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WO2025133653A1 - Dérivés d'imidazole et leur utilisation en tant qu'agents antifibrotiques - Google Patents

Dérivés d'imidazole et leur utilisation en tant qu'agents antifibrotiques Download PDF

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Publication number
WO2025133653A1
WO2025133653A1 PCT/HU2024/050125 HU2024050125W WO2025133653A1 WO 2025133653 A1 WO2025133653 A1 WO 2025133653A1 HU 2024050125 W HU2024050125 W HU 2024050125W WO 2025133653 A1 WO2025133653 A1 WO 2025133653A1
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Prior art keywords
methyl
phenyl
imidazole
carboxamide
alkyl
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Inventor
Mária BALOGH
László ŐRFI
Csaba SZÁNTAI-KIS
Ádám László VANNAY
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Vichem Chemie Kutato Kft
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Vichem Chemie Kutato Kft
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/4164—1,3-Diazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the main effector cells of fibrosis are the myofibroblasts, characterized by increased proliferation rate and excessive production of extracellular matrix. Chronic activation of myofibroblasts leads to the excessive deposition of the extracellular matrix replacing the healthy tissue leading to the impairment and finally to the loss of organ function.
  • the unmet medical need makes it necessary to develop new drugs to hinder organ fibrosis.
  • Receptor tyrosine kinases e.g. platelet-derived growth factor (PDGF) receptor
  • non-receptor tyrosine kinases e.g. c-Abl, c-Kit, Src kinases
  • Inhibitors of these kinases might be useful for the treatment of idiopathic pulmonary fibrosis, renal-, liver- or dermal fibrosis.
  • Gleevec Imatinib
  • This drug can suppress platelet-derived growth factor (PDGF) by inhibiting its receptor (PDGFR- ⁇ ).
  • Pirfenidone reduces renal fibrosis and lung fibrosis through downregulation of the production of profibrotic growth factors (e.g. PDGF) and procollagenes. Based on the above, we can expect that compounds exerting downregulation of the production of profibrotic growth factors (e.g.
  • PDGF PDGF
  • PDGF-R platelet derived growth factor receptor
  • Ar is phenyl, or 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms independently selected from N and S, such as pyrrole, tiophene, imidazole, pyrazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, thiazine; wherein each of the phenyl and the heteroaromatic ring is optionally substituted with 1 or 2 substituents independently selected from C1-4 alkyl, halogen, -OH, -NH 2 , -NHC1-4 alkyl, C1-4 alkoxy; R 1 is H, halogen, C1-2 alkyl, or C1-2 alkoxy; R 2 is H, halogen, or C1-2 alkyl; X 1 is NH or CO X 2 is NH or CO, with the proviso that X 1 and X 2 are not the same; Y is a bond or (CH2)n
  • Ar is a 5-membered heteroaromatic ring comprising 1 or 2 heteroatoms independently selected from N and S; preferably N wherein each of the heteroaromatic ring is optionally substituted with a substituent selected from C1-2 alkyl, halogen, -OH, -NH2, -NHC1-2 alkyl, C1-2 alkoxy, preferably, methyl, methoxy, and halogen.
  • Ar is a 5-membered heteroaromatic ring comprising 2 nitrogen atoms, such as imidazolyl or pyrazolyl, optionally substituted with methyl, preferably imidazole-4-yl, 1-methylimidazol-4-yl, 1-methylimidazol-5-yl, more preferably 1-methylimidazol-5-yl.
  • R 1 is H, methyl, methoxy, fluoro or chloro, preferably hydrogen, methyl, fluoro or chloro, more preferably methyl
  • R 2 is H, fluoro or methyl, preferably H. 5.
  • Y is a bond, or Y is (CH2)n, provided that X 2 is NH, or Y is NH, provided that X 2 is CO; preferably Y is a bond.
  • Z is phenyl, or a 5- or 6-membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S, or a 8-10-membered aromatic bicyclic moiety containing 1-2 heteroatoms, independently selected from N, O and S, preferably N, or 3-, 4-, 5- or 6-membered cycloalkyl group, or a 6-membered saturated heterocyclic ring comprising 1 or 2 heteroatoms independently selected from N, O and S, preferably N, where any of these rings or cyclic groups is optionally substituted 1-3 substituents independently selected from C1-2 alkyl, t-butyl, C1-2 alkoxy, benzyloxy, halogen, trihal
  • Z is phenyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, pyrazolo[1,5-a]pyridinyl, indolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, and tetrahydropyranyl, preferably phenyl where any of these rings or cyclic groups is optionally substituted 1-3 substituents independently selected from methyl, ethyl, methoxy, ethoxy, benzyloxy, halogen, trifluoromethyl, -NO 2 , -CN, -OH, -NH 2
  • Figure 9 Effect of compound VCC380920 on body weight of healthy mice and in the experimental model of bleomycin induced lung fibrosis (BILF).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Non-limiting examples are azirdinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, dioxolanyl, oxasulfuranyl, disulfuranyl, oxazolidin-2-one, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl
  • Non-limiting examples are pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl tetrazinyl, azepinyl, oxepinyl, thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benz
  • heteroaryl groups that contain one or more heteroatoms
  • the point of attachment can be a carbon or heteroatom, as valency permits.
