TW391963B - (3,4-dioxocyclobuten-1-y1) chromene derivatives as smooth muscle relaxants - Google Patents

Description

A7 _ B7___ printed by Bei Gong Xiao F 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (1) The present invention is based on a novel 4- (3,4-dioxycyclobutene-1 with smooth muscle relaxation activity. -Yl) benzoxan-piranes and dihydrocetones, and 3_ (3 * 4-ziaminocyclobutene_buyl) indene and salts thereof, and for the treatment of hypertension and peripheral vascular disease, hyperemia Heart palpitations, diseases caused by transient contraction of urinary smooth muscle, such as incontinence or excessive contraction of gastrointestinal smooth muscle, such as irritable bowel syndrome, asthma and hair loss, and pharmaceutical compositions containing the compound of the present invention. 6-Substituted-4-limylbenzopiperans can be used to treat hypertension, shown in published PCT patent applications WO 92/1 9 611 and WO 9 2/20672, published European patent application EP 01 58 923 and EP 0427606, and U.S. patents 4,925,839, 4,908,378 and 4,616,021. 6-substituted-4-aminotetralin-1-ones having high blood pressure and bronchodilator activity are shown in US Patent No. 208,246 and published European Patent Application EP 0413438. 5-Substituted-3-aminoindanes which can be used to treat hypertension and respiratory disorders are shown in published European patent applications EP 0413438 and EP 0426379. The antihypertensive agent 6-substituted-4-aminobenzobenzonans, tetrahydrofluorenes, or tetrahydroquinoline fluorenes are shown in published European patent application EP0376524. EP0426379 indicates that it is used as a bronchus. Please read it before i.

3 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 5. Description of the invention (2) A7 B7 where Y is N or CR1, J is 0 or NR8, and a and b together form -0- OR-CH2-bond or bond to lower blood pressure and treat respiratory disorders. gg 沭 明 沭 This invention shows compounds represented by formula (I)

Please read the note on the back first, and then install it in the list below.

1 radical C alkoxy, alkane 6 fluoro-per 1 C 6-radical C 1S alkoxyalkyl nitro C oxy, alkane fluoro per I, 6 1 radical -C 0 amidinyl sulfonyl alkyl Amine amine fluorinated alkyl fluoro per amine amine fluorinated amine fluorinated di- or linear amine alkane 12-based sulfonium. Aryl alkyl aryl 10-based carboxy sulfonium hydrogen or carbonyl carbonyl amine bis or -1 02 Economy Printed by the Consumer Cooperatives of the Ministry of Standards of the People's Republic of China and a 0 and 0 nj 1 S composition form a total of 4 linkages or tj --- bonding straight or ο take fluorine from the alkyl group or 1-based C amine It is 12 amine alkyl fluoro all-base 垸 4 This paper size applies to Chinese national standard (CNS> A4 specification (210X297 mm) A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of the invention (3) Fang Or a monocyclic or bicyclic heteroaryl group containing 1 to 3 selected N, 0 or S heteroatoms; and a pharmaceutically acceptable salt thereof. A more preferred compound of the present invention is a compound of formula I, wherein

Ri and 1.2 are each trifluoromethoxy, methoxy, nitro, fluorenyl, chlorine, bromine, fluorine, trifluoromethyl, methanesulfonamido mono- or di-C 1-6 Alkylamino, acetamido, trifluoroacetamido, trimethylsulfonamido, or hydrogen; a and b together form a 0-bond or direct bond; when a and b together form -0 -When linked, 1? 3 and 1 ^ 4 are methyl groups;

