IE53408B1 - Tetrazine derivatives - Google Patents
Tetrazine derivativesInfo
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- IE53408B1 IE53408B1 IE2026/82A IE202682A IE53408B1 IE 53408 B1 IE53408 B1 IE 53408B1 IE 2026/82 A IE2026/82 A IE 2026/82A IE 202682 A IE202682 A IE 202682A IE 53408 B1 IE53408 B1 IE 53408B1
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- imidazo
- carbamoyl
- tetrazin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
Title compds. (I)[R1=halo, C1-4 alkoxy, C3-8 cyclo alkyl, etc.; R2=methyl- or ethyl-carbamoyl were prepd.. Thus, a mixt. contg. 500mg 4[5 -diazo-imidazole-5[4 -carboxamide and 3.0ml methyl iso- cyanate was stirred for 21 days in dark place to give 8-carbamoyl-3- methyl-[3H -imidazo [5,1-d -1,2,3,5-tetrazin-4-one.
Description
This invention relates to new [3H]-imidazo[ 5« 1-d]-1,2,3,5-tetra2in-4-one derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
The compounds of the present invention are the [3H]-imidazof 5,1-d]-1,2,3,5-tetrazin-4-one derivatives of the general formula:-
wherein R represents a hydrogen atom, or a straight- or 10 branched-chain alkyl, alkenyl or alkynyl group containing up to 6 carbon atoms, each such group being unsubstituted or substituted by from one to three substituents selected from halogen (i.e. bromine, iodine or, preferably, chlorine or fluorine) atoms, straight- or branched-chain alkoxy, (e.g. methoxy), alkylthio, alkylsulphinyl and alkylsulphonyl groups containing up to 4 carbon atoms,
and optionally substituted phenyl groups, or R^- represents 2 a cycloalkyl group, and R represents a carbamoyl group which may carry on the nitrogen atom one or two groups selected from straight- and branched-chain alkyl and alkenyl groups, each containing up to 4 carbon atoms, and cycloalkyl groups, e.g. a methylcarbamoyl or dimethylcarbamoyl group.
When the symbol R^ represents an alkyl, alkenyl or alkynyl group substituted by two or three halogen atoms, the aforesaid halogen atcms may be the same or different. When the symbol R1 represents an alkyl, alkenyl or alkynyl group substituted by one, two or three optionally substituted phenyl groups the optional substituents on the phenyl radical(s) may be selected from, for example, alkoxy and alkyl groups containing up to 4 carbon atoms (e.g. methoxy and/or methyl group(s)) and the nitro group:
the symbol R1 may represent, for example, a benzyl or p-methoxybenzyl group. Cycloalkyl groups within the 1 2 definitions of symbols R and R contain 3 to 8, preferably
6, carbon atoms.
Preferred tetrazine derivatives of general formula I are those wherein R^ represents a straightor branched-chain alkyl group containing from 1 to 6 carbon atoms optionally substituted by one or two halogen (preferably chlorine, fluorine or bromine) atoms or by an alkoxy group containing 1 to 4 carbon atoms (preferably methoxy) or by a phenyl group (optionally substituted by one or two alkoxy groups containing from to 4 carbon atoms, preferably methoxy), or R3- represents an alkenyl group containing 2 to 6 carbon atoms (preferably allyl) or a cyclohexyl group.
More particularly preferred tetrazine derivatives are those of general formula I wherein R represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, and more especially from 1 to 3 carbon atoms, unsubstituted or substituted by a halogen, preferably chlorine or fluorine, atom. More especially R^ represents a methyl or 2-haloalkyl, e.g.
2-fluoroethyl or, preferably,2-chloroethyl, group.
Preferably R represents a carbamoyl group or a monoalkylcarbamoyl, e.g. methylcarbamoyl, or monoalkenylcarbamoyl group.
The present invention also includes salts of the compounds of general formula I wherein R3 represents 2 a hydrogen atom and R is as hereinbefore defined, more especially alkali metal, e.g. sodium, salts, and whenever the context so permits reference to the compounds of general formula I in this specification is meant to include reference to the said salts. The salts are particularly useful as interemdiates.
According to a feature of the present invention, the compounds of general formula I, wherein R is as hereinbefore defined and R3 is other than hydrogen, are prepared by the reaction of a compound of the general formula:2
II (wherein R is as hereinbefore defined) with an isocyanate of the general formula:5 R3NCO III wherein R3 represents an alkyl, alkenyl or alkynyl group, optionally substituted by one to three substituents selected from halogen atoms, alkoxy, alkylthio, alkylsulphinyl and alkylsulphonyl groups and optionally substituted phenyl groups, or represents a cycloalkyl group, within the definition of R1 hereinbefore recited. The reaction may be effected in the absence or presence of an anhydrous organic solvent, for exanple a chlorinated alkane, e.g. dichloromethane, or ethyl acetate, acetonitrile, N-methylpyrrolid-2-one or, preferably, hexamethylphosphoramide, at a tenperature between 0° and 70°c, e.g. at the ambient tenperature.
The reaction may be continued for up to 30 days. Light should preferably be excluded from the reaction mixture.
According to a further feature of the present invention, the compounds of general formula I,
534 0 8
1 wherein R xs as hereinbefore defined and R xs other than hydrogen, are prepared by the reaction of a compound (within general formula I) of·the general formula:-
(wherein R is as hereinbefore defined) or an alkali metal, e.g. sodium, salt thereof with a compound of the general formula:R3X V .
wherein R xs as hereinbefore defined, and X represents the acid residue of a reactive ester, for exanple a halogen (e.g. chlorine) atom, or a sulphuric or sulphonic ester residue, e.g. a methoxysulphonyloxy, methanesulphonyloxy, or toluene-£-sulphonyloxy group. When R3 in a compound- of general formula V represents a haloalkyl, haloalkenyl or haloalkynyl group, the acid residue of a reactive ester represented by X will be selected from those known to be not less reactive than the halogen atom substituent in R3. When X in a compound of general formula V represents a halogen atom, an alkali metal salt of the conpound of general formula IV is preferably used and when X in a conpound of general formula V represents a halogen atom and R is a haloalkyl, haloalkenyl or haloalkynyl group wherein the'halogen atom is the same as that represented by X, an excess of the dihalo conpound of general formula V is preferably used.
The reaction of a conpound of general formula IV or alkali metal salt thereof with a conpound of general formula V, wherein R and X are as hereinbefore defined, may be carried out in a suitable anhydrous inert organic solvent, for exanple dichloromethane, acetonitrile or N-methylpyrrolid-2-one or mixtures thereof, at a tenperature of from 0°C to 120°C and, when a conpound of general formula IV is used, in the presence of an acidbinding agent, for exanple an alkali metal, e.g.
sodium or potassium, carbonate or bicarbonate.
