Combination of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine and its derivatives with a JAK inhibitor

Claims

1. A pharmaceutical combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof with a JAK (Janus kinase) inhibitor or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following formula: Where: Z represents C or N; V represents C or N; means an aromatic ring where V is C or N, and when V is N, V ​​is in the ortho-, meta-, or para-position relative to Z; each R independently represents hydrogen, halogen, -CN, hydroxyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, (C3-C6)cycloalkyl, -NO2, -NR1R2, (C1-C4)alkoxy, phenoxy, -NR1-SO2-NR1R2, -NR1-SO2-R1, -NR1-C(=O)-R1, -NR1-C(=O)-NR1R2, -SO2-NR1R2, -SO3H, -O-SO2-OR3, -OP(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3)alkyl, wherein said alkyl is optionally mono- or disubstituted with a hydroxyl group, a group of formula (IIa) or a group of formula (IIIa) where Q is N or O, provided that R” is absent when Q is O; each of R1 and R2 independently represents hydrogen or (C1-C3)alkyl; each of R3 and R4 independently represents hydrogen, Li + , Na + , K + , N + (Ra)4 or benzyl; n is 1, 2 or 3; n' is 1, 2, or 3; each R' independently represents hydrogen, (C1-C3)alkyl, hydroxyl, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3)fluoroalkyl, (C1-C4)alkoxy, -OP(=O)-(OR3)(OR4), -CN, group of formula (IIa) or a group of formula (IIIa) where A represents a covalent bond, oxygen or NH; B represents a covalent bond or NH; m is equal to 1, 2, 3, 4 or 5; p is 1, 2, or 3; each of Ra and Rb independently represents hydrogen, (C1-C5)alkyl, or (C3-C6)cycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, said heterocycle being optionally substituted with one or more Ra, with the proviso that when R' is a group (IIa) or (IIIa), n' may be 2 or 3 only if the other groups R' are different from said group (IIa) or (IIIa); and R” represents hydrogen, (C1-C4)alkyl, or a group of formula (IIa) as defined herein.

2. The pharmaceutical combination according to claim 1, wherein the compound of formula (I) is a compound of formula (Ib) or any of its metabolites, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R, R' and R'' are as defined in paragraph 1.

3. A pharmaceutical combination according to claim 1 or 2, wherein the compound of formula (I) is selected from 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or one of its pharmaceutically acceptable salts or its metabolite.

4. A pharmaceutical combination according to claim 1, containing a metabolite of the compound of formula (I), in particular its glucuronide metabolite.

5. A pharmaceutical combination according to claim 4, containing a glucuronide metabolite of the formula 6. The pharmaceutical combination according to any one of claims 1 to 5, wherein the JAK inhibitor is selected from abrocitinib, baricitinib, BMS-986165, decernotinib (VX509), filgotinib, itacitinib, oclacitinib, peficitinib, fedratinib, deucravacitinib, PF-06651600, PF-06700841, SHR-0302, R333 (R932333), R348 (R932348), ruxolitinib, solcitinib, delgocitinib, isencitinib (TD-1473), TD-3504, tofacitinib and upadacitinib; and, in particular, is upadacitinib and pharmaceutically acceptable salts thereof.

7. A pharmaceutical combination according to any one of claims 1 to 6, wherein the compound of formula (I) is 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and the JAK inhibitor is upadacitinib.

8. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof and a JAK inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8, wherein the compound of formula (I) and the JAK inhibitor are as defined in any one of claims 2 to 7.

10. A pharmaceutical composition according to claim 8 or 9, comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or one of its pharmaceutically acceptable salts and upadacitinib or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.

