CN1227543A - Heterocyclylmethylamino derivatives of cyclobutene-3,4-diones as potassium channel modulators - Google Patents

Heterocyclylmethylamino derivatives of cyclobutene-3,4-diones as potassium channel modulators Download PDF

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CN1227543A
CN1227543A CN97197139A CN97197139A CN1227543A CN 1227543 A CN1227543 A CN 1227543A CN 97197139 A CN97197139 A CN 97197139A CN 97197139 A CN97197139 A CN 97197139A CN 1227543 A CN1227543 A CN 1227543A
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amino
carbon atom
acceptable salt
pharmacy acceptable
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D·R·赫尔布斯特
J·A·布特拉
R·F·格拉瑟法
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Wyeth LLC
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American Home Products Corp
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

The compounds of formula (I) 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 (a), (b), (c), (d) and (e) 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

As the cyclobutene-3 of potassium channel modulating agents, the Heterocyclylmethylamderivatives derivatives of 4-diketone
Background of invention
The present invention relates to the new cyclobutene with pharmacologically active-3, the Heterocyclylmethylamderivatives derivatives of 4-diketone, its preparation method, contain their medicinal compositions, and they are in the purposes by the disorder relevant with smooth muscle contraction of potassium channel adjustment of treatment.These disorders include, but are not limited to this, the urinary incontinence, asthma, premature labor, allergic intestinal syndrome, congestive heart failure, stenocardia, cerebrovascular disease and hypertension.
Stemp etc. (EP-426379) disclose the cyclobutenedione derivatives that amino that a class is described to have hypotensive activity and the active chroman of expansion bronchus replaces.Takeno etc. have reported a series of diamino cyclobutenes-3, the 4-diketone on public patent issue bulletin No.6-92915.Effort in this area through us is open in following United States Patent (USP): 4564867; 5466712; 5403853; 5403854; 5397790 and 5401753.Algieri etc. report several 1-amino-2-Phenylalkylamino-cyclobutene-3 in United States Patent (USP) 4390701,4-diketone series is as the H-2 receptor antagonist.Nohara etc. disclose some relevant 1-amino-2-phenoxyalkyl aminoderivative in United States Patent (USP) 4673747.In addition, Nohara etc. discloses some relevant 1-amino-2-pyridyloxy alkyl amino derivatives in EP-177016.The compound of Nohara etc. is reported as the H-2 receptor antagonist.
The 4-pyridylmethyl aminoderivative of open cyclobutenedione in United States Patent (USP) 5354746 such as Chandrakumar has analgesic activity.The compound of Chandrakumar series needs one or three ring Er Ben Bing Evil azatropylidenes partly to exist.Ife discloses the 3-pyridylmethyl aminoderivative of cyclobutenedione in EP-112704, and reports that it is the H-2 antagonist.The compound of Ife series needs N '-pyridyl-diamino partly to exist.
1 of various replacements, 2-diamino-cyclobutene-3, the synthetic of 4-diketone is described in the following publication: Tietze etc., Chem Ber.1991,124,1215; Tietze etc., Bioconjugate Chem.1991,2,148; Ehrhardt etc., Chem.Ber.1977,1102506 and Neuse etc., LiebigsAnn.Chem.1973,619.
Explanation of the present invention
The invention provides compound or its pharmacy acceptable salt of a class by the formula I representative: Wherein:
R 1And R 2Independent be the straight chained alkyl of hydrogen, a 1-10 carbon atom, the branched-chain alkyl of a 3-10 carbon atom, the cycloalkyl of a 3-8 carbon atom, the bicyclic alkyl of a 4-10 carbon atom or the aralkyl of 7-20 carbon atom, and wherein the aromatic portion of aralkyl can be chosen wantonly by the branched-chain alkyl of the straight chained alkyl of 1-3 1-10 carbon atom, a 1-10 carbon atom, halogen, nitro, cyano group, the alkoxyl group of a 1-6 carbon atom, carbalkoxy, trifluoromethyl or the trifluoromethoxy replacement of a 2-7 carbon atom;
R 3Be the alkanoyl of hydrogen, formyl radical, a 2-7 carbon atom, the alkenoyl of a 3-7 carbon atom, the alkane alkylsulfonyl of a 1-7 carbon atom, the aroyl of a 7-12 carbon atom, the fragrant alkenoyl of a 9-20 carbon atom, the arylsulfonyl of a 6-12 carbon atom, the fragrant alkanoyl of a 8-12 carbon atom or the aralkyl alkylsulfonyl of 7-12 carbon atom; A is selected from:
Figure A9719713900091
Wherein:
N is 0 or 1;
R 4, R 5And R 6Independent is cyano group; nitro; amino; the alkyl of 1-6 carbon atom; the perfluoroalkyl of 1-6 carbon atom; the alkoxyl group of 1-6 carbon atom; the perfluoro alkoxy of 1-6 carbon atom; the alkylamino of 1-6 carbon atom; the dialkyl amido of 2-12 carbon atom; sulfamyl; the alkane sulfonamido of 1-6 carbon atom; the fragrant sulfonamido of 6-12 carbon atom; the alkyl carbonylamino of 2-7 carbon atom; the aryl formamido group of 7-13 carbon atom; the alkanoyl of 2-6 carbon atom; the alkane alkylsulfonyl of 1-6 carbon atom; the perfluor alkane alkylsulfonyl of 1-6 carbon atom; the arylsulfonyl of 6-12 carbon atom; chlorine; bromine; fluorine; iodine; the 1-imidazolyl; carboxyl or hydrogen.
The preferred part of the present invention comprises formula I compound or its pharmacy acceptable salt, wherein:
R 1And R 2Same as above;
R 3Be hydrogen;
A is selected from:
Figure A9719713900101
R wherein 4, R 5And R 6The same definition.
R 1And R 2Preferred independent for hydrogen, methyl, ethyl, just or sec.-propyl, just, different, second month in a season or the tertiary butyl, straight or side chain amyl group or phenylalkyl wherein alkyl be methylene radical or ethylidene and wherein phenyl moiety can choose wantonly by 1-3 the substituting group replacement that is selected from methyl, ethyl, fluorine, chlorine, bromine, nitro, cyano group, methoxyl group, oxyethyl group, methoxyl group oxygen base carbonyl, oxyethyl group oxygen base carbonyl trifluoromethyl and trifluoromethoxy.
R 3Be preferably hydrogen.N preferred 0.
R 4, R 5And R 6Independently be preferably hydrogen, cyano group, nitro, amino, methyl, methoxyl group, chlorine, bromine, fluorine, iodine, trifluoromethyl, trifluoromethoxy or carboxyl.
