GB2129426A

GB2129426A - Compounds of thiatriazines

Info

Publication number: GB2129426A
Application number: GB08325762A
Authority: GB
Inventors: Barry Clive Ross; Jeffrey Daniel Michael; Simon John Cousins
Original assignee: Hoechst UK Ltd
Current assignee: Sanofi Aventis UK Holdings Ltd
Priority date: 1982-09-28
Filing date: 1983-09-27
Publication date: 1984-05-16
Also published as: DK442183A; KR840006226A; PT77402A; GB2129426B; ES8504753A1; PT77402B; ES525943A0; FI833445A0; ES8600262A1; EP0104611A3; ES532485A0; DK442183D0; GB8325762D0; AU1962583A; EP0104611A2; FI833445A; NO833478L; HU192964B; ZA837186B; NZ205732A

Abstract

Compounds of thiatriazines of the general formula <IMAGE> (A represents an optionally substituted phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl radical; X represents -O-, -S- or -CH2; n represents 0 or 1; m represents 2 or 3; p represents 1 or 2; R<3> and R<4> each represents a hydrogen atom or a substituent, or together complete a fused ring) and their salts have histamine H-2 antagonist activity.

Description

1

GB 2 129 426 A 1

SPECIFICATION Thiatriazine derivatives

The present invention relates to thiatriazine derivatives which have histamine H-2 antagonist activity. The invention also relates to processes for the preparation of these derivatives, to 5 pharmaceutical preparations comprising them, and to their use. 5

Histamine is one of a number of naturally occurring physiologically active substances which are thought to interact with specific receptors. In the case of histamine, there are at least two types: one is called H-1 receptor (Ash and Schild, Brit. J. Pharmac. 1966,27 427), and the other is called the H-2 receptor (Black et at Nature 1972,236, 385). The action of histamine at the H-1 receptors, for 10 example, stimulation of bronchial and gastro-intestinal smooth muscle, is blocked by the compounds 10 generally known as "antihistamines", but which are now also called histamine H-1 antagonists, for example, mepyramine. The action of histamine at the H-2 receptors, for example, stimulation of gastric acid secretion and heart rate, is not blocked by mepyramine, but is blocked by other compounds, for example, burimamide and cimetidine.

15 Histamine H-2 antagonists may be used to treat those conditions resulting from stimulation by 15 histamine of H-2 receptors, either alone, for example, in inhibiting gastric acid secretion and thus treating its sequelae, for example, gastric and peptic ulcers; or together with H-1 antagonists, for example, in allergic and certain inflammatory conditions.

The present invention provides compounds of the general formula I, which are histamine H-2 20 antagonists: 20

A - (OL,^ - I - <CH2)m - HE

(I)

in which formula

A represents a phenyl, imidazolyl, thiazolyl, furyl, thienyl, or pyridyl radical; which radical may contain one or two substituents, the first being selected from lower alkyl groups, and the second 25 from lower alkyl, guanidino, and —CH2NR1R2 groups, R1 and R2, which may be the same or 25

different, each representing a hydrogen atom or a (C,—C6)alkyl group, or together with the nitrogen atom to which they are attached, may form a pyrrolidine, piperidine, morpholine, or N-methylpiperazine ring;

X represents —0—, —S—, or —CH2;

30 n represents 0 or 1; 30

m represents 2 or 3;

p represents 1 or 2;

R3 represents a hydrogen atom or a (C,—C6)alkyl, (C2—C6)alkenyl, (C3—C6)alkynyl, phenyl,

phenyl(lower)alkyl, carboxylic acyl(C1—C6), phenyl(lower)acyl, nitrile, or—N(alkyl)2 group; 35 R4 represents a hydrogen atom, a (C,—C6)alkyl, (C2—C6)aikenyl, (C3—C6)alkynyl, phenyl or 35

phenyl(lower)alkyl group, an —0(lower)alkyl or—Oaryl group, a nitrile group, or an —NR5R6 group, in which R5 and R6, which may be the same or different, each represents a hydrogen atom, a (C,—C6)alkyl, (C2—C6)alkenyl, (C3—C6)alkynyl, (C3—C7)cycloalkyl, phenyl or phenyl(lower)alkyl group, a —(CH2)m—X—(CH2)n—A group, or an —NH2 or nitrile group, (m, 40 n, X and A being as defined above), or together with the nitrogen atom to which they are 40

attached may form a 5 or 6 membered ring optionally containing a second nitrogen atom or an oxygen atom, or

R3 and R4 together with the atoms to which they are attached may form a 5 or 6 membered ring,

containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur 45 atoms. 45

This invention also provides salts of a compound of formula I, especially physiologically tolerable salts.

Alkyl, alkenyl, alkynyl, and acyl groups in the present specification may be branched or unbranched and may be unsubstituted or substituted, for example, by one or more groups selected 50 from hydroxyl groups; —OR7 groups in which R7 represents a (C,—C6)alkyl or a phenyl group; (C3— 50 C7)cycloalkyl groups; —NR8R9 groups in which R8 and R9, which may be the same or different, each represents a hydrogen atom, a lower alkyl group, an aryl group or a lower acyl group, and may together witfi the nitrogen atom to which they are attached form a 5 or 6 membered ring; —C00R10 groups in which R10 represents a hydrogen atom, an alkali metal atom, for example, Na or K, or a lower alkyl 55 group; —CONR8R9 in which R8 and R9 are as defined above; lower alkylsulphonyl and arylsulphonyl 55

2

GB 2 129 426 A 2

groups; cyano groups; and phenyl groups which may be substituted by one or two substituents, which may be the same or different selected from a lower alkyl, lower alkoxy, methylenedioxy, phenoxy,

halogen, dimethylaminomethyl, trifluoromethyl, nitro, cyano, sulphonic acid, sulphonamide, amino,

mono- lower alkyl-amino, di-lower alkyl amino groups; aromatic and non-aromatic heterocyclic groups 5 having 5 to 8 ring members and one or two hetero atoms selected from oxygen, sulphur and nitrogen, 5 and optionally having a lower alkyi substituent on a ring nitrogen atom, for example, furyl,

tetrahydrofuryl, thienyl, pyridyl, dihydropyranyl, pyrrolidinyl, N-lower alkyl-pyrrolidinyl and piperidyl groups.

A phenyl group other than a phenyl group A (which is defined above) may be unsubstituted or 10 substituted as defined immediately above for phenyl substituents of aliphatic and acyl groups. 10

In the present specification the term "lower" is used to denote a group having up to 4 carbon atoms. The term "halogen" denotes chlorine, bromine, iodine and fluorine. The term "aryl", unless otherwise described, denotes aromatics having 6 to 12 carbon atoms, such as phenyl, naphthyl,

bisphenylyl, particularly phenyl; aralkyl means aralkyls having 7 to 13 C atoms, such as benzyl, 15 phenethyl. 1 5

It will be appreciated by a worker skilled in the art that a combination of substituents that are incompatible for steric reasons or because of potential inter-reactions should not be chosen. The worker will also use his normal discretion in the number of substituents chosen.

The present invention also provides a process for the production of a compound of the general 20 formula I, which comprises 20

a) reacting a 1,2,4,6-thiatriazine of the general formula II

(0)p M N

(i!)

J A

a in which L1 represents a halogen atom, an alkoxy or aryloxy group, an alkylthio or arylthio group, or an alkylsulphonyl or arylsulphonyl group, p and R4 are as defined above, and R3a is as defined above for R3 25 except that R3a may not represent a hydrogen atom, with a compound of the general formula III 25

A—(CH2)n—X—(CH2)m—NH

in which A, X, m and n are as defined for formula I, or b) re'acting a 1,2,4,6-thiatriazine of the general formula IV

2

(0)p

A3.

30 in which L1 and L2, which may be the same or different, each represents a halogen atom, an alkoxy or 30 aryloxy group, an alkylthio or arylthio group, or an alkylsulphonyl or arylsulphonyl group, and p and R3a are as defined above, with a compound of formula III as defined above, and reacting the resulting compound of formula V

(0)p

I n V

A - (CH^ - X

K

35 with an amino compound HNRsaR6a in which'Rsa and R6a are as defined for R5 and R6 in formula I and, in 35 addition, either or both of Rsa and R6a may represent a trialkylsilyl group, for example, a —(CH3)3Si group; or

3

GB 2 129 426 A 3

c) reacting a 1,2,4,6-thiatriazine of the general formula II as defined above with an amino thiol of formula VI

HXa—(CH2)m—NH2 VI

in which Xa is —0— or —S—, and m is as defined for formula I, and reacting the resulting a 5 compound of formula VII

(o)p

S

/ \

N N

«. - CCH2)„ - 4^^ V"

I3

a in which R3a, R4, p and m are as defined above, with a compound of the general formula VIII

A—(CH2)n1—-L3 VIII

in which A is as defined for formula I, n1 represents 1, and L3 is a suitable leaving group, for example, a 10 halogen atom, a hydroxy group, an alkoxy group, or a sulphonate ester, and, if desired, carrying out any 10 one or more of the following readings in any desired order:—

(i) converting a group R3a into a hydrogen atom,

(ii) converting a group R3 and/or a group R4 into another group R3 and/or R4, respectively,

(iii) converting an acid addition salt of formula I into the corresponding free base or converting a

15 free base into an acid addition salt, 1 5

(iv) oxidising a compound of formula I in which p represents 1 to give the corresponding compound in which p represents 2.

In addition to serving as a substituent in the final product, R3 may also act as a protecting group in the above chemical transformations and may subsequently be removed, for example, by 20 hydrogenolysis or by acid or base catalysed hydrolysis to provide a compound of the general formula I 20 in which the thiatriazine ring carries a hydrogen substituent. Protecting groups which come within the definition of R3 given in formula I are t-butyl, lower alkyl carbonate, benzyl and benzoyl groups, for example.

Oxidation may be carried out by a known method, for example, as described below. 25 Interconversions of substituents may also be carried out by known methods, for example, the 25

hydrolysis of a cyano group to an acid or amide.

Compounds II and III are generally reacted in a solvent or diluent, preferably an alcohol, DMF, or DMSO, at a temperature within the range of from, for example, from 0 to 100°C, generally from 0 to 60°C. The compound of formula III should be reacted in the form of the free base, as shown. If it is 30 initially present in the form of an acid addition salt, for example, as the hydrochloride or hydrobromide, 30 this should be converted into the free base during or, preferably, after reaction with compound II.

Conversion is carried out with a base, for example, triethylamine, sodium hydroxide or potassium hydroxide.

Compound IV is reacted with compound III under conditions similar to those described above, 35 except that generally lower reaction temperatures are preferred in order that the leaving groups L1 and 35 L2 may be displaced selectively.

