Heterocyclic compounds and their therapeutic use

Details Heterocyclic compounds and their therapeutic use Heterocyclic compounds and their therapeutic use

2001-02-09

2002-06-11

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S109000, C544S114000, C544S139000, C548S236000, C548S247000, C514S396000, C514S397000, C514S407000, C514S373000, C514S233800

Reexamination Certificate

active

06403791

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 benzoxazoles 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, the compounds are of formula (i):
wherein
R
1
is C
1-3
alkyl optionally substituted with one or more fluorines;
R
2
is C
1-6
alkyl, cycloalkyl 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 as morpholine, pyrrolidine, piperidine or azetidine;
R
6
is C
1-3
alkyl, and
R
7
and R
8
, which are 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-98/22460. The novel compounds have superior pK, and therefore enhanced bioavailability.
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” 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
.
Another group of compounds of the invention is of formula (i) in which R
2
is ethyl, cyclopropyl or NR
4
R
5
.
In one particular group of compounds of the invention R
3
is a pyrazole group in which R
6
is in particular CH
3
or C
2
H
5
and R
7
is especially CN, Cl, CH
3
, C
2
H
5
, Br or CF
3
. Especially preferred is where R
6
is in particular CH
3
and R
7
is especially CN, CH
3
, or CF
3
.
R
3
in another group of compounds of formula (i) is an imidazole group in which R
6
is in particular CH
3
or C
2
H
5
and R
7
is particularly CN or CH
3
.
A further group of compounds of the invention is where R
3
is an isoxazole group in which R
7
is in particular CH
3
, CF
3
, C
2
H
5
or CN and R
8
is especially CH
3
, CF
3
, C
2
H
5
or CN. Especially preferred is where R
7
is in particular CH
3
, CF
3
, or CN and R
8
, is especially CH
3
, CF
3
, or CN.
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, &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 from suitable carboxylic acids (ii) and amines (iii), as described in WO-A-98/22460
Carboxylic acids of formula (ii) are prepared using standard conditions known to those skilled in the art such as carboxylation of bromides of formula (iv) or (vi) using carbon monoxide gas and an organopalladium catalyst. Amines of formula (iii) are either commercially available, previously described compounds, or are prepared using standard conditions known to those skilled in the art.
Bromides of formula (vi) are either previously described or prepared using standard conditions known to those skilled in the art. For example, compounds of formula (vi) in which R
1
represents methyl and R
2
represents NR
4
R
5
are conveniently prepared from 4-methoxy-2-sulfanylmethylbenzooxazole by displacement of the 2-methylsulfanyl group on heating with the appropriate amine HNR
4
R
5
.
Compounds in which R
1
represents difluoromethyl by be prepared from intermediates in which R
1
represents methyl by demethylation followed by difluoromethylation. Demethylation of compounds of formula (vi) may be carried out under standard conditions known to those skilled in the art, for example by using ethane thiol and sodium hydride in dimethylformamide at elevated temperature, or with boron tribromide in dichloromethane. Difluoromethylation of the phenols (v) may be achieved using any suitable conditions known to those skilled in the art, for example by passing chlorodifluoromethane gas through a solution of the appropriate phenol in a mixture of aqueous sodium hydroxide and dioxane at elevated temperature to give compounds of formula (iv)
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, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease, depression and multi-infarct dementia. PDE IV inhibitors are also useful in conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke and intermittent claudication. Additionally, PDE IV inhibitors could have utility as gastroprotectants. A special embodiment of the therapeutic methods of the present invention is the treatment of asthma.
The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (i). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limit

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