EP2986286A1 - Composés à base de galloyl benzamide utilisés en tant que modulateurs de jnk - Google Patents

Composés à base de galloyl benzamide utilisés en tant que modulateurs de jnk

Info

Publication number
EP2986286A1
EP2986286A1 EP13726263.0A EP13726263A EP2986286A1 EP 2986286 A1 EP2986286 A1 EP 2986286A1 EP 13726263 A EP13726263 A EP 13726263A EP 2986286 A1 EP2986286 A1 EP 2986286A1
Authority
EP
European Patent Office
Prior art keywords
biphenyl
nitro
compound
benzamide
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13726263.0A
Other languages
German (de)
English (en)
Inventor
Saverio CELLAMARE
Angelo Carotti
Angela STEFANACHI
Francesco LEONETTI
Orazio NICOLOTTI
Marco CATTO
Leonardo PISANI
Piero TARDIA
Antonellina INTROCASO
Valentina LEO
Francesco Addabbo
Monica MONTAGNANI
Carmela NACCI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universita degli Studi di Bari Aldo Moro
Original Assignee
Universita degli Studi di Bari Aldo Moro
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universita degli Studi di Bari Aldo Moro filed Critical Universita degli Studi di Bari Aldo Moro
Publication of EP2986286A1 publication Critical patent/EP2986286A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol

Definitions

  • the present invention relates to the use of compounds having a galloyl benzamide structure in the treatment and/or prevention of medical conditions mediated through c-Jun N-terminal kinases (JNKs) and to pharmaceutical compositions comprising said compounds.
  • JNKs c-Jun N-terminal kinases
  • Mitogen-activated protein kinases family is a complex system of signalling components acting as major regulators of multiple physiological processes.
  • MAPK families Erk, p38 MAPKs, and the c-Jun N-terminal kinases (JNKs) have been extensively studied for their role in cell growth, differentiation, apoptosis, and survival.
  • JNKs also termed stress-activated protein kinases (SAPKs)
  • SAPKs stress-activated protein kinases
  • UV ultraviolet
  • cytokines such as tumour necrosis factor-a (TNF-a), interleukin-1 (IL-1), IL-3 or colony-stimulating factors (CSF) or growth factors such as epidermal growth factor (EGF) or platelet-derived growth factor (PDGF).
  • G-protein coupled receptors and the noncanonical Wnt pathway can lead to JNK activation.
  • JNK activation requires a dual phosphorylation on threonine 183 and tyrosine 185 in the enzyme regulatory loop.
  • MKK4 and MKK7 are among upstream MAPK kinases able to phosphorylate JNKs on these activating residues.
  • JNKs are the predominant protein kinase family that phosphorylates c-Jun, a component of the activator protein- 1 (Ap-1) transcription factor complex. Phosphorylation on serine 63 and serine 73 within the transactivation domain potentiates c-Jun transcriptional activity through the loss of repression mediated by histone deacetylase 3, resulting in activation of the AP-1 complex and subsequent genomic response.
  • J Ks play a central role in the inflarnmatory signalling network
  • hyperactivation of JNK signalling is a very common finding in a number of disease states, including inflammatory, metabolic, cardiovascular and neurodegenerative syndromes.
  • JNK activity has been implicated in the development of arthritis, obesity, diabetes, atherosclerosis, abdominal aortic aneurysm, cardiac diseases, liver diseases and tumorigenesis.
  • JNK gene knockout animals is continuing to reveal in vivo functions for these kinases, with tissue-specific roles now being dissected with tissue-specific knockouts. Consequently, JNK inhibitors have been discovered and characterized in the hope that therapeutic inhibition of JNK may provide clinical benefit in many diseases.
  • Some small molecules have been reported to act as ATP-competitive JNK inhibitors. However, many of them exhibit poor kinase selectivity and/or do not inhibit the phosphorylation of well-characterized substrates of JNK in cells.
  • the present invention relates to a compound of formula (I)
  • ⁇ X is -CO- and Y is -NH- or X is -NH- and Y is -CO-;
  • ⁇ Ri R 2 and R 3 are, each independently, -H, -OH or O-alkyl
  • ⁇ R4 is H, -O-alkyl, -halogen, -NH 2 , -NH-alkyl, -N(alkyl) 2 , -NH-acyl, -N0 2 , - CN, -COOH, -COOAlkyl, -CONH 2 , -CONH-alkyl or -CF 3 ,
  • ⁇ Ar is an aryl or a heteroaryl group selected from phenyl, benzo[l,3]dioxolyl, pyrrolyl, thienyl, furanyl, pyridinyl, pyridinyl and pyrimidin-5-yl; wherein the phenyl group is optionally substituted with one or two halogens, a nitro group, one or two alkoxy groups, an acetyl group, a cyano group and one or two alkyl groups;
  • JNKs c-Jun N-terminal kinases
  • Ar is selected from phenyl-3- or 4-yl, 3'-halophenyl-3- or 4-yl, 4'-halophenyl-3- or 4-yl, 3',4'-dihalophenyl-3- or 4-yl, 3',5'-dihalophenyl-3- or 4-yl, 3'-nitrophenyl-3- or 4-yl, 4'-nitrophenyl-3- or 4-yl, 3'-alkoxyphenyl-3- or 4-yl, 4'-alkoxyphenyl-3- or 4-yl, 3',4'-dialkoxyphenyl-3- or 4-yl, 3',5'-dialkoxyphenyl-3- or 4-yl, 3 '-acetylphenyl-3- or 4-yl, 4'-acetylphenyl- 3- or 4-yl, 3'-cyanophenyl-3- or 4-yl, 4'-cyanophenyl-3- or 4-yl, 4'-cyanophen
  • X is -CH- and Y is - NH-.
  • 3 ⁇ 4 R 2 and R 3 are O- alkyl, wherein alkyl is methyl.
  • all R ⁇ R 2 and R 3 are O-alkyl, especially O-methyl, or at least two of R ⁇ R 2 and R 3 are O-alkyl, especially O-methyl and the other is hydrogen.
  • Ar is phenyl, optionally substituted as defined above.
  • Ar is selected from thien-2-yl, benzo[l,3]dioxol-5-yl and pyridin-3-yl.
  • the compound of formula (I) is selected from N-(4-benzo[l,3]dioxol-5-yl-2-nitro-phenyl)-3,4,5- trimethoxybenzamide, N-(3-fluoro-biphenyl-4-yl)-3,4,5-trimethoxybenzamide, 3,4,5- trimethoxy-N-(3-nitro-biphenyl-4-yl)benzamide, N-(3-amino-biphenyl-4-yl)-3,4,5- trimethoxybenzamide, N-(3-acetylamino-biphenyl-4-yl)-3,4,5-trimemoxybenzamide, 3,5-dimethoxy-N-(3-nitro-biphenyl-4-yl)benzamide, 3,4-dimethoxy-N-(3-nitro- biphenyl-4-yl)benzamide, 3 ,4-dimethoxy-N-(3 -nitro-bi
  • halo'Or halogen means fluoro, chloro or bromo.
  • alkyl as used herein, unless otherwise indicated includes saturated, partially unsaturated, or unsaturated hydrocarbon radicals having straight or branched moieties C1-C4.
  • a preferred “alkyl” is methyl.
  • alkoxy as used herein, unless otherwise indicated includes O-alkyl groups wherein alkyl is as defined above.
  • pharmaceutically acceptable salt(s) includes salts of acid or basic groups that may be present in the compounds of formula (I).
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts are those that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as acetate, bicarbonate, bisulfate, bitartrate, hydrobromide, hydrochloride, citrate, phosphate salts.
  • Certain compounds of formula (I) may have asymmetric centres and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula (I), and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula (I), the invention includes the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixture thereof. The compounds of formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
  • JNKs c-Jun N- terminal kinases
  • the compounds of formula (I) may be used in the treatment and/or prevention of several severe human disorders and pathologies, including inflammatory diseases, such as inflammatory bowel disease (IBD), psoriasis, rheumatoid arthritis; diabetes, obesity, atherosclerosis,abdominal aortic aneurysm, liver diseases, CNS disorders, such as Alzheimer's disease, neurodegeneration,cerebral ischemia, retinopathy and acute organ failure such as hepatic failure, pain and cancer.
  • IBD inflammatory bowel disease
  • psoriasis psoriasis
  • rheumatoid arthritis rheumatoid arthritis
  • diabetes obesity, atherosclerosis,abdominal aortic aneurysm
  • liver diseases CNS disorders, such as Alzheimer's disease, neurodegeneration,cerebral ischemia, retinopathy and acute organ failure such as hepatic failure, pain and cancer.