11. Use of a combination according to any one of paragraphs 1-7 in the treatment of inflammatory diseases, disorders or pathological conditions described in detail below: (a) an inflammatory disease, disorder or pathological condition of the pancreas selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis; (b) an inflammatory disease, disorder or pathological condition of the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute renal failure, Berger's disease, Goodpasture's syndrome, Wegener's granulomatosis and acute or chronic kidney transplant rejection; (c) an inflammatory disease, disorder, or pathological condition of the liver selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis, and acute or chronic liver transplant rejection; (d) an inflammatory disease, disorder or pathological condition of the lungs or heart selected from bronchitis, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and acute or chronic rejection of a lung or heart transplant, infection with Coronaviridae and pathological conditions associated therewith, in particular where the Coronaviridae is a Sarbecovirus selected from coronaviruses associated with severe acute respiratory syndrome, even more particularly where the coronaviruses associated with severe acute respiratory syndrome (SARS) are selected from the group consisting of: SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, SARS-CoV-2; including the strains responsible for COVID-19 and mutants thereof; (e) an inflammatory disease, disorder or condition of the skin selected from psoriasis, dermatitis such as eczema, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, rosacea, psoriasis of the folds / inverse psoriasis, lichen planus, seborrheic dermatitis, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne, keloid scar and other inflammatory or allergic conditions of the skin; (e) an inflammatory disease, disorder or pathological condition of the vessels / blood selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, proliferative vascular disease and restenosis, atherosclerosis, axial spondyloarthritis including axial SpA (spondyloarthritis)-giant cell arteritis, and Takayasu's syndrome; (f) an inflammatory disease, disorder or pathological condition of the eye selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, inflammatory disease of the orbit and optic neuritis; (g) an inflammatory disease, disorder or pathological condition of the central or peripheral nervous system selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain including chronic pain, traumatic brain injury including stroke, neurodegenerative disease such as Alzheimer's disease and Parkinson's disease, myelitis, Charcot-Marie-Tooth disease type 1 (including CMT1A and CMT1B), amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, demyelinating polyneuropathy and peripheral neuropathy; (i) an autoimmune disease, disorder or condition selected from Sjogren's syndrome, lupus including lupus involving the skin and kidneys, Guillain-Barré syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease and myocarditis; (k) an inflammatory disease, disorder or pathological condition of the reproductive system selected from endometriosis, uterine fibroids, prostatic dysplasia or growth, and cervical dysplasia; (l) an inflammatory disease, disorder or pathological condition of the bones and / or joints selected from rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, periodontitis and arthritis of the hand, foot, ankle, knee, hip, shoulder, elbow or spine and / or demineralization; (m) an inflammatory disease, disorder, or condition of the digestive tract selected from inflammation associated with colon carcinoma, inflammatory bowel disease including Crohn's disease, ulcerative colitis, and eosinophilic esophagitis; and (n) an inflammatory disease, disorder or condition of the central nervous system selected from multiple sclerosis (MS), relapsing-remitting multiple sclerosis (RRMS); relapsing forms of multiple sclerosis (RMS) and secondary progressive multiple sclerosis (SPMS).

12. The use according to claim 11, wherein the inflammatory disease is inflammatory bowel disease, including ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis.

13. A pharmaceutical combination of a compound of formula (I) as defined in any one of claims 1 to 5, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharmaceutically acceptable salts, prodrugs or metabolites thereof, and a JAK inhibitor or a pharmaceutically acceptable salt thereof for separate administration, time-distributed administration or simultaneous administration to patients suffering from inflammatory diseases, disorders or pathological conditions, in particular as defined in claim 11.

14. A pharmaceutical combination for separate administration, time-distributed administration or simultaneous administration to patients suffering from inflammatory diseases, disorders or pathological conditions according to claim 13, wherein said inflammatory diseases, disorders or pathological conditions are inflammatory bowel disease, including ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis.

15. A pharmaceutical kit, in particular intended for the treatment of inflammatory diseases, disorders or pathological conditions as detailed in paragraph 11, and in particular inflammatory bowel disease, including ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis, comprising: (i) a first galenic composition comprising a compound of formula (I) as defined in any one of claims 1 to 5, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharmaceutically acceptable salts, prodrugs or metabolites, and in particular its glucuronide metabolite of formula (ii) and a second galenic composition comprising a JAK inhibitor or a pharmaceutically acceptable salt thereof, in particular upadacitinib or any of its pharmaceutically acceptable salts.