JPH0859635A - Sulfonamide derivative having antagonistic action on endothelin receptor - Google Patents

Abstract

(57) [Summary] (Corrected) [Configuration] The following formula [In the formula, R ¹ is lower alkyl, R ² is halogen or hydroxy, R ³ is hydrogen, halogen, hydroxy, cyano,
N is 1, such as nitro or optionally substituted alkyl.
2 or 3] or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. [Effects] The above compounds are useful for treating various diseases such as circulatory disorders caused by the action of endothelin.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a compound useful in the field of medicine and its use, and more specifically, a novel sulfonamide derivative and a sulfonamide derivative useful for preventing or treating diseases caused by the action of endothelin. And an endothelin receptor antagonist containing

[0002]

BACKGROUND OF THE INVENTION Endothelin is a vasoconstrictive peptide of 21 amino acids derived from endothelial cells. This peptide acts on many organs such as blood vessels and trachea, and exerts various actions such as smooth muscle contraction through activation of specific receptors on cell membranes. Inferred to be involved in the development of the disease. For example, its hypersecretion is considered to be involved in the development of various pathological conditions such as elevation of blood pressure, ischemic heart disease, cerebral circulation disorder, renal disorder, circulatory failure of various organs, and asthma. Therefore, endothelin receptor antagonists are expected to be effective in treating or preventing the above various endothelin-dependent diseases.

[0003]

A sulfonamide derivative has been disclosed as a compound having an endothelin receptor antagonistic action (European Patent Publication 0558258A1). However, since there is no pharmacological data showing the activity of the compound in this document, its usefulness as an endothelin receptor antagonist is not certain. Therefore, it has been desired to develop a compound having an endothelin antagonism for clinical application.

[0004]

[Means for Solving the Problems] The present inventors have diligently provided in order to provide a compound having an endothelin receptor antagonistic activity,
Through repeated research, it has been found that the novel sulfonamide derivative represented by the following formula I is suitable for that purpose. That is,
The present invention provides formula I:

Embedded image [Wherein R ¹ is lower alkyl; R ² is halogen or hydroxy; R ³ is independently hydrogen; halogen; hydroxy; cyano; nitro; optionally substituted alkyl, optionally substituted Alkenyl, optionally substituted alkynyl, optionally substituted alkoxy,
Optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or substituted Good aralkyl; -C (O) H or -C
_{^{(O) R 6; -CO 2}} H or -CO ₂ R ^6; -SH, -S
^{_{(O) r R 6, -S}} (O) m -OH, -S (O) m -O-R 6, -O
^{_{-S (O) m -R 6,}} -O-S (O) m OH or -O-S
(O) _m -OR ⁶ ; -Z ⁴ -NR ⁷ R ⁸ ; or -Z ⁴ -N (R
¹¹⁾ groups selected from -Z ⁵ -NR ⁹ R ^10; and n,
Represents 0, 1, 2 or 3. Here, R ⁶ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, substituted Optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or optionally substituted aralkyl;

R ⁷ is hydrogen; hydroxy; cyano; optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted Good cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or optionally substituted aralkyl; C (O) H or ^{-C (O) R 6; -CO} 2 H or -
^{_{CO 2 R 6; -SH, -S}} (O) r R 6, -S (O) m -OH, -
_{S (O) m -O-R} 6, -O-S (O) m -R 6, -O-S (O)
_m OH or —O—S (O) _m —OR ⁶ , where Z ⁴ is —S
(O) _r - except when it is; R ⁸ is hydrogen; optionally substituted alkyl, optionally substituted alkenyl,
Optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl,
Optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or optionally substituted aralkyl; -C
(O) H or -C (O) R ^6, provided that Z ⁴ is -C (O) -, R
⁷ is -C (O) H or ^{-C (O) R 6, -CO} 2 H or -
Except when it is CO ₂ R ⁶ ;

