CA2014459C - Formes ciblees d'agents antitumoraux methyltrithio - Google Patents

Formes ciblees d'agents antitumoraux methyltrithio Download PDF

Info

Publication number: CA2014459C
Authority: CA; Canada
Prior art keywords: compound; ch3sss; formula; reacting; protein
Prior art date: 1989-04-14
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Lifetime

Application number

CA002014459A

Other languages

English (en)

Other versions

CA2014459A1 (fr

Inventor

George A. Ellestad

William J. Mcgahren

Martin L. Sassiver

Philip R. Hamann

Lois M. Hinman

Janis Upeslacis

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Wyeth Holdings LLC

Original Assignee

American Cyanamid Co

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.)

1989-04-14

Filing date

1990-04-12

Publication date

2002-06-04

1989-04-14 Priority claimed from US07/339,343 external-priority patent/US5053394A/en

1990-04-12 Application filed by American Cyanamid Co filed Critical American Cyanamid Co

1990-10-14 Publication of CA2014459A1 publication Critical patent/CA2014459A1/fr

2002-06-04 Application granted granted Critical

2002-06-04 Publication of CA2014459C publication Critical patent/CA2014459C/fr

2010-04-12 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

-1 methyltrithio Chemical group 0.000 title claims abstract description 74
239000002246 antineoplastic agent Substances 0.000 title abstract description 9
238000000034 method Methods 0.000 claims abstract description 30
229940079593 drug Drugs 0.000 claims abstract description 26
239000003814 drug Substances 0.000 claims abstract description 26
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 123
150000001875 compounds Chemical class 0.000 claims description 73
238000006243 chemical reaction Methods 0.000 claims description 41
125000003047 N-acetyl group Chemical group 0.000 claims description 37
239000000562 conjugate Substances 0.000 claims description 37
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
206010028980 Neoplasm Diseases 0.000 claims description 35
239000001990 protein-drug conjugate Substances 0.000 claims description 33
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
239000003972 antineoplastic antibiotic Substances 0.000 claims description 27
239000003242 anti bacterial agent Substances 0.000 claims description 22
229940088710 antibiotic agent Drugs 0.000 claims description 20
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
238000001228 spectrum Methods 0.000 claims description 20
230000008569 process Effects 0.000 claims description 19
230000000259 anti-tumor effect Effects 0.000 claims description 17
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
230000009467 reduction Effects 0.000 claims description 15
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
239000000463 material Substances 0.000 claims description 14
125000003396 thiol group Chemical group [H]S* 0.000 claims description 14
125000002346 iodo group Chemical group I* 0.000 claims description 13
235000018102 proteins Nutrition 0.000 claims description 13
108090000623 proteins and genes Proteins 0.000 claims description 13
102000004169 proteins and genes Human genes 0.000 claims description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 claims description 11
150000001299 aldehydes Chemical class 0.000 claims description 11
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
238000002211 ultraviolet spectrum Methods 0.000 claims description 11
239000012634 fragment Substances 0.000 claims description 10
150000003573 thiols Chemical class 0.000 claims description 10
238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 claims description 9
238000002329 infrared spectrum Methods 0.000 claims description 9
NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 8
OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 claims description 8
125000003282 alkyl amino group Chemical group 0.000 claims description 8
125000000837 carbohydrate group Chemical group 0.000 claims description 8
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 8
125000003710 aryl alkyl group Chemical group 0.000 claims description 7
239000008366 buffered solution Substances 0.000 claims description 7
125000005241 heteroarylamino group Chemical group 0.000 claims description 7
238000004519 manufacturing process Methods 0.000 claims description 7
239000002253 acid Substances 0.000 claims description 6
125000003172 aldehyde group Chemical group 0.000 claims description 6
150000001412 amines Chemical class 0.000 claims description 6
239000003795 chemical substances by application Substances 0.000 claims description 6
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 6
230000003647 oxidation Effects 0.000 claims description 6
238000007254 oxidation reaction Methods 0.000 claims description 6
MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 claims description 5
125000003545 alkoxy group Chemical group 0.000 claims description 5
125000003118 aryl group Chemical group 0.000 claims description 5
VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 claims description 5
239000003102 growth factor Substances 0.000 claims description 5
229910052736 halogen Inorganic materials 0.000 claims description 5
230000009257 reactivity Effects 0.000 claims description 5
125000004414 alkyl thio group Chemical group 0.000 claims description 4
125000003277 amino group Chemical group 0.000 claims description 4
239000000427 antigen Substances 0.000 claims description 4
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108091007433 antigens Proteins 0.000 claims description 4
125000001769 aryl amino group Chemical group 0.000 claims description 4
125000001246 bromo group Chemical group Br* 0.000 claims description 4
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
