Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • 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
• • 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
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to novel imidazo heterocyclic compounds, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions.
• the present compounds show a high and selective binding affinity to the histamine H3 receptor indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor.
• histamine H3 receptor The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments (see eg Stark, H.; Schlicker, E.; Schunack, W., Drugs Fut 1996, 21, 507-520; Leurs, R.; Timmerman, H.; Vollinga, R. C, Progress in Drug Research 1995, 45, 107-165). Recently, the human histamine H3 receptor has been cloned, cf Lovenberg, T.W. et al, Molecular Pharmacology, June 1999, 55, 1101 -1107.
• the histamine H3 receptor is a presynaptic autoreceptor located both in the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor show intrinsic, constitutive activity, in vitro as well as in vivo (ie it is active in the absence of an agonist; see eg Morisset et al., Nature 2000, 408, 860-864). This activity can be inhibited by compounds acting as inverse agonists.
• the histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine.
• a histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain.
• a histamine H3 receptor agonist leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine.
• novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art.
• the present invention provides such a contribution to the art being based on the finding that a novel class of imidazo heterocyclic compounds has a high and specific affinity to the histamine H3 receptor.
• the present compounds are useful in the treatment and/or prevention of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial.
• the compounds may find use eg in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.
• Halogen designates an atom selected from the group consisting of F, Cl, Br and I.
• C ⁇ . 6 -alkyl in the present context designates a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms.
• Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, seo-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, tett-pentyl, n-hexyl, isohexyl and the like.
• C 2 - 6 -alkenyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond.
• groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1 ,3- butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1 -pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5- hexenyl and the like.
• C 2 - 6 -alkynyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond.
• groups include, but are not limited to, ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5- hexynyl, 2,4-hexadiynyl and the like.
• C ⁇ -alkoxy in the present context designates a group -O-C ⁇ . 6 -alkyl wherein C ⁇ -alkyl is as defined above.
• Representative examples include, but are not limited to, meth- oxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, fert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy and the like.
• C 143 -alkylthio in the present context designates a group -S-C ⁇ - 6 -alkyl wherein C ⁇ . 6 -alkyl is as defined above.
• Representative examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, butylthio, isobutylthio, seobutylthio, tert- butylthio, n-pentylthio, isopentylthio, neopentylthio, fert-pentylthio, n-hexylthio, isohexylthio and the like.
• Representative examples include, but are not limited to, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, seobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl and the like.
• Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, butylsulfonyl, iso- butylsulfonyl, seobutylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopen- tylsulfonyl, tert-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl and the like.
• C 3 - ⁇ 0 -cycloalky represents a saturated mono-, bi-, tri- or spirocarbocyclic group having from 3 to 10 carbon atoms.
• Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclode- cyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like.
• C 3 . 8 -heterocyclyl represents a saturated 3 to 8 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Repre- sentative examples are pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azirid- inyl, THFyl and the like.
• aryl represents a carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, az- ulenyl, biphenylenyl and the like.
• Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
• arylthio as used herein represents a group -S-aryl wherein aryl is as defined above.
• aryloxy as used herein represents a group -O-aryl wherein aryl is as defined above.
• arylamino as used herein represents a group -NH-aryl wherein aryl is as defined above.
• aryl annulated with C 3 - 8 -heterocyclyl represents a ring system which contains an aryl group as defined herein to which a C 3 - 8 -heterocyclyl group as defined herein is attached and which does not fall under the below definiton of heteroaryl.
• the aryl group and the heterocyclyl group may form fused, bridged or spirocyclic ring systems.
• Representative examples are 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,4-methyienedioxyphenyl, 2,5-methylenedioxyphenyl, 3,5-methylenedioxyphenyl, 3,6- methylenedioxyphenyl, chromanyl, isochromanyl, 2,3-ethylenedioxyphenyl, 3,4-ethylene- dioxyphenyl, 2,4-ethylenedioxyphenyl, 2,5-ethylenedioxyphenyl, 3,5-ethylenedioxyphenyl, 3,6-ethylenedioxyphenyl and the like.
• heteroaryl represents a heterocyclic aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as fu- ranyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1 ,2,3- triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5- triazinyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxa- diazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,
• Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above.
• Non- limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyr- rolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
• heteroarylthio represents a group -S-heteroaryl wherein heteroaryl is as defined above.
• heteroaryloxy represents a group -O-heteroaryl wherein heteroaryl is as defined above.
• heteroarylamino as used herein represents a group -NH-heteroaryl wherein heteroaryl is as defined above.
• Aryl-Ci-e-alkyl "heteroaryl-Ci-e-alkyl” etc. means d-e-alkyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:
• a functional group which can be converted to hydrogen in vivo is intended to include any group which upon administering the present compounds to the subjects in need thereof can be converted to hydrogen eg enzymatically or by the acidic environment in the stomach.
• Non-limiting examples of such groups are acyl, carbamoyl, monoalkylated carbamoyl, dialkylated carbamoyl, alkoxycarbonyl, alkoxyalkyl groups and the like such as d- 6 -alkylcarbonyl, aroyl, C- ⁇ - 6 -alkylcarbamoyl, di-d- 6 -alkylcarbamoyl, d. 6 -alkoxy- carbonyl and C ⁇ . 6 -alkoxy-C ⁇ - 6 -alkyl.
• the phrase "diseases and disorders related to the histamine H3 receptor" is intended to include any disease or disorder in which an effect, either antagonistic or agonistic, on the histamine H3 receptor is beneficial.
