ES2368245T3 - COMBINATIONS FOR THE TREATMENT OF DISEASES THAT INVOLVE A CELL PROLIFERATION. - Google Patents

Abstract

A pharmaceutical composition, comprising effective amounts of: (i) a compound 1 of formula (I): wherein the abbreviations X1, X 2, X 3, X 4 and X 5 used in the Table designate in each case a link to a position in the general formula shown in the Table instead of the corresponding groups R 1, R 2, R 3, R 4 and L nR 5 m, optionally in the form of their racemate tautomers, enantiomers, diastereoisomers and mixtures thereof and optionally in form of its salts by the addition of acids, solvates, pharmacologically acceptable hydrates; and (ii) at least one additional therapeutic agent 2, selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo -2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) -quinazo-canvas or a pharmaceutically acceptable salt thereof, 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone or a pharmaceutically acceptable salt thereof, a platinum compound, selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa and chlorambucil analog, an analogue of pyrimidine or purine or a nucleoside diphosphate reductase inhibitor, selected from the group consisting of cytarabine, 5-fluorouracil (5-FU), permetrexed, tegafur / uracil, mustard uracil, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea and folic acid, a camptothecin, selected from the group consisting of irinotecan and topotecan, a histonadeacetylase inhibitor, selected from the group consisting of SAHA, MD-275, tricostatin A, CBHA, LAQ824 and Valproic acid, an anti-cancer drug from plants, selected from the group consisting of paclitaxel, docetaxel and taxotero.

Description

Combinations for the treatment of diseases that involve cell proliferation

The invention relates to new pharmaceutical compositions for the treatment of diseases that involve cell proliferation, migration or apoptosis of cancer cells or angiogenesis and their preparation. The invention also relates to a method for the treatment of diseases that involve cell proliferation, migration or apoptosis of cancer cells or angiogenesis, a method comprising co-administration to a person in need of such a treatment and / or the co-treatment of a person who

10 you need such a treatment with effective amounts of:

(i) A compound 1 of formula (I) according to claim 1

Ln R5

m

(I)

Wherein the groups L, R1, R2, R3, R4 and R5 have the meanings given in the claims and in the descriptive part, optionally in the form of their tautomers, racemates, enantiomers, diastereoisomers and mixtures thereof and, optionally, in the form of its salts by the addition of acids, solvates, hydrates, polymorphs, physiologically functional derivatives or prodrugs, pharmacologically acceptable; or

(ii) at least one additional chemotherapeutic, immunotherapeutic or immunomodulatory, anti-angiogenic, hormonal or naturally occurring, semisynthetic or synthetic therapeutic agent according to claim 1; I

25 (ii) radiotherapy or radio-immunotherapy.

Background of the invention

Polo-like kinases (PLKs) are serine / threonine kinases that play important roles in

30 regulatory processes in the cell cycle. In the known state of the art four PLKs are described, ie PLK-1, PLK-2, PLK-3 and PLK-4. PLKs play a role in the entrance to and exit of mitosis in mammalian cells. Especially, a central role of PLK-1 was demonstrated with respect to mitosis regulation (Glover et al. 1998, Genes Dev. 12: 3777-87; Qian et al. 2001, Mol Biol Cell. 12: 1791- 9). Overexpression of PLK-1 appears to be strongly associated with neoplastic cells, including cancers (WO 2004/014899). The

35 Overexpression of PLK-1 has been documented for various types of tumors, such as non-small cell lung cancer, squamous cell carcinomas, breast, ovarian or papillary carcinomas as well as colorectal cancers (Wolf et al. 1997, Oncogene 14 , pages 543-549; Knecht et al. 1999, Cancer Res. 59, pages 2794-2797; Wolf et al. 2000, Pathol Res Pract. 196, pages 753-759; Weichert et al. 2004, Br. J. Cancer 90, pages 815-821; Ito et al. 2004, Br. J. Cancer 90, pages 414-418; Takahashi et al. 2003, Cancer Sci. 94, pages

40 148-152).

WO 03/020722 describes compounds similar to formula (I) for the treatment of infectious cancer.

For the treatment of diseases of an oncological nature, a large number of chemotherapeutic, immunotherapeutic or immunomodulatory, antiangiogenic or hormonal agents have already been suggested that can be used as monotherapy (treatment with an agent) or as a combination therapy (simultaneous, separate treatment or sequential with more than one agent) and / or that can be combined with radiotherapy or radio-immunotherapy. In this respect, chemotherapeutic agent means a chemical compound that is produced in nature, semi-synthetic or synthetic that, alone or through additional activation, for example with radiation in the case of radio-immunotherapy, inhibits or kills growing cells, and that it can be used or is approved for use in the treatment of diseases of an oncological nature, which are usually also called cancers. In the literature, these agents are generally classified according to their mechanism of action. In this regard, reference may be made, for example, to the classification made in "Cancer Chemotherapeutic Agents", American Chemical Society, 1995, W.O. Foye Ed.

The effectiveness of chemotherapeutic agents can be improved using combination therapies with other chemotherapeutic, immunotherapeutic, immunomodulatory, antiangiogenic or hormonal compounds. Combination therapies constitute the gold standard without many stipulations of cancer therapy.

Even if the concept of combining various therapeutic agents or therapies has already been suggested, and although various combination therapies and clinical trials are under investigation, there is still a need for new and effective therapeutic compositions for the treatment of cancer diseases that show advantages over conventional therapies.

It is the purpose of the present invention to provide a combination therapy with the PLK inhibitors of formula (I) for the treatment of various carcinogenic diseases.

Description of the invention

Thus, within the meaning of the present invention, the following classes of chemotherapeutic agents are of particular interest, although they do not represent a limitation:

•

Synthetic small molecule VEGF receptor antagonists

•

Small molecule growth factor receptor (GF) antagonists

•

Inhibitors of the EGF receptor and / or the VEGF receptor and / or integrin receptors or any other tyrosine kinase protein receptors that are not classified under synthetic small molecules

•

Small molecule inhibitors of the Ras / Raf / MAPK or P13K / AKT pathways or any other serine / threonine kinases

•

Inhibitors of the Ras / Raf / MAPK or P13K / AKT pathways or any other serine / threonine kinases that are not classified under small synthetic molecules.

•

Inhibitors targeting the EGF receptor and / or the VEGF receptor and / or integrin receptors or any other tyrosine kinase protein receptors, which are antibodies, antibody fragments or synthetically manufactured fusion proteins.

•

Compounds that interact with nucleic acids and that are classified as alkylating agents or platinum compounds

•

Compounds that interact with nucleic acids and that are classified as anthracyclines, as DNA interleavers or as DNA crosslinking agents

•

Anti-metabolites

•

Bleomycin type antibiotics that occur in nature, semi-synthetic or synthetic (antibiotics of the BLM group). Inhibitors of DNA transcription enzymes, especially of topoisomerase I or topoisomerase II inhibitors

•

Chromatin Modifying Agents

•

Mitosis inhibitors, anti-mitotic agents or cell cycle inhibitors

•

Compounds that interact with or that link tubulin

•

Compounds that inhibit mitotic kinesins or other motor proteins that include, but are not limited to Eg5, CENP-E, MCAK, Kid, MKLP-1

•

Proteasome inhibitors

•

Heat Shock Protein Inhibitors

•

Compounds that are directed against the anti-apoptotic function of Bcl-2, Bcl-x1 and similar molecules

•

Enzyme hormones, hormone antagonists or hormone inhibitors or steroid biosynthesis inhibitors

•

Steroids

•

Cytokines, hypoxia selective cytotoxins, cytokine inhibitors, lymphokines, targeted antibodies

against cytokines or oral and parenteral tolerance induction strategies

•

Support agents

•

Anti-inflammatory compounds, such as, but not limited to COX-2 inhibitors

• Chemical radiation sensitizers and protectors 5 • Photochemically activated drugs

•

Synthetic polynucleotides or oligonucleotides

•

Other chemotherapeutic or therapeutic agents that occur in nature, semi-synthetic or synthetic, such as cytotoxic antibodies, antibodies that are directed against surface molecules of cancer cells, antibodies that are directed against growth factors or their receptors, inhibitors of

10 metalloproteinases, oncogenes inhibitors, inhibitors of gene transcription or RNA translation

or of the expression of proteins, or complexes of rare earth elements.

The beneficial effects of the invention are based mainly on the additive and synergistic effects of the combined treatment, on an improved tolerability of the treatment by the patient due, for example, to the administration of low doses of the therapeutic agents involved.

Within the meaning of the present invention, compound 1 has the structure of the following general formula (I) according to claim 1:

Ln R5

m

20 (I)

Thus, this invention relates to a pharmaceutical composition according to claim 1, which comprises effective amounts of:

(I) A compound 1 of formula (I) or, optionally, a polymorph, metabolite, hydrate, preferably the monohydrate, solvate, individual optical isomers or mixtures of the individual enantiomers or their racemates

or a pharmaceutically acceptable salt thereof; Y

(ii)

at least one additional chemotherapeutic or therapeutic agent that is produced in nature, semi-synthetic or synthetic;

30 optionally in combination with one or more pharmaceutically acceptable excipients, and optionally intended for co-treatment with radiotherapy or radio-immunotherapy in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of diseases involving cell proliferation, Migration or apoptosis of cancer cells, or angiogenesis, preferably involving proliferation

35 cell or apoptosis of cancer cells.

In a preferred embodiment, the present invention is directed to a pharmaceutical composition, wherein the additional semi-synthetic or synthetic chemotherapeutic or therapeutic agent 2 is selected from the group consisting of compounds that interact with or bind tubulin, VEGF receptor antagonists

40 synthetic small molecules, small molecule growth factor receptor antagonists, EGF receptor and / or VEGF receptor and / or integrin receptor inhibitors or any other tyrosine kinase protein receptors that are not classified under synthetic small molecules, inhibitors targeting the EGF receptor and / or the VEGF receptor and / or integrin receptors or any other tyrosine kinase protein receptors, which are fusion proteins, compounds that interact with nucleic acids and that are classified as alkylating agents or platinum compounds, compounds that interact with nucleic acids and that are classified as anthracyclines, as DNA interleavers or as DNA crosslinking agents, including small slot DNA binding compounds, anti-metabolites, antibiotics of the type Bleomycin that occur in nature, semi-synthetic or synthetic, enzyme inhibitors s DNA transcriptionists and, especially, topoisomerase I or topoisomerase II inhibitors, chromatin modifying agents, mitosis inhibitors, anti-mitotic agents, cell cycle inhibitors, proteasome inhibitors, enzymes, hormones, hormone antagonists, inhibitors of hormones, steroid biosynthesis inhibitors, steroids, cytokines, hypoxia selective cytotoxins, cytokine inhibitors, lymphokines, antibodies directed against cytokines, oral and parenteral tolerance inducing agents, support agents, sensitizers and protectors of the chemical radiation, photochemically activated drugs, polynucleotides or synthetic oligonucleotides, non-steroidal anti-inflammatory drugs, optionally modified or conjugated, cytotoxic antibiotics, antibodies directed against cancer cell surface molecules, antibodies directed against growth factors or their receptors, inh metalloproteinase, metal, oncogenes inhibitors, gene transcription or RNA translation or protein expression inhibitors, rare earth element complexes and photochemotherapeutic agents.

Preferred compounds include small molecule tyrosine kinase or serine / threonine kinase inhibitors, compounds that interact with nucleic acids classified as alkylating or anthracycline agents, antimetabolites, inhibitors of DNA transcription enzymes, such as topoisomerase I or II, tubulin-binding drugs, anti-mitotic agents, antibodies directed against growth factors or their receptors and antibodies that bind to surface molecules of cancer cells or ligands of these surface molecules in the form of hydrates and / or solvates and, optionally, in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof.

In another preferred embodiment, the present invention is directed to a pharmaceutical combination, wherein the additional semi-synthetic or synthetic chemotherapeutic or therapeutic agent 2 is selected from the group consisting of a VEGF receptor antagonist of small molecules, such as vatalanib (PTK787 / ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG013736, IM-842 or GW-786034, a dual EGFR / HER2 antagonist, such as geftinib, erlotinib, CI-1033 or GW-2016, an EGFR antagonist, such as iressa (ZD-1839), tarceva (OSI-774), PKI-166 , EKB-569, HKI-272 or herceptin, a mitogen-activated protein kinase antagonist, such as BAY-43-9006 or BAY-57-9006, a quinazoline derivative, such as 4 - [(3-chloro- 4-fluorophenyl) -amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((S) tetrahydrofuran-3-yloxy) - quinazo-canvas or 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (homomorpholin-4-yl) -1-ox o-2-buten-1il] ami-no} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline, or a pharmaceutically acceptable salt thereof, a protein kinase receptor antagonist that does not It is classified under synthetic small molecules, such as atrasentan, rituximab, cetuximab, Avastin (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, a protein inhibitor tyrosine kinase, which is a fusion protein, such as VEGFtrap, an alkylating agent or a platinum compound, such as melphalan, cyclophosphamide, an oxazaphosphoryine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin (carmustine, carmustine BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, a mustard nitrogen, such as mechloroethalamine, an ethyleneimine compound, an alkylsulfonate, daunorubicin, doxorubicin (adriamycin), doxorubicin doxorubicin, doxorubicin l , mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mitramycin, cromomycin, olivomycin, a phthalanilide, such as propamidine or stilbamidine, an antramycin, an aziridine, a nitrosourea or one of its derivatives, a pyrimidine or purine analogue or antagonist or a nucleoside diphosphate reductase inhibitor, such as cytarabine, 5-fluorouracil (5-FU), permetrexed, tegafur / uracil, mustard uracil, fludarabine, gemcitabine, capecitabine, mercapiburine, claptabine , thioguanine, methotrexate, pentostatin, hydroxyurea or folic acid, a fleomycin, a bleomycin, a derivative or salt thereof, CHPP, BZPP, MTPP, BAPP, liblomycin, an acridine or a derivative thereof, a rifamycin, an actinomycin , adramycin, a camptothecin, such as irinotecan (camptosar) or topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, a histonadeacetylase inhibitor, such as SAHA, MD-275, tricostat ina A, CBHA, LAQ824, or valproic acid, an anticancer drug from plants such as paclitaxel (taxol), docetaxel or taxoter, a vinca alkaloid such as navelbine, vinblastine, vincristine, vindesine or vinorelbine, a tropolone alkaloid such as colchicine or a derivative thereof, a macrolide, such as maitansin, an ansamitocin or rhizoxine, an antimitotic peptide such as fomopsin or dolastatin, an epipodophyllotoxin or a derivative of podophyllotoxin, such as etoposide or teniposide, a steganacin, a carbamate derivative, antimicrobial such as combrestatin or amphetin, procarbazine, a proteasome inhibitor, such as bortezomib, an enzyme, such as asparaginase, pegylated asparaginase (pegaspargasse) or a thymidine phosphorylase inhibitor, or a gestagen or estrogen, such as stramustine (T-66 ) or megestrol, an anti-androgen, such as flutamide, casedex, anadron or cyproterone acetate, an aromatase inhibitor, such as aminoglutethimide, ana strozole, formestan or letrozole, a GNrH analog, such as leuprorelin, buserelin, goserelin or triptorelin, an anti-estrogen, such as tamoxifen or its citrate salt, droloxifene, trioxifene, raloxifene or zindoxifene, a derivative of 17β-estradiol, such as ICI 164,384 or ICI 182,780, aminoglutethimide, formestane, fadrozol, finasteride, ketoconazole, an LH-RH antagonist, such as leuprolide, a steroid, such as prednisone, prednisolone, methylprednisolone, dexamethasone, budenoside, fluocortone, interferon such as interferon β, an interleukin, such as IL-10 or IL-12, an anti-TNFα antibody, such as etanercept, an immunomodulatory drug, such as thalidomide, its R and S enantiomers and its derivatives, or revived (CC- 5013), a leukotriene antagonist, mitomycin C, an aziridoquinone, such as BMY-42355, AZQ or EO-9, a 2-nitroimidazole, such as misoindazole, NLP-1 or NLA-1, a nitroacridine, a nitroquinoline, a nitropyrazoloacridine, a compound to aromatic nitro of "double function" such as RSU-1069 or RB-6145, CB-1954, an N-oxide of a mustard nitrogen, such as nitromine, a metal complex of a mustard nitrogen, an anti-CD3 or anti-CD25 antibody, an inducing agent for tolerance, a bisphosphonate or derivative thereof, such as minodronic acid or its derivatives (YM-529, Ono-5920, YH-529), zoledronic acid monohydrate, ibandronate sodium hydrate or clodronate disodium, a nitroimidazole, such as metronidazole, misonidazole, benznidazole or nimorazole, a nitroaryl compound, such as RSU-1069, a nitroxyl or N-oxide, such as SR-4233, a halogenated pyrimidine analogue, such as bromodeoxyuridine, iododeoxyuridine, a thiophosphate, such as WR-2721, a photochemically activated drug, such as porfimer, fotofrin, a benzoporphyrin derivative, a feoforbide derivative, merocyanine 540 (MC-540) or tin etioporpurine, an anti-template or an anti-sense RNA or DNA, such as oblimersen, a non-steroidal inflammatory drug, such as acid a cetilsalicílico, mesalazine, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac , fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac, mefenamic acid, meclofenamic acid, fluophenamic acid, nifluminic acid, tolfenamic acid, diflunmimethalamide, flufenimidae, flufenimidae, flufenimidamide, flufenimidamide, flufenimidae, flufenimidae, flufenimidae, flufenimidamide, flufenimidae, flufenimidae, flufenimidamide, flufenimidamide, nichloroxyamide celecoxib, rofecoxib, or a pharmaceutically acceptable salt of a non-steroidal inflammatory drug, a cytotoxic antibiotic, an antibody that is directed against the surface molecules of cancer cells, such as apolizumab or 1D09C3, a metalloproteinance inhibitor, such as TIMP- 1 or TIMP-2, Zinc, an oncogenes inhibitor, such as P53 and Rb, a complex of rare earth elements, such as lanthanide heterocyclic complexes, a photochemotherapeutic agent, such as PUVA, an inhibitor of the ESX / DRP130 / Sur-2 transcription factor complex, an inhibitor of HER- expression 2, such as the modulator of the HSP90 heat shock geldanamicin protein and its 17-allylaminogeldanamicin or 17-AAG derivative, or a therapeutic agent selected from IM-842, tetrathiomolibdate, squalamin, combrestatin A4, TNP-470, marimastat, neovastat, bicalutamide, abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide, denileucine diftitox, aldesleucine, dacarbazine, floxuridine, plicamycin, mitotane, pipobroman, plicamycin and tamoxifentola, tamoxifentola. Preferred compounds include small molecule VEGF receptor antagonists such as vatalanib (PTK787 / ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, EGFR / HER2 antagonists, such as CI1033 or GW-2016, an EGFR antagonist, such as iressa (gefitinib, ZD-1839), tarceva (erlotinib, OSI-774), PKI166, EKB-569, HKI-272 or herceptin, a mitogen-activated protein kinase antagonist , such as BAY43-9006 or BAY-57-9006, atrasentan, rituximab, cetuximab, AvastinR (bevacizumab), IMC-1C11, erbitux (C-225), DC101, EMD-72000, vitaxin, imatinib, an alkylating agent or a platinum compound, such as melphalan, cyclophosphamide, cisplatin, carboplatin, oxaliplatin, satraplatin, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, an analogue or a pyrimidine diphtherine inhibitor or purine inhibitor nucleoside reductase, such as cytarabine, 5-fluorouracil (5-FU), pemetrexed, tegafur / ura cilo, gemcitabine, capecitabine, mercaptopurine, methotrexate, an anti-cancer drug such as paclitaxel (taxol) or docetaxel, a vinca alkaloid such as navelbine, vinblastine, vincristine, vindesine or vinorelbine, an antimitotic peptide, such as dolastatin, an epipodofox a podophyllotoxin derivative, such as etoposide or teniposide, an anti-inflammatory or steroid drug, such as meloxicam, celecoxib, rofecoxib, an antibody directed against the surface molecules of cancer cells, such as apolizumab or 1D09C3 or the HSP90 protein modulator of thermal shock geldanamicin and its derivative 17-allylaminophendanamicin or 17-AAG.

