CN1333774A - Substituted benzofuranodindoles and indenoindoles as novel potassium channel openers - Google Patents

Substituted benzofuranodindoles and indenoindoles as novel potassium channel openers Download PDF

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CN1333774A
CN1333774A CN99815495A CN99815495A CN1333774A CN 1333774 A CN1333774 A CN 1333774A CN 99815495 A CN99815495 A CN 99815495A CN 99815495 A CN99815495 A CN 99815495A CN 1333774 A CN1333774 A CN 1333774A
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indoles
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S·A·安塔内
J·A·布泰拉
J·R·伦诺克斯
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Wyeth LLC
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Abstract

Compounds of Formulae (I) and (II): wherein R1, R<2>, R<3>, X, Y and Z are as defined in the specification which compounds are useful in the treatment of disorders associated with smooth muscle contraction via potassium channel modulation.

Description

To replace benzo furo indoles and indeno [1,2-b] indoles as new potassium channel openers
Background of invention
1. invention field
The present invention relates to a series of substituted tetracyclic heteroaromatic cumarone diindyl and indenos [1 with pharmacological activity, 2-b] indoles, the preparation method who relates to them, be the pharmaceutical composition of component, and they are by regulating the purposes of potassium channel treatment and smooth muscle contraction relative disease.This type of disease includes but not limited to: the urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, stenocardia and cerebrovascular disease.
2. prior art
In current control resting cell membrane potential and influence in the method for cell excitement, regulate potassium channel and still belong to cutting edge technology.The dispersive potassium channel exists in a large number, and, according to structure, function, pharmacological characteristics and door control mechanism they have been carried out classification completely, can be referring to nearest document (Rudy, B. neuroscience 1988,25,729-749; Atwal, K., medical research comment 1992,28,95-127; Primeau, J. etc., contemporary medicinal design 1995,5 (11), 1453-1464).Activating these passages can increase and stride film K+ flux, causes that thus cytolemma is to Nernst K +(90mY) hyperpolarization of direction is subjected to valtage-gated Ga so close to equilibrium potential 2+Passage.As a result, the cell of superactivation becomes and is not easy excitement, has therefore reduced the responsiveness that stimulates again, makes smooth muscle loosening.Because this pharmacological reaction, people treat cardiovascular disorder with regard to the potassium channel activator, metabolic trouble, and central nervous system disease, the potentiality of bronchial asthma and irritable bladder aspect have been carried out big quantity research.
According to Bair, the report of K.W. in WO91/14688 and EP-447703-A1, many assorted Fourth Ring methylamino benzo furo benzazolyl compounds useful as anti-cancer agents and sterilant. Wherein a example is 2-methyl-2-(((10-methyl isophthalic acid 0H-cumarone is (3,2-b) indoles-6-yl) methyl also) amino)-1, ammediol.
The EP-404536-A1 of Sainsbury etc. discloses a series of indenos, and (1,2-b) indoles it is said useful as drug antioxidant and free-radical scavengers.
JP-06-228554 has described a series of indenos, and (1,2-b) indoles is as a kind of component of organic electronic twinkler.
X is-O--S-, SO 2-, or-NR 9Sainsbury, M. in WO90/15799 and EP-409410-B1, described the tetrahydrochysene indeno (1,2-b) a series of related analogs of indoles.
Figure A9981549500103
It is said that these compounds also can be used as antioxidant, with treatment arteriosclerosis, thrombosis, embolism and ParkinsonShi disease.
(1,2-b) (Tetrahedron 1991,47 (25), 4383-4408 for Brown, D.W. etc. for the synthetic and anti-oxidation characteristics of indoles and indoline to have several pieces of papers to report indeno; Brown, D.W. etc., Tetrahedron1993,49 (39), 8919-8932; Graupner, P.R. etc., Tetrahedron Lett.1995,36 (32) 5827-5830; Shertzer, H.G. etc., chemical toxicology, 1991,29 (6) 391-400).Brown, F.C. etc. be also at Tetrahedron Lett.1991, reported among 32 (6) 801-802 synthetic replacement indeno (1, the 2-b) flash-vacuum pyrolysis method of indoles.
Difference with the prior art of the present invention is, need be at general formula (I) and a position of assorted fragrant cumarone diindyl in Fourth Ring (II) and indenoindole replace with substituting group Z, as described later, Z is a carboxylic acid, the bioisostere thing of carboxylic acid, or derivatives thereof.The present invention proves that compound of the present invention has the potassium channel activation, and the smooth muscle loosening characteristic that causes has unique bladder body selectivity.
Summary of the invention
Therefore, the salt that the invention provides the compound shown in the general formula (I) and pharmaceutically approve, Wherein, R 1, R 2And R 3Each is hydrogen, halogen, nitro, cyano group, C naturally 1-10Alkyl, C 3-10Cycloalkyl can halogenated C 1-10Alkoxyl group, amino, C 1-10Alkylamino ,-SO 3H ,-SO 2NH 2,-NHSO 2R 14,
Figure A9981549500112
R 15SO 2-, carboxyl and C 6-12Aryl, or following acyl substituent: formyl radical, C 2-7Alkyloyl, C 3-7Enoyl-, C 1-7Alkyl sulphonyl, C 7-12Aroyl, C 9-20The aryl enoyl-, C 6-12Aryl sulfonyl, C 8-12Aromatic yl silane terephthalamide yl or C 7-12The aralkyl alkylsulfonyl;
Y is-O-and-NR 4
When Y is-NR 4The time, X is-O-;
When Y be-during O-, X is-NR 4
R 4Be hydrogen, C 1-10Alkyl, C 3-10Cycloalkyl, C 6-12Aryl, or following acyl substituent: formyl radical, C 2-7Alkyloyl, C 3-7Enoyl-, C 1-7Alkyl sulphonyl, C 7-12Aroyl, C 9-20The aryl enoyl-, C 6-12Aryl sulfonyl, C 8-12Aromatic yl silane terephthalamide yl or C 7-12The aralkyl alkylsulfonyl;
R 5And R 6Each is hydrogen naturally, C 1-10Alkyl, C 3-10Cycloalkyl, C 6-12Aryl, or fluorine;
A bit substituent Z is selected from
Figure A9981549500121
With
Figure A9981549500123
M is alkali metal cation or alkaline earth metal cation;
R 7Be C 1-10Alkyl, C 3-10Cycloalkyl, C 7-20Aralkyl, or C 6-12Aryl;
R 8And R 9Each is hydrogen naturally, C 1-10Alkyl, C 3-10Cycloalkyl, C 7-20Aralkyl, or C 6-12Aryl;
R 10, R 11, R 12And R 13Each is C naturally 1-10Alkyl;
R 14Be C 1-10Straight chained alkyl;
R 15Be can halogenated C 1-10Straight chained alkyl;
But aroyl is benzoyl and naphthoyl that 1-3 replaces, and substituting group is selected from halogen, cyano group, C separately 1-10Alkyl, C 1-10Alkoxyl group ,-CF 3And phenyl;
Aryl is a naphthyl, the phenyl that phenyl or 1-3 replace, and substituting group is selected from halogen, carboxyl, C separately 1-10Alkyl, nitro, amino, C 1-10Alkoxyl group, and C 1-10Alkylamino;
Condition is, when Z is-CHO, Y is-O-that X is-N-CH 3The time, R 1, R 2And R 3Not hydrogen.
The present invention is the general formula of following subgroup (I) compound and the salt of approval pharmaceutically thereof preferably, and other groups wherein are identical with the above, wherein: when X be-during O-, Y is-NR 4
The salt that is more preferably general formula (I) compound of following subgroup and pharmaceutically approves, other groups wherein are identical with the above, and wherein: Z is-CO 2H; R 1Be halogen or nitro;
A) as Y be-NR 4The time, X is-O-;
B) when Y be-during O-, X is-NR 4
The present invention particularly preferably is following general formula (I) compound or its salt of pharmaceutically approving:
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
8-iodo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
8-chloro-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
Two hydration 8-nitros-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid amide;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylate methyl ester;
(8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-yl)-methyl alcohol;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid hydroxymethyl acid amides;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-formaldehyde (carbaldehyde);
One hydration 8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-nitrile;
8-bromo-1-(1H-tetrazolium-5-yl)-10H-benzo [4,5] furo [3,2-b] indoles;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid (1,2,2-trimethylammonium-propyl group)-acid amides;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid (1,1-dimethyl-propyl group)-acid amides;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid methyl acid amides;
8-bromo-10 methyl isophthalic acid 0H-benzo [4,5] furo [3,2-b] indoles-1-carboxylate methyl esters; With
10H-benzo [4,5] furo [3,2-b] indoles-carboxylic acid.
It is a kind of by regulating the method for potassium channel treatment or inhibition warm-blooded animal and smooth muscle contraction relative disease that the present invention also provides, comprise and give described warm-blooded animal (Mammals is good, the people is especially suitable) general formula (II) compound of significant quantity, or its salt of pharmaceutically approving
Figure A9981549500131
Wherein: wherein, R 1, R 2And R 3Each is hydrogen, halogen, nitro, cyano group, C naturally 1-10Alkyl, C 3-10Cycloalkyl can halogenated C 1-10Alkoxyl group, amino, C 1-10Alkylamino ,-SO 3H ,-SO 2NH 2,-NHSO 2R 14,
Figure A9981549500132
R 15SO 2-, carboxyl and C 6-12Aryl, or following acyl substituent: formyl radical, C 2-7Alkyloyl, C 3-7Enoyl-, C 1-7Alkyl sulphonyl, C 7-12Aroyl, C 9-20The aryl enoyl-, C 6-12Aryl sulfonyl, C 8-12Aromatic yl silane terephthalamide yl or C 7-12The aralkyl alkylsulfonyl;
Y is-NR 4With-CR 5R 6
When Y is-NR 4The time, X is-O-;
When Y is-CR 5R 6The time, X is-NR 4
When Y is-NR 4The time, X is-CR 5R 6
R 4Be hydrogen, C 1-10Alkyl, C 3-10Cycloalkyl, C 6-12Aryl, or following acyl substituent: formyl radical, C 2-7Alkyloyl, C 3-7Enoyl-, C 1-7Alkyl sulphonyl, C 7-12Aroyl, C 9-20The aryl enoyl-, C 6-12Aryl sulfonyl, C 8-12Aromatic yl silane terephthalamide yl or C 7-12The aralkyl alkylsulfonyl;
R 5And R 6Each is hydrogen naturally, C 1-10Alkyl, C 3-10Cycloalkyl, C 6-12Aryl, or fluorine;
A bit substituent Z is selected from
Figure A9981549500142
With
M is alkali metal cation or alkaline earth metal cation;
R 7Be C 1-10Alkyl, C 3-10Cycloalkyl, C 7-20Aralkyl, or C 6-12Aryl;
R 8And R 9Each is hydrogen naturally, C 1-10Alkyl, C 3-10Cycloalkyl, C 7-20Aralkyl, or C 6-12Aryl;
R 10, R 11, R 12And R 13Each is C naturally 1-10Alkyl;
R 14Be C 1-10Straight chained alkyl;
R 15Be can halogenated C 1-10Straight chained alkyl;
But aroyl is benzoyl and naphthoyl that 1-3 replaces, and substituting group is selected from halogen, cyano group, C separately 1-10Alkyl, C 1-10Alkoxyl group ,-CF 3And phenyl;
Aryl is a naphthyl, the phenyl that phenyl or 1-3 replace, and substituting group is selected from halogen, carboxyl, C separately 1-10Alkyl, nitro, amino, C 1-10Alkoxyl group, and C 1-10Alkylamino.
