JPH11240878A - New hydroxamic acid derivative or salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having greater endothelin(ET) receptor antagonism, and useful in the treatment of diseases associated with ET such as cardiovascular diseases. SOLUTION: This new compound (a salt thereof) is shown by formula I (R<1> and R<2> are each a lower alkyl, an aryl or the like; R<3> to R<6> are each H, a halogen or the like), e.g. (±)-4-(1-(1,3-benzodioxol-5-yl-)-2- [(E)-(4chlorophenyl) ethenesulfonyl]amino}-2-oxoethoxy)-N-benzyloxy-3-propylbenzamide. The compound of formula I is obtained by reaction of a carboxylic acid derivative of formula II (Z is a hydroxyl-protecting group) with a sulfonamide of formula III pref. in the presence of a condensation agent fallowed by hydrolysis of the reaction product to form a benzoic acid derivative which, in turn, is amidated with an O-substituted hydroxylamine of the formula R<1> -O-NH2 .

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a drug, particularly a novel hydroxamic acid derivative or a salt thereof having a high affinity for an endothelin receptor, and a drug containing the same, particularly an endothelin receptor antagonist.

[0002]

BACKGROUND OF THE INVENTION Endothelin (ET) is an amino acid 21
Endogenous bioactive peptides consisting of ET
Has a slightly different amino acid sequence ET-1, ET-2,
The presence of three ET-3 isopeptides is known.
ET expresses its physiological action by binding to the ET receptor on the target cell membrane. The ET receptor has been found to be at least two subtypes exist to date, these subtypes are named ET _A receptors and ET _B receptors, respectively. These receptors differ in their affinity for ET. Whereas ET _A receptor has a higher affinity to ET-1, ET-2 than ET-3, ET _B receptors have comparable affinity for three ET. ET and ET receptor are produced or expressed in various cells of various organs, respectively, and various physiological actions resulting therefrom are known.
For example, in blood vessels, ET-1 produced and secreted in vascular endothelial cells is expressed on neighboring vascular smooth muscle cells.
Binds to T _A receptor is strong and sustained vasoconstriction. On the other hand, vascular endothelial cells themselves ET _B receptors are expressed, it ET-1 binds to the nitrogen monoxide (NO)
A vascular endothelium-derived relaxing substance such as PG or PG is produced and released to relax vascular smooth muscle. In fact, ET-1 was experimentally given to rats.
When iv is administered, a sustained increase in pressure is observed after a transient decrease in blood pressure.

[0003] As can be seen from the above-mentioned physiological effects on blood vessels, ET, particularly ET-1, has one aspect as a very potent and long-lasting vasoconstrictive bioactive peptide. The relationship with systemic diseases has been discussed. Nowadays, hypersecretion of ET, particularly ET-1 (specifically, ET-locally or in tissues or circulating blood) is not limited to cardiovascular diseases but in many other diseases.
It has been pointed out that the risk of cardiovascular disease (essential hypertension, pulmonary hypertension,
Erythropoietin-induced hypertension, cyclosporin A-induced hypertension, acute myocardial infarction, unstable angina, chronic heart failure, arteriosclerosis, PTCA (Percutaneous Transliminal Coronary)
Angioplasty), restenosis, Raynaud's syndrome, diabetic peripheral circulation disorder, pulmonary heart, etc.), urinary disorders (urinary incontinence, benign prostatic hypertrophy, dysuria associated with prostatic hypertrophy, etc.), respiratory diseases (bronchial asthma, Chronic respiratory failure, chronic obstructive pulmonary disease, acute respiratory failure, pulmonary edema, interstitial pneumonia, pulmonary fibrosis, adult respiratory distress syndrome, etc., digestive system diseases (peptic ulcer, inflammatory bowel disease (IBD), etc.) ), Rheumatic diseases (rheumatoid arthritis, osteoarthritis, etc.), renal diseases (acute renal failure, chronic renal failure, glomerulonephritis, cyclosporine-induced renal failure,
Diabetic nephropathy), liver disease (liver failure, cirrhosis, ischemic liver injury, etc.), nervous system disease (cerebral vasospasm after subarachnoid hemorrhage, cerebral ischemic injury, etc.), preeclampsia, premature birth, early Myopia,
It has been reported to be associated with diseases such as glaucoma and cancer (GMRUBANYI, MAPOLOKOFF, PharmacologicalRevies, V
ol. 46, No. 3, 325 (1994); Latest Medicine, Vol. 49, No. 3, 335 (1994);
KidneyInternational, 37, 1487-1491, 1990; Lancet, 339,
381-385 (1992); CellMol. Neurobiol., 13, 15-23 (1993);
J. Clin. Endocrinol. Metab., 76, 378-383, 1993; J. Clin. P
athol., 48 (6), 519-524, 1995; Chest, 104 (2), 476-480, 19
93; Am. J. Med., 99 (3), 255-260, 1995; Hepatology, 16,95.
-99,1992 etc.). Therefore, a drug that inhibits the binding between ET and ET receptor (particularly, a drug that inhibits the binding between ET-1 and ET receptor), that is, an ET receptor antagonist, has been eagerly awaited, and it is desired to treat the above-mentioned diseases. It can be an effective prophylactic or therapeutic agent.