As a further feature of the invention, compounds of general formula IV (i.e. compounds of general formula I
2 wherein R represents a hydrogen atom and R is as hereinbefore defined) or alkali metal salts thereof are prepared by the reaction of a compound of general formula II with a conpound of the general formula:R4NC0 VI wherein R4 represents an alkali metal (e.g. sodium) atom or a protecting group such as a benzyl or p-methoxybenzyl group, followed, when R represents a protecting group, by the replacement of the protecting group by a hydrogen atom in the compound thus obtained of the general formula:-
wherein R is as hereinbefore defined, and R represents a protecting group such as a benzyl or js-methoxybenzyl group, by methods known per se. Reaction of a compound of general formula II with a compound of general formula VI wherein R represents a protecting group may be effected as hereinbefore described for the reaction of a compound of general formula II with a compound of general formula III. Reaction of a compound of general formula II with a compound of general formula VI, wherein
R represents an alkali metal atom, may be effected in a suitable inert organic solvent, e.g. ethanol, acetonitrile or N-methylpyrrolidone, optionally in the presence of an acid, at a temperature of from 0° to 120°C. The group R^ of compounds of general formula VII, wherein R is as hereinbefore defined, may be replaced by a hydrogen atom by methods known per se to give a compound of general formula IV.
Compounds of general formula II may be prepared by the application or adaptation of methods known per se. for example methods described by Shealy Y.F., Struck R.F., Holum L.B. and Montgomery J.A., J. Org. Chem.
(1961), 26, 2396.
Compounds of general formulae III, V and VI may be prepared by the application or adaptation of methods known per se.
By the term 'methods known per se' as used in the present specification is meant methods heretofore used or described in the literature.
The new tetrazine derivatives of general formula I possess valuable antineoplastic activity, for example against carcinomas, melanomas, sarcomas, lymphomas and leukaemias. They have proved particularly active in mice at daily doses between 0.5 and 16 mg/kg animal body weight, administered intraperitoneally, against TLX5(S) lymphoma according to the procedure of Gescher et al, Biochem. Pharmacol. (1981), 30., 89, and ADJ/PC6A and M5076 (reticulum cell sarcoma,. Against leukaemia L1210, grafted intraperitoneally, intracerebrally and intravenously, and P388, according to the procedure described in Methods of Development of New Anticancer Drugs (NCI Monograph 45, March 1977, pages 147-149,
National Cancer Institute, Bethesda, United States), the compounds were active both intraperitoneally and orally at doses of between 2.5 and 10 mg/kg animal body weight. Inhibition of both primary tumour and metastasis was obtained against the Lewis lung carcinoma by similar dosage regimes. Against the B16 melanoma and C38 tumour in mice (NCI Monograph 45, op cit.) the compounds were active intraperitoneally at doses of between 6,25 and 25 mg/kg animal body weight.
The tetrazine derivatives also possess valuable immunomodulatory activity and are of use in the treatment of organ grafts and skin grafts and in the treatment of immunological diseases.
Important individual compounds of general formula I include the following:8-carbamoyl-3-methyl-[3H]-imidazo[5,1-d]1,2,3,5-tetrazin-4-one A,
8-carbamoyl-3-n-propyl-[3H]-imidazo[5,1-d]1,2,3,5-tetrazin-4-one b ,
8-carbamoyl-3-(2-chloroethyl)-[3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one c,
3-(2-chloroethyl)-8-methylcarbamoyl-[3H]imidazo[5,1-d]-1,2,3,5-tetrazin-4-one D
8-carbamoyl-3-(3-chloropropyl)-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one E
8-carbamoyl-3-(2,3-dichloropropyl)-Γ3H]imidazo[5,l-d]-l,2,3,5-tetrazin-4-one F
3-allyl-8-carbamoyl-[3H]-imidazo[5,1-d]1,2,3,5-tetrazin-4-one G,
3-(2-chloroethyl)-8-dimethylcarbamoyl[3h]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one Η,
3-(2-bromoethyl)-8-carbamoyl-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one X,
3-benzyl-8-carbamoyl-[3H]-imidazo[5,1-d]1.2.3.5- tetrazin-4-one J, 8-carbamoyl-3-(2-methoxyethyl)-[3H]10 imidazo[5,l-dJ-l,2,3,5-tetrazin-4-one K,
8-carbamoyl-3-cyclohexyl-[3H]-imidazo[5,1-d]1.2.3.5- tetrazin-4-one L, and 8-carbamoyl-3-(ja-methoxybenzyl)-[3H]imidazo[5,l-d]-l,2,3,5-tetrazin-4-one. M
Compounds A and D, and especially C, are of particular importance.
The letters A to M are allocated to the compounds for easy reference later in the specification.
The following Examples illustrate the preparation of compounds of general formula I according to the present invention, and the Reference Example thereafter illustrates the preparation of intermediates.
EXAMPLE 1
Compound A
4[5]-Diazoimidazole-5[4]-carboxamide (500 mg) was suspended in methyl isocyanate (3.0 ml) and stirred in the dark, at ambient temperature, for 21 days. The reaction mixture was then diluted with anhydrous diethyl ether and filtered. The residue was washed quickly with anhydrous methanol, then with anhydrous diethyl ether, and dried in air, in the dark, at ambient temperature, to give 8-carbamoyl-3-methyl-[3H]-imidazo[5,l-d]15 l,2,3,5-tetrazin-4-one, in the form of a light brown microcrystalline solid (198 mg), m.p. 210°C (with effervescence and darkening from 160° to 210°C). [Elemental analysis:- found: C,36.8; H,3.10; 44.2%; C6HgNgO2 requires: C,37.1; Η,3Λ9 ; N,43.3%J.
EXAMPLE 2
Compound B
4[5]-Diazoimidazole-5[4]-carboxamide (300 mg) was suspended in anhydrous dichloromethane (10 ml) and treated with an excess of n-propyl isocyanate. The reaction mixture was then stirred in the dark, at ambient temperature, for 30 days. The reaction mixture was then filtered and the residue was washed quickly with anhydrous diethyl ether, and dried in air. in the dark, at ambient temperature, to give 8-carbaraoyl-3-n-prqpyl-[3H]imidazo[5,l-d]-l,2,3,5-tetrazin-4-one (102 mg), in the form of a pale pink powder, m.p. 167°C (with effervescence). [Elemental analysis:- found: C.43.4; H.4.57; N,38.0%;
C8H10N6°2 re<3uires: C.43.2; H.4.53, N.37.8%].
