EP1644338A1 - 2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases - Google Patents

2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases

Info

Publication number
EP1644338A1
EP1644338A1 EP04723991A EP04723991A EP1644338A1 EP 1644338 A1 EP1644338 A1 EP 1644338A1 EP 04723991 A EP04723991 A EP 04723991A EP 04723991 A EP04723991 A EP 04723991A EP 1644338 A1 EP1644338 A1 EP 1644338A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
lower alkyl
lower alkoxy
alkyl
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04723991A
Other languages
German (de)
French (fr)
Inventor
Daniel Obrecht
Philipp Ermert
Anatol Luther
Martin Eberle
Felix Bachmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aponetics AG
Original Assignee
Aponetics AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aponetics AG filed Critical Aponetics AG
Priority to EP04723991A priority Critical patent/EP1644338A1/en
Publication of EP1644338A1 publication Critical patent/EP1644338A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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.
  • Cell lines are cultured in RPMI-1640 tissue culture medium containing either 5% or 10% fetal calf serum, 0.05 mM 2-mercaptoethanol, 2 mM glutamine and penicillin/streptomycin
  • 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

The invention relates to substituted pyrimidines of formula (I) wherein V represents a bond or CR6R7, W represents a bond, NR8 or oxygen, X represents sulfur, or nitrogen substituted by hydrogen or R5, Y represents -CH2-, -CH2CH2-, -CO- or -CS-, R1 represents unsubstituted or substituted aryl or heteroaryl, and the substituents R2, R3, R4, R5, R6, R7 and R8 have the meanings given in the specification. These compounds are selectively inducing apoptosis in cancer cells and can be used for the treatment of neoplastic and autoimmune diseases. The invention relates also to methods of synthesis of such compounds, to their use as medicaments, to pharmaceutical compositions containing same, and to methods of treatment of neoplastic and autoimmune diseases using such compounds of formula (I) or of pharmaceutical compositions containing same.

