WO2007120083A1

WO2007120083A1 - The use of carboxamide derivatives in the manufacture of a medicament for the treatment of inflammatory, allergic and dermatological conditions

Info

Publication number: WO2007120083A1
Application number: PCT/SE2006/000443
Authority: WO
Inventors: Håkan BLADH; Krister Henriksson; Matti Lepistö
Original assignee: Astrazeneca Ab
Priority date: 2006-04-13
Filing date: 2006-04-13
Publication date: 2007-10-25

Abstract

The use of a compound of formula (I) wherein: X is (CH2)m, O, O(CH2)m or (CH2)mO, Y is (CH2)n, CHR5(CH2)n or CH2)nCHR5; R1 and R4 are, independently, aryl or heteroaryl; each independently optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, alkylthio, CF3, OCF3, OH, nitro, cyano, amino, NH(C1-4, N(C1-4 alkyl)2, methylenedioxy, phenyl, phenoxy, phenyl(C1-4 alkyl) or phenyl(C1-4 alkoxy); wherein the foregoing phenyl rings are optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, CF3 or OCF3; R2, R3 and R5 are, independently, hydrogen or C1-4 alkyl; m and n are, independently, 1 or 2; or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for the treatment of a glucocorticoid receptor mediated disease state.

Description

The use of carboxamide derivatives in the manufacture of a medicament for the treatment of inflammatory, allergic and dermatological conditions .

The present invention relates to the use of carboxamide derivatives as medicaments (for example in the treatment of an inflammatory disease state), to pharmaceutical compositions comprising such derivatives, to certain derivatives and to processes for making such derivatives.

It is known that certain non-steroidal compounds interact with the glucocorticoid receptor (GR) and, as a result of this interaction, produce a suppression of inflammation (see, for example, US6323199). Such compounds can show a clear dissociation between anti-inflammatory and metabolic actions making them superior to earlier reported steroidal and non-steroidal glucocorticoids. The present invention provides further non-steroidal compounds as modulators (for example agonists, antagonists, partial agonists or partial antagonists) of the glucocorticoid receptor capable of having a dissociation between their anti-inflammatory and metabolic actions. The present invention provides the use of a compound of formula (I):

wherein:

X is (CH₂)_m, O, O(CH₂)_m or (CH₂)_mO;

Y is (CH₂)_n, CHR⁵(CH₂)_n or (CH₂)_nCHR⁵; R¹ and R⁴ are, independently, aryl or heteroaryl; each independently optionally substituted by halo, Ci_-6 alkyl, C_1-6 alkoxy, C_1-6 alkylthio, CF₃, OCF₃, OH, nitro, cyano, amino,

NH(C_1-4 alkyl), N(C_1-4 alkyl)₂, methylenedioxy, phenyl, phenoxy, phenyl(C_1-4 alkyl) or phenyl(C_1-4 alkoxy); wherein the foregoing phenyl rings are optionally substituted by halo,

C_1-4 alkyl, C_1-4 alkoxy, CF₃ or OCF₃; R², R³ and R⁵ are, independently, hydrogen or C_1-4 alkyl; m and n are, independently, 1 or 2; or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for the treatment (for example therapy or prophylaxis) of a glucocorticoid receptor mediated disease state. Because of their ability to bind to the glucocorticoid receptor the compounds of formula (I) are useful as anti-inflammatory agents, and can also display antiallergic, immunosuppressive and anti-proliferative actions. Thus, the compounds of formula (I) can be used as medicaments for treatment or prophylaxis of the following pathologic conditions in mammals (such as humans):

(i) Lung diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• chronically obstructive lung diseases of any origin, mainly bronchial asthma •bronchitis of different origins «all forms of restructive lung diseases, mainly allergic alveolitis

• all forms of pulmonary edema, mainly toxic pulmonary edema

• sarcoidoses and granulomatoses, such as Boeck's disease

(ii) Rheumatic diseases/auto-immune diseases/degenerative joint diseases, which coincide with inflammatory, allergic and/or proliferative processes: *all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, collagenoses •reactive arthritis

• inflammatory soft-tissue diseases of other origins

• arthritic symptoms in degenerative joint diseases (arthroses) • traumatic arthritides

