4,5-dihydro-isoxazole derivatives and their pharmaceutical use

Details 4,5-dihydro-isoxazole derivatives and their pharmaceutical use 4,5-dihydro-isoxazole derivatives and their pharmaceutical use

2001-04-06

2003-06-24

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C546S272100, C546S256000, C546S270700, C546S146000, C546S269100, C514S340000, C514S333000, C514S342000, C514S307000, C514S253100, C514S256000, C514S378000, C544S131000, C544S364000, C544S333000, C548S240000

Reexamination Certificate

active

06583141

ABSTRACT:

The present invention is directed to novel isoxazole compounds, methods for their preparation, pharmaceutical compositions comprising these compounds, and their use in therapy, particularly in the prevention and/or treatment of disease states associated with immune cell activation and proliferation.
Higher organisms are characterized by an immune system which protects them against foreign pathogens and endogenous diseases such as tumors and genetic defects. The immune system has developed a series of pathways to protect the host. The primary cells of the immune system are lymphocytes. One class of lymphocytes, T lymphocytes, affects and regulates the cell mediated response of the immune system. They consist of a heterogeneous population of cells with several distinct functional subsets called helper cells, suppressor cells and killer cells.
T lymphocytes are derived from the thymus and circulate through the blood and lymphatic vessels of the body where they can detect and interact with foreign invaders i.e. viruses, allergens, tumors and autoantigens. Upon specific interaction with invading pathogens,
T lymphocytes are activated, resulting in the development of enlarged cells—T cell blasts—which subsequently turn on the machinery for cytokine synthesis, cytokine receptor expression and proliferation. This initiates a cascade of host defense actions involving other lymphocyte subsets.
While the normal immune system is closely regulated, aberrations in the immune response are not uncommon. Many signs and symptoms of infectious, inflammatory and neoplastic diseases evolve as a result of abnormalities in the immune system, especially in T lymphocyte-mediated immunity. Even if these immunocompetent cells are not involved in the initial stage, abnormal regulation of otherwise normal appropriate cellular immune reactions may lead to acute and chronic diseases. These diseases are often of unknown etiology and include systemic rheumatic diseases, organ specific endocrine diseases, inflammatory disease of the gut and skin. The treatments available in relation to said diseases are usually symptomatic or palliative, i.e. most of the drugs prescribed in connection with said diseases are directed at allaying the symptoms and have no curative effect. Thus, a long-felt need exists for an effective means of curing or ameliorating T lymphocyte-mediated pathologies. Such a treatment should ideally control the inappropriate T cell response, rather than merely reducing the symptoms.
Current treatments of immunoinflammatory and proliferative diseases involve the administration of drugs which suppress the immune response. Examples of such drugs include methotrexate, cyclophosphamide, azathioprine, rapamicine, cyclosporin A, FK-506 and leflunomide. The use of these drugs is limited due to the cytotoxic effect (gastrointestinal symptoms, nefro- and hepatotoxicity) on the host and also because they induce global immunosuppression. For example, prolonged treatment with these drugs can lead to infections and malignancies. Steroid compounds like corticosteroids (prednisolone, deflazacort) are also employed in many instances. Although some efficacy of corticosteroids in immunoinflammatory diseases was demonstrated, their long term adverse effects, particularly osteoporosis, have remained a substantial obstacle limiting their routine use.
