JPS5953488A - Novel tetrazine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel tetrazine visiting conductors, processes for their preparation and pharmaceutical compositions containing them.

The present invention relates to the general formula (wherein R1 is cycloargyl, !, !; & or a straight or branched alkyl, alkenyl' or arginyl group having up to 6 carbon water atoms (wherein These argyl, alkenyl, /C alkynyl groups are unsubstituted or straight-chain functionalized with a halogen atom (i.e., bromine, iodine, or preferably chlorine or fluorine), or a carbon atom with 41 carbon atoms. or branched alkoxy, argylthio, alkylsulfinyl and alkylsulfonyl groups, and optionally di-substituted phenyl groups; What about AI? 3
is a wood atom or a group -0R1- (wherein R5 is a hydrogen atom or a 1d return group H4 (where R4 is a halogen atom or a twisted or broad halogen atom containing up to 611 N carbon atoms) , a phenyl group which may be present in some cases, IMgt containing up to 611I!j carbon atoms
-t is a straight-chain or branched alkyl or alknyl group which may contain up to six groups selected from the group consisting of branched alkoxy, alkylthio and alkylsulfonyl groups, or R4 is a cyclo an alkyl group, cyano, hydroquine, di) a or an optionally directly substituted phenoxy group, or a phenoxy group of the formula -coR5, where R5 is an alkyl or alkoxy group having 41 carbon atoms, a hydroxy group or R4 is a phenyl group, which may optionally be a phenyl group, or an arjunonoylamino group spanning up to 6 carbon atoms; % formula % ( is 0.1゛ or 2, R6 has up to 411I! + 1 carbon atoms, optionally k) is a straight or branched alkyl or alkenyl group, a cycloalkyl group or an optionally substituted phenyl group; fn
It is a hydrogen atom or a straight-chain or branched alkyl containing up to 4 degrees of carbon water atoms and having an optionally di-substituted tjunyl substituent. -Mano (
is an alkyl group or a phenyl group or a group -IJT ( 7) 18 is Tamiki j ka niki?
1c is a yellow atom)), and A2 is a group with a yellow atom, or A1 is a nitrogen atom. -O:R5= (
Here, R5 is as defined above) -C9, l
' is r12. or a sulfur atom, and R2 has the formula -B(0)nR6, -8O2NR'R8, -csNR7
R8,-0ONR7,l (P or 1022N) INO
2 (Hereinto these formulas, R6, R7, R8 and R2 are as defined above, and the group -NR7R9 is the group defined above, or -4 or R7 is as defined above. R9 may be a straight-chain or branched alkyl group or an alkenyl group containing up to 4 carbon atoms, optionally substituted with a phenyl substituent; A1 is a group having an optionally substituted F:L-nyl, depending on the case, or A1 is a u jj'; atom, or -01'1t4=
(Here, R4 is as defined in tJrf)
And whether Zl and A2 are self-determined,
or when A1 is a group -CH- and zl is a sulfur A atom and A2 is as defined above, R2 has the formula -8(0)nR6, -8O2NR'R8, -CZ2
NR7R8 or 0Z2NHNO2 (? - a group having n, Rd, 1 (7, R8 and z2 are -c as defined in Section 6rj)), and R2 and/or R5 When is a sulfamoyl or monosubstituted sulfamoyl group and/or R5 is a carboxy group, it also relates to their salts, and in particular to their alkali metal salts, such as the sodium salts.

Uncertainty regarding compounds with the general formula ■, as long as the context allows;
The word "g" in "till" means that the above-mentioned salts are also included. Salts are particularly monovalent as intermediates.

In the definition of formula I, the 1η groups present in place of the phenyl and phenoxy radicals E are, for example, from the group consisting of halogen atoms, alkyl and alkoxy groups containing up to 4 carbon atoms and nitro groups. Can be chosen. Formula 1
The cycloalkyl group within the definition is '5-8 II! I like ±
17< contains 6 carbon atoms. Formula 1 f) 7 and the log ring group in the crosspiece may optionally contain 91 heteroatoms -
9, 5-membered, 6-membered, having 1- or 2 straight-chain or branched alkyl substituents, each having up to 4 carbon atoms and having 3' or 4 carbon atoms;
or a 7-membered heterogroup, such as a piperidino group, or 2-methyl-16-methyl-14-methyl-12,
4-dimethyl-ox or 6,5-dimethyl-piperidino u
, 47koi1 morpholino, pyrrolidin-1-yl, perhydroacebin-1-yl, diradino-yl, 4
-Methyl-piperazin-1-ylma/(, is a 1,4-thiazin-4-yl group.

1l which has priority over British Patent Application No. 2104522 Mei 7a and First British Patent Application No. 8125791
Applications in Japan, such as Kida Patent Application No. 410656, used to be based on the general formula ■ [In the formula 1 (10 is a hydrogen atom, a cycloalkyl group or &J', 6 Ibl
Straight-chain or branched alkyl, alkynyl or alkynyl containing carbon atoms in which these alkyl, alkenyl or alkynyl groups are defined as - or -, up to 4111''''- Straight-chain or branched alkoxy, alkylthio, argylsulfinyl j/and alkylsulfonyl groups containing carbon atoms, and optionally substituted IA-J] 1 to 1 selected from the group consisting of an optional phenyl group; 6° carbon atoms are present), and R1+ is a straight line containing up to 11.4 carbon atoms on its nitrogen atom. This refers to branched alkylthio and alkenyl groups, and Schiff's 9 carbamoyl groups υ with 11 alkyl groups to 11 groups or 21II!11 groups.
Compounds that have [required] are described.

1-iii Tetrazine vj conductor with the notation ■ is, for example, cancer, black 11ii! However, it has significant anti-neoplastic activity in linoleum, hemorrhagic diseases, and hemorrhagic diseases, and these (still have a valuable immunomodulatory effect and disrupt organ function). It is useful for treatment in 8 transplantation and skin transplantation and for the treatment of immunological diseases 7ω.

The compounds of formula I of the present invention exhibit similar but improved properties in certain aspects.

Tetrazine masks having the formula (1) are useful as intermediates in the production of some of the compounds of the present invention having the formula I described below.

Particularly important shields of compounds 1b of formula I include: (i) R1 is methyl or, more particularly, 2;
-haloethyl group, especially 2-chloroethyl group, (if) R2 is of the formula -8OR6, -5o2R6, -E
102NR7:R8, -0ON:FL7Rθ or -C
A group having 0NHNO2, especially 1k, is an alkyl group, such as a methyl group, and then R7 is a hydrogen atom or an alkyl group, especially a methyl group, and R8 is a hydrogen atom or an alkyl group, such as a methyl group. benzyl group which may be substituted by an alkoxy group, e.g. (IV) R6 is a group R4 (where R4 is an alkyl group such as butyl, propyl, ethyl or especially a methyl group), M A2 is a nitrogen atom, (Vll Zl Included are compounds in which one or more of the following: is an oxygen atom, and/or z2 is an oxygen atom.

The N-valent compounds of general formula I include the following: A, 8-(N-hensyl-N-phenylcarbamoyl)-6-methyl-[
3H]-imidazo(5,1-d)-1,2,3,5-tetradi/-4-one, B, 8-(N-benzyl-N
-(4-methoxybenzyl)carbamoyl)-3-(2
-'20loethyl) -(3H)-imidazo(5,1-
(1) -1,2,3,5-tetrazin-4-one, 0
．． 8-(N-benzylcarbamoyl)-3-(2-chloroethyl)-(3H)-imidazo(5+1-a)-
1,2,3,5-tetrazin-4-one, D, 5-(2-chloroethyl) -8-(N-(4-methoxybenzyl)-N-phenylcarbamoyl) -(
3H)-imidazo(5+1-d)-1,2,5,5-tetrazin-4-one E,, 3-<2-chloroethyl)-8-(N-phenylcarbamoyl)-(3)-imidazo [5,1
-4) -1,2,3,5-tetrazin-4-one F, 8
-(N-benzyl-N-phenylcarbamoyl)-3-
(2-chloroethyl)-(3H)-imidazo(5,1
-(1)-1,2,3,5-tetrazin-4-one, 0.3-(2-chloroethyl)-8-(N-methyl-N
-phenylcarbamoyl) -(3H)-imidazo[5
,1-4)-1,2,! 1,5-tetrazin-4-one, R18-carbamoyl-3-(2-chloroethyl)-6
-Methyl-[3H]-imidazo(5,1-a)-1,2
,3,5-tetrazin-4-one,3-(2-chloroethyl)-8-(N,N-dimethylsulfamoyl)-[;n)-imidazo[:5.1-d]-1,2 ，
5,5-tetrazin-4-one-,7,3-(2-chloroethyl)-8-(N-methylsulfamoyl)-[:3H)-imidazo(5,1-d
)-1,2,3,5-tetrazine-4-:A, 3-
(2-chloroethyl)-8-methylsulfonyl-[3H
]-imidazo(5,1-d)-1,2,3,5-tetrazin-4-one L, 3-methyl-8-methylsulfonyl-[3H]
-Imidazo(5,1-d) -1,2,3,5-tetrazin-4-one M,3-(2-riOOethyl) -8-(N-(4-methoxybenzyl)-sulfamoyl)- (3H)-imidazo[5,1-4]-1,2,5,5-teS.

Drazin-4-one, N,3-(2-chloroethyl)-8-sulfamoyl-
[6H]-imidazo(5,1-d)-1,2,3,5-
Tetrazin-4-one, T.

0.3-(2-chloroethylA-)-8-carbamoyl-(3H)-pyrazolo(5,1-(1)-1,2,
3,5-tetrazin-4-one, U.

P, 8-carbamoyl-6-methyl-[6H]-pyrazolo(ski-d) -1+2$3+5-tetrazin-4-one, V・Q
, 3-(2-taloloethyl/l-)-8-pi is lysinocarbonyl[3H]-imidazo(5,1-cl)-1
, 2,3,5-tetrazin-4-one, R,6-butyl-3-(2-chloroethyl)-W.

8-Carbamoyl-(3H)-imidazo(5,1-(1
)-1,2,3,5-tetrazin-4-one, 8-carbamoyl-3-(2-chloroethyl)-6-cyclohexyl-[3H)-imidazo[5+ia]-11213
15-tetrazin-4-o/, 8-carbamoyl-3-(2-chloroethyl)-6-funinethyl(5H)-imidazo[5,1-cl)-1
, 2,3,5-tetrazin-4-one, 6-benzyl-
8-Carbamoyl-3-(2-chloroethyl) -[!
IH:)-imidazo(5,1-4)-1,2,3,5-
Tetrazin-4-one, 8-carbamoyl-3-(2-
chloroethyl)-6-inpropyl-[3H]-imidine[5,1-cl)-1,2,3,5-tetrazine-4-main, ro-(2-chloroethyl)-6-10vir-8 -carbamoyl-[6H]-imidazo(5,1-4)-1,2,
3,5-tetrazin-4-one, X, 8-carbamoyl-W-(2-chloroethyl)-6-nityl
]-imidazo(s, i-a)-1,2,3,5-
Tetrazin-4-one, Y, 5-(2-chloroethyl)
-8-(4-methoxybenzyl)-sulfamoyl-6
-Methyl-(6H)-imidazo(5,1-d)-1,2
, 3,5-tetrazin-4-one, 2.3-(2-chloroethyl)-6-methyl-8-sulfamoyl-[3H]-imidazo(5,1-d)-1,
2,3,5-tetrazin-4-one, AA, 3-(2-
chloroethyl)-8-:)methylsulfamoyl-6-
Methyl-(3H)-kidashi(5,1-d)-1,2
t3s5-tetradi/-4-o/, 3-(2-chloroethyl)-6-methyl-8-methylsulfonyl-[3H]-imidazo[5,1-4)-
1,2,5,5-tetrazine-4-o/■・3-(2
-chloroethyl)-8-(')methylcarbamoyl)
-(:3uJ-pyrazolo(5,1-d)-1,2,3,
5-tetrazin-4-one Dn, 3-(2-chloroethyl)-8-(N-nitrorubamoyl) -(3H)-
imidazo(s,1-a)-1,2,3,5-tetrazin-4-one a, 3-methyl-8-methylsulfonyl-[3H]-pyrazolo(5,1-d)-1,2 ,3
,5-teI-radin-4-oneyt+゛, 3-(2-chloroethyl)-8-methylsulfonyl-[3) Leepyrazolo(5,14)-1,
2,6,5-tetrazin-4-one aG, 5-(2-chloroethyl)-6-methyl-8-methylsulfinyl-(3I()-imidazo(5,1-d
J -1,2,3,5-tetrazin-4-o/% R14,3-(2-chloroethyl)-8-ethylsulfonyl-6-methyl-(3H)-imidazo(5,1-4,
1-1,2,6,5-detradi/-4-one and IL3-(2-chloroethyl)-6-methyl-8-propylsulfonyl-[3H)-imidazo(5,1-d)
-1,2,3,5-tetrazin-4-one.

The 6th self-name, which is A ~ Engineering ■, is the one that appeared in the encounter 9 of course, so that it would be easy to quote it in the middle of Ming #1.

Especially for the heavily armored proboscis, compound I proboscis C, K, L, λi,
0, Q, ](, W, It's J'L.

A new detoshijin exclusive t that takes the general formula ``Blo''
cheno, Pj+arroaco1. J 60th Lane Nogol) 8 So negative < 1 tzst TLX by the operation of 勺Di self-loading 5 (tl) Lymph Il'J
! , and ADJ/PC6A Oj and M5076
It was found to be particularly active at 0.2 to 620 WI per day per body weight when administered intraperitoneally to mice (reticulocyte sarcoma). intraperitoneal) leukemia Ll 210 transplanted intrapallially, intracerebral and intravenously, and “Methoda
of Development of New Anti
cancer drugs' (National
Cancer engineering n5tituto) NOI monograph 4
5, pp. 147-149 (March 1977), these compounds have 1 to 32
It was active both intraperitoneally and orally with an indication of 0yy/#. The dual control of primary tumors and metastases was achieved by Lewis (L
owiθ)1111i cancer was achieved by the same company's therapy.

Mouse BI3 black tumor and (338 tumor (noted above)
Emonograph No. 45), the compound of the present invention is 6.
It was active at intraperitoneal doses of 25 to 404,897 At. The compounds of the present invention are active against subcutaneously implanted mouse colon cancer C26 at oral doses of 2 to 40 gv/At and 0. Compounds having general formula 1 can be prepared by applying methods known per se or by -synthesis. It can be prepared by

According to a feature of the invention, compounds of the general formula I [wherein R2 is sulfamoyl, mono(optionally substituted phenyl)carbamoyl or mono(optionally substituted phenyl)thiocarbamoyl, nitrocarbamoyl or Compounds having a general formula group [where A1 and A2 are the above-mentioned tofu-shi, and Rj2 is sulfamoyl] (other than ditrothiocarpamo-fl group) are phenyl) carno (moyl ma t(ha7))
Depends on the situation! L-(ideyo ifhenyl)naocalha7yl, nitrocarbamoyl nitrothiocarbamoyl M l! A compound having the general formula IV RINOZI A/ (in which n1 and zl are il), wherein 7L is produced by reacting with a compound. This reaction is sad l'Tj! , 8 bales of water 1/soge chlorine [Hyaluriki/
Shi'rie is jitter 10 methane, 'lζ1jr'+'i4
I↓nL, acetonitrile, N-methylpyrrolidin-2-one or hexamethylL#presence of enemy amide-
(Performed at 0°C to 120°C in the absence of water).

The reaction can be quenched for 60 minutes. Preferably the light beam is 4# I! ,ii should be done.

According to another imitation of Kienori, in the general formula 1c formula i
(2 is mono (optionally optional phenyl) carbamoyl or mono (optionally phenyl) thioca/1 + hamoyl,
IS, and Rζ''s A2m and zl are the above-defined phenyl groups, where R15 is a phenyl group optionally substituted by 3 bonds, and R15 is 18 minutes device 'tadashi 7'
It is a pe/zyl group that may be
From a compound that makes 1.- by 1 → combination, water 1 U of the benzyl group which may be present, 1 return by 1 child. It can be prepared by λ111 reactor or by adapting it to 14 months or more.Appropriate reaction conditions include molten hydrogenation (such as radium on charcoal, etc.). and I3i (in a solvent such as ethyl or dimebyl formamide) is encapsulated, - or R
15 is a substituted benzyl group such that the substituent (or at least one of the substituents) is an alkoxyno group (e.g. a methoxy group) in the 0- or p-position according to the benzyl group; Some J4 reactions are preferably by reaction with trifluoro-cju, preferably in the presence of anisole and usually at or near room temperature.

According to yet another feature of the invention, a radical of the general formula (1) in which R1, AI, A2 and zl are as defined above and R2 is a group of the formula -OZ 2NHN02 1:iif; , where z2i is a self-defined formula) is a compound having the general formula (where z2, R1, AζA2 and zl are AiJ notation i
A compound having -Q (7) and oxidation) can be produced by nitration. This reaction is carried out in the presence of a nitrating mixture, such as a mixture of concentrated nitric acid and concentrated nitric acid, at or below room temperature, preferably from O'C to 10C.

According to a further feature of the invention, the invention provides a method of formula I (wherein R
1, AI, A2 and R2 are as defined above and zl is a sulfur atom. And R15 is the formula -8(0)nR6, -8O2NR7
R8, -0Z2NRIR8 or -OZ2NHNO2
, where Rd, R', Re, u and z2 are as defined above. Solvent Examples Evabenzene, toluene, etc. may be carried out in more aromatic solvents such as pyridine or in derivatives such as pyridine or lutidine, preferably at elevated temperatures, such as from 50°C to 120°C.

According to yet another aspect of the present invention, the formula ■ (wherein R
1, AI, A2 and zl are as defined above,
and R2 is a group having the formula -〇〇NR7R1',
Here, R7JL- and R8 are as defined above)
The ratio 6·' has the formula (in the formula, R1, AζA2, zl, R7J, '- and R8 are the above-mentioned numbers), and the combination of phosphorus pentasulfide and the compound of the formula Reaction V (prepared by reaction with phosphorus pentasulfide under the conditions of co-workers as described above).

The salts mentioned above of certain compounds of formula I can be obtained by applying or adapting methods known per se, for example by converting the parent compounds of formula I into aqueous or aqueous salts with alkali metals. It is prepared by reacting with a hydroxide, carbonate or preferably bicarbonate and extracting the salt by methods known per se.

If mixtures of products are obtained in any of the processes mentioned above, they can be prepared by methods known per se, for example by applying or adapting chromatography.
It can be done for a minute.

Compounds having the general formula ■ can be prepared by methods known per se, for example [, ■
, Org, ChemJ Vol. 26, p. 2696 (196
1) and the method described in J. Pharm, Sci. Vol. 57, p. 1044 (196B), and the method described in 6; Examples below. .

The term ``method known per se'' as used herein refers to whether the method itself is used (tf).
The method described in 'C&J Literature' is described in C&J.

In the following, the method for preparing the compounds of general formula I according to the invention will be illustrated by way of examples, and the method for preparing the intermediates will be explained by way of example.

Example 1 Compound A Sodium nitrite (CL449) was dissolved in acetic acid aqueous solution (
2M, 10d) and its solution at 0'C
5-γminoimidazole-4+ 1-r-benzyl-N-phenylcarboxamide salt tikJin: (0,7F, reference 11
1) manufactured as described in 1). 10
Separate the resulting gummy solid into ethyl acetate (2X20ij)
Extracted with. The ethyl acetate extracts were combined, washed with water and kept dry over magnesium sulfate.

The resulting 5-diazoimidazole-4-N-benzyl-
A solution of phenylcarboxamide was treated with methyl isocyanate (5 gj), and the mixture of ItSθ was heated to -11 in the dark for 24 hours.
.

I'll be with you.''You're so brave and procrastinating! Uf Toshi-t
L, Tegu 1.8 station 5 proboscis M #+# l
, after being subjected to medium pressure ram chromatography, 8-
(N-benzyl-1=T-)enylcarbamoyl)-
3-Methyl-(3n)-imidazo[5,1-d)-1
, 2,3,5-tetrazin-4-one (0,229 in the form of a white crystalline solid)
. 168-170°C (decomposition Fj5).

Elemental analysis value: 062.6, H4,41, +122.6
Excellent, so-called jf value: 063.32, H, 1,47, I-T
23.32%. r, R, (KBrBrtisf: 6
100.1735.1620.・〃+ , NMR (DM
SO- (out of 16): 3.75.5.10 and iJ'
! Single fiber at 3.55 ppm, 7.0-7.4
Multiple edges in p pm, m/e 360 (M”
).

Example 2 Compound B Sodium nitrite (3,79) was dissolved in 7 aqueous acetic acid solution (2M, 35J) at 0'C. 5-Aminoimidazole-4-N-pene) in 1,2-dimethoxyethane (10 ml) with JM salt (2,2jl, in Reference Example 2) I treated each sidewalk with a metallurgical tool (manufactured as described in RJL), and the reddish gum separated.
t was extracted with Satose ethyl (2 x 20 Ilt). vinegar rt
Ethyl extract the proboscis, wash it with water, and bg
St. Sodium chloride bathing I washing at night I fighting then i A
I'm going to run out of rlkl sodium.

5-cyaguimidazole-4-N-benzyl-N-(
The production bath solution of 4-, notogishibenzyl) carboxamide is 2-1.
5. Place the ``C mix a'' proboscis in the dark for 24 hours in room 21r + i.
' ♂, release bf L, fc, then evaporate the two combined liquids -C'22:'it and the remainder'+d/! -H
L7ji Ethyl-Cjrj1 侃g L 72 to medium pressure column (1-r I" graph-(-4 attached)'(and 8- ('DT-Benzy-N-(4-methoxybenzyl)carbamoyl)-3- (2-'/loloethyl)
-(5H)-imidazole (5,1-d) -1,2,
3,5-tetrazin-4-one (<1.59) was obtained as a brown oil.

Run/Row 6 Compound C 8-[N-benzyl-N-(4-methoxybenzyl)carbamoyl)-'5-(2-'70ethyl)-(3
H)-imidazo(5+′-d)-L2+”+5-tetrazin-4-one (1,5P, crude material prepared as described in Example 2) and anisole (0,5 mJ
) was dissolved together with trifluoroacetic acid (20 ml/ttW) and left at room temperature for 18 hours.

The mixture was then evaporated to dryness and diluted with ethyl acetate and petroleum ether (-small+'l'(', 6
Seedlings #l with a mixture (2:1 v/v) of [J'~ (30°C)
-r'5-+! '1 was subjected to medium pressure column chromatography to give 8-(N-benzylcarbamoyl)-3-
(2-chloroethyl)-(6n)-imidazo(5,1-
d) -1,2,3,5-tetrazin-4-one (03
4)) in the form of a colorless isomer 4447'c, fn, p+
153-155℃ (1 crystal from diethyl ether)
. Elemental analysis value: 049.9, H3,92, N24.4,
(Jlo, 4%, Fttk 111: 0
5 o, 5 6, H6,94, N25.26, (
J1t165%. Engineering, R, (KBr disk) 337
0゜3150.17h5j? and 1660ctn-'.

NMR (in DMSO-d, 1): Z3 and 8.9pp
Single fil at m, doublet at 4.4 ppm and doublet at 4.0, 4.6 and 9.05 ppm.

Tue) tie 1+114 Compound sodium nitrite (0,6IP) in water (10d) bath P
rV, the solution was stirred at 0 °C and hydrochloric acid (2M, 9
m/) and 1,2-dimethoxyethane (15#E/)
Crude 5-aminoimiguzole-4-N-(4-
methoxybenzyl)-N-phenylcarboxamide (2
, 59, prepared as described in Reference Example 3)
Treat it in small portions with liquid. After 20 minutes, extract with bath liquid LIP version ethethyl 4-methoxybenzyl)-N-phenylcarboxamide (n,
8) is an orange-red oily substance, and fIj7? :.

This oil was dissolved in Tsumugi 1-acid enal (401 J/) and treated with 2-chloroethyl incyanate (8Rt).
” Shita. This mixture was left in the dark for 5 days.

The 6i solution was evaporated to give 2-chloroethyl chloride, and the resulting residue was subjected to medium pressure column chromatography with MIJI with ethyl acetate (2-chloroethyl).
-8-[N-(4-methoxybenzyl)-11-phenylcarbamoyl) -(3H)-imitazo[5,1-
aJ -1,2,3,5-tetrazin-4-one (1,
5jl) in the shape of a glassy object! b″′c longevity.

m, p, 55'CoNMR (in puso-a6): 3
．． A single line centered at 6.5,0 and rL 5 ppul, 31 centered at 6.9 and 4.5 pplo
Multi-fX storage divided into 6.6-7.2 ppm.

■, 'R, (KBr disk) 1740 and 1640
tnz-'.

Example 5 Compound E Ro-(2-chloroethyl)-8-(N-(4-methoxybenzyl)-N-; phenylcarbamoyl)-(
3f-[)-imidazo(5,1-d) -1,2,3,
5-tetrazine-4-o/(1,0), which was prepared in Example 4, and anisole (0,2'
s/) were dissolved together in lifluoroacetic acid (10 ml) and the solution was left at room temperature for 18 hours/ζ. The mixture was then evaporated to dryness and the residue was triturated with diethyl ether to give -(2-chloroethyl)-8-(N-phenylcarbamoyl)-[:,lSH]-imidazo(5
, 1-a) -1,21315-tetrazin-4-one (0,459) was obtained in the form of a tan solid. m, p,
166°C (with decomposition) (after 6 crystals from ethyl acetate)
. Elemental analysis value: 048.4. H6, 22, N 26.
Oq6, ttg value: 04a99. N3.48, N
26.37 chi. ■, T(, (KBr disk): 53
90.1735 and 168 Dent-'. NMR (
in DMSO-d6): a9 and 1 (single line at 13 ppm, double line centered south at 18 ppm, triple line centered at 4.0 and 4.6 ppH1, ZO~7.
multiplet at 9 ppm].

Example 6 Compound F Sodium nitrite (2.8jl) was added to an acetic acid water bath solution (2M1
84ffiJ), and the dissolved acid is []t', -C
', 1 M and then finely ground 5-aminoimidazole-4-19-pene:)ru(T-phenylcarboxamide hydrochloride (2,89), IJJ as described in Reference Example 1. After 10 minutes, the resulting gummy solid was treated with ethyl acetate (3X30+11).
and the extracts were combined, washed with water, then with saturated aqueous sodium chloride solution, and subjected to quartz extraction on -Cmc.

! 5-cyaguimidazole-4-N-benzyl-N-.
Formation of phenylcarboxamide The Yd solution was treated with 2-chloroethyl incyane.-) (9th edition J) and the mixture was left in the dark at room temperature for 4 days.

1 liter of the bath solution was then evaporated to a small volume and the residue was subjected to medium pressure column chromatography, eluting with ethyl acetate, to give 8-(N-benzyl-N-phenylcarbamoyl)-3-( 2-chloroethyl) -(
6H)-imidazo(,5,1-d) -1,2,3,5
-Tetrazin-4-one (LOP) was obtained in the form of glass. Elemental analysis value: 059.3, H4,57, N 1
99, (Ja5 俤, J14 い direct:
C! 5a75, H4,19, N20.56, C
ea67%. ■, R, (KBr disk): 1740 and 164 Qcnr clNMR (Dh180-d
6) Knee 5.2° 7.1.7.3 J? and 8.6
Single m in ppm, triplet centered at 4.0 and 4.6 ppm.

Practical MM Example 7 Compound G Sodium nitrite (11P) in water (50Mt)
The bath liquid was cooled to 0°C and mixed with acetic acid aqueous solution (2M, 40
m) in 5-aminoimidazole-4-N-methyl-N-phenylcarboxamide salt molten salt (4,011%
Each small pudding was treated with a bath solution of Lua' () prepared as described in Reference Example 4.

After 10 minutes, the resulting mixture was diluted with ethyl acetate (4 x 100 m
/) and the extracts 11 and 11 were combined, filtered and strained over magnesium sulfate.

5-diazoimidazole-4-N-phenylcarboxamide production bath solution 2-chloroethyl incyane) (l
ligl) and the mixture was left in the dark on a vortex overnight. The bath solution was then evaporated, separated into a solid solution, and subjected to medium-pressure column chromatography while eluting with ethyl acetate to give a solid (5.75 kg). It was then triturated with dichloromethane. The insoluble residue was recrystallized from a mixture of petroleum ether (boiling point 600-80°C) and ethyl acetate and then from a mixture of ethyl acetate and diisopropyl ether to give 3-(2-chloroethyl)-8- (N-
Methyl-N-phenylcarbamoyl)-(3H)-imidazo[:5,1-4)-1,2,3,5-tetradi/
-4-one (0,89) was obtained in the form of a colorless solid. m,
p, 130-132°. Elemental analysis value: 050.4, N
3.91, N24.9.011cL6%, calculated value: 05
0.55, N3.94, N 25.26, czio, s
Section 5. Engineering, R, (xBr disk): i 750 and 1640an ONMR (J) MS07d6) knee 3
．． Solid wire at 4.7.2 and 8.65 ppm, 3
．． Triplet with 95 and 4.6 ppml C centers.

Example 8 Compound sea urchin (5-diazo-2- in ethyl acetate (45,*l)
Methylimidazole-4-carboxamide (1,54)
, prepared as described in Reference Example 5) was mixed with 2-chloro'1 ethyl isocyanate (6,5,1).
and the mixture was stirred at ambient altitude for 5 days in the dark. The mixture was then diluted with diethyl ether and the resulting solid was evaporated 1. /% diethyl ether and drying in vacuo at ambient temperature to give 8-carbamoyl-3-(2-chloroethyl).
-6-methyl-[3H]-imidazo[:5.1-(1)
-1,2,3,5-tetrazin-4-oy (2,00j
l) was obtained. m, p.

170°C (with decomposition). Elemental analysis value: 03ZO1H3
,49, N 32.8.0113.3%, Calculated value: Oro 144, N3.54, N 32.75, (]ノ16゜8
2%.

Example 9 Compound Sea Urchin 5-Diazoimidazole-4-(N,N-dimethylsulfonamide) in dry ethyl acetate (40aj)
(cL55j1. Manufactured as described in Reference Example 6)
The ld solution of 2-chloroethyl isocyanate 1-(3
, t/) and the mixture was stirred in the dark for 48 hours. The mixture was then evaporated in air below 40°C to a volume of about 15 ml and diluted with dry diethyl ether. The solid that formed was removed.
(2-chloroethyl)-8-(N, N-u methylsulfamoyl)-[:3H)-imidazo(5,1-cl)-
1,2,3,5-tetrazin-4-one ((168j)
) in the form of grayish needle-like crystals.
p, 155-156°C.

Original; h analysis value = C3 (upper 4,) N3.35, N 26.
8, czii, a, idH+i+d: fj3 t
3, N5.62, N27.4. (Jl t6chi.

■,R,1755crn ONMR(j)MSO-d
6): Single wire at 2.80.8.90 ppm, 3
．． Triplet at 99 and 4,62p'9m.

Example 10 Compound J 5-diazoimidazole-4-(N-methylsulfonamide) (0,79
, prepared as described in Reference Example 7) was treated with 2-chloroethyl isocyanate (3 g) and the mixture was stirred for 48 hours in a sealed flask in the dark.

The mixture was then evaporated in vacuo below 35° C. to approximately half its volume and diluted with diethyl ether. The resulting solid was filtered and washed with diethyl ether to give 3-(2-chloroethyl)-8-(N-methylsulfamoyl)-[:3H)-imidazoC5,1-
d]-1,2,3,5-tetradi/-4-one ([L3
29) was obtained in the form of bright pure yellow plates. m, p,
147-148°C. Elemental analysis value: 02a5, N2.9
0, N2a7%, calculated value: 02 B, 7, H6,08
, N2a 7%. I, R, 1745r-Itr
'.

N'hSR (DhTbit)-a4): 2.58
Double line at pp+11, 3.98% 4.61pJ
) 3 in nl & % 1 in 7.94 ppm
劃＠、a Single line at 84 ppm.

Implementation ii The compound is dissolved in 5-diazo-ethyl (50,d)
A solution of 4-methylsulfonylimidazole (prepared as described in Section 11m65P1 Diagnosis 8) was treated with 2-chloroethyl isocyanate (6 liters) and the mixture was kept at room temperature in the dark for 48 hours. Pick up your hands/he. This mixture was then evaporated in the walls and the oily residue was triturated with petroleum ether (boiling point 60-80 DEG C.). The resulting solid was subjected to a medium pressure chromatograph while being treated with 7P'' and mixed crystal with ethyl n'?
ilU L.

6-(2-70ethyl)-8-methylsulfonyl-[6H]-imidazo[5,1-d)-1,2,3,5
-Tetrazin-4-one (0,72jl)
0m, p.

154-155°C. Elemental analysis value: csa6, N2.85
, N2 5.0. C61t 5 俤、Gotoj蓼flli: C60.28、N2.90、
N25.22, Cj? 11.55 yen.

Example 12 Compound 5-diazo-4- in dry ethyl acetate (60g)
Methylsulfonylimidazole (0,652, reference y0
8) was treated with methyl isocyanate (5,5 rnl) and incubated in the dark at room temperature for 6 days. I left it there.

Another portion of melon methyl isocyanate (3.5 ml) was added and the mixture was stirred for 2 days at 41°C and left to stand for 3 days. The mixture was then evaporated to a volume of 10 to 15 #l in a Makabe pot and subjected to medium pressure L7 chromatography under vinegar and ethyl solution to give 3-methyl-8-methylsulfonyl-[3H ]-imidazo(5,1-dJ-1,2,3,5-natokuji/-
4-one (alyp) was prepared in the form of a white crystalline solid. m, p, 185-186°C (with decomposition). Elemental analysis value: 0512. N2.89, N5 (13th section,
Hi#m: 03t 44, H3,08
, N30.56%.

Example 13 Compound M 5-diazoimidazole-4-(N-(4-methoxybenzyl)sulfo/
A solution of amide] (alpha3p%) (prepared in a similar manner to column 9) was treated with 2-chloroethyl incyane) (1,5p) and the mixture was diluted with 48
Stirred at room temperature for an hour.

The resulting black-J" bath solution was filtered and evaporated to dryness. The resulting brown solid was diluted with 11 iffl of petroleum ether.
(1), filtered and subjected to medium pressure chromatography eluting with ethyl acetate to give a white solid.
, this was triturated with petroleum ether, filtered, and then 1:11
Dry at 170℃/10 mHg (2-
ri-a-loethyl)-8-(N-(4-methoxybenzyl)
sulfamoyl) -(6H)-imidazo(5,1-d
)-1,2,6,5-tetrazin-4-oy(0,2j
1) was obtained. m, p, 155-156°C (with decomposition).

■,R,1745ttn %7C search analysis value: 041
9, N3.72, N2Q, 5chi, calculated value: 042.16
, H5,79, N2t07%.

Example 14 Compound N 6-(2-chloroethyl)-8-(N-(4-me)xybenzyl)sulfamoyl)-(5H)-imidazo(5
,,1-d)-1,2,5,5-te)radin-4-oni/(Q,19, prepared as described in Example 15) was dissolved in trifluoroacetic acid (tOa# ) and anisole (3 drops) with m? and the solution was left at room temperature for 2 hours. The mixture was then evaporated in vacuo and the residue was triturated with diethyl ether to give a yellow solid, which was eluted with a mixture of petroleum ether (1 point 60-80'C') and ethyl acetate (1 point). -(2-chloroethyl)-8-sulfamoyl-[6H]-imidazo(s, 1
-a) -1,2,3,5-tetrazin-4-o/(50
) was obtained in the form of a white solid. m, p, 185°C (with decomposition). 1. R, 1750cm, NMR (DM
in SO-d4): a8.7, single line at 8 ppm, triple line at 4.58, 3.95 ppm.

Example 15 Compound O 3-diazopyrazole-4-carboxamide (5,99, f''J,'Ph in ethyl acetate (150*/)
&rm.

8ci, J Vol. 57, p. 1044 C1968) was treated with 2-chloroethyl incyanate (24d) and stirred at ambient temperature in the dark for 7 days.

The mixture was diluted with diethyl ether and the resulting solid was removed and washed with diethyl ether to give the mixture in the form of a creamy solid (a369). m, p, 1
73-174°C (with decomposition).

A sample (tOjl) of the above mixture was heated overnight at 60°C as a foil solution in dimethyl sulfoxide (2OaO).The solution was then evaporated to dryness (below 60°C and [11mr
I'E 7J) to uHg) and the residue was triturated with a mixture of dichloromethane and diethyl ether. Collect the solid that forms and add boiling acetonitrile (ca.
0sJ). The resulting bath liquor was treated with deactivated silica gel (3) containing 20 g of water and the mixture was evaporated to dryness. Transfer the residue onto a column of silica gel.
chromatography using medium pressure chromatography while eluting with ethyl
E and recrystallization of the product from acetonitrile yielded 8-carbamoyl-3-(2-[70ethyl)]
-[5H)-pibzo sail5.1-d)-1,2,3,5-
Tetrazin-4-one ([125jl) was obtained in the form of colorless needles. output, p, 205-204°C (with decomposition). Elemental analysis tC: a;4. a, N2.92, N34
．． 7.0j14.6%, calculated value: O+4.65, N2.
91, N34.64. O/14.61 section.

Example 16 Compound P JikUJ r? Methane (49&t): p and N-methylpyrrolido-2-,onC2,5d)
J, P] 1arm, SC1, J tJE Volume 57 No. 10
AM built as described on page 44 (1968), /'
1. methyl r-socyanate c6
xl) and stirred in the dark for 7 months. This mixture is then diluted with diethyl ether and the resulting solid is needled off to give a mixture in the form of a creamy solid C2,249>. m, p, 179-181°C (with decomposition).

A portion of this solid was treated with a solution of deactivated silica gel (8F, 20% ice content) in dimethyl sulfoxide (10a/p) and the mixture was dissolved in 14. Hanatsu 1+II'! (60℃/0
．． 1 mm) with Ig). Remaining V! The mixture was loaded onto the top of a solid silica gel column and subjected to medium pressure chromatography, eluting with ethyl acetate. Add a small amount of the product
o Grind with aqueous sodium bicarbonate solution and quickly evaporate.
8-Carbamoyl-6-methyl-(3H)-virazo'7(5,1-d)-1,2,3,5-tetrazin-4-one (41fi:9) was prepared in the form of a colorless solid. Obtained.

rn, p, 170°C (with decomposition). NMR (DMSO)
-d6) 1.95.7.45.7.55, a 5 D
Single line in ppm.

r, R, (KBr disk): 6400.516CJ,
1750 and 1680 cm 0 Example 17 Compound Q Sodium nitrite (0,792
) of crude 4-amino-5-piperidinolponylimidazole hydrochloride (4-amino-5-piperidinolponylimidazole hydrochloride) in aqueous acetic acid bath (IM, 17 ttl) in small portions with stirring at 5-10 °C for 5 minutes.
2.1jl, prepared as described in Reference Example 10). This solution was mixed with ethyl acetate (4X45
me) and the extracts were combined, dried over magnesium sulfate and dried at 60 °C/0.1 mm.
Evaporated with Hg. The residue was placed in a desiccator over Q2 pentoxide for 45 minutes to obtain 4-diazo-5-piperidinocarbonylimidazole (1,739) in the form of red crystals pure enough to be used in the next step. I got it from

Crude 4-diazo-5-biberidinoluponylimidazole (1,73) in dry ethyl chloride (55 mg)
(prepared as previously described) with clear 2-l loloethyl incyanate (5,9++tt) and the mixture was stirred in the dark for 2 days at -C for 7t.

The solution was then evaporated at 60° C./[11 nimHg and the 9A fraction was subjected to medium pressure chromatography twice on silica gel, eluting with a mixture of n'l:ethyl acid and acetonitrile (88:12 v/v). Attached. The evaporated fractions were combined and evaporated, and the residue was triturated with petroleum ether (boiling point 40-60°C) to give 6-(2-chloroethyl)-8-bilysinocarbonyl-[3H)-imidazo. (5,1-cl) -1,
2,5,5-tetrazin-4-o/(1,46)) was prepared in the form of pale purple crystals. m, p.

92-94°C. Elemental analysis value: 045.3, H4,98
, N26.1%, it K value: 046.4, H4,8
7.N27.1%.

NMR (in DM80-d6): single fiber at 8.7 ppm, triplet at 4.6 and 4.0 ppm,
Multiplets at 3.2-3.4 and 1.5-18 ppm. Engineering, R, (KBr disk): 1750.16
300++.

Implementation pij'18 Compound R J? in water (5d)? sodium nitrite (t61jl
) was cooled and maintained at 5-10°C, and the mixture was cooled for 5 minutes to 5-amino-2-butylene chloride in hydrochloric acid (IM, 17.7d). -Carboxamide hydrochloride (1,61j', West German Patent No. 23585
A small amount r with the bath solution (manufactured as described in specification No. 09)
2-phthyl-5-diazoimidazole-4-carboxamide (U479 )' was obtained in the form of a yellow solid.

m-1), 109-111°C (decomposition).

A solution of crude 2-butyl-5-diazoimidazole-4-carboxamide (U479.fc, prepared as previously described) in ethyl acetate (14) was treated with 2-chloroethyl isocyanate (15+J). It was then left in the dark for 24 hours. The resulting tan solid was filtered and crystallized from a mixture of ethyl acetate and acetonitrile to give 6-butyl-8-carbamoyl-3-(2-chloroethyl)-(5H)-imidazo (:5.1-d). -1
,2,3,5-tetrazin-4-one (Q, 49ji+
) was obtained in the form of colorless crystals. m-1), 165-16
7°C (with decomposition). Elemental analysis value: C43,9,H4
, 90, N27.9, (J12.0%, calculated value: 044
．． 2, H5,06, N2al, clll, 91° Example 19 Compound S Zutrium nitrite ([1
A stirred solution of a'
1) 5-Amino-2-cyclo2hexylimidazole-4-carbogye! /'midohydrochloride (1,1
F.

[West German Patent No. 235851] No. 9 Meiwa 1 Homare was prepared as described in iα and treated in small portions with a solution of fc).

The resulting orange-red precipitate was filtered and dried in a desiccator over 90% pentoxide for 1 hour to obtain crude 2-cyclohexyl-5-diazoimidazole-4-pure enough to be used in the next step. Carboxamide CO, B69) was obtained.

Crude 2-cyclohexyl-5-:) azoimidazole-4-carboxamide (
n' of 0.86jll, produced as described above)
2-chloroethyl isocyanate) (2,Or+
/) and left in the dark for 24 hours. The resulting solid was filtered and crystallized from ethyl acetate +1) to give 8
-Carbamoyl-3-(2-chloroethyl)-6-cyclohexyl-(!IH)-imimezo(5,1-4)-
1,2,3,5-tetrazin-4-one (Q, 2!+9
) was obtained in the form of colorless crystals. m, p.

245~2/18'c (min pr#"fp"))
. Original cumulative molecular mountain',,f; C47,6, H5,16, r
i25.6. C61113%, iFE calculated value: C4al
, H5, 2B, N25.9.071119 Excellent.

Implementation T/u20 Compound T L.jet in water<4.7ml1) III/l
The stirring dissolution of Itseokum (158P) is 6 and 5 to 1.
The temperature was kept at 0°C, and the mixture was heated with an acetic acid aqueous solution (2M,
1 ad) 5-amino-2-phenethyl in
Imidazole-4-carboxamide JM salt (1,8)
, prepared as described in Reference Example 11) was treated in small portions with kT solution. The resulting yellow precipitate was filtered and dried in a desiccator over pentoxide for 1 hour at °C to give the crude 5-diazo 2, which was pure enough to be used in the next step.
-noenethylimidazole-4-carboxamide (2,
Op) in the form of a yellow solid at 49'/l.

Paddy 5- :) Azo-2-phenethylimidazole-4-carboxamide (
A dark solution of 2, Ojl, prepared by VC as described above) was treated with 2-chloroethyl isocyanate (3.4 mg) and stirred in the dark for 24 hours. The resulting isoform was filtered and redrystallized twice from ethyl acetate to give 8-carbazoyl-6-(2-chloroethyl)-6-7enethyl(3H)-(midazo(5,1-a)-1, 2,3,5-
Tetrazin-4-one (0.44jl) was obtained in the form of colorless crystals. m, p.

179-181°C (with decomposition). Elemental analysis value = 051
．． 8%H4,19,N24.2. (Vl [12%,
Calculated value: 052.0, H4,36, N24.2.
OI! I Q, 2q6° carried out 121 Compound U 2-benzyl-5-diazoimidazole-4-carboxamide (2,
49, a solution of 2-chloroethyl isocyanane)
tl) and the reaction mixture was run for 20 hours at room temperature in the dark.

The reaction mixture was then evaporated to dryness and the cocoon residue was dissolved in petroleum ether (boiling point 60-80°C, 2x30.++/).
The excess 2-chloro'I ethyl incyanate was removed by trituration with dichloromethane (2 x 50 m) to remove the excess 2-chloroI ethyl incyanate.
The desired product was extracted from the chloroethyl urine byproduct. The dichloromethane extract was reduced to 17% and subjected to medium-pressure talomadography in a silica bottle under evaporation and explosion to dryness with ethyl acetate. 1 to 1, evaporate and recrystallize the vinegar from ethyl filter to give benzyl-8-carbamoyl-3-(2-chloroethyl)-(3H)-
Imidazo(5,1-4)-1,2,5,5-tetrazin-4-one (0,7P) Samurai Y'com, p, 161~
163℃ (decomposition)
Analysis I1: C5C4, H5,96, N25.4
, fM1118chi, Hl・Calculated value; C5α55, H3,
94, N25.26.0J1t166%, ■, H,
174Dctn.

