WO1998033763A1 - Substituted hydroxy-anilino derivatives of cyclobutene-3,4-diones - Google Patents

Substituted hydroxy-anilino derivatives of cyclobutene-3,4-diones Download PDF

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Publication number
WO1998033763A1
WO1998033763A1 PCT/US1998/001466 US9801466W WO9833763A1 WO 1998033763 A1 WO1998033763 A1 WO 1998033763A1 US 9801466 W US9801466 W US 9801466W WO 9833763 A1 WO9833763 A1 WO 9833763A1
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compound
carbon atoms
hydroxy
dione
cyclobutene
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PCT/US1998/001466
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French (fr)
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Dominick Anthony Quagliato
Edward Martin Matelan
Madelene Miyoko Antane
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American Home Products Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the present invention relates to novel 1,2-diamino derivatives of cyclobutene 3,4-diones having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them and to their use, via potassium channel modulation, in the treatment of disorders associated with smooth muscle contraction.
  • disorders include, but are not limited to, urinary incontinence, hypertension, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina and cerebral vascular disease.
  • Stemp et al. disclose a class of amino substituted cyclobutenedione derivatives of chromans described as having blood pressure lowering activity and bronchodilatory activity.
  • Takeno et al. Public Patent Disclosure Bulletin No. 6-92915 report a series of diaminocyclobuten-3,4-diones. Our own efforts in this area have been disclosed in the following US Patents: 5,464,867, 5,466,712, 5,403,853, 5,403,854, 5,397,790, and 5,401,753.
  • Rl is straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, hydroxyalkyl of 2 to 10 carbon atoms, fluoroalkyl of 1 to 10 carbon atoms or polyfluoroalkyl of 1 to 10 carbon atoms; and one of R2, R3 and R4 is hydroxyl and the other two are, independently, H, CN, halogen, alkyl of 1 to 3 carbon atoms or hydroxyl; or a pharmaceutically acceptable salt thereof.
  • Preferred compounds of this invention are those wherein Rl is straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 3 to 10 carbon atoms or fluoroalkyl of 1 to 10 carbon atoms. Particularly preferred compounds are those wherein R is tert-butyl, tert-amyl or 2,2,1-trimethylpropyl. Also preferred are compounds wherein one of R2, R3 and R4 is hydroxyl and the other two are, independently, H, CN or alkyl of 1 to 3. More preferred are compounds wherein R2 is H or CN, compounds wherein one of R3 and R4 is hydroxyl and the other is H, CN or alkyl of 1 to 3.
  • R f contains an asymmetric carbon atom
  • R f contains an asymmetric carbon atom
  • R f contains an asymmetric carbon atom
  • Optical isomers may be obtained in pure form by standard separation techniques.
  • the pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable acids.
  • branched chain alkyl groups may include such groups as ⁇ , ⁇ -substituted branched chain alkyl in which the carbon atom adjacent to the nitrogen is tertiary, such as t-butyl, 1,1- dimethylpropyl, 3-methyl-3-pentyl, 3-ethyl-3-pentyl, 2,3-dimethyl-2-butyl, 2,3,3- trimethyl-2-butyl, 2,3-dimethyl-3-pentyl, and any similarly substituted branched alkyl chain.
  • alkyl of 1 to 3 carbon atoms includes methyl, ethyl, i-propyl and n-propyl;
  • cycloalkyl of 3 to 10 carbon atoms includes cyclopropyl, cyclobutyl, cycopentyl, cyclohexyl and cycloheptyl and the term halogen includes chloro, fluoro, bromo and iodo.
  • the present invention also provides a process for the preparation of a compound of formula (I). More particularly, the compounds of formula (I) may be prepared by reacting a compound of formula (II):
  • X and X' is a suitably designed leaving group such as methoxy, ethoxy, butoxy, isopropoxy, halogeno or a similar leaving group, with a compound of formula
  • R ⁇ NH 2 (IV) wherein Rl is as defined hereinbefore or a group of atoms convertible thereto, in a solvent suc ⁇ as ethanol, acetonitrile, or the appropriate arnine (IV) at ambient or elevated temperature.
  • Dichloromethane can be used as a cosolvent.
  • the order of addition of the compound of formula (III) and the compound of formula (IV) to the compound of formula (II) may be reversed.
  • Compounds of formula (I) have been found to relax smooth muscle. They have demonstrated activity at concentrations below 10.0 ⁇ M. They are 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 formula (I) are potassium channel activators which render them useful for treatment of peripheral vascular disease, hypertension, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders.
