WO1999007672A1 - Derivatives of 2,5- and 3,5-disubstituted anilines, their preparation and use - Google Patents

Derivatives of 2,5- and 3,5-disubstituted anilines, their preparation and use Download PDF

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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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French (fr)
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 EP98936271A priority Critical patent/EP1019367A1/en
Priority to AU85341/98A priority patent/AU8534198A/en
Priority to JP2000507208A priority patent/JP2003524574A/en
Publication of WO1999007672A1 publication Critical patent/WO1999007672A1/en

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    • 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
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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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    • 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
    • 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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    • C07D211/06—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
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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
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    • 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
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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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    • C07D231/12—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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    • C07D295/16—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
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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

Substituted anilines of general formula (I) wherein R?1, R2, R3, R4¿ and X are defined in the description, compositions thereof and methods for preparing the compounds are described. The compounds are useful for 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.

Description

Derivatives of 2.5- and 3.5-disubstituted anilines, their Preparation and Use
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Potassium channels play an important role in the physiological and pharmacological control of cellular membrane potential. Amongst the different types of potassium channels are the ATP-sensitive (KATP-) channels which are regulated by changes in the intracellular concentration of adenosine triphosphate. The KATP-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 KATP-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 KATP -channels on pancreatic beta-cells.
The 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. In addition, potassium channel openers can be used as bronchodilators in the treatment of asthma and various other diseases.
Furthermore, 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.
Since some KATP-openers are able to antagonize vasospasms in basilar or cerebral arteries 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.
Recently it has been shown that 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 KATP-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. et al., Metabolism 1991 , 40, 39-46. In obese Zucker rats diazoxide has been shown to decrease insulin secretion and increase insulin receptor binding and consequently improve glucose tolerance and decrease weight gain (Alemzadeh R. et al., Endocrinol. 1993, 133, 705-712). It is expected that such potassium channel openers can be used for treatment of diseases characterized by an overproduction of insulin and for the treatment and prevention of diabetes.
Derivatives of 3,5-bis(trifluoromethyl)aniline, 3,5-dichloroaniline, 2,5- bis(trifluoromethyl)aniline and other, similarly substituted anilines have been previously claimed as crop protecting agents, antibacterials, anti-snails and for other uses, but not as potassium channel openers:
FR 1507886, Chem. Abstr., 70, 19821k, 1969; Agfa A.G., DE 1116534, 1961 , Chem. Abstr., EN, 56, 10329h, 1962; Ciba-Geigy AG, Basel (Schweiz), DE 2617163, 1976, Chem. Abstr., EN, 86, 55279; Hoechst, DE 2546271 , 1977, Chem. Abstr., EN, 87, 64057; Dow Chemical Co., US 3755505, 1970, Chem. Abstr., EN, 79, 104972; Ciba, NL 6516437, 1966, Chem. Abstr., EN, 66, 2329J, 1967; CIBA Ltd., FR 1511325, 1966, Chem. Abstr., EN, 71 , 91052y, 1969; CIBA, CH 495703, 1970, Chem. Abstr., EN, 74, 79613; Ciba, US 3592932, 1971 ; CIBA Ltd., DE 1803084, 1967, Chem. Abstr., EN, 71 , 91119a, 1969; Bayer AG, DE 2623847, 1977, Chem. Abstr., EN, 88, 120822; Labor.J.Berthier S.A., ZA 6706114, 1968, Chem. Abstr., EN, 70, 57467g, 1969.
Amides from 3,5-dichloroaniline and linear aliphatic carboxylic acids have been described as antibacterials (J. Med. Chem. 1983, 26, 1741 ).
DESCRIPTION OF THE INVENTION
The present invention relates to derivatives of 2,5- and 3,5-bis-substituted anilines of the general formula I:
Figure imgf000005_0001
wherein
R1 is hydrogen, trifluoromethyl or halogen;
R is hydrogen, trifluoromethyl or halogen;
R3 is trifluoromethyl or halogen; R4 is straight or branched alkyl, C^-alkenyl or C2.6-alkynyl, optionally substituted with C3.8- 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-R5, wherein Y is -O- or -N(R6)- wherein R5 is straight or branched alkyl, C2.6-alkenyl or C2-6-alkynyl, optionally substituted with C3.8-cycloalkyl, imidazolyl, methoxyphenyi or 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl; or aryl optionally substituted with halogen, cyano or trifluoromethyl; heterocyclyl, optionally substituted with halogen, cyano, benzyl or trifluoromethyl; or aryloxy, optionally substituted with halogen, cyano or trifluoromethyl;
R6 is hydrogen; or straight or branched alkyl optionally substituted with C3.8-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
R5 and R6 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 R5 and R6 are linked to form a saturated or unsaturated isoquinolin ring, optionally substituted with methoxy or dimethoxybenzyl;
X is O or S;
or a pharmaceutically acceptable salts thereof.
with the proviso that R1 and R2 are not both hydrogen at the same time;
and further provided that when R2 is hydrogen and R1 and R3 are chloro, then R4 can not be substituted or unsubstituted aryl or heteroaryl or heterocyclyl; R4 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; R4 can not be n-alkyl;
R4 can not be -(CH2)3-OAr;
R4 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.
When R2 is hydrogen and R1 and R3 are trifluoromethyl, then R4 can not be methyl, pyridyl, ethyl, n-propyl or 2-propylbutyl.
When R1 is hydrogen and R2 and R3 are chloro, then
R4 can not be substituted or unsubstituted aryl or heteroaryl or heterocyclyl; R4 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; R4 can not be n-alkyl, cyclopropyl or 2-propylbutyl; R4 can not be -(CH2)3-OAr or -CH(OH)CH3;
R4 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.
When X is oxygen, R1 is hydrogen and R2 and R3 are trifluoromethyl, then
R4 can not be heterocyclyl;
R4 can not be methyl, unsubstituted or monosubstituted with heteroaryloxy, ammonium, acyl,
1-oximoalkyl, heterocyclyl or 1-iminoalkyl; R4 can not be 2-propylbutyl or cyclopropyl;
R4 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. When X is sulfur, R1 is hydrogen and R2 and R3 are trifluoromethyl, then R4 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;
When R1 is chloro, R2 is hydrogen and R3 is trifluoromethyl, then R4 can not be substituted or unsubstituted aryl or heteroaryl or heterocyclyl;
R4 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; R4 can not be unsubstituted n-alkyl, cyclopropyl, isopropyl, isobutyl, benzyl, 2-ethylpropyl, 2- propylbutyl;
R4 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.
Within its scope 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 scope of the invention also includes all tautomeric forms of the compounds of formula
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. The term "heterocyclyl" as used herein 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. a radical derived from pyrazine, pyrimidine, pyridazine, 1 ,2,4- triazine, 1 ,2,3-triazine or tetrazine; a non-aromatic monocyclic system containing one or more hetero atoms selected from nitrogen, oxygen and sulfur and having 6 or 7 members, e.g. a radical derived from pyran, thiopyran, piperidine, dioxane, oxazine, isoxazine, dithiane, oxathine, thiazine, piperazine, thiadiazine, dithiazine, oxadiazine or oxoazepane as well as the corresponding benzo and dibenzo derivatives.
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 -NH2 and nitro refers to -N02. 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-NH2, - 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. The term "C2.6-alkenyl" as used herein 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.
The term "C2.6-alkynyl" as used herein refers to unsaturated hydrocarbons which contain triple bonds, such as e.g. -C≡CH, -C≡CCH3, -CH2G≡CH, -CH2CH2C≡CH, -CH(CH3)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.
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.
Further, 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.
Further, potassium channel openers promote hairgrowth, therefore, the compounds of the present invention can be used for the treatment of baldness. In 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. In obesity hyperinsulinemia and insulin resistance is very frequently encountered. This condition could lead to the development of non insulin dependent diabetes (NIDDM). 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. In 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.
In early cases of insulin dependent diabetes (IDDM) or in prediabetic cases, 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 KATP-channels may be used for the treatment of NIDDM.
Preferably, the compounds of the present invention may be used for treatment or prevention of diseases of the endocrinological system such as hyperinsulinaemia and diabetes.
Accordingly, in another aspect 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.