Alternatively, R⁷And R⁸Is replaced
Good alkylene or optionally substituted alkenile
Together with the nitrogen atom to which they are attached
Form a saturated or unsaturated 3- to 8-membered aromatic ring
May be; R⁹Is hydrogen; hydroxy; is substituted
Optionally alkyl, optionally substituted alkenyl, position
Optionally substituted alkynyl, optionally substituted
Alkoxy, optionally substituted cycloalkyl, position
Optionally substituted cycloalkylalkyl, substituted
Optionally substituted cycloalkenyl, optionally substituted
Cycloalkenylalkyl, optionally substituted ari
Or optionally substituted aralkyl; -C (O)
H or -C (O) R⁶; -CO₂H or -CO ₂R⁶;-
SH, -S (O)_rR⁶, -S (O)_m-OH, -S (O)_m-O
-R⁶, -OS (O)_m-R⁶, -OS (O)_mOH or
-OS (O)_m-OR⁶; R^TenIs hydrogen; substituted
Optionally alkyl, optionally substituted alkenyl, position
Optionally substituted alkynyl, optionally substituted
Alkoxy, optionally substituted cycloalkyl, position
Optionally substituted cycloalkylalkyl, substituted
Optionally substituted cycloalkenyl, optionally substituted
Cycloalkenylalkyl, optionally substituted ari
Or optionally substituted aralkyl; -C (O)
H or -C (O) R⁶, But Z^FiveIs -C (O)-, R⁹
Is -C (O) H, -C (O) R⁶, -CO₂H or -CO₂
R⁶Except when R¹¹Is hydrogen; substituted
Optionally alkyl, optionally substituted alkenyl, position
Optionally substituted alkynyl, optionally substituted
Alkoxy, optionally substituted cycloalkyl, position
Optionally substituted cycloalkylalkyl, substituted
Optionally substituted cycloalkenyl, optionally substituted
Cycloalkenylalkyl, optionally substituted ari
Or optionally substituted aralkyl; -C (O)
H or -C (O) R⁶Hydroxy, -CO²R⁶Or
CO₂H, but R⁹Or R^TenIs one of the
Si, -CO²R⁶Or CO₂Except when H;

Alternatively, any two of R ⁹ , R ¹⁰ and R ¹¹ are optionally substituted alkylene or optionally substituted alkenylene, together with the nitrogen atom to which they are attached. ^May form a saturated or unsaturated aromatic ring of 3-8 membered ring; Z ⁴ and Z ⁵
Are independently a single bond, -S (O) _r- , -C (O)-, -C.
(S)-, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, substituted Optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or optionally substituted aralkyl; m represents 1 or 2; and r represents 0, 1 or 2. . ] The compound or its pharmaceutically acceptable salt shown by these are provided.

Substituents in alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyl, alkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkylalkylene or alkenylene are hydrogen; halogen; hydroxy; alkoxy;
_{H, -S (O) r Z} 6, -S (O) m -OH, -S (O) m -O
^{Z 6, -O-S (O} ) m -Z 6, -O-S (O) m OH, -O-
S (O) _m -OZ ⁶ ; oxo; nitro; cyano; -C (O)
^{H, -C (O) Z 6} ; -CO 2 H, -CO 2 Z 6; NZ 7 R 8,
-C (O) 1 to 3 radicals selected from the group consisting of NZ ⁷ Z ^8, or ^{_{-S (O) r Z 7 Z}} 8 , and the like. here,
Z ⁶ , Z ⁷ and Z ⁸ are each independently a group selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, or Z ⁷ and Z ⁸ are alkylene or alkenylene and may form a saturated or unsaturated aromatic ring of 3-8 membered ring together with the nitrogen atom to which they are bonded. Note that m is 1 or 2, r is 0,
Represents 1 or 2.

Preferred compounds are those in which R ¹ is methyl and / or
Or a compound in which R ³ is the same or different group selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkoxy, halogen, hydroxy, cyano, nitro and carboxy. The compounds of the present invention may be in the form of pharmaceutically acceptable salts,
For example, alkali metals (sodium, potassium, lithium, etc.), alkaline earth metals (calcium, magnesium, etc.), ammonium or organic bases (dicyclohexylamine, benzathine, N-methyl-D-glucamide, hydrabamine, etc.), amino acids (arginine, Lysine, etc.) and salts with inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) or organic acids (acetic acid, maleic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) Good. These salts are formed by methods known to those skilled in the art.