  • the present invention 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 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 be adapted for other modes of administration, for example, parenteral administration for patient suffering from heart failure.
  • a composition of the invention is in the form of a unit dose.
  • Suitable unit dose forms include tablets, capsules, 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.
  • Sprague-Dawley rats (150-200 g) are rendered unconscious by CO asphyxiation and then euthanized by cervical dislocation.
  • the bladder is removed into warm (37 deg.C) physiological salt solution (PSS) of the following composition (mM): NaCl, 118.4; KC1, 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% 0_; 2/5% CO 2 ; pH 7.4.
  • 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. Following a further 30 minute period of recovery an additional 15 mM KC1 are introduced into the tissue bath.
  • the isometric force developed by the bladder strips is measured using a concentration required to elicit 50% inhibition of pre-drug contractile activity.
  • the (IC 50 concentration) is calculated from this concentration-response curve.
  • 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 compounds of this invention have a pronounced effect on smooth muscle contractility and are useful in the treatment of urinary incontinence, irritable bladder and bowel disease, asthma, hypertension, 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The compound of formula (I), wherein R1 is straight chain alkyl, branched chain alkyl, cycloalkyl, hydroxyalkyl, fluoroalkyl, or polyfluoroalkyl; and one of R?2, R3 and R4¿ is hydroxyl and the other two are, independently, H, CN, halogen, alkyl or hydroxyl; or a pharmaceutically acceptable salt thereof, is useful as a smooth muscle relaxant.

Description

SUBSTTTUTED HYDROXY-ANILTNO DERIVATIVES OF CYCLOBUTENE-3.4-DIONES
BACKGROUND OF INVENTION
The present invention relates to novel 1,2-diamino derivatives of cyclobutene 3,4-diones having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them and to their use, via potassium channel modulation, in the treatment of disorders associated with smooth muscle contraction. Such disorders include, but are not limited to, urinary incontinence, hypertension, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina and cerebral vascular disease.
Stemp et al. (EP-426379) disclose a class of amino substituted cyclobutenedione derivatives of chromans described as having blood pressure lowering activity and bronchodilatory activity. Takeno et al. (Public Patent Disclosure Bulletin No. 6-92915) report a series of diaminocyclobuten-3,4-diones. Our own efforts in this area have been disclosed in the following US Patents: 5,464,867, 5,466,712, 5,403,853, 5,403,854, 5,397,790, and 5,401,753. Several series of l-amino-2- phenylalkylamino-cyclobutene-3,4-diones are reported as H-2 receptor antagonists by Algieri et al. in US Patent 4,390,701. Several related l-amino-2-phenoxyalkylamino derivatives are disclosed by Nohara et al. in US Patent 4,673,747. Additionally, US Patent 5,240,946 and EP-496561 disclose diaminocyclobuten-3,4-diones useful as NMDA antagonists.
The syntheses of variously substituted l,2-diamino-cyclobutene-3,4-diones are described in the following publications: Tietze et al., Chem. Ber. 1991, 124, 1215; Tietze et al., Bioconjugate Chem. 1991, 2, 148; Ehrhardt et al., Chem. Ber. 1977, 110, 2506, Neuse et al., Liebigs Ann. Chem. 1973, 619, Ried et al., Liebigs Ann. Chem. 1973, 619, Kinney et al., J. Med. Chem. 1992, 35, 4702. DESCRIPTION OF THE INVENTION
In accordance with the present invention there is provided a group of compounds of the formula (I):
Figure imgf000004_0001
(I)
wherein:
Rl is straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, hydroxyalkyl of 2 to 10 carbon atoms, fluoroalkyl of 1 to 10 carbon atoms or polyfluoroalkyl of 1 to 10 carbon atoms; and one of R2, R3 and R4 is hydroxyl and the other two are, independently, H, CN, halogen, alkyl of 1 to 3 carbon atoms or hydroxyl; or a pharmaceutically acceptable salt thereof.
Preferred compounds of this invention are those wherein Rl is straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 3 to 10 carbon atoms or fluoroalkyl of 1 to 10 carbon atoms. Particularly preferred compounds are those wherein R is tert-butyl, tert-amyl or 2,2,1-trimethylpropyl. Also preferred are compounds wherein one of R2, R3 and R4 is hydroxyl and the other two are, independently, H, CN or alkyl of 1 to 3. More preferred are compounds wherein R2 is H or CN, compounds wherein one of R3 and R4 is hydroxyl and the other is H, CN or alkyl of 1 to 3.