Furthermore, 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
Figure imgf000012_0001
Figure imgf000012_0002
Substituted anilines can be e.g. reacted with the appropriate carboxylic acid chlorides to yield anilides. Moreover, reaction with isocyanates of isothiocyanates may give ureas or thioureas, respectively. Reaction of substituted anilines with chloroformates may yield carbamates (urethanes). Moreover, substituted arylisocyanates (X = O) or arylisothiocyanates (X = S) may be reacted with primary or secondary aliphatic or aromatic amines to yield ureas or thioureas, respec- tively. Substituted arylisocyanates (X = O) or arylisothiocyanates (X = S) may also be reacted with aliphatic or aromatic alcohols to yield urethanes (carbamates) or thiocarbamates.
7. Abbreviations: The following frequently used abbreviations are intended to have the fol- lowing meanings:
AcOH: glacial acetic acid
DBU: 1 ,8-diazabicyclo[5.4.0]undec-7-ene
DCM: dichloromethane, methylenechloride
DIC: diisopropylcarbodiimide DMF: N,N-dimethyl formamide
EDC: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride, "water-soluble car- bodiimide"
FMoc: fluorenylmethyloxycarbonyl
NMP: N-Methylpyrrolidone R: organic radical
TFA: trifluoroacetic acid
THF: tetrahydrofuran
PHARMACOLOGICAL METHODS
The ability of the compounds to interact with potassium channels can be determined by various methods. When patch-clamp techniques (Hamill O.P., Marty A., Nefer E., Sakman B. and Sigworth F.J., Plϋgers Arch. 1981, 391, 85-100) are used 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:
A section of rat thoracic aorta between the aortic arch and the diaphragm was dissected out and mounted as ring preparations as described by Taylor P.D. et al., Brit. J. Pharmacol. 1994, 111, 42-48.
After a 45 min equilibration period under a tension of 2 g, the preparations were contracted to achieve 80% of the maximum response using the required concentration of phenylephrine. When the phenylephrine response reached a plateau, 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.
In the pancreatic beta-cell the opening of the KATP-channels can be determined by measuring the subsequent change in the concentration of cytoplasmic free Ca2+ concentration according to the method of Arkhammar et al., J. Biol. Chem. 1987, 262, 5448-5454.
-Rb+ efflux from a beta-cell line
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% C02/ 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 86Rb+ and replated into microtiter plates (96 well cluster 3596, sterile, from Costar Corporation, MA, USA) at a density of 50000 cells/well in 100 μl/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 CaCI2, 20 mM sucrose, pH 7.1 ). 80 μL Ringer buffer and 1 μL control- or test compound dissolved in DMSO were added. After incubation for 1 h at room temperature with a lid, 50 μL of the supernatant was transferred to PicoPlates (Packard Instrument Company, CT, USA) and 100 μL 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 32P program.
The calculation of EC50 and Emax was done by SlideWrite (Advanced Graphics Software, Inc., CA, USA) using a four parameter logistic curve: y = (a-d)/(1+(x/c)b)+d, where a = the activity estimated at concentration zero, b = a slope factor, c = the concentration at the middle of the curve and, d = the activity estimated at infinite concentration. EC50 = c and Emax= d, when the curve is turned off at infinite concentrations. 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.
Typical 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. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. 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. Some examples of 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. For parenteral application, particularly suitable are 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:
Active compound 5.0 mg Lactosum 67.8 mg Ph.Eur.
Avicel® 31.4 mg
Amberlite® 1.0 mg
Magnesii stearas 0.25 mg Ph.Eur.
Due to their high degree of activity, 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.
The 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 IC50 of 600 nM.
Examples
Example 1. 1-[3,5-Bis-(trifluoromethyl)phenyl]-3-(2,4-dichlorobenzyl)urea To a solution of 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.
HPLC (254 nm): Elution at 33.98 min, 99.7% pure. LCMS: MH+ calcd.: 431 , found: 431. 1H NMR (300 MHz, DMSO-cfβ): δ = 4.38 (d, J = 7 Hz, 2H), 7.09 (t, J = 7 Hz, 1 H), 7.30-7.62 (m, 6H), 8.11 (s, 2H), 9.52 (s, 1 H). Anal. Calcd. for C16H10CI2F6N2O (431.2): C, 44.57; H, 2.34; N, 6.50. Found: C, 44.53; H, 2.34; N, 6.29.
Example 2. Parallel Synthesis of ten N-acylated 3,5-bis(trifluoromethyl)anilines
Into each of ten test tubes with septum a solution of 3,5-bis(trifluoromethyl)aniline (0.078 mL, 0.5 mmol) in pyridine (0.2 mL) and 1 ,2-dichloroethane (0.5 mL) was placed. Then, while shaking the tubes on a mechanical shaker, to each of the test tubes one acid chloride (0.6 mmol), namely 3-cyanobenzoyl chloride, 2-phenoxypropionyl chloride, butyryl chloride, hep- tanoyl chloride, pivaloyl chloride, cyclopropanoyl chloride, isobutyryl chloride, 2- ethylhexanoyl chloride, 3-cyclopentylpropionyl chloride and 3-phenylpropionyl chloride, was added with a syringe. The resulting mixtures were shaken for 48 h at room temperature. To each test tube brine (2 mL) and ethyl acetate (2 mL) were added, and after shaking for 5 min the aqueous phases were pipetted off and discarded. The organic layers were washed once with 1 N hydrochloric acid (3 mL), once with brine (3 mL) and then dried over magnesium sulfate. The dried ethyl acetate extracts were tranferred into vials and concentrated. Between 156 mg and 63 mg of the corresponding anilides were obtained. Purity and identity of the products was determined by HPLC-MS, and was found to be sufficient for screening.
Example 3. Parallel synthesis of 200 substituted aniline derivatives
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- hydroxycyclohexylamine, 3-hydroxypipehdine, 3-hydroxypyrrolidine, 2-aminoethanol, 3- aminopropanol, 4-aminobutanol, 6-aminohexanol, 4-(2-aminoethyl)morpholine, 3,3,5- thmethyl-5-aminomethyl-1-cyclohexanol, 1-acetylpiperazine, (2-chlorobenzyl)amine, 2- (ethylamino)ethanol, n-butylamine, 2-methyl-2-amino-1-propanol, cyclohexylmethylamine, 4- (2-aminoethyl)pyridine, 4-(ethylaminomethyl)pyridine, 3-(2-pyridylamino)propylamine, 2-(2- aminoethyl)pyridine, 4-(1 -piperidinyl)-4-(aminocarbonyl)piperidine, 1 -(pyrrolidin-1 - ylcarbonylmethyl)piperazine, 1 -(2-furoyl)piperazine, 1 -cyclopropyl-1 -(4- methoxyphenyl)methylamine, synephrine [N-methyl-2-(4-hydroxyphenyl)-2- hydroxyethylamine; racemic], 2-amino-2-phenylethanol (racemic), norephed ne (1-phenyl-2- aminopropanol), 4-amino-1-benzylpiperidine, 1 ,2,3,4-tetrahydropapaverine, desipramine and 3-(aminomethyl)pyhdine. Then to each of the vials (closed with a septum) 0.25 mL of a mixture of acetonitrile and triethylamine (9:1 , vol) was added. Finally solutions of 3,5- bis(thfluoromethyl)phenylisothiocyanate, 3,5-dichlorophenylisothiocyanate, 3,5- bis(thfluoromethyl)phenylisocyanate and 2-chloro-5-(trifluoromethyl)phenylisothiocyanate in acetonitrile (0.6 equivalents) were added to all the vials in such a way that all possible combinations of cyanate/amine were realized. The vials were then shaken for 24 h at room temperature and then concentrated in vacuum. The quality of the compound-array was determined by HPLC-MS of a representative selection of products, and was considered to be sufficient for screening (estimated purity of analyzed samples: 40% to >90%).
