GB2174705A

GB2174705A - Benzodioxin and benzoxazine derivatives

Info

Publication number: GB2174705A
Application number: GB08611154A
Authority: GB
Inventors: Robert Manning Allen; Stephen Robert Fletcher
Original assignee: Hoechst UK Ltd
Current assignee: Sanofi Aventis UK Holdings Ltd
Priority date: 1985-05-07
Filing date: 1986-05-07
Publication date: 1986-11-12
Also published as: PT82530A; DK208886A; GR861132B; DK208886D0; PT82530B; GB8611154D0; JPS61254576A; EP0204148A2; EP0204148A3; GB8511526D0

Abstract

A compound of formula I <IMAGE> in which R<1> and R<2> each represents a hydrogen atom, a C1-4 alkyl group or, together with the nitrogen atom to which they are attached, R<1> and R<2> form a 4 to 8-membered ring which may contain an oxygen atom or another nitrogen atom, which nitrogen atom may have a C1-4 alkyl group as substituent, X represents an oxygen atom or a group NR<4> in which R<4> represents a hydrogen atom, C1-4 alkyl group, a phenyl group or a phen-C1-4-alkyl group, the alkyl, phenyl or phenalkyl group being unsubstituted or substituted, or R<4> represents a nitrogen protecting group; m is 1 to 4; n is 1 or 2; and R<3> represents a group of formula II, III, IV, V or VI <IMAGE> in which R<5> represents a hydrogen atom or a C1-4 alkyl group; and R<6> represents a hydrogen atom or a C1-4 alkyl group, a C2-4 alkenyl group has histamine H-2 antagonist activity, and may be used to produce medicaments.

Description

1

GB 2 174 705A 1

SPECIFICATION

[1,4]benzodioxin and [1,4]benzoxazine derivatives

5 The present invention relates to [1,4]benzodioxin and [1,4]benzoxazine derivatives which have 5

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

Histamine is one of a number of naturally occurring physiologically active substances which are 10 thought to interact with specific receptors. In the case of histamine, there are at least two 10

types: one is called the H-1 receptor (Ash and Schild, Brit. J. Pharmac. 1966, 27, 427), and the other is called the H-2 receptor (Black et al Nature 1972, 236, 385). The action of histamine at the H-1 receptor, for example, stimulation of bronchial and gastro-intestinal smooth muscle, is blocked by the compounds generally known as "antihistamines", but which are now also called 15 histamine H-1 antagonists, for example, mepyramine. The action of histamine at the H-2 recep- 15 tors, 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.

Histamine H-2 antagonists may be used to treat those conditions resulting from stimulation by histamine of H-2 receptors, either alone, for example, in inhibiting gastric acid secretion and thus 20 treating its sequelae, for example, gastric and peptic ulcers; or together with H-1 antagonists, for 20 example, in allegic and certain inflammatory conditions.

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

(i)

(CH2)n - NHR3

NHR5 NHR5 ^ ^NHR5

(ID (HI) (IV)

(V)

]| MM

NHR5 V NHR

£ I? <VI)

6

25

in which formula

30 R' and R2, which may be the same or different, each represents a hydrogen atom, a straight 30 or branched chain alkyl group having from 1 to 4 carbon atoms or, together with the nitrogen atom to which they are attached, R1 and R2 form a 4 to 8-membered ring which may contain an oxygen atom or another nitrogen atom, which nitrogen atom may have an alkyl group having from 1 to 4 carbon atoms as substituent,

35 X represents an oxygen atom or a group NR4 in which R4 represents a hydrogen atom, a 35

straight or branched chain alkyl group having from 1 to 4 carbon atoms, a phenyl group or a phenalkyl group, the alkyl moiety of which has a straight or branched chain and from 1 to 4 carbon atoms,

an alkyl, phenyl or phenalkyl group being unsubstituted or substituted by one or more substitu-40 ents, which may be the same or different, for example, by one or two substituents, especially 40 by one substituent, selected from halogen atoms, straight and branched chain alkyl groups having from 1 to 4 carbon atoms, straight and branched chain alkoxy groups having from 1 to 4 carbon atoms, nitro and trifluoromethyl groups,

or R4 represents a nitrogen protecting group;

45 m represents an integer of from 1 to 4; 45

n represents 1 or 2; and

R3 represents a group of formula II, III, IV, V or VI

o

NCN Fu-> "

n ^ s ^

50 n N N 50

55 o o 55

v- //

CH3 ~ N N ' S >

60 CH3 60

in which formulae

R5 represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms; and

R6 represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 65 carbon atoms, a straight or branched chain alkenyl group having from 2 to 4 carbon atoms, or a 65

2

GB2174705A 2

straight or branched chain alkynyl group having 3 or 4 carbon atoms.

In a compound of formula I, when X represents an oxygen atom, R3 preferably represents a group of formula V or VI, and in formula VI, R8 preferably represents a hydrogen atom or a propargyl group. A preferred value for n is 2. Of particular interest are those compounds in 5 which the group 5

R'

\

N-(CH2)m-

10 / 10

R2

is in the 7-position, especially when n is 2 and R3 preferably represents a group of formula V or VI as described above.

15 When X represents a group NH, n is preferably 2 and R3 preferably represents a group of 15

formula VI in which R6 preferably represents a hydrogen atom. Again, the group

R1

20

NHCHjL

R2

20

is preferably in the 7-position.

