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WO2000063208B1 - Substituted imidazoles, their preparation and use - Google Patents

Substituted imidazoles, their preparation and use

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Publication number
WO2000063208B1
WO2000063208B1 PCT/DK2000/000179 DK0000179W WO0063208B1 WO 2000063208 B1 WO2000063208 B1 WO 2000063208B1 DK 0000179 W DK0000179 W DK 0000179W WO 0063208 B1 WO0063208 B1 WO 0063208B1
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Prior art keywords
alkyl
aryl
heteroaryl
aroyl
heteroaroyl
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WO2000063208A1 (en
Inventor
Florencio Zaragoza Doerwald
Knud Erik Andersen
Tine Krogh Joergensen
Bernd Peschke
Birgitte Schjellerup Wulff
Ingrid Pettersson
Klaus Rudolf
Dirk Stenkamp
Rudolf Hurnaus
Stephan Georg Mueller
Bernd Krist
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Boehringer Ingelheim International GmbH
Novo Nordisk AS
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Boehringer Ingelheim International GmbH
Novo Nordisk AS
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Priority to EP00918714A priority Critical patent/EP1173438A1/en
Priority to JP2000612298A priority patent/JP2002542245A/en
Priority to AU39569/00A priority patent/AU3956900A/en
Publication of WO2000063208A1 publication Critical patent/WO2000063208A1/en
Publication of WO2000063208B1 publication Critical patent/WO2000063208B1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/04—Ortho-condensed systems

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Abstract

A novel class of substituted imidazole compounds (I), pharmaceutical compositions comprising them and use thereof in the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor. More particularly, the compounds are useful for the treatment and/or prevention of diseases and disorders, in which an interaction with the histamine H3 receptor is beneficial.

Claims

165AMENDED CLAIMS[received by the International Bureau on 12 October 2000 (12.10.00); oπginal claims 1-52 replaced by amended claims 1-46 (24 pages)]
1. A compound of the general formula
R- FT
R1 (CH2 (CH 2 n \
v\
Figure imgf000002_0001
wherein
R1 is hydrogen or a functional group, which can be converted to hydrogen in vivo;
R2 is hydrogen, Cι-6-alkyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy or -NR7R8,
wherein R7 and R8 independently are
hydrogen,
Ci-e-alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C3.8-cycloalkyl, which are optionally substituted with
Ci-e-alkyl, d-6-alkoxy, d-6-alkylthio, hydroxy, amino, Cι-6-alkylamino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with 1 66
C-ι-6-alkyl, Ci 6-alkoxy, C1-6-alkylthιo, hydroxy, ammo, d 6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, tπfluoromethyl, tπfluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
Ci-6-alkylsulfonyl optionally substituted with
C3.8-cycloalkyl, Cι-6-alkoxy, Ci 6-alkylthιo, hydroxy, ammo, Ci 6-alkylamιno, dι(Cι-6-alkyl)amιno, halogen, cyano, tπfluoromethyl, tπfluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino, or
R7 and R8, together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with Cι-6-alkyl, Cι-6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, Cι-6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, tπfluoromethyl, tπfluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino;
R3, R4, R5 and R6 independently are
hydrogen, carboxy, Ci 6-alkoxycarbonyl, cyano, tπfluoromethyl, halogen,
C3-8-cycloalkyl optionally substituted with
Cι-6-alkyl, C1-6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, Ci 6-alkylamιno, di- (Cι-6-alkyl)amιno, halogen, cyano, tπfluoromethyl, tπfluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
C-ι-6-alkyl, C .6-alkenyl or C2-6-alkynyl, which are optionally substituted with
C-i-β-alkoxy, C1.6-alkylthιo, hydroxy, cyano, halogen, tπfluoromethyl, tπfluoro- methoxy, carboxy, C-ι-6-alkoxycarbonyl, C3-8-cycloalkyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino, which are optionally substituted with