Description

2,4,6-TRISUBSTITUTED PYRAMIDINE DERIVATIVES USEFUL FOR THE TREATMENT OF NEOPLASTIC AND AUTOIMMUNE DISEASES
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.
Background of the invention
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.
Autoimmune diseases are associated with abnormal lymphoproliferation as a result of defects in the termination of lymphocyte activiation and growth. Often, such diseases are associated with inflammation like rheumatoid arthritis, insulin dependent diabetes mellitus, multiple sclerosis, systemic lupus erythematosus and the like. The treatment of such diseases is focused on anti-inflammatory and immunosuppressive drugs which in numerous cases show severe side effects. Hence, there is a need for alternative drugs with a new mode of action showing less side effects.
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.
In recent years it has become evident that programmed cell death (apoptosis) is as important to the health of a multicellular organism as cell division. By repeated cell division and differentiation throughout development or tissue repair, surplus or even harmful cells are generated. In order to maintain tissue homeostasis these cells have to be removed or killed. The delicate interplay between cell growth and apoptosis in an organism is mirrored in the complex molecular balance that determines whether an individual cell undergoes division, arrests in the cell cycle or commits to programmed cell death. Dysregulation of cell proliferation, or lack of appropriate cell death, has wide ranging clinical implications. A number of diseases associated with such dysregulation involve hyperproliferation, inflammation, tissue remodeling and repair. 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.
As apoptosis is inhibited or delayed in most types of proliferative, neoplastic diseases, 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). Also in autoimmune and transplantation related diseases and pathologies 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. accumulation of 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.
Summary of the invention
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. Detailed description of the invention
The invention relates to compounds of formula (I)
wherein
V represents a bond or CR6R7; W represents a bond, NR8 or oxygen; X represents sulfur, or nitrogen substituted by hydrogen or R5; Y represents -CH2-, -CH2CH2-, -CO- or -CS-;
R1 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, lower alkoxy, halo-lower alkoxy, cycloalkoxy, cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, lower alkylcarbonyloxy, aminocarbonyloxy wherein the nitrogen atom is optionally substituted by one or two substituents selected from alkyl, hydroxyalkyl and aminoalkyl, lower alkoxycarbonyloxy, heterocyclyloxy, heterocyclyl-lower alkoxy, optionally substituted aryloxy, optionally substituted aryl-lower alkoxy, optionally substituted heteroaryloxy, optionally substituted heteroaryl-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, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy- lower alkyl, optionally substituted aryl, optionally substituted aryl-lower alkyl, optionally substituted heleroaryl, optionally substituted heleroaryl-lower alkyl and lower acyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, amino-lower alkoxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, aminocarbonyl wherein the nitrogen atom is optionally substituted by one or two substituents independently selected from alkyl, hydroxyalkyl, alkoxyalkyl and optionally substituted aminoalkyl, or wherein the two substitulens together with the nitrogen atom they are bound to represent a three, four, five or six membered heterocyclic ring, cyano, mercapto, lower alkylmercapto, optionally substituted phenylmercapto, lower alkylsulfinyl, halo-lower alkylsulfinyl, optionally substituted phenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl, optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, or nitro, and wherein two adjacent substituents together with the atoms of aryl or 6 membered ring heteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ring; R2and R3, independently of each other, represent 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or R2 is hydroxy, amino or substituted amino and R3 has the meanings mentioned above; or, provided that Y is -CH2- R2 represents a group S02-R9 or CO-Z-R9 and Z represents a bond, oxygen or NR10, and R3 has the meanings mentioned above; or R2 and R3 together with the nitrogen they are bound to represent a three, four, 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, optionally substituted aminoalkyl, heterocyclyl, heteroaryl, and lower alkoxy; R4 and R5, independently of each other, represent alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, optionally substituted aminoalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkyl, optionally substituted alkenyl, optionally substituted alkinyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; or, provided that X is nitrogen, R4 and R5 together with the nitrogen X they are bound to represent a four, 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; R6 and R7, independently of each other, represent hydrogen or lower alkyl; or R6 and R7 together with the carbon atom they are bound to form a carbocylic or heterocyclic ring;
R8 represents hydrogen or lower alkyl;
R9 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; R10 is hydrogen or has the meanings of R9, or R9 and R10 together with the nitrogen they are bound to represent a three, four, 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, optionally substituted aminoalkyl, heterocyclyl, heteroaryl, and lower alkoxy; and salts thereof. Excluded are compounds of formula (I) wherein V and W represent a bond, X represents nitrogen, Y represents -CO- and R1 is unsubstituted phenyl.
The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:
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.
Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
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. In optionally substituted 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. Examples of heteroaryl 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 R1 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 R1 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. In a fused ring bicyclic derivatives of a 6 membered ring heteroaryl R1, the fused ring may consist of 3 or 4 ring members, heteroaryl then representing a 9 or 10 membered fused- ring bicyclic heteroaromatic group. Examples of 6 membered ring heteroaryl R1 include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and benzo fused derivatives of such monocyclic heteroaryl groups, such as quinolinyl, isoquinolinyl or quinazolinyl, or purinyl.
In optionally substituted heteroaryl, 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.
In optionally substituted alkenyl or alkinyl, 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. Examples of heterocyclyl are 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.
In substituted amino, the substituents are preferably those mentioned as substituents R2 and R3. In particular, 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-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5- naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesuIfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, 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). Examples of 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 R1 is unsubstituted phenyl, for use as medicaments.
The efficacy of the compounds of the invention in inducing apoptosis in tumor cells can be demonstrated as follows:
Relative fluorescent activities of suitable tumor cell lines transfected with green fluorescent protein (GFP) are measured in the presence of compounds of the invention and of standard tumor drugs, using the method described in WO 99/35493. 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 human fibrosarcoma cell line.
Preferred standard drugs as compounds for comparisons are: a) antimetabolites such as 5-fluorouracil (ICN), gemcitabine HCI (Gemzar™, Eli Lilly), b) alkylating agents such as oxaliplatin (Eloxantin™, Sanofi-Synthelabo), dacarbazin (Detimedac™, Medac), cyclo- phosphamide (Endoxan™, Asta) and carboplatin (Paraplatin™, Bristol-Meyers Squibb), c) cell-cycle inhibitor such as vinorelbine (Navelbine™, Robapharm), vinblastine (Velbe™, Eli Lilly), docelaxel (Taxotere™, Aventis), d) DNA breaker (topo-isomerase inhibitor, intercalator, strand breaker) such as doxorubicin HCI (Adriblastin™, Pharmacia-Upjohn), bleomycin (Asla-Medica), irinolecan (Campto™, Aventis), etoposide phosphate (Etopophos™, Bristol- Meyers Squibb), topotecan HCI, (Hycamtin™, GlaxoSmithKline), e) mixtures thereof, f) compounds interfering with the signal transduction pathway, such as caspase activity modifiers, agonists and antagonists of cell death receptors, modifiers of nucleases, phosphatases and kinases such as imatinib mesylate (Gleevec™, Novartis), dexamethasone, phorbol myristate acetate, cyclosporin A, quercetin, tamoxifen (Alexis Corporation, Switzerland).
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: A) Nuclear staining with Hoechst 33342 dye providing information about nuclear morphology and DNA fragmentation which are hallmarks of apoptosis. 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. C) AnnexinV binding assay which reflects the phosphatidylserine content of the outer lipid bilayer of the plasma membrane. This event is considered an early hallmark of apoptosis. D) PI staining for cell cycle distribution which shows any alterations in the distribution among the different phases of the cell cycle. Cell cycle arresting points can be determined. E) Proliferation assay monitoring DNA synthesis by incorporating bromodeoxyuridine (BrdU). Inhibitory effects on growth/proliferation can be directly determined. F) Cystein proteinase dependency, respectively caspase dependency are determined by using specific inhibitors. This provides information about possible involvement of specific proteases in the mechanisms.
On the basis of these studies, a compound of formula (I) according to the invention shows therapeutic efficacy especially against neoplastic diseases and autoimmune diseases. In particular, 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 and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial like neoplasms, mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, blood vessel tumors, lymphatic vessel tumors, osseous and chondromatous neoplasms, giant cell tumors, miscellaneous bone tumors, odontogenic tumors, gliomas, neuroepitheliomatous neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft part sarcomas, Hodgkin's and non Hodgkin's lymphomas, other lymphoreticular neoplasms, plasma cell tumors, mast cell tumors, immunoproliferative diseases, leukemias, miscellaneous myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.
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 (vulgaris, foliaceus, sebaceous and vegetans), bullous and cicatricial pemphigoid, pemphigoid gestationis, epidermolysis bullosa acquisita, linear IgA disease, lichen sclerosus et atrophicus, morbus Duhring, psoriasis vulgaris, guttate, generalized pustular and localized pustular psoriasis, vitiligo, alopecia areata, primary biliary cirrhosis, autoimmune hepatitis, all forms of glomerulonephritis, pulmonal hemorrhage (goodpasture syndrome), IgA nephropathy, pernicious anemia and autoimmune gastritis, inflammatory bowel diseases (including colitis ulcerosa and morbus Crohn), Behcet's disease, Celic-Sprue disease, autoimmune uveitis, autoimmune myocarditis, granulomatous orchitis, aspermatogenesis without orchitis, idiopatic and secondary pulmonary fibrosis, inflammatory diesases with a possibility of autoimmune pathogensesis, such as pyoderma gangrensosum, lichen ruber, sarcoidosis (including Lδfgren and cutaneous/subcutaneous type), granuloma anulare, allergic type I and type IV immunolgical reaction, asthma bronchiale, pollinosis, atopic, contact and airborne dermatitis, large vessel vasculitis (giant cell and Takayasu's arteritis), medium sized vessel vasculitis (polyarteritis nodosa, Kawasaki disease), small vessel vasculitis (Wegener's granulomatosis, Churg Strauss syndrome, microscopic polangiitis, Henoch-Schoenlein purpura, essential cryoglobulinemic vasculitis, cutaneous leukoklastic angiitis), hypersensitivity syndromes, toxic epidermal necrolysis (Stevens- Johnson syndrome, erythema multiforme), diseases due to drug side effects, all forms of cutaneous, organ-specific and systemic effects due to type l-VI (Coombs classification) immunologic forms of reaction, transplantation related pathologies, such as acute and chronic graft versus host and host versus graft disease, involving all organs (skin, heart, kidney, bone marrow, eye, liver, spleen, lung, muscle, central and peripheral nerve system, connective tissue, bone, blood and lymphatic vessel, genito-urinary system, ear, cartillage, primary and secondary lymphatic system including bone marrow, lymph node, thymus, gastro-intestinal tract, including oro-pharynx, esophageus, stomach, small intestine, colon, and rectum, including parts of above mentioned organs down to single cell level and substructures, e.g. stem cells).
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-β or IFN-β, 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.
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.
With the groups of preferred compounds of formula (I) mentioned hereinafter, definitions of substituents from the general definitions mentioned hereinbefore may reasonably be used, for example, to replace more general definitions with more specific definitions or especially with definitions characterized as being preferred.
In particular, the invention refers to compounds of formula (I) wherein
V represents a bond or CR6R7;
W represents a bond, NR8 or oxygen;
X represents sulfur, or nitrogen substituted by hydrogen or R5;
Y represents -CH2-, -CO- or -CS-; R1 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 substitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted aryl, optionally substituted aryl-lower alkyl and lower acyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower acyl, carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, cyano, lower alkylsulfonyl, optionally substituted phenylsulfonyl, halogen, or nitro, and wherein two adjacent substituents together with the atoms of aryl may form a 5 or 6 membered carbocyclic or heterocyclic ring;
