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WO1999007672A1 - Derivees d'anilines 2,5- et 3,5-disubstituees, leur preparation et utilisation - Google Patents

Derivees d'anilines 2,5- et 3,5-disubstituees, leur preparation et utilisation Download PDF

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Publication number
WO1999007672A1
WO1999007672A1 PCT/DK1998/000337 DK9800337W WO9907672A1 WO 1999007672 A1 WO1999007672 A1 WO 1999007672A1 DK 9800337 W DK9800337 W DK 9800337W WO 9907672 A1 WO9907672 A1 WO 9907672A1
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WIPO (PCT)
Prior art keywords
trifluoromethyl
optionally substituted
halogen
pyridyl
hydrogen
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PCT/DK1998/000337
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English (en)
Inventor
Florencio Zaragoza Dorwald
John Bondo Hansen
John Patrick Mogensen
Tina Møller TAGMOSE
Bernard Pirotte
Philippe Lebrun
Pascal De Tullio
Stéphane Boverie
Jacques Delarge
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Novo Nordisk A/S
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Priority to JP2000507208A priority Critical patent/JP2003524574A/ja
Priority to EP98936271A priority patent/EP1019367A1/fr
Priority to AU85341/98A priority patent/AU8534198A/en
Publication of WO1999007672A1 publication Critical patent/WO1999007672A1/fr

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
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    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to derivatives of 2,5- and 3,5-disubstituted anilines, to methods for their preparation, to compositions comprising these compounds, to the use of these compounds as medicaments and their use in therapy e.g. in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the urogenital system, the gastrointestinal system and the endocrinological system.
  • Potassium channels play an important role in the physiological and pharmacological control of cellular membrane potential.
  • the different types of potassium channels are the ATP-sensitive (K ATP -) channels which are regulated by changes in the intracellular concentration of adenosine triphosphate.
  • the K ATP -channels have been found in cells from various tissues such as cardiac cells, pancreatic cells, skeletal muscles, smooth muscles, central neurones and adenohypophysis cells.
  • the channels have been associated with diverse cellular functions, as for example hormone secretion (insulin from pancreatic beta- cells, growth hormone and prolactin from adenohypophysis cells), vasodilation (in smooth muscle cells), cardiac action potential duration and neurotransmitter release in the central nervous system.
  • Modulators of the K ATP -channels have been found to be of importance for the treatment of various diseases.
  • Certain sulfonylureas which have been used for the treatment of non- insulin-dependent diabetes mellitus act by stimulating insulin release through an inhibition of the K ATP -channels on pancreatic beta-cells.
  • potassium channel openers which comprise a heterogeneous group of compounds, have been found to be able to relax vascular smooth muscles and have therefore been used for the treatment of hypertension.
  • potassium channel openers can be used as bronchodilators in the treatment of asthma and various other diseases.
  • potassium channel openers have been shown to promote hair growth, and have been used for the treatment of baldness.
  • Potassium channel openers are also able to relax urinary bladder smooth muscle and can therefore be used for the treatment of urinary incontinence. Potassium channel openers which relax smooth muscle of the uterus can be used for treatment of premature labour.
  • the compounds of the present invention can be used for the treatment of vasospastic disorders such as subarachnoid haemorrhage and migraine.
  • Potassium channel openers hyperpolarize neurons and inhibit neurotransmitter release, and therefore the present compounds may be useful for the treatment of various diseases of the central nervous system, e.g. epilepsia, ischemia and neurodegenerative diseases, and for the treatment of pain.
  • diazoxide (7-chloro-3-methyl-2H-1 ,2,4-benzothiadiazine 1 ,1- dioxide) and certain 3-(alkylamino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide derivatives inhibit insulin release by an activation of K ATP -channels on pancreatic beta-cells (Pirotte B. et al., Biochem. Pharmacol. 1994, 47, 1381-1386; Pirotte B. et al., J. Med. Chem. 1993, 36, 3211-3213. Diazoxide has furthermore been shown to delay the onset of diabetes in BB-rats ( Vlahos W.D.