• collagen diseases of other origins, for example systemic lupus erythematodes, sclerodermia, polymyositis, dermatomyositis, polyarteritis nodosa, temporal arteritis

• Sjogren's syndrome, Still syndrome, Felty's syndrome (iii) Allergies, which coincide with inflammatory, allergic and/or proliferative processes: •All forms of allergic reactions, for example Quincke's edema, hay fever, insect bites, allergic reactions to pharmaceutical agents, blood derivatives, contrast media, etc., anaphylactic shock, urticaria, contact dermatitis (iv) Dermatological diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• atopic dermatitis (mainly in children) •psoriasis

• erythematous diseases, triggered by different noxae, for example radiation, chemicals, burns, etc.

• acid burns

5 • bullous dermatoses

• diseases of the lichenoid group

• itching (for example of allergic origins)

• seborrheal eczema •rosacea Q *pemphigus vulgaris

• erythema exudativum multiforme

• erythema nodosum •balanitis •vulvitis s • inflammatory hair loss, such as alopecia areata

• cutaneous T-cell lymphoma

(v) Nephropathies, which coincide with inflammatory, allergic and/or proliferative processes:

•nephrotic syndrome Q • all nephritides

(vi) Liver diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• acute liver cell decomposition

• acute hepatitis of different origins, for example virally-, toxically- or S pharmaceutical agent-induced

• chronically aggressive and/or chronically intermittent hepatitis

(vii) Gastrointestinal diseases, which coincide with inflammatory, allergic and/or proliferative processes: •regional enteritis (Crohn's disease) 0 • ulcerative colitis

• gastroenteritis of other origins, for example native sprue (viii) Proctological diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• anal eczema

• fissures s •haemorrhoids

•idiopathic proctitis

(ix) Eve diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• allergic keratitis, uvenitis iritis o • conjunctivitis

•blepharitis

• optic neuritis

• chorioiditis

• sympathetic ophthalmia s (x) Diseases of the ear-nose-throat area, which coincide with inflammatory, allergic and/or proliferative processes:

• allergic rhinitis, hay fever

• otitis externa, for example caused by contact dermatitis, infection, etc.

• otitis media o (xi) Neurological diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• cerebral edema, mainly tumor-induced cerebral edema •multiple sclerosis

• acute encephalomyelitis 5 • different forms of convulsions, for example infantile nodding spasms

(xii) Blood diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• acquired haemolytic anemia

• idiopathic thrombocytopenia o (xiii) Tumor diseases, which coincide with inflammatory, allergic and/or proliferative processes: • acute lymphatic leukaemia •malignant lymphoma

• lymphogranulomatoses

• lymphosarcoma

5 • extensive metastases, mainly in breast and prostate cancers

(xiv) Endocrine diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• endocrine orbitopathy

• thyrotoxic crisis

I₀ • de Quervain' s thyroiditis

•Hashimoto's thyroiditis •hyperthyroidism (xv) Transplants, which coincide with inflammatory, allergic and/or proliferative processes; is (xvi) Severe shock conditions, which coincide with inflammatory, allergic and/or proliferative processes, for example anaphylactic shock

(xvii) Substitution therapy, which coincides with inflammatory, allergic and/or proliferative processes, with:

• innate primary suprarenal insufficiency, for example congenital adrenogenital ₂o syndrome

• acquired primary suprarenal insufficiency, for example Addison's disease, autoimmune adrenalitis, meta-infective, tumors, metastases, etc.

• innate secondary suprarenal insufficiency, for example congenital hypopituitarism

• acquired secondary suprarenal insufficiency, for example meta-infective, tumors, ₂₅ etc.

(xviii) Emesis, which coincides with inflammatory, allergic and/or proliferative processes:

• for example in combination with a 5-HT3-antagonist in cytostatic-agent-induced vomiting.