EXAMPLE 3
Compound C
4[5]-Diazoimidazole-5[4]-carboxamide (300 mg) was suspended in anhydrous dichloromethane (10 ml) and
2-chloroethyl isocyanate (1.0 ml) was added. The reaction mixture was then stirred in the dark, at ambient temperature, for 30 days. The cream-coloured suspension thus obtained was filtered and the residue was washed quickly with anhydrous diethyl ether and dried in air, in the dark, to give 8-carbamoyl-3-(2-chloroethyl)-[3hJimidazo[5«l-d]-l,2,3,5-tetrazin-4-one (483 mg), in the form of a cream-coloured powder, m.p. 158°C (with vigorous decomposition). [Elemental analysis:- found: C,34.7j H.3.01: N,34.9%j C^ClNgOj requires:
C.34.7; H,2.91; N,34.7%J.
Repetition of the above procedure has also given 8-carbamoyl-3-(2-chloroethyl)- [3h]-imidazo[5,1-dJ25 l,2,3,5-tetrazin-4-one in another polymorphic form,
m.p. 164-165°C (with decomposition).
EXAMPLE 4
Compound A
A suspension of 4[5j-diazoimidazole-5[4jcarboxamide (1.37 g) in ethyl acetate (20 ml) was treated with methyl isocyanate (7.0 g) and was stirred in a closed vessel in the dark at room temperature for 3 weeks. The resulting solid was filtered off and washed with diethyl ether to give 8-carbamoyl-3-methyl-[3hJ-imidazo[5«1-d]-1,2,3 ,5-tetrazin4-one (1.9 g), in the form of a cream-coloured solid, m.p. 212°C (with effervescence).
This material was recrystallised from three different solvent systems to give three different products, each of which had a slightly different IR spectrum. The three products were probably all polymorphs of 8-carbamoyl-3-methyl-[3H]-imidazo[5,l-d]l, 2,3,5-tetrazin-4-one.
(i) Colourless needles were obtained from a 3:1 v/v mixture of acetone and water, 3410, 3205,
1758, 1730 and 1678 cm-^, m.p. 212°C (with effervescence) (ii) White microcrystals were obtained from a 1:3 v/v mixture of acetone and water, \) 3430, 3200 max
1740 and 1675 cm“\ m.p. 210°C (with effervescence).
(iii) A granular solid was obtained from hot water, \)max 3450, 3380, 3200, 1742, 1688 and 1640 cm-1,
m. p. 215°C (with effervescence) (darkening from 200°C).
EXAMPLE 5
Compound B
A suspension of 4[5]-diazoimidazole-5[4]carboxamide (1.37 g) in acetonitrile (20 ml) was treated with n-propyl isocyanate (6.5 g) and was stirred in a closed vessel in the dark at room temperature for 3 weeks. The resulting pink solid was filtered off, washed with diethyl ether, and recrystallised from a mixture of water and acetone (1:4 v/v), to give 8-carbamoyl3-n-propyl-[3H]-imidazof 5,1-d]-1,2,3,5-tetrazin-4-one (1.6 g), m.p. 170-172°C (with effervescence). By concentration of the recrystallisation mother liquor there was obtained a further quantity (0.2 g) of the same product.
EXAMPLE 6
Compound C
A suspension of 4[5]-diazoimidazole-5[4jcarboxamide (1.0 g) in ethyl acetate (30 ml) was treated with 2-chloroethyl isocyanate (3.3 ml) and the mixture was stirred in the dark, at ambient temperature, for 6 days. The reaction mixture was then diluted with diethyl ether and the resulting solid was filtered off, to give 8-carbamoyl-3-(2-chloroethyl)-[3H]imidazo[5,l-d]-l,2,3,5-tetrazin-4-one (1.6 g) in the form of a colourless solid, m.p. 164-165°C (with decomposition). [Elemental analysis:- found:
C,34.5; H,2.88; N,34.5; Cl,14.6%; C7H7C1N6O2 requires
C,34.65; 11,2.91; N,34.65; Cl,14.61%].
EXAMPLE 7
Compound C
A suspension of 4[5]-diazoimidazole-5[4]carboxamide (5-0 g) in a mixture of dichloromethane (158 ml) and N-methylpyrrolid-2-one (8.3 ml) was treated with 2-chloroethyl isocyanate (16.7 ml) and the mixture was stirred in the dark at ambient temperature for 14 days. The reaction mixture was then diluted with anhydrous diethyl ether and the resulting solid was filtered off and washed with diethyl ether, to give 8-carbamoyl-3-(2-ehloroethyl)-[3H]-imidazo[5,1-d]-1,2,3,5· tetrazin-4-one (6.3 g), in the form of a purple15 tinged solid, m.p. 164-165°C (with decomposition).
[Elemental analysis:- found: C,34.7; H,2.95; 11,34.5;
Cl,14.4%; C7H7ClNgO2 requires: C.34.65; H.2.91; N.34.65
Cl,14.61%].
EXAMPLE 8
Compound C
A suspension of 4[5]-diazoimidazole-5[4]carboxamide (145 g) in ethyl acetate (2175 ml) was treated with 2-chloroethyl isocyanate (478.5 ml) and stirred at 30°C, with the exclusion of light, for
2 days. The mixture was then filtered to give
8-carbamoyl-3-(2-chloroethyl)-[3H]-imidazo[5,1-d] 53408 l,2,3,5-tetrazin-4-one (250 g), in the form of a peachcoloured solid, m.p. 166°C.
EXAMPLE 9
Compound A
A stirred suspension of 4[5j-diazoimidazole5[4]-carboxamide (2.2 g) in a mixture of dichloromethane (70 ml) and N-methylpyrrolid-2-one (3.5 ml) was treated with methyl isocyanate (7.0 ml) and stirred at ambient temperature for 4 weeks. The mixture was diluted with diethyl ether and the resulting solid was filtered off, to give 8-carbamoyl-3-methyl-[3Hj-imidazo[5,l-dJ-l,2,3,5tetrazin-4-one (2.38 g), in the form of a pale purple solid, m.p. 202-203°C (with decomposition). [Elemental analysis:- found: C.36.8; H.2.94; N,43.1%; CgHgNgOj requires: C,37.11; H,3.14; N,43.3%J.
A polymorphic form of 8-carbamoyl-3-methyl[3H]-imidazo[5,l-dJ-l,2«3,5-tetrazin-4-one was obtained by dissolving it in acetonitrile, filtering, concentration of the filtrate to dryness, and trituration of the resulting residue with diethyl ether. This material was in the form of an orange-tinged solid, m.p. about 200°C (with decomposition). [Elemental analysis: C.37.4; H,3.26j N,43.5%J. Its NMR spectrum in dimethylsulphoxide-Dg was identical to that of the abovementioned pale purple solid, but its IR spectrum (KBr disc) showed scxne differences.