In another preferred embodiment, the present invention is directed to a pharmaceutical composition, in which the chemotherapeutic or therapeutic agent 2 that is produced in nature, additional semi-synthetic or synthetic is selected from the group consisting of an anti-carcinogenic drug from of plants, such as paclitaxel (taxol), docetaxel, a vinca alkaloid, such as navelbine, vinblastine, vincristine, vindesine or vinorelbine, an alkylating agent or a platinum compound, such as melphalan, cyclophosphamide, an oxazaphosphorin, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, a mustard nitrogen such as mechlorethamine, an immunomodulatory drug, such as enomomodulating drug, such as enomomodulatory drug, such as enomodomiders and S and its derivatives, or revimid (CC-5013), a compound of ethyleneimine, an alkylsulfonate, daunorubicin, doxorubicin (adri amycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or one of its derivatives, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mitramycin, chromomycin such as olivomycin propamidine or stilbamidine, an antramycin, an aziridine, a nitrosourea or a derivative thereof, an analogue or a pyrimidine or purine antagonist or a nucleoside diphosphate reductase inhibitor such as cytarabine, 5fluorouracil (5-FU), mustard uracil, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, metrotexate, pentostatin, hydroxyurea or folic acid, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, a camptothecin, such as irinotecan (campcan) an amsacrine or analog thereof, a tricyclic carboxamide, a histonadeacetylase inhibitor, such as SAHA, MD-275, tricostatin A, CBHA, LAQ824, or valpr acid Oico, a proteasome inhibitor, such as bortezomib, a small molecule VEGF receptor antagonist, such as vatalanib (PTK-787 / ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD- 6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034, a mitogen-activated protein kinase antagonist, such as BAY-43-9006 or BAY-57-9006, a dual EGFR / HER2 antagonist, such as gefitinib, erlotinib, CI-1033 or GW-2016, an EGFR antagonist, such as iressa (ZD-1839), tarceva (OSI774), PKI-166, EKB-569, HKI -272 or herceptin, a quinazoline derivative, such as 4 - [(3-chloro-4-fluorophenyl) amino] 6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1- il] amino} -7 - ((S) -tetrahydro-furan-3-yloxy) -quinazoline or 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (homomorfolin-4-yl ) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline, or a pharmaceutically acceptable salt thereof, a complex inhibitor of the transcription factor ESX / DRIP130 / Sur-2, an inhibitor of HER-2 expression, such as the geldanamicin HSP90 heat shock protein modulator and its 17-allylaminogeldanamicin derivative or 17-AAG, a protein kinase receptor antagonist that is not classified under small synthetic molecules, such as atrasentan , rituximab, cetuximab, Avastin (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, and an antibody directed against cancer cell surface molecules, such as apolizumab or 1D09C3.

Preferred compounds include small molecule receptor antagonists, such as vatalanib, SU 11248

or AZD-6474, EGFR or HER2 antagonists, such as gefitinib, erlotinib, CI-1033, or Herceptin, antibodies, such as bevacizumab, cetuximab, rituximab, DNA alkylating drugs, such as cisplatin, oxaliplatin or carboplatin, anthracyclines, such such as doxorubicin or epirubicin, an antimetabolite, such as 5-FU, permetrexed, gemcitabine or capecitabine, a camptothecin, such as irinotecan or topotecan, an anti-cancer drug, such as paclitaxel or docetaxel, an epipodophyllotoxin, such as etoposide or tenipidide a proteasome inhibitor, such as bortezomib or anti-inflammatory drugs, such as celecoxib or rofecoxib, optionally in the form of pharmaceutically acceptable salts, in the form of hydrates and / or solvates and, optionally, in the form of individual optical isomers, mixtures of the individual enantiomers or racemates thereof.

In another preferred embodiment, the present invention is directed to pharmaceutical compositions as defined hereinbefore, wherein the chemotherapeutic or therapeutic agent 2 that is produced in nature, additional semisynthetic or synthetic is the quinazoline derivative 4 - [(3 -chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1oxo-2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention is directed to a pharmaceutical composition as defined hereinbefore, wherein the chemotherapeutic or therapeutic agent 2 that is produced in nature, additional semisynthetic or synthetic is the di-maleic acid salt of the compound 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline, or 4 - [(3-chloro-4-fluorophenyl) amino] -6 {[4- (homomorpholin-4-yl) -1-oxo-2-buten-1-yl ] amino} -7 - ((S) -tetrahydrofuran-3-yl) oxy] -quinazoline, or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention is directed to a pharmaceutical composition as defined hereinbefore, wherein the chemotherapeutic or therapeutic agent 2 that is produced in nature, additional semisynthetic or synthetic is 4 - [(3-chloro -4-fluorophenyl) amino] -6 - {[4- (homomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} 7 - ((S) -tetrahydrofuran-3-yl) oxy ] -quinazoline, or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention is directed to a pharmaceutical composition as defined hereinbefore, wherein the chemotherapeutic or therapeutic agent 2 that is produced in nature, additional semisynthetic or synthetic is 3-Z- [1- (4- (N - ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, or a polymorph, metabo -Lite or pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention is directed to a pharmaceutical composition as defined hereinbefore, wherein the additional chemotherapeutic or therapeutic agent 2 that is produced in nature, is semi-synthetic or synthetic, is the monoethanesulfonate salt of 3-Z- [1- (4- (N - ((4-methyl-piperazin-1-yl) -methylcarbonyl) -Nmethyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone.

In another preferred embodiment, the present invention is directed to a pharmaceutical composition as defined hereinbefore, wherein the chemotherapeutic or therapeutic agent 2 that is produced in nature, additional semisynthetic or synthetic is 3-Z- [1- (4-dimethylaminomethylanilino) -1- (4- (2-carboxyethyl) -phenyl) methylene] -6-fluoro-2-indolinone, or a pharmaceutically acceptable polymorph, metabolite or salt thereof.

In another preferred embodiment, the present invention is directed to a pharmaceutical composition, wherein the chemotherapeutic or therapeutic agent that is produced in nature, additional semi-synthetic or synthetic is irinotecan, topotecan, oxaliplatin, docetaxel, paclitaxel, gemcitabine, pemetrexed , cisplatin, carboplatin, bevacizumab, cetuximab, gefitinib or erlotinib, particularly preferably irinotecan, docetaxel, gemcitabine, topotecan or paclitaxel.

In another preferred embodiment, the present invention is directed to a pharmaceutical composition as defined hereinbefore, wherein the additional naturally occurring semi-synthetic or synthetic therapeutic agent 2 is a compound that reduces the transport of hyaluronan mediated by one or more ABC transporters, or a drug transport inhibitor, such as a P-glycoprotein (P-gp) inhibitor molecule or an inhibitor peptide, an MRP1 inhibitor, an antibody directed against and that is capable of blocking the ABC transporter, an anti-sense oligomer, RNAi, siRNA or aptamer directed against one or more ABC transporters. Examples of P-glycoprotein (P-gp) inhibitory molecules according to the present invention are zosuquidar (LY 335973), its salts (especially trichloride salt) and its polymorphs, cyclosporine A (also known as cyclosporine), verapamil or its R isomer, tamoxifen, quinidine, d-alpha-tocopherol-polyethylene glycol 1000 succinate, VX-710, PSC833, phenothiazine, GF120918 (II), SDZ, PSC 833, TMBY, MS-073, S-9788, SDZ 280-446, XR (9051) and derivatives, analogs and functional isomers thereof.

In addition, in the case where the compounds 2 carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium salts or magnesium) and salts formed with suitable organic ligands (for example quaternary ammonium salts).

Compounds 2 can have chiral centers and can be produced in the form of racemates, racemic mixtures and as individual diastereoisomers or enantiomers, all isomeric forms being included in the present invention. Therefore, in the case where a compound is chiral, the separated enantiomers, essentially free of the others, are included within the scope of the invention. In addition, all mixtures of the two enantiomers are included. Polymorphs and hydrates of the compounds of the present invention are also included within the scope of the invention.

The present invention includes within its scope prodrugs of a compound 1 of formula (I) and of the additional active ingredient 2. In general, prodrugs of this type will be functional derivatives of the active compounds or ingredients of this invention that are easily convertible in vivo into the required compound.

In a further embodiment, the invention relates to a composition as defined hereinbefore, which inhibits the proliferation of various human tumor cell lines, which include, but are not limited to Saos-2, H4, MDA-MB- 435S, MDA-MB-453, MCF7, HeLa S3, HCT116, Colo 205, HT29, FaDu, HL-60, K-562, THP-1, HepG2, A549, NCI-H460, GRANTA-519, Raji, Ramos, BRO, SKOV-3, BxPC-3, Mia CaPa-2, DU145, PC-3, NCI-N87, MES-SA, SK-UT-1B and A431.

Another embodiment of the invention relates to the use of a pharmaceutical composition as defined hereinbefore for the preparation of a medicament for the treatment of oncological diseases such as malignant human neoplasms.

In a preferred embodiment, the present invention relates to the use of a pharmaceutical composition as defined hereinbefore, wherein the oncological disease is selected from the group consisting of solid tumors.

In a further preferred embodiment, the invention relates to the use of a pharmaceutical composition as defined hereinbefore, wherein the oncological disease is selected from the group consisting of urogenital cancers (such as prostate cancer, renal cell cancers, bladder cancers), gynecological cancers (such as ovarian cancers, cervical cancers, endometrial cancers), lung cancer, gastrointestinal cancers (such as colorectal cancers, pancreatic cancer, gastric cancer, esophageal cancers, hepatocellular cancers, cholangiocellular cancers) of head and neck, malignant mesothelioma, breast cancer, malignant melanoma or sarcomas of the bones and soft tissue.

In a further preferred embodiment, the invention relates to the use of a pharmaceutical composition as defined hereinbefore, wherein the oncological disease is selected from the group consisting of refractory or recurrent multiple myeloma, acute or chronic myelogenous leukemia, myelodysplastic syndrome , acute lymphoblastic leukemia, Hodgkin lymphoma or not Hodgkin.

In a further preferred embodiment, the disease is hormone-sensitive or hormone-refractory prostate cancer, ovarian carcinoma or small cell lung cancer.

In a further preferred embodiment, the invention relates to the use of a composition defined hereinbefore, wherein the oncological disease is characterized by inappropriate cell proliferation, migration, apoptosis or angiogenesis, preferably by inappropriate cell proliferation. Inappropriate cell proliferation means cell proliferation that results from inappropriate cell development, excessive cell division, cell division at an accelerated rate and / or inappropriate cell survival.

In a further preferred embodiment, the invention relates to the use according to the invention, wherein the disease is cancer selected from the group consisting of carcinomas, sarcomas, melanomas, myelomas, hematologic malignancies, lymphomas and childhood cancers.

Examples of carcinomas within the scope of the invention include, but are not limited to adenocarcinoma (AC), squamous cell carcinoma (SCC) and mixed or undifferentiated carcinomas. Carcinomas within the scope of the invention include, but are not limited to the following histologies:

•

Head and neck tumors: SCC, AC, transient cell cancer, mucoepidermoid cancers, undifferentiated carcinomas:

•

Tumors of the central nervous system: astrocytoma, glioblastoma, meningeoma, neurinoma, schwannoma, ependymoma, hypophysome, oligodendroglioma, medulloblastoma;

•

Bronchial and mediastinal tumors:

○

bronchial tumors:

■

small cell lung cancers (SCLC): oat cell lung cancer intermediate cell cancer, combined oat cell lung cancer;

■

non-small cell lung cancers (NSCLC): SCC, spindle cell carcinoma, AC, bronchioalveolar carcinoma, NSCLC large cell, NSCLC transparent cell;

○

mesothelioma;

○

thymoma;

○

thyroid carcinomas: papillary, follicular, anaplastic, medullary;

•

Tumors of the gastrointestinal tract:

○

esophageal cancers: SCC, AC, anaplastic, carcinoid, sarcoma;

○

gastric cancers: AC, adenoescamoso, anaplastic;

○

colorectal cancers: AC, including inherited forms of AC, carcinoid, sarcoma;

○

anal cancers: SCC, transient epithelial cancer, AC, basal cell carcinoma;

○

pancreatic cancers: AC, including ductal and aquatic, papillary, adenoescamosus, undifferentiated, endocrine pancreatic tumors;

○

hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, hepatoblastoma;

○

biliary carcinomas: AC, SCC, small cells, undifferentiated; gastrointestinal stromal tumors (GIST);

•

gynecological cancers:

○

breast cancers: AC, including invasive ductal, lobular and medullary cancers, tubular, mucinous cancers, Paget carcinoma, inflammatory carcinoma, ductal and lobular carcinoma in situ;

○

ovarian cancers: epithelial tumors, stromal tumors, germ cell tumors, undifferentiated tumors;

○

cervical cancers: SCC, AC, mixed and undifferentiated tumors;

○

endometrial cancers: AC, SCC, mixed tumors, undifferentiated;

○

cancers of the vulva: SCC, AC;

○

vaginal cancers: SCC, AC;

•

urinary tract and testicular cancers:

○

testicular cancers: seminoma;

○

nonseminomatous germ cell tumors: teratoma, embryonic cell carcinoma, choriocarcinoma, yolk sac tumor, mixed Sertoli and Leydig cell tumors;

○

extragonadal germ cell tumors;

○

prostate cancers: AC, small cells, SCC;

○

renal cell cancers: CA, including transparent cell carcinomas, papillary and chromophobes, inherited forms (eg von Hippel-Lindau syndrome), nephroblastoma;

○

urinary bladder cancers: transient (urothelial) cell cancers, SCC, AC;

○

urethral cancers: SCC, transient cell cancers, AC;

○

penile cancers: SCC;

•

Endocrine tissue tumors:

○

thyroid cancers: papillary, follicular, anaplastic, medullary carcinomas, including MEN syndrome;

○

endocrine pancreas tumors;

○

carcinoids;

○

adrenal tumors, for example pheochromocytoma.

Examples of sarcomas within the scope of the invention include, but are not limited to Ewing's sarcoma, osteosarcoma or osteogenic sarcoma, chondrosarcoma, synovial sarcoma, leiomyosarcoma, rhabdomyosarcoma, mesothelial sarcoma or mesothelioma, fibrosarcoma, angiosarcoma, or hemangioendothelioma, liposarcoma, oiposarcoma, oiposarcoma , myoxosarcoma, malignant fibrous histiocytoma, mixed mesenchymal or mesodermal tumor, neuroblastoma and transparent cell sarcoma.

Examples of skin tumors within the scope of the invention include, but are not limited to basal cell carcinomas, Merkel cell carcinoma, sebaceous carcinoma, fibroxanthoma, malignant fibrous histiocytoma and skin sarcoma.

Examples of melanomas within the scope of the invention include, but are not limited to superficial expansive melanoma, nodular and lentigo-malignant melanoma.

Examples of myelomas within the scope of the invention include, but are not limited to immunocytoma, plasmocytoma and multiple myeloma.

Examples of childhood cancers within the scope of the invention include, but are not limited to Wilms' tumor, neuroblastoma, retinoblastoma, rhabdomyosarcoma, Ewing's sarcoma and peripheral primitive neuroectodermal tumors, germ cell tumors and childhood lymphoma, and leukemia.

In another preferred embodiment, the invention relates to the use of a composition as defined hereinbefore, wherein the hematologic cancer is leukemia.

Additional examples of hematological malignancies within the scope of the invention include, but are not limited to acute or chronic leukemia of myeloid, erythroid or lymphatic origin, myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS), such such as chronic myelogenous leukemia, osteomyelofibrosis, polycythemia vera or essential thrombocythemia).

Examples of lymphomas within the scope of the invention include, but are not limited to:

•

Hodgkin lymphoma;

•

non-Hodgkin lymphomas: T and B cell lymphomas

○

B cell lymphomas:

■

Low and intermediate grade: chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), small lymphocytic lymphoma, hair cell leukemia, plasmacytoid lymphoma, mantle cell lymphoma, follicular lymphoma, lymphoma the marginal zone, including MALT lymphoma;

■

high grade: diffuse large B-cell lymphoma (DLBCL), including immunoblastic and centroblastic variants), Burkitt lymphoblastic lymphoma;

○

T-cell lymphoma:

■

Low grade: T-CLL, T-PLL, fungoid mycosis, Sezary syndrome;

■

High grade: anaplastic, T-immunoblastic and lymphoblastic large cells.

In another preferred embodiment, the invention relates to the use according to the invention, wherein the disease is cancer selected from the group consisting of mixed tumors, undifferentiated tumors and metastases thereof.

Examples of mixed tumors within the scope of the invention include, but are not limited to adenoescamosal carcinomas, mixed mesodermal tumors, carcinosarcomas and teratocarcinomas.

