WO2004087679A1 - Derives de pyrimidine trisubstitues en position 2, 4, 6 utiles pour le traitement de maladies neoplasiques et auto-immunes - Google Patents

Derives de pyrimidine trisubstitues en position 2, 4, 6 utiles pour le traitement de maladies neoplasiques et auto-immunes Download PDF

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WO2004087679A1
WO2004087679A1 PCT/EP2004/003296 EP2004003296W WO2004087679A1 WO 2004087679 A1 WO2004087679 A1 WO 2004087679A1 EP 2004003296 W EP2004003296 W EP 2004003296W WO 2004087679 A1 WO2004087679 A1 WO 2004087679A1
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optionally substituted
lower alkyl
lower alkoxy
alkyl
hydroxy
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PCT/EP2004/003296
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Daniel Obrecht
Philipp Ermert
Anatol Luther
Martin Eberle
Felix Bachmann
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Aponetics Ag
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Priority to EP04723991A priority Critical patent/EP1644338A1/fr
Publication of WO2004087679A1 publication Critical patent/WO2004087679A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to novel substituted pyrimidine derivatives, processes for the preparation thereof, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of neoplastic diseases and autoimmune diseases, and a method for the treatment of such a diseases.
  • Cancer is one of the leading causes of death in humans. Although a variety of drugs against neoplastic diseases have been developed and techniques are available such as surgery and radiation therapy, there is still a need for alternative and improved methods of treatment of neoplastic diseases.
  • Apoptosis is a term used to describe a series of cellular events which occur to bring about programmed cell death. There are various apoptotic pathways, some of which have been characterized, whereas others remain to be elucidated. If the balance between cell division and apoptosis is disturbed, life-threatening diseases including cancer, autoimmune disorders, neurodegenerative and cardiovascular diseases may occur.
  • Familiar indications in this category include cancers, restenosis, neointimal hyperplasia, angiogenesis, endometriosis, lymphoproliferative disorders, transplantation related pathologies (graft rejection), polyposis, loss of neural function in the case of tissue remodeling and the like. Such cells may lose the normal regulatory control of cell division, and may also fail to undergo appropriate cell death.
  • induction of apoptosis is an option for treatment of cancer, especially in cancer types which show resistance to classic chemotherapy, radiation and immunotherapy (Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds., Blackwell Publishing, 1999).
  • compounds inducing apoptosis may be used to restore normal cell death processes and therefore can eradicate the symptoms and might cure the diseases. Further applications of compounds inducing apoptosis may be in restenosis, i.e.
  • vascular smooth muscle cells in the walls of arteries, and in persistent infections caused by a failure to eradicate bacteria- and virus-infected cells. Furthermore, apoptosis can be induced or re-established in epithelial cells, in endothelial cells, in muscle cells, and in others which have lost contact with extracellular matrix. These cells are potentially able to colonize other organs and therefore can develop into pathologies like neoplasias, endometriosis and the like.
  • Substituted pyrimidines of formula (I) are selectively inducing apoptosis in cancer cells, and can be used for the treatment of neoplastic and autoimmune diseases.
  • the invention relates to novel compounds of formula (I) as defined hereinafter, to methods of synthesis of such compounds, to compounds of formula (I) for use as medicaments, to pharmaceutical compositions containing compounds of formula (I), to the use of a compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using such compounds of formula (I) or of pharmaceutical compositions containing same.
  • novel compounds of formula (I) as defined hereinafter, to methods of synthesis of such compounds, to compounds of formula (I) for use as medicaments, to pharmaceutical compositions containing compounds of formula (I), to the use of a compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to
  • the invention relates to compounds of formula (I)
  • V represents a bond or CR 6 R 7 ;
  • W represents a bond, NR 8 or oxygen;
  • X represents sulfur, or nitrogen substituted by hydrogen or R 5 ;
  • Y represents -CH 2 -, -CH 2 CH 2 -, -CO- or -CS-;
  • R 1 represents aryl or 6 membered ring heteroaryl which may be substituted by one to four substituents independently chosen from lower alkyl, halo-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-Iower alkyl, halo-lower alkoxy-lower alkyl, acyloxy-lower alkyl, aminoalkyl wherein the nitrogen atom is optionally substituted by one or two substitutents independently selected from alkyl, hydroxyalkyl and alkoxyalkyl, heterocyclyl, heterocyclyl-lower alkyl, optionally substituted aryl, optionally substituted aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, hydroxy,
  • R 8 represents hydrogen or lower alkyl
  • R 9 is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted alkenyl, optionally substituted alkinyl; or aminoalkyl, wherein the nitrogen atom is unsubstituted or substituted by one or two substituents selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, optionally substituted aminoalkyl, optionally substituted aryl, optionally substituted
  • the prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
  • Double bonds in principle can have E- or Z-configuration.
  • the compounds of this invention may therefore exist as isomeric mixtures or single isomers. If not specified both isomeric forms are intended.
  • Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
  • the compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers.
  • the invention relates also to possible tautomers of the compounds of formula (I).
  • Alkyl has from 1 to 12, preferably from 1 to 7 carbon atoms, and is linear or branched. Alkyl is preferably lower alkyl.
  • Lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl.
  • Preferably lower alkyl is methyl or ethyl.
  • Cycloalkyl has preferably 3 to 7 ring carbon atoms, and may be unsubstitued or substituted, e.g. by lower alkyl or lower alkoxy. Cycloalkyl is, for example, cyclohexyl, cyclopentyl, or methylcyclopentyl.
  • Aryl stands for a mono- or bicyclic fused ring aromatic group with 5 to 10 carbon atoms, such as phenyl, 1-naphthyl or 2-naphthyI, or also a partially saturated bicyclic fused ring comprising a phenyl group, such as indanyl, dihydro- or tetrahydronaphthyl.
  • aryl e.g. optionally substituted phenyl
  • substituents are preferably lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, methylenedioxy, halo-lower alkyl, lower alkoxy-lower alkyl, halo, cyano, or nitro.
  • Heteroaryl represents an aromatic group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, and is mono- or bicyclic.
  • Monocyclic heteroaryl includes 5 or 6 membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur and oxygen.
  • Bicyclic heteroaryl includes 9 or 10 membered fused-ring heteroaryl groups.
  • heteroaryl examples include pyrrolyl, thienyl, furyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzo fused derivatives of such monocyclic heteroaryl groups, such as indolyl, benz- imidazolyl or benzofuryl, quinolinyl, isoquinolinyl, quinazolinyl, or purinyl.
  • 6 membered ring heteroaryl R 1 represents heteroaryl as defined hereinbefore, but limited to a 6 membered ring. The definition is not restricted to monocyclic 6 membered ring heteroaryl, but includes also fused ring bicyclic derivatives of 6 membered ring heteroaryl. 6 membered ring heteroaryl R 1 contains a total of 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur and oxygen, in particular 0, 1 , 2, 3 or 4 nitrogen atoms, 0 or 1 sulfur atom, and 0 or 1 oxygen atom.
  • fused ring bicyclic derivatives of a 6 membered ring heteroaryl R 1 the fused ring may consist of 3 or 4 ring members, heteroaryl then representing a 9 or 10 membered fused- ring bicyclic heteroaromatic group.
  • 6 membered ring heteroaryl R 1 include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and benzo fused derivatives of such monocyclic heteroaryl groups, such as quinolinyl, isoquinolinyl or quinazolinyl, or purinyl.
  • substituents are preferably lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, halo-lower alkyl, lower alkoxy-lower alkyl, hydroxy, oxo, amino, halo, or nitro.
  • Alkenyl contains one or more, e.g. two or three, double bonds, and is preferably lower alkenyl, such as 1- or 2-butenyl, 1-propenyl, allyl or vinyl.
  • Alkinyl is preferably lower alkinyl, such as propargyl or acetylenyl.
  • substituents are preferably lower alkyl, lower alkoxy, halo or di(lower alkyl)amino, and are connected with a saturated carbon atom of alkenyl or alkinyl or with an unsaturated carbon atom of alkenyl or alkinyl.
  • Optionally substituted alkenyl is, for example, allyl or methallyl.