In the present specification, "alkyl" means C ₁ -C
Refers to ₁₀ straight or branched chain alkyl groups, with C ₁ -C ₄ "lower alkyl" being preferred. Specific examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. What is "alkoxy"?
It refers to an alkoxy group derived from a C ₁ -C ₁₀ linear or branched alkyl group, and is a C ₁ -C ₄ "lower alkoxy".
Is preferred. Specific examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy. "Aryl" or "aralkyl"
Refers to phenyl, naphthyl and biphenyl or groups derived therefrom, and specific examples include phenyl,
Examples include naphthyl, anthryl and phenanthryl. "Alkenyl", the C ₂ -C _10, refers to at least one straight or branched alkenyl group having a double bond, C ₂ -C ₄ alkenyl group. Specific examples include vinyl, propenyl, butenyl, pentenyl and the like. The term "alkynyl", of C ₂ -C _10, refers to a straight or branched chain alkenyl group having at least one triple bond, C ₂ -C ₄ alkynyl group. Specific examples include ethynyl, propynyl, butynyl, pentynyl and the like.

"Alkylene" means, for example,-(CH ₂ ) _m
It is a linear group represented by-(m = 1 to 5), and specific examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and the like. These may be substituted by 1 to 3 lower alkyl groups. "Alkenylene" means, for example, -CH = CH-CH = CH.
_{-, - CH 2 -CH = CH} -, - CH 2 -CH = CH-C
H ₂ - as in, at least one group having a double bond linked by a single bond, as a specific example, vinylene, propenylene, butenylene, butadienylene, pentenylene and the like. These may be substituted by 1 to 3 lower alkyl groups. “Cycloalkyl” and “cycloalkenyl” refer to C ₁ -C ₃ cyclic hydrocarbon groups, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. "Halogen" refers to fluorine, chlorine, bromine and chlorine.

The compound I of the present invention can be produced, for example, by the method described in European Patent Publication 0558258A. That is, formula II:

[Chemical 3] (In the formula, R ³ is as defined above and X represents halogen), and a sulfonyl halide represented by the formula III:

[Chemical 4] (Wherein R ¹ and R ² are as defined above) and an isoxazole amine is added to a non-aqueous organic solvent (for example, pyridine).
Coupling in to give the compound of formula I above. If the starting material has a reactive group, it may be protected by known methods using suitable protecting groups known to those skilled in the art. For example, benzyl, halobenzyloxycarbonyl, tosyl, etc. can be used as the hydroxy protecting group; and benzyloxycarbonyl, halobenzyloxycarbonyl, acetyl, benzoyl, etc. can be used as the amino protecting group. After the reaction, deprotection by an appropriate method gives the target compound I. The reaction starting materials II and III can be prepared by known methods, for example the above-mentioned European Patent Publication 05582.
58A.

The compound of the present invention has an endothelin receptor antagonistic activity, as is clear from the experimental results described in Test Examples. Therefore, it is considered to be effective for treating various diseases caused by hypersecretion of endothelin, and is effective for preventing and treating cardiovascular diseases such as vasospasm and hypertension. It is also useful for reducing the renal toxicity of the immunosuppressant cyclosporine. When the compound of the present invention is used as a medicine, it can be prepared into an injection, an oral preparation, a suppository and the like together with various carriers, diluents and excipients according to a conventional method. The dose is the target therapeutic effect,
Since it varies depending on the administration method, age, weight, etc., it cannot be specified unconditionally, but the daily dose for oral administration is usually 0.1 mg to 10 g, preferably 1 mg per adult.
mg to 1 g, more preferably 10 mg to 0.1 g. In addition, the daily dose for parenteral administration is 0.1 mg to 1 g, preferably 10 mg to 0.1 g, per adult.
g, more preferably 1 mg to 0.01 g.

Hereinafter, the present invention will be described in more detail with reference to Examples, but these do not limit the present invention in any way.