Without prejudice to the foregoing, the compounds of formula (I) can also be used 30 to treat disorders such as: Conies Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, Bartter's Syndrome, disorders associated with excess catecholamine levels, cirrhosis with edema and ascites, oesophageal varicies, Addison's Disease, muscle weakness, increased melanin pigmentation of the skin, weight loss, Cushing's Syndrome, obesity, hypertension, glucose intolerance, osteoporosis, polyuria, polydipsia, inflammation, 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, modulation of the Thl/Th2 cytokine balance, chronic kidney disease, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, and Little's syndrome, systemic inflammation, inflammatory bowel disease, systemic lupus erythematosus, discoid lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cinhosis, inflammatory scalp alopecia, panniculitis, psoriasis, inflamed cysts, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, dermatomyositis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, lichen planus, erythema nodosum acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma, psychoses, cognitive disorders (such as memory disturbances) mood disorders (such as depression and bipolar disorder), anxiety disorders and personality disorders.

As will be appreciated by one of skill in the art, physiological disorders may present as a "chronic" condition, or an "acute" episode. The term "chronic", as used herein, means a condition of slow progress and long continuance. As such, a chronic condition is treated when it is diagnosed and treatment continued throughout the course of the disease. Conversely, the term "acute"means an exacerbated event or attack, of short course, followed by a period of remission. Thus, the treatment of physiological disorders contemplates both acute events and chronic conditions. In an acute event, compound is administered at the onset of symptoms and discontinued when the symptoms disappear. The present invention further provides a method of treating a glucocorticoid receptor mediated disease state in a mammal (such as man), which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In a still further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an inflammatory condition (such as an arthritic condition (for example osteoarthritis)).

In another aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of allergic (such as an asthmatic or rhinitis) or dermatological condition.

Compounds of of formula (I) can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions. Suitable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate, p- toluenesulphonate, succinate, glutarate or malonate.

The compounds of formula (I) may exist as solvates (such as hydrates) and the present invention covers all such solvates. Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl.

Aryl is, for example, phenyl or naphthyl.

Heteroaryl is an aromatic 5 or 6-membered ring, optionally fused to a benzene ring, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulfur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heteroaryl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), indazolyl, benzimidazolyl,-benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, quinolinyl, isoquinolinyl, a naphthyridinyl (for example [l,6]naphthyridinyl or [l,8]naphthyridinyl) or a benzothiazinyl; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. In one aspect of the invention heteroaryl is indolyl or benzothienyl.

In one particular aspect the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a glucocorticoid receptor mediated disease state, wherein:

R¹ is naphthyl or phenyl (itself optionally substituted by halo, CF₃, OCF₃, C_1-6 alkyl, C_1-6 alkoxy, N(C_1-4 alkyl)₂, phenyl or benzyloxy).

In another aspect the present invention provides the use of a compound of formula

(I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a glucocorticoid receptor mediated disease state, wherein Y is CH₂. In yet another aspect the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a glucocorticoid receptor mediated disease state, wherein

R² is hydrogen. In a further aspect the present invention provides the use of a compound of formula

(I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a glucocorticoid receptor mediated disease state, wherein R³ is Ci_-4 alkyl

(for example methyl).

In a still further aspect the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a glucocorticoid receptor mediated disease state, wherein

X is (CHa)₂.

(I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a glucocorticoid receptor mediated disease state, wherein R⁴ is phenyl. In another aspect the present invention provides a compound:

N-(l-Methyl-3-phenylpropyl)-2-(2-naphthyl)acetamide;

N-(l-Methyl-3-phenylpropyl)-2-[4-(trifluoromethoxy)phenyl]acetamide;

2-(4-Butoxyphenyl)-N-(l-methyl-3-phenylpropyl)acetamide; N-(l-Methyl-3-phenylpropyl)-2-[4-(methylthio)phenyl]acetamide;

2-(4-z5θ-propylphenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

N-(l-Methyl-3-phenylpropyl)-2-[4-(trifluoromethyl)phenyl]acetamide; 2-[4-(Benzyloxy)-3-methoxyphenyl]-N-(l-methyl-3-phenylpropyl)acetamide;

2-(3 ,4-Dichlorophenyl)-N-( 1 -methyl-3-phenylpropyl)acetamide;

2-[4-(Dimethylamino)phenyl]-N-(l-methyl-3-phenylpropyl)acetamide;