The reaction of compound V with an amino compound HNR5aR6a is generally carried out in an alcoholic solvent at a temperature from 0 to 60°C. The reaction in all cases is faster when p=2 than when p=1.

40 A compound of formula I may be converted into its salt form in the usual manner by reaction with 40 an acid. Examples of physiologically tolerable acid addition salts are those with hydrobromic,

hydrochloric, sulphuric, acetic, malonic, maleic, fumaric, succinic, citric, tartaric and isethionic acids.

A compound of formula I in the form of an acid addition salt may be converted into the free base form by reaction with a base in the usual manner.

45 A number of compounds of the type represented by the general formula III are known, see, for 45 example, GB Specification 2,001,624 A; U.S. Patent 3,950,333; U.S. Patent 4,128,658; and Belgian Patents 867,106 and 875,846.

A few examples of the required thiatriazine intermediates represented by the general formulae II, IV and VI are disclosed in the chemical literature, see for example, German specification DE 2,026,625 50 and DE 2,943,703; U.S. patent 4,013,447; Heterocycles 12, 1199 (1979); and Chem. Ber. 109 2107 50 (1976).

However, many of the specific intermediates required for the present invention have not previously been described and form part of the present invention.

4

GB 2 129 426 A 4

Some thiatriazines of the general formula II may be prepared as shown in Scheme I.

Scheme I

nh2SO2NH2

(■")r£V

-OCN

A \ /

10

15

XII

R11 represents an alkyl, dialkylamino, acylamino, nitro, halogen, aryl, nitrile, alkoxy, aryloxy or acyloxy group, and x represents 1 or 2. Preferably one group R11 is present, ortho or, preferably, para to the —OCN group.

Sulphamide IX may be reacted with an aryl cyanate of formula X in the presence of a base, for example, Na2C03, according to the method described in DE 2,026,625 to give a thiatriazine of formula XI. This compound may be alkylated on the nitrogen atom in the 4-position using an alkylating agent, for example, an alkyl halide or alkyl sulphate, for example, methyl iodide, benzyl bromide or dimethyl sulphate.

The alkylation of the 4-amino group may be carried out in a known manner, for example, in the presence of a base, for example, sodium methoxide or di-isopropylethylamine, in a solvent, for example, methanol or acetonitrile, and generally at a temperature within the range of 20 to 100°C.

Certain thiatriazines of the general formula IV may be prepared as shown in Scheme II or Scheme

III.

10

15

5

GB 2 129 426 A 5

Scheme II

(r1<l)x~—\— 0CN + R a " ~ (si(alky1)3)2

XIII

0 \

R3

£

XV

i

°x /O

V

(R WfV°JL J1

XVI

In Scheme II, an aryl cyanate of formula X in which R11 and x are as defined above is reacted with a substituted bis-trialkylsilylamine of formula XIII in which R3a is as defined above to give a compound 5 of formula XIV. The trialkyi group is preferably a trimethyl group. This reaction may be carried out as 5 described in Chem. Ber. 101 3185 (1968). Cyclisation of compound XIV to give the thiatriazine of formula XV may be carried out by reaction of compound XIV with thionyl chloride, thionylaniline or thionyldiimidazoie. A compound XV may be used directly in a condensation reaction with a compound of formula III to give a compound of formula I, or may first be oxidised to the corresponding 1,1-dioxide 10 XVI, using an oxidising agent, for example, a peracid, for example, m-chloroperbenzoic acid, hydrogen 10 peroxide, an alkyl hydroperoxide, for example, t-butyl hydroperoxide, or a permanganate, for example potassium permanganate.

6

GB 2 129 426 A 6

Scheme III

0 0

W* 3

0«=C=N-S-N*=00 + R NH

a 2

XVII

XIX

XX

I

H3

a

Sulphonyl di-isocyanate XVII may be reacted with a primary amine of formula XVIII in which R3a is as defined above according to DE—OS 2,337,867, to provide the thiatriazine of formula XIX.

5 Conversion of this compound to the thiatriazine XX having leaving groups L1 and L2 at the 3 and 5 5

positions (i.e. a compound of formula IV in which p=2) may be accomplished by a variety of methods, for example, by treatment with PCI5 or COCI2/DMF in a solvent, for example, POCI3, CCI4 or CICrf2CH2CI, to give L1=L2=CI, or by treatment with phosphorus pentasulphide or p-methoxyphenylthionophosphine sulphide dimer with subsequent alkylation to give L^L^alkylthio.

10 It will be appreciated by those skilled in the art that it is possible to convert a thiatriazine 10

intermediate of formula IV into a thiatriazine intermediate of formula II by, for example, reaction with a primary or secondary amine NHR5aRBa.

0. 0 0 0

V \ /

/ \ 5

n M R52R6snk .R5

6

i3 R a

IV II

Certain thiatriazines of general formula II may be prepared as shown in Scheme IV.

7

GB 2 129 426 A 7

Scheme IV

2X7

°9

°2 S

^ (vii) JT^ ' ^JT

1 I A X

E12S /V h/Ve4 . L1 ^

I

R\ *3a

II

In the above reaction scheme, R3a, R4 and L1 are as defined above, and R12 represents an alkyl group, for example an alkyl group having up to 4 carbon atoms, especially a methyl group; an aryl 5 group, especially a phenyl group; or an aralkyl group, especially a benzyl group. In compound XXVI, the 5 two groups R12 may be the same or different. In compound XXI, R12 is for example, a methyl group, and in compound XXVI, for example, one of the two groups R12 is a methyl group and the other is a phenyl group, or both are methyl groups, or both are phenyl groups.

Acylaminosulphonylchlorides of formula XXVII are known, see for example, R. Graf, German 10 Specifications 931,225 and 931,467. Dithioiminocarbonates of formula XXVI are also known, see for 10 example, Z. Chem. 8, 459—460 (1968). (The term "known" is used herein to mean in actual use in the art or described in the literature of the art).

An N-substituted isothiourea XXI may be reacted with an acylaminosulphonyi chloride XXVII in the presence of a base, for example, triethylamine or diisopropylethylamine, in an aprotic solvent, for 15 example, dichloromethane, tetrahydrofuran or acetonitrile, generally at a temperature within the range 1 5 • of from —20 to +30°C, to give the key intermediate of formula XXV (reaction i).

8

GB 2 129 426 A 8

A compound of formula XXV may also be prepared from an isothiourea XXI by another route (reactions ii and iii).

First, the isothiourea XXI reacted with a carboxylic acid chloride XXII, in the presence of a base, for example, triethylamine or diisopropylethylamine, in an aprotic solvent, for example, dichloromethane, tetrahydrofuran or acetonitrile, generally at temperature within the range of from —50 to 0°C, to give a mixture of isomers from which the predominant one, compound XXIII, can be separated by conventional means, for example, by fractional crystallisation or by chromatography. Compound XXIII is then reacted with aminosuiphonyl chloride XXIV under conditions analogous to those described above for reaction (i). Migration of the acyl group results in the formation of compound XXV.

Compound XXV may be prepared by a third method (reactions iv and v), which comprises reacting a dithioiminocarbonate XXVI with an acylaminosulphonyl chloride XXVII under conditions analogous to those described above for reaction (i) and then displacing an —SR12 group from the resulting compound XXVIII with primary amine of formula XXIX.

Heating a compound of formula XXV in an aprotic solvent, for example, tetrahydrofuran, dioxane, toluene, xylene or ethylene glycol dimethyl ether, generally at a temperature within the range of from 80 to 160°C, affords a thiatriazine of formula XXX.

In some compounds of formula XXX, the group R12S—is a suitable leaving group L1, i.e. such compounds fall within the general formula II, but in other compounds of formula XXX it is necessary or preferable to convert a group R12S— into a leaving group L1 that is more readily displaced by a nucleophile. Such a conversion may be carried out by known methods, for example, by oxidising the sulphide group R12S—to the corresponding sulphoxide group using, for example, a peracid, for example, m-chloroperbenzoic acid, hydrogen peroxide, or a periodate, perborate or permanganate salt; or by replacing the sulphide group R12S— by a halogen atom, for example, by treating compound XXX with excess chlorine in an inert solvent, for example, chloroform, tetrahydrofuran or ethyl acetate, generally at a temperature within the range of from 20 to 100°C, and preferably in the presence of a catalyst, for example, zinc chloride.

It will be appreciated by those skilled in the art that compounds of the general formula I may exist as one or more tautomeric isomers, especially those structures where R3 represents a hydrogen atom 30 and R4 represents a group —NR5R6 in which R5 or Re represents a hydrogen atom, for example, as

10

15

20

25

10

15

20

25

30

shown below:

(0)p .S

M I?

-M-

(0)p s

— N'

rt KiH

KJL-

(0)p

HN. NH

Jl

H

This tautomerism may also occur when the thiatriazine ring is substituted by carbon substituents:

(o)p

S

N

_KJ

I

H

hi i3

CH-C-

2 II

— fJ

I

H

(0)p S

N

UH

CK-C-

II

0

GB 2 129 426 A

All possible tautomeric forms of formula I are part of the present invention.

It will also be appreciated that when p represents 1, the sulphur-oxygen bond in formula I can exist in two stereoisomeric configurations: R and S. All stereoisomers of formula I are also part of the present invention.

5 Any reference to a compound of formula I herein includes all possible tautomeric and stereoisomeric forms of that compound. Moreover, all possible tautomeric and stereoisomeric forms of any other compound mentioned in the present specification are similarly included within the general references to that compound.

As indicated above, the compounds of the present invention have histamine H-2 antagonist 10 activity. Histamine H2-antagonists have been shown to inhibit gastric acid secretion in a variety of test animals and in man. These compounds are also capable of blocking the gastric secretion stimulated by exogenously administered histamine or pentagastrin; see Brimblecombe et a/., J. Int. Med. Res. 3, 86 (1975).

Compounds of this invention were tested for antisecretory activity in the perfused rat stomach. 15 The method of Gosh and Schild, Brit. J. Pharmacol. 13, 54 (1958) as modified by Lawrence and Smith, Europ. J. Pharmacol. 25, 389 (1974) was used to prepare the test animals and acid secretion was stimulated by infusing either histamine or pentagastrin at a constant rate.

After the secretion plateau was reached, the test compound was administered i.v. and the amount of compound required to inhibit the stimulated secretion by 50% was determined. 20 The ID50 values for some of the compounds of this invention are given in the following Table. Two to four rats were used for each determination.

0„

10

15

20

N N

ID50 (/Umoles/kg)

Rat perfused stomach i.v.