Examples of other undifferentiated tumors or metastases thereof within the scope of the invention include, but are not limited to undifferentiated tumors, carcinomas of unknown origin (CUP), metastasis of unknown origin (MUP). ) and pheochromocytoma, carcinoids.

In a further embodiment, the invention relates to the use of a composition as defined hereinbefore, for the preparation of a medicament for the treatment of autoimmune disorders selected from the group consisting of amyloidosis, systemic lupus erythematosus, rheumatoid arthritis, disease Crohn's disease, multiple sclerosis, systemic sclerosis (scleroderma), mixed connective tissue disease, Sjögren's syndrome, ankylosing spondylitis, autoimmune vasculitis, Behcet's syndrome, psoriasis, autoimmune arthritis, sarcoidosis and diabetes melitus.

In a further embodiment, the invention relates to the use of a composition as defined hereinbefore, for the preparation of a medicament for the treatment of additional non-oncological diseases, such as diabetic retinopathy and rheumatoid arthritis.

In a further embodiment, the invention relates to the use of a composition as defined hereinbefore, wherein the composition according to the invention is administered orally, enterally, transdermally, intravenously, peritoneally or by injection, preferably by intravenously.

In a further embodiment, the invention relates to a pharmaceutical combination preparation kit for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, which comprises a therapeutically effective amount of a compound. 1 of formula (I) according to the present invention, or a pharmaceutically acceptable polymorph, hydrate, metabolite or salt thereof, and at least one additional chemotherapeutic or therapeutic agent 2 that is produced in nature, semi-synthetic or synthetic and , optionally, intended for co-treatment with radiotherapy or radio-immunotherapy, characterized in that the compound 1 of formula (I) is comprised within a first compartment, and the chemotherapeutic or therapeutic agent 2 that occurs in nature, semi- additional synthetic or synthetic is comprised within a second compartment, so that administration to a Patient who needs it can be simultaneous, separate or sequential.

In a preferred embodiment, the invention relates to a pharmaceutical combination preparation kit, wherein the formulation of the compound 1 of formula (I) according to the present invention is for oral administration or injection.

In a further embodiment, the invention relates to the use of a pharmaceutical combination or a pharmaceutical combination preparation kit for the manufacture of a medicament, optionally intended for co-treatment with radiotherapy or radio-immunotherapy, to treat diseases involving a cell proliferation, a migration or apoptosis of cancer cells, or angiogenesis, in a human or non-human mammalian body.

In a further embodiment, the invention relates to the use of an effective amount of a compound 1 of formula (I) or a pharmaceutically acceptable polymorph, hydrate, metabolite or salt thereof, in combination with at least one chemotherapeutic or therapeutic agent 2 which It is produced in nature, semi-synthetic or additional synthetic, for the manufacture of a pharmaceutical combination preparation, optionally intended for co-treatment with radiotherapy or radio-immunotherapy, for simultaneous, separate or sequential use in the treatment of diseases which involve a proliferation of cells, migration or apoptosis of cancer cells, or angiogenesis, in a human or non-human mammalian body.

In a further embodiment, the invention relates to a method for the treatment of diseases that involve cell proliferation, migration or apoptosis of cancer cells, or angiogenesis, a method comprising the simultaneous, separate or sequential co-administration of effective amounts. from:

(i)

a compound 1 of formula (I) or a polymorph, metabolite, hydrate, solvate, an individual optical isomer, mixtures of the individual enantiomers or racemates thereof, or a pharmaceutically acceptable salt thereof; Y

(ii)

at least one chemotherapeutic or therapeutic agent 2 that is produced in nature, semi-synthetic or synthetic, additional;

in the form of a combined preparation, optionally intended for co-treatment with radiotherapy or radioimmunotherapy, to a person in need of such a treatment.

In a further embodiment, the invention relates to the uses described above, characterized by a compound 1 of formula (I), or its polymorph, metabolite, hydrate, solvate, an individual optical isomer, mixtures of the individual enantiomers or racemates of the themselves, or a pharmaceutically acceptable salt thereof, is administered intermittently or in a daily dosage, so that the plasma level of the active substance is between 10 and 5000 nM for at least 12 hours of the dosage range.

The expression "therapeutically effective amount" It must imply the amount of a drug or pharmaceutical agent that will educate the biological or medical response of a tissue, system, animal or human being that is being sought by a researcher or doctor.

As used herein, the term "composition" It is intended to encompass a product comprising the specified ingredients in the specified quantities, as well as any product that results, directly or indirectly, from a combination of the specified ingredients in the specified quantities.

As already mentioned above, within the meaning of the present invention, components 1 and 2 of the composition for a combination therapy can be administered separately (implying that they are formulated separately) or together (which implies to be formulated together). Thus, the administration of one element of the combination of the present invention may be prior, concurrent to or subsequent to the administration of the other element of the combination.

In accordance with the present invention, the elements of the combination of 1 and 2 can be administered orally (including the buccal or sublingual route), enteric, parenteral (for example intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection, or by implant), nasal, vaginal, rectal or topical routes of administration (eg eye drops) and can be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic and pharmaceutically acceptable carriers, adjuvants and conventional vehicles for each route of administration.

In a preferred embodiment, element 1 of the combination according to the invention is administered orally, enterically, transdermally, intravenously, peritoneally or by injection, preferably intravenously.

The pharmaceutical compositions for the administration of components 1 and 2 of this invention may conveniently be presented in a dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of associating the active ingredient with the support consisting of one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately associating the active ingredients with a liquid support or a finely divided solid support, or both, and then, if necessary, by molding the product to the desired dosage form. In pharmaceutical compositions, the active compounds are included in an amount sufficient to produce the desired pharmacological effect.

Pharmaceutical compositions containing active ingredients 1 and 2, separately or together, which are suitable for oral administration, may be in the form of discrete units, such as hard or soft capsules, tablets, troches or tablets, each containing one a predetermined amount of the active ingredients, or in the form of a dispersible powder or granules, or in the form of a solution or a suspension in an aqueous or non-aqueous liquid, or in the form of syrups or elixirs, or in the form of an emulsion of oil in water or an emulsion of water in oil.

Dosage forms intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical formulations and compositions of this type.

The excipients used may be, for example: (a) inert diluents, such as mannitol, sorbitol, calcium carbonate, pregelatinized starch, lactose, calcium phosphate or sodium phosphate; (b) granulating or disintegrating agents, such as povidone, copovidone, hydroxypropyl methylcellulose, corn starch, alginic acid, crospovidone, sodium starch glycolate, croscarmellose or potassium polacriline; (c) binding agents, such as microcrystalline cellulose or acacia; and (d) lubricating agents, such as magnesium stearate, stearic acid, fumaric acid or talc.

In some cases, formulations for oral use may be in the form of hard gelatin or HPMC (hydroxypropylmethylcellulose) capsules, wherein the active ingredients 1 or 2, separately or together, are mixed with an inert solid diluent, for example starch pregelatinized, calcium carbonate, calcium phosphate or kaolin, or are dispensed through a nodule formulation. They can also be in the form of soft gelatin capsules, wherein the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin, medium chain triglycerides or olive oil. The tablets, capsules or nodules may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a delayed or sustained action over a longer period. For example, a time-delaying material, such as cellulose acetate phthalate or hydroxypropylcellulose acetate succinate, or a sustained release material, such as ethyl cellulose or ammonium methacrylate copolymer (type B) can be used.

Liquid dosage forms for oral administration according to the present invention include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Along with inert diluents of this type, the compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, perfuming and preservative agents.

Aqueous suspensions according to the present invention normally contain the active materials 1 and 2, separately or together, in admixture with excipients suitable for the manufacture of aqueous suspensions. Excipients of this type may be (a) suspending agents, such as hydroxyethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; (b) dispersing or wetting agents that can be (b.1) a naturally occurring phosphatide, such as lecithin, (b.2) a condensation product of an alkylene oxide with a fatty acid, for example poly (oxyethylene stearate), (b.3) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example heptadecaethylene oxyethanol, (b.4) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitol monooleate, or (b.5) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

Aqueous suspensions may also contain: one or more preservatives, for example ethyl p-hydroxybenzoate or n-propyl; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions according to the present invention can be formulated by suspending active ingredients 1 and 2, separately or together, in a vegetable oil, for example peanut oil, olive oil, sesame oil, coconut oil, or in an oil mineral, such as liquid paraffin. The oil suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide a swallowable oral preparation. These compositions can be prepared by the addition of an antioxidant, such as ascorbic acid.

Dispersible powders and granules are formulations suitable for the preparation of an aqueous suspension according to the present invention. In these formulations, active ingredients 1 and 2 are present, separately or together, in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable examples of dispersing or wetting agents, suspending agents and preservatives are those already mentioned hereinbefore. Additional excipients may also be present, such as, for example, sweetening, flavoring and coloring agents. Suitable examples of excipients are those already mentioned hereinbefore.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof.

Suitable emulsifying agents may be (a) gums that occur in nature, such as gum acacia and gum tragacanth, (b) phosphatides that occur in nature, such as soy and lecithin, (c) esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, (d) condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs according to the present invention can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Formulations of this type may also contain a preservative and flavoring and coloring agents.

Pharmaceutical compositions containing 1 and 2, separately or together, may be in the form of a sterile injectable aqueous or oleaginous solution or suspension. The suspension can be formulated according to known methods, using suitable dispersing agents or humectants and suspending agents that have been mentioned hereinbefore. A suitable sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic and parenterally acceptable diluent or solvent, for example a solution in 1,3-butane diol. Examples of suitable acceptable vehicles and solvents, which can be employed, are water, Ringer's solution and an isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be used as solvent or suspension medium. For this purpose, any mild fixed oil, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids, such as oleic acid, find use in the preparation of injectable products according to the present invention.

Preparations for parenteral administration according to the present invention containing 1 and 2, separately or together, include sterile aqueous or non-aqueous solutions, suspensions or emulsions.

Examples of solvents or non-aqueous vehicles suitable for preparations according to the present invention are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters, such as ethyl oleate. Dosage forms of this type may also contain adjuvants, such as preservatives, humectants, emulsifiers and dispersants. These can be sterilized, for example, by filtration through a filter that retains bacteria, incorporating sterilizing agents in the compositions, irradiating the compositions or heating the compositions. They can also be manufactured in the form of sterile solid compositions that can be reconstituted in sterile water, or some other sterile injectable medium, immediately before use.

Elements 1 and 2 of the combination of this invention can also be administered in the form of suppositories for rectal administration. Compositions of this type can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and, therefore, will melt in the rectum to release the active ingredient. Materials of this type are cocoa butter, hard fat and polyethylene glycols.

Compositions for oral, nasal or sublingual administration according to the present invention can be prepared with conventional excipients, well known in the art.

For topical administration, elements 1 and 2 of the combination of this invention can be formulated, separately or together, in liquid or semi-liquid preparations. Examples of suitable preparations are: liniments, lotions, applications; oil-in-water or water-in-oil emulsions, such as creams, ointments, gels or pastes, including toothpastes; solutions or suspensions, such as drops.

The dosage of the active ingredients in the compositions according to the present invention can be varied, although the amount of the active ingredients 1 and 2 will be such that a suitable dosage form is obtained. Therefore, the selected dosage and the selected dosage form will depend on the desired therapeutic effect, the route of administration and the duration of treatment. Dosage ranges suitable for the combination range from the maximum tolerated dose for the single agent to lower doses, for example to a tenth of the maximum tolerated dose.

In the following, the present invention is illustrated by examples of pharmaceutical compositions comprising a compound 1 of chemical structure (I) in combination with one of the above-mentioned combination participants 2, and by in vivo combination studies demonstrating the potency of the combination to inhibit proliferation and / or to induce apoptosis of tumor cells. In these examples, compound 1 of chemical structure (I) is 4 - [[(7R) -8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2pteridinyl] amino] -3-methoxy-N- (1-methyl-4-piperidinyl) -benzamide, which is a compound of formula (I) according to the invention (Exemplified compound No. 46 in Table 1).

Combination of exemplified compound No. 46 of Table 1 and irinotecan (Combination study in the HCT 116 colon cancer model)

The purpose of the study

The exemplified compound No. 46 of Table 1 is a potent and selective serine / threonine kinase inhibitor PLK

1. Irinotecan (sold under the trade name Campto®) is a conventional chemotherapeutic agent for the treatment of colorectal carcinomas. Previous studies have shown that exemplified compound No. 46 of Table 1 and irinotecan are active on tumors derived from HCT 116 in mice devoid of the immune system. The objective of the present study was to confirm the anticancer efficacy of suboptimal doses of exemplified compound No. 46 of Table 1, irinotecan and the combination of exemplified compound No. 46 of Table 1 and irinotecan, in the HCT 116 human colon carcinoma model developed as a xenograft in mice devoid of the immune system. To facilitate the detection of additive, synergistic or antagonistic effects, suboptimal doses of both compounds were used.

Study design

Model: HCT 116 human colon carcinoma, developed in the form of subcutaneous xenografts in mice devoid of the immune system.

Treatment groups (10 animals per group):

Controls: vehicle, i.v., once a week for 6 weeks ((q7d) x6)

Example Example 46 of Table 1

30 mg / kg, i.v., once a week for 10 weeks ((q7d) x10)

Irinotecan 12.5 mg / kg, i.p., once a week for 10 weeks ((q7d) x10)

Combination 30 mg / kg of exemplified compound No. 46 of Table 1, iv, once a week for 10 weeks ((q7d) x10) and 12.5 mg / kg of irinotecan, ip, once a week (≈ 1 h after exemplified compound No. 46 of Table 1) for 10 weeks ((q7d) x10)

Tumor volumes and animal weights were recorded 3 times per week. The evaluation of the results of the therapy was based on the absolute volumes of individual tumors.

Material and methods:

The mice were Bom / Tac: NMRI-nu / nu females. The exemplified compound No. 46 of Table 1 was dissolved in hydrochloric acid (0.1 N) diluted with 0.9% NaCl, and injected intravenously into the tail vein. An irinotecan infusion concentrate was diluted with 0.9% NaCl and injected intraperitoneally. The administration volume was 10 mL per kg body weight for both compounds. HCT 116 tumors were established from cultured HCT 116 cells. Tumor volumes were determined three times per week using a calibrator. The weight of the mice was determined as an indicator of tolerability on the same days. Plasma samples were taken on the last day of treatment.

Main results (see Figures 1.1-1.3)

Brief Description of the Figures

Figure 1.1

HCT 116 tumor responses to treatment with 30 mg / kg of exemplified compound No. 46 of Table 1, 12.5 mg / kg of irinotecan or both.

Mice bearing HCT 116 tumors were treated intravenously with 30 mg / kg of exemplified compound No. 46 of Table 1, once a week ((q7d) x10), with 12.5 mg / kg of irinotecan, a once a week ((q7d) x10), with both in parallel ((q7d) x10) or once a week with the vehicle alone, and the medium volumes of the tumors were recorded over time. Day 1 was the first day, day 64 the last day of treatment and day 121 the final day of the study. The triangles indicate the days of treatment.

Figure 1.2

Days until the HCT 116 tumors reached a volume of 1000 mm3.

Mice bearing HCT 116 tumors were treated with 30 mg / kg of exemplified compound No. 46 of Table 1, i.v. once a week ((q7d) x10), with 12.5 mg / kg of irinotecan i.p. once a week ((q7d) x10), or a combination of both compounds ((q7d) x10) at respective doses. Mice treated with vehicle (once a week) were used as controls. Individual days were recorded until HCT 116 tumors reached a volume of 1000 mm3. Each symbol represents an individual tumor. Horizontal lines represent medium days.

Figure 1.3

Change in body weight in response to treatment with 30 mg / kg of exemplified compound No. 46 of Table 1, 12.5 mg / kg of irinotecan or both. Mice bearing HCT 116 tumors were treated intravenously with 30 mg / kg of exemplified compound No. 46 of Table 1, once a week ((q7d) x10), with 12.5 mg / kg of irinotecan, once a week ((q7d) x10), with both in parallel ((q7d) x10) or once a week with the vehicle alone, and the average changes in body weight were recorded over time. Day 1 was the first day, day 64 the last day of treatment and day 121 the final day of the study. The triangles indicate the days of treatment.

Results on day 39 (end of controls):

30 mg / kg of the exemplified compound No. 46 of Table 1, i.v., significantly delays the development of the HCT 116 tumor (T / C = 20%, p <0.001).

12.5 mg / kg of irinotecan, i.p., significantly delay tumor development (T / C = 25%, p <0.001).

The combined administration of 30 mg / kg of the exemplified compound No. 46 of Table 1 and 12.5 mg / kg of irinotecan significantly delays tumor development (T / C = 8%, p <0.001).

30 mg / kg of the exemplified compound No. 46 of Table 1, 12.5 mg / kg of irinotecan and its combination are well tolerated. Control mice gained 10.3% body weight. Mice treated with 30 mg / kg of the exemplified compound No. 46 of Table 1 showed an increase in body weight of 8.6%, mice treated with 12.5 mg / kg of irinotecan gained an average of 5.9%. body weight and mice treated with the combination gained 5.5% body weight.

Results on day 121 (end of study):

Weekly treatment (until day 64) with the exemplified compound No. 46 of Table 1, irinotecan or a combination thereof takes the average time to reach a tumor volume of 1000 mm3 for 33.7 days, 35.1 days or 56.0 days, respectively.

Conclusions

A suboptimal dose treatment of exemplified compound No. 46 of Table 1 or irinotecan significantly delays tumor development and is well tolerated.

Treatment with the suboptimal dose combination of exemplified compound No. 46 of Table 1 and irinotecan shows a significant developmental delay and greater efficacy than any of the compounds alone, without a decrease in tolerability.

Comparison of developmental delay (time until tumor size reaches 1000 mm3) shows an additive / synergistic effect.

Combination of exemplified compound No. 46 of Table 1 and docetaxel (Lung model NCI-H460)

The purpose of the study

The exemplified compound No. 46 of Table 1 is a potent and selective serine / threonine kinase inhibitor PLK

1. Docetaxel (sold under the trade name Taxotere®) is a conventional chemotherapeutic agent for the treatment of lung cancer. Previous studies have shown that the exemplified compound No. 46 of Table 1 is active on xenografts of mice devoid of the immune system derived from the NCI-H460 human lung cancer cell line. The objective of this study was to confirm the anticancer effects of suboptimal doses of the exemplified compound No. 46 of Table 1 and docetaxel in the development of the NCI-H460 tumor when administered alone or in combination. To facilitate the detection of additive, synergistic or antagonistic effects, suboptimal doses of both compounds were used.