  • the present invention relates to derivatives of 2,5- and 3,5-bis-substituted anilines of the general formula I:
  • R 1 is hydrogen, trifluoromethyl or halogen
  • R is hydrogen, trifluoromethyl or halogen
  • R 3 is trifluoromethyl or halogen
  • R 4 is straight or branched alkyl, C ⁇ -alkenyl or C 2 . 6 -alkynyl, optionally substituted with C 3 . 8 - cycloalkyl or aryloxy; or aryl optionally substituted with halogen, cyano or trifluoromethyl; or heterocyclyl optionally substituted with halogen, cyano or trifluoromethyl; or aryloxy optionally substituted with halogen, cyano or trifluoromethyl; or
  • Y-R 5 wherein Y is -O- or -N(R 6 )- wherein R 5 is straight or branched alkyl, C 2 . 6 -alkenyl or C 2 - 6 -alkynyl, optionally substituted with C 3 .
  • R 6 is hydrogen; or straight or branched alkyl optionally substituted with C 3 . 8 -cycloalkyl; or aryl optionally substituted with halogen, cyano or trifluoromethyl; or heterocyclyl, optionally substituted with halogen, cyano or trifluoromethyl; or aryloxy optionally substituted with halogen, cyano or trifluoromethyl;; or
  • R 5 and R 6 are linked to form a 3-8 membered ring which is optionally substituted with straight or branched alkyl or pyrrolidinylcarbonylmethyl; or aryl optionally substituted with halogen, cyano or trifluoromethyl; or furoyl, benzoyl, acetyl, hydroxy, aminocarbonyl; or piperidinyl; or R 5 and R 6 are linked to form a saturated or unsaturated isoquinolin ring, optionally substituted with methoxy or dimethoxybenzyl;
  • X is O or S
  • R 4 can not be substituted or unsubstituted aryl or heteroaryl or heterocyclyl; R 4 can not be methyl, unsubstituted or monosubstituted with aryl, aryloxy, alkylamino, ary- lamino, halogen, heterocyclyl, acyl, 1-iminoalkyl, 1-iminoaryl, aminocarbonyl, 1- hydrazinoalkyl, 1-hydrazinoaryl, alkylthio, arylthio, heterocyclylthio, ammonium or aminoalkyi; R 4 can not be n-alkyl;
  • R 4 can not be -(CH 2 ) 3 -OAr
  • R 4 can not be 2,6-dimethylpiperidin-1-yl, methylamino, butylamino, benzylamino, arylamino, dimethylamino, diethylamino, dipropylamino, dibenzylamino, (methyl)(propargyl)amino, (1- phenylcyclohex-1-yl)methylamino, 4-heteroarylpiperazin-1-yl, (6-methylpyridin-2- yl)methylamino, (4-pyridinylmethyl)(methyl)amino or 2,5-dimethylpyrrolidin-1-yl.
  • R 4 can not be methyl, pyridyl, ethyl, n-propyl or 2-propylbutyl.
  • R 4 can not be substituted or unsubstituted aryl or heteroaryl or heterocyclyl; R 4 can not be methyl, unsubstituted or monosubstituted with aryl, aryloxy, alkylamino, arylamino, halogen, heterocyclyl, acyl, 1-iminoalkyl, 1-iminoaryl, aminocarbonyl, 1- hydrazinoalkyl, 1-hydrazinoaryl, alkylthio, arylthio, heterocyclylthio, ammonium or aminoalkyi; R 4 can not be n-alkyl, cyclopropyl or 2-propylbutyl; R 4 can not be -(CH 2 ) 3 -OAr or -CH(OH)CH 3 ;
  • R 4 can not be arylamino, methylamino, isobutylamino, butylamino, 3-hydroxypropylamino, dimethylamino, [1 -methyl-1 -(4-bromophenyl)ethyl]amino, (methyl)(propargyl)amino, (isopropyl)(propargyl)amino, di(n-butyl)amino, dibenzylamino or (benzyl)(n-butyl)amino.
  • R 4 can not be heterocyclyl
  • R 4 can not be methyl, unsubstituted or monosubstituted with heteroaryloxy, ammonium, acyl,
  • R 4 can not be 2-propylbutyl or cyclopropyl;
  • R 4 can not be benzylamino, 2-phenylethylamino, (l-phenyl)ethylamino, 4-chlorobenzylamino, 2-chlorobenzylamino, 2-(4-chlorophenyl)ethylamino, 3,4-dichlorobenzylamino, (3,4- dichlorobenzyl)(methyl)amino, (2-ethylhex-1-yl)amino, isopropylamino, propylamino, butylamino or 4-methyl-1-piperazinyl.