  • exemplary heteroaryl groups are imidazole, pyrrole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, pyridine, thiazole, pyridazine, pyrimidine, pyrazine, thiazine.
  • the term “aminosulfonyl group” denotes an H2N-S(O) 2 - moiety.
  • Fibroproliferative disorder is a disorder which is characterized by inter alia the presence of progressive fibrosis, in particular wherein at least partially ECM remodeling is shifted towards accumulation of ECM producing cells, like fibroblasts, and/or towards excessive deposition of ECM components leading to impairment or destruction of tissue architecture and/or to gradual decline of organ function.
  • a “neoplasm” is a type of abnormal and excessive growth of tissue.
  • a “non-physiological” or “dysregulated” deposition of ECM occurs when deposition of ECM components leads to impairment, i.e. destruction of tissue architecture and/or tissue function itself.
  • the unregulated or abnormally regulated deposition of ECM components is a particular hallmark of non-physiological ECM deposition or production.
  • deposition of ECM components is considered as “non-physiological” (in case of fibrosis excessive) when there are no signs that regulatory processes of the surrounding healthy tissue in question counteracting deposition are capable of reversing, or at least arresting such deposition.
  • a “subject” as used herein is an individual of an animal species, preferably a vertebrate, more preferably a mammalian or avian species, in particular a mammalian species, highly preferably the individual is a primate, a hominid or a human.
  • the term “mammal’ is known in the art and relates to an animal species of which the female feeds her young on milk from her own body, and exemplary mammals include humans, primates, livestock animals (including bovines, porcines, goats, sheep, horses etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats) all or any of which is contemplated herein.
  • a “patient” is a subject who is or intended to be under medical or veterinarian observation, supervision, diagnosis or treatment.
  • a “treatment” refers to any process, action, application, therapy, or the like, wherein the subject or patient is under aid, in particular medical or veterinarian aid with the object of improving the subject’s or patient’s condition, either directly or indirectly. Improving the subject’s condition may include improving an aesthetic condition (cosmetic treatment) and/or may include, in particular, restoring or maintaining normal function of an organ or tissue, preferably at least partly restoring or maintaining health (medical or veterinarian treatment). Treatment typically refers to the administration of an effective amount of a compound or composition described herein. Treatment may relate to or include medical or veterinarian treatment and cosmetic treatment, in particular medical or veterinarian treatment.
  • Preventing or “prevention” of the development of a disease or condition refers to at least the reduction of likelihood of the risk of or susceptibility to acquiring a disease or disorder, or preferably causing at least one of the clinical symptoms of the disease or disorder not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease.
  • an effective amount or “therapeutically effective amount” are intended to qualify the amount of a therapeutic agent required to relieve to some extent one or more of the symptoms of a condition, disease or disorder, including but not limited to: 1) reducing the number of fibroblasts or myofibroblasts ; 2) reducing the synthesis of the ECM components, and/or increasing the degradation of the ECM component; 3) reducing the size of the fibrous tissue; 4) improving to at least some extent the physiological function of the tissue due to any of 1) to 3); 5) reducing the size of a tumour tissue; 6) inhibits the formation of tumour cell metastases; 7) inhibits immune cell proliferation or activation, including production of cytokines, growth factors or antibodies.
  • the compounds of the invention have pharmaceutical (medicinal), nutritional, and cosmetic uses as well.
  • the IC 50 values for inhibition of PDGFR- ⁇ receptor of the compounds of the general formula (I) are usually smaller than 1000 nM, the favourable compounds exhibit IC50 values smaller than 100 nM.
  • the acid of the general formula (II) is reacted with the amine of the general formula (III) – where in the formula X 1 , X 2 , Y, Z, R 1 and R 2 have the same meanings as defined above – in the presence of an activating agent.
  • the activating agent may be the 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide (EDC).
  • EDC 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide
  • the reaction is carried out in an inert solvent (e.g. pyridine, dichloromethane, tetrahydrofuran, dioxane, N,N-dimethylformamide) at ambient temperature or at the reflux temperature of the reaction mixture. (Scheme 1, Method A).
  • reaction is carried out in the case of acids of the general formula (V) – where Q represents hydroxyl group – in the presence of an activating agent (e.g. 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide (EDC)), in an inert solvent (e.g. pyridine, dichloromethane, tetrahydrofuran, dioxane, N,N-dimethyl-formamide) at ambient temperature or at the reflux temperature of the reaction mixture.