Example 22 Compound V (
A solution of (t2F, n, fc' prepared as described in reference 171116) was treated with 2-chloroethyl isocyanin-1.(5a+1) and the mixture was incubated in the dark at room temperature for 5 days. I left it there. The resulting crystalline solid was filtered and washed with petroleum ether (boiling point 60-80°C) to give 8-carbamoyl-5-C2-'/loloethyl)-6.
-Itubrobyl-(3H)-imidazo(5,1-d)
-1,2,3,5-tetradi/-4-one (n2JF
) was obtained. m, p, 189-190℃ (with decomposition)
. Elemental analysis value: 042.01H4,64, N 29.5
φ, calculated value: C42.19, H4.60, N29.5%
, 1, E, 174 (ll+-+?+-'.

Real L1〕1 にり26 础U＞ 'i”l Vl水（66
) Middle-72s;-:・Noru Ai jl IR Storium (
A solution of 7 u of 5-amino-2-propylimidazole-4-carboA-limide (1,579
s West Germany's 9th coffin number 2558509! #ill'
J! 7'. The resulting precipitate was filtered and dried over phosphorous in a desiccator under VC to obtain a 5-diazo-2-propylimidazole-4-carboxamide for use in the next step. (C1,56
9) in the form of a yellow solid in the form of crude 5-diazo 2-zoC7 bilimidazole-4-carboxamide <
c, s6p, 2-chloroethyl isocyanate, -1・C1,6mt) produced as described above /ζ)
and stirred in the dark for 24 hours. ff to generate
t, IIR was treated with P and washed with ethyl acetate to obtain 8-
Carbamoyl-3-(2-ctaethyl)-6-propyl-[roH]-imidazo[5,1-a)-1,2,
'S, 5-ftraji: / -4-, t/(0,48j
l) was obtained in the form of a pale yellow solid. 711-p, 145
~148°C (with minutes etc.). Elemental analysis value: 041.1,
H4.4, N2a5%, Il'i calculated value: 042.2,
)14.60. N29.5q6°NMR (DMSO-
d6): Single W, I at 17 ppm, 4. Is,
4. ollo, triplet at 2 and 1.0 ppm,
Multiplets at 18 ppm. ]:, R, (KBr disk) 1750°1695cn+.

Run 24 Compound X Sodium nitrite ((14
49) was mixed with acetic acid aqueous solution (
5-amino-2-ethylimidazole-4-carboxamide (0,8P) in 2M, 14gt).

Nishigimushi 7th No. 2358509 1 Toshogawa・μ! '
The precipitate (prepared as described in TW) was dissolved in a mixture of 1 and 2 hours, and then the precipitate was dried in a desiccator for 1 hour on an 11"ri stage X7. - 5-diazo-2-ethylimidazole-4-carboxylic acid which is sufficiently pure to be dried in a container and used in a V-reaper;
mido (o, 62p) in the form of a yellow solid at 19 ko m;
p, 139°C (with min pyp).

Dry vinegar 10, :r chill (22*t)''? Keru coarse 5
A solution of 2-chloroethylisocyano-1.(2,4
-) Dekoro” - Kei left and worshiped 4i2 in the dark at 24:00.

Filter the resulting precipitate and add vinegar R'1. 6LI-fJL, te8-carbamoyl-5-(2-'/
loloethyl)-6-nityru[6n)-imidazo[5
,1-d) -1,2,3,5-tetradi/-4-one ([1!-i9.Sl) was obtained in the form of light gray crystals &01
n, l), 172-174°C (with decomposition). Elemental analysis: 039.7, N3,98, N31. (), Cjl!
13.1%, #Fn fi &; 039.9, H4
, I O.

N31.0, (413,1 yen.

25 Compound '1 No Y dry ethyl acetate (100*t) was mixed with 5-diazo-4-(4-meth)oxybenzyl)sulfamoyl-2-methylimidazole<2.
459, in Reference Example 14 i, self-tuned (fc) and subsequently 2-chloro1-coethyl isocyanate)
(3M#) and the reaction mixture was stirred in the dark at room temperature for 56 hours. This mixture was then further mixed with 2-chloroethyl isocyanate (3r,
tl) -C treatment 44ii 1. [7] The mixture was further stirred at room temperature in the dark for 24 hours. The reaction mixture was then evaporated to dryness and the residue was dissolved in petroleum ether (boiling point 60
Excess 2-chloroethyl isocyanate was removed by trituration at ˜80° C., 3×25a/). Then, dichloromethane (2X 50.z/) was added to the remaining Yu3i Lit material.
The desired product was extracted from the minor and main 1,3-bis(2-chloroethyl)urea products with mf<1:. Dichloromethane extraction! Sift together and evaporate it to dryness.
The solution was purified with ethyl chloride and subjected to medium pressure chromatography on silica gel with QME.
-(2-chloroethyl)-8-(4-methoxybenzylnsulfamoyl-6-methyl-(6)T)-imidazo[,5,1-d)-1,2,3,5-tetrazine-4-
On (1,5□2) was obtained. m, T), 159-16
0°C (with decomposition). Engineering, L 1760crn-'.

Run 26 Compound 2 Trifluoroacetic acid (10+, tj) and anisole (
6-(2-chloroethyl)-8- in 10M4)
(4-Methoxybenzyl)sulfamoyl-6-methyl-[3H]-imidazo I:5,1-C1,) -1,2
,5,5-tetrazin-4-oni/(1,5p, real h1
A solution of Iff L & 124M (prepared as described herein) was allowed to stand overnight at room temperature, the reaction mixture was evaporated in vacuo and the residue was triturated with diethyl ether. The resulting light brown solid was filtered and crystallized from pJ:3-(2-chloroethyl)-
6-Methyl-8-suA-77 moylu[3H]-imidazo(5,1-d)-1,2,3,5-tetrazine-4-
On (115531) 4s*, m, p, 199~
200°C (with decomposition). Elemental analysis value: 029.1,
N3. D2, N2B, 8, C112,1, El 1 [
16chi, calculated value: 028.72, ) (6,10, N28
．． 71, OVl 2.11.810.95 Section. 1. 'R
, 1760, 331Dcnt.

Example 27 Compound AA A solution of 5-diazo-4-dimenalsulfa-7-2-methylimidanyl (1,8,9, prepared as described in Reference Example 15 and 11) in diluted ethyl (100*t) was - Treated with (chloro1ethyl isocyanate) (41/)! The mixture was left at room temperature for 2 days. The mixture was then treated with yet another amount of 2-chloroethyl isocyanate (4H) and left at room temperature for an additional 6 days. The reaction mixture was then evaporated in vacuo and the residue was triturated in a petroleum needle (boiling point 60-8°C, 2x251111). The residual solid was dissolved in ethyl acetate and subjected to medium pressure chromatography on silica gel with ethyl acetate. The appropriate fractions were combined, evaporated to dryness and triturated with petroleum ether < ili point 60-80°C) to give 5-(2-chloroethyl)-8-:)methylsulfamoyl-6-methyl-(3H )-Imidazo I'5.1-4
)-1,2,5,5-tetradi/-4-one (2,17
2) was obtained. m, p, 157-138°C. Elemental analysis:
033.8, N3.91, N25.8.07112.8
9.7 excellent, IT value: G133.7, H4.09, N
26.20, CI! 11.05°Sl [10 yen.

Example 28 Compound BB 5-Diazo- in dry ethyl decate (30 gl)
2-Methyl-4-methylsulfonylimidazole (Q,
4) A solution of fL prepared as described in Example 16 was treated with 2-chloroethyl incyanate (2 ml) and then left at room temperature in the dark for 4 days. This mixed food is then evaporated to dryness, and its residual petroleum ether (
Excess 2-
Chloroethyl isocyanate was removed. The remaining residue was dissolved in ethyl acetate and subjected to medium pressure chromatography on silica gel with heating with egyl acetate to give 3-(2-chloroethyl)-6-methyl-8-methylsulfonyl-C3H'J. -imidazo(5,1-tl)
-1,2,5,5-tetrazin-4-one (0,22)
) was obtained. m, p, 149-150°C. Original J edition analysis Imuni L: 05 6. O, upper 16.65, N 2
3.8, 0J12.7%, 811117 Chi,
h ten ↓ interpretation +I! i:032.94, H3,4
6, N24.01, C112,15, slo, 99
q6° engineering, R, 1745ryn 0 row 29 Compound cc 41, 6-diacibibuzole-4-(N,N-'; methylcarboxamide) salt [yume (191, The aliquot of !1 (produced as described in Reference Example 17) was treated with 2-chloroethyl insiaeide (2,51!
- Stir the solution and -C1,8-diazobicyclo[5,4,0
) Undec-7-, :JZ-7-, :JZ-7-, treated with 1.7non. The resulting solution was stirred overnight at room temperature in the dark.

Dichloromethane was formed and the resulting gum was ground in a petroleum needle (boiling point 60-80°C). "1
7 Tograph (marked with -).

The appropriate fractions are combined, evaporated to dryness and the residue is recrystallized from ethyl acetate to give -(2-chloroethyl)-8-(dimethylcarbamoyl)-(3
H)-pyrazolo(5,1-d)-1,2,5,5-tetrazin-4-one ([1L38)) was obtained in the form of colorless crystals. m, p, 1i 6-118℃ (9 with decomposition)
. Elemental analysis values: C39.7, K3.96, N3α9.
0J15.1ch, calculated value: 059.95. H4,1
0, N5t05 & CJI 3.1%, Eng, R, (K
Br disk): 1770.1650 an, NM
R (in acetone-d6): 3.25 and a 40 p
Single line in pm, 4.25ppm and 4.95pp
Triple line at m.

Conducted t130 Compound DD Stirred concentrated sulfuric acid (2.5 m) was diluted with 8-carbamoyl-3-
(2-chloroethyl)-(3H)-imidazo(5,1
-d) -1,2,3,5-tetrazin-4-oy(02
49s English L! ! 1 Patent No. 2104522 Mei ME). The mixture was cooled to 0°C and treated portionwise with concentrated nitric acid (A-142,14). This vinegar solution was maintained at 4°C for 1 hour, and then poured onto ice. The precipitated solid was collected, washed with water and recrystallized from aqueous acetone to give 3-(2-chloroethyl)-
8-(N-==)rorubamoyl)-[roH]-imidazoC5,1-CL]-1,2,3,5-tetrazine-4
-one (0,2Bp) in the form of colorless crystals. Element system analysis f+ri: C2a6, H1139, c! ! i
2. o.

N33.6≠, BE calculated value: 029.23. K2.1
0, (J12., 'i3, N34.09q6゜Li(,
(K11r disk):52(]0.1750.172
0 and 1620 cm, NMR (DMBO-(L6)
:4.05ppm (J-6Hz) and 4.70pp
triplet at m (J=6Hz), 9.05 pp
Single line at m, wide 'AJfi at 8.25ppm
LD, rn/e2B7. /289(M).

Practical Example 31 Compound Q, FF, M, ) A suitable diazo compound (produced by applying or adapting the method described in Reference Examples below) for use in TH oil and the above implementation β・Ill, 2.
4.6-i6. is ~ 25 Fu・Yohi 27 ~ 29 'l
t'? By operating in the same manner as in the method of

6-Methyl-8-methylsulfonyl-(3H)-pyrazolo(5,1-4)-1,2,3,5-tetrazine-4-
O/(colorless solid form, m, I), 182-184°C)
, 6-(2-chloroethyl)-8-methylsulfonyl-
[3Xi)-pyrazolo(5F1-dJ-1,2,6,5
-tetrazin-11-one (bu, 1jξotgoza) sugi state,
Mt., p, 166-171°C), 3-(2-chloroethyl)-8-ethylsulfonyl-6
-Methyl[6H]-imidazo(5,1-d) -1,2
, 3,5-tetrazin-4-one (m, p, 146-147°C) and 3-ζ2-chloroethyl)-6-methyl-8-zo'1;
! Rusulfonyl [3p■)-imidazo[5,1-d)
-1+2+6,5-tetrazin-4-one (white crystalline solid form, m, p, 85-86°C).

Reference example 1 (+)5-=troimidasol-4-carvone r! y(
A thoroughly mixed mixture of 2, (1) and phosphorus pentachloride (267r) was stirred and heated in an oil bath at 120° C. for 1 hour. The resulting yellow slurry was evaporated at 60 °C/D, 1 mml>H to give 1,6-sinitro 5H110H-diimidazo[1,5-a:1',5'-6,:l pyrazine-
5,10-dione (1,9Or)'! r As a yellow solid! ) ic, melting point 249-251°C (decomposition). 1
．． R, (KBr de f): 1000 pictures -1, VO2
78 (1a+-).

1'-BsrJ Volume 56 No. 684 Tei (192ro)"...
Yohirchem, Ab8, J Volume 59 M! 162
2g+94 using the same method to convert their products to 15-
Contains nitroimidasol-4-carbonyl chloride.

(++) 1. 6-Sinitro 5H, 1rJi(-
Diimidazo r1,5-a: 1', 5'-d
]] Pyrazine-5,10-dione5. El), N-benzylaniline (159) and hitetrahydrofuran (
A mixture of 250 + d) was heated near current for 6 hours. Tetrahydrofuran was distilled off in vacuo, and the remaining gummy material was mixed with dilute salt a (2 N' = 1t) and ethyl acetate (
1t). The insoluble N-benzylaniline hydrochloride was stripped off and the ethyl vinegar layer was separated.

The aqueous phase was acetylated twice more and extracted with ethyl, and the organic phases were combined, washed with dilute salt (B'. (2 N), then water, dried (dried over 1Iir magnesium) and evaporated to dryness. Solidification gave an orange gum. The comb was triturated twice with boiling diethyl ether, and the resulting colorless solid was crystallized from isopro/cenol to give 5-21.'1 imidazole-4-N. -Zundjiru N-phenylcarboxamide (4.(]r) was obtained as colorless flakes. Melting point 237-240°C. Elemental analysis: C 62.3, H
4.2B, N173%X calculated value: C 6'5.35,
T (4.38, N17.38φ. Engineering R (KBr disk)' 1665cn-i.

(1+11 5-nitroimidazole-4-N-benzyl-N-phenyl J ruboxamide (4. O?
): Drying at 26°C and 5°C using a bath + Raney nickel catalyst in I-tanol (450 ml).
Hydrogenation was carried out at atmospheric pressure. After completion of hydrogen absorption (41 detention 5
After 0 min), the mixture was filtered and added with concentrated hydrochloric acid (3.6 min).
rnl) and evaporated to dryness below 40°C.

The residue was triturated with diethyl ether to obtain 5-7'minoimidazole-4-N--:Njiru-t1-phenylcarbogisamide salt (3.829) as a pale yellow solid. , melting point 190-193°C (decomposed). NMR(D
in MOO-d6): single line at 5.05, 7.1-7.2 and 8.4 pl) m.

IR (K'Br case) ' 1 6 4 0 on
”, TI!/s 292 (M+).

Reference example 2 (1) IQ-benzyl-N-(4-methoxybenzyl)
Amine [21.5M, rA. nn. JN44 9
0 Vol. 1891j (1931)], 1,6-dinitro 5H,10H-diimidazo [5,1-a: 1', 5
'-d) Pyrazine-5,10-dione (6,7t, same as the notes in reference cell 1) made by k) i) O'2hi<
e't, 7y of dry detrahydrofuran (2[]Ome)
.

