JPH06500537A - Use of arylhydroxyurea compounds for the treatment of atherosclerosis - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Use of arylhydroxyurea compounds for the treatment of atherosclerosis 〔Technical field〕 The present invention can treat conditions that require suppression of oxidative changes in fat, such as atherosclerosis. Some aryl hydroxyureas in the manufacture of medicines for prevention and treatment The use of the compounds, the medicines obtained therefrom, and the preparation thereof. and for use in the prevention and treatment of such conditions.

[Background technology]

European Patent Specification 0279263 describes 5- and/or 12-lipoxygeners. A new group of compounds that have enzyme-inhibiting properties that can be used to treat asthma, allergies, arthritis, stone rolling, and a group of compounds that can be used in inflammation are described.

[Disclosure of the invention]

We have now demonstrated that the compound EPSO279263 is effective against low-density lipoprotein (LDL). Found that it also has the potential to capture peroxyl radicals related to oxidation. Ta. These compounds may be used to treat conditions where inhibition of oxidative changes in lipids is required, such as atherosclerosis. It is understood that the use in the treatment of microscopic sclerosis is appropriate.

That is, the present invention provides a compound of formula (1) or a physiologically acceptable salt thereof, Alternatively, physiologically functional derivatives can be used to predict symptoms that may inhibit oxidative changes in fat. It is used in the manufacture of medicines for prevention and treatment.

(i) Furyl, chenyl, chenyl 1,1-dioxide, pyryl (py+Bl ), pyridyl, benzofuryl, benzothenyl, benzothenyl 1,1-dio oxide, indolyl, naphthyl, quinolyl, or tetrahydronaphthyl. Both of these are Cl-4 alkyl (which itself optionally contains one or more halogens). (optionally substituted with atoms), CI-4 alkoxy, halo, nitro, amino , alkoxy, Cl-4 alkoxycarbonyl, and hydroxy. optionally substituted with one or more substituents selected, or (ii) phenyl optionally substituted with one or more substituents, the substituents is phenyl (by itself, independently of those mentioned as optional substituents in (i) above) optionally substituted with one or more selected substituents) and in (i) above. Substituted phenyl independently selected from any of the substituents mentioned.

Y is C alkylene or C2-10 alkenylene.

is hydrogen or C1-4 alkyl, and R is hydrogen, C1-4 alkyl, or or substituted phenyl mentioned as an optional substituent in (i) above. independently, R2 is hydrogen, C alkyl, amino, C alkylamine/, di C alk Kylamiba C5-7 cycloalkylamino, C cycloalkyl (CI-4 alkyl )-aminoanilino, N-C1-4alkylanilino or the above Ar This is the basis.

Preferred compounds for use in the preparation of the medicament of the invention include Ar, benxofur-2-yl or benzothiophen-2-yl Y is -CH2- or -CH (Me)-; and Q is as defined above, R is hydrogen and R2 is C I- 4-alkyl, ami/, C,, alkyl ami/, or di-functional derivatives is included.

Particularly preferred compounds for use in the preparation of medicaments according to the invention are N-hydro- xy-N-(1-benzo[b]thiophen-2-ylethyl)urea (N-hyd roxy-N-(1-benxo [b]thien-2-ylefhyl) urea), or their physiologically acceptable salts, or their physiological It is a functional derivative.

Physiologically acceptable salts used in the manufacture of the medicaments of the invention include ammonium alkali metal salts such as sodium salts, sodium and potassium salts, calcium and alkaline earth salts such as magnesium salts, dicyclohexylamine and salts with organic bases, such as salts of N-Mejiru-D-glucamine, as well as arginine. and salts with amino acids such as salts of lysine.

Hereinafter, the compounds of formula (1) above, as well as their physiologically acceptable salts and and physiologically functional derivatives for therapeutic and pharmaceutical aspects of the invention discussed below. is referred to as a "compound of formula (1)".

According to a further aspect of the invention: (a) Prevention of symptoms that require suppression of oxidative changes in fat, such as atherosclerosis and at least one pharmaceutically acceptable compound of formula (I) for use in therapy. a pharmaceutically acceptable carrier, and optionally one or more other therapeutically effective compounds; and (b) symptoms in mammals such as humans involving inhibition of oxidative changes in fat; For example, a method of preventing and treating atherosclerosis, comprising formula (I) as defined above. A specific method is proposed for administering to said mammal a therapeutically effective compound of Served.

The amount of drug according to the invention required to achieve the desired therapeutic effect will, of course, vary. Individual compounds of formula (1) contained therein, route of administration, target of treatment, and treatment will vary depending on the individual illness or disease being treated. Which of the events described above? Appropriate dosages for mammals that also suffer from or are likely to suffer from bed symptoms. ranges from 0.1 to 500 mg of compound/kg body weight. whole body For standard administration, the dosage typically ranges from 0.5 to 0.5 kg of compound/kg body weight. In the range of 500mg. The most preferred dosage is 0.5 to 50 mg/ kg body weight, for example 5 to 25 mg/kg administered 2 to 3 times a day. Ru.

