ZA200403654B - Method of identification of tumor targeting enzymes. - Google Patents
Method of identification of tumor targeting enzymes. Download PDFInfo
- Publication number
- ZA200403654B ZA200403654B ZA200403654A ZA200403654A ZA200403654B ZA 200403654 B ZA200403654 B ZA 200403654B ZA 200403654 A ZA200403654 A ZA 200403654A ZA 200403654 A ZA200403654 A ZA 200403654A ZA 200403654 B ZA200403654 B ZA 200403654B
- Authority
- ZA
- South Africa
- Prior art keywords
- hydroxy
- ethyl
- amino
- pyrano
- methyl
- Prior art date
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Chemical Or Physical Treatment Of Fibers (AREA)
- Enzymes And Modification Thereof (AREA)
Description
RJ
«
Method for identification of tumor targeting enzymes
The present invention relates to a method for identification of enzymes that are preferentially expressed in certain tumor tissue as compared with rapidly growing normal cells or tissue, use of said enzymes for the compound design to generate an active anti- cancer substance selectively in tumor tissue, compounds designed based on said enzymes, their pharmaceutically acceptable salts as well as pharmaceutical composition thereof.
One of the most serious but most important issues in the use of medicines is side effect. Side effects of drugs are mainly caused by non-specific action of drugs; drugs interact with and affect not only target molecules of the drugs but also other molecules that play important roles in maintaining normal physiological processes. Another major cause of the side effects results from non-specific distribution of drugs in many tissue; drugs are incorporated into not only tissue that are to be affected but also to other tissue that should remain unaffected to keep normal physiological functions. Target molecules of most of anti-cancer drugs are widely expressed in many tissue and not specific to certain tissue. On the other hand, disease is usually caused by disregulation of certain molecules in a certain tissue. Thus, to avoid side effects, it is necessary to establish methods by which the drugs affect certain molecules only in certain tissue that are causative of diseases, and present drugs designed by such methods.
Among many diseases, side effects of drugs are particularly concerned in the treatment of cancer patients. Cytotoxic drugs have been widely used for the treatment of cancer and will continue to be regularly used for cancer chemotherapy at least in the next decade. However, the use of cytotoxic drugs is limited due to their insufficient efficacy and severe side effects. In tumor tissue, many cytotoxic drugs including 5-FU, 2’- deoxycytidines, methotrexate, camptothecins and taxanes affect tumor cells at S or M phase of cell cycle, the time when DNA synthesis or mitosis occurs. However, growing tumor cells in tumor tissue are at various stages of cell cycles, and only a small portion of tumor cells is at S or M phase. Therefore, ideal drug exposure time should be, at least, longer than that required for the completion of one cell cycle (ranging from 20 to 40 hours), and ideal dosing regimen for cytotoxic drugs is consecutive daily or continuous treatment to affect all the cancer cells present in tumor tissue. However, cytotoxic drug treatment in such dosing regimens cause severe toxicity on rapidly growing normal cells, particularly on hematopoietic progenitor cells and intestinal crypt cells. Myelosuppression, that is caused by the toxicity on hematopoietic progenitor cells, is the most frequent among various types of side effects of cytotoxic drugs and often results in impairment of host immune responses and fetal infections. Once myelosuppression occurs, it generally takes 2 to 3 weeks to recover from the myelotoxicity, and this is the main reason why many cytotoxic drugs are given once every 3 to 4 weeks. However, this intermittent dosing regimen results in insufficient efficacy of most existing cytotoxic drugs.
Several novel anti-tumor agents with new modes of actions are currently under development. However, they also have some safety problems due to their insufficient tumor selectivity. Indeed, major toxicities of farnesyltransferase inhibitors and epidermal growth factor (EGF) receptor tyrosine kinase inhibitors appear to be myelotoxicity and skin rush, respectively. This is presumably due to the fact that the target enzyme or protein are over-expressed not only in tumor tissue but also other normal tissue such as bone marrow and skin.
On the other hand, capecitabine (an oral fluoropyrimidine) is a cytotoxic drug that is sequentially converted to the active drug 5-FU by enzymes that are highly expressed in the liver and tumors, but not in the growing bone marrow cells [Miwa. M. et al. Design of oral fluoropyrimidine carbamate, capecitabine, which generates 5-furuolouracil selectively in tumors by enzymes concentrated in human liver and cancer tissue. Eur. J. Cancer 34, 1274-1281 (1998)]. As the result, it gives high concentrations of 5-FU selectively in tumor tissue and shows better efficacy profiles compared with those of 5-FU. In addition, it causes little myelotoxicity. These characteristics make the drug available for daily treatment at high dosages even for long duration. It is now being prescribed for the treatment of breast, colorectal and other cancers. Nevertheless, it is still difficult to identify anti-cancer drugs having higher efficacy and safer margins like capecitabine, because there is no established way to pinpoint enzymes and/or proteins among number of those that are expressed in various tissue.
The present invention relates to methods of identifying enzymes for designing compounds that can be converted to active substances selectively in tumors but not in normal growing cells (hereafter called Tumor-Targeting Cytotoxics (TTC)), particularly granulocyte progenitors that are predominantly present in bone marrow. Tumor-targeting cytotoxics , would have tumor selective action with little myelotoxicity. Such compounds can be safely given at higher doses for long periods showing more improved safety and efficacy profiles as compared with those of existing cytotoxics. These compounds therefore could reduce hospitalization that relates to the side effects and can be safely prescribed to outpatients. Other advantages of tumor-targeting cytotoxics include that they will enable us to pursue individualized healthcare therapy (tailored therapy) by measuring the expression levels of their activation enzymes (TTC-activation enzymes). Individual tumors expressing high levels of TTC-activation enzymes will efficiently generate active drugs from tumor-targeting cytotoxics, and therefore, are likely to be highly susceptible to the tumor-targeting cytotoxics.
It is an object of the present invention to provide methods of identifying enzymes for designing anti-cancer compounds that are converted to active substances selectively in tumors, which comprises measuring the expression levels of genes and/or proteins in human tissue and/or cells from normal and tumor origin, comparing the measured expression levels and selecting the enzymes of which mRNA and/or protein levels in tumor tissue are higher by more than two-fold than in normal growing-hematopoietic progenitors, intestine, and/or skin.
It is another object of the present invention to provide methods of identifying anti-cancer compounds that can be converted to active substances selectively in tumors comprising the steps of generating of cells expressing an enzyme of which protein levels in tumor tissue are higher by more than two-fold as compared to normal cells or tissue and determining growth inhibitory activities of said anti-cancer compounds.
It is another object of the invention to provide anti-cancer compounds of the formula (I),
X-Y-Q ey wherein , X is a pro-moiety that is designed to generate an active anti-cancer substance (Q-Y-H) selectively in tumors by the enzymes according to the present a 5 invention;
Q-Y- is a radical derived from the active anti-cancer substance (Q-Y-H) in which Y is -O-, -S- or -N-, and pharmaceutically acceptable salts thereof.
It is another object of the invention to provide anti-cancer compounds represented by the formula (II), ql i
NZ A @® a” Y” ~N NH,
O COR © wherein
Q and Y are the same as defined above,
RC is a side chain of natural or non-natural amino acid
Z is (C1-C3) alkylene or -O-CH(R®)- wherein R’ is hydrogen or straight (C1-C4) alkyl,
R! is hydrogen or methyl, and
R? is hydrogen, branched (C3-C10) alkyl or (C3-C8) cycloalkyl, and pharmaceutically acceptable salts thereof.
It is another object of the invention to provide anti-cancer compounds represented by the formula (III),
Ro 0 on \ RA : ory De 0 ba - am 0
HN Ay oH rR Poo wherein
R’ is the same as defined above,
R* is benzoyl or tert-butoxycarbonyl, and
R’is hydrogen or acetyl, and pharmaceutically acceptable salts thereof.
It is another object of the invention to provide anti-cancer compounds represented by the formula (IV), o B® HH &
J N
HN™ "0 NH, av) 9 o
FY R Rr COR
A
RY 0)
RY R®
HO R wherein
R% R!, R%and R® are the same as defined above,
R® is hydrogen, fluorine, hydroxyl or cyano,
R’ is hydrogen, fluorine or hydroxy, or R%and R’ taken together to form methylidene or fluoromethylidene,
R® is hydrogen or ethynyl,
R’ is hydrogen, fluorine, vinyl or ethynyl, and
R'is hydrogen or hydroxy and pharmaceutically acceptable salts thereof.