Cι-6-alkyl, C1-6-alkoxy, C .6-alkylthιo, hydroxy, ammo, Ci 5-alkylamιno, dι(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, tπfluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo, heteroarylamino or
-CO-NR9R10,
aryl optionally substituted with halogen, cyano, nitro, d-6-alkyl, Cι-6-alkoxy, hydroxy, trifluoromethyl, tπfluoro- methoxy, aryl, heteroaryl, aryloxy, aroyl, heteroaroyl, arylsulfonyl, arylammo, heteroarylamino or -CO-NR9R10,
-CO-NR9R10,
wherein R9 and R10 independently are
hydrogen,
d-6-alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo, heteroarylamino or C3.8-cycloalkyl, which are optionally substituted with
C-ι-6-alkyl, d-6-alkoxy, d-β-alkylthio, hydroxy, ammo, Cι-6-alkylamιπo, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or hetero- arylammo,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with
C-ι-6-alkyl, Cι-6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, Cι-6-alkylamιno, di(Cι.6-alkyl)amιno, halogen, cyano, tπfluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino, 168
C-ι-6-alkylsulfonyl optionally substituted with
C3-8-cycloalkyl, Cι-6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, Cι_6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryi, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino, or
R9 and R10, together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with d.6-alkyl, d-6-alkoxy, Ci 6-alkylthιo, hydroxy, ammo, C-ι-6-alkylamιno, dι(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino, or
R3 and R4, together with the carbon atom to which they are connected, and/or R5 and R6 together with the carbon atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, carbocyclic or heterocyclic ring optionally substituted with C-ι-6-alkyl, C-ι-6-alkoxy, d-6-alkylthιo, hydroxy, ammo, Cι-6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
m, n, p and q independently are 0, 1 or 2;
X is a valence bond, -CH2-, -C(=0)-, -C(=S)-, -S(=0)-, -S(=0)2-, -C(=N-CN)-, -C(=CH-N02)-, -C[=C(CN)2]-, -C(=CH-CN)-, -C(=NR11)- or -C(=N-S(=0)2R11a)-,
wherein R11 is
hydrogen,
d-6-alkyl optionally substituted with 169 aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo, heteroarylamino or C3.8-cycloalkyl, which are optionally substituted with d-6-alkyl, d-6-alkoxy, C1-6-alkylthιo, hydroxy, ammo, Cι-6-alkylamιno, dι(Cι-6-alkyl)ammo, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with Cι-6-alkyl, d-6-alkoxy, d-6-alkylthιo, hydroxy, ammo, C1-6-alkylamιno, di(d-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
d-6-alkylsulfonyl optionally substituted with C3-8-cycloalkyl, d-6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, d-6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
R11a is
Cι-6-alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo, heteroarylamino or C3-8-cycloalkyl, which are optionally substituted with d-6-alkyl, d.6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, d-6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with 170
Cι-6-alkyl, d-6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, Ci 6-alkylamιno, di(Cι.6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
Y is a valence bond, -O- or -N(R12)
wherein R12 is
hydrogen,
d-6-alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo, heteroarylamino or C3 8-cycloalkyl, which are optionally substituted with d-6-alkyl, Cι-6-alkoxy, C-ι-6-alkylthιo, hydroxy, ammo, Cι-6-alkylamιno, di(C1-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with d-6-alkyl, C1-6-alkoxy, d-6-alkylthιo, hydroxy, ammo, Cι-6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
C-ι-6-alkylsulfonyl optionally substituted with
C3.8-cycloalkyl, d-β-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, d-6-alkylamιno, di(C-ι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