Following the procedures described above, the following compounds I have been prepared:
Figure imgf000018_0001
MH+
No R1 R2 R3 R4 X expctd found
1 H -CF3 -CF3 -NH-(CH2)2CH3 O 315 315
2 H -CF3 -CF3 -NH-(cyclohexyl) O 355 355
3 H -CF3 -CF3 -NH-C(CH3)3 O 328 329
4 H -CF3 -CF3 -NH-(4-C6H4CI) O 383 383
5 H -CF3 -CF3 -NH-CH(CH3)2 O 315 315 H -CF3 -CF3 -(3-C6H4CN) 0 359 359
H -CF3 -CF3 -CH(0-P )CH3 o 378 378
H -CF3 -CF3 -(CH2)2CH3 0 300 300
H -CF3 -CF3 -(CH2)5CH3 0 342 342
H -CF3 -CF3 -C(CH3)3 0 314 314
H -CF3 -CF3 cyclopropyl 0 298 298
H -CF3 -CF3 -CH(CH3)2 0 300
H -CF3 -CF3 -CH(Et)(n-butyl) 0 356 356
H -CF3 -CF3 -(CH2)2-(cyclopentyl) 0 354 354
H -CF3 -CF3 -(CH2)2-Ph 0 362 362
H -CF3 -CF3 -NH-(CH2)2-CH(CH3)2 s 359
H -CF3 -CF3 -NH-CH(CH3)2 s 331 331
H -CF3 -CF3 -NH-CH2-CH(CH3)2 s 345
H -CF3 -CF3 -NH-CH2-C(CH3)3 s 359 359
H -CF3 -CF3 -NH-CH2-CF3 s 371
H -CF3 -CF3 -NH-CH2-CCH s 327
H -CF3 -CF3 -N[(CH2)2CH3]2 s 373
H -CF3 -CF3 -NH-(CH2)2-(4-C6H4CI) s 427
H -CF3 -CF3 (4-methyl)piperidin-1 -yl s 371
H -CF3 -CF3 -N[CH2-CH(CH3)2]2 s 401
H -CF3 -CF3 pyrrolidin-1-yl s 343
H -CF3 -CF3 -NH-(CH2)3-(imidazol-1-yl) s 397
H -CF3 -CF3 1 ,2,3,4-tetrahydroisoquinolin-2-yl s 405
H -CF3 -CF3 (2,6-dimethyl)morpholin-4-yl s 387
H -CF3 -CF3 4-[(3-trifluoromethyl)phenyl]piperazin-1 -yl s 502
H -CF3 -CF3 azepin-1-yl s 371
H -CF3 -CF3 (4-benzoyl)piperidin-1 -yl s 461
H -CF3 -CF3 -NH-(CH2)3-Ph s 407
H -CF3 -CF3 -NH-(4-hydroxycyclohexyl) s 387
H -CF3 -CF3 -NH-(3-hydroxycyclo exyl) s 387
H -CF3 -CF3 4-hydroxypiperidin-1 -yl s 373
H -CF3 -CF3 3- ydroxypiperidin-1 -yl s 373
H -CF3 -CF3 3-hydroxypyrrolidin-1-yl s 359
H -CF3 -CF3 -NH-(CH2)2-OH s 333
H -CF3 -CF3 -NH-(CH2)3-OH s 347
H -CF3 -CF3 -NH-(CH2)4-OH s 361
H -CF3 -CF3 -NH-(CH2)6-OH s 389 H -CF3 -CF3 -NH-(CH2)2-(morpholin-4-yl) S 402
H -CF3 -CF3 -NH-CH2-(1 ,3,3-trimethyl-5-hydroxy-1- S 443 cyclohexyl
H -CF3 -CF3 (4-acetyl)piperazin-1-yl S 400
H -CF3 -CF3 -NH-CH2-(2-C6H4CI) S 413
H -CF3 -CF3 -N(Et)-(CH2)2-OH S 361
H -CF3 -CF3 -NH-(CH2)3-CH3 S 345
H -CF3 -CF3 -NH-C(CH3)2-CH2-OH S 361 361
H -CF3 -CF3 -NH-CH2-(cyclohexyl) S 385
H -CF3 -CF3 -NH-(CH2)2-(4-pyridyl) S 394
H -CF3 -CF3 -N(Et)-CH2-(4-pyridyl) S 408 408
H -CF3 -CF3 -NH-(CH2)3-NH-(2-pyridyl) S 423 423
H -CF3 -CF3 -NH-(CH2)2-(2-pyridyl) S 394
H -CF3 -CF3 [4-(piperidin-1-yl)-4-aminocarbonyl]piperidin-1-yl S 483 483
H -CF3 -CF3 4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl S 469
H -CF3 -CF3 4-(2-furoyl)piperazin-1-yl S 452
H -CF3 -CF3 -NH-CH(cyclopropyl)(4-C6H4-OCH3) S 449
H -CF3 -CF3 -N(CH3)-CH2-CH(OH)-(4-C6H4-OH) S 439 439
H -CF3 -CF3 -NH-CH(CH2-OH)-Ph S 409
H -CF3 -CF3 -NH-CH(CH3)-CH(OH)-Ph S 423 423
H -CF3 ~CF3 -NH-(1-benzylpiperidin-4-yl) S 462
H -CF3 -CF3 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1 ,2,3,4- S 615 615 tetrahydroisoquinolin-2-yl
H -CF3 -CF3 -N(CH3)-(CH2)3-(10,11-dihydro-5H- S 538 dibenzo[b,f]azepin-5-yl)
H -CF3 -CF3 -NH-CH2-(3-pyridyl) s 380
H -Cl -Cl -NH-(CH2)2-CH(CH3)2 s 292
H -Cl -Cl -NH-CH(CH3)2 s 264
H -Cl -Cl -NH-CH2-CH(CH3)2 s 278
H -Cl -Cl -NH-CH2-C(CH3)3 Ss 2 29922 291
H -Cl -Cl -NH-CH2-CF3 s 304
H -Cl -Cl -NH-CH2-CCH s 260
H -Cl -Cl -N[(CH2)2CH3]2 s 306
H -Cl -Cl -NH-(CH2)2-(4-C6H4Cl) s 360
H -Cl -Cl (4-methyl)piperidin-1 -yl s 304
H -Cl -Cl -N[CH2-CH(CH3)2]2 s 334
H -Cl -Cl pyrrolidin-1-yl s 276 77 H -Cl -Cl -NH-(CH2)3-(imidazol-1-yl) S 330
78 H -Cl -Cl 1 ,2,3,4-tetrahydroisoquinolin-2-yl S 338
79 H -Cl -Cl (2,6-dimethyl)morpholin-4-yl S 320
80 H -Cl -Cl 4-[(3-trifluoromethyl)phenyl]piperazin-1-yl S 435
81 H -Cl -Cl azepin-1-yl S 304
82 H -Cl -Cl (4-benzoyl)piperidin-1 -yl S 394
83 H -Cl -Cl -NH-(CH2)3-Ph S 340
84 H -Cl -Cl -NH-(4-hydroxycyclohexyl) S 320
85 H -Cl -Cl -NH-(3-hydroxycyclohexyl) S 320
86 H -Cl -Cl 4-hydroxypiperidin-1 -yl S 306
87 H -Cl -Cl 3-hydroxypiperidin-1 -yl S 306
88 H -Cl -Cl 3-hydroxypyrrolidin-1 -yl S 292
89 H -Cl -Cl -NH-(CH2)2-OH S 266
90 H -Cl -Cl -NH-(CH2)3-OH S 280
91 H -Cl -Cl -NH-(CH2)4-OH S 294
92 H -Cl -Cl -NH-(CH2)6-OH S 322
93 H -Cl -Cl -NH-(CH2)2-(morpholin-4-yl) S 335
94 H -Cl -Cl -NH-CH2-(1 ,3,3-trimethyl-5-hydroxy-1- S 376 cyclohexyl
95 H -Cl -Cl (4-acetyl)piperazin-1 -yl S 333
96 H -Cl -Cl -NH-CH2-(2-C6H4CI) s 346
97 H -Cl -Cl -N(Et)-(CH2)2-OH s 294
98 H -Cl -Cl -NH-(CH2)3-CH3 s 278
99 H -Cl -Cl -NH-C(CH3)2-CH2-OH s 294
100 H -Cl -Cl -NH-CH2-(cyclohexyl) s 318
101 H -Cl -Cl -NH-(CH2)2-(4-pyridyl) s 327
102 H -Cl -Cl -N(Et)-CH2-(4-pyridyl) s 341
103 H -Cl -Cl -NH-(CH2)3-NH-(2-pyridyl) s 356
104 H -Cl -Cl -NH-(CH2)2-(2-pyridyl) s 327
105 H -Cl -Cl [4-(piperidin-1 -yl)-4-aminocarbonyl]piperidin-1 -yl s 416
106 H -Cl -Cl 4-(pyrrolidin-1 -ylcarbonylmethyI)piperazin-1 -yl s 402