R2 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; hydroxy, amino or substituted amino; or, provided that Y is -CH2- R2 represents a group S02-R9 or CO-Z-R9 and Z represents a bond, oxygen or NR10; R3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R2 and R3 together with the nitrogen they are bound to represent a three, four, 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, optionally substituted aminoalkyl, heterocyclyl, heteroaryl, and lower alkoxy; R4 represents alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, optionally substituted aminoalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkyl, optionally substituted alkenyl, optionally substituted alkinyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R5 represents lower alkyl; or, provided that X is nitrogen, R4 and R5 together with the nitrogen X they are bound to represent a four, 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; R6 and R7, independently of each other, represent hydrogen or lower alkyl; or R6 and R7 together with the carbon atom they are bound to form a carbocylic or heterocyclic ring;
R8 represents hydrogen or lower alkyl;
R9 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; R10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R9 and R10 together with the nitrogen they are bound to represent a three, four, 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, optionally substituted aminoalkyl, heterocyclyl, heteroaryl, and lower alkoxy; and salts thereof.
In another aspect, the invention refers to compounds of formula (I) wherein
V represents a bond or CR6R7;
W represents a bond, NR8 or oxygen;
X represents sulfur, or nitrogen substituted by hydrogen or R5;
Y represents -CH2- -CO- or -CS-; R1 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 substitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted aryl, optionally substituted aryl-lower alkyl and lower acyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower acyl, carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, cyano, lower alkylsulfonyl, optionally substituted phenylsulfonyl, halogen, or nitro, and wherein two adjacent substituents together with the atoms of aryl may form a 5 or 6 membered carbocyclic or heterocyclic ring; R2 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or, provided that Y is -CH2- R2 represents a group S02-R9 or CO-Z-R9 and Z represents a bond, oxygen or NR10;
R3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R2 and R3 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;
R4 represents alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkinyl, optionally substituted aryl, or optionally substituted arylalkyl; R5 represents lower alkyl; or, provided that X is nitrogen, R4 and R5 together with the nitrogen X 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 or lower alkoxy; R6 and R7, independently of each other, represent hydrogen or lower alkyl; R8 represents hydrogen or lower alkyl;
R9 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; R10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R9 and R10 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.
More particularly, the invention refers to compounds of formula (I) wherein V represents a bond or CR6R7; W represents a bond or NR8;
X represents sulfur, or nitrogen substituted by hydrogen or R5; Y represents -CH2- or -CO-; R1 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, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower acyl, carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, cyano, or halogen, and wherein two adjacent substituents together with the atoms of aryl may form a 5 or 6 membered heterocyclic ring; R2 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or, provided that Y is -CH2-, R2 represents a group S02-R9 or CO-Z-R9 and Z represents a bond, oxygen or NR10;
R3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R2 and R3 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;
R4 represents alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkinyl, optionally substituted aryl, or optionally substituted arylalkyl; R5 represents lower alkyl; or, provided that X is nitrogen, R4 and R5 together with the nitrogen X 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 or lower alkoxy; one of R6 and R7 is hydrogen and the other one is hydrogen or lower alkyl; R8 represents hydrogen or lower alkyl;
R9 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; R10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R9 and R10 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.
Preferably, the invention refers to compounds of formula (I) wherein V represents a bond or CR6R7; W represents a bond or NR8; X represents sulfur; Y represents -CH2- or -CO-; R1 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; R2 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-lower alkyl, optionally substituted heteroaryl-lower alkyl, and lower acyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the lower alkyl group of amino-lower alkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or, provided that Y is -CH2-, R2 represents a group CO-Z-R9 and Z represents a bond, oxygen or NR10;
R3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R2 and R3 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; R4 represents alkyl, alkenyl, alkinyl or optionally substituted aryl-lower alkyl; R6, R7 and R8 represent hydrogen; R9 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 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-lower alkyl, and optionally substituted heteroaryl-lower alkyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of amino-lower alkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;
R10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R9 and R10 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.
More preferably, the invention refers to compounds of formula (I) wherein
V represents a bond; W represents NR8;
X represents sulfur;
Y represents -CH2- or -CO-;
R1 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; R2 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-lower alkyl, optionally substituted heteroaryl-lower alkyl, and lower acyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the lower alkyl group of amino-lower alkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or, provided that Y is -CH2-, R2 represents a group CO-Z-R9 and Z represents a bond, oxygen or NR10;
R3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R2 and R3 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; R4 represents alkyl, alkenyl, alkinyl or optionally substituted aryl-lower alkyl; R8 represents hydrogen; R9 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 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-lower alkyl, and optionally substituted heteroaryl-lower alkyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of amino-lower alkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; R10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R9 and R10 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. Most preferred are the compounds of the Examples, especially the compounds of Examples 23, 40, 41, 51, 52 and 53, and salts thereof.
Especially, 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.
Furthermore, 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.
Method of preparation
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
A) for the synthesis of a compound of the formula (I) wherein the symbols V, W, X, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and Y is -CO- a substituted pyrimidine carboxylic acid of formula (II)
wherein V, W, X, R1 and R4 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)
wherein R2 and R3 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;
B) for the synthesis of a compound of the formula (I) wherein the symbols V, W, X, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and Y is -CH2- or -GH2CH2- a substituted pyrimidine carboxaldehyde of formula (IV)
wherein V, W, X, R1 and R4 are as defined for a compound of formula (I) and n is 0 or 1, is reacted with an amine of formula (III)
R2-NH-R3 (III)
wherein R2 and R3 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;
C) for the synthesis of a compound of the formula (I) wherein the symbols V, W, Y, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and X is sulfur, a substituted thiopyrimidone of formula (V)
or a tautomer thereof, wherein V, W, Y, R1, R2 and R3 are as defined for a compound of formula (I), is reacted with an alkylating agent of formula (VI)
R4-LG (VI) wherein R4 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;
D) for the synthesis of a compound of the formula (I) wherein the symbols V, W, Y, R , R2, R3 and R4 are as defined for a compound of the formula (I) and X is nitrogen, a substituted pyrimidine of formula (VII)
wherein V, W, Y, R1, R2, and R3 are as defined for a compound of formula (I), X' is -SO- or -S02- and R is an alkyl, aralkyl or aryl group, is reacted with an amine of formula (VIII)
R4-XH (VIII)
wherein X and R4 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;
E) for the synthesis of a compound of the formula (I) wherein the symbols X, Y, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and V and W represent a bond, a substituted alkinone of formula (IX)
R1-CO-C≡C-Y-NR2R3 (IX)
wherein the symbols Y, R1, R2 and R3 are as defined for a compound of the formula (I), is reacted with a urea derivative of formula (X)
wherein X and R4 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;
F) for the synthesis of a compound of the formula (I) wherein the symbols X, Y, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and V and W represent a bond, a substituted pyrimidine of formula (XI)
wherein X, Y, R2, R3 and R4 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)
R1-B(OH)2 (XII)
wherein R1 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
G) for the synthesis of a compound of the formula (I) wherein the symbols V, X, Y, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and W represents NR7 or oxygen, a substituted pyrimidine of formula (XI)
wherein X, Y, R2, R3 and R4 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)
_V-W-H (XIII) wherein R1, 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;
and, where the above starting compounds of formula (II) to (XIII) may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt- forming group is present and the reaction in salt form is possible; and any protecting groups in a protected derivative of a compound of the formula (I) are removed;
and, if so desired, 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, and/or 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 pyrazoles.
Derivatives of the acid of formula (II) wherein the carboxy group is in activated form are preferably formed in situ. For example, 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.
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. For example, 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. Alternatively 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.
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.
Tautomers of a thiopyrimidone (V) are, for example, the corresponding compounds wherein the H-atom of the ring nitrogen atom in formula (V) sits on the other nitrogen atom and the two double bonds of the partially saturated pyrimidine ring are shifted such that the three valences of nitrogen are correctly taken into account, or the corresponding tautomers wherein the H-atom of the ring nitrogen atom in formula (V) sits on sulfur and the C=S double bond is shifted into the ring to form a C=N double bond such that the tautomers represent sulfhydrylpyrimidines.
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. Also other customary leaving groups are considered, e.g. 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. Optionally a suitable base is added, in particularly a tertiary amine base such as triethylamine or diisopropylethylamine.
In 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 R4-NH2 if X has the meaning "nitrogen substituted by hydrogen", or a secondary amine of formula R4-NH-R5 if X has the meaning "nitrogen substituted by R5".
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. Optionally a suitable base is added, in particularly a tertiary amine base such as triethylamine or diisopropylethylamine.
The 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. Preferably 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.
The 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. tetrahydrofuran or dimethoxyethane, with moderate heating, for example in a temperature range from approximately +30°C to approximately +150°C, especially approximately around 40°C to 80°C, in the presence of a soluble palladium(O) or related metal catalyst, for example tetrakis(triphenyIphosphine)paIladium. Alternatively, the 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. In addition to the displacement of 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. 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.
Alternatively, 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.
If 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.
The protection of such functional groups by such protecting groups, the protecting groups themselves, and their removal reactions are described for example in standard reference books for peptide synthesis and in special books on protective groups such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in "Methoden der organischen Chemie" (Methods of organic chemistry), Houben-Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, and in T. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York.
In the additional process steps, carried out as desired, 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.
In the conversion of an obtainable compound of formula (I) into another compound of formula (I), Y with the meaning -CO- may, for example, be reduced to Y with the meaning -CH2- Suitable reducing agents are known in the art, and are, for example, metal hydrides, e.g. LiAIH , LiAI(OCH3)3H or other alkoxy-substituted lithium hydrides, NaBH4, or BH3, optionally in the presence of a Lewis base, e.g. AICI3 or BF3, 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 R5-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 R5, under conditions comparable to those described above in process C). Alternatively, alkylation at nitrogen may be performed with an aldehyde under reducing conditions comparable to those described in process B). For example, alkylation to give a compound wherein R5 is methyl is performed with formaldehyde and NaBH4 in methanol.
The same reaction conditions are useful to convert a compound of formula (I), wherein R2 and/or R3 is hydrogen, into a compound of formula (I), wherein R2 and/or R3 is alkyl, respectively. For example, in a compound of formula (I), wherein Y is -CHr- or -CH2-CH2- and R3 is hydrogen, alkylation to give the corresponding compound wherein R3 is methyl is performed with formaldehyde and NaBH4 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.