As explained, the medicament according to the invention comprises at least one compound of formula (I). in combination with a pharmaceutically acceptable carrier and optionally one or more other therapeutically effective compounds. Also included.

Of course, the carrier must be compatible with the other ingredients in the drug and must be compatible with the recipient. Must not be harmful. The compound of formula (1) has a drug content of 0. 1% to 99% by weight ．． 9% by weight.

A typical unit dose of a medicament according to the invention is O, 1 mg to 1 g of active ingredient. contains.

The drug according to the invention can be administered by oral administration, pulmonary, rectal and parenteral (subcutaneous, intramuscular and intravenous). forms suitable for administration (including intravenously). The medicament according to the invention is conveniently presented in unit dosage form and by any method known in the art of pharmacy; It can also be prepared by In all such methods, the compound of formula (1) is combined with one or more and the step of admixing the carrier, which may contain auxiliary ingredients. Generally, the drugs of the invention The agent comprises a compound of formula (I) in a liquid carrier or a finely divided carrier, or both. and then, if necessary, the product, e.g. by squeezing or is manufactured by forming into the required shape by molding.

The medicament according to the invention, which is suitable for oral administration, contains a defined amount of formula (1). Capsules, cachels, tablets or sachets containing the compound Independent unit form such as cake; powder or granule form; solution or aqueous solution or in the form of a suspension in a non-aqueous solution; or in oil-in-water or water-based It may be in the form of a tanine oil emulsion. This drug is also available in pills and pastes. Alternatively, it may be in the form of a paste.

Agents suitable for parenteral administration are typically administered preferably to the intended recipient's blood. The formulation includes a sterile aqueous formulation of a compound of formula (1) that is isotonic with the liquid.

In addition to the above-mentioned ingredients, the medicament according to the invention may contain diluents, buffers, flavoring agents, binders. Choose from agents, surfactants, thickeners, lubricants, preservatives, antioxidants, and emulsifiers may contain one or more additional ingredients. Further, the compound of formula (1) can be used, for example, as an anti-inflammatory compound. biological agents (e.g. antibacterial), antifungal agents, or anti-inflammatory agents, antihistamines; drugs (especially peripherally acting antihistamines), or nonsteroidal anti-inflammatory drugs (NSAID) and at least one other therapeutically effective compound selected from May be used advantageously in combination.

Compounds of formula (1) for use in the manufacture of medicaments of the invention, as well as their physiology Physiologically acceptable salts and physiologically functional derivatives are disclosed in EPSO 279263. It can be manufactured using the method described above.

In order to better understand the invention, the following examples are presented by way of illustration.

[Example of pharmaceutical preparation]

The "active ingredient" in the following formulations is any compound of formula (1) shown above. can be obtained.

Example A: Tablet per pill Active ingredient 5.　0mg Lactose 82.0mg Starch 10.0mg Povidone 2.0mg Magnesium stearate 1. 0mg active ingredients, lactose, and starch mixed with each other.

The powder was granulated using a purified aqueous solution of povidone. Dry and stearinize the granules Magnesium acid was added and compressed to produce tablets (100 mg per tablet).

Example B: Injection solution Active ingredient 10.0mg Water for injections B, P, 1.0ml The active ingredient is dissolved in half the volume of water for injection, then brought to volume and sterilized by filtration. do. The resulting solution is distributed into ampoules under sterile conditions.

biological activity (i) Supplementation of beroxyl radical The ability of the compounds of the present invention to scavenge peroxyl transfer radicals is due to the peroxidation of lylunic acid. Suppressed Biochem, Pharm, 38. 1465 (1989) Measured using the method described. N-Hydroxy-N-(1-benzo[b]thi (offhen-2-ylethyl) urea captures 0.11 peroxyl radicals. It was found to have significant antioxidant activity and an apparent rate constant for Ta.

(i1) Suppression of copper-induced peroxidation of LDL to human low-density lipoprotein (LDL) Addition of copper initiates the peroxidation reaction. This forms a conjugated diene in the fat phase. This necessarily increases the UV absorbance at 234 nm. The bell that breaks the chain The oxyl radical scavenger suppresses this increase in absorbance at 234 nm, and The agent is a basis for assays evaluating the potential of compounds to inhibit LDL peroxidation. used as a standard. For the reaction, 10 μM CuS04 was added to LDL (125 μM g/ml) in phosphate buffered saline solution. test The compound is added as an ethanolic solution, but the ethanol content of the resulting solution is maintained not to exceed 1% v/v. Absorbance at 234 nm is 4 μM butylated hydroxytoluene (BHT) and contains a body. No LDL was continuously monitored as an optical reference. Maximum absorbance The time required to increase to 50% of the value was determined for each test compound and the concentration plotted as a function of degree. From this plot, the production of conjugated diene is 60 minutes. The concentration of the compound required to retard the reaction was calculated. N-hydroxy-N-( Benzo[b]thiophen-2-ylethyl)urea has an I6° of 40.1 μM. It was found that LDL peroxidation was significantly inhibited.

