WO2009018844A1 - Dérivés de thiazole-pipéridine utilisés dans le traitement des maladies hyper-prolifératives - Google Patents

Dérivés de thiazole-pipéridine utilisés dans le traitement des maladies hyper-prolifératives Download PDF

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WO2009018844A1
WO2009018844A1 PCT/EP2007/007057 EP2007007057W WO2009018844A1 WO 2009018844 A1 WO2009018844 A1 WO 2009018844A1 EP 2007007057 W EP2007007057 W EP 2007007057W WO 2009018844 A1 WO2009018844 A1 WO 2009018844A1
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formula
compound
optionally substituted
lower alkyl
alkyl
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PCT/EP2007/007057
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Marcus Otte
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Oridis Biomed Forschungs- Und Entwicklungs Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to thiazole-piperidine derivates that are useful in treating of hyperproliferative diseases, e.g. cancer, preferably liver cancers such as hepatocarcinoma in mammals, especially humans.
  • the invention also relates to the pharmaceutical compositions comprising these compounds and their use for the treatment of hyperproliferative diseases.
  • thiazole- piperidine compounds namely piperidinyl-thiazole carboxylic acid derivatives and their use in treating vascular endothelial factor (VEGF)- mediated disorders (in particular endometrosis and acute macular degenerative disorder), and piperidinyl-thiazole carboxamide derivatives and their use in altering vascular tone including myometrial and endometrial vascular tone, respectively.
  • VEGF vascular endothelial factor
  • mediated disorders in particular endometrosis and acute macular degenerative disorder
  • piperidinyl-thiazole carboxamide derivatives and their use in altering vascular tone including myometrial and endometrial vascular tone, respectively.
  • liver cancer is relatively uncommon in the industrialized western world, it is among the leading causes of cancer worldwide. In contrast to many other types of cancer, the number of people who develop and die from liver cancer is increasing. On a global basis, primary liver cancer such as hepatocarcinoma (HCC) belongs to the most common malignant tumors accounting for about 1 million deaths/year (Bruix, J. et al., 2004, Cancer Cell (5): 215-219). The principal risk factors for liver cancer are viruses, alcohol consumption, food contamination with aflatoxin molds and metabolic disorders.
  • HCC hepatocarcinoma
  • Chronic hepatitis B and C virus infections are the major causes of HCC but damage from alcohol and chronic liver metabolic disorders are also recognized to result in HCC, and the mechanisms responsible for development of a tumor from these different etiologies are likely to differ.
  • the rates of alcoholism and chronic hepatitis B and C continue to increase. The outlook therefore is for a steady increase in liver cancer rates, underscoring the need for new therapies in this area.
  • liver disease varies from mild and reversible fatty liver to progressive chronic liver disease, which results in the development of the life threatening conditions of liver cirrhosis, liver failure and liver cancer.
  • Hepatitis B virus (HBV) infection is a global public health issue. It is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide (Conjeevaram H. S. et al., 2003, Journal of Hepatology, 38: 90-103).
  • Hepatitis C virus (HCV) a major cause of liver-related morbidity and mortality worldwide, represents one of the main public health problems (Alberti A. and Benvegnu L., Journal of Hepatology 2003, 38: 104-118).
  • the HCV infection frequently causes chronic hepatitis, which is linked to the development of liver cirrhosis and HCC (Cyong J.C. et al., 2002, Am J Chin Med, 28: 351-360).
  • Alcoholic liver disease is the commonest cause of cirrhosis in the Western world, currently one of the ten most common causes of death. In the United States, ALD affects at least 2 million people, or approximately 1% of the population. The true incidence of ALD, especially in its milder forms, may be substantially greater because many patients are asymptomatic and may never seek medical attention.
  • the spectrum of ALD ranges from fatty liver (steatosis), present in most, if not all heavy drinkers, through steatohepatitis, cholestasis (characterised by blocked bile excretion from the liver), fibrosis and ultimately cirrhosis (Stewart S. F. and Day CP, 2003, Journal of Hepatology, 38: 2- 13). Although fatty liver is reversible with abstention, it is a risk factor for progression to fibrosis and cirrhosis in patients who continue drinking, particularly when steatohepatitis is present.
  • Non-alcoholic fatty liver disease refers to a wide spectrum of liver damage, ranging from simple steatosis to steatohepatitis, cholestasis, advanced fibrosis and cirrhosis.
  • Steatohepatitis represents only a stage within the spectrum of NAFLD (Anguilo P., 2002, New Engl. J. Med., 346: 1221-1231).
  • the pathological picture resembles that of alcohol-induced liver injury, but it occurs in patients who do not abuse alcohol.
  • NAFLD should be differentiated from steatosis, with or without hepatitis, resulting from secondary causes, because these conditions have distinctly different pathogens and outcomes.
  • fatty liver disease steatosis
  • nutritional e.g. protein-calorie malnutrition, starvation, total parenteral nutrition, rapid weight loss, gastrointestinal surgery for obesity
  • drugs e.g. glucocorticoids, synthetic estrogens, aspirin, calcium-channel blockers, tetracycline, valproic acid, cocaine, antiviral agents, fialuridine, interferon ⁇ , methotrexate, zidovudine
  • metabolic or genetic e.g.
