ZA200601055B - Regioselective synthesis of CCI-779 - Google Patents

Regioselective synthesis of CCI-779 Download PDF

Info

Publication number: ZA200601055B
Authority: ZA; South Africa
Prior art keywords: carbon atoms; phenyl; rapamycin; alkyl; alkenyl
Prior art date: 2003-08-07

Application number

ZA200601055A

Other languages

English (en)

Inventor

Chew Warren

Shaw Chia-Cheng

Original Assignee

Wyeth Corp

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2003-08-07

Filing date

2006-02-06

Publication date

2008-07-30

2006-02-06 Application filed by Wyeth Corp filed Critical Wyeth Corp

2008-07-30 Publication of ZA200601055B publication Critical patent/ZA200601055B/en

Links

CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 title claims description 24
229960000235 temsirolimus Drugs 0.000 title claims description 24
230000015572 biosynthetic process Effects 0.000 title description 10
238000003786 synthesis reaction Methods 0.000 title description 9
125000004432 carbon atom Chemical group C* 0.000 claims description 77
ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 64
229960002930 sirolimus Drugs 0.000 claims description 64
QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 63
238000000034 method Methods 0.000 claims description 47
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 40
230000008569 process Effects 0.000 claims description 34
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 33
150000001875 compounds Chemical class 0.000 claims description 33
125000000217 alkyl group Chemical group 0.000 claims description 31
-1 -(CR12R13)OR10 Chemical group 0.000 claims description 30
125000003342 alkenyl group Chemical group 0.000 claims description 24
229910052739 hydrogen Inorganic materials 0.000 claims description 24
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 23
239000001257 hydrogen Substances 0.000 claims description 23
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
125000000304 alkynyl group Chemical group 0.000 claims description 20
150000008064 anhydrides Chemical class 0.000 claims description 20
150000002009 diols Chemical class 0.000 claims description 17
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
239000000243 solution Substances 0.000 claims description 14
239000002904 solvent Substances 0.000 claims description 13
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 11
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
239000002253 acid Substances 0.000 claims description 10
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
125000004849 alkoxymethyl group Chemical group 0.000 claims description 6
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 5
125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
230000010933 acylation Effects 0.000 claims description 4
238000005917 acylation reaction Methods 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 4
235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
230000002378 acidificating effect Effects 0.000 claims description 3
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
150000007522 mineralic acids Chemical class 0.000 claims description 3
239000003960 organic solvent Substances 0.000 claims description 3
229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
150000002170 ethers Chemical class 0.000 claims description 2
239000007974 sodium acetate buffer Substances 0.000 claims description 2
QOBHKTQNPVOMIX-UHFFFAOYSA-N 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid Chemical compound O1CC(C)(C(O)=O)COB1C1=CC=CC=C1 QOBHKTQNPVOMIX-UHFFFAOYSA-N 0.000 claims 5
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
229910052799 carbon Inorganic materials 0.000 claims 2
UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 claims 1
230000003301 hydrolyzing effect Effects 0.000 claims 1
235000019260 propionic acid Nutrition 0.000 claims 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
238000006243 chemical reaction Methods 0.000 description 23
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 20
239000000203 mixture Substances 0.000 description 20
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
239000000047 product Substances 0.000 description 10
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
238000002360 preparation method Methods 0.000 description 9
125000004429 atom Chemical group 0.000 description 7
238000000746 purification Methods 0.000 description 7
239000011541 reaction mixture Substances 0.000 description 7
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
PTBDIHRZYDMNKB-UHFFFAOYSA-N 2,2-Bis(hydroxymethyl)propionic acid Chemical compound OCC(C)(CO)C(O)=O PTBDIHRZYDMNKB-UHFFFAOYSA-N 0.000 description 5
SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 5
102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 5
108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 5
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
206010028980 Neoplasm Diseases 0.000 description 4
239000010410 layer Substances 0.000 description 4
239000012044 organic layer Substances 0.000 description 4
239000007787 solid Substances 0.000 description 4
DHYSREDHCSRVDY-UHFFFAOYSA-N 1-phenylborinane Chemical compound C1CCCCB1C1=CC=CC=C1 DHYSREDHCSRVDY-UHFFFAOYSA-N 0.000 description 3
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
241000699660 Mus musculus Species 0.000 description 3
125000003710 aryl alkyl group Chemical group 0.000 description 3
125000003118 aryl group Chemical group 0.000 description 3
230000008901 benefit Effects 0.000 description 3
ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 3
239000012267 brine Substances 0.000 description 3
239000006227 byproduct Substances 0.000 description 3
150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
210000004027 cell Anatomy 0.000 description 3
230000022131 cell cycle Effects 0.000 description 3
230000000694 effects Effects 0.000 description 3
239000006260 foam Substances 0.000 description 3
238000006460 hydrolysis reaction Methods 0.000 description 3
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
238000000338 in vitro Methods 0.000 description 3
238000011580 nude mouse model Methods 0.000 description 3
239000011734 sodium Substances 0.000 description 3
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
238000004809 thin layer chromatography Methods 0.000 description 3
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
229960000549 4-dimethylaminophenol Drugs 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
206010006187 Breast cancer Diseases 0.000 description 2
208000026310 Breast neoplasm Diseases 0.000 description 2
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
230000010190 G1 phase Effects 0.000 description 2
206010018338 Glioma Diseases 0.000 description 2
238000004566 IR spectroscopy Methods 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
PUJHOONLYLARKJ-UHFFFAOYSA-N O=C1C(BCC(C1)C(=O)O)=O Chemical compound O=C1C(BCC(C1)C(=O)O)=O PUJHOONLYLARKJ-UHFFFAOYSA-N 0.000 description 2
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
125000003545 alkoxy group Chemical group 0.000 description 2
