DIPHENYLAZETINIDONES SUBSTITUEES PAR DES GROUPES ACIDES, PROCEDE DE FABRICATION, MEDICAMENTS CONTENANT CES COMPOSES ET UTILISATION DE CES MEDICAMENTS

DIPHENYL AZETIDINONES SUBSTITUTED BY ACIDIC GROUPS, METHOD FOR THEIR PRODUCTION, MEDICAMENTS CONTAINING SAID COMPOUNDS AND USE THEREOF

Abrégé français

L'invention concerne des composés de la formule (I) dans laquelle R1, R2, R3, R4, R5 et R6 ont les significations données dans le descriptif, ainsi que les sels physiologiquement acceptables de ces composés. Les composés selon l'invention peuvent par ex. servir d'agents hypolipémiants.

Abrégé anglais

The invention relates to compounds of formula (I), in which R1, R2, R3, R4, R5
and R6 are defined as cited, in addition to their physiologically compatible
salts. The compounds are suitable for use e.g. as hypolipidaemics.

Revendications

33
claims:
1. A compound of the formula I,
<IMG>
in which
R1, R2, R3, R4, R5, R6 independently of one another are (C0-C30)-
alkylene-(LAG)n, where n may be 1 - 5 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,
(C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the
alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), 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;

34
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-
(CH2)n-phenyl, where n may be 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 -(CH2)1-10-SO3H, -(CH2)0-10-P(O)(OH)2, -(CH2)0-10-O-P(O)(OH)2,
-(CH2)0-10-COOH and n may be 1 - 5;
where in each case at least one of the radicals R1 to R6 must have the meaning
(C0-C30)-alkylene-(LAG)n, where n = 1 - 5 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.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;
except for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic
acid
and those compounds in which the radicals R1 - R6 have the meaning
-O-(CH2)1-10-COOH, (C1-C6)-alkylene-COOH or -COOH.
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;
C(=NH)(NH2), 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 may be

35
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 may be 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 (C0-C30)-alkylene-(LAG) and where
one or more carbon atoms of the alkylene radical may be replaced by
-O-, -(C=O)-, -N(CH3)- 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;
C(=NH)(NH2), 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 may be
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 may be 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 -(CH2)1-10-SO3H, -(CH2)0-10-P(O)(OH)2, -(CH2)0-10-O-P(O)(OH)2,
-(CH2)0-10-COOH;
where in each case at least one of the radicals R1 or R3 must have the meaning

36
(C0-C30)-alkylene-(LAG) and where one or more carbon atoms of the alkylene
radical
may be replaced by -O-, -(C=O)-, -N(CH3)- or -NH-,
and its pharmaceutically acceptable salts;
except, for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic
acid
and those compounds in which the radicals R1 - R6 have the meaning
-O-(CH2)1-10-COOH, (C1-C6)-alkylene-COOH or -COOH.
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;
C(=NH)(NH2), 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 may be 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 may be 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-Y-W-(C0-C25)-alkylene-Y'-
W'-(LAG), where one or more carbon atoms of the alkylene radical may
be replaced by -O-;

37
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;
C(=NH)(NH2), 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 may be
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 may be 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;
Y, W, Y' W' independently of one another are NH, NCH3, C=O, O, a bond or
S(O)n,
where n = 0 - 2;
or Y-W or Y'-W' in each case together are a bond.
(LAG) is -(CH2)1-10-SO3H, -(CH2)0-10-P(O)(OH)2, (CH2)0-10-O-P(O)(OH)2,
-(CH2)0-10-COOH;
where in each case at least one of the radicals R1 or R3 must have the meaning
-(CH2)0-1-Y-W-(C0-C25)-alkylene-Y'-W'-(LAG), where one or more carbon atoms of
the alkylene radical may be replaced by -O-;
and its pharmaceutically acceptable salts;
except for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-4-oxoazetidin-2-yl)phenoxy)butyl]methylamino}ethanesulfonic
acid
and those compounds in which the radicals R1 - R6 have the meaning
-O-(CH2)1-10-COOH, (C1-C6)-alkylene-COOH or -COOH.