EXAMPLES Production Example 1 4-Ethyl-5-methyl-3-aminoisoxazole

[Chemical 5] Starting material (85.4mg, 0.352mmol) was treated with trifluoroacetic acid.
Dissolve in (1.5 ml) and stir at room temperature for 1 hour under nitrogen atmosphere. After trifluoroacetic acid was distilled off under reduced pressure, ice water was added to the residue, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer is extracted twice with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give the desired compound. Yield 100%. ¹ H NHR (CDCl ₃ ) δ _ppm : 1.12 (t, 3H, J =
7.6Hz), 2.26 (q, 2H, J = 7.6Hz), 3.83 (br
s, 2H) TLC Rf = 0.71 (ethyl acetate)

Production Example 2 4-iodo-5-methyl-3-
Amino isoxazole

[Chemical 6] The raw material (3.0 g, 30.6 mmol) was dissolved in acetic acid (30 ml),
Iodine monochloride (4.2 ml, 36.72 mm) with stirring under ice cooling
ol) is added. After stirring at room temperature for 3 hours, the reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution to adjust the pH to 8, and then extracted with ethyl acetate. The organic layer is washed successively with water, sodium thiosulfate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by silica gel column chromatography to obtain the target compound. Yield 48
%. ¹ H NHR (CDCl ₃ ) δ _ppm : 2.37 (s, 3H), 4.0
4 (brs, 2H) TLC Rf = 0.67 (hexane / ethyl acetate = 1 /
1)

Production Example 3 4-Bromo-5-methyl-3-
Amino isoxazole

[Chemical 7] The raw material (10.0 g, 101 mmol) was dissolved in acetic acid (50 ml),
Bromine (32.3 g, 102 mmol) was added to 20 while stirring under ice cooling.
Drop in minutes. After stirring for 30 minutes under ice cooling, the reaction solution is diluted with methylene chloride and neutralized with a saturated aqueous sodium carbonate solution. The organic layer is washed successively with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated.
Recrystallization of the residue (methylene chloride 15 ml, hexane 150 ml)
And the target compound is obtained. Yield 66%. ¹ H NHR (CDCl ₃ ) δ _ppm : 2.33 (s, 3H) TLC Rf = 0.37

Production Example 4 4-chloro-5-methyl-3-
Amino isoxazole

Embedded image The raw material (10.0 g, 101 mmol) was dissolved in acetic acid (50 ml),
Chlorine carbon tetrachloride solution (0.92M, with stirring under ice cooling)
121 ml, 111 mmol) are added dropwise over 30 minutes. Under ice cooling 4
After stirring for 0 minutes, the reaction solution is diluted with methylene chloride and neutralized with saturated aqueous sodium hydrogen carbonate solution. The organic layer is washed successively with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue is purified by recrystallization (methylene chloride 15 ml, hexane 60 ml) to obtain the target compound. Yield 71%. ¹ H NHR (CDCl ₃ ) δ _ppm : 2.32 (s, 3H) TLC Rf = 0.42

Example 1 5-Dimethylamino-N- (4
-Chloro-5-methyl-3-isoxazolyl) -1-naphthalenesulfonamide

[Chemical 9] A solution of 4-chloro-5-methyl-3-aminoisoxazole (4.0 g, 30 mmol) obtained in Preparation Example 4 in pyridine (80 ml) was stirred under ice cooling with dansyl chloride (9.8 ml).
g, 36 mmol) is added. After stirring overnight at room temperature, add 2 to the reaction mixture.
Add N hydrochloric acid to bring the pH to 4. It is extracted twice with ethyl acetate, the organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Dissolve the residue in 4 ml of methanol,
Add 4 ml of 2N aqueous sodium hydroxide solution. The suspension is stirred at 90 ° C. for 3 hours. The pH is adjusted to 4 with 2N hydrochloric acid, and the mixture is extracted twice with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography to obtain the target compound. Yield 30%. ¹ H NHR (CDCl ₃ ) δ _ppm : 2.26 (s, 3H), 2.8
9 (s, 6H), 7.05 (brs, 1H) 7.19 (d, 1H, J =
7.4 Hz), 7.58 (dd, 1 H, J = 7.4 Hz, 8.6 Hz),
7.60 (dd, 1H, J = 7.4Hz, 8.6Hz), 8.31 (d,
1H, J = 8.6Hz, 8.49 (dd, 1H, J = 1.2Hz,
7.4 Hz), 8.60 (dd, 1 H, J = 1.2 Hz, 8.6 Hz) TLC Rf = 0.25 (dichloromethane / ethyl acetate =
9/1)

Example 2 5-Dimethylamino-N- (4
-Bromo-5-methyl-3-isoxazolyl) -1-naphthalenesulfonamide