The formula I compound of paying special attention to is:
3-(1,1-dimethyl propyl amino)-4-[(pyridin-4-yl-methyl)-amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
3-(1,1-dimethyl propyl amino)-4-[(pyridin-3-yl-methyl)-amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
3-(1,1-dimethyl propyl amino)-4-[(pyridine-2-ylmethyl) amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
3-tertiary butyl amino-4-[(pyridin-4-yl methyl) amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
3-tertiary butyl amino-4-[(pyridin-3-yl methyl) amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
3-tertiary butyl amino-4-[(pyridine-2-ylmethyl) amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
3-(isopropyl-methyl amino)-4-[(pyridin-4-yl methyl) amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
3-[(5-nitro-cumarone-2-ylmethyl)-and amino-4-(1,2,2-trimethylammonium propyl group amino)-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
3-(1,1-dimethyl-propyl group amino)-4-[(5-nitro-cumarone-2-ylmethyl)-and amino] ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
3-tertiary butyl amino-4-[(5-nitrobenzofuran-2-ylmethyl)-amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
2-{[2-(1,1-dimethyl propyl amino)-3,4-two dioxies-ring but-1-ene base amino]-methyl }-cumarone-5-nitrile or its pharmacy acceptable salt;
2-{[3,4-dioxy-2-(1,2,2-trimethylammonium propyl group amino)-ring but-1-ene base amino]-methyl }-cumarone-5-nitrile or its pharmacy acceptable salt;
2-[(2-tertiary butyl amino-3,4-dioxy-ring but-1-ene base amino)-methyl]-cumarone-5-nitrile or its pharmacy acceptable salt;
2-{[2-(1,1-dimethyl-2-phenylethyl amino)-3,4-dioxy-ring but-1-ene base amino]-methyl }-cumarone-5-nitrile or its pharmacy acceptable salt;
3-[(pyridin-4-yl methyl) amino]-4-(1,2,2-trimethylammonium-propyl group amino)-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt;
2-{[2-(1,1-dimethyl-propyl group amino)-3,4-dioxy-ring but-1-ene base amino]-methyl }-3-chloro-cumarone-5-nitrile or its pharmacy acceptable salt.
Be appreciated that: work as R 1, R 2, R 3, R 4, R 5Or R 6When containing dissimilar chiral centres, the definition of formula I compound comprises in the following discussion having active all possible steric isomer and composition thereof.Particularly, it comprises having described active any racemic modification and any optically active isomer.Optically active isomer can obtain pure product form by standard isolation technique or special the synthesizing of enantiomorph.Understand the crystalline form that the present invention includes all formula I compounds.The compounds of this invention also can be called 3,4-diketone or 1,2-diketone in this manual.The pharmacy acceptable salt of basic cpd of the present invention is those derived from following organic and mineral acid: as lactic acid, Citric Acid, acetate, tartrate, succsinic acid, toxilic acid, propanedioic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, and those salt of similar known acceptable acid.Work as R 4, R 5Or R 6When containing carboxyl, the salt of The compounds of this invention can be formed by alkali such as basic metal (Na, K, Li) or alkaline-earth metal (Ca or Mg).
The present invention also provides the method for preparing the formula I compound.More precisely, the formula I compound can be by making the formula II compound: Wherein X is suitable leavings group, for example: methoxyl group, oxyethyl group, isopropoxy, butoxy, halogen or similar leavings group, with the reaction of formula III compound and prepare,
Figure A9719713900122
R wherein A1And R A2Be respectively the R of the same definition 1And R 2Maybe can change into R 1And R 2Atom.Then with intermediate and the reaction of formula IV compound:
A 1-CH 2NH 2(IV) be A wherein 1For as the A of preceding definition, maybe can change into the atom of A.Reaction set forth above can be carried out under temperature that raises or room temperature in solvent such as acetonitrile, methyl alcohol, ethanol, tetrahydrofuran (THF) Huo diox.In addition, the order of reaction can be opposite, and promptly the formula II compound can at first react with the formula IV compound, then intermediate and the foregoing formula III compound that generates reacted and generation formula I compound.
Formula I compound and pharmacy acceptable salt thereof are loose dose of the unstriated muscle that work by potassium channel activation.Therefore they can be used for treating the disorder relevant with smooth muscle contraction, comprise the unstriated muscle excess shrinkage (as the urinary incontinence) of urethra, or disorder, asthma and the alopecia of GI unstriated muscle excess shrinkage (as irritable bowel trace integration disease).In addition, the formula I compound is the activity of potassium channels agent, is used for the treatment of that peripheral vascular disease, hypertension, congestive heart failure exhaust, apoplexy, anxiety disorder, cerebral anoxia and other neurodegenerative disorder.
Therefore the invention provides medicinal compositions, it comprises The compounds of this invention and pharmaceutically acceptable carrier combinations or associating.More precisely, the invention provides the The compounds of this invention that comprises effective dose and the medicinal compositions of pharmaceutically acceptable carrier.
Said composition preferably is suitable for oral administration.But it also can adopt the alternate manner administration, as to the patients with heart failure parenterai administration.
For obtaining the continuity of administration, composition of the present invention is preferably unit dosage form.Suitable unit dosage form comprise tablet, capsule and be loaded on folliculus or vial in pulvis.These unit dosage forms can contain the The compounds of this invention of 0.1-100mg, preferably contain 2-50mg.Preferred unitary dose contains the The compounds of this invention of 5-25mg.The compounds of this invention can 0.01-100mg/kg the dosage range oral administration, or the dosage range of preferred 0.1-10mg/kg.But these composition administrations every day 1-6 time, more common is every day 1-4 time.
Composition of the present invention can wait and make preparation with vehicle commonly used such as weighting agent, disintegrating agent, tackiness agent, slipping agent, flavouring agent.They are made with method commonly used, as preparing with being similar to the method that is used for known antihypertensive agents, diuretic(s) and beta blocker.
The present invention also provides the The compounds of this invention as active pharmaceutical or therapeutant.The formula I compound is used in particular for inducing unstriated muscle loose.
The present invention also provides the treatment Mammals to comprise the method for people's smooth muscle disorder, and it comprises The compounds of this invention or medicinal compositions to ill Mammals effective dose.
The preparation method of representative compounds of the present invention is described rather than limits with the following example.
Embodiment 1
3-(1,1-dimethyl propyl amino)-4-[(pyridin-4-yl-methyl)-amino]-
Ring fourth-3-alkene-1, the 2-diketone
With 3,4-dibutoxy ring fourth-3-alkene-1, (4.526g, 20mmol) with 1, (1.743g, tetrahydrofuran (THF) 20mmol) (20ml) solution stirred under room temperature 19.5 hours the 1-dimethyl propylamine 2-diketone.Remove and desolvate, residue is gone up chromatography (gravity, chloroform-hexane) at neutral, active III silica (150g).From suitable elutriant, separate white solid, get white product: mp56.5-57.5 ℃ of 4.105g (86%) (55.5 ℃ softening) with the hexane recrystallization.This material 1g is got 0.794g 3-butoxy-4-(1,1-dimethyl propyl amino)-ring fourth-3-alkene-1 with hexane recrystallization secondary, and the 2-diketone is white solid: mp56-57 ℃ (55 ℃ softening); 1HNMR (DMSO-d 6): δ 8.63 and 8.48 (2 br s 1H, rotational isomer), 4.67 (m, br, 2H), 1.67 (m, br, 4H), 1.39 (m, 2H), 1.26 (m, br, 6H), 0.91 (t, 3H), 0.78 (t, 3H) .IR (KBr): 3170,1790,1700cm -1MS (m/z) 239 (M +).