38
4. A compound of the formula I as claimed in one or more of claims 1 to 3,
wherein
(LAG) is a carboxylic acid radical or a sulfonic acid radical,
and its pharmaceutically acceptable salts.
5. A medicament comprising one or more compounds as claimed in one or more
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

39
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
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 02490112 2004-12-15
WO 2004/000805 1 PCT/EP2003/005816
Description
biphenyl azetidinones substituted by acidic groups, method for their
production,
medicaments containing said compounds and use thereof
5.
The invention relates to acid-group-substituted diphenylazetidinones, to their
physiologically acceptable salts and to derivatives having physiological
functions.
Diphenylazetidinones (such as, for example, ezetimibe) and their use for
treating
hyperlipidemia and arteriosclerosis and hypercholesterolemia have already been
described [cf. Drugs of the Future 2000, 25(7):679-685) and US 5,756,470].
It was an object of the invention to provide further compounds having a
therapeutically utilizable hypolipidemic action. In particular, it was an
object to find
novel compounds which, compared to the compounds described in the prior art,
are
absorbed to a very low extent. Very low absorption is to be understood as
meaning
an intestinal absorption of less than 10%, preferably less than or equal to
5%.
In particular, absorption of the novel compounds must be less than that of
ezetimibe.
Pharmaceutically active compounds which are absorbed to a low extent generally
have considerably fewer side-effects.

CA 02490112 2004-12-15
2
Accordingly, the invention relates to compounds of the formula I
1
OH
R6~ .. I
\ a " .R2
N
O R3
R4
in which
R1, R2, R3, R4, R5, R6 independently of one another are (Co-C3o)-
alkylene-(LAG)~, where n may be 1 - 5 and where 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((C1-C6)-alkyl-phenyl)- , -N(CO-(CHZ)~_~o-COOH)- or -NH-;
H, F, CI, Br, I, CF3, N02, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2,
CONH(C~-C6)-alkyl, CON[(C~-Cs)-alkyl]2, (C,-C6)-alkyl, (C2-C6)-alkenyl,
(C2-C6)-alkynyl, O-(C~-C6)-alkyl, where one, more or all hydrogens in the
alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), P03H2, S03H, S02-NH2, SOZNH(C~-Cs)-alkyl,
S02N[(C~-C6)-alkyl]2 , S-(C~-C6)-alkyl, S-(CH2)~-phenyl, SO-(C~-C6)-
alkyl, SO-(CH2)~-phenyl, S02-(C~-C6)-alkyl, SOZ-(CH2)~-phenyl, where n
may be 0 - 6 and the phenyl radical may be 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(C1-C7)-acyl, phenyl,
O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be
mono- to trisubstituted by F, CI, Br, l, OH, CF3, N02, CN, OCF3, O-(C~-

CA 02490112 2004-12-15
3
C6)-alkyl, (C~-C6)-alkyl, NH2, NH(C~=C6)-alkyl, N((C~-C6}-alkyl)2, S02-
CH3, COOH, COO-(C~-C6)-alkyl, CONH2;
(LAG)" is -(CHZ)~_~o-S03H, -(CH2)o-~o-P(0)(OH)2, (CH2)o-~o-0-P(0)(OFi)Z,
~ -(CH2)o_~o-COOH and n may be 1 - 5;
where in each case at least one of the radicals R1 to R6 must have the meaning
(Co-C3o)-alkylene-(LAG), where n = 1 - 5 and where one or more carbon atoms of
the alkylene radical are 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 -NH-,
and their pharmaceutically acceptable salts;
except for the compound 2-{[4-(4-{1-(4-fluorophenylr3-[3-(4-fluorophenyl)-3-
hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic
acid
and those compounds in which the radicals R1 - R6 have the meaning
-O-(CH2)~_~o-COOH, (C~-C6)-alkylene-COOH or -COOH.
Preference is given to compounds of the formula I where at least one of the
radicals
R1 to R6 has the meaning (Co-C3o)-alkylene-(LAG), where one or more carbon
atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N((C~-C6)-
alkyl)-,
-N(CO-(CH2)~_,o-COOH)- or -NH-.
Particular preference is given to compounds of the formula I where one of the
radicals R1 or R3 has the meaning (Co-C3o)-alkylene-(LAG), where one or more
carbon atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N(CH3)-
, or
-N H-.
Very particular preference is given to compounds of the formula I where one of
the
radicals R1 or R3 has the meaning -(CH2)o_~-Y-W-(Co-C25)-alkylene-Y'-W'-(LAG);
where one or more carbon atoms of the alkylene radical may be replaced by
oxygen
atoms and where Y and W independently of one another may be NH, NCH3, C=O,

