TW442473B - Heterocyclylmethylamino derivatives of cyclobutene-3,4-diones - Google Patents

Abstract

The compounds of formula, wherein: R1 is hydrogen or alkyl of 1 to 6 carbon atoms; R2 is alkyl of 1 to 8 carbon atoms which could be substituted by phenyl; R3 is hydrogen; A is non-substituted pyridyl, or benzofuranyl which could be substituted by R4, R5, R6, wherein R4 is nitro or cyano; R5 is hydrogen; R6 is fluoro, chloro, bromo, or iodo; or a pharmaceutically acceptable salt thereof, relax smooth muscles. The compounds of the formula, wherein R1 and R2 are, independently, hydrogen, straight chain alkyl, branched chain alkyl, cycloalkyl, bicycloalkyl or aralkyl, wherein the aromatic moiety of the aralkyl group may be optionally substituted with one to three straight chain alkyl, halogen, nitro, cyano, alkoxy, alkoxycarbonyl, trifluoromethyl or trifluoromethoxy groups; R3 is hydrogen, formyl, alkanoyl, alkenoyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; A is selected from the group consisting of: formulas, wherein n is 0 or 1; R4, R5 and R6 are, independently, cyano, nitro, amino, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, alkylamino, dialkylamino, sulfamyl, alkylsulfonamido, arylsulfonamido, alkylcarboxamido, arylcarboxamido, alkanoyl, alkylsulfonyl, perfluoroalkylsulfonyl, arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl or hydrogen; or a pharmaceutically acceptable salt thereof, relax smooth muscles.

Description

4424 73 Λ7 A 7 B7 V. Description of the invention (1) Invention of the invention You are obsessed with the new pharmacologically active cyclopentadienyl_3,4_diphosphonium heteromethylaminomethyl derivative, and its preparation method contains The pharmaceutical composition of these compounds and their use for the treatment of smooth muscle contraction-related disorders through potassium channel modulation. These conditions include, but are not limited to: urinary incontinence, asthma, preterm birth • irritable bowel syndrome, congestive heart failure, angina pectoris, cerebrovascular disease and hypertension β

Stenip et al. (EP-426379) showed that a class of amines of phenylphosphonium dihydrofuran substituted cyclic butadiene dione derivatives have blood pressure lowering activity and bronchial relaxation activity. Takeno is equivalent to Japanese Patent Publication No. 6-9291, No. 5 and No. 1 of a series of diaminocyclobutene-3 ^ 4-dione. The efforts of the inventors in this field are shown in the following U.S. patents: 5,464,867; 5,466,712; 5,40 3,8 5 3; 5,40 3,854; 5,397,790, and 5,401,753. Aigieri equals U.S. Patent 4,390,701 reports several columns of l-amino-2-phenylalkylaminocyclobutene ... 3,4-dioxines as H-2 receptor antagonists β Hohara equals U.S. Patent 4,673,747 Wakako related 1-amino-2-phenylaminoalkylamino derivative β In addition, ISohara is equal to EP-177G16, which shows several phases of 1-amino-2-pyridylaminoalkylamino derivative. Compounds from Rohara et al. Are reported as H-2 receptor antagonists. Printed by Shelley Consumer Cooperative of China Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) 4-Bft pyridylmethylamino derivatives of cyclobutadione by Chandrakumar equal to US Patent 5,354 , 746 掲 is shown to have analgesic activity. Chandrakumar's listed compounds require the presence of a perylene ring dibenzoxanthene. The 3-pyridylmethylamino derivative of cyclobutene di_ is shown by Ife 掲 in EP-112704 and reported as a H-2 antagonist p Ife 糸 compound. This paper applies the Chinese National Standard (CNS) A4 specification (210 × 297). (Mm) 4424 73 A7 B7 V. Description of the invention (2) The product needs to have an N'-pyridinyldiamine moiety. Various substituted 1,2-diamino-cyclobutene-3,4-di The synthesis of ketones is described in the following publications: Tietze et al., Chem Ber. 1991, 124, 12 15; Tietze eta 1., Bioconjugate Chen. 1991, 2, 14 8; Ehrhardt eta 1., C he b. Be r. 1 97 7, 1 1 0, 2 506, and Ueuse et al., Liebigs Ann. C he b. 1973, 6190 Description of the invention According to the present invention, a group of compounds represented by formula (I) are provided: 〇Vf 〇

Aa / ^ VRi

I I R3 R2 (I) where:

El and R2 are respectively S, Cl-ίο straight chain radical, C3-10 branched radical, C3-8 cycloalkyl, C4-1D bicycloalkyl or C7e2o aralkyl. Wherein the aralkyl moiety The aryl moiety can optionally be from 1 to 3 straight-chain alkyl groups, (: dibrenyl, alkyl, nitro, cyano, Ci-6 alkanoyl, (: 2-? Alkoxy Carbonyl, trifluoromethyl or trifluoromethyl substituted; printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) R 3 is 筮, and the formyl group is t C 2-7 Alkyl, C 3-7 alkenyl, ci-7 alkylsulfonyl, C7-! 2 arylfluorenyl, C9_20 arylalkenyl, Cm arylsulfonyl, C8_! 2 arylalkane Aldehyde, or C 7-12 arylalkylsulfonyl. A 傜 is selected from: This paper size applies Chinese National Standards (CNS) A * See Xi (21 ο X 297 public *) 442473 A7 B7 '(〇) n

Ν 人 Ν Rs

V. Description of the invention (3 R ^ N. R5

Wherein: η is G or 1; E4, and Ue are cyano, nitro, amine, Ci-6 alkyl, Cx'e perfluoroalkyl, C6 alkyl fluoro, Cpe fluorofluorocarbon Group, C 6 alkylamino group, Cm dialkylamino group, sulfamic acid group, C ^ e alkylsulfonamido group, C6-12 arylsulfonamide group, C2-7 alkylcarboxyamido group, C 7-13 aryl carboxamido, C 2-beta alkyl aldehyde, C-e alkyl sulfonyl, Ci-8 gold fluoroalkyl sulfonyl, Ce-i 2 aryl sulfonyl, chlorine, Bromine, fluorine, iodine, 1-oxazolyl, carboxyl, or hydrogen; or its acceptable salt for drug delivery β Please read the notes on the reverse side on this page. Ruyi

Set 2 R and 1 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 442473 A7 B7 V. Description of the invention (4) Among them, R4 & s & Re is defined as before: or its pill acceptability "Salt" (I understand the definition of the compound of formula U), when Ei, R2, R3, 1U, r5 or 86 contains an asymmetric palm center, the gold of unity-part-muj covers racemic modifiers with indicated activity And any optical isomers β Optical isomers can be obtained in pure form by quasi-separation techniques or enantiomeric. Structure-specific synthesis. It is to be understood that the present invention encompasses all compounds of formula u > In the description, the compounds of the present invention are equally named 3,4-dione or 1,2-dione. The salinity-acceptable salts of the base compound of the present invention are derived from the following organic and inorganic acids: lactic acid, citrate, acetic acid, tartaric acid, succinic acid, succinic acid, malonic acid, hydrogen acid, argon Bromic acid, phosphoric acid, nitric acid, acetic acid, methyl beetle acid and similar known acceptable salts β When 114, or £ 6 contains a carboxyl group, the salt of the compound of the present invention can be a base, such as 鹾 金 展 ( Na, K, Li) or alkaline earth metals (Ca or Mg). The present invention also provides a method for preparing a compound of formula (I). By farewell, a compound of formula (U can be passed through a compound of formula (II)

Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives (please read the note on the back and fill in this book ") where X is the appropriate leaving group, such as methyl gas group, ethyl gas group, isopropyl gas group, butane gas Group, halogen atom or similar leaving group reacts with the compound of formula (III): This paper size applies Chinese National Standard (CNS) A4 specification (21 × 297 mm) 4 42473 A7 B7 V. Description of the invention (5) \

HN (ΙΠ) (Please read the notes on the back before filling out this page) 〇a2 Rai & Ra2 is 1 and 112 (as defined above) or can be converted into a group of atoms. The intermediate can then be reacted with a compound of formula (IV): A 1 ——NH 2 (IV) where 1 is A (as defined above) or can be converted into a group of atoms of this group. The aforementioned reaction can be carried out in a solvent such as acetonitrile, methanol, ethanol-tetrahydrofuran or dioxane at elevated or ambient temperature. In addition, the reaction sequence can be reversed, that is, the compound of formula (II) can be initially reacted with a compound of formula (IV), and then the intermediate is reacted with a compound of formula (III) to obtain a compound of formula (I) β as described above. Formula (I) The compounds and their pharmaceutically acceptable salts are smooth muscle relaxants that function through activation of potassium channels. Β is therefore useful in the treatment of disorders related to smooth muscle contraction, urinary smooth muscle contraction-related disorders (such as urinary incontinence), or the gastrointestinal tract (such as irritability Intestinal syndrome '), asthma and hair loss. In addition, when the compound of formula (I) is used as a potassium channel active agent, it can be used to treat peripheral vascular disease, hypertension, congestive heart failure, stroke, anxiety, brain deficiency and other neurodegeneration. Illness * Printed by the Ministry of Economic Affairs and the Central Bureau of Standards, Shellfish Consumer Cooperatives. The present invention provides a pharmaceutical composition comprising a compound of the present invention combined or combined with a drug-acceptable carrier β to be treated separately. The present invention provides a pharmaceutical composition It includes an effective amount of the compound of the present invention and a peony acceptable carrier β composition, which is more suitable for oral administration than it is, but can be designed to be suitable for other administrations. Mode, for example, parenteral administration for patients with heart failure. This paper size 4 is called KH Family Dart Rate (CNS) A4 size (210X297 mm) 442473 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Note (6) To obtain consistency of administration, it is preferred that the composition of the present invention is in a unit dosage form. "Appropriate unit dosage forms include lozenges, capsules, and powders in drug packs or vials. These unit dosage forms contain 0.1 to 1 Dflag of a compound of the present invention. And preferably 2 to 50 mge and more preferably a unit dosage form containing 5 to 25 bg of the compound of the present invention. The compound of the present invention can be administered orally in a dose range of about 0.01 to 100 eg / kg, or preferably 0.1 to 10 ng / kg. Composition It can be administered 1 to 6 times a day, and more commonly 1 to 4 times. The composition of the present invention can be used in formulas such as tincture, disintegration, adhesive, lubricating tincture, flavoring agents, and the like. In a known manner, for example, it can be formulated in a manner similar to known antihypertensive K agents, diuretics, and / 8-blocking agents. The present invention also provides the compounds of the present invention for use as living therapeutic substances. Can be used to induce smoothing Relaxation. The present invention also provides a method for treating smooth muscle disorders in mammals, including humans, which comprises administering an effective amount of a compound or a pharmaceutical composition of the present invention to a diseased lactating milk. The following examples are representative of the compounds of the present invention. Rather than restricting it. g example 1

3- (1.1-Dimethyl-propane-dithiophene-4- "A citronamine" Cyclobutan-3- • an-1 »2-DiBEI 3,4-dibutoxycyclobut-3-ene-1 A solution of 2,2-bis (4.526, 20) 〇1) and 1,2-dimethylpropylamine (1.743g, 20ianol) in tetrahydrofuran (20 * 1} was stirred at room temperature for 19.5 hours. The solvent and residue were removed Material is neutral This paper size is applicable to China National Standard (CNS) Λ4 specification (210X297 mm) -----: ----- ^ Loading ------ Order ----- Ί &gt;; .. · (Please read the precautions on the back before filling out this page} Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs ^ 424 73 A7 B7____ V. Description of the Invention (7), Active III Silica (i50g) Chromatography (gradient, helium-hexane). The white solid separated from the appropriate solvent was recrystallized from hexane to obtain 4.105 g (86%) of a white product: 81? 5 6. 5-5 7 .5 ° 0 (Softening point 55.5) <4> Substance was recrystallized from hexane to obtain 0.734 g of 3-butoxy-4- (1,1-dimethylpropylamino) -cyclobut-3-ene-1, 2-dione is a white solid: up 56-7 5-0 (softening point 55 ° C); 1 H NHR (DHS0-d6): (J8.63 and 8.48 (two

Mbr s 1H, geometric isomers 4.67 (*, br, 2H,), 1.67 (81, br, 4H), 1.39 (1, 2H), 1.26 (m, br, 6H), 0.91 (t, 3H), 0.7 8 (t, 3H). IR (KBr): 3170, 1790, UOOcb'1; US (i / z) 2 3 9 (H +). 3-butyl gas- 4- (1,1-dimethyl) as above Propylamino) butan-3 ** ene-1,2-di- (1.19? G, 5.0aaol) and 4-aminomethyl methylamine (0.541g &gt; in tetrahydrofuran (lOdU solution at room temperature for 23 hours) The β mixture was removed from the solvent and the residue was triturated with diethyl ether and dehydrated to obtain 1.154 g of a light yellow solid β. The crude β product was recrystallized from methanol (secondary) to obtain 0.832 g (61%) of 3- (1,1-dimethylpropylamino). "-[(4-Pyridin-4-ylmethyl,) amino] cyclobut-3-ene-1,2-dione is a white compound: · P 258.0-2 5 9. 5 * 0 dec (softening point 257.5DC); 1 H NHR (DHS0-d6): at 8.56 (b, 2H), 7.86 (m, b γ, 1 Η), 7. 4 6 (s, b γ, 1 Η), 7 . 3 2 (ancestor, 2 H), 4 7 7 (d, 2H), 1.67 (q, 2H), 1. 32 (s, 6H), 0 * 83 (t, 3H). IR (KBr): 3270 , 1730,1650c »-1; MS (tt / z) 273 (H +). Elemental analysis: CisHeiU 〇2 Calculated value: C, 6 5. 91; H 7. 0 1; U, 15. 3 7 : C, 65. 55; H 6.88; Ν · 15.12 This paper size applies to Chinese national standards (CNS} A4 rolling chip (21 〇a 297) *) ---------- VJ ^ .-- (Please read the back first Note $ items fill in this page) 'Order 4 Printed by A7 B7, Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs 5. Description of invention (8) Window example 2 3-Π.1-Second application of a certain propylamino group) -4- Γ 砼 -3-a crucium) -amino hydrazone butan-3-ene-1. 2-dione tetrahydrofuran (IOeL), 3-butane-4- (1,1-dimethylpropylamino) ring Butane-3 -ene-1 t 2 -dione (1.197 g, 5. ga L, prepared as in Example 1) and 3-aminomethylpyridine (0.541g) at room temperature and mixed with 24 The β-reaction substance was stripped of the solvent and residue for 3 hours, and triturated with diethyl ether and dehydrated to obtain 1.28 g of a cream-colored solid. This material was recrystallized from methanol twice to obtain 0.887 g (65%) of 3- (l, l-dimethylpropylamino) -4-[(fluoren-3-ylmethyl) -amino] -cyclobutane- 3-ene-l, 2-di_ is white solid cross: slp263.5-264.5βC (softened viscosity 260.0 ° C); 'Η NMR (DMSO-di): 5 8.57 (m, 1H), 8.52 (m, 1H), 7.80 (m, br, 1H), 7.76 (m, 1H), 7.41 (m, 1H), 7.39 (s, br, 1H), 4.72 (d, 2H), 1.66 (q, 2H), 1.30 (s, 6h), 0.82 (t, 3H). IR (KBr): 3230,1790,1650 cm * 1; MS (m / z): 274 (M + H) +. Elemental analysis: C Η14 K 3 0 2 Calculated: C, 65 · 91; H 7.01; N, 15.37 Found: C, 6 6. 2 3; B 6. 08; N, 15 '38 "Hif. Pyridin-2-even a certain stilbene-fluorenyl group] Cyclobutadiene-3-Insertion-2-Second Age 3-Butyl-4- (1,1-dimethylpropylamino) cyclobutane-3 -Ene-1,2-dione (0.622g, 2.6mmol, prepared as in Example 1) and 2-aminomethylpyridine (0.281g, 2.6πβο1) in a solution of tetrahydrofuran (5bL) and stirred at room temperature for 22 hours The solvent was removed, and the residue was triturated with diethyl ether and dehydrated to obtain 0.665 g of a white solid. The crude product was recrystallized from acetonitrile (secondary) to obtain 0.447 g (63%) -1 0-