It is understood that the definition of the compounds of formula (I), when Rf contains an asymmetric carbon atom, encompasses all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques. The pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable acids. Throughout this specification, reference to branched chain alkyl groups may include such groups as α,α-substituted branched chain alkyl in which the carbon atom adjacent to the nitrogen is tertiary, such as t-butyl, 1,1- dimethylpropyl, 3-methyl-3-pentyl, 3-ethyl-3-pentyl, 2,3-dimethyl-2-butyl, 2,3,3- trimethyl-2-butyl, 2,3-dimethyl-3-pentyl, and any similarly substituted branched alkyl chain. When used herein the term alkyl of 1 to 3 carbon atoms includes methyl, ethyl, i-propyl and n-propyl; the term cycloalkyl of 3 to 10 carbon atoms includes cyclopropyl, cyclobutyl, cycopentyl, cyclohexyl and cycloheptyl and the term halogen includes chloro, fluoro, bromo and iodo.
The present invention also provides a process for the preparation of a compound of formula (I). More particularly, the compounds of formula (I) may be prepared by reacting a compound of formula (II):
Figure imgf000005_0001
wherein X and X' is a suitably designed leaving group such as methoxy, ethoxy, butoxy, isopropoxy, halogeno or a similar leaving group, with a compound of formula
(in):
Ar-NH2 (in)
wherein Ar is the substituted phenyl ring shown hereinbefore or a group of atoms convertible thereto, followed by treatment with a compound of formula (IV):
R^NH 2 (IV) wherein Rl is as defined hereinbefore or a group of atoms convertible thereto, in a solvent suc^ as ethanol, acetonitrile, or the appropriate arnine (IV) at ambient or elevated temperature. Dichloromethane can be used as a cosolvent. The order of addition of the compound of formula (III) and the compound of formula (IV) to the compound of formula (II) may be reversed.
Compounds of formula (I) have been found to relax smooth muscle. They have demonstrated activity at concentrations below 10.0 μM. They are 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 formula (I) are potassium channel activators which render them useful for treatment of peripheral vascular disease, hypertension, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders. The present invention 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 present invention also provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patient suffering from heart failure.
In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules, 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.
The 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 β- blocking agents.
The following examples are presented to illustrate rather than limit the scope of the invention.
EXAMPLE 1
3-(Tert-butylamino -4-(2-hvdroxy-4-cvanophenvO- amino-3-cvclobutene-1.2-dione
A mixture of 3-methoxy-4-nitrobenzonitrile (1.5 g, 0.008 mol) and LiCl (1.07 g, 0.025 mol) in DMF (14 ml) was heated to reflux. The reaction is monitored by TLC (1:1 hexane: ethyl acetate). When the starting material has disappeared (approximately 3 hours), the reaction is cooled and 42 ml of 2.5 N NaOH is added. The solution is extracted with diethyl ether. The aqueous layer is acidified with 73 ml of 2N HC1, then extracted well with ethyl acetate. The organic layer is washed with brine, dried (Na SO4), and filtered. Concentration on a rotary evaporator yields 3-hydroxy-4- nitrobenzonitrile N,N-dimethylformyl hemiacetal . This product is passed through a pad of silica gel (2:1 ethyl acetate : hexane) to yield 3-hydroxy-4-nitrobenzonitrile, 1.31 g (0.00798 mol, 94.75%).