25 When R1 and R2 form a 4 to 8-membered ring which may contain an oxygen atom or another 25 nitrogen atom, which nitrogen atom may have an alkyl group having from 1 to 4 carbon atoms as substituent, such a ring is, for example, a pyrrolidine, piperidine, morpholine or N-methylpiper-azine ring.

R4 may represent a nitrogen protecting group. Such groups are well known in the art and are 30 described, for example, in Protecting Groups in Organic Chemistry, McOmie, Plenum Press, 30

London 1973, Chapter 2, pages 43 to 93, which are incorporated herein by reference, and in Protective Groups in Organic Synthesis, T.W. Green, J. Wiley & Sons Inc. 1981, pages 218 to 287, which are also incorporated herein by reference. (It will be appreciated that some of the groups defined per se for R4 may fall within the general definition of nitrogen protecting groups.) 35 Examples of nitrogen protecting groups are alkoxycarbonyl and aryloxycarbonyl groups, for 35

example, p-nitrobenzyloxycarbonyl and t-butyloxycarbonyl groups; aralkyl groups, especially benzyl and substituted benzyl groups, for example, p-nitrobenzyl and p-methoxybenzyl groups; and arkylcarbonyl groups which may be substituted, for example, by halogen atoms, for example, trifluoromethylcarbonyl groups. Such groups may be removed, if desired, by conventional 40 methods, for example, as described in McOmie and in Greene (see above). An example of a 40

suitable method is acidic cleavage, for example, by treatment with hydrochloric acid.

The present invention also provides salts of compounds of formula I, especially physiologically tolerable salts, for example, salts with hydrochloric, sulphuric, hydrobromic, succinic, tartaric or maleic acid, also oxalate salts. The invention further provides hydrates, and solvates of formula I. 45 It will be understood that the structure given above for formula I is only one of several 45

possible tautomeric and isomeric representations. The present invention includes all tautomeric and isomeric forms of compounds of the general formula I.

The term "lower" is used in the present specification to denote a group, radical or molecule having up to 4 carbon atoms. Any alkyl group in the present specification may have a straight 50 or branched chain. 50

The present invention also provides a process for the production of a compound of formula I,

which comprises (i) reacting a compound of formula VII

(VII)

(CH2>„ " **2

55

in which R\ R2, X, m and n are as defined above, with a compound of formula Ila or Ilia 60 NCH . ho2 60

<IIa) II fj (Ilia)

L NHR5 L NHR5

65 in which L represents a leaving group, for example, a halogen atom or a group -YR7 in which Y 65

3

GB 2 174 705A 3

represents an oxygen or sulphur atom, a group SO or a group S02, and R7 represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted phenalkyl group having from 1 to 4 carbon atoms in the alkyl moiety, wherein a phenyl or phenalkyl group may be substituted by one or 5 two, and especially by one substituent, selected from alkyl, alkoxy, methylenedioxy, phenoxy, 5

halogen, dialkylaminoalkyl (especially dimethylaminomethyl), trifluoromethyl, nitro, cyano, sul-phonic acid, sulphonamide, amino, and mono- and di-alkylamino groups, an alkyl moiety having a straight or branched chain and from 1 to 4 carbon atoms; and R5 is as defined above, to obtain a compound of formula I in which R3 represents a group of formula II or III respectively; or 10 (ii) reacting a compound of formula VII as defined above with a compound of formula VIII 10

(VIII)

n-(ch,)

r'

2/

2'm

:x

JL

(CHA-NH

% *°

^ ^ fru \ N

(CH2)n-NH » *■ CT3

(VIb)

15

in which L is as defined above, and cyclising the resulting compound of formula IX

CH,

(IX) 3

to obtain a compound of formula I in which R3 represents a group of formula V; or 25 (iii) reacting a compound of formula VII as defined above with a compound of formula IVa or 25 Via o o v *

__ (XVa) /-Ss H1 if (Via)

30 n H JL X 30

L "st CH3

in which the two groups L each represents a leaving group as defined above, the two groups L 35 being the same or different with the proviso that in the case of two leaving groups -YR7 the 35 two radicals R7 can be the same or different, but the two groups Y must be the same, to give a compound of formula IVb or VIb respectively,

o

, 11

40 R v x "S ^S ^ 40

4U Y_ . rv-Sr I N » . (ivb)' 4U

45 »VC 45

50 and reacting the resulting compound of formula IVb or VIb with a compound of formula Xa or 50 Xb, respectively

(Xa) H2NR5 H2NR6 (Xb)

55 in which R5 and R6 are as defined above, to give a compound of formula I in which R3 55

represents a group IV or VI, respectively.

A phenyl or phenalkyl group R7 in a leaving group L may be substituted by one or more substituents, especially by one substituent, selected from straight and branched chain alkyl groups having from 1 to 4 carbon atoms, especially methyl groups, halogen atoms, straight and 60 branched chain alkoxy groups having from 1 to 4 carbon atoms, especially methoxy groups, and 60 nitro groups.

In a leaving group L, when Y represents a sulphur atom, R7 preferably represents a lower alkyl group, especially a methyl group, and when Y represents an oxygen atom, R7 preferably represents a methyl or phenyl group, especially a substituted phenyl group, for example, a mono-65 substituted phenyl group, especially a tolyl group or a nitro-phenyl group, for example, an ortho- 65

4

GB 2 174 705A 4

nitrophenyl group.