CA 02490112 2004-12-15
4
O, a bond or S(O)S, where n = 0 - 2, and Y' and W' independently of one
another
may be NH, NCH3, C=O, O, a bond or S(O)~, where n = 0 - 2, or Y-W or Y'-W' in
each case together may be a bond.
Preference is furthermore given to compounds of the formula I where the group
LAG
is a carboxylic acid radical or a sulfonic acid radical.
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. For
medical
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 and/or 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).

CA 02490112 2004-12-15
A further aspect of this invention are prodrugs of the compounds according to
the
invention. Such prod rugs 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.
5 ~ 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 the 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
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/kg/day. 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

CA 02490112 2004-12-15
6
themselves as the compound, but preferably they are present in the form 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
compositions
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 and/or auxiliaries.
Pharmaceutical compo:>itions according to the invention are those which are
suitable
for oral or peroraf (e.g. sublingual) administration, although the most
suitable manner
of administration is dependent in each individual case on the nature and
severity of
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
acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers
of
methacrylic acid and mEahyl methacrylate.
Suitable pharmaceutical compounds for oral administration can be present in
separate units, such as, for example, capsules, cachets, lozenges or tablets,
which
in each case contain a specific amount of the compound of the formula (I); as
a
powder or granules; as ~~ 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

CA 02490112 2004-12-15
7
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.
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 98/08871, 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 A/S in WO 97/26265 and
WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in
stimulating
gluconeogenesis and/or' glycogenolysis, modulators of glucose uptake,
compounds

CA 02490112 2004-12-15
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.
10
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, atonrastatin, 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
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 alpha/gamma 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-

CA 02490112 2004-12-15
9
9952, BMS-201038, R-103757.
In one embodiment of the invention, the compounds of the formula I 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
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,
HMR1171, HMR1586.
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.

CA 02490112 2004-12-15
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.
5
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.
10 In one embodiment of the invention, the compounds of the formula I are
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

CA 02490112 2004-12-15
11
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
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
2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin),
lipase/amylase 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
amphetamine.
In one embodiment, the further active compound is fenfluramine or
dexfenfluramine.
In another embodiment, the further active compound is sibutrarnine.
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 I 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

CA 02490112 2004-12-15
12
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
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:
1
OH
R6~
. _' R2
N
O R3
R4
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.

CA 02490112 2004-12-15
13
The invention furthermore relates to a process for preparing
diphenylazetidinone
derivatives of formula I.
---~ R2
- ,CHZ)x-Y- R11 K5 ~ (CHZ)x
~Y
R4 ' ~ I
II III R4 wJo-2
(CHZ)Z~W,_Y,~(CHZ)Y
~''C 0 - 2
(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-(CHZ)1_~o-COOH) or NH;
R11 can be H or, if Y = (C=O) or (C=S), OH;
W, Y' and W' can, independently of one another and of Y, be -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-(CH2)~_~o-COOH)- or -NH- or a bond;
x, y and z independently of one another can be 0 to 10.
In compound II, -(CH2)x-Y-R11 can alternatively also be attached to one of the
other
two phenyl rings.
The process for preparing compounds of the formula I comprises reacting, for
example, an amine or a hydroxy compound 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.

CA 02490112 2004-12-15
14
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
4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-
1-
yl]benzylamino~butane-1-sulfonic acid (6):
a) 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyl-
oxazolidin-2-one (1 ):
v
°
N~O
F
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 (C26HaaFN04Si); MS
(ESI):
340.28 (MH+- HOSi(CH3)2C(CH3)3).