A preferred content of the present invention is general formula (II) compound or its salt of pharmaceutically approving with following subgroup, by regulating potassium channel, (Mammals is good to the treatment warm-blooded animal, the people is especially suitable) disease relevant with smooth muscle contraction, other groups wherein are with above described identical with regard to general formula (II), wherein:
A) as Y be-NR 4The time, X is-O-;
B) as Y be-CR 5R 6The time, X is-NR 4
C) as Y be-NR 4The time, X is-CR 5R 6
Be more preferably, general formula (II) compound or its salt of pharmaceutically approving with following subgroup, by regulating potassium channel, (Mammals is good to the treatment warm-blooded animal, the people is especially suitable) disease relevant with smooth muscle contraction, other groups wherein are with above described identical with regard to general formula (II), and wherein: Z is-CO 2H; R 1Be halogen or nitro;
A) as Y be-NR 4The time, X is-O-;
B) as Y be-CR 5R 6The time, X is-NR 4
C) as Y be-NR 4The time, X is-CR 5R 6
Be more preferably, with following general formula (II) compound or its salt of pharmaceutically approving, by regulating potassium channel, treatment warm-blooded animal (Mammals is good, and the people the is especially suitable) disease relevant with smooth muscle contraction:
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
8-iodo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
8-chloro-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
Two hydration 8-nitros-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid amide;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylate methyl ester;
(8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-yl)-methyl alcohol;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid hydroxymethyl acid amides;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-formaldehyde;
One hydration 8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-nitrile;
8-bromo-1-(1H-tetrazolium-5-yl)-10H-benzo [4,5] furo [3,2-b] indoles;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid (1,2,2-trimethylammonium-propyl group)-acid amides;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid (1,1-dimethyl-propyl group)-acid amides;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid methyl acid amides;
8-bromo-10 methyl isophthalic acid 0H-benzo [4,5] furo [3,2-b] indoles-1-carboxylate methyl esters;
10H-benzo [4,5] furo [3,2-b] indoles-carboxylic acid;
0.6 hydration 8-iodo-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid;
Half hydration 8-sulfamyl-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid;
8-fluoro-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid;
8-chloro-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid;
8-trifluoromethoxy-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid;
8-chloro-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid, ethyl ester;
8-bromo-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid, ethyl ester;
10,10-dimethyl-3-nitro-5,10-dihydro-indeno [1,2-b] Indole-6-carboxylic acid;
8-bromo-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid; With
3-bromo-5,10-dihydro-indeno [1,2-b] Indole-6-carboxylic acid.
Work as R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13Or R 15When comprising unsymmetrical carbon, general formula (I) and (II) compound comprise having hereinafter described active all possible steric isomer natch.Specifically, the definition of compound comprises various have described active racemic modification and optical isomers.The optical isomer of pure form can obtain by standard isolation technique or enantiomorph specificity synthesis method.The present invention includes the general formula (I) and (II) all crystals form of compound.Those that the pharmaceutically salt of approval of basic cpd of the present invention refers to form with organic acid and mineral acid, described acid are for example: lactic acid, citric acid, acetate, tartrate, fumaric acid, succsinic acid, toxilic acid, propanedioic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic, and the similar known salt of approving.
If R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8Or R 9Contain carboxyl, or Z is when being carboxylic acid, salt of the present invention can be with basic metal (Na, K, Li) or alkaline-earth metal (Ca or Mg) form.
At above general formula (I) with (II) in the compound, unless otherwise mentioned, following term is defined as:
Halogen or halo refer to chlorine, fluorine, bromine and iodine.
Alkyl refers to the side chain or the straight chain of 1 to 10 carbon atom at this, is good with 1-6 carbon atom.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group and hexyl.
Cycloalkyl refers to the saturated rings of 3-10 carbon atom at this, is good with 3-6 carbon atom.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Aryl refers to condense or the carbocyclic ring aromatic base of 6-12 carbon atom of non-condensed at this.Aryl comprises phenyl preferably, Alpha-Naphthyl and betanaphthyl etc., and they can be replaced by 1-3, and substituting group is selected from halogen, carboxyl, C 1-10Alkyl, nitro, amino, C 1-10Alkoxyl group and C 1-10Alkylamino.
Aroyl refers to-C (O) aryl that at this aryl wherein as previously mentioned.Its example comprises benzoyl and naphthoyl, and they can be replaced by 1-3, and substituting group is selected from halogen, cyano group, C 1-10Alkyl, C 1-10Alkoxyl group ,-CF 3And phenyl.
Aralkyl refers to aryl-alkyl group at this, and aryl wherein and alkyl are as previously mentioned.Its example comprises benzyl and styroyl.
Thiazolinyl refers to the side chain or the side chain of 2-12 carbon atom at this, is good with 2-6 carbon atom, contains at least one carbon-to-carbon double bond in the chain.Thiazolinyl is at this and alkenyl synonym, and comprises alkylidene group.The example of thiazolinyl comprises vinyl (ethylidene), propenyl (propylidene) and isobutenyl (isobutylidene).
Alkyloyl is-C (O) alkyl that alkyl wherein as previously mentioned at this.
Enoyl-is-C (O) thiazolinyl that thiazolinyl wherein as previously mentioned at this.
Alkoxyl group is-the O-alkyl that alkyl wherein as previously mentioned at this.The example of alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and tert.-butoxy.
Aromatic yl silane terephthalamide yl is that carbonyl directly is combined in C 1-10On the alkyl, the end of this alkyl is replaced by aforementioned aryl, for example phenylacetic acid.This aryl can be replaced by 1-3, and substituting group is selected from halogen, cyano group, C 1-10Alkyl, C 1-10Alkoxyl group ,-CF 3, phenyl or substituted-phenyl, the substituting group on it is selected from halogen, cyano group, C 1-10Alkyl, C 1-10Alkoxyl group and-CF 3
The aryl enoyl-is that carbonyl directly is combined in C 2-12On the thiazolinyl, the end of this thiazolinyl is replaced by aforementioned aryl.Aryl can be replaced by 1-3, and substituting group is selected from halogen, cyano group, C 1-10Alkyl, C 1-10Alkoxyl group ,-CF 3, phenyl or substituted-phenyl, the substituting group on it is selected from halogen, cyano group, C 1-10Alkyl, C 1-10Alkoxyl group and-CF 3
Alkyl sulphonyl is-SO 2Alkyl, alkyl wherein as previously mentioned.
Aryl sulfonyl is-SO 2Aryl, aryl wherein as previously mentioned.
The aralkyl alkylsulfonyl is aralkyl O 2S-, wherein aralkyl as previously mentioned.
Phenyl refers to 6 yuan of aromatic nucleus at this.
When term was used in combination, unless do explanation in addition, the independent implication of each several part as mentioned above.For example, aryl in the aralkyl and alkyl are respectively as previously mentioned.
Above carbonatoms is the carbon atom in the carbon skeleton, does not comprise the carbon atom in the substituting group.
The present invention also provides and has prepared the general formula (I) and (II) method of compound.General formula (I) and (II) in the compound, X is-O-that Y is-NR 4, R wherein 4As previously mentioned, can prepare according to scheme 1.With the benzofuranone 1 (R wherein that suitably replaces 1, R 2And R 3In aqueous medium, react as previously mentioned), generate corresponding phenylhydrazone 3 with 2-hydrazino-benzoic acid 2.This intermediate of isolated or purified transforms then, or carries out the Fischer-indoles cyclization of microwave-assisted, the benzo that obtains replacing [4,5] furo [3,2-b] indoles 4 with crude product in acidic medium (such as but not limited to formic acid).If R 4Be not hydrogen, then the available standards method is introduced R 4, make carboxylic acid 5.Scheme I
Figure A9981549500181
Perhaps, can be prepared as follows general formula (I) and (II) compound shown in scheme II, X wherein is NR 4, Y is-CR 5R 6, R wherein 4, R 5And R 6As previously mentioned.Can be with the phenylhydrazine 6 (R wherein that suitably replaces 1, R 2And R 3As previously mentioned) with 2,3-dihydro-indone-1-carboxylic acid 7 (R wherein 5And R 6As previously mentioned) reaction obtains phenylhydrazone 8, and phenylhydrazone 8 carries out the Fischer-indoles cyclization of microwave-assisted in the presence of acid (such as but not limited to formic acid), obtain indeno [1,2-b] indoles 9.
Scheme II If R 4Be not hydrogen, then the available standards method is introduced R 4, make carboxylic acid 10.
Can be prepared as follows general formula (I) and (II) compound shown in scheme III, X wherein is-CR 5R 6, Y is-NR 4, R wherein 4, R 5And R 6As previously mentioned.Can with suitably replace 2,3-dihydro-indone (11) (R wherein 1, R 2, R 3, R 5And R 6In aqueous medium, react as previously mentioned), obtain intermediate phenylhydrazone (12) with 2-hydrazino-benzoic acid (2).Can carry out the Fischer-indoles cyclization of microwave treatment to promote in acidic medium (such as but not limited to formic acid), to carry out, the indeno that obtains replacing [1,2-b] indoles (13) to the intermediate phenylhydrazone.If R 4Be not hydrogen, then the available standards method is introduced R 4, make carboxylic acid 14.