The reaction between compound VII and compound Ila, Ilia, IVa, Via or VIII and also between a resulting compound IVb or VIb and compound Xa or Xb respectively, is generally carried out in a solvent, for example, an organic solvent, for example, a lower alcohol, for example,

5 methanol, ethanol or isopropanol, dimethylformamide, tetrahydrofuran or acetonitrile, or in a 5

mixture of two or more of such solvents. The reaction is generally carried out at a temperature within the range of from 5 to 75°C.

Cyclisation of compound IX may be carried out using an acidic medium, for example, aqueous hydrochloric acid and an organic solvent, for example, an alcohol or a ketone especially acetone, 10 at a temperature within the range of from 10 to 50°C, especially at room temperature. 10

A compound of formula VII may be produced from a compound of formula XI, XII or XII

15

20 R1^ (XIIX)

H - (CH,)

(CH2)n -NH - COOR

in which formulae R1, R2, Q, X and n are as defined above, and R8 represents a carboxylic acid 25 protecting group, for example, as described in McOmie (loc. cit.) Chapter 5 pages 183-216 and 25 in Greene (loc. cit.) Chapter 5 pages 152-192, which are incorporated herein by reference, for example, lower alkyl, benzyl, p-nitro-benzyl and, especially, t-butyl groups.

Compound XI is converted to compound VII by reduction, for example, using lithium aluminium hydride, sodium borohydride, or hydrogen in the presence of a hydrogenation catalyst, for 30 example, 10% palladium on charcoal. 30

Compound XII may be converted into compound VII by reduction in the presence of a base, for example, ammonia. Hydrogen and an appropriate hydrogenation catalyst are generally used, for example, rhodium on carbon, for example 5% Rh/C, and the reaction is preferably carried out in a solvent or diluent, for example, an alcohol, for example, methanol or ethanol saturated with 35 ammonia. 35

Compound XIII may be converted into a compound of formula VII by hydrolysis in the presence of an acid, for example, hydrochloric acid.

Compounds of formula XI may be prepared according to the following Reaction Scheme 1:

5

GB 2 174 705A 5

Schtnr 1

0 (CH:)„-OH

XVII

10

15

20

25

HC(CH0m-»

O

30 II. , HC(CHl)m.1

35

40 Ri

XVI

0 ^(ch2)-N3

XIV

R2'

NH

XV

Xla

(CH2)n-N,

15

20

25

30

35

40

45 in which R9 represents an activating group, for example, a sulphonyl group, for example, a 45

toluenesulphonyl, methanesulphonyl or trifluoromethanesulphonyl group, or a trifluoroacetyl group;

X1 has the meanings given above for X with the exception of an -NH- group;

R\ R2, m and n are as defined above.

All four isomers of compound XVII in which (m—1)=0 and X1 represents an oxygen atom are 50 known, as is their conversion into the corresponding isomers of formula XVI, cf A. Funke and 50 A. Paulsen, Gazz. Chim. Ital. 1961, 91, 1268-1281. Other compounds of formulae XVII and XVI may be prepared analogously. (Methods of activating an alcohol, for example, by conversion to a sulphonate ester, for replacement of the hydroxy group are well known.)

Compound XVI is then converted into compound XIV by reaction with an azide, for example, 55 sodium azide. The reaction is generally carried out in a solvent or diluent, for example, dimethyl- 55 formamide, dimethyl sulphoxide or acetone, generally at a temperature within the range of from 20 to 100°C, especially 80°C.

Compound XIV may be converted into compound Xla by reductive amination. By such a method, compound XIV is reacted with a compound of formula XV

6

GB 2 174 705A 6

R1

\

N-H (XV)

5 / 5

R2

in which R1 and R2 are as defined above, in the presence of a reducing agent. The reaction may be carried out with, for example, a borane-pyridine complex or sodium cyanoborohydride, under 10 acidic conditions, and is preferably carried out in a solvent or diluent, for example, an alcohol, 10 for example, methanol. The reaction may be carried out at a temperature within the range of from —10 to 25°C, for example, at room temperature.

To obtain a compound of formula XI wherein X represents NH, a protecting group R4 may be removed from a resulting compound of formula Xla having a protected NH group. The removal 15 of a nitrogen protecting group R4 is carried out in known manner see, for example, McOmie (loc. 15 cit.) and Greene (loc. cit.). (The term "known" is used herein to mean in actual use in the art or described in the literature of the art.)

Alternatively, compounds of formula XI in which n is the integer 2 and X represents an oxygen atom may be produced according to the following Reaction Scheme 2:

20 Sch«mt 2 20

j»*j=0G

25 25

30 J*

X

XXI

35

O^CHjCOOR'

R\

R'/NH

XV

X

30

35

XX

O-^CH.COOR

40

45

50 R\

vn(ch,);

1

0^(01,),OH

°1

o^chO.OR'

XIX

XVIII

45

50

55

60

,yN(CH,)

O^CH,), N,

Xlb in which R1, R2, R9, m and n are as defined above; and R'° represents a carboxylic acid protecting group, as described above in relation to Rs.

Compounds of formula XXII are available commercially.

A compound XXII is reacted with a compound of formula XXIII

55

60

ZCH,CH=CHC00R"

(XXIII)

7

GB 2 174 705A 7

in which R10 is as defined above and Z represents a halogen atom, especially a bromine atom. The reaction is preferably carried out in the presence of a base, for example, an inorganic base, for example, sodium carbonate. The reaction is generally carried out in a solvent or diluent, for example, dimethylformamide, dimethyl sulphoxide, or a ketone, especially acetone.