The mixture was heated at reflux for 18 hours. The tetrahydrone was removed in an empty S'L7, and the remaining oily lII+i form was distributed between dilute salt (2N, 500 mg) and convex (i(,7 ethyl (500 rm)/?"). .Insoluble?=I
-benzyl-N-(4'-methoxylinzyl)amine salt was removed and the acetic acid θnoethyl layer was separated.
Ta. Aqueous) 9) was extracted twice with ethyl acetate and organic)
Wash the combined I41f with dilute salt a2(2'), then water, then saturated aqueous sodium chloride solution, dry each part over thorium sulfate, and evaporate to dryness with water.
Ta. The residual gummy material was subjected to medium pressure column chromatography with vinegar and enal? ;'; Out, 5-nitroimidazole-4-N-benzyl-N-(4-methoxybenzyl)carbogizamide (2,9W) (I=j/(brown solid and (7") out. Melting point 167-170℃f, -
fl (II de L-del (boiling point 60-13 [1c) and isopvs no ζnol (crystallized from the latter j? compound). Elemental phase separation: ('61, H493, N 15.3%,
Calculated value: (”6229, if A, 95, IJ 1
5.29 I regret it.

Engineering R (K13r case): 310 (J ~ 21UO[
l, 1640.151 Tl, 1450 i-yohi 13
7 D an-”.rIJtiT+ (D at 120°C?
JJO-66): 5.76.1, 5.4.6, Z6
About O'7.8 ppm, 685 and 72 +
NMR spectrum at near pH 1. Due to the doubling of the signal caused by rotational disturbance of the bond that binds the carbonyl group to the nitrogen atom of the amide, □(1, is).

(If) 5-21.1 fuimidazole-4-+<-
Benzyl-N-(4-nodoxybenzyl)carbogizamide (2.21 g of dry ethanol (200++r/
) was hydrogenated using a Raney nickel catalyst at a temperature of 1 i and 3 atm. After completion of hydrogen absorption (2 hours 4
8 minute bales), the mixture was allowed to pass and treated with chloride water resistance gas: +
The mixture was evaporated to dryness below 40°C. isopr
” by crushing with a mixture of panol and diethyl needle 5
-aminoimidazole-4-N-benzyl-N-(4-
methoxybenzyl)carbogizamide saltbutyric salt (2.2f
14) as a rubbery solid that divides 'l at 70C or higher. IR (KBr disk) ” 3400~2800
, 1 6 4 0z-'o NMR (methanol-d
4 out of 5)? 3.7, 4.4, 4.5, 72 and 8.
3 ppm K single IIiz 6. 7 and 6. 9
A doublet centered on ppm (of rotational hindrance around the bond connecting the carbonyl group of the amide to the kidney atom of the amide).

Example 3 (+)1.6-Sinitro 5H, 1 1. ITl-
Diimidazo r1,5-a, 1/, 5/-d] pyrazine-5,10-dione (5.5f; produced in the same manner as described in Reference Example 1), N-(4-methoxybenzyl)aniline C 1 4-5'% [Ber-J No. 63B
Tetrahydrone (1930)] and tetrahydrone (250 ate) were heated under reflux for 1214 hours, then 1 furan of tetrahydrone was combined and removed by evaporation in vacuo, and the remaining dark color was removed with salt [n,' 7 (2 h+
, 1000 mI and ethyl acetate (10D OTJ
) and distributed between l−.

Organic Jiso was washed with water for 141 t, dried over polarized magnesium acid, and then dried with seafood. 'ul L. The resulting solid was triturated with diethyl ether to give 5-nitroimidazole-4-N-(4-nodoxybenzyl)-N-phenylcarbogizamide (3.18r) as a pink solid. Melting point 212-215C (after mother crystal from inzolopanol), elemental analysis: C6 [1.4, H4.41,
N160%, ht9 value: C 613'/, Tl4.5
B, 1115, 91 arrogance. NMF( (, DMSO
-d 6) 'r. '/, r), O i- and 7
7pprl] single-win, 6. 7 ~7. 3ppm
Nitayama IL'r! c + engineering R (K.Br disk) 1
66 Dt-tn-1° (++) S-nitroimidazole-4-N-(4-methoxybenzyl)-N-phenylcarboxamide (2,19) in dry ethanol (2
The liquid in 00 ml of λ·-nickel hornworm was hydrogenated at 25° C. and 3 atm at a temperature of 13 months. Hydrogen absorption J
After completion of the reaction (during SIVr), the mixture was filtered and evaporated to dryness. The residue was triturated with total diethyl/I ether to give 5-aminoimidazole-4-N-(4-nodoxybenzyl)-br-phenylcarboxamide (1
, 97) was injected as a rubber-like material.

7 plf of a part of this rubbery substance as its picrate
6 with 6'lZ, i.e. 5-aminoimidazole-
4-1\T-(4-methoxybenzyl)-14-phenylcarboxamide-dissolved in dimethoxyethane (5rne) and a solution of picrin [(D.25r) in 1,2-dimethoxyethane (5++rl) Processed with. The resulting dissected crystals were separated and washed with diethyl ether to give 5-aminoimidazole-a-]-1-(4
-methoxybenzyl)-N-phenynotocarpoxamide biculin (0.071i') with yellow solid fAl and 1
- and it's 11 tons. Melt 1, <207°C (decomposition). Elemental analysis: C49.1, H64, N165%, C24)
] QjN7 ('19: 2ff20 F sweat T value: C
49.1, H 4.29, N 16.69%.

Reference example 4 (1"l 1,6-sinitro 511,1θ engineering 4-diimidazo CI,5-a: 1',5'-d) pyrazine-5.11J-dione (8082, reference, β, 111
61 Shijl (tj and 1i,) [7 and Shi21 construction],
A mixture 1 of N-methylaniline (12.44r) and tetrahydrofuran (40[)+y/) was heated in a forced stream for 24 hours. Next, remove the tetrahydrofuran by vacuum evaporation, and remove the I7 + J pipe dark color h-) body.
Dietino [・Ether de place J! i! did. The residual solid 141Z that remains as a residue was subjected to medium pressure column chromatography, and a mixture of ethyl and methanol (1:
1 v/v) to elute with 5-nitroiotasol-4.
-N-ph1+ruN-phenylcarboxamide (4.6
8f) was obtained as a white solid. Melting point: 193°C. Elemental analysis: C 52.5, H 3.95, N222%, nF calculated value: C 53.66, H 4.09, N22, 76%
. IR 1660cm-'.

(II) 5-nitroimidazole-4-N-methyl-N
A solution of -phenylcarboxamide (1, Ot) in dry ethanol (110+++/') was hydrogenated using a Raney nickel catalyst at 26<0>C and 3 atm. After completion of aqueous absorption (after 1 hour and 69 minutes), the mixture was
7 and treated with dry hydrogen chloride. The solution was then evaporated to dryness to give 5-7minoimitazole-4-N-phthyl-N-phenylcarboxamide salt ([1.9f
) as a grayish-white solid 1! ↓,, melting point 100℃ (minute f).

This compound was characterized as its picrin f'+v salt. i.e. 5-aminoimidazole-4-N-mef
/l--N-phenyl rufogisamide hydrochloride (0.
259) in water (2 tnt) was mixed with picric acid (0.zsy) in 1,2-dimethoxyethane (2me).
3' with the bath liquid inside! l l, ta. Separate the precipitate and 1
, washed with 2-dimethoxyethane, 5-minoimidazole-4-14-methyl-N-phenylcarboxamide picrin = salt (0.12r)'t+! Assuming that is a color solid, it is A4. Melting point: 237-238°C (31'r). Elemental analysis: C 45.3, H 126,
N 21.8 φ、Ro1 White
: C 45.85, H 339, N 22
．． 02%. Engineering R (KBr'/'Isk): 1640a1
-1.

Reference Example 5 Sodium nitrite IV (1. r.l 7 ) in a stirred bath solution (cooled to 1° C.) in 0 ° C. -5-carboxamide hydrochloride (2. [H', West German time W1, 235th
Aqueous acetic acid (prepared as described for 8509 Nioseiwa) was treated with a solution in aqueous acetic acid (2J24J) while maintaining the temperature between 1°C and 0°C. After the addition was complete, the resulting yellow solid was filtered and 5-Diazo-2 by vacuum drying over phosphorus dioxide
-methylimidazole-4-carboxamide (1,26
f) was obtained. Melting point: 175°C (on drying).

Reference Example 6 (1) A stirred aqueous bath of dimethylamine hM (3 [J% w/w, 35 mF) cooled in a cold water bath was mixed with 5-
2) Loimidazole-4-sulfonyl chloride (4
, 152 wetting substances, [Can, J, Chem, J
333 by the method of the 39th @ 501st Sada? From the 5-nitroimidazole-4-thiol ammonium salt of
;1. (manufactured by I) was processed little by little. Add 2 more of the mixture
The mixture was stirred for 0 min and then evaporated in vacuo below 40°C to reduce the total volume by half. The mixture was then treated with salt to make it strongly acidic, and the resulting pale yellow solid was filtered.
Crystallized from dimethylformamide to give 5-nitroimidazole-4-(N,N-dimethylsulfonamide) (2
, 73f) as a brownish plate autumn η1□ is I4I.

Melting point 282-283C (decomposed). Element Foreign News: C27,
3, T-T 3.65, IJ 25.4.814.2%
,'ir'L- value: C27,3,](3,66,N
25.4.8146%.

(II) 5-nitroimidazole-4-(N,1.
A solution of J-dimethylsulfonamide (1,Or) in dry ethanol (100 ml) was prepared using a total Raney nickel catalyst at 24 °C and 6 atm with a 71 carbon addition B.
Shita.

Next, the mixture is θ':+A! L, HA - It was diluted with diethyl ether (200 tnl) and then treated with dry hydroxide gas for 1ψ until it became slightly 11%. Next, all the inclusions are above 30℃] 2:L't'l:,
'i evaporated. Heat dry gas to remove residual solids: x Knorr (
20 mg) and treated with molten Mk charcoal, evaporated to 15 r++/volume, treated with dry diethyl ether (60 mg) and crystallized. The obtained solid was separated in a furnace to give 5-aminoimidazole-4-()J, ↑J-dimethylsulfonamide)k
Ari/lX, (o, at) was obtained as pale yellowish needle-shaped crystals.

Melting point 188-189°C (decomposition). Elemental analysis: C26,
1, H4BO1N 23.6, CI 15.9, s13
．． 9%, C3H10N402S ・Calculated value of Hct: C26,5, ]-14,85, N
24.7, C115,6,814,15%.

(II+) Sodium nitrite (0,3
A stirred solution of 1 g) of 5-aminoimidazole-4-(N,N-')methylsulfonamide) txx ts* salt (0,7f) in dilute hydrochloric acid (2N,
3.1m/! ) was added dropwise. The resulting solid was filtered off and washed with ice-cold water to give 5-diazoimidazole-4-(N,N-dimethylsulponamide) (0,
38g) was obtained. Melting point: 109°C (decomposed). lR218[
].

The aqueous solution of 22101yn-1 was extracted with ethyl at 0°C, the extract was dried over 4A intoxicated magnesium [1, and evaporated in vacuo to give a slightly pure version of -i1+ (11,21t). An inferior chemical product was obtained.

Reference Example 7 (1) A stirred aqueous solution of methylamine (25% W/W N3511II) cooled in a cold water bath was mixed with 5-nitroimidazole 4-sulfonyl chloride (4
, 15F] Humidity 1111j η, rCan, I Cho
According to the method of n+, j Vol. 39, p. 501 3.53
It was treated little by little with 5-nitroimidazole-4-thiol ammonium m (manufactured by RmM). The mixture was stirred for 15 minutes and then evaporated in vacuo below 4010 to reduce the volume by half. Next, the mixture was treated with a J column f:r< to make it strong (i), and the obtained solid was transferred to a furnace L7 and crystallized from water. Ru-4-(N-methylsulfonamide) (2,07
f) was obtained as pale yellow blade-like crystals.

Melting point 260-263°C (decomposed). Elemental analysis' C23,
1, H2, 87, N27.4.5154%, calculated value: C
23.3, N2.93, N272.815.55%.

(n) 5-nitroimidazole-4-(N-methylsulfonamide) (1,Of) in dry ethanol (
The solution in 100 ml was treated with Raney nickel catalyst for 24 hours.
Hydrogenation was carried out at °C and 3 atm. The mixture was then filtered and immediately diluted with diethyl ether (200 mg).
Then it was treated with dry hydrogen chloride gas until it became somewhat dissolute. The mixture was then evaporated in vacuo below 30°C.

The residual solid was dissolved in a minimum volume of hot ethanol and the solution was treated with charcoal, filtered, and diluted with diethyl ether. The obtained solid was separated into 5-amizimidazole-4-(N-methylsulfonamide) hydrochloride (0,6
5? ) was obtained. Melting point 178-180°C (decomposed). Elemental analysis: C22,3, H4,13, N 25.5.0716
Calculated value of 9%, C4HaN40213-HCI: c2
2.6, H4, 26, N 26.35, CL 16.7
%n(lH"l) A stirred solution of sodium nitrite (0,2851) in water (4tne) cooled in an ice bath was
-aminoimit)I-ru 4-(N-methylsulfonamide) hydrochloride (0,557) in dilute hydrochloric acid (2N, 2
．． 8 mg) solution. The resulting solid was separated and washed with ice-cold water to give 5-cyasoimidazole-
4-(N-methylsulfonamide) (0,367) was obtained. Melting point 150℃ (decomposition) 01 elemental analysis: C25,2
, N2.47, N37. []%, calculated value: C25,7
, H2,69, N37.4%, Engineering R2210 Rust-1° aqueous solution was extracted with ethyl acetate at 0°C, the extract was dried over magnesium sulfate and vacuum dried to further extract -rlX (0 , 071) was obtained.

Reference Example 8 A solution of sodium nitrate A (0,59) in water (5 mg) was maintained at 0°C to prepare 5-amino-4-methylsulfonylimitasol salt 6kfn [1, Oy, rJ.

Am, Cbem, Soc, J Vol. 79(3) No. 21
88-2191 (1957)] dilute salt [11'+ (2N, 5 m/ml) was added dropwise to the solution. The solution was stirred for 15 minutes and then diluted with ethyl acetate. (5X 20 ml!). The combined extracts were dried over sodium sulfate and evaporated in vacuo, leaving a yellow oil that crystallized upon collapse, leaving 5-diazo-4-methylsulfonylimidazole (0 ,745') to (4
) fc, melting point 128-130°C. IH2125c
In-1° Reference Example 9 (1) A stirred solution of p-methoxybenzylamine (10r) in water (30mA) was mixed with 5-nitro-imidazole-4-sulfonyl chloride (68t of wet product 'B,
rCan, J, Che+n, -1m Volume 39 No. 5
6.02 of 5-nitroimidazole-4-thiol ammonium 1 (prepared at a boiling point) according to the method described on page 01. The mixture "soon hardens," then it is treated with an impropat tool (20 m/liter), placed in a J umbrella frame, and left overnight.
It was then dissolved in water (150 ml) and carefully treated with dilute hydrochloric acid (2N) until the ff+lj 71'lj Nke2 was just pH 2.

The resulting yellow solid was separated and washed with a few drops of ice-cold water to yield 5-nidroimiguzole-4-[1,J-(4-methoxybenzyl)sulfonamide] (7,429). . Melting point 269-270°C (min M).

(11) 5-nitroimidazole-4-4N-('
4-methoxybenzyl)sulfonamide:](1,07
) in dry ethanol (100 η+/) was hydrogenated over Raney nickel catalyst (50%) at 3 atm for 6 h. The catalyst was quickly removed with b4 using diatomaceous earth, and its v
Immediately treat solution J with concentrated hydrochloric acid (20 mg)311! T, ta. The mixture was evaporated to dryness and the resulting mixture was
It was triturated with rf'i powder and diethyl ether.