EXAMPLE 10
Compound D
A stirred solution of sodium nitrite {0.64 g) in water (4.6 ml) was cooled to 5°-10°C and treated dropwise at that temperature with a solution of 5-amino4-methylcarbamoylimidazole (1.00 g) in aqueous acetic acid (lMj 14.3 ml) during 5 minutes. Stirring was continued at 5°-10°C for 5 minutes. The dark red solution was then extracted with ethyl acetate (4 x 35 ml) and the combined extracts were dried over magnesium sulphate. The resulting solution contained crude 4[5]-diazo-5[4]-methylcarbamoylinu.dazole, which was unstable and was used immediately for the next stage without further purification.
The solution of 4[5)-diazo-5[4]-methylcarbamoylimidazole in ethyl acetate, prepared as described above, was treated with 2-chloroethyl isocyanate (4.3 ml) and was allowed to stand in the dark for 1 day. The solution was then evaporated at 40°C/10 mm Hg and the residue was triturated with petroleum ether (b.p. 40°-60°C) to give an orange gum (4.23 g). This gum was treated with ethyl acetate (50 ml) and filtered, and the filtrate was evaporated at 40°C/10 mm Hg to give an orange gum (2.94 g). This gum was purified by medium pressure column chromatography on silica gel, eluting with a mixture of ethyl acetate and acetonitrile (4:1 v/v).
to give 3-(2-chloroethyl)-8-methylcarbamoyl-[3Hjimidazo[5,l-d]-l,2,3,5-tetrazin-4-one (0.81 g), in the form of a purple solid, m.p. 120-122°C (with decomposition). [Elemental analysis:- found: C,37.3; H,3.58; N,31.9%;
CgHgClNgOj requires: C.37.4; H.3.53; N,32.7%J.
EXAMPLE 11
Compound E
A suspension of 4[5]-diazoimidazole-5[4jcarboxamide (1.0 g) in ethyl acetate (50 ml; dried over anhydrous potassium carbonate) was treated with 3-chloropropyl isocyanate (4.86 g) and the mixture was stirred at ambient temperature for 3 days. The reaction mixture was then diluted with anhydrous diethyl ether and the resulting solid was filtered off, and washed with anhydrous diethyl ether, to give 8-carbamoyl-3-(3-chloropropyl )-[3hJ-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one (1.05 g) in the form of a pink solid, m.p. 153-154°C (with decomposition). [Elemental analysis:- found:
C.37.1; H.3.42; N,32.7; Cl,13.8%; CgHgClN^ requires: C.37.4; H,3.53; N.32.8; Cl,13.8#J.
EXAMPLE 12
Compound F
By proceeding in a manner similar to that described hereinbefore in Exanple 11 but replacing the 3-chloropropyl isocyanate used as a starting material by the appropriate quantity of 2,3-dichloropropyl isocyanate, there was prepared 8-carbamoyl-3-(2,3-dichloropropyl)-[3H] imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, in the form of an off-white solid, m.p. 153-155°C (with decomposition). [Elemental analysis:- found: C,32.7;
H.2.51: N,28.7; Cl,24.1%; CgHgCljNgOj requires C.33.0; H.2.77; N.28.9; Cl,24.4%].
EXAMPLE 13
Compound G
Stirred allyl isocyanate (4.5 ml, redistilled immediately before use) was treated with 4[5]-diazoimidazole-5[4]-carboxamide (1.0 g) and then with hexamethylphosphoramide (20 ml). The mixture was stirred at ambient temperature in the dark for 18 hours and then it was diluted with anhydrous diethyl ether and filtered. The resulting colourless solid was washed with anhydrous diethyl ether, to give 3-allyl8-carbamoyl-[3H]-imidazo[5,1-d]-1,2.3,5-tetrazin-4-one (1.6 g), in the form of a colourless solid, m.p.
149-150°C. [\)may (KBr disc): 1730, 1675 cm1; NMR in DMSO-dg: singlets at 8.75, 7.67 and 7.606; double double triplet at 6.02 6 (J=5.5, 8, 10Hz), double doublet at 5.35 6 (J=1.5, 8 Hz) and 5.20 6 (J=1.5, 10 Hz) and doublet at 4.88 6 (J=5.5)].
EXAMPLE 14
Compound H
A solution of 4[5]-diazo-5[4]-dimethylcarbamoylimidazole (1.59 g; prepared as described in Reference
Exanple 1 hereafter) in dry ethyl acetate (57 ml) was treated with 2-chloroethyl isocyanate (6.36 g) and stirred at room temperature in the dark for 24 hours.
The solution was then evaporated in vacuo at 35°C, finally at 0.1 mm Hg to remove the excess of 2-chloroethyl isocyanate. The residual liquid was purified by medium pressure column chromatography on silica gel, eluting with a mixture of ethyl acetate and acetonitrile (4:1 v/v), to give 3-(2-chloroethyl)-8-dimethylcarbamoyl10 [3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one (0.82 g), in the form of colourless crystals, m.p. 114-116°c.
[Elemental analysis:- found: C,39.7; H.3.95; N,30.8%j C9Hi;lC1N6O2 requires: C.39.9? H.4.10; N,31.0%].
EXAMPLE 15
Compound I
A stirred suspension of 4[5j-diazoimidazole-5[4]carboxamide (1.0 g) in hexamethylphosphoramide (4 ml) was treated with 2-bromoethyl isocyanate (4.5 ml) and the mixture was stirred in the dark, at ambient temperature, for 2 days. The reaction mixture was then diluted with anhydrous diethyl ether and the resulting solid was filtered off, and washed with anhydrous diethyl ether, to give 3-(2-bromoethyl)-8-carbamoyl-[3H]-imidazo[5·1-d]1,2,3,5-te£razin-4-one (1.17 g), in the form of a colourless solid, m.p. 156-157°C (with decomposition). [Elemental analysis:- found: C,29.5; N.2.36; N,29.1; Br,27.3%;
C7H7BrNgO2 requires: C,29.3; H.2.46; N.29.3; Br,27.8%].
EXAMPLE 16
Compound J
By proceeding in a manner similar to that described hereinbefore in Example 15 but replacing the 2-bromoethyl isocyanate used as a starting material by the appropriate quantity of benzyl isocyanate, there was prepared 3-benzyl-8-carbamoyl-[3H]-imidazo[5«l-d]-l,2,3«5-tetrazin-4-one (0.83 g), in the form of a buff-coloured solid, m.p. 176-177°C (with decomposition).