  • Optionally substituted alkinyl is, for example, ethinyl, 3-hydroxy-3-methyl-1-butinyl, 3-amino-1-propinyl or 3-(iM,N-dimethylamino)- 1-r.
  • Heterocyclyl designates preferably a saturated, partially saturated or unsaturated, mono- or bicyclic ring containg 4-10 atoms comprising one, two or three heteroatoms selected from nitrogen, oxygen and sulfur, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a ring nitrogen atom may optionally be substituted by a group selected from lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl and acyl, and a ring carbon atom may be substituted by lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl, heteroaryl, lower alkoxy, hydroxy or oxo.
  • heterocyclyl examples include pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolanyl and tetrahydropyranyl.
  • Acyl designates, for example, alkylcarbonyl, cyclohexylcarbonyl, arylcarbonyl, aryl-lower alkylcarbonyl, or heteroarylcarbonyl.
  • Lower acyl is preferably lower alkylcarbonyl, in particular propionyl or acetyl.
  • Hydroxyalkyl is especially hydroxy-lower alkyl, preferably hydroxym ethyl, 2-hydroxyethyl or 2-hydroxy-2-propyl.
  • Haloalkyl is preferably fluoroalkyl, especially trifluoromethyl or 2,2,2-trifluoroethyl.
  • Halogen is fluorine, chlorine, bromine, or iodine.
  • Lower alkoxy is especially methoxy, ethoxy, isopropyloxy, or tert-butyloxy.
  • Arylalkyl includes aryl and alkyl as defined hereinbefore, and is e.g. benzyl, 1-phenethyl or 2-phenethyl.
  • Heteroarylalkyl includes heleroaryl and alkyl as defined hereinbefore, and is e.g. 2-pyridyl- methyl, 1- or 2-pyrrolylmethyl, 1-imidazolylmethyl, 2-(1-imidazolyl)-ethyl or 3-(1-imidazoIyl)- propyl.
  • Two adjacent substituents which together with the atoms of aryl or heteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ring are, for example, propylene, 1- or 2- oxopropylene, 1- or 2-oxapropylene, 1-oxapropylidene, methylenedioxy, difluoromethylene- dioxy, 1- or 2-azapropylene, 1- or 2-azapropylidene, 1,2- or 1,3-diazapropylidene, 1,2,3- triazapropylidene, 1 ,3-diaza-2-oxopropylene, butylene, 1- or 2-oxabutylene, ethylenedioxy, 1- or 2-azabutylene, or 1- or 2-a ⁇ abuladienylidene, or such groups carrying further substituents as defined hereinbefore.
  • substituted amino the substituents are preferably those mentioned as substituents R 2 and R 3 .
  • substituted amino is alkylamino, dialkylamino, optionally substituted aryl- amino or optionally substituted arylalkylamino.
  • Salts are especially the pharmaceutically acceptable salts of compounds of formula (I).
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula (I) with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesuIfonic acid, ethane-1,2-dis
  • salts for isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates.
  • pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
  • any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
  • the compound of the formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I).
  • pro-drugs include in vivo hydrolysable esters of a compound of the formula (I).
  • the compounds of formula (I) have valuable pharmacological properties.
  • the invention also relates to compounds of formula (I) as defined hereinbefore, including compounds of the formula (I) wherein V and W each represent a bond, X represents nitrogen, Y represents -CO-, and R 1 is unsubstituted phenyl, for use as medicaments.
  • Suitable tumor cell lines are A20.2J, a BALB/c B cell lymphoma, PB-3c, an IL-3 dependent, non tumorigenic mastocyte line isolated from the bone marrow of a DBA 2 mouse, Jurkat, a human acute T cell leukemia cell line, K562, a human chronic myelogenous leukemia cell line, HL60, a human acute promyelocytic leukemia cell line, Ramos and Raji, human B-cell lymphoma cell lines, H9 and Hut78, human T-cell lymphoma cell lines, HeLa and KB, human squamous cell carcinoma cell lines, MCF7, SK-BR-3, PC3, HBL-100, SW480, H460 and H1792, human adeno- carcinoma cell lines and HT-1080, a
  • Preferred standard drugs as compounds for comparisons are: a) antimetabolites such as 5-fluorouracil (ICN), gemcitabine HCI (GemzarTM, Eli Lilly), b) alkylating agents such as oxaliplatin (EloxantinTM, Sanofi-Synthelabo), dacarbazin (DetimedacTM, Medac), cyclo- phosphamide (EndoxanTM, Asta) and carboplatin (ParaplatinTM, Bristol-Meyers Squibb), c) cell-cycle inhibitor such as vinorelbine (NavelbineTM, Robapharm), vinblastine (VelbeTM, Eli Lilly), docelaxel (TaxotereTM, Aventis), d) DNA breaker (topo-isomerase inhibitor, intercalator, strand breaker) such as doxorubicin HCI (AdriblastinTM, Pharmacia-Upjohn), bleomycin (Asla-Medica),
  • Apoptosis is determined in a primary screen using a fluorescence plate reader and then in a secondary screen using FACS (fluorescence activated cell scanning).
  • Compounds causing apoptosis without substantial cytotoxic side effects are chosen for further testing and characterization by using a combination of the following well established assays:
  • B) MTS proliferation assay measuring the metabolic activity of cells. Viable cells are metabolically active whereas cells with compromised respiratory chain show a reduced activity in this test.
  • a compound of formula (I) according to the invention shows therapeutic efficacy especially against neoplastic diseases and autoimmune diseases.
  • the compounds of the invention are active against malignancies, e.g. epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas und adenocarcinomas, adnexal and skin appendage neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal-, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumors, naevi and melanomas, soft tissue tumors
  • malignancies e
  • the compounds of the invention are likewise active against autoimmune diseases, e.g. against systemic, discoid or subacute cutaneous lupus erythematosus, rheumatoid arthritis, anliphospholipid syndrome, CREST, progressive systemic sclerosis, mixed connective tissue disease (Sharp syndrome), Reiter's syndrome, juvenile arthritis, cold agglutinin disease, essential mixed cryoglobulinemia, rheumatic fever, ankylosing spondylitis, chronic polyarthritis, myasthenia gravis, multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, Guillan-Barre syndrome, dermatomyositis/polymyositis, autoimmune hemolytic anemia, thrompocytopenic purpura, neutropenia, type I diabetes mellitus, thyroiditis (including Hashimoto's and Grave' disease), Addison's disease, polyglandular syndrome, pemphigus (vulgar
  • a compound of formula (I) can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations, or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.
  • a compound of formula (I) can, besides or in addition, be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. Particularly preferred is the use of compounds of formula (I) in combination with radiotherapy.
  • Therapeutic agents for possible combination are especially one or more cytostatic or cytotoxic compounds, for example a chemotherapeutic agent or several selected from the group comprising indarubicin, cytarabine, interferon, hydroxyurea, bisulfan, or an inhibitor of polyamine biosynthesis, an inhibitor of protein kinase, especially of serine/threonine protein kinase, such as protein kinase C, or of tyrosine protein kinase, such as epidermal growth factor receptor tyrosine kinase, a cytokine, a negative growth regulator, such as TGF- ⁇ or IFN- ⁇ , an aromatase inhibitor, a classical cytostatic, an inhibitor of the interaction of an SH2 domain with a phosphorylated protein, an inhibitor of Bcl-2 and modulators of the Bcl-2 family members such as Bax, Bid, Bad, Bim, Nip3 and BH3-only proteins.
  • cytostatic or cytotoxic compounds for example
  • a compound according to the invention is not only for the (prophylactic and preferably therapeutic) management of humans, but also for the treatment of other warm-blooded animals, for example of commercially useful animals, for example rodents, such as mice, rabbits or rats, or guinea-pigs. Such a compound may also be used as a reference standard in the test systems described above to permit a comparison with other compounds.
