Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/56—Ring systems containing three or more rings
  • C07D209/58—[b]- or [c]-condensed
  • C07D209/70—[b]- or [c]-condensed containing carbocyclic rings other than six-membered

Definitions

• the present invention relates to a series of substituted tetracyclic heleroaromatic benzofuranoindoles and indenoindoles having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of disorders associated with smooth muscle contraction, via potassium channel modulation.
• disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, and cerebral vascular disease.
• An example disclosed is 2-methyl-2-(((10-methyl-10H-benzofuro(3,2-b)indol-6- yl)methyl)amino)- 1 ,3 -propanediol .
• JP-06-228554 A series of indenoindoles useful as a component in an organic electroluminescent element are disclosed in JP-06-228554.
• X is -0-, -S, -, S0 2 -, or -NR g
• the present invention differs from the prior art by requiring the Z substituent, defined below as a carboxylic acid moiety, a bioisosteric equivalent of a carboxylic acid, or a derivative thereof to be substituted at position a of the tetracyclic heteroaromatic benzofuranoindoles and indenoindoles of Formulae (I) and (II).
• the compounds of this invention have reported potassium channel activation and the resulting smooth muscle relaxing properties are uniquely tissue-selective for bladder tissue.
• R , R and R are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen), amino, alkylamino of 1 to 10 carbon atoms, -SO 3 H, -SO 2 NH 2 , -NHSO 2 R 14 ,
• Y is -O- and-NR 4 ;
• X is -O-, when Y is -NR,;
• X is -NR 4 , when Y is -O- R 4 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms and arylalkylsulfonyl of 7 to 12 carbon atoms;
• R 5 and R 6 are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine;
• Z substituted at position a is selected from the group consisting of
• M is an alkali metal cation or an alkaline earth metal cation
• R 7 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
• R 8 and R 9 are, independently, hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
• R 10 , R n , R 12 and R 13 are independently, alkyl of 1 to 10 carbon atoms;
• R 14 is a straight chain alkyl of 1 to 10 carbon atoms;
• R 15 is a straight chain alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
• aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF 3 , and phenyl;
• aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms;
• R , R and R 3 are not hydrogen when Z is -CHO, Y is -O- and X is -N-CH 3 ; or a pharmaceutically acceptable salt thereof.
• a preferred aspect of this invention includes compounds of Formula (I) including pharmaceutically acceptable salts thereof are those in the subgroup below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
• Y is -NR 4 when X is -O-; More preferred aspects of this invention includes compounds of Formula (I) including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
• Z is -CO 2 H; R, is halogen or nitro;
• X is -O-, when Y is -NR 4 ;
• X is -NR 4 , when Y is -O- ;
• Specifically preferred compounds of this invention according to general Formula (I) are the following compounds or a pharmaceutically acceptable salt thereof:
• this invention also provides a method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals in need thereof, which comprises administering to said warm-blooded animals preferably mammals, most preferably humans an effective amount of a compound of general Formula (II) or a pharmaceutically acceptable salt thereof:
• R , R 2 and R are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen), amino, alkylamino of 1 to 10 carbon atoms, -SO 3 H, -SO 2 NH 2 , -NHSO 2 R 14 ,
• Y is -NR 4 and ⁇ -CR 5 R 6 ;
• X is -O-, when Y is -NR 4
• X is -NR 4 , when Y is -CR,R, ; X is -CR 5 R 6 , when Y is -NR 4 ;
• R 4 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms and arylalkylsulfonyl of 7 to 12 carbon atoms;
• R 5 and R 6 are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine;
• Z substituted at position a is selected from the group consisting of
• M is an alkali metal cation or an alkaline earth metal cation
• R 7 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
• R 8 and R 9 are, independently, hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of
• R 10 , R ⁇ , R 12 and R 13 are independently, alkyl of 1 to 10 carbon atoms;
• R 14 is a straight chain alkyl of 1 to 10 carbon atoms;
• R 15 is a straight chain alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
• aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF 3 , and phenyl;
• aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms;
• a preferred aspect of this invention includes compounds of Formula (II) including pharmaceutically acceptable salts thereof for use as a method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals preferably mammals, most preferably humans in need thereof are those in the subgroups below, wherein the other variables of Formula (II) in the subgroups are as defined above wherein: a) X is -O-, when Y is -NR 4 ;
• X is -NR 4 , when Y is -CR 5 R 6 ; and c) X is -CR 5 R 6 , when Y is -NR 4 .