25

Cimetidine

10.8

25

-NH

o

0.083

-NHCH,

r<5>

0.065

30

-NHCH

0.10

0.022

30

-NKCN

0.34

10

GB 2 129 426 A 10

-NH2 0.15

-N(CH3)2 0.095

-NH 0.12

-NHCH2C=CH 0.12

5 -NH-CH(CH3)2 0.28 5

Accordingly, the present invention provides a pharmaceutical preparation which comprises a compound of the general formula I or a physiologically tolerable salt thereof as active ingredient, in admixture or conjunction with a pharmaceutical^ suitable carrier. The preparation may be in a form suitable for enteral or parenteral administration, for example, for oral or intravenous administration. The 10 preparation may be in unit dosage form, for example, as tablets or capsules, or in unit or multiple dose 10 ampoules or vials. From 0.1 to 10 mg of the active substance may be administered per kg body weight.

The following Examples illustrate the invention.

Example A

(1) 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]-ethyl]amino-4-methyl-5-amino-1,2,4,6-thiatriazine-15 1,1-dioxide 15

To a solution of 4-methyl-3-(4-methylphenoxy)-5-amino-1,2,4,6-thiatriazine-1,1-dioxide (100 mg) in 5 ml of methanol was added a solution of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole (90 mg) in 10 ml of ethanol. The resulting solution was kept at room temperature for 16 hours then refluxed for 4 hours. The solvent was evaporated under vacuum and the residual solid 20 chromatographed on silica gel, eluting with a chloroform/methanol/30% aqueous ammonia mixture to 20 give the title compound as a colourless solid (45 mg).

1H n.m.r. (60 MHz) DMSO S 2.62 (2 H, t), 3.20 (3 H, S), 3.34 (2H, t), 3.61 (2 H, S), 6.54 (1 H, S), 6.81 (4 H, br), 7.44 (1 H, br), 7.60 (1 H, br).

Using analogous reaction conditions the following compounds were prepared:

25 (2) 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthioJ-ethylJamino-4-ethyl-5-amino-1,2,4,6-thiatriazine- 25 1,1-dioxide m.p. 134—6°C.

1H n.m.r. (250 MHz) DMSO S 1.13 (3 H, t), 2.67 (2 H, t), 3.39 (2 H, M), 3.61 (2 H, S), 3.77 (2 H, q), 6.57 (1 H, S), 6.87 (5 H, brS, ex) 7.40 (2 H, brS, ex), 7.64 (1 H, t, ex).

30 (3) 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]-ethyl]amino-4-(4-nitrobenzyl)-5-amino-1,2,4,6- 30 thiatriazine-1,1-dioxide m.p. 160—2° C.

1H n.m.r. (250 MHz) DMSO S 2.50 (2 H,t), 3.37 (2 H,t), 3.54 (2 H,S), 5.21 (2 H,S), 6.50 (1 H,S), 6.84 (6 H,brM), 7.45 and 8.24 (4 H,ABq) 7.46 (1 H,t,ex), 7.80 (1 H,t,ex).

35 The thiatriazines required as starting materials in example A are prepared by the following 35

method:

Example B

(4) 3-(4-Methylphenoxy)-4-methyl-5-amino-1,2,4,6-thiatriazine-1,1-dioxide

A suspension of 5-amino-3-(4-methylphenoxy) 4H-1,2,4,6-thiatriazine-1,1-dioxide (508 mg) in 40 10 ml of methanol was added to a stirred solution of sodium (46 mg) in 20 ml of methanol and the 40

mixture stirred for 15 minutes. The resulting solution was evaporated to dryness and the residual salt suspended in acetonitrile (25 ml). Methyliodide was then added to the stirred suspension and the mixture refluxed for 3 hours, before evaporating to dryness under vacuum. The solid residue was taken up in water and extracted once with ethyl acetate. The ethyl acetate layer was dried and evaporated to 45 a foam which was further purified by chromatography on silica gel, eluting with chloroform/methanol, 45 to give the title compound (120 mg), m.p. 278—280°C.

1H n.m.r. (60 MHz) DMSO S 2.18 (3 H,S), 3.27 (3 H,S), 7.05 (4 H,ABq), 7.60 (2 H,br).

Using analogous reaction conditions the following compounds were prepared:

11

GB 2 129 426 A 11

(5) 3-(4-Methylphenoxy)-4-ethyl-5-amino-1,2,4,6-thiatriazine-1,1-dioxide m.p. 292—5°C.

1H n.m.r. (250 MHz) DMSO S 1.29 (t, 3 H), 2.33 (S, 3 H), 4.01 (q, 2 H), 7.1 5 and 7.27 (ABq, 4 H), 7.88 (br.s,ex, 2 H).

5 (6) 3-(4-Methylphenoxy)-4-(4-nitrobenzyl)-5-amino-1,2,4,6-thiatriazine-1,1-dioxide m.p. 303—7°C.

1H n.m.r. (250 MHz), DMSO S 2.30 (3 H,S), 5.42 (2 H,S), 6.98 and 7.23 (4 H,ABq), 7.57 and 8.31 (4 H,ABq), 8.21 (2 H, br.S,ex).

Example C

10 (7) 3,5-Bis-(4-methylphenoxy)-4-methyl-1,2,4,6-thiatriazine-1-oxide

To freshly prepared 4-methylphenylcyanate (13.3 g) was added bis (trimethylsilyl) methylamine (8.7 g) at room temperature in an inert atmosphere. The resulting mixture was kept at this temperature for 70 hours in a sealed flask. The yellow oil thus obtained was decanted from a small amount of white solid and dissolved in dichloromethane (25 ml), cooled to —5°C and stirred whilst thionyl chloride (2.0 1 5 ml) was added dropwise over 20 mins, not allowing the temperature to exceed 10°C. The solution was then stirred for 1 hr at 10°C. Iced water (10 ml) was cautiously added and the layers separated, the organic phase washed with water (10 ml), dried (MgS04) and evaporated to give an oil. Trituration with ether affords 4-methyl-3,5-d'r-4'-methylphenoxy-1,2,4,6-thiatriazine-1 -oxide as a white solid 3.82 g. Crystallisation from ethanol gave an analytically pure sample as needles, m.p. 231—3°C.

20 ymax (CHCI3) 1670 (s), 1396 (s), 1368 (s), 1172 (m), 1105 (m) cm"1.

1H n.m.r. (60 MHz) CHCI3, S 2.31 (6 H,s), 3.62 (3 H,s), 7.00 (8 H,ABq).

Example D

(8) 3,5-Bis-(4-methylphenoxy)-4-methyl-1,2,4,6-thiatriazine-1,1-dioxide

To a stirred solution of 4-methyl-3,5-di-4'-methylphenoxy-1,2,4,6-thiatriazine-1 -oxide (5.0 g) in 25 chloroform (20 ml) at room temperature a solution of m-chloroperbenzoic acid (3.5 g) in chloroform (10 ml) was added over 1—2 minutes. The exothermic reaction heats the mixture to reflux after a few minutes (cooling may be required) and a white solid precipitates. After heating at reflux for an additional 5 minutes the solid was filtered off and washed with a little cold chloroform to afford the title compound 4.4 g, m.p. 288—289°C.

30 ymax 1690 (s), 1673 (s), 1380 (m), 1160 (m), 831 (m), 823 (m) cm-1.

1H n.m.r. (60 MHz) DMSO S 2.25 (6 H,S), 3.54 (3 H,S), 7.08 (8 H,ABq).

Example E

(9) 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-(4-methylphenoxy)-1,2,4,6-thiatriazine-1,1-dioxide

35 To a stirred solution of 4-methyl-3,5-di-4'-methylphenoxy-1,2,4,6-thiatriazine-1,1-dioxide (4.4 g) in acetonitrile (25 ml) was added 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole (2.8 g) as a solution in ethanol (10 ml). The resulting mixture was stirred at room temperature for 6 hours, evaporated to dryness and chromatographed on silica gel. Elution with a chloroform/methanol/30% aqueous ammonia mixture gave the title compound as a solid (4.4 g) m.p. 194—6°C. 40 'H n.m.r. (250 MHz) DMSO S 2.33 (3 H,S), 2.67 (2 H,t), 3.43 (5 H,m), 3.67 (2 H,S), 6.71 (1 H,S), 7.15—7.29 (8 H, m inc 4 H,ex), 8.18 (1 H,t,ex).

Using analogous reaction conditions the following compounds were prepared:

(10) 3-N-[2-[(5-Methyl-4-imidazolyl)methylthio]ethyl]amino-4-methyl-5-(4-methylphenoxy)-1,2,4,6-thiatriazine-1,1-dioxide

45 1H n.m.r. (60 MHz) DMSO S 2.20 (3 H,S), 2.32 (3 H,S), 2.70 (2 H,t), 3.35 (2 H,t), 3.50 (3 H,S), 3.78 (2 H,S) 7.25 (4 H,ABq), 8.01 (1 H,S).

(11) 3-N-[2-[(5-Dimethylaminomethyl-2-furanyl)methylthio]ethyl]amino-4-methyl-5-(4-methylphenoxy)-1,2,4,6-thiatriazine-1,1-dioxide

1H n.m.r. (60 MHz) DMSO S 2.20 (6 H,S), 2.30 (3 H,S), 2.70 (2 H,t), 3.35 (2 H,t), 3.48 (3 H,S), 50 3.50 (2 H,S), 3.80 (2 H,S), 6.20 (2 H,m), 7.25 (4 H,ABq).

(12) 3-N-[3-[3-( 1 -Piperidinylmethyl)phenoxy]propyl]amino-4-methyl-5-(4-methylphenoxy)-1,2,4,6-thiatriazine-1,1-dioxide

1H n.m.r. (60 MHz) DMSO S 1.55 (broad, 6 H), 2.00 (m, 2 H), 2.30 (m, 6 H), 2.32 (S, 3 H), 3.20 (s, 3 H), 3.50 (S, 2 H), 4.00 (t, 2 H), 7.10 (m, 8 H).

55 (13) 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino~4-methyl-5-(4-methylphenoxy)-1,2,4,6-thiatriazine-1 -oxide m.p. 96—8°C.

1H n.m.r. (250 MHz) DMSO S 2.32 (3 H,S), 2.69 (2 H,m), 3.44 (3 H,S), 3.46 (2 H,m), 3.64 (2 H,S), 6.57 (1 H,S), 6.93 (4 H,brS,ex), 7.10 and 7.24 (4 H,ABq), 7.78 (1 H,t,ex).

5

10

15

20

25

30

35

40

45

50

55

12

GB 2 129 426 A 12

Example F

(14) 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-amino-1,2,4,6-thiatriazine-1,1-dioxide

Ammonia gas (anhydrous) was bubbled into a solution of E (9) (4.2 g) in ethanol/acetonitrile (1:1, 5 50 ml) for a period of 10 minutes at room temperature. The resulting solution was kept at this 5

temperature for 24 hours then evaporated to dryness.

Chromatography of the crude product on silica gel eluting with a chioroform/methanol/30%

aqueous ammonia mixture gave 2.9 g of the title compound.