With top 3-butoxy-4-(1,1-dimethyl propyl amino)-ring fourth-3-alkene-1, (1.197g, 5.0mmol) tetrahydrofuran (THF) (10ml) solution with 4-aminomethyl pyridine (0.541g) at room temperature stirred 23 hours the 2-diketone.Mixed solution removed desolvates, residue with ether grind, dry 1.154g light yellow solid.This crude product is obtained 0.832g (61%) 3-(1,1-dimethyl propyl amino)-4-[(pyridin-4-yl methyl with recrystallizing methanol (secondary))-amino] ring fourth-3-alkene-1,2 diketone, be white solid: mp258.0-259.5 ℃ of decomposition (257.5 ℃ are softening); 1H NMR (DMSO-d 6): δ 8.56 (m, 2H), 7.86 (m, br, 1H), 7.46 (s, br, 1H), 7.32 (m, 2H), 4.77 (d, 2H), 1.67 (q, 2H), 1.32 (s, 6H), 0.83 (t, 3H) .IR (KBr): 3270,1790,1650cm -1MS (m/z) 273 (M +).
Ultimate analysis C 15H 19N 3O 2
Calculated value: C, 65.91; H, 7.01; N, 15.37
Measured value: C, 65.55; H, 6.88; N, 15.12
Embodiment 2
3-(1,1-dimethyl propyl amino)-4-[(pyridin-3-yl-methyl)-amino]-
Ring fourth-3-alkene-1, the 2-diketone
Tetrahydrofuran (THF) (10ml), 3-butoxy-4-(1,1-dimethyl propyl amino) are encircled fourth-3-alkene-1, and 2-diketone (1.197g, 5.0mmol press embodiment 1 preparation) and 3-aminomethyl pyridine (0.541g) at room temperature stirred 24 hours together.With reactant slough solvent, with residue with ether grind, dry 1.228g emulsifiable paste look solid.This material is got 0.887g (65%) 3-(1,1-dimethyl propyl amino)-4-[(pyridin-3-yl methyl with the recrystallizing methanol secondary) amino] ring fourth-3-alkene-1, the 2-diketone is white solid: mp263.5-264.5 ℃ (260.0 ℃ are softening); 1H NMR (DMSO-d 6): δ 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): 3230,1790,1650cm -1MS (m/z): 274 (M+H) +.
Ultimate analysis C 15H 14N 3O 2
Calculated value: C, 65.91; H, 7.01; N, 15.37
Measured value: C, 66.23; H, 7.08; N, 15.38
Embodiment 3
3-(1,1-dimethyl propyl amino)-4-[(pyridine-2-base-methyl) amino]-
Ring fourth-3-alkene-1, the 2-diketone
With 3-butoxy-4-(1,1-dimethyl propyl amino)-ring fourth-3-alkene-1, (0.281g stirred 22 hours under tetrahydrofuran (THF) 2.6mmol) (5ml) the solution room temperature for 2-diketone (0.622g, 2.6mmol press embodiment 1 preparation) and 2-aminomethyl pyridine.Remove and to desolvate, with residue with ether grind, dry 0.656g white solid.Crude product is got 0.447g (63%) 3-(1,1-dimethyl propyl amino)-4-[(pyridine-2-ylmethyl with acetonitrile recrystallization (secondary)) amino]-ring fourth-3-alkene-1, the 2-diketone is white solid: mp192.0-192.5 ℃ (188.5 ℃ are softening); 1H NMR (DMSO-d 6): δ 8.58 (m, 1H), 8.00 (m, br, 1H), 7.82 (m, 1H), 7.58 (s, br, 1H), 7.37 (m, 1H), 7.33 (m, 1H), 4.85 (d, 2H), 1.67 (q, 2H), 1.31 (s, 6H), 0.83 (t, 3H) .IR (KBr): 3210,1790,1660cm -1MS (m/z): 273 (M +).
Ultimate analysis C 15H 19N 3O 2
Calculated value: C, 65.91; H, 7.01; N, 15.37
Measured value: C, 65.78; H, 6.94; N, 15.48
Embodiment 4
3-tertiary butyl amino-4-[(pyridin-4-yl methyl) amino]-ring fourth-3-alkene-1, the 2-diketone
Similar approach with explanation among the embodiment 1 makes 3-tertiary butyl amino-4-[(pyridin-4-yl methyl with suitable starting raw material) amino]-ring fourth-3-alkene-1, the 2-diketone is white solid: mp271.0-271.5 ℃ (269.5 ℃ are softening).
Embodiment 5
3-tertiary butyl amino-4-[(pyridin-3-yl methyl) amino]-ring fourth-3-alkene-1, the 2-diketone
Similar approach with explanation among the embodiment 1 makes 3-tertiary butyl amino-4-[(pyridin-3-yl methyl with suitable starting raw material) amino]-ring fourth-3-alkene-1, the 2-diketone is white solid: mp296.0 ℃ of decomposition (290.5 ℃ are softening).
Embodiment 6
3-tertiary butyl amino-4-[(pyridine-2-ylmethyl) amino]-ring fourth-3-alkene-1, the 2-diketone
Similar approach with explanation among the embodiment 1 makes 3-tertiary butyl amino-4-[(pyridine-2-ylmethyl with suitable starting raw material) amino]-ring fourth-3-alkene-1, the 2-diketone is white solid: mp236.0-236.5 ℃ decomposition.(233.5 ℃ softening).
Embodiment 73-(isopropyl-methyl amino)-4-[(pyridin-4-yl methyl) amino]-ring fourth-3-alkene-1, the 2-diketone
Similar approach with explanation among the embodiment 1 makes 3-(isopropyl-methyl amino)-4-[(pyridin-4-yl methyl with suitable starting raw material) amino]-ring fourth-3-alkene-1, the 2-diketone is white solid: mp214.5-215.0 ℃ decomposition.(211.5 ℃ softening).
Embodiment 8
3-[(5-nitro-cumarone-2-ylmethyl)-amino-4-(1,2,2-trimethylammonium propyl group amine)-
Ring fourth-3-alkene-1, the 2-diketone
0 ℃ of following NaH (3.41g, 80%, add in dimethyl formamide 113.6mmol) (400ml) suspension acetoxime (7.61g, 104.1mmol) in.Stirring is after 1 hour down in 0 ℃, and (10.00ml 94.6mmol), stirs the mixed solution that generates 1 hour to add 4-nitro fluorobenzene by syringe.Add salt solution (400ml), filter and collect the precipitation that generates.With the product washing, vacuum-drying gets 18g (100%) white solid: 1H NMR (DMSO-d 6): δ 8.20 (d, 2H), 7.25 (d, 2H), 2.06 (s, 3H), 2.11 (s, 3H).
With top oxime adducts (10.39g, 53.56mmol) the saturated ethanolic soln reflux in HCl (200ml).After 3 hours, reaction mixture is cooled off, is concentrated into 1/4 volume.Add entry, filter the cyclization product of collecting precipitation and obtain 9.0g (95%) 2-methyl-5-Xiao Ji cumarone: 1H NMR (DMSO-d 6): δ 8.39 (d, 1H), 8.15 (dd, 1H), 7.45 (d, 1H), 6.49 (s, 1H), 2.48 (s, 3H).