111 bodies were taken door to door, washed with diethyl needle,
-aminoimidazole-4-CN-(4-methoxybenzyl)sulfonamide) (0,25F) was obtained. Melting point 1
54-155°C.

(iii) il+i (ii? F?i (0,1
42) Bath liquid in water (5me) 11i1 degree 00
While holding the thread 1rj, 5-aminoimidazole-4-
(Door (4-methoxybenzyl), 1./l,
;j-, 7 amide (0,5r) diluted hydrochloric acid (2N, 10r
nL! ) inside 71! Dropwise treatment was performed with R liquid. The mixture was stirred for an additional 15 minutes at 0°C, then the solids were separated and
Wash with water and use pentoxide 3i'i! After drying, 5-diazoimidazole-4-[N-(4-methoxybenzyl)sulfonamide] (0,3f) was obtained. Melting point 144-1
46°C (decomposition). 1. I (2180cm-”.

Reference Example 10 (1) A bath solution of piperidine (6,4rnl) in dry tetrahydrofuran (92mg) was diluted with 1,6-sinitrodiimidazo[1,5-a:1',5'-d]bimerazine-5.10- dione (4,55M', prepared as described in Reference Example 1) and stirred for 1 hour at room temperature. The mixture was then evaporated and the residue dissolved in dilute hydrochloric acid (2N, 92yf). Extract the # solution with ethyl acetate (5 x 200 ml), combine the extracts, and ht
c dried over magnesium and evaporated. l'
A kl product 4: A mixture of chloroform and methanol (9:
1 v/v). Both appropriate fractions were evaporated and the remaining 11 products were washed with diethyl ether and then with acetic acid to give 4-nitro-5-bilysinocarponylimidazole (2,72y) as a yellow solid. .

Melting point 149-150 Co elemental analysis: C48,2, H5
36, N 25.1%, 1 calculation value: C48.2, H5
, 39, N 25.0%.

(11) 4-=)Rho-5-biveridinocarbonylimiguzole (2,68, prepared as described above) in methanol (27me) and dimethylformamide (27m)
The bath liquid therein was treated with platinum oxide (0,27r) and the agitated mixture was hydrogenated at room temperature and atmospheric pressure. After hydrogen absorption was completed, the mixture was poured out and the P liquid was evaporated in vacuo. Dissolve the residue in dilute hydrochloric acid (2N, 50m/liter,
The solution was filtered through /Fi and the added liquid was evaporated in vacuo. The resulting residue was washed with acetone to obtain 4-amino-5-piperidinocarbonylimidazole salt (2,1f) as a pale green solid. Melting point 175 to 177C was obtained with sufficient purity to be used in the next step.

Reference Example 11 (+) A stirred solution of 2-cyanoethylbenzene (5, of) and benzyl mercaptan (8, or) in dry dioxane (90 wrl) was treated with a trench saturated with hydrogen chloride gas (3 hours) and It was left in room 'lL'+ for 50 minutes. The mixture was then treated with diethyl ether/L, and the precipitate was filtered and washed with diethyl ether and S-benzyl 6-phenylbrobionothioimidate salt (9,79 ) was mixed with a colored solid at -3, ill! point at 158-160°C.

(II) A solution of α-amino-α-cyanoacetamide (shoulder) in ethyl alcohol (20 ni) was prepared using S
-benzy-3-phenylprobionotioimidate hydrochloride (9,7r, prepared as described above) and the mixture was heated to reflux power 1↑ for 15 minutes. The mixture was cooled, and the obtained solid was purified in a furnace and crystallized from methanol to obtain 5-amino-2-phenethylimidazole-4-carboxamide hydrochloride (2,3f) as colorless crystals. Melting point 270-274°C. Elemental analysis: C5
3,8, H5,55, N21.1%, C12I114N
Calculated value of 40.HCl: 054.0, )] 5.67,
N21.0%.

Reference example 12 Nitrous acid (0,52) water maintained at 0-5℃ (15s
nt) solution in 5-amino-2-benzyl-4-carbamoylimidazole (1,21').

West Germany t+! fFF No. 2,358,509) in a bath solution of dilute hydrochloric acid (2N, 1511/). The mixture was stirred for a further 30 minutes at 0°C and the resulting pale yellow solid was separated, washed with water and dried over phosphorus pentoxide in a tumbler to produce 2-benzyl-5-diazoimidazole-4-carboxamide. (
0.8f'). Melting point 121-122°C (decomposed).

IR2180cm-1° Reference Example 15 (1) A solution of imbutyronitrile (6.9t) and benzyl mercaptan (20rn1.) in dry dioxane (100m/) was heated with dry hydrogen chloride gas to
'C for 3 hours. The mixture was then heated to room temperature, the entire screen was closed, and the mixture was left at room temperature for 14 days. Next, add the mixture of 7 to diethyl ether (1t)
The white precipitate was filtered out and washed with diethyl ether to give S-pendylisobutylthioimy.
'-) Salt t'it2 JM (20,31) was obtained. Melting point 165-166℃-8 elemental analysis: C57,1, H7
,0,N 5.9,C1,15,-7,L]13.9chi,C11HI 5NIE-HCl h1 calculated value: C57
,51,H7,IJ2,N 6.1,C1,15,45
, S 13.96 yen.

1) α-amino-α-cyanoacetamide (51)
Q and S-benzylisobutylthioimidate hydrochloride (1t5t, prepared as described above) in dry 2-ethoxyethanol (150tn/liter for 3.0 minutes 11jl Et
& heated. The solvent was evaporated. The resulting dark oil was dissolved in a mixture of chloroform and methanol (4:1 v/v
% 10 ay) and filtered off insoluble material. The P solution was subjected to medium pressure chromatography on silica gel, eluting with a mixture of chloroform and methanol (421 v/h).

The appropriate A fractions (identified by spraying on ninhydrin f-1,1 sol giving a strong yellowish brown color) were combined and evaporated to give 5-amino-2-isopropylimidazole-4-carboxamide hydrochloride. (4,4,1) was obtained as a gummy solid of sufficient purity to be used in the next step.

(ill) was maintained at 0°C. B Sodium nitrate (
A solution of crude 5-amino-2-isopropylimidazole-4-carboxamide hydrochloride (1,1f, prepared as described above) in water (5rrrl) in aqueous vinegar M
(2N, 20tne) dropwise! I!
It was t7. The mixture was then incubated with O'C for an additional 5 minutes and then extracted with ethyl acetate (3 x 20 rae).
7′? Combine 'o extract and magnesilla sulfate!・Smoke dry on the top, concentrate in vacuo to a volume of 20 mL, and then apply medium pressure chromatography on silica gel, eluting with ethyl acetate, to remove the appropriate fractions (2-naphtho-, giving a deep red color).
5-diazo-2-isopropylimidazole-4-carboxamide (0,4sl) was obtained by evaporating to dryness.
0°C (decomposition). XR2170cm-1° Reference Example 14 (I) 2-Methyl-5-nitroimidazole (127r
) water 441 hydrated sodium bath solution (5% w/v, 1
The cooling agent solution in 500ml) was diluted with bromine (16Or) to
The treatment was carried out while maintaining the JiA degree at 15 to 20°C.

The mixture was stirred at room temperature for 5.5 hours and the precipitated solid was dissolved in aqueous hydroxide solution (2N
) was redissolved by treatment.

A sample of the silent material was separated into P, and the P solution was made acidic to pH 1 by treating it with concentrated hydrochloric acid. The obtained white solid was separated, recrystallized from ethanol, and dried over phosphorous oxide in a desiccator to obtain 4-bromo-2-methyl-5-nitroimidazole (151f) as a white crystalline solid. Ta. Melting point 267-268°C.

(11) A stirred solution of 4-bromo-2-methyl-5-nitroimidazole (20.6r, prepared as described above) in an aqueous ammonia bath (5N, 180 m7) was heated at 45 °C.
and treated with a steady flow of hydrogen sulfide gas for 40 minutes. A yellow crystalline solid gradually formed. The mixture was cooled on ice and the solid was separated from P, washed with ice water, dried over phosphorus silicide in a desiccator, and the solid was separated from 4-mercapto-2-
Methyl-5-nitroimidazole ammonium Jm (1
4,6y) was obtained.

It becomes 111-color without melting at 3000 or less.

Elemental analysis: C272, H4,41, N 316.81
8.2%, calculated value for C4H402N3 Nuko4: C
27,27, H4,5B, N31.8.818.2%
.

(Il+) An ice-cooled, vigorously stirred solution of 4-merkat-2-methyl-5-nitroimidazole ammonium salt (prepared as described above) in dilute hydrochloric acid (IN, 120n+7) was prepared as a white Treated with chlorine gas until a solid was formed, the mixture was stirred at 0 °C for a further 30 min, then the solid was separated, washed with water and dried over phosphorus oxide in a desiccator. Chlorosulfonyl-2-,>'Chyl-5-nitroimidazole (
3, Or)'? 1-Old man J.

Melting point 160-162°C (decomposed). Elemental analysis: C20,
8,) 11.73, N 1B, 3, cl 15.7, S
14.6%, calculated value: C21,29, H1,79, N
18.63, C115,72, S 14.21%.

(lv) 4-7 toxybenzylamine (5,48?
) in dry absolute ethanol (20me).
-10rosulfonyl-2-/thiru-5-nitroimidazole (2,25F, prepared as described above) and the mixture was incubated at room temperature for 3 hours. The precipitated yellow solid was separated from P, diluted with ethanol, and removed as 4-methoxybenzylamine hydrochloride. The P solution and the washing solution were combined and evaporated to dryness, and the resulting residue was diluted with water (5
0 gt): '3', make the ship pr11's flip by treating with hydrochloric acid, and vinegar f'
Extracted with ilk ethyl (3 x 20rnl). The combined extracts were dried over magnesium chain acid and evaporated to dryness to give 4-(4-methoxybenzylsulfamoyl)-2
-Methyl-5-nitroimidazole (2,77i obtained as an off-white solid, melting point 167-170°C1, elemental analysis 2C44,2)] 4.32, N112.89.5
Article, calculated value: C44, 17, H432, N 17.
17, ε+9.8. 'S%.

(v) 4-(4-methoxybenzylsulfamoyl)-
2-) f-5-nitroimidazole (4,5r, et al.
Made as instructed; '+'! ) of dry ethanol (12
0ml) using a Raney-Tskel catalyst.
Hydrogen was added at 6 atmospheres per minute. The catalyst was stripped off, washed with dry ethanol (IClthe), and tptL
and the washings were combined, acidified to pH 1 by treatment with concentrated hydrochloric acid, and evaporated to dryness. The resulting residue was triturated with diethyl ether to give 5-amino-4-(4-methoxybenzylsulfamoyl). -2-methyl rmidazole hydrochloride (3,2
I agree with 5f).

Melting point: 186-185°C.

(vl) 5-amino-
h:'j with a solution of 4-(4-methoxybenzylsulfamoyl)-2-methylimidazole hydrochloride (1, prepared as described above) in dilute hydrochloric acid (2N, 10 m/). The mixture was stirred for a further 5 minutes at 0-5°C and an orange solid formed, filtered off, washed with water and dried over phosphorus in a desiccator to give 5-diazo-4-(4
-methoxybenzylsulfamoyl)-2-methyl-imidazole (0.75 g) was obtained. Melting point: 140°C (decomposed). TR2200cm-'.

Reference example 15 (1) Ethanolic solution of dimethylamine (33%
w/v −, 10+IIe) k, treated with 4-chlorosulfonyl-2-methyl-5-nitroimidazole (2,25r, prepared as described in Reference Example 14) in small portions, and cooled to room temperature. The mixture was stirred for an additional 45 minutes. Add the solution to a concentrated salt drinker! p) T1 is acidic,
Then, the obtained white solid FTRJ was separated and washed with ice water.
-Dinotylsulfamoyl-2-methyl-5-nitroimidazole (1,9") was injected. IAjl 1 point 24 [
1-241]. Elemental analysis: C3r], 5, TI4.
24, N 23.8, 813.8 lira, =1
Tain, auto i-1: C3r1.77, H4
, 3, N 23.92, IE 1369%. Nλ4R(
]:++Jr(O-d6 Nakato 2.30 and 2.80
Single line in ppm.

(+1) A solution of 4-dimethylsulfa7yl-2-methyl-5-nitroimidazole (12 V, prepared as described above) in dry ethanol (511 [] tJ) was reacted with a Raney nickel catalyst at 35 atm. Hydrogenated for hours. The catalyst was removed, and at L7, the F solution was made acidic to pH 1 by treating VC with concentrated hydrochloric acid and evaporated to dryness. Triturate with diethyl ether to give 5-amino-4-
Dimethylsulfamoyl-2-methylimidazole (8
．． 5M') was obtained. Melting point 215-217°C (decomposition).

(III) A solution of 711i sodium nitrate (1.Of) in water (15me) was maintained at 0°C and 5-amino-4-dimethylsulfamoyl-2-methylimidazole<2.49) in dilute hydrochloric acid (2 N% 30 m
lJ) Medium (1) in solution? 1. ! The mixture was treated with J and stirred for an additional 10 minutes at 0°C. The mixture was extracted with ethyl acetate (5×30−) and the combined extracts were dried over magnesium sulfate and evaporated to dryness [:JrI].
, triturated with petroleum ether (boiling point 6o~80℃) to give 5-
Diazo-4-dimethylsulfamoyl-2-methylimidazole (1.8r) was obtained. Melting point 85-87°C (decomposed). Engineering R 2 1 8 [] tyy=-1.

Reference example 16 (1) 4-mercapto-2-methyl-5-nidroimiguzol ammonium salt (1 0.5
Methanolic sodium methoxide solution [sodium (2.3f)
(prepared by carefully dissolving 250 Tn/') in dry methanol (250 Tn/') was treated with methyl iodide (10.71/') and heated for 2 hours at R tilt. Heated. The mixture is then evaporated to dryness and residual Jl! 4r was suspended in aqueous sodium hydroxide solution (2N, 1[]Ord).

The suspension was filtered and the suspension was treated with concentrated hydrochloric acid to give 2-methyl-4-methylthio-5
-2l-leumitasol (9.Of) was obtained as a yellow solid. Melting point 236-237C (decomposed).

Elemental analysis: C 34.7, H 4.04, ? -1 2
4.3, 8185%, total τ1 value j C 34.67, H
4.07, N 211.26, ++ 18.51%.

(11) 2-Methyl-4-methlunaor-5-nitroimidazole (3.46r, Mjl 11. [Sea urchin pieces, sojri 2) T-liquid in wood vinegar H (35 mlJ) 6 11 1: Heat in an aqueous perhydrogen bath (30% W, /'V, 35+++/)
Preparation/3, then 711'. i'p/+ 4
(Heat for 10 Q°C -/- for 15 minutes, cool to mold temperature 1, and remove excess hydrogen peroxide (detected by testing the sample with starch and potassium iodide). Sufficient sodium was added to the +, '+' at 1°C.The mixture was then subjected to continuous liquid-liquid extraction VC with 11N vinegar and chilled for 20 hours.The extract was evaporated. and the remaining white solid was dissolved in petroleum ether (boiling point 60-8
2-methyl-4-methylsulfonyl-5-nitroimidazole (3,6t
) was 4t. Melting point: 222-224°C. Elemental analysis: C
' 29.8, H5, 28, N 2n, 6, S 15.
7chi, calculated value: C2927, H3,44, N 20.
4 (3,815,63%.

