WO2001066534A2 - Antagonistes du recepteur d'histamine-3 diamino cycliques et bicycliques - Google Patents

Antagonistes du recepteur d'histamine-3 diamino cycliques et bicycliques Download PDF

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WO2001066534A2
WO2001066534A2 PCT/US2001/006885 US0106885W WO0166534A2 WO 2001066534 A2 WO2001066534 A2 WO 2001066534A2 US 0106885 W US0106885 W US 0106885W WO 0166534 A2 WO0166534 A2 WO 0166534A2
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piperazinyl
propyl
methyl
oxoethyl
phenoxy
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PCT/US2001/006885
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WO2001066534A3 (fr
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Youssef L. Bennani
Lawrence A. Black
Wesley J. Dwight
Ramin Faghih
Robert G. Gentles
Huaqing Liu
Kathleen M. Phelan
Anil Vasudevan
Henry Q. Zhang
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Abbott Laboratories
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Publication of WO2001066534A2 publication Critical patent/WO2001066534A2/fr
Publication of WO2001066534A3 publication Critical patent/WO2001066534A3/fr

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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • 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
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • This invention relates to compounds which may be useful for treating diseases caused or exacerbated by H 3 receptor activity, pharmaceutical compositions containing the compounds, preparation of the compounds, and methods of treatment using the compounds.
  • Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) which are commonly treated with antagonists of histamine or "antihistamines.” It has also been established that histamine receptors exist in at least two distinct types, referred to as Hi and H 2 receptors.
  • a third histamine receptor (the H 3 receptor) is believed to play a role as a neurotransmitter in the central nervous system, where it is thought to be disposed presynaptically on histaminergic nerve endings (Nature, 302, 832-837 (1983)).
  • the existence of the H 3 receptor has been confirmed by the development of selective H 3 agonists and antagonists (Nature, 327, 117-123 (1987)) and has subsequently been shown to regulate the release of other neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs and gastrointestinal tract.
  • H 3 receptor antagonists may have therapeutic utility for a number of indications such as asthma, ardiovasular disorders, gastrointestinal disorders, inflammation, sedatives, sleep regulators, anticonvulsants, and antidepressants.
  • this invention discloses a compound selected from the group consisting of a compound of formula (I)
  • L is absent or optionally substituted cycloalkyl or optionally substituted cycloalkylalkylene;
  • L is absent or alkylene, optionally substituted with aryl
  • R , R , and R are independently hydrogen or alkyl;
  • R is selected from the group consisting of alkoxy, amino, optionally substituted aryl, aryloxy, optionally substituted cycloalkyl, cycloalkoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and -W -C(R )(R a )-NR R a ;
  • R is hydrogen or R ; with the proviso that Q is not absent in compounds of formula (I) and when Q is
  • R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, azido, carboxaldehyde, carboxyl, cyano, halo, hydroxyl, nitro, perfluoroalkyl, and perfluoroalkoxy; or R and R are on adjacent carbon atoms and taken together are -OCH 2 C(O)-; o
  • R is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and hydroxyl;
  • R is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, and a nitrogen protecting group; R and R are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, arylalkoxyalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl;
  • W is absent or is optionally substituted alkylene;
  • R and R a are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl; or
  • R and R together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfone, dihydropyrimidinyl, tetrahydropyrimidinyl, and hexahydropyrimidinyl; or
  • W 1 is an optionally substituted alkylene, and R 11 and R 12 , together with the carbon and nitrogen atom to which they are respectively attached, form an optionally substituted heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl;
  • R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
  • R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, and an hydroxyl protecting group.
  • this invention discloses a compound of formula (I)
  • R , and R are defined above.
  • this invention discloses a compound of formula (I), wherein
  • this invention discloses a compound of formula (I), wherein n is one.
  • this invention discloses a compound of formula (I), wherein n is two.
  • this invention discloses a compound of formula (I), wherein
  • this invention discloses a compound of formula (I), wherein
  • R,2' R X "11 wherein one of R and R is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl; and
  • R and R a are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl.
  • this invention discloses a compound of formula (I), wherein
  • R R wherein R is hydrogen
  • R 11 a , R 12 and R 12a are defined in the embodiment immediately above.
  • this invention discloses a compound of formula (I), wherein the relative stereochemistry of R is depicted by the formula
  • R .11 is hydrogen
  • R l la , R 12 and R 12a are defined in the embodiment proximally above.
  • this invention discloses a compound of formula (I), wherein
  • R , and R , and R are independently selected from the group consisting of hydrogen, alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and ureido; or
  • R and R are taken together on the same carbon and are oxo or thioxo, and R is selected from the group consisting of hydrogen, alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and ureido; and x is one, two, three, or four.
  • this invention discloses a compound of formula (I), wherein
  • R , R , R , and x are defined in the embodiment proximally above.
  • this invention discloses a compound of formula (I), wherein R 4 is
  • F F C ⁇ ⁇ R , R , R and R are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; alkoxy; alkanoyl; alkoxycarbonyl; alkylsulfonyl; amino; aminosulfonyl; azido; carboxamido; carboxy; cyano; halo; hydroxyl; oxo; thioxo; nitro; a nitrogen protecting group; perfluoroalkyl; perfluoroalkoxy; aryloyl; arylsulfonyl; heteroaryloyl; heteroarylsulfonyl; heterocycloalkyloyl; heterocycloalkylsulfonyl; phenyl; a heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl
  • this invention discloses a compound of formula (I), wherein
  • this invention discloses a compound of formula (I), wherein
  • R and R is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl;
  • R and R are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cyclo alkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl; and W is alkylene.
  • this invention discloses a compound of formula (I), wherein the relative stereochemistry of R is depicted by the formula
  • R , R , R , R , and W are defined in the embodiment immediately above.
  • this invention discloses a compound of formula (I), wherein the relative stereochemistry of R is depicted by the formula
  • R , R a , R , R , and W are defined in the embodiment proximally above.
  • this invention discloses a compound of formula (I), wherein R is
  • R is selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl; and
  • R and R together with the carbon and nitrogen atom to which they are respectively attached, are a heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl, wherein the heterocycloalkyl ring formed
  • R and R together can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl; alkenyl; alkynyl; alkoxy; alkanoyl; alkoxycarbonyl; alkylsulfonyl; amino; aminosulfonyl; azido; carboxamido; carboxy; cyano; halo; hydroxyl; oxo; thioxo; nitro; a nitrogen protecting group; perfluoroalkyl; perfluoroalkoxy; aryloyl; arylsulfonyl; heteroaryloyl; heteroarylsulfonyl; heterocycloalkyloyl; heterocycloalkylsulfonyl; phenyl; a heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, iso
  • R , R a , R , R a , and W are defined in the embodiment proximally above. h another embodiment, this invention discloses a compound of formula (I), wherein R is hydrogen.
  • this invention discloses a compound of formula (I), wherein
  • R is hydrogen or halo.
  • this invention discloses a compound of formula (I), wherein R is selected from the group consisting of alkanoyl, aryl, carboxamido, cycloalkyloyl, cyano, halo, heteroaryl, and perfluoroalkyl.
  • this invention discloses a compound of formula (I), wherein o
  • R is cyclopropanoyl
  • this invention discloses a compound of fo ⁇ nula (I), wherein R is 4-cyanophen-4'-yl. In another embodiment, this invention discloses a compound of fo ⁇ nula (I), wherein o
  • R is optionally substituted heteroaryl of the formula
  • R is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, aminoalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocycloalkyl, alkoxycarbonyl, and perfluoroalkyl.
  • this invention discloses a compound of formula (II),
  • this invention discloses a compound of formula (II), wherein
  • L is absent and L is alkylene, optionally substituted with aryl.
  • this mvention discloses a compound of formula (II), wherein Q is -O- or acetylene.
  • this invention discloses a compound of formula (II), wherein n is one.
  • this invention discloses a compound of fo ⁇ nula (II), wherem R is selected from the group consisting of hydrogen, alkyl, alkoxy, amino, aryl, heteroaryl, cycloalkyl, cycloalkoxy, aryloxy, and heterocycloalkyl.