The above-mentioned cumarone that stirs (5.00g, 28.25mmol) and benzoyl peroxide (0.68g adds 1 in tetracol phenixin 2.83mmol) (200ml) solution, 3-two bromo-5, the 5-T10 (4.04g, 14.12mmol).Mixed solution is under agitation used 200 watts of light irradiations 1 hour, cool off, between methylene dichloride/water, distribute.With organic phase water (2 * 100ml) and salt solution (2 * 100ml) washings, dry (MgSO 4), decolouring (gac), vacuum concentration get the 7.12g crude product.With the ethyl acetate/hexane recrystallization get 2-brooethyl-5-Xiao Ji-cumarone of 4.38g (61%), for pale solid: 1HNMR (CDCl 3): δ 8.49 (d, 1H), 8.25 (dd, 1H), 7.58 (d, 1H), 6.91 (s, 1H), 4.59 (s, 2H).
With above-mentioned 2-brooethyl-5-nitrobenzofuran (1.57g, 6.13mmol), potassium phthalimide (1.70g, 9.19mmol) and hexaoxacyclooctadecane-6-6 (0.161g, mixture 0.61mmol) stir under room temperature in acetonitrile (15ml) and spend the night.Solvent removed in vacuo is disperseed residue between ethyl acetate and salt solution.(2 * 50ml) use salt solution (2 * 50ml) washings, dry (MgSO again with 0.1N sodium hydroxide earlier with organic phase 4), concentrate pale solid.With crude product with cold ethylacetate/ether/hexane grind the phthalic imidine product of 1.47g (74%), be white solid: 1H NMR (DMSO-d 6): δ 8.55 (d, 1H), 8.17 (dd, 1H), 7.88 (m, 4H), 7.75 (d, 1H), 5.00 (s, 2H).
(1.45g 4.49mmol) handled 1.5 hours in the ethanol (15ml) that refluxes with hydrazine hydrate (0.38ml) with above-mentioned phthalic imidine adducts.Reaction solution is cooled to 0 ℃, and acidifying (dense HCl) is to pH=1.Filter mixed solution, with solid 6N HCl and water washing.Filtrate is alkalized with salt of wormwood, used ethyl acetate extraction then.With organic phase drying (MgSO 4), concentrate 2-methylamino-5-nitrobenzofuran of 0.74g (86%), be faint yellow solid: 1H NMR (DMSO-d 6): δ 8.55 (d, 1H), 8.11 (dd, 1H), 7.72 (d, 1H), 6.85 (s, 1H), 3.84 (s, 2H), 2.00 (brs, 2H).
Under 0 ℃ to the 2-methylamino-5-nitrobenzofuran that stirs (0.74g adds 3 by syringe in tetrahydrofuran (THF) 3.85mmol) (15ml) liquid, 4-dibutoxy-3-cyclobutene-1, the 2-diketone (1.25ml, 5.78mmol).This mixture was at room temperature stirred 5 hours, then vacuum concentration.Residue is got the 0.83g adducts with ethylacetate/ether/hexane recrystallization, be pale solid.From mother liquor, separate second batch of product (0.17g).Total recovery: 75%. 1HNMR (DMSO-d 6): δ 9.40 and 9.20 (2br m, 1H rotational isomer), 8.60 (d, 1H), 8.20 (dd, 1H), 7.80 (d, 1H), 7.04 (s, 1H), 4.88 and 4.67 (2br m, 2H rotational isomers), 4.60 (t, 2H), 1.67 (m, 2H), 1.30 (m, 2H), 0.85 (m, 3H).
With 3-butoxy-4-[(5-nitrobenzofuran-2-ylmethyl)-amino]-ring fourth-3-alkene-1, (0.250g 0.727mmol) is dissolved in R (+)-2-amino-3 to the 2-diketone, and (0.167N, 6.0ml is in ethanolic soln 1.00mmol) for the 3-dimethylbutane.Mixed solution is diluted with ethanol (1ml) and tetrahydrofuran (THF) (1ml).Add 6.0ml alcoholic acid amine (1.00mmol) after 3 hours again, mixed solution was at room temperature stirred 48 hours.Should heterogeneous mixed solution with ether/ethyl acetate dilution in 1: 1, filter 0.20g (74%) 3-[(5-nitro-cumarone-2-ylmethyl)-amino]-4-(1,2,2-trimethylammonium propyl group amino)-ring fourth-3-alkene-1, (R) isomer of 2-diketone; Mp＞300 ℃; 1H NMR (DMSO-d 6): δ 8.61 (d, 1H), 8.21 (dd, 1H), 7.88 (d and m, 2H), 7.35 (br d, 1H), 7.06 (s, 1H), 4.98 (m, 2H), 3.92 (m, 1H), 1.10 (d, 3H), 0.86 (s, 9H) .IR (KBr): 3180,2950,1800,1650,1550cm -1MS (m/z) 371 (M +).
Ultimate analysis C 19H 21N 3O 5
Calculated value: C, 61.45; H, 5.70; N, 11.31
Measured value: C, 60.52; H, 5.50; N, 11.21
Embodiment 93-(1,1-dimethyl-propyl group amino)-4-[(5-nitro-cumarone-2-ylmethyl)-and amino] ring fourth-3-alkene-1, the 2-diketone
At 3-butoxy-4-[(5-nitrobenzofuran-2-ylmethyl of pressing embodiment 8 preparations)-amino]-ring fourth-3-alkene-1, the 2-diketone (0.25g, and adding uncle amylamine in ethanol 0.727mmol) (5ml) liquid (0.53ml, 4.54mmol).To be reflected at 70 ℃ and stir 18 hours down, at room temperature stir then 48 hours.Filtering precipitate, get 0.22g (85%) 3-(1 with ethyl acetate, ether and petroleum ether, 1-dimethyl-propyl group amino)-and 4-[(5-nitrobenzofuran-2-ylmethyl) amino]-ring fourth-3-alkene-1, the 2-diketone is pale solid: mp283.5-287.5 ℃ (decomposition); 1H NMR (DMSO-d 6): δ 8.61 (d, 1H), 8.18 (dd, 1H), 7.96 (br t, 1H), 7.81 (d, 1H), 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): 3220,2950,1800cm -1MS (m/z) 357 (M +).
Ultimate analysis C 18H 19N 3O 5
Calculated value: C, 60.50; H, 5.36; N, 11.76
Measured value: C, 59.31; H, 5.15; N, 11.53
Embodiment 10
3-tertiary butyl amino-4-[(5-nitrobenzofuran-2-ylmethyl)-amino]-
Ring fourth-3-alkene-1, the 2-diketone
At 3-butoxy-4-[(5-nitrobenzofuran-2-ylmethyl of pressing embodiment 8 preparation)-amino]-ring fourth-3-alkene-1, the 2-diketone (0.25g, add in ethanol 0.727mmol) (5ml) liquid TERTIARY BUTYL AMINE (0.51ml, 4.85mmol).To be reflected at 70 ℃ and stir 18 hours down, at room temperature stir then 48 hours.By the method identical with embodiment 9 handle 0.20g (80%) 3-TERTIARY BUTYL AMINE-4-[(5-nitrobenzofuran-2-ylmethyl) amino]-ring fourth-3-alkene-1, the 2-diketone is pale solid: mp＞300 ℃; 1H NMR (DMSO-d 6): δ 8.61 (d, 1H), 8.20 (dd, 1H), 7.91 (br t, 1H), 7.81 (d, 1H), 7.59 (br s, 1H), 7.07 (s, 1H), 4.98 (d, 2H), 1.36 (s, 9H) .IR (KBr): 3220,2930,1800,1675cm -1MS (m/z) 344.3[M+H] +.
