阅读说明：本技术 用于治疗炎症疾病的喹啉衍生物 (Quinoline derivatives for the treatment of inflammatory diseases ) 是由 P·鲍雷蒂 H·埃尔利希 D·谢雷 J·塔泽 于 2019-12-19 设计创作，主要内容包括：本公开涉及式(I)化合物或其代谢物中的任一种或其药学上可接受的盐,用于治疗和/或预防炎性疾病、障碍或病况,其中各R独立地是氢,卤素,-CN,羟基,(C-(1)-C-(3))氟烷基,(C-(1)-C-(3))氟烷氧基,(C-(3)-C-(6))环烷基,-NO-(2),-NR-(1)R-(2),(C-(1)-C-(4))烷氧基,苯氧基,-NR-(1)-SO-(2)-NR-(1)R-(2),-NR-(1)-SO-(2)-R-(1),-NR-(1)-C(＝O)-R-(1),-NR-(1)-C(＝O)-NR-(1)R-(2),-SO-(2)-NR-(1)R-(2),-SO-(3)H,-O-SO-(2)-OR-(3),-O-P(＝O)-(OR-(3))(OR-(4)),-O-CH-(2)-COOR-(3),(C-(1)-C-(3))烷基；各R’独立地是氢,(C-(1)-C-(3))烷基,羟基,卤素,-NO-(2),-NR-(1)R-(2),吗啉基,吗啉代,N-甲基哌嗪基,(C-(1)-C-(3))氟烷基,(C-(1)-C-(4))烷氧基,-O-P(＝O)-(OR-(3))(OR-(4)),-CN,-NH-SO-(2)-N(CH-(3))-(2)基团,或其它基团。本发明还涉及式(IV)化合物或其药学上可接受的盐,用于治疗和/或预防炎性疾病、障碍或病况,其中V,Z,R,R’,n和n’如上文描述。(The present disclosure relates to compounds of formula (I) or any one of its metabolites or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of an inflammatory disease, disorder or condition, wherein each R is independently hydrogen, halogen, -CN, hydroxy, (C) 1 ‑C 3 ) Fluoroalkyl group, (C) 1 ‑C 3 ) Fluoroalkoxy group, (C) 3 ‑C 6 ) Cycloalkyl, -NO 2 ，‑NR 1 R 2 ，(C 1 ‑C 4 ) Alkoxy, phenoxy, -NR 1 ‑SO 2 ‑NR 1 R 2 ，‑NR 1 ‑SO 2 ‑R 1 ，‑NR 1 ‑C(＝O)‑R 1 ，‑NR 1 ‑C(＝O)‑NR 1 R 2 ，‑SO 2 ‑NR 1 R 2 ，‑SO 3 H，‑O‑SO 2 ‑OR 3 ，‑O‑P(＝O)‑(OR 3 )(OR 4 )，‑O‑CH 2 ‑COOR 3 ，(C 1 ‑C 3 ) An alkyl group; each R' is independently hydrogen, (C) 1 ‑C 3 ) Alkyl, hydroxy, halogen, -NO 2 ，‑NR 1 R 2 Morpholinyl, morpholino, N-methylpiperazinyl, (C) 1 ‑C 3 ) Fluoroalkyl group, (C) 1 ‑C 4 ) Alkoxy, -O-P (═ O) - (OR) 3 )(OR 4 )，‑CN，‑NH‑SO 2 ‑N(CH 3 ) 2 A group, or other group. The invention also relates to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein V, Z, R ', n and n' are as described above, for use in the treatment and/or prevention of an inflammatory disease, disorder or condition.)

1. A compound of formula (I):

or any of its metabolites or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of an inflammatory disease, disorder or condition

Wherein:

z is C or N;

v is C or N;

means an aromatic ring wherein V is C or N, and where V is N, V is ortho, meta or para with respect to Z;

each R is independently hydrogen, halogen, -CN, hydroxy, (C)₁-C₃) Fluoroalkyl group, (C)₁-C₃) Fluoroalkoxy group, (C)₃-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，-O-P(＝O)-(OR₃)(OR₄)，-O-CH₂-COOR₃，(C₁-C₃) Alkyl, optionally mono-or disubstituted with: hydroxy, a group of formula (IIa):

or a group of formula (IIIa):

q is N or O, provided that R' is absent where Q is O; each R₁And R₂Independently is hydrogen or (C)₁-C₃) An alkyl group;

each R₃And R₄Independently of one another is hydrogen, Li⁺，Na⁺，K⁺，N⁺(Ra)₄Or a benzyl group;

n is 1, 2 or 3;

n' is 1, 2 or 3;

each R' is independently hydrogen, (C)₁-C₃) Alkyl, hydroxy, halogen, -NO₂，-NR₁R₂Morpholinyl, morpholino, N-methylpiperazinyl, (C)₁-C₃) Fluoroalkyl group, (C)₁-C₄) Alkoxy, -O-P (═ O) - (OR)₃)(OR₄)，-CN，-NH-SO₂-N(CH₃)₂A group of formula (IIa):

or a group of formula (IIIa):

a is a covalent bond, oxygen or NH; b is a covalent bond or NH;

m is 1, 2, 3, 4 or 5;

p is 1, 2 or 3;

each Ra and Rb is independently hydrogen, (C)₁-C₅) Alkyl or (C)₃-C₆) Cycloalkyl radicals, or

Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5-or 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O and S, said heterocyclic ring being optionally substituted by one or more Ra, with the proviso that in the case where R ' is a group (IIa) or (IIIa), n ' may be 2 or 3 with the proviso that the further R ' group is different from said group (IIa) or (IIIa); and

r' is hydrogen, (C)₁-C₄) Alkyl or a group of formula (IIa) as defined herein,

wherein the inflammatory disease, disorder or condition is selected from:

(a) the inflammatory disease, disorder or condition in the pancreas is selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis;

(b) an inflammatory disease, disorder or condition in the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger disease, goodpasture's syndrome, wegener's granulomatosis and acute or chronic rejection of kidney transplants;

(c) an inflammatory disease, disorder or condition in the liver selected from nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis, and liver transplantation acute or chronic rejection;

(d) an inflammatory disease, disorder or condition in the lung or heart selected from Chronic Obstructive Pulmonary Disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and acute or chronic rejection of lung or heart transplants;

(e) an inflammatory disease, disorder or condition in the skin is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pemphigus paraneoplastic, epidermolysis bullosa postnatans, acne, keloids, and other inflammatory or allergic conditions of the skin;

(f) an inflammatory disease, disorder or condition in the blood/blood vessels selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, proliferative vascular disease and restenosis;

(g) the inflammatory disease, disorder or condition in the eye is selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, retinitis optica, uveitis, orbital inflammatory disease, and optic neuritis;

(h) inflammatory diseases, disorders or conditions in the central or peripheral nervous system are selected from the group consisting of non-viral and viral encephalitis and meningitis, depression, neuropathic pain including chronic pain, traumatic brain injury including stroke, 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 lupus including in the skin and kidney, guillain-barre syndrome, myasthenia gravis, george's thyroiditis, idiopathic purpura, aplastic anemia, graves' disease, and myocarditis;

(k) an inflammatory disease, disorder or condition in the reproductive system selected from endometriosis, uterine fibroids, prostatic dysplasia or growth, and cervical dysplasia; and

(l) The inflammatory disease, disorder or condition in the bone and/or joint is selected from juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and/or demineralization of the hand, foot, ankle, knee, hip, shoulder, elbow or spine.

2. The compound for use according to claim 1, wherein the compound has formula (Ib):

or any one of its metabolites or a pharmaceutically acceptable salt thereof, wherein R, R' and R "are as defined in claim 1.

3. The compound for use according to claim 1 or 2, wherein the compound has formula (Ib'):

or any one of its metabolites or a pharmaceutically acceptable salt thereof, wherein R, R' and R "are as defined in claim 1.

4. A compound of formula (Ib') or any of its metabolites or pharmaceutically acceptable salts thereof for use according to claim 3, wherein:

r independently represents a halogen atom or a group selected from: (C)₁-C₃) Fluoroalkoxy, -NR₁R₂Radical (C)₁-C₄) Alkoxy, -O-P (═ O) (OR)₃)(OR₄) Radical (C)₁-C₃) Alkyl radical, NO₂Group, -A- (CH)₂)_mthe-B-NRaRb radicals (formula IIa) and- (O-CH)₂-CH₂)_p-An O-Ra group (formula IIIa),

n is a number of 1 or 2,

r' represents a hydrogen atom, a halogen atom or a group selected from: -NR₁R₂A radical, -O-P (═ O) (OR)₃)(OR₄) The group, -NH-SO₂-N(CH₃)₂A group, and-A- (CH)₂)_m-B-NRaRb radicals (IIa),

r' is a hydrogen atom, (C)₁-C₄) Alkyl or-A- (CH)₂)_ma-B-NRaRb group (formula IIa),

R₁and R₂Independently is a hydrogen atom or (C)₁-C₃) An alkyl group, a carboxyl group,

R₃and R₄Independently of one another is hydrogen, Li⁺，Na⁺，K⁺，N⁺(Ra)4 or a benzyl group,

a is a covalent bond, an oxygen atom or NH,

b is a covalent bond, and B is a bond,

m is a number of 2, 3 or 4,

p is a number of 1, 2 or 3,

ra and Rb independently represent a hydrogen atom or (C)₁-C₅) Alkyl, Ra and Rb can further form, together with the nitrogen atom to which they are attached, a saturated 5-or 6-membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S, said heterocyclic ring being optionally substituted with one or more Ra.