[Chemical 10] 4-Bromo-5-methyl-3-aminoisoxazole (200 mg, 1.13 mmol) obtained in Preparation Example 3 in pyridine (4 m
l) Add dansyl chloride to the solution while stirring under ice cooling.
(457 mg, 1.70 mmol) is added. After stirring overnight at room temperature, the reaction solution is adjusted to pH 4 with 2N hydrochloric acid. It is extracted twice with ethyl acetate, the organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is dissolved in a mixed solution of 4 ml of THF and 4 ml of methanol, and 5.5 ml of 10% aqueous potassium hydroxide solution is added. The suspension is stirred overnight at room temperature. The pH is adjusted to 4 with 2N hydrochloric acid, and the mixture is extracted twice with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by silica gel column chromatography to obtain the target compound. Yield 30%. ¹ H NHR (CDCl ₃ ) δ _ppm : 2.25 (s, 3H), 2.8
9 (s, 6H), 7.18 (d, 1H, J = 7.4Hz), 7.56 (d
d, 1H, J = 7.4Hz, 8.6Hz), 7.59 (dd, 1H, J =
7.4 Hz, 8.6 Hz), 8.32 (d, 1 H, J = 8.6 Hz),
8.49 (dd, 1H, J = 1.4Hz, 7.4Hz), 8.59 (d,
1H, J = 8.6Hz) TLC Rf = 0.21 (dichloromethane / ethyl acetate =
9/1)

Example 3 5-Dimethylamino-N- (4
-Iodo-5-methyl-3-isoxazolyl) -1-naphthalene sulfonamide

[Chemical 11] 4-Iodo-5-methyl-3-aminoisoxazole (196 mg, 0.875 mmol) obtained in Preparation Example 2 in pyridine
(4 ml) solution, under ice-cooling, with stirring, dansyl chloride
(283 mg, 1.05 mmol) is added. After stirring at room temperature for 24 hours, the reaction solution is adjusted to pH 4 with 2N hydrochloric acid. It is extracted twice with ethyl acetate, the organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is dissolved in 4 ml of methanol and 4 ml of 2N aqueous sodium hydroxide solution is added. The suspension is stirred at 90 ° C. for 2 hours. The pH is adjusted to 5 with 2N hydrochloric acid, and the mixture is extracted twice with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by silica gel column chromatography to obtain the target compound. Yield 36%. ¹ H NHR (CDCl ₃ ) δ _ppm : 2.30 (s, 3H), 2.8
8 (s, 6H), 6.88 (brs, 1H), 7.18 (d, 1H, J =
7.4 Hz), 7.57 (dd, 1 H, J = 7.4 Hz, 8.6 Hz),
7.60 (dd, 1H, J = 7.4Hz, 8.6Hz), 8.31 (d,
1H, J = 8.6Hz, 8.49 (dd, 1H, J = 1.2Hz,
7.4 Hz), 8.59 (d, 1 H, J = 8.6 Hz) TLC Rf = 0.21 (dichloromethane / ethyl acetate =
9/1)

Example 4 5-Dimethylamino-N- (4
-Hydroxy-5-methyl-3-isoxazolyl) -1
-Naphthalenesulfonamide

[Chemical 12] 5-Dimethylamino-N- (4-iodo-5-methyl-3-isoxazolyl) -1-naphthalenesulfonamide (10 mg, 0.022 mmol) obtained in Example 3 was dissolved in THF (0.02).
5 ml), sodium hydride (60% oil suspension, 1.3 mg, 0.033 mmol) was added at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred at 0 ° C. for 30 minutes. After cooling the reaction solution, t-B
uLi (heptane solution, 1.7M, 32.2μl, 0.055mmo
l) is added dropwise and stirring is continued for another 30 minutes. Trimethoxyborane (3.8 μl, 0.033 mmol) was added, and the temperature was -78 ° C.
Stir for 1 hour at 0 ° C. for 30 minutes. Acetic acid (4.0 μl)
And 30% hydrogen peroxide solution (35 μl) are added, and the mixture is stirred at room temperature overnight. The reaction mixture is adjusted to pH 2 with 2N hydrochloric acid.
The aqueous layer is extracted twice with ethyl acetate, and the organic layer is washed with saturated brine. Dry over anhydrous magnesium sulfate and concentrate. The residue is purified by silica gel column chromatography to obtain the target compound. Yield 11%. ¹ H NHR (CDCl ₃ ) δ _ppm : 2.31 (s, 3H), 2.8
8 (s, 6H), 6.88 (brs, 1H), 7.18 (d, 1H, J =
7.4 Hz), 7.57 (dd, 1 H, J = 7.4 Hz, 8.6 Hz),
7.60 (dd, 1H, J = 7.4Hz, 8.6Hz), 8.31 (d,
1H, J = 8.6Hz, 8.49 (dd, 1H, J = 1.2Hz,
7.4 Hz), 8.59 (d, 1 H, J = 8.6 Hz) TLC Rf = 0.72 (ethyl acetate / hexane = 2 /
1)