Ultimate analysis C 17H 17N 3O 5
Calculated value: C, 59.47; H, 4.99; N, 12.24
Measured value: C, 58.86; Hm4.78; N, 11.88
Embodiment 11
2-{[2-(1,1-dimethyl propyl amino)-3,4-dioxy-ring but-1-ene base amino]-
Methyl }-cumarone-5-nitrile
(6.34g 86.64mmol) joins sodium hydride and (is 80% resolvent in the mineral oil with acetoxime in 0 ℃; 2.72g N 90.82mmol) is in the suspension of dinethylformamide (400ml).The suspension that steeps is heated to 25 ℃ more, stirred simultaneously 1 hour.(10.00g 82.51mmol), stirs reaction mixture 15 minutes down at 0 ℃, is warmed to room temperature then to the fluorine benzonitrile in adding.After stirring is spent the night, reaction mixture is poured in the salt solution (300ml).Filter and collect the white precipitate that generates, washing, vacuum-drying.Yield: 13.97g (98%): 1H NMR (DMSO-d 6): δ 7.78 (d, 2H), 7.76 (d, 2H), 2.04 (s, 3H), 2.00 (s, 3H).
Product (13.97g, 80.29mmol) the middle ethanolic soln (400ml) that adds hydrochloric acid to the last period.With mixed solution reflux 4 hours.The cooling reaction mixture is concentrated into 1/3 volume with it.With the reaction mixture dilute with water, the instant precipitation that generates.Filter collecting precipitation, washing, vacuum-drying.Crude product is through HPLC (10: 1 hexane/ethyl acetate) purifying.Yield: 7.26g (58%): 1H NMR (CDCl 3): δ 7.79 (d, 1H), 7.47 (dd, 1H), 7.43 (d, 1H), 6.44 (s, 1H), 2.47 (s, 3H).
Product (3.00g to the last period, 19.08mmol) tetracol phenixin (80ml) solution in add benzoyl peroxide (0.46g, 1.91mmol) and 1,3-two bromo-5, the 5-T10 (2.73g, 9.54mmol), with reaction mixture with 200 watts of light irradiations 1 hour.The cooling reaction solution disperses it between ethyl acetate and sodium bicarbonate.Organic layer with dried over mgso, use Norite (gac) handled, and filters, and is condensed into solid.Crude product ethyl acetate/hexane recrystallization.Yield: 2.40g (59%): 1H NMR (DMSO-d 6): δ 8.49 (d, 1H), 8.25 (dd, 1H), 7.58 (d, 1H), 6.91 (s, 1H), 4.59 (s, 2H).
To the last period product (2.63g, add in acetonitrile 10.27mmol) (30ml) solution potassium phthalimide (2.85g, 15.41mmol) and hexaoxacyclooctadecane-6-6 (0.27g, 1.03mmol).After stirring is spent the night, the vacuum concentration reaction mixture.Residue is disperseed between ethyl acetate and salt solution, form precipitation immediately.Filter collecting precipitation, with ethyl acetate washing, drying.(2 * 50ml) use salt solution (2 * 50ml) washings again with 0.1N sodium hydroxide with organic phase.Vacuum concentrated solution gets another batch solid.Yield: 2.50g (76%): 1H NMR (DMSO-d 6): δ 8.18 (d, 1H), 7.91 (m, 4H), 7.77 (dd, 1H), 7.07 (d, 1 H), 5.00 (s, 2H).
To the last period product (2.50g adds hydrazine hydrate (0.66ml) in ethanol 7.74mmol) (20ml) solution.With mixed solution reflux 1.5 hours.Cooling reaction solution to 0 ℃, being acidified to PH with concentrated hydrochloric acid is 1.Filter mixed solution, filter cake is washed with water with 6N hydrochloric acid again.With the salt of wormwood filtrate of alkalizing, use ethyl acetate extraction.The organic phase dried over mgso is used Norite Handle, concentrate pale solid.Yield: 0.85g (62%): 1H NMR (DMSO-d 6): δ 8.17 (d, 1H), 7.78 (dd, 1H), 7.74 (d, 1H), 6.82 (s, 1H), 3.85 (s, 2H), 2.10 (br s, 2H).
Under 0 ℃, to the last period product (0.84g adds 3 in tetrahydrofuran (THF) 4.40mmol) (15ml) solution, 4-diethoxy-3-cyclobutene-1, the 2-diketone (1.13g, 6.60mmol).Reaction solution is warmed to room temperature, stirred 4 hours.The vacuum concentration reaction solution grinds crude product with ethylacetate/ether/hexane and gets pale solid.With solid filtering, dry desired product.Yield: 1.05g (76%): 1H NMR (DMSO-d 6): δ 9.41 and 9.21 (br m, 1H, rotational isomer), 8.22 (d, 1H), 7.81 (dd, 1H), 7.00 (s, 1H), 4.88 and 4.68 (2br m, 2H, rotational isomers), 4.65 (t, 2H), 1.39 (m, 3H).
To the last period product (0.25g, add in ethanol 0.79mmol) (17ml) solution uncle's amylamine (0.21g, 2.37mmol).Reaction solution is heated to 70 ℃, and stirring is spent the night.Filter the solid that forms, get the 2-{[2-(1 of 0.18g (67%) with ethyl acetate, ether and hexane wash, 1-dimethyl propyl amino)-3,4-dioxy-ring but-1-ene base amino]-methyl }-cumarone-5-nitrile, be pale solid: mp171.1-173.2 ℃. 1H?NMR(DMSO-d 6):δ8.19(d,1H),7.96(t,1H),7.81(d,1H),7.74(dd,1H),7.45(s,1H),6.96(s,1H),4.97(d,2H),1.67(q,2H),1.29(s,6H),0.83(t,3H).IR(KBr):3230,2950,2220,1800cm -1；MS(m/z)337(M +).