(ll+) 2-Methyl-4-methylsulfonyl-5-nitroimidazole (4,9t, fji (prepared as described above), solution M in dry ethanol (40Dnle) was prepared using a Raney nickel catalyst at 345 atm for 30 Water was added for 5 minutes, the lc0 catalyst was removed, the F solution was made acidic to pH 1 by treatment with concentrated hydrochloric acid, evaporated to dryness, and the resulting residue was diluted with diethyl ether containing a little ethanol. The purple solid obtained by trituration was separated by furnace, washed with diethyl ether, and 5-amino-2-methyl-4-methylsulfonylimidazole hydrochloride (4,1?) was added to +1+
is. Melting point 300'CJO), above. Elemental analysis: C273
, H4,51, N 199, C1,17,9, 813
,7%, cut 1ν'4411j, : C2B
, 37, H4, 76, N 19.8, CI 16.7
5.815.15%.

(lv) Sodium nitrite (0,25
A solution of
, 55 t, was treated dropwise with a solution of &1. The mixture was stirred for a further 15 minutes at 0°C and extracted with ethyl acetate (5 x 15ml). The extracts were combined and
Dry over magnesium sulphate and evaporate to dryness. The resulting oil was triturated with petroleum ether (boiling point 60-80°C) to yield 5-diazo-2-if-4-methylsnotofonylimitasol ([1,49). Melting point: 100°C (decomposition). Engineering R21,85on-1 Reference Example 17 (1) α-cyano-N,N-dimethylacetamide (
8,2? , rJ, Chem, Soc, J 195
4th year 1171- to -1 as H6 on 5Jb rock),
A mixture of anhydrous carbon dioxide (21 ml) and ortho-Mrt, z-triethyl (21 ml) was heated to 160-170°C for 90 minutes in a flask fitted with a Mc tire head. , while 26
- ethyl acetate distillate was collected. The one-tone oil obtained by vacuum milling the reaction mixture was treated with ethanol (jDml) and corded again. The residue is 160-170
°C 10.51 nmHg'''c distillation followed by medium pressure chromatography on silica gel eluting with ethyl acetate to give 2-cyano-3-ethoxy-N,N-dimethylzolobenamide (5,3f)-i Obtained as an off-white oily solid of sufficient purity to be used in the next step.

(11) Crude 2-cyano-3-ethogycin N,N-dimethyl lactamide (5,5 t, prepared as described above)
A solution of (7)*hydrazine hydrate (1,58f) in dry ethanol (50ml) was treated dropwise.

After the addition was complete, the mixture was heated for 6 hours and then evaporated to dryness. The residue was subjected to medium pressure chromatography on silica gel, eluting with a mixture of chloroform and methanol (17:3 v/v). Then, appropriate two portions were combined and evaporated to dryness.The resulting residue was dissolved in hot isopropanol (5g) and added with concentrated hydrochloric acid (4ml).
) and collect the resulting crystalline precipitate.
-Aminopyrazole-4-(N,N-dimethylcarboxamide) hydrochloride was obtained as colorless crystals. fusion A',”
, 195℃0 elemental analysis: C37,8, H5,82,
N 29.0, CL 1B, 3%, calculated value: C37,
8, H5,82, N 29.39, CtlB, 6%.

Engineering R (KBr disk): 3500.3400,!
1000-42200.1655 cm −'. N.M.
R (in DMSO-d6), i 5.0 and 8.1
single line at ppm and wide single line at 7.2 ppm.

A saturated solution of (+11) dry hydrogen chloride in dry methanol (70d) was treated with 3-aminopyrazole-4-(N,N-dimethylcarboxamide) hydrochloride (1,39?, prepared as described above). The stirred mixture was cooled to OC and amyl nitrite (2,5
5f) for 15 minutes at 311 liters under force 4. The resulting solution was allowed to stand at 2-4°C for 1 hour and then poured into diethyl needles (800 ni). The resulting solid was collected, washed with diethyl ether, and filtered to give diazopyrazole-4-(
N,N-dimethylcarboxamide) hydrochloride (0,92t
) was obtained as colorless crystals. Melting point: 150°C (explosive).

Elemental analysis 2C35.3, H filter, 79, N 34.3%,
Estimated value of C6H7ON5C1/HCL: C35,74
, H4,00, N 34.74%. Engineering R (KBr disc): 3000-2100.2280.1650cm
-1° The present invention encompasses pharmaceutical compositions comprising at least one compound of the general formula as an active ingredient, together with a pharmaceutical carrier or coating. In clinical practice, compounds of the above general formula will normally be administered orally, rectally, parenterally, such as intraperitoneally or intravenously (eg, by injection), or intravaginally.

One method of providing a pharmaceutically active compound is well known in the art, and the appropriate vehicle depends on factors such as the desired effect, the patient's size, age, sex and condition, and the active compound. It may be decided by a doctor or pharmacist depending on the nature of the condition. The composition may also contain substances such as solid or liquid diluents, wetting agents, preservatives, flavoring agents, and coloring agents, as is commonly practiced in the art.
May contain.

[Summary 1] Solid compositions for administration include compressed tablets, tablets, dispersible powders and granules. In solid compositions, one or more of the active compounds are mixed with at least one inert diluent such as calcium carbonate, potato starch, alginate or lactose. The compositions may also contain additional substances other than inert diluents, such as lubricants such as magnesium stearin, as is customary. The liquid composition for oral administration is made of inert 1"E which is commonly used in the field of JK surgery.
8 Diluent Example V: 1. Kinuta that does not contain water and bIC dynamic paraffin! □J'+r1b L milk washing liquid, bath 1
In addition to inert diluents, such compositions also contain adjuvants such as wetting agents, suspensions, liquids, and elixirs. Polyvinylpyrrolidone, and may contain 1r taste, flavor, aroma and preservatives, etc. ImJ&!lv of the present Komei for oral administration.
The present invention includes absorbent articles, such as capsules of gelatin, which contain one or more active substances with or without diluents or excipients.

Solid compositions for vaginal administration are formulated according to methods known per se, and contain more than one active compound.

Solid composition for rectal administration 11. NananoL itself is formulated according to known methods and thus contains a herbal medicine containing 181 or more active compounds.

Preparations for parenteral administration are sterile aqueous or non-aqueous solutions, friable i 1f1. Contains J-line or emulsion. Non-aqueous solvents or suspending media include, for example, polyethylene glycol, dimethyl sulfoxide, sakaki oil such as olive oil, injectable organic esters such as ethyl oleate, and the like. These compounds may contain auxiliary agents such as preservatives, wet hooking agents, emulsifiers and dispersants.

They may be sterilized, such as by filtration through a bacteria-retaining filter, by incorporating a sterilizing agent into the composition, or by irradiation. They may also be prepared in sterile water or other sterile injectable compositions immediately prior to use.

Although the percentages of active ingredients in the compositions of the invention may vary, it is essential that the proportions of active ingredients be such that a suitable route of administration is achieved for the desired therapeutic effect. It is also true that the 16 unit dosage forms may be administered at about the same time.

In general, formulations for administration by injection, including administration by injection, should normally contain at least 0.025 active substances, and for oral administration, formulations should usually contain It will contain at least 0.1 weight + ii' of active substances. The route of administration used depends on the desired therapeutic effect, the viscosity of administration, route and duration of treatment.

-C Tetrazine derivatives of formula I are generally [0.
1-200 m9/9 weight, preferably 1-20 m
With the administration of g/Ky body control, the odor "C malignant:" (Jr biological example is useful in the treatment of carcinoma melanoma, sarcoma, lymphoid IFIi and leukemia, etc.).

The following composition examples illustrate typical compositions of the present invention.

Composition Example 1 The following ingredients: Tetrazin-4-one dimethylsulfoxy l-" 10
ml to 8-(N-benzyl-N-phenylcarmoyl)-3-methyl-[6H]-imidaso'[5.1-d]
A solution suitable for parenteral administration was prepared by dissolving L2+''p5-tetrazin-4-one in dimethyl sulfoxide. They were dispensed into ampoules and sealed, each containing 100 staves of 8-(
N-Pendit-N-phenylcarbamoyl)-6-methyl-[ 3H]-imidazo[5.1-d:] − ]
Ampoule 1 containing 1.2,3.5-tetrazine-4one
Obtained 0 pieces.

Similar ampoules containing solutions suitable for parenteral administration are
(N-pencyl-11-phenylene/)Jru/comoyl-6-methyl-[3H]-imidaso r5,1-cl)
- Replacement of 1,2,3,5-tetrazin-4-'one by other compounds of the above general formula may be prepared by treatment in various ways.

Composition Example 2 The following ingredients: dimethyl sulfoxide 10 tn
l Peanut oil 90- to 6-(2-chloroethyl)-8-(N-methylsulfamoyl)-[3H]-imitaiso[5,1-d]
- A solution suitable for parenteral administration was prepared by dissolving 1,2,3,5-tetrazin-4-one in dimethyl sulfoxide and adding 7 hems of groundnut. The resulting solution was dispensed into ampoules under aseptic conditions so that each ampoule had a concentration of 10 -. Seal the ampoules and add 100j+9 of 5-(2-chloroethyl)-8-
(N-methylsulfamoyl)-r3H)-imidazo[
Ten ampoules containing 5,1-d)-1,2,3,5-tetrazin-4-one were obtained.

A similar ampoule containing a solution suitable for parenteral administration was prepared using 3-(
2-chloroethyl)-8-(N-methylsulfamoyl)-1jH)-imidazo[5,1-dl-1,2,3
, 5-tetrazin-4-one may be replaced with another compound of the above general formula, but may be prepared by processing in a similar manner.

Composition Example 6 5-(2-chloroethyl)-8-(N-methylsulfamoyl)-[! tH)-imidazo[5,1-a)-1,
Capsules suitable for oral administration were prepared by encapsulating 2,3,5-tetrazin-4-one at a rate of 10r per capsule in S2 size seratin shells.

Similar capsules may be prepared using other compounds of the above general formula or using any other suitable or sized capsule shell.

For patents 1≦11 people Changed to May & Payker Limited Patent attorney Haku Yamashita.

Continuation of page 1 Priority claim @ August 17, 1982 United Kingdom (
GB) ■8223583 ■) During September 14, 1982) United Kingdom (GB) ■82
26169 (91 March 14, 1983 (attack on the United Kingdom (GB))
8306904 @Inventor Christopher Gregory Newton 17 Sunningdale Road, Chelmsford, Sex, King of the United Kingdom 9 Inventor Brian Leslie Pedgrift 9 Marylands Way, Harold Park, Romford, Sex, King of the United Kingdom 0 Inventor: Christopher Smith 20/5, Eversley Road, Penfleet, Essex, United Kingdom Inventor: Colin Geoffrey St., United Kingdom 16/9 Ravenscourt Drive, Hornchurch, Essex, United Kingdom Inventor: Roger Lyon Eytschison Walsh, King of England, Illie Zapadox 38 9 Inventor Peter James Warren, King of England, Irie Ixandria Drive

Claims (1)

