NZ192945A

NZ192945A - Cytostatic compositions containing a triglycidyl isocyanurate

Info

Publication number: NZ192945A
Application number: NZ192945A
Authority: NZ
Inventors: M Budnowski
Original assignee: Henkel Kgaa
Priority date: 1979-02-24
Filing date: 1980-02-22
Publication date: 1984-05-31
Also published as: JPS6354688B2; AU5583080A; ATE716T1; EP0014981A3; CH645893A5; FR2449451A1; IE49274B1; FR2449451B1; AU536270B2; GB2044614B; DE2907349C2; IT1147330B; CA1123740A; IL59453A; GB2044614A; IL59453A0; EP0014981A2; JPS55118484A; ZA801017B; SE8001425L

Abstract

A therapeutic composition with cytostatic action comprising an isocyanurate having the formula I <IMAGE> in which R, R', and R'' which may be the same or different represent hydrogen or alkyl having from 1 to 4 carbon atoms, preferably hydrogen or methyl in an inert pharmaceutically acceptable diluent, carrier or vehicle. The compositions may also contain other alkylating substances such as derivatives of nitrogen mustard or fluoruracil.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 92945 V 1 92945 Dats(s): Complete Specification Filed: ^i Class: . PXj.^P., ■ ■PubHcatiors Dote: .. 3.1. MAY. 198^. P.O. Jos,=rr?si llo: ., ,.. .. %WM\ BECSVED NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION "THERAPEUTIC COMPOSITIONS WITH A CYTOSTATIC ACTION AND METHOD" 3c/ We, HENKEL KOMMANDITGESELLSCHAFT AUF AKTIEN, a company organised and existing under the laws of the Federal Republic of Germany, of Henkelstrasse 67, Dusseldorf, Germany, hereby declare the invention for which £/ we pray that a patent may be granted to rrtx/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page la) r> i O . \ 4 10 15 o 20 1 92945 • BACKGROUND OF THE INVENTION The present invention relates to the use of specific isocyanuratfes having three epoxy groups to treat malignant neoplasias and therapeutic compositions containing the said isocyanurate with a cytostatic action. ' It is known that a number alkylating substances have a cytostatic or cytotoxic effect. The best known compounds are derived from so-called nitrogen mustards. It is also known to use compounds containing at least two epoxide group in the molecule ats cancerostatics. Such compounds are, for example3 4,*1 '-bis-(2,3-epoxypropyl)-di-piperidinyl-(l,lT) and lJ2J-15>l6-diepoxy-^,7s10jl3-tetraoxohexadecane. However these diepoxide compounds bring no substantial improvement ir the cytostatic treatment and are hardly used. Only for the treatment of tumors, they are still used occassionally. The limited solubility of the above mentioned compounds also prevents a wider use. . Various protocols for screening cytostats against animal tumors have been published by Geran, Greenberg, MacDonald, Schumacher and Abbott in "Cancer Chemotherapy Reports" (Sept. 1972) pages 1 to 87. These procedures will be referred to hereinafter by reference to the page(s) of this report. -1® : 1 • 10 15 C 192945 CHj—C V -CH, N N- CH, 0=C C=0 \ / R I C— CH \/ 2 0 R1 i CH' N I CHp- C V ' 0 wherein R, R' and R" are members selected from the group consisting of hydrogen and alkyl having from 1 to 1 carbon atoms, and the remainder to 100# conventional inert aqueous pharmaceutical vehicles. Preferably said minor amount i» from 0.05 to 5% by weight. -2- OBJECTS OP THE INVENTION An object of the present invention is to find easily-soluble, particularly water-soluble compounds with cytostatic or cytotoxic action, which are effective against a great number of malignomas and forms of leukemia. They should have a T/C ratio (see page *17) of at least 150# in at least one of the following leukemias: L 1210 and P 388, melanoma Bl6 and LL-carcinoma produced in animal experiments according to the specifications of the "Cancer Chemotherapy Reports", pages 7,9,11 and 15. Accordingly the invention may be said broadly to consist in a therapeutic composition with a cytostatic action consisting essentially of a minor amount of an Isocyanurate having the formula 0 II R" C / \ 1 J*--.., A yet further object of the present invention is the development of a method for the treatment of malignant neoplasias in. warm-blooded animals comprising administering a cytostatically effective amount of an isocyanurate having the formula 0 II R" C R i- / \ i CHi C—CH- N N—CH. C CH \ y 2 I | 2 \/ 2 0 . I I 0 0=Y^C=0 N R» I i CHo — C — V 2 -CH I 0 wherein R, R1 and R" are members selected from the group consisting of hydrogen and alkyl having from 1 to 1 carbon