  • this invention discloses a compound of formula (II), wherein
  • R and R a are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl,
  • this invention discloses a compound of formula (II), the relative stereochemistry of R is depicted by the formula
  • R , 11 is hydrogen
  • R , R and R are defined in the embodiment immediately above, h another embodiment, this invention discloses a compound of formula (II), wherein the relative stereochemistry of R is depicted by the formula
  • R is hydrogen
  • R , R and R are defined in the embodiment proximally above.
  • this invention discloses a compound of fo ⁇ nula (II), wherein
  • R , and R , and R are independently selected from the group consisting of hydrogen, alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and ureido; or F F f "1
  • R and R are taken together on the same carbon and are oxo or thioxo, and R is selected from the group consisting of hydrogen, alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and ureido; and x is one, two, three, or four.
  • this invention discloses a compound of formula (II), wherein the relative stereochemistry of R is depicted by the formula
  • this invention discloses a compound of formula (II), wherein the relative stereochemistry of R is dep )iicc ⁇ ted by the formula
  • R , R , R , and x are defined in the embodiment proximally above.
  • this invention discloses a compound of formula (II), wherein R 5 is
  • R and R a is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl;
  • R and R are independently selected from the group consisting of hydro gen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, hetero
  • W is alkylene
  • this invention discloses a compound of formula (II), wherein the relative stereochemistry of R is depicted by the formula
  • R , R , R , R , and W are defined in the embodiment immediately above.
  • this invention discloses a compound of formula (II), wherein the relative stereochemistry of R is depicted by the formula
  • R , R , R , R , and W are defined in the embodiment proximally above.
  • this invention discloses a compound of formula (II), wherein R and R are hydrogen.
  • this invention discloses a compound of formula (II), wherein R is alkanoyl or cycloalkyloyl.
  • this invention discloses a compound of formula (II), wherein R is cyclopropanoyl.
  • this mvention discloses a compound of formula (III)
  • this invention discloses a compound of formula (III), wherein
  • L is absent and L is alkylene, optionally substituted with aryl.
  • this invention discloses a compound of formula (III), wherein
  • this invention discloses a compound of formula (III), wherem n is one. In another embodiment, this invention discloses a compound of formula (III), wherein R is selected from the group consisting of hydrogen, alkoxy, and aryl.
  • this mvention discloses a compound of formula (III), wherein R is
  • R,2' wherein one of R and R is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl; and
  • R " and R a are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl.
  • this invention discloses a compound of fo ⁇ nula (III), wherein the relative stereochemistry of R is depicted by the formula
  • this invention discloses a compound of formula (III), wherein the relative stereochemistry of R is depicted by the formula
  • this invention discloses a compound of formula (III), wherein R and R are hydrogen.
  • this invention discloses a compound of formula (III), wherein R is cyclopropanoyl. In another embodiment, this invention discloses a compound of formula (III), o wherein R is 4-cyanophen-4'-yl.
  • this invention discloses a compound of formula (IN)
  • L , L , Q , Q , n, R , R , R , and R are defined above.
  • this invention discloses a compound of formula (IN), wherein
  • this invention discloses a compound of formula (IN), wherein
  • this invention discloses a compound of formula (IN), wherein
  • this invention discloses a compound of formula (IN), wherein
  • this invention discloses a compound of formula (IN), wherein
  • R is alkoxy
  • this invention discloses a compound of formula (IN), wherein R is
  • R and R is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl; and
  • R and R are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl.
  • this invention discloses a compound of formula (IN), wherein the relative stereochemistry of R is depicted by the formula
  • this invention discloses a compound of formula (IN), wherein the relative stereochemistry of R is depicted by the formula
  • this invention discloses a compound of formula (IN), wherein R and R are hydrogen. In another embodiment, this invention discloses a compound of formula (IN), wherem
  • R is cyclopropanoyl.
  • this invention discloses a method for antagonizing the H 3 receptor comprising administering a pharmaceutically acceptable amount ofa compound of fo ⁇ nula (I), or a pharmaceutically acceptable salt thereof, wherein L 1,L2,n, Q 1,Q2,R 1,R2,
  • this invention discloses a method for antagonizing the H 3 receptor comprising administering a pharmaceutically acceptable amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein L,L,n, Q , Q , R , R , and R are defined above.
  • this invention discloses a method for antagonizing the H 3 receptor comprising administering a pharmaceutically acceptable amount of a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein L,L,n, Q,Q,R,R,
  • this mvention discloses a method for antagonizing the H 3 receptor comprising administering a pharmaceutically acceptable amount of a compound of fonnula (IN), or a pharmaceutically acceptable salt thereof, wherein L,L,Q,Q,R,R, R , and R are defined above.
  • this invention discloses a method for treating disorders or diseases which may be alleviated by H 3 receptor activity in a mammal comprising administering to the mammal in recognized need of such treatment a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L,L,n, Q,Q,R,R,R,R,R,R, and R are defined above.
  • this invention discloses a method for treating disorders or diseases which may be alleviated by H 3 receptor activity in a mammal comprising administering to the mammal in recognized need of such treatment a pharmaceutically acceptable amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein L,L,n, Q,Q,R,R,R, and R are defined above.
  • this invention discloses a method for treating disorders or diseases which may be alleviated by H 3 receptor activity in a mammal comprising administering to the mammal in recognized need of such treatment a pharmaceutically acceptable amount of a compound of formula (III), or a pharmaceutically acceptable salt
  • this invention discloses a method for treating disorders or diseases which may be alleviated by H 3 receptor activity in a mammal comprising administering to the mammal in recognized need of such treatment a pharmaceutically acceptable amount of a compound of formula (IN), or a pharmaceutically acceptable salt
  • this invention discloses a composition
  • a composition comprising a
  • this invention discloses a composition comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein L , L , n, Q,Q ,R,R,R,R,R, and R are defined above, and a pharmaceutically acceptable carrier.
  • this invention discloses a composition comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein L , L , n, Q , Q , R , R , R , and R are defined above, and a pharmaceutically acceptable carrier.
  • this invention discloses a composition comprising a composition comprising a
  • this invention discloses a composition
  • a composition comprising a
  • This invention discloses series of asymmetrically ⁇ , ⁇ '-disubstituted 1,4-piperazines (compounds of formula (I), wherein n is one), 1,4-diazepanes (compounds of formula (I), wherein n is two), (lS,4S)-2,5-diazabicyclo(3.2.1)heptanes (compounds of formula (II)), (lR,4R)-2,5-diazabicyclo(2.2.1)heptanes (compounds of formula (III)), and 3,8-diazabicyclo(3.2.1)octanes (compounds of formula (IN)) which may be useful for antagonizing the H 3 receptor and may be therefore useful for treating diseases caused or exacerbated by H 3 receptor activity.
  • acetylene refers to ethyne.
  • alkanoyl refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkenyl refers to a monovalent straight or branched chain hydrocarbon radical having from two to ten carbon atoms and at least one carbon-carbon double bond.
  • alkoxy refers to an alkyl group, as defined herein, connected to the parent molecular moiety through an oxygen atom.
  • alkoxyalkoxy refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through another alkoxy group, as defined herein.
  • alkoxyalkoxyalkyl refers to an alkoxyalkoxy group, as defined herein, attached to the parent molecular moiety tlirough an alkyl group, as defined herein.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through an alkyl group as defined herein.
  • alkoxycarbonyl refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkyl refers to a monovalent straight or branched chain saturated hydrocarbon radical having from one to ten carbon atoms.
  • alkylene refers to a divalent straight or branched chain saturated hydrocarbon diradical having from one to ten carbon atoms.
  • alkylsulfonyl refers to an alkyl group, , as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein.
  • alkynyl refers to a monovalent straight or branched chain hydrocarbon radical having from two to ten carbon atoms and at least one carbon-carbon triple bond.
  • the alkynyl groups of this invention can be optionally substituted with a substituent selected from the group consisting of alkenyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl.
  • amino refers to -NH 2 or a derivative thereof formed by independent replacement of one or both hydrogen atoms thereon with a substituent or substituents independently selected from the group consisting of alkanoyl, alkenyl, alkyl, alkylsulfonyl, alkynyl, aminosulfonyl, aryl, arylalkenyl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylalkenyl, heteroarylsulfonyl, heterocycloalkylalkyl, heterocycloalkyloyl, heterocycloalkylsulfonyl, a nitrogen protecting group, optionally substituted aryl, optionally
  • aminoalkyl refers to an amino group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
  • amino protecting group and “nitrogen protecting group,” as used herein, refer to selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures.
