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

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

Substituted benzofuranoindoles and indeno[1,2-b]indoles as new potassium channel openers

Background of the invention

1. Field of invention

The present invention relates to a series of pharmacologically active substituted tetracyclic heteroaromatic benzofuroindoles and indeno[1,2-b]indoles, their preparation methods and pharmaceutical compositions using them as components , and their use in the treatment of diseases associated with smooth muscle contraction by modulating potassium channels. Such conditions include, but are not limited to: urinary incontinence, asthma, premature birth, irritable bowel syndrome, congestive heart failure, angina, and cerebrovascular disease.

2. Existing technology

Modulation of potassium channels is still at the forefront of current approaches to controlling resting cell membrane potential and influencing cell excitability. Dispersed potassium channels are abundant and, moreover, have been fully classified in terms of structure, function, pharmacological properties and gating mechanisms, see recent literature (Rudy, B. Neuroscience 1988, 25, 729-749; Atwal, K., Medical Research Reviews 1992, 28, 95-127; Primeau, J. et al., Contemporary Drug Design 1995, 5(11), 1453-1464). Activation of these channels increases the transmembrane K+ flux, thereby causing hyperpolarization of the cell membrane towards the Nernst K ⁺ equilibrium potential (-90mY), thereby closing the voltage-gated Ga2 ⁺ channels. As a result, hyperactivated cells become less excitable and therefore less responsive to restimulation, allowing smooth muscle to relax. Because of this pharmacological response, the potential of potassium channel activators to treat cardiovascular disease, metabolic disease, central nervous system disease, bronchial asthma, and irritable bladder syndrome has been extensively studied.

As reported by Bair, KW in WO 91/14688 and EP-447703-A1, a number of heterotetracyclomethylaminobenzofuranoindole compounds are useful as anticancer agents and fungicides. An example of which is 2-methyl-2-(((10-methyl-10H-benzofuro(3,2-b)indol-6-yl)methyl)amino)-1,3 - Propylene glycol.

EP-404536-A1 to Sainsbury et al. discloses a series of indeno(1,2-b)indoles which are said to be useful as pharmaceutical antioxidants and free radical scavengers.

JP-06-228554 describes a series of indeno(1,2-b)indoles as components of an organic electroluminescent body.

据称，这些化合物还可用作抗氧化剂，以治疗动脉硬化，血栓形成，栓塞和Parkinson氏病。X is -O-, -S-, SO ₂ -, or -NR ⁹ Sainsbury, M. described tetrahydroindeno(1,2-b)indoles in WO90/15799 and EP-409410-B1. series of related analogs.

These compounds are also claimed to act as antioxidants in the treatment of arteriosclerosis, thrombosis, embolism and Parkinson's disease.

Several papers have reported the synthesis of indeno(1,2-b)indole and indoline and their antioxidant properties (Brown, D.W. et al., Tetrahedron 1991, 47(25), 4383-4408; Brown, D.W. et al. , Tetrahedron 1993, 49(39), 8919-8932; Graupner, P.R. et al., Tetrahedron Lett. 1995, 36(32) 5827-5830; Shertzer, H.G. et al., Chemical Toxicology, 1991, 29(6) 391-400). Brown, F.C. et al also reported a fast-vacuum pyrolysis method for the synthesis of substituted indeno(1,2-b) indoles in Tetrahedron Lett. 1991, 32(6)801-802.

The difference between the present invention and the prior art is that the a-position of tetracyclic heteroaromatic benzofuroindole and indenoindole shown in general formula (I) and (II) needs to be substituted with substituent Z, as described below Said, Z is a carboxylic acid, a bioisostere of a carboxylic acid, or a derivative thereof. The present invention proves that the compounds of the present invention have potassium channel activation, and the induced smooth muscle relaxation properties have unique bladder tissue selectivity.

Summary of the invention

R₁₅SO₂-，羧基和C_6-12芳基，或以下酰基取代基：甲酰基，C_2-7烷酰基，C_3-7烯酰基，C_1-7烷基磺酰基，C_7-12芳酰基，C_9-20芳基烯酰基，C_6-12芳基磺酰基，C_8-12芳基烷酰基或C_7-12芳烷基磺酰基；Therefore, the present invention provides compounds represented by general formula (I) and pharmaceutically acceptable salts thereof, Wherein, R ₁ , R ₂ and R ₃ are each hydrogen, halogen, nitro, cyano, C _1-10 alkyl, C _3-10 cycloalkyl, halogenated C _1-10 alkoxy, amino , C _1-10 alkylamino, -SO ₃ H, -SO ₂ NH ₂ , -NHSO ₂ R ₁₄ ,

R ₁₅ SO ₂ -, carboxyl and C _6-12 aryl, or the following acyl substituents: formyl, C _2-7 alkanoyl, C _3-7 alkenoyl, C _1-7 alkylsulfonyl, C _{7- 12} aroyl, C _9-20 aryl alkenoyl, C _6-12 arylsulfonyl, C _8-12 aryl alkanoyl or C _7-12 aralkylsulfonyl;

Y is -O- and _-NR4 ;

When Y is -NR ₄ , X is -O-;

When Y is -O-, X is -NR ₄ ;

R ₄ is hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _6-12 aryl, or the following acyl substituents: formyl, C _2-7 alkanoyl, C _3-7 alkenoyl, C _1-7 alkylsulfonyl, C _7-12 aroyl, C _9-20 aryl alkenoyl, C _6-12 arylsulfonyl, C _8-12 aryl alkanoyl or C _7-12 aralkyl Sulfonyl;

R ₅ and R ₆ are each hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _6-12 aryl, or fluorine;

和

The a substituent Z is selected from

and

M is an alkali metal cation or an alkaline earth metal cation;

R ₇ is C _1-10 alkyl, C _3-10 cycloalkyl, C _7-20 aralkyl, or C _6-12 aryl;

R ₈ and R ₉ are each hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _7-20 aralkyl, or C _6-12 aryl;

R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are each C _1-10 alkyl;

R ₁₄ is C _1-10 straight chain alkyl;

R ₁₅ is a halogenated C _1-10 linear alkyl group;

Aroyl is benzoyl and naphthoyl which can be substituted by 1-3, and the substituents are respectively selected from halogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, -CF ₃ and phenyl;

Aryl is naphthyl, phenyl or 1-3 substituted phenyl, and the substituents are each selected from halogen, carboxyl, C _1-10 alkyl, nitro, amino, C _1-10 alkoxy, and C _{1-10 10} alkylamino;

Provided that when Z is -CHO, Y is -O-, X is -N- _CH3 , _R1 , _R2 and _R3 are not hydrogen.

The present invention is preferably the following subgroup of compounds of general formula (I) and pharmaceutically acceptable salts thereof, wherein other groups are the same as above, wherein: when X is -O-, Y is -NR ₄ .

More preferred are the following subgroups of compounds of general formula (I) and pharmaceutically acceptable salts thereof, wherein other groups are the same as described above, wherein: Z is -CO ₂ H; R ₁ is halogen or nitro;

a) When Y is -NR ₄ , X is -O-;

b) When Y is -O-, X is -NR ₄ .

Particularly preferred in the present invention are compounds of the following general formula (I) or pharmaceutically acceptable salts thereof:

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;

8-iodo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;

8-Chloro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;

8-nitro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid dihydrate;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid amide;

Methyl 8-bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylate;

(8-Bromo-10H-benzo[4,5]furo[3,2-b]indol-1-yl)-methanol;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid hydroxymethylamide;

8-bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carbaldehyde (carbaldehyde);

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carbonitrile monohydrate;

8-Bromo-1-(1H-tetrazol-5-yl)-10H-benzo[4,5]furo[3,2-b]indole;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (1,2,2-trimethyl-propyl)-amide;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (1,1-dimethyl-propyl)-amide;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methylamide;

methyl 8-bromo-10methyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylate; and

10H-Benzo[4,5]furo[3,2-b]indole-carboxylic acid.

