FI80273C - PROCEDURE FOR FRAMSTATING OF THERAPEUTIC THERAPEUTIC (3H) -IMIDAZO / 5,1-D / -1,2,3,5, -TETRAZIN-4-ON-DERIVAT. - Google Patents

Description

and 80273

This invention relates to an analogous process for the preparation of new therapeutically useful C'H2-imidazo PS, 1-d / -1,2,3,5-tetrazin-4-one derivatives. This invention relates to an analogous process for the preparation of new therapeutically useful Z'3H / imidazo derivatives. For the preparation of £ 5,1-dJ-1,2,3,5-tetrathin-4-one derivatives of general formula 2

R

VV \,

R O P

wherein R is a straight-chain or branched alkyl group having up to 4 carbon atoms which may be substituted by a halogen atom such as bromine, iodine or preferably 3 chlorine or fluorine, R is a hydrogen atom, a straight-chain or branched alkyl group having up to 4 carbon atoms or cyclohexyl - or a phenethyl group, R is a position of 7 to 59, of the formula -S <0> nR, -SO 2 NR R, -CONR R or CONHNO 2, where n is 1 or 2, R is straight-chain or branched, 7 6 at most 4 an alkyl group containing carbon atoms, R and R, which may be the same or different, each denote a hydrogen atom, a straight-chain or branched alkyl group having up to 4 carbon atoms or a phenylalkyl group which may be substituted by alkoxy and the alkyl moiety of which is straight-chain or branched - 5 7 to 4 carbon atoms, R is the same as the group R or 9 7

it is a phenyl group, and R has the same meaning as the group R

5 9

but it is not a hydrogen atom and is not a group, or R and R

together with the nitrogen atom to which they are attached form a piperidino ring and, when R is a sulfamoyl or monosubstituted su 1 -moyl group, for the preparation of their salts, especially the alkali metal, e.g. sodium salts. Where the context so permits, references in this specification to compounds of general formula I also include salts of these compounds. These salts are very useful intermediates.

The disclosures of GB Patent Application No. 2,104,522 and similar applications filed in other countries, which take precedence over the original GB Patent Application No. 8,125,791, e.g., U.S. Patent Application No. 410,656, describe compounds of the general formula II

11

R

___-OF

"I 11 VV \ ..

O R

Wherein R is a hydrogen atom, a cycloalkyl group or a straight-chain or branched alkyl, alkenyl or alkynyl group having up to 6 carbon atoms, each such alkyl, alkenyl or alkynyl group being unsubstituted or substituted with 1 to 3 substituents, selected from the group consisting of halogen atoms, straight-chain or branched alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl groups having up to 4 carbon atoms and optionally substituted phenyl groups, and R is a carbamoyl group which may have a nitrogen atom 1 or 2 groups selected from straight-chain or branched alkyl and alkenyl groups each having up to 4 carbon atoms and cycloalkyl groups.

Said tetrazine derivatives of formula II have valuable antineoplastic activity against, for example, carcinoma, melanoma, sarcoma, lymphoma and leukemia, and they also have valuable immunological activity and are useful in the treatment of organ and skin cancer, organ and skin cancer.

The compounds of formula I according to the invention have similar properties and, in certain proportions, to an even improved extent.

Said tetrazine derivatives of formula II are useful intermediates in the preparation of certain compounds of formula I, as set forth later in this specification.

Very important classes of compounds of formula I are those which contain one or more of the following groups: (i> R is a methyl or especially 2-haloethyl group, in particular a 2-chloroethyl group; 2 6 6 <ii) R is a group of the formula -SOR, -SOoR, 7 Θ 5 9 6 2 -SO5NR R, -CONR R or -CONHNOo, wherein R is an alkyl group, for example a methyl group, and R or R is a hydrogen atom or an 8 alkyl group; , for example a methyl group, R is a hydrogen atom, or an alkyl group, for example a methyl group, or a benzyl group optionally substituted by an alkoxy group, e.g. a 4-methoxybenzyl group, and R is a benzyl group optionally substituted by an alkoxy group, e.g. a 4-methoxybenzyl group ; and / or 3 (iii) R is an alkyl, e.g. butyl, propyl, ethyl or especially methyl group.

Important individual compounds of general formula I are the following: 4 80273

8- (N-Benzyl-N-phenylcarbamoyl) -3-methyl- [3H7-imidazo-eo-? 5,1-d7-1,2,3,5-tetrathin-4-one, A

8-ZN-Bentyl-N- (4-methoxy-benzyl) -carbamoyl-1-7-3- (2-chloro-ethyl) -Z3HZ-imidateo [5,1-d7-1,2,3,5- tetratein-4-one, β 8 - (N-benzylcarbamoyl) -3- (2-chloroethyl) -Z 3 H 7 -imidat-eoZS, 1-d7-1,2,3,5-tetratein-4-one oni, C

3- (2-Chloroethyl) -8-Ztf- (4-methoxybenzyl) -N-phenylcarbamoyl17-Z3H7-imidazo [1,2-d7-1,2,3,5-tetrate -4-one, D

3- (2-chloroethyl) -8- (N-phenylcarbamoyl] -Z3H7-imidazor-5,1-d7-1,2) 3,5-tetrathin-4-one, E

8- (N-Bentayl-N-phenylcarbamoyl) -3- (2-chloroethyl) -Z3K7-imidazoE2B, 1,1-d7-1,2,3,5-tetrazin-4-one, F

3- (2-chloroethyl) -8- (N-methyl-N-phenylcarbamoyl) -Z3R7-imidateo [2,1-d] -1,2,3,5-tetrathin-4-one, G

3- (2-chloroethyl) -8 - (N, N-dimethylsulfamoyl) -3H-imidazo [Z, 1,1-d7-1] 2,3,5-tetrathin-4-one, I

3- (2-chloroethyl> -8- (N-methylsulfamoyl) -Z3H7-imidazo-e2Z, 1,1-d7-1,2,3,5-tetrathin-4-one, J

3- (2-Chloroethyl) -8-methylsulfonyl-Z3H7-imidateoZB, 1-d7-1,2,3,5-tetrathin-4-one, K

3-methyl-8-methylsulfonyl-3H-imidateo [B, 1-dj-

1.2.3.5-tetratein-4-one, L

3- (2-chloroethyl) -8-ZN- (4-methoxybenzyl) eulfamo-

yl iJ7-Ζ3Η7 "-imidateoZB, 1,1-d7-1,2,3,5-tetratolin-4-one, M

3- (2-chloroethyl) -8-eulfamoyyli-Z3H7-imidateoZB, 1-d? -

1.2.3.5-tetratein-4-one, N

3- (2-chloroethyl) -8-piperidinocarbonyl-Z3H7-imidat-eoZS, 1- <± 7-1,2,3,5-tetrathinin-4-one, Q

3- (2-chloroethyl) -8- (4-methoxybenzyl) eulfamoyl-6-methyl-Z3H7-imidateoZB, 1-d? -1,2,3,5-tetrathinin-4-one, Y

3- (2-chloroethyl) -6-methyl-8-eulfamoyl-Z3H7-imidateoZB, 1-d / -1,2,3,5-tetrathin-4-one, Z

5 80273

3 <2-chloroethyl) -e-dimetyyUeuit, MI) yyli.6_lnatyYli.nw. imidateolB, 1,1'-d7-1,2,3,5-tetrathin-4-one, AA

3- (2-Chloro-ethyl) - «-« .tyl..m.-ethyl.-sulfonyl- «K7-imidateo, 1-47-1,2,3,5-t.-tratein-4-one, BB

j. 3 to <2-chloroethyl> -B- <N-nitrok! Lrbil0oyyli>,

datso / 3,1-d7-1,2,3,5-tetrazin-4-one, DD

3- (2-chloroethyl) -6-metyyu_e_metyylieulfinyyli_ ^ Il7_

imi dat so £ 5.1 -cL7-1,2,3,5 - tat rate in-4-one, GG

3 <2-chloroethyl> 8-etyylieulfonyyli-6-methyl-nH7-

imidateo, 1-cl7-1,2,3,5-1etratein-4-one, HH

and 3- (2-chloroethyl) -6-methyl-8-propyl-8-sulfonyl- [3H7-imidateo] -1,1-d7-1,2,3,5-tetrazin-4-one. I I

The letters A to II denote the compounds described above so that they can be easily labeled later in this specification.

Such compounds which are very important are compounds C, K, L, M and DD, in particular compounds I, J, N and BB and very particularly Z and AA.

These new tetrazine derivatives of general formula I have been found to be highly active in mice at daily doses between 0.2 and 320 mg / kg body weight, administered intraperitoneally against TLX5 (S) lymphoma and using the method of Gescher et al. Biochem. Pharmacol. (1981), 10, 89, and against ADJ / PC6A and M5076 (reticulum cell sarcoma). Against leukemia L1210 administered intraperitoneally, intraperitoneally and intravenously, and against P388 disease using the method described in Methods of Development of New Anticancer Drugs (NCI Monograph 45, March 1977, pages 147-149, National Institute, Bethesda, These compounds were active both intraperitoneally and orally at doses ranging from 1 to 320 mg / kg body weight, and inhibition of both primary tumor 6 80273 and metastases was observed for Lewis lung carcinoma at similar doses in B16 melanoma and mouse C38 tumors. <NCI Monograph 45, op. Cit.), These compounds were active intraperitoneally at doses between 6.25 and 40 mg / kg of animal body weight, and when administered subcutaneously against C2g carcinoma in mice, these compounds were also active orally at doses between 2 and 40 mg. / kg body weight of the animal noa.

Pharmacological comparative tests and their results

In the comparative experiments, such compounds of formula I are used as test compounds

1 2 in which R is a 2-chloroethyl group and R: 11a and R: 11a have the meanings given in the following table. Compound C, known from GB Patent 2,104,522, i.e. 8-carbamoyl-3- (2-chloroethyl) - (3H7-imidazoZT5,1-d7-1,2,3,5-tetrathin-4-one) is used as a reference compound.

Mice are inoculated intravenously with 100,000 cells / mouse cells of the leukemia cell line L1210. After two or three days, the mice are divided into groups. In some groups, each mouse is then orally administered a single dose of a test compound of the invention. In the other groups, each mouse is orally administered one dose of the reference compound. Mice in one group of mice are not given any drug after inoculation and this group is called the control group.

Record how many days each mouse survives. The number of mice that are alive at the end of the experiment is also recorded. The mean survival time <T) of each group is compared to the corresponding time <C> of the control group and expressed as a percentage of £ T / C (%) J in the following table. Figures greater than 100 indicate that the the compounds prolong the lifespan of mice.

The symbol means "greater than".

