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Non-steroidal glucocorticoid inhibitors and their use in treating inflammation, allergy and auto-immune conditions

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Non-steroidal glucocorticoid inhibitors and their use in treating inflammation, allergy and auto-immune conditions


a process for their preparation, to pharmaceutical compositions comprising the compounds and the preparation of said compositions, to intermediates and to use of the compounds for the manufacture of a medicament for therapeutic treatment, particularly for the treatment of inflammation, allergy and/or auto-immune conditions. The present invention provides compounds of formula (I):
Related Terms: Allergy Glucocorticoid

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Inventors: Heather Anne BARNETT, Ian Baxter Campbell, Diane Mary Coe, Anthony William James Cooper, Graham George Adam Inglis, Haydn Terence Jones, Steven Philip Keeling, Simon John Fawcett MacDonald, Iain McFarlane McLay, Philip Alan Skone, Gordon Gad Weingarten, James Michael Woolven
USPTO Applicaton #: #20120277279 - Class: 514407 (USPTO) - 11/01/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai >Five-membered Hetero Ring Containing At Least One Nitrogen Ring Atom (e.g., 1,2,3-triazoles, Etc.) >Tetrazoles (including Hydrogenated) >Pyrazoles >Chalcogen Or Nitrogen Bonded Directly To The Pyrazole Ring By Nonionic Bonding

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The Patent Description & Claims data below is from USPTO Patent Application 20120277279, Non-steroidal glucocorticoid inhibitors and their use in treating inflammation, allergy and auto-immune conditions.

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CROSS REFERENCE TO PRIOR APPLICATIONS

This application is a Divisional of application Ser. No. 12/303,791 filed Dec. 8, 2008 which is a 371 National Phase Entry of Application No. PCT/EP2007/055724 filed Jun. 11, 2007 which claims the priority of GB Application No. GB0611587.7 filed Jun. 12, 2006.

The present invention relates to non-steroidal glucocorticoid receptor binding compounds and a process for their preparation, to pharmaceutical compositions comprising the compounds and the preparation of said compositions, to intermediates and to use of the compounds for the manufacture of a medicament for therapeutic treatment, particularly for the treatment of inflammation, allergy and/or auto-immune conditions.

Nuclear receptors are a class of structurally related proteins involved in the regulation of gene expression. The steroid hormone receptors are a subset of this family whose natural ligands typically comprise endogenous steroids such as estradiol (estrogen receptor), progesterone (progesterone receptor) and cortisol (glucocorticoid receptor). Man-made ligands to these receptors play an important role in human health, in particular the use of glucocorticoid agonists to treat a wide range of inflammatory conditions.

Glucocorticoids exert their actions at the glucocorticoid receptor (GR) through at least two intracellular mechanisms, transactivation and transrepression (see: Schacke, H., Docke, W-D. & Asadullah, K. (2002) Pharmacol and Therapeutics 96:23-43; Ray, A., Siegel, M. D., Prefontaine, K. E. & Ray, P. (1995) Chest 107:139 S; and Konig, H., Ponta, H., Rahmsdorf, H. J. & Herrlich, P. (1992) EMBO J. 11:2241-2246). Transactivation involves direct binding of the glucocorticoid receptor to distinct deoxyribonucleic acid (DNA) glucocorticoid response elements (GREs) within gene promoters, usually but not always increasing the transcription of the downstream gene product. Recently, it has been shown that the GR can also regulate gene expression through an additional pathway (transrepression) in which the GR does not bind directly to DNA. This mechanism involves interaction of the GR with other transcription factors, in particular NFkB and AP1, leading to inhibition of their pro-transcriptional activity (Schacke, H., Docke, W-D. & Asadullah, K. (2002) Pharmacol and Therapeutics 96:23-43; and Ray, A., Siegel, M. D., Prefontaine, K. E. & Ray, P. (1995) Chest 107:139 S). Many of the genes involved in the inflammatory response are transcriptionally activated through the NFkB and AP1 pathways and therefore inhibition of this pathway by glucocorticoids may explain their anti-inflammatory effect (see: Barnes, P. J. & Adcock, I. (1993) Trend Pharmacol Sci 14: 436-441; and Cato, A. C. & Wade, E. (1996) Bioessays 18: 371-378).