• the present invention relates to compounds of the general formula (I):
• R 1 is hydrogen or a functional group, which can be converted to hydrogen in vivo
• R 2 is hydrogen, Ci-e-alkyl, Ci-e-alkoxy, Ci-e-alkylthio, halogen, cyano, trifluoromethyl, hydroxy, thiol or -NR 5 R 6 , wherein R 5 and R 6 independently are hydrogen or C ⁇ - 6 -alkyl,
• n 1 , 2, 3 or 4,
• p O, 1 , 2 or 3
• Y is a valence bond, -O-, -S- or -NR 9 -, wherein R 9 is hydrogen or Ci-e-alkyl
• W is a valence bond, -O-, -S- or -NR 11 -, wherein R 1 is hydrogen or d- 6 -alkyl,
• q 0, 1 , 2 or 3
• aryl and aryloxy which are optionally substituted with one or more substituents selected from Ci-e-alkyl, C ⁇ - 6 -alkoxy, halogen, -OCF 3 or -CF 3 , C ⁇ - 6 -alkyl, C 2 - 6 -alkenyl or C 2 - 6 -alkynyl, which are optionally substituted with one or more substituents selected from
• aryl and aryloxy which are optionally substituted with one or more substituents selected from C ⁇ . 6 -alkyl, Ci-e-alkoxy, halogen, -OCF 3 or -CF 3 ,
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -NR 11 -
• q 0, Z must not be unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V S, W is -NH-, q is 0, Z must not be unsubstituted or substituted aryl,
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -O-
• -(CH 2 ) q -Z must not be unsubstituted methyl or ethyl
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -N(CH 3 )-
• -(CH 2 ) q -Z must not be unsubstituted methyl
• R 3 and R 4 are both hydrogen
• m is 1
• n 2
• p is 0,
• X is a valence bond
• Y is a valence bond
• V O
• W is -NH-
• -(CH 2 ) q -Z must not be unsubstituted propyl
• R 3 and R 4 are both hydrogen, m is 0, n is 3, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -O-
• -(CH 2 ) q -Z must not be unsubstituted methyl or ethyl
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is a valence bond
• q is 0,
• Z must not be unsubstituted or substituted morpholinyl, unsubstituted or substituted piperazinyl, unsubstituted or substituted indolyl, unsubstituted or substituted 2,3-dihydroindolyl, unsubstituted or substituted indolizinyl, unsubstituted or substituted benzoxazinyl, unsubstituted or substituted quinolin-1-yl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted benzo[b]thiophen-3-yl, unsubstituted or substituted benzofuran-3-yl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted phe- nothiazinyl, unsubstituted thien-2-yl, or unsubstit
• R 1 is hydrogen or a functional group, which can be converted to hydrogen in vivo
• R 2 is hydrogen, Ci-e-alkyl, Ci-e-alkoxy, C ⁇ - 6 -alkylthio, halogen, cyano, trifluoromethyl, hydroxy, thiol or -NR 5 R 6 , wherein R 5 and R 6 independently are hydrogen or d-e-alkyl,
• n 0, 1 or 2
• n 1 , 2, 3 or 4,
• p 0, 1 , 2 or 3,
• W is a valence bond, -O-, -S- or -NR 11 -, wherein R 11 is hydrogen or Ci-e-alkyl,
• q 0, 1 , 2 or 3
• ⁇ aryl which is optionally substituted with one or more substituents selected from Ci-e- alkyl, Ci-e-alkoxy, halogen or -CF 3 ,
• Ci-e-alkyl C 2 . 6 -alkenyl or C 2 . 6 -alkynyl
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -NR 11 -
• q 0, Z must not be unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V S, W is -NH-, q is 0, Z must not be unsubstituted or substituted aryl,
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -O-
• -(CH 2 ) q -Z must not be unsubstituted methyl or ethyl
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -N(CH 3 )-
• q is 0,
• Z must not be unsubstituted methyl
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -N(CH 2 CH 3 )-
• -(CH 2 ) q -Z must not be unsubstituted ethyl
• R 3 and R 4 are both hydrogen, m is 0, n is 3, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -O-
• -(CH 2 ) q -Z must not be unsubstituted methyl or ethyl
• R 1 is hydrogen or a functional group, which can be converted to hydrogen in vivo
• R 2 is hydrogen, Ci-e-alkyl, Ci-e-alkoxy, d-e-alkylthio, halogen, cyano, trifluoromethyl, hydroxy, thiol or -NR 5 R 6 , wherein R 5 and R 6 independently are hydrogen or Ci-e-alkyl,
• n O, 1 or 2
• n 1 , 2, 3 or 4,
• p O, 1 , 2 or 3
• Y is a valence bond, -O-, -S- or -NR 9 -, wherein R 9 is hydrogen or Ci-e-alkyl
• W is a valence bond, -O-, -S- or -NR 11 -, wherein R 11 is hydrogen or Ci-e-alkyl,
• q O, 1 , 2 or 3
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -NR 11 -
• q is 0,
• Z must not be aryl or heteroaryl
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V S, W is -NH-, q is 0, Z must not be aryl,
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -O-
• -(CH 2 ) q -Z must not be methyl or ethyl
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V O
• W is -N(CHs)-
• q is 0,
• Z must not be methyl
• R 3 and R 4 are both hydrogen, m is 1 , n is 2, p is 0, X is a valence bond, Y is a valence bond,
• V is O
• W is -N(CH 2 CH 3 )-, -(CH 2 ) q -Z must not be ethyl
• R 3 and R 4 are both hydrogen
• m is 0, n is 3
• p is
• X is a valence bond
• Y is a valence bond
• V is O
• W is -O-, -(CH 2 ) q -Z must not be methyl or ethyl
• R 1 is hydrogen
• R 2 is also hydrogen.
