WO2015004610A1 - Dérivés de 1,5-dihydropyrrol-2-one comme inhibiteurs de l'interaction protéiné-protéine p53-mdm2/mdm4 - Google Patents
Dérivés de 1,5-dihydropyrrol-2-one comme inhibiteurs de l'interaction protéiné-protéine p53-mdm2/mdm4 Download PDFInfo
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- WO2015004610A1 WO2015004610A1 PCT/IB2014/062964 IB2014062964W WO2015004610A1 WO 2015004610 A1 WO2015004610 A1 WO 2015004610A1 IB 2014062964 W IB2014062964 W IB 2014062964W WO 2015004610 A1 WO2015004610 A1 WO 2015004610A1
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- chlorophenyl
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- LZQJWQNTLCGCTB-UHFFFAOYSA-N OC(C(N(C1c(cc2)ccc2Cl)c2cc(Cl)ccc2)=O)=C1C(c(cccc1)c1Cl)=O Chemical compound OC(C(N(C1c(cc2)ccc2Cl)c2cc(Cl)ccc2)=O)=C1C(c(cccc1)c1Cl)=O LZQJWQNTLCGCTB-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/402—1-aryl substituted, e.g. piretanide
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61P37/00—Drugs for immunological or allergic disorders
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to the use of compounds based on 1 ,5-dihydropyrrol- 2-one structure as a medicament, in particular for treating disorders in which p53/Mdm2 and/or p53/Mdm4 protein -protein interactions are disturbed and/or which are sensitive to inhibition of p53/Mdm2 and/or p53/Mdm4 interactions, like cancer. Furthermore, the present invention relates to pharmaceutical compositions comprising the aforementioned compounds and the group of new compounds comprising such a structure.
- p53 protein is a tumour suppressor and transcription factor that responds to cellular stress by regulating the transcription of numerous genes (p21 , Puma, Bax) involved in cell cycle arrest, apoptosis, senescence, and DNA repair.
- p53 gene is inactivated by mutation and/or loss in 50% of solid tumours and 10% of liquid tumours.
- Patients with Li-Fraumeni syndrome which inherit mutated p53 are very susceptible to cancer.
- Mice with damaged p53 gene appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age.
- p53 is an important cell cycle inhibitor and its activity is precisely controlled.
- Two homologous proteins Mdm2 and Mdm4 are the most important negative regulators of p53.
- Mdm2 forms a tight complex with the p53 protein, blocking its ability to regulate target genes and to exert antiproliferative effects. Additionally, Mdm2 promotes the nuclear export and rapid degradation of p53 by the ubiquitin-proteasome system.
- Amplification of the Mdm2 gene is now reported in more than 10% of 8000 various human cancers, including lung and stomach tumors, wherein p53 gene is not damaged.
- a single nucleotide polymorphism in the Mdm2 promoter that leads to 2-3 fold increase in Mdm2 expression correlates with accelerated tumour formation.
- Mdm4 is a homolog of Mdm2 and although itself cannot cause nuclear export and proteosomal degradation of p53, it significantly inhibits p53 activity. In addition to having its own effects on p53, Mdm4 also plays an important role in stabilizing the Mdm2 protein. The importance of Mdm4 in human cancers has emerged in the past 7 years. It was found that Mdm4 is amplified or overexpressed in 10-20% of over 800 various tumours including lung, colon, stomach and breast cancers and, strikingly 65% of retinoblastomas.
- small-molecule non-peptide inhibitors of p53/Mdm2 interaction include nutlins disclosed in Vassilev LT et al. In vivo activation of the p53 pathway by small-molecule antagonists of Mdm2. Science. 2004 Feb 6;303(5659):844-8; piperazine-4-phenyl derivatives disclosed in Luke Richard W A et al., Piperazine-4-phenyl derivatives as inhibitors of the interaction between mdm2 and p53, and EP1112284; chalcones disclosed in Kumar SK et al. Design, synthesis, and evaluation of novel boronic-chalcone derivatives as antitumour agents. J. Med. Chem.
- Mdm2 antagonists reactivate p53 but not in tumours where Mdm4 is overexpressed. This demonstrates the relevance of Mdm4 as a therapeutic target.
- medicaments which not only inhibit the interaction between p53 and Mdm2, but may have additionally the activity of Mdm2 and Mdm4 dual antagonists.
- Pyrrolidone derivatives having the activity of inhibiting interactions of both p53/Mdm2 and p52/Mdm4 are disclosed by Zhuang C et al. Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53- Mdm2 protein-protein interaction. J Med Chem. 2012 Nov 26;55(22):9630-42. Reportedly, these small molecules have nanomolar activity for inhibition both Mdm2 and Mdm4.
- CN102603717 discloses N-alkyl pyrrolidone derivatives of general formula (I)
- n is an integer greater than 0.
- Disclosed compounds application block interaction between receptor p53 and Mdm2 and Mdm4 and exhibit nanomolar inhibitory activity with respect to the p53-Mdm2 and p53-Mdm4 interaction.
- N-aryl and N-heteroaryl-1 ,5-dihydro-pyrrol-2-ones are known in the art. Examples thereof can be found e.g. in the following patent publications.
- WO2008/120725 describes derivatives of N-aryl-1 , 5-dihydro-pyrrol-2-ones with antagonistic activity against P2X3 and/or P2X2 receptors.
- WO 2008/127275 discloses certain 1 ,5-dihydro-pyrrol-2-ones having heteroaryl moiety at nitrogen atom of pyrrolone ring, with activity against bacterial peptidyl tRNA hydrolase.