N-(l-Methyl-3-phenylpropyl)-2-(4-phenoxyphenyl)acetamide; 5 2-(4-Ethoxyphenyl)-N-(l~methyl-3-phenylpropyl)acetamide;

2-(3,5-Dimethylphenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(3-Methylphenyl)-N-(l-memyl-3-phenylpropyl)acetamide;

2-(3-Chlorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(2,6-Dichlorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide; i o 2-(4-Hy droxyphenyl)-N-( 1 -methyl-3 -phenylpropyl) acetamide ;

2-(2-Chloro-6-fluorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(3,4-Difluorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(3-Fluorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

N-(l-Methyl-3-phenylpropyl)-2-[3-(trifluoromethyl)phenyl]acetamide; is 2-(2,4-Dichlorophenyl)-N-(l -methyl-3 -phenylpropyl)acetamide;

2-(l,3-Benzodioxol-5-yl)-N-(l-methyl-3-phenylpropyl)acetamide

(2S)-N-[2-(2,6-Dimethylphenoxy)-l-methylethyl]-2-(6-methoxy-2-naphthyl)propanamide;

2-(4-Biphenylyl)-N-[2-(2,6-dimethylphenoxy)-l-methylethyl]acetamide;

N-[2-(2,6-Dimethylphenoxy)-l-methylethyl]-2-(2-naphthyl)acetamide; 20 2-(l-Methyl-lH-indol-3-yl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(l H-indol-3 -yl)-N-(l -methyl-3 -phenylpropyl)acetamide; or,

2-(l -Benzothien-3-yl)-N-[2-(2,6-dimethylphenoxy)- 1 -methylethyl]acetamide; or a pharmaceutically acceptable salt thereof (for example in free base form).

The compounds of formula (I) can be prepared using or adapting methods 25 disclosed in the art. Starting materials for the preparative methods are either commercially available or can be prepared by literature methods, adapting literature methods. Thus, in another aspect the present invention provides a process for preparing a compound listed above or a pharmaceutically acceptable salt thereof.

In order to use a compound of formual (I), or a pharmaceutically acceptable salt 30 thereof, for the therapeutic treatment of a mammal, said active ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I) (such as a compound listed above), or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition comprising mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition can comprise from 0.05 to 99 %w (per cent by weight), for example from 0.05 to 80 %w, such as from 0.10 to 70 %w (for example from 0.10 to 50 %w), of active ingredient, all percentages by weight being based on total composition.

A pharmaceutical composition of the present invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. Thus, a the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be formulated into the form of, for example, an aerosol, a powder (for example dry or dispersible), a tablet, a capsule, a syrup, a granule, an aqueous or oily solution or suspension, an (lipid) emulsion, a suppository, an ointment, a cream, drops, or a sterile injectable aqueous or oily solution or suspension.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule containing between O.lmg and Ig of active ingredient.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous, intramuscular or intra-articular injection.

Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β- cyclodextrin may be used to aid formulation.

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. Tablets may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. The invention further relates to combination therapies or compositions wherein a

GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with one or more agents for the treatment of any of the above disease states.

For example, for the treatment of rheumatoid arthritis, osteoarthritis, COPP, asthma or allergic rhinitis a GR agonist of the invention can be combined with one or more agents for the treatment of such a condition. Where such a combination is to be administered by inhalation, then the one or more agents is selected from the list comprising:

• a PDE4 inhibitor including an inhibitor of the isoform PDE4D;

• a selective β.sub2. adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;

• a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; • a modulator of chemokine receptor function (such as a CCRl receptor antagonist); or,

• an inhibitor of p38 kinase function.

In another aspect of the invention where such a combination is for the treatment of COPD, asthma or allergic rhinitis the GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, can be administered by inhalation or by the oral route and this is in combination with a xanthine (such as aminophylline or theophylline) which can be administered by inhalation or by the oral route.

Examples of compounds of formula (I) now follow.