其中：其中，R₁，R₂和R₃各自是氢、卤素、硝基、氰基、C_1-10烷基，C_3-10环烷基，可卤代的C_1-10烷氧基，氨基，C_1-10烷基氨基，-SO₃H，-SO₂NH₂，-NHSO₂R₁₄，

R₁₅SO₂-，羧基和C_6-12芳基，或以下酰基取代基：甲酰基，C_2-7烷酰基，C_3-7烯酰基，C_1-7烷基磺酰基，C_7-12芳酰基，C_9-20芳基烯酰基，C_6-12芳基磺酰基，C_8-12芳基烷酰基或C_7-12芳烷基磺酰基；The present invention also provides a method for treating or inhibiting diseases related to smooth muscle contraction in warm-blooded animals by regulating potassium channels, comprising administering an effective amount of the compound of general formula (II) to the warm-blooded animals (mammals are preferred, and humans are especially suitable) , or a pharmaceutically acceptable salt thereof,

Wherein: wherein, R ₁ , R ₂ and R ₃ are each hydrogen, halogen, nitro, cyano, C _1-10 alkyl, C _3-10 cycloalkyl, halogenated C _1-10 alkoxy , amino, C _1-10 alkylamino, -SO ₃ H, -SO ₂ NH ₂ , -NHSO ₂ R ₁₄ ,

R ₁₅ SO ₂ -, carboxyl and C _6-12 aryl, or the following acyl substituents: formyl, C _2-7 alkanoyl, C _3-7 alkenoyl, C _1-7 alkylsulfonyl, C _{7- 12} aroyl, C _9-20 aryl alkenoyl, C _6-12 arylsulfonyl, C _8-12 aryl alkanoyl or C _7-12 aralkylsulfonyl;

Y is -NR ₄ and -CR ₅ R ₆ ;

When Y is -NR ₄ , X is -O-;

When Y is -CR ₅ R ₆ , X is -NR ₄ ;

When Y is -NR ₄ , X is -CR ₅ R ₆ ;

R ₄ is hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _6-12 aryl, or the following acyl substituents: formyl, C _2-7 alkanoyl, C _3-7 alkenoyl, C _1-7 alkylsulfonyl, C _7-12 aroyl, C _9-20 aryl alkenoyl, C _6-12 arylsulfonyl, C _8-12 aryl alkanoyl or C _7-12 aralkyl Sulfonyl;

R ₅ and R ₆ are each hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _6-12 aryl, or fluorine;

和 The a substituent Z is selected from

and

M is an alkali metal cation or an alkaline earth metal cation;

R ₇ is C _1-10 alkyl, C _3-10 cycloalkyl, C _7-20 aralkyl, or C _6-12 aryl;

R ₈ and R ₉ are each hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _7-20 aralkyl, or C _6-12 aryl;

R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are each C _1-10 alkyl;

R ₁₄ is C _1-10 straight chain alkyl;

R ₁₅ is a halogenated C _1-10 linear alkyl group;

Aroyl is benzoyl and naphthoyl which can be substituted by 1-3, and the substituents are respectively selected from halogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, -CF ₃ and phenyl;

Aryl is naphthyl, phenyl or 1-3 substituted phenyl, and the substituents are each selected from halogen, carboxyl, C _1-10 alkyl, nitro, amino, C _1-10 alkoxy, and C _{1-10 10} Alkylamino.

A preferred content of the present invention is to use the following subgroup of compounds of general formula (II) or pharmaceutically acceptable salts thereof, by regulating potassium channels, to treat warm-blooded animals (mammals are preferred, and humans are especially suitable) related to smooth muscle contraction disease, wherein the other groups are the same as described above for general formula (II), wherein:

a) When Y is -NR ₄ , X is -O-;

b) when Y is -CR ₅ R ₆ , X is -NR ₄ ;

c) When Y is -NR ₄ , X is -CR ₅ R ₆ .

More preferably, the following subgroups of compounds of general formula (II) or pharmaceutically acceptable salts thereof are used to treat diseases related to smooth muscle contraction in warm-blooded animals (mammals are preferred, and humans are especially suitable) by regulating potassium channels, Other groups therein are the same as described above for general formula (II), wherein: Z is -CO ₂ H; R ₁ is halogen or nitro;

a) When Y is -NR ₄ , X is -O-;

b) when Y is -CR ₅ R ₆ , X is -NR ₄ ;

c) When Y is -NR ₄ , X is -CR ₅ R ₆ .

More preferably, the following compounds of general formula (II) or pharmaceutically acceptable salts thereof are used to treat diseases related to smooth muscle contraction in warm-blooded animals (mammals are preferred, and humans are especially suitable) by regulating potassium channels:

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;

8-iodo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;

8-Chloro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;

8-nitro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid dihydrate;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid amide;

Methyl 8-bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylate;

(8-Bromo-10H-benzo[4,5]furo[3,2-b]indol-1-yl)-methanol;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid hydroxymethylamide;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carbaldehyde;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carbonitrile monohydrate;

8-Bromo-1-(1H-tetrazol-5-yl)-10H-benzo[4,5]furo[3,2-b]indole;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (1,2,2-trimethyl-propyl)-amide;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (1,1-dimethyl-propyl)-amide;

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methylamide;

Methyl 8-bromo-10methyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylate;

10H-benzo[4,5]furo[3,2-b]indole-carboxylic acid;

0.6 hydrated 8-iodo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid;

8-sulfamoyl-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid hemihydrate;

8-fluoro-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid;

8-Chloro-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid;

8-trifluoromethoxy-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid;

Ethyl 8-chloro-5,10-dihydro-indeno[1,2-b]indole-1-carboxylate;

Ethyl 8-bromo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylate;

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]indole-1-carboxylic acid; and

3-Bromo-5,10-dihydro-indeno[1,2-b]indole-6-carboxylic acid.

When 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 ₁₃ or R ₁₅ contain an asymmetric carbon atom, usually Compounds of formula (I) and (II) of course include all possible stereoisomers having the activities described hereinafter. Specifically, the definition of a compound includes various racemic modifications and optical isomers having said activity. Optical isomers can be obtained in pure form by standard separation techniques or by enantiomer-specific synthesis. The present invention includes all crystal forms of the compounds of general formula (I) and (II). The pharmaceutically acceptable salts of the basic compounds of this invention are those formed with organic and inorganic acids such as: lactic acid, citric acid, acetic acid, tartaric acid, fumaric acid, succinic acid, maleic acid, malonic acid, Acids, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, and similar known and acceptable salts.

If R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ or R ₉ contain a carboxyl group, or Z is a carboxylic acid, the salt of the present invention can be combined with an alkali metal (Na, K , Li) or alkaline earth metals (Ca or Mg).

In the above compounds of general formula (I) and (II), unless otherwise specified, the following terms are defined as:

Halogen or halo refers to chlorine, fluorine, bromine and iodine.

Alkyl here refers to a branched or straight chain of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

Cycloalkyl refers herein to a saturated ring of 3-10 carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Aryl refers here to fused or non-fused carbocyclic aromatic groups of 6 to 12 carbon atoms. Preferred aryl groups include phenyl, α-naphthyl and β-naphthyl, etc., which can be substituted by 1-3, and the substituents are selected from halogen, carboxyl, C _1-10 alkyl, nitro, amino, C _{1 -10} alkoxy and C _1-10 alkylamino.