5 The resulting cyclic compound XXI is then reacted with a compound of formula XV as defined 5 in Reaction Scheme 1 to give a compound of formula XX. This reaction is preferably carried out as described in Reaction Scheme I for the reaction of compounds XIV and XV.

The ester of formula XX is then reduced to give compound XIX. The reduction may be carried out using any one of a variety of reducing agents, for example, a metal hydride, for example, 10 lithium aluminium hydride. The reaction is generally carried out in a solvent or diluent, for 10

example, tetrahydrofuran, an ether, or an alcohol, for example, ethanol.

The hydroxy group of compound XIX is then activated, for example, by the introduction of an activating group R9, for example, as described above in Reaction Scheme 1.

The activated compound XVIII is then converted into the corresponding azide as described in 15 Reaction Scheme 1. 15

Compounds of formula XII in which the radical X represents an oxygen atom may be produced according to the following Reaction Scheme 3.

Scheme 3

20 20

XXV

25 1

5-WrOO,

25

XXIV

30 ~ 30

35 35

in which R', R2 and m are as defined above.

Compound XXV, which is available commercially, is reacted with a compound XXVI

40 ZCH2CH=CHCN (XXVI) 40

in which Z is as defined above, to give a compound XXIV. Compound XXVI (in the form of a cis-trans mixture) is described by W.J. Bailey and J. Bello, J. Org. Chem. (1955), 20, 525. The reaction is carried as decribed above for the reaction of compounds XXII and XXIII. The 45 resulting compound XXIV is then reacted with a compound of formula XV as defined in Reaction 45 Scheme I, under the conditions described in Reaction Scheme I for the reaction of compounds XIV and XV.

Compounds of formula XII in which X represents NR4 may be produced according to the following Reaction Scheme 4:

8

GB 2 174 705A 8

Scheme 4

NH,

OH

10

15

20

25

H

"1

O -^CHjCN

1

0"^CH,CN

Z(CH,)

<"o^CH,CN

30 ^N(ch,),

35

"1

r\

^>(cH,)rQC0l

O^CH.CN

XXXI

XXX

XXIX

XXVIII

XXVII

10

15

20

25

30

35

X lib

O^CH,CN

40 in which R\ R2 and m are as defined above, R11 represents an alkyl group, especially a methyl 40 group, and R12 represents a nitrogen protecting group, for example, as defined above, for example, a carboxylic acyl group, and especially a formyl group.

A compound of formula XXXI is reacted with a compound of formula XXVI as described in Reaction Scheme 3 to give a compound of formula XXX. This compound is then acylated to 45 protect the nitrogen atom, for example, to introduce a formyl protecting group, formic acid is 45 used. It is preferable to carry out the acylation reaction in the presence of an activating agent, for example, acetic anhydride. The reaction temperature is, for example, in the range of from 20 to 60°C, for example, at room temperature.

The resulting compound XXIX is then halogenated, for example, by means of a reagent 50 capable of free radical halogenation at the group R11, for example, there may be used N-bromo- 50 succinimide or a derivative thereof in the presence of light and/or a peroxide, for example,

benzoyl peroxide. The halogenation is carried out with heating, and generally in a solvent or diluent, for example, benzene or a chlorinated hydrocarbon, for example, carbon tetrachloride, to give compound XXVIII. This compound may be isolated, if desired, but is generally reacted in 55 situ with compound XV to give compound XXVII. 55

If R'2 is a protecting group as defined for R4, then compound XXVII is itself a compound of formula XII. If desired, the protecting group R12 may be removed from compound XXVII to give the corresponding -NH- compound of formula Xllb. This reaction is carried out in known manner (see above), for example, by means of a mineral acid, for example, hydrochloric acid. 60 The reaction is generally carried out in a solvent or diluent, for example, an alcohol, for example, 60 methanol.

A compound of formula XIII may be produced according to Reaction Scheme 5 described below:

9

GB 2 174 705A 9

Scheme 5

O

HC(CH

10

15 HC(CHj)

20

O

25 H, * HC(CHS)

30

I

o ^CHjCOOR1

X

m-i CH.COOH

X

m-i c^CHjNHCOOR

35

>wr0Col

CH,NHCOOR

XXI

XXXIII

XXXII

XIII

10

15

20

25

30

35

in which R\ R2, Ra R'° and m are as defined above.

40 Compound XXI, which is described in Reaction Scheme 2, is hydrolysed under acidic or basic 40 conditions, preferably under acidic conditions using, for example, hydrochloric acid, to give compound XXXIII. Compound XXXIII may then be converted into the carbamate XXXII using standard methodology, for example, see C.A. Buehler and D.Pearson, Survey of Organic Synthesis, pages 494-503, Wiley-lnterscience, New York, (1970). In the present case it is advan-45 tageous to use diphenylphosphorylazide in t-butanol for the conversion (see J. Amer. Chem. 45

Soc. (1972), 94, 6203).

Compound XXXII is then reacted with compound XV as described in Reaction Scheme 1 to give compound XIII. As mentioned above, compound XIII is hydrolysed to give compound VII in which the radical X represents an oxygen atom. The hydrolysis is generally carried out using a 50 mineral acid, for example, hydrochloric acid. The reaction is generally carried out in a solvent or 50 diluent, for example, an alcohol, for example, methanol, at a temperature within the range of from 20 to 100°C, and preferably at reflux temperature.