Study design

Model: NCI-H460 human non-small cell lung carcinoma model, developed in the form of subcutaneous xenografts in mice devoid of the immune system.

Treatment groups (intravenous administration, 10 animals per group):

Controls: vehicle, once a week for 4 weeks ((q7d) x4)

Example Example 46 of Table 1

50 mg / kg, once a week for 4 weeks ((q7d) x4)

Docetaxel 15 mg / kg, once a week for 4 weeks ((q7d) x4)

Combination 50 mg / kg of exemplified compound No. 46 of Table 1, once a week for 4 weeks ((q7d) x4) and 15 mg / kg of Docetaxel, once a week (3 days after exemplified compound No. 46 of Table 1) for 4 weeks ((q7d) x4)

Tumor volumes and animal weights were recorded 3 times per week. The evaluation of the results of the therapy was based on the absolute volumes of individual tumors.

Material and methods:

The mice were Bom / Tac: NMRI-nu / nu females. The exemplified compound No. 46 of Table 1 was dissolved in hydrochloric acid (0.1 N) diluted with 0.9% NaCl, and injected intravenously into the tail vein. A docetaxel infusion concentrate was diluted with 0.9% NaCl and injected intravenously. The administration volume was 10 mL per kg body weight for both compounds. NCI-H460 tumors were established from cultured NCI-H460 cells. Tumor volumes were determined three times per week using a calibrator. The weight of the mice was determined as an indicator of tolerability on the same days. Plasma samples were taken on the last day of treatment.

Main results (see Figures 2.1-2.3)

Brief Description of the Figures

Figure 2.1

NCI-H460 tumor responses to treatment with 50 mg / kg of exemplified compound No. 46 of Table 1, 15 mg / kg of docetaxel or both. Mice bearing NCI-H460 tumors were treated intravenously with 50 mg / kg of exemplified compound No. 46 of Table 1, once a week ((q7d) x4), with 15 mg / kg docetaxel, once a week ((q7d) x4), with both in parallel or once a week with the vehicle alone, and the medium volumes of the tumors were recorded over time. Day 1 was the first day, day 25 the last day of treatment and day 43 the final day of the calculation of the median volume of tumors. The triangles indicate the days of treatment.

Figure 2.2

Days until the NCI-H460 tumors reached a volume of 1000 mm3.

Mice carrying NCI-H460 tumors were treated with 50 mg / kg of exemplified compound No. 46 of Table 1, i.v. once a week ((q7d) x4), with 15 mg / kg docetaxel i.v. once a week ((q7d) x4), or a combination of both compounds at the same doses. Mice treated with vehicle (once a week) were used as controls. Individual days were recorded until the NCI-H460 tumors reached a volume of 1000 mm3. Each symbol represents an individual tumor. Horizontal lines represent medium days.

Figure 2.3

Change in body weight in response to treatment with 50 mg / kg of exemplified compound No. 46 of Table 1, 15 mg / kg of docetaxel or both. Mice bearing NCI-H460 tumors were treated intravenously with 50 mg / kg of exemplified compound No. 46 of Table 1, once a week ((q7d) x4), with 15 mg / kg docetaxel, once a week ((q7d) x4), with both in parallel or once a week with the vehicle alone, and average changes in body weight were recorded over time. Day 1 was the first day, day 25 the last day of treatment and day 43 the final day of the calculation of medium body weights. The triangles indicate the days of treatment.

Results on day 17 (end of controls):

50 mg / kg of the exemplified compound No. 46 of Table 1, i.v., once a week does not significantly delay the development of the NCI-H460 tumor (T / C = 65%, p <0.05).

15 mg / kg docetaxel, i.v., once a week significantly delay tumor development (T / C = 42%, p <0.05).

The combined administration of 50 mg / kg of the exemplified compound No. 46 of Table 1 and 15 mg / kg of docetaxel significantly delay tumor development (T / C = 26%, p <0.001).

50 mg / kg of the exemplified compound No. 46 of Table 1 are well tolerated.

15 mg / kg of docetaxel given alone or in combination are not well tolerated. Mice treated with docetaxel 15 mg / kg lost an average of 4.8% body weight until day 17. The combination of exemplified compound No. 46 of Table 1 and docetaxel induced a 8.3% body weight loss. .

Results until day 71 (end of study):

Weekly treatment (until day 25) with the exemplified compound No. 46 of Table 1, docetaxel or a combination thereof takes the average time to reach a tumor volume of 1000 mm3 for 4.0 days, 10.5 days or 28.0 days compared to controls, respectively.

Mice treated with docetaxel 15 mg / kg additionally lost body weight (up to 9.4% on day 24) and a mouse had to be euthanized due to severe body weight loss. Mice treated simultaneously with the exemplified compound No. 46 of Table 1 and docetaxel additionally lost body weight (up to 10.4% on day 24) and two mice had to be euthanized due to severe loss of body weight.

Conclusions

A suboptimal dose treatment of exemplified compound No. 46 of Table 1 does not significantly delay tumor development (T / C = 65%, p> 0.05).

Docetaxel significantly delays tumor development (T / C = 42%, p <0.05).

A combination of exemplified compound No. 46 of Table 1 and docetaxel shows a significant developmental delay compared to controls (T / C = 26%, p <0.001). The difference with the simple treatment with the exemplified compound No. 46 of Table 1 is also significant (p <0.01), which indicates that the two agents could act at least additively.

Combination of exemplified compound No. 46 of Table 1 and gemcitabine (Model of pancreas BxPC-3)

The purpose of the study

The exemplified compound No. 46 of Table 1 is a potent and selective serine / threonine kinase inhibitor PLK

1. Gemcitabine (sold under the brand name Gemzar®) is a conventional chemotherapeutic agent for the treatment of pancreatic adenocarcinomas. The objective of the present study was to confirm the anticancer efficacy of suboptimal doses of the exemplified compound No. 46 of Table 1, gemcitabine and its combination in the human pancreatic adenocarcinoma model BxPC-3, developed as a xenograft in mice devoid of the immune system. To facilitate the detection of additive, synergistic or antagonistic effects, suboptimal doses of both compounds were used.

Study design

Model: BxPC-3 human adenocarcinoma model, developed in the form of subcutaneous xenografts in mice devoid of the immune system.

Treatment groups (10 animals per group):

Controls: vehicle, i.v., once a week for 4 weeks ((q7d) x4)

Example Example 46 of Table 1

50 mg / kg, i.v., once a week for 6 weeks ((q7d) x6)

Gemcitabine 100 mg / kg, i.p., once a week for 6 weeks ((q7d) x6)

Combination 50 mg / kg of exemplified compound No. 46 of Table 1, iv, once a week for 6 weeks ((q7d) x6) and 100 mg / kg gemcitabine, ip, once a week (≈ 1 h after exemplified compound No. 46 of Table 1) for 6 weeks ((q7d) x6)

Tumor volumes and animal weights were recorded 3 times per week. The evaluation of the results of the therapy was based on the absolute volumes of individual tumors.

Material and methods:

The mice were Bom / Tac: NMRI-nu / nu females. The exemplified compound No. 46 of Table 1 was dissolved in hydrochloric acid (0.1 N) diluted with 0.9% NaCl, and injected intravenously into the tail vein. A gemcitabine infusion concentrate was diluted with 0.9% NaCl and injected intraperitoneally. The administration volume was 10 mL per kg body weight for both compounds. BxPC-3 tumors were established from cultured BxPC-3. Tumor volumes were determined three times per week using a calibrator. The weight of the mice was determined as an indicator of tolerability on the same days. Plasma samples were taken on the last day of treatment.

Main results (see Figures 3.1-3.2)

Brief Description of the Figures

Figure 3.1

BxPC-3 tumor responses to treatment with 50 mg / kg of exemplified compound No. 46 of Table 1, 100 mg / kg of gemcitabine or both.

Mice carrying BxPC-3 tumors were treated intravenously with 50 mg / kg of exemplified compound No. 46 of Table 1, once a week ((q7d) x6), with 100 mg / kg gemcitabine, once a the week ((q7d) x6), with both in parallel or once a week with the vehicle alone, and the medium volumes of the tumors were recorded over time. Day 1 was the first day, day 36 the last day of treatment and day 26 the final day of the calculation of the median volume of tumors.

Figure 3.2

Change in body weight in response to treatment with 50 mg / kg of exemplified compound No. 46 of Table 1, 100 mg / kg of gemcitabine or both.

Mice carrying BxPC-3 tumors were treated intravenously with 50 mg / kg of exemplified compound No. 46 of Table 1, once a week ((q7d) x6), with 100 mg / kg gemcitabine once a week. week ((q7d) x6), with both in parallel or once a week with the vehicle alone, and average changes in body weight were recorded over time. Day 1 was the first day, day 36 the last day of treatment and day 43 the last day of the calculation of medium body weights. The triangles indicate the days of treatment.

Results on day 26 (end of controls):

50 mg / kg of the exemplified compound No. 46 of Table 1, i.v., significantly delays the development of the HCT 116 tumor (T / C = 28%).

100 mg / kg gemcitabine, i.p., only marginally delay tumor development (T / C = 65%). They did not go

tolerated higher doses of gemcitabine.

A combined administration of 50 mg / kg of the exemplified compound No. 46 of Table 1 and 100 mg / kg of gemcitabine delay tumor development to the same extent as the exemplified compound No. 46 of Table 1 alone (T / C = 24 %).

50 mg / kg of the exemplified compound No. 46 of Table 1, 100 mg / kg of gemcitabine and its combination were well tolerated. Control mice gained 6.2% body weight. Mice treated with 50 mg / kg of exemplified compound No. 46 of Table 1 showed an increase in body weight of 8.2%, mice treated with 100 mg / kg gemcitabine gained an average of 8.8% body weight and the mice treated with the combination gained 8.5% body weight.

Results on day 43 (end of study):

Weekly treatment (until day 36) with the exemplified compound No. 46 of Table 1 and gemcitabine takes the average time to reach a tumor volume of 1000 mm3 in the same measure. There is no significant difference between the two treatment groups.

Conclusions

A suboptimal dose treatment of exemplified compound No. 46 of Table 1 significantly delays tumor development and is well tolerated. In contrast, the maximum tolerated dose of gemcitabine does not result in significant anti-tumor activity.

Treatment with the suboptimal dose combination of exemplified compound No. 46 of Table 1 and gemcitabine shows a developmental delay comparable to that of exemplified compound No. 46 of Table 1, indicating that the two agents do not act antagonistically In this model.

A process for the manufacture of exemplified compound No. 46 of Table 1, ie compound 4 [[(7R) -8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6- oxo-2-pteridinyl] amino] -3-methoxy-N- (1-methyl-4-piperidinyl) benzamide, is described in WO 03/20722, as well as in WO 04/76454, which are incorporated in This memory as a reference.

However, for the purpose of further completion, a process for the manufacture of compound 4 - [[(7R) -8-cyclopentyl-7-ethyl-5,6,7,8- is also described herein below. tetrahydro-5-methyl-6-oxo-2-pteridinyl] amino] -3-methoxy-N (1-methyl-4-piperidinyl) -benzamide. This method is to be understood as an illustration of the invention, without limiting it to its subject matter.

Synthesis of 4 - [[(7R) -8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl] amino] -3-methoxy-N- ( 1-methyl-4piperidinyl) -benzamide

For synthesis, an intermediate compound Z3 is first prepared as described below.

54.0 g (0.52 mol) of D-2-aminobutyric acid are suspended in 540 mL of methanol and slowly combined with 132 g 45 (1.1 mol) of thionyl chloride while cooling with ice. The mixture is refluxed for 1.5 h and then evaporated. The remaining oil is combined with 540 mL of tert-butyl methyl ether, and the colorless crystals formed are

filter with suction.

Yield: 78.8 g of a compound Z3a (colorless crystals)

74.2 g of compound Z3a and 43.5 mL (0.49 mol) of cyclopentanone are dissolved in 800 mL of dichloromethane. After the addition of 40.0 g (0.49 mol) of sodium acetate and 150.0 g (0.71 mol) of sodium triacetoxyborohydride at 0 ° C, the mixture is stirred for 12 h at room temperature and then add 500 mL of a 20% sodium hydrogen carbonate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water, dried over MgSO4 and evaporated.

Yield: 85.8 g of a compound Z3b (light yellow oil)

40.0 g of compound Z3b and 30.0 g (0.22 mol) of potassium carbonate are suspended in 600 mL of acetone and combined with 45.0 g (0.23 mol) of 2,4-dichloro- 5-nitropyrimidine in 200 mL of acetone, while cooling with ice. After 12 h, an additional 5.0 g of 2,4-dichloro-5-nitropyrimidine is added, and stirred for 3 h. The reaction mixture is evaporated, collected in 800 mL of ethyl acetate and 600 mL of water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water, dried over MgSO4 and evaporated.

Yield: 75.0 g of a compound Z3c (brown oil)

100 g of compound Z3c are dissolved in 650 mL of glacial acetic acid and, at 70 ° C, 20 g of iron powder are added in batches. The mixture is stirred for 1 h at 70 ° C and then for 1.5 h at 100 ° C and then filtered hot through diatomite (diatomaceous earth). The reaction mixture is evaporated, taken up in methanol / dichloromethane, applied to silica gel and purified with ethyl acetate by extraction of Soxhlet. The solvent is separated and the residue is stirred with methanol.

Yield: 30.0 g of a Z3d compound (light brown crystals)

25.0 g of compound Z3d and 6.5 mL (0.1 mol) of methyl iodide are placed in 250 mL of dimethylacetamide and, at -10 ° C, 3.8 g (0.95 mol) of hydride are added. sodium in the form of a 60% dispersion in mineral oil. This is stirred for 20 min at 0 ° C, then for 30 min at room temperature and, finally, ice is added. The reaction mixture is evaporated and combined with 300 mL of water. The precipitate formed is filtered off with suction and washed with petroleum ether.

Yield: 23.0 g of a compound Z3e (colorless solid)

6.0 g of compound Z3e and 5.1 g (31 mmol) of 4-amino-3-methoxybenzoic acid are suspended in 90 mL of ethanol and 350 mL of water, combined with 3.5 mL of concentrated hydrochloric acid and they undergo reflux for 48 h. The reaction mixture is evaporated, the residue is stirred with methanol / diethyl ether and the precipitate formed is filtered off with suction.

Yield: 6.3 g of a compound Z3 (light beige crystals)

4 - [[(7R) -8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl] amino] -3-methoxy-N- (1- Methyl-4-piperidinyl) benzamide is obtained as described below.

0.15 g of compound Z3, 0.12 g of TBTU, 0.12 mL of DIPEA are dissolved in 5 mL of dichloromethane and stirred for 30 minutes at 25 ° C. Then 50 mg of 1-methyl-4-aminopiperidine are added, and the mixture is stirred for an additional 2.5 hours at 25 ° C. The solution is then extracted with water and then evaporated. The residue is dissolved in hot ethyl acetate and crystallized from ether and petroleum ether.

Yield: 0.025 g of white crystals. Mp .: 203 ° C in the form of a base.

All the compounds of formula (I) according to the invention can be prepared by the methods of synthesis A described hereinbelow, while the substituents of general formula (A1) to (A9) have the meanings given hereinbefore. memory. This method is to be understood as an illustration of the invention without limiting it to its subject matter.

Method A

STAGE 1A

A compound of formula (A1) is reacted with a compound of formula (A2) to obtain a compound of formula (A3) (Diagram 1A). This reaction can be carried out in accordance with WO 00/43369 or WO 00/43372. Compound (A1) is commercially available, for example from City Chemical LLC, 139 Allings Crossing Road, West Haven, CT, 06516, USA. Compound (A2) can be prepared by known processes from the literature: (a) F. Effenberger, U. Burkhart, J. Willfahrt Liebigs Ann. Chem. 1986, 314-333;

10 (b) T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373-6374; (c) R.K. Olsen, J. Org. Chem. 1970, 35, 1912-1915; (d) F.E. Dutton, B.H.Byung, Tetrahedron Lett. 1998, 30, 5313-5316; (e) J.M. Ranajuhi, M.M. Joullie Synth. Commun. 1996, 26, 1379-1384).

Diagram 1A

OR R2 N +

O + R1

N

Or R1

+ HN R3 ClCl Cl R3

O R1 O R1

(A2) R2

(A1) OR

(A3) In Step 1A, 1 equivalent of compound (A1) and 1 to 1.5 equivalents, preferably 1.1 equivalents of a base, preferably potassium carbonate, potassium hydrogen carbonate, sodium carbonate or sodium hydrogen carbonate Calcium carbonate, most preferably potassium carbonate, is stirred in a diluent optionally mixed with water, for example acetone, tetrahydrofuran, diethyl ether, cyclohexane, petroleum ether or dioxane, preferably cyclohexane or diethyl ether.

At a temperature of 0 to 15 ° C, preferably 5 to 10 ° C, 1 equivalent of an amino acid of formula (A2), dissolved in an organic solvent, for example acetone, tetrahydrofuran, diethyl ether, cyclohexane or dioxane is added dropwise. The reaction mixture is heated to a temperature of 18 ° C to 30 ° C, preferably at about 22 ° C, with stirring and then stirred for an additional 10 to 24 hours, preferably about 12 hours. Then, the diluent is distilled off, the residue is combined with water and the mixture is extracted two to three times with an organic solvent, such as diethyl ether or ethyl acetate, preferably ethyl acetate. The combined organic extracts are dried and the solvent is distilled off. The residue

30 (compound A3) can be used in Stage 2 without any prior purification.

STAGE 2A

The compound obtained in Step 1A (A3) is reduced in the nitro group and cycled to form the compound of formula (A4) (Diagram 2A).

Diagram 2A

In Step 2A, 1 equivalent of the nitro compound (A3) is dissolved in an acid, preferably glacial acetic acid,

5 formic acid or hydrochloric acid, preferably glacial acetic acid, and is heated to 50 to 70 ° C, preferably to approximately 60 ° C. A reducing agent, for example zinc, tin or iron, preferably iron shavings, is then added to complete the exothermic reaction, and the mixture is stirred for 0.2 to 2 hours, preferably 0.5 hours, at 100 to 125 ° C. , preferably at about 117 ° C. After cooling to room temperature, the iron salt is filtered off and the solvent is distilled off. The residue is collected in a

Solvent or solvent mixture, for example ethyl acetate or dichloromethyl / methanol 9/1 and semi-saturated NaCl solution and, for example, filtered through diatomaceous earth. The organic phase is dried and evaporated. The residue (compound (A4)) can be purified by chromatography or by crystallization or it can be used in the form of the crude product in step 3A of the synthesis.