CA 02490112 2004-12-15
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-
phenyl-
5 ~ oxazolidin-2-one are dissolved in 350 ml of dichloromethane. 19.8 ml of
Hunig base
and 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
10 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
sulfuric 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
15 n-heptane/ethyl acetate 3/1. This gives 4-[5-(tert-butyldimethylsilanyloxy)-
5-(4-fluoro-
phenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentyl-
amino]benzonitrile (2) of molecular weight 707.93 (C4~H46FN305Si); MS (ESI):
590.51
(MH+- C~HsN2).
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 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 toluene/ethyl acetate
50/1.
This gives 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-
(4-

CA 02490112 2004-12-15
16
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 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
2/1.
This gives 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-
oxoazetidin-1-yl]-benzonitrile (4) of molecular weight 430.48 (C26HZSFN20s);
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 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 dichloromethane/methanol/ammonia solution 10/1 /0.1.
This gives 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-

CA 02490112 2004-12-15
17
methoxyphenyl)-azetidin-2-one (5) of molecular weight 434.51 (C26H2~FN203); MS
(ESI): 418.2 (MH+- NH3).
~ f) 4-{4-(3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxo-
azetidin, 1-yl]benzylamino}butane-1-sulfonic acid (6):
At room temperature, 87 mg of the above benzylamine are dissolved in 3 ml of
dry
acetonitrile, 40 pl of 1,4-butanesultone are added and the mixture is heated
under
reflux for 12 h. The cooled reaction solution is concentrated under reduced
pressure
and purified chromatographically (silica gel; dichloromethane/methanol 85/15 +
10%
water). This gives 4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-
methoxyphenyl)-
4-oxoazetidin-1-yl]benzylamino}butane-1-sulfonic acid (6) of molecular weight
570.69
(C3oH35FN206S); MS (ESI): 553.28 (MH+- H20).
Example II
2-[(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-
oxoazetidin-
1-yl]phenoxy}butyl)methylamino]ethylsulfonic acid (8):
~O~.N~S~OH
O ~O
130 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-
4-(4-
methoxyphenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute methanol.
120 mg
of N-methyltaurine in 2 ml of water and 60 mg of potassium carbonate are then
added. The mixture is stirred at 50°C for 24 h. The reaction mixture is
concentrated
using a rotary evaporator and the residue is purified by preparative
chromatography.
Freeze-drying gives the product (50 mg) as an oil.

CA 02490112 2004-12-15
18
C32H39FN20~S ESIMS mlz: 614 (M+)
Example III
[2-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-
oxoazetidin-
1-yl]phenoxy}butylamino)ethyl]phosphonic acid (9):
F H
O~N~P~OH
O OH
200 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-
4-(4-
methoxyphenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute methanol.
165 mg .
of 1-aminoethylphosphate and 247 mg of potassium carbonate dissolved in 3 ml
of
water are then added. The mixture is stirred at 90°C for 8 h. The
reaction mixture is
concentrated using a rotary evaporator and the residue is purified by
preparative
chromatography. Freeze-drying gives the product (47 mg) as an oil.
C3,H38FN20~P ESIMS m/z: 600 (M+)
Example IV
Phosphoric acid mono-{6-[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorofluorophenyl)-
3-
hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butylamino]hexyl}ester (10):
~H
N
O
O-P-OH
F OH