It is another object of the invention to provide anti-cancer compounds represented by the formula (V),
J:
HN (CH, m—” nN on COR © : ™
Pr
Aol
R10
R8 R6
HO R7 wherein ’ m is an integer of 2 or 3,
R% R®RS, R’, R®, R’ and R'® are the same as defined above, [1H and pharmaceutically acceptable salts thereof.
It is another object of the invention to provide anti-cancer compounds represented by the formula (VI),
Rr" Rr“
Rr"
XN 0]
N (VD
R" NT \_ Jo 1,
R° H fo) (CH )n
N aN emo & COM wherein m is an integer of I to 3, nis an integerof 0 to 1,
RC is the same as defined above,
RY is hydrogen or fluorine,
R" is hydrogen, fluorine, methyl or hydroxy,
R" is hydrogen, amino, nitro, or (dimethylamino)methyl,
R" is hydrogen, (C1-C4) alkyl, 4-methylpiperazinylmethyl, tert-butoxyiminomethyl or R” and R", or R"! and R* taken together may form five or six membered ring which may contain one or two hetero atom(s), and may be optionally substituted with (C1-C8) alkyl, amino, (C1-C8) alkylamino, and di-(C1-C4) alkylamino, and pharmaceutically acceptable salts thereof. ’ In the present invention the term “(C1-C3)alkylene” refers to a biradical branched or unbranched hydrocarbon chain containing 1 to 3 carbon atom(s), such as methylene, ethylene, propylene and trimethylene, most preferably ethylene.
In the present invention the term “_0-CH(R®)-“ refers to -O-CH,-, -O-CH(CH3)-, -
O-CH(CH,CH;)-, -O-CH(CH,CH,CH3)-, -O-CH(CH,CH,CH;CH3)-; preferably -0O-
CH,-, -O-CH(CH3)-, and most preferably -O-CH(CHj3)-.
. = 7 -
The term “acetyl” refers to CH3CO-.
The term “cycloalkyl” signifies a saturated, cyclic hydrocarbon group with 3 to 7 “ carbon atoms, preferably with 4 to 7 carbon atoms, more preferably 4 to 6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and the like.
The term “hetero atom” refers to oxygen, nitrogen and sulfur.
The term “mono- and di- alkylamino” refers to an amino substituted with alkyl or di-alkyl as defined above, i.e. alkyl-NH- and di-alklyl-N-. “(C1-C8) alkylamino” refers to methylamino, ethylamino, propylamino, iso-propylamino, butylamino, tert-butylamino, pentylamino, hexylamino, heptylamino and octylamino; preferably butylamino and pentyl amino.
The term “di-(C1-C4)alkylamino” refers to di-methylamino, di-ethylamino, di- propylamino, di-butylamino; preferably di-methylamino and di-ethylamino.
In the definition of R of formula (II), the term “a side chain of natural amino acid” preferably means the side chain of natural amino acids such as methyl, isopropyl, 2- methylpropyl, 1-methylpropyl, benzyl, indol-3-ylmethyl, 2-(methylthio)ethyl and 4- amonobutyl, 3-aminopropyl; more preferably means the side chain of natural lipophilic amino acids such as methyl, 2-methylpropyl, benzyl and indol-3-ylmethyl.
The term “a side chain of non-natural amino acid” preferably means (C5-C12) alkyl, cycloalkylmethyl, substituted or unsubstituted arylmethyl, (cycloalkylthio)methyl, alkylthio-(CH}),- wherein r is an integer of 1 or 2, and the like.
In the above, the term “(C5-C12) alkyl” means straight or branched alkyl chain containing 5 to 12 carbon atoms; more preferably (C8-C12) straight alkyl chain such as n- octyl, nonyl, decyl, undecyl and dodecyl. ° 25 The term “alkylthio-(CH,),-” means alkylthio-methyl or alkylthioethyl having a straight, branched alkyl chain containing 2 to 10 carbon atoms such as ethylthiomethyl, . ethylthioethyl, n-propylthiomethyl, n-butylthiomethyl, n-pentylthiomethyl, n- octylthiomethyl, n-nonylthiomethyl, n-decylthiomethyl, tert-butylthiomethyl and the like; more preferably ethylthioethyl, n-propylthiomethyl and n-butylthiomethyl.
The term “substituted or unsubstituted arylmethyl” preferably means 4- phenylbenzyl, napht-2-ylmethyl, [4-(4-hydroxyphenoxy)phenyl]methyl and (4-lower- alkoxyphenyl)methyl, in which the term “lower-alkoxy” means straight or branched alkyl : chain containing 1to 6 carbon atom(s); preferably methoxy, ethoxy, propoxy, butoxyl and isopropoxy. The most preferable embodiments of “substituted or unsubstituted arylmethy” are 4-phenylbenzyl, napht-2-ylmethyl, (4-methoxylphenyl)methyl and [4-(4- hydroxyphenoxy)phenyl methyl.
In the definition of R? of formula (II), the term “branched (C3-C10) alkyl” means branched alkyl chain containing 3 to 6 carbon atom(s), and preferably means iso-propyl, 2-butyl, 3-pentyl, neopentyl and the like: more preferably iso-propyl and 3-pentyl. The term “(C3-C8) cycloalkyl” means a carbon ring consisting of 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; more preferably cyclopentyl and cyclohexyl.
In the definition of R? of formula (II), the term “straight (C1-C4) alkyl” means straight alkyl chain containing 1 to 4 carbon atom(s), and preferably means methyl, ethyl and n-propyl.
The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition these salts may be prepared form addition of an inorganic base or an organic base to the free acid.
Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary “ amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine,
N diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N- ethylpiperidine, piperidine, polymine resins and the like. Preferred salts are the hydrochlorides. Salt free compounds may be prepared by methods known in the art.
In the present invention “the pro-moiety (X)” is a leaving group that is cleaved off in tumors by the enzyme described above after administration of the compound of formula u (I) or (II), e.g. (X) is a group a formula y H i " . R N ~ ~ ~
O COR O
In the present invention, the term “taxans” means taxol [Front. Biotechnol.
Pharm. (2000), 1, 336-348], taxotere [J. Med. Aromat. Plant Sci. (2001), 22/4A-23/1A 4-5],
IDN 5109 [Chirality, (2000), 12(5/6), 431-441], BMS 188797 [Clinical Cancer Research. 5 (suppl.), 3859, Nov 1999], BMS184476 [J]. Clinical Oncology19:2493-2503, 1 May 2001].
The term “Camptothecins” [(a) Cancer Chemotherapy and Biotherapy: Principle and Practice, 2° Ed., Lippincott-Ravenmeans, page 463-484, (b) Biochim. Biophys. Acta (1998), 1400(1-3), 107-119] means any compounds having camptothecin skelton such as camptothecin, topotecan, SN-38, 9-aminocamptotecin, 9-nitrocamptothecin, lurtotecan [Br. J. Cancer (1998), 78(10), 1329-1336], DX-8951f [Ann. N.Y. Acad. Sci. (2000), 922(Camptotecins), 260-273], BN-80915 [Anti-cancer Drugs (2001), 12(1), 9-19] and the like.
The term “anti-cancer nucleosides” means a cytidine derivative [Cancer
Chemotherapy and Biotherapy: Principle and Practice, 2" Ed, Lippincott-Ravenmeans, page 213-233] such as DFDC (gemcitabine), DMDC [Clin. Cancer Res. (2000), 6(6), 2288- 2294], FMDC [Curr. Opin. Invest. Drugs (PharmaPress Ltd.) (2000), 1(1), 135-140], Ara-
C, decitabine [IDrugs (2000), 3(12), 1525-1533], troxacitabine [Clin. Cancer Res. (2000), 6(4), 1574-1588), 2’-cyano-2’-deoxycytidine (CNDAC), 3’-ethynylcytidine (TAS106) [Jpn.
J. Cancer Res. (2001), 92(3), 343-351], 5-fluoro-5’-deoxycytidine[Bioorg. Med. Che. Lett, (2000), 8, 1697-1706], 5-viny-5’-deoxycytidine, or an adenosine derivative [Cancer
Chemotherapy and Biotherapy: Principle and Practice, 2™ Ed., Lippincott-Ravenmeans, - 25 page 235-252] such as fludarabine, cladribine and the like. . The term “dolastatins” means dolastatin 10 [Curr. Pharm. Des. (1999), 5(3), 139- 162], dolastatin 14, TZT1027 [Drugs Future (1999), 24(4), 404-409], cemadotin and the like.