Rs is an amine group or "-12-co-amine; and β6 is Ci-e alkyl or H. The best compound of the present invention is a compound of formula I wherein: R 1 is CH; R 2 is hydrazone; a and b together -0-linkage; R 3 and R 4 are methyl groups; R is an amine group or a methylamine group; and R e is ”〇” A single ring containing 1-3 heteroatoms selected from N, O or S The term "or bicyclic heteroaryl" means a heteroaryl group selected from the group consisting of: β-morpholine, pyridoxine, 11¾, indole, pyrrole, P-quinazoline, pyrizone, pyrimidine, sulfan, furan, benzofuran, benzo Oxazole, pyrazole, benzoxazole, and benzopyridine. The term alkyl alone or another functional group such as carbonyl, sulfonamido, amine, carbamoyl, and sulfonamide This paper is applicable to China National Standard (CNS) A4 specification (210X297 mm) ('Please read the note on the back iW before filling out this page) -install._ -line A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (4 )-1 1 radical 9 or carboxamido bond * Covers straight and branched hydrocarbyl radicals of 1 1 within the enumerated range of sulphur atom number 9 such as Group 9 ethyl * propyl > isopropyl 1 I group t butyl, tert-butyl, pentyl, neopentyl, hexyl, decyl, etc. Please 1 I perfluorinyl — the term is defined as above Zhiyuan 9 of which all the hydrogen atoms are read first I read 1 I replaced by fluorine atom 0 alkoxy " 'word aa alone or in combination with another functional group such as guess I 1 group on the back to indicate -0 -alkyl Here, the alkyl group is defined as above β C 6 _ 10 Aromatic Note | / Μ 1 group means the phenyl group or the ceryl group 9 any j * r. From the halogen atom 9 fluorenylnitro ¥ ji $ CL-ί 5alkane 3 1, C 1 6 alkoxy 9 or C Ξ 3-ί i cycloalkyl is substituted by 9 and can be used in combination with functional groups such as amino fluorenyl or oxy group. Write this page 1 C 3 ε The fluorenyl--word indicates a 1 1 base of a carboxylic acid derived from 1 to 6 sulfonium atoms such as methyl fluorenyl 9 ethyl fluorenyl f propyl fluorenyl > Linker Amine group »in which all hydrogen atoms are replaced by fluorine atom 1 1 atom 9 Nan. CL-i alkyl substituted by fluorine represents an alkyl group in which-hydrogen or at most several hundred hydrogens are replaced by gas atoms. ί | "Medical_acceptable salt" means an acid addition salt formed from a basic compound of the present invention and a medicinal acceptable acid 1 t Acid includes, but is not limited to, acetic acid) 1 I $ hydrimoic acid 9 Hydrobromic acid 9 sulfuric acid * phosphoric acid * maleic acid fumaric acid I diacid succinic acid citric acid f malonic acid > tartaric acid 9 and methanesulfonic acid 1 1 etc. acid 1 Ι I unlike EP 0426379 Compounds shown $ The compound of the present invention does not contain an intervening atom or intervening group between the bis 1 1 cyclic benzoyl group and the cyclobutadienyl group. 1 It should be understood that the compound of the present invention and its salt may be solvated or hydrated物 分 1 I 离 > and pharmacologically equivalent to the present invention Or a salt thereof together 011 of formula (I) are smooth muscle relaxants. -6-So it can be used to treat high blood 1 1 1 1 1 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm). A7 B7 V. Description of the invention (5) Pressure and terminal vascular disease, congestive Heart failure, conditions caused by excessive contraction of urethral smooth muscle (such as incontinence), or diseases caused by excessive contraction of gastrointestinal smooth muscle (such as irritable bowel syndrome), asthma and hair loss. The invention therefore provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The composition is preferably designed to be suitable for oral administration but may be designed to be suitable for other modes of administration, such as parenteral administration in patients with heart failure. The invention further provides compounds of the invention that are useful as active therapeutic substances. Compounds of formula (I) are particularly useful in the treatment of hypertension and / or smooth muscle relaxation. gg 明 夕 detailed description The compound of the present invention can be prepared by the method of Lieb'eskind et .. al. (J. Or, Che,. 990, 5 5, 5 3 5 9). In particular, the compound of formula (11): Please read the note on the back before binding

In line II, it is based on the sulfonic acid methyl trifluoroacetate or the printed form of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and the tin base or base. The conversion can be as previously defined.

5 a R

u3 B Π S 7 This paper size applies to Chinese National Standards (CNS) A4 specifications (210X297 mm) A7 B7 V. Description of the invention (6) Where Ra5 is typically 0-alkyl can provide compounds of formula IV 〇

Please read the note on the back to print the s printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. For example, when R e is a 0-9LD alkyl group, the Rs is NH2 by ammonia treatment. The preparation method of the compound of the formula I is illustrated in the following specific examples. These statements are for illustration purposes only and are not intended to limit the content of this instruction. Other systems will obviously be self-evident to those in the industry. Reverse reagents and reagents may be commercially available or may be prepared according to standard literature procedures. Example 1 4- (2-isopropoxy-3,4-dioxy-cyclobut-1-enyl) -2,2-dimethyl-211-benzo) 3-piperan-6-formyl Synthesis of Nitrile 2, 2-dimethyl-4- (0-tris (methanesulfonic acid tr if late) -6-fluorenylbenzopiperan) reported by Yoo et al. (EP 5 1 4942 / \ 1) The method is completed by using 2,2-dimethyl-6-cyanobenzodiazepine and trifluoromethanesulfonic anhydride. The preparation of tri- (2-furanyl) -ortho was completed by the procedure of Allen et al. (J. Chem. Soc. (Perk. 1 1) 1 972, 63). 3- (1-methyl ethoxy) -4-tri-n-butyltin group). Preparation of 3-cyclobutane-1,2-dione like borrowed by Lieberkind et al. (J.0rg.Chem.55 , 5359 (1990)). For 2,2-dimethyl- 4- (0-trifluoromethane sulfonated paper) The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (7) Acid group)- 6-cyano-2H-1-benzopyran (559mg; 31.6 8mmol), 720mg (1.68mm on 3-methylethoxy.)-4- (tri-n-butyltinyl) -3 -cyclo Butane-.1., .2-dione, 38.9mg (0.168mraol) of tri- (2-furanyl) o, and 45 7Bg (3.36mmol) of aerated zinc in N-methylpyrrolidone The solution was flushed with nitrogen. To this was added 48.3Bg (0.084mmoi) hydrazone (dibenzylideneacetone). The reaction mixture was then reacted at ambient temperature for 30 minutes, and then stirred at 65 ° F for 1 hour. Reaction. The mixture was diluted with Et 2 0 (75 niL), then washed with saturated HH4C1 aqueous (3x), H20 (3x), brine (3x) and then 10% KF (3x). The organic phase was dried (Ha2S04) and concentrated to obtain 598 mg of material, which was used with 255 mg of 2,2-dimethylacet-4- (0-trifluoromethanesulfonate) -6-cyano-2H-1 -Merging of identical identical rounds of benzopiperans. Purification by chromatography (20% EtO Ac 2-hexane) gave 552 mg (70% yield) of the title compound as a yellow solid, fflP 1 69-1 70 ¾: 1 H-NMR (DMS〇-d 6 · 400MΗζ) δ 7.85 (d.lH), 7.70 (dd, 1H), 7.04 (d, 1H), 6.67 (s, 1 Η), 5.47 (seven peaks, 1 Η), 1.48 (s, 6H), 1 m I --- n — (Please read the note on the back before filling in this page) Order printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and l * 44ppm (c (. 6H); IR (KBr) 2220, 1786, 1 750, 1615, and 1 570cm -1; Mass spectrometry (CI), m / € 323 〇 Elemental analysis: C 19 Η 17 NO 4 Calculated value: C, 70. 58; Thallium, 5. 30; Ν, 4.33 found: C, 70.59; hydrazone, 5.26; Ν, 4.22. Example 2 4-(2-Amino-3,4-dioxy-cyclobut-1 -ene Radical) -2 s 2-dimethyl-2pyrene-benzoluron-piran-6-carbonitrile ammonia gas flow 36 1 mg (1.12mmo 1) 4- (2 · ^ isopropylamino-3, 4 -Dioxin .. The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (8) Cyclobut-1-enyl) A solution of -2,2-dimethyl-2H-benzo / 8-piran-6-carbonitrile in acetonitrile (11 ml) for 30 minutes. The reaction mixture was stirred at ambient temperature for 1.6 hours. The reaction mixture was mixed with water ( 50ml) Ping · 媳, and extracted in 20% THF-CH2C12. The combined organic single extract was dried over anhydrous Na2S04, then concentrated and recrystallized from acetone-petroleum ether to obtain 110 mg of the title compound (35% yield). , Mp > 250t: off-white solid: 1 H-NMR (DMS 0-d 6; 400MΗζ) δ 9.18 (bs.1 Η), 8.68 (bs, 1 Η), 7.79 (d, 1H), 7.67 (dd , lH), 7.01 (d, lH), 6.29 (s, lH), and 1.47 ppm (s, 6H); IR (KBr) 3300, 3100, 1780, 1730, 1720, 1 6 6 5, and 1 6 1 0 c m-1; Mass spectrometry (PBEI), m / e 2 8 1 (Μ + Η), 2 8.0 (M +), 252, and 2 09 〇 (Please read the note on the back before filling this page) Ministry of Economy Analysis of the printed elements of the Consumer Standards Cooperative of the Central Bureau of Standards: C 16 Η 12 N 2 0 3 Calculated values: C, 68.57; Η, 4.32; Ν, 9. 99 Found: C, 68. 47; Η, 4.25; hydrazone, 9.99. Example 3 2,2-Dimethyl-4- (2-methylamino-3,4 -Dioxy-cyclobut-1 -alkenyl) -2H benzo β-piperan-6-carbonitrile at 437 m 8 (1.3 5 π η 〇1) 4- (2 -isopropoxy-3 , 4-Dioxy-cyclobut-1-alkenyl) -2,2-dimethyl-2,2-benzone- 6-carbonitrile in a solution of CH 3 CN (14 bL) was added dropwise to 8. The 03M methylamine in Et0Ho reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted in 20% THF-CH 2 C 1 2. The combined organic extracts were dried (Na 2 SO 4) and purified by flash chromatography (4% MeOH -CHC1 a ) And 210 mg (53% yield) of the title compound was obtained from the crystallization of CH 2 Cl 2 petroleum ether. This paper is in paper size using the Chinese National Standard (CNS) A4 specification (210X297 mm). Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. A7 B7 V. Description of the invention (9), mp 1 93-194 Ό, as a white solid: 1H-NMR (DMS0-d6; 400MHz; main main isomer) S8.7-8.8 (br q, lH), 7.78 (d , lH), 7.67 (dd, lH), 7.01 (d, lH), 6.22 (s, 1H), 3.25 (s, 6H), and 1.46ppm (s, 3H); IRUBr) 2220,1775,1735,1620cm · 1; Mass spectrometric analysis (DCI +), ra / e 295. Elemental analysis 1 C 17 Η 14 Ν 2 0 3 ♦ 0 .25Η 2 1] Calculated value • 'C, 68. 33; Η, 4. 89; Ν, 9.37 Measured value C, 68. 56; Η, 4. 75 Ν, 9.54 Pharmacological bladder smooth muscle The bladder smooth muscle relaxing activity of the compounds of the present invention was established using representative compounds according to standard medical acceptability test procedures as follows: Sturgeon rats (150-200g) use CO2 asphyxia to lose consciousness, Then beheaded and sacrificed. The bladder was transferred into warm (37 Ό) normal saline with the following composition (m Μ). Solution (PSS): NaCl, 1184; KCl, 4.7; CaCl2, 2.5; MgSO 4, 4.7; Η 2 0,1.2; NaHCO 3, 24.9; ΚΗ 2 POL 0, 1.2; ® glucose, 11.1; EDTA, 0.023 to 95% 02; 2/5% (: 02 inflation; 1 ^ 7.4 inflation. Open the bladder and cut into strips with a width of 1-2111111 and a length of 7-10mm. Then the strips are suspended under the initial resting tension of 1.5g In a 10ml tissue bath. The strip is held in place by two surgical clips, one of which is connected to a fixed hook, and the other is connected to an isometric force converter. The preparation usually shows a little contraction afterwards, when using O. lwM carbachol challenged him to recover for 1 hour before washing. Then washed to remove the carbachol and relax the tissue to its resting state activity. After 30 minutes recovery -11-This paper size applies Chinese national standard (CNS> A4 ^ Luo (210X297mm> 'install — (please read the note on the back # ^ before filling out this page) Order A7 B7 printed by the Central Standard Bureau of the Ministry of Economic Affairs and Consumer Cooperatives V. Description of the invention (10) After resumption, 15inM KC1 is introduced into tissues. High KC1 concentration leads to spontaneous contraction (and the previous static bar contraction 2 started). A small increase in tension that overlaps the baseline value. After this increase in contractile activity is stabilized, increasing concentrations of the test compound or vehicle are introduced into the tissue bath. The last minute of the 30-minute challenge versus the