5. The compound of formula (Ib') or any of its metabolites or pharmaceutically acceptable salts thereof for use according to claim 3 or 4, wherein:

r independently represents F, Cl, -NH₂，-N(CH₃)₂，-OCH₃，-O-(CH₂)₃-CH₃，-OCF₃，-CH₃，-O-(CH₂)₂-OH，-O-(CH₂)₂-O-(CH₂)₂-OCH₃，-NO₂A group, -O-P (═ O) (OH) group, -O- (CH)₂)₂-morpholino or-O- (CH)₂)₂-a piperidino group,

n is a number of 1 or 2,

r' represents a hydrogen atom, Cl, -CH₂-CH₂-CH₃，-O-(CH₂)₂-morpholino, -O- (CH)₂)₂-piperidino, -O- (CH)₂)₃-piperidino, -N- (CH)₂)₃-morpholino, -NH-SO₂-N(CH₃)₂Radical, NH₂Or an-O-P (═ O) (OH) group,

r' is a hydrogen atom, -CH₃，-(CH₂)₃-piperidino, - (CH)₂)₂-morpholino, - (CH)₂)₄-morpholino or- (CH)₂)₂-pyrrolidino.

6. The compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use according to any one of claims 3 to 5, selected from:

7.

8. the compound of formula (Ib') or any of its metabolites or pharmaceutically acceptable salt thereof for use according to any one of claims 3 to 6, wherein the compound is 8-chloro-N- (4- (trifluoromethoxy) phenyl) quinolin-2-amine.

9. A compound of formula (IV):

or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of an inflammatory disease, disorder or condition as defined in claim 1, wherein V, Z, R ', n and n' are as described in claim 1.

10. A compound of formula (IV) according to claim 8 for use in the treatment and/or prevention of an inflammatory disease, disorder or condition as defined in claim 1, wherein the compound is of formula (IVb):

or a pharmaceutically acceptable salt thereof, wherein R, n, R ', n' are as defined in claim 1.

11. A compound of formula (IVb) according to claim 8 for use in the treatment and/or prevention of an inflammatory disease, disorder or condition as defined in claim 1, wherein the compound is of formula (IVb'):

or a pharmaceutically acceptable salt thereof, wherein R, n, R ', n' are as defined in claim 1.

12. A compound of formula (IVb') according to claim 10 for use in the treatment and/or prevention of an inflammatory disease, disorder or condition as defined in claim 1, wherein the compound is

Or a pharmaceutically acceptable salt thereof.

13. A compound according to any one of claims 1 to 7 or for use according to any one of claims 8 to 11, wherein the inflammatory disease, disorder or condition is in the liver selected from nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis and liver transplantation acute or chronic rejection.

14. A compound according to any one of claims 1 to 7 or for use according to any one of claims 8 to 11, wherein the inflammatory disease, disorder or condition is in the lung or heart, selected from Chronic Obstructive Pulmonary Disease (COPD), pulmonary fibrosis, pulmonary arterial hypertension, sarcoidosis, myocarditis, pericarditis and acute or chronic rejection of lung or heart transplants.

15. A compound according to any one of claims 1 to 7 or for use according to any one of claims 8 to 11, for use in the treatment of a patient, wherein the level of a compound of formula (I) as defined in any one of claims 1 to 7 or a compound of formula (IV) as defined in any one of claims 8 to 11, or a pharmaceutically acceptable salt thereof, in a blood, plasma, tissue, saliva and/or serum sample of the patient is measured during use.

16. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 or for use according to any one of claims 8 to 11, for use in treating a patient, wherein the presence and/or level of expression of miR-124 in a blood and/or tissue sample of the patient is measured prior to and during use.

17. A compound according to any one of claims 1 to 7 or for use according to any one of claims 8 to 11, wherein the severity of a disease, disorder or condition and/or the efficacy of the monitoring use is monitored with an algorithm that combines miR-124 levels and the levels of a cytokine or a further biomarker, or the levels of a compound of formula (I) as defined in any one of claims 1 to 7 or a compound of formula (IV) as defined in any one of claims 8 to 11, or a pharmaceutically acceptable salt thereof.

Background

Inflammation is a protective response of the immune system to tissue damage and infection. However, inflammatory reactions can harm the body in certain circumstances. In the acute phase, inflammation is characterized by pain, heat, redness, swelling, and loss of function.

Inflammatory diseases include a wide range of conditions, including inflammatory diseases associated with autoimmune diseases, Central Nervous System (CNS) inflammatory diseases, inflammatory diseases of the joints, inflammatory diseases of the digestive tract, and inflammatory skin.

Some quinoline derivatives have been described in WO2010/143169, WO2012/080953, WO2016/009065 and WO2016/009066, the entire contents of which are incorporated herein by reference.

Summary of The Invention

It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are useful in the treatment and/or prevention of various inflammatory diseases, disorders, or conditions. In one aspect, the present invention provides a method for treating an inflammatory disease, disorder or condition, comprising administering to a patient in need thereof a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein.