Glucocortiocoid-selective antiinflammatory agents

Details Glucocortiocoid-selective antiinflammatory agents Glucocortiocoid-selective antiinflammatory agents

1998-02-13

2002-04-30

Aulakh, Charanjit S. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S076000, C546S062000, C546S061000

Reexamination Certificate

active

06380207

ABSTRACT:

TECHNICAL FIELD
The present invention relates to glucocorticoid receptor-selective benzopyrano[3,4-f]quinolines that are useful for treating immune or autoimmune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation, inflamatory disease, immune, and autoimmune diseases in a mammal.
BACKGROUND OF THE INVENTION
Intracellular receptors (IR's) are a class of structurally related proteins involved in the regulation of gene expression. The steroid hormone receptors are a subset of this superfamily whose natural ligands are typically comprised of endogenous steroids such as estradiol, progesterone, and cortisol. Man-made ligands to these receptors play an important role in human health and, of these receptors, the glucocorticoid receptor (GR) has an essential role in regulating human physiology and immune response. Steroids which interact with GR have been shown to be potent antiinflammatory agents. Despite this benefit, steroidal GR ligands are not selective. Side effects associated with chronic dosing are believed to be the result of cross-reactivity with other steroid receptors such as estrogen, progesterone, androgen, and mineralocorticoid receptors which have somewhat homologous ligand binding domains.
Selective GR repressors, agonists, partial agonists and antagonists of the present disclosure can be used to influence the basic, life-sustaining systems of the body, including carbohydrate, protein and lipid metabolism, and the functions of the cardiovascular, kidney, central nervous, immune, skeletal muscle, and other organ and tissue systems, In this regard, GR modulators have proven useful in the treatment of inflammation, tissue rejection, auto-immunity, various malignancies, such as leukemias and lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, and Little's syndrome.
GR modulators are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis , osteoarthritis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, and cirrhosis. GR active compounds have also been used as immunostimulants and repressors, and as wound healing and tissue repair agents.
GR modulators have also found use in a variety of topical diseases such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma.
Selective antagonists of the glucocorticoid receptor have been unsuccessfully pursued for decades. These agents would potentially find application in several disease states associated with Human Immunodeficiency Virus (HIV), cell apoptosis, and cancer including, but not limited to, Kaposi's sarcoma, immune system activation and modulation, desensitization of inflammatory responses, IL-1 expression, anti-retroviral therapy, natural killer cell development, lymphocytic leukemia, and treatment of retinitis pigmentosa. Cogitive and behavioral processes are also susceptible to glucocorticoid therapy where antagonists would potentially be useful in the treatment of processes such as cognitive performance, memory and learning enhancement, depression, addiction, mood disorders, chronic fatigue syndrome, schizophrenia, stroke, sleep disorders, and anxiety.
SUMMARY OF THE INVENTION
In one embodiment of the present invention are compounds represented by Formula I
or pharmaceutically acceptable salts or prodrugs thereof, where
the symbol
- - - -
represents a single or double bond,
provided that no two double bonds are in adjacent positions;
A is —L
1
—R
A
where L
1
is selected from
(1) a covalent bond,
(2) —O—,
(3) —S(O)
t
— where t is 0, 1, or 2,
(4) —C(X)—,
(5) —NR
7
— where R
7
is selected from
(a) hydrogen,
(b) aryl
(c) cycloalkyl of three to twelve carbons,
(d) alkanoyl where the alkyl part is one to twelve carbons,
(e) alkoxycarbonyl where the alkyl part is one to twelve carbons,
(f) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted by 1 or 2 aryl groups,
(g) alkyl of one to twelve carbons,
(h) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons,
(i) alkenyl of three to twelve carbons,
provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen,
(j) alkynyl of three to twelve carbons,
provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen,
(6) —NR
8
C(X)NR
9
— where X is O or S and R
8
and R
9
are independently selected from
(a) hydrogen,
(b) aryl,
(c) cycloalkyl of three to twelve carbons,
(d) alkyl of one to twelve carbons,
(e) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons,
(f) alkenyl of three to twelve carbons,
provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen,
(g) alkynyl of three to twelve carbons,
provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen,
(7) —X′C(X)— where X is previously defined and X′ is O or S,
(8) —C(X)X′—,
(9) —X′C(X)X″— where X and X′ are previously defined and X″ is O or S,
provided that when X is O, at least one of X′ or X″ is O,
(10) —NR
8
C(X)—,
(11) —C(X)NR
8
—,
(12) —NR
8
C(X)X′—,
(13) —X′C(X)NR
8
—,
(14) —SO
2
NR
8
—,
(15) —NR
8
SO
2
—, and
(16) —NR
8
SO
2
NR
9
—
where (6)-(16) are drawn with their right ends attached to R
A
and R
A
is selected from
(1) —OH,
(2) —OG where G is a —OH protecting group,
(3) —SH,
(4) —CN,
(5) halo,
(6) haloalkoxy of one to twelve carbons,
(7) perfluoroalkoxy of one to twelve carbons,
(8) —CHO,
(9) —NR
7
R
7′
where R
7
is defined previously and R
7′
is selected from
(a) hydrogen,
(b) aryl,
(c) cycloalkyl of three to twelve carbons,
(d) alkanoyl where the alkyl part is one to twelve carbons,
(e) alkoxycarbonyl where the alkyl part is one to twelve carbons,
(f) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted by 1 or 2 aryl groups,
(g) alkyl of one to twelve carbons,
(h) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons,
(i) alkenyl of three to twelve carbons,
provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen,
(j) alkynyl of three to twelve carbons,
provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen,
(10) —C(X)NR
8
R
9
,
(11) —OSO
2
R
11
where R
11
is selected from
(a) aryl,
(b) cycloalkyl of three to twelve carbons,
(c) alkyl of one to twelve carbons,
(d) alkyl of one to twelve carbons substituted with 1, 2, 3, or 4 hal

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