Il 7 80273 • fx vDO N r \ 'vj in in imen oor ^ oo © r- oc cc Γ- »> - O cm cm 00 ^ ¾ O mh no - n - 00 nm ic 00 OvOQO mhio ö · - 00 a cm AQ vO «-, & -i {nmjSN NION ΙΑΝΗ * J ifi N (VI N Μ Γ * - CM <H lA (V | n H ^ a A ^ A ΛΛ Λ AA a

------.,. - X

44 44 <0 (0 i. S * 5 | Q rr-.r-.r->. SKn.% Nnn ionn a vo t * - r * »f- i-» nns vCur * ^ - <U <D w - - - v "- · -. -.- · - n .'- 'v' -'- v octis onn 0 000 © 0 vo © moo csmo or— 0 0 r-. 0 0 moo

Q-Jf-X Ci Η ίίϊί O C

W-nX.-. ____ I tJ · Ϊ OOPA OOOA OOP OO © OOP OOO OOO «300

X 0 -JfMr-l c Nh -y CM> —I S3 "CN <—I Ί Μ Η> ί N Η Ί (V>" <»J NH

: (0 C O '

: to c E

J (0 - (0 ~ "'a;

•B

Π3 5 *?. ”TT 0 0 in a r-.r- a a o -u x a a sr <r m m -r x tn μ o <u> X x - aO" "~” C>

Ο -H

<U at x Cl rn m csi cm mm mm X 0 ad -u: (0 C 1-J (0; I = p pf p

CM

y—- m m

cm cm 52 p D

s 2> w ^ 2 2 © 2:

CM CM CM CM

^ ^ ^ ^ _ j - i i - 1 --— n) 3 3 3 3 4J r-Id) I — Id) H (1) rHd) [/) -H 4-1 Ή 4-> - H 4-1 -H 4-> H _ (0U) O'15 = <0tn ftw

rrt 2 4J -H ^ 4-1 -H ** "44-1-1 ** 44 -H

r i'O CO CO CO., LTD

& QJ.C Φ X OJ Ä Ä __Q>>,>> 1 I >> || j> 4> ~! 8 80273 Ογ'-γ-.ν q rv® n vj m m - <© Q oo Ό r ^ - fsi rsi cc r-v 'C_5 kCi -h - - rvn s ® ηιΛ J ®-h - ia cm yOr-i oc

Vv.H CA CM tN CM ΓΝ CM - · · - * mm NO CV1 r-M ^ i — I A sj CM CNI CM -! S- - / \ ^ pNA / n λα Λ 3 ---------—, 3

X

J_I (rt ^ I ny f! N NNSN NNN ® NN NN N NN N NNN NNN (0 cäjmm NNNN VVNN »N ** v" v. 'VVNN "v, v ^ s, sS ^ 3 0303 NOOO - OOO ιΛ ^ Οώ -4000 IA ro O -4 0 0 a ·

—Ι x o O

ω-πχ, -ι i "σ> J! Ο Ο Ο Ά OOO Ά OOO Ά o OO Ά ooo O eo £ 2 7? STCM — I VJ CM —4 VJ CM —I <CM - <-JINH vJ OM - • * OGO ·

MCE

►3 «J - <0

X

r 5 »oo cm cm rv rv 00— rn en« j vr rc m O -U X λ; · Λ p o <u> x x -

X

e>

<L) * H

jjJ X fo cA e *) c "i en cc X 0 X -P X e PI (ö ^ 1 = _ ~ f g" 5 "g

S 8 S

T 1 I

- 3 3 ~ 2 32 32 «* 23 g 32 g 32 £ 33 HO U 'n Ό: 2 ox« -C Sf,> y ____>> i I _> rC _ ^ 9 80273 »CC Μ CM <T uO ιΛ Q sff O 'Ν. CNN CO o *. — I CJ ro ® o ro o * f— os ro a »A oc cm co C5 cm -o vo - <co

N, h {<7 IM CM> - <-rt CM fM -rt> - CO * J CM Π N CO lA CM CM CM I — I

t- ° λΛ ^ \ / \ A / VA A

---------

-P tO

IQJCM Γ ^, ^ Γ ^ ΓΜΓΜ N. N. O 'N »M NN N N N O' Os O» N- O- O ^

C QJ QJ tn 'sS.v.NN' vNNV. N N - "» .'m. ''. N MM M —.M

O C o; 3 rt Is OC O O O O O N PO «NOO CO <T O i — i O O

O: tt ^ C Oi i — i: to O O

μ · γ-ιλ: ή__ I O · * <}

OpCmN CCOvo OOO QOO OOO OOO

* O ^ s7? M Ό CM -H ·>: (M-1 ^ CM (-rt sj (M r-I <PM Ό

X G C

X C ε j <a - (0

•B

G to O O O 'O' NsN.

OO- ^ lA IA CM CM CO PO

O -m Λί. * M P O O> t *: λ: —____ x c> QJ -r-l QJ n n «n n po ro X. o *

M O

X 4-> X G P1 10 ro ro ro δ δ δ jp

CM O

* · Μ CM

PO ^

CM S PM

oi pm C5 a: S N ^ Π Z Z mJ-

CM CM PM

S3 -S3 S3 i i i ----- g - r- QJ # - | CL) r-t QJ * - * Q> P -H -P -H -P ^ tn. (Otn <totn ^ totn

• H N 4J -H <-P -H rtrt -P -H

Ό U Ό P Ό> -i 'O

jc o jg: qj .c qj λ X>>,>> 1>> Λ - - - - - - - ---- - - * 10 80273

The compounds of general formula I can be prepared by methods known per se.

According to an embodiment of the invention, compounds of general formula I are prepared in which R and R have the same meaning as above and R is a group of formula 6 78 59 6 7 -S <O> nR, -SO2NR R or -CONR R, where n, R and R are as defined above, R is as defined above but R 9 is not a hydrogen atom, and R and R are as defined above, but when R is a hydrogen atom, R represents a phenylalkyl group as defined above, by reacting a compound of general formula 3

R

Aa

NN III

12 ^ X Θ R NN2 3 12 where R is as defined above and R is a group having 6 78 59 6 7

has the formula -S <O) -R, -SO 9 NR R or -CONR R, where n, R and R

Il ig is as defined above, R is as defined above but not a hydrogen atom, and R and R are as defined above, but when R is a hydrogen atom, R is a phenylalkyl group as defined above, to react with a compound having is a general formula

R NCO IV

where R is as defined above. The reaction can be carried out with or without an anhydrous organic solvent, for example a chlorinated alkane such as dichloromethane or ethyl acetate, acetonitrile, N-methylpyrrolidin-2-one or hexamethylphosphamide, at a temperature between 0 and 120 ° C. The reaction can take up to 30 days. The reaction mixture is preferably protected from light.

il lt 80273

According to another embodiment of the invention, the preparation 1 3

compounds of general formula I in which R and R are used

have the same meaning as above and R is a sulfamoyl, monosubstituted sulfamoyl or monosubstituted carbamoyl group, of the corresponding compounds of general formula I, wherein R is a group of the formula -SO 0 NR R or -CONR R Wherein R is a benzyl group or an alkoxy-substituted benzyl group, and R and R are as defined above, to replace a benzyl group or an alkoxy-substituted benzyl group with a hydrogen atom. Suitable reaction conditions include, for example, catalytic hydrogenation (using a catalyst such as palladium on carbon, a solvent such as ethyl acetate or dimethylformamide), 13 or when R is an alkoxy-substituted benzyl group in which the alkoxy (e.g. methoxy) group is o- or in the p-position, preferably by reaction with trifluoroacetic acid, preferably in the presence of an aniol, and usually at or near room temperature.

According to another embodiment of the invention, compounds of general formula I wherein R is a group are prepared.

of the formula -CONHNO2 »and R and R have the same meaning as above, by nitration of compounds of general formula V

CONH,

X V

N I I

YV \,

R O R

1 3 where R and R have the same meaning as above. This reaction can be carried out near or below room temperature, preferably between 0 and 10 ° C, in the presence of a nitration mixture such as a mixture of concentrated sulfuric acid and concentrated nitric acid.

12 80273

The aforementioned salts of certain compounds of formula I are prepared using or applying methods known per se, e.g. by reacting a basic compound of formula I with suction hydroxide, carbonate or preferably bicarbonate in a medium containing water or water and an organic medium followed by separation by methods known per se.

When a product mixture is obtained in one of said methods, these products can be separated using or applying methods known per se, for example chromatography.

Compounds of general formula III may be prepared using or applying methods known per se and described by Shealy et al., J. Org. Chem. (1961), 2 £, 2396 and Cheng et al., J. Pharm. Sci. (1968), 57. 1044, and the methods described below in the Preparations.

The term "methods known per se" as used in this specification refers to methods previously used or described in the literature.

The following Examples 1-20 illustrate the preparation of compounds of general formula I according to the invention, and Preparations 1-12 illustrate the preparation of intermediates.

Example 1 Compound A

Sodium nitrite (0.44 g) was dissolved in aqueous acetic acid (2M; 10 ml) at 0 ° C and the solution was stirred at 0 ° C and treated with finely ground 5-aminoimidazole-4-N-benzyl-N-phenylcarboxamide hydrochloride. (0.7 g; prepared as described in Preparation 1) in small portions. After 10 minutes, the resulting gummy solid was extracted with ethyl acetate (2 x 20 mL).

Il, 3 80273

The combined ethyl acetate extracts were washed with water and dried over magnesium sulfate.

The resulting solution of 5-diazoimidazole-4-N-benzyl-N-phenylcarboxamide was treated with methyl isocyanate (5 ml) and the mixture was stirred at room temperature in the dark for 24 h. The solution was then evaporated to a small volume and the residue was chromatographed on medium eluting with to give 3- (N-benzyl-N-phenylcarbamoyl) -3-methyl- [3H] -imidazo [5,1-d] -1,2,3,5-tetrazin-4-one (0.22 g) as a white solid. , in the form of a crystalline solid, m.p. 163-170 ° C (decomposes).

Elemental analysis: C 62.6; H 4.41; K 22.3%; calculated: C 63.32, H 4.47; N 23.32%; I.R. (KEr plate): 3100, 1735, 1620 cm -1; NMR (in DMSO-d 6): - bands at 3.75, 5.10 and 8.55 ppn, many bands at 7.0-7.4 ppm: m / e 36 0 (M + 7_

Example 2 Compound 5

Sodium nitrite (3.7 g) was dissolved in aqueous acetic acid (2M; 35 ml) at 0 ° C and the solution was stirred at 0 ° C and treated with 5-aminoimidazole-4-N-benzyl-N- (4-methoxybenzyl) carboxamide hydrochloride (2.2 g; prepared as in Preparation 2) in 1,2-dimethoxyethane (10 ml) by dropwise addition. A reddish gummy substance separated which was extracted with ethyl acetate (2 x 20 ml). The combined ethyl acetate extracts were washed with water and saturated sodium chloride ·; aqueous solution and dried over sodium sulfate.

