RING-SUBSTITUTED DIPHENYL AZETIDINONES, METHOD FOR THE PRODUCTION THEREOF, MEDICAMENTS CONTAINING SAID COMPOUNDS, AND USE THEREOF

DIPHENYLAZETIDINONES A NOYAU SUBSTITUE, PROCEDES POUR LES PRODUIRE, MEDICAMENTS CONTENANT CES COMPOSES ET LEUR UTILISATION

English Abstract

Disclosed are ring-substituted diphenyl azetidinones of formula I, a method
for the production thereof, medicaments containing said compounds, and the use
thereof for treating hyperlipidemia, arteriosclerosis, and
hypercholesterolemia.

French Abstract

La présente invention concerne des diphénylazétidinones à noyau substitué de formule générale (I), des procédés pour les produire, des médicaments contenant ces composés et leur utilisation pour traiter une hyperlipidémie, une artériosclérose et une hypercholestérolémie.

Claims

56
claims:
1. A compound of the formula I,
<IMG>
in which
R1, R2, R3, R4, R5, R6 independently of one another are (C1-C30)-
alkylene-(LAG)n, where n = 1 - 5 and where one or more carbon atoms
of the alkylene radical are replaced by aryl or heteroaryl radicals
substituted up to three times by R7, or by (C3-C10)-cycloalkyl or
heterocycloalkyl radicals substituted up to four times by R7
and where one or more carbon atoms of the alkylene radical may be
replaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-,
-C=C-, -N((C1-C6)-alkyl)-, -N(phenyl), -N((C1-C6)-alkyl-phenyl)- , -N(CO-
(CH2)1-10-COOH)- or -NH-;
H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2,
CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl,

57
(C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the
alkyl radicals may be replaced by fluorine;
SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2 , S-(C1-C6)-alkyl, S-
(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl,
SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be
substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-
(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-
(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to
trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl,
(C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH,
COO-(C1-C6)-alkyl, CONH2;
R7 is F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2,
CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl,
(C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the
alkyl radicals may be replaced by fluorine;
PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-
(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl,
SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl
radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2,
CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
C(NH)(NH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl,
phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be
mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-
C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-
CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
(LAG)n is a sugar residue, disugar residue, trisugar residue, tetrasugar
residue;
a sugar acid, an amino sugar;

58
an amino acid residue, an oligopeptide residue comprising 2 to 9 amino
acids;
an acyclic, mono-, di- or tricyclic trialkylammonium radical, an acyclic
mono-, di- or tricyclic trialkylammoniumalkyl radical, -O-(SO2)-OH;
-(CH2)0-10-SO3H; -(CH2)0-10-P(0)(OH)2, -(CH2)0-10-O-P(O)(OH)2,
-(CH2)0-10-COOH, -(CH2)0-10-C(=NH)(NH2); -(CH2)0-10-C(=NH)(NHOH);
-NR8-C(=NR9)(NR10R11); where n = 1 - 5 and R8, R9, R10 and R11
independently of one another may be H, (C1-C6)-alkyl, phenyl, (C1-C6)-
alkyl-phenyl, (C3-C8)-cycloalkyl),
and where in each case at least one of the radicals R1 to R6 must have the
meaning
(C1-C30)-alkylene-(LAG)n, where n = 1 - 5 and one or more carbon atoms of the
alkylene radical are replaced by up to trisubstituted aryl or heteroaryl
radicals or by
up to tetrasubstituted (C3-C10)-cycloalkyl or heterocycloalkyl radicals and
may
additionally be replaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-,
-CH=CH-, -C.ident.C-, -N((C1-C6)-alkyl)-, -N(phenyl)-, -N((C1-C6)-alkyl-
phenyl)- , -N(CO-
(CH2)1-10-COOH)- or -NH-;
and its pharmaceutically acceptable salts.
2. A compound of the formula I as claimed in claim 1, wherein
R2, R4, R5, R6 independently of one another are H, F, Cl, Br, I, CF3, NO2,
N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl,
CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-
(C1-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may
be replaced by fluorine;
SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-
(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl,
SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be

59
substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-
(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-
(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to
trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl,
(C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH,
COO-(C1-C6)-alkyl, CONH2;
R1, R3 independently of one another are (C1-C30)-alkylene-(LAG), where one or
more carbon atoms of the alkylene radical are replaced by aryl or
heteroaryl radicals substituted up to three times by R7, or by (C3-C10)-
cycloalkyl or heterocycloalkyl radicals substituted up to three times by
R7 and where one or more carbon atoms of the alkylene radical may be
replaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -N(CH3)-,
-N(phenyl)-, -N(CO-(CH2)1-10-COOH)- or -NH-,
H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2,
CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl,
(C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the
alkyl radicals may be replaced by fluorine;
SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2 , S-(C1-C6)-alkyl, S-
(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl,
SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be
substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-
(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-
(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to
trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl,
(C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH,
COO-(C1-C6)-alkyl, CONH2;

60
R7 is F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2,
CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl,
(C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the
alkyl radicals may be replaced by fluorine;
PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-
(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl,
SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6 and where the
phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3,
NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
C(NH)(NH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl,
phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be
mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-
C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-
CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
(LAG) is a sugar residue, disugar residue, trisugar residue, tetrasugar
residue;
a sugar acid, an amino sugar;
an amino acid residue, an oligopeptide residue comprising 2 to 9 amino
acids;
an acyclic, mono-, di- or tricyclic trialkylammonium radical, an acyclic
mono-, di- or tricyclic trialkylammoniumalkyl radical, -O-(SO2)-OH;
-(CH2)0-10-SO3H; -(CH2)0-10-P(O)(OH)2, -(CH2)0-10-O-P(O)(OH)2,
-(CH2)0-10-COOH, -(CH2)0-10-C(=NH)(NH2); -(CH2)0-10-C(=NH)(NHOH);
-NR8-C(=NR9)(NR10R11); where n = 1 - 5 and R8, R9, R10 and R11
independently of one another may be H, (C1-C6)-alkyl, phenyl, (C1-C6)-
alkyl-phenyl, (C3-C8)-cycloalkyl),
and where in each case at least one of the radicals R1 or R3 must have the
meaning
(C1-C30)-alkylene-(LAG), where one or more carbon atoms of the alkylene
radical are
replaced by up to trisubstituted aryl or heteroaryl radicals or by up to
trisubstituted
(C3-C10)-cycloalkyl or heterocycloalkyl radicals and may additionally be
replaced by

61
-S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -N(CH3)-, -N(phenyl)-, -N(CO-(CH2)1-10-
COOH)- or -NH-;
and its physiologically acceptable salts.
3. A compound of the formula I as claimed in claim 1 or 2, wherein
R2, R4, R5, R6 independently of one another are H, F, Cl, Br, I, CF3, NO2,
N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl,
CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-
(C1-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may
be replaced by fluorine;
SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-
(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl,
SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be
substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-
(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-
(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to
trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl,
(C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH,
COO-(C1-C6)-alkyl, CONH2;
R1, R3 independently of one another are -(CH2)0-1-NH-(C=O)0-1-(C0-C25)-
alkylene-(C=O)0-1-N(R13)0-1-(LAG) or -(CH2)0-1-(C=O)0-1-NH-(C0-C25)-
alkylene-(C=O)0-1-N(R13)0-1-(LAG); where one or more carbon atoms of
the alkylene radical are replaced by aryl or heteroaryl radicals
substituted up to three times by R7, or by (C3-C10)-cycloalkyl or
heterocycloalkyl radicals substituted up to three times by R7 and where
one or more carbon atoms of the alkylene radical may be replaced by
oxygen atoms;

62
H, F, Cl, Br, I, CF3, NO2, N3; CN, COOH, COO(C1-C6)-alkyl, CONH2,
CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl,
(C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the
alkyl radicals may be replaced by fluorine;
SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-
(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl,
SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be
substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-
(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-
(CH2)n-phenyl, where n = 0 - 6, the phenyl ring may be mono- to
trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl,
(C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH,
COO-(C1-C6)-alkyl, CONH2;
R7 is F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2,
CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl,
(C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the
alkyl radicals may be replaced by fluorine;
PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-
(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl,
SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl
radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2,
CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
C(NH)(NH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl,
phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be
mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-
C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-
CH3, COOH, COO-(C1-C6)-alkyl, CONH2;

63
(LAG)n is a sugar residue, disugar residue, trisugar residue, tetrasugar
residue;
a sugar acid, an amino sugar;
an amino acid residue, an oligopeptide residue comprising 2 to 9 amino
acids;
an acyclic, mono-, di- or tricyclic trialkylammonium radical, an acyclic
mono-, di- or tricyclic trialkylammoniumalkyl radical, -O-(SO2)-OH;
-(CH2)0-10-SO3H; -(CH2)0-10-P(O)(OH)2, -(CH2)0-10-O-P(O)(OH)2,
-(CH2)0-10-COOH, -(CH2)0-10-C(=NH)(NH2); -(CH2)0-10-C(=NH)(NHOH);
-NR8-C(=NR9)(NR10R11); where n = 1 - 5 and R8, R9, R10 and R11
independently of one another may be H, (C1-C6)-alkyl, phenyl, (C1-C6)-
alkyl-phenyl, (C3-C8)-cycloalkyl),
R13 is H or CH3;
and where in each case at least one of the radicals R1 or R3 must have the
meaning
-(CH2)0-1-NH-(C=O)0-1-(C0-C25)-alkylene-(C=O)0-1-N(R13)0-1-(LAG) or -(CH2)0-1-
(C=O)0-1-NH-(C0-C25)-alkylene-(C=O)0-1-N(R13)0-1-(LAG) and one or more carbon
atoms of the alkylene radical are replaced by up to trisubstituted aryl or
heteroaryl
radicals or by up to trisubstituted (C3-C10)-cycloalkyl or heterocycloalkyl
radicals and
may additionally be replaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -
N(CH3)-,
-N(phenyl)- or -NH-;
and its physiologically acceptable salts.
4. A compound of the formula I as claimed in one or more of claims 1 to 3,
wherein
LAG is a monosugar residue, an acyclic mono-, di- or tricyclic
trialkylammoniumalkyl radical, a sulfonic acid or a carboxylic acid,
and its pharmaceutically acceptable salts.
5. A medicament comprising one or more compounds as claimed in one or more