  • an activating agent e.g. 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide (EDC)
  • EDC 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide
  • an inert solvent e.g. pyridine, dichloromethane, tetrahydrofuran, dioxane, N,N-dimethyl-formamide
  • Reduction of the nitro group in compounds of the general formula (XIII) can be realized by tin(II)chloride dihydrate in ethyl acetate or by hydrogen transfer reaction using 10% Pd/C catalyst and ammonium formate in methanol – dichloromethane solvent mixture at ambient temperature or at reflux temperature.
  • Scheme 7 The two steps process for the synthesis of the acid intermediate of the general formula (VI) – where in the formula R Ar , R 1 , R 2 have the same meanings as defined above – is shown in Scheme 7.
  • the pharmaceutical compositions contain the compounds of the general formula (I) or their pharmaceutically acceptable derivatives, together with pharmaceutically acceptable carriers and excipients.
  • the inventors aimed to develop novel antiproliferative/antifibrotic compounds targeting PDGFR- ⁇ and - ⁇ , the receptor of PDGF-A, -B, -C, and -D, a core factor responsible for the activation of the myofibroblasts the main effector cells of organ fibrosis.
  • the effect of the compounds derived from computer-aided drug design, were first tested using in vitro biochemical assay investigating the kinase activity of PDGFR- ⁇ and - ⁇ ( Figure 1, Table 7, Table 8) (see Example 64).
  • VCC380920 significantly inhibited the protein level of collagen type I and fibronectin in the lung tissue of bleomycin treated mice ( Figures 9-12). In addition to its positive effects, VCC380920 showed no adverse or toxic effect - based on their behaviour or body weight change - nor in the control or bleomycin treated animals ( Figures 9). The antifibrotic effect of VCC380920 has been proven in additional in vivo experiments, as well (see Example 66).
  • VCC380920 reduced the SiriusRed and also the Masson’s trichrome positive renal area and inhibited the protein amount of ⁇ -SMA and fibronectin and the mRNA expression of Ngal, Fn1, Col1a1 and Col3a1 in the kidney of mice underwent UUO ( Figure 14-16).
  • VCC380920 reduced skin lesions and thickening, and decreased spleen enlargement, characteristic for systematic inflammation in imiquimod induced psoriasis model ( Figures 17-19).
  • the compounds according to the invention are novel antifibrotic compounds targeting PDGFR- ⁇ and - ⁇ .
  • the compounds according to the invention are predicted to have optimal physico-chemical properties to reach good oral bioavailability.
  • the compounds according to the invention have in vitro PDGFR- ⁇ and - ⁇ inhibitory effect in biochemical assay (see Example 64).
  • the compounds according to the invention dramatically reduce the PDGF-B induced proliferation of lung and kidney myofibroblasts (to the level of control cells).
  • VCC380920 treatment improved the survival of mice with bleomycin induced lung fibrosis.
  • VCC380920 has antifibrotic effect in vivo as it is inhibited the protein level of collagen type I and fibronectin in the lung of bleomycin treated mice.
  • VCC380920 Antifibrotic effect of compound VCC380920 has been proven in additional in vivo experiments; it reduced the SiriusRed and Masson’s trichrome positive renal area of mice underwent UUO.
  • VCC380920 inhibited the amount of ⁇ SMA and fibronectin (FN) and the mRNA expression of Ngal, Fn1, Col1a1 and Col3a1 in the kidney of mice underwent UUO (see Example 66).
  • Compound VCC380920 reduced skin lesions and skin thickening and decreased the spleen enlargement characteristic for systemic inflammation in imiquimod induced psoriasis model (see Example 66).
  • the present inventors successfully developed a new lead molecule that significantly inhibits the PDGF-B induced activation of fibroblasts in vitro and the bleomycin or UUO induced lung and kidney fibrosis in vivo.
  • the lead molecule also inhibits skin lesions and thickening and decreased spleen enlargement in imiquimod induced mice model of psoriasis.
  • Cell proliferation and migration in various disorders Fibroblasts are characterized by their intense proliferation, migration, and increased production of ECM during activation, which provided a particular example for inter-relation of these three processes.
  • fibrosis and chronic inflammation go hand in hand. Cytokines, growth factors, etc. produced during the inflammatory response activate fibroblasts i.e.
  • PDGF-BB Different PDGF isoforms, including PDGF-BB and also other factors such as TGF ⁇ or EGF play a significant role in the activation of fibroblasts, such as their proliferation, migration, and the production of the ECM. These growth factors and the fibroblasts also play a role in the development of different tumours and metastasis of them.