The term “anthracyclines” [Cancer Chemotherapy and Biotherapy: Principle and
Practice, 2™ Ed, Lippincott-Ravenmeans, page 409-434] means adriamycin, daunomycin,
idarubicin and the like.
The term “farnesyl transferase inhibitors” means R115777 [Cancer Res. (2001), 8 61(1), 131-137], and the like. " The term “EGF receptor tyrosine kinase inhibitors” means ZD1839 [Drugs (2000), 60(Suppl. 1), 33-40], CP 358774 (OSI-774) [J. Pharmacol. Exp. Thr. (1999), 291(2), 739-748], PD 158780 [J. Med. Chem. (2001), 44(3), 429-440], GW2016 and the like.
In the present specification, following symbols or abbreviations refer to following respective compounds. a) taxol means [2aR- [2a0,4P,4aP,6B,90(oR*,pS*),110,120,1220,12bx] ]-B -(benzoylamino)- o- hydroxybenzenepropanoic acid 6,12b-bis(acetyloxy)-12-(benzoyloxy)- 2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-4a,8,13,13- tetramethyl-5-0x0-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b] oxet-9-yl ester, b) taxotere means [2aR-[2aq, 48,420, 68,90 (0R*,$5*,110, 120, 12a, 12bar)]-B-[[(1,1- dimethylethoxy)carbonyl]Jamino]-o-hydroxybenzenepropanoic acid 12b- (acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,6,11- trihydroxy-4a,8,13,13-tetramethyl-5-0x0-7,11-methano-1H-cyclodeca[3,4]benz[1,2- b]oxet-9-yl ester, ¢) IDN 5109 means (2R,38)-3-[{(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methyl-4-hexenoic acid (3aS,4R,7R,8a$,95,10aR,12a85,12bR,138,13aS)-7,12a-bis(acetyloxy)-13- (benzyloxy)-3a,4,7,8,8a,9,10,10a,12,12a,12b,13-dodecahydro-9-hydroxy-5,8a,14,14- tetramethyl-2,8-dioxo-6,13a-methano-13aH- oxeto[2",3":5',6'|benzo[1',2":4,5] cyclodeca[1,2-d]-1,3-dioxol-4-yl ester, ) d) BMS 188797 means . (2R,38)- B-(benzoylamino)- c-hydroxy benzenepropanoic acid (2aR,48,4aS,6R,98,118,1285,12aR,12bS)-6- (acetyloxy)-12-(benzoyloxy)- 2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-12b- [(methoxycarbonyl)oxy]-4a,8,13,13-tetramethyl-5-0x0-7,11-methano-1H- cyclodeca[3,4]benz|[1,2-b]oxet-9-yl ester, and e) BMS 184476 means (2R,3S)- B-(benzoylamino)- o-hydroxy benzenepropanoic acid . (2aR,4S,4aS,6R,9S,118,125,122aR,12bS)-6,12b-bis(acetyloxy)-12-(benzoyloxy)- 2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-11-hydroxy-4a,8,13,13-tetramethyl-4- « 5 [(methylthio)methoxy]-5-0x0-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]oxet-9- yl ester.
f) camptothecin means 4(S)-ethyl-4-hydroxy-1H-pyrano([3',46,7}indolizino[1,2-b]quinoline- 3,14(4H,12H)-dione,
g) topotecan means (45)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H- pyrano[3',4":6,7]indolizino{1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride h) DX-8951f means
(18,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-2,3,9,10,13,15-hexahydro- 1H,12H-benzo[de]pyrano [3',4':6,7]indolizino [1,2-b]quinoline-10,13-dione,
i) BN-80915 means 5(R)-ethyl-9,10-difluoro-1,4,5,13-tetrahydro-5-hydroxy-3H,15H-oxepino[3',4":6,7] indolizino[1,2-b]quinoline-3,15-dione,
j) 9-aminocamptotecin means (8)-10-amino-4-ethyl-4-hydroxy-1H-pyrano[3',4":6,7]indolizino[1,2-b]quinoline- 3,14(4H,12H)-dione, and k) 9-nitrocamptothecin means 4(S)-ethyl-4-hydroxy-10-nitro-1H-pyrano{3'4',:6,7]-indolizino[ 1,2-b] quinoline-
3,14(4H,12H)-dione.
y 1) DFDC means 2'-deoxy-2',2'-difluorocytidine,
m) DMDC means 2’-deoxy-2’-methylidenecytidine,
n) FMDC means (E)-2'-deoxy-2'-(fluoromethylene)cytidine,
0) Ara-C means 1-(fB-D-arabinofuranosyl) cytosine, ’ p) decitabine means . 4-amino-1-(2-deoxy-f-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one, q) troxacitabine refers to 4-amino-1-{(28,45)-2- (hydroxymethyl )-1,3-dioxolan-4-yl]-2(1H)- pyrimidinone, r) fludarabine refers to 2-fluoro-9-(5-O-phosphono-f-D-arabinofuranosyl)- 9H-purin-6-amine, s) cladribine refers to 2-chloro-2'-deoxyadenosine. t) dolastatin 10 means
N,N-dimethyl-L-valyl-N-[(1S,2R)-2-methoxy-4-[ (2S)-2-[(1R,2R)-1-methoxy-2- methyl-3-0x0-3-[[(1S)-2-phenyl-1-(2-thiazolyl)ethyl}amino] propyl] -1- pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl- L-valinamide, u) dolastatin 14 means cyclo[N-methylalanyl-(2E,4E,10E)- 15-hydroxy-7-methoxy-2-methyl-2,4,10- hexadecatrienoyl-L-valyl-N-methyl-L-phenylalanyl-N-methyl-L-valyl-N-methyl-L- valyl-L-prolyl-N2-methylasparaginyl], v) dolastatin 15 means (18)-1-[[(2S)-2,5-dihydro-3-methoxy-5-oxo-2-(phenylmethyl)-1H-pyrrol-1- yl]carbonyl]-2-methylpropyl ester N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-
L-prolyl- L-proline, w) TZT 1027 means
N,N-dimethyl-L-valyl-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-1-methoxy-2- : 25 methyl-3-o0xo-3-[(2-phenylethyl)amino]propyl]- 1-pyrrolidinyl]-1-[(1S)-1- methylpropyl}-4-oxobutyl]-N-methyl-L-valinamide,
X) cemadotin means
N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-N-(phenylmethyl)-L- prolinamide, y) adriamycin means
(85,108)-10-[(3-amino-2,3,6-trideoxy-L-lyxo-hexopyranosyl)oxy]-7,8,9,10- tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy- naphthacene-5,12- . dione hydrochloride, z) daunomycin means ’ 5 8-acetyl-10-[(3-amino-2,3,6-trideoxy-L-lyxo-hexopyranosyl)oxy]-7,8,9,10- tetrahydro-6,8,11-trihydroxy-1-methoxy-naphthacene-5,12-dione, hydrochloride, aa) idarubicin means (75,98)-9-acetyl-7-[(3-amino-2,3,6-trideoxy-L-lyxo-hexopyranosyl)oxy]-7,8,9,10- tetrahydro-6,9,11-trihydroxy-naphthacene-5,12-dione. bb) ZD 1839 means
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy] -4- quinazolinamine, cc) CP 358774 means
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, dd) PD 158780 means
N*-(3-bromophenyl)-N6-methylpyrido|3,4-d] pyrimidine- 4,6-diamine, and ee) GW 2016 means
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2- methylsulfonyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine. ff) R 115777 refers to 6-[1-amino-1-(4-chlorophenyl)-1-(1-methylimidazol-5-yl)methyl]-4-(3- chlorophenyl)-1-methylquinolin-2(1H)-one.
In the present invention, enzymes that are preferably expressed in tumor tissue thereby activating compounds selectively are identified by analyzing the levels of mRNAs and/or proteins of human tissue. Compounds are then designed from known and/or novel cytotoxic drugs by adding the moieties that mask the biological activities of the . cytotoxic drugs but are recognized and removed by said enzymes selectively in targeting tumor tissue.