atoms, to a warm-blooded animal suffering from a malignant neoplasia*. These and othej? objects of the invention will become more apparent as the description thereof proceeds. DESCRIPTION OP THE INVENTION The problems of the prior art can be overcome and the above-objects achieved by the development and administration of therapeutic compositions containing compounds with a cytostatic action according to the general formula (I) -3- 192945 o n R" C R f / V I CH —-— C CH N N— CH C —CH, i/ I I \/ ' 0 0=C C=0 0 \ / 1 N R' I . • CH0—* C — CH 2 \/ 2 - ' 0 i ' : ' ' where R, R' and R" are either identical or different alkyl radicals with 1 to 4 carbon atoms and/or hydrogens. Preferred are compounds where R, R' and R" are either hydrogen and/or a methyl group. The compounds are to be used as cytostatic substances for the treatment of malignant neoplasias. These compounds can be used, if necessary together with conventiojia pharmaceutical auxiliary substances and/or vehicles. The invention therefore relates to a therapeutic composition with a cytostatic action consisting essentially of from 0.05# to 5# by weight of an isocyanurate having the formula 0 II R" Cv R I / \ ( CH— C — CH-— N N CH_ C CH„ ^ ./ 2 I I \/ 0 0=C C=0 0 \ / R' 1 I CH0— C— CH? - \/ 0 wherein R, R' and R" are members selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms and the remainder to 100# conventional inert aqueous pharme* aceutical vehicles; as well as the method for the treatment of malignant neoplasias employing said isocyanurates. These glycidyl compounds containing an isocyanurate ring are principally known substances. They have already been synthetized in more or less pure form and are used for the production of cross-linked plastics. While the preferred compounds, in which R, R' and R" are hydrogen, are characterized by an astonishingly good solubility in water for this type of compound, or in hydrophilic water-miscible solvents, nobody has ever thought, of using them In hydrous or aqueous hydrophilic solvents, particularly for pharmaceutical purposes or in drugs. If the three substituents R, R' and R" are identical two substances are obtained which are diastereomeric. The same holds true if there is no alkyl radical present, and the substituent is hydrogen. These compounds where R, R' and R" are hydrogen are then called a-triglycidyl isocyanurate or 3-triglycidyl isocyanurate (see Angew. Chemie., (1968), pages 851/2). Their production is described in U.S. Patent. No. 3,300,490 and in U.S. Patent No. 3,337,509. These two compounds are readily obtainable by reacting cyanuric acid with excess epichlorohydrin and dehydrochlorination with formation of the oxirane ring.: The pure products (a and 3 ) can be obtained from the crude product by fractionating cry- 192945 stallization, for example, from methanol, methylene chloride, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, etc. The so-called a-form has, in the pure form, a melting point of 106°C, whle the g-form has a melting point of 158°C. Though a separation is generally not necessary for technical purposes, the therapeutic effectiveness of the two isomers was investigated separately in the present case. Due to the different solubility in water or in mixture with the above-mentioned solvents, a clear separation is readily possible. Pure products show an epoxide oxygen content whicl-is between 16# and 16.2% by weight. Naturally the enant-iomers can also be obtained in more or less pure form from the diastomeric a- and 0-triglyceridyl isocyanurate, and the ef fectiveneiss can be further increased in some cases.. For use as cancerostatics, the active substances should be administered by means of suitable vehicles. In the present case, the use of water, if necessary together with compatible glycol ethers, like ethylene glycol mono-methylether or butylene glycol methylether or propylene glycc methylether were found to be of advantage, particularly if the active substance is administered parenterally. In oral administration, conventional pharmaceutical auxiliary substances and vehicles can be used, provided they show a corres ponding compatibility with the glycidyl compounds. Ordinarily the glycidyl compounds are employed in amounts of from 0.05# to 5% by weight in the therapeutical compositions. -6- i - /%■ .!' ■ ■<1 ■ :C t 92945 In animal experiments, the use of freshly prepared aqueous solutions administered intraperitoneally proved advisable. The maximum