It should be emphasized that reactions analogous to the conversions mentioned in this chapter may also take place at the level of appropriate intermediates.
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.
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.
At all reaction stages, 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. In the preferred embodiment, one starts from those starting materials which lead to the compounds described hereinabove as preferred, particularly as especially preferred, primarily preferred, and/or preferred above all.
In the preferred embodiment, 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. In the preferred embodiment, such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
Starting materials of formula (II) wherein R1 is directly linked to the pyrimidine nucleus (i.e. V and W are a bond), can be prepared in analogy to or according to methods known in the art. For example, 2-hexylmercapto-6-(3,4,5-trimethoxyphenyl)pyrimidin-4-carboxylic acid is prepared as described in D. Obrecht, C. Abrecht, A. Grieder and J. M. Villalgordo, Helv. Chim. Acta 80, 1997, 65-72.
Starting materials of formula (II) wherein R1 is linked to the pyrimidine nucleus via a spacer -V-W- can be prepared in analogy to methods described hereinbefore. In particular, a pyrimidinecarboxylic acid of formula (II), wherein W represents a group NR7 or oxygen and the other substituents are as defined for a compound of formula (I), may be prepared by displacing a leaving group Q in a pyrimidinecarboxylic acid of formula (XIV) or a suitable ester thereof
by an amine or alcohol of formula R1-V-W-H (XIII), optionally in the presence of an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent, in a process related to process G).
Amines of formula (III) are known or may be prepared in analogy to known methods.
Likewise, 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. In particular, 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)
R1-V-W-CO-C=C-(CH2)n-CH(OR)2 (XV)
wherein R1, 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)
wherein X and R4 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.
Starting materials of formula (V) are known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. For example, compounds of formula (V) may be obtained by reaction of a compound of formula (IX) with thiourea, i.e. a compound of formula (X) wherein -XR4 is replaced by -SH (or a tautomer thereof), in a process analogous to process E) described hereinbefore. Alternatively, 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. For example, 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.
Starting materials of formula (IX) and (XV) 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 (XI) are known or can be synthesized in analogy to or according to methods that are known in the art, or also according to any method for the synthesis of a compound of formula (I) described hereinbefore, but replacing substituent R1-V-W- by a substituent Q.
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. For example 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 tautomeric form thereof or a suitable ester thereof, with a halogenating (and dehydrating) reagent. 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.
Pyrimidonecarboxylic acids of formula (XVI), wherein X and R4 have the meanings as defined for compounds of formula (I), are known or may prepared in analogy or according to methods known in the art, e.g. by condensing a ketoester of formula (XVII)
wherein 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. Pharmaceutical preparations, methods, and uses
The present invention relates also to pharmaceutical 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).
A pharmaceutical composition for the prophylactic or especially therapeutic management of a neoplastic disease, autoimmune disease, transplantation related pathology and/or degenerative disease, of a warm-blooded animal, especially a human or a commercially useful mammal requiring such treatment, comprising a novel compound of formula (I) as active ingredient in a quantity that is prophylactically or especially therapeutically active against the said diseases, is likewise preferred.
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.
The pharmaceutical 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.
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).
Suspensions in oil comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes. In respect of such, special mention may be made of 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. As mixtures of fatty acid esters, vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and groundnut oil are especially useful.
The manufacture of injectable preparations is 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.
Pharmaceutical 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. In soft capsules, 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.
Pharmaceutical 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.
For parenteral administration, 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. In the case of an individual having a bodyweight of about 70 kg 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.
The preferred dose quantity, composition, and preparation of pharmaceutical formulations (medicines) which are to be used in each case are described above.
The following Examples serve to illustrate the invention without limiting the invention in its scope. Examples
Abbreviations: DMF = dimethyl formamide; DMSO = dimethyl sulfoxide;
HATU = 0-(7-azabenzotriazol-1-yl)-N,N,N,,N'-tetramethyluronium-hexafluorophosphate;
HBTU = 0-(benzotria∑ol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate; HOAT = 1-hydroxy-7-azabenzotriazole; HOBT = 1-hydroxybenzotriazoIe; MS = mass spectrum; RT = retention time in minutes.
General conditions for HPLC:
Develosil RPAq, 4.6 x 50 mm column No. 1302244 (Phenomenex); program 1: 10% CH3CN; 90% H20 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH3CN; program 2: 20% CH3CN; 80% H20 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH3CN; program 3: 30% CH3CN; 70% H20 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH3CN; program 4: 40% CH3CN; 60% H20 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH3CN; program 5: 60% CH3CN; 40% H20 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH3CN. program 6: 5% CH3CN; 95% H20 + 0.1% trifluoroacetic acid; flow 1.5 ml/min for 2 min; within 5 min to 100%CH3CN.
Example 1: 2-Hexylmercapto-6-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid 3-(4- methylpiperazinyl)propylamide
To a solution of 2-hexylmercapto-6-(3,4,5-trimethoxyphenyl)pyrimidine-4-carboxylic acid (150 mg, 0.37 mmol), HBTU (210 mg, 1.5 equiv.) and HOBT x 1H20 (85 mg, 1.5 equiv.) in DMF, diisopropylethylamine (190μl, 3 equiv.) is added at 4°C, and the mixture is stirred for 30 minutes at 4°C, followed by addition of 1-(3-aminopropyl)-4-methylpiperazine (87 mg, 1.5 equiv.). The reaction mixture is stirred for 5 hours at room temperature, extracted with 0.5 N aqueous HCI solution, the organic layer washed with saturated NaHC03 solution and brine, dried (MgS04) and the solvents evaporated. The residue is chromatographed on Si02 with CH2CI2/MeOH/aq. NH3 (200:20:1) to yield the title compound as a brownish amorphous solid. MS: 546.2 [M+H]+; HPLC (program 3): RT: 3.35 min.
To a solution of this amide (50 mg, 91.6 μmol) in ethanol (1 ml) 4 N HCI/dioxane (10 drops) is added, and the mixture evaporated. The residue is suspended in ethanol/ethyl acetate (1:6), filtered, and the residue dried under reduced pressure to give the hydrochloride of the title compound as a white solid. MS: 546.2 [M+H]+; 1H-NMR (300 MHz, DMSO-d6): 8.99 (br.s, 2 NH); 8.20 (s, 1 arom. H); 7.55 (s, 2 arom. H); 3.91 (s, 2 MeO); 3.76 (s, 1 MeO); 3.8-3.0 (br.m, ~10H); 2.81 (s, NMe); 2.1-1.95 (m, 2H); 1.85-1.7 (m, 2H); 1.55-1.4 (m, 2H); 1.4-1.2 (m, 6H); 0.9-0.8 (m, 3H).
Example 1a: 2-Hexylmercapto-6-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid To a stirred solution of 2-hexylmercapto-6-(3,4,5-trimethoxyphenyl)pyrimidine-4-carboxylic acid tert-butyl ester (1.9 g, 4.45 mmol, Example 1b) in CH2CI2 (10 ml) and water (5 drops), trifluoroacetic acid (10 ml) is added at 4°C, and the mixture stirred for 4 hours at room temperature. The reaction mixture is extracted with water and ethyl acetate, the organic layer washed with brine, dried (MgS04) and the solvent evaporated. The residue is dried under reduced pressure, the solid suspended in ethyl acetate/hexane (1 :3), filtered and dried in vacuo to yield the title acid as a slightly yellow solid. 1H-NMR (300 MHz, DMS0-d6): 8.12 (s, 1 arom. H); 7.45 (s, 2 arom. H); 3.99 (s, 2 MeO); 3.97 (s, MeO); 3.3-3.2 (m, 2H); 1.9-1.8 (m, 2H); 1.6-1.45 (m, 2H); 1.45-1.2 (m, 6H); 0.95-0.85 (m, 3H). The same compound is prepared from 2-hexylmercapto-6-(3,4,5-trimethoxyphenyl)- pyrimidine-4-carboxylic acid methyl ester (Example 1d) by hydrolysis with 2 M aqueous NaOH and methanol (1 :1) for 4 hours, followed by treatment with aqueous HCI and extraction with ethyl acetate.
Example 1b: 2-Hexylmercapto-6-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid tert- butyl ester
To a mixture of tert-butyl 4-oxo-4-(3,4,5-trimethoxyphenyl)butynoate (6.0 g, 18.61 mmol) and S-hexylthiouronium bromide (7.74 g, 1.2 equiv.) in DMF (50 ml), diisopropylethyl amine (4.8 ml, 1.5 equiv.) is added at 4°C withinlO minutes. The reaction mixture is stirred for 18 hours at room temperature followed by extraction with 1 N aqueous NaHS04 solution and ethyl acetate. The organic layer is washed with saturated brine, dried (MgS04), the solvents evaporated and the residue chromatographed on Si02 with ethyl acetate/hexane (1:6 to 1:4) yielding the title compound as slightly yellow solid. 1H-NMR (300 MHz, CDCI3): 7.91 (s, 1 arom. H); 7.41 (s, 2 arom. H); 3.98 (s, 2 MeO); 3.95 (s, MeO); 3.3-3.25 (m, 2 aliph. H); 1.9- 1.75 (m, 2H); 1.67 (s, tBu); 1.6-1.25 (6 aliph. H); 0.95-0.9 (m, 3H).
Example 1c: S-Hexylthiouronium bromide
To a magnetically stirred mixture of thiourea (50 g, 0.66 mol) in dioxane (250 ml) 1-bromo- hexane (100 ml, 0.71 mol) or a corresponding halide is added at room temperature. The reaction mixture is heated for 3 hours at 80°C, cooled to room temperature, and the solvent evaporated. Dry diethyl ether (500ml) is added to the residue, the product crystallized ovemight, filtered and washed with diethyl ether. The solid is dried under reduced pressure to yield the title compound as a white solid. MS: 161 [M+H]+; 1H-NMR (300 MHz, CDCI3): 8.98; 7.91 (br.s, 2H); 3.32 (t, J=7Hz, 2H); 2.8-2.7 (m, 2H);1.55-1.4 (m, 2H); 1.4-1.2 (m, 6H); 0.89 (m, 3H).
Example 1d: 2-Hexylmercapto-6-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid methyl ester
To a mixture of 6-chloro-2-hexylmercaptopyrimidine-4-carboxylic acid methyl ester (100 mg,
0.35 mmol) tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 12.3 mg), Cs2C03 (342 mg, 3 equiv.) and 3,4,5-trimethoxyphenylboronic acid (103 mg, 1.5 equiv.) in degassed dimethoxyethane (1.5 ml) is added under argon. The reaction mixture is stirred for 8 hours at 100°C, cooled to room temperature and extracted with water and ethyl acetate. The organic layer is dried (MgS04), the solvents evaporated and the residue chromatographed on Si02 with ethyl acetate/hexane (1:2) to yield the title compound as an oil. 1H-NMR (300 MHz, CDCI3): 7.90 (s, 1 arom. H); 7.34 (s, 2 arom. H); 3.96 (s, COOMe); 3.90 (s, 2 MeO); 3.87 (s, MeO); 3.25-3.15 (m, 2H); 1.8-1.7 (m, 2H); 1.55-1.35 (m, 2H); 1.35-1.15 (m, 4H); 0.9-0.8 (m, 3H).
Example 1e: 6-Chloro-2-hexylmercaptopyrimidine-4-carboxylic acid methyl ester A mixture of 2-hexylmercapto-6-hydroxypyrimidine-4-carboxylic acid methyl ester (500 mg, 1.85 mmol) and tetramethylammonium chloride in phosphoroxy chloride (POCI3, 3 ml) is heated for 1 hour at 90°C, cooled to room temperature, and the excess of POCI3 is removed under reduced pressure. The residue is extracted with saturated aqueous NaHC03 solution and ethyl acetate, the organic layer washed with brine, dried (MgS04), the solvent evaporated and the residue chromatographed on Si02 with ethyl acetate/hexane (1:6) to yield the title compound as colourless oil. 1H-NMR (300 MHz, CDCI3): 7.62 (s, 1 arom. H); 4.01 (s, MeO); 3.25-3.15 (m, 2H); 1.8-1.7 (m, 2H); 1.55-1.4 (m, 2H); 1.4-1.25 (m, 4H); 0.95- 0.85 (m, 3H).
Example 1f: 2-Hexylmercapto-6-hvdroxypyrimidine-4-carboxylic acid methyl ester
To a suspension of 2-hexylmβrcapto-6~hydroxypyrimidine~4-carboxylic acid (2.2 g, 8.58 mmol) in MeOH (30 ml) concentrated H2S0 (1 ml) is added and the mixture heated for 1 hour at 70°C. The reaction mixture is poured onto water and ethyl acetate, the organic layer extracted with brine, dried (MgS04) and the solvents evaporated. The residue is crystallized from ethyl acetate/hexane (1 :4), filtered and the residue dried under reduced pressure to yield the title compound as a white solid. 1H-NMR (300 MHz, DMSO-d6): 6.63 s, 1 arom. H); 3.83 (s, MeO); 3.2-3.1 (m, 2H); 1.65-1.55 (m, 2H); 1.45-1.2 (m, 6H); 0.9-0.8 (m, 3H).
Example 1α: 2-Hexylmercapto-6-hydroxypyrimidine-4-carboxylic acid To a stirred solution of NaOH (1.66 g) in water (40 ml) at room temperature sodium diethyl oxalacetate sodium salt (6.56 g, 1.5 equiv.) and 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. The suspension is stirred for 30 minutes, filtered, the solid washed with water and ethyl acetate, and dried under reduced pressure to yield the title compound as a white solid. 1H-NMR (300 MHz, DMSO-d6): 13.25 (br.s, 2H, OH); 6.59 (s, 1 arom. H); 3.2-3.1 (m, 2H); 1.75-1.55 (m, 2H); 1.45-1.2 (m, 6H); 0.95-0.8 (m, 3H).
Example 2: 2-Hexylmercapto-6-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid 2-(4- tert-butoxycarbonylpiperazinyl)ethylamide
To a mixture of 2-hexylmercapto-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-carboxylic acid (Example 1a, 150 mg, 0.37 mmol), HATU (210 mg, 1.5 equiv.) and HOAT (85 mg, 1.5 equiv.) in DMF (1.5 ml), diisopropylethylamine (200 μl) is added at 4°C, and the reaction mixture stirred for 30 minutes at 4°C, followed by addition of 1-(2-aminoethyl)-4-tert-butoxycarbonyl- piperazine (127 mg , 1.5 equiv.) in DMF (0.5 ml) at 4°C. The reaction mixture is stirred for 4 hours at room temperature, extracted with ethyl acetate and 0.5 N aqueous HCI solution, the organic layer washed with saturated aqueous NaHC03 solution and brine, dried (MgS04), the solvents evaporated and the residue chromatographed on Si02 with ethanol/ ethyl acetate (1:6), to yield the title compound as an oil. MS: 618.2 [M+H]+; 1H-NMR (300 MHz, DMSO-de): 8.72 (br.t, J=9, NH); 8.19 (s, 1 arom. H); 7.54 (s, 2 arom. H); 3.91 (s, 2 MeO); 3.76 (s, MeO); 3.5-3.4 (m, 2H); 3.35-3.25 (m, 4H); 2.6-2.45 (m,2H); 2.4-2.35 (m, 4H);1.8-1.7 (m, 2H); 1.55-1.4 (m, 2H); 1.40 (s, tBu); 1.35-1.25 (m, 4H); 0.9-0.8 (m, 3H).