Scheme III
Figure A9981549500191
Benzo [4,5] furo [3,2-b] indoles 4, carboxylic acid 5, indeno [1,2-b] indoles 9, carboxylic acid 10, the carboxylic moiety in the indeno of replacement [1,2-b] indoles 13 and the carboxylic acid 14 can form other groups, represents with Z at general formula (I) with (II).For example, can form corresponding carboxylic acid salt with alkali metal base or alkaline-earth metal alkali reaction.In the presence of acid with alcohol (R 7OH, R wherein 7As previously mentioned) can form ester.Also available additive method known in the art prepares ester.
Use appropriate reductant, diisobutylaluminium hydride for example, sodium borohydride, lithium aluminium hydride, ester reduction will generate corresponding alcohol or aldehyde.If only generate alcohol, can be with suitable mild oxidation agent in the acetonitrile that has 4 dust molecular sieves to exist, chlorine lattice acid pyridine or 1 for example, 1,1-triacetyl Oxy-1,1-dihydro-1,2-benzo iodine tetrahydrofuran (benziodoxol)-3-(the 1H)-ketone of mixing, or cross the ruthenic acid tetrapropyl ammonium, it is oxidized to aldehyde.
Can also be by at activator hydrochloric acid 2-dimethylamino isopropyl chloride/4-dimethylaminopyridine for example, or diethylazodicarboxylate/triphenylphosphine exists down, with amine (NHR 8R 9, R wherein 8And R 9As previously mentioned) reaction is converted into corresponding amide with carboxylic moiety.Perhaps, suitable reagent such as available for example thionyl chloride or oxalyl chloride etc. is converted into corresponding chloride of acid with carboxylic acid.Then, in the presence of exogenously added alkali with suitable amine (NHR 8R 9, R wherein 8And R 9As previously mentioned) reaction can obtain required acid amides.
With identical method, the oxyamine (NHR of available suitable replacement 8OH, R wherein 8As previously mentioned) with the corresponding hydroxamic acid of chloride of acid prepared in reaction.In the presence of strong acid,, will generate corresponding nitrile (Z is CN) with urea and carboxylic acid reaction.Nitrile can be converted into tetrazolium by the cyclization that carries out with sodium azide.
In organic solvent such as tetrahydrofuran (THF) or methylene dichloride for example, at suitable alkali or Ag 2O exists down, uses Kim, and K.S. etc. are at J.Med.Chem.1993, and the condition described in 36,2335 is with C1 (R 10) COC (O) R 11The alkanisation carboxylic acid; Or at sodium iodide/N, dinethylformamide exists down, uses Bundgaard, and H. is at Int.J.Pharm.1989, and the condition described in 55,91 is used ClCH 2C (O) N (R 12R 13) cyclisation, will generate the prodrug analogue of biology equivalence.
General formula (I) but and (II) compound and pharmaceutically the approval the salt relaxing smooth muscle.Therefore, they can be used for the treatment of the disease relevant with smooth muscle contraction, this type of disease comprises urinary tract unstriated muscle excess shrinkage (for example urinary incontinence), or gastrointestinal smooth muscle excess shrinkage (for example irritable intestine syndrome), asthma and alopecia.And, general formula (I) and (II) compound have potassium channel activator activity, thereby can be used for treating peripheral vascular disease, congestive heart failure, apoplexy, anxiety, other nerve degenerative diseases such as cerebral anoxia.
Learn in the test at standard drug, The compounds of this invention can powerful relaxing smooth muscle.The compounds of this invention is brought into play its smooth muscle relaxation activity by activating potassium channel.In addition, the unique distinction of The compounds of this invention is that also inherent is higher than selectivity to vascular tissue to bladder body, and this can be reflected in bladder/aorta IC 50Ratio on (table 1).
The present invention also provides a kind of pharmaceutical composition, the carrier that wherein contains compound of the present invention and pharmaceutically approve.Specifically, the invention provides a kind of pharmaceutical composition of the carrier that contains the significant quantity The compounds of this invention and pharmaceutically approve.
Described composition should be made oral dosage form.Yet, also can be made into other formulations, for example be used for the parenteral formulation of patients with heart failure.
In order to obtain the consistence of administration, the present composition should be taked the form of unitary dose.Suitable unit dose shape comprises tablet, capsule and packed or bottled pulvis.Such unit dosage can comprise the 0.1-100mg The compounds of this invention, is advisable with 2-50mg.Be more preferably the unit dosage that contains the 5-25mg The compounds of this invention.The compounds of this invention can be by the oral dose of 0.01-100mg/kg, and 0.1-10mg/kg is then better.But such composition gives 1-6 time every day, is generally every day 1-4 time.
The present composition can be prepared with conventional excipient, filling agent for example, disintegrating agent, tackiness agent, lubricant, mask agent etc.Available ordinary method is prepared, for example with the used similar method of known antihypertensive drug, diuretic(s) and beta-Blocking agent.
The present invention also provides the compound as the active treatment material.General formula (I) and (II) compound induce aspect the smooth muscle loosening effective especially.
The present invention also provides the method for treatment Mammals (comprising the people) unstriated muscle relative disease, comprises the The compounds of this invention or the pharmaceutical composition that give patient's significant quantity.
Following examples illustrate rather than define the method for preparing representative compounds of the present invention.
Embodiment 1
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
Adjacent [(2,3-dihydro-5-bromobenzene and furans-3-subunit) the diazanyl]-phenylformic acid of step 1) preparation
To 5-bromo-3 (2H)-benzofuranone (3.10g, 14.6mmol) [Ellingboe, J. etc., pharmaceutical chemistry magazine 1992,35 (7), 1176-1183] ethanol (100ml) solution in add hydrochloric acid 2-hydrazino-benzoic acid (5.49g, deionized water 29.1mmol) (200ml) solution.Mixture at room temperature stirred 1 hour, left standstill cooling (to 0 ℃) then.Through vacuum filtration and vacuum-drying, obtain 3.65g (72%) title compound brown solid: mp.195 ℃ (dec. (decomposition)), purifying does not directly use.
Step 2) preparation 8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
In microwave oven (700W), in the Teflon test tube of block, hydrazone (embodiment 1 step 1 is prepared) (0.500g, 1.51mmol) 2 minutes irradiation of acceptance in formic acid (2ml, 96%).This mixture of suction filtration while hot, solid vacuum-drying, 0.271g (57%) title compound yellow solid: mp.312-313 ℃; 1H NMR (DMSO-d 6): δ 13.36 (s, 1H), 11.64 (s, 1H), 8.27 (s, 1H), 8.07 (d, 1H), 7.92 (d, 1H), 7.70 (d, 1H), 7.27 (t, 1H); IR (KBr): 3420,1685cm -1MS (m/z) 329 (M +).
To C 15H 8BrNO 3Ultimate analysis:
Calculated value: C, 54.57; H, 2.44; N, 4.24.
Measured value: C, 54.22; H, 2.32; N, 4.30.
Embodiment 2
8-iodo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
Adjacent [(2,3-dihydro-5-iodobenzene and furans-3-subunit) the diazanyl]-phenylformic acid of step 1) preparation
To 5-iodo-3 (2H)-benzofuranone (0.551g, 2.12mmol) [Cagniant, P. etc., Hebd.SeancesAcad.Sci., Ser.C, 1976,282 (21), 993-6] ethanol (100ml) solution in add hydrochloric acid 2-hydrazino-benzoic acid (0.800g, deionized water 4.24mmol) (50ml) solution.Mixture at room temperature stirred 1 hour, left standstill cooling (to 0 ℃) then.Through vacuum filtration and vacuum-drying, obtain 0.480g (58%) title compound brown solid: mp.169 ℃ (dec.), purifying does not directly use.
Step 2) preparation 8-iodo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
In microwave oven (700W), in the Teflon test tube of block, hydrazone (embodiment 2 steps 1 are prepared) (0.480g, 1.22mmol) 2 minutes irradiation of acceptance in formic acid (2ml, 96%).This mixture of suction filtration while hot, solid vacuum-drying, 0.240g (52%) title compound yellow solid: mp.297 ℃ (dec); 1H NMR (DMSO-d 6): δ 13.33 (s, 1H), 11.63 (s, 1H), 8.47 (s, 1H), 8.07 (d, 1H), 7.91 (d, 1H), 7.65 (d, 1H), 7.57 (d, 1H), 7.28 (t, 1H); IR (KBr): 3420,1670cm -1MS (m/z) 377 (M +).
To C 15H 8INO 3Ultimate analysis:
Calculated value: C, 47.77; H, 2.14; N, 3.71.
Measured value: C, 47.61; H, 1.92; N, 3.68.
Embodiment 3
8-chloro-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
Adjacent [(2,3-dihydro-5-chlorobenzene and furans-3-subunit) the diazanyl]-phenylformic acid of step 1) preparation
To 5-chloro-3 (2H)-benzofuranone (0.357g, 2.12mmol) [Ellingboe, J. etc., pharmaceutical chemistry magazine 1992,35 (7), 1176-1183] ethanol (100ml) solution in add hydrochloric acid 2-hydrazino-benzoic acid (0.800g, deionized water 4.24mmol) (50ml) solution.Mixture at room temperature stirred 1 hour, left standstill cooling (to 0 ℃) then.Through vacuum filtration and vacuum-drying, obtain 0.400g (62%) title compound brown solid: mp.190 ℃ (dec.), purifying does not directly use.
Step 2) preparation 8-chloro-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
In microwave oven (700W), in the Teflon test tube of block, hydrazone (embodiment 3 steps 1 are prepared) (0.480g, 1.22mmol) 2 minutes irradiation of acceptance in formic acid (2ml, 96%).This mixture of suction filtration while hot, solid vacuum-drying, 0.240g (52%) title compound yellow solid: mp.303 ℃ (dec); 1H NMR (DMSO-d 6): δ 13.24 (s, 1H), 11.64 (s, 1H), 8.12 (s, 1H), 8.07 (d, 1H), 7.92 (d, 1H), 7.75 (d, 1H), 7.39 (d, 1H), 7.28 (t, 1H); IR (KBr): 3430,1685cm -1MS (m/z) 285 (M +).