  • ASH and NASH alcoholic steatohepatitis and nonalcoholic steatohepatitis
  • HCC liver cancer
  • the invention relates to novel compounds of formula (1), wherein
  • R 1 represents optionally substituted amino, optionally substituted phenyl wherein phenyl substituents are lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, methylenedioxy, 1 ,2- ethylene-dioxy, amino, alkylamino, acetylamino, dialkylamino, di(cyanoalkyl)amino, di(alkoxyalkyl)amino, halo-lower alkyl, lower alkoxy-lower alkyl, phenylthio-lower alkyl, phenylsulfoxy-lower alkyl, phenylsulfonyl-lower alkyl, or halo, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted phenyl- or heteroaryl- alkyl, optionally substituted phenylaminocarbonyl-alkoxyalkyl or a residue of formula (2), wherein R 3 is hydrogen or al
  • R 2 represents optionally substituted phenyl or optionally substituted pyrrolyl, thienyl, furyl, pyrazolyl, triazolyl, oxazolyl, 5-isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and benzo fused derivatives of such monocyclic heteroaryl groups, and salts thereof.
  • the invention further relates to pharmaceutical preparations comprising these compounds and to the use of the compounds for treating hyperproliferative diseases, in particular liver cancer.
  • the invention relates to novel compounds of formula (1),
  • R 1 represents optionally substituted amino, optionally substituted phenyl wherein phenyl substituents are lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, methylenedioxy, 1 ,2- ethylene-dioxy, amino, alkylamino, acetylamino, dialkylamino, di(cyanoalkyl)amino, di(alkoxyalkyl)amino, halo-lower alkyl, lower alkoxy-lower alkyl, phenylthio-lower alkyl, phenylsulfoxy-lower alkyl, phenylsulfonyl-lower alkyl, or halo, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted phenyl- or heteroaryl- alkyl, optionally substituted phenylaminocarbonyl-alkoxyalkyl or a residue of formula (2), wherein R 3 is hydrogen or
  • R 2 represents optionally substituted phenyl or optionally substituted pyrrolyl, thienyl, furyl, pyrazolyl, triazolyl, oxazolyl, 5-isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and benzo fused derivatives of such monocyclic heteroaryl groups, and salts thereof.
  • 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 (1).
  • Alkyl has from 1 to 12, preferably from 1 to 10 carbon atoms, and is linear or branched.
  • Alkyl is preferably lower alkyl, for example, d-Cy-alkyl, preferably Ci-C 4 -alkyl.
  • Lower alkyl has 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, and is e.g. n-hexyl, n-pentyl, butyl, such as n-butyl, sec-butyl, isobutyl or tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. Most preferably lower alkyl is methyl or ethyl.
  • substituents are preferably lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, methylenedioxy, 1 ,2-ethylene-dioxy, amino, alkylamino, acetylamino, dialkylamino, di(cyanoalkyl)amino, di(alkoxyalkyl)amino, halo-lower alkyl, lower alkoxy-lower alkyl, phenylthio-lower alkyl, phenylsulfoxy-lower alkyl, phenylsulfonyl- lower alkyl, or halo.
  • substituents may be those mentioned above for R 1 , and also nitro. Phenyl may be substituted by up to three of the mentioned substituents, for example as in trimethoxyphenyl. Substituents may be in ortho-, meta- or para position.
  • 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 R 1 examples include pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and benzo fused derivatives of such monocyclic heteroaryl groups, such as indolyl, benzimidazolyl, benzopyrazolyl or benzofuryl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl or purinyl, preferably thienyl, pyrazolyl, imidazolyl, isoxazolyl, pyridyl, pyrazinyl, benzimidazolyl or benzopyrazolyl.
  • heteroaryl R 2 examples include pyrrolyl, thienyl, furyl, pyrazolyl, triazolyl, oxazolyl, 5- isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and benzo fused derivatives of such monocyclic heteroaryl groups, such as indolyl, benzimidazolyl, benzopyrazolyl or benzofuryl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl or purinyl, preferably thienyl, pyrazolyl, 5-isoxazolyl, pyridyl, pyrazinyl, benzimidazolyl or benzopyrazolyl.
  • substituents are preferably lower alkyl, halo-lower alky], lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, halo-lower alkoxy, amino optionally substituted by one or two substituents lower alkyl and one substituent lower alkylcarbonyl, halo, or nitro, or another heteroaryl group of those mentioned hereinbefore, e.g. pyridyl, pyrimidinyl or pyrazinyl.
  • Alkenyl contains one or more, e.g. two or three, double bonds, and is preferably lower alkenyl, such as Ci-C 4 -alkenyl, e.g. 1- or 2-butenyl, 1-propenyl, allyl or vinyl.
  • Alkinyl is preferably lower alkinyl, such as Ci-C 4 -alkinyl, e.g. 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.
  • Heterocyclyl designates preferably a saturated, partially saturated or unsaturated, mono- or bicyclic ring containing 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, a ring carbon atom may be substituted by lower alkyl, amino-lower alkyl, phenyl, phenyl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower alkoxy, hydroxy or oxo, or two ring carbons may be annulated by a benzo group.
  • 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 C 1 -C 4 -alkylcarbonyl, in particular propionyl or acetyl.
  • Hydroxyalkyl is especially hydroxy-lower alkyl, preferably hydroxy-CVCXralkyl, e.g. hydroxy methyl, 2-hydroxyethyl or 2-hydroxy-2-propyl.