• More preferred aspects of this invention includes compounds of Formula (II) including pharmaceutically acceptable salts thereof for use as a method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals preferably mammals, most preferably humans in need thereof are those in the subgroups below, wherein the other variables of Formula (II) in the subgroups are as defined above wherein:
• Z is -CO 2 H; R, is halogen or nitro;
• X is -O-, when Y is -NR 4 ;
• X is -NR 4 , when Y is -CR 5 R 6 ;
• X is -CR 5 R 6 , when Y is -NR 4 .
• Formula (II) for use as a method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals preferably mammals, most preferably humans in need thereof are the following compounds or a pharmaceutically acceptable salt thereof:
• the pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
• R R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , or R 9 contains a carboxyl group, or in the cases where Z is a carboxylic acid, salts of the compounds in this invention may be formed with bases such as alkali metals (Na, K, Li) or alkaline earth metals (Ca or Mg).
• Halogen, or halo as used herein means chloro, fluoro, bromo and iodo.
• Alkyl as used herein means a branched or straight chain having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms.
• Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
• Cycloalkyl as used herein means a saturated ring having from 3 to 10 carbon atoms and more preferably from 3 to 6 carbon atoms.
• Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• Aryl as used herein means a homocyclic aromatic radical, whether or not fused, having 6 to 12 carbon atoms.
• Preferred aryl groups include phenyl, alpha-naphthyl and beta-naphthyl and the like optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkyl amino of 1 to 10 carbon atoms.
• Aroyl as used herein refers to -C(O)aryl where aryl is as previously defined. Examples include benzoyl and naphthoyl which may optionally be substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF 3 and phenyl.
• Aralkyl as used herein means an aryl-alkyl group in which the aryl and alkyl group are previously defined.
• exemplary aralkyl groups include benzyl and phenethyl.
• Alkenyl as used herein means a branched or straight chain having from 2 to 12 carbon atoms and more preferably from 2 to 6 carbon atoms, the chain containing at least one carbon-carbon double bond.
• Alkenyl may be used synonymously with the term olefin and includes alkylidenes.
• Exemplary alkenyl groups include ethylene, propylene and isobutylene.
• Alkanoyl as used herein refers to -C(O)alkyl where alkyl is as previously defined.
• Alkenoyl as used herein refers to -C(O)alkenyl where alkenyl as previously defined.
• Alkoxy as used herein means an -O-alkyl group in which the alkyl group is as previously described.
• exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, and t-butoxy.
• Arylalkanoyl as used herein refers to a carbonyl group or radical directly bonded to an alkyl group of 1 to 10 carbon atoms which is terminally substituted by an aryl group as previously defined, for example phenylacetic acid.
• the aryl group may optionally be substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, CF 3 , and phenyl and substituted phenyl where the substituents are selected from halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and -CF 3 .
• Arylalkenoyl as used herein refers to a carbonyl group or radical directly bonded to an alkenyl group of 2 to 12 carbon atoms which is terminally substituted by an aryl group as previously defined.
• the aryl group may optionally be substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF 3 , and phenyl and substituted phenyl where the substituents are selected from halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and -CF 3 .
• Alkylsulfonyl refers to the radical -SO 2 alkyl where alkyl is as previously defined.
• Arylsulfonyl as used herein refers to the radical -SO 2 aryl where aryl is as previously defined.
• Arylalkylsulfonyl as used herein refers to the radical arylalkylO 2 S- where arylalkyl is as previously defined.
• Phenyl as used herein refers to a 6-membered aromatic ring.
• aralkyl refers to an aryl group
• alkyl refers to the alkyl group as defined above.
• the range of carbon atoms defines the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituent groups.
• the present invention also provides a process for the preparation of compounds of Formulae (I) and (II).
• Compounds of Formulae (I) and (II) wherein X is -O- and Y is -NR 4 , where R 4 is as defined above, may be prepared as shown in Scheme 1.
• Treatment of an appropriately substituted benzofuranone 1 where R R 2 and R 3 are hereinbefore defined with 2-hydrazinobenzoic acid 2 in aqueous media affords the corresponding phenyl hydrazone 3.
• This intermediate is either isolated and purified and then converted, or subjected crude to a microwave-facilitated Fischer-indole cyclization in an acidic media such as, but not limited to, formic acid to yield the substituted benzo[4,5]furo[3,2-b] indole 4. Standard procedures may then be utilized to introduce R 4 when R 4 is not a hydrogen atom to prepare carboxylic acid 5.
• Standard procedures may then be utilized to introduce R 4 when R 4 is not a hydrogen atom to give carboxylic acid 10.