15 STAGE 3A

The compound obtained in Step 2A (A4) can be reacted by electrophilic substitution, as shown in Diagram 3A, to obtain the compound of formula (A5).

20 Diagram 3A

H

Or R1

Cl

R2 R3 (A4) (A5)

In Step 3A, 1 equivalent of the amide of formula (A4) is dissolved in an organic solvent, for example

Dimethylformamide or dimethylacetamide, preferably dimethylacetamide, and cooled to about -5 to 5 ° C, preferably 0 ° C.

Then, 0.9 to 1.3 equivalents of sodium hydride and 0.9 to 1.3 equivalents of a methylation reagent, for example methyl iodide, are added. The reaction mixture is stirred for 0.1-3 hours, preferably approximately

1 hour, at about 0 to 10 ° C, preferably at about 5 ° C, and may optionally be allowed to stand for an additional 12 hours at this temperature. The reaction mixture is poured onto ice water and the precipitate is isolated. The resiudo (compound (A5)) can be purified by chromatography, preferably on silica gel, or by crystallization, or it can be used in the form of a crude product in Step 4A.

35 Stage 4A

The amination of the compound (A5) obtained in Step 3A to provide the compound of formula (A9) (Diagram 4A) can be carried out using the known methods of the literature, for variants 4.1 A, from, for example, , (a) MPV Boarland, J.F.W. McOmie J. Chem. Soc. 1951, 1218-1221 or (b) F.H.S. Curd, F.C.

Rose, J. Chem. Soc. 1946, 343-348 for variants 4.2 A from, for example, (a) Banks J. Am. Chem. Soc. 1944, 66, 1131, (b) Ghosh and Dolly J Indian Chem. Soc. 1981, 58, 512-513, or (c) NP Reddy and M. Tanaka Tetrahefdron Lett. 1997, 38, 4807-4810.

4A diagram

For example, in variant 4.1 A, 1 equivalent of compound (A5) and 1 to 3 equivalents, preferably

About 2 equivalents of the compound (A6) are heated without a solvent or in an organic solvent, such as, for example, sulfolane, dimethylformamide, dimethylacetamide, toluene, N-methylpyrrolidone, dimethyl sulfoxide or dioxane, preferably sulfolane, for 0.1 to 4 hours, preferably 1 hour, at 100 to 220 ° C, preferably at about 160 ° C. After cooling, the product (A9) is crystallized by the addition of organic solvents or solvent mixtures, for example diethyl ether / methanol, ethyl acetate, methylene chloride,

15 or diethyl ether, preferably diethyl ether / methanol 9/1, or purified by chromatography.

For example, in variant 4.2 A, 1 equivalent of compound (A5) and 1 to 3 equivalents of compound (A6) are stirred with acid, for example 1-10 equivalents of 10-38% hydrochloric acid and / or an alcohol , for example ethanol, propanol, butanol, preferably ethanol, at reflux temperature for 1 to 48 hours, preferably

20 approximately 5 hours. The precipitated product (A9) is filtered off and, optionally, washed with water, dried and crystallized from a suitable organic solvent.

For example, in variant 4.3 A, 1 equivalent of compound (A5) and 1 to 3 equivalents of compound (A7)

they dissolve in a solvent, for example toluene or dioxane and meet with a phosphine ligand, for example 2,2'bis- (diphenylphosphino) -1,1'-binaphthyl and a palladium catalyst, for example tris (dibenzylidene acetone) ) dipaladium (0) and a base, for example cesium carbonate, and is refluxed for 1-24 h, preferably 17 h. The reaction mixture is purified, for example on silica gel, and the product (A8) is isolated from the solution or 5 is obtained by suitable crystallization. The product (A8) is dissolved in a suitable solvent, for example dioxane, and mixed with acid, for example semi-concentrated hydrochloric acid, for example in the ratio of solvent to acid of

3: 1 Then, the mixture is refluxed for 1-48 h, for example 12 h, and the precipitate formed is isolated. If desired, the product (A9) is purified by crystallization.

10 Stage 5A

5A diagram

+ NH-L-R5

For example, 1 equivalent of compound (A9) is dissolved with 1 equivalent of an activating reagent, for example O-benzotriazolyl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) and a base, for example 1 , 5 equivalents of diisopropylethylamine (DIPEA) in an organic diluent, for example dichloromethane, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, preferably dichloromethane or demitylformamide. After the addition of 1 equivalent of the amine (A10), the reaction mixture is stirred for 0.1 to 24 hours, preferably during

20 approximately 2 hours at 20 ° C to 100 ° C. The product of formula (A11) is obtained, for example, by crystallization or chromatographic purification.

The compounds of general formula (I) can be synthesized analogously to the following synthetic examples. The numbering of the examples corresponds to the numbering used in Table 1. However, these examples

They are intended only as examples of processes to further illustrate the invention, without limiting the invention to its subject matter.

The preparation of some intermediate compounds used to synthesize the compound is also described in the following.

Acid Preparation

To synthesize the compounds of Examples 94 and 95 of Table 1, an intermediate compound Z1 is first prepared

Z1

as described here in the following.

50.0 g (0.48 mol) of methyl D-alanine ester x HCl and 49.1 g (0.50 mol) of cyclohexanone are placed in 300 mL of dichloromethane and then combined with 41.0 g (0, 50 mol) of sodium acetate and 159.0 g (0.75 mol) of sodium triacetoxyborohydride. The mixture is stirred overnight and then 300 mL of a 10% sodium hydrogen carbonate solution is added. The aqueous phase is extracted with dichloromethane. The combined organic phases are

10 washed with 10% sodium hydrogen carbonate solution, dried over Na2SO4 and evaporated.

Yield: 72.5 g of a compound Z1a (transparent liquid)

72.5 g of compound Z1a are placed in 500 mL of water and 76.6 g (0.39 mol) of 2,4-dichloro-5 are added

15 nitropyrimidine in 500 mL of diethyl ether. At a temperature of –5ºC, 100 mL of 10% potassium hydrogen carbonate solution is added dropwise. The mixture is stirred for 3 h at -5 ° C and for an additional 12 h at room temperature. The organic phase is separated and dried over Na2SO4. After evaporation, the product is separated by crystallization.

20 Yield: 48.0 g of a Z1b compound (yellow crystals)

48.0 g of compound Z1b are dissolved in 350 mL of glacial acetic acid and heated to 60 ° C. 47.5 g of iron powder are added, while the temperature rises to 105 ° C. The reaction mixture is stirred for three hours at 80 ° C, then filtered hot through cellulose and evaporated. The residue is stirred in water and

Ethyl acetate is filtered off with suction and the light gray precipitate is washed with ethyl acetate. The filtrate is washed with dilute ammonia and water, the organic phase is dried over Na2SO4, filtered through activated charcoal and evaporated. Some more light gray solids are obtained.

Yield: 29.5 g of a Z1c compound (light gray crystals)

32 32.1 g of compound Z1c are placed in 300 mL of dimethylacetamide and combined with 13 mL (0.2 mol) of methyl iodide. At -5 ° C, 6.4 g (0.16 mol) of sodium hydride are added in batches in the form of a 60% dispersion in mineral oil. After 2 h, the reaction mixture is poured onto 800 mL of ice water. The precipitate formed is filtered off with suction and washed with petroleum ether.

Yield: 33.0 g of a Z1d compound (beige crystals)

4.0 g of compound Z1d and 2.3 g (15 mmol) of 4-amino-3-methylbenzoic acid are suspended in 50 mL of ethanol and 120 mL of water, combined with 2 mL of concentrated hydrochloric acid and subjected at reflux for 48 h. He

The precipitate formed after cooling is filtered off with suction and washed with water, ethanol and diethyl ether.

Yield: 2.9 g of a compound Z1 (colorless crystals)

To synthesize the compounds of Example 188 and Example 203 of Table 1, first an intermediate compound Z2 is prepared

Z2

as described below.

A solution of 128.2 g (0.83 mol) of ethyl ester of D-alanine x HCl and 71.5 g (0.85 mol) of cyclopentanone in 1500 mL of dichloromethane is combined with 70.1 g (0, 85 mol) of sodium acetate and 265.6 g (1.25 mol) of sodium triacetoxyborohydride. The reaction mixture is stirred for 12 h and then poured into 1.5 l of a 10% sodium hydrogen carbonate solution. The aqueous phase is extracted with dichloromethane. The organic phases gathered

10 are dried over Na2SO4 and evaporated.

Yield: 143.4 g of a compound Z2a (colorless oil)

66.0 g of compound Z2a are placed in 500 mL of water and combined with 85.0 g (0.44 mol) of 2,4-dichloro-5

15 nitropyrimidine in 500 mL of diethyl ether. At –5 ° C, 100 mL of 10% potassium hydrogen carbonate solution is added dropwise, and the reaction mixture is stirred for 48 h at room temperature. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried over Na2SO4 and evaporated. The dark red solid is stirred with petroleum ether and filtered with suction.

20 Yield: 88.0 g of a Z2b compound (yellow crystals)

88.0 g of compound Z2b are dissolved in 1000 mL of glacial acetic acid and at 60 ° C they are collected in batches with 85 g of iron powder, while the temperature rises to 110 ° C. It is stirred for 1 h at 60 ° C, then filtered with hot suction through cellulose and evaporated. The brown solid is stirred with 700 mL of water and filtered with

25 suction

Yield: 53.3 g of a Z2c compound (light brown crystals)

53.3 g of compound Z2c are dissolved in 300 mL of dimethylacetamide and combined with 13 mL (0.21 mol) of iodide

30 methyl At -5 ° C, 5.0 g (0.21 mol) of sodium hydride are added in batches in the form of a 60% dispersion in mineral oil. After 12 h the reaction mixture is poured onto 1000 mL of ice water, and the precipitate formed is filtered off with suction.

Yield: 40.0 g of a Z2d compound (colorless crystals)

4.0 g of compound Z2d and 2.8 g (16 mmol) of 4-amino-3-chlorobenzoic acid are suspended in 25 mL of ethanol and 60 mL of water, combined with 3 mL of concentrated hydrochloric acid and combined. under reflux for 43 h. The precipitate formed after cooling is filtered off with suction and washed with water, ethanol and diethyl ether. Yield: 0.9 g of a compound Z2 (colorless crystals)

To synthesize the compounds of Examples 19, 21, 22, 23, 45, 46, 55, 58, 116, 128, 131, 133, 134, 136, 138, 177, 217, 231, 239, 46, 184, 166 and 187 of Table 1, an intermediate compound Z3 is first prepared

Z3 as described below.

54.0 g (0.52 mol) of D-aminobutyric acid are suspended in 540 mL of methanol and slowly combined with 132 g (1.1 mol) of thionyl chloride, while cooling with ice. The mixture is refluxed for 1.5 h and then evaporated. The remaining oil is combined with 540 mL of tert-butyl methyl ether and the colorless crystals formed are filtered off with suction.

Yield: 78.8 g of a compound Z3a (colorless crystals)

74.2 g of compound Z3a and 43.5 mL (0.49 mol) of cyclopentanone are dissolved in 800 mL of dichloromethane. After the addition of 40.0 g (0.49 mol) of sodium acetate and 150.0 g (0.71 mol) of sodium triacetoxyborohydride

15 at 0 ° C, the mixture is stirred for 12 h at room temperature and then 500 mL of a 20% sodium hydrogen carbonate solution is added. The aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water, dried over MgSO4 and evaporated.

Yield: 85.8 g of a compound Z3b (light yellow oil).

20 40.0 g of compound Z3b and 30.0 g (0.22 mol) of potassium carbonate are suspended in 600 mL of acetone and combined with 45.0 g (0.23 mol) of 2,4-dichloro -5-nitropyrimidine in 200 mL of acetone, while cooling with ice. After 12 h, an additional 5.0 g of 2,4-dichloro-5-nitripyrimidine is added, and stirred for 3 h. The reaction mixture is evaporated, collected in 800 mL of ethyl acetate and 600 mL of water, and the aqueous phase is extracted with

25 ethyl acetate. The combined organic phases are washed with water, dried over MgSO4 and evaporated.

Yield: 75.0 g of a compound Z3c (brown oil)

100 g of compound Z3c are dissolved in 650 mL of glacial acetic acid and, at 70 ° C, 20 g of batches are added in batches.

30 iron powder The mixture is stirred for 1 h at 70 ° C, then for 1.5 h at 100 ° C and then filtered hot through diatomaceous earth. The reaction mixture is evaporated, taken up in methanol / dichloromethane, applied to silica gel and purified with ethyl acetate by extraction of Soxhlet. The solvent is separated, and the residue is stirred with methanol.

Yield: 30.0 g of a Z3d compound (light brown crystals)

25.0 g of compound Z3d and 6.5 mL (0.1 mol) of methyl iodide are placed in 250 mL of dimethylacetamide and, at -10 ° C, 3.8 g (0.95 mol) of hydride are added. sodium in the form of a 60% dispersion in mineral oil. Stir for 20 min at 0 ° C, then for 30 min at room temperature and, financially, ice is added. Mix

The reaction is evaporated and combined with 300 mL of water. The precipitate formed is filtered off with suction and washed with petroleum ether.

Yield: 23.0 g of a compound Z3e (colorless solid)

6.0 g of compound Z3e and 5.1 g (31 mmol) of 4-amino-3-methoxybenzoic acid are suspended in 90 mL of ethanol and 350 mL of water, combined with 3.5 mL of concentrated hydrochloric acid and undergo reflux for 48 h. The reaction mixture is evaporated, the residue is stirred with methanol / diethyl ether and the precipitate formed is filtered off with suction.

Yield: 6.3 g of a compound Z3 (light beige crystals)

To synthesize the compound of Examples 81, 82, 93 and 137 of Table 1, an intermediate compound Z4 is first prepared

10 Z4

as described below.

25.0 g (0.19 mol) of ethyl 1-aminocyclopropane-1-carboxylate x HCl and 16.8 g (0.20 mol) of cyclopentanone are

15 dissolved in 300 mL of dichloromethane and combined with 16.4 g (0.20 mol) of sodium acetate and 61.7 g (0.29 mol) of sodium triacetoxyborohydride. It is stirred overnight, and the reaction mixture is then poured onto 400 mL of a 10% sodium hydrogen carbonate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated.

20 Yield: 34.5 g of a compound Z4a (colorless oil)

42.5 g (0.22 mol) of 2,4-dichloro-5-nitripyrimidine in 350 mL of diethyl ether are added to a mixture of 34.5 g of compound Z4a in 350 mL of water. At –5 ° C, the mixture is combined with 80 mL of 10% potassium hydrogen carbonate solution and stirred overnight at room temperature. The aqueous phase is extracted with diethyl ether. The

25 combined organic phases are dried over Na2SO4 and evaporated.

Yield: 53.8 g of a compound Z4b (brown oil)

20.1 g of compound Z4b are dissolved in 200 mL of glacial acetic acid and collected in batches at 60 ° C with 19.1 g

30 of iron powder, during which time the temperature rose to 100 ° C. The mixture is stirred for 3 h at 60 ° C, then filtered with suction through cellulose and evaporated. The residue is stirred in water and ethyl acetate, and the yellow precipitate is filtered off with suction. The filtrate is washed with dilute ammonia and water and the organic phase is dried over Na2SO4 and evaporated. After the addition of additional diethyl ether, additional product is crystallized out.

Yield: 4.0 g of a Z4c compound (yellow crystals)

7.8 g of compound Z4c and 2.6 mL (0.04 mol) of methyl iodide are dissolved in 100 mL of dimethylacetamide and, at -5 ° C, 1.5 g (0.04 mol) of batches are added in batches sodium hydride in the form of a 60% dispersion in mineral oil.

After 2 h, the reaction mixture is poured into ice water, and the precipitate formed is filtered off with suction.

Yield: 7.5 g of a Z4d compound (light brown crystals)

3.0 g of compound Z4d and 1.9 g (11 mmol) of 4-amino-3-methoxybenzoic acid are suspended in 40 mL of ethanol and

45 80 mL of water, meet with 2 mL of concentrated hydrochloric acid and reflux for 20 h. An additional 0.5 g of 4-amino-3-methoxybenzoic acid is added and refluxed for 48 h. The precipitate formed after cooling is filtered off with suction and washed with water, ethanol and diethyl ether.

Yield: 2.1 g of a compound Z4 (colorless crystals) m.p. 222-223 ° C

To synthesize the compounds of Examples 162, 43, 53, 161, 202, 211, 215 and 212 of Table 1, an intermediate compound Z5 is first prepared

Z5

as described below.

10 A mixture of 73.4 mL (0.5 mol) of ethyl 2-bromoisobutyrate, 87.1 mL (0.75 mol) of 3-methyl-1-butylamine, 82.5 g (0.6 mol) of sodium iodide and 76.0 g (0.6 mol) of potassium carbonate in 1000 mL of ethyl acetate is refluxed for 3 days. All salt present is filtered off and the filtrate is evaporated.

15 Yield: 97.0 g of a compound Z5a (red oil)

49.0 g (0.25 mol) of 2,4-dichloro-5-nitropyrimidine and 38.3 g (0.28 mol) of potassium carbonate are suspended in 500 mL of acetone and, at 0 ° C, meet with 93.0 g of compound Z5a in 375 mL of acetone. The reaction mixture is stirred overnight at room temperature, filtered and evaporated. The residue dissolved in ethyl acetate is

20 wash with water, and the organic phase is dried over MgSO4 and evaporated.

Yield: 102.7 g of a compound Z5b (brown oil)

22.7 g of compound Z5b are dissolved in 350 mL of glacial acetic acid and, at 60 ° C, meet in batches with 17.4 g

25 iron powder. After completion of the addition, the mixture is refluxed for 0.5 h, filtered hot and evaporated. The residue is taken up in 200 mL of dichloromethane / methanol (9: 1) and washed with sodium chloride solution. The organic phase is suction filtered through diatomaceous earth, dried over MgSO4, evaporated and purified by column chromatography (eluent: 1: 1 ethyl acetate / cyclohexane).

30 Yield: 1.9 g of a Z5c compound (colorless crystals)

1.9 g of compound Z5c are dissolved in 32 mL of dimethylacetamide and, while cooling with ice, combined with 0.3 g (7 mmol) of sodium hydride in the form of a 60% dispersion in mineral oil . After 10 min, 0.5 mL (7 mmol) of methyl hydride is added and stirred for 3 h at room temperature. The mixture of

The reaction evaporates and meets with water. The precipitate formed is filtered off with suction and washed with petroleum ether.