239000002246 antineoplastic agent Substances 0.000 description 2
125000004104 aryloxy group Chemical group 0.000 description 2
239000000872 buffer Substances 0.000 description 2
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
239000003054 catalyst Substances 0.000 description 2
150000001793 charged compounds Chemical class 0.000 description 2
239000003153 chemical reaction reagent Substances 0.000 description 2
IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
238000005859 coupling reaction Methods 0.000 description 2
ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
239000003480 eluent Substances 0.000 description 2
238000000605 extraction Methods 0.000 description 2
238000001914 filtration Methods 0.000 description 2
230000012010 growth Effects 0.000 description 2
230000007062 hydrolysis Effects 0.000 description 2
238000001727 in vivo Methods 0.000 description 2
238000002329 infrared spectrum Methods 0.000 description 2
230000005764 inhibitory process Effects 0.000 description 2
230000010534 mechanism of action Effects 0.000 description 2
238000012544 monitoring process Methods 0.000 description 2
SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
230000009467 reduction Effects 0.000 description 2
YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
239000001632 sodium acetate Substances 0.000 description 2
235000017281 sodium acetate Nutrition 0.000 description 2
239000012265 solid product Substances 0.000 description 2
239000007858 starting material Substances 0.000 description 2
125000001424 substituent group Chemical group 0.000 description 2
238000011282 treatment Methods 0.000 description 2
VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
SFFSGPCYJCMDJM-UHFFFAOYSA-N 2-[2-(3-oxo-1,2-benzoselenazol-2-yl)ethyl]-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1CCN1C(=O)C(C=CC=C2)=C2[se]1 SFFSGPCYJCMDJM-UHFFFAOYSA-N 0.000 description 1
RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 1
241000969130 Atthis Species 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
208000032612 Glial tumor Diseases 0.000 description 1
102000000588 Interleukin-2 Human genes 0.000 description 1
108010002350 Interleukin-2 Proteins 0.000 description 1
206010061902 Pancreatic neoplasm Diseases 0.000 description 1
108091000080 Phosphotransferase Proteins 0.000 description 1
206010060862 Prostate cancer Diseases 0.000 description 1
208000000236 Prostatic Neoplasms Diseases 0.000 description 1
102000018679 Tacrolimus Binding Proteins Human genes 0.000 description 1
108010027179 Tacrolimus Binding Proteins Proteins 0.000 description 1
ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
229940034982 antineoplastic agent Drugs 0.000 description 1
229940041181 antineoplastic drug Drugs 0.000 description 1
238000013459 approach Methods 0.000 description 1
239000011260 aqueous acid Substances 0.000 description 1
150000001543 aryl boronic acids Chemical class 0.000 description 1
238000010533 azeotropic distillation Methods 0.000 description 1
125000005620 boronic acid group Chemical class 0.000 description 1
201000011510 cancer Diseases 0.000 description 1
230000004663 cell proliferation Effects 0.000 description 1
238000011210 chromatographic step Methods 0.000 description 1
238000004440 column chromatography Methods 0.000 description 1
239000012141 concentrate Substances 0.000 description 1
239000007819 coupling partner Substances 0.000 description 1
239000013078 crystal Substances 0.000 description 1
230000001086 cytosolic effect Effects 0.000 description 1
239000000824 cytostatic agent Substances 0.000 description 1
230000001085 cytostatic effect Effects 0.000 description 1
229940127089 cytotoxic agent Drugs 0.000 description 1
239000002254 cytotoxic agent Substances 0.000 description 1
231100000599 cytotoxic agent Toxicity 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
150000005690 diesters Chemical class 0.000 description 1
238000007865 diluting Methods 0.000 description 1
230000008034 disappearance Effects 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
239000012467 final product Substances 0.000 description 1
125000000524 functional group Chemical group 0.000 description 1
208000005017 glioblastoma Diseases 0.000 description 1
239000003102 growth factor Substances 0.000 description 1
229910052736 halogen Inorganic materials 0.000 description 1
150000002367 halogens Chemical class 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
239000012535 impurity Substances 0.000 description 1
238000010249 in-situ analysis Methods 0.000 description 1
238000011065 in-situ storage Methods 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
238000011221 initial treatment Methods 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
238000002955 isolation Methods 0.000 description 1
208000032839 leukemia Diseases 0.000 description 1
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
201000001441 melanoma Diseases 0.000 description 1
108020004999 messenger RNA Proteins 0.000 description 1
HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
238000002156 mixing Methods 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
125000000896 monocarboxylic acid group Chemical group 0.000 description 1
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
210000000653 nervous system Anatomy 0.000 description 1
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
229910052757 nitrogen Inorganic materials 0.000 description 1
XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
201000002528 pancreatic cancer Diseases 0.000 description 1
FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
102000020233 phosphotransferase Human genes 0.000 description 1
ZFACJPAPCXRZMQ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O.OC(=O)C1=CC=CC=C1C(O)=O ZFACJPAPCXRZMQ-UHFFFAOYSA-N 0.000 description 1
235000011056 potassium acetate Nutrition 0.000 description 1
239000000843 powder Substances 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
125000006239 protecting group Chemical group 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
238000011084 recovery Methods 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
238000010992 reflux Methods 0.000 description 1
230000000717 retained effect Effects 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
230000019491 signal transduction Effects 0.000 description 1
238000006884 silylation reaction Methods 0.000 description 1
241000894007 species Species 0.000 description 1
230000003595 spectral effect Effects 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
239000000725 suspension Substances 0.000 description 1
238000001308 synthesis method Methods 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
238000013518 transcription Methods 0.000 description 1
230000035897 transcription Effects 0.000 description 1
238000013519 translation Methods 0.000 description 1
210000004881 tumor cell Anatomy 0.000 description 1
230000004614 tumor growth Effects 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1
239000004246 zinc acetate Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888