(ii) Suppression of LDL changes by endothelial cells The cultured endothelial cells Cells are quickly captured by macrophage scavenger receptors. Sea urchins can alter low concentration lipoproteins. The changes include peroxidation of LDL, This results in changes in the physicochemical properties of LDL, including an increase in electrophoretic mobility. bell Oxyl radical scavengers have been shown to inhibit endothelial cell changes in LDL. This is measured by the decrease in the electrophoretic mobility of the sample.

0.2 mg of confluent porcine aortic endothelial cells Ha containing ethanolic solutions of LDL/ml and various concentrations of test compounds. m in FIO medium for 24 hours at 37°C. Concentrated ethanol The power was always 0.5% W/V. At the end of incubation, sample The sample was concentrated and changes in electrophoretic mobility relative to native LDL were measured.

A plot of concentration versus relative electrophoretic mobility shows that IC5o (change in LDL) For each sample, the concentration of test compound required to inhibit 50% of the It was measured using N-hydroxy-N-(benzo[b]thiophen-2-ylethyl ) Urea has an IC5o of 0.5 μM and can significantly suppress changes in LDL. Found out.

Country@Investigation Report Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number A61K 31/40 9360-4CI

Claims (11)

[Claims] 1. A compound of formula (I), or a physiologically acceptable salt thereof, or a physiologically acceptable salt thereof; Prevention of symptoms that require suppression of oxidative changes in fat using physical organoleptic derivatives. Use in the manufacture of medicaments for treatment. Ar-Y-Q(I) Here, Ar is (i) Furyl, thienyl, thienyl 1,1-dioxide, pyryl, pyridyl, benzyl nzofuryl, benzothienyl, benzothienyl 1,1-dioxide, indolyl , naphthyl, quinolyl, or tetrahydronaphthyl, all of which are C1-4 alkyl (which is itself optionally substituted with one or more halogen atoms) ), C1-4 alkoxy, halo, nitro, amino, alkoxy, C1- 4-alkoxycarbonyl, and hydroxy-substituted, or (ii) phenyl optionally substituted with one or more substituents, the substituents is phenyl (by itself, independently of those mentioned as optional substituents in (i) above) optionally substituted with one or more selected substituents) and in (i) above. substituted phenyl independently selected from any of the substituents mentioned; Y is C1-10 alkylene or C2-10 alkenylene, Q is ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ Here, R1 is hydrogen, C1-4 alkyl, the group represented by Ar above, or the formula -N (R4) A group of R5 (where R4 is hydrogen or C1-4 alkyl, and R 5 is hydrogen, C1-4 alkyl, or substituted phenyl, and in the above (i) one or more substituents independently selected from those mentioned as optional substituents in optionally substituted phenyl), R2 is hydrogen, C1-4 alkyl, amino, C1-4 alkylamino, di-C1- 4 alkylamino, C5-7 cycloalkylamino, C5-7 cycloalkyl ( C1-4 alkyl)amino, anilino, N-C1-4 alkylanilino, or This is the group represented by Ar above. 2. The use according to claim 1, wherein the compound of formula (I) is as shown in claim 1 and Ar is benzofuran-2-yl or benzothiophene-2 - is il; Y is -CH2- or -CH(Me)-; Q is as shown in claim 1; Yes, R1 is hydrogen, R2 is C1-4 alkyl, amino, C1-4 alkylamino , or di-C1-4 alkylamino, or their physiologically acceptable Uses that are acceptable salts or physiologically functional derivatives. 3. The use according to claim 2, wherein the compound of formula (I) is N-hydroxy-N -(1-benzo[b]thiophen-2-ylethyl)urea or their physiology Use of scientifically acceptable salts or physiologically functional derivatives. 4. The use according to any one of claims 1 to 3, wherein the symptom is atherosclerosis. Use that is inflammatory. 5. A drug for the prevention and treatment of symptoms that require suppression of oxidative changes in fat. and the compound of formula (I) shown in claim 1 or 2, or the compound shown in claim 3 a compound of formula (I), or a physiologically acceptable salt or physiologically acceptable salt thereof; a functional derivative, at least one pharmaceutically acceptable carrier, and optionally one or more Drugs containing other compounds effective in the treatment of. 6. The drug according to claim 5 for the prevention and treatment of atherosclerosis. 7. A medicament according to claim 5 or 6, in a form suitable for oral or parenteral administration. A drug that is a condition. 8. Drugs for preventing and treating conditions that require suppression of oxidative changes in fat A method for producing a compound of formula (I) according to claim 1 or 2, or a compound of formula (I) as shown in claim 3, or a physiologically acceptable compound thereof. salts or physiologically functional derivatives in at least one pharmaceutically acceptable carrier. A method comprising mixing the body and optionally one or more other therapeutically effective compounds. . 9. Claim 8 for the manufacture of a medicament for the prevention and treatment of atherosclerosis. Method described. 10. Prevention and treatment of conditions in mammals that require suppression of oxidative changes in fat. 3. A method for treating the mammal, the method comprising administering the formula (I) according to claim 1 or 2 to the mammal. administration of a therapeutically effective amount of a compound or compound of formula (I) as defined in claim 3; A method that includes 11. 11. The method according to claim 10 for the prevention and treatment of atherosclerosis.