A is a valence bond, Cι-8-alkylene, C2-8-alkenylene, C2.8-alkynylene, C3-8-cyclo- alkylene or phenylene, or 1 7 1 when Y is -N(R12)-, A, together with R12 and the nitrogen atom to which they are connected, may form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring system optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with Cι-6-alkyl, d-6-alkoxy, d-6-alkyl- thio, hydroxy, ammo, Cι-6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aryl-d.6-alkyl, heteroaryl-Cι-6-alkyl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino; and
Z is
C-ι-6-alkyl, optionally substituted with aryl, arylammo, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, Ci 6-alkyl- sulfonyl, sulfonylammo, arylthio, heteroarylthio, aryloxy, acylamino. heteroaryl or C3-8-cycloalkyl, which are optionally substituted with d-6-alkyl, Ci-6-alkoxy, Cι.6-alkylthιo, aryl-d-6-alkyl, heteroaryl-d-6-al- kyl, nitro, arylammo, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, d-6-alkylsulfonyl, sulfonylammo, arylthio, heteroarylthio, aryloxy, acylamino, hydroxy, ammo, d-6-alkylamιno, di- (Ci.6-alkyl)ammo, halogen, cyano, trifluoromethoxy or trifluoromethyl,
aryl, C3-1 -cycloalkyl, C3-i5-cycloalkenyl, aroyl or heteroaryl, which are optionally substituted with aryl-d-6-alkyl, heteroaryl-C-ι.6-alkyl, aryl, heteroaryl, nitro, arylammo, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, Cι-6-alkylsulfonyl, sul- fonylamino, arylthio, heteroarylthio, aryloxy, acylamino, d-6-alkyl, Cι-6-alkoxy, d-6-alkylthιo, C3-8-cycloalkanecarbonyl, hydroxy, ammo, C-ι-6-alkylamιno, di(Cι.6-alkyi)amιno, halogen, cyano, trifluoromethoxy or tπfluoromethyl,
-NR13R14, in which R13 and R14 are both phenyl, which phenyl groups are joined with a C- -alkylene group to form a tπcyclic ring system, 172
-CHR13R14, in which R13 is C1-6-alkyl or phenyl and R14 is phenyl, or R13 and R14 are both Cι-6-alkyl which are joined with Cι-4-alkylene linkers to form a polycarbocyclic ring system, or
-CR13R14R15, in which R13, R14 and R15 are Ci 6-alkyl which are joined with Cι- -alkylene linkers to form a polycarbocyclic ring system,
with the provisos that
when X is -CS-, R1 = R2 = R5 = R6 = hydrogen, m = n = p = 0 and q = 1 , the group -Y-A-Z must not start with the radical -NH-,
when the group -X-Y-A-Z starts with the radical -CH2-, R1 = R2 = R6 = hydrogen, m = n = p = 0 and q = 1 , R5 must not be carboxy or aminocarbonyl;
when X is -CO-, the group -Y-A-Z starts with the radical -NH-, R1 = R2 = R6 = hydrogen, m = n = p = 0 and q = 1 , the remainder of the group -Y-A-Z must not be hydrogen, unsubstituted or C1-6-alkoxy substituted phenyl, unsubstituted C3-8-cycloalkyl or unsubstituted d-6-alkyl;
when X is -CO-, Y is -0-, A is -CH2-, Z is phenyl, R1 = R2 = R3 = R4 = R6 = hydrogen, m = n = p = 0 and q = 1 , R5 must not be carboxy, aminocarbonyl or 4-phenyl- piperazιn-1 -ylcarbonyl;
when X is -CO-, Y is -0-, A is -CH2-, Z is phenyl, R1 = R3 = R4 = R6 = hydrogen, R2 = butyl, m = n = p = 0 and q = 1 , R5 must not be methoxycarbonyl,
when X is -CO-, Y is -0-, A is -CH2-, Z is phenyl, R1 = R2 = R4 = R5 = R6 = hydrogen, m = n = p = 0 and q = 1 , R3 must not be hydrogen, ethyl, isopropyl or phenyl;
when X is -CO-, Y is -0-, A is a valence bond, Z is te/ -butyl, R1 = R2 = R3 = R4 = R hydrogen, m = n = p = 0 and q = 1 , R5 must not be carboxy; when X is -CO-, Y is -0-, A is a valence bond, Z is terf-butyl, R1 = R2 = R4 = R5 = R6 = hydrogen, m = n = p = 0 and q = 1 , R3 must not be 4-cyanophenyl;
when X is -CO-, the group -Y-A-Z starts with the radical -0-, R1 = R2 = R6 = hydrogen, m = n = p = 0 and q = 1 , R5 must not be carboxy, aminocarbonyl or hydrogen;
when -X is -CO-, the group -Y-A-Z starts with the radical -CH<, R1 = R2 = R3 = R4 = R6 = hydrogen, m = n = p = 0 and q = 1 , R5 must not be hydroxymethyl, Cι-6-alkoxy- carbonyl or carboxy; and
when X is -CO-, the group -Y-A-Z is 4-methoxyphenyl, R1 = R2 = R3 = R4 = R6 = hydrogen, m = n = p = 0 and q = 1 , R5 must not be carboxy;
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R1 = R2 = hydrogen.
