasma, which is then converted into blood vessels. It is thought that by breaking down the fibrin that forms the thrombus, the blood is lysed and the obstructed site is opened. Drugs used in this thrombolytic therapy include tissue plasminogen activator, plasminogen activator that activates plasminogen to plasmin (t-PA) and perokinase (t-PA). (UK)), cell-producing substances such as staphylokinase, streptokinase, etc. And their recombinants are known.

t-PA and the like are generally considered to be effective when administered intravenously. However, the half-life in blood is short, and it is quickly removed from the liver. Therefore, these thrombolytic actions in the local area where a thrombus has occurred require a large amount of administration due to the presence of an inhibitory factor in vivo. The transient large dose administration of this thrombolytic agent markedly enhances the thrombolytic effect systemically and is expected to open the occluded site, while severe hemorrhagic symptoms are observed. Etc. have been reported. In addition, animal experiments and clinical cases have shown that reocclusion is likely to occur even when the site of occlusion is temporarily opened by administration of a thrombolytic agent. In addition, since it is an injection, there is also a problem in the administration method that the burden on the patient is long when administered for a long time.

For the above reasons, in order to reduce the burden on patients, the development of orally administrable drugs having a thrombolytic action has been desired. Disclosure of the invention

An object of the present invention is to provide an amidinonaphthyl ester derivative which can be orally administered, has a fibrinolytic promoting action, and exhibits a systemic thrombolytic action.

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, have found that the compound represented by the formula (I) has an excellent thrombolytic action, and completed the present invention. That is, Ming is the formula (I)

(Where R is

Represents )

With respect to the compound represented by The compound of the present invention has a dilysis promoting action, exhibits a strong thrombolytic action, and is also effective for diseases caused by thrombus. Venous thrombosis, myocardial infarction, pulmonary embolism, cerebral embolism, slowly progressing cerebral thrombosis, treatment of thromboembolism associated with vascular surgery and extracorporeal blood circulation, improvement of impaired blood flow, and chronic arterial occlusion It can be used as a therapeutic agent for thrombosis and embolism in general, such as improving various symptoms and treating thrombosis and embolism associated with ischemic cerebrovascular disease.

The compound of the present invention represented by the formula (I) is converted into a corresponding acid addition salt by a known method. The acid that can be used is not particularly limited as long as it is a salt that can be used as a medicament. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, drunk acid, lactic acid, and quencher Acid, methansulfonate, ethanesulfonate, toluenesulfonate, conodic acid, fumaric acid, Organic acids such as leic acid are exemplified.

Due to its pharmacological action, the compound of the present invention can be administered orally or rectally to mammals (including human patients).

The compound of the present invention can be administered as one therapeutic agent or as a mixture with another therapeutic agent. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. Examples of such compositions include tablets, powders, capsules, syrups or aqueous solutions. Additives such as ordinary excipients, lubricants, disintegrants and wetting agents can be used in the oral composition. Oral fluids may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, or the like, or be reconstituted with water or another suitable solvent before use. It may be served as a dry mouth. Said solutions may contain conventional additives such as suspending agents, flavors, diluents or emulsifiers. In addition, when administered rectally, it can be administered as a suppository. Suppositories are cocoa butter, laurin fat, macrogol, grise mouth gelatin, and wite. An appropriate substance such as Tubul, sodium stearate or a mixture thereof may be used as a base, and an emulsifier, a suspending agent, a preservative and the like may be added as necessary.

Specific examples of the excipient and the like used in the above composition are shown below.

Excipients: calcium hydrogen phosphate, synthetic aluminum phosphate Aluminum, magnesium magnesium silicate, aluminum magnesium hydroxide, magnesium magnesium silicate, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, light gay anhydride, gay anhydride , Avicel, various starch dextrin carboxymethyl starch (CMS), lactose. Binders: ethylcellulose (EC), carboxymethylcellulose Na (CMC—Na), low-substituted hydroquinone propylcellulose (L-HPC), hydroquinone methyl Le Loose

(HPMC), methylcellulose (MC), hydroxypropylcellulose (HPC), various starches, dextrins, sodium alginate, gelatin, polyvinyl alcohol

(PVA), polyvinylpyrrolidone (PVP), disintegrants: synthetic aluminum gaymate, metasilicate aluminum

Magnesium acid, CMC—Ca, CMC. Avicel, L—HPC ;, HPMC, MC, various starches, CMS, hydroxypropyl starch (CPS) o

Anti-solidification agent: Polyamic anhydride, Synthetic aluminum manganese lubricant Lubricant: Synthetic aluminum manganate, Gay anhydride, talc Avicel.