daily dose of a- or g-triglycidyl | isocyanurate in mice can be 100 mg/kg of mouse. Pronounced ^ toxic effects appear only at higher doses. The optimum dose was found to be in many cases to be 30 mg to 60 mg/kg of mouse.per day during an application period of 1 to 9 days. - The above-mentioned compounds are effective against ■ - i • ' ■ . various forms of leukemia and malignant neoplasmas, like -j q lung cancer, cancer of the colon, melanomas, ependymoblas- XU j tomas and sarcomas. A clear superiority over cyclophosphamide and fluoruracil was found in many cases. ! . Naturally it is also possible in addition to using | a-triglycidyl isocyanurate and 3-triglycidyl isocyanurates as cancerostatics to employ the other compounds of formula I where R, R' and R" represent at least partly a methyl group! As far as the corresponding solubility exists, the alkyl jj | group R, R' and R" can naturally contain more carbon atoms. J ■ ' ' ! ; A combination therapy with other alkylating sub- : - . ! 2o stances, like derivatives of nitrogen mustard or fluoruracil ■ ' • • :i is naturally also possible. ' The following are examples of the invention without being limitative in any respect. -7- 192945 EXAMPLES The following examples were carried out according to the test specifications of the Natural Cancer Institute, Bethesda, Maryland 20014, published in "Cancer Chemotherapy Reports" part 3, Sept. 72, Vol. 3, No. 2. The active substance used was either a-triglycidyl isocyanurate (mp: 106°C) or B-triglycidyl isocyanurate (mp: 158°C), both with 16.1% epoxide-oxygen content (for preparation see U.S. Patent No. 3,337,509). The preparation of tri(2-methylglycidyl) isocyanurate is described in British Patent Specification 996,72 3, but on repeating the procedure there was only obtained a product . which did not show the expected infrared spectrum. . Therefore, the desired compound was prepared by reaction of the potassium salt of cyanuric acid and methallylchloride followed by the epoxidation of the .triallyl compound intermediate. (a) A mixture of 86 gm potassium salt of cyanuric acid and 95 gm methallylchloride in 391 gm acetic acid nitrile was heated in an autoclav under nitrogen pressure at 150°C during 3 hours. After cooling the mixture was filtered and all volatile material was distilled off in vacuo at 0.1 mm pressure. The crude material was dissolved in cyclo-hexene and, after evaporating, recrystallized from the same solvent. The purified material had a melting point from 84 to 85°C and a iodine number of 264 (calculated: 261,3),. (b) 20 gm of the material received as described before was dissolved in 300 gm of CHjClg and treated with 15.85 gm m-chloroperbenzoicacid. The mixture was allowed to stand for 70 hours in a refrigerator at 4°C. Thereafter, the pre cipitate of 3-chlorobenzoic acid was filtered off. The received organic solution of the epoxide was washed with an aqueous solution of sodiumcarbonate (10% by weight), water for several times and dried with anhydrous sodium sulfate. When no more peracid was present the C^C^ was distilled off in vacuo. The residue was recrystallized using diethylether. Yield:-12.9 gm of white crystalls having a m.p. of 69 to 74°C (55-7% of the theory). Epoxide content: 13.7% by weight (calculated: 14.1%). The infrared spectrum gives typically strong isocyanurate absorptions at 1700 and 1455 cm ^. ^"H-NMR spectroscopy in CDCl^ (reference TMS) shows the protons of the CH^ groups at 1.4 ppm. The two protons on C-atom 1 of the 2-methylglycidyl groups give an AB system at 4.1 ppm, the two pirotons on C-atom 3 an AB system with a smaller coupling constant at 2.6 ppm. The structure 13 is further confirmed by C-NMR and mass spectroscopy. All aqueous 1% injection solutions were prepared fresh just prior to administration. The triglycidyl isocyanurate is also referred to by its initials TGI. ,1 9 2945 EXAMPLE 1 In mice a P 38.8 (leukemia) tumor was emplanted i.p. with 10^ cells/mouse according to protocol 1.200 (page 9). The untreated animals has a mean survival time (m.s.t.) of 10.5 days. After nine days of i.p. treatment with 100 mg/kg of a-TGI per day, the mean life expectancy increased to 285%, compared to the control group (T/C, extension rate). Half of the treated mice lived longer.than ^0 days and must be considered as cured. If only' 50 mg/kg of a-TGI per day were administered i.p. for 9 days, the corresponding values were 200# T/C and 17# cured. The corresponding value