3. A compound according to claim 1 or 2, wherein m = n = p = 0; and q = 1 .
4. A compound according to claim 1 or 2, wherein n = p = 0; and m = q = 1.
5. A compound according to any one of the preceding claims, wherein X is a valence bond, -C(=0)-, -S(=0)2-, -C(=N-CN)-, -C(=CH-N02)- or -C(=N-S(=0)2R11a)-, wherein
R11a is as defined in claim 1.
6. A compound according to claim 5, wherein X is -C(=O)-.
7. A compound according to any one of the preceding claims, wherein A is a valence bond, d-8-alkylene, C2-8-alkenylene or C2-8-alkynylene. 174
8. A compound according to claim 7, wherein A is a valence bond or Cι.8-alkylene.
9. A compound according to claim 8, wherein A is a valence bond, methylene, ethylene or propylene.
10. A compound according to any one of the preceding claims, wherein Z is d-6-alkyl, phenyl, naphthyl, thienyl, cyclopentyl, cyclohexyl, cyclohexenyl, oxazolyl, indanyl, isoquinolyl, benzoyl or tetrahydronaphthyl which are optionally substituted as defined in claim 1.
11. A compound according to claim 10, wherein Z is phenyl or cyclohexyl which are optionally substituted as defined in claim 1.
12. A compound according to claim 10 or 1 1 , wherein Z is unsubstituted or substi- tuted with one to three substituents selected from d-6-alkyl, d-6-alkoxy, halogen, phenyl, di(Cι-6-alkyl)amino, C3-8-cyclopropanecarbonyl, trifluoromethoxy and trifluoromethyl.
13. A compound according to any one of the preceding claims 1 to 9, wherein Z is adamantyl.
14. A compound according to any one of the preceding claims, wherein R3 and R4 independently are
hydrogen;
C3-8-cycloalkyl optionally substituted with d-6-alkyl, Cι-6-alkoxy, Cι-6-alkylthio, hydroxy, amino, Cι-6-alkylamino, di(Cι-6-alkylamino), halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or hetero- arylamino, 175
d-6-alkyl optionally substituted with
C3.8-cycloalkyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino which are optionally substituted with d-e-alkyl, Cι-6-alkoxy, Cι-6-alkylthio, hydroxy, amino, d.6-aikylamino, di(Cι-6-alkylamino), halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
aryl optionally substituted with halogen, cyano, nitro, Cι-6-alkyl, d-6-alkoxy, hydroxy, trifluoromethyl, trifluoro- methoxy, aryl, heteroaryl, aryloxy, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or -CO-NR9R10, wherein R9 and R10 are as defined in claim 1 , or
R3 and R4, together with the carbon atom to which they are connected, form a C3-8-cycloalkyl ring optionally substituted with d-6-alkyl, Cι.6-alkoxy, Cι-6-alkylthio, hydroxy, amino, Cι-6-alkylamino, di(Cι-6-alkylamino), halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino.
