MXPA06007439A - PYRROLO[2,3-b]PYRIDINE DERIVATIVES ACTIVE AS KINASE INHIBITORS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION COMPRISING THEM - Google Patents
PYRROLO[2,3-b]PYRIDINE DERIVATIVES ACTIVE AS KINASE INHIBITORS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION COMPRISING THEMInfo
- Publication number
- MXPA06007439A MXPA06007439A MXPA/A/2006/007439A MXPA06007439A MXPA06007439A MX PA06007439 A MXPA06007439 A MX PA06007439A MX PA06007439 A MXPA06007439 A MX PA06007439A MX PA06007439 A MXPA06007439 A MX PA06007439A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- group
- formula
- optionally substituted
- linear
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title abstract description 55
- 238000002360 preparation method Methods 0.000 title abstract description 23
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1H-pyrrolo[2,3-b]pyridine Chemical class C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 title abstract description 16
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 211
- 102000001253 Protein Kinases Human genes 0.000 claims abstract description 36
- 239000011780 sodium chloride Substances 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 230000000694 effects Effects 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 108060006633 Protein Kinases Proteins 0.000 claims abstract description 21
- 201000011510 cancer Diseases 0.000 claims abstract description 12
- 230000002062 proliferating Effects 0.000 claims abstract description 7
- 206010001897 Alzheimer's disease Diseases 0.000 claims abstract description 5
- 206010003816 Autoimmune disease Diseases 0.000 claims abstract description 4
- 206010047461 Viral infection Diseases 0.000 claims abstract description 4
- 208000001756 Virus Disease Diseases 0.000 claims abstract description 4
- 230000017613 viral reproduction Effects 0.000 claims abstract description 4
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 137
- 230000002401 inhibitory effect Effects 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 125000000623 heterocyclic group Chemical group 0.000 claims description 41
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 38
- -1 alq uilo Chemical group 0.000 claims description 33
- 125000003342 alkenyl group Chemical group 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 229910052701 rubidium Inorganic materials 0.000 claims description 23
- 125000005842 heteroatoms Chemical group 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 22
- 125000000304 alkynyl group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 19
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 17
- 108091000081 Phosphotransferases Proteins 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000003107 substituted aryl group Chemical group 0.000 claims description 15
- 239000000969 carrier Substances 0.000 claims description 13
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- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000002207 metabolite Substances 0.000 claims description 10
- 239000000651 prodrug Substances 0.000 claims description 10
- 229940002612 prodrugs Drugs 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 6
- 125000005466 alkylenyl group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
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- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 5
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
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- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
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- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
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- 125000004104 aryloxy group Chemical group 0.000 claims description 3
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- 206010027476 Metastasis Diseases 0.000 claims description 2
- 125000005091 alkenylcarbonylamino group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 2
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 201000004384 alopecia Diseases 0.000 claims description 2
- 231100000360 alopecia Toxicity 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 230000033115 angiogenesis Effects 0.000 claims description 2
- 125000001769 aryl amino group Chemical group 0.000 claims description 2
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 238000002512 chemotherapy Methods 0.000 claims description 2
- 238000009104 chemotherapy regimen Methods 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims description 2
- 239000000824 cytostatic agent Substances 0.000 claims description 2
- 239000002254 cytotoxic agent Substances 0.000 claims description 2
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 2
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 2
- 125000004986 diarylamino group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 210000000056 organs Anatomy 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 8
- 125000004429 atoms Chemical group 0.000 claims 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 3
- 206010056981 Adenomatous polyposis coli Diseases 0.000 claims 1
- 206010016654 Fibrosis Diseases 0.000 claims 1
- 102000030951 Phosphotransferases Human genes 0.000 claims 1
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- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims 1
- 230000004952 protein activity Effects 0.000 claims 1
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- 239000000126 substance Substances 0.000 abstract description 5
- 229940040608 SPS Drugs 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 172
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 147
- 229920005989 resin Polymers 0.000 description 126
- 239000011347 resin Substances 0.000 description 126
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 102
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 40
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- 150000001412 amines Chemical class 0.000 description 21
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- AIYUHDOJVYHVIT-UHFFFAOYSA-M Caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 16
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 11
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- 238000000926 separation method Methods 0.000 description 6
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- QHOKENWFMZXSEU-UHFFFAOYSA-N tetrabutylazanium;nitrate Chemical compound [O-][N+]([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC QHOKENWFMZXSEU-UHFFFAOYSA-N 0.000 description 5
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
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- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
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- 230000025053 regulation of cell proliferation Effects 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
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- 102000013498 tau Proteins Human genes 0.000 description 1
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- 239000003277 telomerase inhibitor Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 239000010936 titanium Substances 0.000 description 1
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- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
Compounds which are pyrrolo[2,3-b]pyridine derivatives or pharmaceutically acceptable salts thereof, their preparation process and pharmaceutical compositions comprising them are disclosed;these compounds are useful in the treatment of diseases caused by and/or associated with an altered protein kinase activity such as cancer, cell proliferative disorders, Alzheimer's disease, viral infections, auto-immune diseases and neurodegenrative disorders;also disclosed is a process under SPS conditions for preparing the compounds of the invention and chemical libraries comprising a plurality of them.
Description
DERIVATIVES OF PIRROL? R2,3-b1PlRIDINE ACTIVE AS INHIBITORS
OF C1NASA, PROCEDURE FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM
FIELD OF THE INVENTION
The present invention relates to pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors and, more particularly, relates to pyrrolo [2,3-b] pyridine derivatives further substituted at the 5-position, with a method for their preparation, with combinatorial libraries thereof, with pharmaceutical compositions comprising them and with their use as therapeutic agents, particularly in the treatment of diseases related to poorly regulated protein kinases.
BACKGROUND OF THE INVENTION
The malfunction of protein kinases (PK) is the hallmark of numerous diseases. A large amount of the oncogenes and proto-oncogenes involved in human cancers code for PK. Increased PK activities are also implicated in many non-malignant diseases such as benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and postoperative stenosis and restenosis PKs have also been linked in inflammatory conditions and in the multiplication of viruses and parasites. PKs also play a major role in the pathogenesis and development of neurodegenerative disorders. For a general reference to malfunction or lack of PK regulation, see, for example, Current Opinion in Chemical Biology 1999, 3, 459-465.
BRIEF DESCRIPTION OF THE INVENTION
An object of the invention is to provide compounds that are useful in therapy as agents against a group of diseases caused by, and / or related to, a poorly regulated activity of the protein kinase. Another objective is to provide compounds that are endowed with protein kinase inhibitory activity. The present inventors have now discovered that some pyrrolo [2,3-b] pyridine derivatives are endowed with protein kinase inhibitory activity and therefore may be useful in therapy in the treatment of diseases related to poorly regulated protein kinases. More specifically, the compounds of this invention are useful in the treatment of a variety of cancers including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung that includes lung cancer of small cells, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin that include squamous cell carcinoma; Hematopoietic tumors of the lymphoid line including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, lymphocyte B lymphocytes, lymphocytes of T lymphocytes, Hodgkin's lymphoma, non-Hodgkin's lymphoma, tricholeukemia and Burkett's lymphoma, myeloid hematopoietic tumors including leukemias acute and chronic myelogens, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin that include fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system that include astrocytoma, neuroblastoma, glioma and schwannomas; other tumors that include melanoma, seminoma, keratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, follicular thyroid cancer, and Kaposi's sarcoma. Due to the key role of PKs in the regulation of cell proliferation, these pyrrolo [2,3-b] pyridine compounds are also useful in the treatment of a variety of proliferative cell disorders such as, for example, benign prostatic hyperplasia, Familial adenomatosis, polyposis, neurofibromatosis, psoriasis, proliferation of vascular smooth cells associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and postoperative stenosis and restenosis. further, the compounds of the invention are useful in the treatment of Alzheimer's disease, as suggested by the fact that CDK5 is involved in the phosphorylation of tau protein (J. Biochem., 117, 741-749, 1995). The compounds of this invention, as modulators of apoptosis, are useful in the treatment of cancer, viral infections, prevention of the development of AIDS in HIV-infected individuals, autoimmune diseases and degenerative disorders. The compounds of this invention are useful for inhibiting tumor angiogenesis and metastasis, as well as the treatment of rejection of organ transplantation and reverse rejection disease. The compounds of the invention also act as an inhibitor of other protein kinases such as for example cyclin-dependent kinases (cdk) such as cdk2 and cdk5, protein kinase C in different forms, Met, PAK-4, PAK-5, ZC-1. , STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, PL, Chk1, Chk2, HER2, rafl, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, PI3K , Wheel kinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, Nek and therefore is effective in the treatment of diseases associated with other protein kinases. The compounds of the invention are also useful in the treatment and prevention of alopecia induced by radiotherapy or induced by chemotherapy.
DETAILED DESCRIPTION OF THE INVENTION
Pyrrolopyridine derivatives are widely known in the art. As an example, the compound 3-carboxamido pyrrolo [2,3-b] pyridine has been reported as a synthetic intermediate in Chemical Abstracts C.A. 93 (1980): 168162. Some other 3-carboxamido derivatives of pyridine-N-substituted pyridine additionally by indolyl groups are described as 5-HT 2C / 2B antagts (see WO 96/11929); the above 3-carboxamide derivatives further substituted by N- (isoquinol-ethylcyclohexyl) groups are described as antipsychotic agents (see WO 00/24717, WO 00/21951, WO 00/21950, WO 98/50364); 3-carboxamidopyrrolopyridine compounds N-substituted by azabicyclo rings are also described as synthetic intermediates in the preparation of tropyl derivatives having antitussive properties. In addition, the pyrrolopyridine 3-hydrazide derivatives are described as synthetic intermediates for preparing more complex protein kinase inhibitors, as reported in WO 00/71537. The 7-azaindoles as inhibitors of N-terminal C-JUN kinases and therefore useful in the treatment of neurodegenerative disorders are also described in WO 03/082868. However, none of the pyrrolopyridine derivatives of the prior art results in presenting an additional amino group, optionally functionalized in a personal way in the 5-position of the pyrrolopyridine backbone. The pyrrolo [2,3-b] pyridine compounds of broad general formula endowed with therapeutic activity also include protein kinase inhibitory activity and are also described in WO 00/71537;
WO 01/01986; WO 01/58869; WO 99/32111; WO 99/37637; WO 97/03069;
WO 99/58496 and WO 95/28400. The 3-alkenylpyrrolo [2,3-b] pyridine derivatives as inhibitors of protein kinase are also described in WO 01/98299 in the name of the soli-citrant itself. Accordingly, the present invention provides a method for treating diseases caused by and / or associated with an altered protein kinase activity, for administration to a mammal in need thereof, of an effective amount of a compound represented by the formula (I)
wherein R is selected from the group consisting of -Ra, -CORa, -CONRaRb, -S02Ra or -C00R3; RT is a group -NRcRd or -ORc;
wherein Ra, Rb, Rc and Rd are the same or different and each is independently hydrogen or an optionally substituted group, which is selected from linear or branched forms of alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, carbocyclic or heteroaryl aryl or arylalkyl of 1 to 6 carbon atoms, heterocycle or heterocycloalkyl from 1 to 6 carbon atoms or, taken together with the nitrogen atom to which they are attached, either Ra and Rb as well as Rc and Rd can form an optionally substituted 4 to 7 membered heterocycle, which optionally contains a heteroatom or an additional heteroatomic group that is selected from S, O, N or NH; R2 is a group, optionally substituted further, which is selected from the linear or branched form of alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, carbocyclic or heteroaryl aryl or arylalkyl of 1 to 6 carbon atoms, heterocycle or heterocycloalkyl of 1 to 5 carbon atoms; or isomers, tautomers, carriers, metabolites, prodrugs and pharmaceutically acceptable salts thereof. In a preferred embodiment of the method described in the foregoing, the disease caused by and / or associated with an altered protein kinase activity is selected from the group consisting of cancer, proliferative cell disorders., Alzheimer's disease, viral infections, autoimmune diseases and neurodegenerative disorders. Specific types of cancer that can be treated include carcinoma, squamous cell carcinoma, hematopoietic tumors of the myeloid or lymphoid lines, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, keratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, follicular thyroid cancer and Kaposi's sarcoma. In another preferred embodiment of the method described in the foregoing, the proliferative cell disorder is selected from the group consisting of benign prostatic hyperplasia, polyposis of familial adenomatosis, neurofi-bromatosis, psoriasis, proliferation of vascular smooth cells related to atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and postoperative stenosis and restenosis. The present invention further provides a compound represented by the formula (I)
wherein R is selected from the group consisting of -Ra, -CORa -CONRaRb, -S02Ra or -COORa;
R-i is a group -NRcRd or -OR °; wherein Ra, Rb, Rc and Rd are the same or different and each is independently hydrogen or an optionally substituted group, which is selected from linear or branched forms of alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, carbocyclic or aryl heterocyclic or arylalkyl of 1 to 6 carbon atoms, heterocycle or heterocyclealkyl from 1 to 6 carbon atoms or, taken together with the nitrogen atom to which they are attached, either Ra and Rb as well as Rc and Rd can form an optionally substituted 4 to 7 membered heterocycle, which optionally contains a heteroatom or a additional heteroatomic group that is selected from S, O, N or NH; R2 is a group, optionally substituted further, which is selected from the linear or branched form of alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl or arylalkyl of 1 to 6 carbon atoms, heterocycle or heterocycloalkyl of 1 to 6 carbon atoms; or isomers, tautomers, carriers, metabolites, prodrugs and pharmaceutically acceptable salts thereof. Unless otherwise specified, when reference is made to the compounds of formula (I) by themselves, as well as with any pharmaceutical composition thereof or any therapeutic method of treatment comprising them, the present invention includes the entire of the hydrates, solvates, components, metabolites and prodrugs of the compounds of this invention. Prodrugs are any covalently linked compound which releases the medicament of active origin, according to formula (I) in vivo. If a chiral center or other form of an isomeric center is present in a compound of the present invention, it is intended that all forms of such isomers or isomers that include the enantiomers and diastereomers are hereby encompassed. The compounds containing a chiral center can be used as a racemic mixture or as an enantiomerically enriched mixture, or the racemic mixture can be separated using well-known techniques and a single enantiomer can be used alone. In cases where there may be compounds in tautomeric form, such as the keto-enol tautomers, each tautomeric form is contemplated as being included within this invention either existing in equilibrium or predominantly in one form. In the present description, unless otherwise indicated, with the term alkyl of 1 to 6 straight or branched carbon atoms, it is intended that any group such as, for example, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, secbutyl, tertbutyl, n-pentyl, n-hexyl and the like. By the term straight or branched alkenyl or alkynyl of 2 to 6 carbon atoms is meant any unsaturated alkenyl or alkynyl group having 2 to 6 carbon atoms, for example those including vinyl, allyl, 1-propenyl, isopropenyl, -, 2- or 3-butenyl, pentenyl, hexenyl, ethynyl, 1- or 2-propynyl, butynyl, pentynyl, hexynyl and the like. The term cycloalkyl of 3 to 6 carbon atoms is intended to mean a 3-6 membered carbocyclic ring, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless otherwise specified, the term "aryl" is intended to mean a monocyclic or bicyclic, either a carbocycle or a heterocycle with one or two ring portions either fused or linked together by single bonds, wherein minus one of the carbocyclic or heterocyclic rings is automatic; but it also includes 1 or 2 ring portions, where all of the rings are aromatic. Unless otherwise specified, the heterocycle is a 4 to 7 membered ring with 1 to 3 ring heteroatoms or heteroatom groups which are selected from N, NH, O, and S. Non-limiting examples of aryl groups of the invention are, for example, phenyl, indanyl, biphenyl, V- or 3-naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, imidazopyridyl, 1,2-methylenedioxyphenyl, thiazolyl, isothiazolyl, pyrrolyl, pyrrolyl-phenyl , furyl, phenyl-furyl, benzotetrahydrofu-ranyl, oxazolyl, isoxazolyl, pyrazolyl, chromenyl, thienyl, benzothienyl, isoindo-linyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzofuranyl, 1,2,3-triazolyl, 1-phenyl-1 , 2,3-triazolyl and the like.
