Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-09
2001-12-18
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S245000, C548S311400, C548S364400
Reexamination Certificate
active
06331556
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel heterocyclic compounds and to their formulation and use as pharmaceuticals.
BACKGROUND OF THE INVENTION
The modes of action of phosphodiesterases and also tumour necrosis factor (TNF), and the therapeutic utilities of inhibitors thereof, are described in WO-A-97/44337 and U.S. Pat. Nos. 5,925,636 and 5,972,936, the contents of which are incorporated herein by reference. These reference describe benzofurans having such activity.
SUMMARY OF THE INVENTION
This invention provides novel compounds having therapeutic utility, in particular for the treatment of disease states associated with proteins which mediate cellular activity, for example by inhibiting TNF and/or PDE IV. According to the invention, the compounds are of formula (i):
wherein R
1
is C
1-3
alkyl optionally substituted with one or more fluorines;
R
2
is CH
2
OCH
3
or 2 or 3-tetrahydrofuranyl;
R
3
is a pyrazole, imidazole or isoxazole group of partial formula (A), (B) or (C)
R
4
is C
1-3
alkyl; and
R
5
and R
6
, which may be the same or different, each represents C
1-3
alkyl, halogen, CF
3
or CN;
or a pharmaceutically-acceptable salt thereof.
In summary, the compounds of the invention represent a selection within the scope of WO-A-97/44337. The novel compounds have superior in vivo activity.
This invention provides also a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically-acceptable salt thereof.
DESCRIPTION OF THE INVENTION
The term “C
1-3
alkyl” means methyl, ethyl, propyl or isopropyl.
One group of compounds of the invention is of formula (i) in which R
1
is CH
3
or CHF
2
.
R
3
may in particular be a pyrazole of partial formula (A) or an isoxazole of partial formula (C). When R
3
is a pyrazole moiety, R
4
is especially CH
3
and R
5
is particularly CN, CH
3
, Cl or CF
3
. Where R
3
is an isoxazole moiety, R
5
is especially CH
3
, CF
3
or CN and R
6
is particularly CH
3
, CF
3
or CN.
The compounds of the Examples are especially preferred.
It will be appreciated by those skilled in the art that compounds of formula (i) in which R
2
represents tetrahydrofuran contain a chiral centre. This invention extends to both enantiomers and all mixtures thereof, including racemic mixtures.
Certain of the compounds of formula (i) which contain a basic group form acid addition salts. Suitable acid addition salts include pharmaceutically-acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobrornide, and pharmaceutically-acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphate, &agr;-ketoglutarate, &agr;-glycerophosphate and glucose-1-phosphate. The pharmaceutically-acceptable salts of the compounds of formula (i) are prepared using conventional procedures.
Compounds of the invention may be prepared by reaction of an appropriate carboxylic acid of formula (ii) with a suitable amine of formula (iii) as described in WO 97/44337. Carboxylic acids of formula (ii) may be conveniently prepared from compounds of formula (iv) by bromination followed by palladium-catalysed carbonylation as described in WO 97/44337. Amines of formula (iii) are either commercially available, previously described compounds, or are prepared using standard conditions known to those skilled in the art.
Compounds of formula (iv) in which R
1
represents methyl and R
2
represents CH
2
OCH
3
may be conveniently prepared from o-vanillin as shown below. o-Vanillin is treated with bromoacetaldehyde dimethyl acetal in the presence of a base, such as potassium carbonate, in a suitable solvent such as N,N-dimethylformamide, favourably at elevated temperature. The resultant acetal can then be cyclised, for example by heating in acetic acid, to provide 7-methoxybenzofuran-2-carbaldehyde. The aldehyde may be reduced using any suitable reducing agent known to those skilled in the art, such as sodium borohydride. The resultant alcohol may be methylated using any appropriate methylating agent, such as methyl iodide, in the presence of an appropriate base, such as sodium hydride.
Compounds of formula (iv) in which R
1
represents methyl and R
2
represents 3-tetrahydrofuranyl may be prepared from 7-methoxybenzofuran as depicted below. 7-Methoxybenzofuran may be deprotonated by treatment with any suitable base, such as butyllithium, and the resultant anion added to tetrahydrofuran-3-one. The resultant alcohol may be converted to a leaving group, such as a mesylate, and then eliminated. The alkene thus formed may be reduced using any suitable reducing agent, such as Raney nickel and hydrogen.
Compounds of formula (iv) in which R
1
represents methyl and R
2
represents 2-tetrahydrofuranyl may be prepared from 7-methoxybenzofuran-2-carbaldehyde as shown below. A suitably protected Grignard reagent derived from 1,3-propanediol may be added to 7-methoxybenzofuran-2-carbaldehyde, and the protecting group may then be removed. A suitable protecting group may be tert-butyldimethylsilyl, which may be removed using any standard conditions known to those skilled in the art, for example tetrabutylammonium fluoride. Cyclisation of the resultant diol may be achieved using any appropriate conditions, such as p-toluenesulphonic acid and molecular sieves in a suitable solvent such as dicloromethane.
Compounds of formula (iv) in which R
1
represents difluoromethoxy may be prepared by demethylation, and subsequent difluoromethylation, of suitable intermediates in which R
1
represents methyl. Such demethylation may be carried out using any suitable conditions known to those skilled in the art. Suitable conditions include the use of ethane thiolate in an appropriate solvent, such as N,N-dimethylformamide, at a suitable temperature. Suitable temperatures include elevated temperatures, favourably 140° C. Difluoromethylation of the resultant phenols may be carried out using any suitable conditions known to those skilled in the art. Suitable conditions include the use of chlorodifluoromethane and a suitable base in an appropriate solvent at an appropriate temperature. Favourably, the reaction is conducted in dioxane as solvent using aqueous sodium hydroxide as base. Elevated temperatures, such as reflux temperature, may be employed.
The invention includes the prevention and treatment of TNF-mediated disease or disease states, by which is meant any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for instance, is a major component, and whose production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-&bgr; (also known as lymphotoxin) has close structural homology with TNF-&agr; (also known as cachectin), and since each induces similar biological responses and binds to the same cellular receptor, both TNF-&agr; and TNF-&bgr; are inhibited by compounds of the present invention and thus are herein referred to collectively as “TNF” unless specifically delineated otherwise.
PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain,
Dyke Hazel Joan
Lowe Christopher
Montana John Gary
Darwin Discovery Ltd.
Ramsuer Robert W.
Saliwanchik Lloyd & Saliwanchik
Shameem Golam M. M.
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