107 H -Cl -Cl 4-(2-furoyl)piperazin-1 -yl s 385
108 H -Cl -Cl -NH-CH(cyclopropyl)(4-C6H4-OCH3) s 382
109 H -Cl -Cl -N(CH3)-CH2-CH(OH)-(4-C6H4-OH) s 372
110 H -Cl -Cl -NH-CH(CH2-OH)-Ph s 342
111 H -Cl -Cl -NH-CH(CH3)-CH(OH)-Ph s 356
112 H -Cl -Cl -NH-(1-benzylpiperidin-4-yl) s 395 113 H -Cl -Cl 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1 ,2,3,4- S 548 tetrahydroisoquinolin-2-yl
114 H -Cl -Cl -N(CH3)-(CH2)3-(10,11-dihydro-5H- S 471 dibenzo[b,f|azepin-5-yl)
115 H -Cl -Cl -NH-CH2-(3-pyridyl) S 313
116 H -CF3 -CF3 -NH-(CH2)2-CH(CH3)2 O 343
117 H -CF3 -CF3 -NH-CH(CH3)2 O 315
118 H -CF3 -CF3 -NH-CH2-CH(CH3)2 O 329
119 H -CF3 -CF3 -NH-CH2-C(CH3)3 O 343 343
120 H -CF3 -CF3 -NH-CH2-CF3 O 355 355
121 H -CF3 -CF3 -NH-CH2-CCH O 311
122 H -CF3 -CF3 -N[(CH2)2CH3]2 O 357
123 H -CF3 -CF3 -NH-(CH2)2-(4-C6H4CI) O 411
124 H -CF3 -CF3 (4-methyl)piperidin-1-yl O 355
125 H -CF3 -CF3 -N[CH2-CH(CH3)2]2 O 385
126 H -CF3 -CF3 pyrrolidin-1-yl O 327
127 H -CF3 -CF3 -NH-(CH2)3-(imidazol-1-yl) O 381
128 H -CF3 -CF3 1 ,2,3,4-tetrahydroisoquinolin-2-yl O 389
129 H -CF3 -CF3 (2,6-dimethyl)morpholin-4-yl O 371
130 H -CF3 -CF3 4-[(3-trifluoromethyl)phenyl]piperazin-1-yl O 486
131 H -CF3 -CF3 azepin-1-yl O 355
132 H -CF3 -CF3 (4-benzoyl)piperidin-1 -yl O 445
133 H -CF3 -CF3 -NH-(CH2)3-Ph O 391
134 H -CF3 -CF3 -N H-(4-hydroxycyclohexyl ) O 371 371
135 H -CF3 -CF3 -NH-(3-hydroxycyclohexyl) O 371
136 H -CF3 -CF3 4-hydroxypiperidin-1 -yl O 357
137 H -CF3 -CF3 3-hydroxypiperidin-1 -yl O 357
138 H -CF3 -CF3 3-hydroxypyrrolidin-1 -yl O 343 343
139 H -CF3 -CF3 -NH-(CH2)2-OH O 317
140 H -CF3 -CF3 -NH-(CH2)3-OH O 331 331
141 H -CF3 -CF3 -NH-(CH2)4-OH O 345
142 H -CF3 -CF3 -NH-(CH2)6-OH O 373
143 H -CF3 -CF3 -NH-(CH2)2-(morpholin-4-yl) O 386
144 H -CF3 -CF3 -NH-CH2-(1 ,3,3-trimethyl-5-hydroxy-1 - O 427 cyclohexyl
145 H -CF3 -CF3 (4-acetyl)piperazin-1-yl O 384
146 H -CF3 -CF3 -NH-CH2-(2-C6H4CI) O 397 147 H -CF3 -CF3 -N(Et)-(CH2)2-OH O 345 148 H -CF3 -CF3 -NH-(CH2)3-CH3 O 329 149 H -CF3 -CF3 -NH-C(CH3)2-CH2-OH O 345 150 H -CF3 -CF3 -NH-CH2-(cyclohexyl) O 369 151 H -CF3 -CF3 -NH-(CH2)2-(4-pyridyl) O 378 152 H -CF3 -CF3 -N(Et)-CH2-(4-pyridyl) O 392 153 H -CF3 -CF3 -NH-(CH2)3-NH-(2-pyridyl) O 407 154 H -CF3 -CF3 -NH-(CH2)2-(2-pyridyl) O 378 155 H -CF3 -CF3 [4-(piperidin-1-yl)-4-aminocarbonyl]piperidin-1-yl O 467 156 H -CF3 -CF3 4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl O 453 157 H -CF3 -CF3 4-(2-furoyI)piperazin-1-yl O 436 158 H -CF3 -CF3 -NH-CH(cyclopropyl)(4-C6H4-OCH3) O 433 433 159 H -CF3 -CF3 -N(CH3)-CH2-CH(OH)-(4-C6H4-OH) O 423 160 H -CF3 -CF3 -NH-CH(CH2-OH)-Ph O 393 161 H -CF3 -CF3 -NH-CH(CH3)-CH(OH)-Ph O 407 162 H -CF3 -CF3 -NH-(1-benzylpiperidin-4-yl) O 446 163 H -CF3 -CF3 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1 ,2,3,4- O 599 tetrahydroisoquinolin-2-yl
164 H -CF, -CF3 -N(CH3)-(CH2)3-(10,11-dihydro-5H- O 522 dibenzo[b,f]azepin-5-yl)
165 H -CF3 -CF3 -NH-CH2-(3-pyridyl) O 364
166 -Cl H -CF3 -NH-(CH2)2-CH(CH3)2 S 325
167 -Cl H -CF3 -NH-CH(CH3)2 S 297
168 -Cl H -CF3 -NH-CH2-CH(CH3)2 S 311
169 -Cl H -CF3 -NH-CH2-C(CH3)3 S 325 325
170 -Cl H -CF3 -NH-CH2-CF3 S 337
171 -Cl H -CF3 -NH-CH2-CCH S 293
172 -Cl H -CF3 -N[(CH2)2CH3]2 S 339 339
173 -Cl H -CF3 -NH-(CH2)2-(4-C6H4CI) S 394
174 -Cl H -CF3 (4-methyl)piperidin-1-yl S 337 337
175 -Cl H -CF3 -N[CH2-CH(CH3)2]2 S 367
176 -Cl H -CF3 pyrrolidin-1-yl S 309
177 -Cl H -CF3 -NH-(CH2)3-(imidazol-1-yl) S 363
178 -Cl H -CF3 1 ,2,3,4-tetrahydroisoquinolin-2-yl S 371
179 -Cl H -CF3 (2,6-dimethyl)morpholin-4-yl S 353
180 -Cl H -CF3 4-[(3-trifluoromethyl)phenyl]piperazin-1-yl S 468
181 -Cl H -CF3 azepin-1-yl S 337 182 -Cl H -CF3 (4-benzoyl)piperidin-1 -yl S 427
183 -Cl H -CF3 -NH-(CH2)3-Ph S 373
184 -Cl H -CF3 -NH-(4-hydroxycyclohexyl) S 353
185 -Cl H -CF3 -NH-(3-hydroxycyclohexyl) S 353
186 -Cl H -CF3 4-hydroxypiperidin-1 -yl S 339
187 -Cl H -CF3 3-hydroxypiperidin-1 -yl S 339
188 -Cl H -CF3 3-hydroxypyrrolidin-1 -yl S 325
189 -Cl H -CF3 -NH-(CH2)2-OH S 299
190 -Cl H -CF3 -NH-(CH2)3-OH S 313
191 -Cl H -CF3 -NH-(CH2)4-OH S 327
192 -Cl H -CF3 -NH-(CH2)6-OH S 355
193 -Cl H -CF3 -NH-(CH2)2-(morpholin-4-yl) S 368
194 -Cl H -CF3 -NH-CH2-(1 ,3,3-trimethyl-5-hydroxy-1 - S 409 cyclohexyl
195 -Cl H -CF3 (4-acetyl)piperazin-1-yl S 366
196 -Cl H -CF3 -NH-CH2-(2-C6H4Cl) S 380
197 -Cl H -CF3 -N(Et)-(CH2)2-OH S 327
198 -Cl H -CF3 -NH-(CH2)3-CH3 S 311
199 -Cl H -CF3 -NH-C(CH3)2-CH2-OH s 327
200 -Cl H -CF3 -NH-CH2-(cyclohexyl) s 351
201 -Cl H -CF3 -NH-(CH2)2-(4-pyridyl) s 360
202 -Cl H -CF3 -N(Et)-CH2-(4-pyridyl) s 374
203 -Cl H -CF3 -NH-(CH2)3-NH-(2-pyridyl) s 389 38!