  • V represents a bond or CR 6 R 7 ;
  • W represents a bond, NR 8 or oxygen
  • X represents sulfur, or nitrogen substituted by hydrogen or R 5 ;
  • Y represents -CH 2 -, -CO- or -CS-;
  • R 1 represents aryl which may be substituted by one to four substituents independently chosen from lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, heterocyclyl, optionally substituted aryl, optionally substituted aryl-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, optionally substituted aryloxy, optionally substituted aryl-lower alkoxy, amino, aminocarbonyl, aminosulfonyl, amino-lower alkyl or amino-lower alkylamino, wherein the nitrogen atom in each amino is unsubstituted or substituted by one or
  • R 2 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted alkenyl, optionally substituted alkinyl; aminoalkyl, wherein the nitrogen atom is unsubstituted or substituted by one or two substituents selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, optionally substituted aminoalkyl, optionally substituted aryl, optionally substituted
  • R 8 represents hydrogen or lower alkyl
  • R 9 is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted alkenyl, optionally substituted alkinyl; aminoalkyl, wherein the nitrogen atom is unsubstituted or substituted by one or two substituents selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, optionally substituted aminoalkyl, optionally substituted aryl, optionally substituted ary
  • the invention refers to compounds of formula (I) wherein
  • V represents a bond or CR 6 R 7 ;
  • W represents a bond, NR 8 or oxygen
  • X represents sulfur, or nitrogen substituted by hydrogen or R 5 ;
  • Y represents -CH 2 - -CO- or -CS-;
  • R 1 represents aryl which may be substituted by one to four substituents independently chosen from lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, heterocyclyl, optionally substituted aryl, optionally substituted aryl-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, optionally substituted aryloxy, optionally substituted aryl-lower alkoxy, amino, aminocarbonyl, aminosulfonyl, amino-lower alkyl or amino-lower alkylamino, wherein the nitrogen atom in each amino is unsubstituted or substituted by one or two
  • R 3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R 2 and R 3 together with the nitrogen they are bound to represent a five, six or seven membered heterocyclic ring that can be partially or fully unsaturated and may be optionally substituted by one or more groups selected from oxo, lower alkyl, halo-lower alkyl, hydroxy- lower alkyl, lower alkoxy-lower alkyl and lower alkoxy;
  • R 4 represents alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkinyl, optionally substituted aryl, or optionally substituted arylalkyl
  • R 5 represents lower alkyl
  • X is nitrogen
  • R 6 and R 7 independently of each other, represent hydrogen or lower alkyl
  • R 8 represents hydrogen or lower alkyl
  • R 9 is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted alkenyl, optionally substituted alkinyl; aminoalkyl, wherein the nitrogen atom is unsubstituted or substituted by one or two substituents selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, optionally substituted aminoalkyl, optionally substituted aryl, optionally substituted ary
  • the invention refers to compounds of formula (I) wherein V represents a bond or CR 6 R 7 ; W represents a bond or NR 8 ;
  • X represents sulfur, or nitrogen substituted by hydrogen or R 5 ;
  • Y represents -CH 2 - or -CO-;
  • R 1 represents aryl which may be substituted by one to four substituents independently chosen from lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, amino, aminocarbonyl, aminosulfonyl, amino-lower alkyl or amino-lower alkylamino, wherein the nitrogen atom in each amino is unsubstituted or substituted by one or two substitutents selected from lower alkyl, hydroxy- lower alkyl, lower alkoxy-lower alkyl, and lower acyl,
  • R 3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R 2 and R 3 together with the nitrogen they are bound to represent a five, six or seven membered heterocyclic ring that can be partially or fully unsaturated and may be optionally substituted by one or more groups selected from oxo, lower alkyl, halo-lower alkyl, hydroxy- lower alkyl, lower alkoxy-lower alkyl and lower alkoxy;
  • R 4 represents alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkinyl, optionally substituted aryl, or optionally substituted arylalkyl
  • R 5 represents lower alkyl
  • X is nitrogen
  • one of R 6 and R 7 is hydrogen and the other one is hydrogen or lower alkyl
  • R 8 represents hydrogen or lower alkyl
  • R 9 is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted alkenyl, optionally substituted alkinyl; aminoalkyl, wherein the nitrogen atom is unsubstituted or substituted by one or two substituents selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, optionally substituted aminoalkyl, optionally substituted aryl, optionally substituted ary
  • the invention refers to compounds of formula (I) wherein V represents a bond or CR 6 R 7 ; W represents a bond or NR 8 ; X represents sulfur; Y represents -CH 2 - or -CO-; R 1 represents phenyl which is substituted by one to three substituents independently chosen from lower alkyl, lower alkoxy-lower alkyl, hydroxy, lower alkoxy, and lower alkoxy-lower alkoxy, or wherein two adjacent substituents together form ethylenedioxy or methylenedioxy; R 2 represents hydrogen, alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl; amino-lower alkyl, wherein the nitrogen atom is unsubstituted or substituted by one or two substituents selected from lower alkyl, hydroxy-lower alkyl,
  • R 3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R 2 and R 3 together with the nitrogen they are bound to represent a five, six or seven membered heterocyclic ring that can be partially or fully unsaturated and may be optionally substituted by one or more groups selected from oxo, lower alkyl, halo-lower alkyl, hydroxy- lower alkyl, lower alkoxy-lower alkyl and lower alkoxy; R 4 represents alkyl, alkenyl, alkinyl or optionally substituted aryl-lower alkyl; R 6 , R 7 and R 8 represent hydrogen; R 9 is alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl; amino-lower alkyl, wherein the nitrogen atom is unsubstituted or substitute
  • R 10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R 9 and R 10 together with the nitrogen they are bound to represent a five, six or seven membered heterocyclic ring that can be partially or fully unsaturated and may be optionally substituted by one or more groups selected from oxo, lower alkyl, halo-lower alkyl, hydroxy- lower alkyl, lower alkoxy-lower alkyl, and lower alkoxy; and salts thereof.
  • the invention refers to compounds of formula (I) wherein
  • V represents a bond
  • W represents NR 8 ;
  • X represents sulfur
  • Y represents -CH 2 - or -CO-
  • R 1 represents phenyl which is substituted by one to three substituents independently chosen from lower alkyl, lower alkoxy-lower alkyl, hydroxy, lower alkoxy, and lower alkoxy-lower alkoxy, or wherein two adjacent substituents together form ethylenedioxy or methylenedioxy;
  • R 2 represents hydrogen, alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl; amino-lower alkyl, wherein the nitrogen atom is unsubstituted or substituted by one or two substituents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, hydroxy- lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, optionally substituted aminoalkyl, optionally substituted aryl
  • R 3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R 2 and R 3 together with the nitrogen they are bound to represent a five, six or seven membered heterocyclic ring that can be partially or fully unsaturated and may be optionally substituted by one or more groups selected from oxo, lower alkyl, halo-lower alkyl, hydroxy- lower alkyl, lower alkoxy-lower alkyl and lower alkoxy; R 4 represents alkyl, alkenyl, alkinyl or optionally substituted aryl-lower alkyl; R 8 represents hydrogen; R 9 is alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl; amino-lower alkyl, wherein the nitrogen atom is unsubstituted or substituted by one or two substituent
  • the invention relates to the use of a compound of formula (I), a prodrug or a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for the treatment of a neoplastic disease, autoimmune disease, transplantation related pathology and/or degenerative disease.
