Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-09
2001-11-06
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254020, C514S321000, C514S367000, C544S135000, C544S368000, C546S198000, C548S178000
Reexamination Certificate
active
06313116
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 factors (TNF), and the therapeutic utilities of inhibitors thereof; are described in WO-A-97/44036 and U.S. Pat. No. 5,804,588, the contents of which are incorporated herein by reference. WO-A-98/22460 and U.S. patent application Ser. No. 09/422,473, filed Nov. 17, 1997, disclose benzothiazoles that also have 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, novel compounds are of formula (i):
wherein R
1
is C
3-6
cycloalkyl, or C
1-3
alkyl optionally substituted with one or more fluorine atoms;
R
2
is C
1-6
alkyl, C
3-6
cycloalkyl, CF
3
, CH
2
CF
3
, C
2
F
5
or NR
4
R
5
;
R
3
is a pyrazole, imidazole or isoxazole group of partial formula (A), (B) or (C)
NR
4
R
5
is a nitrogen-containing heterocyclic ring, such morpholine, pyrrolidine, piperidine, N-methylpiperazine or azetidine;
R
6
is C
1-3
alkyl; and
R
7
and R
8
, which are the same or different, are each H, C
1-3
alkyl, halogen, CF
3
or CN, provided that both are not H;
or a pharmaceutically-acceptable salt thereof.
In summary, the compounds of the invention represent a selection within the scope of WO-A-98/22460. The novel compounds have superior potency.
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
1-6
alkyl” means a straight or branched chain alkyl moiety having one to six carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. The term “C
1-3
alkyl” includes, for example, methyl, ethyl, propyl and isopropyl.
The term “C
3-6
, cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopropyl, cyclopentyl and cyclohexyl.
The term “halogen” includes, for example, fluorine, chlorine, bromine and iodine.
In one embodiment of the invention, R
1
is optionally F-substituted alkyl, and R
2
is alkyl, cycloalkyl, CF
3
or NR
4
R
5
. In a preferred group of compounds of formula (i), R
1
is CH
3
or CHF
2
. In the same or another preferred group of compounds of formula (i), R
2
is CF
3
, ethyl or cyclopropyl.
R
3
, in compounds of the invention, 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
6
is especially CH
3
and R
7
is particularly CN, CH
3
or CF
3
. Where R
3
is an isoxazole moiety, R
7
is especially CH
3
, CF
3
or CN, and R
8
is particularly CH
3
, CF
3
or CN.
Particularly useful compounds of the invention are those of Examples 1 to 15, below. Especially useful compounds include:
4-methoxy-2-trifluoromethylbenzothiazole-7-carboxylic acid (4-cyano-2-methyl-2H-pyrazole-3-yl)amide and
2-cyclopropyl-4-methoxybenzothiazole-7-carboxylic acid (4-cyano-2-methyl-2H-pyrazole-3-yl)amide.
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 hydrobromide, and pharmaceutically-acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphate,
60
-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 R
3
NH
2
as described in WO-A-98/22460. Carboxylic acids of formula (ii) are prepared from a compound of formula (iii) using standard conditions known to those skilled in the art, either by formylation to provide an aldehyde of formula (iv) followed by an oxidation to provide an acid of formula (ii), or by bromination to provide bromide of formula (v) followed by carboxylation to provide an acid of formula (ii). Examples of these methods are described in WO-A-98/22460. Amines R
3
NH
2
may be commercially available, previously described compounds, or are prepared using standard conditions known to those skilled in the art.
Compounds of formula (iii) or (v) may be prepared from amine (vi) in one of two general methods known to those skilled in the art. Compounds of formula (iii) in which R
2
represents alkyl, cycloalkyl or CF
3
may be prepared as follows. Amine (vi) may be subjected to ring-opening to provide amino-thnol (vii), which may be condensed with anappropiate carboxylic acid or triethylorthopropionate to provide compounds of formula (iii). Alternatively, compounds of formula (v) in which R
2
represents NR
4
R
5
may be prepared from amine (vi) by diazotisation/bromination to give bromide (vii), followed by bromination to give dibromide (ix). Subsequent treatment with an appropriate nitrogen-containing aliphatic heterocycle, such as mobpholine, provides compounds of formula (v).
For example, benzthiazole (vi) can be ring-opened using any standard conditions known to those skilled in the art, for example by refluxing in sodium hydroxide solution. Treatment of the resulting compound with an appropriate carboxylic acid using any suitable conditions known to those skilled in the art provides a compound of formula (iii). Suitable conditions include the use of trimethylsilylpolyphosphate in 1,2-dichlorobenzene. To prepare a compound of formula (v), standard conditions are utilised. Thus diazotisation/bromination may be effected using any appropriate conditions, for example by using potassium bromide and sodium nitrite in sulphuric acid. Bromination may be achieved using, for example N-bromosuccinimde in acetonitrile. Displacement of the 2-bromo substituent may be carried out by treating dibromide (ix) with the appropriate cyclic amine. Elevated temperatures may favourably be employed for this reaction.
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 arthrtis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulone
Buckley George Martin
Davenport Richard John
Dyke Hazel Joan
Haughan Alan Findlay
Kendall Hannah Jayne
Darwin Discovery Ltd.
Saliwanchik Lloyd & Saliwanchik
Stockton Laura L.
LandOfFree
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