15. A compound according to claim 14, wherein R3 and R4 are both hydrogen or are both d-6-alkyl, or R3 and R4, together with the carbon atom to which they are connected, form a C3.8-cycloalkyi ring, or one of R3 and R4 is hydrogen while the other is C3.8-cycloalkyl substituted d-6-alkyl.
16. A compound according to any one of the claims 1 to 15, wherein R5 and R6 are both hydrogen.
17. A compound according to any one of the claims 1 to 16, wherein R3, R4, R5 and R6 are hydrogen.
18. A compound according to any one of the claims 1 to 3, wherein R1 = R2 = hydrogen; R3, R4, R5 and R6 are hydrogen; X is -C(=N-CN)-, -C(=CH-N02)- or 176
-C(=N-S(=0)2R11a)-, wherein R11 a is Cι-6-alkyl or phenyl substituted with d.6-alkyl, Y is -NH-; A is d-8-alkylene; and Z is Cι-6-alkyl, aryl, C3-ι5-cycloalkyl, C3.15-cycloalkenyl, aroyl or heteroaryl, which are optionally substituted as defined in claim 1
19. A compound according to any one of the claims 1 to 3, wherein R1 = R2 = hydrogen; R3, R4, R5 and R6 are hydrogen; X is -S(=0)2-; Y is a valence bond, A is a valence bond or d-8-alkylene; and Z is C1-6-alkyl, aryl, C3.-ι5-cycloalkyl, C3.ι5-cyclo- alkenyl, aroyl or heteroaryl, which are optionally substituted as defined in claim 1
20. A compound according to any one of the claims 1 to 3, wherein R = R2 = hydrogen; R3, R4, R5 and R6 are hydrogen; X is -C(=0)-; Y is -N(R12)-, wherein R12 is hydrogen or Ci-e-alkyl; A is a valence bond or Ci-s-alkylene; and Z is d-s-alkyl, aryl, C3--i5-cycloalkyl, C3.-ι5-cycloalkenyl, aroyl or heteroaryl, which are optionally substituted as defined in claim 1.
21. A compound according to any one of the claims 1 to 3, wherein R1 = R2 = hydrogen; R3, R4, R5 and R6 are hydrogen; X is -C(=0)-; Y is -0-, A is a valence bond or Cι-8-alkylene; and Z is C1-6-alkyl, aryl, C3-ι -cycloalkyl, C3-15-cycloalkenyl, aroyl or heteroaryl, which are optionally substituted as defined in claim 1.
22. A compound according to any one of the claims 1 to 3, wherein R1 = R2 = hydrogen; R3, R4, R5 and RD are hydrogen; X is -C(=0)-; Y is a valence bond; A is a valence bond or Cι-8-alkylene; and Z is Cι-6-alkyl, aryl, C3.ι5-cycloalkyl, C3.ι5-cyclo- alkenyl, aroyl or heteroaryl, which are optionally substituted as defined in claim 1.
23. A compound according to any one of the preceding claims 18 to 22, wherein Z is d-6-alkyl, phenyl, naphthyl, thienyl, cyclopentyl, cyclohexyl, cyclohexenyl, oxazolyl, indanyl, isoquinolyl, benzoyl or tetrahydronaphthyl which are optionally substituted as defined in claim 1.
24. A compound according to claim 23, wherein Z is phenyl or cyclohexyl, which are optionally substituted as defined in claim 1. 177
25. A compound according to any one of the preceding claims 18 to 24, wherein Z is unsubstituted or substituted with one to three substituents selected from Cι-6-alkyl, Ci-6-alkoxy, halogen, phenyl, di(C1-6-alkyi)amιno, C3.8-cyciopropanecarbonyl, tπfluoro- methoxy and trifluoromethyl.
26. A compound according to any one of the claims 1 to 25 for use as a medicament
27. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 1 to 25 together with one or more pharmaceutically acceptable carriers or diluents.