The resulting 5-diazoimidazole-4-N-benzyl-N- (4-methoxybenzyl) carboxamide solution was treated with 2-chloroethyl isocyanate (2 ml) and allowed to stand at room temperature in the dark for 24 h. The solution was then evaporated to a small volume and the residue was subjected to column chromatography under medium pressure and eluted with ethyl acetate to give crude 8- [N-benzyl-N- (4-methoxybenzyl) -carbamoyl] -3- (2-chloroethyl) - [3H7] imidazo [5.1]. -d7 ', 1,2,3,5-tetrazin-4-one (1.5 g) in the form of a brown oil.

Example 3 Compound C

8- [N-Benzyl-N- (4-methoxybenzyl) carbamoyl] -3- (2-chloroethyl) - [3H7] imioazo [5,11] -1,2,3,5-tetrazin-4-one (1, 5 g (crude material prepared as described in Example 2) and anisole (0.5 ml) were dissolved together in trifluoroacetic acid (20 ml) and allowed to stand at room temperature for 18 h.

The mixture was then evaporated to dryness and the residue was subjected to medium pressure chromatography on a column and eluted with a mixture (2: 1 v / v) of ethyl acetate and petroleum ether (b.p. 60-80 ° C) to give 8- (N-benzylcarbamoyl) - 3- (2-chloroethyl) -1H-imidazo [5,1d] -1,2,3,5-tetrazin-4-one (0.34 g) as a colorless solid, m.p. 153-155 ° C (recrystallized from diethyl ether).

Elemental Analysis: C, 49.9; H 3.92; N 24.4; Cl 10.4%; Calculated: C 50.53; H 3.94; N 25.26; Cl 10.65 Ί; I.R. (KBr plate) 3370, 3150, 1755 and 1660 cm-1; NMR (in DMSC): bands at 7.3 and 8.9 ppm; double line at 4.4 ppm and triangular lines at 4.0, 4.6 and 9.05 ppm /.

Example 4 Compound D

Sodium nitrite (0.61 g) was dissolved in water (10 ml) and the solution was stirred at 0 ° C and treated with a solution of crude 5-aminoimidazole-4-N- (4-methoxybenzyl) -N-phenylcarboxamide (2, 5 g, prepared as described in Preparation 3) in hydrochloric acid (2M; 9 ml), and 1,2-dimethoxyethane (15 ml), which solution was added dropwise. After 20 minutes, the solution was extracted with ethyl acetate (3 x 50 ml) and the combined extracts dried over magnesium sulphate and evaporated to give 5-diazoimidazoline, 5,80273 4-N- (4-methoxybenzyl) -N-phenylcarboxamide (2.8 g) as an orange solid. in the form of oil.

This oil was dissolved in ethyl acetate (40 mL) and treated with 2-chloroethyl isocyanate (8 mL). The mixture was allowed to stand in the dark for 5 days. The solution was evaporated to a small volume and the resulting residue was chromatographed on medium pressure under medium pressure and eluted with ethyl acetate to give 3- (2-chloroethyl) -8- [N- (4-methoxybenzyl) -N-phenylcarbamoyl] -7H-imidazo]. -1,2,3,5-tetrazin-4-one (1.5 g) in the form of a glassy product, m.p. 55 ° C.

/ NMR (in DMSO-d 6): bands at 3.6, 5.0 and 8.5 ppm, triple band concentrated at 3.9 and 4.5 ppm, multiline at 6.6-7.2 ppm; I.R. (KBr plate) 1740 and 1640 cm -1.

Example 5 Compound E

3- (2-chloroethyl) -8 / N- (4-methoxybenzyl) -N-sulfamoyl-fenyylikarba / - / 3H / -imidazo / 5, ld / -l, 2,3,5-tetrazine-4-one (1.0 g; prepared as described in Example 4) and anisole (0.2 ml) were dissolved together in trifluoroacetic acid (10 ml) and the solution was allowed to stand at room temperature for 18 h. The mixture was then evaporated to dryness and the residue triturated with diethyl ether. 3- (2-chloroethyl) -3- (N-phenylcarbamoyl) - [3H7] imidazo [5,1-d] -1,2,3,5-tetrazin-4-one (0.43 g) was obtained as a brown solid. in the form of a solid, m.p. 166 ° C (decomposes) (after recrystallization from ethyl acetate). Elemental analysis: C 48.4; H 3.22; N 26.0%; Calculated: C, 48.99; H 3.48; N 26.37%; I.R. (KBr plate): 3390, 1735 and 1680 cm -1; NMR (in DMSO-d 6): bands at 8.9 and 10.3 ppm, double band concentrated at 7.8 ppm, triple bands at 4, 0 and 4.6 ppm, multiline in the range 7.0-7.9 ppm /.

Example 6 Compound F

Sodium nitrite (2.8 g) was dissolved in aqueous acetic acid (2M; 84 ml) and the solution was stirred at 0 ° C and treated with finely ground 5-aminoimidazole-4-N-benzyl-N-phenyl-carboxamide hydrochloride. (2.8 g; prepared as described in Preparation 1) in small portions. After 10 minutes, the resulting gummy solid was extracted with ethyl acetate (3 x 30 mL) and the combined extracts were washed with water and then saturated aqueous sodium chloride solution and then dried over magnesium sulfate.

The resulting solution of 5-diazoimidazole-4-N-benzyl-N-phenylcarboxamide was treated with 2-chloroethyl isocyanate (9 ml) and the mixture was allowed to stand in the dark at room temperature for 4 days. The solution was then evaporated to a small volume and the residue was subjected to medium pressure chromatography and eluted with ethyl acetate to give 8- (N-benzyl-N-phenylcarbamoyl) -3- (2-chloroethyl) - [3H] -imidazo_ / 5, 1d / -1,2,3,5-tetrazin-4-one (1.0 g) in the form of a glassy product.

Elemental analysis: C, 59.3; H 4.57; N 19.9; Cl 8.5 S; Calculated: C 58.75; H 4.19; N 20.56; Cl 8.67%; I.R. (KBr plate): 1740 and 1640 cm NMR (in DMSO-d 6): bands at 5.2, 7.1, 7.3 and 0.6 ppm, triple band concentrated at 4.0 and 4.6 ppm7-

Example 7 Compound G

A solution of sodium nitrite (11 g) in water (50 ml) was cooled to 0 ° C and treated dropwise with a solution of 5-aminoimidazole-4-N-methyl-N-phenylcarboxamide hydrochloride (4.0 g; prepared ”). as described in Preparation 4) in aqueous acetic acid (2M; 40 ml). After 10 min, the resulting mixture was extracted with ethyl acetate (4 x 100 mL) and the combined extracts were filtered and dried over magnesium sulfate.

Il 17 80273

The resulting solution of 5-diazoimidazole-4-N-methyl-N-phenylcarboxamide was treated with 2-chloroethyl isocyanate (11 mL) and the mixture was allowed to stand in the dark at room temperature overnight. The solution was then evaporated to a small volume and the residue was chromatographed on medium pressure and eluted with ethyl acetate to give a solid (5.75 g). This solid was triturated with diisopropyl ether and then dichloromethane. The insoluble residue was recrystallized from a mixture of petroleum ether (b.p. 60-80 ° 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-d] -1,2,3,5-tetrazin-4-one (0.8 g) as a colorless solid, m.p. 130-132 ° C.

[Elemental analysis C 50.4; H 3.91; N 24.9; Cl 10.6%; Calculated: C 50.53; H 3.94; N 25.26; Cl 10.65%; I.R. (KBr plate): 1750 and 1640 cm-1; NMR (in DMSO-De): - band at 3.4, 7.2 and 8.65 ppm, triple band concentrated at 3.95 and 4.6 ppm.]

Example 8 Compound I

A solution of 5-diazoimidazole-4- (N, N-dimethylsulfonamide) (0.55 g; prepared as described in Preparation 5, 80273 18) in dry ethyl acetate (40 mL) was treated with 2-chloroethyl isocyanate (3 mL). and the mixture was stirred in the dark for 48 h. The mixture was then evaporated in vacuo at below 40 ° C to a volume of about 15 ml and diluted with dry diethyl ether. The resulting solid was filtered off to give 3- (2-chloroethyl) -8- (N, N'-dimethylsulfamoyl) - [3H7] imidazo [5,1d] -1,2,3,5-tetrazin-4- onia (0.68 g) in the form of grayish needles, m.p. 155-156 ° C. Elemental analysis: C 30.4; H 3.35; N 26.8; Cl 11.8%; calculated; C 31.3: H 3.62; N 27.4; Cl 11.6%; I.R. 1755 cm-1; NMR (in DMSO-d 6): bands at 2.80, 8.90 ppm, triple bands at 3.99 and 4.62 ppm /.

Example 9 Compound J

A suspension of 5-diazoimidazole-4- (N-methylsulfonamide) (0.7 g; prepared as described in Preparation 6) in ethyl acetate (40 ml) was treated with 2-chloroethyl isocyanate (3 ml) and the mixture was stirred. in a sealed flask in the dark for 48 h. The mixture was then evaporated in vacuo at a temperature below 35 ° C to approximately half volume and diluted with diethyl ether. The resulting solid was separated by filtration and washed with diethyl ether to give 3- (2-chloroethyl) -8- (N-methylsulfamoyl) -N, N-imidazo [5,11] -1,2,3,5-tetrazole. 4-one (0.32 g) in the form of glowing brown plates, m.p. 147-148 ° C.

Elemental analysis: C 28.5; H 2.90; N 23.7%; Calculated: C, 28.7; H 3.08; N 28.7%; I.R. 1745 cm -1; NMR (in DMSO-d 6): double band at 2.58 ppm, triple band at 3.98 and 4.61 ppm, quad band at 7.94 ppm, band at 8.84 ppm δ

, Example 1Q

- Compound K

A solution of 5-diazo-4-methylsulfonylimidazole (0.65 g; prepared as described in Preparation 7)

II

80273 in dry ethyl acetate (50 ml), treated with 2-chloroethyl isocyanate (3 ml) and the mixture stirred at room temperature in the dark for 48 h. The mixture was then evaporated in vacuo and the oily residue triturated with petroleum ether (b.p.

60-80 ° C). The resulting solid was filtered off and chromatographed under medium pressure, eluted with ethyl acetate and the white solid was triturated with petroleum ether and filtered to give 3- (2-chloroethyl) -8-methylsulfonyl- [3H] -imidazo [5,d] - 1,2,3,5-tetrazin-4-one (0.72 g), m.p.