  • the invention provides a method for the treatment of a neoplastic disease, autoimmune disease, transplantation related pathology and/or degenerative disease, which comprises administering a compound of formula (I), a prodrug or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above, in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
  • a compound of the invention may be prepared by processes that, though not applied hitherto for the new compounds of the present invention, are known per se, in particular a process characterized in that
  • V, W, X, R 1 and R 4 are as defined for a compound of formula (I), or a derivative thereof wherein the carboxy group -COOH is esterified or in activated form, is reacted with an amine of formula (III)
  • R 2 and R 3 are as defined for a compound of formula (I), optionally in the presence of a dehydrating agent, an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;
  • V, W, X, R 1 and R 4 are as defined for a compound of formula (I) and n is 0 or 1, is reacted with an amine of formula (III)
  • R 2 and R 3 are as defined for a compound of formula (I), in the presence of a reducing agent and optionally in the presence of an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;
  • R 4 -LG (VI) wherein R 4 is as defined for a compound of formula (I) and LG is nucleophilic leaving group, optionally in the presence of an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;
  • V, W, Y, R 1 , R 2 , and R 3 are as defined for a compound of formula (I), X' is -SO- or -S0 2 - and R is an alkyl, aralkyl or aryl group, is reacted with an amine of formula (VIII)
  • X and R 4 are as defined for a compound of formula (I), optionally in the presence of an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;
  • X and R 4 are as defined for a compound of formula (I), optionally in the presence of an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;
  • X, Y, R 2 , R 3 and R 4 are as defined for a compound of formula (I) and Q is chlorine, bromine, iodine or a sulfonate, is reacted with a boronic acid of formula (XII)
  • R 1 is as defined for a compound of formula (I), or an ester thereof, in the presence of a suitable catalyst, and optionally in the presence of an inert solvent; or
  • X, Y, R 2 , R 3 and R 4 are as defined for a compound of formula (I) and Q is chlorine, bromine, iodine or a sulfonate, is reacted with an amine or alcohol of formula (XIII)
  • R 1 , V and W are as defined for a compound of formula (I), optionally in the presence of an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;
  • an obtainable compound of formula (I) is converted into another compound of formula (I)
  • a free compound of formula (I) is converted into a salt
  • an obtainable salt of a compound of formula (I) is converted into the free compound or another salt
  • a mixture of isomeric compounds of formula (I) is separated into the individual isomers.
  • a derivative of the compound of formula (II) wherein the carboxy group is in activated form is especially a reactive ester, a reactive anhydride or a reactive cyclic amide.
  • Reactive esters of the acid of formula (II) are especially esters obtainable, for example, by transesterification of a corresponding ester with vinyl acetate, or by treatment of the corresponding acid with an isoxazolium reagent, a lower alkoxyacetylene, chloroacetonitrile, N,N'-dicyclohexylcarbodiimide or the like, an N,N-disubstituted cyanamide, a phenol suitably substituted by electron-attracting substituents, a nitro-substituted phenylthiol, N-hydroxy- succinimide, 1-hydroxy-benzotriazole or 1-hydroxy-7-azabenzotriazole, or hexamethyl disilazane and the like.
  • Anhydrides of the acid of formula (II) may be symmetric or preferably mixed anhydrides of that acid, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides or azides, anhydrides with carbonic acid lower alkyl semi-esters, obtainable, for example, by treatment of the corresponding acid with chloroformic acid lower alkyl esters or with 1 -lower alkoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline, anhydrides obtainable with phosphorus oxychloride, or mixed anhydrides with trifluoroacetic acid, organic sulfonic acids or with organic phosphonic acids, and symmetric anhydrides obtainable, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of 1-diethyl- aminopropyne.
  • Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic character, such as amides with imidazole or pyrazo
  • Derivatives of the acid of formula (II) wherein the carboxy group is in activated form are preferably formed in situ.
  • esters with 1-hydroxy-benzotriazole or 1-hydroxy-7- azabenzotriazole can be formed in situ by reacting the acid of formula (II) with 1-hydroxy- benzotriazole or 1-hydroxy-7-azabenzotriazole and the corresponding N,N,N',N'-tetramethyl- uronium hexaflouorophosphate.
  • Another suitable activating agent is chlorotripyrrolidino- phosphonium hexafluorophosphate.
  • the activated compound of formula (II) is reacted with the amine of formula (III) in the presence of a suitable base, preferably a tertiary amine, e.g. triethylamine or a sterically hindered tertiary amine, for example diisopropylethylamine.
  • a suitable base preferably a tertiary amine, e.g. triethylamine or a sterically hindered tertiary amine, for example diisopropylethylamine.
  • the reaction can be carried out in a manner known per se, the reaction conditions being dependent especially on how the carboxy group of the carboxylic acid of formula (II) has been activated, usually in the presence of a suitable solvent, with cooling or heating, for example in a temperature range from approximately -30°C to approximately +150°C, especially approximately around 0°C to room temperature.
  • the reaction of a substituted carboxaldehyde of formula (IV) with an amine of formula (III) is performed under customary reaction conditions used in reductive amination.
  • the carboxaldehyde of formula (IV) is mixed with the amine of formula (III) in a pH range of about pH 3 to pH 6 , for example in the presence of an organic acid such as acetic acid, and the imine formed in situ reduced with a metal hydride, for example a boron hydride, in particular sodium borohydride or, preferably, sodium cyanoborohydride.
  • the imine formed in situ may also be reduced by catalytic hydrogenation, e.g with hydrogen gas under pressure in the presence of a suitable noble metal catalysts, such as palladium or platinum in suitable activated form, e.g. 10% palladium on carbon.
  • a suitable noble metal catalysts such as palladium or platinum in suitable activated form, e.g. 10% palladium on carbon.
  • the reaction can be carried out in a manner known per se, usually in the presence of a suitable solvent, e.g. a polar solvent such as methanol or a dipolar aprotic solvent such as dimethyl formamide or the like, with cooling or heating, for example in a temperature range from approximately -30°C to approximately +150°C, especially approximately around room temperature.
  • a suitable solvent e.g. a polar solvent such as methanol or a dipolar aprotic solvent such as dimethyl formamide or the like
  • cooling or heating for example in a temperature range from approximately -30°C to approximately +150°C, especially approximately around room temperature.
  • Suitable nucleophilic leaving groups LG in an alkylating agent of formula (VI) are for example halides, e.g. chloride or bromide, or sulfonates, e.g. aromatic sulfonic acid ester such as benzenesulfonates, p-toluenesulfonates, p-nitrobenzenesulfonates, or methanesulfonate or trifluormethanesulfonate.
  • halides e.g. chloride or bromide
  • sulfonates e.g. aromatic sulfonic acid ester such as benzenesulfonates, p-toluenesulfonates, p-nitrobenzenesulfonates, or methanesulfonate or trifluormethanesulfonate.
  • sulfonates e.g. aromatic sulfonic acid ester such as benzenesulfon
  • ammonium salts azides, diazonium salts, di(p-toluenesulfonyI)amines, nitrates, oxonium salts, sulfonium salts, or phosphonium salts.
  • Alkylation of a thiopyrimidone of formula (V) with an alkylating agent of formula (VI) is performed in a manner known perse, usually in the presence of a suitable polar or dipolar aprotic solvent, with cooling or heating, for example in a temperature range from approximately -30°C to approximately +150°C, especially approximately around 0°C to room temperature.
  • a suitable base is added, in particularly a tertiary amine base such as triethylamine or diisopropylethylamine.
  • a compound of formula (VII) the residue R with the meaning alkyl, aralkyl or aryl may have any of the meanings listed hereinbefore for the respective substituents.
  • An amine of formula (VIII) is a primary amine R 4 -NH 2 if X has the meaning "nitrogen substituted by hydrogen", or a secondary amine of formula R 4 -NH-R 5 if X has the meaning "nitrogen substituted by R 5 ".
  • the sulfoxide or sulfone of formula (VII) is treated with an amine of formula (VIII) under conditions known per se, usually in the presence of a suitable solvent, e.g. a polar solvent such as an alcohol, e.g. methanol or ethanol, or a dipolar aprotic solvent such as dimethyl sulfoxide or dimethyl formamide, with cooling or heating, for example in a temperature range from approximately -30°C to approximately +150°C, especially approximately around 0°C to room temperature.
  • a suitable base is added, in particularly a tertiary amine base such as triethylamine or diisopropylethylamine.
  • reaction of an alkinone of formula (IX) with a urea derivative of formula (X) is performed under conditions known per se, usually in the presence of a suitable solvent, e.g. a dipolar aprotic solvent such as dimethyl sulfoxide, dimethyl formamide or N-methylpyrrolidone, with cooling or heating, for example in a temperature range from approximately -30°C to approximately +150°C, especially approximately around 0°C to room temperature.
  • a suitable solvent e.g. a dipolar aprotic solvent such as dimethyl sulfoxide, dimethyl formamide or N-methylpyrrolidone
  • the urea derivative is introduced as the corresponding acid salt, e.g. as a hydrochloride or hydrobromide, and a suitable base added to the reaction mixture, in particularly a tertiary amine base such as triethylamine or diisopropylethylamine.