  • Haloalkyl is especially halo-lower alkyl, preferably halo-C r C 4 -alkyl, e.g. fluoroalkyl, especially trifluoromethyl, pentafluoroethyl or 3,3,3-trifluoroethyl.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Lower alkoxy is especially Ci-C 4 -alkoxy, e.g. methoxy, ethoxy, isopropyloxy, or tert- butyloxy.
  • Phenylalkyl includes phenyl and alkyl as defined hereinbefore, and is e.g. benzyl, 1- phenethyl or 2-phenethyl.
  • Heteroarylalkyl includes heteroaryl and alkyl as defined hereinbefore, and is e.g. 2-pyridyl- methyl, 3-pyridyl-methyl, 4-pyridyl-methyl, 1- or 2-pyrrolyl-methyl, 1-imidazolyl-methyl, 2-(1-imidazolyl)-ethyl or 3-(1-imidazolyl)-propyl.
  • substituted amino the substituents are preferably lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, optionally substituted phenyl, optionally substituted phenyl-lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, lower alkylcarbonyl, lower alkylcarbonyl-lower alkyl, cyano-lower alkyl, or the two substituents on nitrogen form together with the nitrogen heteroaryl or heterocyclyl.
  • substituted amino is C 1 - C 4 -alkylamino, di-C 1 -C 4 -alkylamino, or d-C ⁇ alkoxycarbonyl-CrCy-alkylamino.
  • optionally substituted phenylaminocarbonyl-alkoxyalkyl the substituent are those mentioned above under optionally substituted phenyl, in particular lower alkyl and halo.
  • optionally substituted phenylaminocarbonyl-alkoxyalkyl is halo- and C 1 -C 4 -alkyl substituted phenylaminocarbonyl-Ci-C 4 -alkoxy-C 1 -C 4 -alkyl.
  • Salts are especially the pharmaceutically acceptable salts of compounds of formula (1).
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula (1) 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, adamantine- carboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenyl- acetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxy- ethanesulfonic acid, ethane-1
  • 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 (1) 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 (1).
  • pro-drugs include in vivo hydrolysable esters of a compound of the formula (1).
  • the compounds of formula (1) have valuable pharmacological properties.
  • the invention also relates to compounds of formula (1) as defined hereinbefore for use as medicaments.
  • the efficacy of the compounds of the invention in inhibition of proliferation of tumor cell lines can be demonstrated as follows: To determine the inhibition of cell proliferation a luminescent cell viability assay (CellTiter-Glo ® ; Promega, Madison, USA) is implemented. The assay is based on the relation that the ATP content is directly proportional to the number of cells present in the culture.
  • the CellTiter-Glo ® assay is performed to measure the proliferation rate of human hepatoma (HuH7, PLC/PRF/5, Hep3B, SK-Hep1), human hepatoblastoma (HepG2), human colon carcinoma (CX-2), human breast cancer (SK-Br- 3), human ovarian carcinoma (HeLa) and human pancreatic carcinoma (DAN-G) cell lines (see Example 2).
  • a compound of formula (1) according to the invention shows therapeutic efficacy especially against cancer, preferably in liver and pancreas.
  • E-3- ⁇ 4-[4-(3,4-ethylendioxphenyl)-thiazol-2-yl]-piperidin-1-yl ⁇ -1- (3,4-methylendioxyphenyl)-3-oxo-prop-1-ene (compound no. I in Table 1 / Example 2) blocks the proliferation of HuH7 with an EC50 of 0.33 ⁇ M. Further, HepG2 and Hep3B are inhibited with an EC50 of 0.9 and 0.3 ⁇ M, respectively. Compounds of the formula (1) show inhibition of cell proliferation of other tumor cell lines (Table 2 in Example 2), thus suggesting to be useful for treatment of hyperpoliferative diseases, such as cancers.
  • ectopic and orthotopic transplantation of human tumor cells in immune deficient mice like BALB/c nude or SCID mice
  • Tumor type specificity is generated by the selection of cell lines for transplantation.
  • subcutaneously transplantation of human tumor cell lines is a general model to assess the in vivo activity of potential anti-proliferative drug candidates.
  • orthotopic transplantation models offer the ability to analyse the tumor in its typical micro environment (Armengol C. et al., Clin. Can. Res. 2004, 10: 2150- 2157).
  • tumor formation can be supported by inoculation of a tumor cells suspension in extracellular matrix proteins like for example matrigel (10 mg/ml; BD biosciences). Typically tumor formation could be observed after two to four weeks, dependent on the type of tumor cells and support medium used.
  • Treatment start could be either (1) a few days (typically 2-5) after tumor cell inoculation or (2) after a certain tumor size (250 to 450 mm 3 ) has been reached.
  • the time point of treatment start allows distinguishing between inhibition of tumor formation (1) and reduction of tumor mass (2).
  • Statistical analysis comparing tumor growth curves, tumor mass and tumor volume of serum versus placebo treated groups are finally performed.
  • Transplantation of human liver tumor cells into the mouse liver of immune deficient mice or mouse liver tumor cells in immune competent male mouse strains allow not only to compare tumor growth characteristics in treated and non-treated animals but also to compare survival time.