1H NMR: δ, DMSO 7.4 (lH,s), 7.6 (lH,d, J 8.34), 8 (1H, d, J 8.59), 12 (lH,s) MS: (El) [m+] @ m/z 164 A parr bottle was charged with palladium on activated carbon (5%, 0.204 g). A solution of 3-hydroxy-4-nitrobenzonitrile (1.36 g, 0.00829 mol) in 41 ml of ethanol was added. The reaction mixture was placed under 25 psi of hydrogen gas and shaken for 1 hour. TLC (1:1 hexane: ethyl acetate) shows that no starting material remained. The mixture was filtered through Celite® and evaporated to yield 3-hydroxy-4- aminobenzonitrile, 1.08 g (0.00806 mol, 97%). MS: [(-) ESI] [m-H]" @ m/z 133
A solution of 3-hydroxy-4-aminobenzonitrile (1.08 g, 0.008 mol) and diethyl squarate (1.19 ml,0.008 mol) in dry ethanol (22 ml) was heated at 85° C for two days. During the course of the reaction, a tan precipitate forms. TLC (1:1 hexane: ethyl acetate) indicates that no starting material is present. The solid is filtered through a Buchner funnel, washed with cold ethanol, and collected to give 3-ethoxy-4-(2- hydroxy-4-cyanophenyl)amino-3-cyclobutene-l,2-dione, 1.19 g (0.0046 mol, 57%). 1H NMR: 5, DMSO 1.2 (3H, t, J 7.1), 4.38 (2H, q, J 7.1), 7.09 (1H, dd, J 1.8, 15.2),7.1 (1H, d, J 1.9), 7.2 (1H, d, J 8.3), 10.05 (1H, bs), 11.4 (1H, bs) MS: [(-)ESI] [m-H]" @ m/z 257
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-l,2- dione (0.395 g, 0.0015 mol) and tert-butyla ine (4 ml, 0.038 mol) in enough CH2C12 to form a solution (a small amount of dry ethanol was required) was stirred at room temperature for two days. During this time, a precipitate forms. TLC (2:1 ethyl acetate: hexane) indicates a loss of starting material. The reaction is evaporated to a solid on a rotary evaporator. The solid is taken up in ethyl acetate and extracted well with 0.25 N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether to give 3-(tert-butylamino)-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene- 1,2-dione, 0.270 g (0.00095 mol, 62%). 1H NMR: δ DMSO 1.4 (9H, s), 7.13 (1H, d, J 1.75), 7.25 (1H, d, J 1.75), 8.0 (1H, d, J 8.34), 8.7 (lH,bs), 9.5 (1H, bs), 11.0 (1H, bs) MS: (EI) m+ @ m/z 285 EXAMPLE 2
3-(Tert-amylaιτιino -4-(2-hvdroxy-4-cvanophenyl - amino-3-cvclobutene-1.2-dione
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-l,2- dione (0.395 g, 0.0015 mol) and tert-amylamine (4 ml, 0.034 mol) in enough CH2C12 to form a solution (a small amount of dry ethanol was required) was stirred at room temperature for two days. During this time, a precipitate forms. TLC (2:1 ethyl acetate: hexane) indicates a loss of starting material. The reaction is evaporated to a solid on a rotary evaporator. The solid is taken up in ethyl acetate and extracted well with 0.25 N HCl. The organic layer is washed once with distilled water, dried (Na2SO ), and evaporated to a solid. The solid is collected and washed with diethyl ether to give 3-(tert-amylamino)-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene- 1,2-dione, 0.253 g (0.00085 mol, 55%).
1H NMR: δ DMSO 0.85 (3H, t, J 7.5), 1.35 (6H, s), 1.73 (2H, q, J 7.2, 7.5), 7.14 (1H, d, J 1.76), 7.27 (1H, dd,J 1.76, 6.6), 7.97 (1H, d, J 8.35), 8.56 (1H, bs), 9.57 (1H, bs), 10.99 (1H, bs) MS: (El) m+ @ m z 299
EXAMPLE 3
3-(2.2.1-Trimethylpropylamino -4-(2-hvdroxy-4-cvano- phenvPamino-3-cvclobutene-1.2-dione
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanoρhenyl)amino-3-cyclobutene-l,2- dione (0.395 g, 0.0015 mol) and (R)-2,2,l-trimethylpropylamine (0.2 M in ethanol, 23 ml, 0.0046 mol) was stirred at room temperature for two days. TLC (2:1 ethyl acetate: hexane) indicates a loss of starting material. The ethanol is evaporated on a rotary evaporator. The reaction is taken up in ethyl acetate and extracted well with 0.25 N HCl . The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether to give 3- [(R)-2,2,l-trimethylpropylamino]-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene- 1,2-dione, 0.345 g (0.00095 mol, 72%). 1H NMR: δ DMSO 0.90 (9H, s), 1.16 (3H, d, J 6.8), 4.02 (1H, dq, J 14.17,6.81, 3.08), 7.13 (1H, d, J 8.35 ), 7.26 (1H, dd, J 1.76, 6.59), 8.04 (1H, d, J 8.35), 9.48 (1H, bs), 11.0 (1H, bs) MS: (EI) m+ @ m/z 313
EXAMPLE 4
3-(2.2.1-Trimethylpropylaτnino -4-(2-hvdroxy-6-cvano- phenvnamino-3-cvc1obutene-1.2-dione
A mixture of 2-nitro-3-methoxybenzonitrile (2.00 g, 0.0112 mol) and LiCl (1.43 g, 0.034 mol) in DMF (18.7 ml) was heated to reflux. The reaction is monitored by TLC (1:1 hexane: ethyl acetate). When the starting material has disappeared (approximately 3 hours), the reaction is cooled and 56 ml of 2.5 N NaOH is added. The solution is extracted with diethyl ether. The aqueous layer is acidified with 100 ml of 2N HCl, then extracted well with ethyl acetate. The organic layer is washed with brine, dried (Na2SO4), and filtered. Concentration on a rotary evaporator yields 2- nitro-3-hydroxybenzonitrile N,N-dimethylformyl hemiacetal . This product is passed through a pad of silica gel (2:1 ethyl acetate : hexane) to yield 2-nitro-3- hydroxybenzonitrile, 1.31 g (0.00799 mol, 71%). 1H NMR: δ, DMSO 7.49-7.72 (3H, aromatic series of m), 12.0 (1H, bs).
