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US20020042400A1 - Novel alicyclic imidazoles as H3 agents - Google Patents

Novel alicyclic imidazoles as H3 agents Download PDF

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US20020042400A1
US20020042400A1 US09/930,644 US93064401A US2002042400A1 US 20020042400 A1 US20020042400 A1 US 20020042400A1 US 93064401 A US93064401 A US 93064401A US 2002042400 A1 US2002042400 A1 US 2002042400A1
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alkyl
hydrogen
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aryl
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Yajing Rong
Jack Jiang
Ali Syed
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Gliatech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • 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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the present invention is directed to alicyclic imidazoles which interact with the histamine H 3 receptor as agonists, antagonists or inverse agonists; pharmaceutically active compositions containing such compounds; and the use of such compounds in formulations for the control or prevention of disease states in which histamine H 3 receptors are involved, such as allergy, inflammation, hypotension, glaucoma, sleeping disorders, states of hyper- and hypo-motility of the gastro-intestinal tract, cardiovascular disease, hypo- and hyper-activity of the central nervous system, Alzheimer's, schizophrenia, obesity and migraines.
  • diseases states in which histamine H 3 receptors are involved such as allergy, inflammation, hypotension, glaucoma, sleeping disorders, states of hyper- and hypo-motility of the gastro-intestinal tract, cardiovascular disease, hypo- and hyper-activity of the central nervous system, Alzheimer's, schizophrenia, obesity and migraines.
  • Histamine plays a role in regulating attentiveness and cognition in the central nervous system (CNS), and histamine levels in the brain are controlled by the histamine H 3 receptor. Moreover, serotonin, norepinephrine, dopamine and acetylcholine all have been demonstrated to be regulated by the histamine H 3 receptor. These neurotransmitters are known to play a role in many CNS psychiatric disorders involving higher cognitive function and/or emotion. Consequently, compounds affecting H 3 receptor function (as agonists, antagonists or inverse agonists) could have utility in the treatment of a variety of CNS maladies, including but not limited to dementias, attention deficit hyperactivity disorder, depression, anxiety and schizophrenia.
  • CNS maladies including but not limited to dementias, attention deficit hyperactivity disorder, depression, anxiety and schizophrenia.
  • Histamine is also involved in the control of sleep/wake states and appetite. Accordingly, histamine H 3 receptor ligands might be expected to be useful in treating insomnia, narcolepsy, age-related sleep disorders, obesity and anorexia. Although they exist in low density outside of the brain, histamine H 3 receptors are found on the sympathetic and parasympathetic nerve terminals in the periphery, including the vasculature and heart. Thus, compounds that alter histamine H 3 receptor activity might also have clinical utility in treating conditions such as migraine and cardiac dysfunction.
  • the present invention is directed to alicyclic imidazoles which interact with the histamine H 3 receptor as agonists, antagonists or inverse agonists; pharmaceutically active compositions containing such compounds; and the use of such compounds in formulations for the control or prevention of disease states in which histamine H 3 receptors are involved, such as allergy, inflammation, hypotension, glaucoma, sleeping disorders, states of hyper- and hypo-motility of the gastro-intestinal tract, cardiovascular disease, hypo- and hyper-activity of the central nervous system, Alzheimer's, schizophrenia, obesity and migraines.
  • diseases states in which histamine H 3 receptors are involved such as allergy, inflammation, hypotension, glaucoma, sleeping disorders, states of hyper- and hypo-motility of the gastro-intestinal tract, cardiovascular disease, hypo- and hyper-activity of the central nervous system, Alzheimer's, schizophrenia, obesity and migraines.