As indicated above, the compounds of the present invention have histamine H-2 antagonist activity. Accordingly, the present invention provides a pharmaceutical preparation which com-55 prises a compound of the general formula I or a physiologically tolerable salt thereof as active 55 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 preparation may be in unit dosage form, for example, as tablets or capsules, or in unit or multiple dose ampoules or vials. From 0.1 to 10 mg of the active 60 substance may be administered per kg body weight. A preparation of the invention may also 60 comprise one or more pharmaceutically active substances, for example, histamine H-1 antagonists.

The present invention also provides the use of a compound of the general formula I for the manufacture of a medicament, especially for use as a histamine H-2 antagonist, and particularly 65 for treating conditions resulting from stimulation by histamine of H-2 receptors, using a com- 65

10

GB2174705A 10

pound of formula I 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 treating allergic and certain inflammatory conditions.

Examples of preferred compounds of formula I are the following compounds, which are 5 defined in terms of the formula XXXIV, and are also named:

:i

(XXXIV)

10 vJ^2 ° '"Vj-"*3 ' 10

3-Amino-1 -methyl-5-[2-(7-(N-piperidinylmethyl)-2,3-dihydro[ 1,4]benzodioxin-2-yl)ethylamino]-1,2,4-triazole ie compound XXXIV in which

15 3 CH3 N 15

X »= -O- R =

3-Amino-4-methyI-5-[2-(7-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)ethylamino]-20 1,2,4,6-thiatriazine 1,1-dioxide ie compound XXXIV in which 20

, ^ s \

X •= -O- R = N N

X JL

25 I ^2 25

^3

4-Methyl-3-[2-(7-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)ethylamino]-5-propargylam-ino-1,2,4,6-thiatriazine 1,1-dioxide ie compound XXXIV in which 30 30

X » -O- R3

An

.X

NHCH2CSCH

35 CH3 35

3-Amino-4-methyl-5-[2-(7-(N-piperidinylmethyl)-2,3-dihydro[4H][1,4]benzoxazin-2-yl)ethylamino]-1,2,4,6-thiatriazine 1,1-dioxide ie compound XXXIV in which

40 °nn 40

X = -NH- R a N N

45 3 45

In the above compounds and throughout the present specification, the terms "2,3-dihydro[1,4-]benzodioxin and "2,3-dihydro[4H][1,4]benzoxazin" are used to denote the following ring structures A and B respectively.

50 5 4 5 H 50

u> 6r^> 6^VY

7

8 1

J: :ga

8 1

55 55

The compounds of formulae VII, IX, XI, XII, XIII, XIV, XVIII, XIX, XX, XXI, XXII, XXIV,

XXVIII, XXIX, XXX, XXXII and XXXIII are part of the present invention. These compounds may exist in various isomeric and/or tautomeric forms, and the present invention includes all such forms.

60 The following examples illustrate the invention, but are not limiting. 60

Melting points were determined on a Reichert hot-stage apparatus; temperatures are expressed in degrees Celcius; and unless stated otherwise, NMR spectra (250 MHz) were determined in CDCI3. Thin layer chromatography (TLC) was carried out on silica using the solvents given in the text.

11

GB2174705A 11

EXAMPLE 1

2,3-Dihydro-2-(toluenesulphonyloxymethyl)[1,4]benzodioxin-8-carboxaldehyde p-Toluenesulphonyl chloride (4.8g) was added portionwise to a solution of 2,3-dihydro-2-(hydroxymethyl)[1,4]benzodioxin-8-carboxaldehyde (5.0g) in pyridine (20mi) cooled in ice. When 5 the addition was complete (5 minutes) the mixture was warmed to room temperature, stirred for 3 hours and then partitioned between 1N aqueous hydrochloric acid and ethyl acetate. The organic layer was separated, washed with 1N HCI, dried over anhydrous magnesium sulphate and evaporated to give a colourless solid which was recrystallised from isopropanol to give 4.9g of the title compound.

10 omax (Nujol*) 1675, 1600 cm"1

8 2.45 (3H, s); 4.18-4.25 (1H, m); 4.35-4.45 (1H, m); 4.38 (2H, s); 4.55-4.65 (1H, m); 6.95-7.90 (7H, m); 10.15 (1H, s).

*"Nujol" is a Trade Mark

15 EXAMPLE 2

2-(Azidomethyl)-2,3-dihydro[1,4]benzodioxin-8-carboxaldehyde

A suspension of sodium azide (1.3g) in a solution of 2,3-dihydro-2-(p-toluenesulphonyloxyme-thyl)[1,4]benzodioxin-8-carboxaldehyde (4.0g) in dimethylformamide (20ml) was stirred with heating at 80°C for 16 hours. The mixture was then evaporated to dryness, and the residue 20 partitioned between ethyl acetate and water. The organic phase was separated, washed with 1N sodium hydroxide solution, dried (MgS04) and evaporated to give a colourless solid which was recrystallised from isopropanol to give 1,9g of the title compound.

omax (Nujol) 2080, 1675, 1600, 1590 cm '

5 3.6-3.75 (2H, m); 4.11-4.18 (1H, m); 4.30-4.36 (1H, m); 4.50-4.60 (1H, m); 6.95 (1H, t, J 25 9Hz); 7.16 (1H, d, J 9Hz); 7.46 (1H, d, J 9Hz); 10.41 (1H, s).

EXAMPLE 3

2-(Azidomethyl)-2,3-dihydro[ 1,4]benzodioxin-6-carboxaldehyde The title compound was obtained as an oil from 2,3-dihydro-2-(p-toluenesulphonyloxymethy-30 l)[1,4]benzodioxin-6-carboxyaldehyde by a procedure analogous to that described in Example 2. t)max (film) 2100, 1685, 1600, 1585 cm 1

S 3.55-3.65 (2H, m); 4.06-4.16 (1H, m); 4.30-4.35 (1H, m); 4.35-4.50 (1H, m); 7.05 and 7.45 (2H, ABq, J 9Hz); 7.42 (1H, s); 9.89 (1H, s).

35 EXAMPLE 4

2-Azidomethyl-2,3-dihydro-8-(N-piperidinylmethyl)[1,4]benzodioxin

Piperidine (3.5g) was added in one portion to a solution of 2-azidomethyl-2,3-dihydro[1,4]ben-zodioxin-8-carboxaldehyde (1.5g) in methanol (30ml) cooled in ice. A solution of hydrogen chloride in methanol (3.44M, 4.1 ml) was then added, followed by sodium cyanoborohydride 40 (0.88g), and the resulting mixture was stirred for 18 hours at room temperature. The solvent was evaporated and the residue treated with 2N HCI (30ml). The solution was extracted with ethyl acetate and the pH adjusted to 14 with sodium hydroxide pellets. The resulting solution was extracted with ethyl acetate, the organic layer separated, dried (MgS04) and evaporated to afford the title compound as a yellow oil. Pure material (1.74g) was obtained by column 45 chromatography on silica using chloroform/methanol (95:5) as solvent.

S 1.35-1.50 (2H, m); 1.50-1.65 (4H, m); 2.42-2.52 (4H, m); 3.45-3.64 (2H, m); 4.02-4.12 (1H, m); 4.22-4.30 (1H, m); 4.30-4.45 (1H, m); 6.80-7.05 (3H, m).

EXAMPLE 5

50 2-Azidomethyl-2,3-dihydro-6-(N-piperidinylmethyl)[1,4]benzodioxin

The title compound was obtained as a colourless oil from 2-azidomethyl-2,3-dihydro-[1,4]ben-zodioxin-6-carboxaldehyde by a procedure analogous to that described in Example 4.

tU, (film) 2100, 1590 cm 1

55 EXAMPLE 6

2,3-Dihydro-5~formyl[ 1,4]benzodioxin-2-acetic acid methyl ester

A heterogeneous mixture of 2,3-dihydroxybenzaldehyde (6.9g), methyl 4-bromocrotonate (9.8g) and potassium carbonate (15g) in dimethyl formamide (100ml) was stirred at room temperature for 18 hours. The solvent was subsequently evaporated and the residue partitioned between 60 diethyl ether and 1N sodium hydroxide solution. The organic phase was separated, washed with 1N sodium hydroxide solution, then with water, was dried over anhydrous magnesium sulphate and evaporated to give a yellow oil. Bulb to bulb distillation afforded 6.6g of the title compound, b.p. 150-170°C. 0.5 mm Hg.

S 2.66-2.94 (2H, m); 3.77 (3H, s); 4.10-4.20 (1H, m); 4.48-4.56 (1H, m); 4.70-4.80 (1H, m); 65 7.0 (1H, t, J 9Hz); 7.17 (1H, d, J 9Hz); 7.46 (1H, d, J 9Hz); 10.36 (1H, s).

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GB2174705A 12

EXAMPLE 7

2,3-Dihydro-7-formyl[ 1,4]benzodioxin-2-acetic acid methyl ester The title compound was obtained from 3,4-dihydroxybenzaldehyde and methyl 4-bromocroto-5 nate by a procedure analogous to that described in Example 6.

8 2.64-2.92 (2H, m); 3.82 (3H, m); 4.08-4.16 (1H, m); 4.44-4.50 (1H, m); 4.64-4.75 (1H, m); 7.06 (1H, d, J 9Hz); 7.48 (1H, s); 7.50 (1H, d, J 9Hz); 9.90 (1H, s).

EXAMPLE 8

10 2,3-Dihydro-5-(N-piperidinylmethyl)[ 1,4]benzodioxin-2-acetic acid methyl ester

The title compound was obtained from 2,3-dihydro-5-formyl [1,4]benzodioxin-2-acetic acid methyl ester by a procedure analogous to that described in Example 4.

8 1.38-1.50 (2H, m); 1.54-1.65 (4H, m) 2.40-2.50 (4H, m); 2.60-2.86 (2H, m); 3.52 and 3.62 (2H, ABq, J 12Hz); 3.78 (3H, s); 3.96-4.04 (1H, m); 4.35-4.41 (1H, m); 4.60-4.71 (1H, 15 m); 6.78-7.02 (3H, m).

EXAMPLE 9

2,3-Dihydro-7-{N-piperidinylmethyl)[ 1,4]benzodioxin-2-acetic acid methyl ester The title compound was obtained as a yellow oil from 2,3-dihydroxy-7-formyl[1,4]benzodioxin-20 2-acetic acid methyl ester by a procedure analogous to that described in Example 4.

8 1.35-1.50 (2H, m); 1.50-1.65 (4H, m); 2.30-2.40 (4H, m); 2.58-2.85 (2H, m); 3.38 (2H, s); 3.76 (3H, s); 3.94-4.04 (1H, m); 4.28-4.35 (1H, m); 4.56-4.70 (1H, m); 6.80-6.90 (3H, m).