  • R 4 can not be benzylamino, 3,4-dimethylbenzylamino, 4-methoxybenzylamino, 3,4- dichlorobenzylamino, (2-hydroxy-1-methyl-2-phenylethyl)(methyl)amino, isopropylamino, n- propylamino, n-pentylamino, 4-chlorobenzylamino, 1-piperidinyl, 4-morpholinyl, 4-methyl-1- piperazinyl, 2,6-dimethyl-4-thiomorpholinyl, 4-(2-hydroxyethyl)piperazin-1-yl, 4- phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl or 4-ethoxycarbonylpiperazin-1-yl;
  • R 4 can not be substituted or unsubstituted aryl or heteroaryl or heterocyclyl;
  • R 4 can not be methyl, unsubstituted or substituted with aryl, heteroaryl, aryloxy, amino, halogen, heterocyclyl, acyl, 1-iminoalkyl, 1-iminoaryl, aminocarbonyl, 1 -hydrazinoalkyi, 1- hydrazinoaryl, alkylthio, arylthio, heterocyclylthio, ammonium, aminoalkyl; R 4 can not be unsubstituted n-alkyl, cyclopropyl, isopropyl, isobutyl, benzyl, 2-ethylpropyl, 2- propylbutyl;
  • R 4 can not be diisopropylamino, 2,6-dimethylpipehdin-1-yl, methylamino, dimethylamino, (1 ,1-dimethylpropargyl)amino, ethylamino, butylamino, (2-hydroxyprop-1-yl)amino or 1- adamantylamino.
  • the invention includes all diastereomers and enantiomers of compounds of formula I, some of which are optically active, and also their mixtures including racemic mixtures thereof.
  • the salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methane- sulfonic, ethanesulfonic, picric and the like, and include acids related to the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the like.
  • pharmaceutically acceptable acid addition salts such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic
  • heterocyclyl refers to: a monocyclic unsaturated or saturated system containing one, two or three hetero atoms selected from nitrogen, oxygen and sulfur and having 5 members, e.g. a radical derived from pyrrole, furan, thiophene, pyrroline, dihydrofuran, dihydrothiophene, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, thiazole, isoxazole, isothiazole, 1 ,2,3-oxadiazole, furazan, 1 ,2,3-thazole, 1 ,2,3-thiadiazole or 2,1 ,3-thiadiazole; an aromatic monocyclic system containing two or more nitrogen atoms and having 6 members, e.g.
  • Alkyl refers to lower straight, cyclic, bicyclic, fused or branched alkyl having 1 to 15 carbon atoms, preferentially 1 to 6 carbon atoms.
  • Aryl refers to phenyl or phenyl substituted with alkyl or phenyl, or phenyl fused with cycloalkyl, or polycyclic aromatic systems such as naphthyl, anthracenyl, phenanthrenyl, fluorenyl, etc.
  • Alkylene refers to lower straight, cyclic, fused or branched alkylene having 1 to 15 carbon atoms, preferentially 1 to 6 carbon atoms.
  • Heteroaryl refers to any of the possible isomeric, unsubstituted or alkyl-substituted pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadi- azolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, as well as the corresponding benzo and dibenzo derivatives or other fused ring-systems thereof. Heteroaryl is also intended to mean the partially or fully hydrogenated derivatives of the heterocyclic systems enumerated above.
  • Alkoxy refers to -O-alkyl and aryloxy refers to -O-aryl.
  • Cyano refers to -CN, hydroxy refers to -OH, amino refers to -NH 2 and nitro refers to -N0 2 .
  • Dialkylamino refers to -N(alkyl) 2 .
  • Alky- larylamino refers to -N(alkyl)(aryl) and diarylamino refers to -N(aryl) 2 .
  • Halogen refers to -F, - Cl, -Br and -I.
  • Aralkyl refers to -alkylene-aryl.
  • Alkylthio refers to -S-alkyl and arylthio refers to -S-aryl.
  • Alkoxycarbonyl refers to -CO-O-alkyl and aminocarbonyl refers to -CO-NH 2 , - CONH(alkyl), -CONH(aryl), -CO-N(alkyl) 2 , -CO-N(alkyl)(aryl) or -CO-N(aryl) 2 .
  • Acylamino re- fers to -NH-CO-(alkyl), -NH-CO-(aryl), -N(alkyl)-CO-alkyl or -N(alkyl)-CO-aryl.
  • a leaving group refers to a group or atom capable of existing in solution as a negatively charged species, or a positively charged group or atom.
  • C 2 . 6 -alkenyl refers to an unsaturated hydrocarbon chain having 2- 6 carbon atoms and one double bond such as e.g. vinyl, 1-propenyl, allyl, isopropenyl, n- butenyl, n-pentenyl and n-hexenyl.