  • amino protecting groups include trichloroethoxycarbonyl, benzyloxycarbonyl (Cbz), chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-butoxycarbonyl (Boc), para- methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, phthaloyl, succinyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triphenylsiiyl, and the like.
  • Preferred nitrogen protecting groups of this invention are benzyloxycarbonyl (Cbz), and tert-butoxycarbonyl (Boc).
  • aminosulfonyl refers to an amino group, as defined herein, attached to the parent molecular moiety tlirough a sulfonyl group.
  • aryl refers to a six-membered aromatic carbocyclic ring.
  • the aryl groups of this invention are exemplified by phenyl.
  • arylalkenyl refers to an aryl group, as defined herein, attached to the parent molecular moiety through an alkenyl group, as defined herein.
  • arylalkyl refers to an aryl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
  • the aryl part or parts of the arylalkyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxyl, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • arylalkoxyalkyl refers to an aryl group, as defined herein, attached to the parent molecular moiety through an alkoxyalkyl group, as defined herein.
  • aryloxy refers to an aryl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.
  • the aryl part or parts of the arylalkyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxyl, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • aryloyl refers to an aryl group, as defined herein, attached to the parent molecular moiety through a carbonyl group.
  • the aryl part of the aryloyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, aryloxy, azido, carboxaldehyde, carboxamido, carboxyl, cyano, cycloalkyl, halo, hydroxyl, methylenedioxy, perfluoroalkoxy, and perfluoroalkyl.
  • arylsulfonyl refers to an aryl group, as defined herein, attached to the parent molecular moiety through a sulfonyl group.
  • the aryl part or parts of the arylalkyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxyl, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • azido refers to -N 3 .
  • carboxydehyde refers to -CHO.
  • carboxylate refers to an amino group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein.
  • carboxyl refers to -CO 2 H or a derivative thereof formed by replacement of the hydrogen atom thereon with a carboxyl protecting group.
  • carboxy protecting group and “carboxyl protecting group,” as used herein refer to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out.
  • a carboxy-protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent.
  • carboxy- protecting groups are methyl, ethyl or tert-butyl; benzyl; 4-methoxybenzyl; nitrobenzyl; dimethylaminoethyl; pivaloyloxymethyl, propionyloxymethyl; benzoyloxyethyl; methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl; tert-butyloxycarbonyloxymethyl; tert-butyloxycarbonylaminomethyl; methylaminocarbonylaminomethyl; acetylaminomethyl ; 4-methylpiperazinylcarbonyloxymethyl; dimethylaminocarbonylmethyl; (5 -tert-butyl-2-oxo- 1 ,3-dioxolen-4-yl)methyl; and (5-phenyl-2-oxo- 1 ,3-dioxolen-4-yl)methyl.
  • cyano refers to -CN.
  • cyanoalkyl refers to a cyano group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
  • cycloalkoxy refers to cycloalkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.
  • the cycloalkyl part of the cycloalkoxy can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, amino, hydroxyl, and oxo.
  • cycloalkyl refers to a monovalent saturated cyclic hydrocarbon radical having three to seven carbon atoms.
  • cycloalkylalkyl refers to a cycloalkyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
  • the cycloalkyl part or parts of the cycloalkylalkyl can be optionally substituted with one, two, or three a groups independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, amino, aryl, azido, carboxaldehyde, carboxyl, halo, hydroxyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, oxo, perfluoroalkoxy, perfluoroalkyl, thioxo, and uriedo.
  • cycloalkylene refers to a divalent saturated cyclic hydrocarbon diradical having from three to seven carbon atoms.
  • cycloalkyloyl refers to a cycloalkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein.
  • the cycloalkyl part of the cycloalkyloyl can be optionally substituted with one, two, or three groups independently selected from the consisting of alkoxy, alkoxycarbonyl, alkyl, amino, aryl, azido, carboxaldehyde, carboxyl, halo, hydroxyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, oxo, perfluoroalkoxy, perfluoroalkyl, thioxo, and uriedo.
  • cycloalkylsulfonyl refers to a cycloalkyl group, as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein.
  • the cycloalkyl part of the cycloalkylsulfonyl can be optionally substituted with one, two, or three groups independently selected from the consisting of alkoxy, alkoxycarbonyl, alkyl, amino, aryl, azido, carboxaldehyde, carboxyl, halo, hydroxyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, oxo, perfluoroalkoxy, perfluoroalkyl, thioxo, and uriedo.
  • halo or halide
  • heteroaryl refers to a cyclic, aromatic five-or six- membered ring having at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur. The five-membered rings have two double bonds, and the six- membered rings have three double bonds.
  • Heteroaryls of this invention are exemplified by furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • the heteroaryl groups of this invention are connected through a carbon atom in the ring.
  • heteroarylalkenyl refers to a heteroaryl group, as defined herein, attached to the parent molecular moiety tlirough an alkenyl group, as defined herein.
  • heteroarylalkyl refers to a heteroaryl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
  • the heteroaryl part or of the heteroarylalkyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • heteroaryloyl refers to a heteroaryl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein.
  • heteroaryl part of the heteroaryloyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • heteroarylsulfonyl refers to a heteroaryl group, as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein.
  • the heteroaryl part of the heteroarylsulfonyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • heterocycloalkyl refers to a non-aromatic four-, five-or six-membered ring having at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • the four-membered rings have zero double bonds, the five- membered rings have zero or one double bond and the six-membered rings have zero, one or two double bonds.
  • Heterocycloalkyls of this invention are exemplified by tetrahydro furanyl, pyrrolinyl, dioxolanyl, imidazolinyl, pyrazolinyl, pyrazolidinyl, pyranyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, azepanyl, dioxanyl, morpholinyl, dithianyl, dihydropyridazinyl, tetrahydropyridazinyl, dihydropyrazinyl, tetrahydrohydropyrazinyl, and piperazinyl.
  • the heterocycloalkyl groups of this invention can be connected through either a carbon atom or a nitrogen atom in the ring.
  • heterocycloalkylalkyl refers to a heterocycloalkyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
  • the heterocycloalkyl part or parts of the heterocycloalkylalkyl can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • heterocycloalkylalkyloyl refers to a heterocycloalkylalkyl group attached to the parent molecular moiety through a carbonyl group.
  • the heterocycloalkyl part of the heterocycloalkylalkyloyl can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • heterocycloalkyloyl refers to a heterocycloalkyl group attached to the parent molecular moiety through a carbonyl group.
  • the heterocycloalkyl part of the heterocycloalkyloyl can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • heterocycloalkyloylalkyl refers to a heterocycloalkyloyl group attached to the parent molecular moiety through an alkyl group.
  • the heterocycloalkyl part of the heterocycloalkyloylalkyl can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • heterocycloalkylsulfonyl refers to a heterocycloalkyl group attached to the parent molecular moiety through a sulfonyl group.
  • the heterocycloalkyl part of the heterocycloalkylsulfonyl can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • hydroxyl refers to -OH or a derivative thereof fo ⁇ ned by replacement of the hydrogen atom thereon with a hydroxyl protecting group.
  • hydroxyl protecting group refers to selectively introducible and removable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures.
  • hydroxyl protecting groups include groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,
  • hydroxyl protecting groups for this mvention are alkanoyl, benzyl, methanesulfonyl, tert-butyldimethylsilyl, and tert-butyl.
  • hydroxyalkyl refers to a hydroxyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
  • methylenedioxy refers to a -OCH 2 O- group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms.
  • nitro refers to a -NO 2 group.
  • oxo refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
  • perfluoroalkoxy refers to a perfluoroalkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.
  • perfluoroalkyl refers to an alkyl group, as defined herein, in which all of the hydrogen atoms have been replaced with fluoride atoms.
  • pharmaceutically acceptable salt represents salts or zwitterionic forms of the compounds which are water or oil-soluble or dispersible and are suitable for ailments and or diseases without undue toxicity, irritation, and allergic response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts may be prepared during the final isolation and purification of the compounds or separately by reacting a free base group with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoro
  • the basic nitrogen-containing groups can be quaternized with alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; arylalkyl halides such as benzyl and phenethyl bromides.
  • alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl, and steary
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxylic acid-containing group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a 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 metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts and nontoxic quaternary ammonia and amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributlyamine, pyridine, N,N- dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • substituted alkylene refers to an alkylene group, as defined herein, substituted with one or two amino or aryl substituents.
  • the aryl groups substituting the alkylene groups of this invention can be further substituted with one, two, three, four, or five substituents independently selected from the group consisting of amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, and hydroxy.
  • substituted aryl refers to an aryl group, as defined herein, substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl; alkoxy; alkoxycarbonyl; alkenyl; alkyl; alkynyl; alkylsulfonyl; amino; aminosulfonyl; azido; carboxamido; carboxy; cyano; halo; hydroxyl; nitro; perfluoroalkoxy; perfluoroalkyl; aryloyl; arylsulfonyl; heteroaryloyl; heteroarylsulfonyl; heterocycloalkyloyl; heterocycloalkylsulfonyl; phenyl; a heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imi
  • phenyl, the heteroaryl, and the heterocycloalkyl groups substituting the aryl groups of this invention can also be optionally further substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, azido, carboxaldehyde, carboxamido, carboxyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • substituted cycloalkyl refers to an cycloalkyl group substituted with one, two, or three substituents independently selected from the group consisting of alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, oxo, thioxo, and ureido.
  • substituted cycloalkylene refers to a cycloalkylene group independently substituted with one or two fluoride or chloride substituents.
  • substituted heteroaryl refers to a heteroaryl group substituted with one, two, or three, substituents independently selected from the group consisting of alkanoyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, alkynyl, amino, aminoalkyl, aminosulfonyl, aryl, arylalkyl, aryloyl, arylsulfonyl, azido, carboxamido, carboxy, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, halo, heteroaryl, heteroaryloyl, heteroarylsulfonyl, heterocycloalkyl, heterocycloalkyloyl, heterocycloalkyloylalkyl, heterocycloalkylsulfonyl,
  • the phenyl, the heteroaryl, and the heterocycloalkyl groups optionally substituting the heteroaryl groups of this invention can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, azido, carboxaldehyde, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • substituted heterocycloalkyl refers to a heterocycloalkyl group substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl; alkoxy; alkoxycarbonyl; alkenyl; alkyl; alkylsulfonyl; alkynyl; amino; aminosulfonyl; aryloyl; arylsulfonyl; azido; carboxamido; carboxy; cyano; halo; heteroaryloyl; heteroarylsulfonyl; heterocycloalkyloyl; heterocycloalkylsulfonyl; hydroxyl; nitro; a nitrogen protecting group; oxo; perfluoroalkyl; perfluoroalkoxy; thioxo; phenyl; a heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl,
  • the phenyl, the heteroaryl, and the heterocycloalkyl groups substituting the heterocycloalkyl groups of this invention can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, azido, carboxaldehyde, carboxamido, carboxyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
  • sulfonyl refers to a -SO 2 - group.
  • thioxo refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single sulfur atom.
  • thioalkoxy refers to an alkyl group, as defined herein, connected to the parent molecular moiety through a sulfur atom.
  • ureido refers to -NHC(O)NH 2 or a derivative thereof formed by independent replacement of a hydrogen atom or hydrogen atoms thereon by a radical or radicals independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl.
  • ureidoalkyl refers to a ureido group attached to the parent molecular moiety through an alkyl group.
  • Asymmetric centers can exist in the compounds of this invention.
  • This invention contemplates stereoisomers and mixtures thereof. Individual stereoisomers of compounds are prepared by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns.
  • the compounds of this invention can exist as pharmaceutically acceptable prodrugs.
  • pharmaceutically acceptable prodrug represents those prodrugs of the compounds of this invention which are, within the scope of sound medical judgment, 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 this invention.
  • prodrug represents compounds which are 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 N. Stella, Pro-drugs as Novel
  • the compounds can be administered alone, in combination with, or in concurrent therapy with other H 3 antagonists.
  • the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used.
  • the compounds can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof.
  • parenteral includes infusion as well as subcutaneous, intravenous, intramuscular, and intrastemal injection.
  • Parenterally administered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents.
  • the injectable preparation can also be an injectable solution or suspension in a diluent or solvent.
  • acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, dilute acids or bases, dilute amino acid solutions, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
  • the H 3 antagonistic activity of parenterally administered compounds can be prolonged by slowing their absorption.
  • One way to slow the absorption of a particular compound is administering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound.
  • the rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state.
  • Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension.
  • injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides.
  • biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides.
  • the rate of drug release can be controlled.
  • Transdermal patches also provide controlled delivery of the compounds.
  • the rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers can be used to increase absorption.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules, hi these solid dosage forms, the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose.
  • diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose.
  • Capsules, tablets and pills can also comprise buffering agents; and tablets and pills can be prepared with enteric coatings or other release- controlling coatings.
  • Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof.
  • Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents. Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches. The compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers.
  • These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable nonirritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.01 to about 500 mg/kg body weight or preferably from about 0.01 to about 100 mg/kg body weight.
  • Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
  • Representative compounds of the invention include:
  • Sprague-Dawley rat brain cortices were homogenized (1 g tissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA containing protease inhibitor cocktail (Calbiochem) using a polytron set at 20,500 ⁇ m. Homogenates were centrifuged for 20 minutes at 40,000xg. The supernatant was decanted, and pellets were weighed. The pellet was resuspended by polytron homogenization in 40 mL 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and centrifuged for 20 minutes at 40,000 ⁇ g.
  • the membrane pellet was resuspended in 6.25 volumes (per gram wet weight of pellet) of 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and aliquots flash frozen in liquid N? and stored at -70°C until used in assays.
  • Rat cortical membranes (12 mg wet weight/tube) were incubated with ( H)-N- ⁇ -methylhistamme ( ⁇ 0.6 nM) with or without H 3 -HR antagonists in a total incubation volume of 0.5 mL of 50 mM Tris-HCl/5 mM EDTA (pH 7.7). Test compounds were added to the incubation mixtures prior to initiating the incubation assay by addition of the membranes.
  • compound (i) can be converted to compound (ii) by treating the former with a reducing agent in a solvent.
  • 3,8-diazabicyclo(3.2.1)octane, compound (i) was prepared according to the procedure described in Tetrahedron 1992, 48, 4985.
  • Specific examples of reducing agents include LiAlH 4 , BH 3 -THF, and NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2 .
  • Specific examples of solvents include THF, di ethyl ether, and glyme.
  • the conversion of compounds of formula (iii) and (iv) to (v) can be accomplished by combining (iii) and (iv) with a base in a solvent.
  • a base in a solvent.
  • Specific examples of (iii) include cyclopropyl para-hydroxyphenyl ketone, 4-hydroxybenzonitrile, 4- bromophenol, 4-cyano-4'-hydroxybiphenyl, 4-hydroxyacetophenone, 2-(4'- hydroxyphenyl)pyridine, 4-cyano-3-fluorophenol, 4-trifluoromethylphenol, and 4-hydroxy- phenyl-1 -hexanone.
  • (iv), wherein X and X are the same or different halides include l-bromo-2-chloroethane; l-bromo-3-chloropropane; l-bromo-4- chlorobutane; 1,2-dibromoethane; 1,3-dibromopropane; 1,4-dibromobutane; l-chloro-3- phenyl propanol; 1,3-butanediol.
  • bases include K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , LiOH, NaOH, KOH, pyridine, lutidine, TEA, DBU and diisopropylethylamine.
  • solvents include 2-butanone, THF, DMF, NMP, acetone, benzene, toluene, DCM and chlorofonri.
  • the reaction generally proceeds at about 70-80 °C, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 6 hours to about 36 hours and can be selected depending on the reaction temperature.
  • (iii) and (iv) in 2-butanone were treated with K 2 CO 3 and refluxed for about 24 hours.
  • compounds of formula (iii) and (iv) can be combined to form compounds of formula (v) by treating the (iv) with a hydroxyl activating group precursor and a nucleophile.
  • hydroxyl activating groups include trifluoroacetic anhydride, diazo compounds and phosphines, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • diazo compounds include DEAD, and DIAD.