  • reaction of a bromo or iodo substituted pyrimidine of formula (XI) with a suitable boronic acid of formula (XII) or an ester thereof is known as Suzuki reaction, and is preferably executed under conditions known per se for a Suzuki reaction, preferably in a dipolar aprotic solvent such as dimethyl formamide, or in a polar ether, e.g.
  • reaction may also be performed with a compound of formula (XI) wherein Q is chlorine.
  • Further catalysts considered are tetrakis(trimethoxyphosphine)palladium, tris(dibenzylideneacetone)palladium or dichIorobis(triphenylphosphine)palladium(ll), and also nickel catalysts, e.g. dichlorobis(triethylamine)nickel(ll).
  • the reaction is preferably performed in the presence of a base, e.g solid or aqueous sodium or potassium carbonate or potassium hydroxide.
  • Displacement reactions on pyrimidines are well known in the art.
  • a leaving group X'R in position 2 as in a compound of formula (VII) it is likewise possible to displace a leaving group Q in position 4 in a compound of formula (XI) by an amine or an alcohol.
  • a leaving group Q in position 4 may be one of the leaving groups mentioned for Z in an alkylating agent of formula (VI) hereinabove.
  • Such displacement reaction may be performed without a solvent, e.g.
  • amine or alcohol reagent of formula (XIII) in an excess of amine or alcohol reagent of formula (XIII), or in the presence of a suitable solvent, for example a ketone, such as acetone, or an alcohol (if the reagent is an amine), such as ethanol or butanol, or an aromatic hydrocarbon, such as toluene, or a tertiary amine, such as N-methylpryrrolidine, optionally in the presence of an acid binding agent, such as an amine, or in the presence of an organic acid, such as acetic acid or formic acid, or an inorganic acid, such as hydrochloric acid or sulphuric acid.
  • a suitable solvent for example a ketone, such as acetone, or an alcohol (if the reagent is an amine), such as ethanol or butanol, or an aromatic hydrocarbon, such as toluene, or a tertiary amine, such as N-methylpryrrolidine, optional
  • the replacement of a halide as a leaving group Q in a compound of formula (XI) by an amine of formula (XIII) may be performed under conditions of the Buchwald-Hartwig reaction, for example in the presence of palladium acetate and a suitable ligand, such as BINAP, in a suitable solvent, for example an aromatic hydrocarbon, such as toluene, and a suitable base, for example cesium carbonate or sodium t-butoxide, and in a temperature range of between 25° and 100°C.
  • a suitable solvent for example an aromatic hydrocarbon, such as toluene
  • a suitable base for example cesium carbonate or sodium t-butoxide
  • one or more other functional groups for example carboxy, hydroxy or amino, are or need to be protected in a compound of formulas (II) to (XIII), because they should not take part in the reaction, these are such protecting groups as are usually applied in the synthesis of amides, in particular peptide compounds, cephalosporins, penicillins, nucleic acid derivatives and sugars.
  • the protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end products.
  • the specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
  • functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned hereinabove under "protecting groups".
  • the protecting groups are then wholly or partly removed according to one of the methods described there.
  • Y with the meaning -CO- may, for example, be reduced to Y with the meaning -CH 2 -
  • Suitable reducing agents are known in the art, and are, for example, metal hydrides, e.g. LiAIH , LiAI(OCH 3 ) 3 H or other alkoxy-substituted lithium hydrides, NaBH 4 , or BH 3 , optionally in the presence of a Lewis base, e.g. AICI 3 or BF 3 , or also with catalytical hydrogenation with hydrogen and a suitable noble metal catalyst.
  • An obtainable compound of formula (I), wherein X is nitrogen substituted by hydrogen may be alkylated with a compound of formula R 5 -LG, wherein LG is a nucleophilic leaving group as described under formula (VI), to give a compound of formula (I), wherein X is nitrogen substituted by R 5 , under conditions comparable to those described above in process C).
  • alkylation at nitrogen may be performed with an aldehyde under reducing conditions comparable to those described in process B).
  • alkylation to give a compound wherein R 5 is methyl is performed with formaldehyde and NaBH 4 in methanol.
  • Salts of a compound of formula (I) with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula (I) may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
  • Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • suitable basic agents for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralising agents, for example ion exchangers, typically cation exchangers, for example in the H + form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from -100°C to about 190°C, preferably from about -80°C to about 150°C, for example at -80 to +60°C, at -20 to +40°C, at room temperature, or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.
  • solvents or diluents preferably such as are inert to the reagents
  • Salts may be present in all starling compounds and transients, if these contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided the reaction is not thereby disturbed.
  • isomeric mixtures that occur can be separated into their individual isomers, e.g. diastereomers or enantiomers, or into any mixtures of isomers, e.g. racemates or diastereomeric mixtures.
  • the invention relates also to those forms of the process in which one starts from a compound obtainable at any stage as a transient and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention and further processes the said compound in situ.
  • a compound of formula (I) is prepared according to or in analogy to the processes and process steps defined in the Examples.
  • the compounds of formula (I), including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization, i.e. be present as solvates.
  • New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention.
  • such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
  • Amines of formula (III) are known or may be prepared in analogy to known methods.
  • starting materials of formula (IV) are known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art.
  • starting materials of formula (IV) may be obtained by a process related to process E) described above, characterized in that a substituted alkinone of formula (XV)
  • R 1 -V-W-CO-C C-(CH 2 ) n -CH(OR) 2 (XV)
  • R 1 , V, W and n are defined as for a compound of formula (IV) and R is alkyl or aralkyl, or the two substituents R together are a bridging alkylene residue, is reacted with a urea derivative of formula (X)
  • X and R 4 are as defined for a compound of formula (IV), optionally in the presence of an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent; and an obtainable compound wherein the carboxaldehyde group is still in the form of an acetal -CH(OR) 2 is treated with an aqueous acid to generate the free carboxaldehyde function -CHO.
  • compounds of formula (V) may be obtained by reaction of a compound of formula (XV) with thiourea, followed by generating the carboxaldehyde function by hydrolysis of the acetal -CH(OR) 2 function, and reductive amination corresponding to the process B) described hereinbefore.
  • Starting materials of formula (VII) are known or can be synthesized in analogy to or according to methods that are known in the art.
  • compounds of formula (VII) may be obtained by oxidation of corresponding compounds of formula (I) wherein X is sulfur.
  • Suitable oxidising agents are, for example, m-chloroperbenzoic acid and other aromatic peracids, aqueous hydrogen peroxide, sodium iodate, iodobenzene dichloride, osmium tetroxide, or potassium permanganate.
  • Boronic acids of formula (XII) or ester derivatives thereof are known or may be synthesized from the corresponding halides by reaction with butyllithium followed by tri-isopropoxyborate and hydrolysis, or from corresponding halides and diborates in the presence of a suitable palladium catalyst.
  • the cyclic boronic acid neopentylglycol ester is formed from the corresponding bromide with bis(2,2-dimethylpropane-1,3-dioxy)diboron in the presence of dichloro[1 ,1'-bis(diphenylphosphino)ferrocene]palladium.
  • Pyrimidinecarboxylic acids of formula (XIV), wherein the substituents have the meanings as defined for compounds of formula (I) and Q represents bromine or chlorine, may be prepared by reacting a pyrimidonecarboxylic acid of formula (XVI),
  • a preferred reagent used for this transformation is phosphorous oxychloride, optionally in the presence of a suitable solvent, for example an aromatic hydrocarbon, such as toluene, xylene or the like, and optionally in the presence of a catalyst, for example a N,N- dialkylamide, such as dimethylformamide, and/or a phase transfer catalyst, for example a quaternary ammonium salt, such as tetrabutylammonium bromide.
  • a suitable solvent for example an aromatic hydrocarbon, such as toluene, xylene or the like
  • a catalyst for example a N,N- dialkylamide, such as dimethylformamide
  • a phase transfer catalyst for example a quaternary ammonium salt, such as tetrabutylammonium bromide.
  • R is alkyl or an aryl group, with an urea derivative of formula (X) described hereinabove.
  • This transformation may be effected by reacting the two components optionally in the presence of a suitable solvent, for example an alcohol, and a base, for example a metal alcoholate, such as sodium ethoxide, at temperatures ranging from 0-80°C.