Example 3: 2-Hexylmercapto-6-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid 2- piperazinylethylamide
4 N HCI/dioxane (2 ml) is added to a solution of 2-hexylmercapto-6-(3,4,5-trimethoxyphenyI)- pyrimidine-4-carboxylic acid 2-(4-tert-butoxycarbonylpiperazinyl)ethyIamide (Example 2, 160 mg, 0.26 mmol) in EtOH (0.5 ml) at room temperature, and the mixture stirred for 4 hours. Ethyl acetate (5 ml) is added to the suspension, the mixture filtered and the residue dried under reduced pressure to give the hydrochloride of the title compound as a slightly yellow powder. MS: 518.1 [M+H]+; 1H-NMR (300 MHz, DMSO-d6): 9.69 (br.s, 2 NH); 9.14 (br.s, 1 NH); 8.23 (s, 1 arom. H); 7.56 (s, 2 arom. H); 4.65-4.1 (br.m, ~6H); 3.92 (s, 2 MeO); 3.76(8, MeO); 3.7-3.25 (br.m, ~6H); 1.85-1.7 (m, 2H); 1.55-1.4 (m, 2H); 1.4-1.2(m, 4H); 0.9- 0.8 (m, 3H).
Example 4: 2-Hexylmercapto-6-(3.4,5-trimethoxyphenyl)pyrimidine-4-carboxylic acid 4- dimethylaminobenzylamide
To a solution of 2-hexylmercapto-6-(3,4,5-trimethoxyphenyI)-pyrimidin-4-carboxylic acid,
(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/MgS04. 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.
The following compounds are prepared according to Examples 1 to 4:
Table 1 :
The following compounds are likewise prepared according to Examples 1 to 4 starting from 2-hexylmercapto-6-(3,4-methylenedioxyphenyl)pyrimidine-4-carboxylic acid:
Table 2:
Example 39: 3-(4-Methylpiperazinyl)propionic acid 2-hexylmercapto-6-(3.4.5-trimethoxy- phenyl)pyrimidine-4-methylamide
To a mixture of 2-hexylmercapto-6-(3,4I5-trimethoxyphenyl)pyrimidine-4-methylamine hydrochloride (100 mg, 0.24 mmol), HBTU (137 mg, 1.5 equiv.), HOBT (55 mg, 1.5 equiv.) and 3-(4-methylpiperazinyl)propionic acid hydrochloride (58 mg, 1.2 equiv.), diisopropylethylamine (205 ml, 5 equiv.) is added at 4°C, and the reaction mixture is stirred for 30 minutes at 4°C and for 3 hours at room temperature. The reaction mixture is extracted with aq. NaHC03 solution, water and ethyl acetate, the organic layer washed with water and brine, dried (MgS0 ), and the solvents evaporated. The residue is chromatographed on Si02 with CH2CI /MeOH/ aq. NH3 (200:20:1) to yield the title compound as an amorphous solid. MS: 546.2 [M+H]+; HPLC (program 2): RT: 3.63 minutes; 1H-NMR (300 MHz, DMSO-d6): 8.59 (br.t, J=6Hz, NH); 7.62 (s, 1 arom. H); 7.43 (s, 2 arom. H); 4.34 (d, J=6Hz, CH2); 3.89 (s, 2 MeO); 3.75 (s, MeO); 3.25-3.15 (m, 2H); 2.6-2.5 (m, 2H); 2.45-2.25 (m, 10H); 2.12 (s, NMe); 1.8-1.7(m, 2 aliph. H); 1.5-1.25 (m, 6H); 0.9-08 (m, 3H).
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. H-NMR (300 MHz, DMSO-d6): 8.75 (br.s, 3H); 8.15 (s, 2 arom. H); 7.55 (s, 1 arom. H); 4.25-4.1 (m, 2H); 3.90 (s, 2 MeO); 3.76(s, MeO); 3.3-3.2 (m, 2H); 1.8-1.65(m, 2 aliph. H); 1.5-1.2 (m, 8 aliph. H); 0.9-0.8 (m, 3 aliph. H). Example 39b: N-tert-butoxycarbonyl-2-hexylmercapto-6-(3,4,5-trimethoxyphenyl)pyrimidine- 4-methylamine
To a mixture of 4-tert-butoxycarbonylamino-1-(3l4,5-trimethoxyphenyl)-2-butyn-1-one (1.3 g, 3.72 mmol) and S-hexylthiouronium bromide (Example 1c, 1.0 g, 1.2 equiv.) in DMF (10 ml), diisopropylethylamine (0.96 ml, 1.5 equiv.) is added at 4°C within 10 minutes. The reaction mixture is stirred for 18 hours at room temperature followed by extraction with 1 N aqueous NaHS04 solution and ethyl acetate. The organic layer is washed with saturated brine, dried (MgS0 ), the solvents evaporated and the residue chromatographed on Si02 with ethyl acetate/hexane (1 :4 to 1 :2) yielding the title compound pyrimidine as slightly yellow oil. 1H- NMR (300 MHz, CDCI3): 7.36 (s, 2 arom. H); 7.32 (s, 1 arom. H); 5.70 (br.s, NH); 4.45-4.4 (m, 2H); 3.97 (s, 2 MeO); 3.95 (s, 1 MeO); 3.3-3.25 (m, 2 aliph. H); 1.8-1.65(m, 2 aliph. H); 1.49 (s, tBu); 1.45-1.25(m, 6 aliph. H); 0.95-0.85 (m, 3 aliph. H).
Example 40: 2-Hexylmercapto-4-(3-[4-methylpiperazinyl]propylaminomethyl)-6-(3.4.5- trimethoxyphenyl)pyrimidine
To a mixture of 2-hexylmercapto-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-carboxaldehyde (150 mg, 0.38 mmol), 1-(3-aminopropyl)-4-methylpiperazine (91 mg, 1.5 equiv.) in 1 N acetic acid/MeOH (1.5 ml), sodium cyanoborohydride (NaCNBH3, 48 mg, 2.0 equiv.) is added at 4°C. The reaction mixture is stirred for 5 hours at room temperature, extracted with aq. NaHC03 solution and CH2CI2, the organic layer dried (MgS04) and the residue chromatographed on Si02 with CH2CI2/MeOH/aq.NH3 (200:20:1) to yield the title compound as a brownish amorphous solid. MS: 532.2 [M+H]+; HPLC (program 1): RT 3.74 minutes; 1H- NMR (300 MHz, DMSO-d6): 7.76 (s, 1 arom. H); 7.46 (s, 2 arom. H); 3.89 (s, 2 MeO); 3.75 (s, MeO); 3.2-3.1 (m, 2H); 2.6-2.05 (m, 12H); 2.11 (s, NMe); 1.8-1.7 (m, 2H); 1.7-1.65-1.5 (m, 2H); 1.5-1.35 (m, 2H); 1.3-1.2 (m, 4H); 0.9-0.8 (m, 3H).
10 drops of 4 N HCI/dioxane are added to a solution of this amine (32 mg, 60 mmol) in EtOH (1 ml) at room temperature. The mixture is evaporated and the residue crystallized with ethyl acetate/EtOH (3:1), the solid filtered and dried under reduced pressure to yield the dihydrochloride of the title compound as slightly yellow powder. MS: 532.2 [M+H]+; 1H-NMR (300 MHz, DMSO-de): 9.73 (br.s, 2 NH); 8.21 (s, 1 arom. H); 7.57 (s, 2 arom. H); 4.4-4.3 (br.m, 2H); 3.91 (s, 2 MeO); 3.76 (s, MeO); 3.7-3.1 (br.m, ~14H); 2.82 (s, NMe); 2.2-2.0 (m, 2H); 1.8-1.7 (m, 2H); 1.5-1.4 (m, 2H); 1.4-1.2 (m, 4H); 0.9-0.8 (m, 3H).
Example 40a: 2-Hexylmercapto-6-(3.4,5-trimethoxyphenyl)-pyrimidin-4-carboxaldehyde To a solution of 2-hexylmercapto-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-carboxaldehyde diethyl acetal (2.05 g, 4.41 mmol) in 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. The organic layer is washed with brine, dried (MgS04), and the residue crystallized from ethyl acetate/hexane (1 :10) to yield the title compound as a slightly yellow solid. 1H-NMR (300 MHz, CDCI3): 10.01 (s, CHO); 7.80 (s, 1 arom. H); 7.42 (s, 2 arom. H); 3.99 (s, 2 MeO); 3.95 (s, MeO); 3.35-3.3 (m, 2H); 1.9-1.8 (m, 2H); 1.6-1.45 (m, 2H); 1.45-1.3 (m, 6H); 0.95-0.9 (m, 3H).
Example 40b: 2-Hexylmercapto-6-(3.4.5-trimethoxyphenyl)-pyrimidin-4-carboxaldehvde diethyl acetal To a mixture of 4,4-diethoxy-1-(3,4,5-trimethoxyphenyl)-2-butyn-1-one (6.0 g, 18.61 mmol) and S-hexylthiouronium bromide (Example 1c, 7.74 g, 1.2 equiv.) in DMF (50 ml), diisopropylethylamine (4.8 ml, 1.5 equiv.) is added at 4°C within 10 minutes. The reaction mixture is stirred for 18 hours at room temperature followed by extraction with 1 N aqueous NaHS0 solution and ethyl acetate. The organic layer is washed with saturated brine, dried (MgS04), the solvents evaporated, and the residue chromatographed on Si02 with ethyl acetate/hexane (1:6 to 1 :3) yielding the title compound as slightly yellow oil. 1H-NMR (300 MHz, CDCI3): 7.59 (s, 1 arom. H); 7.40 (s, 2 arom. H); 5.41 (s, CH(OCH2CH3)2); 3.97(s, 2 MeO); 3.94 (s, MeO); 3.9-3.65 (m, CH(OCH2CH3)2); 3.3-3.2 (m, 2H); 1.9-1.75 (m, 2H); 1.55- 1.45 (m, 2H); 1.35-1.2 (m, 10H); 0.95-0.85 (m, 3H).
Example 41 : 2-Hexylmercapto-4-(N-methyl-N-3-[4-methylpiperazinyl1propyl-aminomethyl)-6-
(3.4.5-trimethoxyphenyl)pyrimidine
To a mixture of 2-hexylmercapto-4-(3-[4-methylpiperazinyl]propylaminomethyl)-6-(3,4,5- trimethoxyphenyl)pyrimidine (Example 40, 110 mg, 0.21 mmol) in methanol (1.5 ml), sodium methoxide (34 mg, 3 equiv.) and para-formaldehyde (12.6 mg, 2 equiv.) are added. The reaction mixture is stirred for 12 hours at room temperature followed by addition of NaBH (16.0 mg, 2 equiv.). Stirring is continued for an additional 24 hours, and the mixture extracted with aq. NaHC03 solution, water and CH2CI2. The organic layer is dried (MgS04), evaporated, and the residue chromatographed on Si0 with CH2CI2/MeOH/aq. NH3 (60:10:0.5) to yield the title compound as a brownish amorphous solid. MS: 546.2 [M+H]+; 1H-NMR (300 MHz, DMSO-d6): 7.69 (s, 1 arom. H); 7.44 (s, 2 arom. H); 3.89 (s, 2 MeO); 3.74 (s, MeO); 3.57 (s, CH2); 3.2-3.1 (m, 2H); 2.4-2.1 (m, ~10H); 2.25 (s, NMe); 2.09 (s, NMe); 1.8-1.7 (m, 2H); 1.8-1.65 (m, 2H); 1.5-1.35 (m, 2H); 1.35-1.2 (m, 4H); 0.9-0.8 (m, 3H). 10 drops of 4 N HCI/dioxane are added to a solution of this amine (70 mg, 0.13 mmol) in ethanol (1 ml). The mixture is evaporated and the residue crystallized from ethanol/ethyl acetate (1 :4), the solid filtered and dried under reduced pressure to the dihydrochloride of the title compound as a slightly yellow powder. MS: 546.2 [M+H]+; 1H-NMR (300 MHz, DMSO- d6): 8.33 (s, 1 arom. H); 7.57 (s, 2 arom. H); 4.48 (s, CH2); 3.90 (s, 2 MeO); 3.76 (s, MeO); 3.8-2.9 (br.m); 2.86 (s, NMe); 2.72 (s, NMe); 2.15-2.0 (m, 2H); 1.8-1.7 (m, 2H); 1.5-1.4 (m, 2H); 1.4-1.2 (m, 4H); 0.9-0.8 (m, 3H).
Example 42: 2-(N-Hexyl-N-methylamino)-8-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid f3-(4-methylpiperazinyl)propyπamide
To a stirred solution of 2-(N-hexyl-N-methylamino)-6-(3,4,5-trimethoxyphenyl)pyrimidine-4- carboxylic acid (150 mg, 0.37 mmol), HBTU (210 mg, 1.5 equiv.), HOBT (85 mg, 1.5 equiv.) and diisopropylethylamine (253 μl, 4 equiv.) in DMF (1.5 ml), 1-(3-aminopropyl)-4-methyI- piperazine (116 mg, 2 equiv.) in DMF (0.5 ml) is added at 4°C. The reaction mixture is stirred for 24 hours at room temperature, extracted with aq. NaHC03 solution and CH2CI2, the organic layer dried (MgS04), the solvents evaporated and the residue chromatographed on Si02 with CH2CI2/MeOH/aq. NH3 (200:20:1) to give the title compound as a slightly yellow oil. MS: 543.3 [M+H]+; HPLC (program 2): RT 3.82 min.
Example 42a: 2-(N-Hexyl-N-methylamino)-6-(3.4,5-trimethoxyphenyl)pyrimidine-4-carboxylic acid
To a stirred solution of 2-(N-hexyl-N-methylamino)-6-(3,4,5-trimethoxyphenyl)pyrimidine-4- carboxylic acid tert-butyl ester (375 mg, 0.82 mmol) in CH2CI2 (3 ml) and 3 drops of water, trifluoacetic acid (3 ml) is added at 4°C, and the reaction mixture stirred for 4 hours. The mixture is evaporated, the residue co-evaporated three times with toluene and dried in vacuo to yield the title compound as an amorphous solid.
Example 42b: 2-(N-Hexyl-N-methylamino)-6-(3.4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid tert-butyl ester
To a stirred solution of 2-hexylsuIfonyl-6-(3,4,5-trimethoxyphenyl)pyrimidine-4-carboxylic acid tert-butyl ester (500 mg, 1.01 mmol) in DMSO (2 ml), hexylmethylamine (460 μl, 3 equiv.) is added at room temperature, the reaction mixture stirred for 24 hours, extracted with water and ethyl acetate, the organic layer washed with brine, dried (MgS0 ), the solvents evaporated and the residue chromatographed on Si02 with ethyl acetate/hexane (1:6 to1:4) to yield the title compound as a slightly yellow oil. 1H-NMR (300 MHz, CDCI3): 7.45 (s, 1 arom. H); 7.39 (s, 2 arom. H); 3.97(s, 2 MeO); 3.94 (s, MeO); 3.8-3.7(m, 2H); 3.33 (s, NMe); 1.8-1.6 (m, 2H); 1.66 (s, tBu); 1.4-1.2 (m, 6H); 0.9-0.8 (m, 3H). Example 42c: 2-Hexylsulfonyl-6-(3,4.5-trimethoxyphenyl)pyrimidine-4-carboxylic acid tert- butyl ester
To a stirred suspension of 2-hexyImercapto-6-(3,4,5-trimethoxyphenyI)pyrimidine-4- carboxylic acid tert-butyl ester (Example 1b, 3.6 g, 7.78 mmol) and sodium acetate (3.2 g, 5 equiv.) in dichloromethane (40 ml), m-chloroperbenzoic acid (3.36 g, 2.5 equiv.) is added in small portions at 4°C. The reaction mixture is stirred for 30 minutes at 4°C and for 2 hours at room temperature, extracted with saturated aqueous NaHC03 solution and ethyl acetate, the organic layer washed with brine, dried (MgS04), the solvents evaporated and the residue chromatographed on Si02 with ethyl acetate/hexane (1 :3 to 1 :2) to give, after crystallisation from ethyl acetate/hexane (1 :6), the title compound as a slightly yellow solid. 1H-NMR
(300 MHz, CDCI3): 8.40 (s, 1 arom. H); 7.48 (s, 2 H); 4.00 (s, 2 MeO); 3.97 (s, MeO); 3.7-3.6 (m, 2H); 2.05-1.9 (m, 2H);1.68 (s, tBu); 1.6-1.25 (m, 6H); 0.95-0.85 (m, 3H).
The following compounds are prepared according to Example 42:
Table 3:
Example 46: 2-Hexylmercapto-6-(3.4.5-trimethoxyphenylamino)pyrimidine-4-carboxylic acid 2-(4-methylpiperazinyl)-1-phenylethylamide
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 μl) are mixed together and stirred for 6 h at 80°C. NaHC03 (10 ml, sat. aq.) is added, and the reaction mixture extracted twice with ethyl acetate (10 ml), dried over Na2S0 , and the organic layer concentrated. The crude product is purified by silica gel chromatography (CH2Cl2/MeOH 20:1 , 1% aqueous NH3) yielding the title compound as a yellow oil. [M+H : 623.4. HPLC (program 1): RT 4.64 min. 1H-NMR (300 MHz, DMSO-d6): 9.89 (s, 1 H, NH), 8.78 (d, 1H, J=7Hz, NH), 7.4-7,2 (m, 5 arom. H), 7.01 (s, 2H), 6.99 (s, 1H), 5.05 (m, 1 H, CH), 3.78 (s, 6H, 2 OCH3), 3.64 (s, 3H, OCH3), 3.2 (m, 2 H, CH2), 2.4-2.2 (m, 8H, CH2), 2.13 (s, 3H, NCH3), 1.7 (m, 2H, CH2), 1.4 (m, 2H, CH2), 1.25 (m, 6H, CH2), 0.84 (m, 3H, CH3).
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 μl, 0.43 mmol) and DMSO (50 μl) 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 Na2S04, and the organic layer concentrated. The crude product is purified by silica gel chromatography (ethyl acetate / hexane 1 :2) yielding the title compound as a yellow solid. [M+H]+: 451.0. 1H-NMR (300 MHz, DMSO-d6): 9.91 (s, 1 H, NH), 7.04 (s, 1H), 7.00 (s, 2H), 4.32 (q, J=7Hz, 2H, CH2), 3.78 (s, 6H, 2 OCH3), 3.65 (s, 3H, OCH3), 3.14 (t, J=7Hz, 2H, CH2), 1.63 (m, 2H, CH2), 1.32 (t, J=7Hz, 3H, CH3), 1.2 (m, 6H, CH2), 0.86 (t, J=7Hz, 3H, CH3).
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 POCI3 (1 ml, 10.9 mmol) and stirred at 90°C for 40 min in a sealed tube. The reaction mixture is evaporated to dryness, NaHC03 (10 ml, sat. aq.) is added, the mixture extracted twice with ethyl acetate (10 ml), dried over Na2S04, and the organic layer concentrated. The crude product is purified by silica gel chromatography (ethyl acetate/hexane 1 :8) yielding the title compound as a yellow oil. 1H-NMR (300 MHz, DMSO-d6): 7.75 (s, 1 H, CH), 4.36 (q, J=7Hz, 2H, CH2), 3.16 (t, J=7Hz, 2H, CH2), 1.69 (m, 2H, CH2), 1.5-1.2 (m, 9H), 0.87 (t, J=7Hz, 3H CH3).
Example 48c: Ethyl 2-hexylmercapto-θ-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 μl, 1.05 mmol) is added, and the solution stirred at 50°C for 6 h. NaHC03 (10 ml, sat. aq.) is added, the reaction mixture extracted twice with ethyl acetate (300 ml), dried over Na2S04, and the organic layer concentrated to give the title compound as a crude yellow solid. [M+H]+: 285.0. 1H-NMR (300 MHz, DMSO-de): 6.15 (s, 1 H, CH), 4.20 (q, J=7H∑, 2H, CH2), 2.95 (t, J=7Hz, 2H, CH2), 1.7- 1.2 (m, 11H), 0.86 (t, J=7Hz, 3H, CH3).