• the carboxylic acid moiety of substituted benzo [4,5]furo[3,2-b]indole 4, carboxylic acid 5, indeno[l,2-b]indole 9, carboxylic acid 10, substituted indeno[l,2- bjindole 13 and carboxylic acid 14 may be elaborated into other groups represented by Z in Formulae (I) and (II).
• treatment with an alkaline base or alkaline earth base will result in formation of the corresponding carboxylate salts.
• Treatment with an alcohol (R 7 OH, where R 7 is as described above) in the presence of acid will result in formation of an ester.
• Esters may also be formed by other methods known to those versed in the art.
• the carboxylic acid moiety may also be converted to the corresponding amide by treatment with an amine -(NHR 8 R 9 , where R 8 and R 9 are as described above) in the presence of an activating agent such as 2-dimethylaminoisopropyl chloride hydrochloride/4-dimethylaminopyridine, or diethyl azodicarboxylate/ triphenyl phosphine.
• an activating agent such as 2-dimethylaminoisopropyl chloride hydrochloride/4-dimethylaminopyridine, or diethyl azodicarboxylate/ triphenyl phosphine.
• the carboxylic acid may be converted to the corresponding acid chloride derivative using an appropriate agent such as thionyl chloride or oxalyl chloride. Treatment with the appropriate amine -(NHR 8 R 9 , where R 8 and R 9 are as described above) in the presence of an external base would then afford the desired amide.
• the corresponding hydroxamic acid may be prepared by treatment of the acid chloride derivative with an appropriately substituted hydroxylamine (NHR 8 OH, where R 8 is as described above). Treatment of the carboxylic acid with urea in the presence of strong acid will provide the corresponding nitrile (Z is CN). The nitrile may be converted to a tetrazole via a cyclization reaction with sodium azide.
• the compounds of Formulae (I) and (JT) and their pharmaceutically acceptable salts relax smooth muscle. They are therefore useful in the treatment of disorders associated with smooth muscle contraction, disorders involving excessive smooth muscle contraction of the urinary tract (such as incontinence), or of the gastro-intestinal tract (such as irritable bowel syndrome), asthma, and hair loss. Furthermore, the compounds of Formulae (I) and (II) are active as potassium channel activators which render them useful for treatment of peripheral vascular disease, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders.
• Compounds of the present invention potently relax smooth muscle in standard pharmacological tests.
• the compounds of this invention exert their smooth muscle relaxatory activity via activation of potassium channels.
• the compounds of the present invention are unique in that they possess intrinsic selectivity for bladder tissue over vascular tissue as demonstrated by bladder/aorta IC 50 ratios (Table 1).
• the present invention also provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier.
• the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
• compositions are preferably adapted for oral administration. However, they may also be adapted for other modes of administration, for example, parenteral administration for patients suffering from heart failure.
• a composition of the invention is in the form of a unit dose.
• Suitable unit dose forms include tablets, capsules and powders in sachets or vials.
• Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg.
• Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention.
• the compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg.
• Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
• compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and ⁇ -blocking agents.
• the present invention further provides a compound of the invention for use as an active therapeutic substance.
• Compounds of Formula (I) and (II) are of particular use in the induction of smooth muscle relaxation.
• the present invention further provides a method of treating smooth muscle disorders in mammals including man, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention.
• the hydrazone (from Step 1, Example 1 above) (0.500 g, 1.51 mmol) in formic acid (2 mL, 96%) was irradiated for two minutes in a closed cap Teflon vessel in a microwave oven (700W).
• Example 1 The product of Example 1, Step 2 (5.75 g, 17.4 mmol) was combined with concentrated sulfuric acid (3 mL) and methanol (500 mL) and heated in an oil bath (100°C) for three days. The mixture was cooled and concentrated to a residue.
• Step 2 To a solution of the product of Example 1, Step 2 (1.00 g, 3.03 mmol) in diethyl ether (100 mL) and N,N-dimethylformamide (0.40 mL) was added oxalyl chloride (1.00 mL, 11.5 mmol). After one hour the yellow mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (80 mL) and added to a stirring mixture of N-methyl hydroxylamine hydrochloride (1.26 g, 15.1 mmol) in tetrahydrofuran/water (16mL, 15:1) and triethylamine (4.20 mL, 30.3 mmol).
• Example 7 To a solution of the product of Example 7 (0.390 g, 1.23 mmol) in acetonitrile (50 mL) was added a solution of l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)- one (0.522 g, 1.23 mmol) in acetonitrile (20 mL). 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).
• Example 1 The product of Example 1, Step 2 (0.500 g, 1.51 mmol) was thoroughly mixed with ground urea powder (8.67 g, 144 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 for a total of 35 minutes (15-30% power, 700W), then cooled. Crude product was ground and partitioned between water and diethyl ether.