- WO2008/055945 discloses N-aryl-3-hydroxy-1 ,5-dihydro-pyrrol-2-one derivatives and their ability to modulate the activity of glutaminyl cyclase, which catalyses the intramolecular cyclization of N-terminal residues of glutamine into pyroglutamic acid with liberation of ammonia and the intramolecular cyclization of glutamic acid residues to pyroglutamic acid, with liberation of water molecule, said ability making them useful the treatment of ulcers, cancer and other diseases.
- the invention relates to a compound of general formula (I)
- R 1 i is
- heterocyclyl, phenyl, benzene ring fused to 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, and benzene ring fused to 5- or 6-membered heteroaryl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -SH, -NH 2 , -N0 2 , -CN, d-C 6 -alkyl, C 2 -C 6 -alkenyl, -0-(C C 6 - alkyl), -0-(C 2 -C 6 -alkenyl), -S-(C C 6 -alkyl), -S-(C 2 -C 6 -alkenyl), -C(0)0-(C C 6 - alkyl), -C(0)0-(C 2 -C 6 -alkenyl), -OC(0)NH 2 , -OC(0)NH-(C C C C
- Ci-C6-alkyl, C 2 -C6-alkenyl, 5- or 6-membered heterocyclyl with one or two heteroatoms independently selected from N, 0 and S, and phenyl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen; -OH; -0-(Ci-C6-alkyl); -COOH; C(0)0-(Ci-C6- alkyl); -C(0)NH 2 ; -C(0)NH(C C 6 -alkyl); -C(0)N(C C 6 - alkyl) 2 ; -C(0)NH(C 2 -C 6 -alkenyl); -NH(C C 6 -alkyl); -N(C C 6 - alkyl) 2 ; -NHC(0)-(C 6 -alkyl); -NHC(0)-(C C 6 -alkenyl; -NH(C C 6 -alkyl
- Z is C and n is 1 , or Z is S and n is 0;
- X is O and then R 2 is hydrogen, or
- X is NH or S and then R 2 is hydrogen; -(Ci-C6-alkyl) unsubstituted or terminally substituted by one substituent selected from the group consisting of -COOH, -C(0)0-(CrC 6 -alkyl), -NH 2 , NH(C C 6 -alkyl), -N(C C 6 - alkyl) 2 , -NHC(0)(Ci-C6-alkyl), 5-membered heteroaryl with 1 or 2 heteroatoms independently selected from N and O, benzene ring fused to heteroaryl with 1 or 2 heteroatoms independently selected from N and O; or phenyl;
- R 3 is phenyl substituted in the para position by a substituent selected from the group consisting of halogen, methyl and halogenated methyl, and optionally further by one substituent selected from the group consisting of halogen, -(Ci-C6)-alkyl, -0- (CrC 6 )-alkyl, -0-(Ci-C3-alkylene)-C(0)0-(Ci-C 6 -alkyl), and -0-(C C 3 -alkylene)- COOH;
- R 4 is: - isoxazolyl unsubstituted or substituted by one -(Ci-C6-alkyl); or phenyl unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -SH, -NH 2 , -N0 2 , -CN, C C 6 -alkyl, C 2 -C 6 -alkenyl, -0-(C C 6 -alkyl), -0-(C 2 -C 6 -alkenyl), -S-(C C 6 -alkyl), -S-(C 2 -C 6 -alkenyl), -C(0)0-(C C 6 - alkyl), -C(0)0-(C 2 -C 6 -alkenyl), -C(0)NH 2 , -C(0)NH(C C 6 -alkyl), -C(0)N(C C 6 - alkyl) 2
- phenyl, Ci-C6-alkyl, Ci-Ce- alkenyl and phenyl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -SH, -0-(d-C 6 -alkyl), -COOH, C(0)0-(C C 6 -alkyl), -0- (C 2 -C6-alkylene)-COOH, -C3-C6-cycloalkyl, 3- or 6-membered heterocyclyl with one heteroatom selected from N and O, and phenyl unsubstituted or substituted by one -(Ci-C6-alkyl), -0-(Ci-C6-alkyl), S-(Ci-C6-alkyl), phenyl or phenyl substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -SH, -0-(d-
- the compounds of the invention differ from the closest prior art compounds in that they lack an aliphatic linker between pyrrolone ring and R 4 substituent. Surprisingly, despite such modification of the chemical structure, they are endowed with the activity of inhibition of p53/Mdm2 and/or p53/Mdm4 interactions. More surprisingly, their activity is much higher activity compared to compounds known in the art. Importantly, most of them they are also dual Mdm2 and Mdm4 antagonists.
- said medicament is useful for the prevention and/or treatment of diseases, in which p53/Mdm2 and/or p53/Mdm4 interactions are disturbed and/or which are sensitive to inhibition of p53/Mdm2 and/or p53/Mdm4 interactions.
- diseases are in particular immune system diseases, chronic inflammatory conditions, inflammatory and allergic skin diseases associated with proliferative diseases, cancer and viral infections.
- the immune system diseases are autoimmune diseases such as rheumatoid arthritis, graft-versus-host disease, systemic lupus erythematosus, Sjorgen's syndrome, multiple sclerosis, Hashimoto's thyreoiditis, polymyositis; chronic inflammatory conditions are asthma, osteoarthritis, atherosclerosis, Morbus Crohn; inflammatory or allergic conditions of the skin are psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticarial, bullous pemphigoid, pemphigus, epidermolysis bullosa acquisita; hyperproliferative disorder is Li-Fraumeni syndrome; cancer or tumour diseases are benign or malignant tumours, sarcomas, such as rhabdomy
- osteosarcomas carcinoma of the brain, e.g. soft tissue brain tumour, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumours, ovaries, colon, rectum, prostate, pancreas, lung, vagina or thyroid, glioblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, tumour of the neck and head, melanoma, prostate hyperplasia, neoplasia, neoplasia of epithelial character, mammary carcinoma, leukemia, such as B- or T-cell lymphomas, and adrenocortical carcinoma, including metastasis in other organs, respectively; viral infections are herpes, papilloma, HIV, and hepatits.