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 H2S04 (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/CH2Cl2 (400 ml, v/v) and adsorbed on silica gel. The product is purified on a short silica gel column with ethyl acetate/hexane using a gradient 1 :1 → 1 :0 yielding the title compound as a yellowish solid. [M+H]+: 201.0. 1H-NMR (300 MHz, DMSO-d6): 12.7 (bs, 1 H), 12.2 (bs, 1H), 6.32 (s, 1 H, CH), 4.31 (q, J=7Hz, 2H, CH2), 1.31 (t, J=7Hz, 3H, CH3).
Example 46e: 2-Thio-6-pyrimidone-4-carboxylic acid
Thiourea (14.3 g, 0.188 mol) is dissolved in water (120 ml) and stirred at 100°C. Diethyl oxalacetate sodium salt (80 g, 0.381 mmol) is added in portions to this solution within 5 min. The reaction mixture is stirred for 2.5 h and then cooled to 0°C. The solution is acidified by adding aqueous HCI (300 ml, 3 N) and stirred for 5 min. The yellow precipitate is filtered, washed twice with HCI (50 ml, 3 N), twice with water (100 ml) and twice with ethyl acetate (100 ml). The crude product is dried in high vacuum yielding the title compound as a yellow solid. [M-H]": 171.1. 1H-NMR (300 MHz, DMSO-d6): 12.64 (bs, 1H), 11.80 (bs, 1H), 6.27 (s, 1H, CH). The following compounds are prepared according to Example 46 and 46a:
Table 4:
Example 51 : 2-Hexylmercapto-4-(3-[4-methylpiperazinyllpropyl-aminomethyl)-6-(3,4,5- trimethoxyphenylamino)pyrimidine
2-Hexylmercapto-6-(3,4,5-trimethoxyphenylamino)pyrimidine-4-carbaldehyde (Example 51a, 12 mg, 0.0296 mmol) and 1-(3-aminopropyl)-4-methyl-piperazine (10 μl, 0.059 mmol) are dissolved in THF (0.4 ml). After 5 min NaBH(OAc)3 (13 mg, 0.059 mmol) is added and the reaction mixture stirred at room temperature for 2 h. Na2C03 (5 ml, sat. aq.) is added, and the reaction mixture extracted twice with ethyl acetate (4 ml), dried over Na2S04, and the organic layer concentrated. The crude product is purified by silica gel chromatography (CH2CI2/MeOH 20:1 , 1% aqueous NH3) yielding the title compound as a colorless oil. 1H- NMR (300 MHz, DMSO-d6): 9.45 (s, 1 H, NH), 6.96 (s, 2H), 6.52 (s, 1 H), 3.77 (s, 6H, 3
OCH3), 3.63 (s, 3H, OCH3), 3.54 (bs, 2H, CH2), 3.09 (t, J=7Hz, 2H, CH2), 2.33 (m, 8H, CH2), 2.13 (s, 3H, NCH3), 1.59 (m, 2H, CH2), 1.4-1.2 (m, 6H, CH2), 0.84 (m, 3H).
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 H20) 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. 1H-NMR (300 MHz, DMSO-d6): 9.99 (s, 1 H, NH), 9.74 (s, 1 H, CHO), 7.00 (s, 2H), 6.87 (s, 1 H), 3.79 (s, 6H, 3 OCH3), 3.65 (s, 3H, OCH3), 3.60 (m, 4H, CH2), 3.17 (t, J=7Hz, 2H, CH2), 1.65 (m, 2H), 1.4-1.2 (m, 6H, CH2), 0.84 (m, 3H).
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 μl, 0.859 mmol) and DMSO (300 μl) are mixed together and stirred for 5 h at 110°C. NaHC03 (10 ml, sat. aq.) is added, and the reaction mixture extracted twice with ethyl acetate (10 ml), dried over MgS04, and the organic layer concentrated. The crude product is purified by silica gel chromatography (ethyl acetate/hexane 1 :2) yielding the title compound as a yellowish oil. [M+H]+: 480.0. 1H-NMR (300 MHz, DMSO-d6): 9.61 (s, 1H, NH), 6.98 (s, 2H), 6.60 (s, 1 H), 5.16 (s, 1H, CH), 3.77 (s, 6H, 3 OCH3), 3.63 (s, 3H, OCH3), 3.60 (m, 4H, CH2), 3.10 (t, J=7Hz, 2H, CH2), 1.62 (m, 2H), 1.4-1.2 (m, 6H, CH2), 1.16 (t, J=7Hz, 6H, CH3), 0.84 (m, 3H). 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 POCI3 (1 ml, 10.9 mmol) at 0°C and stirred at this temperature for 2 h. The excess POCI3 is removed in vacuo at 20°C, and NaHC03 (5 ml, sat. aq.) is added, the reaction mixture extracted twice with ethyl acetate (5 ml), dried over MgS0 , and the organic layer concentrated. The crude product is purified by silica gel chromatography (hexane/ethyl acetate 30:1) yielding the title compound as a colorless oil. 1H-NMR (300 MHz, DMSO-d6): 7.28 (s, 1 H), 5.35 (s, 1 H, CH), 3.65 (m, 4H, CH2), 3.12 (t, J=7Hz, 2H, CH2), 1.70 (m, 2H), 1.4- 1.2 (m, 6H, CH2), 1.17 (t, J=7Hz, 6H, CH3), 0.87 (m, 3H).
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 μl, 4.56 mmol) is added, and the clear mixture is stirred for 4 h at 60°C. To complete the reaction more 1-bromohexane (100 μl, 0.88 mmol) is added and stirred for 1 h at 60°C. NaHC03 (40 ml, sat. aq.) is added, and the reaction mixture extracted twice with ethyl acetate (40 ml), dried over Na2S04, and the organic layer concentrated to give the title compound as a yellowish solid crude product. 1H-NMR (300 MHz, DMSO-d6): 6.06 (s, 1 H), 5.08 (s, 1 H, CH), 3.55 (m, 4H, CH2), 3.06 (t, J=7Hz, 2H, CH2), 1.62 (m, 2H), 1.4-1.2 (m, 6H, CH2), 1.14 (t, J=7Hz, 6H, CH3), 0.86 (m, 3H).
Example 51 e: 2-Thio-6-pyrimidone-4-carbaldehyde diethyl acetal
According the procedure of: R. A. Nugent et al., J. Med. Chem. 1998, 41 , 3793-3803, ethyl 4,4-diethoxy-3-oxobutanoate (10.8 g, 49.48 mmol) is dissolved in EtOH (20 ml) and added to a solution of thiourea (3.76, 49.48 mmol) and NaOMe (2.67 g, 49.48 mmol) in EtOH (25 ml).
The reaction mixture is heated for reflux for 4 h. The mixture is treated with HCI (200 ml, aq.,
1 N) and the precipitate filtered, washed twice with H20 (100 ml), diethyl ether (100 ml) and dried in high vacuum yielding the title compound as a white solid. 1H-NMR (300 MHz, DMSO- d6): 12.45 (bs, 1 H), 12.25 (bs, 1H), 5.81 (s, 1H), 5.15 (s, 1 H, CH), 3.6 (m, 4H, CH2), 1.16 (t,
J=7Hz, 6H, CH3). The following compounds are prepared according to Example 51, 51a and 51b:
Table 5:
Example 54: 2-Hexylmercapto-6-(3,4.5-trimethoxyphenylamino)pyrimidine-4-carboxylic acid 3-(4-methylpiperazinyl)-propylamide
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.
Cell lines are cultured in RPMI-1640 tissue culture medium containing either 5% or 10% fetal calf serum, 0.05 mM 2-mercaptoethanol, 2 mM glutamine and penicillin/streptomycin
50 μg/ml (complete medium) (Sigma, Buchs, Switzerland). General growth conditions are
37°C and 7.5% C02.
The following mouse cell lines (either EGFP transfected or not) are being used: A20.2J
(ATCC: TIB-208), MC57G (ATCC: CRL-2295). The following human cell lines (either EGFP transfected or not) are being used: HeLa
(ATCC: CCL-2), KB (ATCC: CCL-17), MCF7 (ATCC: HTB-22), SK-BR-3 (ATCC: HTB-30),
SK-Mel 1 (ATCC: HTB-67), SK-Mel 28 (ATCC: HTB-72), PC-3 (ATCC: CRL-1435), SW 480
(ATCC: CCL-228), NCI-H460 (ATCC: HTB-177), NCI-H1792 (ATCC: CRL-5895), HT1080
(ATCC: CCL-21), Jurkat (ATCC: TIB-152), Ramos (ATCC: CRL-1596), Raji (ATCC: CCL-86), H9 (ATCC: HTB-176), Hut78 (ATCC: TIB-161 ), K562 (ATCC: CCL 243), HL-60 (ATCC: CCL
240), U-87MG (ATCC: HTB-14), HepG2 (ATCC: HB-8065), U-2 OS (ATCC: HTB-96), Saos-2
(ATCC: HTB-85), U937 (ATCC: CRL 1593), Hs 578T (ATCC: HTB 126), HBL-100 (ATCC:
HTB 124), Molt-4 (ATCC: CRL 1582).
Example 56: Primary screening setup
All the manipulations are performed under sterile conditions. 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: 104 - 105, 384 well plates: 1500 - 2*104) are plated out 24 hours before treatment either in 75 μl (96 well plates) or 60 μl (384 well plates) complete medium per well in order to ensure appropriate cell spreading. For this purpose a peristaltic pump (e.g. Multidrop by Thermo-Labsystems, Finland) or 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% C02. Subsequently, the compounds under investigation are added at defined concentrations (40 - 80 μM in either 25 μl (96 well plates) or 20 μl (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 μM compound in max 1% DMSO. Immediately after the addition of the compounds to the cells the zero fluorescence value (t = 0 h) is determined by using a fluorescence microplate reader in order to be able to normalize the fluorescence activities. Afterwards, the test plates are further incubated for a total of 48 h at 37°C under 7.5% C02 and are shortly removed only for the purpose of measurement at 8 h, 24 h and 48 h, respectively.
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 μs 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. Kinetics is performed by measuring the relative fluorescence activities at t = 0 h, 8 h, 24 h and 48 h. Crude fluorescence activities are individually normalized for different cell numbers and various optical activities of the test compounds / plate-wells by dividing each value from t = 8 h, 24 h and 48 h by the value of t = 0 h resulting in E(8), E(24) and E(48) values.
Subsequently, 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 (untreated) 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.
All the manipulations are performed under sterile conditions. 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
(P-tubes) 1.4 ml (Matrix, UK), respectively.
Adherent test cells: 2*104- 4*104 of EGFP transfected cells in 0.5 ml complete medium are plated out 24 h before treatment. At t = 0 the medium is removed and 450 μl new complete medium is added. Subsequently, 50 μl complete medium containing the test compound in max. 5% DMSO is added resulting in final concentrations of 20 μM, 10 μM, 3 μM,1 μM and
0.3 μM of the test compounds, respectively. After 48 h incubation the cells are harvested and analyzed with fluorescence activated cell scanning device (FACSCalibur™, BD Biosciences) according to standard procedures. Suspension cells: 105 test cells in 450 μl complete medium are pipetted into P-tubes. 50 μl complete medium containing the compounds (see adherent cells) is added immediately. After 48 h of incubation the test cells are analyzed directly on a FACSCalibur™.
Example 59: Quantification of the secondary screening.
By monitoring the EGFP fluorescence activity in FL1 on a FACSCalibur™, it is possible to distinguish between proliferating cells, apoptotic cells and necrotic cells within the same cell population. The proliferating cells show a high GFP fluorescence activity, the apoptotic population shows an intermediate fluorescence activity whereas the necrotic cells demonstrate a residual fluorescence activity comparable to mock-transfected cells. Within the CellQuest Software (BD Biosciences) three regions are defined in the histogram: M1 comprising the proliferating cells, M2 comprising the apoptotic cell population and M3 comprising the necrotic cell population. As readout the relative abundance of the cells belonging either to M1, M2 or M3 are expressed. Compounds inducing M2 values > 50% and M3 values < 30% are being considered relevant and are further tested and characterized in the tertiary / advanced screening setup.
Example 60: Tertiary screening setup
A) Hoechst 33342 nuclear staining
This assay is performed in 96 well tissue culture plates. Appropriate number of cells (adherent cells: 3 - 5*103, suspension cells: 8 - 10*103) are being seeded out in 80 μl 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 μl complete medium ontaining max 5% DMSO. The final compound concentrations in the assays are 10 μM, 3 μM,1 μM and 0.3 μM, respectively. After 24 h or 48 h incubation at culture conditions, 10 μl medium containing Hoechst 33342 dye (Sigma B-2261) at 2-5 μg/ml are added to each well. The assay plates are then further incubated for 30 minutes and subsequently analyzed with a standard inverted fluorescence microscope.
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
5
B) MTS proliferation assay
The assay is performed in 96 well tissue culture plates. The cells (range : 1.5"103 - 104) are seeded out in 80 μl complete medium 24 h prior to compound treatment. The test compounds are added in 20 μl complete medium containing max 5% DMSO. The final compound concentrations in the assays are 10 μM, 3 μM,1 μM and 0.3 μM, 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 μl 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. IC50 values are determined by graphical analysis and are indicated in the Table 7 in μM concentration.
C) AnnexinV/7-AAD staining
Adherent cells (1 - 2*105) 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 μM. 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 μl complete medium containing AnnexinV-GST (10 μg) is added, mixed and incubated at 4°C for 30 minutes. Subsequently, the cells are washed once with medium and incubated with 100 μl 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 μg/ml 7-aminoactinomycin D (7-AAD) (Molecular Probes A-1310) in 250 μl medium and analyzed on the FACSCalibur™. 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.
Table 8: AnnexinV/7-AAD staining (10 μM)
D) PI staining for cell cycle distribution
1 - 2*105 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 μM or 10 μM. Adherent cells are harvested by trypsinization. The cell suspensions are fixed by adding
2 parts ice cold ethanol 100% while vortexing. Then the samples are stored for > 2 h at - 20°C. Subsequently the cells are washed with PBS once and resuspended in 250 μl PBS containing 50 μg/ml PI (Calbiochem # 537059), then the samples are incubated at 37°C for 30 minutes and subsequently analyzed on a FACSCalibur™ monitoring linear PI fluorescence activity on FL2. . The readout allows the detection of a possible direct or indirect influence of the tested compounds on the cell cycle. The following events can occur: a) Generation of a subG1 peak indicative for DNA fragmentation, b) increase of the cell population arrested in G2M phase. Both events are scored by 1 for weak and 2 for strong occurrence. 0 indicates no occurrence at all. In Table 9 the influences of several tested compounds are demonstrated. Table 9: PI staining for cell cycle distribution
E) BrdU incorporation (proliferation)
Adherent cells are seeded out at 2 - 4*104 cells/well/ml in 24 well tissue culture plates 24 h prior to treatment. Suspension cells are seeded out at 2"105 cells/ml/well in 24 well plates. Compounds are added leading to final concentrations of 3 μM and 10 μM, respectively. Subsequently, BrdU (Molecular Probes #B-23151) at 10 μM 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 FACSCalibur™ 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.
Table 10: BrdU incorporation
F) Caspase dependencies
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 μM 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. An inhibition by zVAD as well as by zFA points towards the involvement of cystein proteinases in the apoptotic cascade. Table 11 demonstrates the protease dependency of the nuclear fragmentation visualized by Hoechst 33342 staining. Table 11 : Caspase dependencies
nd: not determined due to self fluorescence of the compound no effect weak effect strong effect
Example 61 : Preclinical Development. Clonogenic assay
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. The following cells and tumor types are used: 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: Sarcoma Xenograft; TXF: Testicular Cancer Xenograft; UXF: Uterine Body Xenograft; LEXF: Leukemia Xenograft; XF: Miscellaneous Cancer Xenograft. Results are schown in Table 12. Table 12: Clonogenic assay EC 50 values
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 μm. 0.419 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.