125000000753 cycloalkyl group Chemical group 0.000 claims description 4
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
150000002148 esters Chemical class 0.000 claims description 4
125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 4
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IQIYDJRAZKPGKO-REOHCLBHSA-N (2r)-2-amino-3-sulfanylpropanehydrazide Chemical compound NNC(=O)[C@@H](N)CS IQIYDJRAZKPGKO-REOHCLBHSA-N 0.000 claims description 3
BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims description 3
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
239000003153 chemical reaction reagent Substances 0.000 claims description 3
125000005843 halogen group Chemical group 0.000 claims description 3
150000002367 halogens Chemical class 0.000 claims description 3
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
YQWPHBFLHAJVCG-UHFFFAOYSA-N 3-(4-sulfanylphenyl)propanoic acid Chemical compound OC(=O)CCC1=CC=C(S)C=C1 YQWPHBFLHAJVCG-UHFFFAOYSA-N 0.000 claims description 2
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 2
150000001718 carbodiimides Chemical group 0.000 claims description 2
KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
235000019260 propionic acid Nutrition 0.000 claims description 2
239000012279 sodium borohydride Substances 0.000 claims description 2
229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
230000004614 tumor growth Effects 0.000 claims description 2
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 2
JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims 19
150000003512 tertiary amines Chemical class 0.000 claims 10
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 5
239000008351 acetate buffer Substances 0.000 claims 5
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 5
239000012062 aqueous buffer Substances 0.000 claims 4
150000008064 anhydrides Chemical class 0.000 claims 3
230000000174 oncolytic effect Effects 0.000 claims 3
RQPNXPWEGVCPCX-UHFFFAOYSA-N 3-sulfanylbutanoic acid Chemical compound CC(S)CC(O)=O RQPNXPWEGVCPCX-UHFFFAOYSA-N 0.000 claims 2
102000003886 Glycoproteins Human genes 0.000 claims 2
108090000288 Glycoproteins Proteins 0.000 claims 2
241000124008 Mammalia Species 0.000 claims 2
125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 2
239000012304 carboxyl activating agent Substances 0.000 claims 2
XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 claims 1
PBYIIRLNRCVTMQ-UHFFFAOYSA-N 2,3,5,6-tetrafluorophenol Chemical compound OC1=C(F)C(F)=CC(F)=C1F PBYIIRLNRCVTMQ-UHFFFAOYSA-N 0.000 claims 1
MKSXLGXACWUEPT-UHFFFAOYSA-N 3-(4-sulfanylphenyl)propanehydrazide Chemical compound NNC(=O)CCC1=CC=C(S)C=C1 MKSXLGXACWUEPT-UHFFFAOYSA-N 0.000 claims 1
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims 1
SRNHFGGOWAGEPZ-UHFFFAOYSA-N 3-methyl-3-sulfanylbutanehydrazide Chemical compound CC(C)(S)CC(=O)NN SRNHFGGOWAGEPZ-UHFFFAOYSA-N 0.000 claims 1
IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims 1
150000001732 carboxylic acid derivatives Chemical group 0.000 claims 1
XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 1
235000018417 cysteine Nutrition 0.000 claims 1
239000003966 growth inhibitor Substances 0.000 claims 1
IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims 1
239000000047 product Substances 0.000 description 55
210000004027 cell Anatomy 0.000 description 38
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 31
238000002513 implantation Methods 0.000 description 28
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
239000000203 mixture Substances 0.000 description 19
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
230000014759 maintenance of location Effects 0.000 description 17
239000000741 silica gel Substances 0.000 description 17
229910002027 silica gel Inorganic materials 0.000 description 17
239000000243 solution Substances 0.000 description 17
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
239000002904 solvent Substances 0.000 description 16
238000011282 treatment Methods 0.000 description 16
238000003756 stirring Methods 0.000 description 15
BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 14
239000007924 injection Substances 0.000 description 14
238000002347 injection Methods 0.000 description 14
238000005259 measurement Methods 0.000 description 14
238000012360 testing method Methods 0.000 description 14
239000000523 sample Substances 0.000 description 13
238000003359 percent control normalization Methods 0.000 description 11
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
229940086542 triethylamine Drugs 0.000 description 10
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 9
229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 9
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108091003079 Bovine Serum Albumin Proteins 0.000 description 8
229910052786 argon Inorganic materials 0.000 description 8
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239000012894 fetal calf serum Substances 0.000 description 8
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238000004007 reversed phase HPLC Methods 0.000 description 8
208000026310 Breast neoplasm Diseases 0.000 description 7
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 7
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230000003115 biocidal effect Effects 0.000 description 6
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125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 5
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CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
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OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 4
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Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Peptides Or Proteins (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