154-155 ° C.

Elemental analysis: C 30.3; H 2.85; N 25.0; Cl 11.5 S; Calculated: C, 30.28; H 2.90; N 25.22; Cl 11.55%}.

Example \ "\

Compound L

A solution of 5-diazo-4-methylsulfonylimidazole (0.65 g; prepared as described in Preparation 7) in dry ethyl acetate (60 mL) was treated with methyl isocyanate (3.5 mL) and allowed to stand at room temperature. in the dark for 3 days. Additional methyl isocyanate (3.5 ml) was then added and the mixture was heated at -40 ° C for 2 days and then allowed to stand at room temperature for 3 days. The mixture was then evaporated in vacuo to a volume of 10-15 ml. and chromatographed under medium pressure and eluted with ethyl acetate to give 3-methyl-ο-methylsulfonyl- [3H] -imidazo [5,1-d7] -1,2,3,5-tetrazin-4-one (O , 17 g) in the form of a white crystalline solid, mp 185-186 ° C (decomposes).

Elemental analysis: C, 31.2; H 2.89; N 30.3%; Calculated: C, 31.44; H 3.08; H 3 0.56 y.

Example 12 Compound M

A solution of 5-diazoimidazole-4- (N- (4-methoxybenzyl) sulfonamide) (0.3 g; prepared as described in Preparation 8) in dry ethyl acetate (25 mL) was treated with 2- chloroethyl isocyanate (1.5 g) and the mixture was stirred at room temperature for 48 h. The resulting dark solution was filtered and evaporated to dryness. The resulting brown solid was triturated with petroleum ether, filtered off and chromatographed under medium pressure and eluted with ethyl acetate to give a white solid which was triturated with petroleum ether, filtered and dried at 70 ° C / 10 mmHg for 1 h to give 3- (2- chloroethyl) -8- [N- (4-methoxybenzyl) sulfamoyl] -3- (3H) -imidazo [5,1-d] -1,3,3,5-tetrazin-4-one (0.2 g), mp. 155-156 ° C (decomposes); (I.R. 1745 cm • Elemental analysis: C 41.9; H 3.72; N 20.5%; calculated: C 42.16; H 3.79; N 21.07%).

Example .13 Compound N

3- (2-chloroethyl) -8-N- (4-methoxybenzyl) sulfamoyl] -3H-imidazo [5,1-d] [2,3,5,5] tetrazin-4-one (0.1 g; prepared as described in Example 12) was dissolved in trifluoroacetic acid (1.0 ml) and anisole (3 drops) and the solution was diluted. it was allowed to stand at room temperature for 2 h. The mixture was then evaporated in vacuo and the residue triturated with diethyl ether to give a yellow solid which was chromatographed under medium pressure using a mixture of petroleum ether (b.p. 60-80 ° C) and ethyl acetate (1: 1 by volume). / volume) as eluent to give 3- (2-chloroethyl) -8-sulfamoyl- [3H7-imidazo] -1,1-d7-1,2,3,5-tetrazin-4-one (50 mg) as a white solid. in the form of, m.p. 183 ° C (decomposes) /I.R. 1750 cm-1; . - NMR (in DMSO-d 6): bands at 8.8 and 7.8 ppm, triple bands at 4.58 and 3.95 ppm /.

»»

II

2i 80273

Example 14 Compound O

A solution of sodium nitrite (0.79 g) in water (6 ml) was treated with a solution of crude 4-amino-5-piperidinocarbonylimidazole hydrochloride (2.1 g, prepared as described in Preparation 9) in aqueous acetic acid (1M; 17 ml). ), which was added dropwise with stirring at 5-10 ° C for 5 min. within. The solution was extracted with ethyl acetate (4 x 45 ml) and the combined extracts dried over magnesium sulphate and evaporated at 30 ° C / 0.1 mmHg. The residue was dried in a desiccator over phosphorus pentoxide for 45 min to give 4-diazo-5-piperidinocarbonylimidazole (1.73 g) as red crystals which were pure enough to be used in the next step.

A solution of crude 4-diazo-5-piperidinocarbonylimidazole (1.73 g, prepared as described above) in dry ethyl acetate (53 ml) was treated with 2-chloroethyl isocyanate (5.9 ml) and the mixture was stirred in the dark. 2 days. The solution was then evaporated at 30 ° C / 0.1 mmHg and the residue was chromatographed twice on silica gel under medium pressure and eluted with a mixture of ethyl acetate and acetonitrile (88:12 v / v). The corresponding fractions were combined and evaporated and the residue triturated with petroleum ether (b.p. 40-60 ° C) to give 3- (2-chloroethyl) -8-piperidinocarbonyl- [3H] -imidazo [5,1-d] -1 , 2,3,5-tetrazin-4-one (1.46 g) in the form of pale purple crystals, m.p. 92-94 ° C.

[Elemental analysis: - C, 45.3; H 4.98; N 26.1%; Calculated: C, 46.4; H 4.87; N 27.1%; NMR (in DMSO-d 6): band at 8.7 ppm, triple band at 4.6 and 4.0 ppm, multiline at 3.2-3.4 and 1.5-1.8 ppm; I.R. (KBr plate): 1750, 1630 cm-1.] 22 8 0 2 7 3

Example 15 Compound Y

Dry ethyl acetate (100 mL) was treated with 5-diazo-4- (4-methoxybenzyl) pulamoyl-2-methylimidazole (2.45 g, prepared as described in Preparation 10) followed by 2-chloroethyl isocyanate (3 mL). ), and the reaction mixture was stirred in the dark at room temperature for 56 h. The mixture was then treated with additional 2-chloroethyl isocyanate (3 mL) and stirred in the dark at room temperature for another 24 h. The reaction mixture was then evaporated to dryness and the residue triturated with petroleum ether (b.p. 60-80 ° C; 3 x 25 mL) to remove excess 2-chloroethyl isocyanate. The remaining residue was then triturated with dichloromethane (2 x 50 mL) to extract the desired product from the insoluble 1,3-bis (2-chloroethyl) urea by-product. The combined dichloromethane extracts were evaporated and flash chromatographed on silica gel under medium pressure and eluted with ethyl acetate to give 3- (2-chloroethyl) -8- (4-methoxybenzyl) sulfamoyl-6-methyl- [3H] -imidazo]. d7-1,2,3,5-tetrazin-4-one (1.5 g), m.p. 159-160 ° C (decomposes), (I.R. 1760 cm -1).

Example Compound Z

*: A solution of 3- (2-chloroethyl) -8- (4-methoxybenzyl) sulfamoyl-6-methyl- [TH7-imidazo] -5,1-d7-L. 2,3,5-Tetrazin-4-one (1.5 g, prepared as described in Example 15) in trifluoroacetic acid (10 ml) and anisole (10 drops) was allowed to stand at room temperature overnight. The reaction mixture was evaporated in vacuo and the residue was triturated with diethyl ether. The resulting light brown solid was filtered off and recrystallized from acetone to give 3- (2-chloroethyl) -6-methyl-8-sulfamoyl- [1H-imidazo] -1,1-d7-1,2,3,5-tetrazole. -4-one (0.55 g), m.p.

199-200 ° C (decomposes).

Elemental analysis: C 29.1; H 3.02; N 28.8: Cl 12.1; S 10.6%; Calculated: C, 28.72; H 3.10; N 28.71; Cl 12.11, S 10.95%; L. R. 1760, 3310 cm -1.

Il 23 80273

Example _1 7 Compound AA

A solution of 5-diazo-4-dimethylsulfinyl-2-methylimidazole (1.8 g, prepared as described in Preparation 11) in dry ethyl acetate (100 ml) was treated with 2-chloroethyl isocyanate (4 ml). ) and the mixture was allowed to stand for 2 days at room temperature. The mixture was then treated with additional 2-chloroethyl isocyanate (4 ml) and allowed to stand at room temperature for a further 6 days. The reaction mixture was then evaporated in vacuo and the residue triturated with petroleum ether (b.p. 60-80 ° C; 2 x 25 ml). The remaining solid was dissolved in ethyl acetate and subjected to medium pressure chromatography on silica gel and eluted with ethyl acetate. The appropriate fractions were combined, evaporated to dryness and triturated with petroleum ether (b.p. 60-80 ° C) to give 3- (2-chloroethyl) -8-dimethylsulfamoyl-6-methyl- [3H] -imidazo [5,1-] d7-1,2,3,5-tetrazin-4-one (2.17 g), m.p. 137-138 ° C. Elemental analysis: C 33.8; H 3.91; N 25.8; Cl 11.2, S 9.7%; Calculated: C 33.7; H 4.09; N 26.20; Cl 11.05; S 10.0; Example _ 18

: Compound BB

A solution of 5-diazo-2-methyl-4-methylsulfonylimidazole (0.4 g, prepared as described in Preparation 12) in dry ethyl acetate (30 mL) was treated with 2-chloroethyl isocyanate (2 mL) and allowed to stand. at room temperature in the dark for 4 days. The mixture was then evaporated to dryness and the residue was triturated with petroleum ether (b.p. 60-80 ° C; 2 x 25 ml) to remove excess 2-chloroethyl isocyanate. The remaining residue was dissolved in ethyl acetate and chromatographed under medium pressure on silica gel and eluted with ethyl acetate to give 3- (2-chloroethyl) -6-methyl-8-methylsulfonyl- [TH7-imidazo] -1,1-d7-1,2,3 , 5-tetrazin-4-one (0.22 g), m.p. 149-150 ° C.

Elemental analysis: C 33.0; H 3.35; N 23.8; Cl 12.7; S 10.7%; Calculated: C 32.94; H 3.46; N 24.01; Cl 12.15, S 10.99%; 24 80273

Example 19 Compound DD

Stirred concentrated sulfuric acid (2.5 mL) was treated with 8-carbamoyl-3- (2-chloroethyl) - [3H] -imidazo [5,1-d] -1,2,3,5-tetrazin-4-one (O , 24 g, prepared according to GB Patent Publication No. 2,104,522). The mixture was cooled to 0 ° C and treated with dropwise addition of concentrated nitric acid (d = 1.42; 1 mL). The solution was kept at 4 ° C for 1 h and then poured onto ice. The precipitated solids were collected, washed with water and recrystallized from aqueous acetone to give 3- (2-chloroethyl) -8- (N-nitrocarbamoyl) - [3H] -imidazo [5,1-d] -1,2,3 , 5-tetrazin-4-one (0.28 g) in the form of colorless crystals, m.p. 160-161 ° C (decomposes).