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Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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ZA200601055A 2003-08-07 2006-02-06 Regioselective synthesis of CCI-779 ZA200601055B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US49324903P	2003-08-07	2003-08-07

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ZA200601055B true ZA200601055B (en)	2008-07-30

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ZA200601055A ZA200601055B (en)	2003-08-07	2006-02-06	Regioselective synthesis of CCI-779

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US (1)	US7153957B2 (de)
EP (1)	EP1658295B1 (de)
JP (1)	JP4227649B2 (de)
KR (1)	KR20060057605A (de)
CN (1)	CN1829722B (de)
AR (1)	AR045217A1 (de)
AT (1)	ATE365169T1 (de)
AU (1)	AU2004265267A1 (de)
BR (1)	BRPI0412667A (de)
CA (1)	CA2532988A1 (de)
CO (1)	CO5650251A2 (de)
CR (1)	CR8189A (de)
DE (1)	DE602004007145T2 (de)
DK (1)	DK1658295T3 (de)
EC (1)	ECSP066413A (de)
ES (1)	ES2287772T3 (de)
IL (1)	IL173134A0 (de)
MX (1)	MXPA06000951A (de)
NO (1)	NO20060494L (de)
PL (1)	PL1658295T3 (de)
PT (1)	PT1658295E (de)
RU (1)	RU2339639C2 (de)
TW (1)	TW200508241A (de)
UA (1)	UA83245C2 (de)
WO (1)	WO2005016935A2 (de)
ZA (1)	ZA200601055B (de)

Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
WO2002085908A1 (en)	2001-04-24	2002-10-31	Purdue Research Foundation	Folate mimetics and folate-receptor binding conjugates thereof
CA2484640C (en) *	2002-05-15	2012-01-17	Endocyte, Inc.	Vitamin-mitomycin conjugates
AU2003254168A1 (en)	2002-07-30	2004-02-16	Wyeth	Parenteral formulations containing a rapamycin hydroxyester
JP5576007B2 (ja)	2003-01-27	2014-08-20	エンドサイト・インコーポレイテッド	ビタミン受容体結合性薬剤送達結合体
AU2004270154A1 (en) *	2003-09-03	2005-03-17	Wyeth	Amorphous rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid and its pharmaceutical compositions containing the same
DK1701698T3 (da) *	2004-01-08	2008-05-05	Wyeth Corp	Direkte komprimerbart farmaceutisk præparat til oral indgivelse af CCI-779
EP1737869A1 (de)	2004-04-14	2007-01-03	Wyeth a Corporation of the State of Delaware	Regiospezifische synthese von rapamycin-42-esterderivaten
CA2564811A1 (en)	2004-04-14	2005-10-27	Wyeth	Proline cci-779 (proline-rapamycin 42-ester with 2,2-bis (hydroxymethyl) propionic acid) and two-step enzymatic synthesis of proline cci-779 and cci-779 using microbial lipase
ES2313328T3 (es)	2004-04-14	2009-03-01	Wyeth	Procedimiento para la preparacion de 42-esteres de rapamicina y 32-esteres de fk-506 con acido dicarboxilico, precursores para conjugados de rapamicina y anticuerpos.
JP2007534337A (ja) *	2004-04-27	2007-11-29	ワイス	ラパマイシン特異的メチラーゼを用いるラパマイシンの標識
JP5149620B2 (ja) *	2004-07-23	2013-02-20	エンドサイト，インコーポレイテッド	２価リンカーおよびその結合体
SV2006002188A (es)	2004-08-10	2006-03-15	Wyeth Corp	Derivados de cci - 779 y metodos para su preparacion ref. am-101759salvo
WO2006050461A1 (en)	2004-10-28	2006-05-11	Wyeth	Use of an mtor inhibitor in treatment of uterine leiomyoma
EP1856130A1 (de)	2005-02-09	2007-11-21	Wyeth a Corporation of the State of Delaware	Cci-779-polymorph und verwendung
EP1853612A1 (de)	2005-03-02	2007-11-14	Wyeth	Reinigung von rapamycin
WO2006093743A1 (en) *	2005-03-02	2006-09-08	Wyeth	Recovery of cci-779 from mother liquors
WO2006101845A2 (en)	2005-03-16	2006-09-28	Endocyte, Inc.	Synthesis and purification of pteroic acid and conjugates thereof
JP2009504783A (ja) *	2005-08-19	2009-02-05	エンドサイト，インコーポレイテッド	ビンカアルカロイド、類似体および誘導体のリガンド結合体
EP2374480A3 (de)	2005-08-19	2013-05-01	Endocyte, Inc.	Multidrug-Ligandenkonjugate
WO2007056175A2 (en) *	2005-11-04	2007-05-18	Wyeth	41-methoxy isotope labeled rapamycin 42-ester
BRPI0618042A2 (pt)	2005-11-04	2011-08-16	Wyeth Corp	usos de uma rapamicina e de uma herceptina, produto, pacote farmacêutico, e, composição farmacêutica
RU2008120712A (ru) *	2005-12-07	2010-01-20	Вайет (Us)	Способы получения кристаллического рапамицина и определения кристалличности соединений рапамицина при помощи дифференциальной сканирующей калориметрии
RU2008120670A (ru)	2005-12-07	2010-01-20	Вайет (Us)	Масштабируемый способ получения 42-сложного эфира рапамицина из 42-сложного эфира рапамицина бороната
KR20080077618A (ko) *	2005-12-07	2008-08-25	와이어쓰	정제된 결정체 ｃｃｉ-779 의 제조 방법
EP1962819A1 (de) *	2005-12-20	2008-09-03	Wyeth	Steuerung der formstabilität einer cci-779-dosierung durch steuerung der unreinheiten von wirkstoffen
US20070203169A1 (en) *	2006-02-28	2007-08-30	Zhao Jonathon Z	Isomers and 42-epimers of rapamycin ester analogs, methods of making and using the same