[Elemental analysis:- found: C,53.6; H«3.66: N,31.0%; c12HioN6°2 recTuires: C*53.3; H.3.73? N,31.1%].
EXAMPLE 17
Compound K
A suspension of 4[5]-diazoimidazole-5[4]15 carboxamide (0.3 g) in acetonitrile (5 ml) was treated with 2-methoxyethyl isocyanate (0.5 g) and the mixture was stirred at between 45° and 47°C in the dark for 24 hours. The resulting solid was filtered off and washed with diethyl ether, to give crude 8-carbamoyl-320 (2-methoxyethyl)-[3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one (0.45 g), m.p. 145-147°C (with decomposition).
The product was purified by recrystallisation from aqueous acetone to give pink rosettes, or from aqueous dimethylsulphoxide to give colourless needles,
m.p. 164-165°C (with decomposition). [Elemental analysis: C.40.4; H,4.20; N,35.2%; CgH^^NgOj requires: C.40.34; H.4.20; N,35.2%].
. EXAMPLE 18
Compound L
A suspension of 4[5]-diazoimidazole-5[4]carboxamide (0.30 g) in acetonitrile (10 ml) was treated with cyclohexyl isocyanate (1.0 g) and the mixture was stirred at 60°C in the dark for 3 days.
The resulting solid was filtered off and washed with a mixture of ethanol and 0.880 aqueous ammonia (100:0.5 v/v; 20 ml) for one minute, to give 8-carbamoyl3-cyclohexyl-[3H]-imidazo[5 <1-d]-1,2,3,5-tetrazin-4-one (0.015 g), m.p. 196°C (with effervescence).
EXAMPLE 19
Compound J
A suspension of 4[5]-diazoimidazole-5[4]carboxamide (0.4 g) in acetonitrile (10 ml) was treated with benzyl isocyanate (0.6 g) and the mixture was stirred at 60°C in the dark overnight. The reaction mixture was then cooled and filtered, to give 3-benzyl-8carbamoyl-[3H]-imidazof5,1-d]-1,2.3,5-tetrazin-4-one (0.75 g),in the form of a pale pink solid, m.p. 187-188°C (with effervescence).
EXAMPLE 20
Compound M
A suspension of 4r5]-diazoimidazole-5[4]carboxamide (0.1 g) and p-methoxybenzyl isocyanate (0.4 g) in acetonitrile (5 ml) was stirred at
60°C in the dark for 4 hours. The resulting pale pink solid was filtered off, and washed repeatedly with cold diethyl ether, to give 8-carbamoyl-3(p-methoxybenzyl)-[3H]-imidazo[5,l-d]-l,2,3,510 tetrazin-4-one (0.23 g), m.p. 180-182eC (with effervescence).
EXAMPLE 21
By proceeding in a similar manner to the foregoing Examples, there was prepared
8-(N-allylcarbamoyl)-3-(2-chloroethyl)—(3H)-imidazo (5,1-d)-1,2,3,5-tetrazin-4-one (I.R, 1750 cm-1. NMR (in DMSO-dg): multiplets 3.96, 5.06 and 5.84 ?pm: triplets 4.60 and 6.2 ppm: singlet 8.78 ppm), from 5-amino-4allylcarbamoylimidazole via 5-diazo-4-allyIcarbamoy120 imidazole. The 5-amino-4-allylcarbamoylimidazole was prepared from 5-nitro-4-allylcarbamoylimidazole (m.p. 218-220C) by reduction by means of titanous chloride.
.340®
REFERENCE EXAMPLE (i) An intimate mixture of 5-nitroimidazole4-carboxylic acid (2.0 g) and phosphorus pentachloride (2.67 g) was stirred and heated in an oil bath at 120°C for 1 hour. The resulting yellow slurry was evaporated at 60’C/0.1 mm Hg for 30 minutes, to give 1,6-dinitro5H,10H-diimidazo[1,5-a:11,51-djpyrazine-5,10-dione (1.90 g) in the form of a yellow solid, m.p. 249-251°C (with decomposition). (KBr disc) 1750 cm-1;
m/e 278 (M+)J.
Windaus, Ber., 1923, 56« 684 and Gireva, Chem.
Abs. 59, 1622e, using the same method, describe their products as 5-nitroimidazole-4-earbonyl chloride.
(ii) Aqueous dimsthylamine solution (25% w/vj 15 60 ml) was cooled to between 0° and 5°C and treated portionwise, with stirring, with l,6-dinitro-5H,10Hdiimidazo[l,5-a:l*,5’-djpyrazine-5,10-dione (6.0 g) in that temperature range. The resulting deep purple solution was stirred for 2 hours. The solution was evaporated at 50°C/10 mm Hg and then acidified by treatment with concentrated hydrochloric acid, to give an orange solution. This solution was extracted with ethyl acetate (7 x 200 ml), and the combined extracts were dried over magnesium sulphate, and evaporated, to give a yellow solid (6.6 g). This solid was triturated with toluene (50 ml) and then recrystallised from ethyl acetate, to give 5[4]-nitro-4[5]-dimethylcarbamoylimidazole (2.53 g), in the form of yellow crystals, m.p. 193-195°C. [Elemental analysis:- found: C,38.9; H,4.23; N,30.4%; CgHgN^Oj requires: C, 39.1; H,4.38; N,-30.4%].
(iii) A solution of 5[4]-nitro-4[5]-dimethylcarbamoylimidazole (1.62 g) in dry dimethylformamide (32 ml) was treated with platinum oxide (0.32 g) and shaken under hydrogen at atmospheric pressure and room temperature. After 3 hours, hydrogen absorption was complete (710 ml). The mixture was treated with charcoal and filtered through diatomaceous earth. The dark brown filtrate was evaporated at 50°C/0.1 mm Hg and the resulting residue was triturated with diethyl ether to give crude 5[4]-amino-4[5]-dimethylcarbamoylimidazole (1.75 g), in the form of a dark brown crystalline solid, m.p.
179-181°C [\)mav (KBr disc) 1595 cm-1; NMR in M4S0-dc:
x ΙΠαΧ O singlets at 3.2 and 7.06 ]< which was still contaminated with colloidal platinum and which was used in the next stage without further purification.