This paper size applies to Chinese National Standard (CNS) A4 specifications &lt; 21 (, Gong J (please read the notes on the back before filling this page) 1 copy. 4-424 ^ 3. B9H4 A7 B7-V. Invention (9) 3- (1, Budimethylpropylamino) -4-[(pyridin-3-ylmethyl) -amino] Cyclobut-3-ene-1,2-dione is a white solid: BP 192.0-192.5 ° C (softening point 188.5 ° C); 1 H NHR (DMS0-de): &lt; y8.58 (B, lH), S.00 (n, br, lH), 7.S2 (i , lH), 7.58 (s, br, lH), 7.37 (B, lH), 7.33 (B, lH), 485 (d, 2H), 1.67 (q, 2H), 1.31 (s, 6H), 0.83 ( t, 3H). IR (KBr): 3210,1790,1660cm-1; HS (m / z): 2 7 3 (H +) 〇! _ 1 Pack-(Please read the precautions on the back before filling this page ) Two examples-real T-like amines u = s body fixation white is a wide group of dikisamine but tris 0 diamidine TJ chiamin-very string very-4-pyridine Π Β propylene 9. J-6 system 3 2-点 物] FS starting j: Qi Dang Li Li, 3 Cheng | Shuping Sopyid

4T butyl ring i-V-based amine- \ y-based methyl fluorene hydrazine I \ |

P Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Work Cooperative, Example-Application of Real T-Like Amines, Procedure 7

I

° G TIP 3 | 5 Alkene 0. Production 3-29, τ-_ # 环 殳 物 ΪΪ J (£) When -B points are very stringed to a ring 1J Very prime analysis: C 15 B is N a 0 2 Calculate Value: C, 65.91; Η 7.01; Ν, 1 5. 3 7 Measured value: C, 65.78; Η 6.94; Ν, 1 5. 4 8 This paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) ) 4 42473 Α7 Β7

5. Description of the invention (1Q

SB followed a procedure similar to that described in Example 1 using the appropriate starting materials to prepare 3-tert-butanyl-4-[(snarling-3_ylmethylbamido] cyclobutan-3_synthesis_1, 2- The diketone is a white solid: nP 23S.〇- 2 3 6.5 ° C (decomposition) (softening point 2 3 3.5. &Quot; C) 〇 tube 7 propyl-formamidine 4 ^^ (review -4 Dimethylmethylimino 1 ring was prepared in a similar manner to that described in Example 1 using the appropriate "starting material * Preparation 3" * (isopropyl_methylamino) -4-[(pyridin-3-ylmethyl) -Amine] Phenyl-3-ene-1,2-dione as a white solid: BP 214.5-2l5.0 ° C (decomposition) (softening point 211.5 ° C). Fu Li 8 "(5-nitrate And even 眹 _ ~ buylmethyl) Long ~ ji · k (1_, 2,2 -Sanda jibingchi 1 ring-Ding. ： .3 ·: rarely called · 2 嗣-in NaH (3, 4lg, 80%, 113.6ββιο1) printed on dimethylformamidine (400 orders from the Ministry of Economic Affairs, quasi-shellfish consumer cooperatives (please read the precautions on the back before filling out this page) The suspension of eU is in 0〇c was added propane (? * 61g, 104.1ηβο1) β After mixing at 0 ° C for 1 hour, 4-nitronitrobenzene (10.00nL, 94.6mmol,) and all The resulting mixture was stirred for 1 hour. Add saline &lt; 40 0 * L and the resulting precipitate was collected over the knee. The product was washed with water and vacuum dehydrated to obtain 18 g (100%) of a white solid: 1 H UHR (DMS0-de): tf8 .20 (d, 2H), 7.25 (d, 21, 2.06 (s, 31, 2.11 (s, 3H)) as described above, oxime adduct U0.39g, 53.56aiaol) in saturated acetamidine HC1 (200bL ·) After adding for 3 hours under reflux, the reaction mixture is cooled and concentrated -1 2 * This paper is a Chinese standard (CNS) A4 specification (210X297 mm) ¢ 424 73 A7 B7 V. Description of the invention (11) 1/4 body amidine. Add water and filter to collect the amidine product of precipitation to obtain 9.0 g (95%) of 2-methyl-5-nitrobenzofuran: 11! »1 ^ (01 ^ 0- £ 18 ): S 8.39 (d, lH), 8.l5 (dd, lH), 7.45 (d, lH), 6.49 (s, lH), 2.48 (s, 3H). In the former benzofuran (5-00g, 28.25 aB0l) and over-gassed benzamidine (&lt; 0.68 g, 2.83 nntol) were added to a solution of nitrate tetranitrate (200 mL) in 1,3-dibromo-5,5-dimethylethyl Endone urea (4.04%, 14.1281 ^ 〇1). The mixture was irradiated with a 2G0 watt lamp while searching for 1 hour, cooled and partitioned into dichloromethane / water. The organic phase was washed with water (2X ΙΟΟηΟ and brine (2X 100bL), and dehydrated (MgS (U &gt;, decolorization (charcoal)). And vacuum shrinking to obtain 7.12 g of crude product β recrystallized from ethyl acetate / hexane to obtain 4_38 g (61%) of 2-bromomethyl-5-nitrobenzofuran as an off-white solid: 1 H NMUCDCl3 &gt;: δ 8.49 (d, 18), 8.25 (dd, lH), 7.58 (d, lH), 6.91 (s, lfi), 4.59 (s, 2H). 2-Bromomethyl-5-nitrobenzofuran U. 57g, 6.13BIBOU, potassium phthalimide diimide (1.70g, 9,19raiaol), and 1 $-crown-6 (0.161g · Ministry of Economic Affairs _ Central Standards Bureau employee consumer cooperative printed (Please read the note on the back first Please refill this page) 0. 61βιιοΙ &gt; The mixture was stirred overnight at room temperature in acetonitrile (15bL). The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and caladium. The organic phase was 0.1NM sodium oxide (2X 50mL) Then washed with brine (2X 5GbL), dehydrated (HgS04) and concentrated to obtain an off-white solid. The crude product was triturated with cold ethyl acetate / ether / hexane to obtain 1.47 g (74%) of the phthalodiimide adduct as a white solid. :1 Η NO (DHS 0-ds): β (d, 1 Η), 8 · 17 (dd, lH), 7.88 (a, 4H), 7.75 (d, lil), 5.00 (s, 2H). Dialdehyde imine adduct (1.45g, 4.49amol) to hydrate-13-This paper size applies Chinese national standards (CNS &gt; A4 specifications (210X297 public epidemic) A7 B7 Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumption Printed by the cooperative 442473 V. Description of the invention (12) (◦ • 38nL) treated with refluxing ethanol (15raL) for 1.5 hours. The reaction was cooled to fl ° c and acidified (concentrated hydrochloric acid) to P &gt; ί = 1 »The mixture was filtered and solid Wash with 6N Hcl and water. The filtrate was basified with potassium carbonate and then extracted with ethyl acetate. The organic phase was dehydrated (magnesium sulfate) and concentrated to obtain 0.74 g (86%) of 2-aminomethyl-5-nitrobenzo. Furan was a pale yellow solid: 1 H NMR (DHS 0-d6 &lt; ^ 8.55 (d, 1H), 8.11 (dd, 1H), 7.72 (d, 1H), 6.85 (s, 1H), 3.85 (s, 2H ), 2.00 (brs, 2H) o 2-aminomethyl-5-nitrobenzopyran (0.74g, 3.85m no 1) in tetrahydrofuran (15kL) at 0 ° C, add 3 via syringe and add 3 , 4-Dibutane-3-cyclobutene-1,2-dione (l_25raL, 5.78κπol) β mixture was stirred at room temperature 5 hours and then concentrated in vacuo. The residue was crystallized from ethyl acetate / diethyl ether / hexanes to obtain 0.83 g of the adduct as an off-white solid β. The second harvest (0.17 g) was separated from the mother liquor. Total yield: 75%. 1 H NHR (DHSO-dU): 9.40 and 9.20 (2 1)]: 111,111 geometric isomers), 8.60 ((1, 111), 8. 2 0 (dd, 1 Η), 7.80 (d, 1 Η), 7 · 0 4 (s, 1 Η), 4. 8 8 and 4 · 6 7 (2 br η, 2Η, geometric isomers &gt;, 4.60 (t, 2H) l, 1 · 67 ( β, 2B), 1. 30 (β, 2Η), 0.85 (·, 3Η) β 3-butoxy-4- [5-nitrobenzofuran-2-ylmethyl) amino] cyclobutan-3 -Ene-1,2-dione (0.250g, 0.727ηηο1) dissolved in R (+)-2-amino-3,3-dimethylbutane (0.167 (1,6.0 »1,1.0〇1 〇! 11〇1} ethanol strip solution. The mixture was diluted with ethanol (1 m L) and tetramethylfuran (1 b L). After 3 hours, 6.0 nL ethanol ammonium amine (1,000 bar) and the mixture were added to Stir for 48 hours at room temperature. The β heterogeneous mixture was diluted with 1: 1 ether / ethyl acetate and filtered to obtain 0.20 g (74%) of 3-[(5-nitrobenzofuran-2- _ 14-. This paper applies to the standard China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