Yield: 1.6 g of a Z5d compound (colorless crystals)

14.0 g of compound Z5d and 10.0 g (0.06 mol) of 4-amino-3-methoxybenzoic acid are suspended in 200 mL of 40 dioxane and 80 mL of water, combined with 10 mL of concentrated hydrochloric acid and undergo reflux for 40

h. The precipitate formed after cooling is filtered off with suction and washed with water, dioxane and diethyl ether. Yield: 13.9 g of a compound Z5 (colorless crystals)

To synthesize the compounds of Examples 88, 194, 229 and 89 of Table 1, an intermediate compound Z6 is first prepared

Z6

5 as described below.

6.0 g (0.06 mol) of L-2-aminobutyric acid are placed in 80 mL of 0.5 M sulfuric acid and, at 0 ° C, are combined with 5.5 g (0.08 mol) of nitrite sodium in 15 mL of water. The reaction mixture is stirred for 22 h at 0 ° C, combined with ammonium sulfate and filtered. The filtrate is extracted with diethyl ether and the combined organic phase is dried over MgSO4 and

10 evaporates.

Yield: 6.0 g of a Z6a compound (yellow oil)

200 mL of methanol are successively combined with 65.0 mL (0.89 mol) of thionyl chloride and 76.0 g of the compound

15 Z6a in 50 mL of methanol, while cooling with ice. The resulting mixture is stirred for 1 h at 0 ° C and for 2 h at room temperature and then the methanol and the remaining thionyl chloride are removed in vacuo at 0 ° C.

Yield: 40.0 g of a compound Z6b (yellow oil)

20 30.0 mL (0.17 mol) of trifluoromethanesulfonic acid anhydride are placed in 150 mL of dichloromethane and, while cooling with ice, a solution of 20.0 g of the compound is added within one hour Z6b and 14.0 mL (0.17 mol) of pyridine in 50 mL of dichloromethane. The mixture is stirred for 2 h at room temperature and all salt formed is filtered with suction and then washed with 100 mL of water. The organic phase is dried over MgSO4

25 and evaporates.

Yield: 42.0 g of a Z6c compound (light yellow oil)

42.0 g of compound Z6c in 200 mL of dichloromethane are added dropwise, within one hour, to a

A solution of 15.5 mL (0.17 mol) of aniline and 24.0 mL (0.17 mol) of triethylamine in 400 mL of dichloromethane, while cooling with ice. The mixture is stirred for 1 h at room temperature and for an additional 2 h at 35 ° C. The reaction mixture is washed with water, dried over MgSO4 and evaporated. The remaining residue is purified by distillation (95-100 ° C), 1 * 10-3 mbar).

Yield: 14.0 g of a compound Z6d (colorless oil)

14.0 g of compound Z6d and 16.0 g (0.1 mol) of potassium carbonate are suspended in 100 mL of acetone and, at 10 ° C, are combined with 16.0 g (0.08 mol) of 2, 4-dichloro-5-nitropyrimidine. The mixture is stirred for 4 h at 40 ° C, any salts formed are filtered with suction and the filtrate is evaporated. The residue is taken up in 300 mL of ethyl acetate and

40 wash with water. The organic phase is dried over MgSO4 and evaporated.

Yield: 31.0 g of a Z6e compound (brown oil)

31.0 g of compound Z6e are dissolved in 200 mL of glacial acetic acid and, at 60 ° C, are collected in batches with 10 g of iron powder, during which time the temperature rose to 85 ° C. The mixture is stirred for an additional hour at 60 ° C, filtered through diatomaceous earth and evaporated. The residue is stirred with methanol.

Yield: 4.5 g of a Z6f compound (brown crystals)

At –20 ° C, 0.6 g (16 mmol) of sodium hydride in the form of a 60% dispersion in mineral oil are added in batches to a mixture of 4.5 g of compound Z6f and 1.0 mL (16 mmol) of methyl iodide in 100 mL of dimethylacetamide. After 1 h, the reaction mixture is combined with 50 mL of water and evaporated. The residue is stirred with 200 mL of water, the precipitate is filtered off with suction and washed with petroleum ether.

Yield: 4.5 g of a Z6g compound (colorless crystals)

A suspension of 1.5 g of compound Z6g and 1.4 g (8 mmol) of methyl 4-amino-3-methoxybenzoate in 30 mL of toluene is combined with 0.4 g (0.6 mmol) of 2, 2'-bis- (diphenylphosphino) -1,1'-binaphthyl, 0.23 g (0.3 mmol) of

15 tris (dibenzylidenacetone) -dipaladium (0) and 7.0 g (21 mmol) of cesium carbonate and refluxed for 17 h. The reaction mixture is applied to silica gel and purified by column chromatography (eluent: dichloromethane / methanol 9: 1).

Yield: 1.7 g of a Z6h compound (yellow crystals)

20 1.7 g of compound Z6h are dissolved in 50 mL of dioxane, combined with 15 mL of semi-concentrated hydrochloric acid and refluxed for 12 h. After cooling, the precipitate formed is filtered off with suction.

Yield: 1.1 g of a compound Z6 (colorless solid)

To synthesize the compounds of Examples 26, 20, 32, 56, 101, 112 and 209 of Table 1, an intermediate compound Z7 is first prepared

Z7

as described below.

50.0 g (0.36 mol) of methyl ester D-alanine x HCl is suspended in 500 mL of dichloromethane and 35 mL of acetone and combined with 30.0 g (0.37 mol) of sodium acetate and 80.0 g (0.38 mol) of sodium triacetoxyborohydride. The mixture is stirred for 12 h and then poured onto 400 mL of 10% sodium hydrogen carbonate solution. The organic phase is dried over Na2SO4 and evaporated.

40 Yield: 51.0 g of a compound Z7a (yellow oil)

A suspension of 51.0 g of compound Z7a in 450 mL of water is combined with 80.0 g (0.41 mol) of 2,4-dichloro-5-nitropyridine in 450 mL of diethyl ether. At –5 ° C, 100 mL of a 10% potassium hydrogen carbonate solution is added dropwise. The reaction mixture is stirred for 3 h, the organic phase is dried over Na2SO4 and evaporated.

Yield: 74 g of a compound Z7b (yellow oil)

18.6 g of compound Z7b are dissolved in 200 mL of glacial acetic acid and, at 60 ° C, it is combined in batches with 20.0 g of iron powder. The mixture is stirred for 2 h at 60 ° C and then filtered with suction through cellulose. The residue is dissolved in ethyl acetate and washed with water and concentrated ammonia. The organic phase is dried over Na2SO4 and evaporated. The residue is crystallized from diethyl ether.

Yield: 9.8 g of a Z7c compound (colorless crystals)

10 17.0 g of compound Z7c and 7 mL (0.1 mol) of methyl iodide are dissolved in 200 mL of dimethylacetamide and, at -5 ° C, are combined with 4.0 g (0.1 mol) of hydride of sodium in the form of a 60% dispersion in mineral oil. The reaction mixture is stirred for 30 min and then poured onto 300 mL of ice water. The precipitate formed is filtered off with suction and stirred with petroleum ether.

15 Yield: 14.8 g of a Z7d compound (beige crystals)

0.9 g of compound Z7d and 1.5 g (9 mmol) of 4-amino-3-methoxybenzoic acid are heated to 210 ° C for 30 min. After cooling, the residue is stirred with ethyl acetate and the precipitate obtained is filtered off with suction.

20 Yield: 1.2 g of a Z7 compound (gray crystals)

The following acids can be prepared, for example, analogously to the synthesis methods described hereinbefore.

Synthesis of the amino components L-R5 The following amines,

1,1-dimethyl-2-dimethylamino-1-yl-ethylamine and 1,1-dimethyl-2-piperidin-1-yl-ethylamine,

They can be obtained as follows.

The compounds can be prepared according to the following references: (a) S. Schuetz et al. Arzneimittel-Forschung 1971, 21, 739-763, (b) V.M. Belikov et al. Tetrahedron 1979, 26, 1199-1216 and (c) E.B. Butler and McMillan J. 10 Amer. Chem. Soc. 1950, 72, 2878.

Other amines can be prepared as follows in a modified manner compared to the literature described above.

1,1-dimethyl-2-morpholin-1-yl-ethylamine

H2N NO

8.7 mL of morpholine and 9.3 mL of 2-nitropropane are prepared while the reaction is cooled with ice, 7.5 mL of formaldehyde (37%) and 4 mL of a solution are slowly added dropwise NaOH 0.5 mol / l (<10 ° C).

Then, the mixture is stirred for 1 h at 25 ° C and for 1 h at 50 ° C. The solution is treated with water and ether and the aqueous phase is extracted 3 times with ether. The combined organic phase is dried over Na2SO4 and combined with HCl in dioxane (4 mol / l), and the precipitate formed is filtered off with suction. Yield: 21.7 g of a white powder. 5 g of the white powder are dissolved in 80 mL of methanol and, with the addition of 2 g of RaNi, they are treated with hydrogen at 35 ° C and 3.5 kg / cm2 for 40 minutes. This provides 3.6 g of 1,1-dimethyl-2-morpholin-1-yl-ethylamine.

The following amines can be prepared analogously.

1,1-dimethyl-N-methylpiperazin-1-yl-ethylamine

H2N

NN

1,1-dimethyl-2-pyrrolidin-1-yl-ethylamine

H2N

N

1,3-DIMORFOLIN-2-AMINO-PROPANE

NH2

N

N

OR

OR

5 g of 1,3-dimorpholine-2-nitropropane, obtained from Messrs. Aldrich, dissolved in 80 mL of methanol and treated with hydrogen for 5.5 h at 30 ° C and 3.5 kg / cm2 with the addition of 2 g of RaNi. This provides 4.2 g of 1,3-dimorpholin-2-amino-propane.

4-aminobenzylmorpholine

H2N

NO

The preparation of this amine is described in the following reference:

S. Mitsuru et al. J. Med. Chem. 2000, 43, 2049-2063. 4-amino-1-tetrahydro-4H-piran-4-yl-piperidine

20 g (100 mmol) of 4-tert-butyloxycarbonyl-aminopiperidine are dissolved in 250 mL of CH2Cl2 and stirred for 12 h at RT with 10 g (100 mmol) of tetrahydro-4H-pyran-4-one and 42 g ( 200 mmol) of NaBH (OAc) 3. Water and potassium carbonate are then added, the organic phase is separated, dried and the solvent is removed in vacuo. The residue is

20 dissolve in 200 mL of CH2Cl2 and stir for 12 h at RT with 100 mL of trifluoroacetic acid. The solvent is removed in vacuo, the residue is taken up with CHCl3 and evaporated again, then taken up in acetone and the hydrochloride is precipitated with ethereal HCl. Yield: 14.3 g (56%).

Cis-y trans-4-morpholino-cyclohexylamine

N OH2N

N OH2N

3.9 g (30 mmol) of 4-dibenzylcyclohexanone are dissolved in 100 mL of CH2Cl2 and stirred for 12 h at RT with 3.9 g (45 mmol) of morpholine and 9.5 g (45 mmol) of NaBH (OAc )3. Water and potassium carbonate are then added, the organic phase is separated, dried and the solvent is removed in vacuo. The residue is purified through a gel column

30 of silica (approximately 20 mL of silica gel; about 500 mL of ethyl acetate 90 / methane 10 + 1% concentrated ammonia). The appropriate fractions are evaporated in vacuo. Yield: 6.6 g (60%) of cis isomer and 2 g (18%) of trans isomer).

Alternatively, trans-dibenzyl-4-morpholino-cyclohexylamine can be prepared by the following method:

33 g (112 mmol) of 4-dibenzylcyclohexanone are dissolved in 300 mL of MeOH, combined with 17.4 g (250 mmol) of hydroxylamine hydrochloride and stirred for 4 h at 60 ° C. The solvent is evaporated in vacuo, combined with 500 mL of water and 50 g of potassium carbonate and extracted twice with 300 mL of dichloromethane. The organic phase is dried, evaporated in vacuo, the residue is crystallized from petroleum ether, dissolved in 1.5 L of EtOH and heated to 70 ° C. 166 g of sodium are added in batches, and the mixture is refluxed until the sodium dissolves. The solvent is removed in vacuo, the residue is combined with 100 mL of water and extracted twice with 400 mL of ether. The organic phase is washed with water, dried, evaporated in vacuo and the trans isomer is isolated using a column (approximately 1.5 L of silica gel; approximately 2 L of ethyl acetate 80 / methanol + concentrated ammonia at 2 %). Yield: 12.6 g (41.2%).

6.8 g (23 mmol) of trans-1-amino-4-dibenzylaminocyclohexanone are dissolved in 90 mL of DMF and stirred for 8 h at 100 ° C with 5 mL (42 mmol) of 2,2'-dichloroethyl ether and 5 g of potassium carbonate. After cooling, 30 mL of water are added, the precipitated crystals are filtered with suction and purified through a short column (about 20 mL of silica gel, about 100 mL of ethyl acetate). The residue is crystallized from methanol and concentrated HCl in the form of dihydrochloride. Yield: 7.3 g (72.4%).

Trans-4-morpholino-cyclohexylamine

7.2 g (16.4 mmol) of trans-dibenzyl-4-morpholino-cyclohexylamine are dissolved in 100 mL of MeOH and hydrogenated about 1.4 g of Pd / C (10%) at 30-50 ° C. The solvent is removed in vacuo, and the residue is crystallized from ethanol and HCl. concentrated. Yield: 3.9 g (93%).

The cis isomer can be prepared analogously.

Cis-y trans-4-piperidino-cyclohexylamine

Trans-dibenzyl-4-piperidino-cyclohexylamine

2.0 g (6.8 mmol) of trans-1-amino-4-dibenzylaminocyclohexane (see Example 2) are dissolved in 50 mL of DMF and stirred for 48 h at RT with 1.6 g (7 mmol) of 1,5-dibromopentane and 2 g of potassium carbonate. The mixture is cooled, combined with water, extracted twice with 100 mL of dichloromethane, dried and the solvent removed in vacuo. The residue is purified on a column (about 100 mL of silica gel, about 500 mL of ethyl acetate 80 / methanol 20 + 1% concentrated ammonia). The desired fractions are evaporated in vacuo and crystallized from petroleum ether. Yield: 1.2 g (49%).

Trans-4-piperidino-cyclohexylamine

1.7 g (4.8 mmol) of trans-dibenzyl-4-piperidine-cyclohexylamine are dissolved in 35 mL of MeOH and hydrogenated over 350 mg of Pd / C (10%) at 20 ° C. The solvent is removed in vacuo and the residue is crystallized from ethanol and concentrated HCl. Yield: 1.1 g (78%).

The cis isomer can be prepared analogously.

Cis-y trans-4- (4-phenyl-piperazin-1-yl) -cyclohexylamine

N N H2N

N

H2N

4.1 g (25.3 mmol) of 4-dibenzylcyclohexanone are dissolved in 50 mL of dichloromethane and stirred for 12 h at RT with 7.4 g (25.3 mmol) of N-phenylpiperazine and 7.4 g (35 mmol) of NaBH (OAc) 3. Then water and carbonate of

35 5

potassium, the organic phase is separated, dried and the solvent is removed in vacuo. The residue is purified on a silica gel column (ethyl acetate 80 / methanol 20 + 0.5% concentrated ammonia). Yield: 1.7 g (15.8%) of cis isomer and 0.27 g (2.5%) of trans isomer.

Trans-4- (4-phenyl-piperazin-1-yl) -cyclohexylamine 270 mg (0.61 mmol) of trans-dibenzyl- [4- (4-phenyl-piperazin-1-yl) -cyclohexyl] -amine se dissolved in 5 mL of MeOH and hydrogenated over 40 mg of Pd / C (10%) at 20-30 ° C. The solvent is removed in vacuo and the residue crystallizes from ethanol and concentrated HCl. Yield: 110 mg (69%).

The cis isomer can be prepared analogously.

Cis-y trans-4- (4-cyclopropylmethyl-piperazin-1-yl) -cyclohexylamine

9.8 g (33.4 mmol) of 4-dibenzylcyclohexanone are dissolved in 100 mL of dichloromethane and stirred for 12 h at RT with 5.6 g (40 mmol) of N-cyclopropylmethylpiperazine and 8.5 g (40 mmol) from NaBH (OAc) 3. Water and potassium carbonate are then added, the organic phase is separated, dried and the solvent is removed in vacuo. The residue is purified on a silica gel column (approximately 50 mL of silica gel, about 3 L of ethyl acetate 95 / methanol 5 + 0.25% concentrated ammonia). The appropriate fractions are evaporated in vacuo. The cis compound that elutes more rapidly crystallizes from ethyl acetate. The trans compound crystallizes from ethanol + concentrated HCl. Yield: 8.5 g (61%) of cis isomer and 2.2 g (13%) of trans isomer.

cis-4- (4-cyclopropylmethyl-piperazin-1-yl) -cyclohexylamine

8.5 g (20 mmol) of cis-dibenzyl- [4- (4-cyclopropylmethyl-piperazin-1-yl) -cyclohexyl] -amine are dissolved in 170 mL of MeOH and hydrogenated over 1.7 g of Pd / C (10%) at 30-50 ° C. The solvent is removed in vacuo and the residue is crystallized from ethanol and concentrated HCl. Yield: 4.4 g (91%).

The trans isomer can be prepared analogously.

Synthesis of the compounds of claim 1 and reference examples

Example 152

0.15 g of compound Z10, 0.14 g of TBTU, 0.13 mL of DIPEA are dissolved in dichloromethane and stirred for 20 minutes at 25 ° C. Then 90 µL of 1- (3-aminopropyl) -4-methylpiperazine is added and stirred for an additional 2 hours at 25 ° C. The solution is then diluted with dichloromethane and extracted with water. The product is precipitated by the addition of petroleum ether, ether and ethyl acetate to the organic phase. Yield: 0.16 g of solid beige.

Example 164

0.10 g of compound Z10, 0.1 g of TBTU, 0.08 mL of DIPEA are dissolved in 4 mL of dichloromethane and stirred for 20 minutes at 25 ° C. Then 44 µL of dimethylaminopropylamine is added and stirred for an additional 2 hours at 25 ° C. The solution is then diluted with dichloromethane and extracted with water. The product is precipitated by the addition of petroleum ether, ether and acetone to the organic phase. Yield: 0.08 g of yellow solid.