Low resolution mass spectra and accurate mass determination were recorded on a Hewlett-Packard 1100 LC-MS system equipped with APCI ionisation chamber. All solvents and commercial reagents were laboratory grade and used as received. The following abbreviations used in the text:

NMP: l-methyl-2-pyrrolidinone TFA: trifluoroacetic acid HOBT: 1-hydroxybenzotriazole

General synthesis description: The appropriate carboxylic acid (212μL ,0.3M /NMP) was added to 71mg of polystyrene-bound carbodiimide resin (loading 1.2mmol/g) together with HOBT (400μL, 0.185M/NMP). The mixture was stirred for lOminutes before the corresponding amine (142μL, 0.3M/NMP) was added. The reaction mixture was stirred overnight at ambient temperature in a sealed vessel. Resin was removed by filtration and the filtrate was evaporated to dryness. The product was purified on semiprep-HPLC Cig-column (H₂OiCH₃CN, 0.1% TFA buffer, gradient 10% to 95% CH₃CN, 10 min).

The following method was used for LC/MS analysis: Instrument Agilent 1100; Column C₁₈ Waters Symmetry 2.1 x 30 mm 3.5μm; flow rate 0.7 ml/min; Mass APCI; UV-absorption was measured at 254nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA ; Gradient 5-95%/B 8 min, 95% B 2 min.

Example 1 N-Q-Methyl-3-phenylρropylV2-(2-naρhmyl)acetamide

APCI-MS m/z: 318.2 [MH+]. LC rt = 5.8 min. UV 254 nm.

Example 2

2-(4-Biphenylyl)-N-(l-methyl-3-phenylpropyl)acetamide (Chemical Abstracts Registry Number 744206-44-8)

APCI-MS m/z: 344.2 [MH+]. LC rt = 6.2 min. UV 254 nm.

Example 3 N-fl-Methyl-3-phenylpropyD-2-r4-ftrifluoromethoxy)phenyl]acetamide

APCI-MS m/z: 352.1 [MH+]. LC rt = 6.0 min. UV 254 nm.

s Example 4

2-(4-Butoxyphenyl)-N-(l-methyl-3-phenylpropyl)acetamide

APCI-MS m/z: 340.3 [MH+]. LC rt = 6.2 min. UV 254 nm. 0

Example 5 N-(l-Methyl-3-t)henylpropyl)-2-r4-(methylthio)phenvnacetamide

APCI-MS m/z: 314.2 [MH+]. s LC rt = 5.6 min. UV 254 nm.

Example 6

2-C4-Z-? o-propylphenyl)-N-(l -methyl-3 -phenylpropypacetamide

o APCI-MS m/z: 310.3 [MH+] . LC rt = 6.1 min. UV 254 nm.

Example 7

2-(4-BromophenvD-N-f 1 -methyl-3 -phenylpropypacetamide ₅ (Chemical Abstracts Registry Number 432527-57-6)

APCI-MS m/z: 346.1, 348.1 [MH+]. LC rt = 5.9 min. UV 254 nm.

Example 8

N-(^"l-Methyl-3-phenylpropyl)-2-r4-ftrifluoromethvπphenvnacetamide

APCI-MS m/z: 336.2 [MH+]. LC rt = 5.9 min. UV 254 nm.

Example 9

2- [4-f Benzyloxy)- 3-methoxyphenyll-N-( 1 -methyl-3 -phenylpropypacetamide

APCI-MS m/z: 404.2 [MH+]. LC rt = 5.9 min. UV 254 nm.

Example 10

N-(l-Methyl-3-phenylpropyl)-2-(^'4-nitroplienvπacetamide (Chemical Abstracts Registry Number 432496-68-9)

APCI-MS m/z: 313.1 [MH+]. LC rt = 5.3 min. UV 254 nm.

Example 11 2-f3,4-DichlorophenviyN-fl-memyl-3-phenylpropyl)acetamide

APCI-MS m/z: 336.1 [MH+]. LC rt = 6.0 min. UV 254 nm.

Example 12 2-r4-πDimethylammo)ρhenvn-N-(l-methγl-3-phenvtoroτ3yl)acetamide

APCI-MS m/z: 311.2 [MH+]. LC rt = 3.7 min. UV 254 nm.

Example 13

2-(4-Methylphenyl)-N-( 1 -methyl-3 -plienylpropyDacetamide

(Chemical Abstracts Registry Number 599163-16-3)

APCI-MS m/z: 282.1[MH+]. LC rt = 5.5 min. UV 254 nm.