[0004] Such ET receptor antagonists include W
O94 / 21259, quinazoline derivatives, WO95 / 0
No. 3044, benzimidazolinone derivative, WO95 / 0
3,295, a 1,2-diphenylethanesulfonamide derivative is known. Further, in Example 58 of EP 61701, the following benzoic acid derivatives

Embedded image And in Example 9 of WO96 / 08487, the following N-2
-A pyridylmethyl carboxamide compound,

Embedded image Have been reported.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel compound having a superior ET receptor antagonism.

Means for Solving the Problems The inventors of the present invention have proposed E
As a result of research on compounds having a high affinity for the T receptor, a novel hydroxamic acid derivative that differs from the conventional compound in having a hydroxamic acid structure has a high affinity for the ET receptor. The present inventors have found that they have the property and strongly antagonize them, and have completed the present invention.

That is, the present invention relates to a novel hydroxamic acid derivative represented by the following general formula (I) or a salt thereof.
The present invention also relates to a medicament containing the hydroxamic acid derivative, particularly to an ET receptor antagonist.

Embedded image (The symbols in the formula represent the following meanings: R ^{1 is} lower alkyl, lower alkenyl, lower alkynyl, aryl optionally having substituent (s), or heteroaryl optionally having substituent (s); Lower alkyl, lower alkenyl and lower alkynyl may be substituted by cycloalkyl, aryl which may have a substituent or heteroaryl which may have a substituent, R ² : lower alkyl, lower alkenyl , Lower alkynyl, aryl which may have a substituent or heteroaryl which may have a substituent, wherein the lower alkyl, lower alkenyl and lower alkynyl are cycloalkyl, have an aryl or a substituent may be substituted at ^{heteroaryl, R 3, R 4, R} 5, R 6: identical also Different, hydrogen atom, halogen atom, lower alkyl or -O- lower alkyl)

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the compound (I) of the present invention will be described in detail. The term “lower” in the definition of the group represented by the general formula in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. Thus, "lower alkyl" is, for example, methyl, ethyl, and straight-chain or branched propyl, butyl, pentyl and hexyl. Among them, those having 1 to 4 carbon atoms are preferred, and methyl, ethyl, propyl and isopropyl are particularly preferred. The “lower alkenyl” is a straight-chain or branched alkenyl having 2 to 6 carbon atoms, and specifically includes vinyl, propenyl, butenyl, pentenyl and hexenyl. "Lower alkynyl" is straight-chain or branched alkynyl having 2 to 6 carbon atoms, and specifically includes ethynyl, propynyl, butynyl, pentynyl and hexynyl. “Aryl” means an aromatic hydrocarbon ring group, and is preferably an aryl having 6 to 14 carbon atoms. Specific examples include phenyl, naphthyl, indenyl, anthryl, and phenanthryl. Preferred are phenyl and naphthyl.