with 3-TGI for 100 mg/kg of mouse per day were 228# T/C and for 50- mg/kg per day 179# T/C. Healing was observed in 17# of the test animals. - 10 - 192945 Comparison test . A leukemia form of P 388, which was reslstent to cyclophosphamide (NSC 2627.1),. was emplanted in groups of mice and treated with a-TGI or cyclophosphamide. Each group consisted of 10 mice. With daily doses of 40 mg/kg of a-TGI for 1 to 9 days, all mice lived for 60 days (T/C 478%). On the other hand, those treated with 180 mg/kg of mouse of cyclophosphamide did not live even for 30 days (T/C 150$). EXAMPLE 2 Example 1 was repeated with a dose of 25 mg/kg per day for 9 days and the following observations were made: a-TGI showed a T/C of196# and B-TGI a T/C of 174$. EXAMPLE 3 Leukemia L 1210 was produced in mice according to protocol 1.100 (page 7) by i.p. administration of 0.1 ml diluted stimulating solution corresponding to 10^ cells. In the control group the mean survival time was 8 days (m.s.t.) A) One group (6 mice) received from the first to the 9th day 50 mg/kg of mouse per day of a-TGI i.p. The mean survival time rose to 23.8 days corresponding to a T/C of 2S7%. 3 mice lived for 30 days, that is, a healing rate of about 50# was achieved. 11 .1 9 29 4 5 Another group received from the first to the 9th day either 50 or 100 mg/kg of g-TGI per day, i.p. The mean survival time was 16.3 or 25-2 days respectively corresponding to a T/C of 203# or 315# respectively. B) The influence of the treatment plan on the therapeutic effect of a-TGI in tumor L 1210 after 30 days can be seen u from the following Table I. TABLE I 1 (. 10 15 Dependence of the effectiveness on the treatment plan with a-TGI Dose per day in mg/kg 50 mg for 5 x i.p (1st to 5th day) 40 mg for 9 x i.p. (1st to 9th day) Surviving / entire group Leukemic control group mice (not emplanted wit leukemia) 5/10 8/10 7/8 8/8 EXAMPLE 4 20 ; 1/10 homogenate melanoma B 16 were administered i.p ]! ■ I according to protocol 1.300 (page 11) at a rate of 0.5 ml per !■ ' • mouse. 12. I 7X7-tV The control group had a mean survival time of 15*8 (m.s.t.) Treated groups received from the first to the 9th day various amounts of a-TGI i.p. The following Table II shows the mean survival time and T/C in dependence on the dail dose of active substance. TABLE II Effect of a-TGI as a function of the dose mg a-TGI/kg mouse/day ' m.s'.t. (days) 1 T/C 50 37.0 234# 25 36.0 227# 12.5 29.8 188# 'EXAMPLE 5 ,3 ■ According to protocol 1.400 (page 13) cells of a I 1 mmJ 'piece of lung cancer (Lewis) were implanted s.c. in 1 i mice. 40 mg/kg of a-TGI and 90 mg/kg of 3-TGI respectively I were administered daily i.p. to each mouse froiri the first to Ir I the 11th day. The inhibition of-metastases was 92# for a-TGI and for 3-TGI compared to the control group after 23 days. -i±*- ' ' EXAMPLE 6 I In a test group of mice, 1 mm3 of a tissue of ependymoblastoma was implanted intracerebrally. The.mean survival time in the control group was 19.3 days. In a treatment with 40 mg/kg a-TGI daily for 9 days, a T/C of 165# was achieved. ' EXAMPLE 7 Sarcoma 180 was produced by i.p. administration of. 10^ cells/mouse. The untreated control group had a mean survival time of 20.2 days. For the treatment, 30 mg/kg of mouse of a-TGI were administered i.p. on-/as daily basis from 1 to 9 days. A T/C of 183# was observed. EXAMPLE 8 A) Groups of 10 mice were implanted with about 1 mm^ of colon carcinoma 38, s.c. The mean tumor weight in the untreated control group after 20 days was 512 mg/mouse. One group received on the 2nd and 9th day 50 mg/kg j! of mouse daily of a-TGI, and another group additional received 1 the same amount on the 16th day. The mean tumor weight was 153 mg and 183 mg rfespectively per mouse. '. • ' , j ' '■ -43- 10 15 192945 B) A carcinoma was produced by.i.p. implantation (1 mm^ color carcinoma 26) in groups of 10 mice each. The treatment consisted in the i.p. administration of a-TGI. The following Table III shows the results as a function of the amount admini-on the stered/lst, 5th and 9th day. TABLE III mg/kg of mouse 25 mg i.p. 50 mg i.p. 100 mg i.p. Result 25 days all mice survived 60.days; 6 out of 10 mice survived 60 days • 10 mice still alive 49 days all mice still alive 60 days 4 mice still alive A positive comparison by treatment with methyl CCNU (NSC-95441) 10 mg/kg of mouse i.p. showed that only 2 out of 10.mice were still alive on the 60th day (mean surviva time 55 days) - 15 - </div>