Example 14 2-(4-Chlorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide (Chemical Abstracts Registry Number 432503-74-7)

APCI-MS m/z: 302.2 [MH+]. LC rt = 5.6 min. UV 254 nm. Example 15

N-(I -Methyl-3 -phenylpropyl)-2-f 4-phenoxyphenvDacetamide

APCI-MS m/z: 360.2 [MH+]. LC rt = 6.1 min. UV 254 nm.

Example 16 2-(4-Ethoxyρhenyl)-N-(l-methyl-3-phenylpropyl^')acetamide

APCI-MS m/z: 312.2 [MH+]. LC rt = 5.3 min. UV 254 nm.

Example 17 2-(3,5-Dimethylphenyl)-N-(l-methyl-3-phenylpropyl)acetamide

APCI-MS m/z: 296.2 [MH+]. LC rt = 5.8 min. UV 254 nm.

Example 18 2-(3-MethylphenylVN-fl-methyl-3-phenylpropyl)acetamide

APCI-MS m/z: 282.2 [MH+]. LC rt = 5.5 min. UV 254 nm. Example 19 2-f3-ChlorophenviyN-fl-methyl-3-phenylpropyl)acetarnide

APCI-MS m/z: 302.2 [MH+]. LC rt = 5.6 min. UV 254 nm.

Example 20

N-(I-Methyl-3-phenylpropyl)-2-Q-naphthyl)acetamide (Chemical Abstracts Registry Number 694463-44-0)

APCI-MS m/z: 318.2 [MH+]. LC rt = 5.8 min. UV 254 nm.

Example 21 2-f2,6-Dichlorophenyl)-N-fl-methyl-3-phenylpropyl)acetamide

APCI-MS m/z: 336.1 [MH+]. LC rt = 5.8 min. UV 254 nm.

Example 22

2-C4-HvdroxyphenγlVN-(l-methyl-3-phenvlproρyl)acetamide

APCI-MS m/z: 284.2 [MH+]. LC rt = 4.4 min. UV 254 nm. Example 23

2-f3,4-DimethoxyphenylVN-(l-methyl-3-phenylpropyl)acetamide (Chemical Abstracts Registry Number 375358-22-8)

APCI-MS m/z: 328.1 [MH+]. LC rt = 4.8 min. UV 254 nm.

Example 24 2-f2-Chloro-6-fluorophenylVN-(l-methyl-3-phenylpropyl)acetamid.e

APCI-MS m/z: 320.2 [MH+]. LC rt = 5.6 min. UV 254 nm.

Example 25 2-(3.4-Difluorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide

APCI-MS m/z: 304.1 [MH+]. LC rt = 5.4 min. UV 254 nm.

Example 26

2-r4-Fluorophenyl)-N-d-methyl-3-phenylpropyl)acetamide (Chemical Abstracts Registry Number 521299-88-7)

APCI-MS m/z: 286.1 [MH+]. LC rt = 5.3 min. UV 254 nm.

Example 27

2-(3-FluorophenvD-N-( 1 -methyl-3-phenylpropyl)acetamide

APCI-MS m/z: 286.1 [MH+]. LC rt = 5.3 min. UV 254 nm.

Example 28

N-(I -Methyl-3 -phenylpropyl)-2- [3 -f trifluoromethyl)phenvH acetamide

APCI-MS m/z: 336.2 [MH+]. LC rt = 5.9 min._. UV 254 nm.

Example 29

2-(2,4-DichlorophenvD-N-( 1 -methyl-3 -phenylpropyPacetamide

APCI-MS m/z: 336.1 [MH+]. LC rt = 6.0 min. UV 254 nm.

Example 30

2-d _^S-Benzodioxol-S-ylVN-d -methyl-3-phenylpropyr)acetamide

APCI-MS m/z: 312.2 [MH+]. LC rt = 5.0 min. UV 254 nm.