A more selective therapeutic approach involves the use of antibodies or soluble receptors directed to T cell markers (e.g. CD4, CD8, B7, T cell receptor) or to cytokines involved in the disease (e.g. IL-1, IL-2, TNF-&agr;) or their receptors. These alternatives are associated with high production costs. Another proposed therapy involves the induction of tolerance by the oral administration of the antigen which is related to the cause of the disease. However, use of this therapeutic modality is limited due to the difficulty in identifying and purifying the antigen(s) responsible for the autoimmune disease afflicting the patient.
Thus, new compounds with improved therapeutic activity and reduced side effects are needed.
Accordingly, the present invention provides certain isoxazole derivatives having the formula
wherein m, n and p are each independently 0 or 1 and q is 0, 1, 2, 3, 4 or 5; —A
1
═A
2
—A
3
═A
4
— is a bivalent radical of formula
 —N═CH—CH═CH—  (a-1)
—CH═N—CH═CH—  (a-2)
—CH═CH—CH═N—  (a-3)
—CH═CH—N═N—  (a-4)
—N═CH—N═CH—  (a-5)
—N═CH—CH═N—  (a-6)
—CH═CH—CH═CH—  (a-7)
B is a bivalent radical of formula
D is Ar
1
or Het
1
;
Q is a direct covalent bond or a bivalent radical of formula
wherein
X
1
and X
2
are each independently S or O, t is 0, 1 or 2;
X
3
is independently S, O or NR
26
; X
4
and X
5
are each independently N or CH.
L is Ar
1
or Het
1
;
R
1
is selected from hydrogen, halo, hydroxy, C
(1-6)
alkyl, C
(2-6)
alkenyl, C
(2-6)
alkynyl, C
(3-6)
cycloalkyl, C
(3-6)
cycloalkenyl, C
(1-6)
alkyloxy, C
(3-6)
cycloalkenylC(
(1-6)
alkyl, C
(3-6)
cycloalkyloxy, haloC(
(1-6)
alkyl, cyano, guanidine, nitro and NR
17
R
18
;
R
2
and R
3
are each independently selected from hydrogen, halo, C
(1-6)
alkyloxy and C
(1-6)
alkyl where the alkyl moiety may be optionally substituted by one or more hydroxy [for example 1, 2 or 3];
R
4
is selected from hydrogen, C
(1-6)
alkyl, C
(2-6)
alkenyl, C
(2-6)
alkynyl, C
(3-6)
cycloalkyl and
C
(3-6)
cycloalkenyl;
R
5
, R
6
, R
9
and R
10
are each independently selected from hydrogen, hydroxy, halo, C
(1-6)
alkyl, [where the alkyl moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C
(1-6)
alkyloxy, NR
17
R
18
, (SO
2
)R
16
, (C═O)R
16
, Ar
1
and Het
1
], C
(2-6)
alkenyl, C
(2-6)
alkynyl, C
(3-6)
cycloalkyl, C
(3-6)
cycloalkenyl, C
(1-6)
alkyloxy [where the alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo C
(1-6)
alkyloxy, (═O), NR
17
R
18
, (SO
2
)R
16
, (C═O)R
16
, Ar
1
and Het
1
], cyano, (C═O)R
25
, (C═O)OR
16
, (SO
2
)R
16
, aminocarbonyloxy, aminoC
(1-6)
alkyl, NR
17
R
18
, N
3
, Ar
1
and Het
1
;
or
R
5
and R
6
and R
10
together with the carbon atom to which they are attached, form a Het
1
or a C
(2-14)
carbocyclic radical optionally substituted by 1,2 or 3 substituents independently selected from halo, hydroxy, C
(1-6)
alkyl, C
(2-6)
alkenyl, C
(2-6)
alkynyl, C
(3-6)
cycloalkyl, C
(3-6)
cycloalkenyl, C
(1-6)
alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C
(1-6)
alkyloxy, NR
23
R
24
, (C═O)R
22
, C
(6-14)
aryl and C
(1-14)
heterocycle], cyano, (═O), (═NH), (C═O)R
22
, (SO
2
)R
22
, NH(C═O)R
22
, NR
23
R
24
, C
(6-14)
aryl, C
(6-14)
aryl-thio, C
(6-14)
aryloxy [where the aryloxy moiety may be optionally substituted by halo] and C
(1-14)
heterocycle;
R
7
and R
8
are each independently selected from hydrogen, hydroxy, C
(1-6)
alkyl, C
(2-6)
alkenyl, C
(2-6)
alkynyl, C
(3-6)
cycloalkyl, C
(3-6)
cycloalkenyl, hydroxyC
(1-6)
alkyl and C
(1-6)
alkyloxy;
R
11
is selected from hydrogen, hydroxy and C
(1-6)
alkyloxy [where the alkyloxy moiety may be optionally substituted by (C═O)R
16
];
R
12
is selected from hydrogen and hydroxy;
R
13
is selected from hydrogen, hydroxy, halo, C
(1-6)
alkyl, C
(2-6)
alkenyl, C
(2-6)
alkynyl, C
(3-6)
cycloalkyl, C
(3-6)
cycloalkenyl, C
(1-6)
alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, (═O), NR
17
R
18
, (SO
2
)R
16
, (C═O)R
16
, Ar
1
and Het
1
], aminocarbonyloxy, amino(C
(1-6)
alkyl, NR
17
R
18
, N
3
, Ar
1
and Het
1
;
R
14
and R
15
are each

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