  • CNS disorders such as Alzheimer'
  • the compounds of formula (I) may be used to improve successful engraftments.
  • corticosteroids and JNK inhibitors both inhibit many common proinflammatory genes including TNF-R, IL-4, and IL-13, suggesting a common mechanism that may provide therapeutic opportunities that are complementary to existing treatments of respiratory diseases.
  • the present invention relates to a combination of at least a compound of formula (I) or one of its salts and a corticosteroid, and to the use of such a combination in the treatment and/or prevention of respiratory diseases, such as asthma, chronic obstructive pulmonary disorder or acute respiratory distress syndrome.
  • respiratory diseases such as asthma, chronic obstructive pulmonary disorder or acute respiratory distress syndrome.
  • the present invention relates to a method for inhibiting c-Jun N-terminal kinases (JNKs), which comprises administering to a mammal in need thereof an effective amount of at least one compound of formula(I) or a pharmaceutically acceptable salt thereof.
  • JNKs c-Jun N-terminal kinases
  • the present invention relates to a method for the treatment and/or prevention of the above mentioned disorders and pathologies, which comprises administering to a mammal in need thereof an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to the pharmaceutical compositions in which the compound of formula (I) and its pharmaceutically acceptable salts are present as the active principle, especially in admixture with one or more pharmaceutical acceptable carrier.
  • the product of formula (I), either pure or in association with any other pharmaceutically compatible substance can be used in appropriate pharmaceutical forms intended for oral, parenteral, sublingual, rectal, transdermal and topical administration.
  • tablets for oral administration, it is possible for example to use tablets, coated tablets, granules or liquid compositions such as syrups, elixirs, emulsions or solutions.
  • aqueous or non-aqueous injectable sterile compositions for parenteral administration, suppositories for rectal administration and patches for transdermal administration; if appropriate, it is possible to prepare delayed-release forms or forms in which the active principle of formula (I) is included in liposomes or in cyclodextrins.
  • compositions according to the invention advantageously contain, as the active principle, from 0.01 to 20 mg of the compound of formula (I) or one of its pharmaceutically acceptable salts. Other dosage are anyway possible.
  • the appropriate dosage in the therapeutic use of these compositions has to be evaluated in each individual case by considering the characteristics of the subjects to be treated, namely the age, the body weight and the severity of the complaints to be treated.
  • the therapeutic use of the compound of formula (I) provides for the administration of a dosage between 0.01 and 60 mg/day (preferably between 20- 40 mg/day), optionally subdivided into doses to be administered several times a day, the preferred dose regimen being one to three times a day.
  • TNFa Tumor necrosis factor-a
  • Pharmacological inhibitor SP600125 was purchased Sigma- Aldrich (St. Louis, MO).
  • Monoclonal antibody infliximab (Remicade) was from Janssen Biologies B.V. (Leiden, Holland).
  • Cell lysates were prepared using 130 ⁇ of lysis buffer (100 mM NaCl, ,40 mM Hepes, pH 7.5, 1% Triton X-100, lmM Na 3 V0 4 , 4 mM Na 4 P 2 O v , 10 mM EDTA, 1 mM PMSF, 10 mM NaF, 2 ⁇ g/ml aprotinin and 2 ⁇ g/ml leupeptin).
  • lysis buffer 100 mM NaCl, ,40 mM Hepes, pH 7.5, 1% Triton X-100, lmM Na 3 V0 4 , 4 mM Na 4 P 2 O v , 10 mM EDTA, 1 mM PMSF, 10 mM NaF, 2 ⁇ g/ml aprotinin and 2 ⁇ g/ml leupeptin).
  • Equal amounts of protein (30 ⁇ g) were separated by 10% SDS-PAGE and subjected to immunoblotting with the following primary antibodies (dilution 1: 1000): ph-c-Jun (Ser 63) and ph-p65 (Ser 536) (Santa Cruz Biotecnology Inc., CA); JNK, ph-JNK, c-Jun, ph-c-Jun (Ser73), DcBa, ph-ERKl/2 (Thr 202/Tyr 204), p38 MAPK and ph-p38 MAPK (Thr 180/Tyr 182) (Cell Signaling Technology, MA).
  • the ⁇ -actin antibody was from Sigma.
  • FIG. 3 Shows protein levels of phosphorylated JNK, c-Jun and p38 MAPK in NIH-3T3 treated for 10 min with 10 ng/ml TNFa alone and in NIH-3T3 pre-treated with 20 ⁇ SP600125 or 50 ⁇ lm. Bar graphs indicate the mean ⁇ SEM of densitometric analysis for phosphorylated proteins normalized to ⁇ - actin expression * p ⁇ 0.05, ** p ⁇ 0.01 vs. indicated group.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Rheumatology (AREA)
  • Neurosurgery (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation de composés présentant une structure de galloyl benzamide dans le traitement et/ou la prévention d'affections médicales médiées par des kinases N-terminales de c-Jun (JNK) ainsi que des compositions pharmaceutiques comprenant lesdits composés.
EP13726263.0A 2013-04-15 2013-04-15 Composés à base de galloyl benzamide utilisés en tant que modulateurs de jnk Withdrawn EP2986286A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2013/000679 WO2014170706A1 (fr) 2013-04-15 2013-04-15 Composés à base de galloyl benzamide utilisés en tant que modulateurs de jnk

Publications (1)

Publication Number Publication Date
EP2986286A1 true EP2986286A1 (fr) 2016-02-24

Family

ID=48539299

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13726263.0A Withdrawn EP2986286A1 (fr) 2013-04-15 2013-04-15 Composés à base de galloyl benzamide utilisés en tant que modulateurs de jnk

Country Status (2)

Country Link
EP (1) EP2986286A1 (fr)
WO (1) WO2014170706A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018029336A1 (fr) 2016-08-12 2018-02-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes visant à déterminer si un patient a reçu un activateur de la voie de ppar bêta/delta
DK3612519T3 (da) 2017-04-18 2022-03-07 Lilly Co Eli Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl forbindelser
KR102303140B1 (ko) 2018-05-30 2021-09-16 이화여자대학교 산학협력단 신규 바이페닐 유도체 화합물 및 이의 용도
JP2022546410A (ja) * 2019-08-29 2022-11-04 ヒベルセル， インコーポレイテッド Ｐｅｒｋ阻害化合物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ555326A (en) * 2004-12-07 2010-01-29 Toyama Chemical Co Ltd Novel anthranilic acid derivative or salt thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2014170706A1 *

Also Published As

Publication number Publication date
WO2014170706A1 (fr) 2014-10-23

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