By the term heterocycle (for example heterocyclyl) or heterocyclic group is meant a 4- to 7-membered heterocycle and which therefore encompasses aromatic heterocyclic groups also known as heteroaryl groups and currently encompassed by the term aryl. As the heterocycles are saturated or partially unsaturated with 1 to 3 ring heteroatoms or heteroatom groups selected from N, NH, O and S. Examples of 4 to 7 membered heterocyclic groups are, for example, 1, 3 - dioxolane, pyran, pyrrolidine, pyrroline, imidazoline, imidazoli-dine, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran, hexamethyleneimine, 1,4-hexahydrodiazepine, azetidine and the like. When reference is made to the compounds of formula (I), wherein R is a group -CONRaRb and / or RT is a group -NRcRd and Ra and Rb and / or Rc and Rd are taken together with the nitrogen atom to which they are attached, they can also form an optionally substituted 4- to 7-membered heterocycle containing an additional ring heteroatom or a heteroatom group of S, O, N or NH. According to the meanings provided for Ra, Rb, Rc, Rd and 2, any of the above groups may optionally be additionally substituted in any of their free positions by one or more groups, for example 1 to 6 groups that are selected from: halogen, nitro, oxo groups (= 0), carboxy, cyano, alkyl, perfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl; aril; heterocyclyl, amino groups and derivatives thereof such as, for example, alkylamino, dialkylamino, arylamino, diarylamino, ureido, alkylureido or alkylureido; carbonylamino groups and derivatives thereof such as, for example, formylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, hydroxy groups and derivatives thereof, such as, for example, alkoxy, polyfluorinated alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkynyloxy or alkylidenaminoxy; carbonyl groups and derivatives thereof, such as, for example, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl; sulphurized derivatives such as, for example, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, arylsulfonyloxy, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl. In turn, where appropriate, each of the above substituents may be further substituted by one or more of the groups mentioned above. In the present description, unless otherwise specified, the term "halogen atom" is intended to mean a fluorine, chlorine, bromine or iodine atom. By the term alkyl or polyfluorinated alkoxy, it is intended to mean an alkyl or alkoxy group of 1 to 6 carbon atoms straight or branched as defined above, wherein more than one hydrogen atom is substituted by fluorine atoms such as, for example, trifluoromethyl, trifluoromethoxy. 2,2,2-trifluoroethyl, 2,2,2-trifluoroethoxy, 1,2-difiuoroethyl, 1,1,1,3,3-hexafluoropropyl-2-yl and the like. From all of the foregoing, it is evident to a person skilled in the art that any group whose name has been identified as a compound name such as, for example, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, alkoxy, alkylthio, aryloxy, arylalkyloxy, alkylcarbonyloxy and the like, it needs to be designed as conventionally constructed from the parts from which it is derived. Heretofore, as an example, the terms heterocyclylalkyl and cycloalkylalkyl indicate a linear or branched alkyl group that is optionally substituted by a heterocyclic or cycloalkyl group, respectively, as defined above. The term "pharmaceutically acceptable salts" encompasses salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical to the extent that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are acids: hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric and phosphoric. Suitable organic acids can be selected from the classes of organic acids aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carbocyclic and sulphonic. Examples of which are: formic, acetic, trifluoroacetic, propionic, succinic, glycolic, gluconic, lactic, mellic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic , p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethane-suonic, sulphanilic, stearic, cyclohexylaminosulfonic, algenic, hydroxybutyric, galactolic and galacturonic. Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N.N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts can be prepared by conventional means from the corresponding compounds of the present invention, for example by reacting them with the appropriate acid or base. A first class of preferred compounds of the present invention is represented by the derivatives of formula (I) wherein i is a group -NRcRd and Rc and Rd are both hydrogen atoms or one of them is a hydrogen atom and the remainder of R ° or Rd is a linear or branched alkyl or alkenyl group or is an optionally substituted aryl or arylalkyl group; and R and R2 are as defined in the above. Another class of preferred compounds of the invention is represented by the derivatives of formula (I) wherein R is either a group Ra with Ra as a hydrogen atom or a group -S02Ra wherein Ra is a linear or branched alkyl or aryl optionally substituted or an arylalkyl group; and Ri and R2 are as defined in the above. Another class of preferred compounds of the invention is represented by the derivatives of formula (I) wherein R is a -CORa group wherein Ra is linear or branched alkyl, cycloaikyl or an optionally substituted aryl or arylalkyl group; and Ri and R2 are as defined in the above. Another class of preferred compounds of the invention is represented by the derivatives of formula (I) wherein R is a group: -CONRaRb wherein one of Ra and Rb is a hydrogen atom and the other of Ra and Rb is an alkyl group linear or branched, an optionally substituted aryl or arylalkyl group; and Ri and R2 are as defined in the above. Another class of preferred compounds of the invention is represented by the derivatives of formula (I) wherein R is a group: -CONRaRb and wherein Ra and Rb form, together with the nitrogen atom to which they are attached, a heterocyclic ring of 6 members optionally substituted; and R-i and R2 are as defined in the foregoing. Another class of preferred compounds of the invention is represented by the derivatives of formula (I) wherein R2 is a linear or branched alkyl or alkenyl group or is a cycloalicyn, cycloalkylalkyl or an optionally substituted aryl or arylalkyl group; and R and R-i are as defined in the foregoing.
Preferably, within the above classes, R, Ri and R2 are each independently selected in accordance with the meanings indicated in Tables I, II and III of the experimental section. For a reference to any specific compound of formula (I) of the invention, optionally in the form of pharmaceutically acceptable salts, see the experimental section. As stated in the above, a further objective of the present invention is a process for preparing the compounds of formula (I). Therefore, the compounds of formula (I) and pharmaceutically acceptable salts thereof can be obtained by a process comprising: a) reacting an alkaline salt derivative of formylsuccinonitrile following
wherein Alk + indicates Na + or K +, with a suitable amine of formula (II) R2-NH2, (II) wherein R2 is as defined above, under basic conditions, so that the compound of formula (III) is obtained ) b) reacting the compound of formula (III) with a base so that a pyrrole derivative of formula (IV) is obtained
c) reacting the compound of formula (IV) with sodium nitromalonaldehyde so that the compound of formula (V) is obtained
d) reacting the compound of formula (V) under acidic conditions and in the presence of a suitable alcohol of formula (VI) R'-OH (VI) wherein R 'is a linear or branched lower alkyl group so that the compound of formula (VII)
(VII) e) reacting the compound of formula (VII) with tin chloride (11) so that a compound of formula (I) is obtained
wherein R2 and R 'are as defined in the foregoing and, optionally, reacting it according to any of the alternative steps (f.1), (f.2), (f.3) or (f.4) f.1) with any of the compounds of formula (VIII), (IX),
(X) or (XI) RaCOZ (VIII); RaNCO (IX); RaS02Z (X); RaOCOZ (XI) wherein Ra is as defined in the above and Z is a halogen atom, so that the compound of formula (I) is obtained
wherein R 'is as defined in the above and R is a group -CORa, -C0NHR3, -S02Ra or -C00R3; respectively; or f.2) with a suitable amine of formula (Xll) in the presence of triphosgene or a suitable chloroformate HNRaRb (Xll) so as to obtain the above compound of formula (I) wherein R is a group -CONRaRb; or f.3) with a suitable aldehyde or ketone derivative of formula (XIII) under reductive operating conditions Ra-CO-Ra (XIII) wherein each Ra is the same or different as defined above, so that the compound is obtained above of formula (I) wherein R is a group -CH (Ra) Ra; or f.4) with an iodo or aromatic bromine of formula (XIV) Ra-X (XIV) wherein X represents an iodine or bromine atom and Ra represents a carbocyclic or heterocyclic aryl group, in the presence of a suitable palladium catalyst and of a ligand, so that a compound of formula (I) is obtained, wherein R is Ra and the latter has the meanings indicated above; and optionally g) converting the compound of formula (I) that has been obtained with any of steps (e), (f.1), (f.2), (f.3) or (f.4) into another compound of formula (I) and / or in a pharmaceutically acceptable salt thereof. The above procedure is an analogy procedure which can be carried out according to well-known methods. According to step (a) of the process, the alkali salt of formiisuccinonitrile is reacted with a suitable amine of formula (II) wherein R2 is as defined in formula (I), so that the corresponding compound is obtained of formula (III). Preferably, the reaction occurs when starting from a potassium salt of formysuccinonitrile. The reaction is carried out under basic conditions, for example in the presence of sodium methylate, sodium ethylate, sodium hydride, potassium terbutoxide and the like, in a suitable solvent such as toluene or tetrahydrofuran, at a temperature ranging from ambient temperature to reflux. For a general reference to the operating conditions that lead to the preparation of the compound of formula (III), see, for example, J.C.S. Perkin Trans. I: Organic and Bio-Organic Chemistry (1972-1999), (1975), (19), 1910-13; Synthetic Communication, 24 (19), 2697-2705 (1994); and Org. Proc. Res. Dev., 7 (2), 209-213, 2003. According to step (b) of the process, the compound of formula (III) is further reacted under basic conditions without the need for further isolation and purification. Preferably, the reaction is carried out with an alkaline hydroxide, for example an excess of sodium or potassium hydroxide, in a suitable solvent such as a lower alcohol, for example ethanol (for a general reference of the above reaction conditions, see , for example, the magazines mentioned before). According to step (c) of the process, the compound of formula (IV) is reacted with sodium nitromalonaldehyde so that formation of the azaindole bicyclic ring structure of formula (V) is obtained. The reaction is carried out in the presence of a suitable solvent, for example, a lower alcohol, under acidic conditions, for example in the presence of a mineral acid, preferably hydrochloric acid. By the term "lower alcohol" herein is meant any linear or branched alcohol with 1 to 4 carbon atoms; Preferably, the reaction is carried out in the presence of n-propanol. According to step (d) of the process, the compound of formula (V) is converted to the corresponding carboxy ester derivative of formula (VII) by working according to conventional techniques, i.e. in the presence of a lower alcohol suitable in formula (VI). Typically, by using a large excess of the same alcohol, it can serve as a reagent and also as a solvent medium. Preferably, the reaction is carried out with n-propanol so as to generate the compound of formula (VII) wherein R 'represents n-propyl. According to step (e) of the process, the nitro group of compound of formula (VII) is reduced to the corresponding amino derivative. The reduction is preferably carried out in the presence of tin chloride (II) in N-methylpyrrolidone (NMP) according to well-known methods. Clearly, any of the various methods known in the art for reducing nitro groups to amino groups, for example comprising catalytic hydrogenation, can also be used successfully. From the foregoing, it is evident to a person skilled in the art that the above reaction of step (e) allows obtaining a compound of formula (I) wherein R is a hydrogen atom, Ri is a group -ORc in where R c is the alkyl group, R 'is introduced through step (d) of the process, for example n-propyl and R 2 is as stated in formula (I). The compound of formula (I) obtained in this way can then be converted into a variety of derivatives of formula (I) by working as described in any of the steps from (f.1) to (f.4) of the process, according to well-known methods. Typically, the compound of formula (I) of step (e) has an amino group in the 5-position can be reacted; with a compound of formula (VIII) so as to obtain the corresponding carboxyamido derivative wherein R is -CORa wherein Ra is as defined above; with a compound of formula (IX) such that the corresponding ureido derivative is obtained wherein R is -CONHR3 and Ra is as defined above; with a compound of formula (X) such that a sulfonamido derivative is obtained wherein R is -S02Ra wherein Ra is as defined above; with a compound of formula (XI) such that a carbamate derivative is obtained wherein R is -C00R3 and Ra is as defined above; with a compound of formula (Xll) and triphosgene or a suitable chloroformate so that a ureido derivative is obtained wherein R is -CONRaRb and Ra and Rb are as defined above; with a compound of formula (XIII) under reductive operating conditions so that a derivative is obtained in which R is -CH (Ra) Ra and each Ra, same or different and independently from each other, are as defined in the above .
Any of the above reactions is carried out according to conventional methods normally used in the preparation of functionalized amino derivatives from the corresponding amine. Within the compounds of formulas (VIII), (X) or (XI) of step (f.1), Z represents a halogen atom and even more preferably a chlorine atom. In this regard, the compound of formula (I) of step (e) is dissolved in a suitable solvent such as dichloromethane, dimethylformamide, tetrahydrofuran, dioxane or the like and a suitable base such as triethylamine, diisopropylethylamine or sodium carbonate is added to the same. The compound of general formula (VIII), (X) or (XI) is then added and the mixture is stirred for a time from about 2 hours to about 15 hours, at a temperature ranging from about 20 ° C to about 80 °. C. When an isocyanate of general formula (IX) is used, the reaction conditions are the same as those reported in the above except that it may not be required in the base. In all of these reactions, a suitable catalyst such as dimethylaminopyridine can optionally be used. According to step (f.2) of the process, the compound of formula (I) obtained in step (e) can be reacted with an amino derivative of formula (Xll) in the presence of a triphosgene or a chloroformate. such as, for example, 4-nitrophenyl chloroformate.