  • a suitable solvent for example an alcohol
  • a base for example a metal alcoholate, such as sodium ethoxide
  • compositions that comprise a compound of formula (I) as active ingredient and thai can be used especially in the treatment of the diseases mentioned at the beginning.
  • Compositions for enleral administration such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration, to warm-blooded animals, especially humans, are especially preferred.
  • the compositions comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
  • the present invention relates especially to pharmaceutical compositions that comprise a compound of formula (I), a tautomer, a prodrug or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier.
  • the invention relates also to pharmaceutical compositions for use in a method for the prophylactic or especially therapeutic management of the human or animal body, in particular in a method of treating neoplastic disease, autoimmune disease, transplantation related pathology and/or degenerative disease, especially those mentioned hereinabove.
  • the invention relates also to processes and to the use of compounds of formula (I) thereof for the preparation of pharmaceutical preparations which comprise compounds of formula (I) as active component (active ingredient).
  • the pharmaceutical compositions comprise from approximately 1% to approximately 95% active ingredient, single-dose administration forms comprising in the preferred embodiment from approximately 20% to approximately 90% active ingredient and forms that are not of single-dose type comprising in the preferred embodiment from approximately 5% to approximately 20% active ingredient.
  • Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories, or capsules.
  • Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, lip-slicks, drops, sprays, dispersions, etc. Examples are capsules containing from about 0.05 g to about 1.0 g active ingredient.
  • compositions of the present invention are prepared in a manner known perse, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
  • compositions of the active ingredient Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a carrier, for example mannitol, can be made up before use.
  • the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known perse, for example by means of conventional dissolving and lyophilizing processes.
  • the said solutions or suspensions may comprise viscosity-increasing agents, typically sodium carboxymethyl- cellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g. Tween 80 ® (polyoxyethylene(20)sorbitan mono-oleate).
  • viscosity-increasing agents typically sodium carboxymethyl- cellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g. Tween 80 ® (polyoxyethylene(20)sorbitan mono-oleate).
  • Suspensions in oil comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes.
  • liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms.
  • the alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol, especially glycol and glycerol.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and groundnut oil are especially useful.
  • injectable preparations are usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinyl- pyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethyl- cellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • compositions suitable for rectal administration are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • aqueous solutions of an active ingredient in water-soluble form for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable.
  • the active ingredient optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents.
  • Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
  • the present invention relates furthermore to a method for the treatment of a neoplastic disease, autoimmune disease, transplantation related pathology and/or degenerative disease, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above for formula (I), in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
  • the compounds of formula (I) can be administered as such or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment.
  • the daily dose administered is from approximately 0.05 g to approximately 5 g, preferably from approximately 0.25 g to approximately 1.5 g, of a compound of the present invention.
  • the present invention relates especially also to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, especially a compound of formula (I) which is said to be preferred, or a pharmaceutically acceptable salt thereof, as such or in the form of a pharmaceutical formulation with at least one pharmaceutically acceptable carrier for the therapeutic and also prophylactic management of one or more of the diseases mentioned hereinabove, in particular a neoplastic disease, autoimmune disease, transplantation related pathology and/or degenerative disease.
  • DMF dimethyl formamide
  • DMSO dimethyl sulfoxide
  • HATU 0-(7-azabenzotriazol-1-yl)-N,N,N , ,N'-tetramethyluronium-hexafluorophosphate
  • Develosil RPAq 4.6 x 50 mm column No. 1302244 (Phenomenex); program 1: 10% CH 3 CN; 90% H 2 0 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH 3 CN; program 2: 20% CH 3 CN; 80% H 2 0 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH 3 CN; program 3: 30% CH 3 CN; 70% H 2 0 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH 3 CN; program 4: 40% CH 3 CN; 60% H 2 0 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH 3 CN; program 5: 60% CH 3 CN; 40% H 2 0 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH
  • Example 1a 2-Hexylmercapto-6-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid
  • 2-hexylmercapto-6-(3,4,5-trimethoxyphenyl)pyrimidine-4-carboxylic acid tert-butyl ester 1.9 g, 4.45 mmol, Example 1b
  • CH 2 CI 2 10 ml
  • water 5 drops
  • trifluoroacetic acid 10 ml
  • the reaction mixture is extracted with water and ethyl acetate, the organic layer washed with brine, dried (MgS0 4 ) and the solvent evaporated.
  • Example 1b 2-Hexylmercapto-6-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid tert- butyl ester
  • Example 1e 6-Chloro-2-hexylmercaptopyrimidine-4-carboxylic acid methyl ester
  • 2-hexylmercapto-6-hydroxypyrimidine-4-carboxylic acid methyl ester 500 mg, 1.85 mmol
  • tetramethylammonium chloride in phosphoroxy chloride POCI 3 , 3 ml
  • Example 1 ⁇ 2-Hexylmercapto-6-hydroxypyrimidine-4-carboxylic acid
  • NaOH (1.66 g) in water (40 ml) at room temperature
  • sodium diethyl oxalacetate sodium salt (6.56 g, 1.5 equiv.)
  • S-hexylthiouronium bromide (Example 1c, 5.0 g, 20.8 mmol) is added, following the general procedure of G. Doyle Davies, jr. et al., J. Org. Chem. 1961, 26, 2755-2763,.
  • the reaction mixture is stirred for 3 hours at room temperature and poured onto water, ice and 2 H aqueous HCI solution which results in a white precipitate.
  • Example 1a 50 mg, 0.123 mmol in dichloromethane (1 ml), chlorotripyrrolidino- phosphonium-hexafluorophosphate (57 mg, 0.135 mmol) and N,N-diisopropylethylamine (57 mg, 0.135 mmol) is added at room temperature with stirring. After 1 hour 4-dimethyl- aminobenzylamine dihydrochloride (30 mg, 0.135 mmol) is added. After stirring for 12 hours the reaction mixture is filtered over a pad of silicagel/MgS0 4 . The filtrate is evaporated and the product is purified by HPLC to give the title compound. [M+H] + : 539. HPLC (program 3): RT 15.21 min.
  • Example 39a 2-Hexylmercapto-6-(3.4,5-trimethoxyphenyl)pyrimidine-4-methylamine hydrochloride 4
  • N HCI/dioxane (10 ml) is added to N-tert-butoxycarbonyl-2-hexylmercapto-6-(3,4,5- trimethoxyphenyl)pyrimidine-4-methylamine (1.13 g, 2.44 mmol), and the mixture is stirred for 2 hours at room temperature.
  • Ethyl acetate (10 ml) is added to the suspension, and the mixture is filtered, the residue washed with ethyl acetate and dried under reduced pressure to give the title compound as a slightly yellow powder.
  • Example 40a 2-Hexylmercapto-6-(3.4,5-trimethoxyphenyl)-pyrimidin-4-carboxaldehyde
  • 2-hexylmercapto-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-carboxaldehyde diethyl acetal 2.05 g, 4.41 mmol
  • THF 10 ml
  • 95% aqueous formic acid is added at 4°C.
  • the reaction mixture is stirred for 1 hour at room temperature and for 3 hours at 80°C, then cooled to room temperature and extracted with water and ethyl acetate.
  • Example 40b 2-Hexylmercapto-6-(3.4.5-trimethoxyphenyl)-pyrimidin-4-carboxaldehvde diethyl acetal
  • diisopropylethylamine 4.8 ml, 1.5 equiv.
  • Example 42 2-(N-Hexyl-N-methylamino)-8-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid f3-(4-methylpiperazinyl)propy ⁇ amide
  • Example 42a 2-(N-Hexyl-N-methylamino)-6-(3.4,5-trimethoxyphenyl)pyrimidine-4-carboxylic acid
  • Example 42b 2-(N-Hexyl-N-methylamino)-6-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid tert-butyl ester
  • Ethyl 2-hexylmercapto-6-(3,4,5-trimethoxyphenylamino)pyrimidin-4-carboxylate (Example 46a, 75 mg, 0.167 mmol), rac-2-(4-methylpiperazinyl)-1-phenylethyIamine (73 mg, 0.333 mmol) and DMSO (50 ⁇ l) are mixed together and stirred for 6 h at 80°C. NaHC0 3 (10 ml, sat. aq.) is added, and the reaction mixture extracted twice with ethyl acetate (10 ml), dried over Na 2 S0 , and the organic layer concentrated.