  • phosphines include PPh 3 , PEt 3 , DPPE and PMe .
  • nucleophiles include carboxylate anions, phenol anions, thiol anions and alkoxide anions. More prefened are the oxygen anions of cyclopropyl para-hydroxyphenyl ketone, cyclopropyl para-hydroxyphenyl ketone, 4- hydroxybenzonitrile, 4-bromophenol, 4-cyano-4'-hydroxybiphenyl, 4-hydroxyacet ⁇ phenone, 2-(4'-hydroxyphenyl)pyridine, 4-cyano-3-fluorophenol, 4-trifluoromethylphenol, and 4- hydroxy-phenyl-1 -hexanone.
  • solvents include DCM; chloroform; CC1 ; THF; and 1,1,1-trichloroethane.
  • reaction time is generally about one hour to about 16 hours and can be selected depending on the reaction temperature.
  • (iv) and the oxygen anion of para- hydroxy-4-chlorobutyrophenone in about 0 °C DCM is treated with DEAD and PPh 3 , warmed to room temperature and stined for about 16 hours.
  • R , R , and R are defined as in formula (I) and are substituents on the piperazine or diazepane ring.
  • R 4 is synonymous with R 5 in this scheme and is defined in formula (I).
  • Specific examples of (vi) include diamines such as piperazine, trans- 1,4- diaminocyclohexane, 2-methylpiperazine, 2,6-dimethylpiperazine, trans-2,5- dimethylpiperazine, diazepane, and N,N'-dimethyl-l,3-propanediamine.
  • bases include K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , K 3 PO 4 , LiOH, NaOH, and KOH.
  • additives include KI, I 2 , and HI.
  • solvents include acetone, 2-butanone, THF, DCM, and chloroform.
  • the diamine used above can be deprotected by treating the coupled product with a deprotecting agent in a solvent.
  • deprotecting agents include TBAF, HF, H 2 and Pd on carbon, H 2 and Pt on carbon, HCl in methanol, Li/NH 3 , BBr 3 , TsOH, AcOH and heat, ZnBr 2 , HgCl 2 , K 2 CO 3 , Zn, and TFA.
  • solvents include diethyl ether, EtOAc, AcOH, isopropyl acetate, methanol, ethanol, DCM, chloroform, acetonitrile, water, THF and mixtures thereof.
  • reaction usually proceeds at room temperature, it may be run at higher or lower temperatures, as needed.
  • the reaction time is generally about one hour to about 24 hours and can be selected depending on the reaction temperature.
  • the deprotecting agent, solvent, temperature, and time are determined by the nature of the protecting group.
  • the free amine thus formed can then be treated with an acid or an acid derivative, a base and an additive in a solvent.
  • acids or acid derivatives include amino acids, sulfonic acid chlorides, acid anhydrides, acid chlorides, and carboxylic acids.
  • N-Boc-(L)-alanine N-Boc-glycine; N-Boc-4-amino- butyric acid
  • N-Boc-beta-alanine N-Boc-(D)-alanine
  • N-Boc-(L)-proline N-Boc-(D)- proline
  • N-Boc-sarcosine N-Boc-(L)-valine; N-Boc-(D)-valine; N-Boc-(L)-leucine; N-Boc- (D)-leucine; N-Boc-O-benzyl-(L)-serine; N-Boc-O-benzyl-(D)-serine; N-Boc-(S)-pyridyl- phenylalanine; N-Boc-(R)-pyridyl-phenylalanine; N-Boc-(R)-
  • bases include TEA; diisopropylethylamine; pyridine; lutidine; DBU, 2,6-di-tertiary-butylpyridine; and imidazole.
  • additives include DMAP, EDCI, BOPCl, DCC, CDI, ⁇ ATU, PyBOP and combinations thereof.
  • solvents include DCM, chloroform, T ⁇ F, dioxane, diethyl ether, DMF, NMP and acetonitrile.
  • the free amine, an N- protected amino acid, diisopropylethylamine, and DMAP in about 0 °C DCM were treated with EDCI, warmed to room temperature and stined for about 16 hours.
  • the N-protected amine in the coupled product can be can be deprotected by treating it with a deprotecting agent in a solvent.
  • deprotecting agents include ⁇ 2 and Pd on carbon, H and Pt on carbon, HCl in methanol, and TFA.
  • solvents include EtOAc, isopropyl acetate, methanol, ethanol, DCM, and THF.
  • the resulting free amine can be acylated by treating the former with an acid or acid derivative, a base and an additive in a solvent.
  • acids or acid derivatives include amino acids, sulfonic acid chlorides, carboxylic acid chlorides, carboxylic acid anhydrides, and carboxylic acids. More prefened are the following acid derivatives: acetyl chloride; methyl chloroformate; cyclopropyl acetyl chloride; methanesulfonyl chloride; N,N- dimethyl sulfarnoylchloride; 3,3-dimethylbutanoyl chloride; mo ⁇ holine carbamoyl chloride; furanoyl chloride; and 2-thiophenyl chloride.
  • bases include TEA, diisopropylethylamine, pyridine, lutidine, and imidazole.
  • additives include no additive, DMAP, EDCI, BOPCl, DCC, CDI, HATU, PyBOP and mixtures thereof.
  • solvents include DCM, chloroform, diethyl ether, THF, dioxane, DMF, NMP and acetonitrile.
  • the free amine and TEA in about 0 °C DCM were treated an acid chloride, warmed to room temperature and stined for about 6 hours.
  • the free amine can be reductively aminated by treating it with a carbonyl compound, a reducing agent, and an optionally added acid catalyst in a solvent.
  • carbonyl compounds include aldehydes and ketones. More prefened is the following carbonyl compound, acetone.
  • a specific example of an acid catalyst is AcOH.
  • Specific examples of reducing agents include NaBH 4 and NaCNBH 3 .
  • Specific examples of solvents include THF, MeOH, EtOH and acetone.
  • the conversion of (vii) to (viii) can be accomplished by treating the former with a hydroxylamine source and a base in a solvent.
  • hydroxylamine sources include hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine nitrate, hydroxylamine phosphate and aqueous hydroxylamine.
  • bases include TEA, DBU, pyridine, LiOH, NaOH, KOH, K 2 CO 3 , Na 2 CO 3 , and NaHCO .
  • Specific examples of solvents include ethanol, methanol, and isopropanol.
  • reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperatures as needed.
  • the reaction time is generally about eight hours to about 24 hours and can be selected depending on the reaction temperature. In a prefened embodiment,
  • the conversion of (viii) to (ix) can be accomplished by treating the former with an acylating agent, and a base in a solvent.
  • acylating agents include acid anhydrides and acid chlorides. More prefened is acetyl chloride.
  • bases include TEA, diisopropylethylamine, pyridine, lutidine, and imidazole.
  • solvents include acetone, THF, ethyl ether, DCM, chloroform and TBME.
  • the conversion of (ix) to (x) can be accomplished by thermally cyclizing the former in a solvent.
  • solvents include toluene, benzene, xylene, glyme, 2- butanone and NMP.
  • the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperature as needed.
  • the reaction time is generally about four hours to about 48 hours. In a prefened embodiment, (ix) in toluene was refluxed for about 24 hours.
  • the conversion of (vii) to (xi) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include LiOH, NaOH, KOH, K 2 CO 3 , and Na 2 CO 3 .
  • solvents include THF, TBME, methanol, ethanol, water, and mixtures thereof.
  • the conversion of (xii) and (xiii) to (xiv) can be accomplished by a palladium-mediated coupling as in Tetrahedron Letters, 1987, 28(45), 5395-5398, wherein X 3 is a bromide, iodide or a triflate.
  • the conversion of (xiv) to (xv), wherem Z is a leaving group can be accomplished by treating the former with a leaving group precursor and a base in a solvent.
  • Specific examples of leaving group precursors include trifluoroacetic anhydride, trifluormethanesulfonyl chloride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • bases include, TEA, pyridine, lutidine, collidine, diisopropylethylamine, and DBU.
  • solvents include THF, DCM, toluene, pyridine and chloroform.
  • R , R , and R are defined as in formula (I) and are substituents on the piperazine or diazepane ring.
  • R is synonymous with R in this scheme and is defined in formula (I).