28. A pharmaceutical composition according to claim 27 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0J mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to any one of the claims 1 to 25.
29. Use of a compound of the general formula I'
Figure imgf000014_0001
wherein
R1 is hydrogen or a functional group, which can be converted to hydrogen in vivo,
R2 is hydrogen, Cι-6-alkyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy or -NR7R8, wherein R7 and R8 independently are
hydrogen,
d-6-alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C3-8-cycloalkyl, which are optionally substituted with
Cι-6-alkyl, d.6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, d-6-alkylamιno, dι(d-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with d-6-alkyl, d.6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, Ci 6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
d-6-alkylsulfonyl optionally substituted with
C3-8-cycloalkyl, d-6-alkoxy, Cι.6-alkylthιo, hydroxy, ammo, d.6-alkylamιno, dι(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino, or
R7 and R8, together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with d-6-alkyl, C1-6-alkoxy, d-6-alkyithιo, hydroxy, am o, Cι-6-alkylamιno, dι(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino; 179
R3, R4, R5 and R6 independently are
hydrogen, carboxy, C-ι-6-alkoxycarbonyl, cyano, trifluoromethyl, halogen.
C3-8-cycloalkyl optionally substituted with
Cι-6-alkyl, Cι-6-alkoxy, C1-6-alkylthio, hydroxy, amino, d-6-alkylamιno, di- (Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
Cι-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which are optionally substituted with d-6-alkoxy, d-6-alkylthio, hydroxy, cyano, halogen, trifluoromethyl. trifluoromethoxy, carboxy, d-6-alkoxycarbonyl,
C3.8-cycloalkyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, which are optionally substituted with d-6-alkyl, Cι-6-alkoxy, Cι-6-alkylthio, hydroxy, amino, Ci-6-alkylamino, di(Cι.6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or -CO-NR9R10,
aryl optionally substituted with halogen, cyano, nitro, Cι-6-alkyl, C1-6-alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aryloxy, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or -CO-NR9R10,
-CO-NR9R10,
wherein R9 and R10 independently are
hydrogen, 180 d-6-alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo, heteroarylamino or C3.8-cycloalkyl, which are optionally substituted with d-6-alkyl, Cι-6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, C1-6-alkylamιno. di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with d-6-alkyl, Cι-6-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, d-6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
d-6-alkylsulfonyl optionally substituted with
C3-8-cycloalkyl, d-6-alkoxy, d-6-alkylthio, hydroxy, ammo, Cι-6-alkylamino, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino, or
R9 and R10, together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic πng optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with Ci-e-alkyl, d-6-alkoxy, Cι-6-alkylthio, hydroxy, amino, d-6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino, or
R3 and R4, together with the carbon atom to which they are connected, and/or R5 and R6 together with the carbon atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, carbocyclic or heterocyclic ring optionally substituted with d-6-alkyl, d.6-alkoxy, Cι-6-alkylthio, hydroxy, ammo, Ci-e-alkylamino, 18 1
di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, tπfluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
m, n, p and q independently are 0, 1 or 2;
X is a valence bond, -CH2-, -C(=0)-, -C(=S)-, -S(=0)-, -S(=0)2-, -C(=N-CN)-, -C(=CH-N02)-, -C[=C(CN)2]-, -C(=CH-CN)-, -C(=NR11)- or -C(=N-S(=0)2R11a)-,
wherein R11 is
hydrogen,
d-6-alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C3-8-cycloalkyl, which are optionally substituted with d-6-alkyl, Cι-6-alkoxy, d-6-alkylthio, hydroxy, amino, Cι-6-aikylamino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with
Cι-6-alkyl, d-6-alkoxy, C1-6-alkylthio, hydroxy, amino, d-6-alkylamino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
d-6-alkylsulfonyl optionally substituted with