  • CAFs cancer-associated fibroblasts
  • the pathophysiological roles of cancer-associated fibroblasts (CAFs) in the heterogeneous tumour microenvironment have attracted increasing interest.
  • CAFs play crucial roles in tumour progression and the response to chemotherapy.
  • cytokines and chemokines are involved in the activation of CAFs, and some of these form a feedback loop between cancer cells and CAFs.
  • non-inflammatory glomerular diseases minimal change nephritis, focal glomerular sclerosis, membranous nephropathy, fibrillary glomerular disease), glomerular disease associated with Hodgkin's disease, antibiotic, drug (aspirin, ibuprofen, acetaminophen, tacrolimus, cyclosporine, contrast agents, chemotherapy, or heroin toxicity), HIV infection; hereditary nephritis (Alport syndrome), vascular diseases including renal artery stenosis, sickle cell disease, hemolytic uremic syndrome, atypic hemolytic uremic syndrome; tubulointerstitial diseases including pyelonephritis, analgesic nephritis, allergic interstitial nephritis, granulomatous interstitial nephritis, autoimmune interstitial nephritis, non-inflammatory diseases like reflux nephropathy, obstructive ur
  • lung diseases associated with or characterized by fibrosis include bronchitis, asthma, idiopathic pulmonary fibrosis, usual interstitial pneumonia, gas or ionizing radiation induced lung fibrosis, nitrofurantoin, tobacco smoke-induced lung fibrosis, emphysema, chronic obstructive pulmonary disease, tuberculosis, rheumatoid arthritis induced lung fibrosis, systemic lupus erythematosus induced lung fibrosis, sarcoidosis, Wegener’s granulomatosis, nonspecific interstitial pneumonitis, Hamman-Rich Syndrome, diffuse fibrosing alveolitis, inhalation of environmental and occupational pollutants (fume silica, asbestos, nitrogen, and sulfur gases
  • intestinal diseases associated with or characterized by fibrosis include ulcerative colitis, Crohn's disease, Collagenous colitis, microscopic colitis, diversion colitis, necrotizing enterocolitis, chemical colitis, ischemic enterocolitis, Helicobacter pylori-induced gastritis, chronic gastritis, oesophageal subepithelial fibrosis, Barrett's esophagus, gastroesophageal reflux disease, oral submucous fibrosis, oesophageal atresia.
  • hepatic diseases associated with or characterized by fibrosis include nonalcoholic steatohepatitis, autoimmune hepatitis, viral hepatitis (hepatitis A, hepatitis B, hepatitis C, hepatitis D), alcoholic hepatitis, toxic and drug-induced hepatitis, non-alcoholic fatty liver disease, liver cirrhosis, fascioliasis, schistosomiasis, liver fluke induced fibrosis, primary sclerosing cholangitis, Budd-Chiari syndrome, biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, serotonergic agonist drugs: weight loss drugs (fenfluramine, chlorphentermine, aminorex), anti-migraine drugs (ergotamine, methysergide), antiparkinsonian drugs (pergolide, cabergoline), recreational drugs (MDA, MDMA, DOI, he
  • Examples of eye diseases associated with or characterized by fibrosis include diabetic retinopathy, fibrosis of the cornea, neovascular glaucoma, retinopathy of prematurity, age-related macular degeneration, premacular fibrosis, herpetic keratitis, pingueculae, capsular fibrosis, fibrosis of the posterior lens capsule, fibrovascular scarring of the retina, gliosis in the retina, complication of surgery to treat retinal detachment, viral infection of the cornea, retinal injury due to hypoxia or inflammatory changes, trachoma, congenital fibrosis syndrome, levator muscle fibrosis, congenital fibrosis of the ocular muscles, congenital fibrosis of the extraocular muscles, proliferative retinopathy, macularfibrosis, talc retinopathy, subretinal fibrosis, syndrome, sub-conjunctival fibrosis.
  • Examples of metabolic diseases associated with or characterized by fibrosis include type 2 diabetic complications atherosclerosis, arteriosclerosis, diabetic foot, metabolic syndrome, hyperlipidaemia, haemochromatosis, Wilson disease, alfa-1-antitrypsin deficiency, galactosaemia, glycogen storage disease I-IV, VI, IX, XI, urate nephropathy, hyperlipoproteinaemia I.-V., familiar hypercholesterineaemia, mucopolysaccharidosis type I-VII., mucolipidosis III-IV, Fabry disease (angiokeratoma corporis diffusum), pseudoxanthoma elasticum.