• R 3 and R 4 are both hydrogen.
• n is 2.
• n is 3.
• X is a valence bond
• p is 0 or 1.
• Y is a valence bond or -O-.
• W is -NR 11 -, wherein R 11 is as defined for formula (I). R 11 is preferably hydrogen or methyl.
• W is a valence bond
• q is preferably 0, 1 or 2.
• Z is selected from C ⁇ - 6 -alkyl, C 2 . 6 -alkenyl, aryl, aryloxy, heteroaryl, d- ⁇ o-cycloalkyl, Cs-s-heterocyclyl and aryl annulated with C 3 . 8 -heterocyclyl, which are option- ally substituted as defined for formula (I).
• Z is phenyl, which is optionally substituted as defined for formula (I). Z is preferably unsubstituted or substituted with one or two substituents selected from
• Z is unsubstituted or substituted with one or two substituents selected from d-e-alkyl, Ci-e-alkoxy, -CF 3 , -OCF 3 , phenoxy and halogen.
• the invention relates to a compound of the general formula (Ih):
• Z is C 3 . 8 -cycloalkyl or C 3 . 8 -heterocyclyl, which is optionally substituted as defined defined for formula (I) or in any of the above preferred embodiments, and R 1 , R 2 , R 3 , R 4 and R 11 are as defined for formula (I) or in any of the above preferred embodiments
• the invention relates to a compound of the general formula (li):
• R 1 , R 2 , R 3 , R 4 , R 11 , q and Z are as defined for formula (l) or in any of the above preferred embodiments
• the invention relates to a compound of the general formula (li):
• R 1 , R 2 , R 3 , R 4 , R 11 , q and Z are as defined for formula (I) or in any of the above preferred embodiments
• the invention relates to a compound of the general formula (Ik):
• R 1 , R 2 , R 3 , R 4 and Z are as defined for formula (l) or in any of the above preferred embodiments, or
• Z is phenyl, phenoxy, naphthyl or naphthyloxy, which is optionally substituted as defined for formula (I) or in any of the above preferred embodiments
• the invention relates to a compound of the general formula (Im):
• R 1 , R 2 , R 3 , R 4 , q, R 9 , R 11 and Z are as defined for formula (I) or in any of the above preferred embodiments
• the invention relates to a compound of the general formula (In):
• R 1 , R 2 , R 3 , R 4 , q, R 9 and Z are as defined for formula (I) or in any of the above preferred embodiments
• the invention relates to a compound of the general formula (lo):
• R 1 , R 2 , R 3 , R 4 , q, R 11 and Z are as defined for formula (I) or in any of the above preferred embodiments
• the invention relates to a compound of the general formula (Ip):
• R 1 , R 2 , R 3 , R 4 , q, R 9 and Z are as defined for formula (I) or in any of the above preferred embodiments
• the compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the invention. Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
• the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
• Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
• Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
• suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, gly- colic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartahc, ascorbic, pamoic, bismethylene salicylic, ethanedi- sulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glu- tamic, benzenesulfonic, p-toluenesulfonic acids and the like.
• pharma- ceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
• metal salts include lithium, sodium, potassium, magnesium salts and the like.
• ammonium and alkylated ammonium salts include ammonium, methylam- monium, dimethylammonium, thmethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
• Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds are able to form.
• the acid addition salts may be obtained as the direct products of compound synthesis.
• the free base may be dissolved in a suitable solvent containing the ap-litiste acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
• the compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
• the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
• the invention also encompasses active metabolites of the present compounds.
• the compounds of the present invention interact with the histamine H3 receptor and are accordingly useful for the treatment and/or prevention of a wide variety of conditions and disorders in which histamine H3 receptor interactions are beneficial.
• the present invention relates to a compound of the general formula (I) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for use as a pharmaceutical composition.
• the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula (I) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
• R 1 is hydrogen or a functional group, which can be converted to hydrogen in vivo
• R 2 is hydrogen, C ⁇ - 6 -alkyl, C ⁇ - 6 -alkoxy, Ci-e-alkylthio, halogen, cyano, trifluoromethyl, hydroxy, thiol or -NR 5 R 6 , wherein R 5 and R 6 independently are hydrogen or Ci-e-alkyl,
• n is 1 , 2, 3 or 4,
• p 0, 1 , 2 or 3,
• Y is a valence bond, -O-, -S- or -NR 9 -, wherein R 9 is hydrogen or Ci-e-alkyl
• W is a valence bond, -O-, -S- or -NR 11 -, wherein R 11 is hydrogen or Ci-e-alkyl,
• q 0, 1 , 2 or 3
• aryl and aryloxy which are optionally substituted with one or more substituents se- lected from C ⁇ - 6 -alkyl, Ci-e-alkoxy, halogen, -OCF 3 or -CF 3 ,
• aryl and aryloxy which are optionally substituted with one or more substituents selected from Ci-e-alkyl, C ⁇ - 6 -alkoxy, halogen, -OCF 3 or -CF 3 ,
• the invention relates to a method for the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor the method com- prising administering to a subject in need thereof an effective amount of a compound of the formula (I') or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
• the invention relates to compounds with histamine H3 receptor an- tagonistic activity or inverse agonistic activity which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor blockade is beneficial.
• the invention relates to compounds with histamine H3 receptor agonistic activity and which may accordingly be useful in the treat ment of a wide range of conditions and disorders in which histamine H3 receptor activation is beneficial.
• the present compounds are used for the preparation of a pharmaceutical composition for the reduction of weight.
• the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of over- weight or obesity.