CA 02490112 2004-12-15
19
115 mg of 1-(4-fluorofluorophenyl)-3-[3-(4-fluorofluorophenyl)-3-
hydroxypropyl]-4-[4-
(2-fluoromethoxyethoxy)phenyl]azetidin-2-one (7) are dissolved in 6 ml of
absolute
methanol. 130 mg of 6-amino-1-hexyl phosphate in 1.5 ml of water and 107 mg of
, potassium carbonate are then added. The mixture is stirred at 70°C
overnight. The
reaction mixture is concentrated using a rotary evaporator and the residue is
purified
by preparative chromatography. Freeze-drying gives the product as an oil.
CsaHasFzN207P ESIMS m/z: 660 (M+)
Example V
4-f4-[3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-
oxoazetidin-1-yl]phenoxy}butane-1-sulfonic acid (12):
V ~/~
~O~S~OH
160 mg of 3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-
(4-
methoxyphenyl)azetidin-2-one (11 ) are dissolved in 4 ml of absolute
dimethylformamide.
210 mg of powdered potassium carbonate and 42 mg of 1,4,-butanesultone are
added.
The mixture is stirred at room temperature overnight. The reaction solution is
concentrated under oil pump vacuum, taken up in dichloromethane and washed 1x
with
water. The aqueous phase is acidified with 2N hydrochloric acid and extracted
2x with
dichloromethane. The combined organic phases are dried over sodium sulfate and
concentrated. The residue is chromatographed on a 10 g Si02 cartridge
(dichloromethane/
methanol = 5/1 ). The product (72 mg) is obtained as an oil.
C29H3ZFNO~S ESIMS m/z: 557 (M+)

CA 02490112 2004-12-15
Example VI
4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-
2-yl}-
phenoxy)butane-1-sulfonic acid (13):
5
0
vs,o
OH
r
250 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-
hydroxy-
phenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute dimethylformamide.
337 mg
10 of powdered potassium carbonate and 69 NI of 1,4,-butanesultone are added.
The
mixture is stirred at room temperature overnight. The reaction solution is
filtered and
concentrated under oil pump vacuum. The residue is chromatographed on a 10 g
Si02
cartridge (dichloromethane/rnethanol = 5/1 ) and crystallized from diethyl
ether. The
product (131 mg) is obtained as a solid.
15 C28H29F2NO6S ESIMS m/z: 546 (M+)
Example VII
20 3-(4-(1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropylJ-4-
oxoazetidin-2-yl}-
phenoxy)propan-1-sulfonin acid (14):

CA 02490112 2004-12-15
21
0
O~S-OH
F
25Q mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-
hydroxy-
phenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute dimethylformamide.
337 mg
of powdered potassium carbonate and 59 NI of 1,3,-propanesultone are added.
The
mixture is stirred at room temperature overnight. The reaction solution is
filtered and
concentrated under oil pump vacuum. The residue is chromatographed on a 10 g
Si02
cartridge (dichloromethane/methanol = 5/1 ) and crystallized from diethyl
ether. The
product (250 mg) is obtained as a solid.
C2~H2~F2NO6S ESIMS m/z: 532 (M+)
Example VIII
(4-{1-(4-Fluorophenyf)-3-[3-(4-ffuorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-
yl?-
benzylcarbamoyl)methanesulfonic acid (18):
0
p O~ S-OH
N
F O
/ F

CA 02490112 2004-12-15
22
a) 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-
phenyloxazolidine-3-carbonyl)-pentyl]-benzonitrile (15):
Under argon, 2.5 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-
phenyloxazolidin-
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, 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 acetatelheptane. The product is filtered
off with
suction and dried under reduced pressure. This gives the product of molecular
weight 653.81 (C37H37F2N3O4S1); MS (ESI+): 654.3 (M+H+), 582.2 (M+H+-
Si(CH3)3).
b) {1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-
yl}-
benzonitrile (16):
2 g of 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-
phenyl-
oxazolidine-3-carbonyl)-pentyl]-benzonitrile (15) 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 isopropanol/2N sulfuric acid = 10:1 are
added to

CA 02490112 2004-12-15
23
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, CH2C12/methanol = 100:1 ). This gives the product of
molecular weight 418.45 (C25H2oF2N202); MS (DCI+): 419 (M+H+).
c) 4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-
~ hydroxypropyl]-azetidin-2-one (17):
200 mg of {1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2-
yl}-benzonitrile (16) 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,
CH2C12/methanollconc. NH3 = 100:10:1 ). This gives the product of molecular
weight
422.5 (C25H22F2N202); MS (DCI+): 423 (M+H+), 405 (M+H+- H20).
d) (4-{1-(4-Fluorophenyl)-3-(3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-
2-
yl}-benzylcarbamoyl)methanesulfonic acid (18):
A solution of 120 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-
fluoro-
phenyl)-3-hydroxypropyl]azetidin-2-one (17), 48 NI of diisopropylethylamine in
1 ml of
dimethylformamide is added to a solution of 40 mg of sulfoacetic acid, 110 NI
of
diisopropylcarbodiimide, 76 mg of hydroxybenzotriazole in 2 ml of dimethyl-
formamide, 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 544.58 (C2~H26F2N206S~); MS
(ESI) 527.10 (M + H+- H20)