  • type 2 diabetic complications atherosclerosis arteriosclerosis, diabetic foot, metabolic syndrome, hyperlipidaemia, haemochromatosis, Wilson disease, alfa-1-antitrypsin deficiency, galactosaemia, glycogen storage disease I-IV, VI, IX, XI, ur
  • autoimmune diseases associated with or characterized by fibrosis include Type 1 diabetic complications, rheumatoid arthritis, ankylosing spondylitis (Bmürew's disease), systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, CREST-syndrome, polymyositis, dermatomyositis, primary biliary cirrhosis, primary sclerotising cholangitis, vasculitis: giant cell arteritis, Takayasu's arteritis, polyarteritis nodosa, Wegener's granulomatosis, thromboangitis obliternas, sarcoidosis, Goodpasture syndrome, mixed connective tissue disease, Churg-Strauss-syndrome.
  • Examples of skin diseases associated with or characterized by fibrosis include keloid and scars associated with trauma, operations, piercing, acne, chicken pox, infections, cutting, haematoma, spontaneusly, granuloma, tick- granuloma, solaris atrophia, burn injury, pseudocicatrix stellata (Batman purpura), ulcus associated with anthrax, gonorrhoea, ulcus molle, tularaemia, decubitus, diabetic foot ulcer, diabetes skin, necrobiosis lipoidica diabeticorum, varicosits cruris, thrombophlebitis, infections: fascitis necrotisans, ecthyma simplex, ecthyma gangrenosum, phlegmone abscessus, furunculus, carbunculus, anthrax, granuloma venereum, tularaemia, tb
  • coli Proteus, HSV
  • retroperitoneal fibroma cystitis chronica, cystitis after radiotherapy
  • ulcus simplex Heunner
  • Trichomonases tuberculosis (renis, vesicae urinariae, epididymitis, prostata)
  • actinomycosisulcus pelveopeitonitis
  • vulvovaginitis cand. herpes genitalis, genitalis HPV, chronic cervicitis, endometritis, salpingitis, abscessus, tuboovarii, syphilis, gonorrhoea, chlamidya, trichomonas, HPV, ulcus molle, HIV, tuberculosis.
  • fibroproliferative diseases associated with pathological pregnancy associated with or characterized by fibrosis include pruritus gravidarum, bullosus pemphigoid, impetigo herpetiformis, caesarian section (or other operation) rupture corporis uteri, ulcer puerperalis, endometritis, myometritis puerperalis, adnexitis puerperalis, pelveoperitonitis puerperalis, parametritis puerperalis, thrombophlebitis, mastitis puerperalis; in men: penis, prostata, orchis: cavernitisi, induratio penis plastica, prostatitis, abscessus, orchitis, chronic epididymitis; obstructive uropathies associated with anatomical abnormalities posterior urethra valve, subvesical obstruction, vesicouretheral reflux nenhrolithiasis, inflammation
  • cardiovascular diseases associated with or characterized by fibrosis include dilated and hypertrophic cardiomyopathies, myocardial infarction, valvular diseases, arrhythmia, cardiac hypertrophy, hypertension induced cardiac fibrosis, Marfan syndrome, left ventricular fibrosis, myocardial necrosis and apoptosis induced cardiac fibrosis, vascular fibrosis, arteriosclerosis, atherosclerosis, venosclerosis.
  • cardiovascular diseases associated with or characterized by fibrosis include dilated and hypertrophic cardiomyopathies, myocardial infarction, valvular diseases, arrhythmia, cardiac hypertrophy, hypertension induced cardiac fibrosis, Marfan syndrome, left ventricular fibrosis, myocardial necrosis and apoptosis induced cardiac fibrosis, vascular fibrosis, arteriosclerosis, atherosclerosis, venosclerosis.
  • skeletal muscle system diseases associated with or characterized by fibrosis include mye
  • Example 3 N- ⁇ 2-methyl-5-[(4-methylbenzoyl)amino]phenyl ⁇ -1H-imidazole-4-carboxamide (Ia), Method A (Scheme 1)
  • Example 5 4-Chloro-N-(4-methyl-3- ⁇ [(1-methyl-1H-imidazol-5-yl)carbonyl]amino ⁇ phenyl)-pyridine-2-carboxamide (Ia), Method B (Scheme 2) a) 1-Methyl-N-(2-methyl-5-nitrophenyl)-1H-imidazole-5-carboxamide (XIII-2), A mixture of 1-methyl-1H-imidazole-5-carboxylic acid (1.26 g, 0.01 mol), 2-methyl-5-nitroaniline (1.67 g, 0.011 mol), ethyl-3-(3’-dimethylaminopropyl)carbodiimide hydrochloride (2.11 g, 0.011 mol) and pyridine (50 ml) is stirred at room temperature for 40 hours.
