JP2001513527A - Anthranilic acid analogues - Google Patents

Abstract

  (57) [Summary] Formula (I) useful in treating disorders associated with smooth muscle contraction due to modulation of potassium and chloride channels Embedded image [Wherein, R₁, R_TwoAnd R_ThreeIs independently hydrogen, nitro, cyano, C_1-10Haloalkoxy, amino, C_1-10Alkylamino, sulfo, sulfamoyl, C_1-10Alkylsulfonamide, C_2-10Alkyl carboxamide, C_2-10Alkanoyl, C_1-10Alkylsulfonyl, C_1-10Haloalkylsulfonyl, C_1-10Carboxy, C_1-10Haloalkyl or C_6-12Aryl; provided that (1) R₁, R_TwoAnd R _ThreeAre not all hydrogen at the same time, and (2) R₁And R_TwoR is hydrogen._ThreeIs meta-CF_ThreeNot; R_Four, R_FiveAnd R₆Is independently hydrogen, halogen, nitro, cyano, C_1-10Carboalkoxy, C_1-10Haloalkoxy, amino, C_1-10Alkylamino, sulfo, sulfamoyl, C_1-10Alkylsulfonamide, C_2-10Alkyl carboxamide, C_2-10Alkanoyl, C_1-10Alkylsulfonyl, C_1-10Haloalkylsulfonyl, C_1-10Carboxy, C_1-10Haloalkyl, C_1-10Alkyl or C_6-12Aryl; R₇Is hydrogen, metal cation, acetylamide, alkoxyacetoyl, or related moieties that derive the carboxylate in vivo; X, Y and Z are C_3-13Carbocyclic ring, oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, 2H-pyrrole, pyrrole, 2-pyrroline, 3-pyrroline, imidazole, pyrazole, 1,2,3-oxadiazole or 1, 2,3-triazole may be formed], or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to novel amides (I) derived from anthranilic acid and having pharmacological activity, a process for their preparation, pharmaceutical compositions containing them, and potassium channels and chlorine. It relates to their use in the treatment of disorders related to smooth muscle contraction due to modulation of channels. Such disorders include, but are not limited to, urinary incontinence, asthma, preterm birth, irritable bowel syndrome, congestive heart failure, angina, cerebrovascular disease, and the like.

BACKGROUND OF THE INVENTION Modulation of potassium channels remains central to current approaches to controlling the resting cell membrane potential and affecting cell excitability. There are a wide variety of discrete potassium channels, which, in some recent reviews,
It is further classified by function, pharmacological properties and opening and closing mechanism [Rudy, Bee (
Rudy, B.), Neuroscience, 1988, 25,729-749; Atwal, K., Medicinal Research R.
eviews), 1992, 12, 569-591; Gopalakrishnan, M., et al., Drug Development Research, 1993.
Primeau, J. et al., Current Pharmaceutical Design, 1995, 1, 391-406; Edwards, G. Et al., Expert Opinion on Investing Drugs, 1996, 5 (11), 1453-1464].
. The therapeutic potential of potassium channel modulators in cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma and irritable bladder has been greatly explored.

[0003] Interest in the study of chloride channel modulation is growing rapidly [Strange, Kei (
Strange, K.) et al., Kidney International, 1995,
48,994-1003; Franciolini, F. et al., Biochimica et Biophysica Acta, 1990,247]. Various disease states that may be ameliorated by modulation of chloride channels include bronchial asthma, cardiac arrhythmias, cystic fibrosis of the pancreas, renal disease, and the like.

[0004] Harita et al. Disclose a method for producing meta-substituted aromatic amidocarboxylic acid derivatives in Japanese Patent Application No. 49-102692, and disclose an aromatic compound in Japanese Patent Application No. 49-42465. A method for producing cinnamic acid derivatives has been established. Several patents and patent applications have focused on the idea of a drug claim, especially with anti-allergic / anti-asthmatic / anti-histamine activity. Sato (Sato) et al., In Japanese Patent Application No. Sho 57-179976, and (tranilast (tranilast ^R) highlighted a antiallergics) reports a class of anthranilic acid derivatives. Related to these anthranilates is the claim of Japanese Patent Application No. 58-79436 by Aoyanagi et al. Which discloses a process for producing anthranilic acid derivatives. Of further interest is Hungary Patent No. HU 200 996 B, which emphasizes the production of several tranilast analogs. Yukihiko (JP-B-6-0019754) discloses a method for producing an anthranilic acid derivative in which the styrenyl moiety is strictly limited to alkoxy, hydroxy or acyloxy.

Furthermore, Japanese Patent Publication No. 0-2218654 by Tsumoro et al. Discloses aminobenzoic acid derivatives useful as reverse transcriptase inhibitors. Also, Tsumoro (Tsumoro
No. 6-0097946 discloses substituted carboxamide derivatives having activity as leukotriene antagonists and phospholipase inhibitors.

DISCLOSURE OF THE INVENTION According to the present invention, the formula

[0007]

Embedded image

[Wherein, R₁, R_TwoAnd R_ThreeIs independently hydrogen, nitro, cyano, C_1-10Halo alkoxy, amino, C_1-10Alkylamino, sulfo, sulfamoyl, C_1-10 Alkylsulfonamide, C_2-10Alkyl carboxamide, C_2-10Alkanoyl
, C_1-10Alkylsulfonyl, C_1-10Haloalkylsulfonyl, C_1-10Carboki
Si, C_1-10Haloalkyl or C_6-12Aryl; provided that (1) R₁, R_TwoAnd R _Three Are not all hydrogen at the same time, and (2) R₁And R_TwoWhen is hydrogen, R_ThreeIs meta-CF_ThreeNot; R_Four, R_FiveAnd R₆Is independently hydrogen, halogen, nitro, cyano, C_1-10 Carboalkoxy, C_1-10Haloalkoxy, amino, C_1-10Alkylamino,
Ruho, sulfamoyl, C_1-10Alkylsulfonamide, C_2-10Alkyl carb
Oxamide, C_2-10Alkanoyl, C_1-10Alkylsulfonyl, C_1-10Haloalk
Rusulfonyl, C_1-10Carboxy, C_1-10Haloalkyl, C_1-10Alkyl or
C_6-12Aryl; R₇Is hydrogen, a metal cation, acetylamide, alkoxyacetoyl, or a related moiety that derives the carboxylate in vivo; X, Y and Z are C attached to the carbon skeleton_3-13Carbocyclic ring, oxazole
, Isoxazole, thiazole, isothiazole, furan, thiophene, 2H
May form pyrrole, pyrrole, 2-pyrroline, 3-pyrroline, imidazole, pyrazole, 1,2,3-oxadiazole or 1,2,3-triazole
The compound represented by these is provided.

