Pyranoside derivatives

Details Pyranoside derivatives Pyranoside derivatives

2001-10-23

2003-03-04

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S027000, C514S637000, C536S004100, C536S016800, C564S247000, C564S244000, C564S384000, C564S385000, C564S389000

Reexamination Certificate

active

06528491

ABSTRACT:

DETAILED DESCRIPTION OF THE INVENTION
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
wherein
l, m and n denote an integer 0, 1, 2, 3 or 4 and l+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
m is 3,
l and n each denote 0 or 1, and
l+n is 1.
Particularly preferred compounds correspond to formula IA,
wherein R denotes COOH or CH
2
OH.
In particular, the compounds according to the invention 3′-n-propyl-4′-[2-(3-hydroxyphenoxy)-ethoxy]-1,1′-biphenyl-4-carboximidamide-O-&bgr;-D-glucuronide and 3′-n-propyl-4′-[2-(3-hydroxyphenoxy)-ethoxy]-1,1′-biphenyl-4-carboximidamide-O-glucose are potent LTB
4
-antagonists.
The compound of Example 1 is formed in vivo as a metabolite of an LTB
4
-antagonistic compound and has a K
i
-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 LTB
4
-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 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 LTB
4
or another active substance (such as 12-HETE) with the LTB
4
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, &bgr;
2
-adrenergics, steroids taken by inhalation, antihistamines, PDE
4
inhibitors, peptido-leukotriene antagonists and/or PAF antagonists. They may be administered topically, orally, transdermally, nasally, parenterally or by inhalation.
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. For 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:
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, 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
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 &mgr;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 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 (corresponding to U.S. Pat. No. 6,197,824 B1), in the form of the corresponding phenoxide
with a glucose derivative of general formula III,
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 C
1
-C
4
-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.
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, Ag
2
O or CdCO
3
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, BF
3
, AlCl
3
, ZnCl
2
, SnCl
4
or TiCl
4
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 such as, for example, BF
3
, AlCl
3
, ZnCl
2
, SnCl
4
or TiCl
4
, 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.
C
1
-C
4
-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:
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-1,1′-biphenyl]-4-carboximidamide or an acid addition salt thereof is reacted with an alkyl acetobromo-&agr;-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 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 g

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