[Elemental analysis: - C, 28.6; H 1.89; Cl 12.0; N 33.6%; Calculated: C, 29.23; H 2.10; Cl 12.33; N 34.09%; I.R. (KBr plate): 3200, 1750, 1720 and 1620 cm-1.

NMR (in DMSO-d 6): triple band at 4.05 ppm (J = 6 Hz) and 4.70 ppm (J = 6 Hz), band at 9.05 ppm, broad band at 8.25 ppm; m / e 287/289 (M- * ·).]

Example 20 Compounds GG. HH and II

By proceeding in the same manner as described in Examples 1, 2, 4, 6-12, 14, 15, 17 and 18 and using as intermediates the corresponding diazo compounds (prepared using or applying the methods described in the following preparations), the following compounds were prepared: 3- (2-chloroethyl) -6-methyl-8-methylsulfinyl- [3H] -imidazo [5,1] -1,2,3,5-tetrazin-4-one in the form of a yellow solid, m.p. 118-120 ° C; 3- (2-Chloroethyl) -8-ethylsulfonyl-6-methyl- [3H] -imidazo (5,1d] -1,2,3,5-tetrazin-4-one, mp 146-147 ° C and 3- (2-chloroethyl) -6-methyl-8-propylsulfonyl- [3H] -imidazo [5,1] -1,2,3,5-tetrazin-4-one in the form of a white crystalline solid, mp 85-86 ° C.

Preparation 1 (i) A mixture of 5-nitroimidazole-4-carboxylic acid (2.0 g) and phosphorus pentachloride (2.67 g) was stirred

II

80273 vigorously and heated in an oil bath at 120 ° C for 1 h. The resulting yellow slurry was evaporated at 60 ° C / 0.1 mmHg for 30 min to give 1,6-dinitro-5H, 10H-diimidazo / 1,5-a : 1 ', 5'-d / pyrazine-5,10-dione (1.90 g) in the form of a yellow solid, m.p. 249-251 ° C (decomposes).

/I.R. (KBr plate): 1750 cm -1; m / e 278 (M +] 7.

(Windaus, Ber., 1923, j> 6, 684 and Gireva, Chem. Abs., 59, 1622e, using the same method; describe their products as "5-nitroimidazole-4-carbonyl chloride").

(ii) A mixture of 1,6-dinitro-5H, 10H-diimidazo [1,5-a: 1 ', 51-d] pyrazine-5,10-dione (5.8 g), N -benzylaniline (15 g) and tetrahydrofuran (250 ml) were heated at reflux for 6 h. The tetrahydrofuran was evaporated in vacuo and the residual gum was partitioned between dilute hydrochloric acid (2N; 1 liter) and ethyl acetate (1 liter). Insoluble N-benzylaniline hydrochloride was removed by filtration, and the ethyl acetate layer was separated. The aqueous phase was extracted twice more with ethyl acetate and the combined organic phases were washed with dilute hydrochloric acid (2N) and then water, dried over magnesium sulphate and evaporated to dryness to give an orange gum. This material was triturated with twice boiling diethyl ether to give a colorless solid which was crystallized from isopropanol to give 5-nitroimidazole-4-N-benzyl-N-phenylcarboxamide (4.0 g) as colorless flakes, m.p. 237-240 ° C.

Elemental analysis: C 62.3; H 4.28; N 17.3%; Calculated: C 63.35; H 4.38; N 17.38 S; I.R. (KBr plate): 1665 cm -1 (iii) A solution of 5-nitroimidazole-4-N-benzyl-N-phenylcarboxamide (4.0 g) in dry ethanol (450 ml) was hydrogenated at 26 ° C. ° C at 3 atmospheric pressure using Raney nickel as catalyst. When the absorption of hydrogen was complete (after 4 hours, 50 minutes) the mixture was filtered, treated with concentrated hydrochloric acid (3.6 ml) and evaporated to dryness at a temperature below 40 ° C. Trituration of the residue with diethyl ether gave 5-aminoimidazole-4-N-benzyl-N-phenylcarboxamide hydrochloride (3.82 g) as a pale yellow solid, m.p. 190-193 ° C (decomposes).

/ NMR (in DMSO-d 6): bands 5.05, 7.1-7.2 and 8.4 ppm; I.R. (KBr plate): 1640 cm m / e 292 (M +) 7.

Preparation 2 (i) Mixture of N-benzyl-N- (4-methoxybenzyl) amine / 21.9 g; Annalen, (1931), 490, 1897 / 1,6-dinitro-5H, 10H-diimidazo [5,11] -1,5,5'-pyrazine-5,10-dione (6.7 g; prepared as described in Preparation 1) and dry tetrahydrofuran (200 ml), heated to reflux for 18 h. The tetrahydrofuran was evaporated in vacuo and the residual oily solid partitioned between dilute hydrochloric acid (2N, 500 ml) and ethyl acetate (500 ml). Insoluble N-benzyl-N- (4-methoxybenzyl) amine hydrochloride was removed by filtration, and the ethyl acetate layer was separated. The aqueous phase was extracted twice more with ethyl acetate and the combined organic phases were washed with dilute hydrochloric acid (2N), then with water and then with saturated aqueous sodium chloride solution, then dried over sodium sulfate and evaporated to dryness. The residual gum was chromatographed on a column under medium pressure and eluted with: ethyl acetate to give 5-nitroimidazole-4-N-benzyl-N- (4-methoxybenzyl) carboxamide (2.9 g) as a brown solid, m.p. 167-170 ° C (after crystallization from a mixture of petroleum ether (b.p. 60-80 ° C) and isopropanol).

Elemental analysis: C 61.3; H 4.93; N 15.3%; Calculated: C, 62.29; H 4.95; N 15.29%;

II

27 80273 I.R. (KBr plate): 3100-2800, 1640, 1510, 1450 and 1370 cm -1.

NMR (in DMSO-d 6, 120 ° C): band at 3.76, 4.5, 4.6, 7.3 and 7.8 ppm, double bands concentrated at 6.85 and 7.2 ppm.

(The NMR spectrum at room temperature is complicated due to the doubling of the signals caused by the inhibition of the refraction that occurs in the bond connecting the amide carbonyl group to the amide nitrogen tower).

(ii) A solution of 5-nitroimidazole-4-N-benzyl-N- (4-methoxybenzyl) carboxamide (2.2 g) in dry ethanol (200 ml) was hydrogenated at room temperature under 3 atmospheres using Raney nickel as a catalyst. When the absorption of hydrogen was complete (after 2 hours, 48 minutes) the mixture was filtered, treated with hydrogen chloride gas and evaporated to dryness at a temperature below 40 ° C. Trituration with a mixture of isopropanol and diethyl ether gave 5-aninoimidazole-4-N-benzyl-N- (4-methoxybenzyl) carboxamide hydrochloride (2.2 g) as a gummy solid which decomposed at temperatures above 70 ° C.

/I.R. (KBr plate): 3400-2800, 1640 cm -1; NMR (in methanol-d 6): band at 3.7, 4.4, 4.5, 7.2 and 8.3 ppm, double band at 6, 7 and 6.9 ppm, (signals: broadened due to inhibition of refraction in the bond connecting the amide carbonyl group to the amide nitrogen atom / ·

Preparation 3 (i) A mixture of 1,6-dinitro-5H, 10H-diimidazo / 1,5-a: 1 ', 5'-d7pyrazine-5,10-dione (5.5 g, prepared as described in Preparation 1), N- (4-methoxybenzyl) aniline / 14.5 g; Zechmeister et al., Ber., (1930), 63B, 288% and tetrahydrofuran (250 ml) were heated at reflux for 12 h. The tetrahydrofuran was then evaporated in vacuo and the residual dark oil partitioned between dilute hydrochloric acid (2M; 1000 ml) and ethyl acetate: 1000 ml). The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting solid was triturated with diethyl ether to give 5-nitroimidazole-4-N- (4-methoxybenzyl) -N-phenylcarboxamide (3.18 g) as a peach solid, m.p. 212-215 ° C (after recrystallization from isopropanol).

Elemental analysis: C 60.4; H 4.41; N 16.0%; Calculated: C, 61.37; H 4.58; N 15.91%; NMR (in DMSO-d 6): bands at 3.7, 5.0 and 7.7 ppm, multi band in the range 6.7-7.3 ppm; I.R. (KBr plate): 1660 cm -1 (ii) A solution of 5-nitroimidazole-4-N- (4-methoxybenzyl) -N-phenylcarboxamide (2.1 g) in dry ethanol (200 ml), hydrogenated at 25 ° C and 3 atmospheres using Raney nickel as catalyst. After hydrogen absorption was complete (after 5 hours), the mixture was filtered and evaporated to dryness. The residue was triturated with diethyl ether to give 5-aminoimidazole-4-N- (4-methoxybenzyl) -N-phenylcarboxamide (1.9 g) as a gum.

*: {A portion of this gummy substance was characterized as a picrate:: 5-Aminoimidazole-4-N- (4-methoxybenzyl) -N-phenylcarboxamide (0.15 g) was dissolved in dry 1,2-dimethoxyethane (3 ml) and treated with solution. with picric acid (0.25 g) in 1,2-dimethoxyethane (5 ml). The resulting crystals were filtered off and washed with diethyl ether to give 5-aminoimidazole-4-N- (4-methoxybenzyl) -N-phenylcarboxamide picrate (0.07 g) as a yellow solid, m.p. 207 ° C (decomposes).

Elemental analysis: C, 49.1; H 3.64; N 16.5 S; c 24 H 21 N 7 O 9: 2H 2 O: corresponds: C 4 9.1; H 4.29; N 16.69% 7).

Preparation 4 (i) A mixture of 1,6-dinitro-5H, 10H-diimidazo [1,5-a]: 11,51-d7-pyrazine-5,10-dione (8.08 g; prepared in Preparation 1 as described), N-methylaniline 1180273 (12.44 g) and tetrahydrofuran (400 ml) were heated at reflux for 24 h. The tetrahydrofuran was evaporated in vacuo and the residual dark solid was treated with boiling diethyl ether. The residual insoluble solid was subjected to medium pressure chromatography on a column and eluted with a mixture of ethyl acetate and methanol (1: 1 v / v) to give 5-nitroimidazole-4-N-methyl-N-phenylcarboxamide (4.68 g) as a white solid. in the form of a substance, m.p.

193 ° C.

Elemental analysis: C 52.5; H 3.95; N 22.2%; Calculated: C 53.66; H 4.09; N 22.76%; I.R. 1660 cm -1.

(ii) A solution of 5-nitroimidazole-4-N-methyl-N-phenylcarboxamide (1.0 g) in dry ethanol (110 ml) was hydrogenated at 23 ° C and 3 atmospheres under pressure using Raney nickel as catalyst. When hydrogen absorption was complete (after 1 h 39 min), the mixture was filtered and treated with dry hydrogen chloride gas. The solution was then evaporated to dryness to give 5-aminoimidazole-4-N-methyl-N-phenylcarboxamide hydrochloride (0.9 g) as a pale solid, m.p. 100 ° C (decomposes).

