CA2426564A1

CA2426564A1 - Pyranoside derivatives

Info

Publication number: CA2426564A1
Application number: CA002426564A
Authority: CA
Inventors: Ralf Anderskewitz; Kurt Schromm; Franz Birke; Hans Michael Jennewein
Original assignee: Individual
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2000-10-24
Filing date: 2001-10-19
Publication date: 2002-05-02
Also published as: JP2004513100A; WO2002034761A1; DE10052658A1; MXPA03003466A; EP1332151A1; AU2002215965A1

Abstract

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

Description

t 111158-ff Boehringer Ingelheim Pharma KG

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, ' 1/1158-ff Boehringer Ingelheim Pharma KG

__ 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 ' ' 111158-ff Boehringer Ingelheim Pharma KG
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:

1/1158-ff Boehringer Ingelheim Pharma KG

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 1/1158-ff Boehringer Ingelheim Pharma KG
__.
~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 ' 111158-ff Boehringer Ingelheim Pharma KG
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.

1/1158-ff Boehringer Ingelheim Pharma KG
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 1/1158-ff Boehringer Ingelheim Pharma KG
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.

Claims

1. New pyranoside derivatives of 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.

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

wherein R denotes COOH or CH2OH.

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, is reacted with a glucose derivative of general formula III

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.

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.