Ultimate analysis C 19H 19N 3O 3
Calculated value: C, 67.64; H, 5.68; N, 12.46
Measured value: C, 66.87; H, 5.32; N, 12.37
Embodiment 12
2-{[3,4-dioxy-2-(1,2,2-trimethylammonium propyl group amino)-ring fourth-1-
Alkenyl amino]-methyl }-cumarone-5-nitrile
6 sections product in embodiment 1 (0.250g adds alcoholic acid (R)-2-amino-3 in ethanol 0.79mmol) (2ml) solution, and the 3-dimethylbutane (the EtOH liquid of 0.166N, 9.50ml, 1.58mmol).Reaction mixture is heated to 70 ℃, and stirring is spent the night.Filter the solid that forms, with ethyl acetate, ether and hexane wash.Solid vacuum-drying is got the 2-{[3 of 0.22g (79%), 4-dioxy-2-(1,2,2-trimethylammonium-propyl group amino)-ring but-1-ene base amino]-methyl }-(1R) isomer of cumarone-5-nitrile, be pale solid: mp＞300 ℃; 1H NMR (DMSO-d 6): δ 8.18 (d, 1H), 7.80 (dd, 1H), 7.74 (dd, 1H), 7.31 (br d, 1H), 6.95 (s, 1H), 4.96 (m, 2H), 3.91 (br m, 1H), 1.11 (d, 3H), 0.81 (s, 9H) .IR (KBr): 3170,2950,2250,1850,1650,1560cm -1MS (m/z) 351 (M +).
Ultimate analysis C 20H 21N 3O 3
Calculated value: C, 68.36; H, 6.02; N, 11.96
Measured value: C, 68.00; H, 5.83; N, 12.00
Embodiment 13
2-[(2-tertiary butyl amino-3,4-dioxy-ring but-1-ene base amino)-
Methyl]-cumarone-5-nitrile
6 sections product in embodiment 11 (0.250g, add in ethanol 0.79mmol) (17ml) solution TERTIARY BUTYL AMINE (0.17g, 2.37mmol).Reaction mixture is heated to 70 ℃, and stirring is spent the night.Filter the solid that generates, with ethyl acetate, ether and hexane wash.The vacuum-drying solid gets the 2-[(2-tertiary butyl amino-3 of 0.12g (51%), 4-dioxy-ring but-1-ene base amido]-methyl]-cumarone-5-nitrile, be rose pink solid: mp298.9-300.3 ℃; 1H NMR (DMSO-d 6): δ 8.18 (d, 1H), 7.96 (t, 1H), 7.81 (dd, 1H), 7.74 (dd, 1H), 7.57 (s, 1H), 6.95 (s, 1H), 4.96 (d, 2H), 1.35 (s, 9H) .IR (KBr): 3300,2950,2210,1800,1600,1525cm -1MS (m/z) 323 (M +).
Ultimate analysis C 18H 17N 3O 3
Calculated value: C, 66.86; H, 5.30; N, 13.00
Measured value: C, 65.64; H, 4.93; N, 12.57
Embodiment 14
2-{[2-(1,1-dimethyl-2-phenylethyl amino)-3,4-dioxy-ring fourth
-1-alkenyl amino]-methyl }-cumarone-5-nitrile
6 sections product in embodiment 11 (0.23g adds α in ethanol 0.73mmol) (20ml) solution, and the alpha-alpha-dimethyl phenylethylamine (0.33g, 2.19ml).Reaction solution is heated to 70 ℃, and stirring is spent the night.Filter the solid that generates, with ethyl acetate, ether and hexane wash.The vacuum-drying solid gets the 2-{[2-(1,1-dimethyl-2-styroyl amino)-3 of 0.11g (41%), 4-dioxy-ring but-1-ene base amino]-methyl]-cumarone-5-nitrile, be pale solid: mp233.4-235.2 ℃; 1HNMR (DMSO-d 6): 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), 7.06 (d, 2H), 6.94 (s, 1H), 4.97 (d, 2H), 2.98 (s, 2H), 1.31 (s, 6H) .IR (KBr): 3300,3000,2200,1800,1660,1590cm -1MS (m/z) 399 (M +).
Ultimate analysis C 24H 21N 3O 3
Calculated value: C, 72.17; H, 5.30; N, 10.52
Measured value: C, 71.28; H, 5.20; N, 10.33
Embodiment 15
3-[(pyridin-4-yl methyl) amino]-4-(1,2,2-trimethylammonium-propyl group amino)-
Ring fourth-3-alkene-1, the 2-diketone
With the similar approach of explanation among the embodiment 1, utilize suitable starting raw material to prepare 3-[(pyridin-4-yl methyl)-amino]-4-(1,2,2-trimethylammonium-propyl group amino)-ring fourth-3-alkene-1, the 2-diketone is white solid: mp282.5-283.0 ℃ (decomposition).(271.5 ℃ softening)
Embodiment 16
2-{[2-(1,1-dimethyl-propyl group amino)-3,4-dioxy-ring but-1-ene base amino]-
Methyl }-3-chloro-cumarone-5-nitrile
The cumarone adducts that makes in the paragraph 2 with embodiment 11 synthesizes 3-chloro-2-methyl cumarone-5-nitrile (Cross, P.E.; Dickinson, R.P.; Parry, M.J.; Randall, M.J.J.Med.Chem., 1986,29,1643-1650).Yield: 23%: 1H NMR (CDCl 3): δ 7.81 (d, 1H), 7.55 (dd, 1H), 7.47 (dd, 1H), 2.49 (s, 3H).
Method with Synthetic 2-brooethyl-cumarone-5-nitrile in the paragraph 3 that is similar to embodiment 11 makes 3-chloro-2-brooethyl-cumarone-5-nitrile.Yield: 53%: 1H NMR (DMSO-d 6): δ 8.24 (d, 1H), 7.93 (d, 2H), 4.94 (s, 2H).
With the method for the paragraph 4 that is similar to embodiment 11, the product of epimere and potassium phthalimide reaction are generated the phthalic imidine affixture.Yield: 72%: 1H NMR (DMSO-d 6): δ 8.18 (d, 1H), 7.89 (m, 6H), 5.03 (s, 2H).
Method with the paragraph 5 that is similar to embodiment 11 prepares 3-chloro-2-methylamino-cumarone-5-nitrile.Yield: 63%: 1H NMR (DMSO-d 6): δ 8.18 (d, 1H), 7.81 (dd, 2H), 3.85 (s, 2H), 3.21 (br s, 2H).
With the method for the paragraph 6 that is similar to embodiment 11, with above-mentioned aminocompound and 3,4-dibutoxy-3-cyclobutene-1,2-two reactive ketones.Yield: 75%: 1H NMR (DMSO-d 6): δ 9.40 and 9.18 (br m, 1H, rotational isomer), 8.21 (d, 1H), 7.91 (dd, 2H), 4.98 and 4.75 (2br m, 2H, rotational isomers), 4.61 (t, 2H), 1.63 (m, 2H), 1.35 (m, 2H), 0.87 (m, 3H).
To the last period product (0.14g, add in ethanol 0.37mmol) (12ml) solution uncle's amylamine (0.065g, 0.74mmol).Reaction solution is heated to 70 ℃, stirred 13 hours.Filter the solid that generates, with ethyl acetate, ether and hexane wash.The vacuum-drying solid gets the light orange solid.Yield: 0.11g (74%): mp 257.3-258.1 ℃; 1H NMR (DMSO-d 6): δ 8.22 (d, 1H), 7.93 (t, 1H), 7.90 (d, 1H), 7.87 (dd, 1H), 7.40 (s, 1H), 5.05 (d, 2H), 1.66 (q, 2H), 1.29 (s, 6H), 0.80 (t, 3H) .IR (KBr): 3230,2950,2220,1800cm -1MS (m/z) 371 (M +).