To C 15H 8ClNO 3Ultimate analysis:
Calculated value: C, 63.06:H, 2.82; N, 4.90.
Measured value: C, 63.00:H, 2.57; N, 4.98.
Embodiment 4
Two hydration 8-nitros-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
Adjacent [(2,3-dihydro-5-nitrobenzofuran-3-subunit) the diazanyl]-phenylformic acid of step 1) preparation
With 5-nitro-3 (2H)-benzofuranone (0.500g, 2.79mmol) [Tobias, P. etc., Journal of the American Chemical Society, 1969,91 (18), 5171-5173] and hydrochloric acid 2-hydrazino-benzoic acid (0.526g 2.79mmol) is blended in the pyridine (10ml), and normal temperature stirs down and spends the night.Mixture obtains 0.800g (86%) title compound yellow solid through vacuum filtration and vacuum-drying: mp.210 ℃ (dec.), purifying does not directly use.
Step 2) preparation two hydration 8-nitros-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
In microwave oven (700W), in the Teflon test tube of block, hydrazone (embodiment 4 steps 1 are prepared) (0.500g, 1.51mmol) 2 minutes irradiation of acceptance in formic acid (2ml, 96%).This mixture of suction filtration is dissolved in dimethyl sulfone with solid, uses water precipitation again, gets 0.296g (66%) title compound yellow solid: mp.325 ℃ (dec); 1H NMR (DMSO-d 6): 813.42 (s, 1H), 11.82 (s, 1H), 9.07 (d, 1H), 8.26 (d, 1H), 8.13 (d, 1H), 7.97 (d, 1H), 7.95 (s, 1H), 7.32 (t, 1H); IR (KBr): 3380,1675cm -1MS (m/z) 296 (M +).
To C 15H 8N 2O 52H 2The ultimate analysis of O:
Calculated value: C, 54.22; H, 3.64; N, 8.43.
Measured value: C, 54.25; H, 3.48; N, 7.68.
Embodiment 5
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid amide
(0.100g 0.303mmol) is dissolved in the ether (20ml) with the product of embodiment 1 step 2.Under argon atmospher, in this solution, add phosphorus pentachloride (72.0mg, 0.345mmol).Stir after 30 minutes under the room temperature and form yellow mercury oxide.Add the saturated ether (75ml) of ammonia, stirring reaction spends the night.Enriched mixture, chromatography (hexane/ethyl acetate, 1: 1) is collected the acid amides (60mg) of high washing out property.Product with after the ether grinding separation obtains 0.024g (24%) title compound light yellow solid: mp.300-301 ℃; 1H NMR (DMSO-d 6): δ 11.72 (s, 1H), 8.31 (s, 1H), 8.24 (br s, 1H), 7.97 (d, 1H), 7.82 (d, 1H), 7.68 (d, 1H), 7.58 (br s, 1H), 7.47 (d, 1H), 7.22 (t, 1H); IR (KBr): 1650cm -1MS (m/z) 328 (M +).
To C 15H 9BrN 2O 2Ultimate analysis:
Calculated value: C, 54.74; H, 2.75; N, 8.51.
Measured value: C, 54.53; H, 2.72; N, 8.34.
Embodiment 6
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylate methyl ester
(5.75g 17.4mmol) mixes with the vitriol oil (3ml) and methyl alcohol (500ml), and heating is 3 days in 100 ℃ oil bath with the product of embodiment 1 step 2.Cooling and enriched mixture.Grind the concentrating residues thing with ether, obtain 2.40g (40%) title compound brown solid: mp.204-205 ℃; 1H NMR (DMSO-d 6): δ 11.66 (s, 1H), 8.23 (s, 1H), 8.10 (d, 1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.30 (t, 1H), 4.01 (s, 3H); IR (KBr): 3420,1710cm -1MS (m/z) 343 (M +).
To C 16H 10BrNO 3Ultimate analysis:
Calculated value: C, 55.84; H, 2.93; N, 4.07.
Measured value: C, 55.49; H, 2.82; N, 4.01.
Embodiment 7
(8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-yl)-methyl alcohol
(0.025g, 0.659mmol) (0.196g 0.570mmol) is dissolved in the solution that tetrahydrofuran (THF) (5ml) is become to the product of adding embodiment 6 with the lithium aluminium hydride powder.Normal temperature stirred 18 hours down, added deionized water (0.20ml) carefully, added the sodium hydroxide (0.20ml) of 2.5N then, added entry (2ml) then.With diatomite sheet filtering mixt, with dried over mgso filtrate.Crude product is carried out chromatography (hexane/ethyl acetate, 3: 1), obtain 0.060g (33%) title compound white solid: mp.218-219 ℃; 1HNMR (DMSO-d 6): δ 11.25 (s, 1H), 8.01 (s, 1H), 7.68 (d, 2H), 7.49 (d, 1H), 7.25 (d, 1H), 7.14 (t, 1H), 5.38-5.41 (br s, 1H), 4.88 (s, 2H); IR (KBr): 3600-3100 (wide) cm -1MS (m/z) 315 (M +).
To C 15H 10BrNO 2Ultimate analysis:
Calculated value: C, 56.99; H, 3.19; N, 4.43.
Measured value: C, 57.23; H, 2.45; N, 4.45.
Embodiment 8
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid hydroxymethyl acid amides
(1.00ml, 11.5mmol) (1.00g 3.03mmol) is dissolved in ether (100ml) and N, the solution that dinethylformamide (0.40ml) is become to the product of adding embodiment 1 step 2 with oxalyl chloride.After 1 hour, this yellow mixture of vacuum concentration.Residue is dissolved in methylene dichloride (80ml), and stir on the limit, and the limit adds hydrochloric acid N-methyl oxyamine with it, and (1.26g is 15.1mmol) at tetrahydrofuran (THF)/water (16ml, 15: 1) and triethylamine (4.20ml, 30.3mmol) solution that is become.Stirring is spent the night, and mixture is distributed between ethyl acetate and the water.Use the dried over mgso organic phase.Crude product obtains 0.100g (9%) title compound white solid: mp.174-175 ℃ through chromatography (hexane/ethyl acetate, 1: 1); 1H NMR (DMSO-d 6): δ 10.22-11.18 (br s, 2H), 8.12 (s, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.50 (d, 1H), 7.20 (t, 1H), 3.38 (s, 3H); IR (KBr): 1640cm -1MS (m/z) 358 (M +).
To C 16H 11BrN 2O 3Ultimate analysis:
Calculated value: C, 53.50; H, 3.09; N, 7.80.
Measured value: C, 53.33; H, 2.98; N, 7.71.
Embodiment 9
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-formaldehyde
With 1,1,1-triacetyl Oxy-1,1-dihydro-1,2-benzo iodine are mixed, and (0.522g, acetonitrile 1.23mmol) (20ml) solution add embodiment 7 products (0.390g, acetonitrile 1.23mmol) (50ml) solution to tetrahydrofuran-3 (1H)-ketone.With TLC (hexane/ethyl acetate, 1: 1) monitoring reaction.Yellow mixture poured into contain Sulfothiorine (0.187g, saturated solution of sodium bicarbonate 1.18mmol).Distribute mixture, organic phase sodium bicarbonate aqueous solution and salt water washing, dry (MgSO 4), concentrate then.Grind the concentrating residues thing, after the vacuum-drying, obtain title compound yellow solid 0.117g (30%): mp.280-281 ℃; 1H NMR (DMSO-d 6): δ 12.10 (s, 2H), 10.23 (s, 1H), 8.24 (s, 1H), 8.20 (d, 1H), 7.96 (d, 1H), 7.73 (d, 1H), 7.54 (d, 1H), 7.43 (t, 1H); IR (KBr): 1660cm -1MS (m/z) 313 (M +).
To C 15H 8BrNO 2Ultimate analysis:
Calculated value: C, 57.35; H, 2.57; N, 4.46.
Measured value: C, 57.05; H, 2.37; N, 7.86.
Embodiment 10
One hydration 8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-nitrile
(0.500g is 1.51mmol) with urea fine powder (8.67g, 1.44mmol) thorough mixing for the product of embodiment 1 step 2.(2.5g 21.7mmol), adds N then, and dinethylformamide (DMF) (7ml) to add phosphoric acid.(15-30% power, 700W) middle irradiation is 35 minutes, cooling then at microwave oven for reaction mixture.Crude product is pulverized, be distributed between water and the ether.The vacuum concentration organic phase is dissolved in acetone/7 ethers (1: 1) with residue, filters with silica gel plug, with ether and hexane (1: 1) wash-out, obtains 0.088g (19%) title compound light yellow solid: mp.277-280 ℃ (dec); 1H NMR (DMSO-d 6): δ 11.44 (s, 1H), 8.18 (d, 1H), 7.97 (s, 1H), 7.79 (d, 1H), 7.76 (d, 1H), 7.58 (d, 1H), 7.34 (t, 1H); IR (KBr): 2230cm -1
To C 15H 7BrN 2OH 2The ultimate analysis of O:
Calculated value: C, 54.74; H, 2.76; N, 8.51.
Measured value: C, 55.29; H, 2.36; N, 8.22.
Embodiment 11
8-bromo-1-(1H-tetrazolium-5-yl)-10H-benzo [4,5] furo [3,2-b] indoles
The product of embodiment 10 (0.350g, 1.13mmol), NaN3 (0.102g, 1.58mmol) and n-Bu 3(0.43ml 1.58mmol) mixes in dimethylbenzene (5m1) SnCl, and 120 ℃ were stirred 18 hours.Use the TLC monitoring reaction, add DMF (2ml).In 130 ℃ of stirring reactions 18 hours, reaction mixture, with 6NHCl (10ml) dilution, stirred 1 hour, feed N simultaneously 2The solid that vacuum filtration forms is used H 2The O washing.The solid recrystallization from hot methanol, and grind with hot ethyl acetate.Filter and collect title compound (0.15g, 38%), be rice white solid: mp.275-277 ℃ (dec); 1H NMR (DMSO-d 6): δ 11.87 (s, 1H), 8.14 (d, 1H), 5.08 (d, 1H), 8.05 (d, 1H), 7.97 (d, 1H), 7.71 (d, 1H), 7.54 (d, 1H), 7.41 (dd, 1H); IR (KBr): 3360,1440cm -1MS (m/z) 353 (M +).
To C 15H 8BrN 5The ultimate analysis of O:
Calculated value: C, 50.87; H, 2.27; N, 19.77.