Flavoring agents: mannitol, cunic acid, cunic acid Na, sugar Emulsifiers: gelatin, cunic acid, cunic acid Na, polyoxy Silicone-hardened castor oil (HCO—40, 60), macrogol (PEG), propylene glycol fatty acid ester, polyethylene glycol polypropylene Glycol, propylene glycol, raurylsulfate Na, phospholipids.

Stabilizers: sodium bisulfite, borosilicate

Hydrogenated castor oil (HCO—40, 60), PEG propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene propylene glycol. Lenggol, rauryl sulfate Na, various natural and synthetic cyclodextrins, phospholipids. Absorption promoter: Polyoxyethylene hardened castor oil (HCO)

-40,60), PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene propylene glycol, propylene glycol , Rauryl sulfate Na, various natural and synthetic cyclodextrins, and medium chain fatty acid triglycerides. Solubilizing agent: ethanol, HCO—40, HC0-60

Polypropylene glycol fatty acid ester Polyoxyethylene Polyoxypropylene propylene glycol, propylene glycol, lauric sulfate Na, Various natural and synthetic cyclodextrins.

Suspending agent: CMC-Na, HPMC :, MC ;, HPC sodium alginate, gelatin, propylene glycol, lauryl sulfate Na. Coating agent: EC, magnesium gayate, talc, titanium oxide, calcium carbonate, triacetin, carboxime methyl ethyl cellulose (CMEC), cellulose nitrate phthalate (CAP), HPMC, hydroxypropyl methylcellulose Free Rate

(HPMCP), MC, HPC; sodium alginate, polyvinyl acetal getylamino acetoacetate, polyacrylic acid Na, various acrylic acid metaacrylic acids Acid derivatives, polyglycolic acid Na.

Colorant: titanium oxide, tar dye, caramel.

When the compound of the present invention is administered to humans, the dose is 100 to 1 OOO mg / day, preferably 200 to 900 mg Z days, more preferably 400 to 8 mg / day. It can be administered at a dose of 0 O mgZ daily. However, the dose when administered to humans for therapeutic purposes is appropriately adjusted according to the severity of the illness, age and weight.

Next, the present invention will be specifically described with reference to examples. Example 1

6—Amidino 2—Naphthyl 4 — [(2—Acetylaminoethyl) iminomethylethylaminomethylamino] Production of benzoate dihydrochloride

4 1 [(2-acetylaminoethyl) iminomethylamylmethylamino] benzoic acid / hydrobromide 1.5 g 6-amidino-2-naphthol 'methansulfon Acid salt 1.07 g, N, N '— Dicyclohexylcarpoimide (hereinafter abbreviated as DCC) 1.04 g and 4-dimethylaminoaminoviridine (hereinafter abbreviated as DMAP) 5 1.4 10 mg of 5% aqueous pyridine was added to the mg, and the mixture was stirred under ice cooling for 2 hours and then at room temperature for 4 days. After the precipitate was filtered, the filtrate was added dropwise to 300 ml of an ether / aceton mixture (3: 1), and the mixture was stirred under ice-cooling for 24 hours, and the precipitate was collected. To this product, 3 ml of N, N-dimethylformamide (hereinafter abbreviated as DMF) and 5 ml of acetate were added, and 1.8 ml of concentrated hydrochloric acid was further added while stirring with water cooling. This solution was added dropwise to 400 ml of ether / aceton (3: 1), and the mixture was stirred under ice cooling for 1 hour, and then stirred under water cooling for 24 hours. After the supernatant was decanted, this operation was repeated again to obtain a crude product. Then, apply the desired fraction to a silica gel column chromatograph using a mixture of methylethyl ketone-monohydric acetic acid (80: 15: 5) as an elution solvent. The solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of DMF / methanol (1: 1) and 1.5 ml of 6N hydrochloric acid, and cooled to 400 ml with a mixture of ether and acetone (3: 1) with ice. After the mixture was dropped and stirred for 1 hour, the precipitate was collected to obtain 1.11 g of the desired product.

lH-NM (D S0-d6) δ ppm:

10.37 (1H.S) 3.46 (2H, brs)

9.66 (2H.S) 3.29C2H, brs)

9.46 (2H, S) 2.94 (3H.d.J = 3.6 Hz) 8.66 (1H.S) 1.85C3H.S)

8.74 ~ 8, 20C2H.br)

8.30-8.10 (3H, m)

8.09 to 7.87 (lH.m)