This material was dissolved in methanol with warming, and anhydrous hydrogen bromide gas 10 was bubbled through the ice-cooled solution for 5 minutes. Nitrogen was then blown through the ice- 10 cooled solution and the hydrobromide salt crystallised out. 2.27 g m.p. 248—250°C.

Amax 272 nm. E 10,000.

ymax (nujol) 3450—2500 (B), 1655 (m), 1605 (m), 1375 (m), 1135 (m) cm1.

'H n.m.r. (60 MHz) D20 S 2.70 (2 H,t), 3.27 (3 H,S), 3.37 (2 H,t), 3.73 (2 H,S), 6.98 (1 H,S). 15 Using analogous reaction conditions the following compounds were prepared: 1 5

(15) 3-N-[2-[(5-Methyl-4-imidazolyl)methylthio]ethyl]amino-4-methyl-5-amino-1,2,4,6-thiatriazine-1,1-dioxide

1H n.m.r. (60 MHz) DMSO S 2.14 (3 H,S), 2.60 (2 H,t), 3.18 (3 H,S), 3.33 (2 H,t), 3.64 (2 H,S)

6.08 (1 H,br), 7.18 (1 H,br), 7.54 (1 H,S).

20 (16) 3-N-[3-[3-(Dimethylaminomethyl)phenoxy]propyl]amino-4-methyl-5-amino-1,2,4,6- 20

thiatriazine-1,1-dioxide

1H n.m.r. (60 MHz) DMSO S 1.98 (2 H,m), 2:13 (6 H,S), 3.30 (2 H,m), 3.33 (3 H,S), 4.04 (2 H,t),

6.9 (4 H,m).

(17) 3-N-[2-[(5-Dimethylaminomethyl-2-furanyl)methylthio]ethyl]amino-4-methyl-5-amino-1,2,4,6-

25 thiatriazine-1,1,-dioxide 25

1H n.m.r. (60 MHz) DMSO S 2.18 (6 H,S), 2.68 (2 H,t), 3.25 (3 H,S), 3.35 (2 H,t), 3.52 (2 H,S), 3.78(2 H,S), 6.10(2 H,m).

(18) 3-N-[3-[3-(1-Piperidinylmethyl)phenoxy]propyl]amino-4-methyl-5-amino-1,2,4,6-thiatriazine-1,1-dioxide

30 1H n.m.r. (60 MHz) DMSO S 1.43 (broad, 6 H), 1.95 (m, 2 H), 2.30 (m, 6 H), 3.20 (S, 3 H), 3.40 30 (S, 2 H), 3.95 (t, 2 H), 6.85 (m, 4 H).

Example G

Using the appropriate primary or secondary amine in place of the ammonia used in Example F, the compounds listed subsequently were prepared.

35

(19) RS=H, R6=CH3, m.p. 135—7°C.

1H n.m.r. (250 MHz) DMSO 8 2.62 (2 H,t), 2.70 (3 H,S), 3.19 (3 H,S), 3.38 (2 H,t), 3.61 (2 H,S), 6.56 (1 H,S), 6.83 (4 H,br), 7.49 (1 H,br), 7.61 (1 H,br).

(20) RS=H, R6=CH2CH3, m.p. 127—9°C.

40 1H n.m.r. (250 MHz) DMSO S 1.12 (3 H,t), 2.62 (2 H,t), 3.19 (2 H,q), 3.20 (3 H,S), 3.34 (2 H,t), 3.61 (2 H,S), 6.54 (1 H,S), 6.81 (4 H,br), 7.44 (1 H,br), 7.60 (1 H,br).

40

(21) R5=H, R6=(CH2)2CH3, m.p. 202—3°C.

1H n.m.r. (S rms=0) (250 MHz) 0.87 (triplet, 3 H), 1.51 (sextet, 2 H), 2.61 (triplet, 2 H), 3.10 (quartet, 2 H), 3.20 (singlet, 3 H), 3.40 (triplet, 2 H), 3.60 (singlet, 2 H), 6.55 (singlet, 1 H), 6.83 (broad 45 singlet, 4 H,ex), 7.46 (triplet, 1 H,ex) 7.62 (triplet, 1 H,ex). 45

13

GB 2 129 426 A 13

(22) R5=H, R6=(CH2)3CH3, m.p. 96—98°C.

nH n.m.r. (8 rms=0) (250 MHz) 0.85 (multiplet, 3 H), 1.28 (multiplet, 2 H), 1.46 (multiplet, 2 H), 2.60 (triplet, 2 H), 3.14 (multiplet, 2 H), 3.19 (singlet, 3 H), 3.34 (triplet, 2 H), 3.60 (singlet, 2 H), 6.54 (singlet, 1 H), 6.83 (broad singlet, 4 H,ex) 7.46 (very broad singlet, 2 H,ex).

5 (23) R5=H, R6=(CH2)4CH3, m.p. 124—5°C. 5

1H n.m.r. (S rms=0) (250 MHz) 0.87 (triplet, 3 H), 1.28 (multiplet, 4 H), 1.51 (pentet, 2 H), 2.61 (triplet, 2 H), 3.13 (multiplet, 2 H), 3.21 (singlet, 3 H), 3.36 (triplet, 2 H), 3.64 (singlet, 2 H), 6.69 (singlet, 1 H), 7.13 (broad singlet, 4 H,ex), 7.48 (triplet, 1 H,ex), 7.67 (triplet, 1 H,ex).

(24) R5=CH3, R6=CH3, m.p. 120—2°C.

10 1H n.m.r. {§ rms=0) (250 MHz) 2.66 (triplet, 2 H), 2.88 (singlet, 6 H), 3.33 (singlet, 3 H), 3.38 10 (triplet, 2 H), 3.66 (singlet, 2 H), 6.62 (singlet, 1 H), 6.94 (broad singlet, 4 H,ex), 7.84 (triplet, 1 H,ex).

(25) RS=H, R6=CH(CH3)2, m.p. 139—141 °C.

'H n.m.r. (8 rms=0) (250 MHz) 1.16 (doublet, 6 H), 2.62 (triplet, 2 H), 3.21 (singlet, 3 H), 3.36 (triplet, 2 H), 3.61 (singlet, 2 H), 3.90 (multiplet, 1 H), 6.56 (singlet, 1 H), 6.83 (broad singlet, 4 H,ex), 15 7.14 (singlet, 1 H,ex), 7.60 (broad singlet, 1 H,ex). 15

(26) R5=H, R6=CH2CH=CH2, m.p. 204—205°C.

1H n.m.r. (8 rms=0) (250 MHz) 2.67 (triplet, 2 H), 3.26 (singlet, 3 H), 3.38 (triplet, 2 H), 3.65 (singlet, 2 H), 3.82 (doublet of triplets, 2 H), 5.19 (quartet of quartets, 2 H), 5.90 (multiplet, 1 H), 6.60 (singlet, 1 H), 6.86 (broad singlet, 4 H,ex), 7.70 (singlet, 1 H,ex).

20 (27) RS=H, R6=CH2C=CH, m.p. 210—2°C. 20

1H n.m.r. (8 rms=0) (250 MHz} 2.63 (triplet, 2 H), 3.21 (singlet, 3 H), 3.23 (triplet, 1 H), 3.36 (triplet, 2 H), 3.62 (singlet, 2 H), 3.97 (doublet, 2 H), 6.58 (singlet, 1 H), 6.87 (broad singlet, 4 H,ex), 7.72 (triplet, 1 H,ex), 7.78 (triplet, 1 H,ex).

(28) R5=H, R6=CH2CH20CH3, m.p. 113—5°C.

25 1H n.m.r. (5 rms=0) (250 MHz) 2.60 (triplet, 2 H), 3.18 (singlet, 3 H), 3.25 (singlet, 3 H), 3.36 25 (quartet, 4 H), 3.46 (triplet, 2 H), 3.60 (singlet, 2 H), 6.54 (singlet, 1 H), 6.82 (broad singlet, 4 H,ex), 7.55 (singlet, 1 H,ex), 7.65 (singlet, 1 H,ex).

(29) R5= H, R6= —139 " l2t3°C*

'H n.m.r. (5 rms=0) (250 MHz) 0.55 (multiplet, 2 H), 0.71 (multiplet, 2 H)„ 2.62 (triplet, 3 H), 3.16 30 (singlet, 3 H), 3.34 (triplet, 2 H), 3.61 (singlet, 2 H), 6.56 (singlet, 1 H), 6.83 (broad singlet, 4 H,ex), 30 7.53 (singlet, 1 H,ex), 7.63 (triplet, 1 H,ex).

(30) R5= H, R6= ^ , m.p. 136 - 8°C.

'H n.m.r. (8 rms=0) (250 MHz) 1.28 (triplet, 4 H), 1.69 (multiplet, 6 H), 2.63 (triplet, 2 H), 3.21 (singlet, 3 H), 3.36 (triplet, 2 H), 3.60 (multiplet, 1 H), 3.62 (singlet, 2 H), 6.57 (singlet, 1 H), 6.85 35 (broad singlet, 4 H,ex), 7.14 (singlet, 1 H,ex), 7.66 (v. broad singlet, 1 H,ex). 35

(31) R„, R6=—CH2CH2CH2CH2CH2—, m.p. 220—2°C.

1H n.m.r. (8 rms=0) (250 MHz) 1.58 (singlet, 6 H), 2.63 (triplet, 2 H), 3.20 (singlet, 4 H), 3.28 (singlet, 3 H), 3.37 (triplet, 2 H), 3.62 (singlet, 2 H), 6.55 (singlet, 1 H), 6.83 (broad singlet, 4 H,ex), 7.80 (broad singlet, 1 H,ex).

40 (32) R5= H, R6= CH2-Q , m.p. 112 - M°C. 40

1H n.m.r. (5 rms=0) (250 MHz) 2.62 (triplet, 2 H), 3.26 (singlet, 3 H), 3.34 (triplet, 2 H), 3.60 (singlet, 2 H), 4.40 (singlet, 2 H), 6.55 (singlet, 1 H), 6.84 (broad singlet, 4 H,ex), 7.31 (multiplet, 5 H), 7.70 (v. broad singlet, 1 H,ex), 8.06 (v. broad singlet, 1 H,ex).

(33) R5=H, R6=CH2CH20H, m.p. 209—211 °C.

45 2.64 (2 H,t), 3.22 (3 H,s), 3.28 (2 H,t), 3.39 (2 H,t), 3.56 (2 H,t), 3.65 (2 H,s), 4.82 (1 H,br.s,ex), 45 6.60 (1 H,s), 6.87 (4 H,br.s,ex), 7.58 (2 H,v.br.s,ex).

14

GB 2 129 426 A 14

(34) RS=H, R6=CH2CH2CH2OH, m.p. 189—90°C.