64
of claims 1 to 4.
6. A medicament comprising one or more compounds as claimed in one or more
of claims 1 to 4 and at least one further active compound.
7. The medicament as claimed in claim 6, comprising, as further active
compound, one or more compounds which normalize lipid metabolism.
8. The medicament as claimed in claim 6 or 7, which comprises, as further
active compound, one or more
antidiabetics, hypoglycemically active compounds, HMGCoA reductase inhibitors,
cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists,
PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption
inhibitors,
CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT
inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase
inhibitors,
squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors,
insulins;
sulfonylureas, biguanides, meglitinides, thiazolidinediones, .alpha.-
glucosidase inhibitors,
active compounds which act on the ATP-dependent potassium channel of the beta
cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3
agonists,
TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, .beta.3
agonists,
MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin-
reuptake
inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists,
bombesin
agonists, galanin antagonists, growth hormones, growth hormone-releasing
compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin
agonists, DA
agonists (bromocriptine, doprexin), lipase/amylase inhibitors, PPAR
modulators,
RXR modulators or TR-.beta.-agonists or amphetamines.
9. A compound as claimed in one or more of claims 1 to 4 for use as a
medicament for the treatment of impaired lipid metabolism.
10. A process for preparing a medicament comprising one or more of the

65
compounds as claimed in one or more of claims 1 to 4, which comprises mixing
the
active compound with a pharmaceutically acceptable carrier and bringing this
mixture
into a form suitable for administration.
11. The use of the compounds as claimed in one or more of claims 1 to 4 for
preparing a medicament for treating hyperlipidemia.
12. The use of the compounds as claimed in one or more of claims 1 to 4 for
preparing a medicament for lowering the serum cholesterol concentration.
13. The use of the compounds as claimed in one or more of claims 1 to 4 for
preparing a medicament for treating arteriosclerotic manifestations.
14. The use of the compounds as claimed in one or more of claims 1 to 4 for
preparing a medicament for treating insulin resistance.

Description

CA 02490109 2004-12-15
Accordingly, the invention relates to compounds of the formula I
1
OH
R6
\ ~ "' ~ R2
N
R5~ O ~ R3
R4 I
in which
R1, R2, R3, R4, R5, R6 independently of one another are (C~-Cso)-
alkylene-(LAG),, where n = 1 - 5 and where one or more carbon atoms
of the alkyfene radical are replaced by aryl or heteroaryf radicals
substituted up to three times by R7, or by (C3-Coo)-cycloalkyl or
heterocycloalkyl radicals substituted up to four times by R7
and one or more carbon atoms of the alkylene radical may be replaced
by -S(O)"-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-,
-N((C~-C6)-alkyl)-, -N(phenyl), -N((C~-C6)-alkyl-phenyl)- , -N(CO-
(CH2)1_,o-COOH)- or -NH-;
H, F, CI, Br, I, CF3, NOZ, N3, CN, COOH, COO(C~-Cs)-alkyl, CONH2,
CONH(C1-C6)-alkyl, CON[(C~-Cs)-alkyl]2, (C~-C6)-alkyl, (C2-C6)-alkenyl,
(CZ-C6)-alkynyl, O-(C~-C6)-alkyl, where one, more or all hydrogens in the
alkyl radicals may be replaced by fluorine;
SO2-NH2, SOZNH(C~-C6)-alkyl, S02N[(C1-C6)-alkyl]2 , S-(C~-C6)-alkyl, S-
(CH2)"-phenyl, SO-(C~-C6)-alkyl, SO-(CH2)~-phenyl, S02-(C~-C6)-alkyl,
SO2-(CH2)~-phenyl, where n = 0 - 6 and the phenyl radical may be
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
3
substituted up to two times by F, CI, Br, OH, CF3, N02, CN, OCF3, O-
(C,-C6)-alkyl, (C,-C6)-alkyl, NH2;
NH2, NH-(C,-C6)-alkyl, N((C,-C6)-alkyl)2, NH(C~-C~)-acyl, phenyl, O-
(CH2)"-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to
, trisubstituted by F, CI, Br, I, OH, CF3, N02, CN, OCF3, O-(C,-C6}-alkyl:
(C,-C6)-alkyl, NHS, NH(C~-C6)-alkyl, N((C,-C6)-alkyl)2, S02-CHo, COOH,
COO-(C;-C6)-alkyl, CONH2;
R7 is F, CI, Br, l, CF3, N02, N3, CN, COOH, COO(C,-C6)-alkyl, CONH2,
~ CONH(C,-C6)-alkyl, CON[(C~-C6)-alkyl]2e (C~-C6)-alkyl, (C2-Cb}-alkenyi,
(C2-C6)-alkynyl, O-{C~-C6)-alkyl, where one, more or all hydrogens in the
alkyl radicals may be replaced by fluorine;
P03H2, S03H, S02-NH2, S02NH(Cz-C6)-alkyl, S02N[(C1-C6)-alkyl]2 , S-
(C1-C6)-alkyl, S-(CHZ)~-phenyl, SO-{C~-C6)-alkyl, SO-(CH2)~-phenyl;
S02-(C~-Cs)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl
radical may be substituted up to two times by F, CI, Br, OH, CF3, NO~,
CN, OCF3, O-(C~-C6)-alkyl, (C,-C6)-alkyl, NH2;
C(NH)(NH2), NH2, NH-(C,-C6)-alkyl, N((C~-Cs)-alkyl)2, NH(C1-C7)-acyl,
phenyl, O-(CHZ)n-phenyl, where n = 0 -- 6, where the phenyl ring may be
mono- to trisubstituted by F, Cl, Br, I, OH, CF3, N02, CN, OCF~, O-{C~-
C6)-alkyl, (C,,-C6)-alkyl, NH2, NH{C~-C6)-alkyl, N((C~-C6}-alkyi)2, S02-
CH3, COOH, COO-(Ci-Cs)-alkyl, CONHz
(LAG) is a sugar residue, disugar residue, trisugar residue, tetrasugar
residue;
a sugar acid, an amino sugar;
an amino acid residue, an oligopeptide residue comprising 2 to 9 amino
acids;
an acyclic, mono-, di- or tricyciic trialkylammonium radical, an acyclic
mono-, di- or tricyclic trialkylammoniumalkyl radical, -O-(SO2)-OH;
-(CHZ)p_~p-SO3H; -{CH2)o-1o-P{O)(OH)2, -{CH2)o-~o-O-P(O)(OH)2,
-(CH2)o-io-COOH, -(CHZ)o_~o-C(=NH)(NH2); -(CH2)o-,o-C{=NH){NHOH);
REPLACEMENT SHEET (RULE 261