{This compound was characterized as a picrate; A solution of 5-aminoimidazole-4-N-methyl-N-phenylcarboxamide hydrochloride (0.25 g) in water (2 ml) was treated with a solution of picric acid (0.25 g) in 1,2-dimethoxyethane (2 ml). ).

The precipitate was filtered off and washed with 1,2-dimethoxyethane to give 5-aminoimidazole-4-N-methyl-N-phenylcarboxamide picrate (0.12 g) as a yellow solid, m.p. 237-238 ° C (decomposes).

Elemental analysis: C 45.3; H 3.26; N 21.8%; Calculated: C 45.85; H 3.39; N 22.02%; I.R. (KBr plate): 1640 cm.

30 8 0 2 7 3

Preparation 5 (i) A stirred aqueous solution of diethylamine (30% w / w, 35 ml) cooled with a cold water bath was treated with 5-nitroimidazole-4-sulfonyl chloride (4.15 g of a wet material, recently prepared from 3.33 g of 5-nitroimidazole). -4-thiolammonium salt by the method of Fisher et al., Can. J. Chem. 39. 501) in portions. The mixture was stirred for a further 20 min and then evaporated in vacuo below 40 ° C to reduce it to half volume. The mixture was then strongly acidified by treatment with concentrated hydrochloric acid, and the resulting pale yellow solid was filtered off and recrystallized from dimethylformamide to give 5-nitroimidazole-4- (N, N-dimethylsulfonamide) (2.73 g) as brownish plates, m.p. 282-283 ° C (decomposes).

[Elemental analysis: - C, 27.3; H 3.65; N 25.4; S 14.2%; Calculated: C 27.3; H 3.65; N 25.4; S 14.6%].

(ii) A solution of 5-nitroimidazole-4- (N, N-dimethylsulfonamide) (1.0 g) in dry ethanol (100 ml) was hydrogenated at 24 ° C at 3 atmospheres using Raney nickel as catalyst. . The mixture was then filtered and immediately diluted with diethyl ether (200 mL) and treated with dry hydrogen chloride gas until slightly acidic. The mixture was then evaporated in vacuo at a temperature below 30 ° C. The residual solid was dissolved in hot dry ethanol (20 ml) and the solution was treated with charcoal, filtered, evaporated to a volume of 15 ml,

II

3180273 was treated with dry diethyl ether (60 ml) and allowed to crystallize. The resulting solid was filtered off to give 5-aminoimidazole-4- (Ν, Ν-dimethylsulfonamide) hydrochloride (0.8 g) as reddish brown needles, m.p. 188-189 ° C (decomposes).

Elemental analysis: C 26.1; H 4.80; N 23.6; Cl 15.9; S 13.9%; C 5 H 10 N 4 O 2 S: HCl corresponds to: C 26.5; H 4.85; N 24.7; Cl 15.6; S 14.15% 7 · (iii) A stirred solution of sodium nitrite (0.31 g) in water (5 ml) cooled with an ice bath was treated by dropwise addition of a solution of 5-aminoimidazole-4- (Ν, Ν-dimethylsulfonamide). ) hydrochloride (0.7 g) in dilute hydrochloric acid (2N; 3.1 ml). The resulting solid was filtered off and washed with ice-cold water to give 5-diazoimidazole-4- (Ν, Ν-dimethylsulfonamide) (0.38 g), m.p. 109 ° C (decomposes).

/I.R. 2180, 2210 cm -1.

A second crop (0.21 g) of slightly less pure product was obtained by extracting the aqueous solutions at 0 ° C with ethyl acetate, drying the extract over magnesium sulphate and evaporating in vacuo.

Preparation 6 (i) A stirred aqueous solution of methylamine (25% w / w; 35 ml) cooled in a cold water bath was treated with 5-nitroimidazole-4-sulfonyl chloride (4.15 g of a wet material, recently prepared 3.33 g). g of the ammonium salt of 5-nitroimidazole-4-thiol by the method of Fisher et al., op.cit.), which was added portionwise. The mixture was stirred for a further 15 minutes and then evaporated in vacuo at a temperature below · 40 ° C to halve the volume. The mixture was then strongly acidified by treatment with concentrated hydrochloric acid and the resulting solid was filtered off and recrystallised from water to give 5-nitroimidazole-4- (N-methylsulfonamide) (2.07 g) as pale yellow plates, m.p. 260-263 ° C (decomposes).

32 80273 / Elemental analysis: C, 23.1; H 2.87; N 27.4; S 15.4%; calculated; C 23.3; H 2.93; N 27.2; S 15.55% 7.

(ii) A solution of 5-nitroimidazole-4- (N-methylsulfonamide) (0.1 g) in dry ethanol (100 ml) was hydrogenated at 24 ° C and 3 atmospheres under pressure using Raney nickel as catalyst. The mixture was then filtered and immediately diluted with diethyl ether (200 mL) and treated with dry hydrogen chloride gas until slightly acidic. The mixture was then evaporated in vacuo at a temperature below 30 ° C. The residual solid was dissolved in a minimum amount of hot ethanol and the solution was treated with charcoal, filtered and diluted with diethyl ether. The resulting solid was filtered off to give 5-aminoimidazole-4- (N-methylsulfonamide) hydrochloride (0.63 g), m.p. 178-180 ° C (decomposes).

Elemental analysis: C 22.3; H 4.13; N 25.5; Cl 16.9%; C 4 H 9 N 4 O 2 S: HCl corresponds to: C 22.6; H 4.26; N 26.35; Cl 16.7% 7.

(iii) A stirred aqueous solution of sodium nitrite (0.285 g) (4 ml) cooled in an ice bath was treated with dropwise addition of a solution of 5-aminoimidazole-4- (N-methylsulfonamide) hydrochloride (0.55 g). ) in dilute hydrochloric acid (2N; 2.8 ml). The resulting solid was filtered off and washed with ice-cold water to give 5-diazoimidazole-4- (N-methylsulfonamide) (0.36 g), mp 150 ° C (dec).

Elemental analysis: C 25.2; H 2.47; N 37.0%; Calculated: C 25.7; H 2.69; N 37.4%; I.R. 2210 cm "* 7.

>

A second crop (0.07 g) of product was obtained by extracting aqueous solutions at 0 ° C with ethyl acetate, drying the extract over magnesium sulphate and evaporating in vacuo.

Il 33 80273

Preparation 7

A solution of sodium nitrite (0.5 g) in water (5 ml) maintained at 0 ° C was treated by dropwise addition of a solution of 5-amino-4-methylsulfonylimidazole hydrochloride / T, 0 g, thus prepared. as reported by Bennett et al., JACS, 79 (3), 2188-2191, (1957) in dilute hydrochloric acid (2N; 5 mL) The solution was stirred for an additional 15 min and then extracted with ethyl acetate (5 x 20 mL). sodium sulfate and evaporated in vacuo to leave a yellow oil which crystallized on standing to give 5-diazo-4-methylsulphonylimidazole (0.74 g), mp 128-130 ° C.

/T.R. 2125 cm '^ 7.

Preparation 8 (i) A stirred solution of p-methoxybenzylamine (10 g) in water (30 ml) was treated with 5-nitroimidazole-4-sulfonyl chloride (6.8 g of a wet material recently prepared from 6.0 g). -nitroimidazole-4-thiol ammonium salt by the method of Fisher et al., op. cit.). The mixture solidified rapidly, then treated with isopropanol (20 mL) and triturated and allowed to stand overnight.

The resulting solid was filtered off, washed with ice-cold water and then suspended in water (150 ml) and carefully treated with dilute hydrochloric acid (2N) until the suspension reached pH 2. The resulting yellow solid was filtered off and washed with a small amount. ice-cold water to give 5-nitroimidazole-4- [N- (4-methoxybenzyl) sulfonamide] (7.42 g), m.p. 269-270 ° C (decomposes).

(ii) A solution of 5-nitroimidazole-4- [N- (4-methoxybenzyl) sulfonamide] (1.0 g) in dry ethanol (100 ml) was hydrogenated for 6 h at atmospheric pressure using Raney nickel (50 ml) as catalyst. %). The catalyst was quickly separated by filtration through diatomaceous earth and the filtrate was immediately treated with concentrated hydrochloric acid (20 ml). The mixture was evaporated to dryness and the resulting residue was triturated with diethyl ether 34 80273. The solid was filtered off and washed with diethyl ether to give 5-aminoimidazole-4- [N- (4-methoxybenzyl) sulfonamide] (0.25 g), m.p. 154-155 ° C.

(iii) A solution of sodium nitrite (0.14 g) in water (5 ml) was treated by dropwise addition of a solution of 5-aminoimidazole-4- [N- (4-methoxybenzyl) sulfonamide? (0.5 g) in dilute hydrochloric acid (2N; 10 ml) keeping the temperature at 0 ° C. The mixture was stirred at 0 ° C for a further 15 min and the solid was then filtered off, washed with water and dried over phosphorus pentoxide to give 5-diazoimidazole-4- [N- (4-methoxybenzyl) sulfonamide] (0.3 g). mp. 144-146 ° C (decomposes). /f.R. 2180 cm

Preparation 9 (i) A solution of piperidine (6.4 ml) in dry tetrahydrofuran (92 ml) was treated with 1,6-dinitrodiimidazo [1,5-a: 1 ', .5'-d / pyrazine-5,10-dione (4.59 g, prepared as described in Preparation 1) and stirred at room temperature for 1 h. The mixture was then evaporated and the residue was dissolved in dilute hydrochloric acid (2N; 92 ml). Solutions:. extracted with ethyl acetate (3 x 200 ml) and the combined extracts 1 dried over magnesium sulphate and evaporated. The residue was chromatographed under medium pressure on silica; and eluted with a mixture of chloroform and methanol (9: 1 v / v). The appropriate fractions were combined and evaporated and the residue washed with diethyl ether and then ethyl acetate to give 4-nitro-5-piperidinocarbonylimidazole (2.72 g) as a yellow solid, m.p. 149-150 ° C.

Elemental analysis: C 48.2; H 5.33; N 25.1%; Calculated: C 48.1; H 5.39; N 25.0% /.

(ii) A solution of 4-nitro-5-piperidinocarbonylimidazole (2.68 g, prepared as described above); in methanol (27 ml) and dimethylformamide (27 ml), treated with platinum oxide (0.27 g) and the shaken mixture

II

35 8 0 2 7 3 was hydrogenated at room temperature and atmospheric pressure.