  • C 2 . 6 -alkynyl refers to unsaturated hydrocarbons which contain triple bonds, such as e.g. -C ⁇ CH, -C ⁇ CCH 3 , -CH 2 G ⁇ CH, -CH 2 CH 2 C ⁇ CH, -CH(CH 3 )C ⁇ CH, and the like.
  • the compounds of the present invention interact with the potassium channels and hence act as openers or blockers of the ATP-regulated potassium channels, making them potentially useful for the treatment of various diseases of the cardiovascular system, e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases; the pulmonary system; the urogenital system; the gastrointestinal system; the central nervous system and the endocrinological system.
  • various diseases of the cardiovascular system e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases
  • the pulmonary system e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases
  • the pulmonary system e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases
  • the pulmonary system e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases
  • the pulmonary system e
  • the compounds of the present invention may also be used for the treatment of diseases associated with decreased skeletal muscle blood flow such as Reynauds disease and intermittent claudication.
  • the compounds of the invention may be used for the treatment of chronic airway diseases, including asthma, and for treatment of detrusor muscle instability secondary to bladder outflow obstruction and therefore for kidney stones by aiding their passage along the ureter.
  • Potassium channel openers also relax urinary bladder smooth muscle, thus, the compounds of the present invention can be used for the treatment of urinary incontinence.
  • the present compounds could also be used for treatment of conditions associated with disturbances in gastrointestinal mobility such as irritable bowel syndrome. Additionally these compounds can be used for the treatment of premature labor and dysmenorrhea.
  • potassium channel openers promote hairgrowth, therefore, the compounds of the present invention can be used for the treatment of baldness.
  • diseases such as nesidioblastosis and insulinoma in which a hypersecretion of insulin causes severe hypoglycemia the compounds of the present invention may be used to reduce insulin secretion.
  • obesity hyperinsulinemia and insulin resistance is very frequently encountered. This condition could lead to the development of non insulin dependent diabetes (NIDDM).
  • NIDDM non insulin dependent diabetes
  • Potassium channel openers and hence the compounds of the present invention may be used for counteracting the hyperinsulinemia and thereby prevent diabetes and reduce obesity.
  • overt NIDDM treatment of hyperinsulinemia with potassium channel openers, and hence the present compounds can be of benefit in restoring glucose sensitivity and normal insulin secretions.
  • potassium channel openers and hence the present compounds may be used to induce beta-cell rest which may prevent the progression of the autoimmune disease.
  • the title compounds may be used to reduce beta-cell degeneration in type 1 or type 2 diabetes and to normalize insulin secretion and improve insulin resistance in type 2 diabetes.
  • Compounds of the present invention which act as biockers of K ATP -channels may be used for the treatment of NIDDM.
  • the compounds of the present invention may be used for treatment or prevention of diseases of the endocrinological system such as hyperinsulinaemia and diabetes.
  • the invention relates to a compound of the general formula I or a pharmaceutically acceptable salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of hyperinsulinaemia and treatment or prevention of diabetes.
  • the invention also relates to the use of the inventive compounds of formula I as medicaments useful for treating hyperinsulinaemia and treating or preventing diabetes .
  • the compounds of this invention can be prepared by many different routes, obvious to those skilled in the art. Some of these routes are sketched below
  • Substituted anilines can be e.g. reacted with the appropriate carboxylic acid chlorides to yield anilides.
  • reaction with isocyanates of isothiocyanates may give ureas or thioureas, respectively.
  • Reaction of substituted anilines with chloroformates may yield carbamates (urethanes).
  • arylisocyanates O
  • arylisothiocyanates S
  • aliphatic or aromatic alcohols aliphatic or aromatic alcohols
  • EDC N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride, "water-soluble car- bodiimide"
  • NMP N-Methylpyrrolidone R: organic radical
  • the ability of the compounds to interact with potassium channels can be determined by various methods.
  • patch-clamp techniques Hamill O.P., Marty A., Nefer E., Sakman B. and Sigworth F.J., Pl ⁇ gers Arch. 1981, 391, 85-100
  • the ionic current through a single channel of a cell can be recorded.
  • the activity of the compounds as potassium channel openers can also be measured as relaxation of rat aorta rings according to the following procedure:
  • the preparations were contracted to achieve 80% of the maximum response using the required concentration of phenylephrine.
  • potential vasodilatory agents were added cumulatively to the bath in small volumes using half log molar increments at 2 min intervals. Relaxation was expressed at the percentage of the contracted tension. The potency of a compound was expressed as the concentration required to evoke a 50% relaxation of the tissue.