Example 242

0.15 g of compound Z10, 0.14 g of TBTU, 0.13 mL of DIPEA are dissolved in 5 mL of dichloromethane and stirred for 20 minutes at 25 ° C. Then 75 µL of 1- (2-aminomethyl) -piperidine is added and stirred for an additional 2 hours at 25 ° C. The solution is then diluted with dichloromethane and extracted with water. The product is precipitated by the addition of petroleum ether, ether and acetone to the organic phase. Yield: 0.14 g of yellow solid.

Example 188

0.1 g of compound Z2, 0.09 g of TBTU, 0.05 mL of DIPEA are dissolved in 15 mL of dichloromethane and stirred for 20 minutes at 25 ° C. Then 33 mg of 1-methyl-4-aminopiperidine is added and the mixture is stirred for an additional 3 hours at 25 ° C. The solution is extracted with 20 mL of water and then evaporated in vacuo. The product is crystallized using ether. Yield: 0.047 g of white crystals.

Example 203

0.1 g of compound Z2, 0.09 g of TBTU, 0.5 mL of DIPEA are dissolved in 15 mL of dichloromethane and stirred for 30 minutes at 25 ° C. Then 50 mg of 4-amino-1-benzylpiperidine is added and the mixture is stirred for an additional 3 hours at 25 ° C. The solution is extracted with 20 mL of water and then evaporated in vacuo. The residue is then chromatographed on silica gel and the isolated product is crystallized with ether. Yield: 0.015 g of white crystals.

Example 94

0.17 g of compound Z1, 0.19 g of TBTU, 0.11 mL of DIPEA are dissolved in 50 mL of dichloromethane and stirred for 30 minutes at 25 ° C. Then 63 mg of 1-methyl-4-aminopiperidine are added and the mixture is stirred for an additional 17 hours at 25 ° C. To the solution 50 mL of water and 1 g of potassium carbonate are added and the organic phase is separated using a phase separation cartridge, and then evaporated in vacuo. The product is then purified by chromatography on silica gel and the purified product is crystallized with ether. Yield: 0.1 g of white crystals.

Example 95

0.17 g of compound Z1, 0.19 g of TBTU, 0.11 mL of DIPEA are dissolved in 50 mL of dichloromethane and stirred for 30 minutes at 25 ° C. Then 77 mg of exo-3-β-aminotropane is added and the mixture is stirred for an additional 17 hours at 25 ° C. To the solution 50 mL of water and 1 g of potassium carbonate are added and the organic phase is separated using a phase separation cartridge, and then evaporated in vacuo. The product is then purified by chromatography on silica gel and the purified product is crystallized with ether. Yield: 0.03 g of white crystals.

Example 46

0.15 g of compound Z3, 0.12 g of TBTU, 0.12 mL of DIPEA are dissolved in 5 mL of dichloromethane and stirred for 30 minutes at 25 ° C. Then 50 mg of 1-methyl-4-aminopiperidine are added and the mixture is stirred for an additional 2.5 hours at 25 ° C. The solution is then extracted with water and then evaporated. The residue is dissolved in hot ethyl acetate and crystallized from ether and petroleum ether. Yield: 0.025 g of white crystals.

Example 80

0.2 g of compound Z8, 0.2 g of TBTU, 0.1 mL of DIPEA are dissolved in 10 mL of dichloromethane and stirred for 30 minutes at 25 ° C. Then 100 mg of 1-methyl-4-aminopiperidine is added and the mixture is stirred for an additional 17 hours at 25 ° C. The solution is then extracted with a dilute solution of potassium carbonate and evaporated. The residue is crystallized using ether. Yield: 0.12 g of white crystals.

Example 190

0.2 g of compound Z8, 0.2 g of TBTU, 0.3 mL of DIPEA are dissolved in 5 mL of dichloromethane and stirred for 1 h at 25 ° C. Then 0.13 g of 4-amino-1-benzylpiperidine are added and the mixture is stirred for an additional hour at 25 ° C. The solution is then diluted with 10 mL of methylene chloride and extracted with 20 mL of water. The product is then purified on silica gel and crystallized from ethyl acetate. Yield: 0.23 g of compound Z8.

0.23 g of the benzylamine Z8 is dissolved in 10 mL of dmetanol, combined with 50 mg of Pd / C and hydrogenated under 3 bar for 3 h at 25 ° C. By adding petroleum ether and ethyl acetate, white crystals are produced. These are chromatographed on silica gel and crystallized from ethyl acetate and ether. Yield: 0.075 g of white crystals.

Example 196

0.1 g of compound Z10, 0.09 g of TBTU, 0.3 mL of DIPEA are dissolved in 4 mL of dichloromethane and stirred for 20 minutes at 25 ° C. Then 67 mg of xx-amine is added and stirred for an additional 2 hours at 25 ° C. The solution is then diluted with dichloromethane and extracted with water. It is then chromatographed on silica gel and the residue is dissolved in acetone, it is combined with ethereal HCl and the precipitate formed is isolated. Yield: 0.09 g of light yellow solid.

Example 166

0.1 g of compound Z10, 0.11 g of TBTU, 0.14 mL of DIPEA are dissolved in 2 mL of dimethylformamide and stirred for 3 h at 50 ° C. The reaction mixture is then cooled to room temperature in the space of 17 h. Then the dimethylformamide is removed in vacuo, the residue is taken up in dichloromethane and extracted with water. It is then chromatographed on silica gel and the product is crystallized from ethyl acetate and ether. Yield: 0.06 g of yellowish crystals.

Example 81

0.2 g of compound Z4, 0.2 g of TBTU, 0.1 mL of DIPEA are dissolved in 10 mL of dichloromethane and stirred for 30 minutes at 25 ° C. Then 0.1 g of 1-methyl-4-aminopiperidine are added and the mixture is stirred for an additional 17 hours at 25 ° C. The solution is then extracted with an aqueous solution of potassium carbonate and then evaporated. The product is crystallized using ether. Yield: 0.16 g of white crystals.

Example 162

0.1 g of compound Z5, 0.07 g of TBTU, 0.15 mL of DIPEA are dissolved in 5 mL of dichloromethane and stirred for 20 minutes at 25 ° C. Then 0.04 g of 1-methyl-4-aminopiperidine are added and the mixture is stirred for an additional 2 hours at 25 ° C. The solution is then diluted with 15 mL of dichloromethane and extracted with 20 mL of water. The residue is dissolved in MeOH and acetone, combined with 1 mL of ethereal HCl and evaporated. A crystalline product is obtained using ether, ethyl acetate and some MeOH. Yield: 0.1 g of white crystals.

Example 88

0.1 g of compound Z6, 0.12 g of TBTU, 0.12 mL of DIPEA are dissolved in 10 mL of dichloromethane and stirred for 30 minutes at 25 ° C. Then 0.04 g of 1-methyl-4-aminopiperidine are added and the mixture is stirred for an additional 2 hours at 25 ° C. The solution is then diluted with 10 mL of dichloromethane and extracted with 10 mL of water. A crystalline product is obtained using ether, ethyl acetate and petroleum ether. Yield: 0.6 g of white crystals.

Example 89

0.1 g of compound Z6, 0.08 g of TBTU and 0.08 mL of DIPEA are dissolved in 10 mL of dichloromethane and stirred for 30 minutes at 25 ° C. Then 37 µL of N, N-dimethylneopentanediamine are added and the mixture is stirred for an additional 2 hours at 25 ° C. The solution is then diluted with 10 mL of dichloromethane and extracted with 10 mL of water. The product is then chromatographed on silica gel and crystallized from ethyl acetate, ether and petroleum ether. Yield: 0.005 g of white crystals.

Example 26

0.15 g of compound Z7, 0.16 g of TBTU, 1 mL of DIPEA are dissolved in 5 mL of dichloromethane and stirred for 30 minutes at 25 ° C. Then 0.1 g of 4-morpholinocyclohexylamine are added and the mixture is stirred for an additional 17 hours at 25 ° C. The solution is then diluted with 10 mL of 10% potassium carbonate solution, the precipitate is isolated and washed with water. It is then dissolved in dichloromethane and evaporated. The product is crystallized from ethyl acetate. Yield: 0.1 g of white crystals.

Example 9

150 mg of compound Z9 and 93 mg of amine are dissolved in 5 mL of dichloromethane and stirred with 160 mg of TBTU and 1 mL of DIPEA for 12 h at RT. The solvent is removed in vacuo, and the residue is combined with 10 mL of 10% potassium carbonate solution. The precipitate is filtered off with suction, washed with water, collected in dichloromethane, dried and the solvent removed in vacuo. The residue is crystallized from ethyl acetate. Yield: 82.0 mg.

Example 16

150 mg of compound Z8 and 73 mg of transamine are dissolved in 5 mL of dichloromethane and stirred with 160 mg of TBTU and 1 mL of DIPEA for 12 h at RT. The solvent is removed in vacuo, and the residue is combined with 10 mL of 10% potassium carbonate solution. The precipitate is filtered off with suction, washed with water, collected in dichloromethane, dried and the solvent removed in vacuo. The residue is crystallized from ethyl acetate. Yield: 87.0 mg.

Example 37

100 mg of compound Z9 and 42 mg of 3-amino-1-ethyl-pyrrolidine are dissolved in 10 mL of dichloromethane and stirred with 90 mg of TBTU and 0.5 mL of DIPEA for 12 h at RT. The solvent is removed in vacuo, and the residue is combined with 10 mL of 10% potassium carbonate solution. The precipitate is filtered off with suction, washed with water, collected in dichloromethane, dried and the solvent removed in vacuo. The residue is crystallized from ethyl acetate. Yield: 24.0 mg.

Example 120

100 mg of compound Z11 and 73 mg of 4-amino-tetrahydro-4H-pyran-4-yl-piperidine are dissolved in 10 mL of dichloromethane and stirred with 90 mg of TBTU and 0.5 mL of DIPEA for 1 h at RT . The solvent is removed in vacuo, and the residue is combined with 10 mL of 10% potassium carbonate solution. The precipitate is filtered off with suction, washed with water, collected in dichloromethane, dried and the solvent removed in vacuo. The residue is crystallized from ethyl acetate / petroleum ether. Yield: 89 mg.

Example 212

150 mg of compound Z5 and 150 mg of trans-4- (4-cyclopropylmethyl-piperazin-1-yl) -cyclohexylamine (in the form of hydrochloride) are dissolved in 5 mL of dichloromethane and stirred with 160 mg of TBTU and 2 mL of DIPEA for 2 h at TA. The solvent is removed in vacuo, and the residue is combined with 10 mL of 10% potassium carbonate solution. The precipitate is filtered off with suction, washed with water, collected in dichloromethane, dried and the solvent removed in vacuo. The residue is purified on a column (20 mL of silica gel, 300 mL of ethyl acetate 90 / methanol 10

+ 2% concentrated ammonia). The appropriate fractions are evaporated in vacuo and crystallized from ethyl acetate. Yield: 140 mg.

Example 232

390 mg of compound Z11 and 240 mg of trans-4- (4-t-butyloxycarbonyl-piperazin-1-yl) -cyclohexylamine are dissolved in 2.5 mL of NMP and stirred with 482 mg of TBTU and 1 mL of triethylamine for 2 hours TA. Then 100 mL of water and 200 mg of potassium carbonate are added, the precipitate is filtered off with suction, washed with water and purified through a column of silica gel. The appropriate fractions are evaporated in vacuo, dissolved in 2 mL of dichloromethane, combined with 2 mL of trifluoroacetic acid and stirred for 2 h at RT, combined with another 100 mL of water and 200 mg of potassium carbonate and the precipitate. It is filtered with suction and washed with water. Then, the precipitate is purified through a silica gel column. The appropriate fractions are evaporated in vacuo and the residue is crystallized from ethanol and concentrated hydrochloric acid. Yield: 95 mg.

Example 213

60 mg of the compound of Example 232 is dissolved in 10 mL of ethyl acetate and stirred with 1 mL of acetic anhydride and 1 mL of triethylamine for 30 min at RT. The solvent is removed in vacuo, the residue is combined with water and ammonia and the precipitated crystals are filtered with suction and washed with water and a little cold acetone. Yield: 40 mg.

Example 218

1.2 g of compound Z9 and 0.5 g of 1,4-dioxaespiro [4,5] dec-8-ylamine are dissolved in 20 mL of dichloromethane and stirred with 1.28 g of TBTU and 4 mL of triethylamine for 12 hours TA. Then 50 mL of water and 0.5 g of potassium carbonate are added, the organic phase is separated, dried and evaporated in vacuo. The residue is crystallized from ethyl acetate, combined with 25 mL of 1 N hydrochloric acid and 20 mL of methanol and stirred for 30 min at 50 ° C. The methanol is removed in vacuo, the precipitate is filtered off with suction, washed with water and dried. The residue is taken up in 20 mL of dichloromethane, and stirred with 0.5 g of triomorpholine and 0.5 g of NaBH (OAc) 3 for 12 h at RT. Water and potassium carbonate are then added, the organic phase is separated, dried and the solvent is removed in vacuo. The residue is purified on a silica gel column. The appropriate fractions are evaporated in vacuo and the hydrochloride is precipitated with ethereal HCl. Yield: 86 mg of trans isomer; amorphous powder

Example 187

200 mg of compound Z3 in 5 mL of dichloromethane are combined with 0.1 mL of diisopropylethylamine and 180 mg of TBTU and stirred for 30 min. Then 191 mg of 4- (4-methyl-piperazin-1-yl) -phenylamine are added and the mixture is

10 shake overnight. The reaction mixture is combined with water and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is purified by column chromatography (eluent: dichloromethane / methanol 100: 7) Yield: 128 mg (light yellow crystals).

The compounds of formula (I) listed in Table 1, among others, are obtained analogously to the processes

15 described above in this report. The abbreviations X1, X2, X3, X4 and X5, used in Table 1, mean in each case a link to a position in the general formula shown in Table 1 instead of the corresponding groups R1, R2, R3, R4 and L-R5.