- R 4 is phenyl substituted by one, two or three substituents, one of which is a chlorine atom at the meta position relative to the nitrogen atom of the pyrrolone ring.
- R 4 is 4-methoxy-5-chlorophenyl.
- R 4 is 2,4-dimethoxy-5-chlorophenyl.
- R 3 is 4-chlorophenyl
- R 3 is 4-chloro-3- fluorophenyl.
- R 1 is phenyl substituted by -NHC(0)-(CrC 6 -alkyl), -NHC(0)-(C 2 -C 6 -alkenyl), -NHC(0)0-(C C 6 -alkyl), or -NHC(O)- phenyl, wherein alkyl, alkenyl and phenyl may be unsubstituted or substituted as specified above in the definition of R 1 in formula (I).
- R 1 is 3-(3-carboxy-2-(Z)-propenoyl)- aminophenyl.
- Z is C, and n is 1 ; in such a situation the compounds are 4-carbonyl derivatives.
- Z is S, and n is 0; in such a situation the compounds are 4-thio derivatives.
- R 4 is R 4' moiety, and these compounds are represented by the general formula (IA)
- R 1 ' is
- benzene ring fused to a 5 - or 6-membered heterocyclyl with one or two heteroatoms independently selected from N, O, and S;
- heterocyclyl, phenyl, benzene ring fused to 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, and benzene ring fused to 5- or 6-membered heteroaryl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -SH, -NH 2 , -N0 2 , -CN, d -C 6 -alkyl, C 2 -C 6 -alkenyl, -0-(C C 6 - alkyl), -0-(C 2 -C 6 -alkenyl), -S-(C C 6 -alkyl), -S-(C 2 -C 6 -alkenyl), -C(0)0-(C C 6 - alkyl), -C(0)0-(C 2 -C 6 -alkenyl), -OC(0)NH 2 , -OC(0)NH-(C C C
- Ci -C6-alkyl, C 2 -C6-alkenyl and phenyl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen; -OH; -0- (Ci -C 6 -alkyl); -COOH; C(0)0-(C C 6 -alkyl); -C(0)NH 2 ; -C(0)NH(C C 6 - alkyl); -C(0)N (C C 6 -alkyl) 2 ; -C(0)NH(C 2 -C 6 -alkenyl); -NH(C C 6 - alkyl); -N(C C 6 -alkyl) 2 ; -NHC(0)-(C C 6 -alkyl); -NHC(0)-(C 2 -C 6 -alkenyl); 0-(C 2 -C 6 -alkylene)-COOH; -C 3 -C 6
- R 4' is phenyl substituted in meta position relative to the nitrogen atom of the pyrrolone ring by a substituent selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl, and trifluoromethoxy, and additionally one or two substituents independently selected from the group consisting of halogen, -OH, -SH, -NH 2 , -N0 2 , -CN, C C 6 -alkyl, C 2 -C 6 -alkenyl, -0-(C C 6 -alkyl), -O- (C 2 -C 6 -alkenyl), -S-(C C 6 -alkyl), -S-(C 2 -C 6 -alkenyl), -C(0)0-(C C 6 -alkyl), -C(0)0- (C 2 -C 6 -alkenyl), -C(0)NH 2 , -C(0)NH(C C 6 -alkyl), -C
- Ci -C6-alkyl, C 2 -C6-alkenyl and phenyl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -SH, -O- (Ci -C6-alkyl), -COOH, C(0)0-(Ci -C6-alkyl), 3- or 6-membered heterocycle with one heteroatom selected from N and O, and phenyl unsubstituted or substituted by one -(Ci -C6-alkyl), -0-(Ci -C6-alkyl), S-(Ci -C6-alkyl), phenyl or phenyl substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -(Ci -C3-alkyl), and -0- (Ci -C 3 -alkyl);
- R 2 , R 3 , Z, X and n have the meaning as given for the general definition of formula (I).
- R 1 is R 1" moiety and R 4 is R 4" moiety, and these compounds are represented by the general formula (IB)
- R 1 " is phenyl substituted by -NHC(0)-(C C 6 -alkyl), -NHC(0)-(C 2 -C 6 -alkenyl), -NHC(0)0- (Ci -C6-alkyl), or NHC(O) -phenyl, and optionally further by one or two substituents independently selected from the group consisting of halogen, -NO2, -CN, C1 -C6- alkyl, -0-(C C 6 -alkyl), -S-(d-C 6 -alkyl), and -C(0)0-(C C 6 -alkyl),
- Ci -C6-alkyl, C2-C6-alkenyl and phenyl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen; -OH; -0- (Ci -C 6 -alkyl); -COOH; C(0)0-(C C 6 -alkyl); -C(0)NH 2 ; -C(0)NH(C C 6 - alkyl); -C(0)N (Ci -C 6 -alkyl) 2 ; -C(0)NH(C 2 -C 6 -alkenyl); -NH(C C 6 - alkyl); -N(Ci -C 6 -alkyl) 2 ; -NHC(0)-(C C 6 -alkyl); -NHC(0)-(C 2 -C 6 - alkenyl); -NHC(0)-(cyclohexyl) (Ci -C3-al
- - phenyl unsubstituted or substituted by one substituent selected from the group consisting of halogen, -OH, -SH, -NH2, -NO2, -CN, Ci -C6-alkyl, C2-C6-alkenyl, -0- (CrC 6 -alkyl), -0-(C 2 -C 6 -alkenyl), -S-(C C 6 -alkyl), -S-(C 2 -C 6 -alkenyl), -C(0)0-(C C 6 - alkyl), -C(0)0-(C 2 -C 6 -alkenyl), -C(0)NH 2 , -C(0)NH(d -C 6 -alkyl), -C(0)N(C C 6 - alkyl) 2 , -C(0)NH(C 2 -C 6 -alkenyl), -NH(C C 6 -alkyl), -N(C C 6 -alkyl
- Ci -C6-alkyl, C 2 -C6-alkenyl and phenyl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -SH, -O- (C1 -C 6 -alkyl), -COOH, C(0)0-(C C 6 -alkyl), -0-(C 2 -C 6 -alkylene)-COOH, 3- or 6-membered heterocycle with one heteroatom selected from N and 0, phenyl unsubstituted or substituted by one -(Ci -C6-alkyl), -0-(Ci -C6-alkyl), S-(Ci -C6-alkyl), phenyl or phenyl substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -(Ci -C3-alkyl), and
- R 2 , R 3 , Z, X and n have the meaning as given for the definition of general formula (I) .