1.68 (2 H,m), 2.62 (2 H,t), 3.22 (3 H,s), 3.28 (2 H,t), 3.42 (2 H,t), 3.46 (2 H,t), 3.62 (2 H,s), 4.54 (1 H,br.s,ex), 6.57 (1 H,s), 6.84 (4 H,br.s,ex), 7.48 (2 H,br,s,ex).

(35) R5=H, R6=CH(CH3)CH2CH3, m.p. 134—6°C.

5 0.87 (3 H,t), 1.13 (3 H,d), 1.53 (2 H,m), 2.64 (2 H,t), 3.24 (3 H,s), 3.40 (2 H,t), 3.63 (2 H,s), 3.74 5 (1 H,m), 6.58 (1 H,s), 6.85 (4 H,br.s,ex), 7.11 (1 H,d,ex), 7.65 (1 H,br.s,ex).

(36) R5 = H, Rg = CH' mP* 109'111°C

0

2.61 (2 H,t), 3.22 (3 H,s), 3.37 (2 H,t), 3.61 (2 H,s), 4.38 (2 H,d), 6.34 and 6.42 (2 H,m), 6.57 (1 H,s), 6.84 (4 H,br.s,ex), 7.60 (1 H,br,s), 7.69 (1 H,t,ex), 8.01 (1 H,t,ex).

10 (37) R5 = H, Rg = CH^ , mp. 100-2°C 10

0

1.42—2.00 (4 H,m), 2.62 (2 H,t), 3.20 (3 H,s), 3.38 (2 H,t), 3.61 (2 H,s), 3.63 (2 H,m), 3.75 (2 H,m), 4.00 (1 H,m), 6.57 (1 H,s), 6.84 (4 H,br,s,ex), 7.50 (2 H,v.br.s.,ex).

(38) R5 = H, R6 = CH^ J) , mp. 116-8°C

S

2.63 (2 H,t), 3.22 (3 H,s), 3.40 (2 H,t), 3.61 (2 H,s), 4.54 (2 H,d), 6.57 (1 H,s), 6.86 (4 H,br.s,ex), 15 6.98(1 H,dd), 7.06(1 H,d), 7.42(1 H,dd), 7.68(1 H,t,ex), 8.14 (1 H,t,ex). 15

f mp. 111-2 C

2.62 (2 H,t), 3.33 (3 H,s), 3.42 (2 H,t), 3.62 (2 H,s), 4.48 (2 H,br.s), 6.56 (1 H,s), 6.84 (4 H,br.s,ex), 7.28(1 H,m), 7.37(1 H,d), 7.75 (2 H,m, (1 H,ex)), 8.12 (1 H,t,ex),8.51 (1 H,m).

(iio) R5 = H, Rg = CH^ J) , mp. 120-2 C

0

20 1.52 (1 H,m), 2.00 (3 H,m), 2.63 (2 H,t), 3.23 (3 H,s), 3.40 (4 H,m), 3.67 (2 H,s), 3.99 (1 H,q), 20

4.72 (1 H,br.m), 6.40 (1 H,d), 6.77 (1 H,s), 7.26 (4 H,br.s,ex), 7.73 (2 H,q,ex).

(41) R5 = H, Rg = CH/ , mp. 105-6°C

2.63 (2 H,t), 3.24 (3 H,s), 3.43 (2 H,t), 3.61 (2 H,s), 4.29 (2 H,s), 5.99 (2 H,s), 6.57 (1 H,s),

6.78—6.94 (7 H,m, (4 H,ex)), 7.75 (1 H,br.s,ex), 8.00 (1 H,br.s,ex).

/CH2

25 (42) R5 = H, Rg = CH2-CH , mp. 118-20°C

:h2

0.23 (2 H,m), 0.43 (2 H,m), 1.05 (1 H,m), 2.62 (2 H,t), 3.02 (2 H,d), 3.22 (3 H,s), 3.36 (2 H,t), 3.61 (2 H,s), 6.57 (1 H,s), 6.86 (4 H,br.s,ex), 7.70 (2 H,v.br.s.ex).

(43) R5=H, R6=CH2CH2CH2N(CH3)2, m.p. 199—200°C.

1.66 (2 H,m), 2.16 (6 H,s), 2.28 (2 H,t), 2.64 (2 H,t),3.21 (3 H,s),3.21 (2 H,m, superimposed), 30 3.40 (2 H,t), 3.64 (2 H,s), 3.57 (1 H,s), 6.88 (4 H,br.s.ex), 7.72 (2 H,v.br.m, ex). 30

15

GB 2 129 426 A 15

(44) RS=H, R6=CH2CH2N(CH3)2, m.p. 96—8°C.

2.24 (6 H,s), 2.50 (2 H partly obscured by solvent), 2.62 (2 H,t), 3.20 (3 H,s) 3.32 (4 H,m), 3.61

(2 H,s), 6.57 (1 H,s), 6.84 (4 H,br.s,ex), 7.44 (1 H,br.s,ex), 7.70 (1 H,t,ex).

(45) RS=H, R6=CH2CH2NHCH3, m.p. 157—9°C.

5 1.60 (1 H,v.br.s,ex), 2.27 (3 H,s), 2.61 (4 H,m), 3.20 (3 H,s), 3.27 (2 H,t), 3.37 (2 H,t), 3.61 (2

H,s), 6.57 (1 H,s), 6.85 (4 H,br.s,ex), 7.06 (1 H,v.br.s,ex), 7.64 (1 H,br.s,ex).

(46) R5=H, Rb=CH2CH2NH2, m.p. 138—40°C.

Spectrum run in d6-DMSO+5% D20.

2.58 (2 H,t), 2.67 (2 H,t), 3.18 (3 H,s), 3.21 (2 H,t), 3.34 (2 H,t), 3.58 (2 H,s), 6.57 (1 H,s).

10 (47) R5 = H, R6 = CH2CH2/^) , mp. 218-224°C

1.91 (4 H,br.s), 2.65 (2 H,t), 3.11 (6 H,m), 3.29 (3 H,s), 3.44 (2 H,m), 3.54 (2 H,m), 3.63 (2 H,s), 6.63 (1 H,s), 6.93 (4 H,br.s,ex), 7.85 (2 H,t,ex).

(48) R5 = H, Rfi = CH2CH2/ y , mp. 198-200°C

1.45 (2 H,br.s), 1.66 (4 H,br.sl 2.62 (2 H,t), 2.90 (6 H,br.s), 3.23 (3 H,s), 3.37 (2 H,t), 3.45 (2 15 H,m), 3.61 (2 H,s), 6.59 (1 H,s), 6.94 (4 H,br.s,ex), 7.78 (1 H,br.s,ex), 7.82 (1 H,t,ex). 15

10

(49) R5 = H, Rg = CH^ J , mp. 108-10°C

N

^-ch3

1.02 (3 H,t), 1.50—1.88 (4 H,m), 2.14 (2 H,m), 2.28 (2 H,m), 2.62 (2 H,t), 2.76 (1 H,m), 3.00 (2 H,m), 3.20 (3 H,s), 3.36 (2 H,m), 3.62 (2 H,s), 6.58 (1 H,s), 6.85 (4 H,br.s,ex), 7.36 (1 H,v.br.s,ex), 7.64 (1 H,br.s,ex).

20 (50) R5=H,R6=(CH2)5CH3, m.p. 89—91 °C. 20

1H n.m.r. (250 MHz), DMSO 8,0.87 (3 H,m), 1.27 (6 H,m), 1.50 (2 H,m), 2.62 (2 H,t), 3.14 (2 H,t), 3.20 (3 H,s), 3.36 (2 H,m), 3.61 (2 H,s), 6.57 (1 H,s), 6.86 (6 H, broad s,ex).

(51) R5 = H, Rg " • mP" 79-8l°C

1H n.m.r. (250 MHz), DMSO 8, 1.51 (4 H,m), 1.67 (2 H,m), 1.88(2 H,m), 2.63 (2 H,t), 3.21 (3 25 H,s), 3.32 (2 H,m), 3.61 (2 H,s), 3.98 (1 H,m), 6.57(1 H,s), 6.86 (4 H, broad s, ex), 7.19 (1 H,m,ex), 25 7.65 (1 H, broad s,ex).

CH2CH3

/

(52) R5=H, R6=CH2CH2N , m.p. 110—111 °C.

\

ch2ch3

1H n.m.r. (250 MHz), DMSO 8, 0.96 (6 H,t), 2.48 (4 H,q), 2.52 (2 H,t), 2.62 (2 H,t), 3.19 (5 H,m), 3.35 (2 H,m), 3.61 (2 H,s), 6.57 (1 H,s), 6.85 (4 H, broad s,ex), 7.39 (1 H, broad s,ex), 7.63 (1 H, broad 30 s,ex). 30

0

II

(53) RS=H, R6=CH2C—0CH2CH3, m.p. foam.

1H n.m.r. (250 MHz), DMSO 8, 1.21 (3 H,t), 2.64 (2 H,t), 3.27 (3 H,s), 3.39 (2 H,m), 3.66 (2 H,s), 3.92 (2 H,d), 4.13(2 H, quartet), 6.74 (1 H,s),7.21 (4 H, broad s,ex), 7.82-(1 H,t,ex), 8.08(1 H,t,ex).

16

GB 2 129 426 A 16

CH-,0

(54) R5 = H, Rg = CH^ , mp. 148-150°C

1H n.m.r. (250 MHz), DMSO 8 2.64 (2 H,t), 3.29 (3 H,s), 3.37 (2 H,m), 3.61 (2 H,s), 3.82 (3 H,s),

4.36 (2 H,s), 6.57(1 H,s), 6.76—7.31 (8 H, m inc. 4 H,ex), 7.71 (1 H, broad s,ex), 7.87 (1 H, broad s,ex).

5 (55) R5 = H, R6 = CH2Q , mp. 114-115°C 5

och3

1H n.m.r. (250 MHz), DMSO 8, 2.63 (2 H,t), 3.27 (3 H,s), 3.40 (2 H,m), 3.61 (2 H,s), 3.74 (3 H,s),

4.37 (2 H,s), 6.57 (1 H,s), 6.81—7.28 (8 H, m inc. 4 H ex), 7.68 (1 H, broad s,ex), 8.02 (1 H, broad s,ex).