The reaction is carried out in a suitable solvent such as a halogenated hydrocarbon, preferably dichloromethane, in the presence of a base such as, for example, diisopropylethylamine or triethylamine and by working at room temperature. According to step (f.3) of the process, the compound of formula (I) of step (e) is reacted under reductive conditions with an aldehyde or ketone derivative of formula (XIII) so as to obtain the corresponding compound of formula (I) wherein R is as defined in the foregoing. From the foregoing, it is evident that for a person skilled in the art that by using an aldehyde derivative of formula (XIII) wherein one of the two Ra is a hydrogen atom, the corresponding derivative can be obtained wherein R is -CH2Ra. Similarly, by using a ketone derivative, compounds having R as -CH (Ra) Ra can be obtained wherein each Ra is, independently of each other, as stated in the above but different from hydrogen. According to step (f.4) of the process, the compound of formula (I) of step (e) is converted to the corresponding aryl derivative of formula (I) wherein R is Ra and Ra is an aryl group, and therefore, encompasses carbocyclic or heterocyclic aromatic groups. The reaction is carried out according to known methods, with any iodide or aryl bromide of formula (XIV), in the presence of a suitable catalyst, for example, a palladium catalyst such as palladium acetate or Pd2 (dba) 3, and of a suitable ligand. See for a general reference to the above arylation reaction and operating conditions thereof also including solvents, catalysts and ligands, J. Am. Chem. Soo, (2003), 125, 6653-55; JOC (2001), 66, 2560-2565; and JOC (2002), 67, 6479-6486. In addition to the foregoing, it is also evident to a person skilled in the art that, whenever desired, any of the above compounds of formula (I) prepared in this manner can be further converted to other derivatives of formula (I), as is established in step (g) by treatment according to conventional methods. As an example, the compounds of formula (I)
wherein R and R2 are as stated in the above and R 'represent a given alkyl group, for example n-propyl, can be converted to the compounds of formula (I):
(0 h) wherein R and R2 are as defined in the above and Ri is -ORc, wherein Rc is different from n-propyl, through transesterification reactions that are carried out according to well-known methods, for example with a suitable compound of formula (XV) -Rc-OH (XV) under acidic or basic conditions, optionally in the presence of a suitable metal-based catalyst, such as dibutyltin oxide or titanium alkoxides, such as, for example, titanium (IV) ethoxide, titanium (IV) isopropoxide; i) wherein R and R2 are as defined above and R-i is an -OH group, by acid or basic hydrolysis. As a further example, the compounds of formula (I), wherein R and R2 are as defined above and Ri is an -ORc group wherein Rc is an alkyl group which can also be converted into the corresponding amido derivatives of formula (I) j) wherein R-, is -NRQRd, wherein Rc and Rd are as defined above, by treatment with ammonia or with an appropriate amine of formula (XVI) or (XVII) RC-NH2 (XVI); RcRdNH (XVII) optionally in the presence of suitable catalysts such as, for example, sodium cyanide or dimethylaminopyridine. Likewise, the compounds of formula (I), wherein R and R2 are as defined above and Ri is a group -ORc wherein Rc is hydrogen, can also be converted into the corresponding amido derivatives of formula (I ) by reaction with any suitable amine HNRcRd in the presence of a suitable condensing agent, for example dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3'-dimethylaminopropy) carbodiimide (EDC), O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU) or benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP). In addition to the above, the compounds of formula (I), wherein R2 is an aryl group (eg, phenyl, pyridyl, optionally substituted phenyl, and the like) or a hydrocarbon chain wherein the first carbon atom is attached directly to the Nitrogen atom pyrrole is a primary or secondary carbon atom having the formula -CH2- (for example benzyl, ethyl, n-propyl and the like) or -CH < (for example diphenylmethyl, isopropyl and the like) can also be prepared according to an alternative synthesis route. Said route comprises, in particular, a different approach for the preparation of the intermediate compound of formula (Vil) of step (d). Therefore, a further object of the invention is a process for preparing the latter compounds of formula (I) having R2 as an aryl group or a hydrocarbon chain, wherein the first carbon atom is directly attached to the nitrogen atom pyrrole which is a primary or secondary carbon atom and pharmaceutically acceptable salts thereof, which process comprises: k) reacting the methyl ester of 1- (phenylsulfonyl) -1 H -pyrrolo [2,3-b] pyridine-3-carboxylic acid with tetrabutylammonium nitrate (TBAN) in the presence of trifluoroacetic anhydride (TFAA), so that a compound of formula (XVIII) is obtained
(XVIII) I) reacting the compound of formula (XVIII) under conditions of basic or acid hydrolysis so that a compound of formula (XIX) or a salt thereof is obtained
m) reacting the compound of formula (XIX) with a carboxy protecting agent, for example an esterifying agent, so that a compound of formula (XX) is obtained
wherein R 'denotes alkyl, for example methyl;
n) reacting the compound of formula (XX) with a compound of formula (XXI) R2-Z "(XXI) wherein R2 is an aryl group or a hydrocarbon chain having the first carbon atom directly attached to Z ' as a primary or secondary carbon atom, and Z 'is a halogen atom or any suitable leaving group such as tosyl or mesyl, so that a compound of formula (VII) is obtained
wherein R2 and R1 are as defined in the above; and after reacting the above compound of formula (VII) according to the remaining steps of the process, from (e) to (g). Furthermore, the above procedure is an analogous procedure which can be carried out according to well-known methods. In particular, according to step (k) of the process, the nitration of 1- (phenylsulfonyl) -1H-pyrroic [2,3-b] pyridine-3-carboxylic acid methyl ester to provide the compound of formula (XVIII) is carried out with tetrabutylammonium nitrate (TBAN) in the presence of trifluoroacetic anhydride (TFAA). The reaction is carried out in a suitable solvent, for example a halogenated hydrocarbon such as dichloromethane, by treatment at a temperature ranging from 0 ° C to room temperature and for a time ranging from about 10 hours to about 30 hours. According to step (I) of the process, the compound of formula (XVIII) can undergo hydrolysis under basic or acidic conditions. Preferably, the reaction is carried out in the presence of aqueous sodium hydroxide and 2,2,2-trifluoroethanol (TFE) at a temperature ranging from room temperature to about 20 ° C and for a time from 4 hours to a day. According to the operating conditions that are used, the compound of formula (XVIII) can be obtained either in its acid form or, alternatively, as a salt. Preferably, the hydrolysis reaction is carried out under basic conditions, for example in the presence of sodium hydroxide, so that the corresponding sodium salt is obtained. According to step (m) of the process, the compound of formula (XIX) can be esterified according to well-known operating conditions in the presence of suitable alcohols. As an example, this reaction can be carried out in the presence of methanol so as to obtain the corresponding carboxymethylester derivative of formula (XX) wherein R 'denotes methyl. Alternatively, the compound of formula (XX) of step (m) wherein R 'denotes methyl can also be prepared through direct hydrolysis of the compound of formula (XVIII) according to known methods, for example in the presence of potassium tetramethylsilanolate in tetrahydrofuran (THF) or triethylamine (TEA) in methanol. Finally, according to step (n) of the process, the compound of formula (XX) is converted to the compound of formula (VII) by reaction with a suitable compound of formula (XXI) wherein R2 and Z 'have the meanings indicated in the above. The reaction can be carried out in the presence of a suitable base such as, for example, potassium carbonate, sodium hydride, potassium terbutoxide, potassium hexamethyldicilazide (KHMDS), lithium hexamethyldicilazide (LHMDS), sodium hexamethyldicilazide (NHMDS) ), lithium diisopropylamide (LDA) or terbuylimino (pyrrolidino) phosphorane (BTPP) in a suitable solvent such as tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, dimethylacetamide and the like. According to a preferred embodiment, the reaction is carried out with BTPP in dichloromethane. Alternative methods are also known in the art for alkylating the pyrrole nitrogen atom of the pyrrolopyridine cycles, for example from methylidene-activated portions (= CH2) as reported in US Pat.
Perkin 1, (19), 3317-3324, 2000; or Tetrahedron: Asymmetry, 11 (23), 4719-4724, 2000. From all of the foregoing, it is evident to a person skilled in the art that if a compound of the formula (I), prepared from a mixture of isomers, is obtained, In accordance with the above comprehensive process of or with any variant thereof, the separation into single isomers of formula (I), carried out according to conventional techniques, is still within the scope of the present invention. Likewise, the conversion of a compound of formula (I) into a pharmaceutically acceptable salt thereof, or alternatively, the conversion to the free compound (I) of a corresponding salt, according to procedures well known in the art, still it is within the scope of the invention. When the compounds of formula (I) are prepared, according to any variant of the process, all of which are considered to be within the scope of the invention, optional functional groups within the starting materials, the reactants or the intermediates thereof and which give rise to unwanted secondary reactions, need to be adequately protected according to conventional techniques. Likewise, the conversion of the latter into free deprotected compounds can be carried out according to known procedures. The starting materials of the process object of the present invention, which encompass any possible variant as well as any reagent thereof, are known compounds and, if not commercially available by themselves, can be prepared according to well-known methods.
As an example, the alkali salt derivative of formysuccinonitrile can be prepared as described in the references mentioned above (see step (a)), by reacting commercially available butanedinitrile, with ethyl formate under basic conditions. Once obtained, the salt obtained from formysuccinonitrile can be separated from the reaction mixture and then reacted with the amine of formula (II) or, alternatively, it can be reacted directly with the amine of formula (II) in situ , without the need for isolation, as in step (a) of the process In addition, the compound l- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester can be prepared as described in Tetrahedron Letters 40 (1999), 5853-5854. Likewise, the compounds of formula (II), (VI), from (VIII) to (XVII) and (XXI) are known or can be obtained with ease, according to known methods. or intermediary of formula (XIX) of the process is novel, and therefore represents a further objective of the invention. In addition to the above, the compounds of formula (I) can advantageously be prepared according to conbinational chemistry techniques well known in the art by carrying out the aforementioned reactions between the intermediates in a sequential manner and by working under synthesis conditions. in solid phase (SPS).
As an example, the carboxy ester intermediate derivatives of formula (VII) which are obtained in steps (d) or (n) of the above processes can first be converted to the free carboxy acid derivatives by means of hydrolysis carried out in accordance with with conventional methods, it is then easily supported on a polymeric resin, for example by the formation of a carboxamide group. The intermediary supported in this way can subsequently be reacted according to the remaining steps of the process. The above synthesis route can be summarized as follows:
Alternatively, the intermediate compound of formula
(XIX) of step (I) can first be supported on a polymeric resin and then reacted as in the remaining steps of the process, for example by inserting the portion R2 in portion 1 of the azaindole, by reducing the nitro group in the 5-amino position, by functionalization of the amino group itself and separation of the resin so that the desired compounds of formula (I) are obtained. Any of the above reactions is carried out according to known methods, by working as previously reported, to obtain compounds of formula (I) wherein R2 is an aryl group or a hydrocarbon chain having a first carbon atom attached to the nitrogen atom pyrrole as the primary or secondary carbon atom, as stated in the above. This last route of synthesis can be summarized as follows:
Preferably, the above resin is a commercially available polystyrene resin including, for example, Wang resin, Trityl resin, Cl-trityl resin, Rink amide resin, Tentagel OH resin and derivatives thereof. According to a preferred embodiment of the invention, the polystyrene resin is a derivatized formyl polystyrene resin which can be obtained by reacting a commercially available formyl polystyrene resin, for example the resin 4- (4-formyl-3-methoxyphenoxy) butyryl AM,
with a suitable amino derivative under reducing conditions, for example in the presence of sodium borohydride and derivatives thereof, substantially as follows:
NaBH (OAc) 3 (P) -CHO + R-NH2 ^ (p) _CH2_NHR
The reaction can be carried out in a suitable solvent such as dichloromethane and in the presence of acetic acid.