- the present invention relates further to new compounds which is a subgroup of the compounds of general formula (I) as defined above, and is represented by the following general formula (IA):
- R 1 ' is
- heterocyclyl, phenyl, benzene ring fused to 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, and benzene ring fused to 5- or 6-membered heteroaryl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -SH, -NH 2 , -N0 2 , -CN, d -C 6 -alkyl, C 2 -C 6 -alkenyl, -0-(C C 6 - alkyl), -0-(C 2 -C 6 -alkenyl), -S-(C C 6 -alkyl), -S-(C 2 -C 6 -alkenyl), -C(0)0-(C C 6 - alkyl), -C(0)0-(C 2 -C 6 -alkenyl), -OC(0)NH 2 , -OC(0)NH-(C)
- Ci -C6-alkyl, C 2 -C6-alkenyl and phenyl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen; -OH; -0-(C C 6 -alkyl); -COOH; C(0)0-(C C 6 - alkyl); -C(0)NH 2 ; -C(0)NH(C C 6 -alkyl); -C(0)N(C C 6 - alkyl) 2 ; -C(0)NH(C 2 -C 6 -alkenyl); -NH(C C 6 -alkyl); -N(C C 6 - alkyl) 2 ; -NHC(0)-(C C 6 -alkyl); -NHC(0)-(C 2 -C 6 -alkenyl); 0-(C 2 -C 6 - alkylene) -COOH; -C 3 -C 6 -
- R 4' is phenyl substituted in meta position relative to the nitrogen atom of the pyrrolone ring by a substituent selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl, and trifluoromethoxy, and additionally by one or two substituents independently selected from the group consisting of halogen, -OH, -SH, -NH 2 , -N0 2 , -CN, C C 6 -alkyl, C 2 -C 6 -alkenyl, -0-(C C 6 -alkyl), -0- (C 2 -C 6 -alkenyl), -S-(d-C 6 -alkyl), -S-(C 2 -C 6 -alkenyl), -C(0)0-(C C 6 -alkyl), -C(0)0- (C 2 -C 6 -alkenyl), -C(0)NH 2 , -C(0)NH(C C 6 -alkyl), -
- Ci-C6-alkyl, C 2 -C6-alkenyl and phenyl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -SH, -O- (Ci-C6-alkyl), -COOH, C(0)0-(Ci-C6-alkyl), 3- or 6-membered heterocycle with one heteroatom selected from N and O, and phenyl unsubstituted or substituted by one -(Ci-C6-alkyl), -0-(Ci-C6-alkyl), S-(Ci-C6-alkyl), phenyl or phenyl substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -(Ci-C3-alkyl), and -0- (Ci-C 3 -alkyl);
- R 2 , R 3 , Z, X and n have the meaning as given in the general definition of formula (I), and pharmaceutically acceptable salts, steroisomers, tautomers and solvates thereof.
- R 4' is phenyl substituted by one, two or three substituents, one of which is a chlorine atom at the meta position relative to the ring nitrogen atom of the pyrrolone ring.
- R 4' is 4-methoxy-5-chlorophenyl.
- R 4' is 2,4-dimethoxy-5-chlorophenyl.
- R 3 is 4-chlorophenyl.
- R 3 is 4-chloro-3-fluorophenyl.
- R 1 ' is phenyl substituted by -NHC(0)-(C C 6 -alkyl), -NHC(0)-(C 2 -C 6 -alkenyl), -NHC(0)0- (Ci -C6-alkyl), or NHC(0)-phenyl, wherein alkyl, alkenyl and phenyl can be unsubstituted or substituted as specified for the definition of the general formula (I) .
- R 1 ' is 3-(3-carboxy-2-(Z)-propenoyl)aminophenyl.
- Z is C, and n is 1 ; in such a situation the compounds are 4-carbonyl derivatives.
- Z is S, and n is 0; in such a situation the compounds are 4-thio derivatives.