204 -Cl H -CF3 -NH-(CH2)2-(2-pyridyl) s 360
205 -Cl H -CF3 [4-(piperidin-1-yl)-4-aminocarbonyl]piperidin-1-yl s 449
206 -Cl H -CF3 4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl s 435
207 -Cl H -CF3 4-(2-furoyl)piperazin-1 -yl s 418
208 -Cl H -CF3 -NH-CH(cyclopropyl)(4-C6H4 -OCH3) s 415
209 -Cl H -CF3 -N(CH3)-CH2-CH(OH)-(4-C6H4-OH) s 405
210 -Cl H -CF3 -NH-CH(CH2-OH)-Ph s 375 37
211 -Cl H -CF3 -NH-CH(CH3)-CH(OH)-Ph s 389
212 -Cl H -CF3 -NH-(1-benzylpiperidin-4-yl) s 428
213 -Cl H -CF3 1 -(3,4-dimethoxybenzyl)-6,7- -dimethoxy-1 , 2,3,4- s 582 tetrahydroisoquinolin-2-yl
214 -Cl H -CF3 -N(CH3)-(CH2)3-(10,11-di ydro-5H- s 505 dibenzo[b,f]azepin-5-yl)
215 -Cl H -CF3 -NH-CH2-(3-pyridyl) s 346 34 216 H -CF3 -CF3 -NH-CH2-(2,4-C6H3CI2) O 432 432
Example 4. General synthetic pathway to 1-aryl-3-alkylthioureas
A solution of the appropriately substituted aniline (8 mmol) and thiocarbonyidiimidazole (1.43 g ; 8 mmol) in dioxane (30 mL) was heated at 50°C for 48-72 h (until disappearance of the aniline from the reaction mixture monitored by TLC). The appropriate alkylamine (or cycloal- kylalkylamine) (8 mmol) was added to the reaction medium and the resulting solution was heated at 60°C for 4-12 h. The solvent was removed by distillation under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with 4N HCI (50 mL), then with water (50 mL). The organic layer was dried over anhydrous MgS04, filtered, and the filtrate was concentrated to dryness. The residue was dissolved in a small volume of ethanol (5-10 mL). The solution was supplemented with 2N HCI (100 mL) and the resulting precipitate was collected by filtration, washed with water and dried (yields : 20-60%).
The following compounds have been obtained :
1-Cyclohexylmethyl-3-(3,5-dichlorophenyl)thiourea mp 134-135°C. IR (KBr) : 3261 , 3079, 2922, 2850, 1552, 1445, 1337, 1248 cm"1. Anal.
Calcd. for C14H18CI2N2S (317.28) : C, 53.00 ; H, 5.72 ; N, 8.83 ; S, 10.11. Found : C, 53.13 ; H, 6.10 ; N, 9.00 ; S, 10.38.
1 -Cyclohexylmethyl-3-(3,5-difluorophenyl)thiourea mp 125-127°C. IR (KBr) : 3318, 3201 , 2924, 2854, 1626, 1611 , 1565, 1536, 1477, 1262, 1252, 1122 cm"1. Anal. Calcd. for C14H18F2N2S (284.37) : C, 59.13 ; H, 6.38 ; N, 9.85 ; S, 11.28. Found : C, 59.33 ; H, 6.49 ; N, 10.22 ; S, 11.01.
1-Cyclohexylmethyl-3-(2,5-difluorophenyl)thiourea mp 89-91°C. IR (KBr) : 3316, 3168, 2922, 2850, 1553, 1500, 1250, 1212, 1 196, 1184 cm"1. Anal. Calcd. for C14H18F2N2S (284.37) : C, 59.13 ; H, 6.38 ; N, 9.85 ; S, 11.28. Found : C, 59.20 ; H, 6.63 ; N, 10.22 ; S, 11.33.
(R)-1-(1-Cyclohexylethyl)-3-(3,5-difluorophenyl)thiourea mp 121-123°C. IR (KBr) : 3315, 3200, 3043, 2924, 2852, 1625, 1612, 1570, 1525, 1477, 1254, 1120 cm"1. Anal. Calcd. for C15H20F2N2S (298.40) : C, 60.38 ; H, 6.75 ; N, 9.39 ; S, 10.75. Found : C, 60.23 ; H, 6.92 ; N, 9.46 ; S, 11.05.
Example 5 Heptanoic acid (3, 5-bis(trifluoromethyl) phenyl) amide
To a solution of heptanoyl chloride (0.186 ml, 1.1 mmol) in diethyl ether (1 ml) 3,5-bis- (trifluoromethyl)aniline (0.196 ml, 1.3 mmol) was added dropwise. After stirring for 2 h, the precipitate was filtered off and washed with diethyl ether. The filtrate was concentrated to give a sirup, which was purified by flash chromatography using ethyl acetate/heptane 1 :4 and 1 :2 to give the title compound as oily crystals. Yield 0.65 g (83%). The product could be recrystalised from ethanol/water to give oily crystals contaminated with heptanoic chloride (3.67 mol%). MA. Calculated for C15H17NOF6.0.1C7H13CIO: C 53.22%; H 5.23%; N 3.95% Found: C 53.31%; H 5.10%; N 4.06%. El SP/MS: 341 (M+ ). 1H-NMR (DMSO): δ 10.55 (s, 1 H, NH); 8.27 (s, 2H); 7.70 (s, 1 H); 2.35 (t, 2H); 1.60 (p, 2H); 1.3 (m, 6H); 0.88 ppm (t, 3H).
Example 6 N-(3,5-Bis(trifluoromethyl)phenyl)-2-phenoxypropionamide
To a solution of 2-phenoxypropionyl chloride (0.22 g, 1.1 mmol) in diethyl ether (4 ml) 3,5- bis-(trifluoromethyl)aniline (0.200 ml, 1.3 mmol) was added. After stirring for 2.5 h the reaction mixture was filtered and the filtrate concentrated to give a sirup, which was crystalised from toluene to give the title compound as white crystals. Yield 0.321 g (75%).mp 113.5- 114.5°C. MA. Calculated for C17H13N02Fβ: C 54.12%; H 3.47%; N 3.71 % Found: C 54.21%; H 3.49%; N 3.68%. El SP/MS: 377 (M+ ). Η-NMR (DMSO): δ 10.80 (s, 1 H, NH); 8.39 (s, 2H); 7.80 (s, 1 H); 7.3 (m, 2H); 6.95 (m, 3H); 4.94 (q, 1 H); 1.57 ppm (d, 3H). Example 7 1-(3, 5-Bis(trifluoromethyl)phenyl)-3-(4-chlorophenyl)urea
4-Chlorophenylisocyanate (0.175 ml, 1.36 mmol) was added to 3,5-bis-
(trifluoromethyl)aniline (0.233 ml, 1.5 mmol) and stirred for 1 h. The almost solid reaction mixture was recrystalised first from ethyl acetate and then from toluene to give the title compound. Yield 0.315g (61 %). Mp 224.5-225.0°C. El SP/MS: 382 (M+). 1 H-NMR (DMSO): δ 9.42 (br s, 1 H, NH); 9.13 (br s, 1 H, NH); 8.12 (s, 2H); 7.63 (s, 1 H); 7.50 (d, 2H); 7.35 ppm (d, 2H).
Example 8 N-(3, 5-Bis(trifluoromethyl)phenyl)-3-phenylacrylamide
The title compound was prepared from 3,5-bis(trifluoromethyl)aniline and cinnamoyi chloride by a method analogous to the one described in Example 2; LC-MS: m/e 360 (M+ +1).
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 ).

Claims

1. A compound of the general formula I
Figure imgf000028_0001
wherein
R1 and R2 are independently hydrogen, trifluoromethyl or halogen, with the provisio that R1 and R2 are not simultaneously hydrogen;
R3 is trifluoromethyl or halogen;
R4 is straight or branched alkyl optionally substituted with C3.8-cycloalkyl, hydroxy, heterocyclyl, aryloxy, and aryl optionally substituted with halogen or trifluoromethyl, or R4 is Y-R5, Y being -O- or -N(R6)- and R5 and R6 being independently straight or branched alkyl optionally substituted with C3-8-cycloalkyl, hydroxy, heterocyclyl, aryloxy, and aryl optionally substituted with halogen or trifluoromethyl; or R5 and R6 are linked to each other forming a 3-8 membered ring;
X is O or S; or a pharmaceutically acceptable salts thereof.