Example 31 f2S)-N-r2-(2,6-Dimethylphenoxy)-l-methylethyl^"|-2-(6-methoxy-2-naphthvDpropanamide

Chiral

APCI-MS m/z: 392.4 [MH+]. LC rt = 6.4 min. UV 254 m

Example 32 2-(4-Biphenylyl)-N-r2-(2,6-dimethvtohenoxy)-l-methylethyllacetamide

APCI-MS m/z: 374.4 [MH+]. LC rt = 6.5 min. UV 254 nm.

Example 33

N-r2-(2,6-Dimethylphenoxy)-l-methylethyl1-2-(^'2-naphthyl^>)acetamide

APCI-MS m/z: 348.3 [MH+]. LC rt = 6.1 min. UV 254 nm.

Example 34 2-('l-Methyl-lH-indol-3-ylVN-d-methyl-3-phenylpropyl^N)acetamide

APCI-MS m/z: 321.2 [MH+]. LC rt = 5.5 min. UV 254 nm.

Example 35 2-(lH-indol-3-ylVN-fl-methyl-3-phenylpropyl)acetamide

APCI-MS m/z: 307.3 [MH+]. LC rt = 5.1 min. UV 254 nm.

Example 36

2-ri-Benzothien-3-yl)-N-|^"2-(2_n6-dimethylphenoxy)-l-methylethyl]acetamide

APCI-MS m/z: 354.3 [MH+]. LC rt = 6.1 min. UV 254 nm.

GR-ASSAY

Human Glucocorticoid Receptor (GR) Assay

The assay is based on a commercial kit from Panvera/Tnvitrogen (Part number

P2893). The assay technology is fluorescence polarization. The kit utilises recombinant human GR (Panvera, Part number P2812), a Fluoromone™ labelled tracer (GS Red,

Panvera, Part number P2894) and a Stabilizing Peptide 1OX (Panvera, Part number P2815).

The GR and Stabilizing Peptide reagents are stored at -70°C while the GS Red is stored at -

2O⁰C. Also included in the kit are IM DTT (Panvera, Part number P2325, stored at -2O⁰C) and GR Screening buffer 1OX (Panvera, Part number P2814, stored at -70⁰C initially but once thawed stored at room temperature). Avoid repeated freeze/thaws for all reagents.

The GR Screening buffer 1OX comprises 10OmM potassium phosphate, 20OmM sodium molybdate, ImM EDTA and 20% DMSO. Test compounds (lμL) and controls (lμL) in 100% DMSO were added to black polystyrene 384-well plates (Greiner low volume black flat-bottom, part number 784076). 0% control was 100%DMSO and 100% control was lOμM Dexamethasone. Background solution (8μL; assay buffer 1OX, Stabilizing Peptide, DTT and ice cold MQ water) was added to the background wells. GS Red solution (7μL; assay buffer 1OX, Stabilizing

Peptide, DTT, GS Red and ice cold water) was added to all wells except background wells. GR solution (7μL; assay buffer 10X, Stabilizing Peptide, DTT, GR and ice cold water) was added to all wells. The plate was sealed and incubated in a dark at room temperature for 2hours. The plate was read in an Analyst plate reader (LJL Biosystems/Molecular Devices Corporation) or other similar plate reader capable of recording fluorescence polarization (excitation wavelength 530nm, emission wavelength 59OnM and a dichroic mirror at 56 lnm). The IC50 values were calculated using XLfit model 205.

Example No GR IC₅₀ μM

1 0.17

2 0.33

3 0.337

4 0.626

6 0.582

7 1.06

8 1.04

9 1.01

11 1.29

12 1.84

14 1.92

Claims

1. The use of a compound of formula (I) :

wherein:

X is (CH₂)_m, O, O(CH₂)_m or (CH₂)_mO;

Y is (CH₂)_n, CHR⁵(CH₂)_n or (CH₂)_aCHR⁵;

R¹ and R⁴ are, independently, aryl or heteroaryl; each independently optionally substituted by halo, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylthio, CF₃, OCF₃, OH, nitro, cyano, amino, NH(C_1-4 alkyl), N(C_1-4 alkyl)₂, methylenedioxy, phenyl, phenoxy, phenyl(C_1-4 alkyl) or phenyl(C_1-4 alkoxy); wherein the foregoing phenyl rings are optionally substituted by halo, C_1-4 alkyl, C_1-4 alkoxy, CF₃ or OCF₃;

R², R³ and R⁵ are, independently, hydrogen or C_1-4 alkyl; m and n are, independently, 1 or 2; or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for the treatment of a glucocorticoid receptor mediated disease state.