TW200824713A (en) *	2006-10-18	2008-06-16	Wyeth Corp	Processes for the synthesis of individual isomers of mono-PEG CCI-779
US20080276935A1 (en)	2006-11-20	2008-11-13	Lixiao Wang	Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs
US8414525B2 (en)	2006-11-20	2013-04-09	Lutonix, Inc.	Drug releasing coatings for medical devices
US8414526B2 (en)	2006-11-20	2013-04-09	Lutonix, Inc.	Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids
US9700704B2 (en)	2006-11-20	2017-07-11	Lutonix, Inc.	Drug releasing coatings for balloon catheters
US8425459B2 (en)	2006-11-20	2013-04-23	Lutonix, Inc.	Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent
US20080175887A1 (en)	2006-11-20	2008-07-24	Lixiao Wang	Treatment of Asthma and Chronic Obstructive Pulmonary Disease With Anti-proliferate and Anti-inflammatory Drugs
US8414910B2 (en)	2006-11-20	2013-04-09	Lutonix, Inc.	Drug releasing coatings for medical devices
US9737640B2 (en)	2006-11-20	2017-08-22	Lutonix, Inc.	Drug releasing coatings for medical devices
US8998846B2 (en)	2006-11-20	2015-04-07	Lutonix, Inc.	Drug releasing coatings for balloon catheters
US20100104626A1 (en) *	2007-02-16	2010-04-29	Endocyte, Inc.	Methods and compositions for treating and diagnosing kidney disease
NZ580132A (en) *	2007-03-14	2012-11-30	Endocyte Inc	Binding ligand linked drug delivery conjugates of tubulysins to vitamins
TW200845960A (en) *	2007-04-05	2008-12-01	Wyeth Corp	Wortmannin-rapalog conjugate and uses thereof
TW200901989A (en) *	2007-04-10	2009-01-16	Wyeth Corp	Anti-tumor activity of CCI-779 in papillary renal cell cancer
CN104383553A (zh)	2007-06-25	2015-03-04	恩多塞特公司	含有亲水性间隔区接头的共轭物
US9877965B2 (en)	2007-06-25	2018-01-30	Endocyte, Inc.	Vitamin receptor drug delivery conjugates for treating inflammation
WO2009055562A1 (en)	2007-10-25	2009-04-30	Endocyte, Inc.	Tubulysins and processes for preparing
WO2010024898A2 (en)	2008-08-29	2010-03-04	Lutonix, Inc.	Methods and apparatuses for coating balloon catheters
WO2011051960A2 (en)	2009-09-25	2011-05-05	Cadila Healthcare Limited	Process for the preparation of rapamycin derivatives
AU2011210227A1 (en) *	2010-01-28	2012-08-30	Fresenius Kabi Oncology Ltd.	Process for the preparation of Temsirolimus and its intermediates
CN102020661B (zh) *	2011-01-07	2013-02-13	天津市炜杰科技有限公司	一种驮瑞塞尔合成方法
CN102020662B (zh)	2011-01-07	2013-02-13	天津市炜杰科技有限公司	一种驮瑞塞尔制备方法
EP2694520A1 (de) *	2011-04-01	2014-02-12	Sandoz AG	Regioselektive acylierung von rapamycin an der c-42-position
US10080805B2 (en)	2012-02-24	2018-09-25	Purdue Research Foundation	Cholecystokinin B receptor targeting for imaging and therapy
US20140080175A1 (en)	2012-03-29	2014-03-20	Endocyte, Inc.	Processes for preparing tubulysin derivatives and conjugates thereof
JP2015536323A (ja)	2012-10-16	2015-12-21	エンドサイト・インコーポレイテッドＥｎｄｏｃｙｔｅ，Ｉｎｃ．	非天然アミノ酸を含む薬物送達結合体および使用方法
CN104086564B (zh) *	2014-07-30	2019-02-05	江苏奥赛康药业股份有限公司	一种高纯度坦罗莫司的制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5362718A (en) *	1994-04-18	1994-11-08	American Home Products Corporation	Rapamycin hydroxyesters
DE19857765A1 (de) *	1998-12-15	2000-06-21	Clariant Gmbh	Verfahren zur Herstellung von para-Oxadiazolyl-phenyl-boronsäuren
US6277983B1 (en) *	2000-09-27	2001-08-21	American Home Products Corporation	Regioselective synthesis of rapamycin derivatives