• the present compounds are used for the preparation of a pharmaceutical composition for the suppression of appetite or satiety induction.
• the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes, especially Type 2 diabetes (NIDDM (non- insulin dependent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
• disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes, especially Type 2 diabetes (NIDDM (non- insulin dependent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
• the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.
• the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.
• the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 2 diabetes.
• the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to Type 2 diabetes.
• the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the pro- gression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
• the compounds of the present invention may also be used for the treatment of airway disorders such as asthma, as anti-diarrhoeals and for the modulation of gastric acid secretion. Furthermore, the compounds of the present invention may be used for the treatment of diseases associated with the regulation of sleep and wakefulness and for the treatment of narcolepsy and attention deficit disorders.
• the compounds of the invention may be used as CNS stimulants or as sedatives.
• the present compounds may also be used for the treatment of conditions associated with epilepsy. Additionally, the present compounds may be used for the treatment of motion sickness and vertigo. Furthermore, they may be useful as regulators of hypothalamo- hypophyseal secretion, antidepressants, modulators of cerebral circulation, and in the treat- ment of irritable bowel syndrome.
• the compounds of the present invention may be used for the treatment of dementia and Alzheimer's disease.
• the compounds of the present invention may also be useful for the treatment of allergic rhinitis, ulcer or anorexia.
• the compounds of the present invention may furthermore be useful for the treatment of migraine, see R.L. McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50, and for the treatment of myocardial infarction, see C.J. Mackins and R. Levi, Expert Opinion on Investigational Drugs 9 (2000), 2537-2542.
• the present novel compounds may also interact with the vanilloid receptors, the se- rotonin receptors, and the adrenergic receptors and may be useful for the treatment of diseases associated with these receptors.
• the compounds of the present invention may be vanilloid receptor agonists, and thus be useful for the treatment of obesity by enhancement of the metabolic rate and energy expenditure. Further, by virtue of their interaction with the vanilloid receptor the compounds of the present invention may be useful for the treatment of pain or neurogenic inflammation or inflammatory painful conditions.
• the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the vanilloid receptor, such as for the treatment and/or prevention of pain, neurogenic inflammation or obesity.
• the present compounds may interact with the 5-HT3 receptor (sero- tonin-3-receptor) and may accordingly be useful as antiemetics, in particular the chemotherapy-induced emesis.
• 5-HT3 antagonists include treatment of central nervous system disorders such as anxiety, schizophrenia, drug abuse and withdrawal symptoms, and pathological and age-associated amnesia.
• the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the serotonin-3 receptor (5-HT3), such as for the treatment of emesis.
• the present compounds may interact with the adrenergic alpha-2 receptor and thus be useful for the treatment of hypertension and of conditions associated with overexpression or hypersensitization of the adrenergic alpha-2 receptor, especially obesity, withdrawal symptoms to an adrenergic alpha-2 agonist, neurological disorders (especially orthostatic hypotension), multiple system atrophy, diabetes mellitus, benign prostatic hyper- plasia or drug induced sensitization of the adrenergic alpha-2 receptor.
• the compounds of the present invention by virtue of their interaction with the alpha-2 receptor, may be useful as sedatives and hypnotics (sleep inducing agents) or as stimulants.
• the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the alpha-2 adrenergic receptor, such as for use as a sleep inducing agent.
• the present compounds are combined with diet and/or exercise.
• the present compounds may be administered in combination with one or more further pharmacologically active substances in any suitable ratios.
• Such further active agents may be selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
• the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
• Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte- stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists,
• the antiobesity agent is leptin.
• the antiobesity agent is dexamphetamine or amphetamine.
• the antiobesity agent is fenfluramine or dexfenfluramine. In still another embodiment the antiobesity agent is sibutramine.
• the antiobesity agent is orlistat.
• the antiobesity agent is mazindol or phentermine.
• the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.
• Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1 ) derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
• the orally active hypoglycaemic agents preferably comprise imidazolines, sulphony- lureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, ⁇ -glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the ⁇ - cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, D
• the present compounds are administered in combination with insulin.
• the present compounds are administered in combination with a sulphonylurea eg tolbutamide, glibenclamide, glipizide, glimepiride, gli- malariaide or glyburide.
• the present compounds are administered in combination with a biguanide eg metformin.
• the present compounds are administered in combination with a meglitinide eg repaglinide or senaglinide.
• the present compounds are administered in combination with a thiazolidinedione eg troglitazone, ciglitazone, pioglitazone, rosigli- tazone or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference.
• a thiazolidinedione eg troglitazone, ciglitazone, pioglitazone, rosigli- tazone or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference.
• the present compounds may be administered in combination with an insulin sensitizer eg such as those disclosed in WO 99/19313, WO 00/50414, WO 00/63191 , WO 00/63192, WO 00/63193 (Dr. Reddy's
• the present compounds are administered in combination with an ⁇ -glucosidase inhibitor eg miglitol or acarbose.
• an ⁇ -glucosidase inhibitor eg miglitol or acarbose.
• the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
• an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
• the present compounds may be adminis- tered in combination with nateglinide.
• the present compounds are administered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, Iovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
• an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, Iovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
• the present compounds are administered in com- bination with more than one of the above-mentioned compounds eg in combination with metformin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and meformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and Iovastatin; etc.
• a sulphonylurea such as glyburide
• a sulphonylurea and acarbose such as glyburide
• a sulphonylurea and acarbose such as glyburide
• the present compounds may be administered in combination with one or more antihypertensive agents.
• antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin.
• ⁇ -blockers such as alprenolol, atenolol, timolol, pin
• the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
• the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
• compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracistemal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route be- ing preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
• compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropri- ate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
• Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
• Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
• Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
• a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
• the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
• the formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
• a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
• parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.