The "heteroaryl" is a heteroaryl containing 1 to 4 heteroatoms selected from O, S and N, and is a 5- or 6-membered heteroaryl (for example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl , Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazyl, etc., bicyclic heteroaryl (eg, naphthyridinyl and pyridopyrimidinyl etc.) and further condensed with a benzene ring Heteroaryl (eg, quinolyl, isoquinolyl, quinazolinyl, quinolizinyl, quinoxalinyl, cinnolinyl, benzimidazolyl, imidazopyridyl, benzofuranyl, benzoisoxazolyl, benzooxy) Zoriru, benzothiazolyl, oxazolopyridyl, isothiazolone pyridyl and benzothienyl and the like). Further, oxobenzofuranyl and the like in which oxo is substituted on these rings are also included. Preferred are thienyl, imidazolyl, pyridyl and benzofuranyl. “Cycloalkyl” is a saturated hydrocarbon ring group having 3 to 8 carbon atoms, and specifically includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The "optionally substituted aryl" and the "optionally substituted heteroaryl" may have, as a substituent, an aryl or heteroaryl substituent. may be any substituent group used, but preferably a halogen atom, a lower alkyl [the lower alkyl is halogen atom, -O- lower alkyl, _-COOH, -NH 2, -NH- lower alkyl, -
N (lower alkyl) ₂ , which may be substituted with one or more, preferably 1 to 3 substituents selected from the group consisting of -OH, -O-lower alkyl, -COOH, -C
O-O-lower _{alkyl, -NO 2, -CN, -NH 2} ,
—NH-lower alkyl, and —N (lower alkyl) ₂ groups, and the like, and may have one or more, preferably one to three of these substituents. “Halogen atom” is F, C
I, Br, I.

The compound of the present invention has an asymmetric carbon atom, and there are (R) -form and (S) -form optical isomers based on this.
The present invention includes a mixture of these optical isomers and all those isolated. In addition to the above, depending on the type of the substituent, a geometric isomer (cis-trans / or (E) isomer,
(Z) form) and tautomers may exist, and the present invention includes separated forms or mixtures of these isomers. The compound (I) of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent. Such salts are pharmaceutically acceptable salts, and specifically include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and propionic acid. Acid addition salts with organic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, sodium, Examples thereof include salts with inorganic bases such as potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and ammonium salts. Furthermore, the present invention also includes various hydrates, solvates, and polymorphic substances of the compound (I) of the present invention and salts thereof.

(Production Method) The compounds of the present invention and salts thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the types of substituents. Hereinafter, a typical production method of the compound of the present invention will be described. First step

Embedded image (In the formula, Z represents a hydroxy-protecting group, specifically, -O-lower alkyl, -O-aryl, -O-lower alkylene-aryl, and the like. The same applies hereinafter.)

The “lower alkylene” is a divalent group obtained by removing any hydrogen atom from the “lower alkyl”.
Preferably, it is an alkylene having 1 to 4 carbon atoms. In this step, i) reacting a carboxylic acid derivative represented by the general formula (II) with a sulfonamide represented by the general formula (III) and amidating to obtain a compound (IVa);
Further, ii) a reaction of obtaining a compound (IV) by subjecting the compound (IVa) to a hydrolysis reaction. The amidation reaction and hydrolysis reaction in this step can be performed by a conventional method. As the amidation reaction, specifically, compound (II) and compound (III) are used in an approximately equimolar amount or one of them in an excess amount, in an inert solvent or without a solvent, preferably in the presence of a condensing agent and under cooling. Alternatively, it is advantageous to carry out the reaction from room temperature to heating. As the hydrolysis reaction, specifically, in the presence of a base such as sodium carbonate and sodium hydroxide, or an acid such as trifluoroacetic acid and hydrochloric acid, under ice cooling to 100 ° C
It is preferable to carry out under the following temperature conditions. Inert solvents include benzene, toluene, xylene, acetonitrile,
Examples include tetrahydrofuran (THF), ether, dioxane, dimethylformamide (DMF), dimethylacetamide, dimethylsulfoxide, methylene chloride, dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like, and a mixed solvent thereof, depending on various reaction conditions. Selected as appropriate. As a condensing agent, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-
(3′-dimethylaminopropyl) carbodiimide,
1,1-carbonylimidazole (CDI) and the like.

Second step

Embedded image In this step, the benzoic acid derivative represented by the general formula (IV) and the O-substituted hydroxylamine (V) are subjected to an amidation reaction to obtain the present compound (I). The amidation reaction can be performed by a conventional method in the same manner as in the first step. The reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, a salt thereof, or a hydrate. The salt can be produced by subjecting the salt to a usual salt formation reaction. Isolation and purification
Extraction, concentration, evaporation, crystallization, filtration, recrystallization, various chromatography and the like are performed by applying ordinary chemical operations. Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. For example, optical isomers can be separated by a general racemic resolution method, for example, fractional crystallization or chromatography. Optical isomers can also be synthesized from appropriate optically active starting compounds.