Aroyl refers herein to -C(O)aryl, wherein the aryl is as previously described. Examples thereof include benzoyl and naphthoyl, which may be substituted with 1-3 substituents selected from halogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, -CF ₃ and phenyl.

Aralkyl refers herein to an aryl-alkyl group in which the aryl and alkyl are as previously described. Examples thereof include benzyl and phenethyl.

Alkenyl herein refers to a branched or branched chain of 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, containing at least one carbon-carbon double bond in the chain. Alkenyl is herein synonymous with alkenyl and includes alkylene. Examples of alkenyl groups include vinyl (ethylene), propenyl (propylene) and isobutenyl (isobutylene).

Alkanoyl here means -C(O)alkyl, wherein the alkyl is as described above.

The alkenoyl group here is -C(O)alkenyl, wherein the alkenyl group is as described above.

Alkoxy here means -O-alkyl, wherein the alkyl is as described above. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

The arylalkanoyl group, that is, the carbonyl group, is directly bonded to the C _1-10 alkyl group, and the terminal of the alkyl group is substituted by the aforementioned aryl group, such as phenylacetic acid. The aryl group can be substituted by 1-3, and the substituent is selected from halogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, -CF ₃ , phenyl or substituted phenyl, and the substituent on it selected from halogen, cyano, C _1-10 alkyl, C _1-10 alkoxy and -CF ₃ .

An aryl alkenoyl group, that is, a carbonyl group, is directly bonded to a C _2-12 alkenyl group, and the end of the alkenyl group is substituted by the aforementioned aryl group. The aryl group can be substituted by 1-3, and the substituent is selected from halogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, -CF ₃ , phenyl or substituted phenyl, and the substituent on it is selected from from halogen, cyano, C _1-10 alkyl, C _1-10 alkoxy and -CF ₃ .

Alkylsulfonyl is -SO ₂ alkyl, wherein the alkyl is as described above.

Arylsulfonyl is -SO ₂ aryl, wherein the aryl is as described above.

The aralkylsulfonyl group is aralkyl O ₂ S-, wherein the aralkyl group is as described above.

Phenyl here refers to a 6-membered aromatic ring.

When terms are used in combination, unless otherwise specified, the individual meanings of each part are as above. For example, the aryl group and the alkyl group in the aralkyl group are respectively as described above.

The above number of carbon atoms is the carbon atoms in the carbon skeleton and does not include the carbon atoms in the substituents.

The present invention also provides processes for the preparation of compounds of general formula (I) and (II). In the compounds of general formulas (I) and (II), X is -O-, Y is -NR ₄ , wherein R ₄ is as described above, and can be prepared according to Scheme 1. Appropriately substituted benzofuranone 1 (where R ₁ , R ₂ and R ₃ are as described above) is reacted with 2-hydrazinobenzoic acid 2 in aqueous medium to generate the corresponding phenylhydrazone 3 . Isolation or purification of this intermediate followed by conversion, or microwave-assisted Fischer-indole cyclization in an acidic medium (such as but not limited to formic acid) as a crude product yields substituted benzo[4,5]furo[ 3,2-b]indole 4. If _R4 is other than hydrogen, then _R4 can be introduced by standard methods to make carboxylic acid 5. Option I

Alternatively, compounds of the following general formulas (I) and (II) can be prepared as shown in Scheme II, wherein X is NR ₄ , Y is -CR ₅ R ₆ , wherein R ₄ , R ₅ and R ₆ are as previously described . Appropriately substituted phenylhydrazine 6 (wherein R ₁ , R ₂ and R ₃ are as previously described) and 2,3-dihydro-indanone-1-carboxylic acid 7 (wherein R ₅ and R ₆ are as previously described ) reaction to obtain phenylhydrazone 8, which undergoes microwave-assisted Fischer-indole cyclization reaction in the presence of acid (such as but not limited to formic acid) to obtain indeno[1,2-b]indole 9.

Scheme II If _R4 is other than hydrogen, then _R4 can be introduced by standard methods to give carboxylic acid 10.

Compounds of general formulas (I) and (II), wherein X is -CR ₅ R ₆ , Y is -NR ₄ , and wherein R ₄ , R ₅ and R ₆ are as described above, can be prepared as shown in Scheme III. An appropriately substituted 2,3-dihydro-indanone (11) (wherein R ₁ , R ₂ , R ₃ , R ₅ and R ₆ are as described above) and 2-hydrazinobenzoic acid (2) in Reaction in aqueous medium affords intermediate phenylhydrazone (12). The intermediate phenylhydrazone can be microwaved to facilitate Fischer-indole cyclization in acidic media such as but not limited to formic acid to afford substituted indeno[1,2-b]indoles (13). If _R4 is other than hydrogen, then _R4 can be introduced by standard methods to give carboxylic acid 14.

Scheme III

Benzo[4,5]furo[3,2-b]indole 4, carboxylic acid 5, indeno[1,2-b]indole 9, carboxylic acid 10, substituted indeno[1,2- b] The carboxylic acid moieties in indole 13 and carboxylic acid 14 can form other groups represented by Z in general formulas (I) and (II). For example, reaction with an alkali metal base or an alkaline earth metal base can form the corresponding carboxylate salt. Esters can be formed with alcohols (R ₇ OH, where R ₇ is as described above) in the presence of acids. Esters can also be prepared by other methods known in the art.

Reduction of the ester with a suitable reducing agent, such as diisobutylaluminum hydride, sodium borohydride, lithium aluminum hydride, will give the corresponding alcohol or aldehyde. If only alcohols are formed, a suitable mild oxidizing agent such as pyridinium cloramate or 1,1,1-triacetoxy-1,1-dihydro-1,2- Benziodoxol-3-(1H)-one, or tetrapropylammonium perruthenate, oxidizes it to the aldehyde.

It can also be obtained by reacting with amine (-NHR ₈ R ₉ , wherein R ₈ and R ₉ are as previously described) react to convert the carboxylic acid moiety into the corresponding amide. Alternatively, carboxylic acids can be converted to the corresponding acid chlorides using suitable reagents such as thionyl chloride or oxalyl chloride. Then, react with a suitable amine (-NHR ₈ R ₉ , where R ₈ and R ₉ are as described above) in the presence of an external base to obtain the desired amide.

In the same manner, the corresponding hydroxamic acid can be prepared by reacting an appropriately substituted hydroxylamine (NHR ₈ OH, where R ₈ is as described above) with an acid chloride. Reaction of urea with carboxylic acid in the presence of strong acid will generate the corresponding nitrile (Z is CN). Nitriles can be converted to tetrazoles by cyclization with sodium azide.

In an organic solvent such as tetrahydrofuran or dichloromethane, in the presence of a suitable base or Ag ₂ O, using the conditions described by Kim, KS, etc. in J.Med.Chem.1993,36,2335, with C1(R ₁₀ ) COC (O) R ₁₁ alkylated carboxylic acid; or in the presence of sodium iodide/N, N-dimethylformamide, with Bundgaard, H. in Int.J.Pharm.1989,55,91 Cyclization with ClCH ₂ C(O)N(R ₁₂ R ₁₃ ) under the conditions described will generate biologically equivalent prodrug analogs.