"2473 A7 B7 printed by the Shelley Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (13) methylmethyl) amino] -4- (1.2,2-trimethylpropylamino &gt; cyclobutan-3-ene (R) isomer of -1, 2-difluorene: up &gt;3〇βΌ; 1 H HMR (DMSO-d8 &gt;: tf8.61 (d, lH), 8.21 (dd, lH), 7.88 ( d and i, 2H), 7.35 (br d, lH), 7.06 (s, 1H), 4 98 (#, 2H), 3.92 (b, 1H), 1.10 (d, 3H), 0.86 (s, 9H). IR (KBr): 3 1 8 0, 2 950,1880, 1 850, 1550CH'1; MS (n / z): 371 (M +) * Elemental analysis: c 18 Η Ν 3 〇 Calculated value: C, 6 1.. 4 5; Η 5. 70; N, 11.3. Found: C, 6Θ. 52; Η 5.50; N, 11.2. Example 9 f 1 .1-Dimethyl 1 propylamine Base) -4-Γ (· &gt;-华华荣 和 眛 target -5-even W leather 1 capsule even '(瑗 -3_ene-1 * 2-dim in 3-butoxy-4-[( 5-nitrobenzofuran-2-ylmethyl &gt; amino] cyclobut-3-ene-1, 2-dione (0.25 g, 0.7 2 7 κ mo 1) (as an example 8 Preparation) Add ethanol to 5bU of human tertiary ammonium (0.53 n L f 4. 5 4 η 〇1 h reaction at 70 ° C Stir for 18 hours and then stir at room temperature for 48 hours. The gingival sediment product is washed with m and washed with ethyl acetate, diethyl ether and petroleum m to obtain 0.22 g (85% 3- (1, dimethyldimethylamino)- 4-[(5-Nitrobenzofuran-2-ylmethyl) amino] cyclobutan-3-ene-1,2-dione as an off-white solid: BP 283.5-287.5 ° C (decomposition); 1 fl NHR (DMS0-d6 &gt;: 5 8.61 (d, lH), 8.18 (dd, lH), 7.96 (br t, lH), 7.81 (d, lH), 7.46 (br s, 1H), 7. 07 ( s, 1H), 4.99 (d, 2H), 1.66 (q, 2H), 1.30 (s, 6H), 0.82 (t, 3H). IR (KBr): 3 2 2 0, 2 95 0, 1 8 0 0 ca -1; MS (π / z): 3 5 7 (H +). -1 5- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back first—fill out this page) Order

442473 A7 B7 V. Explanation of the invention (14) Elemental analysis: c ^ sHuiuOs 讦 Calculated value: C, 60.50; Η 5.36; N, 11.76 Found: C, 5 9. 3 1; Η 5 _ 1 5; Ν, 11 5 3

3 ~~ 锒 = 丁 盼 可 -4- r (5-liS 很笨 # [(5-nitrobenzofuran-2-ylmethyl) amino] cyclobutene-1,2-dione (0.25g, 0.727ββο1) (prepared as in Example 8.) in ethyl acetate (5bL) Add tertiary amylamine (0.5lnL, 4_85 «DioI) inside. React with? 0 *? Stir for 18 hours and then stir at room temperature for 48 hours." Post-wound treatment in the same manner as in Example 9 to obtain 0.20 g (80%). ) 3-Third-butylamino-4-[(5-nitrobenzofuran-2-ylmethyl> amino] cyclobut-3-ene-1,2-dione is an off-white solid: mp &gt; 30O ° C; 1 H NKR (DMSO-de &gt;: S 8.61 (d, 1H), 8.20 (dd, 1H), 7. 91 (br t, 1H), 7.81 (d, 1H) .7.59 (brs, lfi), 7.07 (s, lH), 4.98 (d, 2H), 1.36 (q, 9H). IR (KBr): 3220,2930, 1800,1675cm &quot;1; MS (b / e): 344.3 [H + H] + e (please read the note on the back before filling this page) Printed element analysis of the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs C 17 Η 17 Ν a 〇5 Calculated value c, 5 9. 47; u 4.99; M, 12.24 Real m value C, 58.86; Η 4.78; Ν, 11.88 Example 11 Ϋ, &quot; f Γ ί 1, 1-Dishenyl propyl m hua) Ί 4-two collars-瑁 T -1- eneval leather 1 formamidine 1-benzofuran-5-W acetone oxime (6 .34 g, 86 * 6 4 n nt 〇1 &gt; added to Q #C to 氲 m (80% in -16- this paper size applies Chinese National Standard (CNS) Λ4 present grid (2 丨 0, public " ) 442473 89. δ. Ϊ A7 B7 V. Description of the invention (15) Rock oil dispersion; 2.72g, 90.82 · μο1;) in Ν, Ν-dimethylmethoxamine (400 mU suspension. Bubbles When the mixture is warmed to 25 * C, it will be stirred for 1 hour. P-Fluorobenzonitrile (10.000 g, 82.51nnol) is added and the reaction mixture is stirred at 0 ° C for 15 minutes and then allowed to warm The temperature was allowed to reach room temperature. After stirring overnight, the reaction mixture was poured into brine (300 mL). The resulting white precipitate (4-isopropylideneaminooxybenzidine) was collected by data collection, washed with water and dehydrated under vacuum. Yield: 13.97 g (98%): 1 H NMR (DHSO-de): &lt; y7.78 (d, 2H), 7.76id, 2fi), 2.04 (s, 3H), 2.00 (s, 3H). The previous product (4-isopropylideneaminooxybenzonitrile) (i3.97 g, 80.2 &amp; mo. Jun (400 bL). The mixture was heated at reflux for 4 hours. The reaction mixture was cooled and concentrated to 1/3 The volume β reaction mixture was diluted with water, and a precipitate was formed after engraving. The precipitate was collected after washing, washed with water, and dehydrated in vacuo. The noodle 2-methyl-benzofuran-5-carbonitrile was purified by HPLC (0, 2, 1 Ethane / ethyl acetate). Yield: 7.26 g &lt; 58%): 1 HN «R (CDCla): ty7.79 (d, lH), 7.47 (dd, lH), 7.43 (d, 1 Η), 6 4 4 (s, 1 Η), 2. 4 7 (s, 3 Η). Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 2-methyl-benzofuran-5-formaldehyde (3.00g, 19.08mmol) in carbon tetrachloride ( (80mL) was added to the solution of over-gasified benzaldehyde &lt; 0.46g, 1.9lBB0l) and 1,3-bromo-5,5-dimethylhydantoin (2.73 茗, 9.54) 〇1) » The reaction mixture was irradiated with a 200 watt lamp for 1 hour. The reaction mixture was cooled and partitioned between ethyl acetate and organic acid. The organic layer was dehydrated with magnesium sulfate, and Enolaide®