A more preferred embodiment of the present invention includes a compound of the formula (I)₁, R_TwoAnd R_ThreeIs independently hydrogen, nitro, cyano, perhaloalkoxy, amino, C_1-10Alkyria
Mino, C_1-10Dialkylamino, C_6-12Arylamino, C_1-10Aralkirami
No, sulfo, sulfamyl, C_1-10Alkylsulfonamide, C_6-12Aryls
Rufonamide, C_2-10Alkyl carboxamide, C_6-12Arylcarboxamide
, C_2-10Alkanoyl, C_6-12Ally Royle, C_2-22Aralkanoyl, C_1-10A
Rukylsulfonyl, C_1-10Perhalosulfonyl, C_6-12Arylsulfonyl, C _2-22 Aralkylsulfonyl, C_1-10Carboxy, C_1-10Haloalkyl, C_1-10Pe
Luhaloalkyl, aryl, haloaryl, perhaloaryl or C_1-10Ara
Ruquil portion; However, (1) R₁, R_TwoAnd R_ThreeAre not all hydrogen at the same time, and (2) R₁And R_TwoR is hydrogen._ThreeIs meta-CF_ThreeNot; R_Four, R_FiveAnd R₆Is independently of one another hydrogen, halogen, nitro, cyano, carboalkoxy, perhaloalkoxy, amino, C_1-10Alkylamino, C_{1- Ten} Dialkylamino, arylamino, C_1-10Aralkylamino, sulfo, sulf
Famil, C_1-10Alkylsulfonamide, C_6-12Arylsulfonamide, C _2-10 Alkyl carboxamide, C_6-12Arylcarboxamide, C_2-10Alkano
Il, C_6-12Ally Royle, C_2-22Aralkanoyl, C_1-10Alkylsulfonyl
, C_1-10Perhalosulfonyl, C_6-12Arylsulfonyl, C_2-22Aral Kills
Ruphonyl, C_1-10Carboxy, C_1-10Linear alkyl, C_1-10Branched alkyl, C _3-10 Cyclic or bicyclic alkyl, C_1-10Haloalkyl, C_1-10Perhalo Archi
Le, C_2-12Alkenyl (single or multiple olefinic), aryl, haloaryl
Le, perhaloaryl or C_1-10Aralkyl; R₇Is hydrogen, alkali metal cation, alkaline earth metal cation, acetyl amide, alkoxyacetoyl, or induces the carboxylate in vivo
X, Y and Z represent C attached to the carbon skeleton_3-13Carbocyclic ring, oxazole
, Isoxazole, thiazole or isothiazole may be formed]
Are included.

[0010] An even more preferred embodiment of the present invention includes a compound of formula (I) wherein R ₁ , R ₂ , R ₃ , R ₄ ,
R ₅ and R ₆ are as defined above; R ₇ is hydrogen, metal cation,

[0011]

Embedded image

[Wherein, R₉, R_Ten, R₁₁And R₁₂Are, independently of one another, hydrogen, C_1-10Linear alkyl, C_1-10Branched alkyl, C_3-10Cyclic or bicyclic, aryl or C _1-10 X, Y and Z are selected from the group consisting of a moiety selected from the group consisting of_3-13Carbocyclic ring, oxazole
, Isoxazole, thiazole or isothiazole may be formed]
Are included.

The most preferred embodiments of the present invention include compounds represented by formula (I) wherein R ₇ may be hydrogen or a metal cation as defined above.

The definition of the compounds of formula (I) is defined as R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , or the ring system formed by X, Y and Z. If contains an asymmetric carbon, it is understood to include all possible stereoisomers having the activities discussed below and mixtures thereof. In particular, this definition includes racemates and optical isomers having the required activity. The optical isomers may be obtained in pure form by standard separation techniques or by enantiomer-specific synthetic methods. The present invention is understood to include all crystalline forms of the compounds of formula (I). Pharmaceutically acceptable salts of the basic compounds of the present invention include organic and inorganic acids such as lactic acid, citric acid, acetic acid, tartaric acid, fumaric acid, succinic acid, maleic acid, malonic acid, hydrochloric acid, hydrobromic acid. , Phosphoric acid, nitric acid,
Salts derived from sulfuric acid, methanesulfonic acid, and similarly known acceptable acids. When R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , or the ring system formed by X, Y and Z contains a carboxy group, the salt of the compound of the present invention is an alkali metal (Na, It may be formed using a base such as K, Ki) or an alkaline earth metal (Ca or Mg).

Further, the present invention provides a method for producing the compound represented by the formula (I). The production method is shown in Schemes 1 to 4.

The isoxazole represented by the formula (I) can be produced by subjecting a compound represented by the formula (II) to a nitrile oxide cycloaddition with a suitable nitrile oxide (III) to obtain a heterocycle (IV). (Scheme 1). The intermediate carboxylic acid (V) is obtained by hydrolysis as described below.

[0017]

Embedded image [Wherein, R ₁ , R ₂ and R ₃ are the same as R ₁ , R ₂ and R ₃ above, and A is
If desired, it may be selected from groups R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ ]

The oxazole represented by the formula (I) may be produced by condensing an appropriate benzoyl chloride (VI) with methyl isocyanoacetate (VII) to obtain a heterocycle (VIII) (Scheme 2). The intermediate carboxylic acid (IV) is obtained by hydrolysis as described below.

[0019]

Embedded image [Wherein R ₁ , R ₃ and R ₃ are the same as R ₁ , R ₂ and R ₃ above]

In a more general sense, compounds of formula (I) can be obtained by reacting a suitably activated compound of formula (IX)
May be produced by reacting a heterocyclic or carbocyclic olefin of the formula (X) with a suitable coupling partner of the formula (X) to obtain a series of compounds of the formula (XI) (Scheme 3). Here, a typical example of the activated intermediate is that M is O-trifluoromethanesulfonate, M ′ is a trialkylstannane, or M is bromide or iodide, and M ′ is boron. It is an acid (boronic acid).