Amino-supported polymer derivatives obtained in this manner, particularly those which are referable as the above derivatized polystyrene-formyl resin, are well known in the art. In general, amides loaded on formyl polystyrene resins also known as methoxybenzaldehyde polystyrene resins sensitive to acid "AMEBA resins" are prepared by amination
standard reductive in the presence of an excess of amine in TMOF / DCE and
NaBH (OAc) 3 or AcOH / DMF and NaCNBH3, for example as reported in Tetrahedron Letters (1997), 38, 7151-7154; J. Am. Chem. Soc. (1998), 120, 5441; and Chem. Eur. J. (1999), 5, 2787. Therefore, a further objective of the present invention is to provide a process for preparing the compounds of formula (I) and
pharmaceutically acceptable salts thereof, which process
comprises: o) converting the compound of formula (VII) which is prepared according to step (d) or (n) of the above-mentioned process into the corresponding carboxy-acid derivative of formula (XXII)
wherein R2 is as stated in formula (I); p) reacting the compound of formula (XXII) with a derivatized formyl polystyrene resin of formula (XXIII) (P) -CH2-NHRC (XXIII) wherein (P) is the resin and Rc is as stated in the formula (I) ) so that a compound of formula (XXIV) is obtained
q) reacting the compound of formula (XXIV) according to step (e) and optionally with any of steps (f.1), (f.2), (f.3) or (f.4) of so that a compound of formula (XXV) is obtained
wherein (P), R2 and Rc are as stated in the above and R is as defined in formula (I); r) separating the resin of the compound of formula (XXV) under acidic conditions so that a compound of formula (I) is obtained wherein R and R2 are as defined in the above, and Ri is a group -NHRC, wherein Rc is as defined in the above; and optionally s) converting the compound thus obtained of formula (I) into another compound of formula (I) and / or pharmaceutically acceptable salts thereof. According to step (o) of the process, the carboxy ester derivative of formula (VII) is hydrolyzed to the corresponding carboxy acid by working according to known methods, for example under acidic or basic conditions. According to step (p) of the process, the reaction is carried out in a suitable solvent, for example NMP, in the presence of diisopropylethylamine (DIEA), dimethylaminopyridine (DMAP) and a suitable condensing agent such as, for example , 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or O-benzotriazolyl tetramethylisouronium tetrafluoroborate (TBTU). According to step (q), the supported compound of formula (XXIV) is first reduced as in step (e) of the process so that the amino derivative is obtained, and optionally further reacted as described above. indicates above, so as to give rise to a variety of compounds functionalized at the 5-position of the pyrrolo ring [2, 3-b] pyridine. The operating conditions are essentially those indicated above by treatment under homogeneous operating conditions. The separation of resin according to step (r) can be carried out under acidic conditions in the presence of suitable acids such as, for example, hydrochloric, trifluoroacetic, methanesulfonic or p-toluenesulfonic acids. Another object of the invention is also a process for preparing the compounds of formula (I) and pharmaceutically acceptable salts thereof, which process comprises: t) reacting the compound of formula (XIX) obtained in step ( I) with a derivatized formyl polystyrene resin of formula (XXIII) (P) -CH2-NHRC (XXIII) wherein (P) is the resin and Rc is as indicated in formula (I), so that a compound of formula (XXVI) u) reacting the compound of formula (XXVI) with a compound of formula (XXI) as described in step (n) so that a compound of formula (XXVII) is obtained
(XXVII)
v) reducing the compound of formula (XXVII) to the corresponding amino derivative of formula (XXVIII) as set forth in step (e)
(XXVIII)
and, optionally, converting it, according to any of steps (f.1), (f.2), (f.3) or (f.4) so as to obtain a compound of formula (XXV) wherein (P), R2 and Rc are as stated in the above and R is as defined in formula (I); w) separating the resin of the compound of formula (XXV) according to step (r) and optionally converting the compound obtained in this manner according to step (s). Clearly, by working in accordance with the techniques of combinational chemistry as indicated in the foregoing, a plurality of compounds of formula (I) can be obtained. Therefore, a further objective of the present invention is to provide a library of two or more compounds of formula (I)
wherein: R is selected from the group consisting of: -Ra, -COR3, -CONRaRb, -S02Ra or -COORa; Ri is a group -NRcRd or -ORc;
wherein R a, R b, R c and R d, each or different, are each independently hydrogen or an optionally substituted group, which is selected from linear or branched alkyl formulas of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl or arylalkyl of 1 to 6 carbon atoms, heterocycle or heterocycloalkyl of 1 to 6 carbon atoms or, taken together with the nitrogen atom to which they are attached, either Ra and Rb as well as Rc and Rd can form an optionally substituted 4 to 7 membered heterocycle, which optionally contains a additional heteroatom or a heteroatom group selected from S, NO NH; R2 is a group, optionally substituted additionally, which is selected from linear or branched forms of alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl or arylalkyl of 1 to 6 carbon atoms, heterocycle or heterocycloalkyl of 1 to 6 carbon atoms; or isomers, tautomers, carriers, metabolites, prodrugs and pharmaceutically acceptable salts thereof. According to a preferred embodiment of the invention, the library mentioned above comprises the compounds of formula (I), wherein Ri is a group -NRcRd and Rc and Rd are both hydrogen atoms or one of them is a hydrogen atom and the remaining one of Rc or Rd is a linear or branched alkyl or alkenyl group or is an optionally substituted aryl or arylalkyl group; and R and R2 are as defined in the above. Also preferred is a library of compounds of formula (I) wherein R is either a group Ra, wherein Ra is a hydrogen atom or a group -S02Ra, wherein Ra is a linear or branched alkyl group or an aryl group or optionally substituted arylalkyl; and Ri and R2 are as defined in the above. Also preferred is a library of compounds of formula (I) wherein R is a -CORa group, wherein Ra is the straight or branched form of an optionally substituted alkyl, cycloalkyl or aryl or arylalkyl group; and Ri and R2 are as defined in the above. Also preferred is a library of compounds of formula (I) wherein R is a group -CONRaRb wherein one of Ra and Rb is a hydrogen atom and the other of Ra and Rb is the straight or branched form of an alkyl group, aryl or optionally substituted arylalkyl; and Ri and R2 are as defined in the above. Also preferred is a library of compounds of formula (I) wherein R is a -CONRaRb group in which Ra and Rb form, together with the nitrogen atom to which they are attached, an optionally substituted 6-membered heterocyclic ring, and Ri and R2 are as defined in the above.
Also preferred is a library of compounds of formula (I) wherein R 2 is a straight or branched form of an alkyl or alkenyl group, or is a cycloalkyl, cycloalkylalkyl or an optionally substituted aryl or arylalkyl group; and Ry Ri are as defined in the above. For a general reference to the above libraries of the compounds of formulas (I) see the experimental section. From all of the foregoing, it is evident to a person skilled in the art that once the library of pyrrolo [2,3-b] pyridine derivatives has been prepared, for example consisting of a few thousand compounds of formula (I ), the library can be used very advantageously for a systematic detection towards given kinases, as has been previously reported. For a general reference to libraries of compounds and use thereof as tools for screening in biological activities see J. Med. Chem. 1999, 42, 2373-2382; and Bioorg, Med. Chem. Lett. 10 (2000), 223-226.
Pharmacology The compounds of formula (I) are active as inhibitors of protein kinase and are therefore useful, for example, in limiting the unregulated proliferation of tumor cells. In therapy, they are used in the treatment of various tumors such as those reported above, as well as in the treatment of other proliferative cell disorders such as psoriasis, vascular smooth cell proliferation associated with atherosclerosis and postsurgical stenosis and restenosis, and in the treatment of Alzheimer's disease. The inhibitory activity of the putative cdk / cyclin inhibitors and the potency of the selected compounds is determined by an assay method based on the use of SPA technology (Amersham Pharmacia Biotech). The assay consists in the transfer of a phosphate portion radioactively labeled by the kinase to a biotinylated substrate. The biotinylated product labeled with the resulting 33P is allowed to bind to SPA beads coated with streptavidin (biotin capacity, 130 pmol / mg) and the light emitted is measured in a scintillation counter.
Assay of inhibition of the activity of cdk2 / cyclin A
Kinase Reaction: Biotinylated in the laboratory, 10 μm ATP (0.1 μCi of P33? -ATP) is added to each well of a 96 well plate in the bottom in U 4 μM of histone H1 substrate (Sigma # H-5505) 1.1 nM cyclin A / CDK2 complex, inhibitor in a final volume of 30 μl of buffer (10 mM TRIS HCl, pH 7.5, 10 mM MgCl 2, 10 mM DTT 7.5 mM + 0.2 mg / ml BSA). After incubation for 60 min at room temperature the reaction is stopped by the addition of 100 μl of PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X-100 and 10 mg / ml of SPA spheres coated with streptavidin. After 20 min incubation, 110 μl of suspension is removed and transferred to a 96-well OPTIPLETE containing 100 μl of 5M CsCI. After 4 hours, the plates are read for 2 min in a Packard TOP-Count radioactivity reader. Determination of IC50: Inhibitors were tested at different concentrations ranging from 0.0015 to 10 μM. The experimental data is analyzed by the GraphPad Prizm computer program using the four parameter logistic equation: y = lower + (upper-lower) / (1 +10 ((log CI5o-X) * slope)) where x is the logarithm of the inhibitor concentration, and it is the response; and starts at the bottom and moves towards the top with a sigmoid shape.
Calculation of Ki:
Experimental method: The reaction is carried out in buffer (10 mM Tris, pH 7.5,
mM MgCl 2, 0.2 mg / ml BSA, 7.5 mM DTT) containing enzyme 3.7 nM, histone and ATP (constant ratio of cold ATP / labeled 1/3000). The reaction is stopped with EDTA and the substrate is retained in a phosphomembrane
(96-well Multiscreen plates from Millipore). After extensive washing, the multiscreen plates are read on a top counter. The control (time zero) is measured for each concentration of ATP and histone.
Experimental design: The reaction rates are measured at four concentrations of ATP, substrate (histone) and inhibitor. A concentration matrix of 80 points is designed around the respective values of ATP and Km
of substrate, and Cl50 values of inhibitor (0.3, 1, 3, 9 times the Km or
Cl50). A preliminary experiment of time course in the absence of inhibitor and at different concentrations of ATP and substrate allows the selection of a single endpoint time (10 min) in the linear range of the reaction for the Ki determination experiment.
Kinetic parameter calculations: Kinetic parameters are calculated by simultaneous non-linear least squares regression using [equation 1] (competitive inhibitor)
with respect to ATP, random mechanism) using the complete data set (80 points):
Y - . _ V im * Á, 'B, - Ka B cc * Ka * Kb -a * Ka B + a * Kb »A- ¥ A * B + a - t» I * (Kb + -) [Equation 1] Where A = ATP concentration, B = substrate concentration, I = inhibitor concentration, Vm = maximum velocity, Ka, Kb, Ki ATP dissociation constants, substrate and inhibitor, respectively. The symbols a and ß are the factor of cooperativity between the substrate and the ATP binding and between the substrate and the inhibitor binding, respectively. In addition, the selected compounds are characterized in a panel of ser / thre kinases strictly related to the cell cycle (cdk2 / cyclin E, cdkl / cyclin B1, cdk5 / p25, cdk4 / cyclin D1) and also to specify in MAPK, PKA, EGFR, IGF1-R, Aurora-2 and Cdc 7.
Assay of inhibition of the activity of cdk2 / cyclin E
Kinase reaction: 10 μM of histone H substrate (Sigma # H-5505) biotinylated in the laboratory, ATP 30 μm (0.3 μCi of P33? -ATP) are added to each well of a 96-well bottom plate. , 4 ng of complex GST-cyclin E / CDK2 1.1 nM, inhibitor in a final volume of 30 μl of buffer (10 mM TRIS HCl, pH 7.5, 10 mM MgCl 2, 7.5 mM DTT + 0.2 mg / ml BSA). After incubation for 60 min at room temperature the reaction is stopped by the addition of 100 μl of PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X-100 and 10 mg / ml of SPA spheres coated with streptavidin. After 20 min of incubation, 110 μl of suspension is extracted and transferred to OPTIPLATE of 96 wells containing 100 μl of 5M CsCl. After 4 hours, the plates are read for 2 min in a Packard TOP-Count radioactivity reader.
Clgn determination: see above
Inhibition assay of cdkl / cyclin B1 activity
Kinase Reaction: Two wells of a 96 well plate in the bottom are added to U, 4 μM of histone H1 substrate (Sigma # H-5505) biotinylated in the laboratory, 20 μm ATP (0.2 μCi of P33? -ATP) , 3 ng of cyclin B / CDK1 complex, inhibitor in a final volume of 30 μl of buffer (10 mM TRIS HCl, pH 7.5, 10 mM MgCl 2, 7.5 mM DTT + 0.2 mg / ml BSA). After 20 min of incubation at room temperature the reaction is stopped by the addition of 100 μl of PBS + 32 mM EDTA + 0.1% Triton X-100 + 500 μM ATP containing 1 mg of SPA spheres. Then a volume of 100 μl is transferred to Optiplate. After incubation for 20 min for substrate retention, 100 μl of 5 M CsCl is added to allow stratification of the spheres in the upper part of the Optiplate and allowed to stand 4 hours before the radioactivity count in a Top-Count instrument.
Clgn determination: see above
Cdk5 / p25 activity inhibition assay The cdk5 / p25 activity inhibition assay is performed according to the following protocol.
Kinase Reaction: To each well of a 96-well plate in the bottom are added U-labeled histone H1 (Sigma # H-5505) 10 μM, ATP 30 μm (0.3 μCi of P33? -ATP), 15 ng of CDK5 / P25 complex, inhibitor in a final volume of 30 μl of buffer (10 mM TRIS HCl, pH 7.5, 10 mM MgCl 2, 7.5 mM DTT + 0.2 mg / ml BSA). After 20 min of incubation at room temperature, the reaction is stopped by the addition of 100 μl of PBS buffer containing 32 mM EDTA., Cold ATP 500 μM, Triton X-100 0.1% and SPA spheres coated with 10 mg / ml streptavidin. After 20 min of incubation, 110 μl of suspension is extracted and transferred to OPTIPLATE 96 wells containing 100 μl of 5 M CsCl. After 4 hours the plates are read for 2 minutes in a Packard Top-Count radioactivity reader.
Clgo determination: see above
Assay of inhibition of the activity of cdk4 / cyclin D1
Kinase reaction: 0.4 μM mouse, 10 μm ATP (0.5 μCi of P33) are added to each well of a 96-well plate in the U-substrate GST-Rb (769-921) (# sc-4112 de Santa Cruz). ? -ATP), 100 ng of GST-CDK4 / GST-cyclin D1, expressed in baculovirus, suitable concentrations of inhibitor in a final volume of 50 μl of buffer (10 mM TRIS HCl, pH 7.5, 10 mM MgCl2, 7.5 mM DTT + 0.2 mg / ml BSA). After 40 min at 37 ° C incubation, the reaction is stopped by the addition of 20 μl of 120 mM EDTA.
Retention: 60 μl of each well is transferred to the MultiScreen plate to allow attachment of the substrate to the phosphocellulose filter. The plates are then washed 3 times with 150 μl / well of PBS, free of Ca ++ / Mg ++ and filtered through the MutiScreen filtration system.
Detection: The filters are allowed to dry at 37 ° C, then 100 μl / well of scintillation liquid is added and the Rb-labeled Rb fragment is detected by radioactivity counting in the Top-Count instrument.
Determination of Clso: see the above
Assay of inhibition of MAPK activity
Kinase Reaction: 10 μM, biotinylated in the laboratory, 15 μM ATP (0.15 μCi of P33? -ATP), 30 are added to each well of a 96-well plate in the bottom on a substrate MBP (Sigma # M-1891). ng of GST-MAPK (Upstate Biotechnology # 14-173), inhibitor in a final volume of 30 μl of buffer (10 mM TRIS HCl, pH 7.5, 10 mM MgCl 2, 7.5 mM DTT + 0.2 mg / ml BSA). After incubation for 35 min at room temperature, the reaction is stopped by adding 100 μl of PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and SPA spheres coated with 10 mg / ml streptavidin. After 20 min of incubation, 110 μl of suspension is extracted and transferred in OPTIPLATE of 96 wells containing 100 μl of 5 M CsCl. After 4 hours the plates are read for 2 min in a Packard Top-Count radioactivity reader.
4
Determination of CIBQ: see above
Inhibition assay of PKA activity
Kinase Reaction: 10 μM ATP, 10 μM, biotinylated in the laboratory, 10 μM ATP (0.2 μCi of P33? -ATP) are added to each well of a 96-well plate in U-bottom substrate histone H1 (Sigma # H-5505) , 0.45 U of PKA (Sigma # 2645), inhibitor in a final volume of 30 μl of buffer (10 mM TRIS HCl, pH 7.5, 10 mM MgCl 2, 7.5 mM DTT + 0.2 mg / ml BSA). After incubation for 90 min at room temperature the reaction is stopped by adding 100 μl of PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and SPA spheres coated with 10 mg / ml streptavidin. After 20 min of incubation, 110 μl of suspension is extracted and transferred in OPTIPLATE of 96 wells containing 100 μl of CsCl 0.5M. After 4 hours the plates are read for 2 min in a Packard Top-Count radioactivity reader.