(Preparation of Starting Compound) The starting compound of the present invention was prepared by a conventional method through the following steps using 3-fluoro-4-methoxybenzoic acid as a starting material.

Embedded image Methyl 3-fluoro-4-hydroxybenzoate m / z 170 (GC-
MS, M ⁺ ) Methyl 4-allyloxy-3-fluorobenzoate m / z 210 (G
C-MS, M ⁺ ) methyl 3-allyl-5-fluoro-4-hydroxybenzoate m /
z 210 (GC-MS, M ⁺ ) Methyl 3-fluoro-4-hydroxy-5-propylbenzoate
m / z 212 (GC-MS, M ⁺ ) methyl 2- (1,3-benzodioxol-5-yl) -2- (2-fluoro-4-methoxycarbonyl-6-propylphenoxy)
Acetate m / z 405 (FAB, M ⁺ +1) 2- (1,3-benzodioxol-5-yl) -2- (2-fluoro-4-
(Methoxycarbonyl-6-propylphenoxy) acetic acid m / z 389 (FAB, M ⁺ -1)

Similarly, the following starting compounds were synthesized. Methyl 2-fluoro-4-hydroxybenzoate m / z 170 (GC-
MS, M ⁺ ) Methyl 4-allyloxy-2-hydroxybenzoate m / z 209
(FAB, M ⁺ +1) methyl 4-allyloxy-2-methoxybenzoate m / z 223 (F
AB, M ⁺ +1) methyl 4-allyloxy-2-fluorobenzoate m / z 211 (F
AB, M ⁺ +1) methyl 3-allyl-4-hydroxy-2-methoxybenzoate m /
z 223 (FAB, M ⁺ +1) methyl 5-allyl-4-hydroxy-2-methoxybenzoate m /
z 223 (FAB, M ⁺ +1) methyl 3-allyl-2-fluoro-4-hydroxybenzoate m /
z 211 (FAB, M ⁺ +1) methyl 5-allyl-2-fluoro-4-hydroxybenzoate m /
z 211 (FAB, M ⁺ +1) Methyl 4-hydroxy-2-methoxy-3-propylbenzoate
m / z 225 (FAB, M ⁺ +1) methyl 4-hydroxy-2-methoxy-5-propylbenzoate
m / z 225 (FAB, M ⁺ +1) Methyl 2-fluoro-4-hydroxy-3-propylbenzoate
m / z 213 (FAB, M ⁺ +1) methyl 2-fluoro-4-hydroxy-5-propylbenzoate
m / z 213 (FAB, M ⁺ +1) methyl 2- (1,3-benzodioxol-5-yl) -2- (3-methoxy-4-methoxycarbonyl-2-propylphenoxy)
Acetate m / z 417 (FAB, M ⁺ +1) methyl 2- (1,3-benzodioxol-5-yl) -2- (5-methoxy-4-methoxycarbonyl-2-propylphenoxy)
Acetate m / z 417 (FAB, M ⁺ +1) methyl 2- (1,3-benzodioxol-5-yl) -2- (3-fluoro-4-methoxycarbonyl-2-propylphenoxy)
Acetate m / z 405 (FAB, M ⁺ +1) methyl 2- (1,3-benzodioxol-5-yl) -2- (5-fluoro-4-methoxycarbonyl-2-propylphenoxy)
Acetate m / z 405 (FAB, M ⁺ +1) 2- (1,3-benzodioxol-5-yl) -2- (3-methoxy-4-
(Methoxycarbonyl-2-propylphenoxy) acetic acid m / z 401 (FAB, M ⁺ -1) 2- (1,3-benzodioxol-5-yl) -2- (5-methoxy-4-
(Methoxycarbonyl-2-propylphenoxy) acetic acid m / z 401 (FAB, M ⁺ -1) 2- (1,3-benzodioxol-5-yl) -2- (3-fluoro-4-
(Methoxycarbonyl-2-propylphenoxy) acetic acid m / z 389 (FAB, M ⁺ -1) 2- (1,3-benzodioxol-5-yl) -2- (5-fluoro-4-
(Methoxycarbonyl-2-propylphenoxy) acetic acid m / z 389 (FAB, M ⁺ -1)

[0016]

The compound of the present invention has a high affinity for the ET receptor and has an excellent antagonism. Therefore,
The compound of the present invention has an action of competitively inhibiting the binding to the ET receptor, and various diseases involving ET, for example, cardiovascular diseases, urinary diseases, respiratory diseases, digestive diseases, rheumatic diseases. It is useful for diseases, kidney disease, liver disease, nervous system disease, pre-eclampsia, premature birth, early myopia, glaucoma, cancer and the like. The effects of the compound of the present invention were confirmed by the following pharmacological tests.