• Phosphoric acid 2.5 g, 21.7 mmol
• DMF N,N-dimethylformamide
• Example 10 The product of Example 10 (0.350 g, 1.13 mmol), NaN 3 (0.102 g, 1.58 mmol), and n-Bu 3 SnCl (0.43 mL, 1.58 mmol) were stirred together in xylenes (5 mL) at 120°C for 18 h. The reaction was monitored by TLC and DMF (2 mL) was added. The reaction was stirred an additional 18 h at 130°C. The reaction mixture was cooled and diluted with 6N HCl (10 mL) and stirred for 1 h while purging with N 2 gas. A solid formed and was vacuum filtered and washed with F O. The solid was recrystallized from hot methanol and then was triturated with hot ethyl acetate.
• step 2 To a heterogeneous mixture of the product of Example 1, step 2 (300 mg, 909 mmol) in anhydrous N,N-dimethylformamide (281 ⁇ L) and CH 2 C1 2 (9.0 mL) at 0°C was added oxalyl chloride (317 ⁇ L, 3.63 mmol). Upon cessation of gas evolution, the mixture was warmed to room temperature and stirred for 1 h, then cooled to 0°C whereupon tert-amyl amine (425 ⁇ L, 3.63 mmol) was added. The reaction mixture was stirred for 12 h, whereupon all volatiles were removed by rotary evaporation.
• step 2 To a heterogeneous mixture of the product of Example 1, step 2 (300 mg, 909 mmol) in anhydrous N,N-dimethylformamide (281 ⁇ L) and CH 2 C1 2 (9.0 mL) at 0°C was added oxalyl chloride (317 ⁇ L, 3.63 mmol). Upon cessation of gas evolution, the mixture was warmed to room temperature and stirred for 1 h, then cooled to 0°C whereupon methylamine (approx. 4-5 mL) was added. The reaction mixture was stirred for 12 h, at which point all volatiles were removed via rotary evaporation.
• oxalyl chloride 317 ⁇ L, 3.63 mmol
• step 2 To a homogeneous solution of the product from Example 1, step 2 (1.78 g, 5.40 mmol) in N,N-dimethylformamide (20 mL) at -5°C was added portionwise 80% sodium hydride (324 mg, 10.8 mmol). The resultant red mixture was stirred for 1 h while slowly warming to room temperature, whereupon it was treated with methyl trifluoromethanesulfonate (1.83 mL, 16.2 mmol), producing a copious precipitate. Additional N,N-dimethylformamide (5 mL) was added to facilitate stirring. The reaction mixture was stirred an additional 1 h, then diluted with water, filtered, and washed consecutively with water and methanol.
• l-Oxo-indan-4-carboxylic acid 0.528 g, 2.99 mmol
• 4- iodophenylhydrazine hydrochloride 0.698 g, 2.58 mmol
• MDS2000 CEM Microwave
• Example 20 The product of Example 20 was converted to its ethyl ester by treatment with sulfuric acid in ethanol to give the title compound as an off-white solid: mp 202-204°C; ⁇ NMR (DMSO-d6,): ⁇ 1.39 (t, 3H), 4.00 (s, 2H), 4.38 (q, 2H), 7.11 (d, IH), 7.48 (d, IH), 7.52 (t, IH), 7.67 (s, IH), 7.79-7.84 (m, 2H), 11.86 (s, IH); MS [El, m z]: 311 [M] + .
• the hydrazone (from Step 1, Example 26 above) (0.620 g, 1.80 mmol) in formic acid (2 mL, 96%) was irradiated for two minutes in a microwave oven (700W) in a closed cap Teflon vessel.
• the smooth muscle (bladder) relaxing activity of the compounds of this invention was established in accordance with standard pharmaceutically accepted test procedures with representative compounds as follows.
• Sprague-Dawley rats (150-200 g) are rendered unconscious by CO 2 asphyxiation and then euthanized by cervical dislocation.
• the bladder is removed into warm (37°C) physiological salt solution (PSS) of the following composition (mM): NaCl, 118.4; KCl, 4.7; CaCl 2 , 2.5; MgSO 4 , 4.7; H 2 O, 1.2; NaHCO 3 , 24.9; KH 2 PO 4 , 1.2; glucose, 11.1; EDTA, 0.023; gassed with 95% O 2 ; 2/5% CO 2 ; pH 7.4.
• PES physiological salt solution
• the bladder is opened and then cut into strips 1-2 mm in width and 7-10 mm in length.
• the strips are subsequently suspended in a 10 mL tissue bath under an initial resting tension of 1.5 g.