The compounds of general formula (I) and (II) and their pharmaceutically acceptable salts relax smooth muscle. They are therefore useful in the treatment of disorders associated with smooth muscle contraction, such as excessive contraction of smooth muscle in the urinary tract (eg urinary incontinence) or gastrointestinal tract (eg irritable bowel syndrome), asthma and alopecia . Moreover, the compounds of the general formulas (I) and (II) have potassium channel activator activity, so they can be used to treat peripheral vascular disease, congestive heart failure, stroke, anxiety, cerebral hypoxia and other neurodegenerative diseases.

Compounds of the invention potently relax smooth muscle in standard pharmaceutical assays. The compounds of the present invention exert their smooth muscle relaxing activity by activating potassium channels. Furthermore, the compounds of the present invention are also unique in their inherent selectivity for bladder tissue over vascular tissue, as reflected in the bladder/aorta _IC50 ratio (Table 1).

The present invention also provides a pharmaceutical composition, which contains the compound of the present invention and a pharmaceutically acceptable carrier. Specifically, the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention and a pharmaceutically acceptable carrier.

The composition is preferably made into an oral dosage form. However, it can also be formulated in other dosage forms, eg parenteral dosage forms for patients with heart failure.

In order to achieve uniformity of administration, the compositions of the invention are preferably presented in unit dosage form. Suitable unit dosage forms include tablets, capsules and powders in sachets or bottles. Such unit dosage forms may contain 0.1-100 mg, preferably 2-50 mg, of a compound of the invention. Even more preferred are unit dosage forms containing 5-25 mg of a compound of the invention. The compound of the present invention can be administered orally at a dose of 0.01-100 mg/kg, more preferably 0.1-10 mg/kg. Such compositions may be administered 1-6 times per day, typically 1-4 times per day.

The composition of the present invention can be formulated with conventional excipients, such as fillers, disintegrants, binders, lubricants, flavor-masking agents and the like. Formulation can be carried out by conventional methods, for example in a manner analogous to that used for known antihypertensives, diuretics and beta-blockers.

The present invention also provides compounds for use as active therapeutic substances. Compounds of general formula (I) and (II) are particularly effective in inducing smooth muscle relaxation.

The present invention also provides a method for treating smooth muscle-related diseases in mammals (including humans), comprising administering to patients an effective amount of the compound or pharmaceutical composition of the present invention.

The following examples illustrate, but do not limit, the methods for preparing representative compounds of the invention.

Example 1

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

Step 1) Preparation of o-[(2,3-dihydro-5-bromobenzofuran-3-ylidene)hydrazino]-benzoic acid

To the ethanol (100ml) solution of 5-bromo-3(2H)-benzofuranone (3.10g, 14.6mmol) [Ellingboe, J. et al., Journal of Medicinal Chemistry 1992,35(7), 1176-1183] A solution of 2-hydrazinobenzoic acid hydrochloride (5.49 g, 29.1 mmol) in deionized water (200 mL). The mixture was stirred at room temperature for 1 hour, then left to cool (to 0°C). After vacuum filtration and vacuum drying, 3.65 g (72%) of the title compound as a brown solid were obtained: mp. 195° C. (dec. (dec.)), which was used without purification.

Step 2) Preparation of 8-bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

Hydrazone (prepared in step 1 of Example 1) (0.500 g, 1.51 mmol) was irradiated in formic acid (2 ml, 96%) in a capped Teflon tube in a microwave oven (700W) for 2 minutes. The mixture was suction filtered while hot, and the solid was dried in vacuo to obtain 0.271 g (57%) of the title compound as a yellow solid: mp.312-313°C; ¹ H NMR (DMSO-d ₆ ): δ13.36 (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 ^{- 1} ; MS (m/z) 329 (M ⁺ ).

Elemental analysis of C ₁₅ H ₈ BrNO ₃ :

Calculated: C, 54.57; H, 2.44; N, 4.24.

Found: C, 54.22; H, 2.32; N, 4.30.

Example 2

8-iodo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

Step 1) Preparation of o-[(2,3-dihydro-5-iodobenzofuran-3-ylidene)hydrazino]-benzoic acid

To 5-iodo-3(2H)-benzofuranone (0.551g, 2.12mmol) [Cagniant, P. et al., Hebd.SeancesAcad.Sci., Ser.C, 1976, 282(21), 993-6] A solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 ml) was added to a solution of ethanol (100 ml). The mixture was stirred at room temperature for 1 hour, then left to cool (to 0°C). After vacuum filtration and vacuum drying, 0.480 g (58%) of the title compound was obtained as a brown solid: mp. 169° C. (dec.), which was used directly without purification.

Step 2) Preparation of 8-iodo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

Hydrazone (prepared in step 1 of Example 2) (0.480 g, 1.22 mmol) was irradiated in formic acid (2 ml, 96%) in a capped Teflon tube in a microwave oven (700W) for 2 minutes. The mixture was suction filtered while it was hot, and the solid was dried in vacuo to give 0.240 g (52%) of the title compound as a yellow solid: mp.297°C (dec); ¹ H NMR (DMSO-d ⁶ ): δ13.33 (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, 1670 cm ^-1 ; MS (m/z) 377 (M ⁺ ).

Elemental analysis of C ₁₅ H ₈ INO ₃ :

Calculated: C, 47.77; H, 2.14; N, 3.71.

Found: C, 47.61; H, 1.92; N, 3.68.

Example 3

8-Chloro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

Step 1) Preparation of o-[(2,3-dihydro-5-chlorobenzofuran-3-ylidene)hydrazino]-benzoic acid

To the ethanol (100ml) solution of 5-chloro-3(2H)-benzofuranone (0.357g, 2.12mmol) [Ellingboe, J. et al., Journal of Medicinal Chemistry 1992,35(7), 1176-1183] A solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 mL). The mixture was stirred at room temperature for 1 hour, then left to cool (to 0°C). After vacuum filtration and vacuum drying, 0.400 g (62%) of the title compound was obtained as a brown solid: mp. 190° C. (dec.), which was used directly without purification.

Step 2) Preparation of 8-chloro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

Hydrazone (prepared in step 1 of Example 3) (0.480 g, 1.22 mmol) was irradiated in formic acid (2 ml, 96%) in a capped Teflon tube in a microwave oven (700W) for 2 minutes. The mixture was suction filtered while it was hot, and the solid was dried in vacuo to obtain 0.240 g (52%) of the title compound as a yellow solid: mp.303°C (dec); ¹ H NMR (DMSO-d ₆ ): δ13.24 (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, 1685 cm ^-1 ; MS (m/z) 285 (M ⁺ ).

Elemental analysis of C ₁₅ H ₈ ClNO ₃ :

Calculated: C, 63.06: H, 2.82; N, 4.90.

Found: C, 63.00: H, 2.57; N, 4.98.

Example 4

8-Nitro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid dihydrate

Step 1) Preparation of o-[(2,3-dihydro-5-nitrobenzofuran-3-ylidene)hydrazino]-benzoic acid

5-Nitro-3(2H)-benzofuranone (0.500g, 2.79mmol) [Tobias, P. et al., Journal of the American Chemical Society, 1969, 91(18), 5171-5173] and 2-hydrazine hydrochloride Benzoic acid (0.526g, 2.79mmol) was mixed in pyridine (10ml), and stirred overnight at room temperature. The mixture was vacuum filtered and dried to afford 0.800 g (86%) of the title compound as a yellow solid: mp. 210°C (dec.), which was used without purification.