Measured value: C, 50.93; H, 2.52; N, 18.06.
Embodiment 12
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid (1,2,2-trimethylammonium-propyl group)-acid amides
To embodiment 1 step 2 product (0.15g adds 5 DMF in methylene dichloride 0.455mmol) (4ml) solution, add then oxalyl chloride (0.12ml, 1.53mmol).Compound at room temperature stirred 1 hour, then vacuum concentration.Residue heavily is dissolved in methylene dichloride (5ml), in this solution, adds 3, and 3-dimethyl-2-aminobutane (0.134ml, 1.00mmol).Reaction mixture stirred 4 hours, then vacuum concentration.Residue is distributed in Na 2CO 3Between the aqueous solution and the ethyl acetate.Dry organic phase and decolouring.Concentrate the residue that obtains and grind, get 0.07g (37%) title amide rice white solid: mp.173-175 ℃ through hexane; 1HNMR (DMSO-d 6): δ 11.69 (s, 1H), 8.26 (s, 1H), 8.19 (d, 1H), 7.79 (d, 1H), 7.87 (d, 1H), 7.67 (d, 1H), 7.50 (d, 1H), 7.24 (m, 1H), 4.41 (m, 1H), 1.17 (d, 3H), 0.96 (s, 9H); IR (KBr): 3390,3300,2960,1640cm -1MS (m/z) 412 (M +).
To C 21H 21BrN 2O 2Ultimate analysis:
Calculated value: C, 61.03; H, 5.12; N, 6.78.
Measured value: C, 59.97; H, 5.32; N, 7.10.
Embodiment 13
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid (1,1-dimethyl-propyl group)-acid amides
To embodiment 1 step 2 product (300mg, anhydrous N 909mmol), add in dinethylformamide (281 μ l) and 0 ℃ of non-homogeneous mixture of methylene dichloride (9.0ml) oxalyl chloride (317 μ l, 3.63mmol).Treat the venting stop after, mixture was risen to stirring at room 1 hour, be cooled to 0 ℃ then, this moment add tert.-amylamine (425 μ l, 3.63mmol).Reaction mixture stirred 12 hours, and rotary evaporation is removed all volatile components then.Solid residue is dissolved in hot acetone-ethanol, and (8: 1,50ml), filtration added entry (50ml) after clarifying, and causes precipitation.Filter, 50 ℃ of high vacuum dry get 111mg (30%) title compound rice white solid: mp.242-244 ℃ (dec) then; 1H NMR (DMSO-d 6): δ 11.66 (s, 1H), 8.28 (d, 1H), 7.94 (d, 1H), 7.83 (d, 1H), 7.77 (s, 1H), 7.68 (d, 1H), 7.48 (dd, 1H), 7.21 (dd, 1H), 1.90 (q, 2H), 1.42 (s, 6H), 0.87 (t, 3H); IR (KBr): 3420,3340,2990,1650,1590,1520,1430,1380,1190,1160,980,900,750cm -1MS (m/z) 398/400 (M +).
To C 20H 19BrN 2O 2Ultimate analysis:
Calculated value: C, 60.16; H, 4.79; N, 7.02.
Measured value: C, 59.53; H, 4.35; N, 6.88.
Embodiment 14
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid methyl acid amides
To embodiment 1 step 2 product (300mg, 909mmol) at anhydrous N, add in the non-homogeneous mixture in 0 ℃ of dinethylformamide (281 μ l) and the methylene dichloride (9.0ml) oxalyl chloride (317 μ l, 3.63mmol).After treating that venting stops, mixture is risen to stirring at room 1 hour, be cooled to 0 ℃ then, add methylamine (about 4-5ml) this moment.Reaction mixture stirred 12 hours, and rotary evaporation is removed all volatile components then.Solid residue is accepted supersound process in acetonitrile (10ml), filter, and washs slightly with acetonitrile then.(8: 1,50ml), filtration added entry (50ml) and causes precipitation, carries out supersound process simultaneously then solid to be dissolved in hot acetone-ethanol.Filter, 50 ℃ of high vacuum dry get 55mg (18%) title compound white solid: mp.264-265 ℃ (dec) then; 1H NMR (DMSO-d 6): δ 11.74 (s, 1H), 8.66 (q, 1H), 8.27 (d, 1H), 7.95 (d, 1H), 7.76 (s, 1H), 7.68 (d, 1H), 7.49 (dd, 1H), 7.23 (dd, 1H), 2.90 (d, 3H); IR (KBr): 3460,3310,3060,1680,1630,1590,1560,1450,1440,1410,1380,1330,1290,1200,1160,1150,1050,860,810,750cm -1MS (m/z) 344/342 (M +).
To C 16H 11BrN 2O 2Ultimate analysis:
Calculated value: C, 56.00; H, 3.23; N, 8.16.
Measured value: C, 55.73; H, 3.08:N, 7.88.
Embodiment 15
8-bromo-10-methyl isophthalic acid 0H-benzo [4,5] furo [3,2-b] indoles-1-carboxylate methyl ester
To embodiment 1 step 2 product (1.789,5.40mmol) at N ,-5 ℃ of solution gradation of dinethylformamide (20ml) add 80% sodium hydride (324mg, 10.8mmol).The red mixture that forms stirred 1 hour, slowly rose to room temperature, and (1.83ml 16.2mmol), generates precipitation in a large number to add the trifluoromethayl sulfonic acid methyl esters.Add N, dinethylformamide (5ml) is in order to stirring.Reaction mixture restir 1 hour with the water dilution, filters, successively water and methanol wash then.Solid acetone-water recrystallization filters.50 ℃ of high vacuum dry get 357mg (19%) title compound white solid: mp.195-196 ℃; 1HNMR (DMSO-d 6): δ 8.31 (d, 1H), 8.04 (dd, 1H), 7.74 (d, 1H), 7.68 (dd, 1H), 7.56 (dd, 1H), 7.29 (dd, 1H), 4.04 (s, 3H), 3.97 (s, 3H); IR (KBr): 3430,2980,1720,1465,1435,1270,1165,1105,1080,940,790,775,730cm -1MS (m/z) 357/359 (M +).
To C 17H 12BrNO 3Ultimate analysis:
Calculated value: C, 57.00; H, 3.38; N, 3.91.
Measured value: C, 56.83; H, 3.17; N, 3.83.
Embodiment 16
10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
To 3-coumaranone (2.63g, dripping hydrochloric acid phenyl hydrazine-2-carboxylic acid in ethanol 20mmol) (50ml) homogeneous solution (6.79g, water 36mmol) (75ml) solution.Stir under the mixture room temperature that forms and filtered in 12 hours, vacuum-drying obtains the corresponding hydrazone of 2.17g (40%), and solid state is white in color.
With above-mentioned phenyl hydrazones (268mg, formic acid 1.0mmol) (5.0ml) suspension is heated to 110 ℃, at this moment, mixture becomes earlier evenly, forms a large amount of precipitations then.Continue heating 5 minutes, solid is collected in ice bath cooling then.Wash solid with water, use the acetone-water recrystallization, vacuum-drying obtains yellow solid: mp.279-280 ℃ of 156mg (62%); 1H NMR (DMSO-d 6): δ 13.28 (m, 1H), 11.65 (s, 1H), 8.09 (ddd, 2H), 7.89 (m, 1H), 7.36 (m, 2H), 7.26 (d, 1H); IR (KBr): 3420,3000 (br), 1670,1600,1435,1290,750,720cm -1MS (m/z) 251 (M +).
To C 15H 9NO 3Ultimate analysis:
Calculated value: C, 71.71; H, 3.61; N, 5.57.
Measured value: C, 71.83; H, 3.39; N, 5.47.
Embodiment 17
0.6 hydration 8-iodo-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid
In Teflon PFA test tube, (0.528g, 2.99mmol) (0.698g 2.58mmol) is mixed into pasty state in the formic acid that is added with 3 concentrated hydrochloric acids (2ml, 96%) with hydrochloric acid 4-iodophenyl hydrazine with 1-oxo-indane-4-carboxylic acid.This test tube in CEM microwave oven (MDS2000) with full power (760W) irradiation 1 minute (T=140C, P＜50PSI), cooled off 2 minutes, and then irradiation 1 minute (T=140C, P＜50PSI).Suction filtration mixture while hot.Solid washs with formic acid, and is dry on glass wool.Grind through chromatography (acetone/hexane) and ether, obtain title compound brown solid (0.059g, 5%): mp.251 ℃; 1H NMR (DMSO-d 6): δ 3.98 (s, 2H), 7.30-7.37 (m, 2H), 7.49 (t, 1H), 7.77-7.80 (m, 2H), 7.89 (d, 1H), 11.82 (s, 1H), 13.53 (s, 1H); MS (EI, m/z): 371 (M +).
To C 16H 10INO 2Ultimate analysis:
Calculated value: C, 49.87; H, 2.72; N, 3.63.
Measured value: C, 49.59; H, 2.81; N, 3.66.
Embodiment 18
Half hydration 8-sulfamyl-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid
With the method for similar embodiment 17, with 1-oxo-indane-4-carboxylic acid (0.528g, 2.99mmol) (0.671g 3.0mmol) changes into title compound brown solid: mp.270-272 ℃ (dec) with hydrochloric acid 4-sulfamoyl phenyl hydrazine; 1H NMR (DMSO-d 6): δ 4.07 (s, 2H), 7.15 (br s, 2H), 7.52 (t, 1H), 7.59-7.63 (m, 2H), 7.80-7.85 (m, 2H), 8.11 (d, 1H), 12.10 (s, 1H), 13.13 (s, 1H); MS (EI, m/z): 328 (M +).
To C 16H 12N 2O 4S0.5H 2The ultimate analysis of O:
Calculated value: C, 56.79; H, 3.88; N, 8.30.
Measured value: C, 56.71; H, 3.49; N, 8.19.
Embodiment 19
8-fluoro-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid
With the method for similar embodiment 17, with 1-oxygen-indane-4-carboxylic acid (1.00g, 5.68mmol) and hydrochloric acid 4-fluorophenyl hydrazine (0.923g 5.68mmol) changes into title compound rice white solid (0.140g, 10%): mp.＞300 ℃; 1H NMR (DMSO-d 6): δ 3.98 (s, 2H), 6.93 (d of t, 1H), 7.38 (d of d, 1H), 744 (d of d, 1H), 7.50 (d, 1H), 7.77-7.80 (m, 2H), 11.72 (s, 1H), 13.43 (s, 1H); MS (EI, m/z): 267 (M +).