After uptake of hydrogen, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in dilute hydrochloric acid (2N; 50 ml), the solution filtered and the filtrate evaporated in vacuo. The resulting residue was washed with acetone to give 4-amino-5-piperidinocarbonylimidazole hydrochloride (2.1 g) as a pale green solid, m.p. 175-177 ° C, which was pure enough to be used in the next step.

Preparation 10 (i) A cooled, stirred solution of 2-methyl-5-nitroimidazole (127 g) in aqueous sodium hydroxide solution (5% w / v; 1500 ml) was treated with bromine (160 g) maintaining the temperature between 15-20 ° C. The mixture was stirred at room temperature for 5.5 h and the precipitated solid was redissolved by treating the mixture with aqueous sodium hydroxide solution (2N). Residues of insoluble material were filtered off and the filtrate was acidified to pH 1 by treatment with concentrated hydrochloric acid. The white solid formed was filtered off, recrystallised from ethanol and dried in a desiccator over phosphorus pentoxide to give 4-bromo-2-methyl-5-nitroimidazole (151 g) as a white crystalline solid, m.p. 267-268 ° C.

(ii) A stirred solution of 4-bromo-2-methyl-5-36 8 0 2 7 3 nitroimidazole (20.6 g, prepared as described above) in aqueous ammonia solution (5N; 180 ml) was heated at 45 ° C. and treated by continuously introducing hydrogen sulfide into it for 40 min. A yellow crystalline precipitate slowly formed. The mixture was cooled with ice and the solid was filtered off, washed with ice water and dried in a desiccator over phosphorus pentoxide to give 4-mercapto-2-methyl-5-nitroimidazole ammonium salt (14.6 g) which darkened without melting below 300 ° C.

Elemental analysis: C 27.2; H 4.41; N 31.6; S 18.2%; C4H4O2N3S: NH4 requires: C, 27.27; H 4.58; N 31.8; S 18.2% / · (iii) Ice-cooled, vigorously stirred solution of the ammonium salt of 4-mercapto-2-methyl-5-nitroimidazole (3.51 g, prepared as described above) in ice-cooled and vigorously stirred dilute hydrochloric acid (IN , 120 ml) was treated with chlorine gas until a white solid formed. The mixture was stirred for a further 30 min at 0 ° C and then the solid was filtered off, washed with water and dried in a desiccator over phosphorus pentoxide to give 4-chlorosulphonyl-2-methyl-5-nitroimidazole (3 .0 g), m.p. 160-162 ° C (decomposes).

Elemental analysis: C 20.8; H 1.73; N 18.3; Cl 15.7; S 14.6%; Calculated: C, 21.29; H 1.79; N 18.63; Cl 15.72; S 14.21% 7- (iv) A cooled solution of 4-methoxybenzylamine (5.48 g) in dry absolute ethanol (20 ml) was treated with 4-chlorosulfonyl-2-methyl-5-nitroimidazole (2.25 g). , prepared as described above) and the mixture was stirred at room temperature for 3 h. The precipitated yellow solid was filtered off, washed with ethanol; and discarded as 4-methoxybenzylamine hydrochloride.

The combined filtrates and washings were evaporated to dryness and the resulting residue was suspended in water (50 ml) and made

II

37 80273 acidified to pH 1 by treatment with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 20 mL). The combined extracts were dried over magnesium sulphate and evaporated to dryness to give 4- (4-methoxybenzylsulphanoyl) -2-methyl-5-nitroimidazole (2.77 g) as a pale solid, m.p. 167-170 ° C.

Elemental analysis: C 44.2; H 4.32; N 17.2; S 9.5%; Calculated: C 44.17; H 4.32; N 17.17; S 9.83% / (v) A solution of 4- (4-methoxybenzylsulfamoyl) -2-methyl-5-nitroimidazole (4.5 g, prepared as described above) in dry ethanol (120 ml) was hydrogenated under 3 atmospheres. under pressure with Raney nickel as catalyst for 30 min. The catalyst was filtered off and washed with dry ethanol (10 ml) and the combined filtrates and washings were 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-methylimidazole hydrochloride (3.25 g), m.p. 183-185 ° C.

(vi) A solution of sodium nitrite (0.3 g) in water (5 ml) maintained at 0-5 ° C was treated by dropwise addition of a solution of 5-amino-4- (4-methoxybenzylsulfamoyl) -2-methylimidazole hydrochloride (1.0 g, prepared as described above) in dilute hydrochloric acid (2N, 10 ml) The mixture was stirred for a further 5 min at 0-5 ° C and the resulting orange solid was filtered off, washed with water and dried in a desiccator. phosphorus pentoxide to give 5-diazo-4- (4-methoxybenzylsulfamoyl) -2-methylimidazole (0.75 g), mp 140 ° C (dec).

/I.R. 2200 cm "* 7.

Preparation 11 (i) A solution of dimethylamine in ethanol (33% w / v, 10 ml) was cooled and stirred and treated with 4-chlorosulfonyl-2-methyl-5-nitroimidazole (2.25 g, prepared as described in Preparation 10). ) and stirred at room temperature for another 45 min. The solution was acidified to pH 1 by treatment with concentrated hydrochloric acid and the resulting white solid was filtered off and washed with cold water to give 4-dimethylsulfamoyl-2-methyl-5-nitroimidazole (1.9 g), m.p. 240-241 ° C.

Elemental analysis: C 30.5: H 4.24; N 23.8; S 13.8%; Calculated: C 30.77; H 4.3; N 23.92; S 13.69%; NMR (in DMSO-d 6) bands at 2.30 and 2.0 SO ppn /.

(ii) A solution of 4-dimethylsulfamoyl-2-methyl-5-nitroimidazole (12 g; prepared as described above) in dry ethanol (300 ml) was hydrogenated at 3.5 atmospheres in the presence of Ranev nickel catalyst for 1 h. Catalyst was separated by filtration and the filtrate was acidified to pH 1 by treatment with concentrated hydrochloric acid and evaporation to dryness. The resulting orange residue was triturated with diethyl ether to give 5-amino-4-dimethylsulfamoyl-2-methylimidazole (8.9 g), m.p. 215-217 ° C (decomposes).

(iii) A solution of sodium nitrite (1.0 g) in water (15 ml) was maintained at 0 ° C and treated by dropwise addition of a solution of 5-amino-4-dimethylsulfamoyl-2-methylimidazole (2.4 g) in dilute hydrochloric acid (214; 30 ml) and stirred for a further 10 min at 0 ° C. The mixture was extracted with ethyl acetate (5 x 30 ml) and the combined extracts dried over magnesium sulphate, evaporated to dryness and triturated with petroleum ether (b.p. 60-80 ° C) to give 5-diazo-4-dimethylsulfamoyl-2-methyl- imidazole (1.8 g), m.p. 85-87 ° C (decomposes).

/1.R. 2180 cm.

Preparation 12 (i) A solution of the ammonium salt of 4-mercapto-2-methyl-5-nitroimidat-Sol (10.5 g, prepared in

II

39 80273 10 as described in sodium methoxide in methanol (prepared by careful dissolution of sodium (2.3 g) in dry methanol (250 ml)), treated with methyl iodide (10.7 g) and heated at reflux for 2 h. The mixture was then evaporated to dryness and the residue suspended in sodium hydroxide. aqueous solution (2N; 100 ml). The suspension was filtered and the filtrate was acidified to pH 1 by treatment with concentrated hydrochloric acid to give 2-methyl-4-methylthio-5-nitroimidazole (9.0 g) as a yellow solid, m.p. 236-237 ° C (decomposes).

Elemental Analysis: C, 34.7; H 4.04; N 24.3; S 18.5%; Calculated: C 34.67; H 4.07; N 24.26; S 18.51% 7 · (ii) A solution of 2-methyl-4-methylthio-5-nitroimidazole (3.46 g, prepared as described above) in glacial acetic acid (35 ml) was heated at 60 ° C and treated by dropwise addition of aqueous hydrogen peroxide (30% w / v, 35 mL). The mixture was then heated at 10 ° C for 15 min, cooled to room temperature and treated with sufficient sodium sulfite to decompose excess hydrogen peroxide (detected by experimentally testing the sample with starch and potassium iodide). The mixture was then extracted continuously with ethyl acetate for 20 h.

The extract was evaporated and the residual white solid was triturated with petroleum ether (b.p. 60-80 ° C) and the precipitate was filtered off to give 2-methyl-4-methylsulphonyl-5-nitroimidazole (3.6 g), m.p. 222-224 ° C. Elemental analysis: C 29.8; H 3.28; N 20.6; S 15.7%; Calculated: C, 29.27; H 3.44; N 20.48; S 15.63% 7 · (iii) A solution of 2-methyl-4-methylsulfonyl-5-nitroimidazole (4.9 g, prepared as described above) in dry ethanol (400 ml) was hydrogenated at 3.5 atmospheres under Raney pressure. in the presence of a nickel catalyst for 30 min. The catalyst was filtered off and the filtrate was acidified to pH 1 by treatment with concentrated hydrochloric acid and evaporated to dryness and the residue was triturated with diethyl ether containing small amounts of ethanol to give a purple solid which was filtered off and washed with dichloromethane. 5-amino-2-methyl-4-methylsulfonylimidazole hydrochloride (4.1 g) was obtained, m.p. above 300 ° C.

[Elemental analysis: - C, 27.3; H 4.51; N 19.9; Cl 17.9; S 13.7%; Calculated: C, 28.37; H 4.76; N 19.8; Cl 16.75; S 15.15%] (iv) A solution of sodium nitrite (0.25 g) in water (5 ml) maintained at 0 ° C was treated by dropwise addition of a solution of 5-amino-2-methyl-4- methylsulfonylimidazole hydrochloride (0.53 g, prepared as described above). The mixture was stirred for an additional 15 min at 0 ° C and extracted with ethyl acetate (5 x 15 mL). The combined extracts were dried over magnesium sulfate and evaporated to dryness. The resulting oil was triturated with petroleum ether (b.p. 60-80 ° C) to give 5-diazo-2-methyl-4-methylsulfonylimidazole (0.4 g), m.p. 100 ° C (decomposes).

[I.R. 2185 cm-1]

The tetrazine derivatives according to the invention can be formulated into pharmaceutical compositions containing as active ingredient at least one compound of the general formula I together with a pharmaceutically acceptable carrier or coating. In clinical practice, the compounds of general formula I are usually administered orally, rectally, parenterally, e.g. intraperitoneally, or intravenously, e.g. by infusion, or vaginally.

Methods for preparing pharmaceutically active compounds are well known in the art, and a suitable medium may be prescribed by a physician or drug specialist depending on factors such as the desired effect, patient size, age, sex, and condition, and the properties of the active compound. The compositions may also contain, as is conventional in the art, materials such as solid or liquid diluents, wetting agents, preservatives, flavoring agents, coloring agents, and the like.