Step 2) Preparation of 8-nitro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid dihydrate

Hydrazone (prepared in step 1 of Example 4) (0.500 g, 1.51 mmol) was irradiated in formic acid (2 ml, 96%) in a capped Teflon tube in a microwave oven (700W) for 2 minutes. The mixture was suction filtered, the solid was dissolved in dimethyl sulfone, and reprecipitated with water to obtain 0.296 g (66%) of the title compound as a yellow solid: mp.325°C (dec); ¹ H 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, 1675 cm ^-1 ; MS (m/z) 296 (M ⁺ ).

Elemental analysis of C ₁₅ H ₈ N ₂ O ₅ ·2H ₂ O:

Calculated: C, 54.22; H, 3.64; N, 8.43.

Found: C, 54.25; H, 3.48; N, 7.68.

Example 5

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid amide

The product from step 2 of Example 1 (0.100 g, 0.303 mmol) was dissolved in diethyl ether (20 mL). To this solution was added phosphorus pentachloride (72.0 mg, 0.345 mmol) under argon atmosphere. After stirring at room temperature for 30 minutes a yellow precipitate formed. Ammonia saturated ether (75ml) was added and the reaction was stirred overnight. The mixture was concentrated and chromatographed (hexane/ethyl acetate, 1:1) to collect the highly eluting amide (60 mg). The isolated product was triturated with ether to give 0.024g (24%) of the title compound as a pale yellow solid: mp.300-301°C; ¹ H NMR (DMSO-d ₆ ): δ11.72(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): 1650 cm ^-1 ; MS (m/z) 328 (M ⁺ ).

Elemental analysis of C ₁₅ H ₉ BrN ₂ O ₂ :

Calculated: C, 54.74; H, 2.75; N, 8.51.

Found: C, 54.53; H, 2.72; N, 8.34.

Example 6

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methyl ester

The product from Step 2 of Example 1 (5.75 g, 17.4 mmol) was mixed with concentrated sulfuric acid (3 ml) and methanol (500 ml), and heated in an oil bath at 100° C. for 3 days. Cool and concentrate the mixture. The concentrated residue was triturated with ether to give 2.40 g (40%) of the title compound as a brown solid: mp.204-205°C; ¹ H NMR (DMSO-d ₆ ): δ11.66(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 , 1710 cm ^-1 ; MS (m/z) 343 (M ⁺ ).

Elemental analysis of C ₁₆ H ₁₀ BrNO ₃ :

Calculated: C, 55.84; H, 2.93; N, 4.07.

Found: C, 55.49; H, 2.82; N, 4.01.

Example 7

(8-Bromo-10H-benzo[4,5]furo[3,2-b]indol-1-yl)-methanol

Lithium aluminum hydride powder (0.025 g, 0.659 mmol) was added to a solution of the product of Example 6 (0.196 g, 0.570 mmol) dissolved in tetrahydrofuran (5 ml). After stirring at room temperature for 18 hours, deionized water (0.20ml) was carefully added, followed by 2.5N sodium hydroxide (0.20ml), and then water (2ml). The mixture was filtered through a pad of celite, and the filtrate was dried over magnesium sulfate. Chromatography (hexane/ethyl acetate, 3:1) of the crude product afforded 0.060 g (33%) of the title compound as a white solid: mp.218-219°C; ¹ HNMR (DMSO-d ₆ ): δ11.25 (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 (width) cm ^-1 ; MS (m/z) 315 (M ⁺ ).

Elemental analysis of C ₁₅ H ₁₀ BrNO ₂ :

Calculated: C, 56.99; H, 3.19; N, 4.43.

Found: C, 57.23; H, 2.45; N, 4.45.

Example 8

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid hydroxymethylamide

Oxalyl chloride (1.00ml, 11.5mmol) was added to a solution of the product from Step 2 of Example 1 (1.00g, 3.03mmol) dissolved in ether (100ml) and N,N-dimethylformamide (0.40ml). After 1 hour, the yellow mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (80ml), and while stirring, it was added N-methylhydroxylamine hydrochloride (1.26g, 15.1mmol) in tetrahydrofuran/water (16ml, 15:1) and triethylamine (4.20 ml, 30.3mmol) of the solution. After stirring overnight, the mixture was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate. The crude product was chromatographed (hexane/ethyl acetate, 1:1) to obtain 0.100 g (9%) of the title compound as a white solid: mp.174-175°C; ¹ H NMR (DMSO-d ₆ ): δ10.22 -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): 1640 cm ^-1 ; MS (m/z) 358 (M ⁺ ).

Elemental analysis of C ₁₆ H ₁₁ BrN ₂ O ₃ :

Calculated: C, 53.50; H, 3.09; N, 7.80.

Found: C, 53.33; H, 2.98; N, 7.71.

Example 9

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carbaldehyde

1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodooxolane-3(1H)-one (0.522g, 1.23mmol) in acetonitrile (20ml ) solution was added to a solution of the product of Example 7 (0.390 g, 1.23 mmol) in acetonitrile (50 ml). The reaction was monitored by TLC (hexane/ethyl acetate, 1:1). The yellow mixture was poured into a saturated solution of sodium bicarbonate containing sodium thiosulfate (0.187 g, 1.18 mmol). The mixture was partitioned and the organic phase was washed with aqueous sodium bicarbonate and brine, dried ( _MgSO4 ) and concentrated. After triturating the concentrated residue and drying in vacuo, the title compound was obtained as a yellow solid 0.117g (30%): mp.280-281°C; ¹ H NMR (DMSO-d ₆ ): δ12.10(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) : 1660 cm ^-1 ; MS (m/z) 313 (M ⁺ ).

Elemental analysis of C ₁₅ H ₈ BrNO ₂ :

Calculated: C, 57.35; H, 2.57; N, 4.46.

Found: C, 57.05; H, 2.37; N, 7.86.

Example 10

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carbonitrile monohydrate

The product of Step 2 of Example 1 (0.500 g, 1.51 mmol) was thoroughly mixed with urea fine powder (8.67 g, 1.44 mmol). Phosphoric acid (2.5 g, 21.7 mmol) was added followed by N,N-dimethylformamide (DMF) (7 ml). The reaction mixture was irradiated in a microwave oven (15-30% power, 700W) for 35 minutes and then cooled. The crude product was crushed and partitioned between water and ether. The organic phase was concentrated in vacuo and the residue was dissolved in acetone/7ether (1:1) and filtered through a plug of silica gel eluting with ether and hexanes (1:1) to afford 0.088 g (19%) of the title compound as a pale yellow solid: mp.277-280°C (dec); ¹ H NMR (DMSO-d ₆ ): δ11.44 (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): 2230 cm ^-1 .

Elemental analysis of C ₁₅ H ₇ BrN ₂ O·H ₂ O:

Calculated: C, 54.74; H, 2.76; N, 8.51.

Found: C, 55.29; H, 2.36; N, 8.22.

Example 11

8-Bromo-1-(1H-tetrazol-5-yl)-10H-benzo[4,5]furo[3,2-b]indole

The product of Example 10 (0.350 g, 1.13 mmol), NaN3 (0.102 g, 1.58 mmol) and n-Bu ₃ SnCl (0.43 ml, 1.58 mmol) were mixed in xylene (5 ml) and stirred at 120° C. for 18 hours. The reaction was monitored by TLC and DMF (2ml) was added. The reaction was stirred at 130°C for 18 hours, the reaction mixture was cooled, diluted with 6N HCl (10 mL), stirred for 1 hour while bubbling _N2 . The solid formed was vacuum filtered and washed with _H2O . The solid was recrystallized from hot methanol and triturated with hot ethyl acetate. The title compound (0.15 g, 38%) was collected by filtration as an off-white solid: mp.275-277°C (dec); ¹ H NMR (DMSO-d ₆ ): δ11.87 (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, 1440 cm ^-1 ; MS (m/z) 353 (M ⁺ ).