  • Specific examples of (vi) include diamines such as piperazine, trans- 1,4-diaminocyclohexane, 2-methylpiperazine, 2,6- dimethylpiperazine, trans-2,5-dimethylpiperazine, diazepane, and N,N'-dimethyl-l,3- propanediamine.
  • bases include K 2 CO 3 , Na 2 CO 3 , NaHCO , K PO ,
  • LiOH, NaOH, and KOH LiOH, NaOH, and KOH.
  • additives include KI, I 2 , and HI.
  • solvents include acetone, 2-butanone, THF, DCM, and chloroform.
  • the conversion of (xiii) to (xvii), wherein Z is a leaving group can be accomplished by treating the former with a leaving group precursor and a base in a solvent.
  • leaving group precursors include trifluoroacetic anhydride, trifluormethanesulfonyl chloride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • bases include, TEA, pyridine, lutidine, collidine, diisopropylethylamine, and DBU.
  • Specific examples of solvents include THF, DCM, toluene, pyridine and chloroform.
  • reaction time is generally about 30 minutes to about 16 hours, hi a prefened embodiment, (xiii) and TEA in 0°C THF were treated with paratoluenesulfonyll chloride and stined for about 16 hours.
  • R , R , and R are defined as in formula (I) and are substituents on the piperazine or diazepane ring.
  • R is synonymous with R in this scheme and is defined in fonnula (I).
  • Z is defined as a leaving group.
  • Specific examples of (vi) include diamines such as piperazine, trans- 1,4-diaminocyclohexane, 2-methylpiperazine, 2,6-dimethylpiperazine, trans-2,5-dimethylpiperazine, diazepane, and N,N'-dimethyl-l,3-propanediamine.
  • bases include K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , K 3 PO 4 , LiOH, NaOH, and KOH.
  • additives include KI, I 2 , and HI.
  • solvents include acetone, 2-butanone, THF, DCM, and chloroform.
  • Example 1A cyclopropyl(4-hvdroxyphenyl)methanone
  • a refluxing solution of sodium hydroxide in water (50% (w/w), 40.4 mL) was treated over a period of 15 minutes with para-hydroxy-4-chlorobutyrophenone (25.0 g, 137 mmol), followed by additional aqueous sodium hydroxide (25% (w/w), 177 mL).
  • Additional para- hydroxy-4-chlorobutyrophenone (25.0 g, 137 mmol) was added portionwise to the reaction mixture, followed by solid sodium hydroxide (40.4 g). A yellow precipitate formed.
  • Example 1A A solution of Example 1A (10 g, 61.7 mmol), K 2 CO 3 (12.7 g, 91.9 mmol), and 1- bromo-3-chloropropane (10.74 g, 68.2 mmol) in 2-butanone (100 mL) was refluxed for 24 hours, cooled to room temperature, filtered, and concentrated. The concentrate was heated to 40°C under vacuum for three hours to afford 13.256g (90%) of the desired product of sufficient purity for subsequent use without further purification.
  • Example IB A mixture of Example IB (10 g, 42 mmol), KI (8.5 g, 51.2 mmol), K 2 CO 3 (8.75 g, 63.3 mmol), and piperazine (10.75 g, 125 mmol) in 2-butanone (500 mL) was refluxed for 48 hours. The reaction mixture was then cooled to room temperature, treated with IM sodium thiosulfate (100 mL) and ethyl acetate (500 mL). The layers were separated, and the organic layer was washed with water and brine, dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by column chromatography on silica gel using 98:2:0.1 to 95:5:0.9 dichloromethane:methanol:concentrated ammonium hydroxide as the eluant to afford 9.931 g (82%) of the desired product.
  • Example 1C A solution of Example 1C (4.5 g, 15.6 mmol), N,N-diisopropylethylamine (8.3 mL, 47.6 mmol), DMAP (380 mg, 3.1 mmol) and N-Boc-(L)-alanine (3.69 g, 19.5 mmol) in dichloromethane (120 mL) at 0°C was treated with EDCI (3.6 g, 18.8 mmol). The reaction mixture was warmed to room temperature, stined for 18 hours, treated with half-saturated NaHCO 3 (100 mL), and extracted with dichloromethane. The combined organic layers were washed sequentially with 0.5 M citric acid, water, and brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by column chromatography on silica gel using
  • Example IE 4-(3-(4-((2S)-2-amino ⁇ ropanoyl)-l-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone
  • Example ID A solution of Example ID (3.0 g, 6.5 mmol) in dichloromethane (30 mL) at 0°C was treated, over a period of 10 minutes, with trifluoroacetic acid (7.5 mL, 97 mmol). The reaction mixture was allowed to warm to room temperature, stined for 24 hours, and concentrated. The concentrate was dissolved in dichloromethane (300 mL) and the solution was washed sequentially with saturated NaHCO 3 , water, and brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was dissolved in methanol (120 mL), treated with L- tartaric acid (1.0 equivalent based on recovered material), stined for 18 hours at room temperature, and concentrated. The concentrate was dissolved in water (25 mL) and lyophilized to afford the desired product in 83% yield.
  • the desired product was prepared according to the method described in Example IB, substituting 4-hydroxybenzonitrile for Example 1 A.
  • Example 2A for Example IB and tert-butyl 1-piperazinecarboxylate for piperazine.
  • Example 2B A mixture of Example 2B (2.0 g, 5.8 mmol), finely divided K 2 CO 3 (4.0 g, 29 mmol), and hydroxylamine hydrochloride (2.0 g, 29 mmol) in absolute ethanol (40 mL) was refluxed for 18 hours, cooled to room temperature, and filtered. The solids were washed with hot ethanol, and the combined filtrates were concentrated to afford 2.05 g, (93.5 %) of the desired product as a white powder.
  • Example 2C A solution of Example 2C (0.11 g, 0.29 mmol) and triethylamine (400 ⁇ L, 2.9 mmol) in acetone (10 mL) was treated with a solution of acetyl chloride (200 ⁇ L, 2.8 mmol) in acetone (1 mL) over 30 minutes, stined for 1 hour, and concentrated.
  • the concentrate was partitioned between water and dichloromethane. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (Na 2 SO 4 ), filtered and concentrated.
  • the concentrate was purified by column chromatography on silica gel using 95:5 dichloromethane :methanol to afford 106 mg (87%) of the desired product.
  • Example 2D A solution of Example 2D (100 mg, 0.24 mmol) in toluene (10 mL) was refluxed for 24 hours and concentrated. The concentrate was triturated with a diethyl ether and dichloromethane mixture to afford 92 mg (95%) of the desired product of sufficient purity for subsequent use without further purification.
  • Example 2E A solution of Example 2E in dichloromethane at room temperature is treated with trifluoroacetic acid, stined for 12 hours, and concentrated. The concentrate is partitioned between dichloromethane and saturated aqueous Na 2 CO 3 . The layers are separated, and the dichloromethane layer is dried (MgSO 4 ), filtered and concentrated to afford the desired product.
  • the desired product is prepared according to the method described in Example ID, substituting Example 2F for Example IC.
  • Example IE The desired product is prepared according to the method described in Example IE, substituting Example 2G for Example ID.
  • Example 3 A for Example IB to afford the desired product.
  • Example 6A l-(4-(3-chloropropoxy)phenyl ethanone
  • the title compound was prepared according to the method described in Example IB, substituting 4-hydroxyacetophenone for Example 1 A to afford the desired product.
  • Example 6A The title compound was prepared according to the method described in Example IC, substituting Example 6A for Example IB to afford the desired product.
  • Example 7A A 0°C solution of Example 7A (4.75 g, 23.2 mmol) and TEA (3.3 mL, 23.7 mmol) in dichloromethane (40 mL) was treated with methanesulfonyl chloride (1.8 mL, 23.4 mmol). The reaction mixture was allowed to warm to room temperature, stined for 2 hours, quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The combined dichloromethane layers were dried (MgSO 4 ), filtered and concentrated to afford of the desired product in quantitative yield and of sufficient purity for subsequent use without further purification.
  • Example 7E cyclopro ⁇ yl(4-(( ' (3R)-3-( ' l-piperazinyl)butyl)oxy)phenyl)methanone
  • a 0 °C solution of Example 7D (1.3 g, 3.5 mmol) in dichloromethane (30 mL) was treated with TFA (4.05 mL, 52 mmol).