[0017] (1-A) ET-1 and human ET _A with human ET _A receptor RT-PCR method from mRNA binding inhibition test Human lung
The cDNA of the receptor is obtained and the expression vector pEF-B
Plasmids were prepared by introduction into OS. Was created plasmid added with DEAE-dextran in culture (cell line derived from African green monkey kidney cells) COS-1 cells, cDNA of human ET _A in COS-1 cells
Was transfected. In addition, normal DMEM (10
After culturing the cells for 3 days in CBS (containing% FBS), COS-1 cells were collected, and a hypotonic buffer (Tris-HCl, 10 mM;
EDTA, 5 mM; pH 7.4), and the cells were disrupted with Polytron. The cell-crushed suspension was subjected to ultracentrifugation (100,000 G, 30 min., 4 ° C.), and the sedimentation (cell membrane fraction) was performed using a Tris buffer (Tris-HCl,
_{50mM; MgCl 2, 10mM; pH7.4} ) resuspended after suspension -80 ° C. (protein content, about 1 mg / m
It was frozen and stored in l). For receptor binding experiments, frozen cell membrane preparations were thawed and the test buffer (Tris-HC
I, 50 mM; MgCl ₂ , 10 mM; bovine serum albumin, 0.01%; pH 7.4). 200 μl of membrane suspension containing 1.25 μg of membrane protein
And test buffer 25 containing different concentrations of test compound
μl and [ ¹²⁵ I] ET-1 (specific activity 2,200 Ci
/ Mmol, final concentration 25pM)
, And filtered with a glass fiber filter using a Brandel cell harvester.
The radioactivity on the glass fiber filter was measured using a gamma counter (counting efficiency 81%). Non-specific binding was determined by using a test buffer containing 0.1 μM ET-1. [ ¹²⁵ I] E of test compound
T-1 binding inhibitory activity was calculated as the concentration (IC ₅₀ ) required to inhibit 50% of specific binding.

[0018] (1-B) ET-1 and human ET _B receptor binding inhibition test human ET _B receptor cDNA (Accession No.S44866, Bioc
chemicaland Biophysical Research Communication Vol.
178, No. 2, 656-663, 1991) using the expression vector pEF-BO.
SET and used to transform human ET _B into COS-1 cells.
The receptor was transiently expressed. COS-1 cells are DEA
After transfection by E-dextran method,
The cells were cultured in DMEM (containing 10% FBS) for 3 days. After the culture, the cells are collected and a hypotonic buffer (Tris-HCl, 1
0 mM; EDTA, 5 mM; pH 7.4), and the cells were disrupted with Polytron. The cell-crushed suspension was ultracentrifuged (100,000 G, 30 min., 4
° C) and precipitation (cell membrane fraction) in Tris buffer (Tris
_{-HCl, 50mM; MgCl 2, 10mM} ; pH7.
After resuspension in 4), the suspension was frozen and stored at -80 ° C (protein amount, about 1 mg / ml). For receptor binding experiments, frozen cell membrane preparations were thawed and tested buffer (Tr
_{is-HCI, 50mM; MgCl 2} , 10mM; bovine serum albumin, 0.01%; were resuspended in pH 7.4). 200 μl of membrane suspension containing 1.25 μg of membrane protein, 25 μl of test buffer containing different concentrations of test compound and [ ¹²⁵ I] ET-1 (specific activity 2,
After incubating 25 μl together at 25 ° C. for 3 hours at 200 Ci / mmol, final concentration 25 pM), the Brand
It filtered with the glass fiber filter using the el cell harvester. Radioactivity measurement on glass fiber filters
The measurement was performed using a gamma counter (a counting efficiency of 81%). Non-specific binding was determined by using a test buffer containing 0.1 μM ET-1. The test compound [
¹²⁵ I] ET-1 binding inhibitory activity is 50% of specific binding.
% Was calculated as the concentration required to control the% (IC ₅₀ ).