C3-8-cycloalkyl, d-6-alkoxy, d-6-alkylthio, hydroxy, amino, d-6-alkylamino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino; 182
R 11a IS
d-6-alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C3-8-cycloalkyi, which are optionally substituted with d-6-alkyl, d.6-alkoxy, d.6-alkylthio, hydroxy, amino, d.6-alkylamino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with d-6-alkyl, d-6-alkoxy, d-6-alkylthio, hydroxy, amino, d.6-alkylamino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
Y is a valence bond, -O- or -N(R12)-,
wherein R12 is
hydrogen,
Ci-e-alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C3-8-cycloalkyl, which are optionally substituted with
Ci-e-alkyl, d-6-alkoxy, Cι-6-alkylthio, hydroxy, amino, d.6-alkylamino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with 183
Cι-6-alkyl, Ci β-alkoxy, Cι-6-alkylthιo, hydroxy, ammo, Cι.6-alkylamιno, di(C1-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
Ci-6-alkylsulfonyl optionally substituted with
C3-8-cycloalkyl, d-6-alkoxy, C1-6-alkylthιo, hydroxy, ammo, Ci 6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroarylamino,
A is a valence bond, Cι-8-alkylene, C2.8-alkenylene, C2-8-alkynylene, C3-8-cyclo- alkylene or phenylene, or
when Y is -N(R12)-, A, together with R12 and the nitrogen atom to which they are connected, may form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring system optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with Cι.6-alkyl, Cι-6-alkoxy, C .6-alkylthιo, hydroxy, ammo, Cι-6-alkylamιno, di(Cι-6-alkyl)amιno, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aryl-Cι-6-alkyl, heteroaryl-Cι-6-alkyl, aroyl, heteroaroyl, arylsulfonyl, arylammo or heteroaryl- ammo; and
Z is -R13, -OR13, -SR13, -NR13R14, -CHR13R14, -CR13R14R15 or =CR13R14,
wherein R 3, R14 and R15 independently are
hydrogen,
d-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which are optionally substituted with aryl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, C1-6-alkyl- sulfonyl, sulfonylammo, arylthio, heteroarylthio, aryloxy, acylamino, heteroaryl or C3.8-cycloalkyl, which are optionally substituted with Ci-e-alkyl, Ci-e-alkoxy, C1-6-alkylthio, aryl-Cι-6-alkyl, heteroaryl-Cι-6-al- kyl, nitro, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, d-6-alkylsulfonyl, suifonylamino, arylthio, heteroarylthio, aryloxy, acylamino, hydroxy, amino, Cι.6-alkyiamino, di- (Cι-6-alkyl)amino, halogen, cyano, trifluoromethoxy or trifluoromethyl,
aryl, C3-ι5-cycloalkyl, C3-i5-cycloalkenyl, C3-ι5-cycloalkynyl, aroyl or heteroaryl, which are optionally substituted with aryl-Cι-6-alkyl, heteroaryl-Cι-6-alkyl, aryl, heteroaryl, nitro, arylamino, het- eroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, d-6-alkyl- sulfonyl, suifonylamino, arylthio, heteroarylthio, aryloxy, acylamino, d-6-alkyl, Cι-6-alkoxy, C1-6-alkylthio, C3-8-cycloalkanecarbonyl, hydroxy, amino, Cι-6-alkylamino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethoxy or trifluoromethyl, where
R13 and R 4 or R13, R14 and R15, when they do not represent hydrogen, may be joined by one or more bridging linkers such as a valence bond, Cι-4-alkylene, C2. -alkenylene, -0-, -S-, -N(R16)-, -C(=0)-, -S(=0)-, -S(=0)2-, -C(R16R17)-, phenylene, biphenylene, -0-d-4-alkylene, -S-Cι.4-alkylene, -N(R16)-Cι-4-alkylene, -N=Cι-4-alkylene, -0-C2-4-alkenylene, -S-C2-4-alkenylene or -N(R 6)-C2-4-alkenylene, to form a mono-, bi- or polycyclic ring system,
wherein R16 and R17 independently are
hydrogen,
Cι-6-alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C3-8-cycloalkyl, which are optionally substituted with Cι-6-alkyl, Cι-6-alkoxy, C1-6-alkylthio, hydroxy, amino, Cι-6-alkyl- amino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with
C -6-alkyl, d-6-alkoxy, Cι-6-alkylthio, hydroxy, amino, Cι-6-alkylamino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
Cι.6-alkylsulfonyl optionally substituted with
C3-8-cycloalkyl, Cι-6-alkoxy, Cι-6-alkylthio, hydroxy, amino, Cι-6-alkyl- amino, di(Cι-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, or
R16 and R17, together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with Cι-6-alkyl, d-6-alkoxy,
Ci-6-alkylthio, hydroxy, amino, d-6-alkylamino, di(C1-6-alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of disorders and diseases related to the histamine H3 receptor.