  • DEN N- nitroso-diethylamine
  • Male C3H/He mice are intoxicated with a single dose of DEN at age six to eight weeks (Example 3). Feeding of phenobarbital starts one week after DEN intoxication and is continued for forty weeks.
  • the liver is typically enlarged around five to six times when compared to non-treated mice.
  • DEN induced mice are subsequently randomized for the treatment with OrBi7239 (40 mg/kg), OrBi7253 (40 mg/kg) and vehicle control. Treatment is performed daily for four days. At day five animals received i.p. BrdU (100 mg/kg). Animals are sacrificed 3 h after BrdU injection. Liver, colon and femur are fixed and paraffin embedded, and sections prepared and labelled with BrdU-specific antibody (abeam, ab2844, dilution 1 : 100) by following a standard protocol known in the art (e.g.
  • the compounds of the invention are active in regard of hyperproliferative, inflammatory, autoimmune and metabolic diseases of liver, pancreas and of any other organ such as breast, colon, lung, prostate, ovary, and kidney.
  • hypoproliferative diseases includes neoplastic diseases, preferably against malignancies, e.g. epithelial neoplasms (cancer).
  • epithelial cancer within the meaning of the invention includes carcinomas of any organ, preferably of the liver (such as hepatocarcinoma), pancreas (e.g. adenocarcinoma of the pancreas), lung, stomach, colon, prostate, kidney, skin and breast, and refers to disorders of these organs in which epithelial cell components of the tissue are transformed resulting in a malignant tumor identified according to the standard diagnostic procedures as generally known to a person skilled in the art.
  • hypopoliferative disease includes squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, 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, melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial
  • Hyperproliferative disease also refers to benign hyperproliferative diseases such as epithelial tumors e.g. adenoma (in particular focal nodular hyperplasia), pancreatic islet cell adenoma, pancreatic adenoma and pancreatic oedema, and other tumors derived from mesenchymal tissue, such as fibroma, lipoma, and naevi.
  • epithelial tumors e.g. adenoma (in particular focal nodular hyperplasia), pancreatic islet cell adenoma, pancreatic adenoma and pancreatic oedema, and other tumors derived from mesenchymal tissue, such as fibroma, lipoma, and naevi.
  • inflammatory diseases represents diseases of various organs caused by viruses, bacteria, fungi, mycoplasms or other microorganisms, in particular inflammatory diseases of liver, such as viral and non-viral hepatitis (e.g. hepatitis B and hepatitis C), and of pancreas, such as chronic or acute pancreatitis.
  • the inflammatory diseases refer to inflammation caused by physiological byproducts of metabolism, such as cholangitis caused by bile acids, or arthritis.
  • autoimmune diseases refers to e.g. systemic, discoid or subacute cutaneous lupus erythematosus, rheumatoid arthritis, antiphospholipid 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, pemphi
  • autoimmune diseases refers to e.g. systemic,
  • Metabolic diseases includes conditions in which there is a deviation from a metabolic process or which is caused by an abnormal metabolic process. Metabolic disease can be congenital due to inherited enzyme abnormality or acquired due to disease of an endocrine organ or failure of a metabolically important organ, preferably of the liver (such as liver cirrhosis).
  • liver disease refers to and comprises all kinds of diseases that preferably affect the anatomy, physiology, metabolic, and/or genetic activities of the liver, that preferably affect the generation of new liver cells, and/or the regeneration of the liver, as a whole or parts thereof, preferably transiently, temporarily, chronically or permanently in a pathological way.
  • liver diseases preferably also included are inherited liver diseases and neoplastic liver diseases.
  • liver cancer in particular hepatocellular carcinoma (HCC), benign liver neoplasms such as adenoma and/or FNH.
  • HCC further comprises subtypes of the mentioned disorders, including liver cancers characterized by intracellular proteinaceous inclusion bodies, HCCs characterized by hepatocyte steatosis, and fibrolamellar HCC.
  • precancerous lesions are preferably also included such as those characterized by increased hepatocyte cell size (the "large cell” change), and those characterized by decreased hepatocyte cell size (the “small cell” change) as well as macro regenerative (hyperplastic) nodules (Anthony, P. in MacSween et al., eds. Pathology of the Liver. 2001 , Churchill Livingstone, Edinburgh).
  • Liver disease is further understood to preferably comprise liver diseases caused by trauma, intoxication, in particular by alcohol, drugs or food intoxication, radiation, infection, cholestasis, immune reactions, insulin resistance, diabetes and by inherited metabolic liver diseases.
  • liver diseases include cirrhosis, alcoholic liver disease, chronic hepatitis, Wilson's Disease, and heamochromatosis.
  • autoimmune diseases of liver Preferably further included are autoimmune diseases of liver.
  • the compounds of the invention are also active in pancreas diseases.
  • Pantenos diseases include all kinds of diseases that preferably affect the anatomy, physiology, metabolic, and/or genetic activities of the pancreas, preferably tumors (such as adenocarcinoma of pancreas), inflammatory diseases of pancreas (e.g. acute pancreatitis and abscess), or adverse reactions in context of pancreatic transplantations, such as graft pancreatitis and pancreatic trombosis (Rosai and Ackerman ' s Surgical PathologyPathology, 9 th edition, Volume one, Mosby, Chapter 15, pg. 1061-1115).
