LU86157A1 - NEW PROCESS FOR THE MANUFACTURE OF VINBLASTIN CONJUGATES AND DERIVATIVES THEREOF - Google Patents
NEW PROCESS FOR THE MANUFACTURE OF VINBLASTIN CONJUGATES AND DERIVATIVES THEREOF Download PDFInfo
- Publication number
- LU86157A1 LU86157A1 LU86157A LU86157A LU86157A1 LU 86157 A1 LU86157 A1 LU 86157A1 LU 86157 A LU86157 A LU 86157A LU 86157 A LU86157 A LU 86157A LU 86157 A1 LU86157 A1 LU 86157A1
- Authority
- LU
- Luxembourg
- Prior art keywords
- protein
- vinblastine
- arm
- compound
- amino
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6805—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a vinca alkaloid
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
« \ Λ"\ Λ
NOUVEAU PROCEDE DE FABRICATION DE CONJUGUES DE LA VINBLASTINE ET DE SES DERIVESNEW PROCESS FOR THE MANUFACTURE OF VINBLASTIN CONJUGATES AND DERIVATIVES THEREOF
Les brevets LU n° 84.78¼ du 29.4.83 et n° 85.161 du 29.12.83 se rapportent à des conjugués de la Vinblastine et de certains de ses dérivés connus avec des protéines ou des fragments de protéines de· formule.générale suivante : CH300C/ -r.Patents LU n ° 84.78¼ dated 29.4.83 and n ° 85.161 dated 29.12.83 relate to conjugates of Vinblastine and certain of its known derivatives with proteins or protein fragments of the following general formula: CH300C / -r.
3 ch3 ΓΟΗ r2 ·..3 ch3 ΓΟΗ r2 · ..
* dans laquelle A représente un "bras" dérive dl un composé bifonctionnel Rj représente un radical protéique éventuellement modifié, R2 représente un groupe méthoxy, un groupe amino ou un radical ester d'acide alpha-aminé lié par une liaison de type amide et dont le groupe ester comporte de 1 à 6 atomes de carbone, R représente un atome d'hydrogène ou un groupe hydroxyle, chaque fois dans les. deux configurations possibles ainsi que leurs sels d'addition avec un acide minéral ou organique. 1 . I...* in which A represents an "arm" derived from a bifunctional compound Rj represents an optionally modified protein radical, R2 represents a methoxy group, an amino group or an alpha-amino acid ester radical linked by an amide-type bond and of which the ester group contains from 1 to 6 carbon atoms, R represents a hydrogen atom or a hydroxyl group, each in. two possible configurations as well as their addition salts with a mineral or organic acid. 1. I ...
' 11 est bien entendu que le bras du type hémlsuccinate, hémlglutarate ou homologue supérieur peut être substitué, par exemple par un groupe amino» éventuellement substitué tout en conservant l'acr tivité qui-caractérise les composés de l'invention.It is understood that the arm of the hemlsuccinate, hemlglutarate or higher homologous type can be substituted, for example by an amino group "optionally substituted while retaining the activity which characterizes the compounds of the invention.
« 2"2
La présente invention a pour objet des modifications et des améliorations relatives à une méthode permettant d'obtenir des conjugués où A représente un "bras" tel que -CO-CCH^-CO-, n variant de 2 à 5 éventuellement substitué par exemple par un groupe ami no ou amino substitué par une technique de condensation ne nécessitant qu'une £tape au lieu des deux étapes requises dans les brevets 'précitée'.The subject of the present invention is modifications and improvements relating to a method making it possible to obtain conjugates where A represents an "arm" such as -CO-CCH ^ -CO-, n varying from 2 to 5 optionally substituted for example by a no or amino friend group substituted by a condensation technique requiring only one step instead of the two steps required in the 'aforementioned' patents.
Les dérivés de la présente Invention sont obtenus par condensation du composé sur l'hydroxyle en C. de la 0-¾ désacétyl Vinblastine ou l'un de ces dérivés.The derivatives of the present invention are obtained by condensation of the compound on the hydroxyl in C. of 0-¾ deacetyl Vinblastine or one of these derivatives.
Le dérivé de la 0-9-désacétylvInblastlne peut être par exemple la vlndéslne, la 0-9-désacétylvlnblastIne couplée en C-3 avec un acide amiwé ou la 0-9-désacétyIdésoxy-9'-vlnbIastine ou un dérivé vInblastInoyl-53 d'ester d'acide aminé.The derivative of 0-9-deacetylvInblastlne can be for example vlndéslne, 0-9-deacetylvlnblastIne coupled in C-3 with a friendwic acid or 0-9-deacétyIdeoxy-9'-vlnbIastine or a derivative vInblastInoyl-53 d amino acid ester.