Elemental analysis of C ₁₅ H ₈ BrN ₅ O:

Calculated: C, 50.87; H, 2.27; N, 19.77.

Found: C, 50.93; H, 2.52; N, 18.06.

Example 12

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (1,2,2-trimethyl-propyl)-amide

To a solution of the product from step 2 of Example 1 (0.15 g, 0.455 mmol) in dichloromethane (4 ml) was added 5 drops of DMF followed by oxalyl chloride (0.12 ml, 1.53 mmol). The compound was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was redissolved in dichloromethane (5ml), and to this solution was added 3,3-dimethyl-2-aminobutane (0.134ml, 1.00mmol). The reaction mixture was stirred for 4 hours, then concentrated in vacuo. The residue was _partitioned between aqueous _Na2CO3 and ethyl acetate. The organic phase is dried and decolorized. The concentrated residue was triturated with hexane to give 0.07 g (37%) of _the title amide as an off-white solid: mp ^. 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, 1640 cm ^-1 ; MS (m/z) 412 (M ⁺ ).

Elemental analysis of C ₂₁ H ₂₁ BrN ₂ O ₂ :

Calculated: C, 61.03; H, 5.12; N, 6.78.

Found: C, 59.97; H, 5.32; N, 7.10.

Example 13

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (1,1-dimethyl-propyl)-amide

Add oxalyl chloride (317 μl, 3.63mmol ). After gassing had ceased, the mixture was warmed to room temperature and stirred for 1 hour, then cooled to 0° C., at which point tert-amylamine (425 μl, 3.63 mmol) was added. The reaction mixture was stirred for 12 hours, then all volatile components were removed by rotary evaporation. The solid residue was dissolved in hot acetone-ethanol (8:1, 50ml), and after clarification by filtration, water (50ml) was added, causing precipitation. Filter and then dry under high vacuum at 50°C to give 111 mg (30%) of the title compound as an off-white solid: mp.242-244°C (dec); ¹ H NMR (DMSO-d ₆ ): δ11.66 (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 ^-1 ; MS (m/z) 398/400 (M ⁺ ).

Elemental analysis of C ₂₀ H ₁₉ BrN ₂ O ₂ :

Calculated: C, 60.16; H, 4.79; N, 7.02.

Found: C, 59.53; H, 4.35; N, 6.88.

Example 14

8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methylamide

Add oxalyl chloride (317 μl, 3.63 mmol). After gas evolution had ceased, the mixture was warmed to room temperature and stirred for 1 hour, then cooled to 0°C, at which point methylamine (ca. 4-5 mL) was added. The reaction mixture was stirred for 12 hours, then all volatile components were removed by rotary evaporation. The solid residue was sonicated in acetonitrile (10ml), filtered and washed slightly with acetonitrile. The solid was then dissolved in hot acetone-ethanol (8:1, 50ml), filtered and water (50ml) added to cause precipitation while sonication. Filter and then dry under high vacuum at 50°C to give 55 mg (18%) of the title compound as a white solid: mp.264-265°C (dec); ¹ H NMR (DMSO-d ₆ ): δ11.74 (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 - 1} ; MS (m/z) 344/342 (M ⁺ ).

Elemental analysis of C ₁₆ H ₁₁ BrN ₂ O ₂ :

Calculated: C, 56.00; H, 3.23; N, 8.16.

Found: C, 55.73; H, 3.08: N, 7.88.

Example 15

8-Bromo-10-methyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methyl ester

To a solution of the product from Step 2 of Example 1 (1.789, 5.40 mmol) in N,N-dimethylformamide (20 ml) at -5°C was added portionwise 80% sodium hydride (324 mg, 10.8 mmol). The resulting red mixture was stirred for 1 hour, slowly warmed to room temperature and methyl trifluoromethanesulfonate (1.83 mL, 16.2 mmol) was added, resulting in a large amount of precipitate. Additional N,N-dimethylformamide (5ml) was added to facilitate stirring. The reaction mixture was stirred for an additional hour, then diluted with water, filtered and washed with water and methanol. The solid was recrystallized from acetone-water and filtered. Dry under high vacuum at 50°C to obtain 357 mg (19%) of the title compound as a white solid: mp.195-196°C; ¹ HNMR (DMSO-d ₆ ): δ8.31 (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, 730 cm ^-1 ; MS (m/z) 357/359 (M ⁺ ).

Elemental analysis of C ₁₇ H ₁₂ BrNO ₃ :

Calculated: C, 57.00; H, 3.38; N, 3.91.

Found: C, 56.83; H, 3.17; N, 3.83.

Example 16

10H-Benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

To a homogeneous solution of 3-coumaranone (2.63g, 20mmol) in ethanol (50ml) was added dropwise a solution of phenylhydrazine-2-carboxylic acid hydrochloride (6.79g, 36mmol) in water (75ml). The resulting mixture was stirred at room temperature for 12 hours, filtered and dried in vacuo to afford 2.17 g (40%) of the corresponding hydrazone as a white solid.

A suspension of the above phenylhydrazone (268mg, 1.0mmol) in formic acid (5.0ml) was heated to 110°C, at which point the mixture first became homogeneous and then a large amount of precipitate formed. Heating was continued for 5 minutes and then cooled in an ice bath to collect the solid. The solid was washed with water, recrystallized with acetone-water, and dried in vacuo to obtain 156 mg (62%) of a yellow solid: mp.279-280°C; ¹ H NMR (DMSO-d ₆ ): δ13.28 (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, 720 cm ^-1 ; MS (m/z) 251 (M ⁺ ).

Elemental analysis of C ₁₅ H ₉ NO ₃ :

Calculated: C, 71.71; H, 3.61; N, 5.57.

Found: C, 71.83; H, 3.39; N, 5.47.

Example 17

0.6 hydrated 8-iodo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

In a Teflon PFA tube, 1-oxo-indane-4-carboxylic acid (0.528 g, 2.99 mmol) and 4-iodophenylhydrazine hydrochloride (0.698 g, 2.58 mmol) were dissolved in formic acid with 3 drops of concentrated hydrochloric acid (2ml, 96%) into a paste. The test tube was irradiated in a CEM microwave oven (MDS2000) at full power (760W) for 1 minute (T=140C, P<50PSI), cooled for 2 minutes, and then irradiated for 1 minute (T=140C, P<50PSI). The mixture was suction filtered while hot. The solid was washed with formic acid and dried on glass wool. After chromatography (acetone/hexane) and trituration with ether, the title compound was obtained as a brown solid (0.059 g, 5%): mp.251°C; ¹ H NMR (DMSO-d ₆ ): δ3.98 (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 ⁺ ).

Elemental analysis of C ₁₆ H ₁₀ INO ₂ :

Calculated: C, 49.87; H, 2.72; N, 3.63.

Found: C, 49.59; H, 2.81; N, 3.66.

Example 18

8-Sulfamoyl-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid hemihydrate

In a similar manner to Example 17, 1-oxo-indane-4-carboxylic acid (0.528g, 2.99mmol) and 4-sulfamoylphenylhydrazine hydrochloride (0.671g, 3.0mmol) were converted into the title compound brown Solid: mp.270-272°C (dec); ¹ H NMR (DMSO-d ₆ ): δ4.07 (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 ⁺ ).

Elemental analysis of C ₁₆ H ₁₂ N ₂ O ₄ S·0.5H ₂ O:

Calculated: C, 56.79; H, 3.88; N, 8.30.