  • Example 46a Ethyl 2-hexylmercapto-6-(3,4.5-trimethoxyphenylamino)pyrimidine-4- carboxylate
  • Ethyl 6-chloro-2-hexylmercapto-pyrimidine-4-carboxylate (Example 46b, 65 mg, 0.215 mmol), 3,4,5-trimethoxyaniline (51 mg, 0.278 mmol), diisopropyl-N-ethylamine (73.5 ⁇ l, 0.43 mmol) and DMSO (50 ⁇ l) are mixed together and stirred for 6 h at 80°C. HCI (10 ml, 0.1 N) is added, and the reaction mixture extracted twice with ethyl acetate (10 ml), dried over Na 2 S0 4 , and the organic layer concentrated.
  • Example 46b Ethyl 6-chloro-2-hexylmercapto-pyrimidine-4-carboxylate
  • Ethyl 2-hexylmercapto-6-pyrimidone-4-carboxylate (Example 46c, 136 mg, 0.478 mmol) and 53 mg tetramethylammonium chloride (52 mg, 0.478 mmol) are dissolved in POCI 3 (1 ml, 10.9 mmol) and stirred at 90°C for 40 min in a sealed tube. The reaction mixture is evaporated to dryness, NaHC0 3 (10 ml, sat.
  • Example 48c Ethyl 2-hexylmercapto- ⁇ -pyrimidone-4-carboxylate
  • Ethyl 2-thio-6-pyrimidone-4-carboxylate (Example 46d, 200 mg, 1 mmol) is dissolved in EtOH (1 ml) and NaOH (0.55 ml, 2 N, aq.).
  • 1-Bromohexane 120 ⁇ l, 1.05 mmol
  • NaHC0 3 (10 ml, sat.
  • Example 46d Ethyl 2-thio-6-pyrimidone-4-carboxylate 2-Thio-6-pyrimidone-4-carboxylic acid (Example 46e, 7.15 g, 0.041 mol) is suspended in THF/EtOH (400 ml, 1:1 v/v), and H 2 S0 4 (15 ml, cone.) is added. The reaction mixture is refluxed for 48 h. Water (400 ml) is added, the reaction mixture twice extracted with ethyl acetate (300 ml), and the organic layer concentrated. The crude product is dissolved in EtOH/CH 2 Cl 2 (400 ml, v/v) and adsorbed on silica gel.
  • EtOH/CH 2 Cl 2 400 ml, v/v
  • Example 51a 2-Hexylmercapto-6-(3.4.5-trimethoxyphenylamino)pyrimidine-4-carbaldehvde 2-Hexylmercapto-6-(3,4,5-trimethoxyphenylamino)pyrimidine-4-carbaldehyde diethyl acetal (Example 51b, 186 mg, 0.388 mmol) is dissolved in formic acid (2 ml, 95% in H 2 0) and stirred for 3 h at 90°C. The reaction mixture is evaporated to dryness, co-evaporated with toluene (10 ml) and dried in high vacuum over night yielding the title compound as a yellow solid.
  • Example 51 b 2-Hexylmercapto-6-(3.4.5-trimethoxyphenylamino)pyrimidine-4-carbaldehyde diethyl acetal 6-Chloro-2-hexylmercapto-pyrimidine-4-carbaldehyde diethyl acetal (Example 51c, 143 mg, 0.429 mmol), 3,4,5-trimethoxyaniIine (157 mg, 0.857 mmol), diisopropyl-N-ethylamine (147 ⁇ l, 0.859 mmol) and DMSO (300 ⁇ l) are mixed together and stirred for 5 h at 110°C. NaHC0 3 (10 ml, sat.
  • Example 51c 6-Chloro-2-hexylmercapto-pyrimidine-4-carbaldehvde diethyl acetal 2-Hexylmercapto-6-pyrimidone-4-carbaldehyde diethyl acetal (Example 51d, 539 mg, 1.714 mmol) is dissolved in POCI 3 (1 ml, 10.9 mmol) at 0°C and stirred at this temperature for 2 h. The excess POCI 3 is removed in vacuo at 20°C, and NaHC0 3 (5 ml, sat. aq.) is added, the reaction mixture extracted twice with ethyl acetate (5 ml), dried over MgS0 , and the organic layer concentrated.
  • Example 51 d 2-Hexylmercapto-6-pyrimidone-4-carbaldehyde diethyl acetal
  • 2-Thio-6-pyrimidone-4-carbaldehyde diethyl acetal (Example 51 e, 1.0 g, 4.34 mmol) is suspended in EtOH (2 ml), and NaOH (2.28 ml, 2 N, aq., 4.56 mmol) is added.
  • 1-Bromo- hexane (519 ⁇ l, 4.56 mmol) is added, and the clear mixture is stirred for 4 h at 60°C.
  • reaction mixture is heated for reflux for 4 h.
  • mixture is treated with HCI (200 ml, aq.,
  • Example 46a Ethyl 2-hexylmercapto-6-(3,4,5-trimethoxyphenylamino)pyrimidin-4-carboxylate (Example 46a) is reacted with 1-(3-aminopropyl)-4-methylpiperazine as described in Example 46. [M+H] + : 561.0. HPLC (program 2): RT 3.78 min. General methods for testing of compounds of the invention:
  • Example 55 Cell cultures and cell lines.
  • mice cell lines (either EGFP transfected or not) are being used: A20.2J
  • the assays are being performed in commercially available 96 or 384 well flat bottom clear microtiter plates (Greiner, Germany) respectively, which are suitable for tissue culture techniques.
  • a defined number of EGFP transfected adherent test cells (96 well plates: 10 4 - 10 5 , 384 well plates: 1500 - 2*10 4 ) are plated out 24 hours before treatment either in 75 ⁇ l (96 well plates) or 60 ⁇ l (384 well plates) complete medium per well in order to ensure appropriate cell spreading.
  • a peristaltic pump e.g. Multidrop by Thermo-Labsystems, Finland
  • another suitable device is used.
  • Cells in suspension are plated out according to the same procedure but 1 h prior to treatment. Between seeding out and treatment or addition of compounds the cells are incubated at 37°C under 7.5% C0 2 . Subsequently, the compounds under investigation are added at defined concentrations (40 - 80 ⁇ M in either 25 ⁇ l (96 well plates) or 20 ⁇ l (384 well plates) complete medium containing max 4% DMSO) with an appropriate device (e.g. liquid handling system, multi channel pipette etc.) resulting in a final concentration in the test well of 10 - 20 ⁇ M compound in max 1% DMSO.
  • an appropriate device e.g. liquid handling system, multi channel pipette etc.
  • Example 57 Measurement and quantification of the primary screening.
  • Relative fluorescence activities of EGFP in compound treated test cells in relation to control cells and cells treated with standard drugs are measured by using a BMG Fluostar microplate fluorescence reader equipped with a filter pair for excitation/emission at 485 nm / 520 nm.
  • the optimum signal to noise ratio is detected by using the time-resolved mode of measurement with a delay of 20 ⁇ s and an integration time over 1 ms. The gain is adjusted in such a way that the control cells produce a fluorescence activity of 90% of the maximum.
  • the E(x) values are further processed by forming the inverse (Q-value) of the products E(8)*E(24)*E(48) which result in numbers > 1 for apoptotic / necrotic activities of the compounds and numbers ⁇ 1 for proliferative activities of the compounds.
  • Controls show values similar to 1.
  • Compounds producing Q values > 2 are being considered relevant in terms of apoptotic / necrotic activity and are subsequently tested in the secondary screening setup.
  • Example 58 Secondary screening setup.
  • the assays are being performed in case of adherent cells in commercially available 24 well flat bottom tissue culture plates (Greiner, Germany) and in case of suspension cells in polypropylene tubes
  • test compounds 0.3 ⁇ M of the test compounds, respectively.
  • FACSCaliburTM fluorescence activated cell scanning device
  • Suspension cells 10 5 test cells in 450 ⁇ l complete medium are pipetted into P-tubes. 50 ⁇ l complete medium containing the compounds (see adherent cells) is added immediately.
