DK161833B - METHOD OF ANALOGUE FOR THE PREPARATION OF N- (VINBLASTINOYL-23) DERIVATIVES OF AMINO ACIDS OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. - Google Patents
METHOD OF ANALOGUE FOR THE PREPARATION OF N- (VINBLASTINOYL-23) DERIVATIVES OF AMINO ACIDS OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. Download PDFInfo
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Description
DK 161833 BDK 161833 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte bisindolalkaloider, nærmere betegnet N-(vinblastinoyl-23)-derivater med den i krav 1 2 5 1's indledning viste formel II, hvor R, R , R og R har de 5 sammesteds angivne betydninger, eller farmaceutisk acceptable syreadditionssalte deraf. Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav 1's kendetegnende del angivne.The present invention relates to an analogous process for the preparation of novel bisindole alkaloids, more specifically N- (vinblastinoyl-23) derivatives of the formula II shown in the preamble of claim 1, wherein R, R, R and R meanings, or pharmaceutically acceptable acid addition salts thereof. The process according to the invention is characterized by the characterizing part of claim 1.
De omhandlede derivater af vinblastin kan anvendes til behandling af leukæmi og maligne tumorer hos mennesker.The subject derivatives of vinblastine can be used to treat leukemia and malignant tumors in humans.
10 Bisindolalkaloider af vinblastintypen er velkendte for bindelser med kulstofskelettet med den almene formel uk /kr 15 oh 1Vinblastine-type bisindole alkaloids are well known for carbon skeletal compounds of the general formula uk / kr 15 oh 1
CHq0oC i 3 i ICH 2 O C in 3 i I
20 Uv, \A J20 Uv, \ A J
I II I
ch3° l /Cx°*b JH0 v o oC—0ch3 ° l / Cx ° * b JH0 v o oC — 0
25 23 L25 23 L
RaRaw
Som eksempler på disse forbindelser kan nævnes vinca-leukoblastin (US patentskrift nr. 3.097.137), leurocristin eller vineristin og leurosidin (US patentskrift nr. 3.205.220), 30 vinglycinat (BE patentskrift nr. 659.112) og vindesin (BE patentskrift nr. 813.168). Den sidstnævnte forbindelse vindes g ved kemisk modifikation af naturligt vinblastin (I, R = OCH^, Ru = COCH^), der kan vindes ved ekstraktion fra blade af Catharanthus roseus.Examples of these compounds are vinca-leukoblastin (U.S. Patent No. 3,097,137), leurocristine or vineristin and leurosidine (U.S. Patent No. 3,205,220), vingic glycinate (BE Patent No. 659,112) and vindesin (BE Patent No. 813,168). The latter compound is obtained g by chemical modification of natural vinblastine (I, R = OCH ^, Ru = COCH ^) obtainable by extraction from leaves of Catharanthus roseus.
35 Vinblastin, vineristin og vindesin er tilgængelige i handelen til brug i humanterapien, navnlig til behandling af leukæmi og visse faste tumorer.Vinblastine, vineristin and vindesin are commercially available for use in human therapy, in particular for the treatment of leukemia and certain solid tumors.
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Imidlertid har disse lægemidler~vist sig at have ugunstige bivirkninger. Vineristin har neurotoxiske virkninger og vinblastin har en høj toxicitet med hensyn til de hæmatopo-etiske væv.However, these drugs have been found to have adverse side effects. Vineristin has neurotoxic effects and vinblastine has a high toxicity to the hematopoietic tissues.
^ Virkningsmekanismen af disse lægemidler minder om den mekanisme der er postuleret for- den antimitotiske virkning af colchicin. Disse lægemidler vil virke ved inhibering af polymerisationen af tubulin til dannelse af mikrotubuler og påfølgende standsning af celledelingen i metafasen.^ The mechanism of action of these drugs is similar to the mechanism postulated for the antimitotic effect of colchicine. These drugs will act by inhibiting the polymerization of tubulin to form microtubules and subsequently stopping cell division in the metaphase.
1q Udnyttelsen af 1:1 komplekser af antitumorale tubilin- bisindolalkaloider er beskrevet i BE patentskrift nr. 854.053.1q The utilization of 1: 1 complexes of antitumoral tubilin bisindole alkaloids is described in BE Patent No. 854,053.
* I nogle tilfælde er der angivet lavere toxicitet og mere effektiv kemoterapeutisk virkning end for de tilsvarende frie alkaloider.* In some cases, lower toxicity and more effective chemotherapeutic effect are indicated than for the corresponding free alkaloids.
1^ Andre kemiske modifikationer af vinblastin er blevet afprøvet. Således er vinglycinat-sulfat (formel I, sulfat,Other chemical modifications of vinblastine have been tested. Thus, vinclinate sulfate (Formula I, sulfate,
Ra = 0CH3, Rb = COCH2N(CH3)2; Cancer Research 1967, 27, 221-227) også blevet afprøvet ved kliniske forsøg men har alment ikke vist sig at være bedre end vinblastin eller vineristin.Ra = OCH3, Rb = COCH2N (CH3) 2; Cancer Research 1967, 27, 221-227) has also been tested in clinical trials but has not been found to be superior to vinblastine or vineristin.
2q BE patentskrift nr. 813.168 beskriver vindesin (formel I, Ra = NH2, Rb = H) og andre vinblastin-C3 karboxamidderiva-ter. Senere rapporter fastslår den terapeutiske interesse for vindesin eller 3-karboxamid-4-0-desacetylvinblastin, men denne forbindelse har vist sig at være inaktiv ved behandling af 25 mus induceret med murin 1210 leukæmi (C.J. Barnett et al., J. Med. Chem. 21, 88, 1978).2q BE Patent No. 813,168 discloses vindesin (Formula I, Ra = NH 2, Rb = H) and other vinblastine-C3 carboxamide derivatives. Later reports establish the therapeutic interest in vindesine or 3-carboxamide-4-O-desacetylvinblastine, but this compound has been found to be inactive in the treatment of 25 mice induced with murine 1210 leukemia (CJ Barnett et al., J. Med. Chem 21, 88, 1978).
De ifølge opfindelsen fremstillede hidtil ukendte forbindelser er i stand til i væsentligt omfang at forsinke dødsfald hos mus der intravenøst er podet med P 388 og L 1210 leu- 3q kæmier.The novel compounds of the invention are capable of substantially delaying the death of mice intravenously inoculated with P 388 and L 1210 leu-3q germs.
Virkninger på eksperimentelt fremkaldte P 388 tumorer har overraskende vist sig at være langt overlegne i forhold til vincaalkaloider. Der er iagttaget talrige totale afhjælpninger deraf.Surprisingly, effects on experimentally induced P 388 tumors have been found to be far superior to vinca alkaloids. Numerous total remedies thereof have been observed.
3^ De ifølge opfindelsen fremstillede forbindelser udviser andre vigtige og uventede fordele sammenlignet med vinblastin og kendte analoger dertil, navnlig vindesin.The compounds of the invention exhibit other important and unexpected advantages over vinblastine and known analogs thereto, especially windsin.
Nærmere bestemt er den toxicitet der er blevet iagttaget 3More specifically, the toxicity observed has been 3
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generelt lavere end den tilsvarende toxicitet hos vindesin eller vineristin.generally lower than the corresponding toxicity of vindesin or vineristin.
Fortrinsvis er ifølge opfindelsen nitroseringsrea-genset natriumnitrit i nærværelse af metanolisk HC1.Preferably, according to the invention, nitrosation-reacted sodium nitrite is in the presence of methanolic HCl.
5 Således fremstilles ætyl-N-(4-0-deacetyl-41-deoxy- vinblastin-23-oyl B)-tryptofanat ifølge opfindelsen ved at omsætte azidet af 4-0-deacetyl-deoxy-4'-vinblastin-23-onsyre med en til fem ækvivalenter af ætyl-L-tryptofanat.Thus, ethyl N- (4-O-deacetyl-41-deoxy-vinblastin-23-oyl B) -tryptophanate of the invention is prepared by reacting the azide of 4-O-deacetyl-deoxy-4'-vinblastin-23-oanoic acid with one to five equivalents of ethyl L-tryptophanate.
En eventuel beskyttelse af tryptofanesteren kan op-10 nås ved kondensering med en benzyl-, t-butyl-, benzyloxy-karbonyl-, t-butoxytrifluoracetylkarbonyl- eller trityl-gruppe.Any protection of the tryptophan ester can be achieved by condensation with a benzyl, t-butyl, benzyloxy-carbonyl, t-butoxytrifluoroacetylcarbonyl or trityl group.
Ved opbygning af sidekæden med tryptofangruppen kan man gå frem på konventionel måde ud fra tilsvarende deriva-15 ter af vinblastin, ved hydrazinolyse efterfulgt af nitrose-ring og omsætning med aminosyreesteren i overensstemmelse med reaktionsskemaet I: Γ-* N2H4 Γ-ΓΊ NaN02 20 CH30H HC1 >f*0C0CH3 o°cBy constructing the side chain with the tryptophan group, one can proceed in conventional manner from corresponding derivatives of vinblastine, by hydrazinolysis followed by nitrosation and reaction with the amino acid ester according to Scheme I: Γ- * N2H4 Γ-ΓΊ NaN02 20 CH HC1> f * 0C0CH3 o ° c
°“ COOCH ψ\ °H° “COOCH ψ \ ° H
C00CH3 HO^ c_nh.n HO C-N3 S 0 25 rh aminosyreester CH2C12 °H 30 HO C-N-d-CO-OR4 / iC00CH3 HO ^ c_nh.n HO C-N3 S 0 25 rh amino acid ester CH2C12 ° H 30 HO C-N-d-CO-OR4 / i
Reaktionsskema IScheme I
hvor R2 og R4 har de i krav 1 angivne betydninger.wherein R 2 and R 4 have the meanings specified in claim 1.
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Det første trin ved fremgangsmåden er at sætte vandfrit hydrazin i overskud til en opløsning af vinblastinbase i vandfrit metanol. Opløsningen opvarmes under en inaktiv atmosfære i 12 timer til 12 dage ved en temperatur mellem ca. 30°C og ^ 70°C. Det foretrækkes navnlig at holde temperaturen omkring 60°C.The first step of the process is to add anhydrous hydrazine in excess to a solution of vinblastine base in anhydrous methanol. The solution is heated under an inert atmosphere for 12 hours to 12 days at a temperature between ca. 30 ° C and ^ 70 ° C. In particular, it is preferred to maintain the temperature at about 60 ° C.
Hydrazidet af bisindolderivatet isoleres derpå ved tilsætning af vand, ekstraktion med diklormetan og koncentrering. Forbindelsen kan senere renses ved præparativ kromato-.The hydrazide of the bisindole derivative is then isolated by the addition of water, extraction with dichloromethane and concentration. The compound can later be purified by preparative chromato-.
1q grafi (neutralt siliciumdioxyd). I tilfælde af vineristin er . det vundne produkt 4-0-deacetyl-deformyl-vincristin-karboxhy-drazid.1q graph (neutral silica). In the case of the wine roast is. the product obtained is 4-O-deacetyl-deformyl-vincristine-carbohydrate.
Under det andet trin omdannes hydrazidgruppen i det modificerede vinblastin til en acylazidgruppe. Denne omdannel-^ se opnås på kendt måde ved at sætte natriumnitrit til hydrazidet opløst i en vandig-sur-metanolblanding.During the second step, the hydrazide group of the modified vinblastine is converted to an acylazide group. This conversion is achieved in known manner by adding sodium nitrite to the hydrazide dissolved in an aqueous-acid-methanol mixture.
Den anvendte syre kan være saltsyre.The acid used may be hydrochloric acid.
Reaktionstemperaturen holdes mellem 0°C og 5°C. Efter ekstraktion med et ikke-vandblandbart aprotisk opløsningsmid- Ί 2Q del, fortrinsvis metylenklorid, koncentreres den organiske fase delvis.The reaction temperature is maintained between 0 ° C and 5 ° C. After extraction with a non-water miscible aprotic solvent Ί 2Q part, preferably methylene chloride, the organic phase is partially concentrated.
Acylazidet isoleres fortrinsvis ikke men sættes direkte til tryptofanesteren eller eventuelt et beskyttet derivat deraf, opløst i metylenklorid.The acyl azide is preferably not isolated but added directly to the tryptophan ester or, optionally, a protected derivative thereof, dissolved in methylene chloride.
25 Den mængde tryptofan der skal anvendes er ca. 1-5 ækvi valenter af det modificerede vinblastinkarboxazid.The amount of tryptophan to be used is approx. 1-5 equivalents of the modified vinblastin carboxazide.
Reaktionsblandingen holdes mellem ca. -3°C og +10°C i 8 til 72 timer og almindeligvis i ca. 15 timer. Overvågning af reaktionen opnås let ved tyndlagskromatografi. Efter kon-2Q centrering kan forbindelsen med formel II omdannes til et sul-fatsalt eller et andet salt afledt af en mineralsk eller organisk syre ved krystallisation fra en metanolisk opløsning af den tilsvarende syre.The reaction mixture is kept between ca. -3 ° C and + 10 ° C for 8 to 72 hours and usually for approx. 15 hours. Monitoring of the reaction is easily achieved by thin layer chromatography. After concentration-2Q centering, the compound of formula II can be converted to a sulfate salt or other salt derived from a mineral or organic acid by crystallization from a methanolic solution of the corresponding acid.
De fremstillede forbindelser kan renses ved konventio-nelle metoder til kromatografi og omkrystallisation.The compounds prepared can be purified by conventional chromatography and recrystallization methods.
Om nødvendigt kan det således vundne 4-0-deacetylvinblastin- derivat genacyleres enten direkte til dannelse af vinblastinde- . .2 rivatet med formel II, hvori R er COCH^ (J. Med. Chem. 22, 5If necessary, the thus obtained 4-O-deacetylvinblastine derivative can be re-acylated either directly to form vinblastine derivative. The derivative of formula II wherein R is COCH 2 (J. Med. Chem. 22, 5
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391, 1979),eller under forudgående dannelse af 3,4-diacetoxy-derivatet efterfulgt af selektiv hydrolyse af 3-acetoxygrup-pen i stilling 3. Hydroxygruppen i stilling 4 kan på konventionel måde forestres med andre aktiverede syrederivater inde-^ holdende 2-9 kulstofatomer. 0-4-formylderivaterne vindes ved formylering (myresyre-eddikesyreanhydrid) af de tilsvarende 0-4-deacetylforbindelser (se BE patentskrift nr. 660.843).391, 1979), or during prior formation of the 3,4-diacetoxy derivative followed by selective hydrolysis of the 3-acetoxy group at position 3. The hydroxy group at position 4 can be conventionally esterified with other activated acid derivatives containing 2- 9 carbon atoms. The 0-4-formyl derivatives are obtained by formylation (formic acid-acetic anhydride) of the corresponding 0-4-deacetyl compounds (see BE Patent No. 660,843).
De ifølge opfindelsen fremstillede hidtil ukendte bis-indolalkaloider kan anvendes til industrielle og navnlig far-1Q maceutiske formål.The novel bis-indole alkaloids prepared according to the invention can be used for industrial and, in particular, pharmaceutical applications.
De omhandlede forbindelser udviser navnlig yderst nyttige antitumoregenskaber hvilket kan udnyttes ved den humane terapi.In particular, the compounds of the present invention exhibit extremely useful antitumor properties which can be utilized in human therapy.
De omhandlede tryptofanderivater kan anvendes til be-1 c- handling af L 1210, P 388 type leukæmi, gliomer, lymfosarcomer og andre leukæmier eller maligne tumorer. I den humane medicin kan de være nyttige til behandling af Hodgkin's syge og mod andre faste tumorer som er tilgængelige for behandling med vinblastin, vineristin eller vindesin. De omhandlede forbindel-2Q ser er også nyttige i veterinærmedicinen til behandling af tumorer hos dyr.The subject tryptophan derivatives may be used for the treatment of L 1210, P 388 type leukemia, gliomas, lymphosarcomas and other leukemias or malignant tumors. In human medicine, they may be useful in the treatment of Hodgkin's disease and against other solid tumors available for treatment with vinblastine, vineristin or vindin. The subject compound 2Qs are also useful in veterinary medicine for the treatment of tumors in animals.
Der kan også komme andre terapeutiske anvendelser i betragtning for de omhandlede hidtil ukendte derivater af bis-indolalkaloider. Det er beskrevet at vinblastin kan anvendes 2^ til behandling af nogle former for arthritis (US patentskrift nr. 4.208.411) og at vineristin kan anvendes til behandling af psoriasis (US patentskrift nr. 3.749.784).Other therapeutic uses may also be considered for the aforementioned novel derivatives of bis-indole alkaloids. It has been disclosed that vinblastine can be used to treat some forms of arthritis (U.S. Patent No. 4,208,411) and that vineristin may be used to treat psoriasis (U.S. Patent No. 3,749,784).
Til deres terapeutiske anvendelse indgives de omhandlede forbindelser, eventuelt i frysetørret form, fortrinsvis 2Q ad parenteral vej, opløst i et farmaceutisk acceptabelt opløsningsmiddel i form af en base eller et farmaceutisk acceptabelt syreadditionssalt. Blandt syreadditionssaltene foretrækkes ugiftige og farmaceutisk acceptable salte såsom salte med uorganiske syrer såsom saltsyre, fosforsyre og svovlsyre eller salte med organiske syrer såsom eddikesyre, propionsyre, ravsyre, vinsyre, oxalsyre, metansulfonsyre og benzensulfonsyre.For their therapeutic use, the subject compounds, optionally in lyophilized form, preferably 2Q by parenteral route, are dissolved in a pharmaceutically acceptable solvent in the form of a base or a pharmaceutically acceptable acid addition salt. Among the acid addition salts, non-toxic and pharmaceutically acceptable salts such as salts with inorganic acids such as hydrochloric acid, phosphoric acid and sulfuric acid or salts with organic acids such as acetic acid, propionic acid, succinic acid, tartaric acid, oxalic acid, methanesulfonic acid and benzenesulfonic acid are preferred.
Passende opløsningsmidler er fysiologisk vand eller andre saltopløsninger som er blevet pufrede, fx med et fosfat.Suitable solvents are physiological water or other saline solutions which have been buffered, eg with a phosphate.
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7 ! | (s,2H), 2,51 (s,lH), 0,93 (2t, 2x3H).7! | (s, 2H), 2.51 (s, 1H), 0.93 (2h, 2x3H).
Massespektrum (elektronisk ionisationssammenstød): 154, 294, 355, 413, 524, 555, 695, 710, 723, 736, 739, 755 (M + 1) -768, 769, 782 beregnet for C42H54Ng°7 754,942.Mass Spectrum (Electronic Ionization Clash): 154, 294, 355, 413, 524, 555, 695, 710, 723, 736, 739, 755 (M + 1) -768, 769, 782 calculated for C42H54Ng ° 7754.942.
5 2. Fremstilling af syreazid af modificeret vineristin5 2. Preparation of acid vinegar of modified vineristin
En opløsning af 850 mg vineristin-monohydrazid A i 20 ml metanol behandles med 63 ml IN HC1 og 175,5 mg natriumnitrit i 15 minutter ved 0°C. Opløsningen holdes ved 0°C og neu-10 traliseres derpå med NaHCO^ ved 0°C og ekstraheres derefter tre gange med diklormetan. De opsamlede organiske faser tørres over Na2S0^, filtreres og koncentreres under vakuum uden opvarmning indtil der opnås en opløsning på ca. 10 ml.A solution of 850 mg of vineristin monohydrazide A in 20 ml of methanol is treated with 63 ml of 1N HCl and 175.5 mg of sodium nitrite for 15 minutes at 0 ° C. The solution is kept at 0 ° C and then neutralized with NaHCO 3 at 0 ° C and then extracted three times with dichloromethane. The collected organic phases are dried over Na 2 SO 4, filtered and concentrated in vacuo without heating until a solution of ca. 10 ml.
15 3. Omsætning med ætyltryptofanat 300 mg ætyltryptofanat tilsættes derpå under omrøring ved ca. 4°C og reaktionen efterprøves ved tic. Efter 10 dage renses reaktionsproduktet ved kromatografisk adskillelse (40 g silikagel 60, elueringsopløsningsmiddel æter/NH^-mættet me-20 tanol i rumfangsforholdet 96:4). Der opsamles fraktioner på 15 ml og disse afprøves ved tic. Den ikke omsatte aminosyre opsamles først (fraktion 30-40). Der skiftes elueringsmiddel (æter/NH^-mættet metanol i rumfangsforholdet 86:14) og de omsatte derivater opsamles som tre fraktioner: fraktion 44 og 25 45: 30 mg? fraktion 46-53: 257 mg? fraktion 54-60: 115 mg).3. Reaction with ethyl tryptophanate 300 mg of ethyl tryptophanate is then added with stirring at ca. 4 ° C and the reaction is tested at tic. After 10 days, the reaction product is purified by chromatographic separation (40 g of silica gel 60, eluting solvent ether / NH 4 -saturated methanol in the 96: 4 volume ratio). 15 ml fractions are collected and tested at tic. The unreacted amino acid is first collected (fraction 30-40). The eluent is changed (ether / NH 4 -saturated methanol in the volume ratio 86:14) and the reacted derivatives are collected as three fractions: fractions 44 and 45: 30 mg? fraction 46-53: 257 mg? fraction 54-60: 115 mg).
Den anden del var ætyl-N-(0-4-deacetyldeformylvincri-stin-23-oyl)-tryptofanat(la) som var homogent ifølge tic.The second part was ethyl N- (0-4-deacetyldformylquinestrin-23-oyl) tryptophanate (1a) which was homogeneous according to tic.
Massespektrum: 984, 970, 956 (M+ + 1) 913, 912, 899 (DCJ isobutan), beregnet for 955,181.Mass Spectrum: 984, 970, 956 (M + + 1) 913, 912, 899 (DCJ isobutane), calculated for 955,181.
30 UV-spektrum (CH^OH): max: 282 (4,20) - 290 (4,18) - " 322 (3,96). min: 254 - 287 - 305.UV spectrum (CH 3 OH): max: 282 (4.20) - 290 (4.18) - "322 (3.96). Min: 254 - 287 - 305.
IR-spektrum, (cm^1): 3400 - 2920 - 1720 - 1660 - 1610 -1485 - 1450 - 1370 - 13^5 - 1330 - 1290 - 1220 - 1165 - 1130 -1025 - 1005 - 920 - 885 - 830 - 740.IR spectrum, (cm ^ 1): 3400 - 2920 - 1720 - 1660 - 1610 - 1485 - 1450 - 1370 - 13 ^ - 1330 - 1290 - 1220 - 1165 - 1130 -1025 - 1005 - 920 - 885 - 830 - 740th
35 NMR-spektrum (CDCl^) 360 MHz (ppm): 8,50 (s,IH), 8,03 (s,2H), 7,77 (d,IH), 7,60 (d,IH), 7,57 (d,IH), 6,95 (s,IH), 6,35 (s,IH), 5,89 (d.d,lH), 5,78 (d,lH), 4,75 (q,lH), 3,88 (s,3H), 3,67 (s,3H), 1,23 (t,3H>, 0,98 (t,3H), 0,89 (t,3H).NMR Spectrum (CDCl3) 360 MHz (ppm): 8.50 (s, 1H), 8.03 (s, 2H), 7.77 (d, 1H), 7.60 (d, 1H), 7.57 (d, 1H), 6.95 (s, 1H), 6.35 (s, 1H), 5.89 (dd, 1H), 5.78 (d, 1H), 4.75 (q , 1H), 3.88 (s, 3H), 3.67 (s, 3H), 1.23 (t, 3H>, 0.98 (t, 3H), 0.89 (t, 3H).
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I almindelighed kan forbindelserne anvendes i humanterapien på analog måde med den teknik og med de begrænsninger der er for anvendelsen af andre alkaloider af vincatypen.In general, the compounds can be used in human therapy by analogy with the technique and with the limitations of the use of other vinca type alkaloids.
Det aktive stof distribueres i almindelighed ved en 5 dosologi der varierer mellem 0,01 mg til ca. 5 mg/kg i afhængighed af derivatet og det terapeutiske skema der tilpasses.The active ingredient is generally distributed at a dosology ranging from 0.01 mg to approx. 5 mg / kg depending on the derivative and therapeutic schedule being adapted.
De samlede doser over en uge vil i almindelighed variere mellem 0,1 og ca. 35 mg/kg.The total doses over a week will generally range from 0.1 to about 10. 35 mg / kg.
Forbindelserne kan indarbejdes i præparater i form af 1q enhedsdoser på 2-900 mg.The compounds can be incorporated into preparations in the form of 1q unit doses of 2-900 mg.
De omhandlede forbindelser kan anvendes alene eller i kombination med andre carcinostatiske midler indbefattet fx alkyleringsmidlerne, antimetaboliterne såsom metotrexat, 5-fluoruracil, 6-merkaptopurin, 6-tioguanin, cystosinarabino-j,. siderne og antibiotika såsom actinomycin D, daunorubicin, ad-riamycin og cis-diaminodiklorplatin. Navnlig kan de hidtil ukendte vinblastinderivater anvendes i kombination.The compounds of this invention can be used alone or in combination with other carcinostatic agents including, for example, the alkylating agents, antimetabolites such as methotrexate, 5-fluorouracil, 6-mercaptopurine, 6-thioguanine, cystosinabinoj. the sites and antibiotics such as actinomycin D, daunorubicin, adriamycin and cis-diaminodichloroplatin. In particular, the novel vinblastine derivatives can be used in combination.
Fremgangsmåden ifølge opfindelsen belyses nærmere i det følgende ved hjælp af nogle eksempler.The process according to the invention is illustrated in the following by means of some examples.
2020
Eksempel 1 1Example 1 1
Fremstilling af 0-4-deacetyl-N-deformyl-vincristin-mono- hydrazid A___ 985 mg vincristinbase opløses i en blanding af 10 ml 25 vandfri hydrazin og 10 ml metanol. Reaktionsblandingen holdes på 60°C under omrøring i 22 timer. Derpå behandles reaktionsblandingen med vand og derefter med vand mættet med NaCl. Den vandige opløsnings ekstraheres otte gange med 15 ml diklorme- tan. De forenede organiske faser behandles-med 20 ml vand, 30 derefter med 25 ml vand mættet med NaCl og tørres til sidst på Na2S0^. Efter filtrering og koncentrering under vakuum er der vundet 900 mg 0-4-deacetylvincristin-monohydrazid (renhed over 90%).Preparation of 0-4-deacetyl-N-deformyl-vincristine monohydrazide A 985 mg of vincristine base is dissolved in a mixture of 10 ml of anhydrous hydrazine and 10 ml of methanol. The reaction mixture is kept at 60 ° C with stirring for 22 hours. Then, the reaction mixture is treated with water and then with water saturated with NaCl. The aqueous solution is extracted eight times with 15 ml of dichloromethane. The combined organic phases are treated with 20 ml of water, then with 25 ml of water saturated with NaCl and finally dried on Na 2 SO 4. After filtration and concentration in vacuo, 900 mg of 0-4-deacetylvincristine monohydrazide (purity above 90%) is obtained.
NMR-spektrum (CDC13, 360 MHz): 9,76 (s,lH), 8,37 (s,IH), 35 8,06 (s,IH), 7,53 (d,lH), 7,24 og 7,07 (m,3H), 6,82 (s,lH), 6,22 (s,1), 5,87 (dd,lh), 5,67 (d,lH), 5,43 (s,IH),4,03 (s,lH), 3,94 (s,3H), 3,86 (s,IH), 3,73 (s,3H), 3,52 (s, 3H), 2,82 .NMR Spectrum (CDCl3, 360 MHz): 9.76 (s, 1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.53 (d, 1H), 7.24 and 7.07 (m, 3H), 6.82 (s, 1H), 6.22 (s, 1), 5.87 (dd, 1h), 5.67 (d, 1H), 5.43 ( s, 1H), 4.03 (s, 1H), 3.94 (s, 3H), 3.86 (s, 1H), 3.73 (s, 3H), 3.52 (s, 3H), 2.82.
- . .: -i : DK 161833 B j 8 | | Ætyl-N-(0-4-deacetylvincristin-23-oyl)-tryptofanat(Ib)-. .: -i: DK 161833 B j 8 | | Ethyl N- (0-4-deacetylvincristin-23-oyl) -tryptofanat (Ib)
Detdeformylerede derivat la (257 mg) genformyleres ved anvendelse af den fremgangsmåde der er beskrevet i BE patentskrift nr. 811.110.The deformylated derivative Ia (257 mg) is re-formulated using the procedure described in BE Patent No. 811,110.
5 Det således vundne råprodukt renses ved kromatografisk adskillelse under anvendelse af en 20 cm's kolonne (silikagel, 30 g) og efter hinanden tre elueringsmidler: æter/NH^-mættet metanol i rumfangsforholdene henholdsvis 92:8, 88:12 og 86:14.The crude product thus obtained is purified by chromatographic separation using a 20 cm column (silica gel, 30 g) and successively three eluents: ether / NH 2 -saturated methanol at volume ratios 92: 8, 88:12 and 86:14 respectively.
Effluenten opsamles som fraktioner på 15 ml. Fraktionerne 44- 1 q 54 (34,1 mg) indeholdt det N-genformylerede derivat (Ib).The effluent is collected as 15 ml fractions. Fractions 44-1 q 54 (34.1 mg) contained the N-gene formulated derivative (lb).
Massespektrum (isobutan DCI): 1011,997, 983 (M+ + 1), 970, 982, 996, 998, 999, 1012 beregnet for C56Hg6Ng°io = 983,192.Mass spectrum (isobutane DCI): 1011.997, 983 (M + +1), 970, 982, 996, 998, 999, 1012 calculated for C56 Hg6 Ng ° io = 983.192.
UV-spektrum (CH^OH): max: 270 (4,18) - 290 (4,11) 1 c plateau 280 (4,12) skulder (4,03).UV Spectrum (CH 2 OH): max: 270 (4.18) - 290 (4.11) 1 c plateau 280 (4.12) shoulder (4.03).
rij IR-spektrum (KBr): bånd ved 3400 - 3040 - 2960 - 2920 -2880 - 2850 - 1735 - 1725 - 1680 - 1670 - 1665 - 1610 - 1490 -1450 - 1225 - 745.high IR spectrum (KBr): bands at 3400 - 3040 - 2960 - 2920 - 2880 - 2850 - 1735 - 1725 - 1680 - 1670 - 1665 - 1610 - 1490 - 1450 - 1225 - 745.
2g Eksempel 2 Ætyl-N-(0-4-deacetyldeoxy-4'-vinblastin-23-oyl-B)-tryptofanat (Ic)_ O-4-Deacetyldeoxyvinblastinhydrazidet fremstilles ved den fremgangsmåde der er beskrevet i US patentskrift nr.Example 2 The ethyl N- (0-4-deacetyldoxyoxy-4'-vinblastin-23-oyl-B) -tryptophanate (Ic) -O-4-deacetyldoxyoxyblastine hydrazide is prepared by the process described in U.S. Pat.
^ 4.203.898 (spalte 24 linje 51 og følgende).^ 4,203,898 (column 24 line 51 et seq.).
500 mg af hydrazidet i 12 ml metanol behandles derefter med 37 ml IN HC1 og 104 mg NaNC^ i 15 minutter ved 0°C. Opløsningen neutraliseres derefter med NaHCOg og.ekstraheres seks gange med 15 ml diklormetan. De organiske faser tørres på ^ Na2S0^ og koncentreres til et rumfang på ca. 10 ml.500 mg of the hydrazide in 12 ml of methanol are then treated with 37 ml of 1N HCl and 104 mg of NaNCl for 15 minutes at 0 ° C. The solution is then neutralized with NaHCO 3 and extracted six times with 15 ml of dichloromethane. The organic phases are dried over 2 Na 2 SO 4 and concentrated to a volume of ca. 10 ml.
Azidet i opløsning bringes derpå i kontakt med 300 mg ætyltryptofanat ved 4°C under omrøring. Reaktionen afprøves ved tic (æter, metanol). Efter 6 dage er reaktionen tilendebragt og reaktionsproduktet renses ved søjlekromatografi på silikagel (18 cm, 30 g) eluering med fraktioner på 15 ml.The azide in solution is then contacted with 300 mg of ethyl tryptophanate at 4 ° C with stirring. The reaction is tested by tic (ether, methanol). After 6 days, the reaction is completed and the reaction product is purified by column chromatography on silica gel (18 cm, 30 g) eluting with 15 ml fractions.
Der anvendes følgende elueringsmidler i rækkefølge:The following eluents are used in sequence:
DK 161833BDK 161833B
9 æter/NH^-mættet metanol i rumfangsforholdet 96/4: fraktionerne 1-49 - - - - - 92/8: - 50-57 - - - - - 86/14: - 71-90 5 Fraktionerne 50-57 indeholder det ønskede reaktionspro dukt Ic (108 mg).9 ether / NH 2 -saturated methanol in the volume ratio 96/4: fractions 1-49 - - - - - 92/8: - 50-57 - - - - - 86/14: 71-90 5 Fractions 50-57 contain the desired reaction product Ic (108 mg).
Sulfatet fremstilles ved æterudfældning (2% HjSO^/æta- nol) .The sulfate is prepared by ether precipitation (2% H 2 SO 4 / ethanol).
UV-spektrum af sulfat (CH^OH): max: 224 (4,63) - 272 10 (4,32). min: 247 (4,03). skulder: 286 (4,22) - 312 (3,72).UV spectrum of sulfate (CH 2 OH): max: 224 (4.63) - 272 (4.32). min: 247 (4.03). shoulder: 286 (4.22) - 312 (3.72).
IR-spektrum (KBr) af sulfat: 3420 - 3060 - 2960 - 2930 -2880 - 2600 (svag) - 1725 - 1660 - 1615 - 1500 - 1455 - 1430 -1375 - 1230 - 1105 - 1060 - 1015 - 920 - 745 cm"1.Sulfate IR spectrum (KBr): 3420 - 3060 - 2960 - 2930 - 2880 - 2600 (weak) - 1725 - 1660 - 1615 - 1500 - 1455 - 1430 - 1375 - 1230 - 1105 - 1060 - 1015 - 920 - 745 cm "1.
NMR-spektrum (CDCl^) 360 MHz af basen i ppm: 9,46 (s,lH), 15 8,34 (s,IH), 7,92 (s,IH), 7,67 (d,lH), 7,59 (d,lH), 7,53 (d,lH), 7,30 (d,lH), 6,51 (s,lH), 6,04 (s,lH), m. omkring s. centre ret ved 5,81, 4,94 (q,lH), 4,18 (d,lH), 4,05 (q,2H), 3,77 (s,3H), 3,58 (s,RH), 3,47 (s,lH), 2,82 (s,2H), 2,77 (s,3H), 2,59 (S,IH), 1,14 (t,3H), 0,95 (t,3H), 0,87 (t,3H).NMR Spectrum (CDCl3) 360 MHz of the base in ppm: 9.46 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H), 7.67 (d, 1H) , 7.59 (d, 1H), 7.53 (d, 1H), 7.30 (d, 1H), 6.51 (s, 1H), 6.04 (s, 1H), m. centers right at 5.81, 4.94 (q, 1H), 4.18 (d, 1H), 4.05 (q, 2H), 3.77 (s, 3H), 3.58 (s, RH), 3.47 (s, 1H), 2.82 (s, 2H), 2.77 (s, 3H), 2.59 (S, 1H), 1.14 (t, 3H), 95 (t, 3H), 0.87 (t, 3H).
+ 2Q Massespektrum af basen: DCI isobutan, M + 1 ved 954, M + 14 + 1+ ved 968, M + 28 + 1+ ved 982, ioner ved 153 - 155 - 157 - 171 - 172 - 185 - 186 - 199 - 213 - 223 - 227 - 255 - 257 - 279 - 281 - 283 - 285 - 349 - 398 - 459 - 516 - 569 - 952 - 953 - 955 - 967 - 969 - 981 - 983, beregnet for 25 C56H68N6°8= ”3, 208.+ 2Q Mass spectrum of the base: DCI isobutane, M + 1 at 954, M + 14 + 1+ at 968, M + 28 + 1+ at 982, ions at 153 - 155 - 157 - 171 - 172 - 185 - 186 - 199 - 213 - 223 - 227 - 255 - 257 - 279 - 281 - 283 - 285 - 349 - 398 - 459 - 516 - 569 - 952 - 953 - 955 - 967 - 969 - 981 - 983, calculated for 25 C56H68N6 ° 8 = ”3, 208.
Akut toxicitet - bestemmelse af LDcn -O uAcute toxicity - determination of LDcn -O u
Den akutte toxicitet af den ifølge eksempel 2 fremstillede forbindelse: ætyl-N-(0-4-deacetyldeoxy-41-vinblastin-23-30 oyl-B)-tryptofanat er bestemt på NMRI-hunmus. Stigende doser er blevet indgivet intravenøst i en enkelt indsprøjtning. Den procentuelle dødelighed er bestemt som funktion af tiden. LDsQ-værdierne for den ovennævnte forbindelse (deoxy-VTrpE) og et referenceprodukt: deoxyvinblastin (deoxy VBL) er angivet 35 nedenfor.The acute toxicity of the compound of Example 2: ethyl N- (0-4-deacetyldoxy-41-vinblastin-23-30 oyl-B) tryptophanate is determined on female NMRI mice. Increasing doses have been administered intravenously in a single injection. The percentage mortality is determined as a function of time. The LDsQ values of the above compound (deoxy-VTrpE) and a reference product: deoxyvinblastine (deoxy VBL) are given below.
i 10i 10
DK 161833 BDK 161833 B
Lægemiddel —50Drug — 50
Deoxy VBL 20Deoxy VBL 20
Deoxy VTrpE (dvs. forbindelse Ic) 91,5 : 5 !Deoxy VTrpE (i.e. compound Ic) 91.5: 5!
Forbindelsen deoxy VTrpE er således mindre toxisk end referenceforbindelsen.Thus, the deoxy VTrpE compound is less toxic than the reference compound.
Antitumoral virkning 10 Den kemoterapeutiske virkning af sulfatsaltet af deoxy- VTrpE er blevet undersøgt på lymfoblastisk leukæmi L 1210 og P 388.Antitumoral effect 10 The chemotherapeutic effect of the sulfate salt of deoxy VTrpE has been investigated on lymphoblastic leukemia L 1210 and P 388.
1. L 1210 15 DBA2 hunmus er blevet podet med 10^ leukæmiceller. Pro duktet indgives ad intravenøs vej dagen efter podningen i en dosis på 50 mg/kg. Dødeligheden hos dyrene iagttages som funktion af tiden. Den nedenfor viste tabel 1 angiver de vundne 20 resultater med forbindelsen ifølge eksempel 2 (Ic). I den afprøvede dosis er forbindelsen mere aktiv end vinblastin. Denne overlegenhed er blevet fastslået ved sammenligning med deoxy-vinblastin.1. L 1210 15 DBA2 female mice have been seeded with 10 5 leukemia cells. The product is administered by the intravenous route the day after inoculation at a dose of 50 mg / kg. The mortality of the animals is observed as a function of time. Table 1 below shows the 20 results obtained with the compound of Example 2 (Ic). At the dose tested, the compound is more active than vinblastine. This superiority has been established by comparison with deoxy-vinblastine.
25 2. P 388 4 DBA2 hunmus podes intravenøst med 10 leukæmiceller. Produkterne indgives intravenøst dagen efter podningen. Dødeligheden hos dyrene iagttages som funktion af tiden. Resultatet fremgår i tabel 1. Deoxy VTrpE er tydeligt mere aktiv end 30 referenceforbindelsen og viser en højere procentuel mængde overlevende individer i lang tid.2. P 388 4 DBA2 female mice are grafted intravenously with 10 leukemia cells. The products are administered intravenously the day after inoculation. The mortality of the animals is observed as a function of time. The result is shown in Table 1. Deoxy VTrpE is clearly more active than the reference compound and shows a higher percentage of surviving individuals for a long time.
1111
DK 1618.33 BDK 1618.33 B
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Claims (3)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU83822A LU83822A1 (en) | 1981-12-08 | 1981-12-08 | N- (VINBLASTINOYL-23) DERIVATIVES OF AMINO ACIDS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| LU83822 | 1981-12-08 |
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| DK541882A DK161833C (en) | 1981-12-08 | 1982-12-07 | METHOD OF ANALOGUE FOR THE PREPARATION OF N- (VINBLASTINOYL-23) DERIVATIVES OF AMINO ACIDS OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. |
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| JP (1) | JPS58116491A (en) |
| AT (1) | AT390958B (en) |
| AU (1) | AU564951B2 (en) |
| BE (1) | BE895262A (en) |
| CA (1) | CA1198422A (en) |
| CH (1) | CH655727A5 (en) |
| DD (1) | DD205906A5 (en) |
| DE (1) | DE3245269A1 (en) |
| DK (1) | DK161833C (en) |
| ES (1) | ES517942A0 (en) |
| FR (1) | FR2517680B1 (en) |
| GB (1) | GB2111055B (en) |
| GR (1) | GR77280B (en) |
| HU (1) | HU187803B (en) |
| IE (1) | IE55283B1 (en) |
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| ATE64396T1 (en) * | 1983-04-29 | 1991-06-15 | Omnichem Sa | CONJUGATED VINBLASTIN COMPOUNDS AND THEIR DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| US4667030A (en) * | 1985-06-17 | 1987-05-19 | Eli Lilly And Company | Hydrazide succinimide derivatives of antineoplastic indole-dihydroindole alkaloids |
| US4675400A (en) * | 1985-06-17 | 1987-06-23 | Eli Lilly And Company | Bifunctional derivatives of 4-desacetyl indole-dihydroindole alkaloids |
| EP0233101A1 (en) * | 1986-01-13 | 1987-08-19 | Ire-Celltarg S.A. | Vinblastine derivatives and pharmaceutical compositions containing them |
| US4906086A (en) * | 1987-06-19 | 1990-03-06 | Honda Giken Kogyo Kabushiki Kaisha | Rearview mirror device for motorcycles |
| FR2626882B1 (en) * | 1988-02-08 | 1991-11-08 | Ire Celltarg Sa | VINCA DERIVATIVE CONJUGATES COMPRISING A DETERGENT CHAIN IN POSITION C-3 |
| US10377774B2 (en) * | 2013-04-19 | 2019-08-13 | Jinan University | Vinblastine derivatives, preparation method therefor and application thereof |
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| US3848234A (en) * | 1973-04-04 | 1974-11-12 | Sperry Rand Corp | Multi-processor system with multiple cache memories |
| IL48685A (en) * | 1975-01-09 | 1980-03-31 | Lilly Co Eli | Amides of vincadioline and vinblastine |
| OA06421A (en) * | 1980-06-10 | 1981-09-30 | Omnium Chimique Sa | Process for the preparation of N- (vinblastinoyl-23) derivatives of amino acids and peptides. |
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