2. A compound of the general formula
Figure imgf000028_0002
wherein
R1 is hydrogen, trifluoromethyl or halogen;
R2 is hydrogen, trifluoromethyl or halogen;
R3 is trifluoromethyl or halogen;
R4 is straight or branched alkyl, C2.6-alkenyl or C2.6-alkynyl, optionally substituted with C3.8- 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-R5, wherein Y is -O- or -N(R6)- wherein R5 is straight or branched alkyl, C^-alkenyl or C2.6-alkynyl, optionally substituted with C3.8-cycloalkyl, imidazolyl, methoxyphenyi or 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl; or aryl optionally substituted with halogen, cyano or trifluoromethyl; or heterocyclyl, optionally substituted with halogen, cyano, benzyl or trifluoromethyl; or aryloxy, optionally substituted with halogen, cyano or trifluoromethyl;
R6 is hydrogen; or straight or branched alkyl optionally substituted with C3.8-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
R5 and R6 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
R5 and R6 are linked to form a saturated or unsaturated isoquinolin ring, optionally substituted with methoxy or dimethoxybenzyl; X is O or S;
or a pharmaceutically acceptable salts thereof.
with the proviso that R1 and R2 are not both hydrogen at the same time;
3. A compound of the general formula I
Figure imgf000030_0001
wherein
R1 is hydrogen, trifluoromethyl or halogen;
R2 is hydrogen, trifluoromethyl or halogen;
R3 is trifluoromethyl or halogen;
R4 is straight or branched alkyl, C2.6-alkenyl or C2.6-alkynyl, optionally substituted with C3.8- 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-R5, wherein Y is -O- or -N(R6)- wherein R5 is straight or branched alkyl, C2.6-alkenyl or C2.6-alkynyl, optionally substituted with C3.8-cycloalkyl, imidazolyl, methoxyphenyi or 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl; or aryl optionally substituted with halogen, cyano or trifluoromethyl; heterocyclyl, optionally substituted with halogen, cyano, benzyl or trifluoromethyl; or aryloxy, optionally substituted with halogen, cyano or trifluoromethyl; R6 is hydrogen; or straight or branched alkyl optionally substituted with C3.8-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
R5 and R6 are linked to form a 3-8 membered ring which is optionally substituted with straight or branched alkyl, optionally substituted with pyrrolidinylcarbonylmethyl (??); or aryl optionally substituted with halogen, cyano or trifluoromethyl; or furoyl, benzoyl, acetyl, hydroxy, aminocarbonyl; or piperidinyl; or
R5 and R6 are linked to form a saturated or unsaturated isoquinolin ring, optionally substituted with methoxy or dimethoxybenzyl;
X is O or S;
or a pharmaceutically acceptable salts thereof.
with the proviso that R1 and R2 are not both hydrogen at the same time;
and further provided that:
when R2 is hydrogen and R1 and R3 are chloro, then
R4 can not be substituted or unsubstituted aryl or heteroaryl or heterocyclyl; R4 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; R4 can not be n-alkyl; R4 can not be -(CH2)3-OAr; R4 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; and further provided that: when R2 is hydrogen and R1 and R3 are trifluoromethyl, then R4 can not be methyl, pyridyl, ethyl, n-propyl or 2-propylbutyl; and further provided that:
when R1 is hydrogen and R2 and R3 are chloro, then R4 can not be substituted or unsubstituted aryl or heteroaryl or heterocyclyl; R4 can not be methyl, unsubstituted or monosubstituted with aryl, aryloxy, alkylamino, arylamino, halogen, heterocyclyl, acyl, 1-iminoaikyl, 1-iminoaryl, aminocarbonyl, 1- hydrazinoalkyi, 1-hydrazinoaryl, alkylthio, arylthio, heterocyclylthio, ammonium or aminoalkyi; R4 can not be n-alkyl, cyclopropyl or 2-propylbutyl; R4 can not be -(CH2)3-OAr or -CH(OH)CH3;
R4 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; and further provided that:
when X is oxygen, R1 is hydrogen and R2 and R3 are trifluoromethyl, then R4 can not be heterocyclyl; R4 can not be methyl, unsubstituted or monosubstituted with heteroaryloxy, ammonium, acyl, 1-oximoalkyl, heterocyclyl or 1-iminoalkyl; R4 can not be 2-propylbutyl or cyclopropyl;
R4 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; and further provided that:
when X is sulfur, R1 is hydrogen and R2 and R3 are trifluoromethyl, then R4 can not be benzylamino, 3,4-dimethylbenzylamino, 4-nnethoxybenzylamino, 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; and further provided that:
when R1 is chloro, R2 is hydrogen and R3 is trifluoromethyl, then
R4 can not be substituted or unsubstituted aryl or heteroaryl or heterocyclyl; R4 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, aminoalkyi; R4 can not be unsubstituted n-alkyl, cyclopropyl, isopropyl, isobutyl, benzyl, 2-ethylpropyI, 2- propylbutyl; R4 can not be diisopropylamino, 2,6-dimethylpiperidin-1-yl, methylamino, dimethylamino, (1 ,1-dimethylpropargyl)amino, ethylamino, butylamino, (2-hydroxyprop-1-yl)amino or 1- adamantylamino.
4. A compound according to claiml , 2 or 3, wherein R1 is hydrogen and R2 and R3 are trifluoromethyl.
5. A compound according to claim 1 , 2 or 3, wherein R1 is hydrogen and R2 and R3 are chloro.
6. A compound according to claim 1 , 2 or 3, wherein R1 is hydrogen and R2 and R3 are fluoro.
7. A compound according to claim 1 , 2 or 3, wherein R2 is hydrogen and R1 and R3 are fluoro.
8. A compound according to claim 1 , 2 or 3, wherein R2 is hydrogen, R is chloro and R3 is trifluoromethyl.
9. A compound according to any of the preceding claims, wherein X = O and R4 = -NH-R5, R5 being lower straight or branched alkyl, optionally substituted with C3.8-cycloaikyl, halogen, hydroxy, heterocyclyl, aryloxy, and aryl optionally substituted with halogen or trifluoromethyl.
10. A compound according to any of the preceding claims, wherein X = S and R4 = -NH-R5, R5 being lower straight or branched alkyl, optionally substituted with C3.8-cycloalkyl, halogen, hydroxy, heterocyclyl, aryloxy, and aryl optionally substituted with halogen or trifluoromethyl.
11. A compound according to any of the preceding claims, wherein X = O and R4 is lower straight or branched alkyl, optionally substituted with C3.8-cycloalkyl, halogen, hydroxy, heterocyclyl, aryloxy, and aryl optionally substituted with halogen or trifluoromethyl.
12. A compound according to claim wherein X is S and R4 is N-R5 wherein R5 is alkyl substituted with cyclohexyl.
13. A compound according to claim 4 wherein X is O and R4 is alkyl, phenyl substituted with chloro or O-R5, wherein R5 is phenyl.
14. A compound selected from the group consisting of
1-[3,5-Bis-(trifluoromethyl)phenyl]-3-(2,4-dichlorobenzyl)urea
1-Cyclohexylmethyl-3-(3,5-dichlorophenyl)thiourea
1-Cyclohexylmethyl-3-(3,5-difluorophenyl)thiourea
1-Cyclohexylmethyl-3-(2,5-difluorophenyl)thiourea (R)-1 -(1 -Cyclohexylethyl)-3-(3,5-difluorophenyl)thiourea
Heptanoic acid (3,5-bis(trifluoromethyl)phenyl)amide
N-(3,5-Bis(thfluoromethyl)phenyl)-2-phenoxypropionamide
1-(3,5-Bis(trifluoromethyl)phenyl)-3-(4-chlorophenyl)urea
N-(3,5-Bis(trifluoromethyl)phenyl)-3-phenylacrylamide or 2-Phenylcyclopropanecarboxylic acid (3,5-bis(trifluoromethyl)phenyl)-amide.