[Claims] 1) General formula I a substituted or branched alkyl, alkenyl or alkynyl group (wherein the alkyl, alkenyl or alkynyl group is unmodified or contains a hydrogen atom, up to 4 carbon atoms -t/ , 1 to 6 1s selected from the group consisting of alkoxy, argyldio, alkylsulfinyl and alkylsulfonyl groups, and optionally substituted phenyl groups.
iY! 16 substituents), and A1 is a hydrogen atom or group -CR6=r, where R5 is a hydrogen atom and a spanning substituent R4 (where R4 is a halogen atom). or a halogen atom, a phenyl group having up to 6 carbon atoms, which may be substituted by 18 groups, a barbed chain or a branched alkoxy group containing up to 3 carbon atoms; is a straight-chain or branched alkyl- or alkenyl group which may contain 6 substituents selected from the group consisting of alkylthio and argylsulfonyl groups, or R4 is a straight-chain or branched alkyl- or alkenyl group of 6 to 8 carbon atoms; A cycloalkyl group containing atoms, cyano, hydroquine, dil-, phenoxy group, which may be substituted by anastomosis (.), or a phenoxy group of the formula -COR5 (wherein R5 is an alkyl or alkoxy group having up to 4 carbon atoms, a hydroxyl group or an optionally p-substituted phenyl group - or a group having up to 6 carbon atoms
Alkanoylamino group with rd child -ch Ruka, or R4><, -F:(+')nR6, -802
1 R7R8- or -czzsql<7RB (where 11 &J' El, 1' or 2, 1 (6 contains up to 4 glues, "V, 11p and is replaced by the platform t+ The 11-branched alkyl group with the phenyl ta substituent which may be -11≦:+'+-11 is the alkenyl 211 (, cycloalkylnod with 6 to 8 carbon atoms k3-; An optionally substituted phenyl group, R7 and II'' are the same or different, each is a hydrogen atom, or L7 contains 4 carbon atoms and optionally Is it a branched or branched alkyl or alkenyl group which may have a good phenyl substituent, or is a cycloalkyl group having 13' of 6 to 8 carbon atoms? or a phenyl group which may optionally be substituted, or the group -NR7R, a is a heterocyclic group and Zl is an oxygen or sulfur atom). ] and A2 is a nitrogen atom, or A1 is nitrogen 1!', and if 'A' is present in the j child, A2 is a nitrogen atom' or a group -CR5= (here, R5 is 9 as defined above). ), Zl is oxygen or %'+e yellow atom, and R2 has the formula -8(0)0.R6, -8O
2NR7R", -C8NR7R8, -C8NR7R8 or 1022NHNO2 (where η, R6,
R7, R8 and Zl are as defined above and the group -NR'R9 represents a heterocyclic group or ox/C is R
7 is as defined above and R9 is a straight-chain or branched alkyl or alkenyl group containing up to 4 carbon atoms, optionally with one phenyl substituent; is an optionally substituted phenyl group), or -4
fc is A1 is a fiber atom or a group -CH32 (here R4
(as defined above) and zl and A
2 is as defined above, or A1 is a group -cH
= and zl is a yellow atom tp)t) and A
If 2 is 9 through the above fixed emblem, then ](l is the formula-8
(0) nR6, -r, s O2FI R' ■(aM
-CZ2NR' R8-f fc is cz2sqHNo2
(wherein these formulas are: n, f (6,1, H+j and z2 are as defined above)), and R2 and/or R5 are sulfamoyl or 1. When R6 is a monosubstituted sulfamoyl group and/or R6 is a carboxy group, salts thereof. 2) R1 is not defined in the first paragraph of the jlIi2 box of the patent claim: L. Ride. Chiri) (2 is deception-6) - pc,
r 2 rooms Itomariko' 2 and 4 'CO corpse first atoms 4 animals i 4
1 (1al-i or 2) selected from the group consisting of branched alkyl and alkenyl groups, and cycloalkyl groups containing 5 to 8 carbon atoms;
), 1- is an optionally substituted carbamoyl group, and AI is a group -CR4= (where R4 is a halogen atom and optionally a phenyl group optionally substituted with 6) is an Mf chain or a branched alkyl or alkenyl group containing 6 to 6 carbon atoms, or R4 contains 3 to 8 carbon atoms; is cycloargyl)
p, l are nitrogen atoms, and Zl is i! The tetrazine derivative according to claim 1, which is an I2 elementary atom. 3] R1 is before + + d 'l'l'i'Ful'l search anchor 1st) JJ K 'ji As you rightly say 4
-)su, 1(2 is λ(-8(su),,lma/koO''-8
02NB71(' (Here, n is o, 1° and t is 2-
(!Ali, R6 is a branched atom in the straight chain 1 containing a carbon atom in +11 1. Al or an alkenyl group, a cycloalkyl group I containing 6 to 8 atoms and 1 carbon atom (, -fl is a phenyl group optionally substituted by 1, R7 and R8 is an iα-chain sweetener containing a charcoal-7 at 411. is a branched alkyl or alkenyl group, but is a cyclo-1'rukyl group containing - or 3 to 8 carbons, J, q 14; ξ Even if you are J, you can still reach 71 nil).
4j〕'), A is rsJL:, must be Umiko, and zl is oxygen Ha; L child nil 1, "f exposed n1j
The first song in the range of search if: 'if evening's Detrazine Nishiki Totai. 4) When R1 is πl'ifi'j, the range [fl(defined in the first term) is 6J, R2 is 6J,
o) nR6, -8O21'JR7R8
2, 16 is 4 carbons 11 which may optionally have a jiff 4'A soenyl jLL group; 4. straight or branched alkyl or alkenyl radicals containing 3 to 8 carbon atoms, dichlorofurgyl radicals containing 3 to 8 carbon atoms, optionally fi'J 4i
It is a phenyl group which may be substituted with phenyl group, ]:(7:1.
- and R8 are 1. -d- "or different, respectively, water" fii: the atom is a phenyl u substituent (L has 9 4 (IMj
The carbon atom at 1 is a chain or branched alkyl or alkenyl group, or a cycloalkyl group containing 3 to 8 carbon atoms, or a cycloalkyl group containing 3 to 8 carbon atoms, or
"・shiai v(: f6: JiA! is a group that makes 1 (also a good phenyl), and A1 is the chamber "J
f=Eko deshi, A2 is the group -Q'[%5-(here R''
is a child of hydrogen C) or TJIJ ML 'l'
Claim 18J is the substituent 1 (which is 4) as defined in Claim 1, and zl is an oxygen atom or a sulfur atom. Tetrazine derivative of fire. 5) T (1 is as defined in Section 281 of the Patent Request), and 112 is on the nitrogenous atom (1) optionally substituted phenyl group and optionally substituted 1a; two groups separated from the phenylalkyl group, which may be substituted by ``7,1'', optionally substituted by ``7,1'' or ``ft'', optionally substituted by -(- Good phenylargyl group, -
j: fc k, L (III) In the case of 1 piece, υ1
Hue January Pamas FC & 1JJ
J Even if substituted by combination, u11 containing "diiso L, nyl(γ-alkyl group and 1-4 carbon atom)-"
Carpamo having a branched alkyl group [Luno,
! shi, A-1-ybl J, l, =CH-te, A2 ka'4 element j Kyoko, and 21 is ti): 4t
+Tetrazine derivatives according to claim 1 by Prince Oji 1) 6) The optional fh substituents on the phenyl and phenoxy groups are halogen atoms, alkyl and alkoxy containing up to 4 carbon atoms Claims IJJi Nos. 1 to 5 selected from the group consisting of
4 tetrazine derivatives of any of the above. 7) Cyclo) L-gyl group is Schiff0hegysyl, the above l
G5. Any one of the ranges 1 to 68'j for permission BL°f tslr Ij・V's tetrazine nN', □j
0 bodies. 8) In the form of a plucked monkey, ノ, 1 may optionally be ', S'; 1 (t? 4- or 2 j/1 buttons or 0-branched alkyl 1 t) containing carbon atoms, 5 no, 60' or 7
141'), which is an elliptic group of shellfish. 9) R1 is methyl or 2- is a haloethyl group, (it) R2 is of the formula -8OR6, -E'+02'l
t6, -fi(:)2NR7R8, -CONR7R8 changed Q go C'04IHJ-1+)2 (here R6, R
7 and 1<" ki −+'++i n is a group with ``ki −+'++i n'' (as defined in the 51st term of the ``Kumami box'') υ, (ill) of A I and A2. one is a nitrogen atom and the other is a group -CRa- (wherein R6 is as defined in claim 1 above); (iv) R5 is) l:' j radical R4 (where 1('
Its: 6 $1-f IA is an argyl group with one hydrogen atom), M A2 is a nitrogen atom, (vl) zl is an oxygen atom, and /゛ or υ1llz2 is an oxygen atom Said to have one or more of! 1'f bi1-
Of quality! 411 tetrazine molecules listed in α section 1 uC1. 10) The above-mentioned special i-1+ claim wherein R1 is 2-croethylyl [11 (Etc) Tetrazine compound according to item 9., 11) R2 is a group -8OR6, -8o
2R6, -8O2NR7H8, -CONR7R''-f or -CONHI・]02 (where] (6 is an alkyl group containing up to 4 carbon atoms, It is an alkyl group containing a carbon water atom with
An alkyl group having an alkyl group; E or an alkoxy group as the case may be; 9th beat self 71. Q's Tetrazine Poem/+1 child・1・. 12) The detrazine and visceral compounds according to item 9 or item 11, wherein the alkyl group is methyl. 13) 8-carbamoyl-3-(2-chloroethyl)-
6-methyl-[:! IH)-imidazo[5,1-d:1
-1.2,3.5-tetrazin-4-one. 14) 3-(2-chloroethyl)-6-methyl-8-sulfamoyl-[3H)-imidazo[5,1-d:)-
1,2,3,5-tetrazin-4-one. 15) 3-(2-chloroethyl)-8-dimethylsulfamoyl-6-methyl-[3H]-imidazo[5,1-
d) -1,2,! 1.5-tetrazin-4-one. 16) 3-(2-chloroethyl)-H-C dimethylcarbamoyl)-[IH]-pyrazolo[5,1-d)-1,
2,6,5-tetrazin-4-one. 17) 5-(2-chloroethyl)-8-(N,N-
dimethylsulfamoyl)-[3H]-imidazo[5,
1-d]-1,2,3,5-tetrazin-4-one. 1B) 3-(2-chloroethyl)-8-(N-methylsulfamoyl)-4IH)--f midazo[5,1-d)
-1,2,3,5-tetrazin-4-one. 19) 3-(2-chloroethyl)-8-sulfamoyl-[5H]-imidazo[5,1-d]-1,2,3,5
-Tetdin-4-one. 20) 3-(2-chloroethyl)-6-methyl-8-methylsulfonyl-[3H:] -(mitaso[5,1-c
1]-1,2,3,5-tetrazin-4-one. 21) 8-(1(-benzylcarbamoyl-chloro a)
Enal:), -[3 1'l]-Iimidazo5.
1-d]-1.2,5.5-tetrazin-4-one. 22) 3-(2-chloroethyl)-8-methylsulfonyl-[5Ico]-imidazo[5, 1-d:] - 1
．． 2,3.5-tetrazin-4-one. 26) 3-Methyl-8-methylsulfonyl-[3H]-
imidazo r5,1-d]-1,2,3,5-tetrazin-4-one. 24) 3-(2-Chloronyl)-E! , -CN-C
4-Nodoxybenzyl)-sulfamoyl]-[March]
-imidazo[5,1-cl]-1,'/, 5,5-tetrazin-4-one. 25) 8-carbamoyl-6-(2-riI]loethyl)
-[3t(Kobira Zoro (5,1-r Low 1.2,3.
5-tetrazin-4-one 1. 26) 3-(2-chloroethyl)-8-piperidinocarbonyl-[5B]-imidazo[5,1-dJ -1,2
, 3,5-tetrazin-4-one 5゜27) 6-punano+-8-carbamo 1-l-3-(2-chloroethyl)
-[3H)-imidazo[5,1-d') -1,2,3
,5-,5-drazin-4-one 7.28) B-carbamoyl-6-(2-chloroethyl)-6-propyl-[
6H]-imidazo[5,1-d) -1,2,3,5-
Tetrazin-4-one. 29) B-carbamoyl-5-(2-chloroethyl)-
6-Nichiru[51i)-Imidasotomis,t-6]-1
,2,S,5-. 7-1-radin-4-one. 5 [1)! I-(2-chloroethyl)-3-(N-ditropunolbamoyl)-4,5)33-imidazo[5,
1-a)-1,2,5,5-tetrazin-4-one1.
51) 8-(+j-benzyl-11-phenylcatmoyl)-6-methyl-[3H]-imitazo[5.1
-a] - 1.2,5.5-tetrazine-4-mene, B-[ps-benzyl-N-(,4-methoxyindyl)carbamoyl"l-3-(2-/'rolloethyl)-[ 15H]-imidazo[5.1-cl]-1
, 2,3.5-razin-4-one, 6-(2-chloroethyl)-8-[N-(4-medoxybenzyl]-
N-phenylcarbamoyl]-[3H)-imidazo['
5,1-d]-]1.2,3.5-tetrazin-4one, 3-(2-chloroethyl)-8-(N-phenylcarbamoyl)-un]-imidazo[5,1-dJ-1.2
, 3.5-tetrazin-4-one, 8-(?\I-N-phenylcarbamoyl)-3-(2-chloroethyl)-r3n)-imidazo[5,1-61-1
．． 2,3.5-tetrazin-4-one, 3-(2-riΩloethyl)-8-(N-methyl-N-phenylcarbamoyl)-[3H]-imidazo[5.1-
dJ-1.2,3.5-tetrazin-4-one 8-galva. eIru-3-methyl-[3H)-virazoo
[5-1-dJ-1,2j,5-tetrazine-
4-one, 8-carbamoyl-6-(2-chloroethyl)-6-cyclohexyl-[3H]-imidazo[5,l-dJ-
1.2,5.5-tetrazin-4-one, ε3-calhamoinol,-3+-(2-chloroethyl)-6-phenethyl-[OPI]-imidazo[5,1-dJ-1.2,5 .5-tetrazine-4
-one, 6-benzyl-8-carbamoyl-3-(2-
chloroethyl)-[roH]-imidazo5,1-ci
)-1.2,5.5-tetrazin-4-one 8-rubamoyl-3-(2-chloroethyl)-6-inpropyl-[6H]-imidazo(5.1-d2l-1.2
,3.5-tetrazin-4-one 6-(2-roenal)-8-(4-methoxybenzyl)-sulfamoyl-6-methyl-[5r-T)-imidazor5+i
-d]- 1.2,3,,15-tetrazin-4-one, 6-nonal-8-methyltono-1bonyl-[3H]-pyrazolo[5,1-dJ -1,7,,5,5-cutrazine -4-one, 6-(,'2-chloroethyl)-)3-methylsulfonyl-[3H]-virazoLl [5,1-dg] -1,
2,3,5-tetrazin-4-one, 6-(2-chloroethyl)-6-methyl-8-methylsulfonyl r 3■I]--(mitaso[5,1-dJ-
1,7,3,5-tetrazin-4-one, 3-(2-chloroedyl)-E-[tylsulfonyl-6-methyl-r3to-r midazo[5,1-dJ-1,2, 3,5
-tetrazin-4-one and 3-(2-chloroethyl)-6-methyl-8-propylsulfonyl-[61(''
-imidazo[5,1-dl -1,2,3,5-tetrazin-4-one. 32) In the above case, i'1b is the desired range! General formula l shown in song 1 [wherein R2 is sulfamoyl, mono (phenyl which may be replaced with ji, , i by 75 combinations]) carbamoyl; 4y-tj mono (set by a gift) Sa fl
4, good phenyl) thiocarbamoyl, 21.L
J Carbamoyl or Nido [1 thiol/l] (￥
・r, 'II is outside of Jit] To create a 4-button'7-jin-scanning body D'! (), general formula 11
1 [In the formula, A1 and A2 are the previous ¥iL: 'lselfH't is also as determined in the 1st JL3,
Ishi? ') (1 n is sulfamoyl, 7) (' phenyl, which is j7t k'4 -C is also good) carbamoyl, also t1 mono ('Q+ (i!, 11 white 4-fuza) 1 optional phenyl) thiocarba 7/I
/l/, nitro force /l・/rimoyl stopper is nitrothiocarreno, 1's r', l'll
'aL'? 'f ii'l°stroke 1] seeking II'ij
! A compound having the 112 si'pj -; 33) A method of reacting with a compound having the general formula l shown in claim 1 above.
In the formula, R2 is a mono(optionally substituted phenyl)carbamoyl or mono(optionally substituted phenyl)thiocarbamoyl group, and R1, A1, A2j1. Yohizl is the above 'F':W
In order to prepare a tetrazine compound having the general formula (wherein R12 is J, !l as the case may be), t1z is a phenyl group which may be substituted, R16 is a benzyl group which may be optionally substituted, and 22 is as defined in No. 1 m of the above-mentioned range)
It is possible to debenzylate a compound having a hydrogen atom by applying or adapting a method known per se to the hydrogen atom of the benzyl group, which may optionally have one substituted hydrogen atom. i4) 1iJ-self'l! I'f'F'7 Range of occupancy No. 1 shown in the first term. ．． -7 general formula I (in the formula 1(1
, l, 1, A2 and Zl are i+I itc; defined in Claims 1 Kawaki 1J'4 and 2 is a group having the formula -cz 2Nntvo 22, and zl is 11 (The scope of the patent tf'iV sought LNI No. 18il' (-definite re service 7i-fl)
In order to produce tetrazine K '7+' which does not contain
The corresponding compound having the general formula (wherein Z2, R1, A1, A2 and zl are 9 as defined in claim 1 above) is converted into -CZ2NH7 by di)o
How to convert to 2NHNO2. 35) The general formula ■(
In preparing a tetrazine visiting conductor having the formula (wherein R1, A1, A2 and R2 are as defined in claim 181 above, and Zl is a sulfur atom), the general formula Middle R1, A1 fu・yohi R2 & 1 said'
l':f Is it defined in the first term of the scope of permission requirements? and R15 54 -8(0)nR6, -8
O2NT(7R", -CZ2hTR7R"i
or 1022NT (a group having NO2, where R
6, R7, R8, n and zl are as defined in the first part of the claim. 36) General formula I (
In the formula, R1, A1, A2 and Zl are as defined in the preceding If claim 1, and R2 is the formula -
A group having C8NR7B8, where R7 and R
8 is for producing a tetrazine derivative having a fixed value in the 1st m range of the above-mentioned 0 clause,
General formula (wherein R1, A1, A2, zl, R7 and R8
is as defined in Scope No. 1 of the said Patent No. 81)) with phosphorus pentasulfide and anti-L1. ,
A method consisting of converting -CONR7<8 groups total -0 days to NR7R8 groups. 37) The resulting tetrazine product has the general formula I (wherein F2 and/-
In addition, ll''iR5 is a compound having sulfamoyl and a monosubstituted sulfamoyl group, or R5 is a carboxy group, and this product is converted into a salt using a well-known method. Said claims 52 to 36 consist of converting into an alkali metal salt.
The method mentioned in one of the sections. 38) Pharmaceutical 4! ↓Fl--detrazine according to any one of claims 1 to 31? A pharmaceutical composition containing at least one of the following as an active ingredient. 69) A pharmaceutical composition according to claim 38, particularly as substantially as described with respect to Composition Examples 1.2 or 5. 40) For use in the treatment of malignant neoplasms such as cancer, melanoma, sarcoma, lymphoma 1 and leukemia, the general formula
(2, A1, A2 and zl are
A tetrazine product with a constant yield of F+, and 1...shi).