[0021]

Embedded image Wherein X, Y, Z, R ₁ , R ₂ and R ₃ are the same as X, Y, Z, R ₁ , R ₂ and R ₃ described above. Yields the intermediate carboxylic acid (XII).

Subsequently, the intermediate carboxylic acid (V), (VI) or (XII) is prepared according to the following established coupling method (method A: (COCl) ₂ , catalyst DMF, CH ₂ Cl ₂ , then The acid chloride obtained is added as such to a solution of anthranilic acid in aqueous sodium hydroxide solution; Method B: diisopropylcarbodiimide, DMAP, CH ₂ Cl ₂ ,
Then methyl anthranilate is added; or Method C: (COCl) ₂ , catalyst D MF, CH ₂ Cl ₂ or SOCl ₂ , and then treating the resulting acid chloride as is with triethylamine and methyl anthranilate) 1 Using the formula (XI
Coupling to an appropriately derivatized amine of anthranilic acid of formula II) can give an amide of formula (I) (Scheme 4). When the ester represented by (XIII) is used, the final hydrolysis yields the free acid (R ₇ ＨH).

[0023]

Embedded image

In addition to CH ₂ Cl ₂ , the above reaction may be carried out in an aprotic solvent such as diethyl ether, dichloroethane, dioxane, THF, etc. at low to room temperature. When sodium hydroxide is used as the base, it will be sufficient to list other inorganic bases such as lithium hydroxide and potassium hydroxide. Similarly, if desired, any trialkylamine may be used in place of triethylamine.

As mentioned above, the compounds of formula (I) and their pharmaceutically acceptable salts have been found to relax smooth muscle. They are therefore disorders associated with smooth muscle contraction, i.e. disorders involving excessive smooth muscle contraction of the ureter (e.g. incontinence) and disorders involving excessive smooth muscle contraction of the gastrointestinal tract (e.g. It is useful for treating intestinal syndrome, etc.), asthma and alopecia. In addition, compounds of formula (I) are active as potassium channel activators and are therefore useful in the treatment of peripheral vascular disease, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders. Will be useful. In addition, the compounds of formulas (I) and (II) are also active as chloride channel blockers and are therefore also useful in treating the above disorders.

The compounds of the present invention are characterized by their effective property of relaxing smooth muscle in vitro. The compounds of the present invention exert their smooth muscle relaxing activity by activating potassium channels and / or blocking chloride channels (Table I). The comparative compound tranilast was shown not to be an effective and bladder-selective smooth muscle relaxant.

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the present invention in combination with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.

[0028] These compositions are preferably for oral administration. However, they may be for other modes of administration, for example, parenteral administration to patients with heart failure.

[0029] To achieve consistency of administration, the compositions of the present invention are preferably in unit dosage form. Suitable unit dosage forms include tablets, capsules, powders in sachets or vials, and the like. Such unit dosage form may contain the compound of the present invention in an amount of 0.1 to 100 mg, preferably 2 to 50 mg. A more preferred unit dosage form contains 5 to 25 mg of a compound of the present invention. The compound of the present invention can be orally administered in a dose range of about 0.01 to 100 mg / kg, preferably in a dose range of 0.1 to 10 mg / kg. Such compositions may be administered 1 to 6 times a day, more usually 1 to 4 times a day.

The composition of the present invention may contain conventional additives such as a filler, a disintegrant, a binder, a lubricant,
The preparation may be made using a flavoring agent or the like. They are formulated in a conventional manner, for example, in a manner similar to that used for known antihypertensives, diuretics and β-blockers.

Further, the present invention provides a compound of the present invention for use as an active therapeutic substance. The compounds of the formula (I) are used in particular for inducing smooth muscle relaxation.

Further, the present invention provides a method of treating a smooth muscle disorder in a mammal, including a human. Such methods comprise administering to the affected mammal an effective amount of a compound or pharmaceutical composition of the present invention.

Examples The following examples are provided to illustrate, rather than limit, methods of making representative compounds of the present invention.

Example 1 2-{[2- (4-trifluoromethyl-phenyl) -cyclopenta-1-encarbonyl] -amino} -benzoic acid Step 1) (O-trifluoromethylsulfonyl) -cyclopenta-2 Preparation of 2-Enoic acid methyl ester Triethylamine was added to a homogeneous solution of 2-carbomethoxycyclopentanone (4.00 mL, 32.2 mmol) in 1,2-dichloroethane (50 mL) at 0 ° C.
(5.84 mL, 41.9 mmol) was added. The resulting mixture was kept at 0 ° C. and trifluoromethanesulfonyl anhydride (6.50 mL, 38.7 mmol) was added via syringe pump over 0.5 h. After the addition was completed, the temperature was maintained for a further 2 hours, after which it was subsequently diluted with ethyl acetate (50 mL), filtered through a short plug of silica, eluted with 30% ethyl acetate-hexane and concentrated. The residue was subjected to flash chromatography (eluted with 10% ethyl acetate-hexane) to obtain 6.14 g (69%) of a pale yellow oily substance. ¹ H NMR (CDCl ₃ ) δ 3.79 (s, 3 H), 2.68-2.78 (m, 4 H), 1.88-2.08 (m, 2 H).

Step 2) Preparation of 2- [4- (trifluoromethyl-phenyl)]-cyclopentenoic acid methyl ester The above enol triflate (1.77 g, 6.44 mimol) in anhydrous dioxane, 4- (trifluoro Methyl) -phenyltrimethylstannane [Morlein, SM, Journal of Organometallic Chem., 1987, 319, 29-39] (1.81 g) To a mixture of 5.86 mmol) and anhydrous lithium chloride (745 mg, 17.6 mmol) was added tetrakis- (triphenylphosphine) palladium (0) (203 mg, 0.176 mmol). After heating the obtained mixture to 110 degreeC, it stirred for 12 hours. After cooling to room temperature, the reaction mixture was concentrated to a slurry and ether (100 mL)
And filtered through a short pad of silica, concentrated and flash chromatographed (eluted with 5% ether-petroleum ether) to give 1.155 g (73%) of a clear, colorless oil. Obtained. ¹ H NMR (CDCl ₃ ) δ 7.50 (ABq, 4H), 3.63 (s, 3H), 2.85 (m, 4H), 2.02 (m, 2H).