7.65 (1H, dd, Jl = 8.7 J2 = 2.0 ~ 2.3Hz)

7.52 (2H.d, J = 8.6Hz) Example 2

6—Amidino 2—Naphthyl 4 Manufacture of monomorpholine methyl benzoate 2 methansulfonate

4 Monomorpholinomethyl benzoic acid 3 g, 6-Amidino-2-naphthol 'methansulfonate 3 g, DMAP 0.3 g, pyridine 40 ml and DMF 1 The 5 ml mixed solution was stirred under ice cooling. Then, 3.1 g of DCC was added, and the mixture was stirred for 1 hour under ice cooling and for 2 days under water cooling. After the reaction, the precipitate was filtered and washed with 15 ml of DMF. The resulting solution was slowly dropped into 45 O ml of ether with ice cooling and stirring. After stirring at the same temperature for 15 minutes, the supernatant was decanted, and 450 ml of ether was added to the residue, followed by stirring at room temperature for 24 hours. The supernatant was further decanted, and 200 ml of acetate was added to the residue, followed by stirring at room temperature for 24 hours. The precipitated crystals were collected, dissolved in 30 ml of DMF, added with 3 g of activated carbon under ice cooling, and stirred for 30 minutes. Next, the insoluble matter was removed and washed with 10 ml of DMF. The solution was slowly added dropwise to 200 ml of acetone with stirring under ice-cooling. In addition, 1.8 g of acid was added, and the mixture was stirred for 24 hours under water cooling. The supernatant was decanted, 20 O ml of acetate was added to the residue, and the mixture was stirred overnight at room temperature, and the precipitate was collected by filtration to obtain 3.8 g of the desired product.

lH-NMR (DMS0-d6) δ ppm:

9.15 (2H, S) 3.29 (4H, br)

9.30 (2H, S) 2.45 (6H, S)

8.62 (1H.S)

8.30 (2H, d. J = 8.2Hz)

8.28-8.19 (2H, ra)

8.05 (1H.d, J = 2.0Hz)

7.93 to 7.89 (1H, m)

7.85 (2H, d, J = 8.2Hz)

(7.7K1H.dd, Jl = 8.9, J2 = 2.0Hz)

4.55 (2H.S)

4.02-3.98C2H.br)

3.78-3.70 (2H, br) Example 3

6—Amidino 2—Naphthyl 4-piperidinomethylbenzoate 2 Manufacture of methane sulfonate

4 — piperidinomethyl benzoic acid 2 g, 6 — amidine 2 — naphthol 'methane sulfonate 2.06 g

A mixed solution of 0.2 g of DMAP, 15 ml of pyridine and 55 ml of DMF was stirred under ice cooling. Then DCC 2.0 g was added and reacted. The same operation as in Example 2 was performed to obtain 2.3 g of the desired product.

lH-NMR (D S0-d6) δ ppm:

9.52 (2H.S)

9.32 (2H.S)

8.62 (1H.S)

8.29 (2H, d, J = 7.9Hz)

8.24-8.19 (2H.m)

8.05 (1H.d, J = 2. OHz)

7.93 ~ 7.90 (1H, m)

7.84 (2H.d, J = 7.9Hz)

7.69 (1H, dd. Jl = 8.9, J2 = 2. OHz)

4.47 (2H, d, J = 4.3Hz)

3.38 ~ 3, 33 (2H, m)

2.99-2.95 (2H.m)

2.45 (6H, S)

1.81 to 1.69 (6H, m) Formulation example 1

Compound of the present invention 100 mg

Lactose 30 mg

Avicel 30 mg

Carboxycellulose 20 mg Conodic acid 18 mg

Magnesium stearate 2 mg Fill the capsules with a total amount of 20 Omg or press them into tablets Formulation example 2

Compound of the present invention l O O mg

Lactose 50 0 mg

Avicel 20 mg

Carboxycellulose 20 mg

Conodic acid 8 mg

Magnesium stearate 2 mg

Fill the capsules with the total amount of 20 O mg, or compress the tablets into tablets. Formulation example 3

Compound of the present invention 100 mg Lactose 45 mg Corn starch 27 mg Low-substituted hydroxypropylcell Π77-27 mg Magnesium stearate 1 mg Or hit the tablet. . Formulation example 4

0.2 g of the compound of the present invention

1 g for Witetsu Buzol The above is formulated into a suppository by a conventional method.

Industrial applicability

The following pharmacological tests confirmed that the compound of the present invention has a fibrinolytic accelerating action and exhibits an excellent thrombolytic action, and is therefore effective for various diseases caused by thrombus.