The normal and tumorous human tissue used for the analyses include tissue from brain, esophagus, heart, lung, breast, stomach, liver, pancreas, gallbladder, small intestine, colon, rectum, kidney, bladder, ovary, uterus, testis, prostate, skin, bone, bone marrow, and blood. Preferably, as normal cells granulocyte progenitors are used to compare expression levels of genes and/or proteins between tumor and normal tissue and to select genes ) and/or proteins that are preferably expressed in tumor tissue. After human tissue is resected during surgeries, it is preferable that it is immediately frozen in liquid nitrogen or ) 5 acetone containing dry ice with or without being embedded in O.C.T. compound (Sakura-
Seiki, Tokyo, Japan, Catalog No. 4583) and stored at temperatures below —70 or -80°C until use.
If the tumor tissue contains large portion of normal cells, tumor cells are isolated from the tissue that is embedded in OCT prodrugs by laser capture microdissection (Ohyama H, et al. Laser capture microdissection-generated target sample for high-density oligonucleotide array hybridization. Biotechniques 29, 530-536 (2000), Leethanakul C, et al., Gene expression profiles in squamous cell carcinomas of the oral cavity: use of laser capture microdissection for the construction and analysis of stage-specific cDNA libraries.
Oral Oncol 36, 474-83 (2000)). For micirodissection, frozen sections of between 6 and 10 micro meter thickness are fixed with 70 % ethanol, stained with Mayer's hematoxylin,and then dehydrated with ethanol gradient and xylene. Microdissection of tumor cells are performed by means of laser capture microdissection apparatus (Olympus, Tokyo, Japan,
Model LM200), and the RNA in tumor cells is extracted using a commercially available kit (Micro RNA Isolation Kit, Stratagene, La Jolla, CA, USA).
The human granulocyte progenitors that are most susceptible to cytotoxic drugs are prepared by expanding CD34-positive mononuclear cells on mouse stromal cells in the presence of several cytokines including Fit3-ligand, stem cell factor (SCF) and thrombopoietin (TPO). The CD34-positive mononuclear cells either in human umbilical cord blood or bone marrow are incubated with and bound to an anti-CD34 antibody that is conjugated with magnetic beads and purified by means of magnetic assisted cell sorting (MACS) (Miltenyi, et. al. In: Hematopoietic stem cells: The mulhouse mannual, 201-213,
AlphaMed press, Dayton (1994)). The purified CD34-positive mononuclear cells that sustain abilities to differentiate into various types of hematopietic cells are expanded in \ culture dishes and the percentage of granulocyte progenitors in culture are confirmed by examining the expression of CD34 after staining the cells with a fluorescence-conjugated
N anti-CD 34 antibody. Usually, more than 90 % of the cells in culture become CD34- positive granulocyte progenitors after expansion. The abilities of these granulocyte progenitors to differentiate into myeloblasts and then to myelocytes and granulocytes are tested by treating them with granulocyte colony stimulating factor (G-CSF) or interleukin- 3 (IL3) in combination with granulocyte-macrophage colony stimulating factor (GM —
CSF) and G-CSF. The cell lineage and stages of the differentiation are confirmed by monitoring the cell surface antigens (CD antigens) such as CD11, CD13, and CD15 by ] fluorescence assisted cell sorting (FACS) with FACSCalibur (Becton Dickinson, Franklin
Lakes, New Jersey, USA) and/or by microscopy after staining the cells with Giemsa stain . 5 (Diff-Quick ) (Midori-Juji.Co. Osaka, Japan, Catalog N0.16920) or Leishman stain (Merck,
Darmstadt, Germany, Catalog No.1.05387.0500). FACS data is analyzed by FACSCalibur
CELLQuest software according to the FACSCalibur mannual , FACStation ver.1.1 (Becton-
Dickinson, Franklin Lakes, New Jersey, USA.).
Enzymes and proteins that are expressed in certain tumor tissue is searched by measuring their mRNAs and/or protein levels in human tissue and cells. Expression levels of mRNAs are determined by known methods such as DNA microarray (Schena, M. et al.
Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270, 467-470 (1995), and Lipshutz, R. J. et al. High density synthetic oligonucleotide arrays. Nature Genetics 21, 20-24 (1999)), reverse transcription polymerase reaction (hereafter referred to as RT-PCR) (Weis, J.H. et al. Detection of rare mRNAs via quantitative RT-PCR, Trends Genetics 8, 263-264 (1992), and Bustin, S.A.
Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays, J. Mol. Endocrinol. 25, 169-193 (2000)), northern blotting and in situ hybridization (Parker, R.M. & Barnes, N.M. mRNA: detection in situ and northern hybridization, Methods Mol. Biol. 106, 247-283 (1999)), RNase protection assay (Hod, Y.A.
Simplified ribonuclease protection assay, Biotechniques 13, 852-854 (1992), Saccomanno,
C.F. et al. A faster ribonuclease protection assay, Biotechniques 13, 846-850 (1992)), western blotting (Towbin, H. et al. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets, Proc. Natl. Acad. Sci. U S A 76, 4350-4354 (1979), Burnette, W.N. Western blotting: Electrophoretic transfer of proteins form sodium dodecyl sulfate-polyacrylamide gels to unmodified nitrocellulose and radioiodinated protein A, Anal. Biochem. 112, 195-203 (1981)), ELISA assays (Engvall, E. & Perlman, P.
Enzyme-linked immunosorbent assay (ELISA): Quantitative assay of immunoglobulin G,
Immunochemistry 8: 871-879 (1971)), and protein arrays (Merchant, M. & Weinberger, ) 30 S.R. Review: Recent advancements in surface-enhanced laser desorption/ionization-time of flight-mass spectrometry, Electrophoresis 21, 1164-1177 (2000), Paweletz, C.P. et al. ' Rapid protein display profiling of cancer progression directly from human tissue using a protein biochip, Drug Development Research 49, 34-42 (2000)). More preferably, DNA microarray and RT-PCR are used for high-throughput analysis and quantitative analysis of mRNA expression, respectively.
Claims (45)
1. A method of identifying of an enzyme for designing an anti-cancer compounds that is selectively converted to active substances in tumors, which method comprises comparing the expression levels of genes and/or proteins in human tissue and/or cells from normal and tumor origin, and selecting an enzyme of which mRNA and/or protein levels in tumor tissue are higher by more than two-fold as compared to normal cells or tissue.
2. The method according to claim 1, wherein the enzyme is identified by means of analyses of DNA microarray, polymerase chain reaction, northern blotting and in situ hybridization, differential displays, RNase protection assay, protein arrays, western blotting, two dimensional gel electrophoresis or enzyme-linked immumosorbent assay.
3. The method according to claim 2, wherein the enzyme is identified by means of the analyses of DNA microarray or polymerase chain reaction.
4. The method according to any one of claims 1 to 3, wherein the normal cells or tissue are from hematopoietic progenitors derived from bone marrow or umbilical cord blood, intestine, or skin.
5. The method according to any one of claims 1 to 3, wherein the human tissue and/or cells from tumor origin is from brain, lung, esophagus, breast, stomach, pancreas, liver, colon, rectum, kidney, ovary, uterus, bladder, prostate, skin, and blood.
6. Use of the enzymes, identified by the method according to any one of claims 1 to 5, for obtaining, identifying and/or designing anti-cancer compounds that can be converted to active substances selectively in tumors.
7. The use of claim 6, wherein said enzymes are microsomal dipeptidase, arylsulfatase
. A, pyrroline 5’-carboxyreductase, dehydrodiol dehydrogenase, carbonylreductase, lysyl hydroxylase, prolidase, dihydropyrimidinase, glutamine:fructose-6-phosphate amidotransferase, UDP-galactose ceramide galactosyl transferase, lysyl oxidase, enolase, glucose-6-phosphate dehydrogenase, stearoyl-coenzyme A desaturase, epoxide hydrolase or aldolase C.
8. The use of claim 7, wherein said enzymes are microsomal dipeptidase, dihydrodiol dehydrogenase, pyrroline 5’-carboxyreductase, carbonylreductase and lysyl hydroxylase, preferably microsomal dipeptidase
9. A method of identifying anti-cancer compounds that can be converted to active substances selectively in tumors comprising the steps. (a) generating of cells expressing an enzyme of which protein levels in tumor tissue are higher by more than two-fold as compared to normal cells or tissue; and (b) determining growth inhibitory activities of said anti-cancer compounds.
