WO1990010638A1 - Antitumoral agents with an affinity for steroid hormone receptors - Google Patents
Antitumoral agents with an affinity for steroid hormone receptors Download PDFInfo
- Publication number
- WO1990010638A1 WO1990010638A1 PCT/EP1990/000344 EP9000344W WO9010638A1 WO 1990010638 A1 WO1990010638 A1 WO 1990010638A1 EP 9000344 W EP9000344 W EP 9000344W WO 9010638 A1 WO9010638 A1 WO 9010638A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- cytostatic
- dichloromethane
- mmol
- conjugates
- Prior art date
Links
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- 108020003113 steroid hormone receptors Proteins 0.000 title claims abstract description 4
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/66—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to halogen atoms or to nitro or nitroso groups
- C07C275/68—N-nitroso ureas
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
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- C—CHEMISTRY; METALLURGY
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Definitions
- Cytostatics that are used clinically to treat malignant tumors often have severe toxicity, particularly myelotoxicity, hepatoxicity, nephrotoxicity and lung toxicity, which are dose-limiting factors and limit clinical effectiveness
- the object of the invention is accordingly compounds which achieve an accumulation in the tumor tissue through this linkage, which should result in an increase in the tumor-specific effect and a reduction in the systemic toxicities.
- Zytostati kakonjugate with such carrier molecules that have a binding affinity for steroid hormone receptors.
- the cytostatics and carriers are linked via
- Suitable fasteners usually amide or ester bonds are made.
- N-mustard derivatives and N- (2-chloroethyl) -N-nitrosoureas are alkylating agents. Some representatives are clinically established antineoplastics. Others show pronounced
- -oligopeptides have a free acid group which is responsible for
- Linkage can be exploited via a connecting element with carrier molecules.
- N- (2-chloroethyl) -N '- (2-hydroxyethyl) -N-nitrosourea and N, N-bis- (2-chloroethyl) aminoethylamine can be
- Link hydroxyl or amino group Linking antineoplastic antibiotics such as mitomycin, adriamycin, daunomycin, epirubicin, as well
- Anthracenedione derivatives such as mitoxantrone and amethantrone is via an amino. or hydroxyl group.
- Antineoplastic metal complexes such as
- (1,2ridiominoethane) -cis-dichloroplatin (n) are connected via a suitable connecting element e.g. COOH or -OH bound to the carrier molecule.
- a suitable connecting element e.g. COOH or -OH bound to the carrier molecule.
- Steroids on the one hand and non-steroidal ones serve as receptor-affine carriers
- steroid hormone repetitive affinity compounds on the other hand.
- the term steroid includes compounds with the basic structure of the Estran-s, Androstan and Pregnan series.
- Non-steroidal receptor-affine compounds are preferably those from the series of 2- [4- (1,2-diphenyl-1-butenyl) phenoxy] ethylamines. preferred starting materials, supports and connecting elements between supports and
- Steroids preferably those with a basic structure from the Estrans, Androstani or Pregnan (Gonan) series.
- Hydroxy-bearing steroids are preferably used from the group consisting of Estra 1,3,5 (10) triene, Androstane, Androst-4-ene, Androst-5-ene, Estr-4-ene, Estr-5 (10) ene, Estra- 4,9,11-triene, Pregn-4-ene,
- hydroxyl group (s) are preferably esterified in position 11, 17 or 21.
- non-steroidal steroid receptor-affine compounds preferably from the
- Antitumor agents are preferably used: - carboxalkyl groups
- the conjugates are produced by linking the connecting element on the one hand to the antitumor agent, and on the other hand to the steroid receptor-affine carrier via an ester or an amide bond.
- the esterification is preferably carried out with carbonyldiimidazole or dicyclohexylcarbodiimide (DCC) with or without the addition of p3dimethylaminopyridine (DMAP).
- DCC dicyclohexylcarbodiimide
- DMAP p3dimethylaminopyridine
- the amidation takes place by means of dicyclohexylcarbodiimide or carbonyldiimidazole with or without the addition of p-dimethylaminopyridine or via an active N-hydroxysuccinimide ester or via an azide of the acid.
- the esterification or amidation is carried out at room temperature.
- the reaction time is between 1 - 24 h, at room temperature or a little less at a slightly elevated temperature, e.g. 1 - 12 h.
- the conjugates are presented in pure form either by column chromatography on suitable adsorbents, preferably on silica gel, eluted with a suitable solvent or solvent mixture, or by recrystallization.
- Example 1 17ß-O- (CNC-1-alanylaminohexylamino-1,4-dioxo-butyl) estradiol 1.4 g (3 mmol)
- Tetrahydrofuran (THF) dissolved and slowly a solution of 1.05 g (3.6 mmol) of N- (CNC-L-alanyloxy) tetrahydropyrrole in 10 ml of THF is added dropwise. After 4 hours you do that
- estradiol-17-succinato-HECNU-ester-3-tetrahydropyranol ether is prepared and the protective group is split off with p-toluenesulfonic acid
- Example 4 is presented analogously to example 3, with the difference that the steroid hormone is none
- Example 5 is presented analogously to example 4,
- Example 6 17ß-O- (CNC-aminoethoxy-1,4-dioxo-butyl) -19-nortestosterone
- Adriamycin hydrochloride (0.055 mmol) suspended in 12 ml of absolute dimethylformamide. To release the
- Dichloromethane / triethylamine are 2 ml at 0 ° C.
- Acetylmelphalan are dissolved in dichloromethane and at 0 ° C with 660 mg (3.5 mmol) DCC and 370 mg (3.5 mmol)
- UV septa 3300, 2940, 1760, 1650, 1610, 1510, 1465, 1440, 1370, 1290, 1240, 1218, 1198, 1180, 1035, 840 UV septa:
- the mixture is acidified with ice-cold NaHSO 4 solution and extracted twice with dichloromethane.
- the organic phase is washed with saturated NaCl solution, dried over sodium sulfate, evaporated, the residue taken up in acetonitrile, the suspension is filtered and evaporated.
- UV-Spectrum 1370, 1290, 1240, 1220, 1200, 1175, ' 1110, 1030, 1020, 840 UV-Spectrum:
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention concerns cytostatic conjugates, e.g., antineoplastic alkylants, antibiotics, anthracene diones, metal complexes and substances of vegetable origin or semisynthetic derivatives, which are linked by means of suitable connecting elements, in particular by an amide and/or ester bond with carrier molecules that possess a binding affinity for steroid hormone receptors. In the process for manufacturing these products, the connecting element is linked in a known manner on the one hand with an antitumoral agent and on the other hand with the carrier with the steroid receptor affinity, in particular by an amide and/or ester bond.
Description
Steroidhormonrezeptor-affine Antitumorwirkstoffe Steroid hormone receptor-affine antitumor agents
Zytostatika, die klinisch zur Behandlung maligner Tumoren eingesetzt werden, weisen häufig schwerwiegende Toxiziät, insbesondere Myelotoxizität, Hepatoxizität, Nephrotoxizität und Lungentoxizität auf, die dosislimitierende Faktoren darstellen und die klinische Effektivität begrenzen Cytostatics that are used clinically to treat malignant tumors often have severe toxicity, particularly myelotoxicity, hepatoxicity, nephrotoxicity and lung toxicity, which are dose-limiting factors and limit clinical effectiveness
(Eisenbrand G. et al: in Experimental und clinical (Eisenbrand G. et al: in Experimental and clinical
chemotherapy. Vol. III, Georg Thieme Verlag, 1984, 35-91). chemotherapy. Vol. III, Georg Thieme Verlag, 1984, 35-91).
Zahlreiche menschliche Tumoren, vor allem Mammacarcinome, Prostatacarcinome, bestimmte Gastrointestinaltumoren und bestimmte Hirntumoren enthalten Hormonrezeptoren. Dies bietet die Möglichkeit einer gezielten Therapie durch Numerous human tumors, especially mammary carcinomas, prostate carcinomas, certain gastrointestinal tumors and certain brain tumors contain hormone receptors. This offers the possibility of targeted therapy
Verknüpfung von Zytostatika mit rezeptoraffinen Trägern. Linking cytostatics with receptor-affine carriers.
Aufgabe der Erfindung sind demnach Verbindungen, welche durch diese Verknüpfung eine Anreicherung im Tumorgewebe erreichen, was eine Erhöhung der tumorspezifischen Wirkung und eine Verringerung der systemischen Toxizitäten mit sich bringen sollte. The object of the invention is accordingly compounds which achieve an accumulation in the tumor tissue through this linkage, which should result in an increase in the tumor-specific effect and a reduction in the systemic toxicities.
Gegenstand der vorliegenden Patentanmeldung sind The subject of the present patent application are
Zytostati kakonjugate mit solchen Trägermolekülen, die eine Bindungsaffinität zu Steroidhormonrezeptoren aufweisen. Die Verknüpfung von Zytostatika und Trägern erfolgt über Zytostati kakonjugate with such carrier molecules that have a binding affinity for steroid hormone receptors. The cytostatics and carriers are linked via
geeignete Verbindungselemente, wobei in der Regel Amid- oder Esterbindungen geknüpft werden. Suitable fasteners, usually amide or ester bonds are made.
N-Lost-Derivate und N-(2-Chlorethyl)-N-nitrosoharnstoffe sind Alkylantien. Einige Vertreter sind klinisch etablierte Antineoplastika. Weitere zeigen ausgeprägte N-mustard derivatives and N- (2-chloroethyl) -N-nitrosoureas are alkylating agents. Some representatives are clinically established antineoplastics. Others show pronounced
antineoplastische Aktivität in experimentellen antineoplastic activity in experimental
Untersuchungen. Chlorambucil, Mephalan bzw. Acetylmelphalen,
N,N-Bis(2-Chlorethyl)-phosphorsäurediamid und Investigations. Chlorambucil, mephalan or acetylmelphalen, N, N-bis (2-chloroethyl) phosphoric acid diamide and
N-[N-(2-Chlorethyl)-N-nitrosocarbamy17aminosäuren oder N- [N- (2-chloroethyl) -N-nitrosocarbamy17 amino acids or
-oligopeptide besitzen eine freie Säuregruppe, die zur -oligopeptides have a free acid group which is responsible for
Verknüpfung über ein Verbindungselement mit Trägermolekülen ausgenutzt werden kann. Linkage can be exploited via a connecting element with carrier molecules.
N-(2-Chlorethyl)-N'-(2-hydroxyethyl)-N-nitrosoharnstoff und N,N-Bis-(2-Chlorethyl)-aminoethylamin lassen sich über N- (2-chloroethyl) -N '- (2-hydroxyethyl) -N-nitrosourea and N, N-bis- (2-chloroethyl) aminoethylamine can be
Hydroxyl- bzw. Aminogruppe verknüpfen. Die Verknüpfung von antineoplastischen Antibiotika, wie Mitomycin, Adriamycin, Daunomycin, Epirubicin, sowie Link hydroxyl or amino group. Linking antineoplastic antibiotics such as mitomycin, adriamycin, daunomycin, epirubicin, as well
Anthracendionderivate wie Mitoxantron und Amethantron wird über eine Amino. oder Hydroxylgruppe vorgenommen. Anthracenedione derivatives such as mitoxantrone and amethantrone is via an amino. or hydroxyl group.
Antineoplastische Metallkomplexe wie z.B. Antineoplastic metal complexes such as
(1,2ridiominoethan)-cis-dichloroplatin (n) werden über ein geeignetes Verbindungselement z.B. COOH oder -OH an das Trägermolekül gebunden. Als rezeptoraffine Träger dienen Steroide einerseits und nichtsteroidale (1,2ridiominoethane) -cis-dichloroplatin (n) are connected via a suitable connecting element e.g. COOH or -OH bound to the carrier molecule. Steroids on the one hand and non-steroidal ones serve as receptor-affine carriers
steroidhormonrezpetoraffine Verbindungen andererseits. Der Ausdruck Steroid umfaßt Verbindungen mit dem Grundgrüst der Estran-s, Androstan und Pregnanreihe. Nicht steroidale rezeptoraffine Verbindungen sind vorzugsweise solche aus der Reihe der 2-[4-(1,2-diphenyl-1-butenyl)-phenoxy]-ethylamine. im folgenden werden bevorzugte Ausgangsmaterialen, Träger und Verbindungselemente zwischen Träger und steroid hormone repetitive affinity compounds on the other hand. The term steroid includes compounds with the basic structure of the Estran-s, Androstan and Pregnan series. Non-steroidal receptor-affine compounds are preferably those from the series of 2- [4- (1,2-diphenyl-1-butenyl) phenoxy] ethylamines. preferred starting materials, supports and connecting elements between supports and
Antitumorwirkstoff gezeigt: Antitumor drug shown:
Ausgangsmaterialien: Starting materials:
1. Unter Antitumorwirkstoffen werden folgende klinisch 1. Among anti-tumor agents, the following are clinical
etablierten bzw. experimentell hochwirksamen Verbindungen verstanden:
Lost-Derivateestablished or experimentally highly effective compounds understood: Lost derivatives
- 4-[Bis(2-chlorethyl)amine]-phenylbuttersäure - 4- [bis (2-chloroethyl) amine] phenylbutyric acid
(Chlorambucil) (1) (Chlorambucil) (1)
- 4-[Bis(2-chlorethyl)amino]-L-phenylalanin (Melphalan) (2) - 4-[Bis(2-chlorethyl)amino]--N-acetyl-L-phenylalanin - 4- [bis (2-chloroethyl) amino] -L-phenylalanine (melphalan) (2) - 4- [bis (2-chloroethyl) amino] - N-acetyl-L-phenylalanine
(Acetylmelphalan) (3) (Acetylmelphalan) (3)
- N,N-Bis(2-Chlorethyl)aminoethylamin (Mustamin) (4)- N, N-bis (2-chloroethyl) aminoethylamine (mustamine) (4)
- N,N-Bis(2-Chlorethyl)-phosphorsäurediamid (5) CNC-Derivate- N, N-bis (2-chloroethyl) phosphoric acid diamide (5) CNC derivatives
- N-(2-Chlorethyl)-N'-(2-hydroxyethyl)-N-nitrosoharnstoff- N- (2-chloroethyl) -N '- (2-hydroxyethyl) -N-nitrosourea
(HECNU) (6)(HECNU) (6)
- N-[2-(2-Chlorethyl)-N-nitrosocarbamoyl]-aminosäure (7) oder oligopeptide (8) (CNC-aminosäuren, CNC-oligopeptide) - N- [2- (2-chloroethyl) -N-nitrosocarbamoyl] amino acid (7) or oligopeptide (8) (CNC amino acids, CNC oligopeptides)
Antitumor Antibiotica Antitumor antibiotics
- Adriamycin (9) - Adriamycin (9)
- Daunomycin (10) - Daunomycin (10)
- Epirubicin (11) - epirubicin (11)
- Idarubicin (12) - Idarubicin (12)
- Esorubicin (13) - Esorubicin (13)
- Aclarubicin (14) - aclarubicin (14)
- Carubicin (15) - Carubicin (15)
- Mitomycin (16) - Mitomycin (16)
- Bleomycin (17) - bleomycin (17)
Anthracendione -1,4-Dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino] -9.10-anthracendion (Metoxantron) (18) Anthracendione -1,4-dihydroxy-5,8-bis [[2 - [(2-hydroxyethyl) amino] ethyl] amino] -9.10-anthracendione (metoxantrone) (18)
-5.8-Bis-[[2-[(2-hydroxyethyl)amino]ethyl]'amino]-9.10-antrhacendion (Ametantron) (19)
Metallkomplexe-5.8-bis - [[2 - [(2-hydroxyethyl) amino] ethyl] ' amino] -9.10-antrhacendione (ametantrone) (19) Metal complexes
- N-Aminoalkyl-(1,2-diaminoethan)cis-dichloroplatin (II) (20)- Carboplatin (21)- N-aminoalkyl- (1,2-diaminoethane) cis-dichloroplatin (II) (20) - carboplatin (21)
- PHIC (22)- PHIC (22)
- Hydroxy-SDACH (23)- Hydroxy-SDACH (23)
- Cispt(II)-Citrat- Cispt (II) citrate
- CisPt(II)-Bisascorbat- CisPt (II) bisascorbate
- DACCP (24) - DACCP (24)
Pflanzeninhaltsstoffe bzw. semisynthetische DerivatePlant ingredients or semi-synthetic derivatives
- Vinblastin (25)- Vinblastine (25)
- Vincristin (26)- Vincristine (26)
- Vindesin (27)- Vindesin (27)
- vinzolidin (28)- vinzolidin (28)
- Etoposid (VM26) (29)- etoposide (VM26) (29)
- Teniposid (VP16) (30) - Teniposide (VP16) (30)
2. Als Träger dienen: 2. Serve as carrier:
Steroide, vorzugsweise solche mit Grundgerüst aus der Estrans, Androstani oder Pregnan- (Gonan) -Reihe. Steroids, preferably those with a basic structure from the Estrans, Androstani or Pregnan (Gonan) series.
Vorzugsweise werden Hydroxygruppenrjtragende steroide eingesetzt aus der Gruppe der Estra 1,3,5(10 )triene, Androstane, Androst-4-ene, Androst-5-ene, Estr-4-ene, Estr-5(10)ene, Estra-4,9,11-triene, Pregn-4-ene, Hydroxy-bearing steroids are preferably used from the group consisting of Estra 1,3,5 (10) triene, Androstane, Androst-4-ene, Androst-5-ene, Estr-4-ene, Estr-5 (10) ene, Estra- 4,9,11-triene, Pregn-4-ene,
Pregna-4,6-diene. Pregna-4,6-diene.
Vorzugsweise werden die Hydroxygruppe(n) in Position 11, 17 oder 21 verestert. Weiterhin werden nichtsteroidale steroidrezeptoraffine Verbindungen, vorzugsweise aus derThe hydroxyl group (s) are preferably esterified in position 11, 17 or 21. Furthermore, non-steroidal steroid receptor-affine compounds, preferably from the
Reihe der 2[4(1,2-diphenyl-1-butenyl)-phenoxγ]etylamine eingesetzt.
3. Als Verbindungselement zwischen Träger und Series of 2 [4 (1,2-diphenyl-1-butenyl) -phenoxγ] ethylamines used. 3. As a connecting element between the carrier and
Antitumorwirkstoff werden vorzugsweise eingesetzt: - Carboxalkylgruppen Antitumor agents are preferably used: - carboxalkyl groups
HOOC-(CH2)n-, n= 1-11HOOC- (CH 2 ) n -, n = 1-11
- Aminoalkylgruppen - aminoalkyl groups
NA2(CH2)n-, n = 1-12 NA 2 (CH 2 ) n -, n = 1-12
- Aminoalkylcarbonsäuren - Aminoalkyl carboxylic acids
NH2-(CH2)n-COOH, n = 1-11NH 2 - (CH 2 ) n -COOH, n = 1-11
- ω-Carboxyalkyl-1-oxo-aminoalkylamine - ω-carboxyalkyl-1-oxo-aminoalkylamines
NH2-(CH2)n-NH-CO- (CH2)m - COOH, n =1-11, m =1-12 NH 2 - (CH 2 ) n -NH-CO- (CH 2 ) m - COOH, n = 1-11, m = 1-12
- ω-Carboxalkyl -1-oxot-aminoalkylaminoalkylamin - ω-Carboxalkyl -1-oxot-aminoalkylaminoalkylamine
NH2- ( CH2)n-NH- ( CH2 )n - NH- CO- ( CH2 ) m-COOH , NH 2 - (CH 2 ) n -NH- (CH 2 ) n - NH-CO- (CH 2 ) m -COOH,
n = 1- 11 , m = 1-12 n = 1-11, m = 1-12
Hydroxylierte Di-, und TricarbonsäurenHydroxylated di- and tricarboxylic acids
- Milchsäure - lactic acid
- Weinsäure - tartaric acid
- Tartronsäure - tartronic acid
- Apfelsäure - malic acid
- Citronensäure - citric acid
Ethylendiamin-di-, tri- und tetracarbonsäure Ethylenediamine di-, tri- and tetracarboxylic acid
Amino- oder Oligopeptide (bis Hexapeptid) aus identischen oder unterschiedlichen Aminosäurebausteinen unter Amino or oligopeptides (up to hexapeptide) from identical or different amino acid building blocks
vorzugsweiser Verwendung von folgenden alpha-Aminosäuren - Glycin preferred use of the following alpha-amino acids - glycine
- Alanin - Alanine
- valin - valine
- Leucin - Leucine
- Isoleucin - isoleucine
- Methionin - methionine
- Sarkosin
- Prolin- Sarcosine - Proline
- Hydroxyprolin- hydroxyproline
- Cystein- cysteine
- Cystin- cystine
- phenylalanin- phenylalanine
- Tyrosin- tyrosine
- Tryptophan- tryptophan
- Lysin Tris-shydroxymethylaminomethan-imonoster von hydroxylierten oder nicht hydroxylierten Dicarbonsäuren bzw. Ethylendiamin- di-, tri-, oder tetracarbonsäure. - Lysine Tris-shydroxymethylaminomethan-imonoster of hydroxylated or non-hydroxylated dicarboxylic acids or ethylenediamine di-, tri-, or tetracarboxylic acid.
Die Herstellung der Konjugate erfolgt durch Verknüpfung von Verbindungselement einerseits mit dem Antitumorwirkstoff, andererseits mit dem steroidrezeptoraffinen Träger über eine Ester- oder eine Amid-Bindung. The conjugates are produced by linking the connecting element on the one hand to the antitumor agent, and on the other hand to the steroid receptor-affine carrier via an ester or an amide bond.
Die Veresterung erfolgt bevorzugt mit Carbonyldiimidazol oder Dicyclohexylcarbodiimid (DCC) mit oder ohne Zusatz von p3Dimethylaminopyridin (DMAP). Die Amidierung erfolgt mittels Dicyclohexylcarbodiimid oder Carbonyldiimidazol mit oder ohne Zusatz von p-Dimethylaminopyridin oder über einen aktiven N-Hydroxysuccinimid Ester bzw. über ein Azid der säure. The esterification is preferably carried out with carbonyldiimidazole or dicyclohexylcarbodiimide (DCC) with or without the addition of p3dimethylaminopyridine (DMAP). The amidation takes place by means of dicyclohexylcarbodiimide or carbonyldiimidazole with or without the addition of p-dimethylaminopyridine or via an active N-hydroxysuccinimide ester or via an azide of the acid.
Die Veresterung bzw. Amidierung wird bei Raumtemperatur vorgenommen. Allgemein ist die Reaktionsdauer zwischen 1 - 24 h, bei Zimmertemperatur oder etwas weniger bei leicht erhöhter Temperatur, z.B. 1 - 12 h. The esterification or amidation is carried out at room temperature. Generally the reaction time is between 1 - 24 h, at room temperature or a little less at a slightly elevated temperature, e.g. 1 - 12 h.
Folgende Lösungsmittel werden bevorzugt verwendet: The following solvents are preferred:
n-Hexan, Dichlormethan, Chloroform, Ether, Aceton, n-hexane, dichloromethane, chloroform, ether, acetone,
Tetranydrofuran, Methanol, Ethanol, Acetonitril, bzw. deren Gemische. Die Reindarstellung der Konjugate erfolgt entweder säulenchromatographisch an geeigneten Adsorptionsmitteln,
bevorzugt an Kieselgel, eluiert mit geeignetem Lösungsmittel oder Lösungsmittelgemisch, oder durch Umkristallisation. Tetranydrofuran, methanol, ethanol, acetonitrile, or their mixtures. The conjugates are presented in pure form either by column chromatography on suitable adsorbents, preferably on silica gel, eluted with a suitable solvent or solvent mixture, or by recrystallization.
Die folgenden Beispiele erläutern die Erfindung. Beispiel 1 17ß-O-(CNC-1-alanylaminohexylamino-1,4-dioxo-butyl)estradiol 1,4 g (3 mmol) The following examples illustrate the invention. Example 1 17ß-O- (CNC-1-alanylaminohexylamino-1,4-dioxo-butyl) estradiol 1.4 g (3 mmol)
17ß-O(Aminohexylamino-l,4-dioxo-butyl)-estradiol und eine Spatelspitze 4-Dimethylaminopyridin werden in 20 ml 17ß-O (aminohexylamino-l, 4-dioxo-butyl) -estradiol and a spatula tip 4-dimethylaminopyridine are in 20 ml
Tetrahydrofuran (THF) gelöst und langsam wird eine Lösung von 1,05 g (3,6 mmol) N-(CNC-L-alanyloxy)-tetrahydropyrrol in 10 ml THF zugetropft. Nach 4 h versetzt man das Tetrahydrofuran (THF) dissolved and slowly a solution of 1.05 g (3.6 mmol) of N- (CNC-L-alanyloxy) tetrahydropyrrole in 10 ml of THF is added dropwise. After 4 hours you do that
Reaktionsgemisch mit 40 ml Dichlormethan und schüttelt je 3 mal mit gesättigter NaHSO.- und NaHCO3-Lösung aus. Die Dichlormethanphase wird über Natriumsulfat getrocknet und unter Vakuum zur Trockne eingeengt. Das Rohprodukt wird durch Säulenchromatographie auf Kieselgel gereinigt. Reaction mixture with 40 ml dichloromethane and shake out 3 times with saturated NaHSO.- and NaHCO 3 solution. The dichloromethane phase is dried over sodium sulfate and concentrated to dryness in vacuo. The crude product is purified by column chromatography on silica gel.
Elutionsmittel: Ether(Aceton 10:2. Eluent: ether (acetone 10: 2.
Weißes, amorphes Pulver, Ausbeute: 51 % White, amorphous powder, yield: 51%
Elementaranalyse Elemental analysis
C34H5 0ClN5O7 , MW 676 , 25 g/mol C 34 H 5 0 ClN 5 O 7 , MW 676, 25 g / mol
C H N C H N
Ber . ( % ) : 60 , 4 7 , 45 10 , 4 Ber. (%): 60, 4 7, 45 10, 4
Ge f . ( % ) : 59 , 1 6 , 86 9 , 9 Ge f. (%): 59, 1 6, 86 9, 9
1H-NMR (in CDCl3) 1 H-NMR (in CDCl 3 )
δ (PPm) 7,6(d,1H), 7,3-7,0 (m, 1H), 6,7-6,4 (m,4H), δ (PPm) 7.6 (d, 1H), 7.3-7.0 (m, 1H), 6.7-6.4 (m, 4H),
5,9 (t,1H), 4,6(m,2H), 4,1 (t,2H), 3,5 (t,2H), 2,0 (d,1H), 5.9 (t, 1H), 4.6 (m, 2H), 4.1 (t, 2H), 3.5 (t, 2H), 2.0 (d, 1H),
0,8 (s,3H) 0.8 (s, 3H)
IR (KBr) cm-1: 3300, 2930, 2560, 1730, 1650, 1500, 1450,IR (KBr) cm -1 : 3300, 2930, 2560, 1730, 1650, 1500, 1450,
1010, 735
Beispiel 2 1010, 735 Example 2
17 ß-O-(CNC-L-alanylaminohexylamino-1,4-dioxo-butyl)19-nortestosteron Die Darstellung von 17 ß-O- (CNC-L-alanylaminohexylamino-1,4-dioxo-butyl) 19-nortestosterone The representation of
17ß-O-(CNC-L-alanylaminohexylamino-l,4-dioxo-butyl)-19nortesto sterOn erfolgt analog zu Beispiel 1 unter Verwendung von 17ß-O- (CNC-L-alanylaminohexylamino-l, 4-dioxo-butyl) -19nortesto sterOn is carried out analogously to Example 1 using
1,4g (3 mmol) 1.4g (3mmol)
17ß-0-(Aminohexylamino-1,4-dioxo-butyl)-19-nortestosteron. Weißes, amorphes Pulver, Ausbeute 37 % 17β-0- (aminohexylamino-1,4-dioxo-butyl) -19-nortestosterone. White, amorphous powder, yield 37%
Elementaranalyse Elemental analysis
C34H52ClN5O7, MW 678'27 9(mol C 34 H 52 ClN 5 O 7 , MW 678'27 9 (mol
Elementaranalyse : Elemental analysis:
C H N C H N
Ber. (%): 60,2 7,72 10,3 Ber. (%): 60.2 7.72 10.3
Gef. (%): 60,1 8,17 10,9 Found (%): 60.1 8.17 10.9
1H-NMR (in CDCl3) 1 H-NMR (in CDCl 3 )
δ (ppm) 7,6 (d, 1H), 5,7 (s, 1H), 4,6 (m, 2H), δ (ppm) 7.6 (d, 1H), 5.7 (s, 1H), 4.6 (m, 2H),
4,1 (t, 2H), 3,5 (m, 2H), 2,6 (d, 4H), 0,7 (s, 3H) IR (KBr) cm-1: 3400, 2920, 2860, 1710, 1660, 1450, 735 4.1 (t, 2H), 3.5 (m, 2H), 2.6 (d, 4H), 0.7 (s, 3H) IR (KBr) cm -1 : 3400, 2920, 2860, 1710 , 1660, 1450, 735
Beispiel 3 Example 3
17ß-O-(CNC-aminoethoxy-1,4-dioxo-butyl)-estradiol 17ß-O- (CNC-aminoethoxy-1,4-dioxo-butyl) -estradiol
Man stellet den Estradiol-17-succinato-HECNU-ester-3-tetrahydropyranolether her und spaltet die Schutzgruppe mit p-Toluolsulfonsäure ab The estradiol-17-succinato-HECNU-ester-3-tetrahydropyranol ether is prepared and the protective group is split off with p-toluenesulfonic acid
Ansatz: Approach:
1,2 g Estradiol-3-tetrahydropyranylether 1.2 g estradiol-3-tetrahydropyranyl ether
1,5 g HECNU-Hemisuccinat in 30 ml abs. THF 1.5 g HECNU hemisuccinate in 30 ml abs. THF
1,1 g DCC + 0,1 g DMAP
Nach ca. 30 sec entsteht ein weißer Niederschlag. Es wird noch 1 h bei Raumtemperatur gerührt. Dabei tritt deutliche Farbvertiefung von gelb nach rotbraun ein. Nach weiteren 3 h im Kühlschrank wird einrotiert, in Dichlormethan aufgenommen und mit Dichlormethan/THF - 50/1 über Kieselgel filtriert. DC (Dichlormethan/THF = 25/1): Rf = 0,62. 1.1 g DCC + 0.1 g DMAP A white precipitate forms after approx. 30 sec. The mixture is stirred for a further 1 h at room temperature. The color deepens from yellow to reddish brown. After a further 3 h in the refrigerator, the mixture is concentrated using a rotary evaporator, taken up in dichloromethane and filtered through silica gel with dichloromethane / THF - 50/1. TLC (dichloromethane / THF = 25/1): R f = 0.62.
Es wird in THF mit einer Spatelspitze p-Toluolsulfonsauregel filtriert. Wenn die gelbe Verunreinigung die Säule verlassen hat, wird das gewünschte Produkt mit CH2Cl2/THF = 20/1 eluiert. Mehrmaliges Abrotieren mit Ether liefert It is filtered in THF with a spatula tip of p-toluenesulfonic acid gel. When the yellow impurity has left the column, the desired product is eluted with CH 2 Cl 2 / THF = 20/1. Repeated spinning with ether provides
schließlich in 63% Ausbeute einen hochviskosen gelben Stoff. DC (Dichlormethan/THF = 10/1): Rf = 0,72 finally a highly viscous yellow substance in 63% yield. TLC (dichloromethane / THF = 10/1): R f = 0.72
Elementaranalyse: C27H35C1N3O7 NW 549,0 g/mol Elemental analysis: C 27 H 35 C1N 3 O 7 NW 549.0 g / mol
C H N Cl C H N Cl
Ber. (%): 59,1 6,43 7,7 6,5 Ber. (%): 59.1 6.43 7.7 6.5
Gef. (%) 58,9 6,67 7,5 6,7 Found (%) 58.9 6.67 7.5 6.7
1H-NMR (in do,-DMS0) 1 H-NMR (in do, -DMS0)
δ(PPm): 9,01 (s, 1H), 8,92 (t, 1H), 7,15 (d, 1H), δ (PPm): 9.01 (s, 1H), 8.92 (t, 1H), 7.15 (d, 1H),
6,61 (d, 1H), 6,50 (s, 1H), 4,73 (m, 1H), 4,20 (m,4H), 3,72 (m, 4H), 2,80 (s, 4H), 1-2,4 (m), 0,88 (s, 3H) IR (KBr) cm-1: 3405, 2970, 2933, 1732, 1532, 1499, 6.61 (d, 1H), 6.50 (s, 1H), 4.73 (m, 1H), 4.20 (m, 4H), 3.72 (m, 4H), 2.80 (s , 4H), 1-2.4 (m), 0.88 (s, 3H) IR (KBr) cm -1 : 3405, 2970, 2933, 1732, 1532, 1499,
1448, 1350, 1286, 1248, 1164, 1083, 1448, 1350, 1286, 1248, 1164, 1083,
1008, 963 1008, 963
Beispiel 4 Example 4
17ß-O-(CNC-aminoethoxy-l,4-dioxobutyl)-dihydrotestosteron 17ß-O- (CNC-aminoethoxy-l, 4-dioxobutyl) dihydrotestosterone
Die Darstellung von Beispiel 4 erfolgt analog zu Beispiel 3 mit dem Unterschied, daß das Steroidhormon keine Example 4 is presented analogously to example 3, with the difference that the steroid hormone is none
Schutzgruppe trägt.
Ansatz: Protective group. Approach:
1,0 g Dihydrotestosteron 1.0 g dihydrotestosterone
1,8 g HECNU-hemisuccinat 1.8 g HECNU hemisuccinate
50 ml abs. THF 50 ml abs. THF
1,2 g DCC 1.2 g DCC
0,1 g DMAP 0.1 g DMAP
Hellgelbes amorphes Pulver Light yellow amorphous powder
Elementaranalyse: Elemental analysis:
C28H42CLN3O7 MW 568,1 g/mol C 28 H 42 CLN 3 O 7 MW 568.1 g / mol
C H N Cl C H N Cl
Ber. (%): 59,2 7,80 7,4 6,2 Ber. (%): 59.2 7.80 7.4 6.2
Gef. (%): 59,5 7,89 7,1 6,5 Found (%): 59.5 7.89 7.1 6.5
Beispiel 5 Example 5
17ß-O-(CNC-aminoethyl-1,4-dioxobutyl)-testosteron 17ß-O- (CNC-aminoethyl-1,4-dioxobutyl) testosterone
Die Darstellung von Beispiel 5 erfolgt analog zu Beispiel 4, Example 5 is presented analogously to example 4,
Ansatz: Approach:
1,5 g (10 mmol) Testosteron 1.5 g (10 mmol) testosterone
1,8 g (6 mmol) HECNU-hemisuccinat 1.8 g (6 mmol) HECNU hemisuccinate
50 ml abs. THF 50 ml abs. THF
1,2 g (6 mmol) DCC + 0,1 g DMAP 1.2 g (6 mmol) DCC + 0.1 g DMAP
Reaktionsdauer: 8 h Response time: 8 h
DC (Dichlormethan/THF = 25/1): R. = 0,26 TLC (dichloromethane / THF = 25/1): R. = 0.26
Ausbeute: 1,6 g (56 % d. Th.) Yield: 1.6 g (56% of theory)
Hellgelber viskoser Stoff Light yellow viscous fabric
Elementaranalyse : Elemental analysis:
C28H40ClN3O7 MW 566,1 g/mol C 28 H 40 ClN 3 O 7 MW 566.1 g / mol
C H N C H N
Ber. (%) 59,4 7,12 7,4 Ber. (%) 59.4 7.12 7.4
Gef. (%) 59,1 7,13 7,4 1H-NMR (in d6-DMSO)
δ (PPm) 8,85 (t, 1H), 5,56 (s, 1H), 4,52 (m, 1H), 4,09 (m,Found (%) 59.1 7.13 7.4 1H-NMR (in d 6 -DMSO) δ (PPm) 8.85 (t, 1H), 5.56 (s, 1H), 4.52 (m, 1H), 4.09 (m,
4H), 3,60 (m, 4H), 2,52 (s, 4H), 0,8-2, 4(m), 1,13 (s, 3H), 0,75 (s, 3H) IR (KBr) cm-1: 3395, 2946, 1734, 1671, 1531, 1492, 1332, 4H), 3.60 (m, 4H), 2.52 (s, 4H), 0.8-2, 4 (m), 1.13 (s, 3H), 0.75 (s, 3H) IR (KBr) cm -1 : 3395, 2946, 1734, 1671, 1531, 1492, 1332,
1272, 1232, 1161, 1083, 1040, 1010, 962 1272, 1232, 1161, 1083, 1040, 1010, 962
Beispiel 6 Example 6
17ß-O-(CNC-aminoethoxy-1,4-dioxo-butyl)-19-nortestosteron Die Herstellung von Beispiel 6 erfolgt analog wie Beispiel 4 17ß-O- (CNC-aminoethoxy-1,4-dioxo-butyl) -19-nortestosterone The preparation of Example 6 is carried out analogously to Example 4
Ansatz: Approach:
1,4 g (5 mmol) 19-Nortestosteron 1.4 g (5 mmol) 19-nortestosterone
1,8 g (6 mmol) HFCNU-hemisuccinat 1.8 g (6 mmol) HFCNU hemisuccinate
50 ml abs. THF 50 ml abs. THF
1,2 g (6 mmol) DCC + 0,1 g DMAP 1.2 g (6 mmol) DCC + 0.1 g DMAP
Reaktionsdauer: 6 Stunden Response time: 6 hours
Aufarbeitung: Refurbishment:
Chormatographie über SiO2 mit Dichlormethan/THF - 50/1 ergibt eine viskose Masse. Chromatography over SiO 2 with dichloromethane / THF - 50/1 gives a viscous mass.
Ausbeute: 1,4 g ( 52 % d. Th.) Yield: 1.4 g (52% of theory)
DC (Dichlormethan/THF = 25/1): R = 0,21 TLC (dichloromethane / THF = 25/1): R = 0.21
Elementaranalyse: Elemental analysis:
C27H3gClN3O7 MW 552,1 g/mol C 27 H 3g ClN 3 O 7 MW 552.1 g / mol
C M N C M N
Ber. (%): 58,7 6,94 7,6 Ber. (%): 58.7 6.94 7.6
Gef. (%) 58,5 7,27 7,4 Found (%) 58.5 7.27 7.4
Beispiel 7 Example 7
Allgemeine Darstellungsvorschrift für General presentation instructions for
O[N,N-Bis-(2-chlorethyl)-diamidophosphoryloxy]-L-tyrosin- (steroid)-17ß-ester Hydrochlorid
Eine Lösung von 15 mmol (3,9 g) O [N, N-bis (2-chloroethyl) diamidophosphoryloxy] -L-tyrosine (steroid) -17β-ester hydrochloride A solution of 15 mmol (3.9 g)
N,N-Bis-(2-chlorethyl)-phosphorsäureamiddichlorid unter 15 mmol (5,57 g) N-tert.Butyloxycarbonyl-L-Thyrosinbenzylester in 45 ml trockenem Benzol wird am Rückfluß erhitzt und N, N-bis (2-chloroethyl) phosphoric acid amide dichloride under 15 mmol (5.57 g) of N-tert-butyloxycarbonyl-L-thyrosine benzyl ester in 45 ml of dry benzene is heated to reflux and
tropfenweise über einen Zeitraum von 15 min mit einer Lösung von 17 mmol (2,37 ml) trockenem Triethylamin in 15 ml dropwise over a period of 15 min with a solution of 17 mmol (2.37 ml) of dry triethylamine in 15 ml
trockenem Benzol versetzt. Das Reaktionsgemisch wird weitere 3 h am Rückfluß gekocht. Nach Abkühlen auf Raumtemperatur wird solange Ammoniakgas eingeleitet (ca. 15 min) bis das Zwischenprodukt dünnschichtchromatographisch nicht mehr nachgewiesen werden kann. Das ausgefallene Ammoniumchlorid wird abgesaugt, das Filtrat eingeengt und der Rückstand an Kieselgel säulenchromatographisch gereinigt. added dry benzene. The reaction mixture is refluxed for a further 3 h. After cooling to room temperature, ammonia gas is introduced (approx. 15 min) until the intermediate product can no longer be detected by thin layer chromatography. The precipitated ammonium chloride is filtered off with suction, the filtrate is concentrated and the residue is purified by column chromatography on silica gel.
Laufmittel: Ethylformiat Mobile solvent: ethyl formate
Ausbeute: 7,8 g (90 %). Yield: 7.8 g (90%).
15 mmol (8,62 g) 15 mmol (8.62 g)
0-[N,N-Bis(2-chlorethyl)diamidophosphoryloxy]-N-tert-butyloxycarbonyl-L-Tyrosinbenzylester werden in 20 ml absolutem 0- [N, N-Bis (2-chloroethyl) diamidophosphoryloxy] -N-tert-butyloxycarbonyl-L-tyrosine benzyl esters are dissolved in 20 ml of absolute
Ethanol gelöst und mit einer Spatelspitze Dissolved ethanol and with a spatula tip
Palladium/Kohlenstoff-Katalysator versetzt. Die Palladium / carbon catalyst added. The
anschließende Hydrogenolyse bei Normaldruck wird solange durchgeführt, bis der Wasserstoffverbrauch beendet ist (ca. 1 h). Nach Filtration wird die ethanolische Lösung zur Subsequent hydrogenolysis at normal pressure is carried out until the hydrogen consumption has ended (approx. 1 h). After filtration, the ethanolic solution becomes
Trockene eingeengt. Durch mehrmaliges Behandeln mit Dry evaporated. By repeated treatment with
trockenem Diethylether erhält man einen farblosen Schaum. dry diethyl ether gives a colorless foam.
Ausbeute: 7,05 g (97 %) 4 mmol (1,94 g) Yield: 7.05 g (97%) 4 mmol (1.94 g)
O-[N,N-Bis-(2-chlorethyl)diamidophosphoryloxy]-N-tert.butyl- oxycarbonyl-L-Tyrosin werden in 30 ml Dichlormethan gelöst und mit 4,4 mmol (713 mg) Carbonyldiimidazol versetzt. Nach Beendigung der Gasentwicklung wird die Reaktionslösung 20 min im ültraschallbad behandelt. Nach Zugabe von 4 ml des Steroidalkohols wird das Reaktionsgemisch nochmals 30 min beschallt und anschließend 2 Tage bei Raumtemperatur
gerührt. Nach Entfernen des Lösungsmittels wird der O- [N, N-bis- (2-chloroethyl) diamidophosphoryloxy] -N-tert.butyl-oxycarbonyl-L-tyrosine are dissolved in 30 ml dichloromethane and 4.4 mmol (713 mg) carbonyldiimidazole are added. After the evolution of gas has ended, the reaction solution is treated in an ultrasound bath for 20 min. After adding 4 ml of the steroid alcohol, the reaction mixture is sonicated again for 30 min and then for 2 days at room temperature touched. After removing the solvent
Rückstand säulenchromatographisch aufgearbeitet (an The residue was worked up by column chromatography (on
Kieselgel). Die Produkte werden als farblose Schäume Silica gel). The products are called colorless foams
isoliert. isolated.
5 mmol 5 mmol
Oτ/N,N-Bis-(2-chlorethyl)diamidophsophoryloxy7'-N-tert-butyloxycarbonyl-L-tyrosin-steroid-17ßester werden unter Eiskühlung mit 12 ml 0,2 N Salzsäure in Eisessig versetzt und ca. lh gerührt (DC-Kontrolle). Die Lösung wird zur Trockene Oτ / N, N-bis- (2-chloroethyl) diamidophsophoryloxy7'-N-tert-butyloxycarbonyl-L-tyrosine-steroid-17ßester are mixed with ice cooling with 12 ml of 0.2 N hydrochloric acid in glacial acetic acid and stirred for approx. 1 h (TLC -Control). The solution becomes dry
eingeengt, der Rückstand in 2 ml Methanol aufgenommen und tropfenweise unter Rühren in 1 1 Diethylether eingetragen. Das Produkt fällt flockig weiß aus. Nach dem Abtritten wird das farblose Pulver noch 2mal mit Diethylether gewaschen und anschließend im Hochvakuum getrocknet. concentrated, the residue taken up in 2 ml of methanol and added dropwise with stirring in 1 1 of diethyl ether. The product turns out flaky white. After the removal, the colorless powder is washed twice with diethyl ether and then dried under high vacuum.
Ausbeute: 50 - 70 % Yield: 50 - 70%
Auf diese Weise wurden die folgenden Verbindungen In this way the following connections were made
hergestellt. manufactured.
O-[N,N-Bis-(2-chlorethyl)-diamidophosphoryloxy]-L-tyrosin-di-hydrotestosteron-17ß-ester hydrochlorid O- [N, N-bis (2-chloroethyl) diamidophosphoryloxy] -L-tyrosine-di-hydrotestosterone-17β-ester hydrochloride
Elementaranalyse : Elemental analysis:
C32H49C13N305P MW 693,1 C 32 H 49 C1 3 N 3 0 5 P MW 693.1
C H N C H N
Ber. (%): 55,4 7,13 6,0 Ber. (%): 55.4 7.13 6.0
Gef. (%): 55,1 7,00 6,2 Found (%): 55.1 7.00 6.2
IR (KBr) cm-1: 2950-2800, 1730, 1700, 1500, 1220 IR (KBr) cm -1 : 2950-2800, 1730, 1700, 1500, 1220
O-[N,N-Bis-(2-chlorethyl)-diamidophosphoryloxy]-L-tyrosinestradiol-17ß-ester hydrochlorid O- [N, N-bis (2-chloroethyl) diamidophosphoryloxy] -L-tyrosinestradiol-17β-ester hydrochloride
Elementaranalyse:
C31H43C12N3O5P MW 675,03 g/mol Elemental analysis: C 31 H 43 C1 2 N 3 O 5 P MW 675.03 g / mol
C H N C H N
Ber. (%): 55,1 6,42 6,2 Ber. (%): 55.1 6.42 6.2
Gef. (%): 55,1 6,42 5,9 Found (%): 55.1 6.42 5.9
1H-NMR (in CD3OD) 1H-NMR (in CD 3 OD)
δ (ppm): 7,3 (s, 4H), 6,4-7,2 (m, 3H), 4,8 (t, 1H) δ (ppm): 7.3 (s, 4H), 6.4-7.2 (m, 3H), 4.8 (t, 1H)
4,3 (m, 1H), 3,0-4,0 (m, 12H), 1,0-3,0 (m, 15H) 0,72 (s, 3H) O-[N,N-Bis(2-chlorethyl)-diamidophosphoryloxy]-L-tyrosin-19-nortestosteron-17ß-ester hydrochlorid 4.3 (m, 1H), 3.0-4.0 (m, 12H), 1.0-3.0 (m, 15H) 0.72 (s, 3H) O- [N, N-Bis (2-chloroethyl) diamidophosphoryloxy] -L-tyrosine-19-nortestosterone-17β-ester hydrochloride
Elementaranalyse Elemental analysis
C31H45C12N3O5P MW 677,05 g/mol C 31 H 45 C 12 N 3 O 5 P MW 677.05 g / mol
C H N C H N
Ber. (%): 54,6 6,65 6,2 Ber. (%): 54.6 6.65 6.2
Gef. (%): 53,6 6,53 6,2 Found (%): 53.6 6.53 6.2
1-NMR (in CD3OD) 1-NMR (in CD 3 OD)
δ (ppm): 7,29 (s, 4H), 5,8 (s, 1H), 4,32 (d, 1H), 4,0-3,2 (m, 12H), 2,4-1,1 (m, 22H), 0,82 (s, 3H) δ (ppm): 7.29 (s, 4H), 5.8 (s, 1H), 4.32 (d, 1H), 4.0-3.2 (m, 12H), 2.4-1 , 1 (m, 22H), 0.82 (s, 3H)
Beispiel 8 N[N(Androstan-3-on-17-oxy-1,4-dioxo-butyl)-L-alanyl-leucyl]-adriamycin Example 8 N [N (Androstan-3-one, 17-oxy-1,4-dioxobutyl) -L-alanyl-leucyl] adriamycin
In einem typischen Ansatz wurden 32 mg In a typical batch, 32 mg
Adriamycin-Hydrochlorid (0,055 mmol) in 12 ml absolutem Dimethylformamid suspendiert. Zur Freisetzung der Adriamycin hydrochloride (0.055 mmol) suspended in 12 ml of absolute dimethylformamide. To release the
Aminogruppe wurden 7,ul absolutes Triethylamin zugesetzt. Anschließend wurde die Reaktionsmischung in Amino group was added to 7, ul of absolute triethylamine. The reaction mixture was then in
Stickstoff-Atmosphäre mit einer Lösung von 174 mg Nitrogen atmosphere with a solution of 174 mg
DHT-Succ-Ala-Leu-N-Hydroxysuccinimidester in 3ml DHT-Succ-Ala-Leu-N-hydroxysuccinimide ester in 3ml
Dimethylformamid versetzt. Da nach DC-Abschätzung nach 12h
nur ca. halber Umsatz zu erkennen war, wurden nochmals Dimethylformamide added. Since according to the DC estimate after 12h only about half the sales were recognizable, were again
4 μl Triethylamin zugespritzt. Nach insgesamt 2d wurde in Chloroform aufgenommen und mehrfach mit dest. Wasser 4 μl of triethylamine are injected. After a total of 2 d was taken up in chloroform and repeatedly with dist. water
extrahiert. Die wässrigen Phasen wurden mit Chloroform reextrahiert. Nach Abziehen des Chloroforms am extracted. The aqueous phases were re-extracted with chloroform. After removing the chloroform on
Rotationsverdampfer wurde das zurückbleibende Rotary evaporator became the one that remained
Dimethylformamid im ölpumpenvakuum bei Raumtemperatur abgezogen. Der Rückstand wurde mehrfach über eine Dimethylformamide removed in an oil pump vacuum at room temperature. The backlog was over one
Kieselgel-60-Platte (20x20 cm) (Chloroform/Methanol 15:1) chromatographiert. Es wurden 43 mg (70 % DC-reine rotorangeChromatograph silica gel 60 plate (20x20 cm) (chloroform / methanol 15: 1). 43 mg (70% DC-pure red-orange
Substanz erhalten. Get substance.
Rf-Wert (Chloroform/Methanol 9:1) 0,32 R f (chloroform / methanol 9: 1) 0.32
Massenspektrum (FAß) : Molpeak m/c 1100 Mass spectrum (FASS): Molpeak m / c 1100
1H-NMR (in CDCl3) 1H-NMR (in CDCl 3 )
δ (ppm): 13,98 (s, 1H), 13,28 (s, 1H), 8,07 (d, 1H, 7,80 (t, 1H), 7,40 (d, 1H), 7,05 (d, 1H), 6,68 (d, 1H), 6,12 (d, 1H), 5,51 (d, 1H), 5,27 (m, 1H), 4,75 (d, 1H), 4,30 (m, 1H), 4,25 (m, 1H), 4,10 (m, 1H), 4,09 (s, 3H) , 3,98 (m, 1H), 3,79 (m, 1H), 3,22 (d, 1H), 3,05 (m, 2H), 2,60 (m, 1H), 2,42 (m, 2H), 1,48 (d, 3H), 1,31 (d, 3H), 0,95 (d, 3H), 0,90 (d, 3H), 0,78 (s, 3H), 0,62 (s, 3H) δ (ppm): 13.98 (s, 1H), 13.28 (s, 1H), 8.07 (d, 1H, 7.80 (t, 1H), 7.40 (d, 1H), 7 , 05 (d, 1H), 6.68 (d, 1H), 6.12 (d, 1H), 5.51 (d, 1H), 5.27 (m, 1H), 4.75 (d, 1H), 4.30 (m, 1H), 4.25 (m, 1H), 4.10 (m, 1H), 4.09 (s, 3H), 3.98 (m, 1H), 3, 79 (m, 1H), 3.22 (d, 1H), 3.05 (m, 2H), 2.60 (m, 1H), 2.42 (m, 2H), 1.48 (d, 3H) ), 1.31 (d, 3H), 0.95 (d, 3H), 0.90 (d, 3H), 0.78 (s, 3H), 0.62 (s, 3H)
Beispiel 9 Example 9
1-[4-(2[6-CNC-aminohexyl]-acetylaminoethoxy)-phenyl]-1-(4- acetylphenyl)-2-phenyl-but-1-en 1- [4- (2 [6-CNC-aminohexyl] acetylaminoethoxy) phenyl] -1- (4-acetylphenyl) -2-phenylbut-1-ene
5,5 g (12 mmol) 5.5 g (12 mmol)
1-[4-(2-[6-aminohexyl]-aminoethoxy)-phenyl]-1-(4-hydroxyphenyl)-2-phenyl-but-1-en, 12mmol CNC-azid und 10 ml 1- [4- (2- [6-aminohexyl] aminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-phenylbut-1-ene, 12 mmol CNC-azide and 10 ml
Essigäsureanhydrid Säulenchromatographie über Kieselgel (Dichlormethan/THF = 30 : 1/d = 4,5 cm; 1 = 60 cm). Acetic anhydride column chromatography on silica gel (dichloromethane / THF = 30: 1 / d = 4.5 cm; 1 = 60 cm).
Ausbeute: 1,7 g (21 %) gelblichweißer, harziger, zähviskoser Stoff Yield: 1.7 g (21%) of a yellowish-white, resinous, viscous substance
Rf-Wert (Dichlormethan/Ether/Petrolether = 1:1:1): 0,15
Elementaranalyse: C37H45ClN4O6 MW: 677,26 g/mol R f value (dichloromethane / ether / petroleum ether = 1: 1: 1): 0.15 Elemental analysis: C 37 H 45 ClN 4 O 6 MW: 677.26 g / mol
C H N Cl C H N Cl
Ber . (% ) : 65 , 6 6 , 69 8 , 3 5 , 2 Ber. (%): 65, 6 6, 69 8, 3 5, 2
Gef. (%): 65 , 6 6 , 89 8 , 1 5 , 4 Found (%): 65, 6 6, 89 8, 1 5, 4
1H-NMR (in CDCl3): 1 H-NMR (in CDCl 3 ):
δ (ppm) 7,3-6,41 (m 13H), 4,25-3,9 (m 4H), 3,8-3,3 (m, 8H) δ (ppm) 7.3-6.41 (m 13H), 4.25-3.9 (m 4H), 3.8-3.3 (m, 8H)
2,48 (q, 2H), 2,33/2,21 (2a, 3H), 2,12/2,05 (2s,3H) 1,8-1,3 (m, 8H), 0,91 (t 3H) 2.48 (q, 2H), 2.33 / 2.21 (2a, 3H), 2.12 / 2.05 (2s, 3H) 1.8-1.3 (m, 8H), 0.91 (t 3H)
Ir (KBr) cm-1 Ir (KBr) cm -1
3400, 2980, 2940, 1760, 1730, 1640, 1610, 1530, 1510, 1485, 1442, 1370, 1240, 1220, 1200, 1180, 1080, 1020, 965, 705 3400, 2980, 2940, 1760, 1730, 1640, 1610, 1530, 1510, 1485, 1442, 1370, 1240, 1220, 1200, 1180, 1080, 1020, 965, 705
UV-Spektrum: λmax[nm] (280,0) 239,5 ε 14990 25860 Massenspektrum: UV spectrum: λ max [nm] (280.0) 239.5 ε 14990 25860 mass spectrum:
m/e 568, 316, 211 m / e 568, 316, 211
Beispiel 10 Example 10
1-[4-(2-[2-CNC-alanyl-aminoethylamid]-acetylaminoethoxy)-phenyl]- 1-(4-acetylphenyl)-2-phenyl-but-1-en zu 600 mg (1,5 mmol) 1- [4- (2- [2-CNC-alanylaminoethylamide] acetylaminoethoxy) phenyl] - 1- (4-acetylphenyl) -2-phenylbut-1-ene at 600 mg (1.5 mmol)
1-[4-(2-[2-aminoethyl]-aminoethoxy)-phenyl]-1-(4-hydroxy- phenyl)-2-phenyl-but-1-en in 30 ml Dichlormethan und 5 ml Pyridin werden bei 0°C 470 mg (1,5 mmol) 1- [4- (2- [2-aminoethyl] aminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-phenylbut-1-ene in 30 ml dichloromethane and 5 ml pyridine are at 0 ° C 470 mg (1.5 mmol)
CNC-alanyl-hydroxysuccinimidester in Dichlormethan getropft
Nach beendeter Reaktion (ca. 1 h; DC-Kontrolle) werden noch 10 ml Essigsäureanhydrid zugegeben. CNC alanyl hydroxysuccinimide ester dropped in dichloromethane After the reaction has ended (about 1 h; TLC control), 10 ml of acetic anhydride are added.
Nach 1 h wird die Reaktionsmischung mit eiskalter After 1 h the reaction mixture is ice cold
gesättigter NaHSO4-Lösung sauer gestellt und zweimal mit Dichlormethan extrahiert. Die vereinigte organische Phase wird mit gesättigter NaHCO3- und gesättigter NaCl-Lösung gewaschen, über Natriumsulfat getrocknet und einrotiert. Säulenchromatographie über Kieselgel (Dichlormethan/Methanol = 30:1/d= 5 cm; 1 = 55 cm). saturated NaHSO 4 solution acidified and extracted twice with dichloromethane. The combined organic phase is washed with saturated NaHCO 3 and saturated NaCl solution, dried over sodium sulfate and evaporated. Column chromatography on silica gel (dichloromethane / methanol = 30: 1 / d = 5 cm; 1 = 55 cm).
Ausbeute: 470 mg (45 %) gelblichweißer, harziger Stoff Yield: 470 mg (45%) yellowish white, resinous substance
FP: 70-73°C, sintert ab 50°C FP: 70-73 ° C, sinters from 50 ° C
Rf-Wert (Dichlormethan/Methanol = 30:1): 0,24 R f (dichloromethane / methanol = 30: 1): 0.24
Elementaranalyse: C36H42ClN5O7 MW: 692,23 g/mol Elemental analysis: C 36 H 42 ClN 5 O 7 MW: 692.23 g / mol
C H N C H N
Ber. (%): 62,5 6,12 10,1 Ber. (%): 62.5 6.12 10.1
Gef. (%): 61,8 6,23 9,7 Found (%): 61.8 6.23 9.7
1H-NMR (in CDCl3) 1 H-NMR (in CDCl 3 )
δ (ppm) 7,45 (d, 1H), 7,3-6-45 (m, 13H), 4,52 (m, 1H), δ (ppm) 7.45 (d, 1H), 7.3-6-45 (m, 13H), 4.52 (m, 1H),
4,3-4,05 (m, 4H) 3,85-3,35 (m, 8H), 4.3-4.05 (m, 4H) 3.85-3.35 (m, 8H),
2,48 (q, 2H), 2,33/2,21 (2s, 3H), 2,12/2,05 (2s, 3H), 1,5 (d, 3H), 0,91 (t, 3H) 2.48 (q, 2H), 2.33 / 2.21 (2s, 3H), 2.12 / 2.05 (2s, 3H), 1.5 (d, 3H), 0.91 (t, 3H)
IR (KBr) cm-1 IR (KBr) cm -1
3330, 2980, 2940, 1755, 1730, 1680, 1635, 1610, 1510, 1490, 3330, 2980, 2940, 1755, 1730, 1680, 1635, 1610, 1510, 1490,
1444, 1370, 1240, 1220, 1200, 1080, 1020, 705 1444, 1370, 1240, 1220, 1200, 1080, 1020, 705
UV-Spektrum: UV spectrum:
(280,0) 239,5 (280.0) 239.5
λmax[nm] λ max [nm]
ε 14360 24570 ε 14360 24570
Massenspektrum: Mass spectrum:
m/e 625, 583, 316
Be ispiel 11 m / e 625, 583, 316 Example 11
CNC-alanyl-bisdesmethyltamoxifenamid CNC alanyl bisdesmethyltamoxifenamide
Zu 270 mg (0,7 mmol) To 270 mg (0.7 mmol)
1-[4-(2-aminoethoxy)-phenyl]-1,2-diphenyl-but-1-en und 160 mg (0,7 mmol) CNC-alanin in Dichlormethan werden bei 0°C 160 mg (0,8 mmol) DCC gegeben.Nach 2 h (DC-Kontrolle) wird der Dicyclohexylharnstoff abfiltriert, die Lösung einrotiert, der Rückstand in Acetonitril aufgenommen, die Suspension filtriert, einrotiert und mit Diethylether aufgeschäumt. Säulenchromatographie über Kieselgel 1- [4- (2-aminoethoxy) phenyl] -1,2-diphenylbut-1-ene and 160 mg (0.7 mmol) CNC alanine in dichloromethane are 160 mg (0.8 mmol) DCC. After 2 h (TLC control), the dicyclohexylurea is filtered off, the solution is spun in, the residue is taken up in acetonitrile, the suspension is filtered, spun in and foamed with diethyl ether. Column chromatography on silica gel
(Dichlormethan(Ether/Petrolether = 2:1:1/d=3 cm; 1= 45 cm). Ausbeute: 160 mg (41 %) gelber, harziger Stoff (Dichloromethane (ether / petroleum ether = 2: 1: 1 / d = 3 cm; 1 = 45 cm). Yield: 160 mg (41%) yellow, resinous substance
Fp: 51-55°C, sintert ab 42°C Mp: 51-55 ° C, sinters from 42 ° C
Rf-Wert (Dichlormethan/Ether/Petrolether = 1:1:1): 0,37 R f value (dichloromethane / ether / petroleum ether = 1: 1: 1): 0.37
Elementaranalyse: C30H33ClN4O4 MW: 549,08 g/mol Elemental analysis: C 30 H 33 ClN 4 O 4 MW: 549.08 g / mol
C H N Cl C H N Cl
Ber. (%): 65,6 6,06 10,2 6,5 Ber. (%): 65.6 6.06 10.2 6.5
Gef. (%): 65,3 6,26 9,8 6,7 Found (%): 65.3 6.26 9.8 6.7
1H-NMR (in CDCl3) : 1 H-NMR (in CDCl 3 ):
(ppm) 7,4-7,1 (2s, 10H), 6,9-6,45 (4H), 4,55 (m, 1H), 4,1 (t, 2H), 3,94 (t, 2H), 3,65 (t, 2H), 3,45 (t, 2H), 2,45 (q, 2H) 1,5 (d, 3H), 0,91 (t, 3H) (ppm) 7.4-7.1 (2s, 10H), 6.9-6.45 (4H), 4.55 (m, 1H), 4.1 (t, 2H), 3.94 (t , 2H), 3.65 (t, 2H), 3.45 (t, 2H), 2.45 (q, 2H) 1.5 (d, 3H), 0.91 (t, 3H)
IR (KBr) cm-1 IR (KBr) cm -1
3330, 2980, 2940, 1725, 1670, 1610, 1525, 1510, 1492, 1444, 3330, 2980, 2940, 1725, 1670, 1610, 1525, 1510, 1492, 1444,
1242, 1175, 1080, 969, 705 1242, 1175, 1080, 969, 705
UV-Sepktrum: UV septa:
( 276 , 1 ) 238 ,1 (276, 1) 238, 1
λ max [nm] λ max [nm]
ε 11040 27950
Massenspektrum: ε 11040 27950 Mass spectrum:
m/e 440 300 m / e 440 300
Beispiel 12 Example 12
4-Hydroxy-bisdesmethyltamoxifen-succinato-HECNU-ester Zu einer Losung von 3,1 g (10,5 mmol) HECNU-hemisuccinat, 1,3 g (11 mmol) N-Hydroxysuccinimid und einer Spatelspitze DMAP in Dichlormethan werden bei 0°C 2,2 g (11 mmol) DCC zugegeben. Nach vollständiger Bildung des 4-Hydroxy-bis-desmethyltamoxifene-succinato-HECNU-ester At a solution of 3.1 g (10.5 mmol) of HECNU-hemisuccinate, 1.3 g (11 mmol) of N-hydroxysuccinimide and a spatula tip DMAP in dichloromethane at 0 ° C 2.2 g (11 mmol) DCC added. After complete formation of the
N-Hydroxysuccinimidesters (DC-Kontrolle) wird die Suspension zu 3,6 g (10 mmol) N-hydroxysuccinimide ester (TLC control) the suspension is 3.6 g (10 mmol)
1-[4(2-aminoethoxy)-phenyl]-1-(4-hydroxyphenyl)-2-phenyl-but-1-en in Dichlormethan /Pyridin filtriert. Filter 1- [4 (2-aminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-phenylbut-1-ene in dichloromethane / pyridine.
Nach 4 h wird eiskalte NaHSO4-Lösung zugegeben. Nach After 4 h, ice-cold NaHSO 4 solution is added. To
zweimaligem Extrahieren mit Dichlormethan wird die extracting twice with dichloromethane
organische Phase mit gesättigter NaHCO3- und dreimal mit NaCl-Lösung gewaschen. Nach Trocknen über Natriumsulfat wird einrotiert, der Rückstand in Acetonitril aufgenommen, organic phase with saturated NaHCO 3 - and washed three times with NaCl solution. After drying over sodium sulfate, the mixture is evaporated, the residue is taken up in acetonitrile,
filtriert, einrotiert und mit Ether aufgeschäumt. filtered, evaporated and foamed with ether.
Säulenchromatographie über Kieselgel Column chromatography on silica gel
(Dichlormethan/Methanol=100:1-30:1/d=5,5 cm; 1= 55cm). (Dichloromethane / methanol = 100: 1-30: 1 / d = 5.5 cm; 1 = 55cm).
Ausbeute: 4,3 g (67,5%) gelber, zähviskoser Stoff Yield: 4.3 g (67.5%) of yellow, viscous substance
Rf-Wert (Dichlormethan/Methanol=20:1) : 0 ,3 R f value (dichloromethane / methanol = 20: 1): 0.3
H-NMR (in CDCl3) H-NMR (in CDCl 3 )
δ (ppm) 7,465 (m, 1H), 7,19-6,45 (m, 13H) 6,05/5,97 (2t, 1H), 4,315/4,285 (2t 1:1, 2H), 4,16 (m, 2H), 4,1-4,04 (m, 2H), 3,91-3,54 (5m, 4H), 3,49 (m, 2H), 2,61 (m, 2H), δ (ppm) 7.465 (m, 1H), 7.19-6.45 (m, 13H) 6.05 / 5.97 (2t, 1H), 4.315 / 4.285 (2t 1: 1, 2H), 4, 16 (m, 2H), 4.1-4.04 (m, 2H), 3.91-3.54 (5m, 4H), 3.49 (m, 2H), 2.61 (m, 2H) ,
2,555-2,41 (m, 2H), 2,48 (q, 2H), 0,925/0,92 (2t, 3H)
Beispiel 13 2.555-2.41 (m, 2H), 2.48 (q, 2H), 0.925 / 0.92 (2t, 3H) Example 13
1-[4-(2-[6-Chlorambucilaminohexyl]-aminoethoxy)-phenyl]-1-(4-hydroxyphenyl)-2-(4-methoxyphenyl)-but-1-en 1- [4- (2- [6-Chlorambucilaminohexyl] aminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2- (4-methoxyphenyl) but-1-ene
Eine Lösung von 1,83 g (6mmol) Chlorambucil, 799 mg (6,5 mmol) N-Hydroxysuccinimid und 1,34 g (6,5 mmol) DCC wird bei 0°C in Dichlormethan 2 h gerührt. Anschließend wird das A solution of 1.83 g (6 mmol) of chlorambucil, 799 mg (6.5 mmol) of N-hydroxysuccinimide and 1.34 g (6.5 mmol) of DCC is stirred at 0 ° C. in dichloromethane for 2 h. Then that will
Gemisch zu einer Lösung von 2,93 g (6 mmol) Mixture to a solution of 2.93 g (6 mmol)
1-[4-(2-[6-aminohexyl]-aminoethoxy)-phenyl] 1- [4- (2- [6-aminohexyl] aminoethoxy) phenyl]
-1-(4-hydroxyphenyl)-2-(4-methoxyphenyl)-but-1-en in 30 ml Triethylamin filtriert. Nach weiteren 2 h (DC-Kontrolle) wird eiskalte NaHSO4-Lösung zugegeben und dreimal mit Filter -1- (4-hydroxyphenyl) -2- (4-methoxyphenyl) but-1-ene in 30 ml triethylamine. After a further 2 h (TLC control), ice-cold NaHSO 4 solution is added and three times with
Dichlormethan extrahiert. Die vereinigte organische Phase wird mit gesättigter NaHCO3- und NaCl-Lösung gewaschen, über Na2SO4 getrocknet und einrotiert. Extracted dichloromethane. The combined organic phase is washed with saturated NaHCO 3 and NaCl solution, dried over Na 2 SO 4 and evaporated.
Säulenchromatographie über Kieselgel (Dichlormethan/THF= 7,3 + 0,5-2% Methanol/ d= 6cm, 1= 55 cm) Column chromatography on silica gel (dichloromethane / THF = 7.3 + 0.5-2% methanol / d = 6cm, 1 = 55 cm)
Ausbeute: 2,63 g (57%) weißer, harziger Stoff Yield: 2.63 g (57%) white, resinous substance
Fp: 55-58°C sintert ab 50°C Mp: 55-58 ° C sinters from 50 ° C
Rf-Wert (Dichlormethan/Methanol=9:1) : 0,34 R f value (dichloromethane / methanol = 9: 1): 0.34
Elementaranalyse: C45H57C12N3O4 MW: : 774 , 89 g/mol Elemental analysis: C 45 H 57 C1 2 N 3 O 4 MW:: 774.89 g / mol
C H N Cl C H N Cl
Ber. (%): 69 , 8 7 ,41 5 , 4 9 , 2 Ber. (%): 69, 8 7, 41 5, 4 9, 2
Gef. (%): 69 , 9 7 , 68 5 , 2 9 , 3 Found (%): 69, 9 7, 68 5, 2 9, 3
1H-NMR (in CDCl3): 1 H-NMR (in CDCl 3 ):
(ppm) 7,2-6,4 (m, 16H), 5,65 (t, 1H), 4,2-3,9 (m, 2H), 3,73 (s, 3H), 3,64 (s, 8H), 3,3-2,9 (m, 4H), 2,8-2,35 (m, 6H) 2,2-2,0 (m, 2H), 2,0-1,8 (m, 2H), 1,7-1,2 (m, 8H), 0,91 (t, 3H) (ppm) 7.2-6.4 (m, 16H), 5.65 (t, 1H), 4.2-3.9 (m, 2H), 3.73 (s, 3H), 3.64 (s, 8H), 3.3-2.9 (m, 4H), 2.8-2.35 (m, 6H) 2.2-2.0 (m, 2H), 2.0-1, 8 (m, 2H), 1.7-1.2 (m, 8H), 0.91 (t, 3H)
IR (KBr) cm-1 IR (KBr) cm -1
3300, 2940, 1645, 1610, 1510, 1460, 2440, 1360, 1240, 1175, 1035, 830
UV-Spektrum 3300, 2940, 1645, 1610, 1510, 1460, 2440, 1360, 1240, 1175, 1035, 830 UV spectrum
λmax[nm] 289,1 252,6 ε 18510 36070 λ max [nm] 289.1 252.6 ε 18510 36070
Massenspektrum Mass spectrum
m/s 774/776/778 736 m / s 774/776/778 736
Beispiel 14 Example 14
1-[4-(2-[6-(N-Acetyl-melphalan)-aminohexyl]-acetylaminoethoxy)-phenyl]-1-(4-acetylphenyl)-2-(4-methoxyphenyl)-but-1-en 1- [4- (2- [6- (N-Acetyl-melphalan) aminohexyl] acetylaminoethoxy) phenyl] -1- (4-acetylphenyl) -2- (4-methoxyphenyl) but-1-ene
Zu einer Lösung von 1,5 g (5 mmol) Melphalan in To a solution of 1.5 g (5 mmol) melphalan in
Dichlormethan/Triethylamin werden bei 0°C 2 ml Dichloromethane / triethylamine are 2 ml at 0 ° C.
Essigsäureanhydrid gegeben. Nach 1 h Rühren wird NaHCO3- Lösung zugegeben und weitere 2 h gerührt. Anschließend wird mit gesättigter NaHSO4-Lösung sauer gestellt und zweimal mit Dichlormethan extrahiert. Die organische Phase wird mit NaCl-Lösung gewaschen, über Natriumsulfat getrocknet und einrotiert. Die so gewonnenen 1,15 g (3,2 mmol) Given acetic anhydride. After stirring for 1 h, NaHCO 3 solution is added and the mixture is stirred for a further 2 h. The mixture is then acidified with saturated NaHSO 4 solution and extracted twice with dichloromethane. The organic phase is washed with NaCl solution, dried over sodium sulfate and evaporated. The 1.15 g (3.2 mmol) thus obtained
Acetylmelphalan werden in Dichlormethan gelöst und bei 0°C mit 660 mg (3,5 mmol) DCC und 370 mg (3,5 mmol) Acetylmelphalan are dissolved in dichloromethane and at 0 ° C with 660 mg (3.5 mmol) DCC and 370 mg (3.5 mmol)
N-Hydroxysuccinimid umgesetzt. Nach beendeter Reaktion N-hydroxysuccinimide implemented. After the reaction has ended
(DC-Kontrolle) wird diese Suspension zu einer Lösung von 1,56 (3,2 mmol) (TLC control) this suspension becomes a solution of 1.56 (3.2 mmol)
1-[4-(2-/Ε-aminohexyl]-aminoethoxy)-phenyl]-1-(4hydroxyphenyl)2-(4-methoxyphenyl)-but-1-en (4OH-4'OMe-HD-TAM) in eiskaltem Dichlormethan/Triethylamin filtriert .Nach 2 h wird eiskalte NaHSO .-Lösung zugegeben. Anschließend wird 1- [4- (2- / Ε-aminohexyl] aminoethoxy) phenyl] -1- (4hydroxyphenyl) 2- (4-methoxyphenyl) but-1-ene (4OH-4'OMe-HD-TAM) in Filtered ice-cold dichloromethane / triethylamine. After 2 hours, ice-cold NaHSO. solution is added. Then will
zweimal mit Dichlormethan extrahiert und die organische extracted twice with dichloromethane and the organic
Phase mit gesättigter NaHCO3- und NaCl-Lösung gewaschen, über Na2SO4 getrocknet und einrotiert. Phase washed with saturated NaHCO 3 and NaCl solution, dried over Na 2 SO 4 and evaporated.
Rohausbeute: 3,44 g Crude yield: 3.44 g
Säulenchromatographie über Kieselgel Column chromatography on silica gel
(Dichlormethan/Methanol=7:3/ d=4 cm, 1=10 cm)
Ausbeute: 2,7 g 4-OH-4'OMe-HD-TAM-(N-acetyl-elphalan)amid, leicht verunreinigt, aber das restliche 4OH-4'O e-HD-TAM kann abgetrennt werden. Di.ese 2,7 g werden in Dichlormethan gelöst und nach Zugabe von 3 ml Essigsäureanhydrid und 3 ml Triethylamin bei 0°C gerührt. Nach beendeter Acetylierung (DC-Kontrolle) wird NaHCO3Lösung zugegeben und weitere 2 h gerührt. (Dichloromethane / methanol = 7: 3 / d = 4 cm, 1 = 10 cm) Yield: 2.7 g of 4-OH-4'OMe-HD-TAM- (N-acetyl-elphalan) amide, slightly contaminated, but the remaining 4OH-4'O e-HD-TAM can be separated off. Di.ese 2.7 g are dissolved in dichloromethane and stirred at 0 ° C after adding 3 ml of acetic anhydride and 3 ml of triethylamine. After the acetylation (TLC control) has ended, NaHCO 3 solution is added and the mixture is stirred for a further 2 h.
Anschließend wird mit gesättigter NaHSO4 und NaCl-Lösung gewaschen, über Natriumsulfat getrocknet und einrotiert. Säulenchromatographie über Kieselgel It is then washed with saturated NaHSO 4 and NaCl solution, dried over sodium sulfate and evaporated. Column chromatography on silica gel
(Dichlormethan/Methanol/Petrolether = 76:4:20/d=6 cm, 1 = 70 cm). (Dichloromethane / methanol / petroleum ether = 76: 4: 20 / d = 6 cm, 1 = 70 cm).
Ausbeute: 1,56 g (54%) weißer, harziger Stoff Yield: 1.56 g (54%) white, resinous substance
Fp: 78-80°C sintert ab 65°C Mp: 78-80 ° C sinters from 65 ° C
Rf-Wert (Dichlormethan/Methanol=9: 1) : 0,57 R f value (dichloromethane / methanol = 9: 1): 0.57
Elementaranalyse: C50H62Cl2N4O7 MW: 901,97 g/mol Elemental analysis: C 50 H 62 Cl 2 N 4 O 7 MW: 901.97 g / mol
C H N Cl C H N Cl
Ber. (%) 66,6 6,93 6,2 7,9 Ber. (%) 66.6 6.93 6.2 7.9
Gef. (%) 66,5 7,18 6,1 7,9 Found (%) 66.5 7.18 6.1 7.9
1H-NMR (in CDCl3): 1 H-NMR (in CDCl 3 ):
(ppm) 7,22-6,51 (m, 16H), 4,55/4,48 (2m, 1H), 4,16-3,94 (m, 2H), 3,76/3,75 (2s, 3H), 3,73-3,59 (m, 8H), 3,51-2,87 (m, 8H), 2,44 (m, 2H) , 2,31-1,96 (15s, 9H), 1,66-1,2 (m, 8H), 0,915 (m, 3H) (ppm) 7.22-6.51 (m, 16H), 4.55 / 4.48 (2m, 1H), 4.16-3.94 (m, 2H), 3.76 / 3.75 ( 2s, 3H), 3.73-3.59 (m, 8H), 3.51-2.87 (m, 8H), 2.44 (m, 2H), 2.31-1.96 (15s, 9H), 1.66-1.2 (m, 8H), 0.915 (m, 3H)
IR (KBr) cm-1 IR (KBr) cm -1
3300, 2940, 1760, 1650, 1610, 1510, 1465, 1440, 1370, 1290, 1240, 1218, 1198, 1180, 1035, 840
UV-Sepktrum: 3300, 2940, 1760, 1650, 1610, 1510, 1465, 1440, 1370, 1290, 1240, 1218, 1198, 1180, 1035, 840 UV septa:
λmax[nm] 287,3 258,6 ε 16080 35420 λ max [nm] 287.3 258.6 ε 16080 35420
Massenspektrum: Mass spectrum:
m/e 901/903/905 m / e 901/903/905
Beispiel 15 Example 15
1-[4-(2[N-Mustamin-5-carboxypentyl]-aminoethoxy)-phenyl]1-(4-acetylphenyl)-2-(4-methoxyphenyl)-but-1-en Zu einer Lösung von 3,6 g (6 mmol) 1- [4- (2 [N-Mustamin-5-carboxypentyl] aminoethoxy) phenyl] 1- (4-acetylphenyl) -2- (4-methoxyphenyl) but-1-ene to a solution of 3.6 g (6 mmol)
1-[4-(2-[N-carboxypentyl]-acetylaminoethoxy)phenyl]-1-(4-acetylphenyl)-2-(4-methoxyphenyl)-but-1-en in Dichlormethan bei 0°C werden 1,4 g (6,5 mmol) DCC und 750 mg (6,5 mmol) N-Hydroxysuccinimid gegeben. Nach 2 h wird diese Suspension zu einer Lösung von 1,6 g (6 mmol) Mustaminhydrochlorid in 10 ml Triethylamin filtriert. 1- [4- (2- [N-carboxypentyl] acetylaminoethoxy) phenyl] -1- (4-acetylphenyl) -2- (4-methoxyphenyl) but-1-ene in dichloromethane at 0 ° C becomes 1.4 g (6.5 mmol) of DCC and 750 mg (6.5 mmol) of N-hydroxysuccinimide. After 2 h this suspension is filtered to a solution of 1.6 g (6 mmol) mustamine hydrochloride in 10 ml triethylamine.
Nach weiteren 2 h wird mit eiskalter NaHSO4-Lösung sauer gestellt und zweimal mit Dichloremthan extrahiert. Die organische Phase wird mit gesättigter NaCl-Lösung gewaschen, über Natriumsulfat getrocknet, einrotiert, der Rückstand in Acetonitril aufgenommen, die Suspension filtriert und einrotiert. After a further 2 h, the mixture is acidified with ice-cold NaHSO 4 solution and extracted twice with dichloromethane. The organic phase is washed with saturated NaCl solution, dried over sodium sulfate, evaporated, the residue taken up in acetonitrile, the suspension is filtered and evaporated.
Rohausbeute: 3,7 g Crude yield: 3.7 g
Säulenchormatographie über Kieselgel (Dichlormethan/THF =85:15 + Methanol 0-2%/d=6 cm, 1=70 cm) Column chromatography over silica gel (dichloromethane / THF = 85: 15 + methanol 0-2% / d = 6 cm, 1 = 70 cm)
Ausbeute: 820 mg (18%) farbloses zähviskoses öl, ergibt beim Einrotieren mit etherischer HCl einen blassgelben, harzigen, hygroskopischen Stoff Yield: 820 mg (18%) colorless viscous oil, when rotated in with ethereal HCl gives a pale yellow, resinous, hygroscopic substance
Fp: 53-59°C sintert ab 48°C (Hydrochlorid) Mp: 53-59 ° C sinters from 48 ° C (hydrochloride)
Rf-Wert (Dichlormethan/Methanol= 9:1): 0,8
1H-NMR (in CDCl3):R f value (dichloromethane / methanol = 9: 1): 0.8 1 H-NMR (in CDCl 3 ):
δ (ppm) 7,3-6,4 (m, 12H), 4,2-3,9 (m, 2H), 3,77 (s, 3H), 3,55 (t, 4H), 3,47-3,15 (m, 4H), 2,9 (t, 4H), 2,68 (t, 2H), 2,5-1,9 (m, 12H) 1,8-1,2 (m, 6H), 0,91 (t, 3H) δ (ppm) 7.3-6.4 (m, 12H), 4.2-3.9 (m, 2H), 3.77 (s, 3H), 3.55 (t, 4H), 3, 47-3.15 (m, 4H), 2.9 (t, 4H), 2.68 (t, 2H), 2.5-1.9 (m, 12H) 1.8-1.2 (m , 6H), 0.91 (t, 3H)
IR-(KBr) cm IR (KBr) cm
3300, 2960, 1760, 1740, 1650, 1610, 1550, 1510, 1455, 1435, 3300, 2960, 1760, 1740, 1650, 1610, 1550, 1510, 1455, 1435,
1370, 1290, 1240, 1220, 1200, 1175,' 1110, 1030, 1020, 840 UV-Sepktrum: 1370, 1290, 1240, 1220, 1200, 1175, ' 1110, 1030, 1020, 840 UV-Spectrum:
λmax[nm] 285,1 239,2 ε 11370 15520 Massenspektrum: λ max [nm] 285.1 239.2 ε 11370 15520 mass spectrum:
m/e 754, 712 m / e 754, 712
Beispiel 16 Example 16
N-(Bisdesmethyltamoxifen)-1,4-dioxo-butyl-aminoethylamino- ethylamin-cis-dichloroplatin(ll) N- (bisdesmethyltamoxifene) -1,4-dioxo-butyl-aminoethylamino-ethylamine-cis-dichloroplatin (ll)
0,5 mmol (264 mg) 0.5 mmol (264 mg)
N-(Bisdesmethyltamoxifin)-1,4-dioxo-butyl-aminoethylamino- ethylamin werden mit 0, 5mmol (207 mg) K2PtCl4 in 5 ml H2O/DMF (1:1) gerührt. Nach 3 Tagen setzt sich ein N- (Bisdesmethyltamoxifin) -1,4-dioxo-butylaminoethylaminoethylamine are stirred with 0.5 mmol (207 mg) K 2 PtCl 4 in 5 ml H 2 O / DMF (1: 1). After 3 days it starts
Niederschlag ab. Dann werden 50 ml 5 %ige KCl-Lösung zugesetzt. Der Niederschlag wird abgenutscht, mit lNCHl und dann mit H2O gewaschen. Das schwachgelbe Pulver wird über P2O5 getrocknet.
Precipitation. Then 50 ml of 5% KCl solution are added. The precipitate is filtered off, washed with 1NCHl and then with H 2 O. The pale yellow powder is dried over P 2 O 5 .
Claims
1. Zytostatikakonjugate, z.B. antineoplastisch wirkende 1. Cytostatic conjugates, e.g. antineoplastic
Alkylantien, Antibiotika, Anthracendione, Metallkomplexe und Pflanzeninhaltsstoffe bzw. semisynthetische Derivate, die über geeignete Verbindungselemente, insbesondere mittels einer Amid- und/oder Esterbindung mit solchen Trägermolekülen, die eine Bindungsaffinität zu Alkylating agents, antibiotics, anthracenediones, metal complexes and plant constituents or semisynthetic derivatives which have suitable connecting elements, in particular by means of an amide and / or ester bond with those carrier molecules which have a binding affinity
steroidhormonrezeptoren aufweisen, verknüpft sind. have steroid hormone receptors, are linked.
2. zytostatikakonjugate nach Anspruch 1, dadurch 2. cytostatic conjugates according to claim 1, characterized
gekennzeichnet, daß die Verknüpfung über freie characterized that the link via free
Säuregruppen, Hydroxylgruppen oder Aminogruppen erfolgt ist. Acid groups, hydroxyl groups or amino groups is done.
3. Zytostatikakonjugate nach Anspruch 1 oder 2, dadurch 3. Cytostatic conjugates according to claim 1 or 2, characterized
gekennzeichnet, daß als rezeptoraffine Träger Steroide einerseits und nichtsteroidale characterized as steroid on the one hand and non-steroidal as receptor-affine carrier
steroidhormonrezeptoraffine Verbindungen andererseits vorliegen. steroid hormone receptor-affine compounds on the other hand are present.
4. zytostatikakonjugate nach Anspruch 3, dadurch 4. cytostatic conjugates according to claim 3, characterized
gekennzeichnet, daß als Steroide solche mit dem characterized in that as steroids such with the
Grundgerüst der Estran-, Androstan- oder Pregnanreihe und als nichtsteroidale rezeptoraffine Verbindungen solche aus der Reihe der Basic structure of the Estran, Androstan or Pregnan series and as non-steroidal receptor-affine compounds those from the series of
2[4(1,2-diphenyl-1-butenyl)-phenoxy]phenylamine vorliegen, 2 [4 (1,2-diphenyl-1-butenyl) phenoxy] phenylamine are present,
5. zytostatikakonkugate nach Anspruch 1 bis 4, dadurch 5. cytostatic conjugates according to claim 1 to 4, characterized
gekennzeichnet, daß das Verbindungselement zwischen characterized in that the connecting element between
Träger und Antitumorwirkstoff Carboxy- C1-C11-Alkylgruppen, Amino-C1-C12-Alkylgruppen, Carrier and antitumor agent carboxy-C 1 -C 11 -alkyl groups, amino-C 1 -C 12 -alkyl groups,
Amino-C1-C11-Alkylcarbonsäuren, Amino-C 1 -C 11 -alkylcarboxylic acids,
ω-Carboxy-C1-C12-Alkyl-1-oxo-amino-C1-C11-alkylaminn, ω-carboxy-C1-C12-Alkyl-1-oxo-amino-C1 C11-talkylamino ω-carboxy-C 1 -C 12 alkyl-1-oxo-amino-C 1 -C 11 alkylamine, ω-carboxy-C 1 -C 12 alkyl-1-oxo-amino-C 1 C 11 -talkylamino
-C1-C11alkylamine, Hydroylierte Di- und -C 1 -C 11 alkylamines, hydroylated di- and
Tricarbonsäuren, Ethylendiamin-di-, tri- und Tricarboxylic acids, ethylenediamine-di-, tri- and
tetracarbonsäure, Amino- oder Oligopeptide (bis tetracarboxylic acid, amino or oligopeptides (to
Hexapaptid) aus identischen oder unterschiedlichen Hexapaptid) from identical or different
Aminosäurebausteinen unter vorzugsweiser Verwendung von alpha-äAminosäuren, Tris .hydroxymethylaminomethan^monoster von hydroxylierten oder nicht hydroylierten Amino acid building blocks, preferably using alpha-amino acids, tris .hydroxymethylaminomethane ^ monoster of hydroxylated or non-hydroylated
Dicarbonsäuren oder Ethylendiamindi-, tri- oder Dicarboxylic acids or ethylenediaminedi-, tri- or
tetracarbonsäure, abgeleitet ist. tetracarboxylic acid.
6. Verfahren zur Herstellung der Zytostatikakonjugate nach Anspruch 1 bis 5, dadurch gekennzeichnet, daß in an sich bekannter Weise das Verbindungselement einerseits mit dem Antitumorwirkstoff und andererseits mit dem 6. A method for producing the cytostatic conjugates according to claim 1 to 5, characterized in that the connecting element on the one hand with the antitumor agent and on the other hand with the
steroidrezeptoraffinen Träger, insbesondere über eine Ester- oder über eine Amidbindung verknüpft wird. steroid receptor-affine carrier, in particular is linked via an ester or via an amide bond.
7. Verfahren nach Anspruch 6, dadurch gekennzeichnet, daß die Veresterung mit Carbonyldiimidazol oder 7. The method according to claim 6, characterized in that the esterification with carbonyldiimidazole or
Dicyclohexylcarbodiimid mit oder ohne Zusatz von Dicyclohexylcarbodiimide with or without the addition of
p-rDimethylaminopyridin und die Amidierung mittel p-rDimethylaminopyridine and the amidation medium
Dicyclohexylcarbodiimid oder Carbonyldiimidazol mit oder ohne Zusatz von p-Dimethylaminopyridin oder über einen aktiven N-Hydroxysuccinimidester bzw. über ein Azid der Säure erfolgt. Dicyclohexylcarbodiimide or carbonyldiimidazole with or without the addition of p-dimethylaminopyridine or via an active N-hydroxysuccinimide ester or via an azide of the acid.
8. Verfahren nach Anspruch 6 bis 7, dadurch gekennzeichnet, daß die Veresterung bzw. Amidierung bei Raumtemperatur für eine Zeitdauer von 1 - 24 h, oder bei leichtem 8. The method according to claim 6 to 7, characterized in that the esterification or amidation at room temperature for a period of 1 - 24 h, or with light
Erwärmen 1 -12 h erfolgt. Warm up 1 -12 h.
9. Verfahren nach einem der Ansprüche 6 bis 8, dadurch gekennzeichnet, daß ein organisches Lösungsmittel oder Lösungsmittelgemisch verwendet wird, das alle 9. The method according to any one of claims 6 to 8, characterized in that an organic solvent or solvent mixture is used, all
Reaktionskomponenten löst. Reacts components.
10. Verfahren nach Anspruch 6 bis 9, dadurch gekennzeichnet, daß die Reindarstellung der Konjugate 10. The method according to claim 6 to 9, characterized in that the pure representation of the conjugates
säulenchromatographisch an geeigneten column chromatography on suitable
Adsorptionsmitteln, insbesondere an Kieselgel und dann Eluieren mit geeignetem Lösungsmittel oder Adsorbents, especially on silica gel and then eluting with a suitable solvent or
Lösungsmittelgemisch oder durch Umkristallisation erfolgt. Solvent mixture or by recrystallization.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19893907290 DE3907290A1 (en) | 1989-03-07 | 1989-03-07 | STEROID HORMONE RECEPTOR AFFINES ANTITUARY ACTIVE SUBSTANCES |
| DEP3907290.8 | 1989-03-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1990010638A1 true WO1990010638A1 (en) | 1990-09-20 |
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ID=6375718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1990/000344 WO1990010638A1 (en) | 1989-03-07 | 1990-03-02 | Antitumoral agents with an affinity for steroid hormone receptors |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE3907290A1 (en) |
| WO (1) | WO1990010638A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994029327A1 (en) * | 1993-06-07 | 1994-12-22 | British Technology Group Limited | Anticancer compounds |
| EP0646592A1 (en) * | 1993-10-05 | 1995-04-05 | Kureha Kagaku Kogyo Kabushiki Kaisha | Estradiol derivative-alkylating agent conjugate |
| EP1023315A1 (en) * | 1997-05-14 | 2000-08-02 | Sloan-Kettering Institute For Cancer Research | Methods and compositions for destruction of selected proteins |
| US8063249B1 (en) | 2008-04-25 | 2011-11-22 | Olema Pharmaceuticals, Inc. | Substituted triphenyl butenes |
| US9796683B2 (en) | 2015-05-29 | 2017-10-24 | Eisai R&D Management Co., Ltd. | Tetrasubstituted alkene compounds and their use |
| US10640483B2 (en) | 2016-11-28 | 2020-05-05 | Eisai R&D Management Co., Ltd. | Salts of indazole derivative and crystals thereof |
| US11826430B2 (en) | 2019-05-14 | 2023-11-28 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
| US11834458B2 (en) | 2021-03-23 | 2023-12-05 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
| US11952349B2 (en) | 2019-11-13 | 2024-04-09 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
| US12006314B2 (en) | 2021-05-03 | 2024-06-11 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0489220A1 (en) * | 1990-12-02 | 1992-06-10 | American Cyanamid Company | Cytotoxic N,N'-bis (succinyl-peptide-) derivatives of 1,4-bis (aminoalkyl)-5,8-dihydroxyanthraquinones and antibody conjugates thereof |
| EP0688787A4 (en) * | 1993-12-29 | 1996-04-17 | Iskra Industry Co Ltd | Medicinal composition for bone resorption inhibition and osteogenesis acceleration |
| DE19831648B4 (en) * | 1998-07-15 | 2004-12-23 | Stiebel Eltron Gmbh & Co. Kg | Process for the functional adaptation of control electronics to a gas heater |
| DE10012120A1 (en) * | 2000-03-13 | 2001-09-27 | Ktb Tumorforschungs Gmbh | New ligand, comprising therapeutic or diagnostic agent bonded non-covalently with substance having high affinity to transport molecule |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2201419A (en) * | 1987-02-24 | 1988-09-01 | Erba Farmitalia | Anthracycline-oestrone derivatives |
-
1989
- 1989-03-07 DE DE19893907290 patent/DE3907290A1/en not_active Withdrawn
-
1990
- 1990-03-02 WO PCT/EP1990/000344 patent/WO1990010638A1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2201419A (en) * | 1987-02-24 | 1988-09-01 | Erba Farmitalia | Anthracycline-oestrone derivatives |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994029327A1 (en) * | 1993-06-07 | 1994-12-22 | British Technology Group Limited | Anticancer compounds |
| EP0646592A1 (en) * | 1993-10-05 | 1995-04-05 | Kureha Kagaku Kogyo Kabushiki Kaisha | Estradiol derivative-alkylating agent conjugate |
| US5478818A (en) * | 1993-10-05 | 1995-12-26 | Kureha Kagaku Kogyo Kabushiki Kaisha | Estradiol derivative-alkylating agent conjugate with reduced hormonal activity, process for preparing the same, compounds useful for the preparation thereof, and growth inhibiting composition containing the conjugate or estradiol derivative |
| US5480878A (en) * | 1993-10-05 | 1996-01-02 | Kureha Kagaku Kogyo Kabushiki Kaisha | Method for treating prostatic hypertrophy with estradiol derivatives |
| US5491138A (en) * | 1993-10-05 | 1996-02-13 | Kureha Kagaku Kogyo Kabushiki Kaisha | Estradiol derivative alkylating agent conjugate with reduced hormonal activity, process for preparing the same, compounds useful for the preparation thereof, and growth inhibiting composition containing the conjugate or estradiol derivative |
| US5561125A (en) * | 1993-10-05 | 1996-10-01 | Kureha Kagaku Kogyo Kabushiki Kaisha | Estradiol derivative and growth inhibiting composition thereof |
| US5633393A (en) * | 1993-10-05 | 1997-05-27 | Kureha Kagaku Kogyo Kabushiki Kaisha | Estradiol derivative-alkylating agent conjugate with reduced hormonal activity, process for preparing the same, compounds useful for the preparation thereof, and growth inhibiting compositon containing the conjugate or estradiol derivative. |
| EP1023315A4 (en) * | 1997-05-14 | 2004-12-29 | Sloan Kettering Institutefor C | Methods and compositions for destruction of selected proteins |
| EP1023315A1 (en) * | 1997-05-14 | 2000-08-02 | Sloan-Kettering Institute For Cancer Research | Methods and compositions for destruction of selected proteins |
| JP2009256388A (en) * | 1997-05-14 | 2009-11-05 | Sloan-Kettering Inst For Cancer Research | Method for destruction of selected protein and conjugated compound |
| US8063249B1 (en) | 2008-04-25 | 2011-11-22 | Olema Pharmaceuticals, Inc. | Substituted triphenyl butenes |
| US9796683B2 (en) | 2015-05-29 | 2017-10-24 | Eisai R&D Management Co., Ltd. | Tetrasubstituted alkene compounds and their use |
| US10851065B2 (en) | 2015-05-29 | 2020-12-01 | Eisai R&D Management Co., Ltd. | Tetrasubstituted alkene compounds and their use |
| US10640483B2 (en) | 2016-11-28 | 2020-05-05 | Eisai R&D Management Co., Ltd. | Salts of indazole derivative and crystals thereof |
| US11826430B2 (en) | 2019-05-14 | 2023-11-28 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
| US11952349B2 (en) | 2019-11-13 | 2024-04-09 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
| US11834458B2 (en) | 2021-03-23 | 2023-12-05 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
| US12006314B2 (en) | 2021-05-03 | 2024-06-11 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3907290A1 (en) | 1990-09-13 |
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