CA 02490112 2004-12-15
24
Example IX
{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-
yl]-
benzylcarbamoyl}methanesulfonic acid (19):
o.,
/ \
OH
F I / ~N \
O I / N IIO
~~'~OH
O O
A solution of 60 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-
propyl]-4-(4-methoxyphenyl)azetidin-2-one (5) in 1 ml of dimethylformamide is
added
to a solution of 20 mg of sulfoacetic acid, 55 NI of diisopropylcarbodiimide,
38 mg of
hydroxybenzotriazole in 1 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
556.61 (C28H29F~N20~S~); MS (ESI) 539.05 (M + H+- H20)
Example X
N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-
2-yl}-
benzyl)succinaminic acid (20):

CA 02490112 2004-12-15
OH
O
O
F
F
A solution of 100 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-
fluoro-
phenyl)-3-hydroxypropyl]azetidin-2-one (17), 33 NI of triethylamine in 2 ml of
5 dimethylformamide is added to a solution of 279 mg of succinic acid, 92 pl
of
diisopropylcarbodiimide, 80 mg of hydroxybenzotriazole in 2 ml of dimethyl-
formamide, 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 10/90). This gives the product of molecular weight 522.55 (C2~H26F2N206S~);
MS
(ESI) 545.19 (M + Na+)
15 Example XI
F
{2-[2-({4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-
oxoazetidin-
1-yl]benzylcarbamoyl}methoxy)ethoxy]ethoxy}acetic acid (21 ):
01
OH
v
~N ~
O// I / N ~0,~ OH
~O O
IOI ' IO
A solution of 64 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-

CA 02490112 2004-12-15
26
propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 21 NI of triethylamine in 1 ml
of
dimethylformamide are added to a solution of 327 mg of 3,6,9-
trioxaundecanedioic
acid, 57 NI of diisopropylcarbodiimide, 50 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 638.70
(C34H3gF~N2Og);
MS (ESI) 639.27 (M + H+)
Example XII
4-((3-Carboxypropionyl)-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-
methoxy-
phenyl)-4-oxoazetidin-1-yl]benzyl}amino)-4-oxobutyric acid (22):
H
'O
O
F H
O I~N
O
O
A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-
propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 23 NI of triethylamine in 1 ml
of
dimethylformamide is added to a solution of 190 mg of succinic acid, 63 pl of
diisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml of dimethyl-
formamide, 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 634.4 (C34H35F1N2Og); MS
(ESI-
neg.) 633.22 (M - H+)

CA 02490112 2004-12-15
27
Example XIII
11-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-
oxoazetidin-1-
yl]benzylcarbamoyl}undecanoic acid (23):
F H
N
OH
O
A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-
propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 23 pl of triethylamine in 1 ml
of
dimethylformamide is added to a solution of 371 mg of dodecanedioic acid, 63
NI of
diisopropylcarbodiimide, 55 mg of hydroxybenzotriazofe 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 646.81 (C38H4~F~N206);
MS
(ESI) 647.35 (M + H+)
Table 1: Compounds of the formula I
R2
R3
R4 I