EXAMPLE 10

25 2,3-Dihydro-2-(2-methanesulphonyloxyethyl)-5-(N-piperidinylmethyl)[ 1,4]benzodioxin

A solution of 2,3-dihydro-5-(N-piperidinylmethyl)[ 1,4]benzodioxin-2-acetic acid methyl ester (6.6g) in dry ether (50 ml) was added dropwise to a suspension of lithium aluminium hydride (3.8g) in ether (250ml) cooled in ice such that the temperature of the reaction did not exceed 25°C. When the addition was complete (30 minutes), the ether was heated to reflux temperature 30 and maintained at that temperature for 90 minutes. The mixture was then cooled in ice and the excess lithium aluminium hydride destroyed by the addition of ethyl acetate. Water (25ml) was then added and the resulting white precipitate removd by filtration through Celite (Trade Mark). The organic phase was separated, washed with brine, dried (MgS04) and evaporated to give 6.0g of 2,3-dihydro-2-(2-hydroxyethyl)-5-(N-piperidinylmethyl)[1,4]benzodioxin as a pale yellow 35 oil, which appeared as a single spot on TLC using chloroform/methanol (9:1) as solvent.

The crude product (5.2g) was taken up in methylene chloride (150ml). Triethylamine (3.5g) and methanesulphonyl chloride (3.4g) were added successively, and the resulting mixture was stirred at room temperature for 18 hours. The mixture was then washed with a 2N sodium carbonate solution (20ml), water, (20ml), and dried (MgS04). Evaporation afforded 4.5 g of material com-40 prising a mixture of the title compound and the starting material. The desired compound was purified by column chromatography on silica using chloroform/methanol mixtures as eluant to afford 3.35 g of the title compound.

8 1.38-1.50 (2H, m); 1.50-1.64 (4H, m); 2.02-2.14 (2H, m); 2.40-2.50 (4H, m); 3.08 (3H, s); 3.46-3.62 (2H, m); 3.90-4.00 (1H, m); 4.28-4.40 (2H, m); 4.46-4.55 (2H, m); 6.78-7.00 (3H, 45 m).

EXAMPLE 11

2,3-Dihydro-2-(2-methanesulphonyloxyethyl)-7-(N-piperidinylmethyl)[1,4]benzodioxin The title compound was obtained from 2,3-dihydro-7-(N-piperidinylmethyl)[1,4]benzodioxin-2-50 acetic acid methyl ester by a procedure analogous to that described in Example 10.

8 1.38-1.50 (2H, m); 1.50-1.64 (4H, m); 2.04-2.14 (2H, m); 2.35-2.42 (4H, m); 3.08 (3H, s); 3.40 (2H, s); 3.92-4.00 (1H, m); 4.25-4.30 (1H, m); 4.30-4.42 (1H, m); 4.46-4.54 (2H, m); 6.82-6.92 (3H, m).

55 EXAMPLE 12

2-(2-Azidoethyl)-2,3-dihydro-5-(N-piperidinylmethyl)[1,4]benzodioxin

The title compound was obtained as an oil from 2,3-dihydro-2-(2-methanesulphonyloxyethyl)-5-(N-piperidinylmethyl)[1,4]benzodioxin by a procedure analogous to that described in Example 2. umax (film) 2100, 1600 cm 1 60 8 1.35-1.48 (2H, m); 1.52-1.64 (4H, m); 1.75-2.00 (2H, m); 2.36-2.50 (4H, m); 2.40-2.65 (4H, m); 3.88-3.96 (1H, m); 4.25-4.35 (2H, m); 6.78-6.98 (3H, m).

EXAMPLE 13

2-(2-Azidoethyl)-2,3-dihydro-7-(N-piperidinylmethyl)[1,4]benzodioxin 65 The title compound was obtained as an oil from 2,3-dihydroxo-2-(2-methanesulphonyloxyethyl)-

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GB2174705A 13

7-(N-piperidinylmethyl)[1,4]benzodioxin by a procedure analogous to that described in Example 2. «max (film) 2100, 1580 cm"1

5 1.40-1.50 (2H, m); 1.52-1.65 (4H, m); 1.82-2.02 (2H, m); 2.35-2.45 (4H, m); 3.41 (2H, s); 3.58-3.65 (2H, m); 3.90-4.00 (1H, m); 4.25-4.35 (2H, m); 6.80-6.92 (3H, m).

5

EXAMPLE 14

2,3-Dihydro-5-formyl[ 1,4]benzodioxin-2-acetonitrile

The title compound was obtained as an oil from 2,3-dihydroxybenzaldehyde and 4-bromocro-tonitrile by a procedure analogous to that described in Example 6.

10 S 2.86 (2H, d, J 6Hz); 4.25-4.35 (1H, m); 4.50-4.70 (2H, m); 6.98 (1H, t, J 7Hz); 7.22 (1H, d, J 7Hz); 7.52 (1H, d, J 7Hz); 10.35 (1H, s).

EXAMPLE 15

2,3-Dihydro-7-formyl[1,4]benzodioxin-2-acetonitrile 15 The title compound was obtained as colourless crystals (m.p. 93-95°C.) from 3,4-dihydroxy-benzaldehyde and 4-bromocrotonitrile by a procedure analogous to that described in Example 6. omax (film) 2240, 1695, 1275 cm~1

S 2.84 (2H, d, J 6Hz); 4.14-4.21 (1H, m); 4.41-4.46 (1H, m); 4.52-4.64 (1H, m); 7.05 (1H, d, J 9Hz); 7.50-7.55 (2H, m); 9.84 (1H, s).