  • the reaction mixture was allowed to warm to room temperature and stined overnight.
  • the reaction mixture was concentrated and treated with NaOH (1 N), to a pH of approximately 12, followed by extraction with dichloromethane.
  • the dichloromethane layers were combined, dried (Na 2 SO ), filtered, and concentrated to afford 954 mg, (90%) of the desired product of sufficient purity for subsequent use without further purification.
  • Example 8D tert-butyl 4-(riS)-3-(4-(cyclopropylcarbonyl phenoxy)- 1 -methylpropyl)- 1 -piperazinecarboxylate
  • the title compound was prepared according to the method described in Example 7D, substituting Example 8C for Example 7C to afford the desired product.
  • Example 8E cyclopropyl(4-(((3S)-3-(l-piperazinyl butyl oxy phenyl)methanone The title compound was prepared according to the method described in Example 7E, substituting Example 8D for Example 7D to afford the desired product.
  • Example 10 4'-(3-(l -piperazinvDpropoxyXI '-biphenyl)-4-carbonitrile
  • Example 10A 4'-(3-(l -piperazinvDpropoxyXI '-biphenyl)-4-carbonitrile
  • Example 10A The title compound was prepared according to the method described in Example IC, substituting Example 10A for Example IB.
  • Example 12 tert-butyl 2-(4-(3-(4-bromophenoxy propyl -l-piperazinyl)-2-oxoethylcarbamate
  • the desired product was prepared according to the method described in Example ID, substituting Example 3B for Example IC and N-Boc-glycine for N-Boc-(L)-alanine.
  • Example 3B for Example IC
  • N-Boc-4-amino-butyric acid for N-Boc-(L)- alanine.
  • Example 14 The desired product was prepared according to the method described in Example IE, substituting Example 14 for Example ID.
  • Example 16 tert-butyl qR)-2-f4-(3-f4-bromophenoxy) propyl)- 1 -piperazinyl)- 1 -methyl-2-oxoethylcarbamate
  • the desired product was prepared according to the method described in Example ID, substituting Example 3B for Example IC and N-Boc-(D)-alanine for N-Boc-(L)-alanine.
  • Example 3B The desired product was prepared according to the method described in Example ID, substituting Example 3B for Example IC.
  • the desired product was prepared according to the method described in Example ID, substituting Example 3B for Example 1 C and N-Boc-(L)-proline for N-Boc-(L)-alanine.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 20 for Example ID.
  • Example 3B for Example IC and N-Boc-(D)-proline for N-Boc-(L)-alanine.
  • the desired product was prepared according to the method described in Example IB, substituting 4-trifluoromethylphenol for Example 1A.
  • Example 24C tert-butyl (lR)-l-me hyl-2-oxo-2-(4-f3-(4-
  • Example IC The desired product was prepared according to the method described in Example IC, substituting Example 2 A for Example IB.
  • Example 25A for Example IC
  • N-Boc-(D)-alanine for N-Boc-(L)-alanine.
  • the desired product was prepared according to the method described in Example IB, substituting 4-cyano-3-fluorophenol for Example 1 A.
  • Example 26B 2-fluoro-4-(3-(l-piperazinyl)propoxy)benzonitrile The desired product was prepared according to the method described in Example IC, substituting Example 26A for Example IB.
  • Example 26C tert-butyl 3 -(4-(3 -(4-cyano-3 -fluorophenoxy)prop yl)- 1 -piperazinyl)-3-oxopropylcarbamate
  • the desired product was prepared according to the method described in Example ID, substituting Example 26B for Example IC and N-Boc-beta-alanine for N-Boc-(L)-alanine.
  • Example 27 tert-butyl (lR)-2-(4-(3-(4-(aminocarbonyl)-3-fluorophenoxy) propyl)- 1 -piperazinyl)- 1 -methyl-2-oxoethylcarbamate
  • Example 27A tert-butyl (lR)-2-(4-(3-(4-cvano-3-fluoro ⁇ henoxy) propyl)- 1 -piperazinyl)- 1 -methyl-2-oxoethylcarbamate
  • Example 26B for Example IC and N-Boc-(D)-alanine for N-Boc-(L)-alanine.
  • Example 27A A mixture of Example 27A, finely divided K 2 CO 3 and hydroxylamine hydrochloride in absolute ethanol was refluxed for 18 hours. The hot reaction mixture was filtered and the remaining solids were washed with hot ethanol. The combined filtrates were concentrated to the desired product in quantitative yield and of sufficient purity for subsequent use without further purification.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 28 for Example ID.
  • Example 30 N-((lR)-2-(4-(3-( , 4-acetylphenoxy)propyl)-l-piperazinyl)-l-methyl-2-oxoethyl)acetamide
  • a 0 °C solution of Example 29 (1 mmol) and TEA (1.1 mmol) in dichloromethane (10 mL) was treated with acetyl chloride (1 mmol). After stirring for four hours at 0 °C, the reaction mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. The crude material was purified tlirough silica gel chromatography to afford the desired product in 83% yield.
  • Example 33 A tert-butyl 4-((lR -3-(4-acetylphenoxy)-l-methylpropyl)-l-piperazinecarboxylate
  • Example 7D The desired product was prepared according to the method described in Example 7D, substituting 4-hydroxy acetophenone for Example 1 A.
  • Example 33C tert-butvUlRV2-r4-((lR)-3-(4-acetylphenoxy)
  • Example 6B for Example IC and N-Boc-(D)-proline for N-Boc-(L)-alanine.
  • Example 6B for Example IC
  • N-Boc-(L)-proline for N-Boc-(L)-alanine.
  • the desired product was prepared according to the method described in Example 7B, substituting Example 29 for Example 7A.
  • Example 7B The desired product was prepared according to the method described in Example 7B, substituting Example 29 for Example 7A and N,N-dimethyl sulfamoylchloride for methanesulfonyl chloride.
  • Example IB The desired product was prepared according to the method described in Example IB, substituting 4-hydroxy-phenyl-l -hexanone for Example 1A.
  • Example 39B for Example IC
  • N-Boc-sarcosine for N-Boc-(L)-alanine.
  • Example 39D l-( , 4-(3-( ' 4-(( m ethylamino)acetyl)-l-piperazinyl)propoxy)phenvD-l-hexanone
  • the desired product was prepared according to the method described in Example IE, substituting Example 39C for Example ID.
  • Example 41 1 -(4-(3-(4-(3 -aminopropano yl)- 1 -piperazinyl)propoxy)phenyl)- 1 -hexanone
  • Example 41 A tert-butyl 3-( ' 4-( ' 3-(4-hexanoylphenoxy)propyl)-l-piperazinyl)-3-oxopropylcarbamate
  • the desired product was prepared according to the method described in Example ID, substituting Example 39B for Example IC and N-Boc-beta-alanine for N-Boc-(L)-alanine.
  • Example 4 IB l-(4-(3-(4-(3-aminopropanoyl)-l-piperazinyl)propoxy)phenyl)-l-hexanone
  • the desired product was prepared according to the method described in Example IE, substituting Example 41A for Example ID.
  • Example 39B for Example IC
  • N-Boc-(D)-alanine for N-Boc-(L)-alanine.
  • Example 39B for Example IC
  • N-Boc-(L)-valine for N-Boc-(L)-alanine.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 43 for Example ID.
  • Example 39B for Example IC
  • N-Boc-(D)-valine for N-Boc-(L)-alanine.
  • Example 39B for Example IC
  • N-Boc-(L)-leucine for N-Boc-(L)-alanine.
  • Example 39B for Example IC
  • N-Boc-(D)-leucine for N-Boc-(L)-alanine.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 49 for Example ID.
  • Example 39B for Example IC and N-Boc-O-benzyl-(L)-serine for N-Boc-(L)- alanine.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 51 for Example ID.
  • Example 52 A (1 mmol) in methanol (10 mL) was treated with Pd/C (10%, 40 mg) and hydrogen gas for 16 hours. The reaction mixture was filtered and concentrated to afford the desired product of sufficient purity for subsequent use without further purification. .