  • tumors such as adenocarcinoma of pancreas
  • inflammatory diseases of pancreas e.g. acute pancreatitis and abscess
  • adverse reactions in context of pancreatic transplantations such as graft pancreatitis and pancreatic trombosis (Rosai and Ackerman ' s Surgical PathologyPathology,
  • Preferred embodiment for the use of compounds of formula (1 ) is the treatment of hyperproliferative disorders of the liver such as liver cancer (in particular HCC), focal nodular hyperplasis (FNH), viral and non-viral hepatitis and liver cirrhosis.
  • liver cancer in particular HCC
  • FNH focal nodular hyperplasis
  • viral and non-viral hepatitis and liver cirrhosis are examples of hyperproliferative disorders of the liver.
  • Another preferred embodiment is the treatment of hyperproliferative disorders of the pancreas like pancreas carcinoma, pancreatic islet cell adenoma, pancreatic adenoma and pancreatic oedema by using the compounds according to the invention.
  • Another preferred embodiment is the treatment of other hyperproliferative, malignant transformation typically characterized by increasing genomic alterations during disease progression like gene translocation, gene amplification, loss of heterozygocity and telomere shortening as for example carcinomas of liver, pancreas, colon, lung, breast, prostate and other organs such as ovary, uterus, kidney.
  • leukemias such as acute leukemia, acute panmyeolosis, myeloid sarcoma, myelodysplastic syndromes, chronic myeloid leukemia, polycythemia vera, chronic lymphocytic leukemia, prolymphocyte leukemia, hairy cell leukemia, plasma cell leukaemia; lymphomas (e.g.
  • B-cell lymphoma T-cell lymphoma, Hodgkin ' s lymphoma, lymphoplasmacytic lymphoma
  • myeolomas such as plasma cell myeloma and osteosclerotic myeloma
  • sarcomas including osteosarcoma, chodrosarcoma, giant cell tumors, fibrosarcoma, liposarcoma, angiosarcoma, lymphangiosarcoma, leiomyosarcoma, rhabdomyosarcoma, celar celll sarcoma, epitheloid sarcoma, Ewing ' s sarcoma
  • melanomas such as plasma cell myeloma and osteosclerotic myeloma
  • sarcomas including osteosarcoma, chodrosarcoma, giant cell tumors, fibrosarcoma, liposarcoma, angiosarcoma, lymphangio
  • a further preferred embodiment is the treatment of benign and semi-malignant hyperproliferative diseases like psoriasis and basalioma by compounds according to the invention.
  • Compounds of formula (1) are particularly valuable in treating hyperproliferative diseases.
  • compounds of formula (1) are more particularly valuable in treating liver cancers.
  • the invention further comprises the use of compounds of formula (1) for the preparation of a medicament for treating hyperproliferative diseases, in particular those that are listed hereinbefore.
  • a compound of formula (1) 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 (1) 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 (1) in combination with chemotherapy.
  • 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.
  • the invention refers to compounds of formula (1) wherein R 1 is optionally substituted amino, for example amino substituted by lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy- lower alkyl, optionally substituted phenyl, optionally substituted phenyl-lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkyl, cyano-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heteroaryl or heterocyclyl.
  • R 1 is optionally substituted amino, for example amino substituted by lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy- lower al
  • the invention refers to compounds of formula (1) wherein R 1 is C 1 - C 4 -alkylamino, di-d ⁇ -alkylamino or Ci-C 4 -alkoxycarbonyl-C 1 -C 7 -alkylamino, in particular C 1 -C 4 -alkoxycarbonyl-C 1 -C 7 -alkylamino.
  • the invention refers to compounds of formula (1) wherein R 1 is optionally substituted phenyl wherein phenyl substituents are lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, methylenedioxy, 1 ,2-ethylene-dioxy, amino, alkylamino, acetylamino, dialkylamino, di(cyanoalkyl)amino, di(alkoxyalkyl)amino, halo-lower alkyl, lower alkoxy-lower alkyl, phenylthio-lower alkyl, phenylsulfoxy-lower alkyl, phenylsulfonyl- lower alkyl, or halo, in particular phenyl with up to three of the mentioned substituents, for example as in trimethoxyphenyl.
  • Substituents may be in ortho-, meta- or para position. Also preferred is methylenedioxyphenyl, 1 ,2-ethylene-dioxyphenyl, bromophenyl, fluorophenyl, di-CrC ⁇ alkylaminophenyl, dKcyano-CrC ⁇ alkyOamino and phenylsulfoxy- C 1 -C 4 -alkyl, in particular di(cyano-C 1 -C 4 -alkyl)amino and phenylsulfoxy-CrC 4 -alkyl.
  • the invention refers to compounds of formula (1) wherein R 1 is optionally substituted heteroaryl, for example pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzopyrazolyl, benzofuryl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl or purinyl, preferably thienyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, benzimidazolyl or benzopyrazolyl,
  • pyridyl pyrimidinyl or pyrazinyl.
  • R 1 is optionally substituted pyridyl, thiazolyl or benzopyrazolyl, in particular fluoro-CrCi-alkoxy-pyridyl, such as 2- (2,2,2-trifluoroethoxy)-3-pyridyl, pyrazinyl-thiazolyl, such as 2-pyrazinyl-4-thiazolyl, or 3- benzopyrazolyl.