CA 02490109 2004-12-15
4
NR8-C(=NR9)(NR10R11 ); where n = 1 - 5 and R8, R9, R10 and R11
independently of one another may be H, (C~-C6)-alkyl, phenyl, (C~-C6)-
alkyl-phenyl, (C3-C8)-cycloalkyl),
and where in each case at least one of the radicals R1 to R6 must have the
meaning
(C~-C3o)-alkylene-(LAG), where n = 1 - 5 and one or more carbon atoms of the
alkylene radical are replaced by aryl or heteroaryl radicals substituted up to
three
times by R7, or by (C3-Coo)-cycloalkyl or heterocycloalkyl radicals
substituted up to
four times by R7 and one or more carbon atoms of the alkylene radical may be
replaced by -S(O)~-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-,
-N((C~-C6)-alkyl)-, -N(phenyl)-, -N((C~-C6)-alkyl-phenyl)- , -N(CO-(CH2)~_~o-
COOH)- or
-N H-;
and their physiologically acceptable salts.
Preference is given to compounds of the formula I where at least one of the
radicals
R1 to R6 the meaning (C~-C3o)-alkylene-(LAG), where n = 1 - 5 and one or more
carbon atoms of the alkylene radical are replaced by aryl or heteroaryl
radicals
substituted up to three times by R7, or by (C3-C,o)-cycloalkyl or
heterocycloalkyl
radicals substituted up to four times by R7 and one or more carbon atoms of
the
alkylene radical may be replaced by -S(O)S , where n = 0 - 2, -O-, -(C=O)-, -
(C=S)-,
-CH=CH-, -C=C-, -N((C~-C6)-alkyl)-, -N(phenyl)-, -N((C~-C6)-alkyl-phenyl)-, -
N(CO-
(CHZ)~_~o-COOH)- or-NH-.
Particular preference is given to compounds of the formula I where one of the
radicals R1 or R3 the meaning (C~-C3o)-alkylene-(LAG), where one or more
carbon
atoms of the alkylene radical are replaced by aryl or heteroaryl radicals
substituted
up to three times by R7, or by (C3-Coo)-cycloalkyl or heterocycloalkyl
radicals
substituted up to three times by R7 and one or more carbon atoms of the
alkylene
radical may be replaced by -S(O)"-, where n = 0 - 2, -O-, -(C=O)-, -N(CH3)-, -
N(phenyl)-, -N(CO-(CH2)~_~o-COOH)- or -NH-.
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
a
Very particular preference is given to compounds of the formula I where at
least one
of the radicals R1 or R3 the meaning -(CH2)o_~-NH-(C=O) o_~-(Co-C25)-alkylene-
(C=O)o_1-N(R13)o_~-(LAG) or -(CHZ)o-~°(C=O)o-1-NH-(Co-C25)-alkylene-
(C=O)o_1-
N(R13)o_1-(LAG); where one or more carbon atoms of the alkylene radical are
5 ~ replaced by aryl or heteroaryl radicals substituted up to three times by
R7, or by (C~-
C~o)-cycloalkyl or heterocycloalkyi radicals substituted up to three times by
R7 and
one or more carbon atoms of the alkylene radical may be replaced by oxygen
atoms,
NH, N(CH3) or S02 , and where R13 may be H or CH3.
Preference is furthermore given to compounds of the formula I where the group
LAG
is a monosugar residue, an acyclic mono-, di- or tricyclic
trialkylammoniumalkyl
radical, a sulfonic acid or a carboxylic acid.
An aryl radical is to be understood as meaning a phenyl, naphthyi, biphenyl,
tetrahydronaphthyi, alpha or beta-tetralone, indanyl or indan-1-onyl radicaP.
A heteroaryl radical is to be understood as meaning a pyridyl, pyrimidinyl,
pyrazinyl,
pyridazinyl, pyridazin-3-onyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,4-
triazolyl, indolyl,
benzimidazolyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl or
isothiazolyl radical.
Heterocycloalkyl radicals are to be understood as meaning (C3-C,o)-cycloalkyl
radicals in which at least one and up to three carbon atoms independently of
one
another are replaced by NRB, O or S(O)~ , where n = 0 - 2. Examples are the
azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1,4-dioxanyl,
tetrahydrofuryl,
piperazinyl or thiepanyl radical.
An acyclic trialkylammonium radical is to be understood as meaning the
following
group
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
6
Alk~
(CHZ)n I
\N+ Alkz
H
in which n = 0 to 10 and Alk~ and Alk2 independently of one another each
denote a
straight-chain or branched alkyl radical having 1 to 20 carbon atoms.
An acyclic trialkylammoniumalkyl radical is to be understood as meaning the
following group
Alk~
(CHz\ I
N+ Alkz
AIk3
in which n = 0 to 10 and Alk~, AIk2, AIk3 independently of one another each
denote a
straight-chain or branched alkyl radical having 1 to 20 carbon atoms.
A mono- or di- or tricyclic trialkylammonium radical is to be understood as
meaning,
for example, radicals such as
Hue.-.(CHz)m (CHZ)P H CHZ)m
(CHZ)m- ~N
N .,
N N
\ H\(CH2)P
(CH2)n
Or (CHZ)n '(CHZ)n
or
where n, m and p independently of one another can be 0 - 10 and one or more
CH2
groups independently of one another may be replaced by O, S(O)~, where n = 0-
2,
NH, N-(C~-Coo)-alkyl, N-phenyl or N-CH2-phenyl.
A mono- or dicyclic trialkylammoniumalkyl radical is to be understood as
'meaning,
for example, radicals such as
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
Alk~\ '°~'~
\N'(CHz)m (CHz)P (CHz)m rlJ(CHz)m-~-N
N /
N L'''---~-~''~~r "~'(CHz)P
(CHz)n Or (CHz)n Alk~ ar "_----(CH2)n
Or
Alk~
~~Alk~
N (CH2)n (CHz)n
(CHz)p CHz)m (CHz)~ CHz)m
(CH )n
z ~.~\,. ~ ,
N ~N
,,.
(CH2)m~ ar Alk~ ~'Alky Alk, 'Alk,
or
(CHz)m-( ' N
. _ (CHz)n , . . . _
. ~k ~. \(CHz)P
where n, m and p independently of one another can be 0 - 10 and one ar more
CHZ
groups independently of one another may be replaced by O, S(O)~, where n = 0-
2,
NH, N-(C~-Coo)-alkyl, N-phenyl or N-CH2-phenyl and Alk~ is a straight-chain or
branched alkyl radical having 1 to 20 carbon atoms.
Owing to their increased solubility in water, compared to the parent
compounds,
pharmaceutically acceptable salts are particularly suitable for medical
applications.
These salts must have a pharmaceutically acceptable anion or cation. Suitable
pharmaceutically acceptable acid addition salts of the compounds according to
the
invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic
acid,
phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric
acid, and
of organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid,
citric acid,
ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic
acid, lactic
acid, lactobionic acid, malefic acid, malic acid, methanesulfonic acid,
succinic acid, p-
toluenesulfonic acid, tartaric acid and trifluoroacetic acid, for example. Far
medical
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
8
purposes, very particular preference is given to using the chloride salt.
Suitable
pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts
(such
as sodium and potassium salts) and alkaline earth metal salts (such as
magnesium
and calcium salts).
The scope of the invention also includes salts having a pharmaceutically
unacceptable anion, which salts may be useful intermediates for preparing or
purifying pharmaceutically acceptable salts andlor for use in nontherapeutic,
for
example in vitro, applications.
Here, the term "derivative having physiological function" refers to any
physiologically
acceptable derivative of a compound according to the invention, for example an
ester, that is able, upon administration to a mammal, for example man, to form
such
a compound or an active metabolite (directly or indirectly).
A further aspect of this invention are prodrugs of the compounds according to
the
invention. Such prodrugs can be metabolized in vivo to give a compound
according
to the invention. These prodrugs may or may not be active in their own right.
The compounds according to the invention can also be present in various
polymorphous forms, for example as amorphous and crystalline polymorphous
forms. The scope of the invention includes all polymorphous forms of the
compounds according to fihe invention, which form a further aspect of the
invention.
Hereinbelow, all references to "compound(s) of the formula (I)" refer to a
compound
or compounds of the formula (I) as described above, and to their salts,
solvates and
derivatives having physiological function, as described herein.
The compounds of the formula I and their pharmaceutically acceptable salts and
derivatives having physiological function are ideal medicaments for treating
an
impaired lipid metabolism, in particular hyperlipidemia. The compounds of the
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
9
formula I are also suitable for modulating the serum cholesterol concentration
and
for preventing and treating arteriosclerotic manifestations.
The compounds) of the formula (I) can also be administered in combination with
~ other active compounds.
The amount of a compound of the formula (I) required to achieve the desired
biological effect depends on a number of factors, for example on the specific
compound chosen, on the intended use, on the mode of administration and on the
clinical condition of the patient. In general, the daily dose is in the range
from 0.1 mg
to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of bodyweight,
for
example 0.1-10 mg/kglday. Tablets or capsules may contain, for example, from
0.01
to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically
acceptable
salts, the abovementioned weight data relate to the weight of the diphenyl-
azetidinone-ion derived from the salt. For the prophylaxis or therapy of the
abovementioned conditions, the compounds of the formula (I) can be used
themselves as the compound, but preferably they are present in the farm of a
pharmaceutical composition with an acceptable carrier. The carrier must of
course
be acceptable in the sense that it is compatible with the other constituents
of the
composition and is not harmful to the health of the patient. The carrier can
be a solid
or a liquid or both and is preferably formulated with the compound as an
individual
dose, for example as a tablet, which can contain from 0.05% to 95% by weight
of the
active compound. Further pharmaceutically active substances can also be
present,
including further compounds of the formula (I). The pharmaceutical
campositions
according to the invention can be prepared by one of the known pharmaceutical
methods, which essentially consist in mixing the constituents with
pharmacologically
acceptable carriers andlor auxiliaries.
Pharmaceutical compositions according to the invention are those which are
suitable
for oral or peroral (e.g. sublingual) administration, although the most
suitable manner
of administration is dependent in each individual case on the nature and
severity of
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
the condition to be treated and on the type of the 'compound of the formula
(I) used
in each case. Coated formulations and coated delayed-release formulations are
also
included in the scope of the invention. Acid-resistant and enteric
formulations are
preferred. Suitable enteric coatings include cellulose acetate phthalate,
polyvinyl
5 ~ acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic
polymers of
methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration can be present in
separate units, such as, for example, capsules, cachets, lozenges or tablets,
which
10 in each case contain a specific amount of the compound of the formula (I);
as a
powder or granules; as a solution or suspension in an aqueous or nonaqueous
liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned,
these
compositions can be prepared according to any suitable pharmaceutical method
which includes a step in which the active compound and the carrier (which can
consist of one or more additional constituents) are brought into contact. In
general,
the compositions are prepared by uniform and homogeneous mixing of the active
compound with a liquid and/or finely divided solid carrier, after which the
product, if
necessary, is shaped. For example, a tablet can thus be prepared by pressing
or
shaping a powder or granules of the compound, if appropriate with one or more
additional constituents. Pressed tablets can be produced by tableting the
compound
in free-flowing form, such as, for example, a powder or granules, if
appropriate mixed
with a binder, lubricant, inert diluent and/or a (number of) surface-active/
dispersing agents) in a suitable machine. Shaped tablets can be produced by
shaping the pulverulent compound moistened with an inert liquid diluent in a
suitable
machine.
Pharmaceutical compositions which are suitable for peroral (sublingual)
administration include lozenges which contain a compound of the formula (I)
with a
flavoring, customarily sucrose and gum arabic or tragacanth, and pastilles
which
include the compound in an inert base such as gelatin and glycerol or sucrose
and
gum arabic.
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
11
Suitable other active compounds for the combination preparations are:
all antidiabetics mentioned in Rote Liste 2001, Chapter 12. They can be
combined
with the compounds of the formula I according to the invention in particular
to
achieve a synergistically enhanced action. The active compound combination can
be
administered either by separate administration of the active compounds to the
patient or in the form of combination preparations comprising a plurality of
active
compounds in a pharmaceutical preparation.
Antidiabetics include insulin and insulin derivatives, such as, for example,
Lantus~ or
HMR 1964, GLP-1 derivatives, such as, for example, those disclosed by Novo
Nordisk A/S in WO 98108871, and oral hypoglycemic active compounds.
The oral hypoglycemic active compounds preferably include sulfonylureas,
biguadines, meglitinides, oxadiazolidinediones, thiazolidinediones,
glucosidase
inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers,
such
as, for example, those disclosed by Novo Nordisk AIS in WO 97126265 and
WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in
stimulating
gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds
which modulate lipid metabolism, such as antihyperlipidemic active compounds
and
antilipidemic active compounds, compounds which reduce food intake, PPAR and
PXR agonists and active compounds which act on the ATP-dependent potassium
channel of the beta cells.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an HMGCoA reductase inhibitor such as
simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin,
rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a cholesterol absorption inhibitor, such as,
for
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
12
example, ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a PPAR gamma agonist, such as, for example,
~ rosiglitazone, pioglitazone, JTT-501, GI 262570.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a PPAR alpha agonist, such as, for example,
GW
9578, GW 7647.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a mixed PPAR alphalgamma agonist, such as,
for
example, GW 1536, AVE 8042, AVE 8134, AVE 0847.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a fibrate, such as, for example, fenofibrate,
clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an MTP inhibitor, such as, for example, Bay
13-
9952, BMS-201038, R-103757.
In one embodiment of the invention, the compounds of the formula 1 are
administered in combination with a bile acid absorption inhibitor, such as,
for
example, HMR 1453.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a CETP inhibitor, such as, for example, Bay
194789.
In one embodiment of the invention, the compounds of the formula I are
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
13
administered in combination with a polymeric bile acid adsorber, such as, for
example, cholestyramine, colesolvam.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an LDL receptor inducer, such as, for
example,
r
HMR1171, HMR1586. °
I
I
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an ACAT inhibitor, such as, for example,
avasimibe.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an antioxidant, such as, for example, OPC-
14117.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a lipoprotein lipase inhibitor, such as, for
example;
NO-1886.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an ATP citrate lyase inhibitor, such as, for
example,
SB-204990.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a squalene synthetase inhibitor, such as, for
example, BMS-188494.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a lipoprotein{a) antagonist, such as, for
example,
CI-1027 or nicotinic acid.
In one embodiment of the invention, the compounds of the formula I are
REPLACEMENT SHEET (RULE 261