Ultimate analysis C 19H 18Cl 1N 3O 3
Calculated value: C, 61.38; H, 4.88; N, 11.30
Measured value: C, 60.75 H, 4.81; N, 11.11
Confirm that with representation compound the loose activity of unstriated muscle of The compounds of this invention is as follows according to acceptable experimental technique on the standard pharmaceutical:
(150-200g) passes through CO with the Sprague-Dawley mouse 2Suffocating makes it stupor, separately puts to death by neck then.Bladder is placed warm (37 ℃) normal saline solutions (PSS) that contain following component (mM): NaCl, 118.4; KCl, 4.7; CaCl 2, 2.5; MgSO 4, 4.7; H 2O, 1.2; NaHCO 3, 24.9; KH 2PO 4, 1.2; Glucose, 11.1; EDTA, 0.023; Use 95%O 2Inflation; 2/5%CO 2PH7.4.Open bladder, be cut into wide 1-2mm then.The bar of long 7-10mm.Then these are suspended in the 10ml tissue bath first resting tension 1.5g.These are fixed by two operation clips, and a clip connects a fixed hook and the transmitter of another clip equal proportion power of connection (isome tric force).These prepared products that demonstrate little autonomous contraction were usually recovered 1 hour, excite with 0.1 μ M carbachol then.The flush away carbachol allows organizational slack arrive its static activity level again.After recovering 30 minutes again, in tissue bath, add 15mM KCl again.The increase of KCl concentration significantly increases the amplitude (and formerly the contraction propagation on the immobilized bar) of the autonomous contraction that a small amount of that is attached on the basic tension force increases.Stable along with the contraction activity level of this increase, the concentration of in tissue bath, press increment increase testing compound or medium.In last minute of exciting in 30 minutes, measure the contraction activity of each compound or concentration of medium.
Need cause that with one 50% prodrug shrinks the active concentration (IC that suppresses 50Concentration) measure the equal proportion power of bladder bar, and from concentration-response curve, calculate equal proportion power.The active percent inhibition of maximum collapse that causes by testing compound when also writing down the concentration that is less than or equal to 30 μ M testing compounds.
This result of study sees Table I.
The table I
Inhibition to isolating mouse bladder bar contraction
Compound n IC 50μ M
Embodiment 14 0.42 ± 0.06
Embodiment 25 1.25 ± 0.39
Embodiment 34 1.25 ± 0.34
Embodiment 46 3.0 ± 0.2
Embodiment 54 2.63 ± 0.22
Embodiment 64 11.45 ± 4.3
Embodiment 74 *I=27.3 ± 7%
Embodiment 84 *C=8.5 ± 1.4%
Embodiment 93 *I=22.2 ± 7.4%
Embodiment 10 4 *I=11.5 ± 3.2%
Embodiment 11 4 1.56 ± 0.16
Embodiment 12 2 3.75 ± 1.44
2 *I=5.5±4％
Embodiment 13 3 *I=19.94 ± 8.5%
Embodiment 14 2 *I=31.9 ± 6.4%
Embodiment 15 4 2.45 ± 0.99
Embodiment 16 2 1.3 ± 0.63
*Percent inhibition at 30 μ M
*Percentage shrinking percentage at 3 μ M
In addition, we are according to Malmgrem etc., J.Urol.142:1134, the draft of explanation in 1989, measure the active over-drastic ability that has loose bladder (the compeling flesh) unstriated muscle of the clear-headed female mouse of loose bladder as the inhibition of embodiment 1 compound of other compounds represented of the present invention, therefore alleviated the urinary incontinence.
Use the female mouse of Sprague-Dawley, weight range 190-210g.25 animals of each preparation.After making hypertrophy of bladder, the each experiment with 4-8 animal.
Compound is dissolved among the PEG-200, with volume gastric intubation or the intravenous administration of 5ml/kg.During primary dcreening operation, it is each group of one group that all medicines give 4 mouse with any oral dose of 10mg/kg.
Alkyl halide anesthesia with animal.Midline incision exposes bladder and urethra, is pricking a 4-0 silk ribbon around the urethra near-end to produce partly obturation having a stainless steel strip (1mm diameter) in the presence of.Remove then and do not lure steel bar with abdomen area operation U-shaped pin sealing, to the Pemcilin G Benzathine-R of every mouse 150,000 units.Allow animal spend for 6 weeks to produce enough hypertrophies of bladder.After 6 weeks, remove silk ribbon under alkyl halide anesthesia, the conduit (PE60) that will have a latch closure places in the bladder top, with capsule linear system with seam jail.Conduit is passed under skin, by taking out at nape portion opening.The belly that cuts is sewed up the end sealing that conduit is exposed.For protecting from infection, to mouse injection Pemcilin G Benzathine-R (150000 units/mouse).After 2 days animal is carried out the Bladder Volume pressure detection.Animal is placed metabolism case (metabolic cages), conduit (using "T"-shaped junctor) is connected on Statham pressure transmitter (P23D6 type) and the Harrard infusion pump.To be connected with a power conversion transmitter (Grass FTO 3) plastic beaker place below the mouse case to collect and record urine amount.Allow animal rest 15-30 minute, begin to pour into salt solution (with 20ml/hr speed perfusion 20 minutes) in the Bladder Volume pressure calibrating phase first time then.The after date of Bladder Volume calibrating first 2 hours is taken vehicle or testing compound to mouse, carries out the Bladder Volume calibrating second time after 1 hour.
Write down following urine dynamical variable:
Basis bladder pressure=Bladder Volume pressure calibrating minimum bladder pressure of phase
Bladder pressure before threshold pressure=face is urinated
The urinate volume of volume=discharge
Urinate peak pressure power during pressure=drainage
The average spoke degree of bladder pressure fluctuation during constitutive activity=the fill urine
Result's expression:
Before and after compound administration, calculate the mean value of each variable.To each compound, the variation of its variable that records is compared with the value before the treatment, represent with percent inhibition.Also data are carried out two directions (2-way) variance analysis and determine that remarkable (p＜0.05) in measuring variable changes.
This result of study sees Table II
The table II
To autonomous inhibition of shrinking in the body
Compound number of animals dosage mg/kg (oral) % reduces (F) *
Embodiment 13 10-8 ± 4
*The autonomous percentage reduced rate that shrinks sum in the bladder model of mouse hypertrophy
Therefore, The compounds of this invention has obvious influence to smooth muscle contraction and can be used for treating the urinary incontinence, supersensitivity bladder and intestinal disease, asthma, hypertension, apoplexy and similar disease mentioned above, and they give potassium channel activatory compound by, parenteral route oral to the patient of this kind of needs treatment or suction and have come therapeutic action.