• the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
• One example is an acid addition salt of a com- pound having the utility of a free base.
• a compound of the formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above.
• Physiologically acceptable salts of a compound with a hydroxy group include the an- ion of said compound in combination with a suitable cation such as sodium or ammonium ion.
• solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
• aqueous solutions should be suitable buffered if necessary and the liquid dilu- ent first rendered isotonic with sufficient saline or glucose.
• the aqueous solutions are par- ticulariy suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
• the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
• Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
• solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
• liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
• the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
• compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the .disclosed routes of administration.
• the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
• Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
• These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
• the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
• the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
• the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liq- _u ⁇ cks.uspension or solution.
• a typical tablet which may be prepared by conventional tabletting techniques, may contain:
• Active compound (as free compound or salt thereof) 5.0 mg Lactosum Ph. Eur. 67.8 mg
• the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
• the preparation of the compounds of this invention can be realised in many different ways.
• the starting imidazole derivatives of the formulae (II), (IX) and (XIV) may be prepared according to procedures described in literature (see eg Croat. Chem. Acta. 1973, 45, 297. J. Am. Chem. Soc. 1976, 98, 984.).
• the other reactants are either known compounds or com- pounds that may be prepared in analogy with the preparation of similar known compounds.
• the carboxylic acid group of a compound of the formula (II) wherein m, n and p are as defined above may be activated and reacted with a compound of the formula (III) wherein R 11 , q and Z are as defined above.
• This amidation reaction may be carried out in a suitable solvent like eg DCM at a temperature of up to reflux for the solvent used for eg 1 -200 hours.
• a primary amine of the formula (V) wherein q and Z are as defined above can be attached to a functionalised polystyrene via reductive amination to give a secondary solid supported amine of the formula (VI).
• the secondary amine of the formula (VI) can then be acy- lated with an activated carboxylic acid of the formula (II) wherein m, n and p are as defined above to give a solid supported amide of the formula (VII).
• the amide of the formula (VII) may then be cleaved from the solid support to give the amide of the formula (lb).
• the alcohol group in a compound of the formula (IX) wherein m, n and p are as defined above and Pg represents a protecting group like eg triphenylmethyl (trityl) may be reacted with a double activated formate compound of the formula (X) like eg 4-nitrophenyl chloroformate to give an activated carbonate derivative of the formula (XI).
• the activated carbonate derivative of the formula (XI) may then be reacted with amines of the formula (XII) wherein R 11 , q and Z are as defined above to give a carbamate of the formula (XIII). Removal of the protecting group from a compound of the formula (XIII) is accomplished with dilute acid to give a compound of the formula (Id).
• the amino group in a compound of the formula (XVI) wherein m, n and p are as defined above may be reacted with an activated carboxylic acid of formula (XVII) wherein q and Z are as defined above to give an amide of the formula (If).
• Activation of the carboxylic acid may be accomplished using GDI or HOAt/DIC.
• the carboxylic acid may be acti- vated as the acid chloride by thionyl chloride.
• Activation of the carboxylic acid may be carried out in a suitable solvent like eg DCM or DMA at a temperature of up to reflux for the solvent used for eg 1-200 hours.
• the amino group in a compound of the formula (XVIII) wherein m, n and p are as defined above may be reacted with an isocyanate or isothiocyanate of formula (XIX) wherein q, V and Z are as defined above to give an urea or thiourea of the formula (Ig).
• This reaction may be carried out in a suitable solvent like e.g. an alcohol at a temperature of up to reflux for the solvent used for e.g. 1-200 hours.
• CDI carbonyldiimidazole
• DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
• DIPEA diisopropylethylamine
• DMA ⁇ /,/V-dimethylacetamide
• TFA trifluoroacetic acid
• THF tetrahydrofuran
• HibarTM RT 125-4 5.0 ⁇ m, 4.0 x 125 mm; gradient elution, 5% to 80% solvent B (0.1% TFA in acetonitrile) in solvent A (0.1% TFA in water) within 10 min, 2.0 ml/min, detection at 214 nm, temperature 35 °C.
• Example 1 4,5,6,7-Tetrahydro-1H-benzimidazole-5-carboxylic acid ((1S)-(naphth-1-yl)ethyl)- amide
• Step 1 4,5.6.7-Tetrahydro-1H-benzimidazole-5-carboxylic acid, hydrochloride salt
• Step 2 To a suspension of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid, hydrochloride (1.1 g, 5 mmol) in DCM (40 ml), DIPEA (1.3 ml, 7.5 mmol), DIC (1.2 ml, 7.5 mmol) and HOAt (0.75 g, 5.5 mmol) were added and the mixture was stirred for 1 hour under an atmosphere of nitrogen. (S)-(-)-1-(Naphth-1-yl)ethylamine (0.86 g, 5 mmol) was added and the mixture was stirred at room temperature for 2 days.
• Example 8 4,5,6,7-Tetrahydro-1 H-benzimidazole-5-carboxylic acid ⁇ /-methyl- ⁇ /-(2-(2- naphthyl)ethyl)amide
• Step 1 2,3-D ' ⁇ hvdrobenzofuran-7-carboxylic acid amide
• the reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and washed with a 10% aqueous sodium hydrogensulphate solution. The aqueous phase was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (400 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The remaining crystals were washed with ethyl acetate (3 x 100 ml) and dried in vacuo to give 5.21 g of 2,3-dihydrobenzofuran-7-carboxylic acid amide.
• Example 16 Piperidine-1 -carboxylic acid 4,5,6,7-tetrahydro-1H-benzimidazol-4-ylmethyl ester, oxalic acid salt
• Step 1 1-Triphenylmethyl-4,5.6,7-tetrahydro-1H-benzimidazole-4-carboxylic acid ethyl ester
• Step 2 4-Hvdroxymethyl-1 -triphenylmethyl-4.5.6.7-tetrahydro-1 H-benzimidazole
• Example 17 /V-Cyclohexyl-/V-methyl carbamic acid 4,5,6,7 ⁇ tetrahydro-1H-benzimidazol-4- ylmethyl ester, oxalic acid salt
• Example 18 ⁇ /-Benzyl- ⁇ /-methyl carbamic acid 4,5,6,7-tetrahydro-1H-benzimidazol-4- ylmethyl ester, oxalic acid salt
• Example 21 4,5,6,7-Tetrahydro-1 H-benzimidazole-5-carboxylic acid ⁇ /-methyl-/V-(4- (trifluoromethyl)benzyl)amide
• Step 1 A/-Methyl-/V-((4-Trifluoromethyl)benzyl)amine
• Step 2 0.207 g (61 %) of the title compound was prepared by a similar procedure as described in Example 1.
• Step 1 4-Trifluoromethylcvclohexanecarboxylic acid amide
• the title compound was transferred into its hydrochloric salt, by lyophilization with 0.5 M hydrochloric acid.
• Example 25 4,5,6,7-Tetrahydro-1H-benzimidazole-5-carboxylic acid ⁇ /-methyl-/V-((4'-(tri- fluoromethyl)biphenyl-2-yl)methyl)amide
• Step 1 4'-(Trifluoromethyl)biphenyl-2-carboxylic acid methylamide
• the crude product was purified by flash chromatography on silica (400 g) using DCM/methanol/- 25% aqueous ammonia (100:10:1) as eluent, to give 2.35 g of ⁇ /-methyl-/V-((4'-(trifluoro- methyl)biphenyl-2-yl)methyl)amine.
• Step 1 4,5,6 J-Tetrahvdro-1H-benzimidazole-5-carboxylic acid methyl ester
• reaction mixture was stirred overnight at room temperature, acidified with 10% NaH 2 PO 4 solution to pH 6 and extracted with ethyl acetate (2 x 150 ml). The organic layer was dried (magnesium sulphate) and evaporated to yield 9.3 g (89%) of the intermediate acid as a white solid.
• This acid (4.5 g, 11.0 mmol) was dissolved in DCM (50 ml) and cooled to 4°C, followed by addition of A/-(3-dimethylaminopropyl)-A/-ethyl- carbodiimide hydrochloride (2.23 g, 12.1 mmol), ⁇ /-methoxy- ⁇ /-methylamine hydrochloride (1.59 g, 16.5 mmol) and H ⁇ nig's base (4.8 ml, 27.5 mmol). The reaction mixture was stirred for 30 min. at 4°C and overnight at room temperature, followed by extraction with water (100 ml) and ethyl acetate (2 x 150 ml).
• Step 3a Preparation of ketones from Z-(CH?) ⁇ -Li compounds: To 0.3 mmol of the corresponding Z-(CH 2 ) q bromide in THF (1 ml) was added at
• Step 3b Preparation of ketones from Grignard reagents.
• Z-(CH ) ⁇ -Mq-Hal 0.75 mmol of the corresponding Grignard solution was freshly prepared and added to a solution of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid /V-methoxy-/V-methyl ⁇ amide (0.25 mmol) in THF (1 ml) between room temperature and 50°C. Work-up and depro- tection were performed similarly as described above in Step 3a.
• Step 1 5-Amino-4.5,6,7-tetrahvdro-1 H-benzimidazole. dihydrochloride salt
• Step 1 1 (3)-Triphenylmethyl-4,5.6.7-tetrahydro-1H-benzimidazole-5-carboxylic acid methyl ester
• Example 52 ⁇ /-[2-(4,5,6,7-Tetrahydro-1 H-benzimidazol-5-yl)ethyl]-2-(4-trifluoromethoxy- henyl)acetamide, hydrochloride
• Step 1 2-(1 (3)-Triphenylmethyl-4.5.6.7-tetrahydro-1H-benzimidazol-5-yl)ethylamine oxalate
• Example 53 Naphthalene-1 -carboxylic acid [2-(4,5,6,7-tetrahydro-1H-benzimidazol-5- yl)ethyl]amide, hydrochloride
• Example 52 By a similar procedure as described in Example 52 the title compound was prepared starting from 2-(1(3)-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)ethylamine ox- alate and 1-naphthoic acid.
• Step 1 4-(4-Chlorophenyl)- ⁇ /-methylbutyramide
• Step 2 ⁇ /-r4-(4-Chlorophenyl)butv ⁇ - ⁇ /-methylamine
• Step 1 ⁇ /-Methyl-2-phenoxybenzamide
• Step 2 ⁇ /-Methyl-/ ⁇ /-(2-phenoxybenzyl)amine
• the title compound was transferred into its hydrochloride salt by lyophilization with 0.1 N hydrochloric acid (40 ml).
• Example 56 4,5,6, 7-Tetrahydro-1H-benzimidazole-5-carboxylic acid ⁇ /-[4-(4 ⁇ fluorophenyl)- butyl]- ⁇ /-methylamide
• Step 1 4-(4-Fluorophenyl)butyric acid
• chlorotrimethylsilane (10.6 ml, 84.1 mmol) was added dropwise to a solution of 4-(4-fluorophenyl)-4-oxobutanoic acid (15.0 g, 76.5 mmol) and triethylamine (11.7 ml, 84.1 mmol) in THF (200 ml).
• the reaction mixture was stirred for 20 min at 0 °C.
• the solid was filtered off.
• the solvent was removed from the solution.
• the residue was dissolved in DCM (200 ml).
• Triethylsilane 40 ml, 252 mmol was added.
• the residue was dissolved in a mixture of a 32% aqueous solution of sodium hydroxide (100 ml), water (50 ml), and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2 x 100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo.
• Example 57 4,5,6,7-Tetrahydro-1H-benzimidazole-5-carboxylic acid ⁇ /-methyl-/V-[2-(1- naphthyloxy)ethyl]amide
• Step 1 ⁇ /-Methyl-2-(1-naphthyloxy)acetamide
• Step 2 A/-Methyl-A/-r2-(1-naphthyloxy)ethyl1amine
• the residue was dissolved in a mixture of terf-buyl methyl ether (200 ml) and a 20% aqueous solution of sodium hydroxide (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2 x 100 ml). The combined organic layers were dried over magnesium sulphate.
• the crude product was purified by flash chromatography on silica (200 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give1.94 g of ⁇ /-methyl-/V-[2-(1- naphthy!oxy)ethyl]amine.
• the title compound was transferred into its hydrochloride salt. For this it was dissolved in ethyl acetate (5 ml) and DCM (5 ml). A 3.5 M solution of hydrogen chloride in ethyl acetate (0.48 ml) was added. The crystals were collected.
• Example 58 4,5,6,7-Tetrahydro-1H-benzimidazole-5-carboxylic acid ⁇ /-methyl- ⁇ /-[2-(3- trifluoromethylphenyl)ethyl]amide
• Step 1 ⁇ /-Methyl-2-(3-trifluoromethylphenyl)acetamide
• the reaction mixture was stirred for 56 hours and successively diluted with ethyl acetate (200 ml). It was washed with a 10% aqueous solution of sodium hydrogensulphate (300 ml). The aqueous phase was extracted with ethyl acetate (2 x 150 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (300 ml) and dried over magnesium sulphate. The solvent was removed in vacuo.
• Step 2 A/-Methyl- ⁇ /-r2-(3-(trifluoromethyl)phenyl)ethyllamine
• the crude product was purified by flash chromatography on silica (300 g), using a mixture of DCM/methanol/25% aqueous ammonia (first: 100:10:1 , then 100:20:2, then 100:30:3) as eluent, to give 3.77 g of ⁇ /-methyl- ⁇ /-[2-(3-(trifluoromethyl)phenyl)ethyl]- amine.
• the title compound was transferred into its hydrochloride salt by lyophilization of its solution in 0.1 N hydrochloric acid (40 ml).
• Step 2 ⁇ -r2- ⁇ 2-Chlorophenyl)ethvn- ⁇ /-methylamine
• the crude product was purified by flash chromatography on silica (300 g), using a mixture of DCM/methanol/25% aqueous ammonia (first: 100:10:1 , then: 100:20:2, then 100:30:3) as eluent, to give 3.82 g of ⁇ /-[2-(2-chlorophenyl)ethyl]- ⁇ /- methylamine.
• the title compound was transferred into its hydrochloride salt by lyophilization of its solution in 0.1 N hydrochloric acid (40 ml).
• Step 1 2-((1 -Triphenylmethyl-4.5.6,7-tetrahydro-1 H-benzimidazol-5-yl)methyl)isoindole-1.3- dione and 2-((3-triphenylmethyl-4.5,6.7-tetrahydro-3H-benzimidazol-5-yl)methyl)isoindole- 1 ,3-dione
• Diethyl azodicarboxylate (0.9 ml, 5.70 mmol) was added dropwise to a suspension of a mixture of 1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole-5-methanol and 3- triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole-5-methanol (1.50 g, 3.80 mmol, prepared as described in Example 51), phthalimide (0.56 g, 3.80 mmol), and triphenylphosphine (1.50 g, 5.70 mmol) in THF (50 ml). The reaction mixture was stirred for 3 hours at room temperature.
• the crude product was puri- fied by flash chromatography on silica (90 g), using a mixture of DCM/methanol/25% aqueous ammonia (100:10:1 as eluent, to give 3.92 g of a mixture of 2-((1-triphenylmethyl-4,5,6,7- tetrahydro-1 H-benzimidazol-5-yl)methyl)isoindole-1 ,3-dione and 2-((3-triphenylmethyl- 4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methyl)isoindole-1 ,3-dione which contained triphenylphosphine as impurity.
• the crude product was purified by flash chromatography on silica (90 g), using a mixture of DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.47 g of a mixture of ((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5- yl)methyl)amine and ((3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5- yl)methyl)amine.
• Step 3 1 -Cyclohexyl-3-((1 -triphenylmethyl-4.5.6.7-tetrahvdro-1 H-benzimidazol-5- yl)methyl)thiourea and 1 -cvclohexyl-3-((3-triphenylmethyl-4,5,6 1 7-tetrahvdro-3H- benzimidazol-5-yl)methyl)thiourea
• Cyclohexylisothiocyanate (0.45 ml, 3.05 mmol) was added at 0 °C to a mixture of ((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methyl)amine and ((3- triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methyl)amine (0.60 g, 1.53 mmol) in DCM (5 ml). The reaction mixture was stirred for 3 hours at 0 °C. The solvent was removed in vacuo.
• the crude product was purified by flash chromatography on silica (90 g), using a mixture of DCM/methanol/ammonia (100:10:1) as eluent, to give 770 mg of a mixture of 1- cyclohexyl-3-((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methyl)thiourea and 1-cyclohexyl-3-((3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5- yl)methyl)thiourea.