CA 02490109 2004-12-15
14
administered in combination with a lipase inhibitor, such as, for,example,
Orlistat.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with insulin.
~ In one embodiment, the compounds of the formula I are administered in
combination
with a sulfonylurea, such as, for example, tolbutamide, glibenclamide,
glipizide or
gliclazide.
In one embodiment, the compounds of the formula I are administered in
combination
with a biguanide, such as, for example, metformin.
In another embodiment, the compounds of the formula I are administered in
combination with a meglitinide, such as, for example, repaglinide.
In one embodiment, the compounds of the formula I are administered in
combination
with a thiazolidinedione, such as, for example, troglitazone, ciglitazone,
pioglitazone,
rosiglitazone, or the compounds disclosed by Dr. Reddy's Research Foundation
in
WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl-
methoxy]phenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in
combination
with an a-glucosidase inhibitor, such as, for example, miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in
combination
with an active compound which acts on the ATP-dependent potassium channel of
beta cells, such as, for example, tolbutamide, glibenclamide, glipizide,
gliazide or
repaglinide.
In one embodiment, the compounds of the formula I are administered in
combination
with more than one of the abovementioned compounds, for example in combination
with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide
and
metformin, insulin and a sulfonylurea, insulin and metformin, insulin and
troglitazon,
insulin and lovastatin, etc.
In a further embodiment, the compounds of the formula I are administered in
combination with CART agonists, NPY agonists, MC3 and MC4 agonists, orexin
agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists,
urocortin
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
agonists, ~i3-agonists, MCH (melanine-concentrating hormone) antagonists, CCK
agonists, serotonin reuptake inhibitors, mixed serotonin and noradrenergic
compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth
hormone, growth hormone-releasing compounds, TRH agonists, decoupling protein
5 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin),
lipaselamylase inhibitors, PPAR modulators, RXR modulators or TR-~ agonists.
in one embodiment of the invention, the further active compound is leptin.
In one embodiment, the further active compound is dexamphetamine or
10 amphetamine.
In one embodiment, the further active compound is fenfluramine or
dexfenfluramine.
In another embodiment, the further active compound is sibutramine.
In one embodiment, the further active compound is Orlistat.
In one embodiment, the further active compound is mazindol or phentermine.
In one embodiment, the compounds of the formula I are administered in
combination
with fiber, preferably insoluble fiber, such as, for example, Caromax°.
The
combination with Caromax~ can be given in one preparation or by separate
administration of compounds of the formula 1 and Caromax~. Here, Caromax~ can
also be administered in the form of food, such as, for example, in bakery
goods or
muesli bars. Compared to the individual active compounds, the combination of
compounds of the formula I with Caromax'~ is, in addition to an enhanced
action, in
particular with respect to the lowering of LDL cholesterol, also characterized
by its
improved tolerability.
It goes without saying that each suitable combination of the compounds
according to
the invention with one or more of the compounds mentioned above and optionally
one or more further pharmacologically active substances is included in the
scope of
the present invention.
The invention furthermore provides both stereoisomer mixtures of the formula I
and
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
16
the pure stereoisomers of the formula I, and diastereomer mixtures of the
formula I
and the pure diastereomers. The mixtures are separated by chromatographic
means.
~ Preference is given to both racemic and enantiomerically pure compounds of
the
formula I of the following structure:
F
R2
R3
Sugar residues are to be understood as meaning compounds which are derived
from
aldoses and ketoses which have 3 to 7 carbon atoms and may belong to the D or
the
L series; also included are amino sugars, sugar alcohols or sugar acids.
Glucose,
mannose, fructose, galactose, ribose, erythrose, glycerolaldehyde,
sedoheptulose,
glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid,
galactonic acid, mannonic acid, glucamine, 3-amino-1,2-propanediol, glucaric
acid
and galactaric acid may be mentioned by way of example.
Disugars are saccharides composed of two sugar units. Di-, tri- or
tetrasaccharides
are formed by acetal-like binding of two or more sugars. Here, the bonds may
be in
the a- or ~i-form. Lactose, maltose and cellobiose may be mentioned by way of
example.
If the sugar is substituted, the substitution is preferably at the hydrogen
atom of an
OH group of the sugar.
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
17
Suitable protective groups for the hydroxyl groups of the sugars are
substantially:
benzyl, acetyl, benzoyl, pivaloyl, trityl, tert-butyldimethylsilyl,
benzylidene,
cyclohexylidene or isopropylidene protective groups.
The term "amino acids" or "amino acid residues" refers, for example, to the
stereoisomeric forms, i.e. the D or L forms, of the following compounds:
alanine glycine proline
cysteine histidine glutamine
aspartic acid isoleucine arginine
glutamic acid lysine serine
phenylalanine leucine threonine
tryptophan methionine valine
tyrosine asparagine
2-aminoadipic acid 2-aminoisobutyric acid
3-aminoadipic acid 3-aminoisobutyric acid
beta-alanine 2-aminopimelic acid
2-aminobutyric acid 2,4-diaminobutyric
acid
4-aminobutyric acid desmosine
piperidine carboxylic acid 2,2-diaminopimelic
acid
6-aminocaproic acid 2,3-diaminopropionic
acid
2-aminoheptanoic acid N-ethylglycine
2-(2-thienyl)glycine 3-(2-thienyl)alanine
penicillamine sarcosine
N-ethylasparagine N-methylisoleucine
hydroxylysine 6-N-methyllysine
allo-hydroxylysine N-methylvaline
3-hydroxyproline norvaline
4-hydroxyproline norleucine
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
18
isodesmosine ornithine
allo-isoleucine
N-methylglycine
For abbreviating the amino acids, the conventional notation was used (cf.
Schroder,
Lubke, The Peptides, Volume I, New York 1965, pages XXII-XXIII; Houben-Weyl,
Methoden der Organischen Chemie [Methods of organic chemistry], Volume XV/1
and 2, Stuttgart 1974). The amino acid pGlu denotes pyroglutamyl, Nal denotes
3-(2-
naphthyl)alanine, azagly-NH2 denotes a compound of the formula NH2-NH-CONH2
and D-Asp denotes the D form of aspartic acid. According to their chemical
nature,
peptides are acid amides, and :on hydrolysis they decompose into amino acids.
An oligopeptide is to be understood as meaning a peptide constructed of 2 to 9
of
the amino acids mentioned above.
Suitable protective groups (see, for example, T.W. Greene, "Protective Groups
in
Organic Synthesis") for amino acids are primarily:
Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMV), Asp(OBzI), Asp(OBut), Cys(4-MeBzl),
Cys(Acm), Cys(SBut), Glu(Obzl), Glu(Obut), His(Tos), His(Fmoc), His(Dnp),
His(Trt),
Lys(CI-Z), Lys(Boc), Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Trp(Mts),
Trp(CHO), Tyr(Br-Z), Tyr(Bzl) or Tyr(But).
Amino protective groups that are preferably used are the benzyloxycarbonyl (Z)
radical, which can be removed by catalytic hydrogenation, the 2-(3,5-
dimethyloxyphenyl)propyl(2)oxycarbonyl(Ddz) or trityl (Trt) radical, which can
be
removed by weak acids, the t-butylcarbamate (BOC) radical, which can be
removed
by 3M hydrochloric acid, and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical,
which
can be removed using secondary amines.
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
19
The invention furthermore relates to a process for preparing
diphenylazetidinone
derivatives of formula I.
R6
R2
--.- R2
O / (CHz)x-Y- R12 ~ ,( ~2)x
~~ r Y
I
R4 R4 ~ v
s w i
,,
(CHZ)Y~ ~ _ ~
{CHZ)z W
~ i
~(CHz)v~W ~ a . s
(LAG)
Y can be S, O, (C=O), (C=S), CH=CH, C-C, N((C,-C6)-alkyl), N(phenyl), N((C,-
C6)-
alkyl-phenyl), N(CO-(CH2)~_1o-COOH) or NH;
R12 can be H or, if Y = (C=O) or (C=S), OH;
W can, independently of Y, be an up to trisubstituted aryl or heteroaryl
radical or an
up to tetrasubstituted (C3-Coo)-cycloalkyl or heterocycloalkyl radical or -
S(O)~-: where
n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C-C-, -N((C1-C6)-alkyl)-, -
N(phenyl),
N((C1-C6)-alkyl-phenyl)-, -N(CO-(CH2);_~p-COOH)- or -NH- or a bond;
v, x, y and z independently of one another can be 0 to 10.
In compound II, -(CH2)x-Y-R12 can alternatively also be attached to one of the
other
two phenyl rings.
The process for preparing compounds of the formula I comprises, for example,
reacting an amine of the formula II with an alkylating or acylating agent
which,
preferably in the omega position, carries a further functionality- if
appropriate in
protected form. This functionality is (after deprotection) used for attaching
(LAG), for
example with the formation of ether, amine or amide bonds.
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
The examples below serve to illustrate the invention in more detail, without
limiting
the invention to the products and embodiments described in the examples.
Example I
5 2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-
2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid
(7):
a) 3-[5-(tert-butyldimethylsilanylopy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyl-
oxazolidin-2-one (1 ):
~,k
0
H~O
27 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one,
13.6 g
of tert-butyldimethylsilyl chloride and 10.2 g of imidazole are dissolved in
36 ml of
dimethylformamide and stirred at 60°C for 90 min. After the reaction
has ended, the
mixture is dissolved in ethyl acetate and extracted two times with water. The
organic
phase is dried over magnesium sulfate, filtered and concentrated under reduced
pressure. This gives 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-
pentanoyl]-
4-phenyloxazolidin-2-one (1 ) of molecular weight 471.65 (CZ6H~FN04Si); MS
(ESI):
340.28 (MH+- HOSi(GH3)ZC(CH3)3).
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
21
b) 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-
2
(2-oxo- 4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile (2}:
16.2 g of 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-
, phenyloxazolidin-2-one (1 ) are dissolved in 350 ml of dichloromethane. 19.8