2. A method of treating a glucocorticoid receptor mediated disease state in a mammal, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof.

3. A use or method as claimed in claim 1 or 2 wherein the glucocorticoid receptor mediated disease state is an inflammatory condition.

4. A use or method as claimed in claim 1 or 2 wherein the glucocorticoid receptor mediated disease state is an allergic or dermatological condition.

5. A use or method as claimed in any one of the preceding claims wherein R is naphthyl or phenyl (itself optionally substituted by halo, CF₃, OCF₃, C_1-6 alkyl, C_1-6 alkoxy, N(C_1-4 alkyFh, phenyl or benzyloxy).

6. A use or method as claimed in any one of the preceding claims wherein Y is CH₂.

7. A use or method as claimed in any one of the preceding claims wherein R² is hydrogen.

8. A use or method as claimed in any one of the preceding claims wherein R³ is C_1-4 alkyl.

9. A use or method as claimed in any one of the preceding claims wherein X is (CBb)₂.

10. A use or method as claimed in any one of the preceding claims wherein R⁴ is phenyl.

11. A compound: N-( 1 -Methyl-3-phenylpropyl)-2-(2-naphthyl)acetamide;

N-(l-Methyl-3-phenylpropyl)-2-[4-(trifiuoromethoxy)phenyl]acetamide;

2-(4-Butoxyphenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

N-(l-Methyl-3-phenylpropyl)-2-[4-(methylthio)phenyl]acetamide;

2-(4-wo-propylphenyl)-N-(l-methyl-3-phenylpropyl)acetamide; N-(l-Methyl-3-phenylpropyl)-2-[4-(trifluoromethyl)phenyl]acetamide;

2-[4-(Ben2yloxy)-3-methoxyphenyl]-N-(l-methyl-3-phenylpropyl)acetamide;

2-(3,4-Dichlorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-[4-(Dimethylamino)ρhenyl]-N-(l-methyl-3-phenylpropyl)acetamide;

N-(l-Methyl-3-phenylpropyl)-2-(4-phenoxyphenyl)acetamide; 2-(4-Ethoxyρhenyl)-N-(l-methyl-3-phenylρropyl)acetamide;

2-(3,5-Dimethylphenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(3-Methylphenyl)-N-(l-methyl-3-phenylpropyl)acetamide; 2-(3-Chlorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(2,6-Dichlorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(4-Hydroxyphenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(2-Chloro-6-fluorophenyl)-N-( 1 -methyl-3 -phenylpropyl)acetamide; s 2-(3,4-Difluorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(3 -Fluorophenyl)-N-( 1 -methyl-3 -phenylpropyl)acetamide;

N-(l-Methyl-3-phenylpropyl)-2-[3-(trifluoromethyl)phenyl]acetamide;

2-(2,4-Dichlorophenyl)-N-(l-methyl-3-phenylpropyl)acetamide;

2-(l,3-Benzodioxol-5-yl)-N-(l-methyl-3-phenylpropyl)acetamide; o (2S)-N-[2-(2,6~Dimethylphenoxy> 1 -methylethyl]-2-(6-methoxy-2~ naphthyl)propanarnide ;

2-(4-Biphenylyl)-N-[2-(2,6-dimethylphenoxy)-l-methylethyl]acetamide;

N- [2-(2 ,6-Dimethy lphenoxy)- 1 -methylethyl] -2-(2-naphthyl) acetamide ;

2-(l-Methyl-lH-indol-3-yl)-N-(l-methyl-3-phenylpropyl)acetamide; s 2-(lH-indol-3-yl)-N-(l-methyl-3-phenylpropyl)acetamide; or,

2-(l-Benzothien-3-yl)-N-[2-(2,6-dimethylphenoxy)-l-methylethyl]acetamide; or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound as claimed in claim 11, or a 0 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.