L'activation peut être effectuée de manière classique par traitement avec un chloroformiate- d'alkyle, de préférence le Chloroform late d'éthyle ou d'isobutyle, en présence d'une base aminée telle la N-méthyl pl péri dîne ou la N-méthyl morpholine ou la triéthylamlne.Activation can be carried out conventionally by treatment with an alkyl chloroformate, preferably ethyl or isobutyl chloroform late, in the presence of an amino base such as N-methyl pli-diene or N -methyl morpholine or triethylamine.
Le conjugué obtenu est Isolé au moyen de méthodes classiques utilisées en biochimie.The conjugate obtained is isolated using conventional methods used in biochemistry.
Les protéines qui peuvent être avantageusement utilisées sont en particulier l'albumine de sérum bovin ou humain/ la fétulne ou des immunoglobulines, ces dernières étant éventuellement obtenues par la i technique des anti-corps monoclonaux. Dans ce dernier cas, l'utilisation d'anti-corps monoclonaux d'origine humaine et montrant une certaine spécificité vis-à-vis de tumeurs humaines s'avère particulièrement Intéressante.The proteins which can be advantageously used are in particular bovine or human serum albumin / fetulne or immunoglobulins, the latter possibly being obtained by the technique of monoclonal antibodies. In the latter case, the use of monoclonal antibodies of human origin and showing a certain specificity vis-à-vis human tumors is particularly interesting.
Les protéines utilisées peuvent également être traitées afin d'être sélectivement modifiées. Ces modifications . permettent d'obtenir des conjugués protéiques qui seront, lors de leur utilisation thérapeutique, préférentiellement concentrées au niveau de certains tlssuS/ par exemple au niveau du foie. Il est ainsi possible, préalablement à la condensation du dérivé de la Vinblastine à la protéine, de gâlactosyler cette dernière.The proteins used can also be processed in order to be selectively modified. These modifications . allow protein conjugates to be obtained which, during their therapeutic use, are preferably concentrated at the level of certain tlssuS / for example at the level of the liver. It is thus possible, prior to the condensation of the derivative of Vinblastine with the protein, to galactosylate the latter.
La galactosylatlon est effectuée en appliquant par exemple le mode opératoire décrit par G. Wilson dans The Journal of Blochemlstry, 253 (7) 2070-2072, 1978.Galactosylation is carried out by applying, for example, the procedure described by G. Wilson in The Journal of Blochemlstry, 253 (7) 2070-2072, 1978.
Les exemples suivants Illustrent de manière non limitative les caractéristiques de l'Invention :The following examples illustrate, without limitation, the characteristics of the invention:
Exemple 1 : Couplage de l'albumine humaine succlnylée CAHS) avec la 0-9-désacétyl Vinblastine.Example 1: Coupling of succinylated human albumin CAHS) with 0-9-deacetyl Vinblastine.
a-) 269 pl d'une solution à 9% (V/v) de N-méthylmorpholIne (N.mM) dans la dlméthylformamlde (DMFA) et 312 μΐ d'une solution à 9% ( /v) d'Isobu-tylchloroformlate Cl B CF) dans la DMFA sont ajoutés à 9,6 ml de DMFA contenant 67,5 mgr d'albumlte sérique humaine succylînée.a-) 269 μl of a 9% solution (V / v) of N-methylmorpholine (N.mM) in dlmethylformamlde (DMFA) and 312 μΐ of a 9% solution (/ v) of Isobu- tylchloroformlate Cl B CF) in DMFA are added to 9.6 ml of DMFA containing 67.5 mgr of succylated human serum albumin.