To C 16H 10FNO 2Ultimate analysis:
Calculated value: C, 71.91; H, 3.77; N, 5.24.
Measured value: C, 71.33; H, 3.78; N, 5.22.
Embodiment 20
8-chloro-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid
With the method for similar embodiment 17, with 1-oxo-indane-4-carboxylic acid (1.00g, 5.68mmol) and hydrochloric acid 4-chloro-phenyl-hydrazine (1.03g 5.75mmol) changes into title compound light brown solid (0.230g, 14%): mp.＞300 ℃; 1H NMR (DMSO-d 6): δ 4.00 (s, 2H), 7.10 (d of d, 1H), 7.46 (d, 1H), 7.51 (d, 1H), 7.66 (d, 1H), 7.78-7.81 (m, 2H), 11.83 (s, 1H), 13.57 (s, 1H); MS (EI, m/z): 283 (M +).
To C 16H 10ClNO 2Ultimate analysis:
Calculated value: C, 67.74; H, 3.55; N, 4.94.
Measured value: C, 67.08; H, 3.69; N, 4.78.
Embodiment 21
8-trifluoromethoxy-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid
Method with similar embodiment 17, with 1-oxo-indane-4-carboxylic acid (1.00g, 5.68mmol) and hydrochloric acid 4-Trifluoromethoxyphen-l hydrazine (1.30g 5.68mmol) changes into title compound light brown solid (0.160g, 8%): mp.256-265 ℃ (dec); 1H NMR (DMSO-d 6): δ 4.03 (s, 2H), 7.05-7.08 (m, 1H), 7.49 (d, 1H), 7.53 (d, 1H), 7.61 (d, 1H), 7.79-7.83 (m, 2H), 11.92 (s, 1H), 13.08 (s, 1H); MS (EI, m/z): 333 (M +).
To C 17H 10F 3NO 3Ultimate analysis:
Calculated value: C, 61.27; H, 3.02; N, 4.20.
Measured value: C, 61.82; H, 3.15; N, 4.32.
Embodiment 22
8-chloro-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid, ethyl ester
In ethanol,, be translated into ethyl ester, obtain title compound rice white solid: mp.202-204 ℃ (dec) with the product of vitriolization embodiment 20; 1H NMR (DMSO-d 6): δ 1.39 (t, 3H), 4.00 (s, 2H), 4.38 (q, 2H), 7.11 (d, 1H), 7.48 (d, 1H), 7.52 (t, 1H), 7.67 (s, 1H), 7.79-7.84 (m, 2H), 11.86 (s, 1H); MS (EI, m/z): 311 (M +).
To C 18H 14F 3ClNO 2Ultimate analysis:
Calculated value: C, 60.69; H, 3.96; N, 3.93.
Measured value: C, 60.47; H, 3.76; N, 3.78.
Embodiment 23
8-bromo-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid, ethyl ester
Method with similar embodiment 17, with 1-oxygen-indane-4-carboxylic acid (1.00g, 5.68mmol) and hydrochloric acid 4-bromophenyl hydrazine reaction generation 8-bromo-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid, press the method for embodiment 22 then, be translated into ethyl ester, obtain title compound brown solid: mp.198-200 ℃; 1HNMR (DMSO-d 6): δ 1.39 (t, 3H), 4.00 (s, 2H), 4.37 (q, 2H), 7.22 (d, 1H), 7.42 (d, 1H), 7.52 (t, 1H), 7.79-7.84 (m, 3H), 11.86 (s, 1H); MS (EI, m/z): 355 (M +).
To C 18H 14BrNO 2Ultimate analysis:
Calculated value: C, 69.35; H, 4.53; N, 4.49.
Measured value: C, 69.17; H, 4.39; N, 4.37.
Embodiment 24
10,10-dimethyl-3-nitro-5,10-dihydro-indeno [1,2-b] Indole-6-carboxylic acid
With 6-nitro-3,3-dimethyl-1-(2, the 3-bihydrogen-1-indenone) (0.612g, 2.98mmol) [Smith, J.G. etc., organic preparation and generation, 1978,10 (3), 123-131] and hydrochloric acid 2-hydrazino-benzoic acid (0.562g, 2.98mmol) formic acid (2ml, 96%) solution be contained in the Teflon test tube of adding a cover irradiation in microwave oven (700W) 2 minutes.The suction filtration mixture carries out chromatography (hexane/ethyl acetate 1: 1) and petroleum ether/ethyl ether grinding to crude product.Obtain 0.178g (19%) title compound yellow solid after the vacuum-drying: mp.310 ℃; 1H NMR (DMSO-d 6): δ 13.43 (s, 1H), 11.85 (s, 1H), 8.95 (s, 1H), 8.12 (d, 1H), 7.98 (d, 1H), 7.81 (m, 2H), 7.19 (t, 1H), 1.59 (s, 1H); IR (Kbr): 3460,1670cm -1MS (m/z): 322 (M +).
To C 18H 14N 2O 4Ultimate analysis:
Calculated value: C, 67.08; H, 4.38; N, 8.69.
Measured value: C, 66.29; H, 4.45; N, 8.37.
Embodiment 25
8-bromo-5,10-dihydro-indeno [1,2-b] indoles-1-carboxylic acid
With 1-oxo-4-indane carboxylic acid (0.528g, 2.98mmol) [Aono, T. etc., chemicals is learned communique, 1978,26 (4), 1153-61] and hydrochloric acid 2-hydrazino-benzoic acid (0.566g, 2.98mmol) formic acid (2ml, 96%) solution be contained in the Teflon test tube of adding a cover irradiation in microwave oven (700W) 2 minutes.The suction filtration mixture.Crude product is dissolved in acetone (1: 1), handles with decolorizing charcoal, filter, concentrate, vacuum-drying obtains title compound white solid: mp.328-330 ℃ (dec); 1H NMR (DMSO-d6): δ 13.43 (s, 1H), 11.85 (s, 1H), 7.78-7.83 (m, 3H), 7.50 (t, 1H), 7.43 (d, 1H), 7.21 (d, 1H), 4.00 (s, 2H); IR (Kbr): 3440,1690cm-1; MS (m/z): 327 (M+).
To C 16H 10BrNO 2Ultimate analysis:
Calculated value: C, 58.56; H, 3.07; N, 4.27.
Measured value: C, 58.57; H, 2.88; N, 4.30.
Embodiment 26
3-bromo-5,10-dihydro-indeno [1,2-b] Indole-6-carboxylic acid
Adjacent [(2,3-dihydro-6-bromine indenes-3-subunit) the diazanyl]-phenylformic acid of step 1) preparation
To 6-bromo-(2, the 3-bihydrogen-1-indenone) (0.447g, 2.12mmol) [Adamczyk, M. etc., organic chemistry magazine 1984,49,4226-4237] ethanol (100ml) solution in add hydrochloric acid 2-hydrazino-benzoic acid (0.800g, deionized water 4.24mmol) (50ml) solution.Mixture stirred 1 hour, left standstill then and was cooled to 0 ℃.The hydrazone that is settled out obtains 0.628g (86%) title compound yellow solid: mp.186 ℃ (dec.) through vacuum filtration and vacuum-drying.
Step 2) preparation 3-bromo-5,10 dihydros-indeno [1,2-b] Indole-6-carboxylic acid
In microwave oven (700W), in the Teflon test tube of block, hydrazone (embodiment 26 steps 1 are prepared) (0.620g, 1.80mmol) 2 minutes irradiation of acceptance in formic acid (2ml, 96%).This mixture of suction filtration while hot, solid vacuum-drying, 0.360g (61%) title compound yellow solid: mp.245-247 ℃; 1H NMR (DMSO-d 6): δ 13.43 (s, 1H), 11.73 (s, 1H), 8.32 (s, 1H), 7.86 (d, 1H), 7.78 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 7.16 (t, 1H), 3.71 (s, 2H); IR (KBr): 3460,1650cm -1MS (m/z) 327 (M +).
To C 16H 10BrNO 2Ultimate analysis:
Calculated value: C, 58.56; H, 3.07; N, 4.27.
Measured value: C, 58.62; H, 2.83; N, 4.22.
Embodiment 27-32 is with suitable benzonitrile and 1-oxo-indane-4-carboxylic acid, presses the method preparation of embodiment 17.
Embodiment 27
8-bromo-7-methoxyl group-5,10 dihydros-indeno [1,2-b] indoles-1-carboxylic acid
Embodiment 28
8-bromo-6-methoxyl group-5,10 dihydros-indeno [1,2-b] indoles-1-carboxylic acid
Embodiment 29
8-chloro-7-methoxyl group-5,10 dihydros-indeno [1,2-b] indoles-1-carboxylic acid
Embodiment 30
8-chloro-6-methoxyl group-5,10 dihydros-indeno [1,2-b] indoles-1-carboxylic acid
Embodiment 31
8-bromo-9-methoxyl group-5,10 dihydros-indeno [1,2-b] indoles-1-carboxylic acid
Embodiment 32
8-bromo-6-methoxyl group-5,10 dihydros-indeno [1,2-b] indoles-1-carboxylic acid
Embodiment 33-36 prepares with suitable benzofuranone and 2-hydrazino-benzoic acid, the method for pressing embodiment 1.
Embodiment 33
8-bromo-7-methoxyl group-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
Embodiment 34
8-chloro-7-methoxyl group-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
Embodiment 35
8-chloro-9-methoxyl group-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
Embodiment 36
8-chloro-6-methoxyl group-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid
As described below, carry out the pharmaceutically test of approval of standard with representative compounds, determine (bladder) smooth muscle relaxation activity of The compounds of this invention.