10. The method of claim 9, wherein said enzyme is an enzyme of claims 6 to 9.
11. Anti-cancer compounds of the formula (I), X-Y-Q (I) wherein X is a pro-moiety that is designed to generate an active anti-cancer substance (Q-Y-H) selectively in tumors by the enzymes according to any one of claim 6-9; Q-Y- is a radical derived from the active anti-cancer substance (Q-Y-H) in which Y is -O-, -S- or -N-, and pharmaceutically acceptable salts thereof.
12. The compound of claim 11, wherein the radical (Q-Y-) of an active anti-cancer substance (Q-Y-H) is that of taxans, camptothecins, anti-cancer nucleosides, dolastatins, anthracyclins, farnesyltransferase inhibitors or EGF receptor tyrosine kinase inhibitors.
13. The compound of claim 12, wherein the active anti-cancer substance (Q-Y-H) isa taxan selected from the group consisting of a) taxol [2aR- [2a0,4B,4aB,68,90(0R*,BS*),110,120,12a0;, 12bot] }-B - ’ (benzoylamino)- o-hydroxybenzenepropanoic acid 6,12b- bis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b- dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11- methano-1H-cyclodeca[3,4]benz[1,2-b] oxet-9-yl ester, b) taxotere
[2aR-[2ac;, 4B,4ac, 68,90 (0R*,$5%,11a, 120, 12a0, 12ba)]-B-[[(1,1- dimethylethoxy)carbonylJamino]-a-hydroxybenzenepropanoic acid
. 12b-(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b- dodecahydro-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-0x0-7,11- - 5 methano-1H-cyclodeca[3,4]benz[1,2-b] oxet-9-yl ester, c¢) IDN5109 (2R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methyl- 4-hexenoic acid (3aS,4R,7R,8aS$,9S,10aR,12aS,12bR,13S,13aS)-7,12a- bis(acetyloxy)-13-(benzyloxy)-3a,4,7,8,8a,9,10,10a,12,12a,12b,13- dodecahydro-9-hydroxy-5,8a,14,14-tetramethyl-2,8-dioxo-6,13a- methano-13aH-oxeto[2",3":5',6']benzo[1',2":4,5]cyclodeca[ 1,2-d]-1,3- dioxol-4-yl ester, d) BMS 188797 (2R,3S)- B-(benzoylamino)- a-hydroxy benzenepropanoic acid (2aR,45,4a85,6R,9S,118,125,12aR,12bS)-6- (acetyloxy)-12-(benzoyloxy)- 2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-12b- [(methoxycarbonyl)oxy]-4a,8,13,13-tetramethyl-5-0x0-7,11-methano- 1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester, and e) BMS 184476 (2R,3S)- B-(benzoylamino)- a-hydroxy benzenepropanoic acid (2aR,4S,4a5,6R,95,118,125,12aR,12bS)-6,12b-bis(acetyloxy)-12- (benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-11-hydroxy- 4a,8,13,13-tetramethyl-4- [ (methylthio)methoxy]-5-0xo0-7,11-methano- 1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester.
14. The compound of claim 12, wherein the active anti-cancer substance (Q-Y-H) is a camptothecin selected from the group consisting of ‘ a) camptothecin: 4(S)-ethyl-4-hydroxy-1H-pyrano[3’4"6,7]indolizino[1,2-b]quinoline- ' 3,14(4H,12H)-dione, b) topotecan (45)-10-[(dimethylamino)methyl}-4-ethyl-4,9-dihydroxy-1H- pyrano[3’4%6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione
- 1u4 - monohydrochloride c) DX-8951f . (15,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-2,3,9,10,13,15- hexahydro-1H,12H-benzo{de]pyrano [3°,46,7]indolizino [1,2- ’ 5 blquinoline-10,13-dione,
d) BN-80915 5(R)-ethyl-9,10-difluoro-1,4,5,13-tetrahydro-5-hydroxy-3H,15H- oxepino[3',4":6,7] indolizino[1,2-b]quinoline-3,15-dione,
e) 9-aminocamptotecin
(S)-10-amino-4-ethyl-4-hydroxy-1H-pyrano(3',4":6,7 Jindolizino[1,2- b]quinoline-3,14(4H,12H)-dione,
f) 9-nitrocamptothecin 4(S)-ethyl-4-hydroxy-10-nitro-1H-pyrano|[3',4',:6,7] -indolizino[ 1,2 b]quinoline-3,14(4H,12H)-dione,
g) (95)-9-ethyl-9-hydroxy-1-pentyl-1H,12H- pyrano([3”,4”:6’,7’]indolizino[1’,2:6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione, h) (95)-9-ethyl-9-hydroxy-2-methyl-1-pentyl- 1H,12Hpyrano[3”,4”:6’,7’]indolizino{1’,2’:6,5]pyrido[4,3,2- de]quinazoline- 10,13(9H,15H)-dione, and i) (95)-9-ethyl-9-hydroxy-2-hydroxymethyl-1-pentyl-1H,12H- pyrano[3”,4”:6’7’lindolizino[1°2":6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione. } 25
15. The compound of claim 12, wherein the active anti-cancer substance (Q-Y-H) is an anti-cancer nucleoside selected from the group consisting of . a) DEDC 2'-deoxy-2',2'-difluorocytidine, b) DMDC 2’-deoxy-2’-methylidenecytidine,
c¢) FMDC (E)-2'-deoxy-2'-(fluoromethylene)cytidine, } d) Ara-C 1-(B-D-arabinofuranosyl)cytosine, e) decitabine 4-amino-1-(2-deoxy-f-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)- one, f) troxacitabine 4-amino-1-[(25,48)-2-(hydroxymethyl)- 1,3-dioxolan-4-yl]-2(1H)- pyrimidinone, g) fludarabine 2-fluoro-9-(5-O-phosphono-fB-D-arabinofuranosyl)- 9H-purin-6- amine, and h) cladribine 2-chloro-2'-deoxyadenosine.
16. The compound of claim 12, wherein the active anti-cancer substance Q-Y-H is a dolastatin selected from the group consisting of a) dolastatin 10 N,N-dimethyl-L-valyl-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-1- methoxy-2-methyl-3-o0xo0-3-[[(1S)-2-phenyl-1-(2- thiazolyl)ethylJamino]propyl]-1-pyrrolidinyl]-1-[(1S)-1-methylpropyl}-4- oxobutyl]-N-methyl- L-valinamide, b) dolastatin 14 cyclo[N-methylalanyl-(2E,4E,10E)-15-hydroxy-7-methoxy-2-methyl- 2,4,10-hexadecatrienoyl-L-valyl-N-methyl-L-phenylalanyl-N-methyl-L- ) valyl-N-methyl-L-valyl-L-prolyl-N2-methylasparaginyl],
. ¢) dolastatin 15 (18)-1-[[(2S)-2,5-dihydro-3-methoxy-5-o0xo-2-(phenylmethyl)-1H- pyrrol-1-yl]carbonyl]-2-methylpropyl ester N,N-dimethyl-L-valyl-L- valyl-N-methyl-L-valyl-L-prolyl- L-proline,
d) TZT 1027 N,N-dimethyl-L-valyl-N-[(1S,2R)-2-methoxy-4-[ (2S)-2-[(1R,2R)-1- methoxy-2-methyl-3-0x0-3-[(2-phenylethyl)amino] propyl] -1- pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl] -N-methyl-L- } 5 valinamide, and e) cemadotin N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-N- (phenylmethyl)-L-prolinamide.
17. The compound of claim 12, wherein the active anti-cancer substance (Q-Y-H) is an anthracycline selected from the group consisting of a) adriamycin (8S,10S)-10-{(3-amino-2,3,6-trideoxy-L-lyxo-hexopyranosyl)oxy]- 7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)- 1-methoxy- naphthacene-5,12-dione hydrochloride, b) daunomycin 8-acetyl-10-[(3-amino-2,3,6-trideoxy-L-lyxo-hexopyranosyl)oxy]- 7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-naphthacene-5,12- dione, hydrochloride, and ¢) idarubicin: (7S,98)-9-acetyl-7-[(3-amino-2,3,6-trideoxy-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxy- naphthacene-5,12-dione.
18. The compound of claim 12, wherein the active anti-cancer substance (Q-Y-H) is an EGF receptor tyrosine kinase inhibitor or a farnesyltransferase inhibitor.