Clgn determination: see the above EGFR activity inhibition assay
Kinase Reaction: 10 μM, biotinylated in the laboratory, 2 μM ATP (0.04 μCi of P33? -ATP), 33 are added to each well of a 96-well plate in the bottom on a substrate MBP (Sigma # M-1891). ng of insect cells expressing GST-EGFR inhibitor in a total volume of 30 μl of buffer (Hepes, 50 mM, pH 7.5, 3 mM MgCl 2, 3 mM MnCl 2, 1 mM DTT, 3 μM NaV03 + 0.2 mg / ml BSA). After incubation for 20 min at room temperature, the reaction is stopped by the addition of 100 μl of PBS buffer containing
32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and SPA spheres coated with 10 mg / ml streptavidin. After 20 min of incubation, 110 μl of suspension is extracted and transferred in OPTIPLATE of 96 wells containing 100 μl of 5 M CsCl. After 4 hours the plates are read for 2 min in a Packard Top-Count radioactivity reader.
Clgn determination: see above
IGF1-R activity inhibition assay The IGF1-R activity inhibition assay is performed according to the following protocol.
Enzyme activation: IGF-1 R must be activated by autophosphorylation before starting the experiment. Just before the test, a concentrated enzyme solution (694 nM) is incubated for half an hour at 28 ° C in the presence of 100 μM ATP and then diluted to the working dilution in the indicated buffer. Kinase Reaction: 10 μM biotinylated peptide substrate (PRIMM), 0-20 μM inhibitor, 6 μM ATP, 1 μCi P33 β -ATP and GST-IGF1 are added to each well of a 96-well plate in a U-bottom. -R 6 nM (pre-incubated for 30 min at room temperature with cold 60 μM cold ATP) in a final volume of 30 μl of buffer (50 mM Hepes, pH 7.9, 3 mM MgCl 2, 1 mM DTT, 3 μM NaVo 3). After incubation for 35 min at room temperature, the reaction is stopped by adding 100 μl of PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and SPA spheres coated with 10 mg / ml streptavidin. After 20 min of incubation, 110 μl of suspension is extracted and transferred in OPTIPLATE of 96 wells containing 100 μl of 5 M CsCl. After 4 hours the plates are read for 2 min in a Packard Top-Count radioactivity reader.
Inhibition assay of Aurora-2 activity
Kinase reaction: Add to each well of a 96-well plate in U-bottom biotinylated peptide (4 repeat sequences of LRRWSLG) 8 μM, 10 μM ATP (0.5 μCi of P33? -ATP), Aurora inhibitor 2 7.5 ng in a final volume of 30 μl of buffer (Hepes, 50 mM, pH 7.0, 10 mM MgCl 2, 1 mM DTT, 0.2 mg / ml BSA and 3 μM orthovanadate). After 60 minutes of incubation at room temperature the reaction is stopped and the biotinylated peptide is retained by adding 100 μl of slurry suspension.
Stratification: 100 μl of 5 M CsCI2 is added to each well and allowed to stand 4 hours before the radioactivity count is performed on the Top-Count instrument.
Determination of CI5o "- see above
Inhibition assay of Cdc7 / dbf4 activity The inhibition assay of Cdc7 / dbf4 activity is carried out according to the following protocol.
The biotin-MCM2 substrate is transphosphorylated by the Cdc7 / dbf4 complex in the presence of ATP labeled with? 33-ATP. The substrate of phosphorylated biotin-MCM2 is then retained by spheres of SPA coated with streptavidin and the degree of phosphorylation is evaluated by β-counting. The Cdc7 / dbf4 activity inhibition assay is performed in 96-well plates, according to the following protocol. To each well of the plate are added: - 10 μl of substrate (biotinylated MCM2, final concentration 6 μM) - 10 μl of enzyme (Cdc7 / dbf4, final concentration 17.9 nM) - 10 μl of test compound (12 increasing concentrations) in the range nM to μM to generate a dose-response curve) - 10 μl of a mixture of cold ATP (final concentration 2 μM) and radioactive ATP (molar ratio with cold ATP 1/5000) which is then used to start the reaction which is allowed to take place at 37 ° C. The substrate, the enzyme and the ATP are diluted in 50 mM HEPES, pH
7. 9, which contains 15 mM MgCl 2, 2 mM DTT, 3 μM NaV03, 2 mM glycerophosphate and 0.2 mg / ml BSA. The solvent for the test compounds also contains 10% DMSO. After incubation for 60 minutes, the reaction is stopped by adding to each well 100 μl of PBS, pH 7.4 containing 50 mM EDTA, 1 mM cold ATP, 0.1% Triton X100 and SPA spheres coated with 10 mg / ml streptavidin.
After 20 min of incubation, 110 μl of suspension is extracted and transferred to OPTIPLATE of 96 wells containing 100 μl of 5M CsCl. After 4 hours the plates are read for 2 min in a Packard Top-Count radioactivity reader.
Clgo Determination: see the above. The compounds of formula (I) of the present invention, suitable for administration to a mammal, for example to humans, are administered by the usual routes and the dosage level depends on the age, weight, conditions of the patient and route of administration. For example, a suitable dosage adopted for oral administration of a compound of formula (I) preferably ranges from about 10 to about 500 mg per dose, from 1 to 5 times daily. The compounds of the invention can be administered in a variety of dosage forms, for example orally, in the form of tablets, capsules, sugar or film-coated tablets, liquid solutions or suspensions.; rectally in the form of suppositories; parenterally, for example intramuscularly or by intravenous and / or intrathecal and / or intraspinal injection or infusion. In addition, the compounds of the invention can be administered either as single agents or, alternatively in combination with known anticancer treatments such as radiotherapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic type agents, alkylating agents, antimetabolites, hormonal agents, immunological agents, interferon-like agents, cyclooxygenase inhibitors (for example COX-2 inhibitors), metalomatrizprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, agents against growth factor receptor, agents against HER , agents against EGFR, antiangiogenesis agents, farnesiltrans-ferase inhibitors, ras-raf signal translation pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase inhibitors II and the like, optionally within formulation It is liposomal of them. If formulated as a fixed dose, such combination products use the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within the approved dosage range. The compounds of formula (I) can also be used sequentially with known anticancer agents when a combined formulation is inappropriate. The present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent).
The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and administered in a pharmaceutically suitable form. For example, solid oral forms may contain, together with the active compound, diluents such as, for example, lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disaggregation agents, for example a starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; colorants; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates and in general non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations can be prepared in a known manner, for example by means of mixing, granulating, tabletting or compression, sugar coating or a film coating process. Liquid dispersions for oral administration can also be, for example, syrups, emulsions and suspensions. The syrups may contain as carrier, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol.
The suspensions and emulsions may contain, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol, and if desired, a suitable amount of hydrochloride. of lidocaine. The solutions for intravenous injections or infusion may contain as carrier, for example, sterile water or they may preferably be made in the form of sterile aqueous isotonic saline solutions or they may contain propylene glycol as a carrier. The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty ester surfactant or lecithin. The following examples are included herein to better illustrate the present invention without presenting any limitation thereto. Experimental section General Methods Instant chromatography is performed on silica gel
(Merck grade 9395, 60A). The retention times of high pressure liquid chromatography (CLAP, t.r.) are determined by:
Method 1 (HPLC 1): Instruments: Hewlett Packard 1312A binary pump; Gilson 215 self-tailer coupled with a 1 ml syringe, Polymer Labs PL1000 evaporative light scattering detector (ELSD) and Micromass ZMD mass spectrometer operating in the positive ionization mode of electrospray. The eluent of the LC is divided and approximately 200 μl / min enters the mass spectrometer, 800 μl / min to the ELS. Chromatographic condition: the mobile phases of CLAP consist of 0.1% trifluoroacetic acid in CLAP grade water (A) or 1% trifluoroacetic acid in CLAP grade acetonitrile (B). The CLAP gradient is shown in the following table.
Travel time: 2.4 minutes Flow rate: 1 ml / min Injection volume: 3 μl Column temperature: ambient (20 ° C) Column: 50 s 2.0 mm Hypersil C18 BDS; 5 μm ELS detector: Nebulizer, Temperature 80 ° C Evaporation temperature, 90 ° C Gas flow 1.5 l / h MS detector: m / z 150-800 @ 0.5 seconds / scan, 0.1 second delay between exploration 25V cone voltage , source temperature 140 ° C Drying gas 350 l / h Retention times in ELSD (CLAP, tr) are given in minutes. The mass is given as a proportion m / z.
Method 2 (HPLC 2): Instruments: CLAP Waters 2790 system equipped with a 996 Waters PDA detector and a single quadrupole mass spectrometer Micromass mod. ZQ equipped with an electrospray ion source (ESI). Chromatographic condition: column RP18 Waters x Terra (4.6 x
50 mm, 3.5 μm); mobile phase A is 5 mM ammonium acetate buffer (pH 5.5 with acetic acid / acetonitrile 95: 5) and mobile phase B H20 / acetonitrile (5:95). The gradient of 10 to 90% of B in 8 minutes, retention of 90% of B 2 minutes. UV detection at 220 nm and 254 nm. Flow rate, 1 ml / min. injection volume 10 μl. Full scan, mass range from 100 to 800 urn. Hair voltages of 2.5 KV; source temperature is 120 ° C; the cone is 10 V. Retention times (CLAP, t.r.) are given in minutes at 220 nm or at 254 nm. The mass is given as m / z ratio.
When necessary, the compounds were purified by preparative CLAP on a Waters Symmetry C18 column (19 x 50 mm, 5 μm) using preparative Waters 600 CLAP equipped with a 996 Waters PDA detector and a Micromass mod single quadrupole mass spectrometer. ZQ, ionization of electron spray in the positive mode. Mobile phase A is water with 0.01% TFA and mobile phase B is acetonitrile. The gradient of 10 to 90% of B in 8 minutes, retention of 90% of B for 2 min. Flow rate of 20 ml / min. The H-NMR spectrometry is performed on a unique Bruker AVANCE 400MHz bay instrument with gradients. It is equipped with a QNP probe (interchangeable 4-core probe - 1H, 13C, 19F and 31P) (NMR method 1) or with a Mercury VX instrument operating at 400.45 MHz equipped with a 5 mm double resonance probe [1 H (15N-31P) ID_PFG Varian] (NMR method 2). As indicated above, various compounds of the formula (I) of the invention have been synthesized in parallel, according to the combinational chemistry techniques. In this regard, some compounds prepared in this way have been conveniently and unambiguously identified, for example by the coding system of frames IV through IX, together with the retention times of CLAP (methods 1 and 2) and the mass. Each code, which identifies a specific compound or one of formula (I) consists of four units A-M-B-C.
A represents any substituent R-r [see formula (I)] and is attached to the remainder of the azaindole moiety through the carbon atom of the carbonyl group so as to obtain azaindole derivatives which are substituted at the 3-position; each radical (substituent) A is represented in the following Table I. B represents any substituent R- [see formula (I)] and is attached to the remainder of the azaindole portion through the nitrogen atom of the group
NH so that azaindole derivatives are obtained which are substituted in the 5-position; each radical (substituent) B is represented in the following Table II. C represents any substituent R2- [see formula (I)] and is attached to the remainder of the azaindole moiety through an indole nitrogen atom so that azaindole derivatives are obtained which are substituted in the 1-position; each radical (substituent) C is represented in the following Table III. M refers to the central nucleus of the trivalent azaindole portion which is substituted at position 1 by groups C, at position 3 (through the carbonyl group) by groups A and at position 5 (through the group NH) by groups B, substantially as follows:
For ease of reference, each of the groups A, B or C in Tables I, II and III has been identified with the appropriate chemical formula that also indicates the point of attachment with the rest of the molecule M. Just as an example , compound A3-M-B5-C2 of Table IV (entry 1) represents an azaindol M which is substituted at position 5 by group B5 (through the NH group), at position 3 by group A3 (a through group CO) and in position 1 through group C2; likewise, compound A9-M-B9-C2 of table IX (entry 40) represents an azaindol M that is substituted at position 5 by group B9 (through the NH group), at position 3 by the group A9 (through group CO) and in position 1 through group C2, as follows:
A3-M-B5-C2
A9-M-B9-C2 TABLE I Groups A
TABLE II Groups B
TABLE III Groups C
EXAMPLE 1 Preparation of 1-tert-butyl-5-nitro-1 H-p.rrolor2,3-b1pipd_no-3-carbor..trilo
To a solution of 5.85 g (35.8 mmol) of 5-amino-1-terbutyl-1 H-pyrrolo-3-carbonitrile, which is prepared as described in Org. Proc. Res. Dev., 7 (2), 209-213, 2003, in 120 ml of n-propanol sodium nitromyalonaldehyde (6.02 g, 43.0 mmol) is added in portions under stirring at room temperature. The resulting mixture is treated dropwise with 37% hydrochloric acid (4.6 ml, 55.2 mmol) and heated at 100 ° C for 2 hours. The reaction mass is concentrated under vacuum to 1/3 of the initial volume and maintained at 4 ° C for 18 hours. The precipitate is filtered off, washed thoroughly with 35 ml of 15% aqueous ethanol and 5 ml of water and finally dried to provide 7.14 g of the title compound as a light brown solid. p.f. = 216-218 ° C Yield = 81.5% 1 H NMR (DMSO): 1.77 (s, 9H), 8.81 (s, 1 H), 8.90 (d, 1 H, J = 2.63 Hz), 9.26 (d, 1 H) , J = 2.63 Hz).
EXAMPLE 2 Preparation of the propyl ester of 1-terbutyl-5-nitro-1H-pyrrolor-2,3-blpyridin-3-carboxylic acid
To a suspension of 5.0 g (20.47 mmoles) of 1-tert-butyl-5-nitro-1 H-pyrrolo [2,3-b] pyridine-3-carbonitrol in 125 ml of n-propanol are added with stirring 7.78 g of acid p-toluenesulfonic. The mixture is refluxed for 40 hours and then cooled to room temperature and diluted with 70 ml of tert-butyl methyl ether. The precipitate is filtered off and the clear filtrate is concentrated under vacuum to a small volume (approximately 40-50 ml). The suspension is cooled to -5 / 0 ° C and maintained at this temperature for 2 hours. The solid is filtered, washed with 20 ml of a 1: 1 mixture of n-propanol and tert-butyl methyl ether and dried to give 5.50 g of the title compound as a cream colored solid. p.f. 116-120 ° C Yield = 88% 1 H NMR (DMSO): 1.00 (t, 3H), 1.70-1.80 (m, 2H), 1.80 (s, 9H),
4. 27 (t, 2H), 8.42 (s, 1H), 9.01 (d, 1H, J = 2.63 Hz), 9.22 (d, 1 H, J = 2.63 Hz).