(Norite) (activated carbon), filtered and concentrated to a solid. The crude 2-bromomethyl-benzofuran-5-carbonitrile was recrystallized from ethyl acetate / hexane. Yield: 2.40 g (59%): 1 H NHR (DHSO-de): 8.49 (d, lH), 8.25 (dd, lH), 7-58 (d, lH), fi.91 (s, lH) 4.59 (s, 2H). -1 7- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1424 73 m 3, i 4 V. Description of the invention (16) 2-Bromomethyl-benzofuran-5-A Nitrile (2,638, 10.27 Yuan 〇1) was added to the solution of acetamidine (30 ') anti-ferment imine (2.85g, 15.41bbo1) and 18-crown-6 (0.27 g, 1.03b mol) . After searching overnight, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and brine, and a precipitate formed immediately. The precipitate was collected by filtration, washed with acetic acid and dehydrated. The organic phase was washed with 0.1 N sodium hydride (2 X 5 G n L) and then brine (2 X 50 β L). The solution was concentrated in vacuo to obtain another batch of solid (2- (1,3-dioxy-1,3-dihydro-isoindol-2-ylmethyl) -benzofuran-5-carbonitrile). Yield 2.50 g &lt; 76%): 4 NMR (DMS0-d6): i 8.18 (d, 1H), 7,91 (ra, 4H), 7.77 (dd, 1H), 7.74 (d, 1H), 7.07 ( d, 1H), 5.00 (s, 2H &gt;. 2- (1,3-dioxy-1,3 · dihydro-isoindole-2-ylmethyl) -benzofuran-5-carbonitrile ( 2.50g, 7.74_t) Add hydrazone hydrate (0.66niL) to a solution of ethanol (20raL). »The mixture is heated at reflux for 1.5 hours. The reaction mixture is cooled to 0 ° C and acidified with concentrated hydrochloric acid to pH 1β. 6N retention acid was then washed with water. The filtrate was tritiated with potassium sulphate and extracted with ethyl acetate. Organic similar magnesium sulfate was dehydrated, treated with Nolte @ and concentrated to obtain an off-white solid (2-aminomethyl-benzofuran) -5-carbonitrile). Yield: 0.85 g (62%): 1 H NHR (DHS0-de): &lt; y8.17 (d, lH), 7,78 (dd, lH), 7.74 &lt; d, lH), 6.82 (s, 1H), 3.85 (s, 2Fi), 2.10 (brs, 2H). Printed 2-Aminomethyl-benzofuran-5-carbonitrile (0.84g, 4.40roraol) in a solution of tetrahydrofuran (15raL) in the solution of tetrahydrofuran (15raL) by adding 3 at 0 °. , 4-Diethyl gas-3-cyclobutene-1,2-dione (1.13 mega, 6.60 ιηβι〇Π. The reaction mixture was warmed to room temperature and stirred for 4 hours. The β reaction mixture was concentrated in vacuo and the crude product was acetic acid Ethyl ether / diethyl ether / hexane »# off-white solid. The solid obtained 2-[(2-ethylchloro-3,4-dioxy-cyclobut smallenylamino) -methyl] -benzopyran -5-carbonitrile. Yield: 1.05 g (76%): 4 NMR (DMSO-di): 5 9, 41 and 9. 2 1 (bt * κ, 1 H, geometric isomer), β _ 2 2 (d, 1 Η), 7. 8 1 (dd, UI) -1 8-Paper size tn * Household rate &lt; CNS) A4 size (210X297 mm) 442473 sa 3. ί t A7 B7 5 Explanation of the invention (17), 7.00 (8,11, 4.88 and 4.68 (2 1 ^ 11,211, geometric isomers), 4.65 (t, 2H), 1.39 (fit, 3H) β