30. Use according to claim 29, wherein R1 = R2 = hydrogen; R3, R4, R5 and R6 are hydrogen; X is -C(=0)-; Y is -N(R12)-, wherein R12 and A, together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsatu- rated, heterocyclic ring system optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C1-6-alkyl, Cι-6-alkoxy, Cι-6-alkylthio, hydroxy, amino, Cι-6-alkylamino, di(Cι-6-alkylamino), halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aryl-Cι-6-alkyl, hetero- aryl-Cι.6-alkyl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino; and Z is -R13, wherein R13 is hydrogen.
31. Use of a compound as defined in claim 29 for the preparation of a medicament for the treatment and/or prevention of disorders and diseases, in which an inhibition of the histamine H3 receptor has a beneficial effect.
32. Use of a compound as defined in claim 29 for the preparation of a medicament having H3 antagonistic action.
33. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the reduction of weight.
34. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the treatment and/or prevention of overweight or obesity.
35. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the suppression of appetite or satiety induction.
36. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity.
37. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.
38. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.
39. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 2 diabetes.
40. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to Type 2 diabetes.
41. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
42. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the.serotonin-3 receptor (5-HT3), such as for use in the treatment of emesis.
43. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the vanilloid receptor, such as for use in the treatment of pain, neurogenic inflammation or obesity.
44. Use of a compound as defined in claim 29 for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the alpha-2 adrenergic receptor, such as for use as a sleep inducing agent.
45. A method for the treatment of treatment and/or prevention of disorders or diseases related to the H3 histamine receptor the method comprising administering to a subject in need thereof an effective amount of a compound according to claim 29 or a pharmaceutical composition comprising the same. 188
46. The method according to claim 45, wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.
189
STATEMENT UNDER ARTICLE 19
With reference to Article 19 PCT we hereby enclose a new set of claims which has been delimited from the prior art reference cited in the International Search Report The amendments performed are not considered to extend beyond the disclosure of the international application as filed
The contents of original claims 12, 16, 17 and 18 have been incorporated in claim 1
Original claims 10 to 12 and 16 to 18 have been deleted
New claims 2 to 9 correspond to original claims 2 to 9, new claims 10 to 12 to original claims 13 to 15, new claims 13 to 17 to original claims 19 to 23, new claims 18 to 29 to original claims 25 to 36, new claim 30 to original claim 24 and new claims 31 to 46 to original claims 37 to 52, respectively
The new set of claims is considered novel and inventive over the cited reference
With reference to the International Search Report dated 14 August 2000 we disagree that the claims are so complicated that a meaningful search is not possible, see eg original claims 25 to 32 which are quite narrow in scope
Accordingly, we respectfully request that the International Searching Authority reconsider the matter and carry out a search of the claims or some of the claims so that they can be examined during the Chapter II procedure
For your consideration we enclose the results of our own substructure search of new claims 3 and 4 The search was carried out in Registry/CAplus and revealed 19 and 0 references, respectively The new set of claims is considered novel and inventive over the references revealed
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