- R 1 " is phenyl substituted by -NHC(0)-(C C 6 -alkyl) or -NHC(0)-(C 2 -C 6 -alkenyl), -NHC(0)0- (Ci -C6-alkyl), NHC(O) -phenyl, and optionally further by one or two substituents independently selected from the group consisting of halogen, -NO2, -CN, C1 -C6- alkyl, -0-(C C 6 -alkyl), -S-(d-C 6 -alkyl), and -C(0)0-(C C 6 -alkyl),
- Ci -C6-alkyl, C2-C6-alkenyl and phenyl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen; -OH; -0- (Ci-C 6 -alkyl); -COOH; C(0)0-(C C 6 -alkyl); -C(0)NH 2 ; -C(0)NH(C C 6 - alkyl); -C(0)N(Ci-C 6 -alkyl) 2 ; -C(0)NH(C 2 -C 6 -alkenyl); -NH(C C 6 - alkyl); -N(Ci-C 6 -alkyl) 2 ; -NHC(0)-(C C 6 -alkyl); -NHC(0)-(C 2 -C 6 - alkenyl); -NHC(0)-(cyclohexyl)(Ci-C3-alkylene)-
- - phenyl unsubstituted or substituted by one substituent selected from the group consisting of halogen, -OH, -SH, -NH 2 , -N0 2 , -CN, Ci-C6-alkyl, C 2 -C6-alkenyl, -0-(Ci- C 6 -alkyl), -0-(C 2 -C 6 -alkenyl), -S-(C C 6 -alkyl), -S-(C 2 -C 6 -alkenyl), -C(0)0-(C C 6 - alkyl), -C(0)0-(C 2 -C 6 -alkenyl), -C(0)NH 2 , -C(0)NH(C C 6 -alkyl), -C(0)N(C C 6 - alkyl) 2 , -C(0)NH(C 2 -C 6 -alkenyl), -NH(d-C 6 -alkyl), -N(C C
- Ci-C6-alkyl, C 2 -C6-alkenyl and phenyl are unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -SH, -0- (C1 -C 6 -alkyl), -COOH, C(0)0-(C C 6 -alkyl), -0-(C 2 -C 6 -alkylene)-COOH, 3- or 6-membered heterocycle with one heteroatom selected from N and 0, and phenyl unsubstituted or substituted by one -(Ci-C6-alkyl), -0-(Ci-C6-alkyl), S-(Ci-C6-alkyl), phenyl or phenyl substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, -(Ci-C3-alkyl), and -0-(Ci)
- R 2 , R 3 , Z, X and n have the meaning as defined for the general definition of formula (I),
- R 1 " is 3-(3-carboxy-2-(Z)-propenoyl)aminophenyl.
- R 1 " is 3-(3-carboxy-2-(E)-propenoyl)aminophenyl.
- Z is C, and n is 1 ; in such a situation the compounds are 4-carbonyl derivatives.
- Z is S, and n is 0; in such a situation the compounds are 4-thio derivatives.
- Compounds as described above can be administered in the treatment of diseases mentioned herein in the form of a pharmaceutical composition or a pharmaceutical formulation containing them.
- the present invention further relates to a pharmaceutical composition
- a pharmaceutical composition comprising as active ingredient a compound of general formula (I), in particular a compound of formula (IA) or a compound of formula (IB), in combination with at least one pharmaceutically acceptable excipient.
- the present invention also provides use of a compound of general formula (I), in particular a compound of formula (IA) or a compound of formula (IB), for the preparation of a medicament for the treatment and/or prevention of diseases, in which interactions p53/Mdm2 and/or p53/Mdm4 are disturbed and/or which are sensitive to inhibition of interactions p53/Mdm2 and/or p53/Mdm4.
- a compound of general formula (I) in particular a compound of formula (IA) or a compound of formula (IB)
- the present invention also provides a method for the treatment and/or prevention of diseases, in which interactions p53/Mdm2 and/or p53/Mdm4 are disturbed and/or which are sensitive to inhibition of interactions p53/Mdm2 and/or p53/Mdm4, comprising administering a therapeutically effective amount of a compound of general formula (I), in particular a compound of formula (IA) or a compound of formula (IB) or a pharmaceutical composition comprising as an active ingredient a compound of general formula (I), in particular a compound of formula (IA) or a compound of general formula (IB), in combination with at least one pharmaceutically acceptable excipient.
- a compound of general formula (I) in particular a compound of formula (IA) or a compound of formula (IB)
- a pharmaceutical composition comprising as an active ingredient a compound of general formula (I), in particular a compound of formula (IA) or a compound of general formula (IB), in combination with at least one pharmaceutically acceptable excipient
- the compounds according to the invention may also exist in one or more tautomeric forms. Such forms, although not explicitly indicated in the above formula, are within the scope of the present invention. Accordingly, the compounds may be present as a mixture of tautomers or as individual tautomer.
- C1 -C3 alkyl means a saturated, straight or branched hydrocarbon substituent having 1 to 3 carbon atoms.
- Examples of Ci -C3-alkyl groups are methyl, ethyl, n-propyl, and iso-propyl.
- C1 -C6 alkyl means a saturated, straight or branched hydrocarbon substituent having 1 to 6 carbon atoms.
- Examples of Ci -C6-alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, and n-hexyl.
- C2-C6-alkenyl means a saturated, straight or branched hydrocarbon substituent having 2 to 6 carbon atoms containing one carbon - carbon double bond.
- Examples of C2-C6-alkenyl groups are ethylene, n-propylene, n-butylene, n-pentylene, and n-hexylene.
- Ci-C3-alkylene group means a group derived by removing another hydrogen atom from the Ci-C3-alkyl group, thereby forming a divalent rest.
- Examples of Ci-C3-alkylene groups are methylene, 1 ,2-ethylene and 1 ,3-propylene.
- C3-C6-cycloalkyl means a saturated, cyclic hydrocarbon substituent having 3 to 6 carbon atoms.
- Examples of C3-C6-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- C3-C6-cycloalkyl is cyclopropyl group.
- halogen means a substituent selected from F, CI, Br and I.
- the term faced5- or 6-membered heteroaryl with one or two heteroatoms independently selected from N, 0, and S means a monocyclic heteroaromatic substituent.
- Examples of the 5- or 6-membered heteroaryl substituent are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyridyl, pyrimidyl, 2-oxo-1 ,2- dihydropyridyl, quinolinyl.
- Heteroaryl can be unsubstituted or substituted with substituents such as those indicated in the definition of the general formula (I).
- the term faced5- or 6-membered heterocyclyl with one or two heteroatoms independently selected from N, 0, S" and proceedings5- or 6-membered heterocyclyl with one nitrogen atom” in the context of the present invention means a saturated or partially unsaturated heterocyclic ring of the indicated type and number of heteroatoms in the ring.