Step 3) Preparation of 2- [4- (trifluoromethyl-phenyl)]-cyclopentenoic acid To a homogeneous solution of the above methyl ester (1.60 g, 5.92 mmol) in THF (20 mL) at room temperature 1.00N lithium hydroxide aqueous solution (17.8 mL, 17
(0.8 mmol). The resulting biphasic mixture was stirred vigorously for 16 hours, after which time
All volatiles were removed by evaporation on a rotary evaporator.
The remaining aqueous solution was washed with ether (3 × 100 mL), acidified to pH 2 with concentrated hydrochloric acid (1.73 mL), and partitioned with ether (300 mL). The aqueous layer was then saturated with solid ammonium chloride and extracted again (2 × 150 mL). The combined organic extracts were dried over magnesium sulfate, treated with Norite, and treated with Celite (Celite).
ite) and concentrated to a solid. After trituration with ether-hexane, filtration and drying under reduced pressure gave 1.38 g (91%) of an off-white solid. ¹ H NMR (DMSO-d ₆ ) δ 12.37 (s, 1H), 7.65 (ABq, 4H), 2.75-
2.91 (m, 4H), 1.92-2.02 (m, 2H).

Step 4) Preparation of 2-{[2- (4-trifluoromethyl-phenyl) -cyclopenta-1-encarbonyl] -amino} -benzoic acid The above carboxylic acid in anhydrous dichloromethane (3 mL) at 0 ° C. (500 mg, 1.95 mmol) and anhydrous DMF (4 drops) to an oxalyl chloride
(340 μL, 3.90 mmol) was added dropwise. The resulting mixture was warmed to room temperature and 2.
Stirred for 5 h, after which it was concentrated to a light brown oil and excess oxalyl chloride was removed under reduced pressure. The acid chloride was then added as such to a homogeneous solution of anthranilic acid (535 mg, 3.90 mmol) in 2.5 N aqueous sodium hydroxide solution (3.12 mL, 7.80 mmol) at 5 ° C., which immediately gave a white color. Precipitation occurred. The reaction mixture was then warmed to room temperature, after which it was diluted with a minimum amount of water to facilitate stirring. Stirring was continued for another 1.5 hours. This mixture is concentrated hydrochloric acid (
(0.75 mL) was added to acidify to pH 2 and diluted with 2.0 N hydrochloric acid and stirred for 1.5 hours. The suspension was filtered, washed with water, air dried and subsequently recrystallized from methanol to give 118 mg (16%) of an off-white crystalline solid. Melting point 225
^{1 to} 225.9 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 13.51 (brs, 1H), 11.28 (s, 1H), 8.56 (dd, 1H), 7.92 ( dd, 1H), 7.60 (ABq
, 4H), 7.12 (ddd, 1H), 2.91 (m, 4H), 2.03 (m, 2H); IR (KBr) 3121,966,1700,1662,1636,1586,1528, 1450,1381,1321,1205,1163,1131,106
6,1017,837,755,694 cm ^-1 ; MS (m / z) 375 [M ⁺ ]. Elemental analysis (as _{C 20 H 16 F 3 NO 3} ): Calculated: C, 64.00; H, 4.30 ; N, 3.73 Found: C, 63.79; H, 4.08 N, 3.57.

Example 2 2-{[5- (4-trifluoromethyl-phenyl) -oxazole-4-carbonyl] -amino} -benzoic acid Step 1) 5- (4-trifluoromethyl-phenyl) -oxazole Preparation of 4-Carboxylic Acid Methyl Ester To a mixture of 4-trifluoromethylbenzoyl chloride (8.42 g, 40.4 mmol) and triethylamine (12.3 g, 122 mmol) in anhydrous THF was added methyl isocyanoacetate ( (3.60 g, 36.3 mmol) were added. The resulting mixture was stirred at room temperature for 72 hours, after which all volatiles were removed by evaporation on a rotary evaporator to give a residue. This was partitioned between ethyl acetate (300 mL) and water (100 mL). The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution
100 mL), washed with brine (100 mL), dried over magnesium sulfate, treated with nolite, filtered through celite, and concentrated to give a brown solid 9
.27 g (94.2%) were obtained. This was subjected to the next reaction without further purification.

Step 2) Production of 5- (4-trifluoromethyl-phenyl) -oxazole-4-carboxylic acid In the same manner as in Step 3 of Example 1, commercially available 5- (4-trifluoromethyl-carboxylic acid)
The title intermediate was prepared from (phenyl) -oxazole-4-carboxylic acid methyl ester (83%).

Step 3) Preparation of 2-{[5- (4-trifluoromethyl-phenyl) -oxazole-4-carbonyl] -amino} -benzoic acid methyl ester In the same manner as in Step 4 of Example 1, 5- (4-Trifluoromethyl-phenyl) -oxazole-4-carbonyl chloride was prepared from carboxylic acid. The title intermediate was prepared analogously to Step 1 of Example 15 from the indicated acid chloride and methyl anthranilate. Flash chromatography (eluting with 17% ethyl acetate-hexane) provided a white solid (92%).

Step 4) Production of 2-{[5- (4-trifluoromethyl-phenyl) -oxazole-4-carbonyl] -amino} -benzoic acid The title compound was obtained in the same manner as in Step 3 of Example 1. Was prepared from the above methyl ester (45%). Melting point 231 to 232 ° C; ¹ H NMR (DMSO-d ₆ ) δ 13.53 (
br s, 1H), 12.51 (s, 1H), 8.74-8.78 (m, 2H), 8.16 (ABq, 4H), 8.02 (dd, 1H), 7.62 (ddd, 1H), 7.21 (ddd, 1 H); IR (KBr) 3449, 3245, 3080, 3022, 2647, 2559, 1669, 1607, 1585, 1519, 1466, 1451, 141
0,1327,1261,1151,1126,1060,1017,993
880, 848, 792, 761, 662 cm ^-1 ; MS (m / z) 376 [M ⁺ ]. Elemental analysis (as _{C 18 H 11 F 3 N 2} O 4): Calculated: C, 57.46; H, 2.95 ; N, 7.45 Found: C, 57.62; H, 3 .19; N, 7.01.