Claims (14)

1. following formula: compound or its pharmacy acceptable salt
Figure A9719713900021
Wherein:
R 1And R 2Independent be the straight chained alkyl of hydrogen, a 1-10 carbon atom, the branched-chain alkyl of a 3-10 carbon atom, the cycloalkyl of a 3-8 carbon atom, the bicyclic alkyl of a 4-10 carbon atom or the aralkyl of 7-20 carbon atom, and wherein the aromatic portion of aralkyl can be chosen wantonly by the branched-chain alkyl of the straight chained alkyl of 1-3 1-10 carbon atom, a 1-10 carbon atom, halogen, nitro, cyano group, the alkoxyl group of a 1-6 carbon atom, carbalkoxy, trifluoromethyl or the trifluoromethoxy replacement of a 2-7 carbon atom;
R 3Be the alkanoyl of hydrogen, formyl radical, a 2-7 carbon atom, the alkenoyl of a 3-7 carbon atom, the alkane alkylsulfonyl of a 1-7 carbon atom, the aroyl of a 7-12 carbon atom, the fragrant alkenoyl of a 9-20 carbon atom, the arylsulfonyl of a 6-12 carbon atom, the fragrant alkanoyl of a 8-12 carbon atom or the aralkyl alkylsulfonyl of 7-12 carbon atom; A is selected from:
Figure A9719713900031
Wherein:
N is 0 or 1;
R 4, R 5And R 6Independent is cyano group; nitro; amino; the alkyl of 1-6 carbon atom; the perfluoroalkyl of 1-6 carbon atom; the alkoxyl group of 1-6 carbon atom; the perfluoro alkoxy of 1-6 carbon atom; the alkylamino of 1-6 carbon atom; the dialkyl amido of 2-12 carbon atom; sulfamyl; the alkyl sulfinyl amino of 1-6 carbon atom; the fragrant sulfinyl amino of 6-12 carbon atom; the alkyl carbonylamino of 2-7 carbon atom; the aryl formamido group of 7-13 carbon atom; the alkanoyl of 2-6 carbon atom; the alkane alkylsulfonyl of 1-6 carbon atom; the perfluor alkane alkylsulfonyl of 1-6 carbon atom; the aryl sulfonyl of 6-12 carbon atom; chlorine; bromine; fluorine; iodine; the 1-imidazolyl; carboxyl or hydrogen.
2. according to compound or its pharmacy acceptable salt, the wherein R of claim 1 3For hydrogen, A are selected from as follows:
Figure A9719713900032
3. according to the compound of claim 1 or 2, R wherein 1And R 2Independent be hydrogen, methyl, ethyl, just or sec.-propyl, just, different, second month in a season or the tertiary butyl, straight or side chain amyl group or phenylalkyl, wherein alkyl be methylene radical or ethylidene and wherein phenyl moiety can choose wantonly by 1-3 the substituting group replacement that is selected from methyl, ethyl, fluorine, chlorine, bromine, nitro, cyano group, methoxyl group, oxyethyl group, methoxyl group oxygen base carbonyl, oxyethyl group oxygen base carbonyl, trifluoromethyl and trifluoromethoxy.
4. according to claim 1,2 or 3 compound, wherein R 4, R 5And R 6Independent is hydrogen, cyano group, nitro, amino, methyl, methoxyl group, chlorine, bromine, fluorine, iodine, trifluoromethyl, trifluoromethoxy or carbonyl.
5. according to the compound of the claim of any front, it is selected from: 3-(1,1-dimethyl propyl amino)-4-[(pyridin-4-yl-methyl)-and amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 3-(1,1-dimethyl propyl amino)-4-[(pyridin-3-yl-methyl)-amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 3-(1,1-dimethyl propyl amino)-4-[(pyridine-2-ylmethyl) amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 3-tertiary butyl amino-4-[(pyridin-4-yl methyl) amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 3-tertiary butyl amino-4-[(pyridin-3-yl methyl) amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 3-tertiary butyl amino-4-[(pyridine-2-ylmethyl) amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 3-(isopropyl-methyl amino)-4-[(pyridin-4-yl methyl) amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 3-[(5-nitro-cumarone-2-ylmethyl)-and amino-4-(1,2,2-trimethylammonium propyl group amino)-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 3-(1,1-dimethyl-propyl group amino)-4-[(5-nitro-cumarone-2-ylmethyl)-and amino] ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 3-tertiary butyl amino-4-[(5-nitrobenzofuran-2-ylmethyl)-amino]-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 2-{[2-(1,1-dimethyl propyl amino)-3,4-dioxy-ring but-1-ene base amino]-methyl }-cumarone-5-nitrile or its pharmacy acceptable salt; 2-{[3,4-dioxy-2-(1,2,2-trimethylammonium propyl group amino)-ring but-1-ene base amino]-methyl }-cumarone-5-nitrile or its pharmacy acceptable salt; 2-[(2-tertiary butyl amino-3,4-dioxy-ring but-1-ene base amino)-methyl]-cumarone-5-nitrile or its pharmacy acceptable salt; 2-{[2-(1,1-dimethyl-2-phenylethyl amino)-3,4-dioxy-ring but-1-ene base amino]-methyl }-cumarone-5-nitrile or its pharmacy acceptable salt; 3-[(pyridin-4-yl methyl) amino]-4-(1,2,2-trimethylammonium-propyl group amino)-ring fourth-3-alkene-1,2-diketone or its pharmacy acceptable salt; 2-{[2-(1,1-dimethyl-propyl group amino)-3,4-dioxy-ring but-1-ene base amino]-methyl }-3-chloro-cumarone-5-nitrile or its pharmacy acceptable salt.
6. medicinal compositions, it comprises by each defined formula I compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier among the claim 1-5.
7. reduce the method for the disadvantageous effect of smooth muscle contraction, it comprises and gives formula I compound or its pharmacy acceptable salt by each definition among the claim 1-5 to the oral or non-enteron aisle of the patient of this treatment of needs.
8. according to the method for claim 7, wherein unstriated muscle shrinks unfriendly and causes the urinary incontinence.
9. according to the method for claim 7, wherein unstriated muscle shrinks unfriendly and causes allergic intestinal syndrome.
10. formula I compound or its pharmacy acceptable salt according to each definition among the claim 1-5 is used as active medicinal or therapeutant.
11. the detrimental action that is used to reduce smooth muscle contraction according to formula I compound or its pharmacy acceptable salt of each definition among the claim 1-5.
12. according to the formula I compound of claim 11, wherein unstriated muscle shrinks unfriendly and causes the urinary incontinence.
13. according to the formula I compound of claim 11, wherein unstriated muscle shrinks unfriendly and causes the urinary incontinence.
14. preparation is gone by the formula I compound of each definition among the claim 1-5 or the side of its pharmacy acceptable salt, it comprises makes the formula II compound: Wherein X is suitable leavings group, reacts with the formula III compound: R wherein A1And R A2Be respectively the R of the same definition 1And R 2Maybe can change into R 1And R 2Atom.Make the reaction of its product and formula IV compound then:
A 1-CH 2NH 2(IV) be A wherein 1For as the A of preceding definition, maybe can change into the atom of A.And obtain the formula I compound, and optional its pharmacy acceptable salt that changes into; Or in addition, make as the formula II compound of preceding definition with as the formula IV compound reaction of preceding definition, make then its product with as the formula III compound reaction of preceding definition and obtain the formula I compound, and optional its pharmacy acceptable salt that changes into.
CN97197139A 1996-06-17 1997-06-10 Heterocyclylmethylamino derivatives of cyclobutene-3,4-diones as potassium channel modulators Pending CN1227543A (en)

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