A parr bottle was charged with palladium on activated carbon (5%, 0.196g). A solution of 2-nitro-3-hydroxybenzonitrile (1.31 g, 0.008 mol) in 40 ml of ethanol was added. The reaction mixture was placed under 25 psi of hydrogen gas and shaken for 1 hour. TLC (1:1 hexane: ethyl acetate) shows that no starting material remained. The mixture was filtered through Celite® and evaporated to yield 2-amino-3- hydroxybenzonitrile, 1.01 g (0.0075mol, 94%).
1H NMR: δ, DMSO 6.00-6.14 (2H, aromatic series of m), 7.15 (1H, d, J 8.5), 10.3
(1H, bs)
MS: (EI) m+ @ m/z l34
A solution of 2-amino-3-hydroxybenzonitrile (1.00 g, 0.0075 mol) and diethyl squarate (1.10 ml,0.0075 mol) in dry ethanol (20 ml) was heated at 85° C for three days. During the course of the reaction, a tan precipitate forms. The solid is filtered through a Buchner funnel, washed with cold ethanol, adsorbed on silica gel, and flash chromatographed using hexane / ethyl acetate (2:1) as the eluant to give 3-ethoxy-4-(2- hydroxy-6-cyanophenyl)amino-3-cyclobutene-l,2-dione, 0.50 g (0.0019 mol, 26%). 1H NMR: δ, DMSO 1.4 (3H, t, J 8.9), 4.7 (2H, q, J 8.9), 7.2-7.4 (3H, aromatic series of m), 10.7 (1H, s), 10.8 (1H, s) MS: (El) m+ m/z @ 258.
A mixture of 3-ethoxy-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-l,2- dione (0.250 g, 0.00097 mol) and (R)-2,2,l-trimethylpropylamine (0.2 M in ethanol, 9.7 ml, 0.0019 mol) was stirred at room temperature for two days. TLC (2:1 ethyl acetate: hexane) indicates a loss of starting material. The reaction is evaporated on a rotary evaporator. The residue is taken up in ethyl acetate and extracted well with 0.25 N HCl . The organic layer is washed once with distilled water, dried (Na2SO ), and evaporated to a solid. The solid is collected and washed with diethyl ether with several drops of ethyl acetate to give 3-[(R)-2,2,l-trimethylpropylamino]-4-(2-hydroxy-6- cyanophenyl)amino-3-cyclobutene-l,2-dione, 0.230 g (0.00073 mol, 76%) 1H NMR: δ DMSO 0.91 (9H, s), 1.17 (3H, d, J 7.25), 3.98 (3H, aromatic series of m), 7.5 (1H, d, J 9.66), 9.33 (1H, bs), 10.75 (1H, bs) MS: (EI) m+ @ m/z 313.