last minute of each compound or The concentration of the vehicle was used to measure the contractile activity. The bladder strips exhibited equiangular strength. The concentration required to elicit 50% of the pre-dose contraction activity inhibition (IC so concentration) was determined. The pre-dose contraction activity was calculated from the concentration-response curve. The maximum percentage of contractile activity inhibition stimulated by the test compound was also recorded for test compound concentrations less than or equal to 30 wM. Aortic smooth muscle The aortic smooth muscle relaxing activity of the compounds of the present invention was pseudo-established as representative compounds according to standard medical acceptability test procedures as follows : Sturgeon rats (150-200g) became conscious by CO2 asphyxiation, then beheaded and sacrificed. Thoracic aorta was moved into warm (37 * C) Krebs-. Henseleit solution. Aortic fat and loose extraarterial were removed Membrane and cut into 3-4mm wide rings. Then the rings were suspended in a 10ml tissue bath between two stainless steel wire tissues One pin tissue is mounted on the hook, while the other tissue is mounted on the isometric force converter. The static tension is set at 1.0 g. The tissue is allowed to recover for 60 minutes, and then the experiment is started. The KM KCI challenge elicited contraction. Then the tissue was washed fresh! (rebs-Henseleit solution was washed repeatedly for 30 minutes and allowed to return to baseline tension. Then 25mM KC1 was introduced into the tissue bath to stimulate contraction and allow it to stabilize for not less than 45 minutes -12- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back before filling this page) ---- Order '39136S a? B7 V. Description of the invention (11) The clock is printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, and then the test compound or vehicle is gradually added to the group / Ah weaving bath. 〇 Use a force converter to measure the isometric force generated by the aortic annulus and record it on the oscillograph. 〇 The percentage inhibition of the contractile force induced by each concentration of the test compound is used to draw the subsequent expansion-response curve. The concentration required to induce 50% of the drug's contractile activity inhibitory effect (IC 50 m. Degrees. For test compound concentrations less than or equal to 30 U M is also recorded. The percentage of maximum contractile activity inhibition stimulated by the test compound is also recorded. The results of the analysis are shown in the following table. 10 丄 ea Early-release rat bladder bovine m-pulse group contraction inhibitory compound 1C 50 or (30 / ζ Μ lower body IC S. or (30 U Μ contraction of main cystic % Inhibition)% Inhibition of Arterial Constriction Example 20 .39 ± 0.04 «Μ 0 .15 ± 0.02 U Μ Example 3 4 .1 ± 1.8 .8 t Μ 0. 56 ± 0.04 U Μ Therefore, the compound of the present invention has a significant effect on the contractility of smooth muscle. 9 It can be used for the treatment of hypertension. 9 Urinary incontinence > Irritating bladder and bowel disease. 9 Asthma > Stroke and similar diseases. These diseases are suitable for parenteral or aspiration. The compound is administered to a patient in need by a human route. Pharmaceutical composition When the compound of the present invention is used to treat smooth muscle contraction or related disorders, the compound is formulated into a dosage form 9 such as a tablet 9 capsules and the like. Can be administered alone or in combination with conventional carriers > carriers such as m acid m * magnesium stearate talc 9 sugar > lactose 9 pectin 9 dextrin 9 starch > gelatin 9 west yellow 13- (please (Read the note on the back # ^ and then fill out this page)