Use CO 2The Sprague-Dwaley rat (150-200g) of suffocating is lost consciousness it, kills with cervical dislocation then.Take out bladder, put into temperature (37 ℃) physiological saline (PPS) of following composition (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; The O of feeding 95% 22/5%CO 2PH7.4.Cut bladder open, be cut into wide 1-2mm, the bar of long 7-10mm.These are suspended in the 10ml tissue bath, and initial resting tension is 1.5g.Clamp strip of muscle with two operating forcepses, one of them is connected on the fixed hook, and another is fixed on the isometric force transducer.Prepared product shows slight spontaneous contraction usually, allows it recover 1 hour, stimulates with 0.1 μ M carbachol then.The flush away carbachol allows organizational slack to its tranquillization level then.Continue to recover in tissue bath, to introduce 15mM KCl after 30 minutes.The rising of KCl concentration has strengthened the amplitude (previous unresponsive strip of muscle also begins to shrink) of spontaneous contraction greatly, and is overlapping with basic tensity.This enhanced is shunk activity stabilizedization, in tissue bath, introduce the testing compound or the carrier of the concentration of going forward one by one then.The last minute that stimulated at 30 minutes is measured the contraction activity of each concentration compound or carrier.
According to above-mentioned concentration-reaction normal curve, with suppressing to shrink active 50% required concentration (IC before the drug treating 50Concentration) determine the bladder muscle cutlet etc. appearance power.Write down the active maximum per-cent that suppresses that contracts that causes when each testing compound concentration is less than or equal to 30 μ M simultaneously.
As described below, carry out the pharmaceutically test of approval of standard with representative compounds, determine (aorta) smooth muscle relaxation activity of The compounds of this invention.
Use CO 2The Sprague-Dwaley rat (150-200g) of suffocating is lost consciousness it, kills with cervical dislocation then.Take out bladder, put into temperature (37 ℃) physiological saline (PSS) of following composition (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; The O of feeding 95% 22/5%CO 2PH7.4.Remove the adventitia of endaortic fat and absent-mindedness, be cut into the ring of wide 3-4mm.In 10ml tissue bath, these rings are suspended between two Stainless Steel Wire tissue holders.A clip is connected on the fixed hook, and another is fixed on the isometric force transducer.Rest tension is set at 1g.Before on-test, allow organized renewing 60 minutes.Stimulate tissue with the PSS that contains 25mM KCl, cause contraction.With fresh PSS repeated washing tissue 30 minutes, allow it return to baseline tension force then.In tissue bath, introduce the PSS that contains 30-35mM KCl then, cause contraction, stablize more than 45 minutes.(also can use as required such as norepinephrine, PGF2a, histamine, angiotensin II, endothelium (blood vessel contracts) peptide or the PSS that contains 80mM KCl stimulate contraction).In tissue bath, introduce the testing compound or the carrier of the concentration of going forward one by one with accumulate mode.
Firmly conductograph measure that aortic annulus produces etc. appearance power, and be recorded on the polygraph.Suppress the present invention with each concentration convergent force of testing compound and be depicted as concentration-response curve.By the required concentration (IC of convergent force before this curve calculation 50% inhibition medication 50Concentration).[in the 20-80% interval of maximum reaction, it is linear that Log concentration-response curve is substantially.Therefore, can determine the IC of medicine by the linear regression analysis (x=log concentration, y=% suppresses) of data point in should the interval to curve 50Concentration.] write down each testing compound concentration simultaneously and be lower than the active maximum per-cent that suppresses that contracts that causes when equaling 30 μ M.Use data mean value to carry out primary dcreening operation from two animals.
Above-mentioned research the results are shown in Table I.
Embodiment ?n Bladder body IC 50(μM) ?n Aortic tissue IC 50(μM) Aorta IC 50/ bladder body IC 50The ratio
????1 ?8 ?15.1±4.7 ?4 ??118.8±21.8 ?????7.9
????2 ?8 ??6.1±3.0 ?3 ????128±16.9 ??????21
????3 ?6 ??5.8±1.5 ?4 ??268.0±82.3 ?????46.2
????4 ?8 ??6.3±2.6 ?3 ????125±13.8 ?????19.8
????5 ?2 ?1＝13.5％* ?????---
????6 ?4 ?1＝31％* ?????---
????8 ?3 ?19.8±4.02 ?3 ????8.1±3.6 ?????0.41
????9 ?2 ?1＝19％* ?????---
????10 ?4 ?1＝10.1％* ?????---
????11 ?2 ?1＝30.9％* ?????---
????12 ?2 ?13.9±0.95 ?3 ?????25±3.9 ?????1.8
????13 ?2 ?1＝28.5％* ?????---
????14 ?3 ?1＝4.8％* ?????---
????15 ?2 ?1＝4.5％* ?????---
????16 ?4 ?31.0±6.5 ?????---
????17 ?8 ?10.1±3.2 ?????---
????18 ?2 ?1＝5.2％* ?????---
????19 ?6 ?12.5±5 ?3 ????46.6±18.7 ????3.74
????20 ?5 ?22.6±1.8 ????---
????21 ?4 ?15.4±4.8 ????---
????22 ?2 ??1＝8％* ????---
????23 ?2 ??1＝20％* ????---
???24** ?4 ??5.2±1.8 ?4 ????17.2±2.3 ????3.3
????25 ?8 ??4.4±0.95 ?6 ???109.6±12.4 ?????25
????26 ?7 ??8.6±3.0 ?4 ???210.4±45 ????24.5
*: the inhibition per-cent during 30 μ M.
Tested the ability of the external lax complete rat bladder of several The compounds of this invention.Test method is as follows.
With Nembutol  (50mg/kg, i.p.) the female Sprague-Dawley rat of anesthesia body weight 200-300g.After the holonarcosis, expose bladder and urethra by midline incision.In urethra, put the stainless steel bar of a diameter 1mm, with 4-0 silk ligature ligation urethra end.After extracting stainless steel bar out, cause exit portion to block.Sew up a wound then, give the microbiotic Bicillin  of animal 15,000 units.After 6 weeks, use CO 2Asphyxial rat.The bladder that will be used for shrinking analysis is placed on temperature (37 ℃) physiological saline (PSS) of following composition (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; The O of feeding 95% 22/5%CO 2PH7.4.
Link to each other with one section polyethylene tube (PE-200) with the silk ligature bladder urethra opening end that will exsomatize.The other end of pipe is connected with the pressure conductograph, measures the bladder pressure that produces.Bladder places 372 tissue baths that contain PSS, and fills with PSS to obtain optimal retraction.On Grass7D type polygraph, show and the monitoring bladder contracts.
After stable, in tissue bath, introduce the testing compound or the carrier of the concentration of going forward one by one.The last minute that stimulated at 30 minutes is measured the contraction activity of each concentration compound or carrier.
According to above-mentioned concentration-reaction normal curve, with suppressing to shrink active 50% required concentration (IC before the drug treating 50Concentration) determine the bladder muscle cutlet etc. appearance power.Write down each testing compound concentration simultaneously and be lower than the active maximum per-cent that suppresses that contracts that causes when equaling 30 μ M.In this test, the IC of embodiment 24 compounds 50Be 5 μ M.
Test according to standard pharmaceutical, compound of the present invention has selectivity to bladder body, smooth muscle contraction had remarkable effect, can be used for the aforementioned therapies urinary incontinence, irritability bladder and bowel syndrome, asthma, diseases such as apoplexy, can with the coupling of potassium channel activator, can give the patient by oral, parenteral or absorption.

Claims (21)

1. the compound shown in the general formula (I) or its salt of pharmaceutically approving:
Figure A9981549500021
Wherein, R 1, R 2And R 3Each is hydrogen, halogen, nitro, cyano group, C naturally 1-10Alkyl, C 3-10Cycloalkyl can halogenated C 1-10Alkoxyl group, amino, C 1-10Alkylamino ,-SO 3H ,-SO 2NH 2,-NHSO 2R 14, R 15SO 2-, carboxyl and C 6-12Aryl, or following acyl substituent: formyl radical, C 2-7Alkyloyl, C 3-7Enoyl-, C 1-7Alkyl sulphonyl, C 7-12Aroyl, C 9-20The aryl enoyl-, C 6-12Aryl sulfonyl, C 8-12Aromatic yl silane terephthalamide yl or C 7-12The aralkyl alkylsulfonyl;
Y is-O-and-NR 4
When Y is-NR 4The time, X is-O-;
When Y be-during O-, X is-NR 4
R 4Be hydrogen, C 1-10Alkyl, C 3-10Cycloalkyl, C 6-12Aryl, or following acyl substituent: formyl radical, C 2-7Alkyloyl, C 3-7Enoyl-, C 1-7Alkyl sulphonyl, C 7-12Aroyl, C 9-20The aryl enoyl-, C 6-12Aryl sulfonyl, C 8-12Aromatic yl silane terephthalamide yl or C 7-12The aralkyl alkylsulfonyl;
R 5And R 6Each is hydrogen naturally, C 1-10Alkyl, C 3-10Cycloalkyl, C 6-12Aryl, or fluorine;
A bit substituent Z is selected from
Figure A9981549500031
With
M is alkali metal cation or alkaline earth metal cation;
R 7Be C 1-10Alkyl, C 3-10Cycloalkyl, C 7-20Aralkyl, or C 6-12Aryl;
R 8And R 9Each is hydrogen naturally, C 1-10Alkyl, C 3-10Cycloalkyl, C 7-20Aralkyl, or C 6-12Aryl;
R 10, R 11, R 12And R 13Each is C naturally 1-10Alkyl;
R 14Be C 1-10Straight chained alkyl;
R 15Be can halogenated C 1-10Straight chained alkyl;
But aroyl is benzoyl and naphthoyl that 1-3 replaces, and substituting group is selected from halogen, cyano group, C separately 1-10Alkyl, C 1-10Alkoxyl group ,-CF 3And phenyl;
Aryl is a naphthyl, the phenyl that phenyl or 1-3 replace, and substituting group is selected from halogen, carboxyl, C separately 1-10Alkyl, nitro, amino, C 1-10Alkoxyl group, and C 1-10Alkylamino;
Condition is, when Z is-CHO, Y is-O-that X is-N-CH 3The time, R 1, R 2And R 3Not hydrogen.
2. according to the compound shown in the claim 1 or its salt of pharmaceutically approving, wherein, when Y is-NR 4The time, X is-O-.
3. according to the compound shown in the claim 1 or its salt of pharmaceutically approving, wherein, when Y is-NR 4, and R 1Be halogen or nitro, and Z is-CO 2During H, X is-O-.