////
fj Jfj J
if * / · * * 3 * • %if * / · * * 3 * •%
La solution est agitée pendant 15 min. Le mélange est refroidi à -15°C et ajouté à une solution froide de 19,2 mgr de désacétylvtnblastlne dans la DMFA. Le mélange est agité à -15°C pendant 3 heures ; 6 ml d'H„o sont ajoutés et la suspension résultante mise à dlalyser contre de VH 0. La solution est concentrée par utraflltratlon et chromato-graphlee sur une colonne de séphadex G25 équilibrée dans une solution de NaCl 9 °/o0 pH 7,5. Les fractions contenant le conjugué sont réunies et concentrées par ultrafiltration. Le contenu en protéine est mesuré par la technique de Lowry· et le contenu en alcaloïde estimé par mesure de la radioactivité. Le conjugué obtenu contient 0,8 môles ’ d'alcaloïde par môle de protéine.The solution is stirred for 15 min. The mixture is cooled to -15 ° C and added to a cold solution of 19.2 mgr of deacetylvtnblastlne in DMFA. The mixture is stirred at -15 ° C for 3 hours; 6 ml of H 2 O are added and the resulting suspension put to analyze against VH 0. The solution is concentrated by utraflltratlon and chromatographed on a column of Sephadex G25 equilibrated in a solution of NaCl 9 ° / o0 pH 7, 5. The fractions containing the conjugate are combined and concentrated by ultrafiltration. The protein content is measured by the Lowry · technique and the alkaloid content estimated by measuring the radioactivity. The conjugate obtained contains 0.8 moles of alkaloid per mole of protein.
b) 12,3 pl de N.mM Cl 12 pM) et 1^,6 pi d'IBCF (112 pM) sont ajoutés à 0°C à une solution d'albumine sérique humaine succlnylée (67,5 mg/9,6 ml H-0). Le mélange est agité à 0°C pendant 15 min et ajouté' à une solution de 18,8 mgr (25 pM) de sel sulfate de désacétylvlnblastlne dans 0,5 ml d'eau. La solution est agitée à 0°C pendant 3 heures et dialysée contre de l'eau. Le mélange est chromatographlé sur une colonne de séphadex G 25 équilibrée dans une solution de NaCJ 9 ®/00 pH 7,5. Les fractions contenant le conjugué sont réunies et concentrées par ultrafiltration. Le contenu en protéine est estimé par la technique de Lowry et le contenu en alcaloïde par radioactivité. Le conjugué obtenu contient 1 môle de vinca par môle de protéine.b) 12.3 μl of N.mM Cl 12 μM) and 1.6 μl of IBCF (112 μM) are added at 0 ° C. to a solution of succylated human serum albumin (67.5 mg / 9, 6 ml H-0). The mixture is stirred at 0 ° C for 15 min and added to a solution of 18.8 mgr (25 µM) of deacetylvinyl sulfate salt in 0.5 ml of water. The solution is stirred at 0 ° C for 3 hours and dialyzed against water. The mixture is chromatographed on a column of Sephadex G 25 equilibrated in a solution of NaCJ 9® / 00 pH 7.5. The fractions containing the conjugate are combined and concentrated by ultrafiltration. The protein content is estimated by the Lowry technique and the alkaloid content by radioactivity. The conjugate obtained contains 1 mole of vinca per mole of protein.
Exemple 2 : Couplage de l'albumine humaine succlnylée (AHS) avec la vlndéslne.Example 2: Coupling of succlnylated human albumin (AHS) with vlndéslne.
195,5 pl d'une solution à 4% de N.mM dans la DMFA et 231,1 pî d'une solution à 4% d'IMCF dans la DMFA sont ajoutés à 0°C à 3,1» ml de DMFA contenant 50 mg. d'albumine sérique humaine succyllnée. Après 15 min, le mélange est ajouté à 100 pM (55,6 mgr) de vlndéslne dissoute dans 500 ul de DMFA. Le mélange est agité à 0°C pendant 2U heures et dialysé contre de l'eau. La solution est chromatographlée sur une colonne de séphadex G 25. Le conjugué obtenu contient 8,8 môles de vlndéslne par môle de protéine.195.5 μl of a 4% solution of N.mM in DMFA and 231.1 μl of a 4% solution of IMCF in DMFA are added at 3.1 ° C. to 3.1 "ml of DMFA containing 50 mg. of succyllized human serum albumin. After 15 min, the mixture is added to 100 µM (55.6 mgr) of enzyme dissolved in 500 µl of DMFA. The mixture is stirred at 0 ° C. for 2 hours and dialyzed against water. The solution is chromatographed on a column of Sephadex G 25. The conjugate obtained contains 8.8 moles of vlndéslne per mole of protein.
Exemple 3 : Couplage de l'albumine humaine galactosylée succlnylée (AHgS) avec la DAVLB.Example 3: Coupling of succlnylated galactosylated human albumin (AHgS) with DAVLB.
Suivant le procédé décrit dans l'exemple 1 a), mais en · remplaçant l'albumine humaine succlnylée (AHS) par l'albumine humaine galactosylée succlnylée (AHgS), on obtient le conjugué qui contient 12,5 môles d'alcaloïde par môle de protéine.According to the process described in example 1 a), but by replacing succlnylated human albumin (AHS) by galactosylated succinylated human albumin (AHgS), the conjugate is obtained which contains 12.5 moles of alkaloid per mole of protein.
Exemple *4 : Couplage Immunoglobulines non spécifiques de sérum de chèvre succînylées (IgGS) avec la N-Ob - désacétyl- vlnblastInoyl-23 Isoleucinate d'éthyle.Example * 4: Coupling of non-specific succinylated goat serum immunoglobulins (IgGS) with ethyl N-Ob-deacetyl-vlnblastInoyl-23 Isoleucinate.
Suivant le procédé décrit dans l'exemple 1 b), on obtient un conjugué qui contient 8 môles d'alcaloïdes par môle de protéine.According to the method described in Example 1 b), a conjugate is obtained which contains 8 moles of alkaloids per mole of protein.
AAT
fi ' --------- ^fi '--------- ^
Claims (11)
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LU86157A LU86157A1 (en) | 1985-11-12 | 1985-11-12 | NEW PROCESS FOR THE MANUFACTURE OF VINBLASTIN CONJUGATES AND DERIVATIVES THEREOF |
AT86870042T ATE89567T1 (en) | 1985-11-12 | 1986-04-08 | CONJUGATES OF VINBLASTINE AND ITS DERIVATIVES, PROCESSES FOR THE PREPARATION OF THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE CONJUGATES. |
EP86870042A EP0222722B1 (en) | 1985-11-12 | 1986-04-08 | Conjugates of vinblastine and its derivatives, process for preparing them and pharmaceutical compositions containing these conjugates |
DE8686870042T DE3688451D1 (en) | 1985-11-12 | 1986-04-08 | VINBLASTIN CONJUGATES AND ITS DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE CONJUGATES. |
GR862436A GR862436B (en) | 1985-11-12 | 1986-09-24 | Method for preparing conjugate compounds of vinblastine and its derivatives and pharmaceutical compositions containing the conjucate compounds |
AU63401/86A AU577206B2 (en) | 1985-11-12 | 1986-09-30 | Conjugates of vinblastine and protein |
DK473286A DK164107C (en) | 1985-11-12 | 1986-10-03 | CONJUGATES OF VINBLASTIN OR DERIVATIVES THEREOF, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
HU864190A HU196217B (en) | 1985-11-12 | 1986-10-06 | Process for production of new vinblastin-ensime-conjugates and their derivatives and medical compounds containing such substances |
OA58971A OA08424A (en) | 1985-11-12 | 1986-10-07 | New conjugates of vinblastine and its derivatives, process for their preparation and pharmaceutical compositions containing these conjugates. |
IL80279A IL80279A0 (en) | 1984-04-25 | 1986-10-10 | New conjugates of vinblastine and its derivatives,a process for their preparation and pharmaceutical compositions containing the same |
ZA867805A ZA867805B (en) | 1985-11-12 | 1986-10-15 | New conjugates of vinblastine and its derivatives,a process for their preparation and pharmaceutical compositions containing the same |
NZ21812786A NZ218127A (en) | 1984-04-30 | 1986-10-30 | Conjugates of vinblastine and pharmaceutical compositions |
JP61269474A JPS62246599A (en) | 1985-11-12 | 1986-11-12 | Novel composite of vinblastine and its derivative and its production and pharmocological composition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LU86157A LU86157A1 (en) | 1985-11-12 | 1985-11-12 | NEW PROCESS FOR THE MANUFACTURE OF VINBLASTIN CONJUGATES AND DERIVATIVES THEREOF |
LU86157 | 1985-11-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
LU86157A1 true LU86157A1 (en) | 1987-06-26 |
Family
ID=19730582
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
LU86157A LU86157A1 (en) | 1984-04-25 | 1985-11-12 | NEW PROCESS FOR THE MANUFACTURE OF VINBLASTIN CONJUGATES AND DERIVATIVES THEREOF |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0222722B1 (en) |
JP (1) | JPS62246599A (en) |
DE (1) | DE3688451D1 (en) |
LU (1) | LU86157A1 (en) |
ZA (1) | ZA867805B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5006652A (en) * | 1988-08-08 | 1991-04-09 | Eli Lilly And Company | Intermediates for antibody-vinca drug conjugates |
US6319894B1 (en) * | 1997-01-08 | 2001-11-20 | The Picower Institute For Medical Research | Complexes and combinations of fetuin with therapeutic agents |
WO2000006582A1 (en) * | 1998-07-31 | 2000-02-10 | Goldsmith Seeds, Inc. | Trimeric and polymeric alkaloids |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0121388B1 (en) * | 1983-03-30 | 1990-06-13 | Lilly Industries Limited | Immunoglobulin conjugates |
DE3484691D1 (en) * | 1983-04-29 | 1991-07-18 | Omnichem Sa | CONJUGED VINBLASTIN COMPOUNDS AND THEIR DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
US4522750A (en) * | 1984-02-21 | 1985-06-11 | Eli Lilly And Company | Cytotoxic compositions of transferrin coupled to vinca alkaloids |
-
1985
- 1985-11-12 LU LU86157A patent/LU86157A1/en unknown
-
1986
- 1986-04-08 EP EP86870042A patent/EP0222722B1/en not_active Expired - Lifetime
- 1986-04-08 DE DE8686870042T patent/DE3688451D1/en not_active Expired - Lifetime
- 1986-10-15 ZA ZA867805A patent/ZA867805B/en unknown
- 1986-11-12 JP JP61269474A patent/JPS62246599A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
EP0222722A2 (en) | 1987-05-20 |
EP0222722A3 (en) | 1989-09-06 |
DE3688451D1 (en) | 1993-06-24 |
ZA867805B (en) | 1987-06-24 |
EP0222722B1 (en) | 1993-05-19 |
JPS62246599A (en) | 1987-10-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4870162A (en) | Conjugates of vinblastine, a process for their preparation and their use in therapy | |
CA1238000A (en) | Homologues of aprotinin with, in place of lysine, other aminoacids in position 15, process for their preparation and their use as medicaments | |
EP0269188B1 (en) | Cytotoxic conjugates useful in therapy, and process for obtaining them | |
CA1336119C (en) | Vinca derivative conjugates containing a c-3 detergent chain | |
EP0080401B1 (en) | Carcinostatic medicaments for treating t-leukemias, constituted by the ricin a chain and a specific monoclonal antibody | |
JPH07505634A (en) | Novel opiate derivatives, protein and polypeptide opiate-derived conjugates and labels | |
FR2622192A1 (en) | MONOPHOSPHORYL LIPID DERIVATIVES AND PROCESS FOR THEIR PREPARATION | |
HU188314B (en) | Process for production of preparatives suitable for treating of melanoma | |
EP0232693A2 (en) | Conjugates of vinblastine and its derivatives, process for their preparation and pharmaceutical compositions containing them | |
EP0322262B1 (en) | Basic protein phospholipase a2 of an elapide snake venom, amino acid sequence thereof, derivatives and fragments thereof, process for obtaining them, therapeutic compositions and diagnostic agents containing them | |
AU3940493A (en) | Novel amphetamine derivatives and protein and polypeptide amphetamine derivative conjugates and labels | |
KR0133130B1 (en) | Drug conjugates with methyl olthio-antitumor target form and their preparing method | |
US5298491A (en) | Derivatives of endogenous mediators, their salts, method of preparation, applications and compositions in which they are present | |
JPH11504646A (en) | Peptide compounds inhibiting the release of metalloproteases and TNF and their therapeutic use | |
EP0255424B1 (en) | Immunotoxins, process for preparing them and pharmaceutical compositions containing them | |
LU86157A1 (en) | NEW PROCESS FOR THE MANUFACTURE OF VINBLASTIN CONJUGATES AND DERIVATIVES THEREOF | |
US5238837A (en) | Superoxide dismutase derivatives | |
CA1335686C (en) | Vinblastin and pharmaceutical composition comprising them | |
US4767745A (en) | Conjugates of leukotrienes with proteins | |
US4954638A (en) | Leukotriene by amides and hydrazides | |
US4582703A (en) | Cytotoxic medicament formed from the association of at least one immunotoxin and chloroquin | |
JPS638427B2 (en) | ||
LU86212A1 (en) | NOVEL CONJUGATES OF VINBLASTINE AND DERIVATIVES THEREOF, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
Shields et al. | Synthesis of a S‐(Carboxymethyl) cysteine Analog of (L‐2‐Amino‐6‐adipyl)‐L‐cysteinyl‐D‐valine and its Cell Free Biosynthetic Conversion into 6‐[2‐(D‐2‐Amino‐2‐carboxyethyl) thio) acetamido] penicillanic Acid | |
LU84784A1 (en) | NOVEL PROTEIN CONJUGATES OF VINBLASTIN, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC USE |