Example 3 Lithium 2-{[5- (4-trifluoromethyl-phenyl) -oxazole-4-carbonyl] -amino} -benzoate 2-{[5- (4-tri- To a solid mixture of fluoromethyl-phenyl) -oxazole-4-carbonyl] -amino} -benzoic acid (500 mg, 1.33 mmol) and lithium hydride powder (10.6 mg, 1.33 mmol) at room temperature , T
HF (15 mL, distilled from sodium benzophenone ketyl) was added. Heterogeneous
The mixture was heated at reflux for 40 hours, producing a large amount of white precipitate. Then room it
Cool to warm, dilute with THF (85 mL), filter through celite, and concentrate to white.
Color solid. This solid was then triturated with ether (40 mL, distilled from sodium benzophenone ketyl) for 72 hours to give a pale white suspension. This was filtered under a nitrogen atmosphere, washed with ether (40 mL) and finally under high vacuum at 80
Drying at <RTIgt; C </ RTI> provided 311 mg (61%) of a white powder. Melting point 356.3-357.3
° C (decomposition);¹1 H NMR (DMSO-d₆) δ 15.13 (s, 1H), 8.69 (s, 1H)
, 8.63 (dd, 1H), 8.42 (d, 1H), 8.01 (dd, 1H), 7.89 (d, 1H), 7.30 (ddd, 1H), 7.00 ( ddd, 1H); IR (KBr) 3412, 3140, 3091, 3062, 2920, 1651, 1590, 1527,
1449, 1375, 1324, 1160, 1126, 1073, 1062, 9
01,883,780,759,680cm^-1MS (m / z) 389 [(M + Li) ⁺ ]. Elemental analysis results (C₁₈H_TenF_ThreeN_TwoO_FourAs Li): Calculated: C, 56.51; H, 2.62; N, 7.33 Found: C, 56.02; H, 2.44; N, 7.28.

Example 4 2-{[3-methyl-5- (4-trifluoromethyl-phenyl) -isoxazole-4
-Carbonyl] -amino} -benzoic acid Step 1) Preparation of 3- [4- (trifluoromethyl-phenyl)]-prop-2-ynoic acid methyl ester Triphenylphosphine (75) in dichloromethane (250 mL) at 0 ° C. .
32 g, 287.1 mmol) and α, α, α-p-tolualdehyde (10.00 g,
(57.43 mmol) to a homogeneous solution of carbon tetrachloride (47.62 g, 143.6 mmol) as a solution in dichloromethane (50 mL). The reaction mixture was stirred at 0 ° C. for 5 minutes, then warmed to room temperature and stirred for another 4.5 hours, after which it was poured into a vigorously stirred slurry of celite (100 g) in petroleum ether (1500 mL). It is. The resulting mixture was stirred for 0.5 hours, filtered through a pad of silica and concentrated to a brown oil. This oil was dissolved in petroleum ether (150 mL), treated with Norite, filtered through Celite and concentrated to give 13.82 g (73%) of the intermediate dibromoolefin as a clear, colorless oil. .

Without further purification, the dibromoolefin was treated with anhydrous THF (115 mL).
And cooled to -78 ° C. To this solution, 2.5 M butyl lithium (18.4 mL, 46.0 mmol) was added dropwise over 1 hour by a syringe pump. The resulting mixture was then stirred at −78 ° C. for 0.5 h, then treated with methyl chloroformate (5.0 mL, 64.7 mmol) and slowly warmed to room temperature before it was concentrated An oily residue was obtained. This was partitioned between ether (500 mL) and water (250 mL). The organic layer was washed with brine (100 mL), dried over magnesium sulfate, treated with Norite, filtered, concentrated, and flash chromatographed (eluted with 2% ether-petroleum ether) to give a white solid. 3.13 g (66%) were obtained. ¹ H N MR (DMSO-d ₆ ) δ 7.86 (ABq, 4H), 3.79 (s, 3H).

Step 2) Preparation of 3-Methyl-5- (4-trifluoromethyl-phenyl) -isoxazole-4-carboxylic acid methyl ester 3- [4-(-) in anhydrous benzene (2.5 mL) at room temperature To a homogeneous solution of methyl (trifluoromethyl-phenyl)]-prop-2-enoate (1.00 g, 4.38 mmol) and phenyl isocyanate (857 μL, 7.89 mmol) was added benzene (1.5 mL). )) And a homogeneous solution of nitroethane (315 μL, 4.38 mmol) and distilled triethylamine (5 drops) were added dropwise. The resulting mixture is
Stirred for minutes, at which time a precipitate formed. The reaction mixture was heated at reflux for 12 hours, after which it was cooled to room temperature, diluted with ether (100 mL) and filtered to remove all solids. Then, the filtrate was partitioned sequentially with a 1.0 N aqueous sodium hydroxide solution (50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, treated with Norite, concentrated, and subjected to flash chromatography (gradient elution: 10-15-20% ether-petroleum ether) to give a white solid 900 mg.
mg (72%). ¹ H NMR (DMSO-d ₆ ) δ 8.00 (ABq, 4H), 3.77 (s, 3H), 2.44 (s, 3H).

Step 3) Preparation of 3-methyl-5- (4-trifluoromethyl-phenyl) -isoxazole-4-carboxylic acid The above methyl ester (865 mg, 3.19) in THF (10 mL) at room temperature.
(Mmol), a 1.00 N aqueous solution of lithium hydroxide (9.57 mL, 9.57 mmol) was added. The resulting biphasic mixture was stirred vigorously for 16 hours, after which all volatiles were removed by evaporation on a rotary evaporator. The remaining aqueous solution was washed with ether (3 × 50 mL), acidified to pH 2 with concentrated hydrochloric acid (0.93 mL), and partitioned with ether (300 mL). The aqueous layer was then saturated with solid ammonium chloride and extracted again (2 × 150 mL). The combined organic extracts were dried over magnesium sulfate, treated with Norite, filtered through celite, and concentrated to a solid. After trituration with ether-hexane, filtration and drying under reduced pressure gave 735 mg (89%) of a white crystalline solid.