  • n is an integer of zero to six
  • p is an integer of zero to two
  • q is an integer of zero to four;
  • T is selected from the group consisting of —NR 6 R 7 , —N(R 8 )C(NR 9 )R 10 , —CN, —OH, —H, —OR 11 , —OC(O)R 12 , —C(O)R 13 , —C(O)NH 2 , —C(N—OH)H, —SC(S)R 14 , —NR 15 C(S)R 16 , —NR 17 C(O)R 18 , —SC(NR 19 )R 20 , —OC(NR 21 )R 22 , R 23 , —N(R 24 )C(O)N(R 25 ), —N(R 26 )C(O), and —O(O)NR 27 R 28 ;
  • R 1 is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, —CF 3 , —N(C 1 -C 3 alkyl)—C(O)(C 1 -C 3 alkyl), —NHC(O)NH(C 1 -C 3 alkyl), —NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), —C 1 -C 3 alkylamino, alkenylamino, alkynylamino, di(C 1 -C 3 alkyl)amino, —C(O)O—(C 1 -C 3 alkyl), —C(O)NH—(C 1 -C 3 alkyl), —CH ⁇ NOH, —PO 3 H 2
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, —CF 3 , —NO 2 , amino, —CN, carboxy, —N(C 1 -C 3 alkyl)—C(O)(C 1 -C 3 alkyl), —NHC(O)NH(C 1 -C 3 alkyl), —NHC(O)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; and pharmaceutically acceptable salts thereof;
  • n may be an integer of zero to three;
  • R 1 may be hydrogen,
  • R 2 , R 3 , R 4 and R 5 may each independently be hydrogen, halogen, hydroxyl, lower alkyl, alkenyl, alkynyl or aryl;
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 R 19 , R 20 , R 21 , R 22 and R 23 may each be hydrogen, lower alkyl, alkenyl, alkynyl, aryl and heterocyclyl.
  • Presently preferred compounds of Formula I have T as —N(R 8 )C(NR 9 )R 10 , —OC(O)R 12 , —C(O)R 13 , —C(O)NH 2 , —C(N—OH)H, —SC(S)R 14 , —NR 15 C(S)R 16 , —NR 17 C(O)R 18 , —SC(NR 19 )R 20 or —OC(NR 21 )R 22 when n is zero or T as —NR 6 R 7 , —CN, —OH, —H, —OR 11 or R 23 when n is one.
  • n is an integer of zero to three
  • T is selected from the group consisting of —NR 6 R 7 , —N(R 8 )C(NR 9 )R 10 , —CN, —OH, —H, —OR 11 , —OC(O)R 12 , —C(O)R 13 , —C(O)NH 2 , —C(N—OH)H, —SC(S)R 14 , —NR 15 C(S)R 16 , —NR 17 C(O)R 18 , —SC(NR 19 )R 20 , —OC(NR 21 )R 22 and R 23 ;
  • R 1 is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, —CF 3 , —N(C 1 -C 3 alkyl)—C(O)(C 1 -C 3 alkyl), —NHC(O)NH(C 1 -C 3 alkyl), —NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -C 1 -C 3 alkylamino, alkenylamino, alkynylamino, di(C 1 -C 3 alkyl)amino, —C(O)O—(C 1 -C 3 alkyl), —C(O)NH—(C 1 -C 3 alkyl), —CH ⁇ NOH, —PO 3 H 2
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, —CF 3 , —NO 2 , amino, —CN, carboxy, —N(C 1 -C 3 alkyl)—C(O)(C 1 -C 3 alkyl), —NHC(O)NH(C 1 -C 3 alkyl), —NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
  • R 1 may be hydrogen;
  • R 3 may be hydrogen or lower alkyl;
  • R 4 and R 5 may each be hydrogen, halogen, hydroxyl, lower alkyl, alkenyl, alkynyl or aryl; and
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 may each be hydrogen, lower alkyl, alkenyl, alkynyl, aryl or heterocyclyl.
  • Presently preferred compounds of Formula II have T as —N(R 8 )C(NR 9 )R 10 , —OC(O)R 12 , —C(O)R 13 , —C(O)NH 2 , —C(N—OH)H, —SC(S)R 14 , —NR 15 C(S)R 16 , —NR 17 C(O)R 18 , —SC(NR 19 )R 20 or —OC(NR 21 )R 22 when n is zero or T as —NR 6 R 7 , —CN, —OH, —H, —OR 11 or R 23 when n is one.
  • T is selected from the group consisting of —N(R 8 )C(NR 9 )R 10 , —OC(O)R 12 , —C(O)R 13 , —C(O)NH 2 , —C(N—OH)H, —SC(S)R 14 , —NR 15 C(S)R 16 , —NR 17 C(O)R 18 , —SC(NR 19 )R 20 and —OC(NR 21 )R 22 ;
  • R 3 is selected from the group consisting of hydrogen and lower alkyl
  • R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, aryl and heterocyclyl;
  • R 3 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
  • T is selected from the group consisting of —NR 6 R 7 , —CN, —OH, —H, —OR 11 and R 23 ;
  • R 3 is selected from the group consisting of hydrogen and methyl
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, alkenyl, alkynyl and aryl; and,
  • R 6 , R 7 , R 11 and R 23 are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, aryl and heterocyclyl;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 11 and R 23 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
  • Formulae I-IV also encompass esters, carbamates, aminals, amides, optical isomers or pro-drugs thereof.