2-[(2-Ethyl-3,4-dicyclobut-1-anylamino) -methyl] -benzo-pyran-5-carboxamidine (0_25 g, 0.79 round 〇1) in ethanol (17raL) was added to the solution of tertiary amylamine (0.21g, 2.37_1). The reaction mixture was heated at 70 ° C and allowed to stir overnight. "The solid was formed by filtration and washed with ethyl acetate, ether and hexane to obtain 0.18 g (67%) 2- {[2- (1,1-dimethylpropylamine Group) -3,4-diamino-cyclobut-1-enylamino] methylbenzofuran-5-carbonitrile is an off-white solid: ap 171 · 1-173 · 2ΐ5; 1 H HMR (DHSO- d 6): δ 8.19 (d, lH), 7.96 (t, lH), 7.81 (d, lH), 7.74 (dd, lH), 7.45 (s, lH), 6.96 (s, lH), 4.97 (d , 2H), 1.67 (q, 2H), 1.29 (s, 6e), 0.83 (t, 3H) .IR (RBr): 3230, 2950,2220,1800cm-1; MS (in / z): 3 3 7 (M +) e Elemental Analysis: CisHigNs 03 Calculated Values: C, 67.64; H 5.68; N, 12.46 Found: C, 66 · 87; H 5.32; N, 12.37 WM 12, 2-Γ 3.4-2 Argon-2- (1.2 .2- = Zhoushi-Rui Zhehuan-1--1-A certain amine even 1 A) -Rong-Tianbiao Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau ----- -: ------- {Please read the notes on the back before filling out this page.) 2-[(2-ethoxy-3,4-bicyclobutane-l-anthyl) in Example 11 « ) Methyl] -benzofuran-5-carbonitrile (0.250g, 79rarao 1) in a solution of ethanol &lt; 2raL) was added ethanol based fluorene-2 -amino-3,3- Methylbut Institute (0 · 1 6 6 N to E t 0 Η, 9. 5 0 a L, 1 · 5 8 a a ο 1). The mixture was heated at 0 ° C and allowed to stir overnight. The resulting solid was washed with ethyl acetate, ether and hexane. The solid was dehydrated under vacuum to give 0.22 g (79%) of 2-{[3, 4-dioxo- 2- (1, 2, 2-trimethylpropylamino) -cyclobutane- I- -1 9-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 142473 14 A7 B7 Printed by the Consumers' Cooperatives of the Bureau of Standards and Loss of the Ministry of Economic Affairs 5. Description of the invention (18) Alkenylamino] methyl)- The (1R) isomer of benzofuran-5-carbonitrile is an off-white solid: BP &gt; 300: 1 H NMR (DHSO-d6): 戌 8.18 (d, 1H), 7.80 (dd, 1 Η), 7.74 (dd, 1H), 7.31 (br d.lH), 6.9 5 (s, 1 H), 4 3 6 (n, 2 H), 3 9 1 (brb, 1 H), 1. 1 1 ( d, 3 H), 0.81 (s, 9H). IRUBr): 3 1 7 0, 2 9 5 0, 2 2 5 0, 1 8 5 0, 1 6 5 0, 1 5 6 0 cm * 1; HS (n / z): 351 (H +) 〇 Elemental analysis: C20H21U3 〇3 Calculated value: c, 68 · 36: Η 6 · 02; N, 1 1. .96 Found: C, 68.00; Η 5. 83; N , 12.00 Tube Example 13_ C flute = Butanidine-3.4-Diarginyl-Cyclobutenylamine) Tian Tianyan-茏 # 味 楠 -IS-Shinonitrile in Example 11 2-[(2-ethoxy -3,4-dioxy-cyclobutenylamino) -methyl] -benzofuran-5-carbonitrile (0.250 g, 79! Moi) in Solution of ethanol (17raL) tributylamine (0.17g, 2.37raraol) »Reaction Mix_ Heat in 7D * C and let it mix overnight. The resulting solid was filtered and washed with ethyl acetate, ether and hexane. The solid was dehydrated in vacuo to obtain 0.12S (51%) 2-[(2-third butylamino-3,4-dioxy-cyclobutane- 1-alkenylamino) methyl] -benzofuran-5-carbonitrile is pale peach-colored solid: «« P 298-8-30 (K3 &quot;C; 1 H NHR (DHS0-de): δ 8.18 ( d, lH), 7.96 (t, lH), 7.81 (dd, lH), 7.? 4 (dd, lH), 7,57 (s, lH), 6.95 (s, lH), 4.96 (d, 2H ), 1.35 (s, 9H) .IR (iCBr): 3300, 2 9 50, 2210, 1800, 1660, 1525cm-1; HS («/ z): 3 2 3 (M +) ○ Elemental analysis: C1BH17N3 〇3 Calculated value: C · 6 6. 8 6; Η 5 · 3 0; N, I 3 · 0 〇 Measured value: C, 65 · β4; H 4.93; Ν, 12.δ7 * 20- This paper size applies to China Standard (CNS., 2! 〇x2M mm) (Please read the precautions on the back before writing this page)

"2473 89.9.1 毳 a7 _ B7 f printed by the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China F. 5. Description of the invention (19) Example 1 4 2- ί Γ 2- (1.1- 二甲 1.1-2- 架 甚- 7, an amine &gt; Ί4 · -digas butylenyl amine: I 1-Rong Pingtian is blind to Example 11 2-[(2-ethoxy-3,4-dioxy · Cyclobutan-1- (succinyl) -methyl] -benzofuran-5-carbonitrile (0.23g, 0.73roraol) in a solution of ethanol (20raL) was added with λα, α-dimethylthupylamine (〇 .33g, 2.19nraol) »The reaction mixture was heated at 70 ° C and allowed to stir overnight. The resulting solid was filtered and washed with ethyl acetate, ether and hexane. The β solid was dehydrated in vacuo to obtain 0.1 Ig (41%) 2- ( [2- (1,1-dimethyl-2-phenyl-ethylamino) -3,4-diaminocyclobut-1-diylamino] methyl) -benzopyran-5- AW is an off-white solid: mp 233.4-235.2'C; NMR (DMSO-d6): δ 8.20 (d, 1H), 7.89 (t, 1H), 7.81 (dd, 1H), 7.74 (dd, 1H), 7.36 (s, 1H), 7.23 (m, 3H) f 7.06 (d, 2H), 6.94 (s, 1H), 4.97 (d, 2H), 2.98 (s, 2H), 1.31 (s, 6H). IR ( KBr): 3300, 3000, 2200, 1800, 1660, 1590 car 1; MS (m / z) 399 (M +). 'Elemental analysis: C24H2iN3 03 Calculated: C, 72 · 17; H 5.30; H, 10.52 Found: C, 7 1.. 28; H 5. 20; N, 10 f 33 Tube 1 5 3-Γ igftidine-4- Jishenxi) Amine Ί-4-Π.2.2-Tris-Cyclo-propylamino) -Phenidine- ·? -Ene-1.2-diaa A procedure similar to that described in Example 1 was used to prepare 3- [ (Pyridine-4-ylmethyl) amino] -4- (1,2,2-trimethyl-propylamino) -cyclobutan-3-ene-1,2-dione as a white solid: bp 282_5- 283 &quot; C (decomposition) (softening point 2 7 1. 5 ° C &gt; β Example 1 ft -21- This paper size applies to China National Standard (CNS) A4 size (210X297 mm) (Please read the back (Please fill in this page again)

442473 W- 1 4 A7 B7 V. Description of the invention (20) 2-f Dimethyl-propylamine and even diargon-pyridin-1-ene and even 1S even) tritium- 芏 # 1 »Sight- 5-Shen Wax 3-Chloro-2-methylbenzofuran-5-carbonitrile from 2-methyl-benzofuran-5-carbonitrile at 1.1 equivalents of thionyl chloride (SozCl2) in chloroform under reflux. (Such as Cross, PE,; Dickinson, R_P ·;

(Parry, H.J .; Randall Hed. Chen., 198 6, 29, 1643 1650). The mixture was cooled, quenched with ice, and extracted with ethyl acetate. Drying and concentrating gave 3-chloro-2-methylbenzonan-methyl-5-formamidine. Yield 23%: 1H NMR (CDCb): δ 7.81 (d, 1H), 7.55 (dd, 1H), 7.47 (dd, 1H), 2.49 (s, 3H) »3-N-2-bromomethyl- Benzofuran-5-carbonitrile is prepared from 2-bromomethylmonobenzofuran-5-carbonitrile similar to that synthesized in the third paragraph of Example 11. Yield: 53%: 1 H NKR (DHS0-d6): &lt; J8.24 (d, lH), 7.93 (d, 2 Η), 4.94 &lt; s, 2 Η) 0 7-chloro-2 -Aminomethylbenzofuran-5-carbonitrile reacts with potassium titanamidate in a manner similar to paragraph 4 of Example 11 to obtain 3-chloro-2- (1,3-dioxy-1,3-di Hydrogen-iso-indol-2-ylmethyl) -benzofuran-5-formamidine. Yield: 72%: WNMRiDMSO-de): &lt; 5 8.18 (d, 1H), 7,89 (ra, 6H), 5.03 (s, 2H) 3-chloro-2-aminomethyl-benzene well furan -5-Formamidine was prepared in a manner similar to paragraph 5 of Example 11. Yield: 63%: 1 H NyR (DHS0-de &gt;:

8.18 (dilH), 7.81 (dd, 2H), 3.85 (s, 2B), 3.21 (br s, 2H) 〇3-Chloro-2-aminomethyl-benzofuran-5-forman and 3,4 -Dibutoxy-3-cyclobutene-1,2-dione was reacted in a similar manner to Example 6 at paragraph 6. Yield: 75%: 1 H NHR Zhengong Consumer Cooperative Co., Ltd., Central Standards Bureau, Ministry of Economic Affairs (please read the notes on the back before filling this page) (DHS0-d6 &gt;: &lt; J9.40 and 9.18 (br m , lH, geometric isomer), 8 · 2 1 &lt; d, 1 Η), 7.9 1 (dd, 2 Η), 4.9 8 and 4 · 7 5 (2 bra, 2 Η, geometrical difference Structure), 4.61 (2Η), 1.63 (β, 2Η), 1.35 (β, 2Η), 0.87 (β, 3Η) 〇3-chloro- 2-[(2-ethoxy-3,4- Dioxy-cyclobut-1-enylamino) -methyl] benzofuran-5-methylamine (0, 14g, 0.37mraol) in a solution of ethanol (12roL) -22- This paper applies to China National Standard (CNS &gt; A4 Specification (2 丨 0X297) i424 7〇A7 B7 V. Description of Invention (21)

Triamylamine (0.065 g, 0.74 iBB01) was added. The mixture was heated at 70 ° C and allowed to stir for 13 hours. Solids were formed over time and washed with ethyl acetate, ether and hexane. The solid was dehydrated in vacuo to obtain a light orange solid. Yield: 0.1 lg (74%): RP 257.3-258. 1 * C; 1 H NKR (DMSO-de): δ 8.22 (d, 1H), 7.93 (t , lH), 7.90 (d, lH), 7.87 (dd, lH), 7.40 (s, lH), 5.05 (d, 2H), 1.66 (q, 2H), 1.29 (s, 6H), 0.8fl (t , 3H) .IR (KBr): 3230, 2950, 2220, 1800cm * 1; HS (b / z): 371 (H +) 0 Elemental analysis: CisBisCIi N3 〇3 Calculated value: C, 61.38; H 4.88; ϋ, 11.30 Found: C, 6 0. 7 5; Η 4. 81; N, 11.11 The smooth muscle relaxing activity of the compounds of the present invention was established using representative compounds according to standard test procedures as follows: 200g) Asphyxiation with disulfonated sulfonate becomes unconscious, and then euthanasia with neck. The bladder is warmed up 37 &lt; Ό &gt; &amp; Aqueous saline solution (PSS) has the following composition: UM): iJaCl, li8 * ** IKC 1 »4.7; C a C 1 2, 2.5; H g S 0 4, 4 7; H 2 0, 1.2; Na] IC 0 24.9; KH 2 P 0 4, 1.2; Glucose, 11.1; EDTA, add gas 95% 02; 2/5% C02; pH 7,4. Open Ying Ying and cut into the seal 51 of the Central Bureau of Standards of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, one of which is connected to a fixed fishing and the other is connected to an equal power converter. Preparations usually show a small spontaneous contraction, allowing them to recover for 1 hour (pick the goods at 0.1 // Η carbachol after 51. Then carbachol is washed away and mixed with any 23- (Please read the precautions on the back before filling this page ) A strip with a width of 1-2bbi and a long strip. The strip is then suspended at the beginning 5 and suspended in a 10raL tissue bath. The strip is fixed with two surgical clips to position each paper Λ scale. Chinese National Standard (CNS) Λ4 size (2 丨 0x297) (Mm) 44247 Α7 Β7 V. Description of the invention (22) Others have reached the level of resting activity. After recovering 30 minutes, the i5aM iiCl was introduced into the hunger bath. Increasing the concentration of KC1 led to spontaneous contraction (and in the previously stationary The length of the contraction is increased by a slight increase in the basic tension. After the contraction force is stabilized, the concentration of the test compound or vehicle is increased. The introduction of β in the tissue bath during the last 30 minutes of provocation. The concentration of each compound or vehicle was used to measure the contractile activity. The equal force of the bladder strips was measured using the concentration required to induce 50% of the pre-dose contraction activity inhibitory effect (IC50 concentration) and calculated from the concentration response curve. The test compound induces The percentage of maximum contractile activity inhibition is also recorded for test compounds less than or equal to 30 # Μ test compounds. _Research Results_ The results are shown in Table I. (Please read the precautions on the back before filling out this page) Order the staff of the Central Bureau of Standards of the Ministry of Economic Affairs Cooperatives printed -24-Paper and silver ΛΛ4 (210x297 mm) size of the CNS 424 Α7 Β7 V. Description of the invention (23)

Table I Contraction inhibiting compounds of isolated rat bladder strips η IC so Μ Example 1 4 0.42 ± 0.06 Example 2 1.25 ± 0.39 Example 3 4 1.25 ± 0.34 Example 4 6 3.0 ± 0.2 Example 5 4 2.63 ± 0.22 Example 6 4 11.45 ± 4.3 Example? 4 * 1 = 27.3 ± 7% Example 8 4 **. = 8'5 ± 1.4% Example 9 3 * 1 = 22: 2 ± 7.4% Example 10 4 * 1 = 11.5 ± 3.2% Example 11 4 1.56 ± 0.16 Example 12 2 3.75 ± 1.44 2 * 1 = 5.5 ± 4% Example 1 3 3 * 1 = 19.94 ± 8.5% Example 14 2 * 1 = 31.9 ± 6.4% Example 15 4 2.45 ± 0.99 Example 16 2 1.3 ± 0.63 Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs &quot; at 30 / UK Inhibition percentage ** at 30 # Percent shrinkage of Η In addition, the inventor test Example 1 compound (as the representative of other compounds of the present invention) inhibits hypertrophy of conscious female rats with hypertrophic bladder-25-This paper is for China National Habitat (CNS) A4 specification (210 × 297 mm) 442473 A7 B7 V. Description of the invention (24) High reactivity of bladder smoothing machine (forced muscle), so according to Ma 1 agrea et al., J. Urol. 142: 1134, 1389. Stoppering to improve urinary incontinence e Use up to 25 female Sprague-Dawley rats weighing 190 to 210 g each time. After bladder hypertrophy, use 4-8 heads. The compound was dissolved in PEG-20 and administered at a volume of 5 Bl / fcg via a gastric tube or intravenously. For preliminary screening, all drugs were pre-treated with lOiegAg Oral doses were administered to 4 rats of limulus molybdenum. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). The rats were anesthetized with halothane. The bladder was exposed after midline incision. And urethra in the presence of a stainless steel rod (Ian diameter) tied a 4-0 silk thread to the proximal urethra. Partial obstruction was created. Then the rod was removed and the abdomen was closed with a surgical needle. Each rat received 150,000 units 1 ^ ( ^ 11111 (:-1 ^ Any animal developed hypertrophic bladder hypertrophy for 6 weeks ^ After 6 weeks, the ligature was removed under halothane anesthesia, and a catheter with a sleeve (PE6〇) was placed on top of the urinary bladder and in a handbag The suture fixation "catheter formed a tunnel under the skin and opened to the outside through the neck back. Suture the abdominal incision and close the free end of the catheter. To prevent play, rats were injected with bicillin CR (15D0G0 units / rat two days later, Animals were evaluated for cysteine measurement. Animals were placed in metabolic cages, and catheters were connected (using a "T" type connector) to a Stangham pressure converter (tanuki P23Db) and connected to a Harvard round injection sun barrel. β plastic cup overlapped to A volume shift converter (Grass FT03) was placed in a rat cage to collect and calculate urine output. 譲 The rats were rested for 15-30 minutes and then started the first period of saline infusion (20 Bl / hr for 20 minutes). ) «&Gt; Two hours after the initial cystemic period, rats were dosed with vehicle or test compound quantitatively and a second bladder measurement was performed one hour later. This paper scale is applicable to the Chinese national standard (CSS) A4it (210X297 foot) 4424 7 3 A7 B7 V. Description of the invention (25) Record the following urodynamic changes: Basic cystic pressure = minimum bladder pressure during the bladder measurement period Threshold pressure == bladder drive urination volume immediately before urination = void volume urination pressure = peak pressure during spontaneous spontaneous activity = mean amplitude of bladder flare fluctuation during urine injection result j: Calculate each before and after compound administration Mean value of the variable "• For each compound, the measured change of the variable is compared with the value obtained before the treatment, and it is expressed as the percentage of inhibition. The data was subjected to a two-way variable analysis to determine the significance of the measured variable (P &lt; 0 0 5) changes. The results of the study are shown in Table II.