ml of
Hunig base an,d 10.14 g of 4-[(4-methoxyphenylimino)methyl]benzonitrile are
added,
and the solution is cooled to -10°C. 8.52 ml of trimethylsilyl triflate
are added to the
cooled solution, and the mixture is stirred at -10°C for 30 min. The
solution is then
cooled to -30°C, and 44 ml of titanium tetrachloride solution are
added. The reaction
mixture is stirred at from -30 to -40°C for 2 h. The solution is then
allowed to warm to
room temperature and the reaction solution is washed successively with 200 ml
of
2N sulfuiic acid, 300 ml of 20% strength sodium hydrogen sulfite solution and
sat.
sodium chloride solution. The organic phase is dried over magnesium sulfate
and
concentrated under reduced pressure, and the residue is purified on silica gel
using
n-heptane/ethyl acetate 3/1. This gives 4-[5-(tert-butyldimethylsilanyloxy)-5-
(4-
fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyioxazolidine-3-
carbonyl)pentylamino]benzonitrile (2) of molecular weight 707.93
(C4~H46FN3~5S1);
MS (ESI): 590.51 (MH+- C7H5N2).
c) 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-
methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile (3):
13.2 g of 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-
methoxyphenyl)-
2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile (2) are
dissolved
in 380 ml of methyl tert-butylether, 18.6 ml of N,O-
bis(trimethylsilyl)acetamide and
1.86 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran
are
added and the mixture is stirred at room temperature for 2 h. After the
reaction has
ended, 10 ml of acetic acid are added, the reaction mixture is concentrated
under
reduced pressure and the residue is purified on silica gel using toluenelethyl
acetate
5011. This gives 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-
fluorophenyl)propyl]-2-(4-
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
22
methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (3) of molecular weight 544.75
(C32H37FN2O3S1); MS (ESI): 545.56 (M+H+).
d) .4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-
oxoazetidin-
1-yl]- benzonitrile (4):
3.5 g of 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-
methoxyphenyl}-4-oxoazetidin-1-yl]-benzonitrile (3) are dissolved in 65 ml of
tetrahydrofuran, 0.74 ml of acetic acid and 8.03 ml of a 1 M solution of
tetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is
stirred
at room temperature for 2 h. Another 4.82 ml of the tetrabutylammonium
fluoride
solution are then added, and the mixture is stirred at reflux temperature for
another
3 h. The cooled reaction mixture is concentrated under reduced pressure and
the
residue is purified by silica gel chromatography using n-heptane/ethyl acetate
2l1.
This gives 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-
oxoazetidin-1-yl]-benzonitrile (4) of molecular weight 430.48 (C26Hz3FN20s);
MS
(ESI): 431.24 (M+H+).
e) 1-(4-Aminomethylphenyl}-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-
methoxyphenyl)-azetidin-2-one (5):
1.22 g of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4.-
oxoazetidin-1-yl]-benzonitrile (4) are dissolved in 90 ml of ethanol, 10 ml of
conc.
ammonia solution and an excess of Raney nickel are added, and the mixture is
stirred at 60°C and a hydrogen pressure of 10 bar for 8 h. Overnight,
the reaction
mixture cools to room temperature, and the next day, the catalyst is removed,
the
filtrate is concentrated under reduced pressure and the residue is purified by
silica
gel chromatography using dichloromethanelmethanollammonia solution 1011/0.1.
This gives 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
23
methoxyphenyl)-azetidin-2-one (5) of molecular weight 434.51 (CZ6H2~FN203); MS
(ESI): 418.2 (MH+- NH3).
, f) 2,3,4,5,6-Pentahydroxyhexylamide of 4,4'-oxybisbenzoic acid (6):
At room temperature, 0.52 g of 4,4'-oxybisbenzoic acid and 0.36 g of D-
glucamine
are suspended in 10 ml of dry dimethylformamide, 0.31 g of HOBt and 0.39 g of
EDC are added and the mixture is stirred at room temperature for 12 h. The
reaction
mixture is evaporated to dryness and dried under high vacuum. The residue is
thoroughly titrated with water, the resulting suspension is filtered and the
residue is
titrated with methanol and filtered again. The filtrate is concentrated to
half of its
volume using a rotary evaporator, and the solution is cooled in an ice bath.
The
resulting precipitate is filtered off with suction, washed with a little ice-
cooled
methanol and dried under reduced pressure. This gives the 2,3,4,5,6-
pentahydroxyhexylamide of 4,4'-oxybisbenzoic acid (6) of molecular weight
421.40
(C2oH23N09); MS (ESI): 422.28 (MH+).
g) 2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-
yl]benzylcarbamoyl}phenoxy)benzoic acid (7):
87 mg of the compound prepared under e) and 90 mg of the compound prepared
under f) are, at room temperature, dissolved in 3 ml of dry dimethylformamide,
31
mg of HOBt and 39 mg of EDC are added and the mixture is stirred at room
temperature for 12 h. The reaction mixture is evaporated to dryness under high
vacuum and the residue is titrated with dichloromethane, filtered off with
suction,
washed with dichloromethane and dried under reduced pressure. This gives the
2,3,4,5,6-pentahydroxyhexylamide of 4-(4-{4-[3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
24
2-(4-methoxyphenyl)-4.-oxoazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid
(7)
with a molecular weight 837.90 (C46H48FN30»); MS (ESI): 838,39 (MH+).
Example II
2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-
oxo-4-
phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid (9):
i~
OH
v~N w ~ O w H ~H ~H ~
O ~ r ~ ~ ~ I ~ N~,,i~OH
O O OOH OOH
a) 1-(4-Aminomethylphenylr3-(3-hydroxy-3-phenylpropyl)-4-phenylazetidin-2-
one (8):
i~
OH
v
O N ~ i NHi
This compound is prepared as described above for 1-(4-aminomethylphenyl)-3-[3-
(4-
fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one, except that
3-[5-
(tert-butyldimethylsilanyloxy)-5-phenylpentanoyl]-4-phenyloxazolidin-2-one and
4-
(benzylideneamino)benzonitrile are used. This gives 1-(4-aminomethylphenyl)-3-
(3-
hydroxy-3-phenylpropyl)-4-phenylazetidin-2-one (8) of molecular weight 386.50
(CZSH2sN202); MS (ESI): 370.2 (MH+-NH3).
b) 2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-
oxo-4-phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid (9):
The benzylamine from Ila is reacted with the 2,3,4,5,6-pentahydroxyhexylamide
of
4,4'-oxybisbenzoic acid from If as described in Example I. This gives the
2,3,4,5,6-
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-
phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid (9) of molecular
weight
789.89 (C45H47N3O~p); MS (ESI): 790.26 (MH~).
5
Example III
2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-
2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzylcarbamoyl}-benzyl)-benzoic acid
(10~:
o~
/ \~
H
v
O N I ~ H I ~ ~ H OH H
~N \ ~ N OH
ao
i~> O OH OH
The compound of Example III is obtained analogously to the procedure of
Example 1,
except that the 2,3,4,5,6-pentahydroxyhexylamide of diphenylmethane-4,4'-
dicarboxylic acid is used. This gives the 2,3,4,5,6-pentahydroxyhexylamide of
4-(4-
{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-
yl]-
benzylcarbamoyl}benzyl)benzoic acid (10) of molecular weight 835.93
(Ca~HsoFNa~,o)~ MS (ESI): 836.18 (MH+).
Example IV
1-[4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hyd roxypropyl]-4-
oxoazetidi n-2-
yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (13):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
26
a) 4-[4-(4-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-
fluorophenyl)-3- hydroxypropyl]azetidin-2-one (12):
3.0 g of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-
hydroxyphenyl)- azetidin-2-one (11 ) 7.0 g of 1,4-bisbromomethylbenzene and
5.0 g
of potassium carbonate are dissolved in 100 ml of dimethylformamide and
stirred at
room temperature for 90 min. After the reaction has ended, the mixture is
dissolved
in ethyl acetate and extracted two times with water. The organic phase is
dried over
magnesium sulfate, filtered and concentrated under reduced pressure. The
residue
is purified by flash chromatography (n-heptanelethyl acetatej. Yield 3.2 g of
colorless
crystals (12) of molecular weight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2
(MH+).
b) 1-[4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropylJ-4-
oxoazetidin-2- yl)phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane
bromide (13):
180 mg of (12) and 300 mg of 1,4-diazabicyclo[2.2.2]octane (DABCO) are
dissolved
in 5ml of toluene and stirred at 80°C for 90 min. After the reaction
has ended, the
mixture is allowed to cool and the colorless solid is filtered off with
suction. This gives
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
27
195 mg of product (13) of molecular weight 704.66 (C38H4oBrF2N3O3); MS (ESI):
624.30 (MH+).
Example V
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl )-3-hydroxypropyl]-4-(4-{4-[(2,3,4,
5,6-
pentahydroxyhexylamine)methyl]benzyloxy~phenyl)azetidin-2-one (14)
OH
O
OH
60 mg of (12) and 150 mg of glucamine are dissolved in 5ml of
dimethylformamide
and stirred at 80°C for 90 min. After the reaction has ended the
mixture is dissolved
in ethyl acetate and extracted two times with water. The organic phase is
dried over
magnesium sulfate, filtered and concentrated under reduced pressure. The
residue
is purified by flash chromatography (methylene chloridelmethanol/conc. ammonia
30/10/3). Yield 33 mg of a colorless solid (14) of molecular weight 692.76
(C38H42F2N208); MS (ESI): 693.5 (MH+)
Example VI
1-[2-(4-{1-(4-Fluorophenyl)-3-(3-(4-fluorophenyl)-3-hyd roxypropyl]-4-
oxoazetid in-2-
yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (16):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
' 28
a) 4-[4-(2-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-
fluorophenyl)-3-hydroxypropyl]-azetidin-2-one (15):
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-
azetidin-2-one (11 ) is reacted with 1,2-bisbromomethylbenzene and potassium
carbonate analogously to Example IV, giving a colorless solid (15) of
molecular
weight 592.49 (Cs2H28BrF2N03); MS (ESI): 592.2 (MH+).
b) 1-[4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2- yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane
bromide (16):
(15) and DABCO are dissolved in toluene and reacted analogously to Example lV,
giving the product (16) as a colorless solid of molecular weight 704.66
(C38H4oBrF2N303); MS (ESI): 624.30 (MH+).
REPLACEMI=NT SHEET (RULE 26)