  • Presently preferred compounds include 4-(trans-2-cyano-cyclopropyl) imidazole, 4-(trans-2-aminocarbonyl-cyclopropyl) imidazole, 4-(trans-2-amidino-cyclopropyl) imidazole, 4-(trans-2-aminomethyl-cyclopropyl) imidazole, 4-(trans-2-N-hydroxyimino-cyclopropyl) imidazole, 4-(trans-2-hydroxymethyl-cyclopropyl) imidazole, 4-(trans-2-N-methylamidino-cyclopropyl) imidazole, 4-(trans-2-aminomethyl-2-methyl-cyclopropyl) imidazole, 4-(trans-2-amidino-2-methyl-cyclopropyl) imidazole and pharmaceutically acceptable salts thereof.
  • the present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention; and a method for regulation of histamine H 3 receptors in a mammal by agonism, antagonism, or inverse agonism of said receptors, comprising administering to a mammal in need of such regulation a therapeutic amount of a compound of the present invention.
  • alkyl refers to C 1 -C 12 straight or branched, substituted or unsubstituted saturated chain radicals derived from saturated hydrocarbons by the removal of one hydrogen atom, unless the term alkyl is preceded by a C x -C y designation.
  • Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl among others.
  • alkenyl refers to a substituted or unsubstituted straight-chain or substituted or unsubstituted branched-chain alkenyl radical containing from 2 to 10 carbon atoms.
  • alkenyl radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl and the like.
  • alkynyl refers to a substituted or unsubstituted straight or substituted or unsubstituted branched chain alkynyl radical containing from 2 to 10 carbon atoms.
  • examples of such radicals include, but are not limited to ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
  • lower modifying “alkyl”, “alkenyl”, “alkynyl” or “alkoxy” refers to a C 1 -C 6 unit for a particular functionality.
  • lower alkyl means C 1 -C 6 alkyl.
  • aliphatic acyl refers to radicals of formula alkyl-C(O)—, alkenyl-C(O)— and alkynyl-C(O)— derived from an alkane-, alkene- or alkyncarboxylic acid, wherein the terms “alkyl”, “alkenyl” and “alkynyl” are as defined above.
  • alkyl alkenyl
  • alkynyl alkynyl radicals
  • examples of such aliphatic acyl radicals include, but are not limited to, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propiolyl and methylpropiolyl, among others.
  • cycloalkyl refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including, but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl among others. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. “Cycloalkyl” includes cis or trans forms. Furthermore, the substituents may either be in endo or exo positions in the bridged bicyclic systems.
  • cycloalkenyl as used herein alone or in combination refers to a cyclic carbocycle containing from 4 to 8 carbon atoms and one or more double bonds.
  • examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl and the like.
  • cycloalkylalkyl as used herein refers to a cycloalkyl group appended to a lower alkyl radical, including, but not limited to cyclohexylmethyl.
  • halo or halogen as used herein refers to I, Br, Cl or F.
  • haloalkyl refers to a lower alkyl radical, to which is appended at least one halogen substituent, for example chloromethyl, fluoroethyl, trifluoromethyl and pentafluoroethyl among others.
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is as defined above.
  • suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • alkenoxy refers to a radical of formula alkenyl-O—, provided that the radical is not an enol ether, wherein the term “alkenyl” is as defined above.
  • suitable alkenoxy radicals include, but are not limited to, allyloxy, E- and Z-3-methyl-2-propenoxy and the like.
  • alkynoxy refers to a radical of formula alkynyl-O—, provided that the radical is not -ynol ether.
  • suitable alkynoxy radicals include, but are not limited to, propargyloxy, 2-butynyloxy and the like.
  • carboxyl refers to a carboxylic acid radical, —C(O)OH.
  • thioalkoxy refers to a thioether radical of formula alkyl-S—, wherein “alkyl” is as defined above.
  • carboxydehyde refers to —C(O)R wherein R is hydrogen.
  • alkoxyalkoxy refers to R c O—R d O— wherein R c is lower alkyl as defined above and R d is alkylene wherein alkylene is —(CH 2 ) n′ — wherein n′ is an integer from 1 to 6.
  • alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy among others.
  • alkylamino refers to R e NH— wherein R e is a lower alkyl group, for example, ethylamino, butylamino, among others.
  • alkenylamino refers to a radical of formula alkenyl-NH—or (alkenyl) 2 N—, wherein the term “alkenyl” is as defined above, provided that the radical is not an enamine.
  • alkenylamino radical is the allylamino radical.