EXAMPLE 3 Preparation of 1-tert-butyl-5-nitro-1H-pyrrolor-2,3-b-pyridine-3-carboxylic acid
To a suspension of 5.00 g (16.38 mmol) of the propyl ester of 1-tert-butyl-5-nitro-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid in 50 ml of 95% ethanol, 2M NaOH is added (50 ml, 100 mmol) under stirring. The mixture is heated to reflux for 1 hour, obtaining the complete consumption of the substrate. The resulting solution is cooled to room temperature and concentrated under reduced pressure to a suspension which is diluted with 250 ml of water and washed with 100 ml of a 1: 1 mixture of diethyl ether and ethyl acetate. The aqueous layer is treated with 5M HCl (37 ml, 185 mmol) under efficient stirring, at room temperature. The precipitate is filtered off, washed twice with 10 ml of water and dried to give 3.84 g of the title compound as a white solid.
p.f. = 278-281 ° C, with decomposition Yield = 89% 1 H NMR (DMSO): 1.79 (s, 9H), 8.36 (s, 1 H), 9.03 (d, 1 H, J = 2.63 Hz), 9.20 (d , 1 H, J = 2.63 Hz), 12.77 (broad s, 1 H).
EXAMPLE 4 Preparation of methyl 5-nitro-1- (phenylsulfonyl-M-pyrrolor-2,3-b-pyridine-3-carboxylate)
To an ice-cooled solution of 187.7 g (0.616 mmol) of tetrabutylammonium nitrate in 2.07 I of dichloromethane, trifluoroacetic anhydride (85.7 mL, 0.616 mmol) is added dropwise over a period of 25 minutes under nitrogen. This mixture is transferred slowly, by means of a cannula, to a preformed solution of 150.0 g (0.474 mmol) of the methyl ester of 1- (phenylsulfonyl) -1H-pyrrolo [2,3, b] pyridine-3-carboxylic acid in 2.7 l of dichloromethane at + 4 ° C. The reaction mixture is stirred at + 4 ° C for 4 hours and then maintained at this temperature for an additional 23 hours. The cold reaction mass is poured into 2.3 I of water and stirred for 1 hour. The aqueous layer is separated and extracted again with 1 l of dichloromethane. The combined organic extracts are concentrated under vacuum to a thick yellow suspension which is treated with 1.05 I of methanol. The suspension is cooled to 0 ° C and stirred for an additional 1 hour before it is filtered, washed with methanol and dried to give 128 g of the pure title compound as a yellow curled solid (Yield = 74.7%). p.f. 195-196 ° C 1 H NMR (DMSO): 3.91 (s, -3 H), 7.64-7.69 (m, 2 H), 7.76-7.81 (m, 1 H), 8.25-8.27 (m, 2 H), 8.74 (s) , 1 H), 8.96 (d, 1 H, J = 2.58 Hz), 9.27 (d, 1 H, J = 2.58 Hz).
EXAMPLE 5 Preparation of disodium 5-nitro-1H-pyrroloF2,3-b1pyridine-3-carboxylate
To a suspension of 95.7 g (0.265 mmoles) of the compound of Example 4 in 1.34 I of 2,2,2-trifluoroethanol is added 0.545 I of 17% NaOH over a period of 40 minutes under vigorous stirring. the yellow-orange mixture is heated to reflux for 16 hours and then cooled to 0 ° C and stirred for an additional 2 hours. The precipitate is filtered off, washed with acetone and dried to give 79.8 g of the title compound as an orange crystalline solid (Yield = 93.1% as tetrahydrate). p.f. = > 230 ° C 1 H NMR (DMSO): 7.83 (broad s, 1 H), 8.89 (d, 1 H, J = 2.80 Hz), 9.07 (broad s, 1 H).
EXAMPLE 6 Preparation of 5-nitro-1H-pyrrolor2,3-b1pyridine-3-carboxylic acid
To a clear solution of the compound of Example 5 (88.10 g, 0.35 mmol) in 2.65 I of water is added dropwise concentrated HCl (52.6 mL, 0.526 mol) diluted with 105 mL of water over a period of 50 minutes under effective agitation to room temperature. The resulting suspension is cooled to + 4 ° C and stirred for an additional 1 hour. The precipitate is filtered off, washed with water and finally dried to give 55.6 g of the title compound as a light yellow powder (Yield = 98.5% (title 95%), mp = 282-285 ° C, with NMR decomposition). 1H (DMSO): 8.41 (d, 1H, J = 2.83 Hz), 9.00 (d, 1H, J = 2.59 Hz), 9.16 (d, 1 H, J = 2.59 Hz), 12.5-13.0 (broad s, 1 H), 13.14 (s, 1 H).
EXAMPLE 7
General procedure: loaded with 4-fluorobenzylamine (corresponding to fragment A3 of Table I) on the methoxybenzaldehyde polystyrene resin sensitive to acid (AMEBA II resin). The resin 4- (4-formyl-3-methoxyphenoxy) butyryl AM [copoly (styrene-1% dvb) 100-200 mesh] (1.5 g, 1 equivalent, loaded 0.94 mmole / g) is expanded in DCM and then filtered . A mixture of THF / DCM (4: 5, 15 ml), 6 equivalents of 4-fluorobenzylamine and 6 equivalents of AcOH is added. After 15 min NaBH (OAc) 3 is added and the reaction is stirred overnight at room temperature. After filtration, the resin is washed with methanol (x3) DMF / DCM (1: 1) (x3) and DCM (x5).
EXAMPLE 8
Step 8.1: loaded with the azaindol scaffold on the resin of example 7
To the resin (1.5 g, 077 mmol / g, 1.16 mmol) of Example 7 in 15 ml of anhydrous DMF is added 5-nitro-1 H -pyrrolo-2,3-b] pyridine-3-carboxylic acid (0.359 g, 1.73 g. mmoles), TBTU (0.556 g, 1.73 mmoles) and DIPEA (0.44 g, 3.48 mmoles). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 25 ml of DMF, 25 ml of DCM, 25 ml of DMF, 25 ml of DCM, 25 ml of MeOH, 25 ml of DCM, 25 ml of MeOH, 25 ml of DCM, 25 ml of MeOH , TBME (25 ml x 2) and dried under vacuum to provide 1.70 g of 7-azaindole bound to resin.
Verification of resin loading The verification of resin loading is carried out to demonstrate the complete loading of the building block on the resin and that no oligomerization has occurred while coupling with TBTU. Benzoyl chloride is used in order to top off the amine charged with unreacted resin (ie, 4-fluorourobenzylamine, for example 8) and to acylate 1-NH azaindole. The absence of benzamide (ie, N- (4-fluorobenzyl) benzamide, for example 8) in the separate mixture demonstrates the quantitative loading of the scaffold on the resin. The presence of 1-N-benzoylazaindole or 1-NH-azaindole demonstrates that a homogeneous coupling of 3-carboxy-5-nitro-7-azaindole has not occurred during the resin loading step. To the resin obtained after the procedure described in example 8 (step 8.1) (0.035 g, 0.027 mmol) in 1 ml of DCM is added DIPEA (0.025 g, 0.265 mmole) and benzoyl chloride (0.038, 0.265 mmole) . The reaction mixture is stirred for 4 hours and the resin is isolated by filtration. The resin is washed sequentially with 1 ml of DMF, 1 ml of DCM, 1 ml of DMF, 1 ml of DCM, 1 ml of MeOH, 1 ml of water, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH , 1 ml of DCM, 1 ml of MeOH, TBME (1 ml x 2) and then air-dried. The product is separated from the resin (1 ml of TFA / 60% / DCM for 20 minutes) to give an off white solid (0.007 g, 64%). LCMS (HPLC) (indole? / -benzoylated): m / z 419 [M + f @ t.r. 1.56 min (97% by detection of ELS).
Step 8.2: N-alkylation of 7-azaindole bound to resin
To the resin (0.85 g, corresponding to 0.58 mmoles) of step (8.1) in 20 ml of anhydrous DCM is added BTPP (0.540 g, 1.74 mmoles) and iodomethane (R2, corresponding to fragment C2 of table III, 0.821 g, 5.8 mmoles). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 25 ml of DMF, 25 ml of DCM, 25 ml of DMF, 25 ml of DCM, 25 ml of MeOH, 25 ml of DCM, 25 ml of MeOH, 25 ml of DCM, 25 ml of MeOH , TBME (25 ml x 2) and dried under vacuum to provide 1.85 g of 7-azaindole-N-methylated resin. 0.01 g of the resin (1 ml of TFA / 60% DCM for 20 minutes) is removed to give an off-white solid (0.0015 g, 60%). LCMS: m / z 329 [M + H] + @ t.r. 1.72 min (94% @ 215 nm).
Step 8.3: Reduction of the nitro group To 0.85 g of the resin of step (8.2) in 10 ml of NMP is added tin chloride (II) dihydrate (1.3 g, 5.8 mmol). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 10 ml of DMF, 10 ml of DCM, 10 ml of DMF, 10 ml of DCM, 10 ml of MeOH, 10 ml of water, 10 ml of MeOH, 10 ml of DCM, 10 ml of MeOH. , 10 ml of DCM, 10 ml of MeOH, TBME (10 ml x 2) and dried under vacuum to provide 0.825 g of 5-amino-7-azaindole N-methylated bound to corresponding resin. 0.01 g of the resin (1 ml of TFA / 60% DCM for 20 minutes) are removed to give an off-white solid (0.0015 g, 65%). LCMS (HPLC): m / z 299 [M + H] + @ t.r. 0.97 min (100% by detection of ELS). The resin bound above azaindole is further reacted according to the following alternative steps so that the carboxamido, sulfonamido and ureido derivatives are obtained.
Preparation of A3-M-B5-C2
Stage 8.4: Topping up with acid chloride derivatives
To the resin of step (8.3) (0.11 g, corresponding to 0.077 mmoles) in 1 ml of DCM is added Hunig's base (0.050 g, 0.385 mmoles) followed by benzoyl chloride (group -CORa corresponding to fragment B5 from Table II, 0.054 g, 0.385 mmoles). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 1 ml of DMF, 1 ml of DCM, 1 ml of DMF, 1 ml of DCM, 1 ml of MeOH, 1 ml of water, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH. , 1 ml of DCM, 1 ml of MeOH, TBME (1 ml x 2) and then air-dried. The resin is stirred in an acetonitrile / ammonia solution (1 ml, 4: 1) and then isolated by filtration. The resin is washed sequentially with 1 ml of DMF, 1 ml of DCM, 1 ml of DMF, 1 ml of DCM, 1 ml of MeOH, 1 ml of water, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH , 1 ml of DCM, 1 ml of MeOH, TBME (1 ml x 2) and then air-dried. The product is separated from the resin [60% TFA / DCM 3 x (3x 0.5 ml)] to give an off-white solid (0.026 g, 84%) which corresponds to the compound A3-M-B5-C2 (see entry 1 of the table) IV next). LCMS (HPLC) m / z 403 [M + H] + @ t.r. 1.29 min (100% by detection of ELS). Following the procedure described in example 8 and using an appropriate reagent as indicated in the method of the invention, by supporting any suitable amine on the resin by functionalization of position 1 of the azaindole portion with any suitable reagent, by acylating the function amino in the 5-position of the azaindole portion with any suitable acyl chloride derivative and in finally carrying out the resin separation, the following compounds of Table IV are also prepared.
TABLE IV
Preparation of A3-M-B1-C2
Stage 8.5: Topped up with sulfonyl chloride derivatives
To the resin of step (8.3) (0.11 g, corresponding to 0.077 mmol) in 1 ml of DCM is added pyridine (0.030 g, 0.385 mmol), DMAP (0.001 g, 0.0077 mmol) and methanesulfonyl chloride (group - S02Ra corresponding to fragment B1 of table II, 0.044 g, 0.385 mmoles). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 1 ml of DMF, 1 ml of DCM, 1 ml of DMF, 1 ml of DCM, 1 ml of MeOH, 1 ml of water, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH. , 1 ml of DCM, 1 ml of MeOH, TBME (1 ml x 2) and then air-dried. The product is separated from the resin (60% TFA / DCM, 3 x (3 x 0.5 ml)] to provide an off-white solid (0.024 g, 83%) corresponding to the compound A3-M-B1-C2 (see entry 33 from Table V below) LCMS (HPLC_1) m / z 377 [M + Hf @ tr 1.12 min (97.5% by detection of ELS) Following the procedure described in example 8 and using an appropriate reagent as indicated in the procedure of the invention, by supporting any suitable amine on the resin by functionalization of the 1-position of the azaindole portion with any suitable reagent, by sulfonating the amino function at the 5-position of the azaindole portion with any suitable sulfonyl chloride derivative and finally carry out the separation of resin, you can also prepare the following compounds from table V.
TABLE V
Step 8.6: Phenyl carbamate (and formation of bis-phenyl carbamate)
To the resin of step (8.3) (0.25 g, corresponding to 0.19 mmoles) in 10 ml of DCM is added triethylamine (0.39 g, 3.85 mmole), and phenyl chloroformate (0.603 g, 3.85 mmole). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 10 ml of DMF, 10 ml of DCM, 10 ml of DMF, 10 ml of DCM, 10 ml of MeOH, 10 ml of DCM, 10 ml of MeOH, 10 ml of DCM, 10 ml of MeOH, TBME ( 10 ml x 2) and dried under vacuum to provide 0.275 g of the corresponding azaindole bound to resin which is further reacted according to the next step.
Preparation of A3-M-B9-C2
Stage 8.7: Formation of ureide derivatives
To the resin in stage (8.6) (0.11 g, corresponding to
0. 077 mmol) in 1 ml of DCM is added piperidine (group -CONRaRb corresponding to fragment B9 of table II, 0.131 g, 1.54 mmoles). The reaction mixture is stirred at room temperature for 72 hours and then the resin is isolated by filtration, the resin is washed sequentially with 1 ml of DMF, 1 ml of DCM, 1 ml of DMF, 1 ml of DCM, 1 ml of MeOH, 1 ml of water, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH, TBME (1 ml x 2) and then air-dried. The product is separated from the resin (60% TFA / DCM, 3 x (3 x 0.5 ml) to provide an off-white solid (0.027 g, 87%) corresponding to the compound A3-M-B9-C2 (see entry 64). from Table VI below) LCMS (HPLC_1): m / z 410 [M + H] + @ tr 1.21 min (86% by ELS deprotection) Following the procedure described in example 8 and using any suitable reagent as indicated the method of the invention, that is by supporting any suitable amine on the resin by functionalization of the 1-position of the azaindole portion with any suitable reagent, by preparing the carbamate derivative at the 5-position of the azaindole moiety, by converting it into the derivative If the corresponding ureide is reacted by reaction with any suitable amine, and finally by carrying out the resin separation, the following compounds of Table VI are also prepared.