19. The compound of claim 18, wherein the active anti-cancer substance (Q-Y-H) is an ; EGF receptor tyrosinkinase inhibitor selected from the group consisting of a) ZD 1839 ; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]- 4-quinazolinamine, b) CP 358774 N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,
c) PD 158780 N*-(3-bromophenyl)-N6-methylpyrido[3,4-d]pyrimidine- 4,6-diamine, ] and d) GW2016 N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2- methylsulfonyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine.
20. The compound of claim 18, wherein the active anti-cancer substance (Q-Y-H) is farnesyltransferase inhibitor R 115777 of the formula 6-[1-amino-1-(4- chlorophenyl)-1-(1-methylimidazol-5-yl)methyl}-4-(3-chlorophenyl)-1- methylquinolin-2(1H)-one.
21. The compound of claim 11 represented by the formula (II), 0 RI i NX ZN @ Q hid NH, O COR © wherein Q and Y are as defined in claim 11, RC is a side chain of natural or non-natural amino acid Z is (C1-C3) alkylene or -O-CH(R®)- wherein R® is hydrogen or straight (C1- C4)alkyl, R' is hydrogen or methyl, and R? is hydrogen, branched (C3-C10) alkyl or (C3-C8) cycloalkyl, or pharmaceutically acceptable salts thereof.
22. The compound of claim 21, wherein (Q-Y-H) is taxol or taxotere represented by the formula (III),
S a © on Rt “he 0] yao ~ ~ y o™ Z a 6 O Ory SP am o 0] rn Ay OH rR #0 wherein R% is as defined in claim 21, R* is benzoyl or tert-butoxycarbonyl, and R’is hydrogen or acetyl, or pharmaceutically acceptable salts thereof.
23. The compound of claim 22 wherein R® is methyl, benzyl or 2-methylpropyl.
24. The compound of claim 22 and 23 selected from the group consisting of a) 13-((2R,35)-2-{(55)-[5-((2S)-2-amino-4-methyl-pentanoylamino)-5- hydroxycarbonyl]pentanoyloxy}-3-benzoylamino-3- phenylpropionyloxy)-20.-benzyloxy-40,10B-diacetoxy-1p,7p-dihydroxy- _ 5PB,20-epoxy-tax-11-en-9-one, b) 130-((2R,35)-2-{(55)-[5-((2S)-2-amino-propinoylamino)-5- hydroxycarbonyl] pentanoyloxy}-3-benzoylamino-3- phenylpropionyloxy)-20-benzyloxy-40,108-diacetoxy-18,7B-dihydroxy- 58,20-epoxy-tax-11-en-9-one, and ¢) 13-((2R,35)-2-{(5S)-[5-((2S)-2-amino-3-phenyl-propinoylamino)-5- hydroxycarbonyl]pentanoyloxy}-3-benzoylamino-3- ’ phenylpropionyloxy)-2a-benzyloxy-4c, 10p-diacetoxy-18,7 B-dihydroxy- 58,20-epoxy-tax-11-en-9-one, and pharmaceutically acceptable salts thereof.
25. The compound of claim 21, wherein (Q-Y-H) is an anticancer nucleoside, represented by the formula (IV),
o rH ® N Aol Ho 9 0 0 N - (@) aw Rr" R® R® HO R’ wherein R% R!, R%and R® are as defined in claim 21, R°® is hydrogen, fluorine, hydroxyl or cyano, R is hydrogen, fluorine or hydroxy, or R®and R taken together form methylidene or fluoromethylidene, R® is hydrogen or ethynyl, R’ is hydrogen, fluorine, vinyl or ethynyl, and RY is hydrogen or hydroxy, and pharmaceutically acceptable salts thereof.
26. The compound of claim 25, wherein R® is a hydrogen, fluorine, hydroxyl, R’ is a fluorine or hydroxy or R®and R’ taken together form methylidene or fluoromethylidene.
27. The compound of claim 25 and/or 26, wherein R? is 2-methylpropyl, cyclohexylmethyl, 2-naphtylmethyl, 4-phenylbenzyl, (4- cyclohexylcyclohexyl) methyl, alkylthiomethyl, cyclohexylthiomethyl or 4- alkoxybenzyl, and Ris hydrogen or methyl.
28. The compound of any one of claims 25 to 27 selected from the group consisting of a) (2R)-((2S)-amino-3-cyclohexyl-propionylamino)-(3S)-[1-((4S)- ) hydroxy-(5R)-hydroxymethyl-3-methylene-tetrahydro-furan-(2R)-yl)- 2-ox0-1,2-dihydro-pyrimidine-4-ylcarbamoyloxy]-butyric acid, b) (2R)-((2S)-Amino-4-methyl-pentanoylamino)-(3S)-[1-((4S)-hydroxy- (5R)-hydroxymethyl-3-methylene-tetrahydro-furan-(2R)-yl)-2-o0x0-1,2- dihydro-pyrimidin-4-ylcarbamoyloxy]-butyric acid,
c) (2R)-((2S)-Amino-3-biphenyl-4-yl-propionylamino)-(3S)-[1-((45)- hydroxy-(5R)-hydroxymethyl-3-methylene-tetrahydro-furan-(2R)-y1)- 2-0x0-1,2-dihydro-pyrimidin-4-ylcarbamoyloxy]-butyric acid,
d) 2(R)-[2(S)-Amino-3-biphenyl-4-yl-propionylamino]-3-{1-[4(S)-
) 5 hydroxy-5(R)-hydroxymethyl-3-methylene-tetrahydro-furan-2(R)-yl]- 2-0x0-1,2-dihydro-pyrimidin-4-ylcarbamoyloxy}-propionic acid,
e) (2R)-((2S)-Amino-3-naphthalen-2-yl-propionylamino)-(3S5)-[1-((4S)- hydroxy-(5R)-hydroxymethyl-3-methylene-tetrahydro-furan-(2R)-yl)- 2-0x0-1,2-dihydro-pyrimidin-4-ylcarbamoyloxy]-butyric acid,
f) (2R)-{(2S)-Amino-3-[4-(4-hydroxy-phenoxy)-phenyl]- propionylamino}-3-[1-((4S)-hydroxy-(5R)-hydroxymethyl-3- methylene-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4- ylcarbamoyloxy]-butyric acid,
g) (2R)-[(2S)-amino-3- (4-methoxy-phenyl)-propionylamino] -(38)-[1-
[(4S)-hydroxy-(5R)-hydroxymethyl-3-methylene-tetrahydro-furan-2- yl}-2-o0x0-1,2-dihydro-pyrimidin-4-ylcarbamoyloxy]-butyric acid,
h) (2R)-[(2S)-Amino-4-ethylsulfanyl-butyrylamino]-(3S)-[1-[(4S)- hydroxy-(5R)-hydroxymethyl-3-methylene-tetrahydro-furan-(2R)-yl]- 2-0x0-1,2-dihydro-pyrimidin-4-ylcarbamoyl]-butyric acid,
i) (2R)-((2S)-Amino-3-cyclohexyl-propionylamino)-(35)-{1-(3,3- difluoro-(4R)-hydroxy-(5R)-hydroxymethyl-tetrahydro-furan-2-yl)-2- 0x0-1,2-dihydro-pyrimidin-4-ylcarbamoyloxy]-butyric acid,
j) 2(8)-[2(S)-amino-3-cyclohexyl-propionylamino)-3-[1-(3,3-difluoro- 4(R)-hydroxy-5(R)-hydroxymethyl-tetrahydro-furan-2(R)-yl)-2-oxo-
1,2-dihydro-pyrimidin-4-ylcarbamoyloxy]-2(S)-methyl-propionic acid,
’ k) 2(R)-[2(S)-amino-3-cyclohexyl-propionylamino]-3-{1-[3,3-difluoro- 4(R)-hydroxy-5(R)-hydroxymethyl-tetrahydro-furan-2(R)-yl]-2-oxo- ’ 1,2-dihydro-pyrimidin-4-ylcarbamoyloxy}-2(R)-methyl-propionic acid,
D (28,3S)-2-(2-amino-3-cyclohexyl-propionylamino)-3-[1-{(4R,5R)-3,3-
difluoro-4-hydroxy-5-hydroxylmethyl-tetrahydro-furan-2-yl}-2-oxo- 1,2-dihydro-pyridine-4-ylcarbamoyloxy]-2-methyl-butyric acid,
m) (2R,3R)-2-(2-amino-3-cyclohexyl-propionylamino)-3-[1-{(4R,5R)-3,3- difluoro-4-hydroxy-5-hydroxylmethyl-tetrahydro-furan-2-yl}-2-oxo- 1,2-dihydro-pyridine-4-ylcarbamoyloxy]-2-methyl-butyric acid, and n) (2R)-[(2S)-amino-3-cyclohexyl-propionylamino]-(35)-[1-[(4S)-
. 5 hydroxy-(5R)-hydroxymethyl-3-methylene-tetrahydro-furan-(2R)-yl]- 2-0x0-1,2-dihydro-pyrimidine-4~ylcarbamoyloxy]-butyric acid isopropyl ester, and pharmaceutically acceptable salts thereof.