  • Example 43 1-Methyl-N-[2-methyl-5-(piperidin-4-ylcarbamoyl)phenyl]-1H-imidazole-5-carboxamide hydrochloride (Ib)
  • R Ar Me
  • R 1 Me
  • R 2 H
  • Y (CH 2 )n
  • n 0,
  • Z piperidin-4-yl
  • a mixture of tert-butyl 4-[(4-methyl-3- ⁇ [(1-methyl-1H-imidazol-5- yl)carbonyl]amino ⁇ benzoyl)amino]piperidine-1-carboxylate (0.156 g, 0.353 mmol) and HCl/dioxane (3.5 ml) is stirred at ambient temperature for 90 minutes.
  • Example 44 The compounds (Ib) of Example 44, Example 45, and Example 46 have been prepared according to Method C (Scheme 3) as described in Example 28 and their data are demonstrated in Table 2 (see below Example 63).
  • Example 52 N-[5-( ⁇ 4-[(2E)-3-(dimethylamino)prop-2-enoyl]phenyl ⁇ carbamoyl)-2-methylphenyl]-1-methyl-1H- imidazole-5-carboxamide (Ib)
  • a mixture of N- ⁇ 5-[(4-acetylphenyl)carbamoyl]-2-methylphenyl ⁇ -1-methyl-1H-imidazole-5-carboxamide (Example 49) (0.795 g, 2.11 mmol) and N,N-dimethylformamide dimethylacetal (
  • Example 53 1-methyl-N-(2-methyl-5- ⁇ [4-(1H-pyrazol-3-yl)phenyl]carbamoyl ⁇ phenyl)-1H-imidazole-5-carboxamide (Ib)
  • R Ar Me
  • R 1 Me
  • Y (CH 2 )n
  • n 0,
  • Z 4-(1H-pyrazol-3-yl)phenyl
  • a mixture N-[5-( ⁇ 4-[(2E)-3-(dimethylamino)prop-2-enoyl]phenyl ⁇ carbamoyl)-2-methylphenyl]-1-methyl- 1H-imidazole-5-carboxamide (Example 52) (0.227 g, 0.526 mmol), hydrazine hydrate (0.038 ml) and ethanol (15 ml) is stirred at reflux temperature for 5 hours.
  • TGFB-R1 Assay buffer 20 mM HEPES pH 7.5 + 1 mM DTT + 3 mM MgCl2 + 3 mM MnCl2 + 0.01 V/V% Tween20. The final TGFBR1 concentration was 6 nM. Casein (Sigma-Aldrich) was used as substrate at a final concentration of 0.01 mg/ml. The final ATP concentration was 13 ⁇ M.
  • PAK2 Assay buffer 20 mM HEPES pH 7.5 + 1 mM DTT + 2 mM MgCl2 + 0.01 V/V% Triton X-100. The final PAK2 concentration was 5 nM.
  • TAMRA-KA10 (Genecust) was used as substrate at a final concentration of 400 nM. The final ATP concentration was 218 ⁇ M.
  • c-Abl Assay buffer 20 mM TRIS pH 8 + 1 mM DTT + 0.4 mM MgCl2 + 0.4 mM MnCl2 + 0.01 V/V% Tween20. The final c-Abl concentration was 6 nM.
  • TAMRA-KA12 (Genecust) was used as substrate at a final concentration of 400 nM. The final ATP concentration was 0.6 ⁇ M.
  • Akt1 Assay buffer 20 mM MES pH 6 + 1 mM DTT + 10 mM MgCl2 + 2 mM MnCl2 + 0.01 V/V% Triton X-100. The final Akt1 concentration was 5 nM. TAMRA-PKAtide (Genecust) was used as substrate at a final concentration of 400 nM. The final ATP concentration was 40 ⁇ M. Results First the PDGFR-A and PDGFR-B inhibitory effects of VCC compounds were investigated by a single point screening method. Thirty-four compounds resulted higher than 50% inhibitory effect, presuming them as potential PDGFR-B kinase inhibitors (Table 7).
  • slides were permeabilized with Cytofix/Cytoperm (BD Pharmingen) for 15 minutes at room temperature (RT), washed with Perm/Wash Buffer solution (BD Pharmingen), and incubated with primary antibody specific for ⁇ -SMA (sc-53015; mouse, 1:1000, Santa Cruz Biotechnology) or PDGFR-B (ab124332; rabbit, 1:100, Abcam) for 1 hour at RT.
  • Slides were incubated with anti-mouse Alexa Fluor 488® conjugated secondary antibody (1:1000, A11001; Thermo Fisher Scientific) or anti-rabbit Alexa Fluor 568® conjugated secondary antibody (1:1000, A10042; Thermo Fisher Scientific) for 30 minutes at RT.