  • MS (ESI(+)) m/z 406 (M+H) + ; H NMR (300 MHz, DMSO-d 6 ) ⁇ 8.05 (br s, 2H), 7.85 (d, 2H), 6.92 (d, 2H), 4.31 (br s, IH), 4.05 (t, 2H), 3.60-3.50 (m, 2H), 3.34 (m, 4H), 2.82 (t, 2H), 2.42 (m, 6H), 2.05 (br s, 2H), 1.50 (m, 2H), 1.21 ( m, 4H), 0.79 (t, 3H).
  • Example 53B l-(4-(3-f4-((2S)-2-amino-3-(benzyloxy)propanoyl) - 1 -piperazinyl)propoxy)phenyl)- 1 -hexanone
  • the desired product was prepared according to the method described in Example IE, substituting Example 53 A for Example ID.
  • Example 39B for Example IC andN-Boc-(S)-4-pyridyl-phenylalanine forN- Boc-(L)-alanine.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 54 for Example ID.
  • the desired product was prepared according to the method described in Example ID, substituting Example 39B for Example 1 C and N-Boc-(L)-histidine for N-Boc-(L)-alanine.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 58 for Example ID.
  • Example 7E for Example IC
  • N-Boc-beta-alanine for N-Boc-(L)-alanine.
  • Example 60B (4-(((3R)-3 -(4-(3 -aminopropano yl)- 1 -piperazinyl)butyl)oxy)phenyl)(cvclopropyl)methanone
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 60A for Example ID.
  • Example 7E for Example IC and N-Boc-(D)-alanine for N-Boc-(L)-alanine.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 61 for Example ID.
  • the desired product was prepared according to the method described in Example ID, substituting N-Boc-(D)-alanine for Boc-(L)-alanine.
  • Example 65B cyclopropyl(4-(((3R)-3-(4-((methylamino)acetvP-l-piperazinvPbutvPoxy)phenyl)methanone
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 65A for Example ID.
  • Example 66A tert-butyl ( IR)- 1 -((4-(3 -(4-(cycloprop ylcarbonyl)phenoxy)propyP- 1 -piperazinvDcarbonvD-
  • Example 66B The desired product was prepared according to the method described in Example ID, substituting N-Boc-(2R)-2-amino-3,3-dimethylbutanoic acid for N-Boc-(L)-alanine.
  • Example 66B N-Boc-(2R)-2-amino-3,3-dimethylbutanoic acid for N-Boc-(L)-alanine.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 66A for Example ID.
  • the desired product was prepared according to the method described in Example ID, substituting N-Boc-(2R)-2-amino-4,4-dimethylpentanoic acid for N-Boc-(L)-alanine.
  • the desired product was prepared according to the method described in Example ID, substituting N-Boc-(2R)-2-amino-butanoic acid for N-Boc-(L)-alanine.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 69A for Example ID.
  • Example 70 cvclopropyl(4-f3-(4-((2R)-2-(methylamino)-3- phenylpropano yl)- 1 -piperazinyl)propoxy)phenyl)methanone
  • Example 70A tert-butyl (lR)-l-benzyl-2-(4-(3-(4-(cyclopropylcarbonvP phenoxy)propyl)-l-piperazinyl)-2-oxoethyl(methvPcarbamate
  • the desired product was prepared according to the method described in Example ID, substituting N-Boc-(L)-N-methylphenyl alanine for N-Boc-(L)-alanine.
  • Example 70B cyclopropyl( , 4-( ' 3-r4-( ' r2R)-2-(methylamino)-3-phenylpropanovP-l- ⁇ iperazinvPpropoxy)phenyl)methanone
  • the desired product was prepared according to the method described in Example IE, substituting Example 70A for Example ID.
  • the desired product was prepared according to the method described in Example ID, substituting N-CBz-(D)-O-tert-butyl-serine for N-Boc-(L)-alanine.
  • the desired product was prepared according to the method described in Example 52B, substituting Example 72 for Example 52A.
  • the desired product was prepared according to the method described in Example ID, substituting N-Boc-(D)-O-tert-butyl-threonine for N-Boc-(L)-alanine.
  • the desired product was prepared according to the method described in Example ID, substituting N-Boc-(D)-O-benzyl-threonine for N-Boc-(L)-alanine.
  • the desired product was prepared according to the method described in Example ID, substituting N-Boc-(D)-2,6-diamino-carbonyl hexanoic acid for N-Boc-(L)-alanine.
  • the desired product was prepared according to the method described in Example ID, substituting N-Boc-(D)-phenylalanine for N-Boc-(L)-alanine.
  • the desired product was prepared according to the method described in Example ID, substituting N-Boc-(D)-4-Fluoro-phenylalanine for N-Boc-(L)-alanine.
  • Example IE The desired product was prepared according to the method described in Example IE, substituting Example 80 for Example ID.
  • the desired product was prepared according to the method described in Example ID, substituting (2R)-2-azetidinone-4-carboxylic acid for N-Boc-(L)-alanine.

Abstract

Cette invention se rapporte à des composés représentés par la formule (I), à des composés représentés par la formule (II), à des composés représentés par la formule (III) et à des composés représentés par la formule (IV), ou à des sels de ceux-ci acceptables sur le plan pharmaceutique, qui sont utiles comme antagonistes du récepteur de H3. Des procédés de production de ces composés et des procédés de traitement utilisant ces composés sont également décrits.
PCT/US2001/006885 2000-03-09 2001-03-05 Antagonistes du recepteur d'histamine-3 diamino cycliques et bicycliques WO2001066534A2 (fr)

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WO2003004480A2 (fr) 2001-07-02 2003-01-16 Novo Nordisk A/S Piperazines et diazepanes substitues
WO2003024928A2 (fr) 2001-09-14 2003-03-27 Novo Nordisk A/S Nouveau derives d'aminoazetidine, d'aminopyrrolidine et d'aminopiperidine
WO2003050099A1 (fr) * 2001-12-10 2003-06-19 Ortho-Mcneil Pharmaceutical, Inc. Phenylalkynes
US6673829B2 (en) 2001-09-14 2004-01-06 Novo Nordisk A/S Aminoazetidine,-pyrrolidine and -piperidine derivatives
WO2004050623A1 (fr) * 2002-12-02 2004-06-17 Ortho-Mcneil Pharmaceutical, Inc. Procedes pour l'elaboration de derives phenylalkyniques
US6906060B2 (en) 2002-06-06 2005-06-14 Novo Nordisk A/S Substituted hexahydropyrrolo[1,2-a]pyrazines, octahydropyrido[1,2-a]-pyrazines and decahydropyrazino[1,2-a]azepines
US6992096B2 (en) 2003-04-11 2006-01-31 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
US7101898B2 (en) 2002-02-01 2006-09-05 Novo Nordisk A/S Amides of aminoalkyl-substituted azetidines, pyrrolidines, piperidines and azepanes
WO2007003604A2 (fr) 2005-07-04 2007-01-11 Novo Nordisk A/S Medicaments
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WO2007137968A1 (fr) 2006-05-29 2007-12-06 High Point Pharmaceuticals, Llc Benzodioxolylcyclopropylpipérazinylpyridazines
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US7446103B2 (en) 2002-10-22 2008-11-04 Glaxo Group Limited Bicyclic benzamide compound as histamine H3 receptor ligand useful in the treatment of neurological diseases
WO2008154126A1 (fr) 2007-06-11 2008-12-18 High Point Pharmaceuticals, Llc Nouveaux antagonistes hétérocycliques de h3
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WO2003004480A2 (fr) 2001-07-02 2003-01-16 Novo Nordisk A/S Piperazines et diazepanes substitues
US7208497B2 (en) 2001-07-02 2007-04-24 Novo Nordisk A/S Substituted piperazines and diazepanes
WO2003024928A2 (fr) 2001-09-14 2003-03-27 Novo Nordisk A/S Nouveau derives d'aminoazetidine, d'aminopyrrolidine et d'aminopiperidine
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US7314937B2 (en) 2002-03-21 2008-01-01 Eli Lilly And Company Non-imidazole aryl alkylamines compounds as histamine H3 receptor antagonists, preparation and therapeutic uses
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US7446103B2 (en) 2002-10-22 2008-11-04 Glaxo Group Limited Bicyclic benzamide compound as histamine H3 receptor ligand useful in the treatment of neurological diseases
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