- Examples of the 5- or 6-membered heterocyclyl are 2,5-dihydropyrrole, dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazolinyl, oxazolidinyl, thiazolidinyl, oxothiolanyl.
- Heterocyclyl can be unsubstituted or substituted with substituents such as those indicated in the definition of the general formula (I).
- the term “ges3 - or 6-membered heterocyclyl with one heteroatom selected from N and O" in the context of the present invention means a saturated heterocyclic ring.
- Examples of 3- or 6-membered heterocyclyl are piperidinyl and oxiranyl.
- the compounds according to the invention may be either acidic or basic, they may form the corresponding addition salts with suitable acids or bases.
- Acid addition salt refers to those salts which retain the biological activity of the free bases and which are not biologically undesirable.
- Acid addition salts may be formed with inorganic acids (mineral) acids or organic acids.
- acids may be mentioned in particular hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric, carbonic, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalene- sulfonic such as 2-naphthalenesulfonic, pamoic, xinafoic, and hexanoic acid.
- Acid addition salt thereof can be prepared in a simple manner by reacting a compound of formula (I) with a suitable inorganic or organic acid, in an amount substantially equimolar with respect to compound (I), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated, for example by crystallisation and filtration.
- a suitable solvent such as an organic solvent
- the free bases of the compounds can be converted into the corresponding hydrochloride salt by treating a solution of the compound, for example in methanol, with a stoichiometric amount of hydrochloric acid or hydrogen chloride in methanol, ethanol or diethyl ether, followed by evaporation of a solvent.
- pharmaceutically acceptable base addition salts include salts derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium salts and the like.
- Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as i so propylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine and triethanolamine.
- Substituents in the general formulas for the scheme above have the same meanings as in formula (I) .
- Such type of transformations are described for example in Ma K et al. Bioorganic and Medicinal Chemistry Letters 201 1 , vol. 21 , p. 6724 - 6727; Sakhno Y. I .
- ketoesters are either commercially available or can be prepared in a Claisen type cross condensation reaction between the respective methyl ketone and diethyl oxalate in the presence of a base.
- the corresponding methyl ketones are commercially available.
- the preparation of such keto esters is described in detail in Zhang, J. et al. Bioorganic & Medicinal Chemistry Letters, 2000, vol. 10, p. 2575 - 2578; Takeda Pharmaceutical Company Limited Patent: EP2005957 A1 , 2008; Pei, Y. et al. Tetrahedron Letters, 1993, vol. 34, p. 7509 - 7512; Nagarapu, L. et al. European Journal of Medicinal Chemistry, 2010, vol. 45, p.
- thio-ketoesters can be obtained by direct reaction between a thiol and ethyl bromopyruvate in the presence of an organic base.
- an organic base Preferably, triethylamine or pyridine is used.
- the preparation of such thio-ketoesters is described in detail in, for example, Hutchinson, J.H. et al. Tetrahedron Letters, 1992 , vol. 33, p. 4713 - 4716; Beck. J. Tetrahedron, 1994 , vol. 50, p. 4691 - 4698; Wang, B. et al. US2003/13656 A1 , 2003.
- the corresponding aldehydes R 3 CHO and amines R -NH2 are either commercially available or can be prepared by suitable methods known in the art of organic synthesis.
- Corresponding thiols are commercially available or can be obtained by reduction of sulfonyl chlorides, as, for example, disclosed in Bellale E. V., et al. Synthesis, 2009, p. 3211 -3213.
- Said reactions of nucleophilic substitution reaction with thiol or amine can be carried out in a manner known in the art in the presence of an acid (acetic or trifluoroacetic acid), at room temperature or elevated temperature.
- an acid acetic or trifluoroacetic acid
- Such reaction is described in detail in Gein, V. L. et al. Russian Journal of Organic Chemistry, 2011 , vol. 47, No. 1 p. 95 - 99.
- Compounds according to the invention are useful for the prevention and/or treatment of diseases, in which p53/Mdm2 and/or p53/Mdm4 interactions are disturbed and/or which are sensitive to inhibition of p53/Mdm2 and/or p53/Mdm4 interactions.
- the compounds according to the invention are useful for the prevention and/or treatment of diseases associated with dysregulation of the cell cycle and apoptosis, i.e. immune diseases such as for example autoimmune diseases and conditions associated with the rejection of tissue/organ transplant such as rheumatoid arthritis, graft-versus-host disease, systemic lupus erythematosus, Sjorgen's syndrome, multiple sclerosis, Hashimoto's thyreoiditis, polymyositis; chronic inflammatory conditions are asthma, osteoarthritis, atherosclerosis, Morbus Crohn; inflammatory or allergic conditions of the skin are psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticarial, bullous pemphigoid, pemphigus, epidermo
- osteosarcomas carcinoma of the brain, e.g. soft tissue brain tumour, kidney, liver, adrenal gland, bladder, brest, stomach, gastric tumours, ovaries, colon, rectum, prostate, pancreas, lung, vagina or thyroid, glioblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumour of the neck and head, melanoma, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, a mammary carcinoma, a leukemia, such as B- or T-cell lymphomas, adrenocortical carcinoma, including metastasis in other organs, respectively; viral infections are herpes, papilloma, HIV, hepatits.
- the compounds of formula (I) according to the invention can be administered as a chemical compound, but typically will be used in the form of pharmaceutical compositions, comprising a compound according to the invention or a pharmaceutically acceptable salt thereof as defined above as active ingredient, in combination with pharmaceutically acceptable carriers and excipients.
- compositions according to the invention can be administered by any route, preferably oral or parenteral, and will be in a form of a formulation designed for use in medicine, depending on the intended route of administration.
- Compositions for oral administration may be in a solid or liquid form.