(56) Rg = H, Rg = CHQ-OCH3 , mp. 118-120°C

10 1H n.m.r. (250 MHz), DMSO S, 2.63 (2 H,t), 3.25 (3 H,s), 3.37 (2 H,m), 3.61 (2 H,s), 3.73 (3 H,s), 10

4.32 (2 H,s), 6.57 (1 H,s), 6.89 (2 H, broad s,ex), 6.90 and 7.27 (4 H,ABq), 7.71 (2 H, broad s,ex), 8.01 (2 H, broad s,ex).

och3

(57) R5 .= H, Rg = 0CH3 , mp. 159-160°C

1H n.m.r. (250 MHz), DMSO S 2.63 (2 H,t), 3.25 (3 H,s), 3.37 (2 H,m), 3.61 (2 H,s), 3.74 (3 H,s), 15 3.76 (3 H,s), 4.31 (2 H,s), 6.58 (1 H,s), 6.83—7.02 (7 H, m inc. 4 H,ex), 7.73 (1 H, broad s,ex), 8.01 (1 15 H, broad s,ex).

ch3

(58) R5 = H, Rg = CH^_^ , mp. 129-130°C

'H n.m.r. (250 MHz), DMSO S, 2.30 (3 H,s), 2.64 (2 H,t), 3.27 (3 H,s), 3.40 (2 H,m), 3.62 (2 H,s), 4.37 (2 H,s), 6.57 (1 H,s), 6.84 (4 H, broad s,ex), 7.06—7.27 (4 H,m), 7.71 (1 H, broad s,ex), 8.01 (1 H, 20 broad s,ex). 20

CH,

(59) R5 = H, Rg = CH2-A A , mp. 140-141°C

'H n.m.r. (250 MHz), DMSO 8, 2.30 (3 H,s), 2.64 (2 H,t), 3.28 (3 H,s), 3.39 (2 H,m), 3.62 (2 H,s), 4.36 (2 H,s), 6.57(1 H,s), 6.86 (4 H, broad s,ex), 7.18 (4 H,m), 7.69 (1 H, broad s,ex), 7.91 (1 H, broad s,ex).

25 (60) R5 = H, Rg = CH2^~^>-CH3 , mp. 129-130°C 25

'H n.m.r. (250 MHz), DMSO 8, 2.28 (3 H,s), 2.64 (2 H,t), 3.26 (3 H,s), 3.38 (2 H,m), 3.62 (2 H,s), 4.35 (2 H,s), 6.56 (1 H,s), 6.83 (4 H, broad s,ex), 7.08—7.24 (4 H,ABq), 7.80 (2 H, broad s,ex).

f

(61) Rg = H, Rg = CH2-^ ^

'H n.m.r. (250 MHz), DMSO 8, 2.64 (2 H,t), 3.28 (3 H,s), 3.40 (2 H,m), 3.62 (2 H,s), 4.42 (2 H,s), 30 6.57 (1 H,s), 6.84 (4 H, broad s,ex), 7.05—7.43 (4 H,m), 7.69 (1 H, broad s,ex), 8.07 (1 H, broad s,ex). 30

17

GB 2 129 426 A 17

(62) R5 = H, Rg = CH^~^F , mp. 127-128°C

'H n.m.r. (250 MHz), DMSO S, 2.63 (2 H,t), 3.26 (3 H,s), 3.39 (2 H,m), 3.61 (2 H,s), 4.38 (2 H,s), ■ 6.57 (1 H,s), 6.86 (4 H, broad s,ex) 7.13—7.42 (4 H,m), 7.72 (1 H, broad s,ex), 8.08 (1 H, broad s,ex).

(63) R5 = H, Rg = , mp.

5 'H n.m.r. (250 MHz), DMSO S, 2.64 (2 H,t), 3.28 (3 H,s), 3.40 (2 H,m), 3.62 (2 H,s), 4.49 (2 H,d), 5

6.57 (1 H,s), 6.83 (4 H, broad s,ex) 7.58—7.71 (5 H, m inc. 1 H ex), 8.11 (1 H,t,ex).

/=\ CH3

(64) R5 = H, Rg = ch2\V //n/X » mp- 228-230°C

\gh3

1H n.m.r. (250 MHz), DMSO S, 2.63 (2 H,t), 2.86 (6 H,s), 3.23 (3 H,s), 3.40 (2 H,m), 3.61 (2 H,s), 4.26 (2 H,s), 6.57 (1 H,s), 6.69 and 7.17 (4 H,ABq), 6.84 (4 H broad s,ex), 7.66 (1 H, broad s,ex), 7.90 10 (1 H, broad s,ex). 10

(65) R5 = H, Rg = (CH^-^ , mp. 2l4-215°C

'H n.m.r., (250 MHz), DMSO, <5, 2.63 (2 H,t), 2.85 (2 H,t), 3.1 6 (3 H,s), 3.39 (4 H,m), 3.62 (2 H,s), 6.58 (1 H,s), 6.86 (4 H, broad s,ex), 7.27 (5 H,m), 7.63 (2 H, broad s,ex).

(65a) R5=H, R6=C=N.

15 *H n.m.r. (250 MHz), DMSO S, 2.64 (2 H,t), 3.24 (3 H,s), 3.34 (2 H,m), 3.62 (2 H,s), 6.56 (1 H,s), 1 5

6.57 (1 H, broad s,ex), 6.82 (4 H, broad s,ex), 7.94 (1 H, broad s,ex).

(65b) R5 = H, Rg = CH2CH2^'VvNH mp. 216-18°C

'H n.m.r. (250 MHz) D20, S 2.72 (2 H,t), 2.95 (2 H,t), 3.20 (3 H,s), 3.42 (2 H,t), 3.60 (2 H,t), 3.72 (2 H,s), 6.84(1 H,s), 7.11 (1 H,s), 8.16(1 H,s).

20 (66) 3N-[3-[3-(1-Piperidinylmethyl)phenoxy]propyl]amino-4-methyl-5-(2-dimethylamino 20

ethyl)amino-1,2,4,6-thiatriazine-1,1-dioxide

1H n.m.r. (250 MHz) DMSO, 8, 1.45 (m, 6 H), 2.07 (m, 2 H), 2.14 (s, 6 H), 2.34 (s, 4 H), 2.40 (t, 2 H), 3.24 (s, 3 H), 3.28 (m, 4 H), 3.40 (s, 2 H), 4.02 (t, 2 H), 6.85 (m, 4 H), 7.21 (t, 1 H).

Example H

25 (67) 3-N[2-[(2-Guanidino-4-thiazolyl)methyIthio]ethyl]amino-4-methyl-5-methylamino-1,2,4,6- 25 thiatriazine-1-oxide

This compound was prepared by procedures analogous to those given in examples C, E and F above with omission of the oxidation step given in example D.

m.p. 98—101 °C.

30 1H n.m.r. (60 MHz) DMSO <5 2.55 (2 H,t), 2.60 (3 H,d), 3.12 (3 H,s), 3.35 (2 H,t), 3.56 (2 H,s), 30 6.50 (1 H,s).

Also prepared by this method was

(68) 3-N-[2-[(2-Guanidino-4-thiazoIyl)methylthio]ethyl]amino-4-methyl-5-amino-1,2,4,6-thiatriazine-1 -oxide

35 m.p. 171—3°C. 35

'H n.m.r. (250 MHz) DMSO S, 2.64 (2 H,m), 3.19 (3 H,s), 3.38 (2 H,m), 3.62 (2 H,s), 6.56 (1 H,s), 6.89 (6 H,br.s,ex), 7.22 (1 H,t,ex).

Example I

(69) 3-N-[2-((2-Guanidino-4-thiazolyl)methylthio)ethyl)amino-4H-5-amino-1,2,4,6-thiatriazine-1,1 -40 dioxide 40

To a solution of 3-N-[2-((2-Guanidino-4-thiazolyl)methylthio)ethyl)amino-4-(4-nitrobenzyl)-5-amino-1,2,4,6-thiatriazine-1,1-dioxide (200 mg) in ethyl acetate (30 ml) aqueous sodium carbonate

18

GB 2 129 426 A 18

solution (24 mg in water, 10 mi) and 10% palladium on charcoal (200 mg) were added. This mixture was hydrogenated at 50 p.s.i. for 3 hrs. on a Parr hydrogenator. The reaction mixture was filtered through "Hyflow" (filter aid) and the layers separated and the aqueous layer freeze dried to give the title compound (114 mg) as the sodium salt.

1H n.m.r. (250 MHz) D20 S, 2.72 (2 H,t), 3.41 (2 H,t), 3.76 (2 H,s), 6.76 (1 H,s).

5 13C n.m.r. (250 MHz), D20/DMS0, S 32.03, 32.40, 40.68,108.60, 149.24, 158.50, 161.20, 5

163.63, 175.66.

Example J

(70) 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-phenyl-5-methyl-1,2,4,6-thiatriazine- 1,1 -dioxide

10 To a stirred solution of 53 mg of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole in 5 ml of 10

ethanol was added dropwise in 5 ml of dry acetonitrile 51 mg of 3-chloro-4-phenyl-5-methyl-1,2,4,6-thiatriazine-1,1 -dioxide. The reaction was stirred for 30 minutes at room temperature and then the solvent evaporated in vacuo. The product was purified by column chromatography on silica gel, eluting with chloroform/methanol 9:1, to yield 76 mg of the title compound as an amorphous solid. 15 1H n.m.r. (250 MHz) DMSO S, 1.80 (S, 3 H), 2.53 (t, 2 H), 3.28 (m, 2 H), 3.60 (s, 2 H), 6.70 (s, 1 15

H), 7.52—7.63 (m, 5 H).

Using analogous reaction conditions the following compounds were prepared:

(71) 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-phenyl-1,2,4,6-thiatriazine-1,1 -dioxide

20 m.p. 238—40°C (decomp.). 20

1H n.m.r. (250 MHz) DMSO S, 2.70 (t, 2 H), 3.20 (s, 3 H), 3.46 (m, 2 H), 3.67 (s, 2 H), 6.65 (s, 1 H), 7.5—7.67 (m, 5 H).

(72) 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-methyl-1,2,4,6-thiatriazine-1,1,-dioxide

25 1H n.m.r. (250 MHz) DMSO S, 2.33 (3 H,s), 2.63 (2 H,t), 3.29 (3 H,s), 3.39 (2 H,m), 3.78 (2 H,s), 25 7.19 (1 H,s), 7.99 (1 H,t,ex), 8.21 (4 H,br.s.ex).

The chlorothiatriazines required as starting materials in example I are prepared by the following methods (Example K):

Example K

30 (73) 3-Chloro-4-phenyl-5-methyl-1,2,4,6-thiatriazine-1,1-dioxide 30

54 mg of 3-methylthio-4-phenyl-5-methyl-1,2,4,6-thiatriazine-1,1-dioxide was suspended in 5 ml of dry ethylacetate with stirring and chlorine gas bubbled slowly through until the solid had dissolved. Some cooling was required to maintain the reaction at room temperature. Excess chlorine was removed by concentration of the ethyl acetate solution in vacuo and the product was crystallized 35 by addition of hexane. The crystalline solid was collected and recrystallized from ethyl acetate/hexane 35 as white needles, yielding 32 mg of the title compound, m.p. 198—200°C.