Claims

<div class="application article clearfix printTableText" id="claims">



192945 

EXAMPLE 9 

In mice a P 388 (leukemia) tumor was emplanted i.p. 

with 10^ cells/mouse accordingtto protocol 1.200 (page 9)» The untreated animals has a mean survival time (m.s.t.) of 10 days. 

After nine days of i.p. treatment with 100 mg/kg of tri-(2-methylglycidyl) isocyanurate per day, the mean life expectancy increased to 170 %, compared to the control group (T/C, extension rate). 

If only 50 mg/kg of tri-(2-methylglycidyl) isocyanurate per day were administered i.p. for 9 days, the corresponding values were 150 % T/C. 

The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood however,'that other expedients known to those skilled in the art, or disclosed herein, may be employed without departing ■ from the spirit of the invention or the scope of the appended claims. 

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WHAT WE CLAIM IS: 

i; A therapeutic composition with a cytostatic action consisting essentially of a minor amount of an isocyanurate having the formula o ' 

t - 

R" C 

I- / \ 

ch2— c-\/ 

o : 

-CH 

2 

N' 

I 

N- 

R 

I 

ch2— c. 

CH. 

\/ 0 . 

0=C C=0 

x»/ 

i ¥ - 

CHp—C —CHp 

2 \/ 

0 

wherein R, R' and R" are members selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, and the remainder to 100J? conventional inert aqueous pharmaceutical vehicles.
2. The therapeutic composition of claim 1 wherein ; R, R' and R" are selected from the group consisting of hydrogen methyl and mixtures thereof.
3. The therapeutic composition of claim 2 wherein R, R1 and, R" are hydrogen. -
4. The therapeutic composition of claim 3 wherein said isocyanurate is a-triglycidyl isocyanurate, 3-trigly.cidyl isocyanurate or mixtures thereof, or - one of the optically active forms of said triglycidyl isocyariurates.
5. The therapeutic composition of any one of claims 

1 to 4 wherein said minor amount is from ,0.05 to 5% by weight. 

-17- 

t 

.*• 

1 

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3 

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1 

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1 

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1 

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\c\xcms 

\
6. A method for the treatment of malignant neoplasias in warm-blooded animals excluding humans comprising administering a cytostatically effective amount of an isocyanurate having the formula 

0 . 

U 

Rn C R 

I /\ I 

, CH_— C CH — N N —CH.— C—.CH 

\/ 2 l |. \/ 2 

0 0 

o=c c=o 

\ y 

N R' 

1 I 

CH0— C — CHa 

, W 2 

' . o. 

wherein R, R' and R" are members selected from.the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, to a warm-blooded animal suffering from a malignant neoplasia;.
7: The method of claim £ wherein.R, R' and R" are selected from the group consisting of hydrogen, methyl and mixtures thereof.
8. The method of claim 7 wherein R, R1 and R" are hydrogen.
9. The method of claim 8 wherein said isocyanurate is a-triglycidyl isocyanurate, B-triglycidyl isocyanurate or mixtures thereof, or one of the optically active forms of said triglycidyl isocyanurates. 

Vv-WvA \ c 

"y His/their authorise? 

' \ j ° Pi SOV.. 



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