15. A compound of formula I selected from the group consisting of:
Figure imgf000034_0001
R1 R2 R3 R4 X
H -CF3 -CF3 -NH-(CH2)2CH3 o
H -CF3 -CF3 -NH-(cyclohexyl) o
H -CF3 -CF3 -NH-C(CH3)3 o
H -CF3 -CF3 -NH-(4-C6H4CI) o
H -CF3 -CF3 -NH-CH(CH3)2 o
H -CF3 -CF3 -(3-C6H4CN) o
H -CF3 -CF3 -CH(0-Ph)CH3 o
H -CF3 -CF3 -(CH2)2CH3 o
H -CF3 -CF3 -(CH2)5CH3 o
H -CF3 -CF3 -C(CH3)3 o
H -CF3 -CF3 cyclopropyl o
H -CF3 -CF3 -CH(CH3)2 o
H -CF3 -CF3 -CH(Et)(n-butyl) o
H -CF3 -CF3 -(CH2)2-(cyclopentyl) o
H -CF3 -CF3 -(CH2)2-Ph o
H -CF3 -CF3 -NH-(CH2)2-CH(CH3)2 s
H -CF3 -CF3 -NH-CH(CH3)2 s
H -CF3 -CF3 -NH-CH2-CH(CH3)2 s
H -CF3 -CF3 -NH-CH2-C(CH3)3 s
H -CF3 -CF3 -NH-CH2-CF3 s
H -CF3 -CF3 -NH-CH2-CCH s
H -CF3 -CF3 -N[(CH2)2CH3]2 s
H -CF3 -CF3 -NH-(CH2)2-(4-C6H4CI) s
H -CF3 -CF3 (4-methyl)piperidin-1 -yl s
H -CF3 -CF3 -N[CH2-CH(CH3)2]2 s
H -CF3 -CF3 pyrrolidin-1-yl s
H -CF3 -CF3 -NH-(CH2)3-(imidazol-1-yl) s
H -CF3 -CF3 1 ,2,3,4-tetrahydroisoquinolin-2-yl s
H -CF3 -CF3 (2,6-dimethyl)morpholin-4-yl s
H -CF3 -CF3 4-[(3-trifluoromethyl)phenyl]piperazin-1-yl s
H -CF3 -CF3 azepin-1-yl s
H -CF3 -CF3 (4-benzoyl)piperidin-1-yl s
H -CF3 -CF3 -NH-(CH2)3-Ph s H -CF3 -CF3 -NH-(4-hydroxycyclohexyl) S
H -CF3 -CF3 -NH-(3-hydroxycyclohexyl) s
H -CF3 -CF3 4-hydroxypiperidin-1-yl s
H -CF3 -CF3 3-hydroxypiperidin-1 -yl s
H -CF3 -CF3 3-hydroxypyrrolidin-1 -yl s
H -CF3 -CF3 -NH-(CH2)2-OH s
H -CF3 -CF3 -NH-(CH2)3-OH s
H -CF3 -CF3 -NH-(CH2)4-OH s
H -CF3 -CF3 -NH-(CH2)6-OH s
H -CF3 -CF3 -NH-(CH2)2-(morpholin-4-yl) s
H -CF3 -CF3 -NH-CH2-(1 ,3,3-trimethyl-5-hydroxy-1 -cyclohexyl s
H -CF3 -CF3 (4-acetyl)piperazin-1 -yl s
H -CF3 -CF3 -NH-CH2-(2-C6H4CI) s
H -CF3 -CF3 -N(Et)-(CH2)2-OH s
H -CF3 -CF3 -NH-(CH2)3-CH3 s
H -CF3 -CF3 -NH-C(CH3)2-CH2-OH s
H -CF3 -CF3 -NH-CH2-(cyclohexyl) s
H -CF3 -CF3 -NH-(CH2)2-(4-pyridyl) s
H -CF3 -CF3 -N(Et)-CH2-(4-pyridyl) s
H -CF3 -CF3 -NH-(CH2)3-NH-(2-pyridyl) s
H -CF3 -CF3 -NH-(CH2)2-(2-pyridyl) s
H -CF3 -CF3 [4-(piperidin-1-yl)-4-aminoca╬╣ Γûábonyl]piperidin-1-yl s
H -CF3 -CF3 4-(pyrrolidin-1 -ylcarbonylmethyl)piperazin-1 -yl s
H -CF3 -CF3 4-(2-furoyl)piperazin-1 -yl s
H -CF3 -CF3 -NH-CH(cyclopropyl)(4-C6H4- ΓûáOCH3) s
H -CF3 -CF3 -N(CH3)-CH2-CH(OH)-(4-C6l- 14-OH) s
H -CF3 -CF3 -NH-CH(CH2-OH)-Ph s
H -CF3 -CF3 -NH-CH(CH3)-CH(OH)-Ph s
H -CF3 -CF3 -NH-(1 -benzylpiperidin-4-yl) s
H -CF3 -CF3 1 -(3,4-dimethoxybenzyl)-6,7- ΓÇódimethoxy-1 , 2,3,4- s tetrahydroisoquinolin-2-yl
H -CF3 -CF3 -N(CH3)-(CH2)3-(10,11-dihyd╬╣ ro-5H-dibenzo[b,f]azepin-5-yl) s
H -CF3 -CF3 -NH-CH2-(3-pyridyl) s
H -Cl -Cl -NH-(CH2)2-CH(CH3)2 s
H -Cl -Cl -NH-CH(CH3)2 s
H -Cl -Cl -NH-CH2-CH(CH3)2 s
H -Cl -Cl -NH-CH2-C(CH3)3 s H -Cl -Cl -NH-CH2-CF3 S
H -Cl -Cl -NH-CH2-CCH S
H -Cl -Cl -N[(CH2)2CH3]2 S
H -Cl -Cl -NH-(CH2)2-(4-C6H4CI) S
H -Cl -Cl (4-methyl)piperidin-1 -yl S
H -Cl -Cl -N[CH2-CH(CH3)2]2 S
H -Cl -Cl pyrrolidin-1-yl S
H -Cl -Cl -NH-(CH2)3-(imidazol-1-yl) S
H -Cl -Cl 1 ,2,3,4-tetrahydroisoquinolin- -2-yl S
H -Cl -Cl (2,6-dimethyl)morpholin-4-yl S
H -Cl -Cl 4-[(3-trifluoromethyl)phenyl]piperazin- 1-yl S
H -Cl -Cl azepin-1-yl S
H -Cl -Cl (4-benzoyl)piperidin-1 -yl S
H -Cl -Cl -NH-(CH2)3-Ph S
H -Cl -Cl -N H-(4-hydroxycyclohexyl ) S
H -Cl -Cl -NH-(3-hydroxycyclohexyl) S
H -Cl -Cl 4-hydroxypiperidin-1 -yl s
H -Cl -Cl 3-hydroxypiperidin-1 -yl s
H -Cl -Cl 3-hydroxypyrrolidin-1 -yl s
H -Cl -Cl -NH-(CH2)2-OH s
H -Cl -Cl -NH-(CH2)3-OH s
H -Cl -Cl -NH-(CH2)4-OH s
H -Cl -Cl -NH-(CH2)6-OH s
H -Cl -Cl -N H-(CH2)2-(morpholin-4-yl) s
H -Cl -Cl -NH-CH2-(1 ,3,3-trimethyl-5-hydroxy-1 -cyclohexyl s
H -Cl -Cl (4-acetyl)piperazin-1 -yl s
H -Cl -Cl -NH-CH2-(2-C6H4CI) s
H -Cl -Cl -N(Et)-(CH2)2-OH s
H -Cl -Cl -NH-(CH2)3-CH3 s
H -Cl -Cl -NH-C(CH3)2-CH2-OH s
H -Cl -Cl -NH-CH2-(cyclohexyl) s
H -Cl -Cl -NH-(CH2)2-(4-pyridyl) s
H -Cl -Cl -N(Et)-CH2-(4-pyridyl) s
H -Cl -Cl -NH-(CH2)3-NH-(2-pyridyl) s
H -Cl -Cl -NH-(CH2)2-(2-pyridyl) s
H -Cl -Cl [4-(piperidin-1 -yl)-4-aminocarbonyl]piperidin-1 -yl s
H -Cl -Cl 4-(pyrrolidin-1 -ylcarbonylmethyl)piperazin-1 -yl s 4-. -n- 41. CO CO CO CO CO eo CO eo CO eo to ro ro ro ro I M ro ro ro o ro _┬╗. O CD CO -vl Oi cn 4^ CO ro ΓÇö o CD 00 OJ cn 41. eo ro ΓÇö^ o o o CD 00 cn cn co ro ->Γûá CD oo
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X
Figure imgf000038_0001
o -π oτι o-π -oπ τoι -oπ -oπ o-π -oπ τoι τoι τoι τoι oτι oτι τoι τoι oτι oτι τoι o-π τoι τoι τoι -oπ oτι oτι o — —o o o o o o o o
o o O O O O O O O O O O O O O O O O O O O O O O O O O O O O
Tl Tl o Tl o Tl o Tl o TI o O Tl τι τι τι τι τι -π τι τι τι τι τι τι τι τι τ| -π τι τι τι τι —
Figure imgf000038_0002
o o o o o o o o o o o o o o o o o o o o o o o o o o o ω Λ ω co ω to ω ω ω
143 H -CF3 -CF3 -NH-(CH2)2-(morpholin-4-yl) O
144 H -CF3 -CF3 -NH-CH2-(1 ,3,3-trimethyl-5-hydroxy-1 -cyclohexyl O
145 H -CF3 -CF3 (4-acetyl)piperazin-1-yl O
146 H -CF3 -CF3 -NH-CH2-(2-C6H4CI) O
147 H -CF3 -CF3 -N(Et)-(CH2)2-OH O
148 H -CF3 -CF3 -NH-(CH2)3-CH3 O
149 H -CF3 -CF3 -NH-C(CH3)2-CH2-OH O
150 H -CF3 -CF3 -NH-CH2-(cyclohexyl) O
151 H -CF3 -CF3 -NH-(CH2)2-(4-pyridyl) O
152 H -CF3 -CF3 -N(Et)-CH2-(4-pyridyl) O
153 H -CF3 -CF3 -NH-(CH2)3-NH-(2-pyridyl) O
154 H -CF3 -CF3 -NH-(CH2)2-(2-pyridyl) O
155 H -CF3 -CF3 [4-(piperidin-1 -yl)-4-aminocarbonyl]piperidin-1 -yl O
156 H -CF3 -CF3 4-(pyrrolidin-1 -ylcarbonylmethyl)piperazin-1 -yl O
157 H -CF3 -CF3 4-(2-furoyl)piperazin-1-yl O