  • the invention refers to compounds of formula (1) wherein R 1 is heterocyclyl, in particular pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolanyl and tetrahydropyranyl, optionally substituted at a ring nitrogen atom by a group selected from lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl and acyl, at a ring carbon atom by lower alkyl, amino-lower alkyl, phenyl, phenyl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower alkoxy, hydroxy or oxo, or on two ring carbons by a benzo group.
  • R 1 is heterocyclyl, in particular pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl,
  • R 1 is optionally substituted pyrrolidinyl or dioxolanyl, in particular oxo-N-(heteraryl-alkyl)-pyrrolidinyl, such as 2-oxo-N- (2-thienylmethyl)-4-pyrrolidinyl, or benzo-1 ,4-dioxolanyl.
  • the invention refers to compounds of formula (1) wherein R 1 is optionally substituted phenylalkyl or optionally substituted heteroarylalkyl, in particular phenyl-d-d-alkyl with a halo substituent on phenyl and an amino substituent on alkyl, preferably fluorophenyl-acetylamino-d-Gralkyl, such as 2-(2-fluorophenyl)-1-
  • the invention refers to compounds of formula (1) wherein R 1 is optionally substituted phenylaminocarbonyl-alkoxyalkyl, in particular wherein the substituents are lower alkyl and halo, preferably halo- and d-C 4 -alkyl substituted phenylaminocarbonyl-CrC ⁇ alkoxy-Ci-C ⁇ alkyl, such as 4-chloro-2-methylphenylamino- carbonylmethoxymethyl.
  • the invention refers to compounds of formula (1) wherein R 1 is a residue of formula (2),
  • R 3 is hydrogen or alkyl and R 4 is optionally substituted phenyl, optionally substituted heteroaryl, carboxy, alkoxycarbonyl, optionally substituted aminocarbonyl or cyano.
  • R 1 is a residue of formula (2) and R 3 is hydrogen or C r C 4 -alkyl and R 4 is optionally substituted phenyl, optionally substituted pyrazolyl, or Ci-C 4 -alkoxycarbonyl.
  • R 1 is a residue of formula (2) and R 3 is hydrogen or methyl and R 4 is trimethoxyphenyl, methylenedioxyphenyl, pyrazolyl substituted by methyl and halo, or d-C 4 -alkoxycarbonyl.
  • R 2 represents optionally substituted phenyl, in particular phenyl substituted by halo, nitro, dialkylamino and/or ethylenedioxy, in particular 4-chloro- 3-nitrophenyl, 3-bromophenyl, 4-diethylaminophenyl or 3,4-ethylenedioxyphenyl.
  • R 2 represents optionally substituted 5-isoxazolyl, such as alkoxycarbonyl-5-isoxazolyl, e.g. 3-ethoxycarbonyl-5-isoxazolyl.
  • R 1 and R 2 have one of the preferred meanings listed above, and most preferred are the compounds of the Example 2 (Table 1), especially the compound of formula (1) wherein R 1 is a residue of formula (2), R 2 is 3,4-ethylenedioxyphenyl, R 3 is hydrogen and R 4 is 3,4-methylenedioxyphenyl; the compound of formula (1) wherein R 1 is a residue of formula (2), R 2 is 4-chloro-3- nitrophenyl, R 3 is hydrogen and R 4 is ethoxycarbonyl; the compound of formula (1) wherein R 1 is 3-(1 H-benzimidazol-2-yl)-propyl and R 2 is 3-bromo-phenyl; and the compound of formula (1) wherein R 1 is 2-(2-fluorophenyl)-1-(acetylamino)-ethyl and R 2 is 3-ethoxycarbonyl-isoxazol-5-yl (compounds No. I, XVII, X and III in Example 1
  • the most preferred embodiment is the compound of formula (1) wherein R 1 is a residue of formula (2), R 2 is 3,4-ethylenedioxyphenyl bound to the carbon atom of the thiazole ring adjacent to nitrogen, R 3 is hydrogen and R 4 is 3,4- methylenedioxyphenyl.
  • the invention relates to the use of a compound of formula (1), a prodrug or a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for the treatment of a hyperproliferative disease.
  • the invention provides a method for the treatment of a hyperproliferative disease, which comprises administering a compound of formula (1), 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 warmblooded 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 the reaction of an ⁇ -bromoketone of formula (3),
  • the residue R 1 CO in formula (4) is a protecting group, e.g. tert-butoxycarbonyl, which can be eliminated by acid treatment to yield the free piperidine (H in place of residue R 1 CO) and thereafter be replaced by another residue R 1 CO by condensation with the corresponding acid R 1 COOH or a reactive derivative thereof under conditions well known in the art, e.g. as used in peptide synthesis.
  • All process steps described here can be carried out under known reaction conditions, 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, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from -100 0 C to about 190 0 C, preferably from about -80 0 C to about 15O 0 C, for example at -80 0 C to +6O 0 C, at -20 0 C to +40 0 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 used and able to dissolve these, in the absence or presence of catalysts, con
  • compositions that comprise a compound of formula (1) as active ingredient and that can be used especially in the treatment of the diseases mentioned at the beginning.