(iv) A stirred solution of sodium nitrite (0.79 g) in water (5.7 ml) was cooled to between 5° and 10°C and treated, dropwise, within this temperature range, with a solution of 5[4]-amino-4[5]-dimethylcarbamoylimidazole (1.75 g) in aqueous acetic acid (1M; 17.6 ml) during 5 minutes. The resulting solution was extracted with ethyl acetate (4 x 40 ml), the combined extracts were dried over magnesium sulphate and evaporated at 30°C/10 mm Hg, to give 4[5j-diazo-5[4]-dimethylcarbamoylimidazole (1.59 g), in the form of orange crystals, m.p. 101-103°C (with decomposition) [Elemental analysis:- found:
C,42.6; H,4.17? N,41.4%; CgH^NgO requires: C,43.6;
H,4.27; N.42.4%].
The present invention includes within its scope pharmaceutical compositions which comprise, as active ingredient, at least one tetrazine derivative of general formula I, together with a pharmaceutical carrier or coating. In clinical practice the compounds of general formula I will normally be administered orally, rectally, vaginally or parenterally, e.g. intravenously or intraperitoneally.
Methods of presentation of pharmaceutically active compounds are well known in the art and a suitable vehicle may be determined by the physician or pharmacist, depending upon such factors as the effect sought, the size, age, sex and condition of the patient and on the properties of the active compound. The compositions may also contain, as is usual in the art, such materials as solid or liquid diluents, wetting agents, preservatives, flavouring and colouring agents.
Solid compositions for oral administration include compressed tablets, pills, dispersible powders, and granules. In such solid compositions one or more of the active compounds is, or are, admixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid, or lactose. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate. Liquid Compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs containing inert -diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions may also comprise adjuvants, such as wetting and suspending agents, e.g. polyvinylpyrrolidone, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention, for oral administration, also include capsules of absorbable material such as gelatin containing one or more of the active substances with or without the addition of diluents or excipients.
Solid compositions for vaginal administration include pessaries formulated in manner known per se and containing one or more of the active compounds.
Solid compositions for rectal administration include suppositories formulated in manner known per se and containing one or more of the active compounds.
Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
Examples of non-aqueous solvents or suspending media are polyethylene glycol, dimethyl sulphoxide, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions may also include adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilising agents in the compositions, or by irradiation. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage for the therapeutic effect desired shall be obtained. Obviously several unit dosage forms may be administered at about the same time.
In general, the preparations should normally contain at least 0.025% by weight of active substance when required for administration by injection; for oral administration the preparation will normally contain at least 0.1% by weight of active substance. The dose employed depends upon the desired therapeutic effect, the route of administration and the duration of the treatment.
β
The tetrazine derivatives of general formula I are useful in the treatment of malignant neoplasms, for example carcinomas, melanomas, sarcomas, lymphomas and leukaemias, at doses which are generally between 0.1 and 200, preferably between 1 and 20, mg/kg body weight per day.
The following Composition Examples illustrate pharmaceutical compositions according to the present invention.
COMPOSITION EXAMPLE 1
A solution suitable for parenteral administration was prepared from the following ingredients:8-Carbamoyl-3-(2-chloroethyl)-[3H]imidazo[5,l-d]-l,2,3,5-tetrazin-4-one 1.0 g
Dimethyl sulphoxide 10 ml
Arachis oil 90 ml by dissolving the 8-carbamoyl-3-(2-chloroethyl)-[3H]imidazo[5,l-dJ-l,2,3,5-tetrazin-4-one in the dimethyl sulphoxide and adding the arachis oil. Ώιβ resulting solution was divided, under aseptic conditions, into ampoules at an amount of 10 ml per ampoule. The ampoules were sealed, to give 10 ampoules each containing 100 mg of 8-carbamoyl-3-(2-chloroethyl)-[3h]-imidazo[5,1-d]1.2.3.5- tetrazin-4-one.
Similar ampoules containing solutions suitable for parenteral administration may be prepared by proceeding in a similar manner but replacing the 8-carbamoyl-3-(2-chloroethyl)-[3Hj-imidazo-[5,1-d]1.2.3.5- tetrazin-4-one by another compound of general formula I.
COMPOSITION EXAMPLE 2
Capsules suitable for oral administration were prepared by placing 8-cafbam0yl-3-(2-chloroethyl)-[3H]imidaso[ 5,1-d]-1,2,3,5-tetrazin-4-one into gelatin shells of number 2 size at a rate of 10 mg per capsule.
Similar capsules may be prepared by using another compound of general formula I or any other conveniently sized capsule shells.
Claims (11)
1. [ 3H] -Imidazo[ 5,1-d] -1,2,3,5-tetrazin-4-one derivatives of the general formula:- wherein R 1 represents a hydrogen atom, or a straightor branched-chain alkyl, alkenyl or alkynyl group containing up to 6 carbon atoms, each such group being unsubstituted or substituted by from one to three substituents selected from halogen atoms, straightor branched-chain alkoxy, alkylthio, alkylsulphinyl and alkylsulphonyl groups containing up to 4 carbon atoms, and optionally substituted phenyl groups, or R 3- represents a cycloalkyl group containing from 3 to 8 carbon atoms, and R represents a carbamoyl group which may carry on the nitrogen atom one or two groups selected from straight- and branched-chain alkyl and alkenyl groups, each containing up to 4 carbon atoms, and cycloalkyl groups containing from 3 to 8 carbon atoms and - when R 3 represents hydrogen alkali metal salts thereof.
2. Tetrazine derivatives according to claim 1 wherein R 1 represents an alkyl, alkenyl or alkynyl group substituted by one, two or three optionally substituted phenyl groups and the optional substituents on the phenyl 5 radical(s) are selected from alkoxy and alkyl groups containing up to 4 carbon atoms, and the nitro group.
3. Tetrazine derivatives according to claim 1 wherein R^ represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms 10 optionally substituted by one or two halogen atoms or by an alkoxy group containing 1 to 4 carbon atoms or by a phenyl group optionally substituted by one or two alkoxy groups containing from 1 to 4 carbon atoms, or R 1 represents an alkenyl group containing 2 to 6 carbon 15 atoms or a cyclohexyl group.
4. Tetrazine derivatives according to claim 3 wherein the halogen atom(s) is (or are) chlorine, fluorine and/or bromine, the alkoxy group(s) is (or are) methoxy, and the alkenyl group is allyl. 20 5. Tetrazine derivatives according to claim 1 wherein R^ represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, unsubstituted or substituted by a halogen atom. 6. Tetrazine derivatives according to claim 5 wherein R 1 represents an alkyl group containing 1 to 3 carbon atoms unsubstituted or·substituted by a halogen atom.