Reference Example 1 5-Dimethylamino-N- (4
-Ethyl-5-methyl-3-isoxazolyl) -1-naphthalene sulfonamide

[Chemical 13] 4-Ethyl-5-methyl-3-aminoisoxazole (19.2 mg, 0.152 mmol) obtained in Preparation Example 1 in pyridine
Dansyl chloride (69.8 mg, 0.258 mmol) was added to the solution (0.5 ml) under ice cooling with stirring. After stirring overnight at room temperature, the reaction solution is adjusted to pH 4 with 2N hydrochloric acid. It is extracted twice with ethyl acetate, the organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by silica gel column chromatography to obtain the target compound. Yield 35%. ¹ H NHR (CDCl ₃ ) δ _ppm : 1.01 (t, 3H, J =
8.6 Hz), 2.21 (s, 3H), 2.30 (q, 2H, J = 8.
6Hz), 2.88 (s, 6H), 7.16 (brs, 1H), 7.17
(d, 1H, J = 7.4Hz), 7.53 (dd, 1H, J = 7.4H
z, 8.6Hz), 7.55 (dd, 1H, J = 7.4Hz, 8.6H
z), 8.32 (d, 1H, J = 8.6Hz), 8.36 (dd, 1H,
J = 1.4Hz, 7.4Hz), 8.56 (d, 1H, J = 8.6H
z) TLC Rf = 0.37 (dichloromethane / ethyl acetate =
9/1)

The anti-endothelin action of the compound of the present invention was examined by the method shown in the following test examples. In addition, as a control compound, the compound of Example 1 described in EP0558258A (BM
S-182874, J. Med. Chem. 1994, 37 , 329) was used. Test Example 1 Inhibitory effect of ¹²⁵ I-labeled endothelin 1 on receptor binding Rat smooth muscle cell A7r5 derived from rat aorta was treated with 25 pM ¹²⁵ I-labeled endothelin 1 at 37 ° C. in the presence or absence of a test compound. Incubated for time.
After completion of the reaction, ¹²⁵ I bound to the membrane component with glass fiber filter paper
-Separating labeled endothelin-1 and gamma-counter-
The radioactivity was measured at. The specific binding was determined by subtracting the nonspecific binding obtained under the condition containing 10 ⁻⁷ M of non-radioactive endothelin 1. Table 1 shows the concentration (nM) of the compound of the present invention that inhibits the specific binding of ¹²⁵ I-labeled endothelin 1 to the membrane component by 50%.

Table 1 Table 1 Endothelin receptor antagonist compounds IC ₅₀ ( μM ) Example 1 0.013 Example 2 0.014 Example 3 0.02 Example 4 0.025 Control * 0.085 *: 5- Dimethylamino-N- (3,4-dimethyl-5
-Isoxazolyl) -1-naphthalenesulfonamide

[0024]

As is clear from the above test examples, the compound of the present invention antagonizes the binding of endothelin to the endothelin receptor and specifically suppresses the action of endothelin. Therefore, the compound of the present invention can be expected to have a preventive or therapeutic effect on diseases caused by the action of endothelin, for example, diseases such as elevated blood pressure, ischemic heart disease, cerebral circulation disorder, renal disorder, circulatory failure of various organs, asthma and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number in the agency FI Technical indication location A61K 31/42 AED (72) Inventor Masafumi Fujimoto 1102-99 Minamitawara-cho, Ikoma-shi, Nara (72) Invention Toshio Konoike 3-15-8 Honmachi, Suita City, Osaka Prefecture