CA 02490112 2004-12-15
28
EX. R1, R2 R3, R5, Mo~ecularMolecular
R4 R6
weight weight
of the (found)
free
base
or acid
(calculated)
XIV . ~ para-F, para-F,531.58 532.4
H
,~g~ , H
OH
pare H (MH+)
XV " Para-F, para-F,502.54 503.3
H
Para r H (MH+)
v,ll , H
~
S~oH
o
XVI para-F, H I Para-F,514.58 515.4
N
) H (MH+)
,
H
para
,
S~oH
o
XVII para-O-CH3, ~p para-F,
H s~ 599.68 599.21
"
w~ H (M+)
~N
~
,
H
o
oH
XVili para-O-CH3, H para-F,739.95 740.42
H
~N~S~ H (MH+)
.H
~
~
p
0
OH
XIX para-O-CH3, p para-F,599.60 600.34
H ~
N~
' H (MH+)
OH
.H
para
~
"
off
XX para-O-CH3, ~ para-F,534.59 534.4
H ~
~~
pare
~N~ H (MH')
,
H
"
doff
_ XXI ~ . H para-F, para-F,578.66 561.25
_ p.,. ~p H
~
OH H (MH+-
H20)
XXII ~",~~ ,H para-F, para-F,634.77 617.31
OH H
H (MH+-
HZO)
XXIII para-F, H ~ para-F,585.65 567.70
H
para H (MH+-
~H
H~
OH
H20)
XXIV para-O-CH3, pare -F, 557.64 55
H ~ Pa ..19
.
H
~S
o
H n
ff ( )

CA 02490112 2004-12-15
29
XXV ~H~ Para-F, para-F,660.70 660.28
~P H
.~
pua ~
O
~
O
H (M')
XXVI para-0-CH3, p~,;,~ para-F,600.62 600.24
H ~N~
~~P
.H
O
~
p
H (M')
XXVIi para-O-CH3, ~ para-F,614.73 597.32
H
~
\
~5,~
,"
H (M_
H20)~'
~~I~p wn ~N N~II para-F, para-F,-559.64-__-560.4
," H
H (MH')
1
XXIX N para-F, para-F,545.61 546.3
Iq H
,
," H (MH+)
pace ~"~
S.
" o off
XXX para-F, para-F,727.91 710.23
H
" H (MH'_
~H~s~ ,H
0 ~OH
N "~
H pact' H20)
XXXI para-O-CH3, para-F,753.93 752.32
H
~ H (M-H+);
."
~
O
H measured
H~
~",
in
negative
mode
XXXII ~N para-F, para-F,573.62 572.09
H
N .H
~
~
5 H (M-H+);
0
off
measured
in
negative
mode
XXXIII~ para-F, para-F,587.67 586.18
H
part ~H HN
~ H H (M-H+);
o H measured
in
negative
mode
Using the method described below, the activity of the compounds of the formula
I
according to the invention was examined:

CA 02490112 2004-12-15
Effect on cholesterol absorption + 3H-taurocholic acid excretion using fecal
excrement of mice. rats or hamsters
5 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.
10 Additionally, the animals are labeled s.c. with 3H-TCA (taurocholic acid)
(for example
1 pCi/mouse up to 5 NCi/rat) 24 hours prior to the peroral administration of
the test
meal ("C-cholesterol in Intralipid~ 20, Pharmacia-Upjohn).
Cholesterol absorption test: 0.25 mUmouse Intralipid ~ 20 (Pharmacia-Upjohn)
15 ((spiked with 0.25 pCi of '4C-cholesterol in 0.1 mg of cholesterol) is
administered
perorally by gavage.
Test substances are prepared separately in 0.5% methylcellulose (Sigma)/5%
Solutol
(BASF, Ludwigshafen) or a suitable vehicle.
20 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
25 3H-taurocholic acid (TCA) is determined after 24 hours.
The livers are removed and homogenized, and aliquots are incinerated in an
oximate
(Model 307, Packard) to determine the amount of '4C-cholesterol which had been
taken up/absorbed.
Evaluation:
Feces samples:

CA 02490112 2004-12-15
31
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
I
according to the invention
Example No. EDSO (liver) [mg/mouse]
I 1.0
II > 0.1
IV 0.3
VIII 0.3
IX < 1.0
X < 1.0
XIII < 0.1
XVI I I 0.005
XXI 0.1
XXII 0.1
XXV 0.3
XXVIII 0.3

CA 02490112 2004-12-15
32
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):
OH
OH
,,, -~.
F N
O
F
Reference structure:
Ezetimibe

Dessin représentatif