(2) Inhibition test on big ET-1 hypertension in awake rats Male Wistar rats weighing 250 to 350 g were anesthetized with sodium pentobarbital (60 mg / kg intraperitoneal administration). A catheter for measuring systemic arterial blood pressure was inserted into the carotid artery, and a catheter for administering big ET-1 was inserted into the jugular vein. Experiments were performed 2-3 days after surgery. Awake rats with big E
T-1 was administered intravenously every hour at a dose of 0.5 nmol / kg. The test compound was orally administered at a dose of 3 mg / kg 30 minutes after the third administration of big ET-1.
The activity of the test compound was evaluated based on the degree of inhibition (%) of big ET-1 pressurization.

The pharmaceutical composition comprising the compound (I) of the present invention or a salt thereof and a pharmaceutically acceptable carrier is one or more of the compound represented by the general formula (I) or a salt thereof. And pharmaceutical carriers, excipients, and other additives commonly used for formulation, and can be prepared by a commonly used method. Administration is oral administration by tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration by injections such as intravenous injection and intramuscular injection, suppositories, transdermal and the like. Is also good. As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. It is mixed with magnesium acid. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, commonly used inert diluents, For example, it contains purified water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol,
Vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (trade name) and the like. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the preparation of a sterile solid composition which is dissolved in sterile water or a sterile solvent for injection before use. Usually, in the case of oral administration, the daily dose is about 0.001 to 30 mg / kg, preferably 0.1 to 5 mg / kg per body weight, which is divided into single doses or 2 to 4 doses. Administration. When administered intravenously, the daily dose should be about 0.001 to 30 per body weight.
mg / kg is appropriate, and it is administered once or several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

[0022]

The present invention will be described in detail below with reference to examples. The compound of the present invention is not limited to the compounds described in the following Examples, and further includes the compound represented by the general formula (I), a salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, It encompasses all geometric and optical isomers and polymorphs. Further, when the raw material used in the present invention is novel, it will be described as a reference example. Reference Example 1-a Methyl 4-[(1,3-benzodioxol-5-yl) (carboxy) methoxy] -3-propylbenzoate 79
Amidation using CDI from 3 mg and 1 g of (E) -2- (4-chlorophenyl) ethenesulfonamide gave (±) -4- (1- (1,3-benzodioxole-5-). 673 mg (55%) of yl) -2-{[(E) -2- (4-chlorophenyl) ethenesulfonyl] amino} -2-oxoethoxy) -3-propylbenzoate
Was obtained as a colorless solid. The compounds of Reference Examples 1-b to 1-n were obtained in the same manner as in Reference Example 1-a. Tables 1 and 2 show the chemical structural formulas and physical property data of Reference Examples 1-a to 1-s. Reference Example 2-a The compound (538 mg) obtained in Reference Example 1-a was hydrolyzed by a conventional method to give (±) -4- (1- (1,3-benzodioxol-5-yl) -2-yl. ｛[(E) -2- (4-
Chlorophenyl) ethenesulfonyl] amino {-2-oxoethoxy) -3-propylbenzoic acid 441 mg (84
%) As a colorless solid. The compounds of Reference Examples 2-b to 2-n were obtained in the same manner as in Reference Example 2-a. Reference Example 2-a
Tables 3 and 4 show the chemical structural formulas and physical property data of the compounds (2-s).

Example 1-a 299 mg of the compound obtained in Reference Example 2-a was dissolved in 6 ml of THF, 181 mg of CDI was added, and the mixture was heated under reflux for 1 hour. The reaction solution was allowed to cool to room temperature, and 175 mg of O-benzylhydroxylamine hydrochloride, 1,8-diazabicyclo [5,4,0]-
160 μl of 7-undecene was added, and the mixture was heated under reflux overnight. The solvent was distilled off under reduced pressure, 0.5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless solid. Ether was added thereto, and the mixture was pulverized and collected by filtration to obtain (±) -4- (1- (1,3-benzodioxol-5-yl) -2-{[(E) -2- ( 4-Chlorophenyl) ethenesulfonyl] amino {-2-oxoethoxy) -N-benzyloxy-3-propylbenzamide (329 mg, 93%) was obtained as a colorless solid.