Claims (4)

[Claims] 1. Formula I: [Wherein R ¹ is lower alkyl; R ² is halogen or hydroxy; R ³ is independently hydrogen; halogen; hydroxy; cyano; nitro; optionally substituted alkyl, optionally substituted Alkenyl, optionally substituted alkynyl, optionally substituted alkoxy,
Optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or substituted Good aralkyl; -C (O) H or -C
_{^{(O) R 6; -CO 2}} H or -CO ₂ R ^6; -SH, -S
^{_{(O) r R 6, -S}} (O) m -OH, -S (O) m -O-R 6, -O
^{_{-S (O) m -R 6,}} -O-S (O) m OH or -O-S
(O) _m -OR ⁶ ; -Z ⁴ -NR ⁷ R ⁸ ; or -Z ⁴ -N (R
¹¹⁾ groups selected from -Z ⁵ -NR ⁹ R ^10; and n,
Represents 1, 2 or 3. Wherein R ⁶ is optionally substituted alkyl, optionally substituted alkenyl,
Optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl,
Optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or optionally substituted aralkyl; R
⁷ is hydrogen; hydroxy; cyano; optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, Optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or optionally substituted aralkyl; -C (O) H or ^{-C (O) R 6; -CO} 2 H or -CO ₂ R ^6; -S
_{H, -S (O) r R} 6, -S (O) m -OH, -S (O) m -O-
^{R 6, -O-S (O} ) m -R 6, -O-S (O) m OH or -
_{O-S (O) m -OR} 6, provided that Z ⁴ is -S (O) _r - except when it is; R ⁸ is hydrogen; optionally substituted alkyl, alkenyl optionally substituted, Optionally substituted alkynyl, optionally substituted alkoxy,
Optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or substituted Good aralkyl; -C (O) H or -C
(O) R ⁶ , except when Z ⁴ is -C (O)-and R ⁷ is -C (O) H or -C (O) R ⁶ , -CO ₂ H or -CO ₂ R ^6. Or R ⁷ and R ⁸ are optionally substituted alkylene or optionally substituted alkenylene, together with the nitrogen atom to which they are attached, a saturated or unsaturated 3-8 membered ring. May form a saturated aromatic ring; R ⁹ is hydrogen; hydroxy; optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or substituted. Which may be aralkyl; -C (O) H
Or ^{-C (O) R 6; -CO} 2 H or -CO ₂ R ^6; -S
_{H, -S (O) r R} 6, -S (O) m -OH, -S (O) m -O-
^{R 6, -O-S (O} ) m -R 6, -O-S (O) m OH or -
O—S (O) _m —OR ⁶ ; R ¹⁰ is hydrogen; optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, substituted Optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or optionally substituted Good Aralkyl; -C (O) H
Or -C (O) R ^6, provided that, Z ⁵ is -C (O) -, R ⁹ is -C (O) H, -C ( O) R 6, -CO 2 H or -CO ₂ R ⁶
R ¹¹ is hydrogen; optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted. Cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl or optionally substituted aralkyl; -C (O) H or -C (O) R ^6; hydroxy, -CO ² R ⁶ or CO ₂
H, provided that either R ⁹ or R ¹⁰ is hydroxy,
-CO ² R ⁶ or CO ₂ H; or any two of R ⁹ , R ¹⁰ and R ¹¹ are optionally substituted alkylene or optionally substituted alkenylene. And may form, together with the nitrogen atom to which they are bonded, a 3-8 membered saturated or unsaturated aromatic ring; Z ⁴ and Z ⁵ are independently a single bond; S (O) _r- , -C (O)-, -C (S)-, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylalkyl,
Optionally substituted aryl or optionally substituted aralkyl; m is 1 or 2; and r is 0, 1
Or represents 2. ] The compound shown by these, or its pharmaceutically acceptable salt. 2. The compound according to claim 1, wherein R ¹ is methyl. Wherein R ³ is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkoxy, halogen, hydroxy, cyano, identical or different radicals selected from the group consisting of nitro and carboxy, claim 1 or 2 The described compound. 4. An endothelin receptor antagonist containing the compound according to claim 1.