Step 4) Preparation of 2-{[3-methyl-5- (4-trifluoromethyl-phenyl) -isoxazole-4-carbonyl] -amino} -benzoic acid in anhydrous dichloromethane (5 mL) at 0 ° C. The above carboxylic acid (1.00 g, 4
Oxalyl chloride (760 μL, 8.69 mmol) was added dropwise to a heterogeneous mixture of (.34 mmol) and anhydrous DMF (2 drops). The resulting mixture was warmed to room temperature and stirred for 2.5 hours, after which it was concentrated to a heterogeneous yellow mixture and the excess oxalyl chloride was removed under reduced pressure. The acid chloride was then treated with anthranilic acid (1.5) in 2.5 N aqueous sodium hydroxide (6.95 mL, 17.4 mmol) at 5 ° C.
(19 g, 8.69 mmol) immediately produced a white precipitate.
The reaction mixture was then warmed to room temperature, after which it was diluted with a minimum amount of water to facilitate stirring. Stirring was continued for another 1.5 hours. The mixture was acidified to pH 2 by adding concentrated hydrochloric acid (1.63 mL), diluted with 2.0N hydrochloric acid and stirred for 1.5 hours. The suspension was filtered, washed with water, air-dried and subsequently recrystallized from methanol. The title compound was separated from unreacted starting material by exhaustively methylating the acid group with (trimethylsilyl) diazomethane. Isolated 2-{[3-methyl-5- (4-trifluoromethyl-phenyl) -isoxazole-4-carbonyl] -amino}-
Hydrolysis of benzoic acid methyl ester in the same manner as in step 2 of this example gives the title compound.
(60%). 204.6-205.5 ° C .; ¹ H NMR (DMSO-d ₆ ) δ1 3.52 (brs, 1H), 11.47 (s, 1H), 8.42 (d, 1H), 7. 97 (ABq, 4H), 7.93 (dd, 1H), 7.64 (ddd, 1H), 7.23 (ddd, 1H), 2.47 (s, 3H); IR (KBr) 3374 , 3118,2987,265 6,1681,1659,1604,1585,1532,1441,1263.
, 1166, 1075, 1014, 905, 847, 762, 719, 701c
m ^-1 ; MS (m / z) 380 [M ⁺ ]. Elemental analysis results (as C ₁₉ H ₁₃ F ₃ N ₂ O ₄ ): Calculated: C, 58.47; H, 3.36; N, 7.18 Found: C, 58.22; H, 3 .24; N, 7.02.

The smooth muscle relaxing activity of the compounds of the present invention was established for representative compounds according to standard pharmaceutically acceptable test methods as follows.

Sprague-Dawley rats (150-200 g) are suffocated with CO ₂ to lose consciousness and then euthanized by dislocation of the neck. It retrieves the bladder, the following composition (mM) (NaCl, 118.4; KCl, 4.7; CaCl 2, 2 5;. MgSO 4, 4.7; H 2 O, 1.2; NaHCO 3, 24 .9; KH ₂ PO ₄ , 1
.2; treated with 95% O ₂ , 2/5% CO ₂ ; pH 7.4) in warm (37 ° C.) saline solution (PSS). After incision of the bladder, the bladder is cut into strips 1 to 2 mm wide and 7 to 10 mm long. The strips are subsequently suspended in a 10 mL tissue bath with an initial resting tension of 1.5 g. These strips are held in place by two surgical clips. One of the clips attaches to a fixed hook and the other attaches to an isometric contraction tension transducer. These samples usually show small spontaneous contractions,
After time recovery, induction with 0.1 μM carbachol is performed. The carbachol is then washed away and the tissue is allowed to relax to a resting level of its activity. After an additional 30 minutes of recovery, an additional 15 mM KCl is placed in the tissue bath. This increase in KCl concentration is superimposed on a small increase in basal tension, leading to a large increase in spontaneous contraction amplitude (and the onset of contraction of a previously stationary strip). After this elevated level of contractile activity has stabilized, the concentration of test compound or excipient in the tissue bath is gradually increased. Contractile activity is measured for the concentration of each compound or excipient during the last minute of the 30 minute induction.

The isometric contraction tension generated by bladder strips was measured using the concentration required to induce 50% inhibition of contractile activity before drug administration (IC ₅₀ concentration) and the concentration-response curve Calculate from The maximum inhibition rate (%) of the contractile activity induced by the test compound was 3%.
Record for test compound concentrations below 0 μM.

The results of this test are shown in Table I.

[0052]

[Table 1]

Furthermore, the compounds of the present invention inhibit the ability of hypertrophic bladder smooth muscle (detrusor) in hypertensive conscious female rats to thereby alleviate urinary incontinence in rats, The following methods reported by Malmgrem (A. Malmgrem, KE Ansersson
), C. Sjogren, P.O.Andersthorn (PO Ans
ersson), Effects of Pinacidil & Cromakalim (BRL 34915)
On-Bladder Function in Rats with Detrouser Instability ("Effects of Pinacidil and Cromakalim (BRL 34915) on Bladder Function in Rats with Detrusor Instability", Journal of Urology (J. Urol .), 1
42: 1134, 1989).

[0054] Female Sprague-Dawley rats weighing 190-210 g are used. Prepare up to 25 animals each time. After bladder hypertrophy occurs, 4-8 animals are used per test.

The compound is dissolved in PEG-200 and administered in a volume of 5 mL / kg by gavage or intravenously. For the primary screening, all drugs are orally administered to groups of four rats orally at an arbitrary dose of 10 mg / kg.

The animals are anesthetized with halothane. A midline incision exposes the bladder and urethra, and a 4-0 silk ligature is tied around the proximal urethra in the presence of a stainless steel rod (1 mm diameter) to partially occlude. Then, the rod is removed. Using surgical staples, the abdomen is sutured and each rat is given 150,000 units of Bicilin CR. For these animals, bladder hyperplasia is allowed to fully develop for 6 weeks. Six weeks later, under halothane anesthesia, the ligature is removed, a cuffed catheter (PE60) is placed in the dome of the bladder, and fixed with a purse string suture. The catheter passes under the skin and is exposed outside the body through a hole in the back of the neck. Suture the abdominal incision,
Seal the free end of the catheter. These rats are injected with Bacillin CR (150,000 units / rat) to prevent infection. Two days later, the animals are evaluated by intravesical pressure measurement. The animals were placed in a metabolic cage and the catheter was connected to the Statham pressure transducer (P23Db) using a T-shaped connector.
) And Harvard infusion pump. Under the rat's basket,
Place a plastic beaker connected to a force-displacement transducer (Grass FTO3), collect urine, and record the amount. After resting the animals for 15-30 minutes, infusion of saline (20 mL / hr for 20 minutes) is started and a first intravesical pressure measurement is performed. Two hours after the first cystometry, the vehicle is administered a vehicle or test compound, and one hour later a second cystometry is performed.

The following urodynamic variables are recorded: basal bladder pressure = minimum bladder pressure when measuring intravesical pressure threshold pressure = bladder pressure immediately before voiding Urination volume = discharge volume Urination pressure = peak pressure during voiding Spontaneous activity = Average amplitude of bladder pressure fluctuation at filling

Display of Results: The mean value of each variable is calculated before and after compound administration. For each compound, the change in measured variable is compared to the value obtained before treatment and expressed as percent inhibition. Also, a two-way analysis of variance is performed on these data to determine significant changes (p <0.05) in the measured variables.

Criteria for activity: The most characteristic finding in this rat model is the spontaneous bladder contraction that occurs on filling. A compound that inhibits spontaneous contraction by at least 50% orally or intravenously at 10 mg / kg (arbitrarily selected dose) is considered active.

(Industrial Applicability) Therefore, the compound of the present invention has a remarkable effect on the contractility of smooth muscle and activates the potassium channel and / or blocks the chloride channel. It is useful for the treatment of diseases which can be improved by oral administration, parenteral administration or inhalation treatment of patients in need, such as urinary incontinence, irritable bladder and bowel diseases, asthma, hypertension, stroke and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 A61P 9/10 11/06 11/06 13/00 13/00 C07D 261/18 C07D 261 / 18 263/34 263/34 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Skyler Adam Antein United States 08648 Lawrenceville, NJ Marie Court No. 14214 (72) Inventor John Anthony Butera United States 08510 Lawrence Spring Drive No. 6 F-Term (Clarksburg, NJ) 4C056 AA01 AB01 AC01 AC02 AD01 AE03 BA03 BB14 BC01 FA03 FA04 FB16 FC01 4C086 AA01 AA03 BC67 BC69 MA0 4 NA14 ZA36 ZA59 ZA66 ZA81 ZA94 4C206 AA01 AA03 GA32 MA04 NA14 ZA36 ZA66 ZA81 ZA94 4H006 AA01 AA03 AB20 BJ20 BJ50 BM10 BM71 BS30 BT32 BV64

Claims (12)