  • Compositions for enteral administration such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous (e.g. chemoembolization and continuous infusion), 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 (1), 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, inflammatory disease, autoimmune disease, metabolic 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 (1) thereof for the preparation of pharmaceutical preparations which comprise compounds of formula (1) 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-sticks, 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 carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g. Tween 80 ® (polyoxyethylene(20)sorbitan mono-oleate).
  • viscosity-increasing agents typically sodium carboxymethylcellulose, 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 semisynthetic 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 methyl- cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, 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 hydroxypropyl- methylcellulose 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 polyoxy- ethylene 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 polyoxy- ethylene 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, inflammatory disease, autoimmune disease, metabolic disease, transplantation related pathology and/or degenerative disease, which comprises administering a compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above for formula (1), in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
  • the compounds of formula (1) 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 (1), or a pharmaceutically acceptable salt thereof, especially a compound of formula (1) 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.
  • Figure 1 Comparative analysis of BrdU incorporated into hepatocytes after treating DEN- mice with OrBi7239 (40 mg/kg per day, 4x; see Figure 1 B) and vehicle control (see Figure 1A), respectively (magnification 100x).
  • An arrow “a” shows significant reduction of BrdU incorporation (by -30%) into DNA in the nucleus compartment of the liver cells upon treatment with OrBi7239.
  • Figure 2 Comparative analysis of BrdU incorporated into epithelial cells of the basal lamina of the colon after treating DEN-mice with OrBi7239 (40 mg/kg per day, 4x , see Figure 2B) and vehicle control (see Figure 2A), respectively (magnification 100x).
  • An arrow “b” shows significant reduction of BrdU incorporation (by ⁇ 20%) into DNA in the nucleus compartment of the epithelial cells in colon upon treatment with OrBi7239.
  • eq Equivalent(s); DMF: Dimethylformamide; RT: Room temperature; ON: Over night; TEA: Triethylamine; DCM: Dichloromethane; TFA: Trifluoroacidic acid; MeCN: Acetonitrile; DIPEA: Diisopropylethylamine; HBTU: 2-(1 H-benzotriazole-1-yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate; TLC: Thin layer chromatography
  • a luminescent cell viability assay (CellTiter- Glo ® ; Promega, Madison, USA) is implemented. The assay is based on the relation that the ATP content is directly proportional to the number of cells present in the culture, see Technical Bulletin No. 228 ,,CellTiter-Glo® Luminescent Cell viability Assay", Revised 2/04. Promeg, Madison, USA.
  • the CellTiter-Glo ® assay is performed to measure the proliferation rate of human hepatoma (HuH7, PLC/PRF/5, Hep3B, SK-Hep1), human hepatoblastoma (HepG2), human colon carcinoma (CX-2), human breast cancer (SK-Br- 3), human ovarian carcinoma (HeLa) and human pancreatic carcinoma (DAN-G) cell lines.
  • 3000 viable cells (viability > 90%) are seeded in opaque-walled 96-well plates and incubated for 24 hours in DMEM, supplemented with 2 mM glutamin. Cell proliferation is stimulated by addition of FCS to a final concentration of 10% (v/v). Simultaneously the compounds I to XVII (see Table 1 and 2) are added in a concentration range of 0 to 20 ⁇ M. Triplicates are measured for each concentration. Cells and compounds (see Table 1 and 2) are incubated for a period of 48 hours in a volume of 140 ⁇ l cell culture medium (10% (v/v) FCS, 2 mM Glutamin, DMEM).
  • the compounds are solved in 60% to 100% (v/v) DMSO at a concentration of 2 mM.
  • the final DMSO concentration under assay conditions never exceeded 1% (v/v).
  • Throughout the assay cells are kept in a humidified incubator (95% rH) at 37 0 C and 5% CO 2 .
  • the final cell number is determined after 48 hour of incubation. Therefore 140 ⁇ l CellTiter-Glo ® Reagent is added in each well.
  • the contents are mixed on an orbital shaker for 2 minutes at room temperature. After subsequent incubation for additional 10 minutes at room temperature the luminescence signal was recorded within 30 min.
  • EC50 values are calculated using the four-parametric Hill equation (Sigma Plot).
  • Control values are: (1) 10% (v/v) FCS, 2 mM Glutamin, DMEM -> maximum cell number and (2) 2 mM Glutamin, DMEM -> initial cell number.
  • E-3- ⁇ 4-[4-(3,4-ethylendioxphenyl)-thiazol-2-yl]-piperidin-1-yl ⁇ -1-(3,4-methylendioxyphenyl)- 3-oxo-prop-1-ene blocks the proliferation of HuH7 with an EC50 of 0.33 ⁇ M. Furthermore, HepG2 and Hep3B are inhibited with an EC50 of 0.9 and 0.3 ⁇ M, respectively.
  • Table 1A Inhibition of HuH7 proliferation by compounds I to IV (EC50: effective concentration reducing cell proliferation by 50%)
  • Table 1 B Inhibition of HuH7 proliferation by compounds V to IX (EC50: effective concentration reducing cell proliferation by 50%).
  • Table 1C Inhibition of HuH7 proliferation by compounds X to XV (EC50: effective concentration reducing cell proliferation by 50%).
  • Table 1 D Inhibition of HuH7 proliferation by compounds XVI to XV (EC50: effective concentration reducing cell proliferation by 50%).
  • compounds of the formula 1 also show inhibition of cell proliferation of other tumour cell lines (see Table 2).