- the solid preparations may be for example tablets or capsules prepared by conventional means with pharmaceutically acceptable inactive ingredients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, carboxymethylcellulose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g.
- magnesium stearate, talc or silica magnesium stearate, talc or silica
- disintegrants e.g., crospovidone, corn starch or sodium starch glycolate
- wetting agents e.g., sodium lauryl sulphate
- the tablets may be coated by methods well known in the art by conventional coatings, release delaying/controlling coatings or enteric coatings.
- Liquid preparations for oral administration may be in a form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable inactive ingredients such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
- suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
- emulsifying agents e.g. lecithin or acacia
- non-aqueous vehicles e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils
- preservatives e.g., methyl or propyl p-hydroxybenzoates or sorbic acid.
- Formulations may also contain suitable buffer systems, flavoring
- Formulations for oral administration may be suitably formulated by methods known to those skilled in the art to obtain a controlled release of the active compound.
- Parenteral administration includes administration by intramuscular and intravenous injection and intravenous infusion.
- Compositions for parenteral administration may be in unit dosage form, e.g. in ampoules or in multidose containers with preservative.
- the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
- the active ingredient may be in powder form for reconstitution with a suitable media such as sterile pyrogen-free water.
- a method of treatment using compounds of the invention will involve administering a therapeutically effective amount of a compound according to the invention, preferably in the form of a pharmaceutical composition, to a subject in need of such treatment.
- a proposed dosage of the compounds according to the invention is from 0.1 to about 1000 mg per day, in single dose or in divided doses. It will be apparent to the skilled person that the selection of the dose required to achieve the desired biological effect will depend on a number of factors such as the particular compound, use, method of administration, the age and condition of the patient, and the precise dosage will be ultimately determined at the discretion of the attending physician.
- UPLC/MS analyses were performed on a UPLC liquid chromatograph equipped with PDA detector and SQD MS detector, operating under ESI (+) or ESI(-) using C18 column, 2.1 mm ⁇ 50 mm, 1 .7 ⁇ (AQUITY UPLC BEH or equivalent).
- HPLC or LC/MS grade methanol, HPLC grade water, HPLC or LC/MS grade formic acid and p. a. grade 25% solution of ammonia were used to analyses. Operating conditions were the following: mobile phase flow 0.35 ml/min, wavelength 210 - 400 nm, injection volume 1 ⁇ , column temperature 60°C, autosampler temperature 5°C, gradient elution with a linear course:
- Example 1 B Preparation of 3-hydroxy-1 ,5-dihydropyrrol-2-one system (Method A, general procedure).
- Benzaldehyde (1 eq), amine (1 eq), ketoester (1 eq), were dissolved in an organic solvent (dioxane, EtOH, THF, AcOH, DCM).
- the reaction was carried out at a temperature within the range of 20° C to reflux temperature of the solvent for 2 h to 3 days. The reaction was monitored using thin layer chromatography. After completion of the reaction, the product was purified by column chromatography (S1O2), eluting with a hexane:ethyl acetate 1 :1 -> AcOEt:MeOH 9:1 gradient.
- Example 1 C Preparation of 3-hydroxy-1 ,5-dihydropyrrol-2-one system (Method B, general procedure).
- Benzaldehyde (1 eq) and amine (1 eq) were dissolved in an organic solvent (dioxane, EtOH, THF, AcOH, DCM).
- the Schiff base was generated for about 1 hour at a temperature within the range of 20° C to reflux temperature of the solvent.
- the Schiff base was isolated and added to a solution of an equimolar amount of keto ester.
- the reaction was carried out at a temperature within the range of 20° C to reflux temperature of the solvent for 2 h to 3 days (TLC).
- TLC column chromatography
- the product was purified by column chromatography (S1O2), eluting with hexane:ethyl acetate 1 :1 -> AcOEt:MeOH 9:1 gradient.
- This example uses the N-Boc-3-aminoacetophenone, which was converted according to Method B in corresponding N-protected 1 ,5-dihydropyrrol-2-one,
- any isomer N- of Boc-acetophenone can be used.
- the Boc group was removed by TFA at room temperature, for example, as described in Raghavanpillai A. at al. Journal of Fluorine Chemistry 135 (2012) 187-194, to provide the corresponding amine.
- the amine was subjected to further transformations.
- the resulting compound with the free amine group (1 eq) and maleic anhydride (1 eq) were dissolved in DMF.
- the reaction was carried out at room temperature for 20 h.
- the product was isolated after addition of water to the reaction mixture, followed by filtration, washing and drying of the resulting precipitate.
- Example 1 E The preparation of compounds substituted in the 3-position (Method D)
- Previously synthesized corresponding 3-amino or thiol substituted-1 ,5-dihydropyrrol-2-one can be further subjected to aminolysis in appropriate solvents (dioxane, MeOH, EtOH, THF), with and appropriate amine at temperature form r.t. to 80°C.
- Example 2A A reduction of sulfonyl chlorides in the presence of triphenylphosphine (general procedure)
- Aryl or alkyl thiol (1 eq) was dissolved in an appropriate organic solvent (Et20, THF or a mixture) under inert atmosphere and cooled to 0°. Then, pyridine or triethylamine (1.1 eq) was added in one portion. The solution was stirred for several minutes, before ethyl bromopyruvate (1 .1 eq) was added dropwise at 0°. The reaction proceeded at the same temperature. After its completion, as indicated by TLC, the mixture was diluted with water, acidified with 1 N HCl and extracted with ethyl acetate.
- Example 2C Preparation of 3-hydroxy-1 ,5-dihydropyrrol-2-one system (Method 2A, general procedure).
- Example 2D Preparation of 3-hydroxy-1 ,5-dihydropyrrol-2-one system (Method 2B, general procedure).