'H n.m.r. (250 MHz) CDCI3, S, 2.07 (s, 3H), 7.36—7.62 (m, 5 H).

Mass spec. 259 (M+2), 257 (m/e), 216 (M—CH3CN), 117 (M—C6H5NCN).

Also prepared using this procedure:

40 (74) 3-Chloro-4-methyl-5-methyl-1,2,4,6-thiatriazine-1,1 -dioxide 40

1H n.m.r. (250 MHz) DMSO S, 2.40 (3 H,s), 3.28 (3 H,s).

Example L

(75) 3-Chloro-4-methyl-5-phenyl-1,2,4,6-thiatriazine-1,1-dioxide

100 mg of 3-methylthio-4-methyl-5-phenyl-1,2,4,6-thiatriazine-1,1-dioxide was suspended in a 45 solution of 5 mg anhydrous zinc chloride in 10 ml ethyl acetate. Chlorine gas was bubbled slowly 45

through until a clear solution had formed, while maintaining the reaction at ambient temperature with some cooling. Excess chlorine and some of the solvent was removed under vacuum, and the product was crystallized by addition of hexane, yielding 74 mg of the title compound as white needles.

1H n.m.r. (60 MHz), CDCIa/acetone-dg, 3.63 (s, 3 H), 7.60 (broad s, 5 H).

50 Example M 50

(76) 3-Methyithio-4-phenyl-5-methyl-1,2,4,6-thiatriazine-1,1-dioxide

2.8 g of 1-phenyl-2-methyl-3-(N'-acetyl)sulphamoyl-isothiourea was dissolved in 50 ml of diglyme and refluxed for 5 hours under a nitrogen atmosphere. The solution was filtered through cotton wool, and the solvent evaporated in vacuo. The residual solid was crystallized from ethanol/hexane, 55 yielding 370 mg of the title compound, m.p. 295—99°C (decomp.). 55

1H n.m.r. (250 MHz) CDCI3, S, 1.90 (s, 3 H), 2.30 (s, 3 H), 7.58—7.71 (m, 5 H).

Using this procedure the following were prepared:

19

GB 2 129 426 A

19

(77) 3-Methylthio-4-methyl-5-phenyl-1,2,4,6-thiatriazine-1,1-dioxide m.p. 188—-90°C.

1H n.m.r. (250 MHz) CDCI3, S, 2.58 (s, 3 H), 3.41 (s, 3 H), 7.55 (m, 5 H).

(78) 3-Methylthio-4-methyl-5-methyl-1,2,4,6-thiatriazine-1,1 -dioxide

5 m.p. 233—235°C. 5

1H n.m.r. (250 MHz) DMSO, <5, 2.38 (3 H,s), 2.46 (3 H,s), 3.45 (3 H,s).

Example N

(79) 1-Phenyl-2-methyl-3-(N'-acetyl)sulphamoyl isothiourea

2.23 g of 1 -acetyl- 1-phenyl-2-methylisothiourea (see: H. Wheeler, Am. Chem. J., 27, 270 (1902) 10 was dissolved in 50 ml of dry acetonitrile and stirred at room temperature. 1.25 g of triethylamine in 10 10 ml of dry acetonitrile and 1,47 g of aminosulphonyi chloride in 10 ml of dry acetonitrile were added dropwise simultaneously. The reaction was left to stir for 30 minutes, then evaporated to dryness in vacuo. The residue was partitioned between dichloromethane and water, and the aqueous layer extracted once again with dichloromethane. The combined organic layers were washed once with 15 water, dried over MgS04 and evaporated, to give the title compound as a white crystalline solid: 2.8 g. 1 5 m.p. 144—148°C.

1H n.m.r. (250 MHz), CDCI3, S, 2.18 (s, 3 H), 2.36 (s, 3 H), 7.32—7.45 (m, 5 H).

Using this procedure the following were obtained:

(80) 1,2-Dimethyl-3-(N'-benzoyl)sulphamoyl isothiourea

20 1H n.m.r. (60 MHz) CDCI3, S, 2.37 (s, 3 H), 3.10 (d, 3 H), 7.3—8.1 (m, 5 H). 20

The n.m.r. and thin layer chromatography of the crude product from this preparation indicated the presence of some cyclized thiatriazine. The crude material was converted cleanly to the thiatriazine by heating according to example M.

(81) 1,2-Dimethyl-3-(N'-acetyl)-sulfamoyl isothiourea

25 1H n.m.r. (60 MHz) CDCI3, 5, 2.14 (3 H,s), 2.44 (3 H,s), 3.06 (3 H,d). 25

Example O

(82) 1-Benzoyl-1,2-dimethylisothiourea

2.32 g of N,S-dimethyl isothiourea hydriodide salt was stirred in suspension in 40 ml of tetrahydrofuran at —20°C. 2.1 g of triethylamine was added, followed by dropwise addition of 1.4 g of 30 benzoyl chloride. The reaction was stirred for 30 minutes at —20°C and then allowed to warm to 30

ambient. The solvent was evaporated in vacuo and the residue purified by column chromatography on silicagel, eluting with ethyl acetate-hexane to yield 1.1 g of the title compound as a gum.

1H n.m.r. (60 MHz) CDCI3, <5, 2.23 (s, 3 H), 3.33 (s, 3 H), 7.1—7.6 (m, 5 H).

The isomeric 1,2-dimethyl-3-benzoylisothiourea was obtained as a 1:1 mixture with the above by 35 carrying out the above procedure at ambient temperature in dichloromethane as solvent: 35

1H n.m.r. (60 MHz) CDCI3, S, 2.62 (s, 3 H), 3.02 (d, 3 H), 7.1 5—8.30 (m, 5 H).

(83) 1 -Acetyl-1,2-dimethylisothiourea

^ n.m.r. (60 MHz) DMSO, S, 2.48 (3 H,s), 2.66 (3 H,s), 3.45 (3 H,s).

Example P

40 (84) 3-N[2-((2-Guanidino-4-thiazolyl]methylthio)ethyl)amino-4-methyl-5-ethoxy-1,2,4,6- 40

thiatriazine-1,1-dioxide

To a solution of sodium (0.23 g) in ethanol (100 ml), 3-N[2-((2-guanidino-4-thiazolyl)methylthio)]ethyl)amino-4-methyl-5-(4-methylphenoxy)-1,2,4,6-thiatriazine-1,1-dioxide (5.00 g) was added and the mixture stirred and heated at reflux for 1 hour. The reaction mixture was 45 cooled and evaporated to dryness and the residue chromatographed on silica gel. Elution with 45

chioroform/methanol mixtures gave the title compound (3.21 g) as white solid m.p. 188—190°C.

1H n.m.r. (60 MHz) DMSO, S, 1.23 (3 H,q), 2.61 (2 H,t), 3.22 (3 H,s), 3.35 (3 H,m), 3.60 (2 H,s), 4.47 (2 H,q), 6.50 (1 H,s), 6.73 (3 H,br.s,ex), 7.75 (1 H,br.s,ex).

Claims

Claims

50 1. A compound of the general formula I,

<>

50

A - (CH2)n - I - (CH2)

(I)

in which

20

GB 2 129 426 A 20

A represents a phenyl, imidazolyl, thiazolyl, furyl, thienyi, or pyridyl radical; which radical may contain one or two substituents, the first being selected from lower alkyl groups, and the second from lower alkyl, guanidino, and —CH2NR1R2 groups, R1 and R2, which may be the same or different, each representing a hydrogen atom or a (C,—C6)alkyl group, or together with the

5 nitrogen atom to which they are attached, may form a pyrrolidine, piperidine, morpholine, or 5

N-methylpiperazine ring;

X represents —0—, —S—, or —CH2;

n represents 0 or 1;

m represents 2 or 3;

10 p represents 1 or 2; 10

R3 represents a hydrogen atom or a (C,—C6)alkyl, (C2—C6)alkenyl, (C3—C6)alkynyl, phenyl,

phenyl(lower)alkyl, carboxylic acyKC,—C6), phenyl(lower)acyl, nitrile, or—N(alkyl)2 group; R4 represents a hydrogen atom, a (Cn—C6) alkyl, (C2—C6)alkenyl, (C3—C6)alkynyl, phenyl or phenyl(lower)alkyl group, an —O(lower)alkyl or —Oaryl group, a nitrile group, or an —NR5R6

15 group, in which R5 and R6, which may be the same or different, each represents a hydrogen 15

atom, a (C,—C6)alkyl, (C2—C6)alkenyl, (C3—C6)alkynyl, (C3—C7)cycloalkyl, phenyl or phenyl(lower)alkyl group, a —(CH2)m—X—(CH2)n—A group, or an —NH2 or nitrile group, (m, n, X and A being as defined above), or together, with the nitrogen atom to which they are attached may form a 5 or 6 membered ring optionally containing a second nitrogen atom or

20 an oxygen atom, or 20

R3 and R4 together with the atoms to which they are attached may form a 5 or 6 membered ring,

containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms.

2. A compound as claimed in claim 1, wherein an alkyl, alkenyl, alkynyl, or acyl group is branched

25 or unbranched and is unsubstituted or substituted. 25

3. A compound as claimed in claim 2, wherein an alkyl, alkenyl, alkynyl or acyl group is substituted by one or more groups selected from hydroxyl groups; —OR7 groups in which R7 represents a (C,—C6)alkyl group or a phenyl group; (C3—C7)cycloalkyl groups; —NR8R9 groups in which R8 and R9,

which may be the same or different, each represents a hydrogen atom, a lower alkyl group, an aryl

30 group or a lower acyl group, and may together with the nitrogen atom to which they are attached form 30 a 5 or 6 membered ring; —COOR10 groups in which R10 represents a hydrogen atom, an alkali metal atom, or a lower alkyl group; —C0NR8R9 in which R8 and R9 are defined above; lower alkylsulphonyl and arylsulphonyl groups; cyano groups; and phenyl groups which may be substituted by one or two substituents, which may be the same or different, selected from lower alkyl, lower alkoxy,

35 methylenedioxy, phenoxy, halogen, dimethylaminomethyl, trifluoromethyl, nitro, cyano, sulphonic acid, 35 sulphonamide, amino, mono-lower alkylamino and di-lower alkylamino groups; aromatic and non-aromatic heterocyclic groups having 5 to 8 ring members and one of two heteroatoms selected from oxygen, nitrogen and sulphur, and optionally having a lower alkyl substituent on a ring nitrogen atom.

4. A compound as claimed in claim 1, wherein a phenyl group (other than a phenyl group A), is

40 substituted as defined for a phenyl group in claim 3. 40

5. A compound as claimed in claim 1, wherein A represents an unsubstituted or substituted thiazolyl, 2-furanyl or phenyl group; X represents —0— or —S—; m is 2 or 3; n is 0 or 1; p is 1 or 2; R3 represents a hydrogen atom or a methyl or ethyl group; R4 represents an amino, —NHR6, (C,—

C4)alkyl or phenoxy group, R6 representing a (C1—C6)alkyl group or a substituted (C,—C4)alkyl group.