Despite the effectiveness of glucocorticoids in treating a wide range of conditions, a number of side-effects are associated with pathological increases in endogenous cortisol or the use of exogenous, and particularly systemically administered, glucocorticoids. These include reduction in bone mineral density (Wong, C. A., Walsh, L. J., Smith, C. J. et at (2000) Lancet 355:1399-1403), slowing of growth (Allen, D. B. (2000) Allergy 55: suppl 62, 15-18), skin bruising (Pauwels, R. A., Lofdahl, C. G., Latinen, L. A. et al. (1999) N Engl J Med 340:1948-1953), development of cataracts (Cumming, R. G., Mitchell, P. & Leeder, S. R. (1997) N Engl J Med 337:8-14) and dysregulation of lipid and glucose metabolism (Faul, J. L., Tormey, W., Tormey, V. & Burke, C. (1998) BMJ 317:1491; and Andrews, R. C. & Walker, B. R. (1999) Clin Sci 96:513-523). The side-effects are serious enough often to limit the dose of glucocorticoid that can be used to treat the underlying pathology leading to reduced efficacy of treatment.

It has been suggested that excessive activation of the transactivation-GRE pathway may mediate some of these side-effects (see Schacke, H., Docke, W-D. & Asadullah, K. (2002) Pharmacol and Therapeutics 96:23-43). Development of glucocorticoids that selectively modulate the transrepression pathway compared with the transactivation pathway may therefore have a superior anti-inflammatory to side-effect therapeutic index, allowing more effective and safer treatment of the patient. This new class of glucocorticoids could be used to treat more effectively and more safely the whole spectrum of disease currently treated by current glucocorticoids.

Current known glucocorticoids have proved useful in the treatment of inflammation, tissue rejection, auto-immunity, various malignancies, such as leukemias and lymphomas, Cushing\'s syndrome, 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, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little\'s syndrome, inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythemnatosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, 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 dermatitis, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform and cutaneous T-cell lymphoma.

Glucocorticoids are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, polyarteritis nodosa, Wegener\'s granulomatosis, giant cell arteritis, rheumatoid arthritis, osteoarthritis, seasonal rhinitis, allergic rhinitis, vasomotor 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. Glucocorticoids have also been used as immunostimulants and repressors and as wound healing and tissue repair agents.

A number of conditions where a key component of the pathology is inflammation within the central nervous system (CNS) are currently treated with high doses of glucocorticoid agents. It is understood that these high doses are required primarily because the steroidal agents are actively removed from the brain by specific transporters, and therefore high systemic concentrations must be achieved in order to reach therapeutic doses within the CNS. Agents which showed a higher propensity to partition into the brain would allow these therapeutic concentrations to be achieved within the CNS with a significant reduction in the systemic glucocorticoid burden, resulting in an reduced risk from the known systemic effects of glucocorticoids (such as osteoporosis, diabetes, myopathy, skin thinning and weight gain).

Inflammatory or auto-immune conditions of the nervous system where such an approach may prove valuable include but are not limited to multiple sclerosis, cerebral vasculitis, neurosarcoidosis, Sjogren\'s syndrome, systemic lupus erythematosis, acute or chronic inflammatory polyradiculopathy, Alzheimer\'s disease, neoplastic diseases of the nervous system including meningioma, lymphoma and malignant meningitis, and trauma and infectious diseases of the nervous system such as tuberculosis. Other conditions include spinal cord injury and brain injury, for example post-infarction (stroke).

There remains a need to find further compounds which bind to the glucocorticoid receptor.