CA 02490109 2004-12-15
29
Example VII
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{2-[(2,3,4,5,6-
pentahydroxyhexylamine)methyl]benzyloxy}phenyl)azetidin-2-one (17):
HO H~ OH a
c
OH
(15) and glucamine are dissolved in dimethylformamide and reacted analogously
to
Example V, giving the product (17) as a colorless solid of molecular weight
692.76
(C38H42F2N208); MS (ESI): 693.5 (MH+)
Example VIII
1-[3-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hyd roxypropyl]-4-
oxoazetidin-2-
yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (19):
a) 4-[4-(3-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-
fluorophenyl)-3- hydroxypropyl]azetidin-2-one (18):
REPLACEMENT SHEET (RULE 26~

CA 02490109 2004-12-15
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-
hydroxyphenyl)azetidin-2-one (11 ) is reacted with 1,3-bisbromomethylbenzene
and
5 potassium carbonate analogously to Example IV, giving a colorless solid (18)
of
mqlecular weight 592.49 (C32H2sBrF2N03); MS (ESI): 592.2 (MH+).
b) 1-[3-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl~3-hydroxypropyl]-4-
10 oxoazetidin-2- yl)phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane
bromide (19):
(18) and DABCO are dissolved in toluene and reacted analogously to Example IV,
giving the product (19) as a colorless solid of molecular weight 704.66
15 (C38H4oBrF2N3O3); MS (ESI): 624.30 (MH+).
Example IX
20 1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{3-
[(2,3,4,5,6-
pentahydroxyhexylamine)methyl]benzyloxy)phenyl)azetidin-2-one (20):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
31
(18) and glucamine are dissolved in dimethylformamide and reacted analogously
to
Example V, giving the product (20) as a colorless solid of molecular weight
692.76
(C38H42FZN208); MS (ESI): 693.5 (MH+).
F
Example X
1-[4'-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hyd roxypropyl]-4-
oxoazetidin-2-
yl}phenoxymethyl)biphenyl-4-ylmethyl]-4-aza-1-azoniabicyclo[2.2.2]octane
bromide
(22):
a) 4-[4-(4'-Bromomethylbiphenyl-4-ylmethoxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-
fluorophenyl)-3-hydroxypropyl]azetidin-2-one (21 ):
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-
azetidin-2-one (11 ) is reacted with 4,4'-bisbromomethylbiphenyl and potassium
carbonate analogously to Example IV, giving a colorless solid (21 ) of
molecular
weight 668.54 (C38H32BrF2N03); MS (ESI): 668.1 (MH+).
REPLACEMENT SHEET (RULE 26)
Br

CA 02490109 2004-12-15
32
b) 1-[4'-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2- yl}phenoxymethyl)biphenyl-4-ylmethyl]-4-aza-1-
azoniabicyclo[2.2.2]octane bromide (22):
.
(21 ) and DABCO are dissolved in toluene and reacted analogously to Example
IV,
giving the product (22) as a colorless solid of molecular weight 780.76
(C44H~BrF2N3O3); MS (ESI): 700.3 (MH+).
Example XI
1-(4-FI uorophenyl)-3-[3-(4-fluorophenyl)-3-hyd roxypropyl]-4-(4-{4'-
[(2,3,4,5,6-
pentahydroxyhexylamine)-methyl]-biphenyl-4-ylmethoxy}-phenyl)-azetidin-2-one
(23):
(21 ) and glucamine are dissolved in dimethylformamide and reacted analogously
to
Example V giving the product (23) as a colorless solid of molecular weight
768.86
(C~H46FZN20$); MS (ESI): 769.3 (MH+).
Example XII
1-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-
oxoazetidin-1-
yl]-phenoxymethyl}-benzyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide (26):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
33
o-
/ \
H
Br /~
\ ~N
N \''(~\
p ~ N
O
a) 3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-
methoxyphenyl)-azetidin-2-one (24):
o-
i~
OH
N ~ i
OH
This compound is prepared as described above for 1-(4-aminomethylphenyl)-3-[3-
(4-
fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (steps a, b,
c,
and d), except that 4-[(4-methoxybenzylidene)-amino]-phenol is used. This
gives 3-
[3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-
azetidin-2-one (24) of molecular weight 421.47 (C25H2aFN04); MS (ESI): 422.2
(MH+).
b) 1-[4-(4-bromomethylbenzyloxy)-phenyl]-3-[3-(4-fluorophenyl)-3
hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (25):
a--
/ \~,
OH
N \
0 I~
O
/~Br
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
34
3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4.-(4-
methoxyphenyl)-
azetidin-2-one is reacted with 1,4-bisbromomethylbenzene and potassium
carbonate
analogously to Example IV, giving a colorless solid (25) of molecular weight
604.52
(C33H31BrFNOq); MS (ESI): 605.2 (MH+).
c) 1-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-
oxoazetidin-1-yl]-phenoxymethyl}-benzyl)-4.-aza-1-azoniabicyclo[2.2.2]octane
bromide (26):
(25) and DABCO are dissolved in toluene and reacted analogously to Example IV,
giving the product (26) as a colorless solid of molecular weight 716.70
(C39H43BrFN3O4); MS (ESI): 636.3 (MH+).
Example XIII
3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-1-(4-{4-[(2,3,4,5,6-
pentahydroxyhexylamine)-methyl]-benzyloxy}-phenyl)-azetidin-2-one (27):
(25) and glucamine are dissolved in dimethylformamide and reacted analogously
to
Example V, giving the product (27) as a colorless solid of molecular weight
704.80
(C39H45FN2O9); MS (ESI): 705.31 (MH+).
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
Example XIV
1-[4-(4-{3-[1-(4-Fluorophenyl)-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl]-1-
hydroxypropyl}-phenoxymethyl)-benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane
bromide
5 ~ (30):
o-
/ \
OH
\ / \
o~/ N \
O
F
a) 1-(4-Fluorophenyl)-3-[3-hydroxy-3-(4-hydroxyphenyl)-propyl]-4-(4-
10 methoxyphenyl)-azetidin-2-one (28):
o-
i\
H
v
HO' ~ ~N ~ i
F
This compound is prepared as described above for 1-(4-aminomethylphenyl)-3-[3-
(4-
15 fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one, except
that 3-[5-
(4-hydroxyphenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one and (4-
fluorophenyl)-(4-methoxybenzylidene)-amine are used. This gives 1-(4-
fluorophenyl)-
3-[3-hydroxy-3-(4-hydroxyphenyl)-propyl]-4-(4-methoxyphenyl)-azetidin-2-one
(28) of
molecular weight 421.47 (C25H2aFN04); MS (ESI): 422.2 (MH+).
b) 3-{3-[4-(4-Bromomethylbenzyloxy)-phenyl]-3-hydroxypropyl}-1-(4-
fluorophenyl)-4-(4-methoxyphenyl)-azetidin-2-one (29):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
36
1-(4-Fluorophenyl}-3-[3-hydroxy-3-(4-hyd roxyphenyl)-propyl]-4-(4-
methoxyphenyl)-
azetidin-2-one is reacted with 1,4-bisbromomethylbenzene and potassium
carbonate
analogously to Example IV, giving a colorless solid (29) of molecular weight
604.52
(C33H3~BfFNO4); MS (ESI): 605.2 (MH+).
c) 1-[4-(4-{3-[1-(4-Fluorophenyl)-2-(4-methoxyphenyl)-4.-oxoazetidin-3-yl]-1-
hydroxypropyl}-phenoxymethyl)-benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane
bromide (30):
(29) and DABCO are dissolved in toluene and reacted analogously to Example IV,
giving the product (30) as a colorless solid of molecular weight 716.70
(C39H43BrFN3O4); MS (ESI): 636.3 (MH+).
Example XV
1-{4-[ (4-{ 1-(4-F I a o ro p h a nyl )-3-[3-(4-fl a oro p h a n yl )-3-hyd
roxyp ro pyl]-4-oxo azeti d i n-2-
yl}-benzylcarbamoyl)-methyl]-benzyl}-4-aza-1-azoniabicyclo[2.2.2]octane
trifluoroacetate (35):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
37
H
'~---N
O
F~O_
F F
a)~ 1-(4-Carboxymethylbenzyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide (31):
At 70°C, 1.0 g of (3-bromomethylphenyl) acetic acid in 5 ml of dimethyl
sulfoxide are
added to a solution of 1.5 g of 1,4-diazabicyclo[2.2.2]octane in 10 ml of
dimethyl
sulfoxide. After 1 h, 100 ml of water are added and the mixture is freeze-
dried. The
residue is digested with acetone. The residue contains the product of
molecular
weight 261.35 (cation: C,5H2~N202+); MS (ESI) 261.1 (M+).
b) 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-
phenyloxazolidine-3-carbonyl)-pentyl]-benzonitrile (32):
Under argon, 2.5 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4.-
phenyfoxazolidin-
2-one are dissolved in 30 ml of dichloromethane, 3.9 g of 4-[(4-
fluorophenylimino)-
methyl]-benzonitrile are added and the mixture is cooled to -10°C. 6.4
ml of
diisopropylethylamine and, over a period of 30 min, 4.05 ml of trimethylsilyl
chloride
are added to this mixture so that the temperature does not exceed -5°C
The
mixture is stirred at this temperature for 1 additional hour and then cooled
to -25°C.
0.8 ml of titanium tetrachloride are then added slowly. The dark mixture is
stirred at
from - 25 to -30°C overnight and then decomposed using 35 ml of a 7
percent
strength solution of tartaric acid and then stirred at room temperature for
another
hour. 15 ml of a 20 percent strength solution of sodium bicarbonate are then
added,
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
38
and the mixture is again stirred for 1 hour. Following phase separation, the
organic
phase is washed with 30 ml of water, dried over magnesium sulfate and
concentrated to about 10 ml. Following the addition of 2 ml of
bistrimethylsilylacetamide, the mixture is heated at reflux for 30 min and
then
concentrated under reduced pressure. The residue is crystallized using ethyl
acetate/heptane. The product is filtered off with suction and dried under
reduced
pressure. This gives the product of molecular weight 653.81 (C.37H37FZN3O4SI);
MS
(ESI+): 654.3 (M+H+), 582.2 (M+H+-Si(CH3)3):
c) {1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-
yl}-
benzonitrile (33):
2 g of 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-
phenyl-
oxazolidine-3-carbonyl)-pentyl]-benzonitrile are dissolved in 20 ml of methyl-
tert-butyl
ether and, together with 100 mg of tetrabutylammonium fluoride trihydrate and
1.3 ml
of bistrimethylsilyl acetamide, heated at 40°C for about 1 h. The
reaction is
monitored by thin-layer chromatography. After the reaction has ended, 0.2 ml
of
glacial acetic acid is initially added and the mixture is stirred for 30 min
and then
concentrated. 20 ml of a mixture of isopropano112N sulfuric acid = 10:1 are
added to
the residue, and the mixture is stirred for 1 hour. Following addition of a
spatula tip of
solid sodium bicarbonate, the mixture is again concentrated under reduced
pressure,
the residue is taken up in ethyl acetate and the organic phase is washed with
water
and dried, and the residue is, after removal of the solvent, purified by
column
chromatography (Si02, CH2CI21methanol = 100:1 ). This gives the product of
molecular weight 418.45 (C25H2oF2N202); MS (DCI+): 419 (M+H+).
d) 4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-azetidin-2-one (34):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
39
200 mg of {1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2-
yl}-benzonitrile are dissolved in 20 ml of ethanol and, with 0.5 ml of conc.
ammonia,
hydrogenated over Raney nickel at a hydrogen pressure of 75 bar and at
25°C for 30
hours. The catalyst is filtered off with suction, the mixture is concentrated
under
~ reduced pressure and the residue is purified by column filtration (Si02,
CH2CI21methanollconc. NH3 = 100:10:1 ). This gives the product of molecular
weight
422.5 (C25H22F2N202); MS (DCI+): 423 (M+H+), 405 (M+H+- H20).
e) ~ 1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-aza-1-azonia-
bicyclo[2.2.2]octane; trifluoroacetate (35):
A solution of 70 mg 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-
fluorophenyl)-3-hydroxypropyl]-azetidin-2-one, and 23 NI of triethylamine in
0.5 ml of
dimethylformamide is added to a solution of 84 mg of 1-(4-carboxymethylbenzyl)-
4-
aza-1-azoniabicyclo[2.2.2]octane bromide, 64 NI of diisopropylcarbodiimide and
56 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture is
stirred at room temperature for 12 h. The reaction solution is concentrated
and
separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic
acid)/acetonitrile (0.1 % trifluoroacetic acid) = 80/20 -> 10/90). This gives
the product
of molecular weight 665.81 (cation: CQpH43F2N4O3); MS (ESI) 665.33 (M+).
Example XVI
1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2-
yl}-benzylcarbamoyl)-methyl]-benzyl}-1-azoniabicyclo[2.2.2]octane
trifluoroacetate
(37):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
a) 1-(4-Carboxymethylbenzyl)-1-azoniabicyclo[2.2.2]octane bromide (36):
5 The synthesis is carried out analogously to Example XVa) starting with 1.67
g of 1-
azabicyclo[2.2.2]octane. This gives the product of molecular weight 260.36
(cation:
C~6H22N~02+); MS (ESI) 260.1 (M+).
10 b) 1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2-yl)-benzylcarbamoyl)-methyl]-benzyl}-1-
azoniabicyclo[2.2.2]octane trifluoroacetate (37):
The synthesis is carried out analogously to Example XVe) starting with 70 mg
of 4-
15 (4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-
azetidin-2-one and 85 mg of 1-(4-carboxymethylbenzyl)-1-
azoniabicyclo[2.2.2]octane
bromide. This gives the product of molecular weight 664.82 (cation:
C4~H~,FzN303+);
MS (ESI) 664.33 (M+).
Example XVII
1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2-
yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4-dimethylpiperazin-1-ium
trifluoroacetate
(39):
REPLACEMENT SHEET (RULE 26)
r h'
' F F