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 391963 A7 A 7 B7 V. Description of the invention (12) Capsule, methylcellulose, carboxymethyl cellulose sodium, low melting wax, cocoa Fat, etc. Diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, tablet disintegrating agents and the like can be used. The compound may also be injected intravenously or parenterally, in which case the mash is used in the form of a sterile solvent containing other solutes such as sufficient salt or glucose to adjust the solution to isotonicity. For administration by inhalation or insufflation, the compound can be formulated in an aqueous or partially aqueous solution and then used as an aerosol. The compounds can also be formulated as dry aerosol inhalation formulations. Dosage requirements will vary with the particular composition used, the route of administration, the severity of the symptoms, and the particular individual being treated. Treatment usually begins in small doses, below the optimal dose of the compound. The dose is then increased until the optimum effect of the situation is reached. Generally speaking, the compounds of the present invention are most desirably administered at a concentration that will achieve effective results without causing any harmful or adverse side effects, can be administered as a single dose, or can be divided into convenient small units at appropriate times during the day if appropriate Time to administer. (Please read the notes on the back before filling this page)

、 1T Printed bags for employees' cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -14- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

33196S g D8 #, patent application scope No. 84106298 "(3,4-dioxetane-1-yl > benzopiperan derivatives for smooth muscle relaxants" patent (as amended in January 89) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs: R1 is cyano ;: a @ b _ 共 _ 同 Forming -〇- linkage; R3 and R4 are separately 1-star 5 "alkyl; R5 is amine or monoalkylamine; is ^^ or its old L-acceptable salt. 2. For the compound in the scope of application for item 1, R1 is ammonia-based …-,-A and b together form a 0- linkage .; R3 and trans 4 are methyl groups; R5 is amine or Cy-monoalkylamine; and R6 is fluorene. Compounds of which, trl. This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 33196S g D8 #, application scope of patent No. 84106298 "(3,4-II for smooth muscle relaxants) Oxycyclobutene-1-yl > Benzopiperan Derivatives "(Revised January 89) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs: R1 is cyano ;: a @ b _ 共 _ 同 Forming -〇- linkage; R3 and R4 are separately 1-star 5 "alkyl; R5 is amine or monoalkylamine; is ^^ or its old L-acceptable salt. 2. For the compound in the scope of application for item 1, R1 is ammonia-based …-,-A and b together form a 0- linkage .; R3 and trans 4 are methyl groups; R5 is amine or Cy-monoalkylamine; and R6 is fluorene. Compounds, among them. Trl. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) Printed by the Intellectual Property Bureau Employee Consumer Cooperative of the Ministry of Economic Affairs A8391963? 1 D8 VI. Patent scope R! Is CN; a and b form a -0-bond-linkage: R3 and R4 are methyl groups; R5 is limb or methylamine; and R6 is fluorene. 4. If the compound in the first scope of the patent application, it is selected From: 4- (2-aminodi 3,4 · dioxy · cyclobut-1-enyl) -2,2-dimethyl-2fluorene-benzocol-piperan-6-carbonitrile— , Or 〃 2,2-dimethyl-4- (2-methylamino-3,4- (Oxy, aryl-cyclo, but-1-enyl)-·., · '.. · 2 Η -Benzocardiac leisurely, 6 -methyl-nitrile. 5.-a kind of treatment and cardiovascular, respiratory, Gastrointestinal and urinary smooth muscle contraction-regulation related pharmaceutical composition, suitable for the treatment. The effective amount of the following formula ^ / 之-^ compound: (Please read the precautions on the back before filling this page) 〇 Among them: R1 is' chloro. A and b together form -0-bond 丄 -2 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) A8 68 391963_ g88__ VI. Patent application scope R3 and R4 They are divided into Ci-6 bases; R5 is amine or Cy monoalkylamine; (Please read the notes on the back before filling this page) R6 is Η; or its pharmaceutically acceptable salt. 6. The pharmaceutical composition according to item 5 of the scope of patent application "wherein the compound used is selected from the following compounds, where \ is cyano; a and b together form a -0- linkage; R3 and R4 are methyl; R5 is an amine group or < ^. 6-monoalkylamine; and R6 is fluorene. 7. The pharmaceutical composition according to item 5 of the scope of patent application, wherein the compound used is selected from the following compounds, wherein: Ri is CN; a and co-same as _ 遽 遽 ..-_ 9 · linkage; r3 And r4 is methyl; r5 is amine or methylamino: and R6 is fluorene. 8. If the pharmaceutical composition under the scope of patent application No. 5 is used, the compound printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is used to select a compound selected from the following compounds:-. A 4- (2-amino group- 3,4_dioxy-cyclobut-1-enyl) -2,2-dimethyl-2fluorene-benzene, _-filament .._. _ ^ Or mono 2,2-dimethyl-4- (2-methylamino-3,4-dioxy-cyclobut-1-enyl) -2H-benzo stone-piran-6- Armor. -3- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)