Table II Spontaneous contraction of animals with involuntary contraction in vivo Dose * g / fcg (oral)% Red (F) «Example 1 3 10 -8 ± 4 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (Please read the back Please note this page to fill in again} &quot; Percentage reduction of total spontaneous contraction in the bladder model of hypertrophic rats. The compound of the present invention has a significant effect on the contractility of smooth muscle, and can be used to treat urinary incontinence, irritating bladder and bowel Disease, asthma, hypertension, stroke, and similar diseases mentioned above. These diseases can be administered to patients in need of oral or parenteral or inhalation (it can be treated with potassium channel activating compounds to improve the condition) -2 7- This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

4 4 A8 B8 C8 D8 I ^ • Smart g. 〆 一一 "&quot; No. 86 1 08282" Hybrid of cyclobutene-3,4-dione 丨 Cyclopyridine: A patent case (revised in September 89) A Scope of patent application: 1. A compound of the formula W Α * 'Νι r3, several N〆1 R2 (I) where: h is hydrogen or cli &gt; 6 group; R2 is Cp8 alkyl group which may be substituted by phenyl group: R 3 is nitrogen, A is unsubstituted pyridyl or benzofuranyl which may be substituted by R4, R5, R6; Please. Yuan read back ^ -1 Note * Matters 4! 4-This page) Yang -f &gt;, = u 线 经 ^-# 清 丛 时 4Printed by the total Xiaogong Consumer Cooperative, where R4 is nitro or Cyano: R5 is hydrogen: R6 is fluorine 'chlorine, bromine or iodine; or a pharmaceutically acceptable salt thereof. 2. The compound according to item 1 of the scope of patent application, which is 3- (1,1 ~ dimethylpropylamino) -4-[(pyridin-4-ylmethylimino) cyclobut-3-ene 1,2 -dione or its pharmaceutically acceptable salt. 3. If the compound in the scope of patent application is No. 1, it is 3- (1, dimethyl dimethyl ether. This paper applies Chinese national standard (CNS &gt; Λ4 specification ( 210X2W (Meal. Meal) 42 4 7 points Ss C8 D8, six, patent application scope propylamino) -4- [pyridin-3-ylmethylplamino] cyclobut-3-ene-1,2-dione Or a pharmaceutically acceptable salt thereof. 4. The compound as described in claim 1 of the patent scope, which is 3- (1, dimethyldimethylamino) -4- [pyridin-2-ylmethylphenylamino ] Cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof. 5. If the compound of the scope of application for item 1 is 3-tert-butylamino-4-[(Sttidine 4-Alkylmethyl) -amino] cyclobut-3-ene-1,2-di_ or a pharmaceutically acceptable salt thereof. 6. If the compound in the scope of patent application item 1 is 3-third Butylamino-4-[(pyridin-3-ylmethylbuminyl) cyclobut-3-ene-1,2-dicopper or a pharmaceutically acceptable salt thereof. 7. If applied The compound of the first item of the patent scope is 3-tert-butylamino-4-[(pyridin-2-ylmethyl) -amino] cyclobut-3-ene-1,2-dione or its medicine Acceptable salts. 8. The compound according to item 1 of the scope of patent application, which is 3- (isopropyl-methylamino) -4-[(pyridin-4-ylmethyl) -amino], cyclobutyl -3-ene-1,2- Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy 1 _-arenepyrene 3- and butylamine (5propyl f group 3 methyl is tris, 2, 2 compounds 1 'T chemical base amine nitrate.: ------ Order one ^- -----, {) Ύ (Please read the precautions on the back before filling this page) The salinity accepts the medicinal base compound of the medicinal ring 1 0 No. 5- Wai [(范 I iiiI 专丨 Please Φ aminoamine polyfuran benzyl t—, diyl 1-amine &gt; (1-based 3-methyl as its base 2-circle 2 * fan 7 liene-specific 3-please V as salt accept The medicine can be 0 or diamine, but the 3rd _ 3 is the item of its combination. Le Guang and 4 ·; **, "« & l t; · 蠓 隼 (CNS) ΜΑϋ (210X297 mm) A8 B8 C8 D8 442473 6. Application for a patent scope of the base 4-[(5-nitro-benzofuran-2-ylmethyl) amino] ring But-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof β 12. As the compound in the scope of application for patent No. 1, it is 2- ([2- (1, dimethyl propylamino) -3,4-diazyl-cyclobut-benenylamino] methyl) benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof. 13. The compound as claimed in item 1 of the patent application, which is 2-[[3,4-diamino-2- (1,2,2-trimethylpropylamino) cyclobut-butenylamino] Methylbenzofuran-5-carboxonitrile or a pharmaceutically acceptable salt thereof. 14. The compound according to item 1 of the scope of patent application, which is 2-[(2-third-butylamino-3,4-dioxy-cyclobut-butenylamino] methyl] benzofuran- 5-carbonitrile or a pharmaceutically acceptable salt thereof. 15. The compound according to item 1 of the scope of patent application, which is 2-{[2- (1, 1-dimethyl-2-phenyl · ethylamino) -3,4-dioxy-cyclobut-1-anylamino] methyl) benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof. 16. The compound according to item 1 of the scope of patent application, which is 3-[(pyridine-4-ylmethyl) amino] -4-(1,2,2-trimethyl-propylamino) pyrimidine-3 -Ene-1,2-dione or a pharmaceutically acceptable salt thereof β 17 · As the compound in the scope of application for patent 1, it is 2-([2- (1, budimethyl-propylamino) -3 , 4-Dioxo-cyclobut-benenylamino] methyl) -3-amino-benzofuran-5-carboxine or a pharmaceutically acceptable salt thereof. 18.-A pharmaceutical composition that reduces the adverse effects of smooth muscle contraction, including the active ingredient as a compound in the scope of patent application No. 1. This paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 0 &gt; &lt; 297 mm) — „, ----- rt— (Please read the precautions on the back before filling this page). Order Economy Printed by the Ministry of Standards and Technology Bureau of Shellfish Consumer Cooperatives * 442473 Λ 8 Β8 C8 D8 The scope of application for patents is a group of medicine doctors. The forbidden items are lost. Myocardial smoothing should be used in its medicinal items i 18 thorns from the arch bow Fan Yanli to receive the patent, please do not apply as myopathic syndrome. Intestinal matter. Note: It is difficult to install on this page), X, τ line. Warp. ^-. Ministry of Finance and Economics. 4 ^ 9; 工 消 # Cooperative prints the paper standard applicable to China National Standard (CNS) A4 specification UlOX: ^ 7) 442473 A5 B5 IV. Abstract of the Chinese Invention (Name of the invention: Cyclobutene-3,4-dione heterocyclic methylamine derivative supplement compound, Qv • 〇 AN Ir3 N, I R2 Ri (I) λ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, where Ri is hydrogen or Cw alkyl; R2 is a Alkyl substituted C ^ 8 alkyl; R3 is hydrogen; A is unsubstituted pyridyl or benzofuranyl which may be substituted by r4, r5, R6; wherein R4 is nitro or fluorenyl; r5 is hydrogen;% It is fluorine, chlorine, bromine or iodine; or its pharmaceutically acceptable salt, which can relax smooth muscle. -2- This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) (谙 Read the precautions on the back before reading (Fill in the columns of this bundle)