CA 02490109 2004-12-15
41
H
t
O ~ N\~
~.~.-N
O
F /~O_
F F F
a) 1-(4-Carboxymethylbenzyl)-1,4-dimethylpiperazin-1-ium bromide (38):
The synthesis is carried out analogously to Example XVa) starting with 1.02 ml
of
1,4-dimethylpiperazine. This gives the product of molecular weight 263.36
(ration:
C~5H23N2O2+); MS (ESI) 263.1 (M+).
b) 1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4-dimethyl-piperazin-1-
ium trifluoroacetate (39):
The synthesis is carried out analogously to Example XVe) starting with 70 mg
of 4-
(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-
azetidin-2-one and 86 mg of 1-(4-carboxymethylbenzyl)-1,4-dimethylpiperazin-1-
ium
bromide. This gives the product of molecular weight 667.82 (ration:
CQOH~sF2N40~*);
MS (ESI) 667.34 (M+).
- 20
Example XVIII
4-{4-[(4-{1-(4-FI uorophe nyl)-3-[3-(4-fluorophenyl )-3-hyd roxypropyl]-4-
oxoazetid in-2-
yl}-benzylcarbamoyl)-methyl]-benzyl}-4-methylmorpholin-4-ium trifluoroacetate
(41 ):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
42
a) , 4-(4-Carboxymethylbenzyl)-4.-methylmorpholin-4-ium bromide (40):
The synthesis is carried out analogously to Example XVa) starting with 1.65 ml
of N-
methylmorpholine. This gives the product of molecular weight 250.32-(cation:
C~4H2aN~03+); MS (ESI) 250.1 (M+).
b) 4-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-methylmorpholin-4-ium
trifluoroacetate (41 ):
The synthesis is carried out analogously to Example XVe) starting 70 mg of 4-
(4-
aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-
azetidin-2-one and 82 mg of 4-(4-carboxymethylbenzyl)-4.-methylmorpholin-4-ium
bromide. This gives the product of molecular weight 654.78 (cation:
C39H42F2N3O4+);
MS (ESI) 654.31 (M+)
Example XIX
1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4.-
oxoazetidin-2-
yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4,7-trimethyl-[1,4,7]triazonan-1-ium
trifluoroacetate (43):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
43
H
.s
i
~J ~~N ~,', /
'~ '~~ ~ N
i l
r'
N
I
F
F~O_
F
a) 1,4,7-Trimethyl-1-[4-(2-oxopropyl)-benzyl]-[1,4,7]triazonan-1-ium bromide
(42):
The synthesis is carried out analogously to Example XVa) starting with 500 mg
of
1,4,7-trimethyl-(1,4,7]triazonane. This gives the product of molecular weight
321.47
(cation: C~sH3~N302+); MS (ESI) 321.2 (M+).
b) 1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4,7-trimethyl-
[1,4,7]triazonan-1-ium trifluoroacetate (43):
The synthesis is carried out analogously to Example XVe) starting 70 mg of 4-
(4-
aminomethylphenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-hydroxypropyl]-
azetidin-2-one and 200 mg of 1,4,7-trimethyl-1-[4-(2-oxopropyl)-benzyl]-
[1,4,7]triazonan-1-ium bromide. This gives the product of molecular weight
724.92
(cation: C4pH45F2N4~3+)~ MS (ESI) 724.40 (M+)
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
44
Example XX
1-[4-({4-[3-(3-Hyd roxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]-
benzylcarbamoyl}-methyl)-benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane
trifluoroacetate
,
0
OH
F O_
v
~N ~ F F
I ~ N
O ~ ~ N
~N
The synthesis is carried out analogously to Example XVe) starting 60 mg of 1-
(4-
aminomethylphenyl)-3-(3-hydroxy-3-phenylpropyl)-4-phenylazetidin-2-one (8) and
82
mg of 1-(4-carboxymethylbenzyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide.
This
gives the product of molecular weight 629.83-(cation: C4pH45F2N4~3+); MS (ESI)
629.35 (M+)
Example XXI
N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-
2-yl}-
benzyl)-2-{4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}-acetamide
(46):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
H
i
F
E
k
t
f
P
a) {4-[(2,3,4,5,6-Pentahydroxyhexylamino)-methyl]-phenyl}-acetic acid (45):
5
The synthesis is carried out analogously to Example XVa) starting with 989 mg
of 6-
aminohexane-1,2,3,4,5-pentaol. This gives the product of molecular weight
329.35
(C,5H23N~0~); MS (ESI) 330.2 (M + H+).
b) N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4.-
oxoazetidin
2-yl}-benzyl)-2-{4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}
acetamide (46):
The synthesis is carried out analogously to Example XVe) starting 70 mg of 4-
(4-
aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-
azetidin-2-one and 110 mg of {4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyl]-
phenyl}-acetic acid. This gives the product of molecular weight 733.82
(C4oH45F2N308+); MS (ESI) 734.32 (M + H+).
Example XXII
N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-
2-yl}-
benzyl)-2-(4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-
acetamide (48):
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
46
H
a) (4-{[Methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-acetic
acid
(47):
The synthesis is carried out analogously to Example XVa) starting with 1.06 g
of 6-
methylaminohexane-1,2,3,4,5-pentaol. This gives the product of molecular
weight
343.38-(C~6Ha5N~07); MS (ESI) 344.2 (M + H+)
b) N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin
2-yl}-benzyl)-2-(4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}
phenyl)-acetamide (48):
The synthesis is carried out analogously to Example XVe) starting 70 mg of 4-
(4-
aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-
azetidin-2-one and 114 mg of (4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-
methyl}-phenyl)-acetic acid. This gives the product of molecular weight 747.84
~C41H47F2N3~8+). MS (ESI) 748.35 (M + H+).
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
47
Table 1: Compounds of the formula I
R6
R5
R4
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
48
Ex. R1, R2 R3, R4 R5, Salz MolecularMolecular
Rfi
weight Hrelght
of the (found)
free
base
or acid
(calculated)
I para-F, H para-Cf 651.78 651.31
I~H , / . ."
F, (M+)
CN H
N
V ~ ~ ~ para-F, H para-CF3C 651.78 651.31
"
"
~ , F,
H 00' (M')
-
o~.",~o para-F, H para-- 567.64 577.25
. H
off F~ (MH+)
H
para-F, H para-- 662.69 663.22
F '
H
, (MH
)
XXVIIpara-O-CH3, ~,~ para-CF3C 745.85 746.34
H
" ~ F, pOH (MH')
H
XXVIIIpara-O-CH3, ~ para-CF3C 759.88 760.35
H
a ~H F. OOH '
H {MH
)
para-F, H para-- 739.82 740.33
F r
H
~ (MH
)
para-F, H para-CF3C 695.84 659.34
"' ~p ~~\~\i F' OO {M'')
v// ~" H
'N
~N
I r .H para-F, H para-CF3C 709.86 709.35
F, 00_ (M+)
H
M
I " ara-F, H -
p para- 614.60 597.18
~" F' (MH+_
H H
~N / O
0 off HZO)
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
49
XXXIII" para-F, H para- - I 620.65T621.24
~
~ H F3 ~MH?~
H
r"~ o i !
' a
i
i
o rx, '
XXXIV ara-F, H ~ -
p para- ' 606.65607
32
-" ,", ,
Fp *'
H
i
(MH
s
i
XXXV ~, para-F, H ~ para-CF3C 681.33681.5
~ ,~ F, , (M..~
' H ~ 00-
!
XXXVIpara-O-CHa, ~ ,~ n para- I CI- 755.92i 755,36
H !
o.., ,~ V~ ~ ; ;,
F, j ' ~M~
H ,
l
xxxvnpara-O-CH3, ~~ ~Jp~~N i~ -X 615.71616.21
H \ ht
p i
~ a
, ~ ~MH
,5~ ~
" ~ ,
a ~
Xxxvut- N" ' para-F, H para- CF3C 554.65555.20
E
1 i .H! ~ F,H
M, ~ OOH (MH
1 I
; ,
XXXIX~ para-F, H ~ para-; - 606.65607.39
1,
o-s ~ / , ~' ~ F, (MH"~
NH v H
s
, 1
pa ra ~
XL para-O-CH3, para- CI~ 775.95775.40
H s
a ~-' '.~~"~~. " , ;
~~ F, ~M ~
H
, '
~~
xU ~ ara-O-CHI, ara- CI 699_85! 699.33
H ~~ P
p
(~'" , H ~
I >~ .~, ~J , " ' ((yt'~~
i
I
xm ~ para-O-CH3, ~"" ~ ~-.~ para- ' HCI 651.74652.38
H - ~ !
~~,~, '~ ' ' ° (MHp)
3
XLIII para-O-CH3, H .-...~~~e..:~.~..,~..,~l~J N para- i Br i 860.51 860.6
~..~ F~ H ~M°,,
i
XLIV 9, para-O-CH3, H ~~ N N__~~N" , ~ ' para- ~ - 595.67 596.38
,, ~ ~~ v~~J~
NH, F~ H ~MH~ }
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
XLV para-O-CH3, " p para-CF3C652.73 653.37
H
~ F +
"lf ~ H
.H
~ "~ , OOH MH
( )
XLVI para-O-CH3, para-- 618.68 617.33
H
~~ ~~ ~ F
,oH H
,H
s
o , t
y I NI-H':
0
measured
In
negative
mode
XLVIIpara-O-CH3, para-- 730.81 731.41
H
~ F,
" ~ ." H (MH~)
,t
XLVIIpara-O-CH3, ~~ ~,p - -
I H para- 672.76 655.28
\ I r \ ~" F' (MH'_
H
"o
HZO)
IL para-O-CH3, para-- 658.73 659.27
H
"' ~'" \ ~ ~ ~ " F, (MH+)
'" H
0
L para-O-CH3, ~n ~N para-- 710.78 693.25
H
'H F' (MH'_
H
" Hz0)
Ll para-O-CH3, Para H -- para-CI' 663.82 663.28
H ~
..-.NO \ I CN- I F, (M+)
H H
N
Lii para-O-CH3, Pay FarH - 588.68 589.34
H ~
~N .'..
off (MH
)
, H
0
LI para-O-CH3, ~ ~N~o para-- 674.73 657.35
II H
" F +
H
0
' ' _
OH (MH
Hz0)
LIV para-O-CH3, oara ~N ; para-- 633.70 615.70
H
H F, (M+
H _
OS. OH
I-Izo)
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
51
LV para-O-CH3, H ~ ~N ~ ~ para- 666.72 666.33
is Br i ; t.
- N~ . ~
. i , M
a ~ I C )
I i ~ ,
i i ~ I
i
LVl ~,~ ~N \ i para-F, H para- ~ 654.68654.31
f ~ Br '
~ '
o I ~ F. H , ' *;
j ,H I I (M .
I ~ 5 I
i
LVII ~ ~N ~ para-F, H para- 687.35 687.4
I-
H i F. H ~M*~
~l' ~N~N~~;
,
I
LVIIIPay ~N~ para-F, H ; para- 571.65 572.4
~ - ~
H i ~ F. H tMH..)
'~
S
~~ i
~OH
i i i
LIX ~ ,oH I para-F, H i para- 621.66 622.33
~ -
~
~ i
~ H 1 MH
w ~
i ~
H H
LX para-O-CH3, H p ~, ~ para- 801.98 784.21
0 -
"
~ F
~
y.-~.,.~..A.. , ~M~
~ , H f _
"
I
i
H2O)
LXI ~ para- ! 775.90
t - r
para-O-CH3, H ' 758.18
_~
H H
i o F~ H ~ ~ ~M~
0 4 _
f ~ H2 _'
t
LXII para-O-CH3, ~ _ i para- ~ 882.04~ 883.49
~ -
H ~ ~~a.~-..-..-~o~ ~ F, H (MHO
p p =''~ i . _.
__ .. _ i _ ~ '~_
__ -____
REPLACEMENT SHEET (RULE 26)