  • the opening of the K ATP -channels can be determined by measuring the subsequent change in the concentration of cytoplasmic free Ca 2+ concentration according to the method of Arkhammar et al., J. Biol. Chem. 1987, 262, 5448-5454.
  • the RIN 5F cell line was grown in RPMI 1640 with Glutamax I, supplemented with 10% fetal calf serum (from GibcoBRL, Scotland, UK) and maintained in an atmosphere of 5% C0 2 / 95% air at 37 °C.
  • the cells were detached with a Trypsin-EDTA solution (from GibcoBRL, Scotland, UK), resuspended in medium, added 1 mCi/mL 86 Rb + and replated into microtiter plates (96 well cluster 3596, sterile, from Costar Corporation, MA, USA) at a density of 50000 cells/well in 100 ⁇ l/well, and grown 24 hours before use in assay.
  • the plates were washed four times with Ringer buffer (150 mM NaCI, 10 mM Hepes, 3.0 mM KCI, 1.0 mM CaCI 2 , 20 mM sucrose, pH 7.1 ).
  • Ringer buffer 150 mM NaCI, 10 mM Hepes, 3.0 mM KCI, 1.0 mM CaCI 2 , 20 mM sucrose, pH 7.1 .
  • 80 ⁇ L Ringer buffer and 1 ⁇ L control- or test compound dissolved in DMSO were added. After incubation for 1 h at room temperature with a lid, 50 ⁇ L of the supernatant was transferred to PicoPlates (Packard Instrument Company, CT, USA) and 100 ⁇ L MicroScint40 (Packard Instrument Company, CT, USA) was added. The plates were counted in TopCount (Packard Instrument Company, CT, USA) for 1 min/well at the 32 P program.
  • the compounds according to the invention are effective over a wide dose range. In general satisfactory results are obtained with dosages from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg, per day.
  • a most preferable dosage is about 5 mg to about 200 mg per day.
  • the exact dosage will depend upon the mode of administra- tion, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
  • oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
  • compositions include a compound of formula I or a pharmaceutically acceptable salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • auxiliary agents emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
  • the compounds of the invention may be administered to a mammal, especially a human, in need of such treatment, prevention, elimination, alleviation or amelioration of various diseases as mentioned above and especially of diseases of the endocrinological system such as hyperinsulinaemia and diabetes.
  • results obtained from screening of the compounds of the present invention show, that some of these are potent potassium channel openers.
  • the most active compounds of this invention show an IC 50 of 600 nM.
  • Example 1 1-[3,5-Bis-(trifluoromethyl)phenyl]-3-(2,4-dichlorobenzyl)urea
  • 2,4-dichlorobenzylisocyanate (0.22 g, 1.09 mmol) in toluene (4.5 mL) 3,5- bis(thfluoromethyl)aniline (0.16 mL, 1.03 mmol) and t ethylamine (0.3 mL) were added and the resulting mixture was heated to 90 °C for 2 h. The mixture was then concentrated and the residue recrystallized from ethyl acetate (10 mL). 0.15 g (34%) of the title compound was obtained as colourless needles, mp 196-198 °C.
  • An array of 200 different aniline derivatives was prepared in the following way: Into 200 vials 0.1 mmol of 50 different amines was placed.
  • the amines were: isoamylamine, isopropylamine, isobutylamine, neopentylamine, 2,2,2-trifluoroethylamine, propargylamine, dipropylamine, 2-(4-chlorophenyl)ethyiamine, 4-methylpiperidine, diisobutylamine, pyr- rolidine, 3-(imidazol-1-yl)propylamine, 1 ,2,3,4-tetrahydroisoquinoline, cis-2,6- dimethylmorpholine, 1-[(3-trifluoromethyl)phenyl]piperazine, azepine, 4-benzoylpiperidine, (3-phenylpropyl)amine, 4-hydroxycyclohexylamine (cis/trans-mixture), trans-3- hydroxycyclohe
  • Example 9 2-Phenylcyclopropanecarboxylic acid (3,5-bis(trifluoromethyl)phenyl)-amide The title compound was prepared from 3,5-bis(trifluoromethyl)aniline and 2- phenylcyclopropanecarboxylic acid chloride by a method analogous to the one described in Example 2; LC-MS: m/e 374 (M + +1 ).