Claims

Claims
1. A compound of formula (I)
wherein
V represents a bond or CR6R7;
W represents a bond, NR8 or oxygen;
X represents sulfur, or nitrogen substituted by hydrogen or R5;
Y represents -CH2-, -CH2CH2- -CO- or -CS-; R1 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-lower 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, lower alkoxy, halo-lower alkoxy, cycloalkoxy, cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, lower alkylcarbonyloxy, aminocarbonyloxy wherein the nitrogen atom is optionally substituted by one or two substituents selected from alkyl, hydroxyalkyl and aminoalkyl, lower alkoxycarbonyloxy, heterocyclyloxy, heterocyclyl-lower alkoxy, optionally substituted aryloxy, optionally substituted aryl-lower alkoxy, optionally substituted heteroaryloxy, optionally substituted heteroaryl-lower alkoxy; amino, aminoearbonyl, 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, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy- lower alkyl, optionally substituted aryl, optionally substituted aryl-lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl and lower acyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, amino-lower alkoxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, aminoearbonyl wherein the nitrogen atom is optionally substituted by one or two substituents independently selected from alkyl, hydroxyalkyl, alkoxyalkyl and optionally substituted aminoalkyl, or wherein the two substitutens together with the nitrogen atom they are bound to represent a three, four, five or six membered heterocyclic ring, cyano, mercapto, lower alkylmercapto, optionally substituted phenylmercapto, lower alkylsulfinyl, halo-lower alkylsulfinyl, optionally substituted phenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl, optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, or nitro, and wherein two adjacent substituents together with the atoms of aryl or heteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ring;
R2and R3, independently of each other, represent 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or R2 is hydroxy, amino or substituted amino and R3 has the meanings mentioned above; or, provided that Y is -CH2- R2 represents a group S02-R9 or CO-Z-R9 and Z represents a bond, oxygen or NR10, and R3 has the meanings mentioned above; or R2 and R3 together with the nitrogen they are bound to represent a three, four, 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, optionally substituted aminoalkyl, heterocyclyl, heteroaryl, and lower alkoxy; R4 and R5, independently of each other, represent alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, optionally substituted aminoalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkyl, optionally substituted alkenyl, optionally substituted alkinyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; or, provided that X is nitrogen, R4 and R5 together with the nitrogen X they are bound to represent a four, 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; R6 and R7, independently of each other, represent hydrogen or lower alkyl; or R6 and R7 together with the carbon atom they are bound to form a carbocylic or heterocyclic ring;
R8 represents hydrogen or lower alkyl;
R9 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; R 0 is hydrogen or has the meanings of R9, or R9 and R10 together with the nitrogen they are bound to represent a three, four, 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, optionally substituted aminoalkyl, heterocyclyl, heteroaryl, and lower alkoxy; and salts thereof; with the exception of the compounds of formula (I) wherein V and W represent a bond, X represents nitrogen, Y represents -CO-, and R1 is unsubstituted phenyl.
2. The compound of formula (I) according to claim 1 wherein
V represents a bond or CR6R7;
W represents a bond, NR8 or oxygen; X represents sulfur, or nitrogen substituted by hydrogen or R5;
Y represents -CH2- -CO- or -CS-;
R1 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, aminoearbonyl, 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, optionally substituted aryl, optionally substituted aryl-lower alkyl and lower acyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower acyl, carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, cyano, lower alkylsulfonyl, optionally substituted phenylsulfonyl, halogen, or nitro, and wherein two adjacent substituents together with the atoms of aryl may form a 5 or 6 membered carbocyclic or heterocyclic ring; R2 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; hydroxy, amino or substituted amino; or, provided that Y is -CH2- R2 represents a group S02-R9 or CO-Z-R9 and Z represents a bond, oxygen or NR10;
R3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R2 and R3 together with the nitrogen they are bound to represent a three, four, 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, optionally substituted aminoalkyl, heterocyclyl, heteroaryl, and lower alkoxy;
R4 represents alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, optionally substituted aminoalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkyl, optionally substituted alkenyl, optionally substituted alkinyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R5 represents lower alkyl; or, provided that X is nitrogen, R4 and R5 together with the nitrogen X they are bound to represent a four, 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; R6 and R7, independently of each other, represent hydrogen or lower alkyl; or R6 and R7 together with the carbon atom they are bound to form a carbocylic or heterocyclic ring; R8 represents hydrogen or lower alkyl; R9 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; R10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R9 and R10 together with the nitrogen they are bound to represent a three, four, 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, optionally substituted aminoalkyl, heterocyclyl, heteroaryl, and lower alkoxy; and salts thereof.
3. The compound of formula (I) according to claim 1 wherein
V represents a bond or CR6R7;
W represents a bond, NR8 or oxygen; X represents sulfur, or nitrogen substituted by hydrogen or R5;
Y represents -CH2- -CO- or -CS-;
R1 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, aminoearbonyl, 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, optionally substituted aryl, optionally substituted aryl-lower alkyl and lower acyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower acyl, carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, cyano, lower alkylsulfonyl, optionally substituted phenylsulfonyl, halogen, or nitro, and wherein two adjacent substituents together with the atoms of aryl may form a 5 or 6 membered carbocyclic or heterocyclic ring;
R2 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or, provided that Y is -CH2- R2 represents a group S02-R9 or CO-Z-R9 and Z represents a bond, oxygen or NR10;
R3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R2 and R3 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;
R4 represents alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkinyl, optionally substituted aryl, or optionally substituted arylalkyl;
R5 represents lower alkyl; or, provided that X is nitrogen, R4 and R5 together with the nitrogen X 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 or lower alkoxy; R6 and R7, independently of each other, represent hydrogen or lower alkyl; R8 represents hydrogen or lower alkyl; R9 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; R10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R9 and R10 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.
4. The compound of formula (I) according to claim 1 wherein
V represents a bond or CR6R7;
W represents a bond or NR8;
X represents sulfur, or nitrogen substituted by hydrogen or R5; Y represents -CH2- or -CO-;
R1 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, aminoearbonyl, 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, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower acyl, carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, cyano, or halogen, and wherein two adjacent substituents together with the atoms of aryl may form a 5 or 6 membered heterocyclic ring; R2 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or, provided that Y is -CH2- R2 represents a group S02-R9 or CO-Z-R9 and Z represents a bond, oxygen or NR10;
R3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R2 and R3 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;
R4 represents alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkinyl, optionally substituted aryl, or optionally substituted arylalkyl;
R5 represents lower alkyl; or, provided that X is nitrogen, R4 and R5 together with the nitrogen X 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 or lower alkoxy; one of R6 and R7 is hydrogen and the other one is hydrogen or lower alkyl; R8 represents hydrogen or lower alkyl; R9 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; R10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R9 and R10 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.
5. The compound of formula (I) according to claim 1 wherein V represents a bond or CR6R7; W represents a bond or NR8; X represents sulfur; Y represents -CH2- or -CO-;
R1 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; R2 represents hydrogen, alkyl, optionally substituted arylalkyl, optionally substituted hetero- arylalkyl, 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-lower alkyl, optionally substituted heteroaryl-lower alkyl, and lower acyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the lower alkyl group of amino-lower alkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or, provided that Y is -CH2- R2 represents a group CO-Z-R9 and Z represents a bond, oxygen or NR10;
R3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R2 and R3 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; R4 represents alkyl, alkenyl, alkinyl or optionally substituted aryl-lower alkyl; R6, R7 and R8 represent hydrogen;
R9 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 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-lower alkyl, and optionally substituted heteroaryl-lower alkyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of amino-lower alkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;
R10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R9 and R10 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.
6. The compound of formula (I) according to claim 1 wherein
V represents a bond; W represents NR8; X represents sulfur;
Y represents -CH2- or -CO-; R1 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; R2 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-lower alkyl, optionally substituted heteroaryl-lower alkyl, and lower acyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the lower alkyl group of amino-lower alkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or, provided that Y is -CH2- R2 represents a group CO-Z-R9 and Z represents a bond, oxygen or NR10; R3 represents hydrogen, lower alkyl, or optionally substituted aryl-lower alkyl; or R2 and R3 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; R4 represents alkyl, alkenyl, alkinyl or optionally substituted aryl-lower alkyl; R8 represents hydrogen;
R9 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 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-lower alkyl, and optionally substituted heteroaryl-lower alkyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of amino-lower alkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;
R10 is hydrogen, lower alkyl or optionally substituted aryl-lower alkyl; or R9 and R10 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.
7. The compound of formula (I) according to claim 1 wherein
V and W represent a bond; X represents sulfur; Y represents -CO-; R1 represents 3,4,5- trimethoxyphenyl; R2 represents 2-(4-methylpiperazinyl)-1-phenylethyl; R3 represents hydrogen; R4 represents n-hexyl; and salts thereof.
8. The compound of formula (I) according to claim 1 wherein
V and W represent a bond; X represents sulfur; Y represents -CH2-; R1 represents 3,4,5- trimethoxyphenyl; R2 represents 3-(4-methylpiperazinyl)propyl; R3 represents hydrogen; R4 represents n-hexyl; and salts thereof.
9. The compound of formula (I) according to claim 1 wherein
V and W represent a bond; X represents sulfur; Y represents -CH2-; R1 represents 3,4,5- trimethoxyphenyl; R2 represents 3-(4-methylpiperazinyl)propyl; R3 represents methyl; R4 represents n-hexyl; and salts thereof.
10. The compound of formula (I) according to claim 1 wherein
V represents a bond; W represents NR6; X represents sulfur; Y represents -CH2-; R1 represents 3,4,5-trimethoxyphenyl; R2 represents 3-(4-methylpiperazinyl)propyl; R3 represents hydrogen; R4 represents n-hexyl; R6 represents hydrogen; and salts thereof.
11. The compound of formula (I) according to claim 1 wherein
V represents a bond; W represents NR6; X represents sulfur; Y represents -CH2-; R1 represents 3,4,5-trimethoxyphenyl; R2 represents 2-(4-methylpiperazinyl)-1-phenylethyl; R3 represents hydrogen; R4 represents n-hexyl; R6 represents hydrogen; and salts thereof.
12. The compound of formula (I) according to claim 1 wherein
V represents a bond; W represents NR6; X represents sulfur; Y represents -CH2-; R1 represents 3,5-dimethoxyphenyl; R2 represents 2-(4-methylpiperazinyl)-1-phenylethyl; R3 represents hydrogen; R4 represents n-hexyl; R6 represents hydrogen; and salts thereof.
13. A process for the preparation of a compound of formula (I) according to claim 1 , characterized in that
A) for the synthesis of a compound of the formula (I) wherein the symbols V, W, X, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and Y is -CO-, a substituted pyrimidine carboxylic acid of formula (II)
wherein V, W, X, R1 and R4 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)
wherein R2 and R3 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;
B) for the synthesis of a compound of the formula (I) wherein the symbols V, W, X, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and Y is -CH2- or -CH2CH2-, a substituted pyrimidine carboxaldehyde of formula (IV)
wherein V, W, X, R1 and R4 are as defined for a compound of formula (I) and n is 0 or 1, is reacted with an amine of formula (III)
R2-NH-R3 (III)
wherein R2 and R3 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;
C) for the synthesis of a compound of the formula (I) wherein the symbols V, W, Y, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and X is sulfur, a substituted thiopyrimidone of formula (V)
or a tautomer thereof, wherein V, W, Y, R1, R2 and R3 are as defined for a compound of formula (I), is reacted with an alkylating agent of formula (VI)
R4-LG (VI)
wherein R4 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;
D) for the synthesis of a compound of the formula (I) wherein the symbols V, W, Y, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and X is nitrogen, a substituted pyrimidine of formula (VII)
wherein V, W, Y, R1, R2, and R3 are as defined for a compound of formula (I), X' is -SO- or -S02- and R is an alkyl, aralkyl or aryl group, is reacted with an amine of formula (VIII)
R4-XH (VIII)
wherein X and R4 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;
E) for the synthesis of a compound of the formula (I) wherein the symbols X, Y, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and V and W represent a bond, a substituted alkinone of formula (IX) R1-CO-C=C-Y-NR2R3 (IX)
wherein the symbols Y, R1, R2 and R3 are as defined for a compound of the formula (I), is reacted with a urea derivative of formula (X)
wherein X and R4 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;
F) for the synthesis of a compound of the formula (I) wherein the symbols X, Y, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and V and W represent a bond, a substituted pyrimidine of formula (XI)
wherein X, Y, R2, R3 and R4 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)
R1-B(OH)2 (XII)
wherein R1 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
G) for the synthesis of a compound of the formula (I) wherein the symbols V, X, Y, R1, R2, R3 and R4 are as defined for a compound of the formula (I) and W represents NR7 or oxygen, a substituted pyrimidine of formula (XI)
wherein X, Y, R2, R3 and R4 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)
R1_V-W-H (XIII)
wherein R1, 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;
and, where the above starting compounds of formula (II) to (XIII) may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt- forming group is present and the reaction in salt form is possible; and any protecting groups in a protected derivative of a compound of the formula (I) are removed;
and, if so desired, 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, and/or a mixture of isomeric compounds of formula (I) is separated into the individual isomers.
14. A compound of formula (I)
wherein
V represents a bond or CR6R7;
W represents a bond, NR8 or oxygen;
X represents sulfur, or nitrogen substituted by hydrogen or R5;
Y represents -CH2- -CH2CH2-, -CO- or -CS-; R1 represents aryl or 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-lower 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 heleroaryl-lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, hydroxy, lower alkoxy, halo-lower alkoxy, cycloalkoxy, cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, lower alkylcarbonyloxy, aminocarbonyloxy wherein the nitrogen atom is optionally substituted by one or two substituents selected from alkyl, hydroxyalkyl and aminoalkyl, lower alkoxycarbonyloxy, heterocyclyloxy, heterocyclyl-lower alkoxy, optionally substituted aryloxy, optionally substituted aryl-lower alkoxy, optionally substituted heteroaryloxy, optionally substituted heteroaryl-lower alkoxy; amino, aminoearbonyl, 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, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy- lower alkyl, optionally substituted aryl, optionally substituted aryl-lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl and lower acyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, amino-lower alkoxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, aminoearbonyl wherein the nitrogen atom is optionally substituted by one or two substituents independently selected from alkyl, hydroxyalkyl, alkoxyalkyl and optionally substituted aminoalkyl, or wherein the two substitutens together with the nitrogen atom they are bound to represent a three, four, five or six membered heterocyclic ring, cyano, mercapto, lower alkylmercapto, optionally substituted phenylmercapto, lower alkylsulfinyl, halo-lower alkylsulfinyl, optionally substituted phenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl, optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, or nitro, and wherein two adjacent substituents together with the atoms of aryl or heteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ring; R2and R3, independently of each other, represent 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or R2is hydroxy, amino or substituted amino and R3 has the meanings mentioned above; or, provided that Y is -CH2- R2 represents a group S02-R9 or CO-Z-R9 and Z represents a bond, oxygen or NR10, and R3 has the meanings mentioned above; or R2 and R3 together with the nitrogen they are bound to represent a three, four, 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, optionally substituted aminoalkyl, heterocyclyl, heteroaryl, and lower alkoxy; R4 and R5, independently of each other, represent alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, optionally substituted aminoalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkyl, optionally substituted alkenyl, optionally substituted alkinyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; or, provided that X is nitrogen, R4 and R5 together with the nitrogen X they are bound to represent a four, 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; R6 and R7, independently of each other, represent hydrogen or lower alkyl; or R6 and R7 together with the carbon atom they are bound to form a carbocylic or heterocyclic ring; R8 represents hydrogen or lower alkyl;
R9 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 aryl- lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, heterocyclyl, optionally substituted alkenyl, optionally substituted alkinyl, lower acyl, cycloalkylcarbonyl, optionally substituted arylcarbonyl, lower alkylsulfonyl, and optionally substituted phenylsulfonyl, or the two substituents on nitrogen form together with the nitrogen atom heterocyclyl, and wherein the alkyl group of aminoalkyl can be substituted by one or two substituents selected from hydroxy, lower alkoxy, optionally substituted amino, heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; R10 is hydrogen or has the meanings of R9, or R9 and R10 together with the nitrogen they are bound to represent a three, four, 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, optionally substituted aminoalkyl, heterocyclyl, heteroaryl, and lower alkoxy; and salts thereof; for use as a medicament.
15. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 14 or a pharmaceutically acceptable salt of such a compound and a pharmaceutically acceptable carrier.
16. Use of a compound of formula (I) as defined in claim 14 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.
17. A method of treating a neoplastic disease, autoimmune disease, transplantation related pathology and/or degenerative disease comprising administering an effective amount of a compound of formula (I) according to claim 14 to a patient in need thereof. Application No
INTERNATIONAL SEARCH REPORT
PCT/EP2004/003296
A. CLASSIFICATION OF SUBJECT MATTER
IPC 7 C07D239/40 C07D239/42 C07D403/12 C07D401/06 C07D405/04 C07D401/04 A61K31/505 A61P35/00 A61P37/00
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
IPC 7 C07D
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
EPO-Internal , CHEM ABS Data
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category " Citation of document, with indication, where appropriate of the relevant passages Relevant to claim No
WO 02/48148 A (GLAXO GROUP LTD 1-15 ;CHAMBERLAIN STANLEY D (US); HARRIS PHILIP ANTHONY) 20 June 2002 (2002-06-20) exampl es 50 , 51 ,74 , 75
US 2002/019404 Al (SHUD0NG WANG AND PETER 1-17 M. FISCHER) 14 February 2002 (2002-02-14) col umn 1 - col umn 2 ; cl ai m 1 ; fi gure 1
US 2003/004161 Al (VERTEX PHARMACEUTICALS 1-17 INCORPORATED) 2 January 2003 (2003-01-02) tabl e 5 : Compounds I I Ia-49 to I I Ia-51 , IIIa-55, IIIa-58 and IIIa-62 col umn 1 - col umn 2 ; cl aim 1
-/--
Θ Further documents are listed in the continuation of box C _Ώ Patent family members are listed in annex
° Special categories of cited doc ments
"T" later document published after the international filing date or pπority date and not in conflict with the application but
"A" document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention
'E' earlier document but published on or after the international "X" document of particular relevance, the claimed invention filing date cannot be considered novel or cannot be considered to
"L" document which may throw doubts on pnoπty claimfs) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another "Y1 document of particular relevance, the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the
'O' document referring to an oral disclosure, use exhibition or document is combined with one or more other such docuother means ments, such combination being obvious to a person skilled
■P" document published prior to the international filing dale but in the art later than the pπority date claimed ■&' document member of the same patent family
Date of the actual completion of the international search Date of mailing of the international search report
14 June 2004 23/06/2004
Name and mailing address of the ISA Authorized officer
European Patent Office, P B 5818 Patentlaan 2 NL - 2280 HV Ri|SWI|k
Tel (+31-70) 3 0-2040, Tx 31 651 epo nl, Fax (+31-70) 340-3016 Schuemacher , A
EP04723991A 2003-04-01 2004-03-29 2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases Withdrawn EP1644338A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP04723991A EP1644338A1 (en) 2003-04-01 2004-03-29 2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP03405219 2003-04-01
EP03405642 2003-09-03
PCT/EP2004/003296 WO2004087679A1 (en) 2003-04-01 2004-03-29 2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases
EP04723991A EP1644338A1 (en) 2003-04-01 2004-03-29 2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases

Publications (1)

Publication Number Publication Date
EP1644338A1 true EP1644338A1 (en) 2006-04-12

Family

ID=33133024

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04723991A Withdrawn EP1644338A1 (en) 2003-04-01 2004-03-29 2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases

Country Status (2)

Country Link
EP (1) EP1644338A1 (en)
WO (1) WO2004087679A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115093400A (en) * 2021-09-18 2022-09-23 重庆华森制药股份有限公司 AhR inhibitor and application and preparation method thereof

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL1789044T3 (en) 2004-09-06 2011-04-29 Basilea Pharmaceutica Ag Phenylaminopyridines and phenylaminopyrazines
US7589088B2 (en) * 2004-12-29 2009-09-15 Bristol-Myers Squibb Company Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US20060178388A1 (en) 2005-02-04 2006-08-10 Wrobleski Stephen T Phenyl-substituted pyrimidine compounds useful as kinase inhibitors
WO2006127588A2 (en) * 2005-05-24 2006-11-30 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
JP5342450B2 (en) 2006-12-15 2013-11-13 ブリストル−マイヤーズ スクイブ カンパニー Arylpropionamide, arylacrylamide, arylpropinamide, or arylmethylurea analogs as factor XIa inhibitors
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
CN101965336B (en) 2008-01-04 2015-06-17 英特利凯恩有限责任公司 Certain chemical entities, compositions and methods
DK2663309T3 (en) 2011-01-10 2017-06-19 Infinity Pharmaceuticals Inc METHODS FOR PRODUCING ISOQUINOLINONES AND SOLID FORMS OF ISOQUINOLINONES
PL2753606T3 (en) 2011-09-02 2018-02-28 Purdue Pharma L.P. Pyrimidines as sodium channel blockers
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
WO2015160975A2 (en) 2014-04-16 2015-10-22 Infinity Pharmaceuticals, Inc. Combination therapies
JP7054681B2 (en) 2016-06-24 2022-04-14 インフィニティー ファーマシューティカルズ， インコーポレイテッド Combination therapy
WO2018014802A1 (en) 2016-07-18 2018-01-25 National Institute Of Biological Sciences, Beijing Apoptosis inhibitors

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2001242629B2 (en) * 2000-03-29 2005-08-11 Cyclacel Limited 2-substituted 4-heteroaryl-pyrimidines and their use in the treatment of proliferative disorders
WO2001085700A2 (en) * 2000-05-08 2001-11-15 Janssen Pharmaceutica N.V. Hiv replication inhibiting pyrimidines and triazines
ATE300541T1 (en) * 2000-12-15 2005-08-15 Glaxo Group Ltd PYRAZOLOPYRIDINE DERIVATIVES
ES2265450T3 (en) * 2000-12-21 2007-02-16 Vertex Pharmaceuticals Incorporated PIRAZOL COMPOUNDS USED AS INHIBITORS OF PROTEIN QUINASA.
EP1401833A2 (en) * 2001-05-28 2004-03-31 Aventis Pharma S.A. Chemical derivatives and the use thereof as an anti-elomerase agent
CA2450934A1 (en) * 2001-06-19 2002-12-27 Marco Dodier Pyrimidine inhibitors of phosphodiesterase (pde) 7
WO2003078423A1 (en) * 2002-03-15 2003-09-25 Vertex Pharmaceuticals, Inc. Compositions useful as inhibitors of protein kinases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004087679A1 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115093400A (en) * 2021-09-18 2022-09-23 重庆华森制药股份有限公司 AhR inhibitor and application and preparation method thereof
CN115093400B (en) * 2021-09-18 2023-09-05 北京华森英诺生物科技有限公司 AhR inhibitor, application and preparation method thereof

Also Published As

Publication number Publication date
WO2004087679A1 (en) 2004-10-14

Similar Documents

Publication Publication Date Title
US7423157B2 (en) Substituted benzimidazoles and their use for inducing apoptosis
JP6759514B2 (en) Compounds active against bromodomain
US8486996B2 (en) Aroylfuranes and aroylthiophenes
RU2415853C2 (en) Benzimidazoles used as protein kinase inhibitors
AU2003295396A1 (en) Heteroaryl-pyramidine derivatives as jak inhibitors
BRPI0720635A2 (en) ORGANIC COMPOUNDS AND THEIR USES
US7385061B2 (en) Furazanobenzimidazoles
US7612064B2 (en) Sulfopyrroles
WO2004087679A1 (en) 2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases
CA2578047C (en) Phenylaminopyridines
JP2007505888A (en) Substituted triazole derivatives as oxytocin antagonists
EP1655284A1 (en) 2-Phenylsulfopyrroles
EP1433789A1 (en) Pyrrolopyrazines and their use as selective apoptosis inducers

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060112

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20051103

D17P Request for examination filed (deleted)