- Benzaldehyde (1 eq) and amine (1 eq) were dissolved in an organic solvent (dioxane, EtOH, THF, AcOH, DCM).
- the Schiff base was generated for about 1 hour in the range of 20° C to reflux temperature of the solvent. After this time, the Schiff base was isolated and added to a solution of an equimolar amount of keto ester 1 .
- the reaction was carried out at temperature 20° C to reflux temperature of the solvent for 2 h to 3 days. After completion of the reaction, the product was purified by column chromatography (S1O2), eluting with hexane:ethyl acetate 8:1 -> 0:1 gradient.
- N-substituted derivatives include reduction of the nitro group, followed by acylation of the free amine moiety as described in Matuszak N. et al. J. Med. Chem. 52 (2009) 7410-7420. Reducion of the nitro group was performed using tin chloride dihydrate in ethanol as described in Bellamy F.D. et al. Tetrahedron Letters, 25 (1984) 839-842, but other known methods may be used.
- This example uses the methyl or ethyl carboxylate derivative, which was converted according to Method B in corresponding 3-hydroxy-1 ,5-dihydropyrrol-2-one.
- the ester group was hydrolysed using sodium or lithium hydroxide at room temperature, for example, as described in Ottesen, L.K. et al. Organic Letters 8 (2006) 1771 - 1773, to provide the corresponding acid.
- the carboxylic acid derivative was subjected to further transformations.
- the carboxylic acid obtained after hydrolysis, (1 .0 eq), an amine or amine hydrochloride (1 .0-2.0 eq), triethylamine (1 .0-2.0 eq), carboxyl activating agent (DCC/EDG, 1 .0-2.0 eq) and DMAP (0.1 -0.3 eq) were dissolved in anhydrous methylene chloride and stirred at room temperature, under an inert atmosphere for 24-48h.
- the reaction mixture was diluted with methylene chloride, washed with 1 N HCl, brine, dried and evaporated in vacuo.
- the product was isolated by column chromatography or preparative HPLC.
- Fluorescence polarization measures the rotational movement of molecules in a homogenous suspension.
- Mdm2 protein amino acids 1 -111
- Mdm4 amino acids 1 -185
- FAM fluorescein- labelled
- TMR tetramethylrhodamine-labelled
- the peptide Upon excitation of the fluorescent ligand with linearly polarized light, the peptide rotates faster and emits light which is perpendicularly polarized. If the peptide is bound by Mdm2 or Mdm4, rotation will slow down and the perpendicular component will decrease. Disruption of the formation of the peptide-Mdm2 or peptide-Mdm4 complex due to an inhibitor molecule binding to the p53 binding site of Mdm2 or Mdm4 results in faster rotation of the peptide.
- Fluorescence polarization experiments were read on Tecan Infinite M1000 reader with the 470 nm excitation and 520 nm emission filters for fluorescein or 530 nm and 570 nm for tetra methyl rhod a mine respectively.
- the fluorescence polarization was measured in black 96-well plates (Corning, CLS3991 ) in room temperature.
- the test is performed by combining successive dilution of compounds diluted in dimethyl sulfoxide (DMSO, 5% final concentration) with 130 nM Mdm2 (or Mdm4) in reaction buffer (PBS, 0.1% CHAPS, 5 mM DTT (dithiothreitol)). After 15 minutes of incubation in room temperature fluorescence peptide was added (10 nm FAM-labelled or 200 nM TMR-labelled. Final reading was performed after 90 minutes of incubation. IC50 values were calculated using GraphPad Prism5 and next transformed to Ki values (Kenakin T. Pharmacologic analysis of drug-receptor interaction. 3 rd edition, Raven Press, New York 1997).
- Table 2 Mdm2 and Mdm4 inhibitory activity of representative compounds of the present invention.
- Nutlin-3a was used as a reference compound (Vassilev LT et al. In vivo activation of the p53 pathway by small-molecule antagonists of Mdm2. Science. 2004 Feb 6;303(5659):844-8).
- IC50 value for nutlin-3a obtained in our test (0,1 ⁇ ) is consistent with literature and certified that buffer composition, test conditions and purity of proteins were appropriate.
- Mdm2 protein amino acids 1 -111
- Mdm4 amino acids 1 - 185 were purified and then all tags were removed. It improved reliability of our data in context of their specificity. Additionally purity of Mdm2 and Mdm4 was controlled and always was >95 .
- Reaction buffer was optimized by adding 5 mM DTT and 0.1% zwitterionic detergent CHAPS to reduce effect of nonspecific interactions.
- the present invention provides new inhibitors of p53- Mdm2 and p53-Mdm4 interaction having very high activity that may find use in the treatment of the diseases mentioned above.
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Abstract
La présente invention concerne un composé de formule générale (I), où Z est C et n vaut 1, ou Z est S et n vaut 0, R4 est un groupe isoxazolyle non susbtitué ou substitué par un groupe alkyle –(C1-C6), ou un groupe phényle non substitué ou substitué, et les autres substituants ont la signification donnée dans la description, utile comme médicament. Les composés sont des inhibiteurs des interactions p53/Mdm2 et/ou p53/Mdm4 et peuvent être utiles dans le traitement de maladies du système immunitaire, d'états inflammatoires chroniques, de maladies de peau inflammatoires et allergiques associées à des maladies prolifératives, du cancer ou d'infections virales.
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WO2017201449A1 (fr) | 2016-05-20 | 2017-11-23 | Genentech, Inc. | Conjugués anticorps-protac et procédés d'utilisation |
WO2020074403A1 (fr) * | 2018-10-08 | 2020-04-16 | Universität Zürich | Molécules modulatrices de l'appétit |
WO2023056069A1 (fr) | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Conjugués agent de dégradation-anticorps et leurs procédés d'utilisation |
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