EXAMPLE 5
3-(Tert-amylamino)-4-(2-hvdroxy-6-cvanophenyl - amino-3-cvclobutene-1.2-dione
A mixture of 3-ethoxy-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-l,2- dione (0.250 g, 0.00097 mol) and tert-amylamine (1.13 ml, 0.0097 mol) was stirred in enough CH2C12 to form a solution at room temperature for two days. During this time a precipitate forms. The reaction solvent is evaporated on a rotary evaporator, the residue is taken up in ethyl acetate and extracted well with 0.25 N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and gives 3-(tert-amylamino)-4-(2-hydroxy-6-cyanophenyl)- amino-3-cyclobutene-l,2-dione, 0.135g (0.00045 mol, 46%). 1H NMR: δ, DMSO 0.88 (3H, t, 7.5), 1.37 (6H, s), 1.72 (2H, q, J 7.5), 7.18-7.24 (aromatic series of m), 7.76 ( 1H, bs), 9.47 (lH,bs), 10.75 (1H, bs) MS: (El) m+ @ m/z 299
EXAMPLE 6
3-(2-Hvdroxy-6-methylDhenylaτnino -4-(2.2.1-trimethyl- propylamino -cvclobut-3-ene-1.2-dione
A solution of 2-amino-3-methylphenol (3.6 g, 29.2 mmol) and diethyl squarate (5 g, 29.4 mmol) in dry ethanol (80 mL) was heated to reflux for two days, then allowed to stand at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was suspended in ethyl acetate (50 mL). Hexane (50 mL) was added to produce a slurry, which was filtered, and rinsed with three portions of hexane:ethyl acetate (1:1). The resulting solid was suspended in dichloromethane (200 mL) and methanol (20 mL), stirred at room temperature for 30 minutes, and filtered. The precipitate was suspended in hot dichloromethane, filtered hot, and dried to give 3-ethoxy-4-(2-hydroxy-6-methyl- phenylamino)-cyclobut-3-ene-l,2-dione, 1.56 g (6.3 mmol, 22%). 1H NMR: δ, DMSO 1.10-1.52 (3H, two overlapping multiplets, rotamers), 2.12 (3H, s), 2.50 (3H, s), 4.30-4.80 (2H, two overlapping multiplets, rotamers), 6.62 (1H, d), 6.70 (1H, d), 7.00 (1H, t), 9.62 (1H, s), 9.90 and 10.0 (1H, two overlapping brs, rotamers)
3-Ethoxy-4-(2-hydroxy-6-methyl-phenylamino)-cyclobut-3-ene-l,2-dione (0.4 g, 1.62 mmol) and (R)-2-amino-3,3-dimethylbutane (16 mL of a 0.2 M solution in absolute ethanol, 3.20 mmol) in dichloromethane (4 mL) was heated at 80°C for 4 hours. The reaction mixture was cooled, concentrated under reduced pressure, and the resulting residue was trituated with hexane:ethyl acetate (1:1) to produce a solid, which was filtered and rinsed with hexane:ethyl acetate (1:1). Chromatography with 10% methanol in dichloromethane gave (R)-3-(2-hydroxy-6-methylphenylamino)-4-(2,2,l- trimethylpropyl-amino)-cyclobut-3-ene-l,2-dione, 0.24 g (0.79 mmol, 49%). [α]25 D = +10.25° (6.4 mg/mL, DMSO). 1H NMR: δ, DMSO 0.89 (9H, br s), 1.13 (3H, br m), 2.15 (3H, s), 3.95 (1H, br m), 6.67 (1H, d, J = 7.2), 6.72 (1H, d, J = 7.2), 6.96 (1H, t, J = 7.8), 7.15 (1H, br s), 8.75 (1H, br s), 9.70 (1H, br s) MS: (El) m+ @ m/z 302
(S)-3-(2-hydroxy-6-methylphenylamino)-4-(2,2,l-trimethylpropylamino)- (cyclobut-3-ene-l,2-dione is produced by the same method by substituting (S)-2- amino-3,3-dimethylbutane for the (R)-2-amino-3,3-dimethylbutane employed in the preceding paragraph.
EXAMPLE 7
3-tert-Butylamino-4-(2-hvdroxy-6-methyl-phenylamino - cvclobut-3-ene-1.2-dione
3-Ethoxy-4-(2-hydroxy-6-methyl-phenylamino)-cyclobut-3-ene- 1 ,2-dione (0.4 g, 1.62 mmol) in t-butylamine (4.8 mL) and dichloromethane (4.8 mL) was allowed to stand at room temperature for 7 days. The slurry was filtered, rinsed with ethyl acetate, and dried. Chromatography with 10% methanol in dichloromethane, followed by trituration with 5% ethyl acetate in hexane gave 3-tert-butylamino-4-(2-hydroxy-6- methyl-phenylamino)-cyclobut-3-ene-l,2-dione, 0.18 g (0.66 mmol, 41%). 1H NMR: δ, DMSO 1.41 (9H, br s), 2.14 (3H, s), 6.66 (1H, d, J = 7), 6.71 (1H, d, J = 7), 6.95 (1H, t, J = 7), 7.60 (1H, br s), 8.78 (1H, br s), 9.70 (1H, br s) MS: (El) m+ @ m/z 274
The smooth muscle 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 asphyxiation and then euthanized by cervical dislocation. The bladder is removed into warm (37 deg.C) physiological salt solution (PSS) of the following composition (mM): NaCl, 118.4; KC1, 4.7; CaCl2, 2.5; MgSO4, 4.7; H2O, 1.2; NaHCO3, 24.9; KH2PO4, 1.2; glucose, 11.1; EDTA, 0.023; gassed with 95% 0_; 2/5% CO2; pH 7.4. 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 μM carbachol. The carbachol is then washed out and the tissue allowed to relax to its resting level of activity. Following a further 30 minute period of recovery an additional 15 mM KC1 are introduced into the tissue bath. This increase in KC1 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. Following stabilization of this enhanced level of contractile activity, incremental increases in the concentration of test compound or vehicle are introduced into the tissue bath. Contractile activity is measured for each compound or vehicle concentration during the last minute of a 30 minute challenge.
The isometric force developed by the bladder strips is measured using a concentration required to elicit 50% inhibition of pre-drug contractile activity. The (IC50 concentration) is calculated from this concentration-response curve. 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 μM.
The results of this study are shown in Table I.
Table I
Inhibition of Contractions in Isolated Rat Bladder Strips
Figure imgf000015_0001
Hence, the compounds of this invention have a pronounced effect on smooth muscle contractility and are useful in the treatment of urinary incontinence, irritable bladder and bowel disease, asthma, hypertension, 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.

Claims

1. A compound of the formula
Figure imgf000016_0001
(I)
wherein:
Rl is straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, hydroxyalkyl of 2 to 10 carbon atoms, fluoroalkyl of 1 to 10 carbon atoms or polyfluoroalkyl of 1 to 10 carbon atoms; and one of R2, R3 and R4 is hydroxyl and the other two are, independently, H, CN, halogen, alkyl of 1 to 3 carbon atoms or hydroxyl; or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in Claim 1 wherein Rl is straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 3 to 10 carbon atoms or fluoroalkyl of 1 to 10 carbon atoms or a pharmaceutically acceptable salt thereof.
3. A compound as claimed in Claim 1 or Claim 2 wherein Rl is tert- butyl, tert- amyl or 2,2,1-trimethylpropyl.
4. A compound as claimed in any one of Claims 1 to 3 wherein one of R2, R3 and R4 is hydroxyl and the other two are each independently selected from H, CN and alkyl of 1 to 3.
5. A compound as claimed in any one of Claims 1 to 4 wherein R2 is H or CN.
6. A compound as claimed in any one of Claims 1 to 5 wherein one of R3 and R4 is hydroxyl and the other is selected from H, CN and alkyl of 1 to 3.
7. The compound of Claim 1 which is 3-(tert-butylamino)-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-l,2- dione,
3-(tert-amylamino)-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-l,2- dione,
3-(2,2, 1 -trimethylpropylamino) -4- (2-hydroxy-4-cyanophenyl)amino-3- cyclobutene- 1 ,2-dione,
3-(2,2,l-trimethylpropylamino)-4-(2-hydroxy-6-cyanophenyl)amino-3- cyclobutene- 1 ,2-dione,
3-(tert-amylamino)-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-l,2- dione,
3-(2-hydroxy-6-methylphenylamino)-4-(2,2,ltrimethylpropylamino)-cyclobut- 3-ene-l,2-dione,
3-tert-butylamino-4-(2-hydroxy-6-methyl-phenylamino)-cyclobut-3-ene-l,2- dione or a pharmaceutically acceptable salt of any of these.
8. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 7.
9. A method for reducing the adverse effects of smooth muscle contractions which comprises administering, orally or parenterally, to a patient in need thereof, a compound as claimed in any one of Claims 1 to 7.
10. A method as claimed in Claim 9 wherein the smooth muscle adversely contracting causes urinary incontinence or irritable bowel syndrome.
11. A compound as claimed in any one of Claims 1 to 7 for use as a medicament.
12. Use of a compound as claimed in any one of Claims 1 to 7 for the manufacture of a medicament for use as a medicament for reducing the adverse effects of smooth muscle contractions.
13. A process for the preparation of a compound as claimed in any one of Claims 1 to 7 comprising reacting a compound of formula (V):
Figure imgf000018_0001
(V)
wherein each of R^┬╗ R^ and R4 are as defined in Claim 1 or a group of atoms convertible thereto,
with a compound of formula (IV):
R NH2 (╬╣v)
wherein Rl is as defined in Claim 1 or a group of atoms convertible thereto,
to provide the desired compound of formula I.
PCT/US1998/001466 1997-01-30 1998-01-27 Substituted hydroxy-anilino derivatives of cyclobutene-3,4-diones WO1998033763A1 (en)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1107943A1 (en) * 1998-08-28 2001-06-20 Smithkline Beecham Corporation Process for making 2-amino-5-cyanophenol
WO2002083624A1 (en) * 2001-04-16 2002-10-24 Schering Corporation 3,4-di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands
US6495576B2 (en) 2001-02-07 2002-12-17 Abbott Laboratories Aminal diones as potassium channel openers
US6878709B2 (en) 2002-01-04 2005-04-12 Schering Corporation 3,4-di-substituted pyridazinediones as CXC chemokine receptor antagonists
US6903131B2 (en) 2001-10-12 2005-06-07 Schering Corporation 3,4-di-substituted maleimide compounds as CXC chemokine receptor antagonists
JP2005534684A (en) * 2002-07-30 2005-11-17 シェーリング　コーポレイション 3,4-Disubstituted cyclobutene-1,2-diones as CXC chemokine receptor ligands
US7132445B2 (en) 2001-04-16 2006-11-07 Schering Corporation 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
US7338968B2 (en) 2003-12-19 2008-03-04 Schering Corporation Thiadiazoles AS CXC- and CC- chemokine receptor ligands
US7671212B2 (en) 2003-12-22 2010-03-02 Schering Corporation Isothiazole dioxides as CXC- and CC-chemokine receptor ligands
US7691856B2 (en) 2002-10-09 2010-04-06 Schering Corporation Thiadiazoledioxides and thiadiazoleoxides as CXC- and CC-chemokine receptor ligands
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US7897606B2 (en) 2005-06-29 2011-03-01 Schering Corporation 5,6-di-substituted oxadiazolopyrazines and thiadiazolopyrazines as CXC-chemokine receptor ligands
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5403853A (en) * 1993-11-17 1995-04-04 American Home Products Corporation Substituted N-aryl-1,2-diaminocyclobutene-3,4-diones
US5506252A (en) * 1993-11-17 1996-04-09 American Home Products Corporation Substituted N-heteroaryl and N-aryl-1,2-diaminocyclobutene-3,4-diones

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5403853A (en) * 1993-11-17 1995-04-04 American Home Products Corporation Substituted N-aryl-1,2-diaminocyclobutene-3,4-diones
US5506252A (en) * 1993-11-17 1996-04-09 American Home Products Corporation Substituted N-heteroaryl and N-aryl-1,2-diaminocyclobutene-3,4-diones

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1107943A4 (en) * 1998-08-28 2002-07-24 Smithkline Beecham Corp Process for making 2-amino-5-cyanophenol
EP1107943A1 (en) * 1998-08-28 2001-06-20 Smithkline Beecham Corporation Process for making 2-amino-5-cyanophenol
US6495576B2 (en) 2001-02-07 2002-12-17 Abbott Laboratories Aminal diones as potassium channel openers
US7947720B2 (en) 2001-04-16 2011-05-24 Schering Corporation 3,4-di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
WO2002083624A1 (en) * 2001-04-16 2002-10-24 Schering Corporation 3,4-di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands
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AU2010212484B2 (en) * 2001-04-16 2012-04-12 Merck Sharp & Dohme Corp. 3,4-Di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands
US7132445B2 (en) 2001-04-16 2006-11-07 Schering Corporation 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
US7964646B2 (en) 2001-04-16 2011-06-21 Schering Corporation 3,4-DI-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
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US7691856B2 (en) 2002-10-09 2010-04-06 Schering Corporation Thiadiazoledioxides and thiadiazoleoxides as CXC- and CC-chemokine receptor ligands
US7786149B2 (en) 2003-12-19 2010-08-31 Schering Corp. Thiadiazoles as CXC- and CC- chemokine receptor ligands
US7338968B2 (en) 2003-12-19 2008-03-04 Schering Corporation Thiadiazoles AS CXC- and CC- chemokine receptor ligands
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