  • Table 2 Inhibition of DAN-G 1 SK-Br-3, HeLa, and CX-2 proliferation by compounds I and V (EC50: effective concentration reducing cell proliferation by 50%; »: much greater than).
  • OrBi7239 and OrBi7253 block cell proliferation (EC 50 between 0.3 and 3 ⁇ M in various cell lines including hepatocarcinoma cells).
  • the compounds induce reduction of cells in the S-phase (FACS analysis) and therefore an accumulation of the cells in the G1 as well as G2 phase is observed.
  • a compound of formula (1) according to the invention shows therapeutic efficacy especially against cancer, preferably in liver and pancreas.
  • Example 3 In vivo analysis of cell proliferation in DEN- induced liver tumours, normal epithel and bone marrow.
  • DEN N-nitroso-diethylamine induced growth of liver tumors supported by the administration of phenobarbital in C3H/He mice is used to test the activity of potential drug candidates against liver tumors (Kemp C. et al., Proc. Natl. Acad. Sci. USA 1989, 86: 7505-7509 and Shiota G. et al., Carcinogenesis 1999, 20: 59-63).
  • Male C3H/He mice are intoxicated with a single i.p. dose of DEN (90 ⁇ g/kg) at age 6-7 weeks.
  • DEN-induced mice receiving phenobarbital (0.07% w/w) containing standard diet for 40 weeks are subsequently randomized for treatment with OrBi7239 (40 mg/kg), OrBi7253 (40 mg/kg) and vehicle control.
  • the treatment is performed daily for four days.
  • At day five animals receive i.p. BrdU (100 mg/kg).
  • Animals are sacrificed 3 h after BrdU injection. Liver, colon and femur are prepared, fixed and paraffin-embedded. Finally, the sections are labelled with BrdU-specific antibody (abeam, ab2844, dilution 1 :100) by following a standard protocol known in the art (e.g.
  • a compound of formula (1) according to the invention shows therapeutic efficacy especially against cancer, preferably in liver and pancreas.

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Abstract

Cette invention se rapporte à des composés de formule (1) dans laquelle R1 représente un groupe amino éventuellement substitué, un groupe phényle éventuellement substitué, un groupe hétéroaryle éventuellement substitué, un groupe hétérocyclyle éventuellement substitué, un groupe phényl-alkyle ou hétéroaryl-alkyle éventuellement substitué, un groupe phénylaminocarbonyl-alcoxyalkyle éventuellement substitué ou un groupe alcényle tel que défini dans la description. Ces composés sont utilisés dans le traitement des maladies hyper-prolifératives, en particulier dans le cancer du foie.
PCT/EP2007/007057 2007-08-09 2007-08-09 Dérivés de thiazole-pipéridine utilisés dans le traitement des maladies hyper-prolifératives WO2009018844A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
JP2016534124A (ja) * 2013-08-29 2016-11-04 ベイラー カレッジ オブ メディスンＢａｙｌｏｒ Ｃｏｌｌｅｇｅ Ｏｆ Ｍｅｄｉｃｉｎｅ 代謝並びに体重関連疾患の処置のための組成物および方法

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WO2004058751A1 (fr) * 2002-12-24 2004-07-15 Metris Therapeutics Limited Derives du piperidinyl-thiazole carboxamide modificateurs du tonus vasculaire
WO2006073167A1 (fr) * 2005-01-07 2006-07-13 Ono Pharmaceutical Co., Ltd. Derives de la pyrrolidine
WO2007056170A2 (fr) * 2005-11-02 2007-05-18 Bayer Healthcare Ag Derives pyrrolo-[2,1-f]-[1,2,4]-triazin-4-ylamines inhibiteurs de la igf-1r kinase pour le traitement des cancers et autres maladies hyperproliferatives
WO2007064553A2 (fr) * 2005-11-29 2007-06-07 Merck & Co., Inc. Derives de thiazole comme modulateurs de recepteurs cxcr3
EP1813606A1 (fr) * 2004-11-18 2007-08-01 Takeda Pharmaceutical Company Limited Composé amide

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2004058751A1 (fr) * 2002-12-24 2004-07-15 Metris Therapeutics Limited Derives du piperidinyl-thiazole carboxamide modificateurs du tonus vasculaire
EP1813606A1 (fr) * 2004-11-18 2007-08-01 Takeda Pharmaceutical Company Limited Composé amide
WO2006073167A1 (fr) * 2005-01-07 2006-07-13 Ono Pharmaceutical Co., Ltd. Derives de la pyrrolidine
WO2007056170A2 (fr) * 2005-11-02 2007-05-18 Bayer Healthcare Ag Derives pyrrolo-[2,1-f]-[1,2,4]-triazin-4-ylamines inhibiteurs de la igf-1r kinase pour le traitement des cancers et autres maladies hyperproliferatives
WO2007064553A2 (fr) * 2005-11-29 2007-06-07 Merck & Co., Inc. Derives de thiazole comme modulateurs de recepteurs cxcr3

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016534124A (ja) * 2013-08-29 2016-11-04 ベイラー カレッジ オブ メディスンＢａｙｌｏｒ Ｃｏｌｌｅｇｅ Ｏｆ Ｍｅｄｉｃｉｎｅ 代謝並びに体重関連疾患の処置のための組成物および方法

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