CA002014459A 1989-04-14 1990-04-12 Formes ciblees d'agents antitumoraux methyltrithio Expired - Lifetime CA2014459C (fr)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US07/339,343 US5053394A (en)	1988-09-21	1989-04-14	Targeted forms of methyltrithio antitumor agents
US07/339,343		1989-04-14

Publications (2)

Publication Number	Publication Date
CA2014459A1 CA2014459A1 (fr)	1990-10-14
CA2014459C true CA2014459C (fr)	2002-06-04

Family

ID=23328581

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002014459A Expired - Lifetime CA2014459C (fr)	1989-04-14	1990-04-12	Formes ciblees d'agents antitumoraux methyltrithio

Country Status (2)

Country	Link
CA (1)	CA2014459C (fr)
PH (1)	PH27270A (fr)

1990
- 1990-04-11 PH PH40367A patent/PH27270A/en unknown
- 1990-04-12 CA CA002014459A patent/CA2014459C/fr not_active Expired - Lifetime

Also Published As

Publication number	Publication date
PH27270A (en)	1993-05-04
CA2014459A1 (fr)	1990-10-14

Legal Events

Date	Code	Title	Description
1996-05-03	EEER	Examination request
2010-04-12	MKEX	Expiry

Publication	Publication Date	Title
US5053394A (en)	1991-10-01	Targeted forms of methyltrithio antitumor agents
US5770701A (en)	1998-06-23	Process for preparing targeted forms of methyltrithio antitumor agents
JP3234980B2 (ja)	2001-12-04	新規な二官能性化合物を含むコンジュゲートの製法
US5824805A (en)	1998-10-20	Branched hydrazone linkers
US5556623A (en)	1996-09-17	Antibody-drug conjugates
US5006652A (en)	1991-04-09	Intermediates for antibody-vinca drug conjugates
US5094849A (en)	1992-03-10	Cytotoxic antibody conjugates of hydrazide derivatized vinca analogs via simple organic linkers
PL172837B1 (pl)	1997-12-31	Preparat farmaceutyczny zawierajacy koniugaty tioeterowe PL PL PL PL PL
EP0313873B1 (fr)	1994-09-28	Formes cibles d'agents méthyltrithio antitumoraux
HU208161B (en)	1993-08-30	Process for producing cytotoxic active ingredient - antibody conjugates and pharmaceutical compositions
CZ298024B6 (cs)	2007-05-30	Zpusoby prípravy monomerních konjugátu nosice a derivátu calicheamicinu
WO2008033475A2 (fr)	2008-03-20	Composés cytotoxiques activés destinés à se fixer à des molécules de ciblage dans le traitement de maladies touchant des mammifères
EP0392384A2 (fr)	1990-10-17	Formes ciblés d'agents méthyltrithio antitumoraux
CA2014459C (fr)	2002-06-04	Formes ciblees d'agents antitumoraux methyltrithio
CA1341315C (fr)	2001-11-06	Formes ciblees d'agents antitumoraux methyltrithio
KR0159767B1 (ko)	1998-11-16	메틸-트리티오기를 갖는 화합물로 부터 제조된 항종양항균 물질인 치환 디설파이드, 그의 목적 형태및 그의 제조 방법
CA2239183C (fr)	2006-08-29	Segments de liaison hydrazone ramifies