PYRANOSIDE DERIVATIVES

DERIVES DE PYRANOSIDE

English Abstract

The invention relates to novel pyranoside derivatives of general formula (I),
to methods for the production thereof, and to their use as medicaments.

French Abstract

L'invention concerne de nouveaux dérivés de pyranoside de formule générale (I), des procédés permettant de les produire et leur utilisation comme médicaments.

Claims

9
Claims
1. New pyranoside derivatives of general formula I
<IMG>
wherein
l, m and n denote an integer 0, 1, 2, 3 or 4 and l+m+n.ltoreq.4
- in the form of their racemates, in enantiomerically pure or enriched form,
optionally as pairs
of diastereomers and as the free bases or salts, preferably with
physiologically acceptable
acids.
2. Compounds of formula I according to claim 1, wherein
m is 3,
1 and n each denote 0 or 1, and
1+n is 1.
3. Compounds of formula IA
<IMG>
wherein R denotes COOH or CH2OH.

10
4. 3'-n-Propyl-4'-[2-(3-hydroxyphenoxy)-ethoxy]-1,1'-biphenyl-4-
carboximidamide-O-.beta.-D-glucuronide.
5. 3'-n-Propyl-4'-[2-(3-hydroxyphenoxy)-ethoxy]-1,1'-biphenyl-4-
carboximidamide-O-glucose.
6. Compounds of formulae I or IA according to one of claims 1 to 5 for use as
pharmaceutical compositions.
7. Process for preparing compounds of general formulae I or IA according to
one
of claims 1 to 5, characterised in that a hydroxybenzamidine of formula II,
<IMG>
is reacted with a glucose derivative of general formula III
<IMG>
wherein l, m and n are defined as in claim 1, and in the event that n>0 the
carboxyl group is
optionally protected in the form of a C1-C4-alkylester and the hydroxyl groups
are protected
in the form of acyl groups with an aliphatic or aromatic carboxylic acid, and
X denotes a leaving group which may be substituted by a phenoxide oxygen, as
the phenoxide
and optionally the ester groups are saponified.
8. Process according to claim 6, characterised in that the reaction is carried
out in
the presence of an acidically reacting catalyst or a Lewis acid.

11
9. Process according to claim 6, characterised in that the reaction is carried
out in
the presence of a basically reacting transition metal compound.
10. Pharmaceutical preparation containing a compound according to one of
claims
1 to 5 and pharmaceutically acceptable carriers and excipients.
11 Use of compounds according to one of claims 1 to 5 for preparing a
medicament.
12. Use of compounds according to claim 10 for preparing a medicament with an
LTB4-antagonistic activity.
13. Use of compounds of general formula I or IA according to one of claims 1
to 5,
the stereoisomers thereof as well as the acid addition salts thereof for
preparing a medicament
for the therapeutic treatment of arthritis, asthma, chronic obstructive
pulmonary disease,
psoriasis, ulcerative colitis, gastro- or enteropathy induced by nonsteroidal
antiphlogistics,
cystic or pulmonary fibrosis, Alzheimer's disease, shock, reperfusion
damage/ischaemia,
atherosclerosis, multiple sclerosis, autoimmune diseases, malignant neoplasia,
alveolitis.
14. Method of treating and/or preventing diseases in which LTB4-antagonists
develop a therapeutic benefit, by administering a therapeutically effective
amount of one or
more compounds of general formula I according to one of claims 1 to 5, the
stereoisomers
thereof or the acid addition salts thereof.

Description

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74408fft.204
New pyranoside derivatives
The present invention relates to new pyranoside derivatives, processes for
preparing them as
well as their use as medicaments. The new pyranoside derivatives correspond to
general
formula I
NH
(HOCI-1
(~~n
(HOC
(I)
to wherein
1, m and n denote an integer 0, l, 2, 3 or 4 and I+m+n_<4
- in the form of their racemates, in enantiomerically pure or enriched form,
optionally as pairs
of diastereomers and as the free bases or salts, preferably with
physiologically acceptable
acids.
Preferred compounds of formula I are those wherein
mis3,
1 and n each denote 0 or 1, and
1+nis 1.
Particularly preferred compounds correspond to formula IA,