  • Hidex Chameleon Microplate Reader Triathler, Plate Chameleion, 300SL Lablogic Systems, Inc., Brandon, FL, USA
  • LDH assay To detect viability and cytotoxic effect of VCC compounds, LDH assay was performed as previously described [Korzeniewski & Callewaert, 1983]. All reagents were purchased from Sigma-Aldrich. Absorbance was recorded at 570 nm and at 690 nm as background in a Hidex Chameleon Microplate Reader using MikroWin 2000 software. SiriusRed assay To determine the extent of collagen deposition, SiriusRed assay was performed, as previously described [Walsh et al., 1992]. All reagents were purchased from Sigma-Aldrich. Absorbance was determined at 544 nm and at 690 nm as background using Hidex Chameleon Microplate Reader using MikroWin 2000 software.
  • RNA isolation, cDNA synthesis, real-time RT-PCR Total RNA was isolated from cells by Geneaid Total RNA Mini Kit (Geneaid Biotech Ltd.). Equal RNA was reverse-transcribed using Maxima First Strand cDNA Synthesis Kit for RT-qPCR (Life Technologies) to generate first-stranded cDNA.
  • the mRNA expressions were determined by real-time RT-PCR using LightCycler 480 SYBR Green I Master enzyme mix on a Light Cycler 480 system (Roche Diagnostics, Mannheim, Germany). Nucleotide sequences and species specificity of the applied primer pairs and the lengths of the resulted PCR products are shown in Table 9.
  • Results were analyzed by Light-Cycler 480 software version 1.5.0.39 (Roche Diagnostics). Relative mRNA expression was determined by comparison with Rn18s as internal control using the ⁇ Ct method. Data were normalized and presented as the ratio of their control values. Table 9. Applied primer pairs and the length of the resulted PCR products. F means forward primer and R means reverse primer. Statistical analysis of mRNA expression Statistical evaluation was performed by GraphPad Prism 6.01 software. After testing normality with Kolmogorov-Smirnov test, row data of Western blot and real-time RT-PCR measurements were analyzed with Mann–Whitney U-test to determine differences between the corresponding groups. p ⁇ 0.05 was considered as statistically significant.
  • Results are presented as a ratio of control group and illustrated as violin plot, indicating the data distribution in the given group, or as mean ⁇ SD at dot plots. The Brief description of the figures contains the corresponding n values and the statistical tests.
  • MTT and LDH assays VCC380920 treatment decreased the PDGF-B induced proliferation of primary lung fibroblasts as revealed by MTT assay ( Figure 4b). Based on results derived from LDH assay ( Figure 4c), there was no detectable cytotoxic effect at the examined concentrations.
  • C) Score (MTT-based screening method) of primary lung fibroblasts and renal fibroblasts The in vitro effect of compounds was investigated on various fibroblast cell lines. Proliferation and viability of cells was determined by MTT assay within a defined concentration range of VCC compounds. The in vitro effect of compounds was quantified by a sigmoid curve-based scoring method, wherein score values include antiproliferative efficiency on PDGF-B treated cells, compensated by cytotoxicity on untreated cells, if it was observable. This scoring system was validated in two ways.
  • the antiproliferative effect of 35 compounds was subjectively categorised (effective – uncertain – not effective) by independent persons based on their graphs, derived from MTT assays. Score values of compounds belonging to these groups were well separated. ROC analysis of these data determined suitable threshold value to identify certainly effective compound with perfect specificity and sensitivity. Second, 14 randomly selected compounds were ordered by independent persons based on their MTT graphs. As the correlation between subjective and score value-based order was almost perfect, this scoring system is suitable not only for distinguish between effective and not effective compounds, but for ordering them based on their effectiveness. The score values of VCC compounds determined on lung and kidney fibroblast showed positive correlation, suggesting that their antiproliferative effect is mostly independent of the origin of the investigated cell.
  • the in vitro efficiency of VCC compounds was determined by MTT assay on PDGF-B treated primary lung fibroblasts (Table 10, Figure 3).
  • the in vitro antiproliferative effects of compounds according to the invention on lung fibroblasts is shown in Figure 3.
  • the in vitro efficiency of VCC compounds was determined by MTT assay on PDGF-B treated NRK-49F cells (Table 10, Figure 6).
  • mice were used in the experiments 6-8 weeks old male C57BL/6J mice were used. All animals were kept in plastic cages under 12-hour dark/light cycle at constant temperature (24 ⁇ 0.2°C) with free access to standard rodent chow and drinking water.
  • Bleomycin induced lung fibrosis (BILF) Lung fibrosis was induced by 50 mg/kg bleomycin in 100 ⁇ l saline injected ip. at day 0, 3, and 7, respectively (n 6-8/group). Experiment was terminated 21 days after the initiation of BILF, lungs and spleens were surgically removed. To examine the effect of VCC380920, mice were daily treated with 50 mg/kg in 100 ⁇ l of DMSO ip. Control mice were treated with vehicle only.
  • mice were daily treated with 50 mg/kg in 100 ⁇ l of DMSO ip, or topically with Aldara Cream containing 5% IMQ and 2% VCC380920.