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Abstract

L'invention porte sur des anilines substituées de la formule générale (I) dans laquelle R?1, R2, R3, R4¿ et X sont tels que définis dans la description, sur leurs compositions et sur les procédés de préparation des composés. Ces composés sont utiles dans le traitement de pathologies du système nerveux central, du système cardio-vasculaire, du système pulmonaire, du système urogénital, du système gastro-intestinal et du système endocrinien.
PCT/DK1998/000337 1997-08-05 1998-07-24 Derivees d'anilines 2,5- et 3,5-disubstituees, leur preparation et utilisation WO1999007672A1 (fr)

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JP2000507208A JP2003524574A (ja) 1997-08-05 1998-07-24 ２，５−及び３，５−二置換アニリン誘導体、その調製及び使用
EP98936271A EP1019367A1 (fr) 1997-08-05 1998-07-24 Derivees d'anilines 2,5- et 3,5-disubstituees, leur preparation et utilisation
AU85341/98A AU8534198A (en) 1997-08-05 1998-07-24 Derivatives of 2,5- and 3,5-disubstituted anilines, their preparation and use

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US6329395B1 (en) 1998-06-08 2001-12-11 Schering Corporation Neuropeptide Y5 receptor antagonists
FR2820136A1 (fr) * 2001-01-26 2002-08-02 Aventis Pharma Sa Nouveaux derives de l'uree, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation
EP1233947A4 (fr) * 1999-12-01 2003-01-02 Bristol Myers Squibb Co Preparation de derives de 4-arylquinoleine-2-one 3-substituee
US6586446B1 (en) 1999-10-15 2003-07-01 Bristol-Myers Squibb Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
WO2004002531A1 (fr) 2002-06-26 2004-01-08 Ono Pharmaceutical Co., Ltd. Remedes pour les maladies provoquees par la contraction ou la dilatation vasculaire
US6686391B2 (en) 1995-08-04 2004-02-03 University Of Arizona Foundation N-chlorophenylcarbamate and N-chlorophenylthiocarbamate compositions
US6723730B2 (en) 2000-07-20 2004-04-20 Neurogen Corporation Capsaicin receptor ligands
US6784200B2 (en) 2000-10-13 2004-08-31 Bristol-Myers Squibb Pharma Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
EP1489071A1 (fr) * 2003-06-18 2004-12-22 4Sc Ag Dérivés de 3,4-dihydro-1H-isoquinoline N-substitués utilisés comme modulateurs de canaux de potassium
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US10125116B2 (en) 2009-03-20 2018-11-13 Brandeis University Compounds and methods for treating mammalian gastrointestinal microbial infections
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US6329395B1 (en) 1998-06-08 2001-12-11 Schering Corporation Neuropeptide Y5 receptor antagonists
WO2000047556A1 (fr) * 1999-02-08 2000-08-17 University College Cork Agents complexants
US6960666B2 (en) 1999-10-15 2005-11-01 Bristol-Myers Squibb Pharma Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US7550500B2 (en) 1999-10-15 2009-06-23 Bristol-Myers Squibb Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US6586446B1 (en) 1999-10-15 2003-07-01 Bristol-Myers Squibb Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
EP1233947A4 (fr) * 1999-12-01 2003-01-02 Bristol Myers Squibb Co Preparation de derives de 4-arylquinoleine-2-one 3-substituee
US6723730B2 (en) 2000-07-20 2004-04-20 Neurogen Corporation Capsaicin receptor ligands
US6784200B2 (en) 2000-10-13 2004-08-31 Bristol-Myers Squibb Pharma Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
WO2002059102A3 (fr) * 2001-01-26 2003-01-09 Aventis Pharma Sa Derives de l'uree, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et utilisation
FR2820136A1 (fr) * 2001-01-26 2002-08-02 Aventis Pharma Sa Nouveaux derives de l'uree, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation
US7071335B2 (en) 2002-02-01 2006-07-04 Euro-Celtique S.A. 2-pyridinyl-1-piperazine therapeutic agents useful for treating pain
US7256193B2 (en) 2002-02-01 2007-08-14 Euro-Celtique S.A. Therapeutic agents useful for treating pain
EP1522314B1 (fr) * 2002-06-26 2014-03-05 Ono Pharmaceutical Co., Ltd. Remèdes pour les maladies provoquées par la contraction ou la dilatation vasculaire
US8765783B2 (en) 2002-06-26 2014-07-01 Ono Pharmaceuticals Co., Ltd. Pharmaceutical composition for treatment of disease due to vascular constriction or vasodilation
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AU8534198A (en) 1999-03-01
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