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2
__
R O O / O~
HO OH \
OH
wherein R denotes COOH or CHZOH.
In particular, the compounds according to the invention 3'-n-propyl-4'-[2-(3-
hydroxyphenoxy)-ethoxy]-1,1'-biphenyl-4-carboximidamide-O-(3-D-glucuronide and
3'-n-
propyl-4'-[2-(3-hydroxyphenoxy)-ethoxy]-l,l'-biphenyl-4-carboximidamide -O-
glucose are
potent LTB4- antagonists.
The compound of Example 1 is formed in vivo as a metabolite of an LTB4-
antagonistic
to compound and has a Ki-value of 3.6 nM in the receptor binding test.
As has been found, the compounds of formula I are characterised by their
versatility of use in
the therapeutic field. Particular emphasis should be laid on those
applications for which the
LTB4-receptor-antagonistic properties play a part. The following should be
mentioned in
particular:
arthritis, asthma, chronic obstructive lung diseases such as chronic
bronchitis, psoriasis,
ulcerative colitis, gastro- or enteropathy induced by nonsteroidal
antiphlogistics, cystic or
pulmonary fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia
such as stroke
2o or cardiac infarct, atherosclerosis, multiple sclerosis, autoimmune
diseases, malignant
neoplasia, alveolitis.
The new compounds may also be used to treat illnesses or conditions in which
the passage of
cells from the blood through the vascular endothelium into the tissues is of
importance (such
as metastasis) or illnesses and conditions in which the combination of LTBq,
or another active

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substance (such as 12-HETE) with the LTB4 receptor has an influence on cell
proliferation
(e.g. chronic myeloid leukaemia).
The new compound may also be used in conjunction with other active substances,
e.g. those
which are used for the same indications, or e.g. with antiallergic agents,
secretolytics,132-
adrenergics, steroids taken by inhalation, antihistamines, PDE4 inhibitors,
peptido-leukotriene
antagonists and/or PAF antagonists. They may be administered topically,
orally,
transdermally, nasally, parenterally or by inhalation.
l0 The activity can be investigated pharmacologically and biochemically using
tests as disclosed
for example in WO 93/16036, pp. 15 to 17; reference is hereby made to the
contents of this
publication.
The therapeutic or prophylactic dose depends - apart from the potency of the
individual
compounds and the patient's body weight - on the nature and gravity of the
condition. Far
oral administration the dosage is between 10 and 500 mg, preferably between 20
and 250 mg.
By inhalation the amount of active substance delivered to the patient is
between about 0.5 and
25, preferably between about 2 and 20 mg.
Solutions for inhalation generally contain between about 0.5 and 5 % of active
substance. The
new compounds may be administered in conventional preparations, e.g. as plain
or coated
tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups,
aerosols for
inhalation, ointments and suppositories.
The following Examples show some possible ways of formulating the
preparations:

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4
Examples of formulations --
1. Tablets
Composition:
Active substance according to the invention 20 parts by weight
Stearic acid 6 parts by weight
Glucose 474 parts by weight
The ingredients are processed in the usual way to form tablets weighing 500
mg. If desired,
l0 the active substance content may be increased or reduced and the quantity
of glucose reduced
or increased accordingly.
2. Suppositories
Composition:
Active substance according to the invention 100 parts by weight
Powdered lactose 45 parts by weight
Cocoa butter 1555 parts by weight
2o The ingredients are processed in the usual way to form suppositories
weighing 1.7 g.
3. Powder for inhalation
Micronised powdered active substance (compound of formula I; particle size
about 0.5 to 7
~.m) is packed into hard gelatine capsules in quantities of 5 mg, optionally
with the addition of
micronised lactose. The powder is inhaled from conventional inhalers, e.g.
according to DE-A
33 45 722, to which reference is hereby made.
The compounds according to the invention compound are prepared using methods
known per
3o se from the prior art. Thus, the compounds of general formula I may be
prepared by reacting
the 3'-n-propyl-4'-[2-(3-hydroxyphenoxy)-ethoxy]-1,1'-biphenyl-4-
carboximidamide of
formula II known from WO 98/11062, in the form of the corresponding phenoxide