The compounds of Examples 1-b to 1-u were obtained in the same manner as in Example 1-a. Example 1-b (±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N-benzyloxy-3-propylbenzamide Example 1-c (±) -4- (1- (1,3-benzodioxole-5
-Yl) -2-{[(E) -2- (2-chlorophenyl) ethenesulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide Example 1-d (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-{[(E) -2- (3-chlorophenyl) ethenesulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide Example 1-e (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-{[(benzo [b] thiophen-2-yl) ethenesulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide Example 1-f (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-{[(4-isopropylphenyl) sulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide Example 1-g (±) -4- (1- (1 , 3-Benzodioxole-5
-Yl) -2-{[(E) -2- (2,6-dichlorophenyl) ethenesulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide Example 1-h (±) -Potasium 2- (1,3-benzodioxol-5-yl) -2- (4-benzyloxycarbamoyl-2-propylphenoxy) -N-[(E) -2-pyridylethene] sulfonylacetamidate Example 1-i (±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-{[(E) -2- (3-pyridyl) ethenesulfonyl] amino} -2-oxoethoxy) -N-
Benzyloxy-3-propylbenzamide Example 1-j (±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-{[(E) -2-thienylethenesulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide

Example 1-k (±) -4- (1- (1,3-benzodioxol-5)
-Yl) -2-{[(E) -2- (3-thienyl) ethenesulfonyl] amino} -2-oxoethoxy) -N-
Benzyloxy-3-propylbenzamide Example 1-1 (±) -Potasium 2- (1,3-benzodioxol-5-yl) -2- (4-benzyloxycarbamoyl-2-propylphenoxy) -N -Methylsulfonylacetamidate Example 1-m (±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-{[(E) -2- (2,6-dimethylphenyl) ethenesulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide Example 1-n (± ) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-{[(E) -2- (1-methyl-2-phenyl) ethenesulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide Example 1-o ( ±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-{[(E) -2- (1-ethyl-2-phenyl) ethenesulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide Example 1-p ( ±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-oxo-2-{[(2-phenylethyl) sulfonyl] amino} ethoxy) -N-benzyloxy-3-propylbenzamide Example 1-q (±) -4- (1- (1 , 3-Benzodioxole-5
-Yl) -2-oxo-2-{[(2-thienylethyl) sulfonyl] amino} ethoxy) -N-benzyloxy-3-propylbenzamide Example 1-r (±) -4- [1- (1 , 3-Benzodioxole-5
-Yl) -2-ethenesulfonylamino-2-oxoethoxy] -N-benzyloxy-3-propylbenzamide Example 1-s (±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-{[(E) -2- (4-methylphenyl) ethenesulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide Example 1-t (±)- 4- (1- (1,3-benzodioxol-5)
-Yl) -2-{[(2-methoxyethoxy) sulfonyl] amino} -2-oxoethoxy) -N-benzyloxy-3-propylbenzamide Example 1-u (±) -4- (1- (1 , 3-Benzodioxole-5
-Yl) -2-{[(E) -2- (4-pyridyl) ethenesulfonyl] amino} -2-oxoethoxy) -N-
Benzyloxy-3-propylbenzamide

Further, in the same manner as in Example 1-a,
-A to 2-p and the compounds of Examples 3-a to 3-e were obtained. Example 2-a (±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N- (imidazol-4-yl) methoxy-3-propylbenzamide Example 2-b (±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N- (2-methylphenyl) methoxy-3-propylbenzamide Example 2-c (±)- 4- (1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N- (3-methylphenyl) methoxy-3-propylbenzamide Example 2-d (±)- 4- (1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N- (2-chlorophenyl) methoxy-3-propylbenzamide Example 2-e (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N- (3-chlorophenyl) methoxy-3-propylbenzamide Example 2-f (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N- (2-propenyl) methoxy-3-propylbenzamide Example 2-g (±) -potassium 2- (1,3-benzodioxol-5-yl) -2- [4- (1-phenylethoxy)
Carbamoyl-2-propylphenoxy] -N-
[(E) -2-Phenylethene] sulfonylacetamidate Example 2-h (±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -3-propyl-N-pyridylmethoxybenzamide Example 2-i (±) -potassium 2- (1 , 3-Benzodioxol-5-yl) -N-[(E) -2-phenylethene]
Sulfonyl-2- [4- (3-pyridylmethoxy) carbamoyl-2-propylphenoxy] acetamidate Example 2-j (±) -4- (1- (1,3-benzodioxole-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N- (2-fluorophenyl) methoxy-3-propylbenzamide