4. according to the compound shown in the claim 1 or its salt of pharmaceutically approving, wherein, when Y is-O-, and R 1Be halogen or nitro, and Z is-CO 2During H, X is-NR 4
5. according to the compound shown in the claim 1 or its salt of pharmaceutically approving, shown in compound be selected from:
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
8-iodo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
8-chloro-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
Two hydration 8-nitros-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid amide;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylate methyl ester;
(8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-yl)-methyl alcohol;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid hydroxymethyl acid amides;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-formaldehyde;
One hydration 8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-nitrile;
8-bromo-1-(1H-tetrazolium-5-yl)-10H-benzo [4,5] furo [3,2-b] indoles;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid (1,2,2-trimethylammonium-propyl group)-acid amides;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid (1,1-dimethyl-propyl group)-acid amides;
8-bromo-10H-benzo [4,5] furo [3,2-b] indoles-1-carboxylic acid methyl acid amides;
8-bromo-10 methyl isophthalic acid 0H-benzo [4,5] furo [3,2-b] indoles-1-carboxylate methyl esters; With
10H-benzo [4,5] furo [3,2-b] indoles-carboxylic acid.
6. one kind is passed through to regulate the pharmaceutical composition that warm-blooded animal and smooth muscle contraction relative disease were treated or suppressed to potassium channel, comprise general formula (II) compound that gives described warm-blooded animal significant quantity, or its salt of pharmaceutically approving, and one or more pharmaceutically approve carrier or excipient Wherein: wherein, R 1, R 2And R 3Each is hydrogen, halogen, nitro, cyano group, C naturally 1-10Alkyl, C 3-10Cycloalkyl can halogenated C 1-10Alkoxyl group, amino, C 1-10Alkylamino ,-SO 3H ,-SO 2NH 2,-NHSO 2R 14,
Figure A9981549500042
R 15SO 2-, carboxyl and C 6-12Aryl, or following acyl substituent: formyl radical, C 2-7Alkyloyl, C 3-7Enoyl-, C 1-7Alkyl sulphonyl, C 7-12Aroyl, C 9-20The aryl enoyl-, C 6-12Aryl sulfonyl, C 8-12Aromatic yl silane terephthalamide yl or C 7-12The aralkyl alkylsulfonyl;
Y is-NR 4With-CR 5R 6
When Y is-NR 4The time, X is-O-;
When Y is-CR 5R 6The time, X is-NR 4
When Y is-NR 4The time, X is-CR 5R 6
R 4Be hydrogen, C 1-10Alkyl, C 3-10Cycloalkyl, C 6-12Aryl, or following acyl substituent: formyl radical, C 2-7Alkyloyl, C 3-7Enoyl-, C 1-7Alkyl sulphonyl, C 7-12Aroyl, C 9-20The aryl enoyl-, C 6-12Aryl sulfonyl, C 8-12Aromatic yl silane terephthalamide yl or C 7-12The aralkyl alkylsulfonyl;
R 5And R 6Each is hydrogen naturally, C 1-10Alkyl, C 3-10Cycloalkyl, C 6-12Aryl, or fluorine;
A bit substituent Z is selected from
Figure A9981549500051
Figure A9981549500052
With
Figure A9981549500053
M is alkali metal cation or alkaline earth metal cation;
R 7Be C 1-10Alkyl, C 3-10Cycloalkyl, C 7-20Aralkyl, or C 6-12Aryl;
R 8And R 9Each is hydrogen naturally, C 1-10Alkyl, C 3-10Cycloalkyl, C 7-20Aralkyl, or C 6-12Aryl;
R 10, R 11, R 12And R 13Each is C naturally 1-10Alkyl;
R 14Be C 1-10Straight chained alkyl;
R 15Be can halogenated C 1-10Straight chained alkyl;
But aroyl is benzoyl and naphthoyl that 1-3 replaces, and substituting group is selected from halogen, cyano group, C separately 1-10Alkyl, C 1-10Alkoxyl group ,-CF 3And phenyl;
Aryl is a naphthyl, the phenyl that phenyl or 1-3 replace, and substituting group is selected from halogen, carboxyl, C separately 1-10Alkyl, nitro, amino, C 1-10Alkoxyl group, and C 1-10Alkylamino.
7. pharmaceutical composition according to claim 6, wherein, when Y is-NR 4The time, X is-O-.
8. pharmaceutical composition according to claim 6, wherein, when Y is-CR 5R 6The time, X is-NR 4
9. pharmaceutical composition according to claim 6, wherein, when Y is-NR 4The time, X is-CR 5R 6
10. pharmaceutical composition according to claim 6, wherein, when Y is-NR 4, and R 1Be halogen or nitro, and Z is-CO 2During H, X is-O-.
11. pharmaceutical composition according to claim 6, wherein, when Y is-CR 5R 6And R 1Be halogen or nitro, and Z is-CO 2During H, X is-NR 4
12. pharmaceutical composition according to claim 6, wherein, when Y is-NR 4, and R 1Be halogen or nitro, and Z is-CO 2During H, X is-CR 5R 6
13. the method by the treatment of adjusting potassium channel or inhibition warm-blooded animal and smooth muscle contraction relative disease comprises general formula (II) compound that gives described warm-blooded animal significant quantity, or its salt of pharmaceutically approving, Wherein: wherein, R 1, R 2And R 3Each is hydrogen, halogen, nitro, cyano group, C naturally 1-10Alkyl, C 3-10Cycloalkyl can halogenated C 1-10Alkoxyl group, amino, C 1-10Alkylamino ,-SO 3H ,-SO 2NH 2,-NHSO 2R 14, R 15SO 2-, carboxyl and C 6-12Aryl, or following acyl substituent: formyl radical, C 2-7Alkyloyl, C 3-7Enoyl-, C 1-7Alkyl sulphonyl, C 7-12Aroyl, C 9-20The aryl enoyl-, C 6-12Aryl sulfonyl, C 8-12Aromatic yl silane terephthalamide yl or C 7-12The aralkyl alkylsulfonyl;
Y is-NR 4With-CR 5R 6
When Y is-NR 4The time, X is-O-;
When Y is-CR 5R 6The time, X is-NR 4
When Y is-NR 4The time, X is-CR 5R 6
R 4Be hydrogen, C 1-10Alkyl, C 3-10Cycloalkyl, C 6-12Aryl, or following acyl substituent: formyl radical, C 2-7Alkyloyl, C 3-7Enoyl-, C 1-7Alkyl sulphonyl, C 7-12Aroyl, C 9-20The aryl enoyl-, C 6-12Aryl sulfonyl, C 8-12Aromatic yl silane terephthalamide yl or C 7-12The aralkyl alkylsulfonyl;
R 5And R 6Each is hydrogen naturally, C 1-10Alkyl, C 3-10Cycloalkyl, C 6-12Aryl, or fluorine;
A bit substituent Z is selected from
Figure A9981549500071
Figure A9981549500072
With
Figure A9981549500073
M is alkali metal cation or alkaline earth metal cation;
R 7Be C 1-10Alkyl, C 3-10Cycloalkyl, C 7-20Aralkyl, or C 6-12Aryl;
R 8And R 9Each is hydrogen naturally, C 1-10Alkyl, C 3-10Cycloalkyl, C 7-20Aralkyl, or C 6-12Aryl;
R 10, R 11, R 12And R 13Each is C naturally 1-10Alkyl;
R 14Be C 1-10Straight chained alkyl;
R 15Be can halogenated C 1-10Straight chained alkyl;
But aroyl is benzoyl and naphthoyl that 1-3 replaces, and substituting group is selected from halogen, cyano group, C separately 1-10Alkyl, C 1-10Alkoxyl group ,-CF 3And phenyl;
Aryl is a naphthyl, the phenyl that phenyl or 1-3 replace, and substituting group is selected from halogen, carboxyl, C separately 1-10Alkyl, nitro, amino, C 1-10Alkoxyl group, and C 1-10Alkylamino.
14. method according to claim 13 is when Y is-NR 4The time, X is-O-.
15. according to the described method of claim 13, wherein, when Y is-CR 5R 6The time, X is-NR 4
16. method according to claim 13, wherein, when Y is-NR 4The time, X is-CR 5R 6
17. method according to claim 13, wherein, when Y is-NR 4, and R 1Be halogen or nitro, and Z is-CO 2During H, X is-O-.
18. method according to claim 13, wherein, when Y is CR 5R 6And R 1Be halogen or nitro, and Z is-CO 2During H, X is-NR 4
19. method according to claim 13, wherein, when Y is-NR 4, and R 1Be halogen or nitro, and Z is-CO 2During H, X is-CR 5R 6
20. method according to claim 13, wherein the improper contraction of unstriated muscle causes the urinary incontinence.
21. method according to claim 13, wherein the improper contraction of unstriated muscle causes irritable bowel syndrome.
CN99815495A 1998-12-04 1999-12-03 Substituted benzofuranodindoles and indenoindoles as novel potassium channel openers Pending CN1333774A (en)

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CN101137361B (en) * 2005-03-10 2010-11-24 Anygen株式会社 Potassium channel opener having benzofuroindole skeleton
CN106632360A (en) * 2016-09-27 2017-05-10 上海道亦化工科技有限公司 Compound based on benzofuroindole and organic electroluminescent device thereof
CN109942545A (en) * 2019-04-15 2019-06-28 中国药科大学 Competitive sour retarding agent of potassium ion containing indole structure and preparation method thereof and purposes

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RU2008105071A (en) 2005-07-14 2009-08-20 Айрм Ллк (Bm) COMPOUNDS AND COMPOSITIONS AS TRO MIMETICS
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WO2016126721A1 (en) 2015-02-02 2016-08-11 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as hdac inhibitors
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* Cited by examiner, † Cited by third party
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SE8902273D0 (en) * 1989-06-22 1989-06-22 Univ Cincinnati INDENOINDOLE COMPOUNDS I
SE8902274D0 (en) * 1989-06-22 1989-06-22 Univ Cincinnati INDENOIDOLE COMPOUNDS II
WO1991014688A1 (en) * 1990-03-20 1991-10-03 The Wellcome Foundation Limited Hetero polycyclic biocidal compounds and their use in medecine

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CN101137361B (en) * 2005-03-10 2010-11-24 Anygen株式会社 Potassium channel opener having benzofuroindole skeleton
CN106632360A (en) * 2016-09-27 2017-05-10 上海道亦化工科技有限公司 Compound based on benzofuroindole and organic electroluminescent device thereof
CN109942545A (en) * 2019-04-15 2019-06-28 中国药科大学 Competitive sour retarding agent of potassium ion containing indole structure and preparation method thereof and purposes

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