  • FACSCaliburTM fluorescence activated cell scanning device
  • Example 59 Quantification of the secondary screening.
  • This assay is performed in 96 well tissue culture plates. Appropriate number of cells (adherent cells: 3 - 5*10 3 , suspension cells: 8 - 10*10 3 ) are being seeded out in 80 ⁇ l complete medium. Adherent cells are incubated for 24 h for proper spreading out before addition of test compounds while suspension cells are immediately treated with test compounds after seeding out. The test compounds are added in 20 ⁇ l complete medium ontaining max 5% DMSO. The final compound concentrations in the assays are 10 ⁇ M, 3 ⁇ M,1 ⁇ M and 0.3 ⁇ M, respectively.
  • the readout allows the determination of the fraction of apoptotic nuclei as well as other morphological criteria specific for apoptosis as a function of the treatment. Results are indicated in Table 6. The following scores are used: 0 relating to no activity, 1 relating to weak activity comprising less than 50% of the cells and score 2 relating to strong activity comprising more than 50% of the cells. Table 6: Hoechst 33342 nuclear staining
  • the assay is performed in 96 well tissue culture plates.
  • the cells (range : 1.5"10 3 - 10 4 ) are seeded out in 80 ⁇ l complete medium 24 h prior to compound treatment.
  • the test compounds are added in 20 ⁇ l complete medium containing max 5% DMSO.
  • the final compound concentrations in the assays are 10 ⁇ M, 3 ⁇ M,1 ⁇ M and 0.3 ⁇ M, respectively.
  • the assay plates are incubated for 72 h at culture conditions.
  • the MTS reagent is prepared according to the manufacturer's protocol (Promega G1111 ). 20 ⁇ l MTS reagent are added to each well, the assay plates are quickly spun and incubated for another 3 h at culture conditions. Subsequently, the plates are shortly shaked and absorption measured with a microplate-reader at 492 nm.
  • IC 50 values are determined by graphical analysis and are indicated in the Table 7 in ⁇ M concentration.
  • Adherent cells (1 - 2*10 5 ) are 24 h prior to compound treatment seeded into 24 well tissue culture plates. Suspension cells are pipetted into P-tubes immediately before treatment. Test compounds are added leading to a final concentrations of 10 ⁇ M. After 24 h treatment cells are harvested (in case of adherent cells by trypsinization) and transferred to FACS tubes (BD Biosciences). After centrifugation and removal of the supernatant, 100 ⁇ l complete medium containing AnnexinV-GST (10 ⁇ g) is added, mixed and incubated at 4°C for 30 minutes.
  • the cells are washed once with medium and incubated with 100 ⁇ l anti-GST Alexa 488 (Molecular Probes A-11131 ) in medium diluted 1 :500 for 30 minutes at 4°C. Then, cells are washed once and stained with 1 ⁇ g/ml 7-aminoactinomycin D (7-AAD) (Molecular Probes A-1310) in 250 ⁇ l medium and analyzed on the FACSCaliburTM. AnnexinV is measured in FL1 whereas 7-AAD is measured in FL3. In Table 8 the percentage of positively stained cells after treatment with the respective compounds are indicated. The following scores are used: Score 0 relates to less than 10%, score 1 relates to more than 10% but less than 50% and score 2 relates to more than 50% positivity.
  • 7-AAD 7-aminoactinomycin D
  • 1 - 2*10 5 cells are seeded into 24 well tissue culture plates and incubated for 24 h prior to compound addition. Compounds are added for 24 h in a final concentration of 3 ⁇ M or 10 ⁇ M. Adherent cells are harvested by trypsinization. The cell suspensions are fixed by adding
  • Adherent cells are seeded out at 2 - 4*10 4 cells/well/ml in 24 well tissue culture plates 24 h prior to treatment. Suspension cells are seeded out at 2"10 5 cells/ml/well in 24 well plates. Compounds are added leading to final concentrations of 3 ⁇ M and 10 ⁇ M, respectively. Subsequently, BrdU (Molecular Probes #B-23151) at 10 ⁇ M final concentration is added and the plates are incubated for 48 h. After the incubation cells are processed according to standard procedures. The detection of the incorporated BrdU is done with the anti- bromodeoxyuridine Mab PRB-1 , Alexa Fluor 660 conjugate (Molecular Probes #A-21306).
  • the analysis is performed on a FACSCaliburTM by monitoring the fluorescence activity on FL3.
  • the readout reflects DNA synthesis which is a hallmark for proliferation.
  • the scores are defined the following: 0 for no activity, 1 for a moderate inhibition and 2 for strong inhibition of proliferation.
  • Table 10 indicates inhibitory activities of several tested compounds on proliferation.
  • Caspase dependencies are being evaluated by combining the compound treatment with the pan-caspase inhibitor zVAD or its control peptide zFA (ICN Pharmaceuticals # FK009 and FK029, respectively). Both peptides are being used at 20 ⁇ M concentration. In case of caspase dependencies a clear inhibition of the specific readout in all apoptosis tests should be detected. By comparing the readout of zVAD and zFA treated samples with the compound control it is possible to detect caspase resp. cystein proteinase dependencies. In case of inhibition by zVAD but not by zFA a clear caspase dependency is obvious.
  • the colony formation of human tumor xenografts passaged in nude mice, of murine tumors, and of human bone marrow is investigated in vitro using a double-layer agar assay described by Fiebig et al. (Colony assay with human tumor xenografts, murine tumors and human bone marrow. Potential for anticancer drug development. European Journal of Cancer and Clinical Oncology 1987, 23:937-948).
  • the molar concentration at which 50%, 70% and 90% of colony forming ability inhibition is found, is determined and is depicted as EC50, EC70 and EC90 values, respectively.
  • AKM Human Bone Marrow stem cells
  • AT Animal Tumor
  • BXF Bladder Cancer Xenograft
  • CEXF Cervix Xenograft
  • CXF Colorectal Xenograft
  • GXF Gastric Xenograft
  • HNXF Head and Neck Xenograft
  • LXF Lung A Adeno Lung Cancer Xenograft, L: Large Cell Lung Cancer Xenograft
  • E Epidermoid Cell Lung Cancer Xenograft
  • S Small Cell Lung Cancer Xenograft
  • MAXF Breast Xenograft
  • MEXF Melanoma Xenograft
  • OVXF Ovarian Cancer Xenograft
  • PAXF Pancreas Xenograft
  • PXF Mesothelioma Xenograft
  • RXF Renal Xenograft
  • SXF Pancreas Xeno
  • Example 62 Soft Capsules 5000 soft gelatin capsules, each comprising as active ingredient 0.05 g of one of the compounds of formula (I) mentioned in the preceding Examples, are prepared as follows: 250 g pulverized active ingredient is suspended in 2 liter Lauroglykol® (propylene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground in a wet pulverizer to produce a particle size of about 1 to 3 ⁇ m. 0.419 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
  • Lauroglykol® propylene glycol laurate, Gattefosse S.A., Saint Priest, France

Abstract

La présente invention a trait à des dérivés de pyrimidines substitués de formule (I), dans laquelle : V représente une liaison ou CR6R7 ; W représente une liaison, NR8 ou oxygène ; X représente soufre, ou azote substitué par hydrogène ou R5 : Y représente -CH2-, -CH2CH2-, -CO- or -CS-; R1 représente aryle ou hétéroaryle substitué ou non substitué ; et les substituants R2, R3, R4, R5, R6, R7 et R8 sont tels que définis dans la description. Ces composés induisent l'apoptose de manière sélective dans ces cellules cancéreuses et peuvent être utilisés pour le traitement de maladies néoplasiques et auto-immunes. L'invention a également trait à des procédés de synthèse de tels composés, à leur utilisation en tant que médicaments, aux compositions pharmaceutiques en contenant, et aux procédé de traitement de maladies néoplasiques et auto-immunes mettant en oeuvre de tels composés de formule (I) ou de compositions pharmaceutiques en contenant.
PCT/EP2004/003296 2003-04-01 2004-03-29 Derives de pyrimidine trisubstitues en position 2, 4, 6 utiles pour le traitement de maladies neoplasiques et auto-immunes WO2004087679A1 (fr)

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