• Step 1 3-(4-Chlorophenyl)- ⁇ /-((1-triphenylmethyl-4,5,6,7-tetrahvdro-1H-benzimidazol-5- vPmethvPpropionamide and 3-(4-chlorophenyl)-/ ⁇ /-((3-triphenylmethyl-4 1 5.6 -tetrahydro-3H- benzimidazol-5-yl)methyl)propionamide
• the aqueous phase was extracted with ethyl acetate (3 x 60 ml). The combined organic layers were washed with water (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo.
• the crude product was purified by flash chromatography on silica (40 g), using a mixture of DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.69 g of a mixture of 3-(4-chlorophenyl)-/ ⁇ /-((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benz- imidazol-5-yl)methyl)propionamide and 3-(4-chlorophenyl)- ⁇ /-((3-triphenylmethyl-4,5,6,7- tetrahydro-3H-benzimidazol-5-yl)methyl)propionamide.
• the title compound was transferred into its hydrochloride salt by dissolving the title compound in ethyl acetate (30 ml) and addition of a 3.5 M solution of hydrogen chloride in ethyl acetate (3 ml). The precipitation was collected and dried.
• Step 1 2-(4-Chlorophenyl)- ⁇ /-((1-triphenylmethyl-4.5.6.7-tetrahvdro-1H-benzimidazol-5- vDmethvDacetamide and 2-(4-chlorophenyl)-N-((3-triphenylmethyl-4,5,6J-tetrahvdro-3H- benzimidazol-5-yl)methyl)acetamide
• the aqueous phase was extracted with ethyl acetate (3 x 60 ml). The combined organic layers were washed with water (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo.
• the crude product was purified by flash chromatography on silica (40 g), using first ethyl acetate/heptane (1 :1 , 200 ml) and subsequently a mixture of DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.38 g of a mixture of 2-(4-chlorophenyl)-/V-((1- triphenylmethyl-4,5,6,7-tetrahydro-1 H-benzimidazol-5-yl)methyl)acetamide and 2-(4-chloro- phenyl)- ⁇ /-((3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-y
• the crude product was purified by flash chromatography on silica (40 g), using a mixture of DCM/methanol/25% aqueous ammonia (100:10:1 ) as eluent, to give 0.18 g of the title compound.
• the title compound was transferred into its hydrochloride salt by lyophilization of a solution of title compound in 0.1 N hydrochloric acid (20 ml).
• Example 64 4-(4-Chlorophenyl)- ⁇ /-((4,5,6,7-tetrahydro-1 H-benzimidazol-5-yl)methyl)butyr- amide
• Step 1 4-(4-Chlorophenyl)- ⁇ /-((1-triphenylmethyl-4,5.6.7-tetrahvdro-1H-benzimidazol-5- yl)methyl)butyramide and 4-(4-chlorophenyl)- ⁇ /-((3-triphenylmethyl-4,5.6.7-tetrahydro-3H- benzimidazol-5-yl)methyl)butyramide
• the aqueous phase was extracted with ethyl acetate (3 x 60 ml). The combined organic layers were washed with water (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo.
• the crude product was purified by flash chromatography on silica (40 g), using ethyl acetate/heptane (1 :1 ; 300 ml) and successively DCM/methanol/25% aqueous ammonia (100:10:1 ) as eluent, to give 0.43 g of a mixture of 4-(4-chlorophenyl)- ⁇ /-((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5- yl)methyl)butyramide and 4-(4-chlorophenyl)- ⁇ /-((3-triphenylmethyl-4,5,6,7-tetrahydro-3H- benzimidazoI-5-yl)
• the title compound was transferred into its hydrochloride salt by dissolving the title compound in ethyl acetate (30 ml) and addition of a 3.5 M solution of hydrogen chloride in ethyl acetate (3 ml). The precipitation was collected and dried.
• the potassium salt of phthalimide (4.4 g, 24 mmol) was dissolved in DMF (20 ml) and 1-chloro-4-(3-bromopropyl)benzene (4.67 g, 20 mmol) was added. The mixture was stirred at 80 °C for 16 hours. Water (50 ml) and DCM (50 ml) were added, the phases were separated and the aqueous phase extracted with DCM (2 x 50 ml). The combined organic phases were washed with sodium hydroxide (0.2 M, 50 ml), dried (magnesium sulphate), filtered and concentrated in vacuo.
• Step 2 To a slurry of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride
• Example 65 By a similar procedure as described in Example 65, the title compound was pre- pared from 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid and 3-benzimidazol-1-yl- propylamine.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Medicinal Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Diabetes (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Immunology (AREA)
• Emergency Medicine (AREA)
• Child & Adolescent Psychology (AREA)
• Pulmonology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Anesthesiology (AREA)
• Psychiatry (AREA)
• Endocrinology (AREA)
• Hospice & Palliative Care (AREA)
• Otolaryngology (AREA)
• Nutrition Science (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Applications Claiming Priority (5)

Publications (1)

Family

ID=26068796

Family Applications (1)

Country Status (4)

Cited By (1)

Families Citing this family (15)

Family Cites Families (4)

• 2001
  • 2001-03-16 WO PCT/DK2001/000188 patent/WO2001068652A1/en not_active Application Discontinuation
  • 2001-03-16 JP JP2001567743A patent/JP2003527395A/ja active Pending
  • 2001-03-16 AU AU2001244088A patent/AU2001244088A1/en not_active Abandoned
  • 2001-03-16 EP EP01916934A patent/EP1268484A1/de not_active Withdrawn

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events