Found: C, 56.71; H, 3.49; N, 8.19.

Example 19

8-fluoro-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

In a similar manner to Example 17, 1-oxo-indane-4-carboxylic acid (1.00 g, 5.68 mmol) and 4-fluorophenylhydrazine hydrochloride (0.923 g, 5.68 mmol) were converted into the title compound as an off-white solid ( 0.140g, 10%): mp.>300°C; ¹ H NMR (DMSO-d ₆ ): δ3.98 (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 ⁺ ).

Elemental analysis of C ₁₆ H ₁₀ FNO ₂ :

Calculated: C, 71.91; H, 3.77; N, 5.24.

Found: C, 71.33; H, 3.78; N, 5.22.

Example 20

8-Chloro-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

In a similar manner to Example 17, 1-oxo-indane-4-carboxylic acid (1.00 g, 5.68 mmol) and 4-chlorophenylhydrazine hydrochloride (1.03 g, 5.75 mmol) were converted into the title compound as a light brown solid (0.230g, 14%): mp.>300°C; ¹ H NMR (DMSO-d ₆ ): δ4.00 (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 ⁺ ) .

Elemental analysis of C ₁₆ H ₁₀ ClNO ₂ :

Calculated: C, 67.74; H, 3.55; N, 4.94.

Found: C, 67.08; H, 3.69; N, 4.78.

Example 21

8-Trifluoromethoxy-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

In a similar manner to Example 17, 1-oxo-indane-4-carboxylic acid (1.00 g, 5.68 mmol) and 4-trifluoromethoxyphenylhydrazine hydrochloride (1.30 g, 5.68 mmol) were converted into the title Compound light brown solid (0.160g, 8%): mp.256-265°C (dec); ¹ H NMR (DMSO-d ₆ ): δ4.03 (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 ⁺ ).

Elemental analysis of C ₁₇ H ₁₀ F ₃ NO ₃ :

Calculated: C, 61.27; H, 3.02; N, 4.20.

Found: C, 61.82; H, 3.15; N, 4.32.

Example 22

8-Chloro-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid ethyl ester

The product of Example 20 was treated with sulfuric acid in ethanol to convert it into ethyl ester to obtain the title compound as an off-white solid: mp.202-204°C (dec); ¹ H NMR (DMSO-d ₆ ): δ1.39( 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 ⁺ ).

Elemental analysis of C ₁₈ H ₁₄ F ₃ ClNO ₂ :

Calculated: C, 60.69; H, 3.96; N, 3.93.

Found: C, 60.47; H, 3.76; N, 3.78.

Example 23

8-Bromo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid ethyl ester

In a similar manner to Example 17, 1-oxo-indane-4-carboxylic acid (1.00 g, 5.68 mmol) was reacted with 4-bromophenylhydrazine hydrochloride to generate 8-bromo-5,10-dihydro-indeno [1,2-b]indole-1-carboxylic acid, and then according to the method of Example 22, it was converted into ethyl ester to obtain the title compound as a brown solid: mp.198-200°C; ¹ HNMR (DMSO-d ₆ ): δ1.39(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 ⁺ ).

Elemental analysis of C ₁₈ H ₁₄ BrNO ₂ :

Calculated: C, 69.35; H, 4.53; N, 4.49.

Found: C, 69.17; H, 4.39; N, 4.37.

Example 24

10,10-Dimethyl-3-nitro-5,10-dihydro-indeno[1,2-b]indole-6-carboxylic acid

6-nitro-3,3-dimethyl-1-(2,3-dihydro-1-indanone) (0.612g, 2.98mmol) [Smith, JG et al., Preparation and Formation of Organic Matter, 1978, 10(3), 123-131] and 2-hydrazinobenzoic acid hydrochloride (0.562g, 2.98mmol) in formic acid (2ml, 96%) in a capped Teflon test tube and irradiated in a microwave oven (700W) 2 minutes. The mixture was filtered off with suction, the crude product was chromatographed (hexane/ethyl acetate 1:1) and triturated with petroleum ether/diethyl ether. After vacuum drying, 0.178g (19%) of the title compound was obtained as a yellow solid: mp.310°C; ¹ H NMR (DMSO-d ₆ ): δ13.43(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 ^-1 ; MS (m/z): 322 (M ⁺ ).

Elemental analysis of C ₁₈ H ₁₄ N ₂ O ₄ :

Calculated: C, 67.08; H, 4.38; N, 8.69.

Found: C, 66.29; H, 4.45; N, 8.37.

Example 25

8-Bromo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

1-oxo-4-indane carboxylic acid (0.528g, 2.98mmol) [Aono, T. et al., Chem. (0.566g, 2.98mmol) in formic acid (2ml, 96%) in a capped Teflon tube and irradiated (700W) in a microwave oven for 2 minutes. The mixture was filtered with suction. The crude product was dissolved in acetone/ether (1:1), treated with decolorizing charcoal, filtered, concentrated, and dried in vacuo to give the title compound as a white solid: mp.328-330°C (dec); 1H NMR (DMSO-d6): δ13.43(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, 1690 cm-1; MS (m/z): 327 (M+).

Elemental analysis of C ₁₆ H ₁₀ BrNO ₂ :

Calculated: C, 58.56; H, 3.07; N, 4.27.

Found: C, 58.57; H, 2.88; N, 4.30.

Example 26

3-Bromo-5,10-dihydro-indeno[1,2-b]indole-6-carboxylic acid

Step 1) Preparation of o-[(2,3-dihydro-6-bromoinden-3-ylidene)hydrazino]-benzoic acid

To 6-bromo-(2,3-dihydro-1-indanone) (0.447g, 2.12mmol) [Adamczyk, M. et al., Journal of Organic Chemistry 1984,49,4226-4237] in ethanol (100ml) solution A solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 mL) was added. The mixture was stirred for 1 hour, then left to cool to 0°C. The precipitated hydrazone was vacuum filtered and dried in vacuo, yielding 0.628 g (86%) of the title compound as a yellow solid: mp. 186°C (dec.).

Step 2) Preparation of 3-bromo-5,10-dihydro-indeno[1,2-b]indole-6-carboxylic acid

Hydrazone (prepared in step 1 of Example 26) (0.620 g, 1.80 mmol) was irradiated in formic acid (2 ml, 96%) in a capped Teflon tube in a microwave oven (700W) for 2 minutes. The mixture was suction filtered while it was hot, and the solid was dried in vacuo to give 0.360 g (61%) of the title compound as a yellow solid: mp.245-247°C; ¹ H NMR (DMSO-d ₆ ): δ13.43 (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, 1650 cm ^-1 ; MS (m/z) 327 (M ⁺ ).

Elemental analysis of C ₁₆ H ₁₀ BrNO ₂ :

Calculated: C, 58.56; H, 3.07; N, 4.27.

Found: C, 58.62; H, 2.83; N, 4.22.

Examples 27-32 were prepared as in Example 17 using the appropriate benzonitrile and 1-oxo-indane-4-carboxylic acid.

Example 27

8-Bromo-7-methoxy-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

Example 28

8-Bromo-6-methoxy-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

Example 29

8-Chloro-7-methoxy-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

Example 30

8-Chloro-6-methoxy-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

Example 31

8-Bromo-9-methoxy-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

Example 32

8-Bromo-6-methoxy-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid

Examples 33-36 were prepared as in Example 1 using the appropriate benzofuranone and 2-hydrazinobenzoic acid.