Solid form preparations for oral administration include compressed tablets, pills, dispersible powders, and granules. In such solid mixtures, one or more active compounds are mixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid or lactose. The compositions may also contain, in a conventional manner, additives in addition to inert diluents, e.g. lubricants such as magnesium theatrate. Liquid mixtures for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. In addition to inert diluents, such compositions can also include adjuvants, such as wetting and suspending agents, e.g., polyvinylpyrrolidone, and sweetening, flavoring, perfuming, and preservative agents. Compositions for oral administration also include capsules of an absorbable material, such as gelatin, containing one or more active ingredients with or without diluents or excipients.

Solid compositions for vaginal administration comprise pessaries prepared in a manner known per se and containing one or more active compounds.

Solid compositions for rectal administration include suppositories formed in a manner known per se and containing one or more active compounds.

Formulations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents or suspending agents include polyethylene glycol, dimethyl sulfoxide, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Such compositions may also contain additives such as preservatives, wetting agents, emulsifying agents and dispersing agents. They can also be sterilized, e.g. by filtration through a bacteria-retaining filter, by adding sterilizing agents to the mixture or by irradiation. They may also be prepared in the form of sterile solid mixtures which can be dissolved in sterile water or other sterile injectable medium immediately before use.

The percentage of active substance in the mixtures may vary, it being necessary that the amount be such that a suitable dosage will be obtained in order to obtain a therapeutic effect. It will be appreciated that multiple dosage unit regimens may be administered at approximately the same time. In general, these preparations should normally contain at least 0.025% by weight of active ingredient when administered by injection, which includes administration by infusion. For oral administration, the preparation usually contains at least 0.1% by weight of active ingredient. The dosage used depends on the desired therapeutic effect, the mode of administration and the duration of treatment.

The tetrazine derivatives of general formula I are useful in the treatment of malignant neoplasms, e.g. carcinoma, melanoma, sarcoma, lymphoma and leukemia, in doses generally between 0.1 and 200, preferably between 1 and 20 mg / kg body weight per day.

The following connection examples illustrate pharmaceutical compositions.

Mixture Example 1

A solution suitable for patenteral administration was prepared from the following ingredients: 11 43 80273 8- (N-Benzyl-N-phenylcarbamoyl) -3-methyl- [3H] -imidazo [5,1-d] -1,2,3 1,5-Tetrazin-4-one Dissolve 1.0 g of dimethyl sulfoxide in 10 ml of 8- (N-benzyl-N-phenylcarbamoyl) -3-methyl- [3H] -imidazo [5,1-d] -1,2,3 , 5-tetrazin-4-one in dimethyl sulfoxide. The resulting solution was dispensed under aseptic conditions into ampoules, 1.1 ml per ampoule. The ampoules were sealed to give 10 ampoules each containing 100 mg of 8- (N-benzyl-N-phenylcarbamoyl) -3-methyl- [3H] -imidazo [5,1-d] -1,2,3,5- tetrazine-4-one.

Similar ampoules containing solutions suitable for parenteral administration can be prepared by the same procedure but substituting 8- (N-benzyl-N-phenylcarbamoyl) -3-methyl- [3H] -imidazo [5,1] -1,2,3,5- tetrazin-4-one with another compound of general formula I.

Mixture Example 2

A solution suitable for patenteral administration was prepared from the following ingredients: 3- (2-chloroethyl) -8- (N-methylsulfamoyl) - [3H] -imidazo [5,1-d] -1,2,3, 5-Tetrazin-4-one 1.0 g of dimethyl sulfoxide by dissolving 10 ml of arrack oil in 90 ml of 3- (2-chloroethyl) -8- (N-methylsulfamoyl) - [3H] -imidazo [5,1] -1,2,3 , 5-tetrazin-4-one in dimethyl sulfoxide and adding arrack oil. The resulting solution was dispensed under aseptic conditions into ampoules, each vial containing 10 ml of solution. The ampoules were sealed to give 10 ampoules, each containing 100 mg of 3- (2-chloroethyl) -8- (N-methylsulfamoyl) - [3H] -imidazo [5,1] -1,2,3,5-tetra- ratin-4-one with another compound of formula I.

44 80273

Mixture Example 3

Capsules suitable for oral administration were prepared by sealing 3- (2-chloroethyl) -8- (N-methylsulfamoyl) - [3H] -imidazo [5,1-d] -1,2,3,5-tetrazin-4-one in gelatin capsules. No. 2, 10 mg per capsule.

Similar capsules may be prepared using another compound of general formula I or another suitably sized capsule shell.

Il

Claims (1)

45 8 0 2 7 3 Claim An analogous process for the preparation of new therapeutically useful -imidazo [5,1-d7-1,2,3,5-tetrathin-4-one derivatives of the general formula 2R VJ I Is \ 1 ROR wherein R is a straight-chain or branched alkyl group having up to 4 carbon atoms which may be substituted by a halogen atom, R is a hydrogen atom, a straight-chain or branched alkyl group having up to 4 carbon atoms or 2 cyclohexyl, benzyl or phenethyl groups, of the formula -S <0> nR, -SO2NR R, -CONR R or CONHNO2, where n is 1 or 2, R is a straight-chain or branched alkyl group having up to 4 carbon atoms, R and R, which may be similar or different, each represents a hydrogen atom, a straight-chain or branched alkyl group having up to 4 carbon atoms or a phenylalkyl group which may be substituted by alkoxy and the alkyl moiety of which is straight-chain or ha radical and contains up to 4 carbon atoms, R is the same as the group R or 9. it is a phenyl group, and R is the same as the group R.59 but is not a hydrogen atom or an alkyl group, or R and R together form its nitrogen atom with which they are attached, a piperidino ring and, when R is a sulfamoyl or monosubstituted sulfamoyl group, for the preparation of their salts, characterized in that, a) for the preparation of a tetrazine derivative 13 of general formula I wherein R and R is as defined above 2 6 7 8 and R is a group of the formula -S <O) -R, -SO 0 NR R or 59 6 7 n 2 -CONR R, where n, R and R are as defined above, 8 R means the same as above but is not a hydrogen atom, and R 5 and R are the same as above, but when R is a 9 hydrogen atom, R is a phenyl alkyl group as defined above, a compound of the general formula is obtained: 3 R NN III 3 12 where R has the same meaning as above and R is a group of the formula -S (O) „R, -SO-> NR R or -CONR R, where n, R, R, 7 8 9 n 2 R, R and R are as defined in a) above, to react with a compound of general formula: R NCO IV wherein R is as defined above, b> to prepare a tetrazine derivative of general formula I wherein R and R are as defined in formula 2 I and R are a group of the formula -SO 2 NHR or g 1 -CONHR, a compound of the general formula is debenzylated: 17 NNI VIII Yv '1, ROR 47 80273 47 17 7 13 9 13 wherein R is a group of the formula is the formula -SO 2 NR R or -CONR R, wherein R is a benzyl group or an alkoxy-substituted benzyl group, and R and R are as defined above, to replace one or both benzyl groups or alkoxy-substituted benzyl groups with a hydrogen atom, or c) such a general formula I to prepare a tetrazine derivative according to claim 1, wherein R and R have the same meaning as in formula 2 and R is a group of the formula -CONHNO2, a compound corresponding to the nitrate of the general formula: conh2 NI VN I w, R OR 1 3 in which R and R have the same meaning as in formula I , to convert a group -CONH 2 to a group -CONHNO 2, and if desired d) converting the obtained tetrazine product of general formula I, wherein R is a sulfamoyl or monosubstituted sulfamoyl group, into a salt, preferably an alkali metal salt. , β 80273 Analog-free formulation of a therapeutically active compound (3H) -imidazo [5,1-d] -1,2,3,5-tetrazin-4-one derivative with the formula YV \, R or color R is used as a substituent or a alkyl group having up to 4 cycatoms, the alkyl group being eubetitated with a halogen atom, R as a substituent as an alkyl group having up to 4 cyclohexyl, benzyl or phenyl in the group consisting of -S <0> nR, SO2NR R, -CONR R or C0NHN02, color n in the case of 1 or 2, R in the group consisting of 9 or 10 alkyl groups having up to 4 chapters, R and R, lika eller olika, betecknar envar en väteatom, en rakkedjig eller grenad alkylgrupp med upp verti 4 kolatomer eller en phenylyläikylgrupp eom kan vara eubetituerad med alkoxi och Väre alkyldel är rakkedjig eller grenad och innehäller D y upp account 4 kolatomer, R R or a protecting group and a phenyl group, and R is selected from the group consisting of R, which may be attached to an alkyl group, or R and R to a group attached to the quaternary group. 2 The atom to which the group is attached to the piperidine, and to the group consisting of eulfamoyl or monohydric acid. ealter därav, kännetecknat av att II 80273 49 a> för f rämetä1Ining av tetrazinderivat med den allmänna for-13 2 mein I color R och R har ovan angiven betydelee och R be- 6 7 Θ tecknar en grupp med formuleln -SCOl ^ R, -SO-, NR R eller 5 9 6 7 n «8 -CONR R, color n, R och R har ovan angiven betydelee, R har ovan angiven betydelee, men betecknar icke en väteatom, 5 9 5 och R och R har ovan angiven betydelee, men di R betecknar 9 en väteatom, betecknar R en ovan definierad feny1 a 1kylgrupp, omeättee en förening med den allmänna formuleln: 3 RO NN III © R N2 3 12 color R har ovan angiven betydelee och R är en grupp med 6 7 8 5 9 5 6 formeln -S (O) _R, -SOoNR R or -CONR R, color n, R * R, 7 8 9n £ R, R and R are specified in point (a) of this Regulation: (b) for the purpose of determining the tetrazine form of the formula I, 13 2 color R and R in the case of a group of formulas I and R be- 7 9 techniques and groups of formulas -SO2NHR or -CONHR, debeney-lerae and förening with the following formulas: 17 N. NI VIII W \, ROR 50 80273 17 7 13 color R is a group in the form of a group -SQ NR R or 9 13 13 -CONR R, color R is a group in the form of an alkoxy group and R and the group R is an angular betydelae, for which one or more a benzyl group or an alkoxy substituent having a substituent, or c) a compound having the same tetrazine content as all of the following: for the purposes of this Regulation: con h2 NiSs * t »NVNII Yvv 1 3 color R and R in detail of the form I, for the case of CONC 2 in the group -C0NHN02, and in the same way, en aulfamoyl- or monoaubatitu-erad aulfamoylgrupp account aalt, företrädeavia et alkalime-tallealt. Il