  • Protein isolation and Western blot Tissue samples were homogenized in lysis buffer containing 50 mM HEPES, 150 mM NaCl, 1% Triton X- 100, 5 mM EDTA, 5 mM EGTA, 20 mM sodium pyrophosphate, 20 mM NaF, 0.2 mg/mL phenylmethylsulfonyl fluoride, 0.01 mg/mL leupeptin, and 0.01 mg/mL aprotinin (pH 7.4; each substance was obtained from Sigma- Aldrich). Protein concentration was determined in triplicates by a detergent-compatible protein assay (Bio-Rad, Hercules, CA).
  • RNA isolation, cDNA synthesis, real-time RT-PCR Total RNA was isolated from tissue samples by Geneaid Total RNA Mini Kit (Geneaid Biotech Ltd.). Equal RNA was reverse-transcribed using Maxima First Strand cDNA Synthesis Kit for RT-qPCR (Life Technologies) to generate first-stranded cDNA. The mRNA expressions were determined by real-time RT-PCR using LightCycler 480 SYBR Green I Master enzyme mix on a Light Cycler 480 system (Roche Diagnostics, Mannheim, Germany). Nucleotide sequences and species specificity of the applied primer pairs and the lengths of the resulted PCR products are shown in Table 11.
  • Results were analyzed by Light-Cycler 480 software version 1.5.0.39 (Roche Diagnostics). Relative mRNA expression was determined by comparison with Rn18s as internal control using the ⁇ Ct method. Data were normalized and presented as the ratio of their control values. Table 11. Applied primer pairs and the length of the resulted PCR products. F means forward primer and R means reverse primer. Graphical analysis of skin lesions Skin symptoms of IMQ induced psoriasis, like skin lesions was investigated by graphical analysis. The mice were photographed with standard settings, then the skin redness was analysed based on the histogram of red pixels using ImageJ software.
  • VCC380920 decreased the protein levels of collagen I and fibronectin extracellular matrix component markers in the experimental model of BILF RT-PCR
  • the effect of compound VCC380920 on fibrotic mRNA in the experimental model of bleomycin induced lung fibrosis (BILF) is shown in Figure 13.
  • VCC380920 decreased the mRNA expression of Col1a1 and Fn1 extracellular matrix component markers in the experimental model of BILF.
  • UUO induced renal fibrosis The in vivo effect of VCC380920 was investigated in the mice model of unilateral ureteral obstruction (UUO) induced renal fibrosis.
  • Treatment with VCC380920 resulted in decreased renal level of fibrotic markers, including fibrotic tissue area, protein and mRNA levels of ⁇ -SMA, fibronectin, collagens and Ngal injury marker ( Figures 14- 16). Histology The effect of compound VCC380920 on UUO induced renal histological changes is shown in Figure 14. As can be seen therein, treatment with VCC380920 decreased fibrotic tissue area. Western blot The effect of compound VCC380920 on fibrotic protein levels in the experimental model of UUO induced renal fibrosis is shown in Figure 16. As can be seen therein, treatment with VCC380920 decreased protein amount of ⁇ -SMA and fibronectin.

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Abstract

Selon certaines estimations, dans les pays développés, 45 % des décès sont attribués à la fibrose des organes. Indépendamment de la maladie primaire, la pathophysiologie de la fibrose montre un mécanisme de chevauchement élevé dans les différents organes. Les cellules effectrices principales de la fibrose sont les fibroblastes activés, se caractérisant par un taux de prolifération accru et une production excessive de matrice extracellulaire. L'activation chronique des myofibroblastes entraîne le dépôt excessif de matrice extracellulaire remplaçant le tissu sain, ce qui conduit à l'altération puis à la perte de fonction organique. Les besoins médicaux non satisfaits créent la nécessité de développer de nouveaux médicaments pour empêcher la fibrose des organes. L'invention vise à développer de nouveaux composés antifibrotiques ciblant des PDGFR, dont PDGFR-A et -B, un élément de la voie centrale responsable de l'activation des fibroblastes, qui sont les cellules effectrices principales de la fibrose des organes. L'effet des composés développés a été d'abord testé au moyen d'un essai biochimique in vitro étudiant l'activité kinase de PDGFR-A et -B. L'effet inhibiteur des composés sur la prolifération induite par PDGF-B de myofibroblastes provenant du poumon et du rein a été étudié in vitro. L'un des composés les plus prometteurs a en outre été étudié in vivo, également.
PCT/HU2024/050125 2023-12-21 2024-12-19 Dérivés d'imidazole et leur utilisation en tant qu'agents antifibrotiques Pending WO2025133653A1 (fr)

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WO2020172609A1 (fr) * 2019-02-21 2020-08-27 Marquette University Ligands hétérocycliques de par1 et procédés d'utilisation
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