Example 33

8-Bromo-7-methoxy-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

Example 34

8-Chloro-7-methoxy-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

Example 35

8-Chloro-9-methoxy-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

Example 36

8-Chloro-6-methoxy-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid

The (bladder) smooth muscle relaxing activity of the compounds of the invention was determined using representative compounds as described below in standard pharmaceutically accepted assays.

Sprague-Dwaley rats (150-200 g) were rendered unconscious by _CO2 asphyxiation and killed by cervical dislocation. The bladder was removed and placed in warm (37°C) physiological saline (PPS) with the following composition (mM): NaCl, 118.4; KCl, 4.7; CaCl ₂ , 2.5; MgSO ₄ , 4.7; H ₂ O, _1.2 ; 24.9; KH ₂ PO ₄ , 1.2; Glucose, 11.1; EDTA, 0.023; 95% O ₂ ; 2/5% CO ₂ ; pH 7.4. The bladder was dissected and cut into strips with a width of 1-2mm and a length of 7-10mm. The strips were suspended in a 10ml tissue bath with an initial resting tension of 1.5g. Clamp the muscle strip with two surgical forceps, one of which is connected to a fixed hook, and the other is fixed to the isovolumic force conduction instrument. Preparations usually exhibiting mild spontaneous contractions were allowed to recover for 1 hr and then stimulated with 0.1 [mu]M carbachol. The carbachol is then washed away, allowing the tissue to relax to its resting level. After continuing to recover for 30 min, 15 mM KCl was introduced into the tissue bath. Elevated KCl concentrations greatly enhanced the amplitude of spontaneous contractions (strips of previously unresponsive muscle also began to contract), overlapping with basal tension. This enhanced contractile activity is stabilized prior to the introduction of increasing concentrations of the test compound or vehicle to the tissue bath. Contractile activity of each concentration of compound or vehicle was determined during the last minute of the 30 min stimulation.

According to the above-mentioned concentration-response standard curve, the concentration required to inhibit the contractile activity by 50% ( _IC50 concentration) before drug treatment was used to determine the isovolumic capacity of the bladder muscle strips. At the same time, the maximum inhibition percentage of contraction activity caused by the concentration of each test compound lower than or equal to 30 μM was recorded.

The (aortic) smooth muscle relaxing activity of the compounds of the invention was determined using representative compounds as described below in standard pharmaceutically acceptable assays.

Sprague-Dwaley rats (150-200 g) were rendered unconscious by _CO2 asphyxiation and killed by cervical dislocation. The bladder was removed and placed in warm (37°C) physiological saline (PSS) with the following composition (mM): NaCl, 118.4; KCl, 4.7; CaCl ₂ , 2.5; MgSO ₄ , 4.7; H ₂ O, _1.2 ; 24.9; KH ₂ PO ₄ , 1.2; Glucose, 11.1; EDTA, 0.023; 95% O ₂ ; 2/5% CO ₂ ; pH 7.4. The fat and loose adventitia in the aorta were removed and cut into rings with a width of 3-4mm. The rings were suspended between two stainless steel wire tissue clamps in a 10 ml tissue bath. One clip is connected to the fixed hook, and the other is fixed to the isovolumic conductometer. The resting tension was set at 1 g. The tissue was allowed to recover for 60 minutes before the test was started. Tissues were stimulated with PSS containing 25 mM KCl, causing contraction. The tissue was then repeatedly washed with fresh PSS for 30 min to allow it to return to baseline tension. PSS containing 30-35 mM KCl was then introduced into the tissue bath to induce contraction, which was stable for more than 45 min. (Contraction can also be stimulated as needed with agents such as norepinephrine, PGF2a, histamine, angiotensin II, endothelin (vasoconstrictor) or PSS containing 80 mM KCl). Increasing concentrations of test compound or vehicle are introduced into the tissue bath in an additive fashion.

The isovolumic force produced by the aortic ring was measured with a force conduction meter and recorded on a multi-channel physiological apparatus. Concentration-response curves were drawn for the present invention to inhibit the contraction force at each concentration of the compound to be tested. The concentration required for 50% inhibition of predose inotropy ( _IC50 concentration) was calculated from this curve. [The Log concentration-response curve is essentially linear in the 20-80% interval of maximum response. Therefore, the _IC50 concentration of the drug can be determined by linear regression analysis (x = log concentration, y = % inhibition) of the data points in this interval of the curve. ] Simultaneously record the maximum inhibition percentage of contraction activity caused by the concentration of each compound to be tested when the concentration is lower than or equal to 30 μM. Primary screening was performed using the average of data from two animals.

The results of the above studies are shown in Table I. Example no Bladder tissue IC ₅₀ (μM) no Aortic tissue IC ₅₀ (μM) Aortic IC ₅₀ /bladder tissue IC ₅₀ ratio 1 8 15.1±4.7 4 118.8±21.8 7.9 2 8 6.1±3.0 3 128±16.9 twenty one 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 --- twenty one 4 15.4±4.8 --- twenty two 2 1 = 8%* --- twenty three 2 1 = 20%* --- twenty four** 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

*: Percent inhibition at 30 μM.

Several compounds of the invention were tested for their ability to relax intact rat bladders in vitro. The test method is as follows.

Female Sprague-Dawley rats weighing 200-300 g were anesthetized with Nembutol(R) (50 mg/kg, ip). After full anesthesia, the bladder and urethra were exposed through a midline incision. A stainless steel rod with a diameter of 1 mm was placed in the urethra, and the end of the urethra was ligated with a 4-0 silk ligature. After the stainless steel rod is pulled out, the outlet is partially blocked. The wound was then closed and the animals were given 15,000 units of the antibiotic Bicillin(R). After 6 weeks, rats were asphyxiated with _CO2 . Bladders for contraction analysis were placed in warm (37°C) physiological saline (PSS) of the following composition (mM): NaCl, 118.4; KCl, 4.7; _CaCl2 , 2.5; _MgSO4 , 4.7; _H2O , 1.2 ; NaHCO ₃ , 24.9; KH ₂ PO ₄ , 1.2; Glucose, 11.1; EDTA, 0.023; 95% O ₂ ; 2/5% CO ₂ ; pH 7.4.

Connect the open end of the isolated bladder urethra to a section of polyethylene tubing (PE-200) with a silk ligature. The other end of the tube is connected to a pressure transducer to measure the resulting bladder pressure. The bladder was placed in a 372 tissue bath containing PSS and filled with PSS for optimal contraction. Bladder contractions were demonstrated and monitored on a Grass7D multi-channel physiograph.

After stabilization, increasing concentrations of test compound or vehicle are introduced into the tissue bath. Contractile activity of each concentration of compound or vehicle was determined during the last minute of the 30 min stimulation.

According to the _above -mentioned concentration-response standard curve, the concentration required to inhibit the contractile activity by 50% (IC50 concentration) before drug treatment was used to determine the isovolumic capacity of the bladder muscle strips. At the same time, the maximum inhibition percentage of contraction activity caused by the concentration of each compound to be tested was lower than or equal to 30 μM was recorded. In this assay, the compound of Example 24 had an _IC50 of 5 [mu]M.

According to standard pharmaceutical tests, the compound of the present invention has selectivity to bladder tissue, has significant effect on smooth muscle contraction, can be used for the aforementioned diseases such as treatment of urinary incontinence, irritated bladder and bowel syndrome, asthma, apoplexy, and can be combined with potassium channel activation It can be administered to patients orally, parenterally or by adsorption.

Claims (21)

1. the compound shown in the general formula (I) or its salt of pharmaceutically approving:

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

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,

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

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.

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

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.

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.