5. 7. Tetrazine derivatives according to claim 1 or 5 wherein R represents a methyl or 2-haloalkyl group. 8. Tetrazine derivatives according to claim 5,
6. Or 7 in which the halogen atom on the alkyl group is chlorine or fluorine.
7. 10 9. Tetrazine derivatives according to claim 1 wherein R 1 represents a 2-fluoroethyl or 2-chloroethyl group. 10. Tetrazine derivatives according to claim 1 wherein R 1 represents a benzyl or p-methoxybenzyl group. 15
8. 11. Tetrazine derivatives according to any one of claims 1 to 10 wherein R represents a carbamoyl group, a monoalkylcarbamoyl group containing up to 4 carbon atoms in the alkyl radical, or a monoalkenylcarbamoyl group containing up to 4 carbon atoms in the alkenyl radical. 20 12. Tetrazine derivatives according to claim 1 wherein R 1 represents a straight- or branched-chain alkyl, alkenyl or alkynyl group containing from 1 to 6 carbon atoms, each such group being unsubstituted or substituted 2 by from one to three halogen atoms, and R represents the carbamoyl group. S34U8 13. 8-Carbamoyl-3-methyl-]3H)-imidazo]5,1-d]1.2.3.5- tetrazin-4-one. 14. 8-Carbamoyl-3-n-propyl-]3H]-imidazo]5.1-d]1.2.3.5- tetrazin-4-one. 5 15. 8-Carbamoyl-3-(2-chloroethyl)-]3H]-imidazo[5,l-d]-l,2,3,5-tetr azin-4-one. 16. 3-(2-Chloroethyl)-8-methylcarbamoyl-]3H]imidazo[5,l-d]-l,2,3,5-tetrazin-4-one. 17. 8-Carbamoyl-3-(3-chloropropyl)-Γ3H]-imidazo10 ]5,1-d]-1,2,3,5-tetrazin-4-one. 18. 8-Carbamoyl-3-(2,3-dichloropropyl)-] 3H]imidazo[5,1-d] -1,2,3,5-tetrazin-4-one. 19. 3-Allyl-8-carbamoyl-]3H]-imidazo]5,l-d]1.2.3.5- tetrazin-4-one. 15 20. 3-(2-Chloroethyl)-8-dimethylcarbamoyl]3H]-imidazo]5,1-d]-1,2,3,5-tetrazin-4-one. 21. 3-(2-Bromoethyl)-8-carbamoyl-]3h]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one. 22. 3-Benzyl-8-carbamoyl-]3H]-imidazo]5,1-d]20 l,2,3,5-tetrazin-4-one. 23. 8-Carbamoyl-3-(2-methoxyethyl)-]3H]imidazo]5,l-d]-l,2,3,5-tetrazin-4-one. 24. 8-Carbamoyl-3-cyclohexyl-]3H]-imidazo]5,1-d] 1,2,3,5-tetrazin-4-one. 25 25. 8-Carbamoyl-3-(]D-methoxybenzyl)-]3H]imidazo]5,1-d]-1,2,3,5-te trazin-4-one. 26. 8-(N-Allylcarbamoyl)-3-(2-chloroethyl)-(3H) 5340® imidazo (5,1-d)-1,2,3,5-tetrazin-4-one. 27. A process for the preparation of a tetrazine derivative of the general formula depicted in claim 1«
9. 1 2 wherein R and R are as defined in claim 1 but excluding 5 hydrogen from the definition of R^, which comprises reacting a compound of the general formula: II (wherein R is as defined in claim 1) with an isocyanate of the general formula:R 3 NC0 III wherein R represents an alkyl, alkenyl or alkynyl group containing up to 6 carbon atoms, each such group being unsubstituted or substituted by one to three substituents selected from halogen atoms, alkoxy, alkylthio, alkyl15 sulphinyl and alkylsulphonyl groups containing up to 4 carbon atoms, and optionally substituted phenyl groups, or R 3 represents a cycloalkyl group containing 3 to 8 carbon atoms. 28. A process for the preparation of 20 a tetrazine derivative of the general formula depicted . ·®940« -u 1 2 in claim 1, wherein R and R are as defined in claim 1 but excluding hydrogen from the definition of R^, which comprises reacting a compound of the general formula: (wherein R is as defined in claim 1) or an alkali metal salt thereof with a compound of the general formula :R 3 X V wherein R 3 is as defined in claim 27, and X represents the acid residue of a reactive ester. 29. A process according to claim 28 wherein X represents a halogen atom or a methoxysulphonyloxy, metharesulphonyloxy or toluene-g-sulphonyloxy group. 30. A process for the preparation of a tetrazine derivative of the general formula depicted in . 1 2 claim 1» wherein R represents a hydrogen atom and R is as defined in claim 1, or an alkali metal salt thereof which comprises reacting a compound of the general formula: II 5 3 10 8 with a compound of the general formula:· R 2 * 4 NC0 VI wherein R represents an alkali metal atom or a 4 protecting group, followed, when R represents a protecting group, by the replacement of the protecting group by a hydrogen atom in the compound thus obtained of the general formula: v Yv 0 VII 2 5 10 wherein R is as defined in claim 1 and R represents a protecting group, by methods known per se» 31. A process according to claim 30 in which the 4 5 protecting groups represented by R and R are benzyl or j>-methoxybenzyl.