9
TABLE VI
EXAMPLE 9 Stage 9.1:
To the Rink resin (corresponding to fragment A9 of Table I, 11 g, 0.85 mmol / g 9.35 mmol) in 15 ml of anhydrous DMF are added 5-nitro-1 H -pyrrolo [2,3-b] pyridine- 3-carboxylic acid (2.9 g, 14.03 mmole), TBTU (4.5 g, 14.03 mmole) and DIPEA (3.62 g, 28.05 mmole). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 25 ml of DMF, 25 ml of DCM, 25 ml of DMF, 25 ml of DCM, 25 ml of MeOH, 25 ml of DCM, 25 ml of MeOH, 25 ml of DCM, 25 ml of MeOH , TBME (25 ml x 2) and dried under vacuum to provide 12.5 g of 7-azaindole bound to resin. 0.01 g of the resin (1 ml of 40% TFA / DCM) is removed to give an off white solid (0.0014 mg, 82%). LCMS (HPLC): m / z 207 [M + H] + @ t.r. 0.79 min (80% by detection of ELS).
Stage 9.2: N-alkylation of 7-azaindole bound to resin
To the resin of stage (9.1) (1.6 g, corresponding to
1. 36 mmoles) in 20 ml of anhydrous DCM, add BTPP (1.278 g, 4.08 mmol) and iodomethane (group R2 corresponding to fragment C2 of table III, 1.938 g, 13.6 mmol). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 20 ml of DMF, 20 ml of DCM, 20 ml of DMF, 20 ml of DCM, 20 ml of MeOH, 20 ml of DCM, 20 ml of MeOH, 20 ml of DCM, 20 ml of MeOH, TBME. (20 ml x 2) and dried under vacuum to provide 1.8 g of N-alkylated 7-azaindole bound to resin. 0.01 g of the resin (1 ml of 40% TFA / DCM) is removed to give an off-white solid (0.0015 g, 83%) LCMS: m / z 221 [M + H] + and 262 [M + MeCN + H] + @ tr 1.35 min (65% @ 215 nm).
Step 9.3: Reduction of the nitro group To 1.6 g of the resin from step (9.2) in 20 ml of NMP is added tin chloride (II) dihydrate (3.1 g), 13.6 mmoles). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 20 ml of DMF, 20 ml of DCM, 20 ml of DMF, 20 ml of DCM, 20 ml of MeOH, 20 ml of water, 20 ml of MeOH, 20 ml of DCM, 20 ml of MeOH, 20 ml of DCM, 20 ml of MeOH, TBME (20 ml x 2) and dried under vacuum to provide 0.825 g of 5-amino-7-azaindole bound to resin. 0.01 g of the resin (1 ml of 40% TFA / DCM) is removed to give an off white solid (0.0012 g, 75%). LCMS: (HPLCJ): m / z 191 [M + H] + @ t.r. 0.59 min (100% by detection of ELS). The above resin bound azaindole is further reacted according to the following alternative steps so that the carboxamido, sulfonamido and ureido derivatives are obtained.
Preparation of A9-M-B5-C2
Stage 9.4: Topped with acid chloride derivatives To the resin of step (9.3) (0.11 g, corresponding to 0.085 mmol) in 1 ml of DCM is added Hunig's base (0.055 g, 0.425 mmol) followed by chloride benzoyl (group -CORa corresponding to fragment B5 of Table II, 0.060 g, 0.425 mmol). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 1 ml of DMF, 1 ml of DCM, 1 ml of DMF, 1 ml of DCM, 1 ml of MeOH, 1 ml of water, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH, TBME (1 ml x 2) and then air-dried. The resin is stirred in a solution of acetonitrile / ammonia (1 ml, 4: 1) for 4 hours and then isolated by filtration. The resin is washed sequentially with 1 ml of DMF, 1 ml of DCM, 1 ml of DMF, 1 ml of DCM, 1 ml of MeOH, 1 ml of water, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH , 1 ml of DCM, 1 ml of MeOH, TBME (1 ml x 2) and then air-dried. The product is separated from the resin (TFA 40% / DCM, 3 x 0.5 ml) to give a whitish solid (0.017 g, 68%) corresponding to the compound A9-M-B5-C2 (see entry 3 of the following table VII) ). LCMS (HPLC): m / z 295 (M + H] + @ tr 0.92 min (88% by ELS detection). By working in an analogous manner and using any suitable starting material and reagent of the process the following compounds are also prepared from the box Vil.
TABLE VII
Preparation of A9-M-B4-C2
Stage 9.5: Topped with sulfonyl chloride derivatives To the resin of step (9.3) (0.11 g, corresponding to
0. 085 mmoles) in 1 ml of DCM is added pyridine (0.034 g, 0.425 mmoles),
DMAP (0.001 g, 0.0085 mmoles) and benzenesulfonyl chloride (group -S02Ra corresponding to fragment B4 of Table III, 0.075 g, 0.385 mmoles). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 1 ml of DMF, 1 ml of DCM, 1 ml of DMF, 1 ml of DCM, 1 ml of MeOH, 1 ml of water, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH , 1 ml of DCM, 1 ml of MeOH, TBME (1 ml x 2) and then air-dried. The product is separated from the resin (TFA 40% / DCM, 3 x 0.5 ml) to give an off white solid (0.022 g, 80%) corresponding to the compound A9-M-B4-C2 (see entry 24 of table VIII following). LCMS (CLAP_1): m / z 331 [M + H] + @ t.r. 0.96 min (81% by detection of ELS). By working in an analogous way and by using any suitable initial material and reagent of the process the following compounds of Table VIII are also prepared
TABLE VIII
Step 9.6: Formation of phenyl carbamate (and bisphenyl carbamate) To the resin of step (9.3) (0.60 g corresponding to 0.51 mmole) in 10 ml of DCM are added triethylamine (1.03 g, 10.2 mmole) and chloroformate. phenyl (1597 g, 10.2 mmol). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 10 ml of DMF, 10 ml of DCM, 10 ml of DMF, 10 ml of DCM, 10 ml of MeOH, 10 ml of DCM, 10 ml of MeOH, 10 ml of DCM, 10 ml of MeOH , TBME (10 ml x 2) and dried under vacuum to provide 0.65 g of 7-azaindole bound to resin. 0.01 g of the resin (1 ml of 40% TFA / DCM) is removed to give an off white solid (0.001 g, 69%). LCMS (CLAP_1) (carbamate of mono and bis phenyl): m / z 311 [M + H] + @ t.r. 1.03 min (77% by detection of ELS) and m / z 431 [M + H] + @ t.r. 1.31 min (12% by detection of ELS).
Preparation of A9-M-B9-C2
Step 9.7: Formation of ureide derivatives To the resin of step (9.6) (0.11 g, corresponding to 0.085 mmol) in 1 ml of DCM is added piperidine (group -CONRaRb corresponding to fragment B9 of Table II, 0.143 g, 1.7 mmoles). the reaction mixture is stirred at room temperature for 72 hours and then the resin is isolated by filtration. The resin is washed sequentially with 1 ml of DMF, 1 ml of DCM, 1 ml of DMF, 1 ml of DCM, 1 ml of MeOH, 1 ml of water, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH, 1 ml of DCM, 1 ml of MeOH , TBME (1 ml x 2) and then air-dried. The product is separated from the resin (TFA 40% / DCM, 3 x 0.5 ml) to give an off-white solid (0.020 g, 79%) corresponding to compound A9-M-B9-C2 (see entry 40 of table IX) following). LCMS (CLAP_1): m / z 302 [M + H] + @ t.r. 0.86 min (91% by detection of ELS). By working in an analogous manner and using any suitable initial material and reagent of the procedure, the following compounds of Table IX are also prepared.
TABLE IX
EXAMPLE 10
Stage 10.1: Loading of the azaindol scaffold on the resin To the AMEBA II resin (0.1 g, 1 mmol / g, 0.1 mmol) in
DCM / DMF (1: 1, 2 ml), 3 equivalents of 1-tert-butyl-5-nitro-1 H -pyrrolo [2,3-b] pyridine-3-carboxylic acid, 1.5 equivalents of DIC, 0.5 equivalents are added of DMAP and 1 equivalent of DIPEA. The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 2 ml of DMF, 2 ml of DCM, 2 ml of DMF, 2 ml of DCM, 2 ml of MeOH, 2 ml of DCM, 2 ml of MeOH, 2 ml of DCM, 2 ml of MeOH , 2 ml of DCM and dried under vacuum to provide 7-azaindole bound to resin.
Step 10.2: Reduction of the nitro group To the resin of step (10.1) (0.1 g, 1 mmol / g, 0.1 mmol) in 2 ml of NMP is added 10 equivalents of tin (II) chloride dihydrate. The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 5 ml of DMF, 5 ml of DCM, 5 ml of DMF, 5 ml of DCM, 5 ml of MeOH, 5 ml of water, 5 ml of MeOH, 5 ml of DCM, 5 ml of MeOH , 5 ml of DCM, 5 ml of MeOH, 5 ml of DCM and dried under vacuum to provide the 5-amino-7-azaindole bound to resin. 0.01 g of the resin (1 ml of 20% TFA / DCM for 20 minutes) are removed to provide the corresponding amine. LCMS (CLAP_2): m / z 323 [M + H] + t.r. 5.2 min.
Preparation of A1-M-B6-C9
Stage 10.3: Topped with acyl chloride derivatives To the resin of step (10.2) (0.1 g, corresponding to
0. 1 mmoles) in 1 ml of DCM are added 5 equivalents of Hunig's base, followed by acetyl chloride (group -CORa corresponding to fragment B6 of Table II, 5 equivalents). The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 2 ml of DMF, 2 ml of DCM, 2 ml of DMF, 2 ml of DCM, 2 ml of MeOH, 2 ml of water, 2 ml of MeOH, 2 ml of DCM, 2 ml of MeOH. , 2 ml of DCM, 2 ml of MeOH, DCM (1 ml x 2) and then dried. The resin is stirred in a solution of acetonitrile / ammonia (1 ml, 4: 1) for 4 hours and then isolated by filtration, the compound 5- (acetylamine) -N-benzyl-1-terbutyl is separated from the resin. 1 H-pyrrolo [2,3-b] pyridin-3-carboxamide having the code A1-M-B6-C9, [TFA 20% / DCM, 3 x (3 x 0.5 ml)]. LCMS (CLAP_2): m / z 365 [M + H] + t.r. 5.4 min.
Preparation of A1-M-B14-C9
Stage 10.4: Topped with sulfonyl chloride derivatives To the resin in step (10.2) (0.1 g, corresponding to
0. 1 mmol) in 1 ml of DCM are added 5 equivalents of DIPEA,
0. 1 equivalent of DMAP and 4- (acetylamino) benzenesulfonyl chloride (group
-S02Ra, corresponding to fragment B14 of Table II, 5 equivalents).
The reaction mixture is stirred at room temperature for 20 hours and then the resin is isolated by filtration. The resin is washed sequentially with 2 ml of DMF, 2 ml of DCM, 2 ml of DMF, 2 ml of DCM, 2 ml of MeOH,
2 ml of water, 2 ml of MeOH, 2 ml of DCM, 2 ml of MeOH, 2 ml of DCM,
2 ml of MeOH, DCM (1 ml x 2) and then dried under vacuum. The compound 5- ( { [4- (acetylamino) phenyl] sulfonyl}. Amino) -N-benzyl-1-terbutyl-1 H -pyrrolo [2,3-b] pyridin-3 is separated from the resin. -carboxamide having the code A1-M-B14-C9, (TFA
% / DCM, 3 x (3 x 0.5 ml). LCMS (CLAP_2): m / z 520 [M + H] + t.r. 6.0 min.
Preparation of A1-M-B15-C9
Stage 10.5: Topped with derivatives of socianate To the resin of stage (10.3) (0.1 g, corresponding to
0. 1 mmoles) in 1 ml of DCM is added butyl isocyanate (group -CONRaRb corresponding to fragment B15 of Table II, 10 equivalents). The reaction mixture is stirred at room temperature for 48 hours and then the resin is isolated by filtration. The resin is washed sequentially with 2 ml of DMF, 2 ml of DCM, 2 ml of DMF, 2 ml of DCM, 2 ml of MeOH, 2 ml of water,
2 ml of MeOH, 2 ml of DCM, 2 ml of MeOH, 2 ml of DCM, 2 ml of MeOH,
DCM (1 x 2) and then dried under vacuum. The compound N-benzyl-1-tert-butyl-5 is separated from the resin. { [(butylamino) carbonyl] amino} -1 H-pyrrolo [2,3-b] pyridine-3-carboxamide having the code A1-M-B15-C9, TFA 20% / DCM, 3 x (3 x 0.5 ml). LCMS (CLAP_2): m / z 422 [M + H] + t.r. 6.5 min.
Claims (31)
1. -The use of pyrrole [2,3-b] pyridine, represented by the formula (I) where R is -Ra, -Ra or -COORa; R-, is -NRcRd or -ORc; wherein Ra, Rb, R ° and Rd are the same or different and each is independently hydrogen or an optionally substituted group in a further manner, which is selected from straight or branched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 straight or branched carbon atoms, linear or branched alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, heterocyclic aryl or arylalkyl of 1 to 6 carbon atoms, heterocycle or heterocycloalkyl of 1 to 6 carbon atoms or, taken together with the nitrogen atom to which they are attached, either Ra and Rb as well as Rc and Rd can form an optionally substituted 4 to 7 membered heterocycle, which optionally contains a additional heteroatom or a heteroatom group selected from S, O, N or NH; R2 is a group, optionally substituted additionally, which is selected from straight or branched alkyl of 1 to 6 carbon atoms, straight or branched alkenyl of 2 to 6 carbon atoms, straight or branched alkynyl of 2 to 5 carbon atoms. , cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, or heteroaryl aryl or arylalkyl of 1 to 6 carbon atoms, heterocycle or heterocycloalkyl of 1 to 6 carbon atoms; or isomers, tautomers, carriers, metabolites, prodrugs and pharmaceutically acceptable salts thereof, for preparing a medicament for treating conditions or diseases caused by and / or associated with altered protein kinase activity in a mammal.
2. The use claimed in claim 1, wherein the - disease caused by and / or associated with an altered protein kinase activity is a cell proliferative disorder that is selected from the group that - consists of cancer, Alzheimer's disease, viral infections, autoimmune diseases and neurodegenerative disorders. ---
3. The use claimed in claim 2, wherein the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lines, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, keratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, follicular thyroid cancer and Kaposi's sarcoma.