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__.
~2
HO / O~
(B)
with a glucose derivative of general formula III,
(OH)m
(HOCH2y \ .O ( III )
X
(HOOC)n
wherein l, m and n are as hereinbefore defined, and in the event that n>0 the
carboxyl group is
optionally protected in the form of a C1-C4-alkylester and the hydroxyl groups
are protected
in the form of acyl groups with an aliphatic or aromatic carboxylic acid, and
X denotes a leaving group which may be substituted by a phenoxide oxygen, as
the phenoxide
and optionally the ester groups are saponified.
to The compounds according to the invention may moreover be prepared from an
optionally
protected glucose derivative (III) and the abovementioned phenol (II) using
basic heavy metal
compounds such as, for example, Ag20 or CdC03 in inert solvents such as
toluene or
dichloromethane. If desired, the product may be liberated by saponification of
the protecting
groups.
The compounds (I) may also be prepared from derivatives of formula (III) and
the
abovementioned phenol (II) using Lewis acids such as, for example, BF3 ,
A1C13, ZnCl2,
SnCl4 or TiCl4 or from alkoxide derivatives of these Lewis acids in inert
solvents such as
toluene, dichloromethane etc.
Moreover, the compounds according to the invention may be prepared from an
optionally
protected derivative (III) with X=OH and the abovementioned phenol using acid
catalysts
such as, for example, methanesulphonic acid or tetrafluoroboric acid or using
Lewis acids

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such as, for example, BF3, AlCl3, ZnCl2, SnCl4 or TiCl4, or from alkoxide
derivatives of
these Lewis acids in inert solvents such as aliphatic, aromatic, alkyl-
substituted aromatics or
in a halogenated hydrocarbon - preferably in toluene or in dichloromethane.
C1-C4-alkyl for the purposes of the preparation processes described above
generally denotes a
branched or unbranched hydrocarbon group with 1 to 4 carbon atom(s), which may
optionally
be substituted by one or more halogen atom(s), preferably fluorine, which may
be identical to
or different from one another. The following hydrocarbon groups are mentioned
as examples:
l0 methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl,
2-methylpropyl and
1,1-dimethylethyl.
In a particularly preferred embodiment of the process according to the
invention , 4'-[2-(3-
hydroxyphenoxy)ethoxy]-3'-propyl-1,l'-biphenyl]-4-carboximidamide or an acid
addition salt
15 thereof is reacted with an alkyl acetobromo-a-D-glucuronate in the presence
of a base,
preferably a metal alkoxide, particularly sodium methoxide, most preferably in
the form of a
30% solution in methanol, in an inert solvent, preferably an ether such as for
example
diethylether or tetrahydrofuran, a polyether such as for example
dimethoxyethane, an alcohol
such as, for example, methanol or ethanol, or a mixture of these solvents at a
temperature
2o from - 80 to + 100 °C, from -40 to +80 °C, particularly from -
25 to + 40°C. Under the
preferred conditions described above, the reaction is generally over in 2 to
36 hours,
preferably 6 to 18 hours.
The compounds according to the invention may be prepared, starting from
compounds known
25 from the prior art, using the processes described in the following
Examples, inter alia.
Various other embodiments of the process will be apparent to anyone skilled in
the art from
the present specification. It is specifically pointed out, however, that these
Examples and the
related description are provided solely as an illustration and are not to be
regarded as
restricting the invention.

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Example 1 -
NH
~2
O
HO O ~ I O~O
HO~~~~~ ~~~~~OH \
OH
3'-n-propyl-4'-[2-(3-hydroxyphenoxy)-ethoxy]-l,1'-biphenyl-4-carboximidamide-O-
~i-D-
glucuronide
4 g of 4'-[2-(3-hydroxyphenoxy)ethoxy]-3'-propyl-l,1'-biphenyl]-4-
curb°ximidamide
monochloride, 3.8 ml of sodium methoxide (as a 30% solution in methanol) in
100 ml of
dimethoxyethane are slowly added in two batches at -20-30°C to 3 - 5 g
of methyl
cetobromo-a-D-glucuronate in 50 ml of methanol and stirred for 12 hours. The
mixture is
to combined with ether and the supernatant is poured off. The oil is filtered
in ethyl acetate
/methanol over a little silica gel and concentrated by evaporation. The
residue is stirred in 100
ml of methanol and a solution of 0.5 g of LiOH in 5 ml of water for 90 minutes
at ambient
temperature and concentrated by evaporation. After purification by
chromatography, 1.1 g of
the target compound are obtained, m.p.. >100°C (decomposition).
Example 2
NH
HO-CH2 O / O~
",
HO OH
OH
3'-n-propyl-4'-[2-(3-hydroxyphenoxy)-ethoxy]-1,1'-biphenyl-4-carboximidamide -
O-glucose

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The compound is prepared using the method in Example 1 from 3'-n-propyl-4'-[2-
(3-
hydroxyphenoxy)-ethoxy]-1,1'-biphenyl-4.-carboximidamide and
tetraacetylbromoglucose.