Table 1 Examples according to claim 1 and reference examples

5

H X2 CH3 R X3 CH3 CH3 H3C X4 OR CH3 X5 NH3C H3C CH3CH3CH3

6

H X2 CH3 R X3 CH3 CH3 H3C X4 OR CH3 X5 N CH3

7

H X2 CH3 R X3 CH3 CH3 H3C X4 OR CH3 X5 N CH3 CH3

8

H X2 CH3 R X3 CH3 CH3 H3C H X5 NH3C H3C CH3CH3CH3

9

H X2 CH3 R X3 CH3H3C X4 OR CH3 X5 N O

10

H X2 CH3 R X3 CH3 CH3 H3C H X5 N

eleven

H X2 CH3 R X3 CH3 CH3 H3C H X5 N CH3

12

H X2 CH3 R X3 CH3 CH3 H3C H X5 N CH3 CH3

13

H X2 CH3 R X3 X4 OR CH3 X5 N H3C CH3

14

H X2 CH3 R X3 H X5 N H3C CH3

fifteen

H X2 CH3 R X3 X4 OR CH3 X5 N

16

H X2 CH3 R X3 X4 OR CH3 X5 N

17

H X2 CH3 R X3 X4 OR CH3 X5 N H3C

18

H X2 CH3 R X3 H X5 N H3C

19

H X2 CH3 R X3 X4 OR CH3 X5 N

twenty

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N H3C

twenty-one

H X2 CH3 R X3 X4 OR CH3 X5 N CH3CH3 H3C H3C CH3

22

H X2 CH3 R X3 X4 OR CH3 X5 N H3C

2. 3

H X2 CH3 R X3 X4 OR CH3 X5 N H3C CH3

24

H X2 CH3 R X3 X4 OR CH3 X5 N O

25

H X2 CH3 R X3 X4 OR CH3 X5 N

26

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N O

27

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N O

28

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N O

29

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N

30

H X2 CH3 R X3 X4 OR CH3 H3C H3C X5 N CH3 CH3 CH3

31

H X2 CH3 R X3 H H3C H3C X5 N CH3 CH3 CH3

32

H X2 CH3 R H3C X3 CH3 X4 OR CH3 H3C H3C X5 N CH3 CH3 CH3

33

H X2 CH3 R H3C X3 CH3 H X5 N H3C H3C CH3 CH3 CH3

3. 4

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N

35

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N

36

H X2 CH3 R X3 X4 OR CH3 X5 N

37

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N H3C

38

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N O

39

H X2 CH3 R X3 H3C CH3 H X5 N H3C

40

H X2 CH3 R X3 X4 OR CH3 X5 N O

41

H X2 CH3 R X3 X4 OR CH3 X5 N CH3

42

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N CH3

43

X1 CH3 X2 CH3 X3 H3C CH3 X4 or H3C X5 N CH3

44

H X2 CH3 R X3 H X5 N CH3

Four. Five

H X2 CH3 R X3 X4 or H3C X5 N CH3

46

H X2 CH3 R X3 X4 or H3C X5 N CH3

47

H X2 CH3 R X3 H X5 N CH3

48

H X2 CH3 R X3 H X5 N CH3

49

H X2 CH3 R X3 X4 OR CH3 X5H3C CH3N

fifty

H X2 CH3 R X3 CH3 CH3 H3C X4 OR CH3 X5 H3C H3C N

51

H X2 R X3 X4 OR CH3 X5 CH3 H3C N CH3 CH3

X2 CH3

X3 CH3 Or CH3 X5 CH3 H3C

52

H R CH3 H3C X4 N CH3 CH3

53

X1 CH3 X2 CH3 X3 H3C CH3 X4 OR CH3 X5 CH3 H3C N CH3 CH3

54

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5H3C CH3N

55

H X2 CH3 R X3 X4 OR CH3 X5H3C CH3N

56

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5H3C CH3N

57

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 CH3 H3C N CH3 CH3

58

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N CH3 CH3

59

H X2 CH3 R X3 X4 or H3C X5 N CH3

60

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N CH3 CH3

61

X1 CH3 X2 CH3 X3 CH3 CH3 Or H3C X4 X5 N CH3

62

H X2 CH3 R X3 X4 OR CH3 N H3C H3C X5

63

H X2 CH3 R X3 X4 OR CH3 NO X5

64

H X2 CH3 R X3 X4 OR CH3 N X5

65

H X2 CH3 R X3 X4 OR CH3 NO X5

66

H X2 CH3 R X3 X4 OR CH3 N X5

67

H X2 CH3 R X3 X4 OR CH3 N H3C CH3 X5

68

H X2 CH3 R X3 H N H3C X5

69

H X2 CH3 R X3 H NO X5

70

H X2 CH3 R X3 H N X5

71

H X2 CH3 R H3C X3 CH3 X4 or H3C X5 N O

72

H X2 CH3 R H3C X3 CH3 X4 or H3C X5 N

73

H X2 CH3 R H3C X3 CH3 H X5 N CH3CH3

74

H X2 CH3 R H3C X3 CH3 X4 or H3C X5 N CH3 CH3

75

H X2 CH3 R X3 X4 OR CH3 X5N H3C CH3

76

H X2 CH3 R X3 X4 OR CH3 X5NH3C H3C

77

H X2 CH3 R H3C X3 CH3 H X5 N

78

H X2 CH3 R H3C X3 CH3 H X5 N O

79

H X2 CH3 R X3 H X5 N H3C

80

H X2 CH3 R X3 X4 OR CH3 X5 N H3C

81

H X2 R X3 X4 OR CH3 X5 N CH3

82

H X2 R X3 X4 OR CH3 X5 N CH3

83

H X2 CH3 R X3 X4 H3C N H3C X5

84

H X2 CH3 R X3 X4 OR CH3 X5 N CH3

85

H X2 CH3 R X3 H X5 N CH3

86

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N CH3 CH3

87

H X2 CH3 R X3 X4 OR CH3 X5H3C CH3N

88

H X2 CH3 R X3 X4 or H3C X5 N CH3

89

H X2 CH3 R X3 X4 or H3C X5 CH3 CH3 N H3C CH3

90

H X2 CH3 R X3 CH3H3C X4 OR CH3 X5 CH3 H3C N H3C CH3

91

H X2 CH3 R X3 X4 OR CH3 X5 N CH3

92

H X2 CH3 R X3 H X5 N CH3

93

H X2 R X3 H X5 N H3C

94

H X2 CH3 R X3 X4 H3C X5 N CH3

95

H X2 CH3 R X3 X4 H3C X5 N CH3

96

H X2 CH3 R X3 X4 or H3C X5 N CH3

97

H X2 CH3 R X3 X4 or H3C X5 N O

98

H X2 CH3 R X3 X4 OR CH3 X5 N

99

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N N

100

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N N

101

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N

102

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N

103

H X2 CH3 R X3 X4 OR CH3 X5 N

104

H X2 CH3 R X3 X4 OR CH3 X5 N

105

H X2 CH3 R X3 X4 OR CH3 X5 N N

106

H X2 CH3 R X3 X4 OR CH3 X5 N N CH3

107

H X2 CH3 R X3 X4 OR CH3 X5 N N

108

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N O

109

H X2 CH3 R X3 X4 OR CH3 X5 N O

110

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N N

111

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N O

112

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N N

113

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N N CH3

114

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N H3C CH3

115

H X2 CH3 R X3 X4 OR CH3 X5 N

116

H X2 CH3 R X3 X4 OR CH3 X5 N O

117

H X2 CH3 R X3 X4 OR CH3 X5 N H3C H3C CH3 CH3 CH3

118

H X2 CH3 R X3 X4 OR CH3 X5 N H3C CH3

119

H X2 CH3 R X3 X4 OR CH3 X5 N H3C

120

H X2 CH3 R X3 X4 OR CH3 X5 N O

121

H X2 CH3 R X3 X4 OR CH3 X5 N H3C

122

H X2 CH3 R X3 X4 OR CH3 X5 N H3C CH3

123

H X2 CH3 R X3 X4 OR CH3 X5 N H3C

124

H X2 CH3 R X3 X4 OR CH3 X5 N H3C CH3

125

H X2 CH3 R X3 X4 OR CH3 X5 N

126

H X2 CH3 R X3 X4 OR CH3 X5 N

127

H X2 CH3 R X3 X4 O CH3 X5 N

128

H X2 CH3 R X3 X4 O CH3 X5 N

129

H X2 CH3 R X3 CH3H3C X4 O CH3 X5 N

130

H X2 CH3 R X3 X4 O CH3 X5 N O

131

H X2 CH3 R X3 X4 O CH3 X5 N O

132

H X2 CH3 R X3 CH3H3C X4 O CH3 X5 N

133

H X2 CH3 R X3 X4 O CH3 X5 N O

134

H X2 CH3 R X3 X4 O CH3 X5 N N

135

H X2 CH3 R X3 CH3H3C X4 O CH3 X5 N

136

H X2 CH3 R X3 X4 OR CH3 X5 N

137

H X2 CH3 R X3 X4 OR CH3 X5 N O

138

H X2 CH3 R X3 X4 OR CH3 X5 N

139

H X2 CH3 R X3 H3C CH3 X4 or H3C X5 N CH3

140

H X2 CH3 R X3 H3C CH3 X4 or H3C X5 N CH3

141

H X2 CH3 R X3 H3C CH3 X4 or H3C X5 N O

142

H X2 CH3 R X3 H3C CH3 X4 or H3C X5 N

143

H X2 CH3 R X3 H3C CH3 H X5 N O

144

H X2 CH3 R X3 H3C CH3 H X5 N CH3

145

H X2 H3C R X3 CH3 CH3 H3C X4 OR CH3 X5 N CH3

146

H X2 CH3 R X3 H3C CH3 X4 O CH3 X5 N CH3

147

H X2 H3C R X3 H3C CH3 CH3 H X5 N CH3

148

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N

149

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N CH3 CH3

150

H X2 CH3 R X3 H3C CH3 H X5 N

151

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N O

152

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N N CH3

153

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N CH3CH3

154

H X2 CH3 R X3 H3C CH3 H X5 N N CH3

155

H X2 CH3 R X3 H3C CH3 H X5 N O

156

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N O

157

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N

158

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N CH3CH3

159

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N CH3 CH3

160

H X2 CH3 R H3C X3 CH3 X4 OR CH3 X5 N CH3 CH3 CH3H3C

161

X1 CH3 X2 CH3 X3 H3C CH3 X4 or H3C X5 N CH3 CH3

162

X1 CH3 X2 CH3 X3 H3C CH3 X4 or H3C X5 N CH3

163

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N

164

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N CH3 CH3

165

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N CH3 CH3

166

H X1 CH3 R X3 X4 OR CH3 X5 N O

167

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N CH3

168

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 CH3 CH3 N H3C H3C

169

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N

170

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N

171

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N CH3

172

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N CH3

173

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N H3C H H

174

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N

175

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N H3C CH3

176

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 CH3 H3C N H3C CH3

177

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N H3C CH3

178

H X2 CH3 R X3 CH3H3C X4 OR CH3 X5 N

179

H X2 CH3 R X3 CH3H3C X4 OR CH3 X5 N

180

H X2 CH3 R X3 X4 or H3C X5 N

181

H X2 CH3 R X3 O X4 OR CH3 X5 N

182

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N O

183

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 CH3 H3C N O

184

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N O

185

H X2 CH3 R X3 OR H3C X4 OR CH3 X5 CH3 H3C N O

186

H X2 CH3 R X3 X4 OR CH3 X5 N N CH3

187

H X2 CH3 R X3 X4 OR CH3 X5 N N CH3

188

H X2 CH3 R X3 X4 Cl X5 N CH3

189

H X2 CH3 R X3 X4 OR CH3 X5 N O

190

H X2 CH3 R X3 X4 OR CH3 X5 N

191

H X2 R X3 H3C CH3 X4 or H3C X5 N CH3

192

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N O

193

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N O

194

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N O

195

H X2 CH3 R X3 CH3 CH3 X4 OR CH3 X5 CH3 H3C N O

196

H X2 CH3 R X3 CH3H3C X4 OR CH3 X5 CH3 H3C N N CH3

197

H X2 X3 CH3H3C X4 OR CH3 X5 CH3 H3C N N CH3

198

H X3 X2 R X4 or H3C X5 N CH3

199

H X3 X2 R X4 or H3C X5 N O

200

H X3 X2 R X4 OR CH3 X5 N CH3

201

H X3 X2 R X4 OR CH3 X5 N

202

X1 CH3 X2 CH3 X3 CH3H3C X4 OR CH3 X5 N O

203

H X2 CH3 R X3 X4 Cl X5 N

204

H X2 CH3 R X3 CH3 CH3 X4 OR CH3 X5 N

205

H X2 CH3 R X3 CH3 CH3 X4 OR CH3 X5 N O

206

H X2 CH3 R X3 CH3 CH3 CH3 X4 OR CH3 X5 N N

207

H X2 CH3 R X3 CH3 CH3 CH3 X4 OR CH3 X5 N O

208

H X2 CH3 R X3 CH3 CH3 CH3 X4 OR CH3 X5 N N

209

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N N CH3

210

H X2 CH3 R X3 X4 OR CH3 X5 N N CH3

211

X1 CH3 X2 CH3 X3 H3C CH3 X4 OR CH3 X5 N O

212

X1 CH3 X2 CH3 X3 H3C CH3 X4 O CH3 X5 N N

213

H X2 CH3 R X3 X4 O CH3 X5 N N CH3O

214

H X2 CH3 R H3C X3 CH3 X4 O CH3 X5 N N CH3

215

X1 CH3 X2 CH3 X3 H3C CH3 X4 O CH3 X5 N N CH3

216

H X2 CH3 R X3 X4 O CH3 X5 N N CH3

217

H X2 CH3 R X3 X4 O CH3 X5 N N CH3

218

H X2 CH3 R X3 H3C CH3 X4 O CH3 X5 N S

219

H X2 CH3 R X3 H3C CH3 X4 O CH3 X5 N O

220

H X2 CH3 R X3 CH3 CH3 CH3 X4 OR CH3 X5 N O

221

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N N CH3

222

H X2 CH3 R X3 H3C CH3 X4 OR CH3 X5 N N CH3

223

H X2 CH3 R X3 X4 OR CH3 X5 N CH3

224

H X2 CH3 R X3 OR CH3 X4 OR CH3 X5 N CH3

225

H X2 CH3 R X3 OR CH3 H X5 N CH3

226

H X2 CH3 R X3 OR CH3 X4 or H3C X5 N CH3

227

H X2 CH3 R X3 OR CH3 X4 OR CH3 X5H3C CH3N

228

H X2 CH3 R X3 CH3H3C X4 OR CH3 X5 N CH3H3C

229

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N

230

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N

231

H X2 CH3 R X3 X4 OR CH3 X5 CH3 H3C N

232

H X2 CH3 R X3 X4 OR CH3 X5 N N

233

H X1 CH3 R X3 CH3 CH3 CH3 X4 OR CH3 X5 N OH3C CH3

2. 3. 4

H X1 CH3 R X3 CH3H3C X4 OR CH3 X5 N OH3C CH3

235

H X1 CH3 R X3 CH3H3C X4 OR CH3 X5 N S O

236

H X1 CH3 R X3 CH3H3C X4 OR CH3 X5 N S O

237

H X1 CH3 R X3 CH3H3C X4 OR CH3 X5 N

238

H X1 CH3 R X3 X4 OR CH3 X5 N

239

H X1 CH3 R X3 X4 OR CH3 X5 CH3 H3C N O

240

H X1 CH3 R X3 X4 OR CH3 X5 CH3 H3C N H3C CH3

241

H X1 CH3 R X3 H3C CH3 X4 OR CH3 X5 CH3 H3C N

N

CH3

242

H X1 CH3 R X3 H3C CH3 X4 OR CH3 X5 N

X1

CH3 X3 CH3 X5

OR

243

H R H3C CH3 X4 N CH3

CH3

244

H X1 CH3 R X3 H3C CH3 X4 OR CH3 X5 N N CH3

Claims (19)

1.-A pharmaceutical composition, comprising effective amounts of: (i) a compound 1 of formula (I): wherein the abbreviations X1, X2, X3, X4 and X5 used in the Table designate in each case a link to a position in the general formula shown in the Table instead of the corresponding groups R1, R2, R3, R4 and Ln- R5m, 10 optionally in the form of their racemate tautomers, enantiomers, diastereoisomers and mixtures thereof and optionally in the form of their salts by the addition of pharmacologically acceptable acids, solvates, hydrates; Y (ii) at least one additional therapeutic agent 2, selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo- 2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) -quinazo-canvas or a pharmaceutically acceptable salt thereof, 3-Z- [1- (4- (N- ((4-Methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) 1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone or a pharmaceutically acceptable salt thereof, a compound of platinum, selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa and chlorambucil of an analogue pyrimidine or purine or a nucleoside diphosphate 20 reductase inhibitor, selected from the group consisting of cytarabine, 5-fluorouracil (5-FU), permetrexed, tegafur / uracil, mustard uracil, fludarabine, gemcitabine, capecitabine, mercaptopurin a, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea and folic acid, a camptothecin, selected from the group consisting of irinotecan and topotecan, a histonadeacetylase inhibitor, selected from the group consisting of SAHA, MD-275, tricostatin A, CBHA, LAQ824 and valproic acid, an anti-cancer drug from plants, selected from the group that 25 consists of paclitaxel, docetaxel and taxotero. 2. The pharmaceutical composition according to claim 1, wherein compound 1 is selected from the following compound OR CH3 H OR R5 m-Ln N N R1 N R2 H R3 R4 R1 R2 R3 R4 Example Ln-R5m Config. R1 or R2 H R wherein the abbreviations X1, X2, X3, X4 and X5 used in the Table mean in each case a link to a position in the general formula shown in the Table instead of the corresponding groups R1, R2, R3, R4 and L- R5 3. The pharmaceutical composition according to claim 1, wherein compound 1 is selected from the following compound OR CH3 H OR R5 N m-Ln N R1 N R2 H R4 R3 R1 R2 R3 R4 Example Ln-R5m Config. R1 or R2 H R 10 where the abbreviations X1, X2, X3, X4 and X5 used in the Table mean in each case a link to a position in the general formula shown in the Table instead of the corresponding groups R1, R2, R3, R4 and Ln -R5m. 4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the additional therapeutic agent 2 is the quinazoline derivative 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4 - (N, N-dimethylamino) -1-oxo-215 buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline or a pharmaceutically acceptable salt thereof. 5. The pharmaceutical combination according to any one of claims 1 to 3, wherein the additional therapeutic agent 2 is the di-maleic acid salt of compound 4 - [(3-chloro-4-fluorophenyl) amino] - 6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline or 4 - [(3-chloro -4-fluorophenyl) -amino] -6 {[4- (homomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yl) oxy] -quinazoline, or tautomers, stereoisomers or a pharmaceutically acceptable salt thereof. 6. The pharmaceutical combination according to any one of claims 1 to 3, wherein the additional therapeutic agent 2 is 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (homomorfolin -4-yl) -1-oxo-2-buten-1-yl] amino} -7 - ((S) tetrahydrofuran-3-yl) oxy] -quinazoline, or tautomers, stereoisomers or a pharmaceutically acceptable salt of the same. 7. The pharmaceutical combination according to any one of claims 1 to 3, wherein the additional therapeutic agent 2 is 3-Z- [1- (4- (N - ((4-methyl-piperazin-1-yl ) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof. 8. The pharmaceutical combination according to any one of claims 1 to 3, wherein the additional therapeutic agent 2 is the 3-Z- monoethanesulfonate salt [1- (4- (N - ((4-methyl-piperazin -1-yl) -methylcarbonyl) -N-methylamino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone. 9. The pharmaceutical combination according to any one of claims 1 to 3, wherein the additional therapeutic agent 2 is 3-Z- [1- (4-dimethylaminomethylanilino) -1- (4- (2-carboxyethyl) phenyl ) methylene] -6-fluoro-2-indolinone, or a pharmaceutically acceptable salt thereof. 10. The pharmaceutical composition according to any one of claims 1 to 3, wherein the additional therapeutic agent 2 is selected from the group consisting of irinotecan, topotecan, oxaliplatin, docetaxel, paclitaxel, gemcitabine, pemetrexed, cisplatin or carboplatin. 11. A pharmaceutical composition according to any one of claims 1 to 10 for use in the treatment of an oncological disease. 12. Use according to claim 11, wherein the oncological disease is selected from the group consisting of solid tumors. 13. Use according to claim 11, wherein the oncological disease is selected from the group consisting of urogenital cancers, lung cancers, gastrointestinal cancers, head and neck cancer, malignant mesotheliomas, breast cancer, malignant melanoma, cancers Children and bone and soft tissue sarcomas. 14. Use according to claim 11, wherein the oncological disease is selected from the group consisting of refractory or recurrent multiple myeloma, acute or chronic myelogenous leukemia, myelodysplastic syndrome, myeloproliferative syndromes, acute lymphoblastic leukemia, Hodgkin lymphoma or not from Hodgkin. 15.-A pharmaceutical combination preparation kit for the treatment of diseases that involve cell proliferation, migration or apoptosis of cancer cells, or angiogenesis, comprising a therapeutically effective amount of: (i) a compound 1 of formula (I) as defined in any one of claims 1 to 3; Y (ii) at least one additional therapeutic agent 2 as defined in any one of claims 1 to 10; and, optionally, intended for co-treatment with radiotherapy or radio-immunotherapy; characterized in that the compound 1 of formula (I) is comprised within a first compartment, and the additional therapeutic agent 2 is comprised within a second compartment, so that administration to a patient in need may be simultaneous, separate or sequential. . 16. The pharmaceutical combination preparation kit according to claim 15, wherein the formulation of compound 1 of formula (I) is for oral administration or injection. 17. A pharmaceutical composition according to any one of claims 1 to 10 or a pharmaceutical combination preparation kit according to claims 15 or 16, for the manufacture of a medicament, optionally intended for co-treatment with radiotherapy or radio-immunotherapy, for use in the treatment of diseases that involve a proliferation of cells, a migration or apoptosis of cancer cells, or angiogenesis, in a human or non-human mammalian body. 18. A pharmaceutical combination preparation comprising an effective amount of a compound 1 of formula (I) as defined in any one of claims 1 to 3 in combination with at least one additional therapeutic agent 2 as defined in any one of claims 1 to 10, optionally intended for co-treatment with radiotherapy or radio-immunotherapy, for simultaneous, separate or sequential use in the 10 treatment of diseases that involve cell proliferation, migration or apoptosis of cancer cells, or angiogenesis, in a human or non-human mammalian body. 19. Use according to any one of claims 11 to 14, 17 or 18, characterized in that the compound 1 of formula (I), or its pharmaceutically acceptable hydrate or salt is administered intermittently or in a 15 daily dosage, so that the plasma level of the active substance is between 10 and 5000 nM for at least 12 hours of the dosing interval.