In one embodiment, the present invention provides compounds of formula (I):

wherein R1 is selected from hydrogen, methyl, ethyl and 2-fluoroethyl; R2 and R3 are each independently selected from bromine, chlorine, fluorine, —CHF2, —CF3 and —OCHF2, or R2 is —SO2CH3 and R3 is hydrogen; n is an integer selected from 0, 1 and 2, when n is 1, X is selected from chlorine and fluorine, and when n is 2, each X is fluorine; and salts and solvates thereof (hereinafter “compounds of the invention”).

In a further embodiment, the present invention provides compounds of formula (IA):

wherein R1 is selected from hydrogen, methyl and ethyl; and when R1 is hydrogen or methyl, R2 and R3 are each independently selected from chlorine and fluorine, or when R1 is ethyl, R2 and R3 are each independently selected from chlorine and fluorine, or R2 is —SO2CH3 and R3 is hydrogen; and salts and solvates thereof.

The compounds of formula (I) each contain a chiral centre and there are two possible enantiomers of each compound of formula (I).

The terms Enantiomer 1 and Enantiomer 2 are used herein to refer to the enantiomers of a compound of formula (I), based on the order of their elution using the chiral chromatography methodology described herein. Enantiomer 1 refers to the first enantiomer to elute, and Enantiomer 2 refers to the second enantiomer to elute.

It will be appreciated by those skilled in the art that although the absolute retention time on chromatography can be variable, the order of elution remains the same when the same column and conditions are employed. However, the use of a different chromatography column and conditions may alter the order of elution.

It will be appreciated by those skilled in the art that at least one isomer (e.g. one enantiomer of the racemate) has the described activity. The other isomers may have similar activity, less activity, no activity or may have some antagonist activity in a functional assay.

A mixture of enantiomers, such as a racemic mixture, may be preferred. Thus, in one embodiment of the invention the compound of formula (I) is the racemic mixture (the racemate).

Alternatively, a single enantiomer may be preferred, for example the enantiomer 1. Thus, in one embodiment of the invention the compound of formula (I) is the enantiomer 1. In a further embodiment of the invention the compound of formula (I) is the enantiomer 2.

It will be appreciated by those skilled in the art that, for compounds of formula (I) wherein rotation of the aryl-carbonyl bond becomes less facile due to ortho substitution on the aromatic ring, for example when R1 is methyl or ethyl, R2 is chlorine and R3 is fluorine, an axis of asymmetry may be observed thus introducing atropisomerism into the compound and creating the possibility of four isomers namely atropisomer 1, enantiomer 1 (A1E1); atropisomer 1, enantiomer 2 (A1E2); atropisomer 2, enantiomer 1 (A2E1); and atropisomer 2, enantiomer 2 (A2E2). Any comment relating to the biological activity of an isomer or stereoisomer should be taken to include these atropisomers. It will be appreciated by those skilled in the art that where there is a non 1:1 ratio of atropisomers, that this ratio can change depending on the half life of interconversion.

It will be further appreciated by those skilled in the art that, for compounds of formula (I) wherein rotation is restricted around the C(O)—NR1 bond due to substitution of the amide, for example when R1 is ethyl or 2-fluoroethyl, rotamers may be observed. Any comment relating to the biological activity of an isomer or stereoisomer should be taken to include these rotamers. It will be appreciated by those skilled in the art that there may not be a 1:1 ratio of rotamers as the ratio can change depending on the half life of interconversion.

The terms “stereoisomer” and “isomer” as used herein encompass enantiomer, atropisomer and/or rotamer.

The compounds of the invention are glucocorticoid receptor binders. Accordingly, it has been found that at least one of the possible enantiomers of each of the compounds of formula (I) binds to the glucocorticoid receptor.



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stats Patent Info
Application #
US 20120277279 A1
Publish Date
11/01/2012
Document #
13548573
File Date
07/13/2012
USPTO Class
514407
Other USPTO Classes
International Class
/
Drawings
0


Allergy
Glucocorticoid


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