29. The compound of claim 21, wherein (Q-Y-H) is an anticancer nucleoside, represented by the formula (V), 0] H 0 a oun NH y x" cory °C Vv) oP > R10 R8 R6 Ho RZ wherein m is an integer of 2 or 3, and R% R*R%, R’, R®, R® and R!? are as defined in claim 25, and pharmaceutically acceptable salts thereof.
30. The compound of claim 29, wherein : RS is hydrogen, fluorine or hydroxyl, R’ is fluorine or hydroxy, or R%and R taken together to form methylidene or fluoromethylidene.
31. The compound of claims 29 and 30, wherein R is cyclohexylmethyl, 2- , naphtylmethyl, 4-phenylbenzyl, benzyl, indol-3-ylmethyl or 4-alkoxybenzyl.
32. The compound of any one of claims 29 to 31 selected from the group consisting of a) (2R)-[(2S)-amino-3-(1H-indol-3-yl)propionylamino]-4-[1-((4S)- hydroxy-(5R)-hydroxymethyl-3-methylenetetrahydrofuran-2-yl)-2-oxo- 1,2-dihydropyrimidin-4-ylcarbamoyl}-butyric acid,
b) (2R)-((2S)-amino-3-cyclohexylpropionylamino)-4-[1-((4S) -hydroxy- (5R)-hydroxymethyl-3-methylenetetrahydrofuran-2-yl)-2-oxo-1,2- dihydropyrimidin-4-ylcarbamoyl] butyric acid, c) (2R)-((2S)-amino-3-biphenyl-4-ylpropionylamino)-4-[1-((4S)- ‘ 5 hydroxy-(5R)-hydroxymethyl-3-methylenetetrahydrofuran-2-yl)-2-oxo- 1,2-dihydropyrimidin-4-ylcarbamoyl]butyric acid, and d) (2R)-((2S)-amino-3-naphthalen-2-ylpropionylamino)-4-[1-((4S)- hydroxy-(5R)-hydroxymethyl-3-methylenetetrahydrofuran-2-yl)-2-oxo- 1,2-dihydropyrimidin-4-ylcarbamoyl] butyric acid, and pharmaceutically acceptable salts thereof.
33. The compound of claim 21, wherein (Q-Y-H) is camptothecin or its derivative, represented by the formula (VI), R® RB" R% RN 0 N A" 0 VD R i { wy CHM No 4 CO,H wherein m is an integer of 1 to 3, n is an integer of 0 to 1, Ris as defined in claim 22, R" is hydrogen or fluorine, R'? is hydrogen, fluorine, methyl or hydroxy, Ris hydrogen, amino, nitro or (dimethylamino)methyl, . R'is hydrogen, (C1-C4) alkyl, (4-methylpiperazinyl)methyl or (tert- butoxyimino)methyl ; or R” and R™, or R*! and R* taken together form 5 or 6 membered ring which optionally contains 1 or 2 hetero atom(s), and are optionally substituted with 1 to 3 substituant(s) selected from a group consisting of (C1-C8) alkyl, amino, (C1-C8) alkylamino and/or di-(C1-C4) alkylamino, and pharmaceutically acceptable salts thereof.
34. The compound of claim 33, wherein R" is hydrogen, R'? is hydrogen or hydroxy, R" is hydrogen or (dimethylamino)methyl and R"* is hydrogen or ethyl. }
35. The compound of claims 33 and 34, wherein R® 2-methylpropyl, cyclohexylmethyl, benzyl, indol-3-ylmethyl, 4-aminobutyl, or 4-aminopropyl. ’ 5
36. The compound of any one of claims 33 to 35 selected from the group consisting of a) 20-O-[(S)-tryptophyl-y -(S)-glutamyl]-20-(S)-camptothecin, b) 20-O-[(S)-valyl-y -(S)-glutamyl]-20(S)-camptothecin, c) 20-O- [(S)-phenylalanyl-y -(S)-glutamyl]-20(S)-camptothecin, d) 20-O-[(S)-leucyl-y-(S)-glutamyl]-20(S)-camptothecin, e) 20-O-[(R)-leucyl-y-(S)-glutamyl]-20(S)-camptothecin, f) 20-O- [(R)-phenylalanyl-y -(S)-glutamyl]-20(S)-camptothecin, g) 20-O- [(S)-tryptophyl-y-(R)-glutamyl]-20(S)-camptothecin, h) 20-O- [(R)-tryptophyl-y -(R)-glutamyl]-20(S)-camptothecin, i) 20-O- [(S)-phenylalanyl-y -(R)-glutamyl]-20(S)-camptothecin, i) 20-O- [(S)-leucyl-y -(R)-glutamyl]-20(S)-camptothecin, k) 20-O- [(R)-tryptophyl-y -(S)-glutamyl]-20(S)-camptothecin, 1) 20-O- [(R)-phenylalanyl-y -(R)-glutamyl]-20(S)-camptothecin, m) 20-O- [(R)-leucyl-y-(R)-glutamyl]}-20(S)-camptothecin, n) 7-ethyl-10-hydroxy-20-O-[(R)-tryptophyl-(R)-homoglutamyl]-20(S)- camptothecin, 0) 7-ethyl-10-hydroxy-20-O-[(R)-tryptophyl-y-(R)-glutamyl}-20(S)- camptothecin, p) 7-ethyl-10-hydroxy-20-O-[(S)-phenylalanyl-y-(R)-glutamyl}-20(S)- camptothecin, q) 7-ethyl-10-hydroxy-20-O-[(S)-phenylalanyl-y-(S)-aspartyl]-20(S)- camptothecin, . r) 7-ethyl-10-hydroxy-20-O-[(S)-leucyl-y-(S)-aspartyl]-20(S)- camptothecin, : s) 20-O- [(S)-tryptophyl-B-(R)-aspartyl]-20(S)-camptothecin, t) 20-O-[(S)-phenylalanyl-B-(R)-aspartyl] -20(S)-camptothecin, u) 20-O-[(R)-phenylalanyl-B-(R)-aspartyl]-20(S)-camptothecin, v) 20-O- [(S)-phenylalanyl-f-(S)-aspartyl]-20(S)-camptothecin,
w) 20-O- [(S)-leucyl-B-(R)-aspartyl]-20(S)-camptothecin, x) 20-O- [(S)-valyl-B-(R)-aspartyl]-20(S)-camptothecin,
. y) 7-ethyl-10-hydroxy-20-O-[(S)-cyclohexylalanyl-(R)-glutamyl]-20(S)- camptothecin, v 5 z) 7-ethyl-10-hydroxy-20-O-[(S)-cyclohexylalanyl-(S)-glutamyl] -20(S)- camptothecin, aa) 20-O-[(S)-lysyl-y-(S)-glutamyl]-20-(S)-camptothecin, and bb) 20-O-[(S)-ornithyl-y-(S)-glutamyl]-20-(S)-camptothecin, cc) (98)-9-ethyl-9-[(L)-tryptophyl-(L)-y-glutamyloxy] -1-pentyl-1H,12H- pyrano[3”,4”:6’,7’ ]indolizino[1’,2’:6,5] pyrido[4,3,2-de]quinazoline- 10,13(9H,15H)-dione hydrochloride, dd) (9S)-9-ethyl-9-[(L)-cyclohexylalanyl-(D)-y-glutamyloxy]-1-pentyl- 1H,12H-pyrano(3”,4”:6’,7 Jindolizino[1’,2":6,5]pyrido[4,3,2- de]quinazoline-10,13(9H,15H)-dione hydrochloride, ee)(9S)-9-ethyl-9-[(L)-phenylalanyl-(D)-y-glutamyloxy]- 1-pentyl- 1H,12H- pyrano(3”,4”:6’,7’ Jindolizino[1’,2’:6,5] pyrido[4,3,2-de]quinazoline- 10,13(9H,15H)-dione hydrochloride, : ff)(9S)-9-ethyl-9-[(L)-leucyl-(D)-y-glutamyloxy]-1-pentyl-1H,12H- pyrano(3”,47:6’,7 Jindolizino[1’,2’:6,5] pyrido[4,3,2-de]quinazoline- 10,13(9H,15H)-dione hydrochloride, 88)(9S)-9-ethyl-9-[(L)-lysyl-(L)-y-glutamyloxy]-1-pentyl-1H,12H- pyrano[3”,4”:6°,7 Jindolizino[1’,2’:6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione dihydrochloride, hh)(9S)-9-ethyl-9-[(L)-valyl-(D)-y-glutamyloxy]-1-pentyl-1H,12H- pyrano[3”,4”:6’,7 Jindolizino[1’,2’:6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochloride
. i1)(98)-9-ethyl-9-[(L)-ornithyl-(L)-y-glutamyloxy]- 1-pentyl- 1H,12H- pyrano[3”,4”:6’,7’lindolizino[1’,2’:6,5]pyrido[4,3,2-de] quinazoline- . 10,13(9H,15H)-dione dihydrochloride, ji)(98)-9-ethyl-9-[(L)-leucyl-(D)-y-glutamyloxy]-1-pentyl-1H,12H- pyrano[3”,4”:6°,7’ lindolizino[1,2’:6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione methanesulfonic acid salt,
uu) (98)-9-ethyl-9-[ (D)-cyclohexylalanyl-(L) -y-glutamyloxy]-1-pentyl-1H,12H- pyrano[3”,4”:6’,7’Jindolizino[1°,2’:6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochloride, vv) (95)-9-ethyl-9-[(L)-lysyl- (D)-y-glutamyloxy]-1-pentyl-1H,12H- ' 5 pyrano[3”,4™:6’,7’[indolizino[1’,2’:6,5]pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione dihydrochloride, ww) (9S)-9-ethyl-9-[ (L)-tryptophyl- (D)-y-glutamyloxy]-1-pentyl-1H,12H- pyrano[3”,4”:6°,7’lindolizino[1’,2’:6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochloride, xx) (95)-9-ethyl-9-[(L)-leucyl-(L)-y-glutamyloxy]-1-pentyl-1H, 12H- pyrano[3”,4”:6’,7’]indolizino[1’,2":6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochloride, 7Y)(95)-9-ethyl-9-[glycyl-(D)-y-glutamyloxy] - 1-pentyl-1H,12H- pyrano[3”,4”:6’,7’]indolizino[1’,2’:6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochloride, 2z)(9S)-9-ethyl-9- [(L)-alanyl-(D)-y-glutamyloxy]- 1-pentyl-1H,12H- pyrano(3”,4”:6’,7’ Jindolizino[1’,2’:6,5]pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochlorid, aaa)(9S)-9-ethyl-9-[(L)-phenylalanyl-(D) -B-aspartyloxy]-1-pentyl-1H,12H- pyrano(3”,4”:6’,7’Jindolizino[1’,2’:6,5]pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochloride, the salt free compounds and other pharmaceutically acceptable salts thereof.
37. The compound of claims 33 and 34 which is (9S5)-9-ethyl-9-[(L)-lysyl-(L)-y- glutamyloxy]-1-pentyl-1H, 12H-pyrano[3”,4™:6’,7 |indolizino[1’,2’:6,5] pyrido[4,3,2- de]quinazoline-10,13(9H,15H)-dione dihydrochloride, the salt free compounds and other pharmaceutically acceptable salts thereof.
38. A process for the preparation of compounds of formula (I) according to any one of . claims 11 to 37 wherein a compound Q-Y-H is condensed with a reactive derivative of X.
39. A pharmaceutical composition containing a compound according to any one of claims 11 to 37. . ~ kk)(9S)-9-ethyl-9-[(D)-lysyl-(L)-y-glutamyloxy] -1-pentyl-1H,12H- pyrano|[3”,4”:6’,7’ Jindolizino[1’,2:6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione dihydrochloride, 11) (95)-9-ethyl-9-[(L)-phenylalanyl-(L)-B-aspartyloxy]-1-pentyl-1H,12H- . 5 pyrano(3”,4”:6’,7’Jindolizino[1’,2:6,5]pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochloride, mm)(95)-9-ethyl-9-[(L)-cyclohexylalanyl-(D)-f-aspartyloxy]-1-pentyl- 1H,12H-pyrano[3”,4™:6’,7’]indolizino([1’,2’:6,5]pyrido[4,3,2- de]quinazoline-10,13(9H,15H)-dione hydrochloride,
nn) (95)-9-ethyl-9-[(L)-cyclohexylalanyl-(L)-f-aspartyloxy] -1-pentyl-1H,12H- pyrano[3”,4”:6’,7’ Jindolizino[1’,2:6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochloride,
00)(9S)-9-ethyl-9-[(L)-tryptophyl-(L)-B-aspartyloxy] - 1-pentyl-1H,12H- pyrano(3”,47:6’,7’ Jindolizino[1’,2:6,5]pyrido[4,3,2-de] quinazoline-
10,13(9H,15H)-dione hydrochloride,
pp)(98)-9-ethyl-9-[(L)-ornithyl-(D)-y-glutamyloxy]-1-pentyl-1H,12H- pyrano[3”,4”:6’,7’]indolizino[1°,2":6,5] pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione dihydrochloride, qq) (98)-9-ethyl-9-[(L)-leucyl-(D)-B-aspartyloxy]-1-pentyl-1H,12H- pyrano[3”,4”:6’,7’Jindolizino[ 1’,2’:6,5)pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochloride, 11)(9S)-9-ethyl-9-[(L)-valyl-(D)-B-aspartyloxy]-1-pentyl-1H,12H- pyrano[3”4:6’,7’}indolizino{1’,2’:6,5] pyrido[4,3,2-de]quinazoline- 10,13(9H,15H)-dione hydrochloride, s5)(95)-9-ethyl-9-[(L)-leucyl- (L)-B-aspartyloxy]-1-pentyl-1H,12H- pyrano[3”,47:6’,7’Jindolizino[1’,2’:6,5] pyrido(4,3,2-de]quinazoline- . 10,13(9H,15H)-dione hydrochloride, tt)(98)-9-ethyl-9-[(L)-cyclohexylglycyl-(L)-y-glutamyloxy]-1-pentyl-1H,12H- ' pyrano[3”,4”:6’,7’)indolizino[1’,2":6,5]) pyrido[4,3,2-de] quinazoline- 10,13(9H,15H)-dione hydrochloride,
»” LJ
40. The pharmaceutical composition according to claim 39 which is suitable for oral or -parenteral administration.
41. Use of an anti-cancer compound according to any one of claims 11 to 37 for the preparation of medicaments.
42. The use according to claim 41 for the preparation of medicaments for the treatment of cell proliferative disorders.
43. The use according to claim 41 or 42 for the preparation of medicaments for the treatment of cancer.
44. The use according to any one of claims 41 to 43 for the preparation of medicaments for the treatment of colorectal cancer, lung cancer, breast cancer, stomach cancer, cervical cancer and bladder cancer.
45. The compound of any one of claims 11 to 37 for use in therapy. AMENDED SHEET
Applications Claiming Priority (1)
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EP01127401 | 2001-11-23 |
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ZA200403654B true ZA200403654B (en) | 2005-05-24 |
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ZA200403654A ZA200403654B (en) | 2001-11-23 | 2004-05-13 | Method of identification of tumor targeting enzymes. |
Country Status (4)
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CN (1) | CN1911921A (en) |
GT (1) | GT200200241A (en) |
UY (1) | UY27547A1 (en) |
ZA (1) | ZA200403654B (en) |
-
2002
- 2002-11-18 CN CN 200610086816 patent/CN1911921A/en active Pending
- 2002-11-22 UY UY27547A patent/UY27547A1/en not_active Application Discontinuation
- 2002-11-22 GT GT200200241A patent/GT200200241A/en unknown
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2004
- 2004-05-13 ZA ZA200403654A patent/ZA200403654B/en unknown
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UY27547A1 (en) | 2003-06-30 |
CN1911921A (en) | 2007-02-14 |
GT200200241A (en) | 2003-06-20 |
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