158 H -CF3 -CF3 -NH-CH(cyclopropyl)(4-C6H4-OCH3) O
159 H -CF3 -CF3 -N(CH3)-CH2-CH(OH)-(4-C6H4-OH) O
160 H -CF3 -CF3 -NH-CH(CH2-OH)-Ph O
161 H -CF3 -CF3 -NH-CH(CH3)-CH(OH)-Ph O
162 H -CF3 -CF3 -NH-(1-benzylpiperidin-4-yl) O
163 H -CF3 -CF3 1 -(3,4-dimethoxybenzyl)-6J-dimethoxy-1 ,2,3,4- O tetrahydroisoquinolin-2-yl
164 H -CF3 -CF3 -N(CH3)-(CH2)3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl) O
165 H -CF3 -CF3 -NH-CH2-(3-pyridyl) O
166 -Cl H -CF3 -NH-(CH2)2-CH(CH3)2 S
167 -Cl H -CF3 -NH-CH(CH3)2 S
168 -Cl H -CF3 -NH-CH2-CH(CH3)2 S
169 -Cl H -CF3 -NH-CH2-C(CH3)3 S
170 -Cl H -CF3 -NH-CH2-CF3 S
171 -Cl H -CF3 -NH-CH2-CCH S
172 -Cl H -CF3 -N[(CH2)2CH3]2 S
173 -Cl H -CF3 -NH-(CH2)2-(4-C6H4CI) S
174 -Cl H -CF3 (4-methyl)piperidin-1-yl S
175 -Cl H -CF3 -N[CH2-CH(CH3)2]2 S
176 -Cl H -CF3 pyrrolidin-1-yl S
177 -Cl H -CF3 -NH-(CH2)3-(imidazol-1-yl) S
178 -Cl H -CF3 1 ,2,3,4-tetrahydroisoquinolin-2-yl S 179 -Cl H -CF3 (2,6-dimethyl)morpholin-4-yl S
180 -Cl H -CF3 4-[(3-trifluoromethyl)phenyl]piperazin-1-yl S
181 -Cl H -CF3 azepin-1-yl S
182 -Cl H -CF3 (4-benzoyl)piperidin-1 -yl S
183 -Cl H -CF3 -NH-(CH2)3-Ph S
184 -Cl H -CF3 -NH-(4-hydroxycyclohexyl) S
185 -Cl H -CF3 -NH-(3-hydroxycyclohexyl) S
186 -Cl H -CF3 4-hydroxypiperidin-1 -yl S
187 -Cl H -CF3 3-hydroxypiperidin-1 -yl S
188 -Cl H -CF3 3-hydroxypyrrolidin-1 -yl S
189 -Cl H -CF3 -NH-(CH2)2-OH S
190 -Cl H -CF3 -NH-(CH2)3-OH S
191 -Cl H -CF3 -NH-(CH2)4-OH S
192 -Cl H -CF3 -NH-(CH2)6-OH S
193 -Cl H -CF3 -NH-(CH2)2-(morpholin-4-yl) S
194 -Cl H -CF3 -NH-CH2-(1 ,3,3-trimethyl-5-hydroxy-1 -cyclohexyl S
195 -Cl H -CF3 (4-acetyl)piperazin-1 -yl S
196 -Cl H -CF3 -NH-CH2-(2-C6H4CI) S
197 -Cl H -CF3 -N(Et)-(CH2)2-OH S
198 -Cl H -CF3 -NH-(CH2)3-CH3 S
199 -Cl H -CF3 -NH-C(CH3)2-CH2-OH s
200 -Cl H -CF3 -NH-CH2-(cyclohexyl) s
201 -Cl H -CF3 -NH-(CH2)2-(4-pyridyl) s
202 -Cl H -CF3 -N(Et)-CH2-(4-pyridyl) s
203 -Cl H -CF3 -NH-(CH2)3-NH-(2-pyridyl) s
204 -Cl H -CF3 -NH-(CH2)2-(2-pyridyl) s
205 -Cl H -CF3 [4-(piperidin-1 -yl)-4-aminocarbonyl]piperidin-1 -yl s
206 -Cl H -CF3 4-(pyrrolidin-1 -ylcarbonylmethyl)piperazin-1 -yl s
207 -Cl H -CF3 4-(2-furoyl)piperazin-1 -yl s
208 -Cl H -CF3 -NH-CH(cyclopropyl)(4-C6H4-OCH3) s
209 -Cl H -CF3 -N(CH3)-CH2-CH(OH)-(4-C6H4-OH) s
210 -Cl H -CF3 -NH-CH(CH2-OH)-Ph s
211 -Cl H -CF3 -NH-CH(CH3)-CH(OH)-Ph s
212 -Cl H -CF3 -NH-(1-benzylpiperidin-4-yl) s
213 -Cl H -CF3 1 -(3,4-dimethoxybenzyl)-6,7-dimethoxy-1 ,2,3,4- s tetrahydroisoquinolin-2-yl
214 -Cl H -CF3 -N(CH3)-(CH2)3-(10,11-dihydro-5H-dibenzo[b,f]azep in-5-yl) S 215 -Cl H -CF3 -NH-CH2-(3-pyridyl) S
216 H -CF3 -CF3 -NH-CH2-(2,4-CeH3Cl2) O
and pharmaceutically acceptable salts thereof.
16. Compounds according to any one of the preceding claims which are active as potassium channel openers.
17. A pharmaceutical composition comprising a compound according to claim 1 or 2 or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
18. A pharmaceutical composition for use in the treatment of diseases of the endocrinological system such as diabetes comprising a compound according to claim 1 or 2 or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
19. A pharmaceutical composition for use in the treatment of diseases of the endocrinological system such as diabetes comprising a compound according to any of the claims 1 - 15 or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
20. The pharmaceutical composition according to claim 17 to 19 in the form of an oral dosage unit or parenteral dosage unit.
21. A pharmaceutical composition according to claim 17 to 19 wherein said compound is administered as a dose in a range from about 0.05 mg to 1000 mg, preferably from about 0.1 mg to 500 mg and especially in the range from 50 mg to 200 mg per day.
22. A compound according to any one of the claims 1 - 15 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use.
23. A compound according to any one of the claims 1 - 15 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use in the treatment or prevention of diseases of the endocrinological system, such as diabetes.
24. The use of a compound according to any one of the claims 1 - 15 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form as a medicament.
25. The use of a compound according to any of the claims 1 - 15 for preparing a medicament.
26. The use of a compound according to any one of the claims 1 - 15 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system, such as diabetes.
27. A method of treating or preventing diseases of the endocrinological system, such as diabetes in a subject in need thereof comprising administering an effective amount of a compound according to any of the claims 1 - 15 to said subject.
28. A process for the manufacture of a medicament to be used in the treatment or prevention of diseases of the endocrinological system, such as diabetes which process comprising bringing a compound of formula I according to any of the claims 1 - 15 or a pharmaceutically acceptable salt thereof into a galenic dosage form.
29. Any novel feature or combination of features as described herein.
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US6960666B2 (en) 1999-10-15 2005-11-01 Bristol-Myers Squibb Pharma Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
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