(1) Effect of improving lethality on mouse lung thrombosis lethal model In the experiment, 10 mgZ kg of the compound of the present invention was orally administered to ddy male mice fasted for 6 hours. The positive control group was orally administered sepimostat mesilate, which exerts a thrombolytic effect by oral administration of human. Six hours later, thrombin 10 units was injected intravenously from the tail vein to induce thrombus by injecting Z mice, and after 16 hours, thrombin was determined to be alive or dead, and the effect of improving lethality was evaluated by the survival rate. Indicated. Table 1 shows the results.

Table 1 Compound viability () Example 18 5.

Example 2 75.0

Example 3 7 1.4

Positive control 8 0

Water 2 6. From the above results, it was proved that the compound of the present invention had an effect comparable to a control compound having an excellent thrombolytic action.

(2) Blood Plasmid-Like Activity Assay Using Synthetic Substrates In the experiments, fast-fed SD male rats (11-week-old) were used. 30 mg / kg of the compound of the present invention was orally administered, and blood was collected from the descending aorta with time as blood added with citrate and centrifuged to obtain plasma. Water was orally administered to the control group.

The obtained plasma was incubated with 0.1 M borate buffer (pH 8.5) and Boc-Va Leu-Lys-MCA at 37 ° C for 30 minutes, and the reaction was stopped by adding 15% acetic acid. When the fluorescence intensity was measured and the brassin-like activity was determined, the compound of the present invention showed a strong increase in the blood brassin-like activity. Table 2 shows the results.

Table 2 Compound Plasmin-like activity Example 1 0 .05 2 nmol / min / ml

Water 0.03 1 n m o l Z min Zm l

The above results clearly show that the compound of the present invention exhibits a strong thrombolytic action.

(3) Plus Minogen's Initiative 15 PAI-1 antigen determination test

The PAI-11 antigen was measured using the plasma obtained in the above test (2).

Beforehand, a monoclonal antibody against PAI

1 OmM carbonate buffer diluted solution with 96-well microtiter

• 1001 was added on the plate, and left for 4 hours. After washing four times with 1 OmM phosphate buffer containing 0.1% Tween20, a standard solution and a plasma sample were added. After leaving at room temperature for 2 hours and washing 4 times again, the enzyme-labeled PAI-1 polyclonal antibody was added at 100 t / t.

1 was added and reacted at room temperature for 2 hours. After washing the excess antibody, add 10 1 of citrate buffer containing 1 Omg of 0-phenylenediamine and 0.1% hydrogen peroxide, and add 3 ^OeC .

The color was allowed to stand for 30 minutes. After stopping the reaction by adding 501 in 2N sulfuric acid, the absorbance at 405 nm was measured with a microplate reader to determine the amount of PAI-11 antigen in the plasma sample. Table 3 shows the results.

Table 3 Compound PAI-1 antigen amount Example 3 37.7 ng / m 1

Water SA. Zng Zm l In the control mechanism of thrombolysis, t-PA released into plasma is almost immediately inhibited by its specific inhibitor PAI-1 and its activity is lost. A decrease in -1 results in enhanced thrombolytic activity. The group administered with the compound of the present invention reduced the blood PAI-1 antigen level.

The toxicity of the compound of the present invention was very low, and it was determined that there would be no problem in administering it to humans or mammals.

Claims

Formula (I) within the scope of the claim

(Where R is

Or

Represents )

Or an acid addition salt thereof which can be used as a medicament.

2. In equation (I), R

The compound according to claim 1, which is or an acid addition salt thereof usable as a medicament.

3. A medicament comprising the compound according to claim 1 or claim 2 or an acid addition salt thereof which can be used as a medicament, alone or in combination with one or more pharmaceutically acceptable carriers. Formulation.

4. The pharmaceutical preparation according to claim 3, which is a therapeutic agent for thrombosis.

5. The medicament according to claim 3 or 4, which is a thrombolytic agent. Formulation.

6. The pharmaceutical preparation according to claim 3 or 4, which is a fibrinolysis promoter.

7. Use of the compound according to claim 1 or 2 as a therapeutic agent for thrombosis.

8. Use of the compound according to claim 1 or 2 as a thrombolytic agent.

9. Use of the compound according to claim 1 or 2 as a fibrinolysis accelerator.

10. A method for treating thrombosis, which comprises administering the pharmaceutical preparation according to any one of claims 3 to 6.

11. A thrombolytic therapy comprising administering the pharmaceutical preparation according to any one of claims 3 to 6.