  • alkynylamino refers to a radical of formula alkynyl-NH— or (alkynyl) 2 N— wherein the term “alkynyl” is as defined above, provided that the radical is not an amine.
  • alkynylamino radicals is the propargyl amino radical.
  • dialkylamino refers to R f R g N— wherein R f and R g are independently selected from lower alkyl, for example diethylamino, and methyl propylamino, among others.
  • amino refers to H 2 N—.
  • alkoxycarbonyl refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group.
  • alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl among others.
  • aryl or “aromatic” as used herein alone or in combination refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group which is an aromatic ring containing at least one endocyclic N, O or S atom such as furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyra
  • aralkyl refers to an aryl substituted alkyl radical, wherein the terms “alkyl” and “aryl” are as defined above.
  • suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, triphenylmethyl, pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl, indolylmethyl, thienylpropyl and the like.
  • alkenyl refers to an aryl substituted alkenyl radical, wherein the terms “aryl” and “alkenyl” are as defined above.
  • arylamino refers to a radical of formula aryl-NH—, wherein “aryl” is as defined above.
  • arylamino radicals include, but are not limited to, phenylamino(anilido), naphthlamino, 2-, 3-, and 4-pyridylamino and the like.
  • biasing refers to a radical of formula aryl-aryl, wherein the term “aryl” is as defined above.
  • thioaryl refers to a radical of formula aryl-S—, wherein the term “aryl” is as defined above.
  • aryl is as defined above.
  • An example of a thioaryl radical is the thiophenyl radical.
  • aroyl refers to a radical of formula aryl-CO—, wherein the term “aryl” is as defined above.
  • suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl, pyridylcarbonyl and the like.
  • heterocyclyl refers to a non-aromatic 3- to 10-membered ring containing at least one endocyclic N, O, or S atom.
  • the heterocycle may be optionally aryl-fused.
  • the heterocycle may also optionally be substituted with at least one substituent which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl among others.
  • substituent is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl among others.
  • alkylheterocyclyl refers to an alkyl group as previously defined appended to the parent molecular moiety through a heterocyclyl group.
  • heterocyclylalkyl refers to a heterocyclyl group as previously defined appended to the parent molecular moiety through an alkyl group.
  • the term “aminal” as used herein refers to a hemi-acetal of the structure R h C(NR i R j )(NR k R l )— wherein R h , R i , R j , R k and R l are each independently hydrogen, alkyl or any other suitable substituent.
  • esters refers to —C(O)R m , wherein R m is hydrogen, alkyl or any other suitable substituent.
  • carbamate refers to compounds based on carbamic acid, NH 2 C(O)OH.
  • substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraph
  • the linkers are typically short chains of 1-3 atoms containing any combination of —C—, —C(O)—, —NH—, —S—, —S(O)—, —O—, —C(O)O— or —S(O)O—. Rings may be substituted multiple times.
  • Electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, and aryl lower alkanoyl among others.
  • Electron donating groups include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide among others.
  • substituents may have electron donating or electron withdrawing properties under different chemical conditions.
  • present invention contemplates any combination of substituents selected from the above-identified groups.
  • the most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio and alkyldithio.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.
  • Chiral moieties refers to substituents having a chiral center.
  • “Sulfonamido” as used herein refers to —SO 2 NH 2 .
  • LAH lithium aluminum hydride
  • TFA trifluoroacetic acid
  • EDTA ethylene diamine tetraacetic acid
  • the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1 et seq.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecan
  • the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients.
  • therapeutically effective amount means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.0001 to about 1000 mg/kg/day.
  • more preferable doses can be in the range of from about 0.001 to about 5 mg/kg/day.
  • the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • the present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable diluent.
  • the present invention includes one or more compounds as described above formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, or the like.
  • compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed of a fine wire mesh), or via a biodegradable polymer.
  • intracoronary stent a tubular device composed of a fine wire mesh
  • biodegradable polymer a biodegradable polymer.
  • the compounds may also be complexed to ligands, such as antibodies, for targeted delivery.
  • compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.
  • compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like.
  • the preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
  • prodrugs of the compounds of the present invention represent those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • Prodrugs of the present invention may be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems , V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design , American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.
  • the present invention contemplates both synthetic compounds of Formulae I-IV of the present invention, as well as compounds formed by in vivo conversion to compounds of the present invention.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • the compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates.
  • solvated forms including hydrated forms, such as hemi-hydrates.
  • pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
  • the aldehyde 1 was prepared according to a procedure described in Phillips et al., U.S. Pat. No. 6,008,240. Using aldehyde 1 as the starting material, a number of compounds of Formula I may be prepared. For example, the oxime cyclopropyl imidazole 2 was synthesized from aldehyde 1 by removing the trityl protective group using HCl followed by treatment with hydroxyamine, and alcohol 3 was obtained by reducing aldehyde 1.
  • the reaction mixture was slowly poured into a slurry of 15 g of silica gel in chloroform (50 mL), stirred for 10 minutes, and filtered. The silica gel was further washed with methanol. The combined solvent was concentrated under vacuum to give a residue, which was purified on a silica gel column, using a mixed solvent consisting of methylene chloride/methanol/ammonium hydroxide 85/15/5 (v/v/v) as the eluent to give the N-methyl amidine product (89 mg, 45% yield).
  • Histamine H 3 receptor affinity was determined in rat cerebral cortical membranes with [ 3 H]NAMHA as previously described (Tedford et al., 1995). Animals were euthanized by rapid decapitation and cerebral cortical tissues were harvested and frozen on dry ice. Cerebral cortical membranes were prepared in 50 mM sodium-phosphate buffered saline (pH 7.5 at 4° C.) containing: EDTA (10 mM), phenylmethylsulfonyl fluoride (0.1 mM), chymostatin and leupeptin (each 0.2 mg/50 mL). The final membrane pellets were resuspended in water and stored frozen at ⁇ 80° C. prior to use. Protein concentrations were determined using the Coomassie Plus Protein Assay (Pierce, Rockford Ill.).
  • Competition binding was carried out in a total volume of 0.2 mL of 50 mM sodium-phosphate buffer (pH 7.4) using ⁇ 1 nM [ 3 H]NAMHA ([ 3 H]—N ⁇ -methylhistamine, available from NEN Research Products of Boston, Mass.) and 0.003 to 10,000 ⁇ M concentrations of the test compounds.
  • Non-specific binding was determined using 10 ⁇ M thioperamide. Samples were incubated for 40 minutes at 25° C. and subsequently filtered through Whatman GF/C glass fiber filters pre-soaked in binding buffer with 0.3% polyethyleneimine, using an Inotech cell harvester (Inotech Biosystems International, Lansing Mich.).
  • Example 1 4-(trans-2-cyano- ⁇ 8.81(s, 1H), 7.42(1, 1H), 2.75 (m, 20 cyclopropyl)imidazole 1H), 2.0 (m, 1H), 1.74 (m, 1H), 1.59 trifluoroacetic acid salt (m, 1H)
  • Example 2 4-(trans-2- ⁇ 8.80 (s, 1H), 7.25 (s, 1H), 2.55 (m, 127 aminocarbonyl- 1H), 2.0 (m, 1H), 1.55 (m, 1H), 1.35 cyclopropyl)imidazole (m, 1H) trifluoroacetic acid salt
  • Example 3 4-(trans-2-amidino- ⁇ 8.84 (s, 1H), 7.45 (m, 1H), 2.8 (m, 6.7 cyclopropyl)imidazo
  • Example 4 4-(trans-2- ⁇ 8.79 (s, 1H), 7.35 (s, 1H), 3.12 (m, 4.5 aminomethyl- 1H), 2.97 (m, 1H), 2.10 (m, 1H), 1.54 cyclopropyl)imidazole (m, 1H), 1.20 (m, 2H) di-hydrochioric acid salt
  • Example 6 4-(trans-2- ⁇ 8.50 (s, 1H), 7.15 (s, 1H), 3.65 (m, 263 hydroxymethyl- 1H), 3.55 (m, 1H), 1.90 (m, 1H), 1.51 cyclopropyl)imidazole (m, 1H), 1.10 (m, 2H). trifluoroacetic acid salt
  • Example 7 4-(trans-2-N- ⁇ 8.84 (s, 1H), 7.55 (m, 1H), 2.86 (s, 114 methylamidino- 3H), 2.75 (m, 1H), 2.33 (m, 1H), 1.87 cyclopropyl)imidazole (m, 1H), 1.75 (m, 1H). di-hydrochloric acid salt

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AU2001285442A1 (en) 2002-02-25
EP1313470A1 (fr) 2003-05-28
WO2002013821A1 (fr) 2002-02-21
JP2004506012A (ja) 2004-02-26
US6794405B2 (en) 2004-09-21
EP1313470A4 (fr) 2005-02-16
CA2419073A1 (fr) 2002-02-21

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