10. 15 32. A process for the preparation of a tetrazine derivative of the general formula depicted in claim 1, wherein R and R are as defined in claim 1, or - when R 1 represents hydrogen - an alkali metal salt thereof substantially as hereinbefore described with especial reference to any of Examples 1 to 21. 33. Pharmaceutical compositions which comprise, 5 as active ingredient, at least one tetrazine derivative as claimed in any one of claims 1 to 26 in association with a pharmaceutical carrier or coating. 34. Pharmaceutical compositions according to claim 33 substantially as hereinbefore described with 10 especial reference to Composition Example 1 or 2. 35. Tetrazine derivatives of the general formula 1 2 depicted in claim 1, wherein R and R are as defined in claim 1, for use in the treatment of malignant neoplasms. 15 36. Tetrazine derivatives of the general formula 1 2 depicted in claim 1, wherein R and R are as defined in claim 1, for use in the treatment of carcinomas, melanomas, sarcomas, lymphomas and leukaemias. 37. Tetrazine derivatives of the general formula 1 2
11. 20 depicted in claim 1, wherein R and R are as defined in claim 1, for use in the treatment of organ grafts and skin grafts and in the treatment of immunological diseases.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8125791 | 1981-08-24 |
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| IE53408B1 true IE53408B1 (en) | 1988-11-09 |
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| IE (1) | IE53408B1 (en) |
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| LU (1) | LU84347A1 (en) |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260291A (en) * | 1981-08-24 | 1993-11-09 | Cancer Research Campaign Technology Limited | Tetrazine derivatives |
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| GB2125402B (en) * | 1982-08-17 | 1985-11-13 | May & Baker Ltd | New tetrazine derivatives |
| FR2531958B1 (en) * | 1982-08-17 | 1986-10-31 | May & Baker Ltd | NEW DERIVATIVES |
| US4517182A (en) * | 1983-05-24 | 1985-05-14 | Warner-Lambert Company | 3-(Haloethyl)-4-oxopyrazolo-[5,1-d]-1,2,3,5-tetrazine-8-carboxamide composition |
| GB8616125D0 (en) * | 1986-07-02 | 1986-08-06 | May & Baker Ltd | Compositions of matter |
| AU622330B2 (en) * | 1989-06-23 | 1992-04-02 | Takeda Chemical Industries Ltd. | Condensed heterocyclic compounds having a nitrogen atom in the bridgehead for use as fungicides |
| EP2275425A1 (en) * | 2003-12-30 | 2011-01-19 | Chemagis Ltd. | Novel crystalline forms of temozolomide |
| JP5475235B2 (en) | 2005-01-21 | 2014-04-16 | アステックス・セラピューティクス・リミテッド | Pharmaceutical compounds |
| AR060635A1 (en) | 2006-04-27 | 2008-07-02 | Banyu Pharma Co Ltd | DERIVATIVES OF 1,2-DIHIDRO-3H-PIRAZOLO [3,4-D] PIRIMIDIN-3-ONA, PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEM AND THEIR USE IN THE TREATMENT OF CANCER |
| JP2008081492A (en) | 2006-08-31 | 2008-04-10 | Banyu Pharmaceut Co Ltd | New aminopyridine derivative having aurora a selective inhibitory action |
| US8916552B2 (en) | 2006-10-12 | 2014-12-23 | Astex Therapeutics Limited | Pharmaceutical combinations |
| WO2008044045A1 (en) | 2006-10-12 | 2008-04-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
| CA2703489A1 (en) | 2007-10-23 | 2009-04-30 | Banyu Pharmaceutical Co., Ltd. | Pyridone-substituted-dihydropyrazolopyrimidinone derivative |
| PE20091101A1 (en) * | 2007-12-18 | 2009-07-26 | Pharminox Ltd | 3-SUBSTITUTED-4-OXO-3,4-DIHYDRO-IMIDAZO [5,1-d] [1,2,3,5-TETRACINE-8-CARBOXYL ACID AMIDES AND ITS USE |
| EP2367828B1 (en) * | 2008-11-24 | 2014-06-11 | Reliance Life Sciences Pvt., Ltd. | Process for the preparation of tetrazine derivatives |
| EP2403339B1 (en) | 2009-03-06 | 2017-01-18 | Merck Sharp & Dohme Corp. | Combination cancer therapy with an akt inhibitor and other anticancer agents |
| WO2010149968A1 (en) | 2009-06-23 | 2010-12-29 | Pharminox Limited | 3-substituted-8-substituted-3h imidazo[5,1-d][1,2,3,5-tetrazin-4-one compounds and their use |
| RU2462466C1 (en) * | 2011-06-24 | 2012-09-27 | Автономная Некоммерческая Организация "Научно-Исследовательский Центр Биотехнологии Антибиотиков И Других Биологически Активных Веществ "Биоан" | Substituted azolo[1,2,4,5]tetrazines - inhibitors of antibacterial serine-threonine protein kinases |
| US20140271657A1 (en) | 2011-10-12 | 2014-09-18 | Children's Medical Center Corporation | Combinatorial compositions and methods of treating hemoglobinopathies |
| IL261721B (en) | 2016-03-15 | 2022-07-01 | Oryzon Genomics Sa | Combinations of lsd1 inhibitors for use in the treatment of solid tumors |
| KR101847342B1 (en) * | 2017-05-08 | 2018-04-11 | (주)센텍코리아 | Wearable body fat burning measurement device |
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| DE2932305A1 (en) * | 1979-08-09 | 1981-02-26 | Basf Ag | Pyrrolo-, pyrazolo-, imidazo- and thiazolo-tetrazin-4-one derivs. - prepd. from amino-azole cpds. by diazotisation and reaction with isocyanate |
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- 1982-08-23 NL NL8203286A patent/NL192739C/en not_active IP Right Cessation
- 1982-08-23 AT AT0319182A patent/AT380256B/en not_active IP Right Cessation
- 1982-08-23 AU AU87493/82A patent/AU571430B2/en not_active Expired
- 1982-08-23 DE DE1999175037 patent/DE19975037I2/en active Active
- 1982-08-23 CA CA000409950A patent/CA1197247A/en not_active Expired
- 1982-08-23 IT IT22938/82A patent/IT1152505B/en active Protection Beyond IP Right Term
- 1982-08-23 BE BE0/208860A patent/BE894175A/en not_active IP Right Cessation
- 1982-08-23 GB GB08224155A patent/GB2104522B/en not_active Expired
- 1982-08-23 SU SU823482389A patent/SU1447284A3/en active
- 1982-08-23 JP JP57144902A patent/JPS5843975A/en active Granted
- 1982-08-23 DK DK377882A patent/DK161147C/en not_active IP Right Cessation
- 1982-08-23 CH CH5007/82A patent/CH655114A5/en not_active IP Right Cessation
- 1982-08-23 NZ NZ201668A patent/NZ201668A/en unknown
- 1982-08-23 GR GR69093A patent/GR76863B/el unknown
- 1982-08-23 FI FI822921A patent/FI73434C/en not_active IP Right Cessation
- 1982-08-23 UA UA3482389A patent/UA5971A1/en unknown
- 1982-08-23 SE SE8204817A patent/SE448543B/en not_active IP Right Cessation
- 1982-08-23 IE IE2026/82A patent/IE53408B1/en not_active IP Right Cessation
- 1982-08-23 HU HU822708A patent/HU186107B/en unknown
-
1993
- 1993-06-19 LV LV930621A patent/LV5511A3/en unknown
- 1993-09-29 LT LTRP1286A patent/LT2436B/en not_active IP Right Cessation
- 1993-11-16 GE GEAP19931653A patent/GEP19960641B/en unknown
- 1993-12-03 LV LV931303A patent/LV5621A3/en unknown
-
1999
- 1999-04-01 NL NL990010C patent/NL990010I2/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260291A (en) * | 1981-08-24 | 1993-11-09 | Cancer Research Campaign Technology Limited | Tetrazine derivatives |
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Free format text: SPC008/1999, 20020429, EXPIRES: 20020823 |
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| MK9A | Patent expired |