[Claims] (1) Formula (1)[Wherein, R₁, R_TwoAnd R_ThreeIs independently hydrogen, nitro, cyano, C_1-10Halo alkoxy, amino, C_1-10Alkylamino, sulfo, sulfamoyl, C_1-10 Alkylsulfonamide, C_2-10Alkyl carboxamide, C_2-10Alkanoyl
, C_1-10Alkylsulfonyl, C_1-10Haloalkylsulfonyl, C_1-10Carboki
Si, C_1-10Haloalkyl or C_6-12Aryl; provided that (1) R₁, R_TwoAnd R _Three Are not all hydrogen at the same time, and (2) R₁And R_TwoWhen is hydrogen, R_ThreeIs meta-CF_ThreeNot; R_Four, R_FiveAnd R₆Is independently hydrogen, halogen, nitro, cyano, C_1-10 Carboalkoxy, C_1-10Haloalkoxy, amino, C_1-10Alkylamino,
Ruho, sulfamoyl, C_1-10Alkylsulfonamide, C_2-10Alkyl carb
Oxamide, C_2-10Alkanoyl, C_1-10Alkylsulfonyl, C_1-10Haloalk
Rusulfonyl, C_1-10Carboxy, C_1-10Haloalkyl, C_1-10Alkyl or
C_6-12Aryl; R₇Is hydrogen, a metal cation, acetylamide, alkoxyacetoyl, or a related moiety that derives the carboxylate in vivo; X, Y and Z are C attached to the carbon skeleton_3-13Carbocyclic ring, oxazole
, Isoxazole, thiazole, isothiazole, furan, thiophene, 2H
May form pyrrole, pyrrole, 2-pyrroline, 3-pyrroline, imidazole, pyrazole, 1,2,3-oxadiazole or 1,2,3-triazole
A compound represented by the formula: 2. R₁, R_TwoAnd R_ThreeIs independently hydrogen, nitro, cyano, perhaloalkoxy, amino, C_1-10Alkylamino, C_1-10Dialkylamino
, C_6-12Arylamino, C_1-10Aralkylamino, sulfo, sulfamyl, C _1-10 Alkylsulfonamide, C_6-12Arylsulfonamide, C_2-10Alkyl
Carboxamide, C_6-12Arylcarboxamide, C_2-10Alkanoyl, C_6-12 Ally Royle, C_2-22Aralkanoyl, C_1-10Alkylsulfonyl, C_1-10Pell
Halosulfonyl, C_6-12Arylsulfonyl, C_2-22Aralkylsulfonyl, C _1-10 Carboxy, C_1-10Haloalkyl, C_1-10Perhaloalkyl, aryl, ha
Loaryl, perhaloaryl or C_1-10Aralkyl portion; provided that (1) R₁ , R_TwoAnd R_ThreeAre not all hydrogen at the same time, and (2) R₁And R_TwoR is hydrogen._ThreeIs meta-CF_ThreeNot; R_Four, R_FiveAnd R₆Are independently of one another hydrogen, halogen, nitro, cyano, carboalkoxy, perhaloalkoxy, amino, C_1-10Alkylamino, C_{1- Ten} Dialkylamino, arylamino, C_1-10Aralkylamino, sulfo, sulf
Famil, C_1-10Alkylsulfonamide, C_6-12Arylsulfonamide, C _2-10 Alkyl carboxamide, C_6-12Arylcarboxamide, C_2-10Alkano
Il, C_6-12Ally Royle, C_2-22Aralkanoyl, C_1-10Alkylsulfonyl
, C_1-10Perhalosulfonyl, C_6-12Arylsulfonyl, C_2-22Aral Kills
Ruphonyl, C_1-10Carboxy, C_1-10Linear alkyl, C_1-10Branched alkyl, C _3-10 Cyclic or bicyclic alkyl, C_1-10Haloalkyl, C_1-10Perhalo Archi
Le, C_2-12Alkenyl (single or multiple olefinic), aryl, haloaryl
Le, perhaloaryl or C_1-10Aralkyl; R₇Induces the carboxylate in hydrogen, an alkali metal cation, an alkaline earth metal cation, acetyl amide, alkoxyacetoyl, or in vivo.
X, Y and Z are bonded to the carbon skeleton by C_3-13Carbocyclic ring, oxazole
The compound of claim 1, which may form an isoxazole, a thiazole or an isothiazole. 3. R₇Is hydrogen, metal cation,[Wherein, R₉, R_Ten, R₁₁And R₁₂Are, independently of one another, hydrogen, C_1-10Linear alkyl, C_1-10Branched alkyl, C_3-10Cyclic or bicyclic, aryl or C _1-10 X, Y and Z are selected from the group consisting of moieties selected from the group consisting of_3-13Carbocyclic ring, oxazole
The compound of claim 1, which may form an isoxazole, a thiazole or an isothiazole. 4. The compound according to claim 1, wherein R ₇ may be hydrogen or a metal cation. 5. A method for preparing 2-{[2- (4-trifluoromethyl-phenyl) -cyclopenta-
The compound according to claim 1, which is [1-enecarbonyl] -amino} -benzoic acid. 6. A method for preparing 2-{[5- (4-trifluoromethyl-phenyl) -oxazole-
The compound according to claim 1, which is 4-carbonyl] -amino} -benzoic acid. 7. A method for preparing 2-{[5- (4-trifluoromethyl-phenyl) -oxazole-
The compound according to claim 1, which is a lithium salt of 4-carbonyl] -amino} -benzoic acid. 8. The compound according to claim 1, which is 2-{[3-methyl-5- (4-trifluoromethyl-phenyl) -isoxazole-4-carbonyl] -amino} -benzoic acid. 9. A compound of the formula[Wherein, R₁, R_TwoAnd R_ThreeIs independently hydrogen, nitro, cyano, C_1-10Halo alkoxy, amino, C_1-10Alkylamino, sulfo, sulfamoyl, C_1-10 Alkylsulfonamide, C_2-10Alkyl carboxamide, C_2-10Alkanoyl
, C_1-10Alkylsulfonyl, C_1-10Haloalkylsulfonyl, C_1-10Carboki
Si, C_1-10Haloalkyl or C_6-12Aryl; provided that (1) R₁, R_TwoAnd R _Three Are not all hydrogen at the same time, and (2) R₁And R_TwoWhen is hydrogen, R_ThreeIs meta-CF_ThreeNot; R_Four, R_FiveAnd R₆Is independently hydrogen, halogen, nitro, cyano, C_1-10 Carboalkoxy, C_1-10Haloalkoxy, amino, C_1-10Alkylamino,
Ruho, sulfamoyl, C_1-10Alkylsulfonamide, C_2-10Alkyl carb
Oxamide, C_2-10Alkanoyl, C_1-10Alkylsulfonyl, C_1-10Haloalk
Rusulfonyl, C_1-10Carboxy, C_1-10Haloalkyl, C_1-10Alkyl or
C_6-12Aryl; R₇Is hydrogen, a metal cation, acetylamide, alkoxyacetoyl, or a related moiety that derives the carboxylate in vivo; X, Y and Z are C attached to the carbon skeleton_3-13Carbocyclic ring, oxazole
, Isoxazole, thiazole, isothiazole, furan, thiophene, 2H
May form pyrrole, pyrrole, 2-pyrroline, 3-pyrroline, imidazole, pyrazole, 1,2,3-oxadiazole or 1,2,3-triazole
Or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.
A pharmaceutical composition consisting of a body. 10. A method for reducing the detrimental effects of smooth muscle contraction, comprising the steps of:
For patients who need it, the formula[Wherein, R₁, R_TwoAnd R_ThreeIs independently hydrogen, nitro, cyano, C_1-10Halo alkoxy, amino, C_1-10Alkylamino, sulfo, sulfamoyl, C_1-10 Alkylsulfonamide, C_2-10Alkyl carboxamide, C_2-10Alkanoyl
, C_1-10Alkylsulfonyl, C_1-10Haloalkylsulfonyl, C_1-10Carboki
Si, C_1-10Haloalkyl or C_6-12Aryl; provided that (1) R₁, R_TwoAnd R _Three Are not all hydrogen at the same time, and (2) R₁And R_TwoWhen is hydrogen, R_ThreeIs meta-CF_ThreeNot; R_Four, R_FiveAnd R₆Is independently hydrogen, halogen, nitro, cyano, C_1-10 Carboalkoxy, C_1-10Haloalkoxy, amino, C_1-10Alkylamino,
Ruho, sulfamoyl, C_1-10Alkylsulfonamide, C_2-10Alkyl carb
Oxamide, C_2-10Alkanoyl, C_1-10Alkylsulfonyl, C_1-10Haloalk
Rusulfonyl, C_1-10Carboxy, C_1-10Haloalkyl, C_1-10Alkyl or
C_6-12Aryl; R₇Is hydrogen, a metal cation, acetylamide, alkoxyacetoyl, or a related moiety that derives the carboxylate in vivo; X, Y and Z are C attached to the carbon skeleton_3-13Carbocyclic ring, oxazole
, Isoxazole, thiazole, isothiazole, furan, thiophene, 2H
May form pyrrole, pyrrole, 2-pyrroline, 3-pyrroline, imidazole, pyrazole, 1,2,3-oxadiazole or 1,2,3-triazole
Or a pharmaceutically acceptable salt thereof, orally or parenterally.
The method that consists of doing. 11. The method of claim 10, wherein the detrimental smooth muscle contraction causes urinary incontinence. 12. The method of claim 10, wherein the detrimental smooth muscle contraction causes irritable bowel syndrome.