4. The use claimed in claim 1, wherein the proliferative cell disorder is selected from the group consisting of benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, fibrosis. pulmonary arthritis, glomerulonephritis and postoperative stenosis and restenosis. 5. -The use of a compound represented by the formula: wherein R is -Ra, -CORa, -CONRaRb, -S02Ra or -COORa; Rt is a group -NRcRd or -ORc; wherein Ra, Rb, Rc and Rd are the same or different and each is independently hydrogen or an optionally substituted group, which is selected from linear or branched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 atoms linear or branched carbon, linear or branched 2- to 6-carbon alkynyl, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, or heterocyclic aryl or arylalkyl of 1 to 6 carbon atoms, or heterocycle or heterocycloalkyl of 1 to 6 carbon atoms or, taken together with the nitrogen atom to which they are attached, either Ra and Rb as well as Rc and Rd can form an optionally substituted 4 to 7 membered heterocycle, which optionally contains a additional heteroatom or a heteroatom group selected from
S, O, N or NH; R2 is a group, optionally substituted additionally, which is selected from straight or branched alkyl of 1 to 6 carbon atoms, linear or branched alkenyl of 2 to 6 carbon atoms, linear or branched alkynyl of 2 to 6 carbon atoms. , cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, heterocyclic aryl or arylalkyl of 1 to 6 carbon atoms, heterocycle or heterocycloalkyl of 1 to 5 carbon atoms; or isomers, tautomers, carriers, metabolites, precursors and pharmaceutically acceptable salts thereof, for preparing a medicament for inhibiting tumor angiogenesis or metastasis in a mammal.
6. The use claimed in claim 1, wherein the condition caused by or associated with an altered cjase protein activity is rejection of organ transplantation or reverse rejection disease.
7.-The use of a compound of the formula: wherein R is -Ra, -CORa, -CONRaRb, -S02Ra or -COORa; R-i is a group -NRcRd or -ORc; wherein Ra, Rb, Rc and Rd are the same or different and each is independently hydrogen or an optionally substituted group, which is selected from linear or branched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 atoms linear or branched carbon, linear or branched alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, heterocyclic aryl or arylalkyl of 1 to 6 carbon atoms, or heterocycle or heterocycloalkyl of 1 to 6 carbon atoms or, taken together with the nitrogen atom to which they are attached, either Ra and Rb as well as Rc and Rd can form an optionally substituted 4 to 7 membered heterocycle, which optionally contains an additional heteroatom or heteroatom group selected from S, O, N and NH; R2 is a group, optionally substituted additionally, which is selected from straight or branched alkyl of 1 to 6 carbon atoms, straight or branched alkenyl of 2 to 6 carbon atoms, straight or branched alkynyl of 2 to 6 carbon atoms. , cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, aryl or arylalkyl of 1 to 6 carbon atoms, heterocycle or heterocycloalkyl of 1 to 6 carbon atoms; or isomers, tautomers, carriers, metabolites, prodrugs and pharmaceutically acceptable salts thereof, for preparing a medicament for treating or preventing alopecia induced by radiotherapy or induced by chemotherapy in a mammal.
8. The use claimed in claim 1, wherein a radiotherapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent is also administrable.
9. The use claimed in claim 1, wherein the mammal is a human.
10. A method for inhibiting protein kinase activity, characterized in that it comprises contacting the kinase with an effective amount of a compound of formula (I), having the formula: wherein R is -Ra, -CORa, -CONRaRb, -S02Ra or -COORa; R-, is a group - NRcRd or -ORc; wherein Ra, Rb, Rc and Rd are identical or different and each is independently hydrogen or an optionally substituted group, which is selected from linear or branched alkyl of 1 to 6 carbon atoms, alkenyl from 2 to 6. linear or branched carbon atoms, linear or branched alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, aryl or arylalkyl of 1 to 6 carbon atoms, or heterocycle or heterocycloalkyl of 1 to 6 carbon atoms or, taken together with the nitrogen atom to which they are attached, either Ra and Rb as well as Rc and Rd can form an optionally substituted 4 to 7 membered heterocycle, which optionally contains a heteroatom additional or heteroatom group selected from S, O, N and NH; R2 is a group, optionally substituted additionally, which is selected from straight or branched alkyl of 1 to 6 carbon atoms, linear or branched alkenyl of 2 to 6 carbon atoms, linear or branched alkynyl of 2 to 6 carbon atoms. , cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, aryl or arylalkyl of 1 to 6 carbon atoms, or heterocycle or heterocycloalkyl of 1 to 6 carbon atoms; or isomers, tautomers, carriers, metabolites, prodrugs and pharmaceutically acceptable salts thereof.
11. A compound of formula (I) wherein R is selected from the group consisting of: -Ra, -CORa, -CONRaRb, -S02Ra or -COORa; Ri is a group -NRcRd or -ORc; wherein Ra, Rb, Rc and Rd are the same or different, are each independently hydrogen or an optionally substituted group, which is selected from linear or branched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 atoms linear or branched carbonlinear or branched alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, heterocyclic aryl or arylalkyl of 1 to 8 carbon atoms, or heterocycle or heterocycloalkyl of 1 to 6 carbon atoms or, taken together with the nitrogen atom to which they are attached, either Ra and Rb as well as R ° and Rd can form an optionally substituted 4- to 7-membered heterocycle, optionally containing an additional heteroatom or a group heteroatom that is selected from S, O, N and NH; R2 is a group, optionally substituted additionally, which is selected from straight or branched alkyl of 1 to 6 carbon atoms, linear or branched alkenyl of 2 to 6 carbon atoms, linear or branched alkynyl of 2 to 6 carbon atoms. , cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, aryl or arylalkyl of 1 to 6 carbon atoms, or heterocycle or heterocycloalkyl of 1 to 6 carbon atoms; or isomers, tautomers, carriers, metabolites, prodrugs and pharmaceutically acceptable salts thereof.
12. The compound of formula (I) according to claim 11, further characterized in that R-i is a group -NRcRd and Rc and Rd are both hydrogen atoms or one of them is a hydrogen atom and the remaining of Rc and Rd are alkyl or alkenyl groups, or is an optionally substituted aryl or arylalkyl group.
13. The compound of formula (I), according to claim 11, further characterized in that R is a hydrogen atom or a group -S02Ra, wherein Ra is linear or branched alkyl or optionally substituted aryl or a group Arylalkyl.
14. The compound of formula (I) according to claim 11, further characterized in that R is -CORa, wherein Ra is a linear or branched alkyl, cycloalkyl or an optionally substituted aryl group or arylalkyl.
15. The compound of formula (I), according to claim 11, further characterized in that R is -CONRaRb, wherein one of Ra and Rb is a hydrogen atom and the other of Ra and Rb is a linear alkyl or branched, an optionally substituted aryl group or arylalkyl.
16. - The compound of formula (I) according to claim 1, further characterized in that R is -CONRaRb, wherein Ra and Rb "form, together with the nitrogen atom to which they are attached, a 6-membered heterocyclic ring optionally substituted
17. The compound of formula (I) according to claim 11, characterized in that R2 is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl or an optionally substituted aryl or arylalkyl group
18. The compound of formula (I) ), according to any of claims 12, 13, 14, 15, 16 or 17, further characterized in that Ra, Rb, Rc and Rd are each independently selected from A1-A9, B1-B15 or C1-C9.
19. The compound of formula (I) according to claim 11, further characterized in that any of Ra, Rb, Rc, Rd and R2, is optionally substituted by groups that are independently selected from: halogen, nitro, groups oxo (= 0), carboxy, cyano, alq uilo, polyfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl; aril; heterocyclyl, amino groups and derivatives thereof such as, alkylamino, dialkylamino, arylamino, diarylamino, ureido, alkylureido and arylureido; carbonylamino groups and derivatives thereof such as, formylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, hydroxy groups and derivatives thereof, such as alkoxy, polyfluorinated alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkynyloxy or alkylidenaminoxy; carbonyl groups and derivatives thereof, such as, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl; sulphurated derivatives such as alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, aryisulfinyl, arylsulfonyloxy, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl.
20. The compound of formula (I), according to claim 11, further characterized in that it is a compound selected from the following compounds: A3-M-B5-C2, A3-M-B6-C2, A4-M-B5 -C2, A4-M-B6-C2, A7-M-B5-C2, A7-M-B6-C2, A6-M-B5-C2, A6-M-B6-C2, A1-M-B5-C2 , A1-M-B6-C2, A5- M-B5-C2, A5-M-B6-C2, A8-M-B5-C2, A8-M-B6-C2, A2-M-B5-C2, A2 -M-B6-C2, A3-M-B5-C5, A3-M-B6-C5, A4-M-B5-C5, A4-M-B6-C5, A7-M-B5-C5, A7-M -B6-C5, A6-M-B5-C5, A6-M-B6-C5, A1-M-B5-C5, A1-M-B5-C5, A5-M-B5-C5, A5-M-B6 -C5, A8-M-B5-C5, A8-M-B6-C5, A2-M-B5-C5, A2-M-B6-C5, A3-M-B1-C2, A3-M-B4-C2 , A4-M-B1-C2, A4-M-B4-C2, A7-M-B1-C2, A7-M-B4-C2, A6-M-B1-C2, A6-M-B4-C2, A1 -M-B1-C2, A1-M-B4-C2, A5-M-B1-C2, A5-M-B4-C2, A8-M-B1-C2, A8-M-B4-C2, A2-M -B1-C5, A3-M-B1-C5, A3-M-B4-C5, A4-M-B1-C5, A4-M-B4-C5, A7-M-B1-C5, A7-M-N4 -C5, A6-M-B1-C5, A6-M-B4-C5, A1-M-B2-C5, A1-M-B4-C5, A5-M-B4-C5, A5-M-B4-C5 , A8-M-B1-C5, A8-M-B4-C5, A2-M-B1-C5, A2-M-B4-C5, A3-M-B9-C2, A3-M-B10-C2, A4 -M-B10-C2, A1-M-B10-C2, A5-M-B10-C2, A3-M-B9-C5, A7-M-B9-C5, A1-M-B9-C5, A1-M-B10-C5, A9-M-B5-C1, A9-M-B7-C1, A9-M-B5-C2, A9-M-B7-C2, A9- M-B5-C3, A9-M-B7-C3, A9-M-B8-C3, A9-M-B5-C3, A9-M-B5-C5, A9-M-B5-C6, A9-M-B7-C6, A9 -M-B8-C6, A9-M-B5-C7, A9-M-B6-C7, A9-M-B8-C7, A9-M-B5-C8, A9-M-B7- C8, A9-M -B8-C8, A9-M-B13-C2, A9-M-B13-C5, A9-M-B13-C6, A9-M-B13-C8, A9-M-B1-C1, A9-M-B4 -C2, A9-M-B3-C3, A9-M-B1-C4, A9-M-B3-C4, A9-M-B1-C5, A9-M-B3-C5, A9-M-B4-C5 , A9-M-B2-C6, A9-M-B3-C6, A9-M-B4-C6, A9- M-B3-C7, A9-M-B1-C8, A9-M-B2-C8, A9 -M-B3-C8, A9-M-B4-C8, A9-M-B9-C1, A9-M-B9-C2, A9-M-B10-C2, A9-M-B11-C2, A9-M -B9-C3, A9-M-B10-C3, A9- M-B11-C3, A9-M-B9-C4, A9-M-B10-C4, A9-M-B11-C4, A9-M-B9 -C5, A9-M- B12-C5, A9-M-B10-C5, A9-M-B11-C5, A9-M-B9-C6, A9-M-B12-C6, A9-M-B10-C6 , A9-M-B11-C6, A9-M-B9-C7, A9-M-B12-C7, A9-M-B10-C7, A9-M-B11-C7, A9-M-B9-C8, A9 -M-B12-C8, A9-M-B10-C8, A9-M-B11-C8.
21. A library comprised of two or more compounds of formula (I) wherein R is selected from the group consisting of: -Ra, -CORa, -CONRaRb, -S02Ra or -COORa; R, is a group -NRcRd or -ORc; wherein Ra, Rb, Rc and Rd are the same or different, and each is independently hydrogen or an optionally substituted group, which is selected from linear or branched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 linear or branched carbon atoms, linear or branched alkynyl of 2 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 6 carbon atoms, aryl or arylalkyl of 1 to 8 carbon atoms, or heterocycle or heterocycloalkyl of 1 to 6 carbon atoms or, taken together with the nitrogen atom to which they are attached, either Ra and Rb as well as Rc and Rd can form an optionally substituted 4- to 7-membered heterocycle, optionally containing an additional heteroatom or a group 5 heteroatom that is selected from S, O, N and NH; R2 is a group, optionally substituted additionally, which is selected from alkyl of 1 to 6 straight or branched carbon atoms, alkenyl of 2 to 6 carbon atoms - linear or branched carbon, linear or branched alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 1 to 0 6 carbon atoms, aryl or arylalkium of 1 to 6 carbon atoms, or heterocycle or heterocycloalkyl of 1 to 6 carbon atoms; or isomers, tautomers, carriers, metabolites, prodrugs and pharmaceutically acceptable salts thereof.
22. The library according to claim 21, further characterized in that R: is a group -NRcRd and Rc and Rd are both hydrogen atoms or one of them is a hydrogen atom and the remainder of Rc or Rd are groups alkyl or alkenyl, or is an optionally substituted aryl or arylalkyl group.
23. The library according to claim 21, further characterized in that R is a hydrogen atom or a -S02Ra group, wherein Ra is linear or branched alkyl or aryl or an optionally substituted arylalkyl group.
24. The library according to claim 21, further characterized in that R is a -CORa group, wherein Ra is a linear or branched alkyl, cycloalkyl or an optionally substituted aryl or arylalkyl group.
25. The library according to claim 21, further characterized in that R is -CONRaRb, wherein one of Ra and Rb is hydrogen and the other of Ra and Rb is a linear or branched alkyl, an aryl or arylalkyl group optionally substituted .
26. The library according to claim 21, further characterized in that R is -CONRaRb, wherein Ra and Rb form, together with the nitrogen atom to which they are attached, an optionally substituted 6-membered heterocyclic ring.
27. The library according to claim 21, further characterized in that R2 is an alkyl, alkenyl, cycloalkyl, cycloalkylalkyl or an optionally substituted aryl or arylalkyl group.
28. The library according to claim 21, further characterized in that the compound in the library is a compound that is included in the lists of tables IV, V, VI, VII, VIII or IX.
29. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 11 and at least one pharmaceutically acceptable excipient, carrier and / or diluent.
30. The pharmaceutical composition according to claim 29, further characterized in that it comprises one or more chemotherapeutic agents.
31. A kit comprising a compound according to claim 11 optionally associated with a pharmaceutical excipient, carrier and / or diluent and one or more chemotherapeutic agents.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB0330042.3 | 2003-12-24 |
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MXPA06007439A true MXPA06007439A (en) | 2006-10-17 |
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