2004
- 2004-07-15 PT PT04778398T patent/PT1658295E/pt unknown
- 2004-07-15 KR KR1020067002610A patent/KR20060057605A/ko not_active Ceased
- 2004-07-15 MX MXPA06000951A patent/MXPA06000951A/es active IP Right Grant
- 2004-07-15 EP EP04778398A patent/EP1658295B1/de not_active Expired - Lifetime
- 2004-07-15 AU AU2004265267A patent/AU2004265267A1/en not_active Abandoned
- 2004-07-15 DE DE602004007145T patent/DE602004007145T2/de not_active Expired - Fee Related
- 2004-07-15 UA UAA200602447A patent/UA83245C2/ru unknown
- 2004-07-15 RU RU2006106910/04A patent/RU2339639C2/ru not_active IP Right Cessation
- 2004-07-15 BR BRPI0412667-0A patent/BRPI0412667A/pt not_active IP Right Cessation
- 2004-07-15 CN CN2004800217944A patent/CN1829722B/zh not_active Expired - Fee Related
- 2004-07-15 PL PL04778398T patent/PL1658295T3/pl unknown
- 2004-07-15 ES ES04778398T patent/ES2287772T3/es not_active Expired - Lifetime
- 2004-07-15 JP JP2006522574A patent/JP4227649B2/ja not_active Expired - Fee Related
- 2004-07-15 DK DK04778398T patent/DK1658295T3/da active
- 2004-07-15 WO PCT/US2004/022860 patent/WO2005016935A2/en not_active Ceased
- 2004-07-15 AT AT04778398T patent/ATE365169T1/de not_active IP Right Cessation
- 2004-07-15 CA CA002532988A patent/CA2532988A1/en not_active Abandoned
- 2004-07-30 US US10/903,062 patent/US7153957B2/en not_active Expired - Fee Related
- 2004-08-04 AR ARP040102778A patent/AR045217A1/es unknown
- 2004-08-05 TW TW093123422A patent/TW200508241A/zh unknown
2006
- 2006-01-12 IL IL173134A patent/IL173134A0/en unknown
- 2006-01-13 CR CR8189A patent/CR8189A/es not_active Application Discontinuation
- 2006-01-31 NO NO20060494A patent/NO20060494L/no not_active Application Discontinuation
- 2006-02-06 ZA ZA200601055A patent/ZA200601055B/en unknown
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Publication number	Publication date
NO20060494L (no)	2006-03-06
RU2006106910A (ru)	2007-09-20
ES2287772T3 (es)	2007-12-16
JP2007501783A (ja)	2007-02-01
JP4227649B2 (ja)	2009-02-18
ECSP066413A (es)	2006-09-18
RU2339639C2 (ru)	2008-11-27
CR8189A (es)	2006-10-04
UA83245C2 (en)	2008-06-25
PT1658295E (pt)	2007-09-25
AU2004265267A1 (en)	2005-02-24
EP1658295A2 (de)	2006-05-24
CO5650251A2 (es)	2006-06-30
PL1658295T3 (pl)	2007-11-30
KR20060057605A (ko)	2006-05-26
WO2005016935A3 (en)	2005-04-07
CA2532988A1 (en)	2005-02-24
US7153957B2 (en)	2006-12-26
DK1658295T3 (da)	2007-09-24
EP1658295B1 (de)	2007-06-20
TW200508241A (en)	2005-03-01
MXPA06000951A (es)	2006-03-30
AR045217A1 (es)	2005-10-19
WO2005016935A2 (en)	2005-02-24
ATE365169T1 (de)	2007-07-15
US20050033046A1 (en)	2005-02-10
BRPI0412667A (pt)	2006-09-26
IL173134A0 (en)	2006-06-11
DE602004007145T2 (de)	2008-02-28
CN1829722A (zh)	2006-09-06
CN1829722B (zh)	2010-10-27
DE602004007145D1 (de)	2007-08-02
HK1085482A1 (en)	2006-08-25

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