• the strips are held in place by two surgical clips one of which is attached to a fixed hook while the other is attached to an isometric force transducer.
• the preparations which usually exhibit small spontaneous contractions, are allowed to recover for a period of 1 hour prior to a challenge with 0.1 ⁇ M carbachol.
• the carbachol is then washed out and the tissue allowed to relax to its resting level of activity.
• an additional 15 mM KCl are introduced into the tissue bath. This increase in KCl concentration results in a large increase in the amplitude of spontaneous contractions (and initiation of contractions in previously quiescent strips) superimposed upon a small increase in basal tone.
• the isometric force developed by the bladder strips is measured using a concentration required to elicit 50% inhibition of pre-drug contractile activity (IC50 concentration) and is calculated from this concentration-response curve.
• IC50 concentration concentration required to elicit 50% inhibition of pre-drug contractile activity
• the maximum percentage inhibition of contractile activity evoked by a test compound is also recorded for concentrations of test compound less than or equal to 30 ⁇ M.
• the smooth muscle (aorta) relaxing activity of the compounds of this invention was established in accordance with standard pharmaceutically accepted test procedures with representative compounds as follows.
• the tissues are to recover for a period of 60 min prior to beginning the experiment. Tissues are challenged with PSS containing 25 mM KCl to elicit a contracture. The tissues are then washed repeatedly with fresh PSS over a period of 30 min and allowed to recover to baseline tension. PSS containing 30-35 mM KCl is then introduced into the tissue bath to evoke a contracture that is allowed to stabilize for not less than 45 min. (Other stimuli such as norepinephrine, PGF2a, histamine, angiotensin II, endothelin or PSS containing 80 mM KCl may also be used to evoke a contracture as necessary).
• PSS containing 25 mM KCl to elicit a contracture.
• PSS containing 30-35 mM KCl is then introduced into the tissue bath to evoke a contracture that is allowed to stabilize for not less than 45 min.
• PSS containing 80 mM KCl may also be used to evoke
• test compound or vehicle Increasing concentrations of test compound or vehicle are then added to the tissue bath in a cumulative fashion. Isometric force development by the aortic rings is measured using a force transducer and recorded on a polygraph. The percentage inhibition of contractile force evoked by each concentration of a given test compound is used to generate a concentration-response curve. The concentration of test compound required to elicit
• IC 50 concentration 50% inhibition of pre-drug contractile force
• a 4-0 silk ligature was tied around the proximal end of the urethra in the presence of a 1 mm diameter stainless steel rod. The rod was then removed resulting in a partial outlet obstruction. The wound was closed with surgical staples and the animals received 15,000 units of Bicillin® antibiotic. After a 6 week period the animals were asphyxiated with CO 2 gas.
• Bladders for contractile analysis were placed in a physiological salt solution (PSS) at 37°C of the following composition (in mM): NaCl (118.4), KCl (4.7), CaCl 2 (2.5), MgSO 4 (1.2), KH 2 PO 4 (1.2), NaHCO 3 (24.9) and D- glucose (11.1) gassed with CO 2 -O 2 (95%-5%) to achieve a pH of 7.4.
• PSS physiological salt solution
• the isolated bladders were secured through the urethral opening with a silk ligature to a length of polyethylene tubing (PE-200). The opposite end of the tubing was connected to a pressure transducer to monitor developed bladder pressure.
• the bladders were placed in a tissue bath containing PSS at 37°C and inflated with PSS to achieve optimal contractions. Bladder contractions were displayed and monitored on a Grass model 7D polygraph.
• the compounds of this invention are selective for bladder tissue and have a pronounced effect on smooth muscle contractility and are useful in the treatment of urinary incontinence, irritable bladder and bowel disease, asthma, stroke, and similar diseases as mentioned above, which are amenable to treatment with potassium channel activating compounds by administration, orally, parenterally, or by aspiration to a patient in need thereof.

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• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Neurology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Urology & Nephrology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 1999
  • 1999-12-03 EP EP99965977A patent/EP1135393A2/en not_active Withdrawn
  • 1999-12-03 WO PCT/US1999/028619 patent/WO2000034285A2/en not_active Application Discontinuation
  • 1999-12-03 BR BR9915900-7A patent/BR9915900A/pt not_active Application Discontinuation
  • 1999-12-03 CA CA002350590A patent/CA2350590A1/en not_active Abandoned
  • 1999-12-03 AU AU21636/00A patent/AU2163600A/en not_active Abandoned
  • 1999-12-03 CN CN99815495A patent/CN1333774A/zh active Pending
  • 1999-12-03 JP JP2000586730A patent/JP2002531569A/ja active Pending

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