Example 2-k (±) -4- (1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N- (1-naphthyl) methoxy-3-propylbenzamide Example 2-1 (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -3-propyl-N- (3-thienyl) methoxybenzamide Example 2-m (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -3-propyl-N- (2-thienyl) methoxybenzamide Example 2-n (±) -potassium 2- (1,3-benzodioxol-5-yl) -2- [4- (2-methoxybenzyl)
Oxycarbamoyl-2-propylphenoxy] -N-
[(E) -2-phenylethene] sulfonylacetamidate Example 2-o (±) -4- (1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N- (3-methoxybenzyl) oxy-3-propylbenzamide Example 2-p (±)- Potassium 2- (1,3-benzodioxol-5-yl) -2- (4-methoxycarbamoyl-2
-Propylphenoxy) -N-[(E) -2-phenylethene] sulfonylacetamidate

Example 3-a (±) -4- (1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N-benzyloxy-3-fluoro-5-propylbenzamide Example 3-b (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N-benzyloxy-2-fluoro-3-propylbenzamide Example 3-c (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N-benzyloxy-2-methoxy-3-propylbenzamide Example 3-d (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N-benzyloxy-2-fluoro-5-propylbenzamide Example 3-e (±) -4 -(1- (1,3-benzodioxol-5)
-Yl) -2-oxo-2-{[(E) -2-phenylethenesulfonyl] amino} ethoxy) -N-benzyloxy-2-methoxy-5-propylbenzamide

Hereinafter, Examples 1-a to 1 are shown in Tables 5 to 10.
-U, 2-a to 2-p, and 3-a to 3-e show chemical structural formulas and physicochemical properties. The symbols shown in Tables 1 to 10 have the following meanings. Rf. : Reference example number Ex. : Example number Me: methyl Et: ethyl nPr: normal propyl iPr: isopropyl mp. : Melting point NMR: nuclear magnetic resonance spectrum (DMS unless otherwise specified)
O-d ₆ , TMS internal standard δ; ppm) In addition, a, b, and c in (parentheses) indicate measurement conditions, a indicates 300 MHz, b indicates 400 MHz, and c indicates 500 MHz. m / z: mass spectrometry value

[0030]

[Table 1]

[0031]

[Table 2]

[0032]

[Table 3]

[0033]

[Table 4]

[0034]

[Table 5]

[0035]

[Table 6]

[0036]

[Table 7]

[0037]

[Table 8]

[0038]

[Table 9]

[0039]

[Table 10]

The compounds having the chemical structural formulas shown in Table 11 can be easily prepared in substantially the same manner as in the above-mentioned Examples or Production Methods, or by applying a slight modification obvious to those skilled in the art. Can be manufactured. The compounds listed in Table 11 may have various, tautomeric, geometric, and optical isomers, and the compound of the present invention includes an isolated form of each of the isomers or a mixture thereof. .

[Table 11]

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/00 609 A61K 31/00 609J 609F 609G 611 611C 613 613 629 629A 643 643D 31/36 31/36 31/38 601 31 / 38 601 31/41 31/41 31/425 602 31/425 602 31/44 613 31/44 613 31/505 601 31/505 601 C07D 405/12 213 C07D 405/12 213 233 233 239 239 257 257 409 / 12 317 409/12 317 417/12 317 417/12 317 (72) Inventor Masanao Sanagi Miyukigaoka, Tsukuba, Ibaraki 21 Yamanouchi Pharmaceutical Co., Ltd.

Claims (3)

[Claims] 1. A hydroxamic acid derivative represented by the following general formula (I) or a salt thereof: (The symbols in the formula represent the following meanings: R ^{1 is} lower alkyl, lower alkenyl, lower alkynyl, aryl optionally having substituent (s), or heteroaryl optionally having substituent (s); Lower alkyl, lower alkenyl and lower alkynyl may be substituted by cycloalkyl, aryl which may have a substituent or heteroaryl which may have a substituent, R ² : lower alkyl, lower alkenyl , Lower alkynyl, aryl which may have a substituent or heteroaryl which may have a substituent, wherein the lower alkyl, lower alkenyl and lower alkynyl are cycloalkyl, have an aryl or a substituent may be substituted at ^{heteroaryl, R 3, R 4, R} 5, R 6: identical also Different, hydrogen atom, halogen atom, lower alkyl or -O- lower alkyl) 2. A medicament comprising the hydroxamic acid derivative according to claim 1 or a salt thereof. 3. The medicament according to claim 2, which is an endothelin receptor antagonist.