CA 02490109 2004-12-15
52
Using the method described below, the activity of the compounds of the formula
I
according to the invention was examined:
Effect on cholesterol absorption + 3H-taurocholic acid excretion using fecal
excrement of mice, rats or hamsters
NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups of n=4-6) are
kept in
metabolic cages, where they are fed with a standard diet (Altromin, Lage
(Lippe)).
The afternoon prior to the administration of the radioactive tracers (~4C-
cholesterol),
the feed is removed and the animals are adapted to grates.
Additionally, the animals are labeled s.c. with 3H-TCA (taurocholic acid) (for
example
1 NCilmouse up to 5 NCi/rat) 24 hours prior to the peroral administration of
the test
meal ('4C-cholesterol in Intralipid~ 20, Pharmacia-Upjohn).
Cholesterol absorption test: 0.25 mllmouse Intralipid ~ 20 (Pharmacia-Upjohn)
((spiked with 0.25 NCi of '4C-cholesterol in 0.1 mg of cholesterol) is
administered
perorally by gavage.
Test substances are prepared separately in 0.5% methylcellulose (Sigma)15%
Solutol (BASF, Ludwigshafen) or a suitable vehicle.
The administration volume of the test substance is 0.5 ml/mouse. The test
substance
is administered immediately prior to the test meal (Intralipid labeled with
~4C-
cholesterol) (cholesterol absorption test).
The feces are collected over a period of 24 h: fecal elimination of '4C-
cholesterol and
3H-taurocholic acid (TCA) is determined after 24 hours.
The livers are removed and homogenized, and aliquots are incinerated in an
oxirnate
(Model 307, Packard) to determine the amount of 14C-cholesterol which had been
taken uplabsorbed.
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53
Evaluation:
Feces samples:
The total weight is determined, the sample is made up with water to a defined
~ volume and then homogenized, and an aliquot is evaporated to dryness and
incinerated in an oximate (Model 307 from Packard for the incineration of
radioactively labeled samples): the amount of radioactive 3H-H20 and '4C-C02
is
extrapolated to the amount of 3H-taurocholic acid and '4C-cholesterol,
respectively,
that is excreted (dual isotope technique). The ED2oo values as dose from a
dose-
effect curve are interpolated as those doses at which the excretion of TCA or
cholesterol is doubled, based on a control group treated at the same time.
Liver samples:
The amount of '4C-cholesterol taken up by the liver is based on the
administered
dose. The EDSO values are interpolated from a dose-effect curve as the dose at
which the uptake of '4C-cholesterol by the liver is halved (50%), based on a
control
group.
The EDSO values below demonstrate the activity of the compounds of the formula
l
according to the invention
Example No. EDso (liver) [mg/mouse]
I < 0.1
I I < 1.0
IV < 0.1
V < 0.1
VI 0.3
VII < 1.0
VIII < 1.0
IX < 0.1
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54
XV < 1.0
XXIII 0.3
XXV 0.3
XXVI 0.1
XXVII 0.3
XXIX 0.3
XXXI 0.3
X)CXVI 0.03
XX7CVI I 0.1
XXXVIII 0.1
XLI 0.03
XLIII 0.3
XLIV 0.3
XLVI 0.3
XLVIII ' 0.03
L 0.1
LII 0.3
LI I I 0.03
As can be seen from the table, the compounds of the formula I have very good
cholesterol-lowering action.
Bioabsorption:
The bioabsorption of the compounds of the formula I was examined using the
Caco
cell model (A.R. Hilgers et al., Caco-2 cell monolayers as a model for drug
transport
across the intestinal mucosa, Pharm. Res. 1990, 7, 902).
From the measured data, it can be seen that the bioabsorption of the compounds
of
the formula I according to the invention is considerably lower than that of
the
compounds described in the prior art (reference structure):
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CA 02490109 2004-12-15
OH
OH
\ , w
F N
O
F
Reference structure:
Ezetimibe
REPLACEMENT SHEET (RULE 26)

Representative Drawing