45 6. A compound as claimed in claim 1, wherein A represents a 2-guanidino-4-thiazolyl group; X 45

represents —S—; m is 2; n is 1; p is 1 or 2; R3 represents a hydrogen atom or a methyl or ethyl group;

and R4 represents an amino, methyl, 4-methoxyphenyl or NHR6 group, in which R6 is as defined in claim 1.

7. A compound as claimed in claim 6, wherein p is 2; R3 is a methyl group; and R4 is an amino or

50 —NHR6 group. 50

8. 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4H-5-amino-1,2,4,6-thiatriazine-1,1-dioxide.

9. 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-amino-1,2,4,6-thiatriazine-1,1-dioxide.

55 10.3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-ethyl-5-amino-1,2,4,6- 55

thiatriazine-1,1-dioxide.

11.3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-(2-dimethylaminoethyl]amino-1,2,4,6-thiatriazine-1,1-dioxide.

12. 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-(2-

60 thienyl)methylamino-1,2,4,6-thiatriazine-1,1-dioxide. 60

13. 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-[2-(1-piperidinyl)ethyl]amino-1,2,4,6-thiatriazine-1,1-dioxide.

14. 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-[2-(1-pyrrolidinyl)ethyl]amino-1,2,4,6-thiatriazine-1,1-dioxide.

21

GB 2 129 426 A 21

15. 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-(diethylaminoethyl)amino-l,2,4,6-thiatriazine-1,1-dioxide.

1 6. 3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-amino-1,2,4,6-thiatriazine-1 -mono-oxide.

5 17.3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]amino-4-methyl-5-methyl-1,2,4,6- 5

thiatriazine-1,1-dioxide.

18. 3-N-[3-[3-(1-Piperidinylmethyl)phenoxy]propyl]amino-4-methyl-5-amino-1,2,4,6-thiatriazine-1,1-dioxide.

19. 3-N-[3-[3-( 1 -Piperidinylmethyl)phenoxy]propyl]amino-4-methyl-5-(2-

10 dimethylaminethyl)amino-1,2,4,6-thiatriazine-1,1 -dioxide. 10

20. A compound as claimed in claim 1, substantially as described in any one of Examples 3, 9 to 17, 19 to 37, 39 to 43,45,46,49 to 51, 53 to 65, 67, 70, 71 and 84 herein.

21. A salt of a compound as claimed in any one of claims 1 to 20.

22. A physiologically tolerable salt of a compound as claimed in any one of claims 1 to 20.

15 23. A process for the production of a compound of the general formula I as claimed in claim 1, 15 which comprises a) reacting a 1,2,4,6-thiatriazine of the general formula II

(0)P

..'Si ,11,

is in which L1 represents a halogen atom, an alkoxy or aryloxy group, an alkylthio or arylthio group, or an 20 alkylsulphonyl or arylsulphonyl group, p and R4 are as defined in claim 1, and R3a is as defined in claim 20 1 forR3 except that R3a may not represent a hydrogen atom, with a compound of the general formula III

A—(CH2)n—X—(CHa)m—NH2 III

in which A, X, m and n are as defined in claim 1, or b) reacting a 1,2,4,6-thiatriazine of the general formula IV

25

(0)p

N II IV 25

in which L1 and L2, which may be the same or different, each represents a halogen atom, an alkoxy or aryloxy group, an alkylthio or arylthio group, or an alkylsulphonyl or arylsulphonyl group, and p and R3a are as defined above, with a compound of formula ill as defined above, and reacting the resulting compound of formula V

(0)p ■ «

30 A, - (CH,)„ - X - (CH2)m - J\l2 V 30

2 n

R'

>3

a with an amino compound HNR5aR6a in which R5a and R6a are as defined for R5 and R6 in claim 1 and, in addition, either or both of R5a and R6a may represent a trialkylsilyl group; or c) reacting a 1,2,4,6-thiatriazine of the general formula II as defined above with an amino compound of formula VI

35

HXa—(CH2)m—NH2

VI 35

22

GB 2 129 426 A 22

in which Xa is —0— or —S—, and m is as defined in claim 1, and reacting the resulting compound of formula VII

(o)p

S

n/nn

VII

- <CK2>» - ""

]?

a in which R3a, R4, p and m are as defined above, with a compound of the general formula VIII

5 A—(CH2)n, —L3 VIII 5

in which A is as defined in claim 1, n' represents 1, and L3 is a suitable leaving group, for example, a halogen atom, a hydroxy group, an alkoxy group, or a sulphonate ester, and, if desired, carrying out anyone or more of the following reactions in any desired order:—

(i) converting a group R3 into a hydrogen atom,

10 (ii) converting a group R3 and/or a group R4 into another group R3 and/or R4, respectively, 10

(iii) converting an acid addition salt of formula I into the corresponding free base or converting a free base into an acid addition salt,

(iv) oxidising a compound of formula I in which p represents 1 to give the corresponding compound in which p represents 2.

15 24. A process as claimed in claim 23, wherein R3a represents a t-butyl, lower alkyl carbonate, 15

benzyl or benzoyl group, which is removed from the resulting compound of formula I.

25. A process as claimed in claim 23, wherein a compound of the general formula II is produced by reacting a compound of formula IX with a compound of formula X

IX NH2S02NH2 (R11) 1 ! OCN

20 in which x represents 1 or 2 and R11 represents an alkyl, dialkylamino, acylamino, nitro, halogen, aryl, 20 nitrile, alkoxy, aryloxy or acyloxy group, in the presence of a base and, if desired, alkylating the resulting amino group at the 4-position in the resulting compound of formula XI

0 0

V

N

XI

X HH.

H

26. A process as claimed in claim 23, wherein a compound of formula IV is produced by reacting 25 a compound of formula X

.11. _ x

(R )„ —TT^J 0CN

in which R11 is as defined in claim 25, with a compound of formula XIII

R3a—N—(Si(alkyl)3)2 XIII

in which R3 is as defined in claim 23, cyclising the resulting compound of formula XIV

25

23

GB 2 129 426 A 23

(alkyl)^,Si(alkyl)3

ji-°—(r11)

XIV

N-

k and, if desired, oxidising the resulting compound of formula XV

0 +

N/SXN

t

R3 a to give the corresponding dioxide.

5 27. A process as claimed in claim 23, wherein a compound of formula IV is prepared by reacting 5

a compound of formula XVII

0 0

\/

0=C=N—S—N=C=0 XVII

with a compound of formula XVIII

R3aNH2 XVIII

10 in which R3a is as defined in claim 23, and introducing the groups L1 and L2 as defined in claim 23 into 10 the resulting compound of formula XIX

0 0

W/

s.

" NH

JU

XIX

w 0

R3 a

28. A process as claimed in claim 23, wherein a compound of formula IV is converted into a compound of formula II by reaction with a primary or secondary amine NHR5aR6a in which Rsa and R6a

15 are as defined in claim 23. 15

29. A process as claimed in claim 23, wherein a compound of formula II is produced by converting the group R12 in a compound of formula XXX

°2

IT

X

E12S ^ ^ S ^ R

4 xxx

24

GB 2 129 426 A 24

in which R3a and R4 are as defined in claim 23 and R12 represents an alkyl, aryl or aralkyl group, into a group L1 as defined in claim 23 or, if R12S already represents a group L1, converting this group into another group L1.

30. A process as claimed in claim 29, wherein a sulphide group R12S— is oxidised to the corresponding sulphoxide, or is replaced by a halogen atom.

31. A process as claimed in claim 29 or claim 30, wherein a compound of formula XXX is produced by heating a compound of formula XXV

0, 0

l 2

2T ~JJH " ^R4

„ A

B. S BH

in which R3a, R4 and R12 are as defined in claim 29, in an aprotic solvent.

10 32. A process as claimed in claim 31, wherein a compound of formula XXV is produced by 10

reacting a compound of formula XXI

HHg

XXI

R12S "

I 3 R5

a in which R3a and R12 are as defined in claim 29, with a compound of formula XXVII

0

XXVII

a

HH302C1

15 in which R4 is as defined in claim 23, in the presence of a base and in an aprotic solvent.

33. A process as claimed in claim 31, wherein a compound of formula XXV is produced by reacting a compound of formula XXI as defined in claim 32 with a compound of formula XXII

15

R4—C—CI

XXII

in which R4 is as defined in claim 29, in the presence of a base and in an aprotic solvent to give a 20 compound of formula XXIII

HH 0

XXIII

R12S"^ e4

R"

which is then reacted with a compound of formula XXIV

20

nh2so2ci

XXIV

in the presence of a base and in an aprotic solvent.

25

GB 2 129 426 A

25

34. A process as claimed in claim 31, wherein a compound of formula XXV is produced by reacting a compound of formula XXVI

r12s

XXVI

se

12

in which each group R12 is as defined in claim 29, the two groups R12 being the same or different, with a compound of formula XXVII as defined in claim 32, in an aprotic solvent and in the presence of a base, to give a compound of formula XXVIII

r1 2s

JT

se eh

12

R

XXVIII

which is then reacted with a compound of formula XXIX

R3aNH2

XXIX

10 in which R3a is as defined in claim 23, to give a compound of formula XXV. 10

35. A process as claimed in claim 23, carried out substantially as described in any one of Examples 1 to 3, 9 to 72, and 84.

36. A compound as claimed in claim 1, whenever produced by a process as claimed in any one of claims 23 to 35.

15 37. A pharmaceutical preparation which comprises a compound of formula I as claimed in any \ 5

one of claims 1 to 20 or claim 36, or a physiologically tolerable salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier.

38. A compound of formula I as claimed in any one of claims 1 to 20 or claim 36, or physiologically tolerable salt thereof, for use as a medicament.

20 39. A compound of formula XII 20

0v JO

V

fM IM

oXJL

NH,

XII

in which R3a is as defined in claim 23, and R11 and x are as defined in claim 25. 40. A compound of formula XVI

0 0

V

(R11).

■O1

N N

\ .

N

XVI

25 in which R3a, R11 and x are as defined in claim 39.

25

26

GB 2 129 426 A 26

41. A compound of formula XXV

in which R3a, R4 and R12 are as defined in claim 40. 42. A compound of formula XXVIII

XXV

r12s

H

?2 ss se be"

12

XXVIII

in which R4 and R12 are as defined in claim 33. 43. A compound of formula XXIII

R12S

XX

I

R

E-

XXIII

in which R3a, R4 and R12 are as defined in claim 29, with the exception of those compounds in which R3a 10 represents a phenyl group. 10

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1984. Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.