20

EXAMPLE 16

2,3-Dihydro-5-(N-piperidinylmethyl)[ 1,4]benzodioxin-2-acetonitrile

The title compound was obtained as an oil from 2,3-dihydro-5-formyl[1,4]benzodioxin-2-ace-tonitrile by a procedure analogous to that described in Example 4. The product was shown to 25 be homogeneous by TLC using chloroform/methanol/ammonia (9:1:0.1) as solvent.

5 1.38-1.50 (2H, m); 1.54-1.65 (4H, m); 2.40-2.50 (4H, m); 2.82 (2H, d, J 6Hz); 3.48-3.64 (2H, m); 4.08-4.16 (1H, m); 4.35-4.42 (1H, m); 4.50-4.60 (1H, m); 6.84-7.08 (3H, m).

EXAMPLE 17

30 2,3-Dihydro-7-(N-piperidinylmethyl)[ 1,4]benzodioxin-2-acetonitrile

The title compound was obtained as an oil from 2,3-dihydro-7-formyl[1,4]benzodioxin-2-ace-tonitrile by a procedure analogous to that described in Example 4. The product was shown to be homogeneous by TLC using chloroform/methanol (9:1) as solvent.

S 1.38-1.50 (2H, m); 1.50-1.65 (4H, m); 2.55-2.64 (4H, m); 2.82 (2H, d, J 6Hz); 3.38 (2H, s); 35 4.05-4.60 (3H, m); 6.85-6.94 (3H, m).

EXAMPLE 18

2,3-Dihydro-7-methyl-[4H][1,4]benzoxazine-2-acetonitrile A mixture of 6-amino-3-methylphenol (12g), 4-bromocrotonitrile (15.32g) and sodium hydrogen 40 carbonate (7.36g) in dry methanol (300ml) was stirred at ambient temperature for 16 hours. Potassium carbonate (120mg) was added and stirring continued at ambient tempeature for 45 minutes. The mixture was filtered and the solvent evaporated to give an oil which was partitioned between ether and 1N NaOH solution. The organic phase was separated and extracted with 1N HCI. The acidic phase was neutralised and the product extracted with ether. The ether 45 extract was dried (MgSO„) and evaporated to give 7.6g of the title compound as a red oil.

omax (film) 3400, 2250, 1620, 1590 cm '

S 2.22 (3H, s); 2.76 (2H, d, J 6Hz); 3.24-3.34 (1H, m); 3.45-3.54 (1H, m); 3.60-3.80 (1H, broad s); 4.44-4.54 H, m); 6.53 and 6.63 (2H, ABq, J 9Hz); 6.65 (1H, s). m/e 188 (m )

50 EXAMPLE 19

2,3-Dihydro-4-formyl-7-methyl[1,4]benzoxazine-2-acetonitrile

Acetic anhydride (11.1ml) was added dropwide to a solution of 2,3-dihydro-7-methyl-[4H][1,4]-benzoxazine-2-acetonitrile (2.5g) in 98% formic acid (34ml) such that the temperature did not exceed 60°C. The resulting mixture was stirred at ambient temperature for 3 hours and then 55 quenched with ice-water (12ml). The mixture was reduced in volume and partitioned between chloroform and 1N NaOH solution. The organic phase was separated, washed with 1N NaOH, with brine, and with water, dried (MgS0„), and evaporated to give 3g of a red oil which partially solidified on standing.

omax (film) 3500, 3320, 2250, 1670 cm 1 60 S 2.32 (3H,s); 2.75-2.97 (2H, m); 3.38-3.46 (1H, m); 4.36-4.55 (2H, m); 6.84 and 7.15 (2H, ABq, J 9Hz); 6.89 (1H, s). m/e 216 (nr)

EXAMPLE 20

2,3-Dihydro-4-formyl-7-(N-piperidinylmethyl)[1,4]benzoxazine-2-acetonitrile 65 A solution of 2,3-dihydro-4-formyl-7-methyl[1,4]benzoxazine-2-acetonitrile (1 g) in carbon tetra-

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GB2174705A 14

chloride (40ml) was heated at reflux and a mixture of N-bromosuccinimide (0.83g) and benzoyl peroxide (5 mg) was added portionwise over 10 minutes. The resulting solution was heated for 3 hours, cooled to room temperature, and chloroform was added until the mixture was homogeneous. The mixture was washed with sodium carbonate solution (twice), and with brine, dried 5 (MgS0„), and evaporated to afford a yellow oil. The oil was taken up in dry methanol (50ml), piperidine (0.91ml) was added and the mixture stirred at ambient temperature for 1 hour. The solvent was evaporated and the residual oil subjected to column chromatography on silica using chloroform/methanol mixtures as eluant to give 0.26g of the title compound as a pale yellow solid, m.p. 114-116°C.

10 omax (CHCI3 solution) 2900-2600, 2230, 1675 cm~1

8 1.36-1.50 (2H, m); 1.50-1.65 (4H, m); 2.30-2.42 (4H, m); 2.70-2.90 (2H, m); 3.30-3.40 (1H, m); 3.40 (2H, s); 4.30-4.54 (2H, m); 6.94 and 7.13 (2H, ABq, J 9Hz), 7.00 (1H, s); 8.83 (1H, s).

m/e 299 (m+)

15

EXAMPLE 21

2,3-Dihydro-7-(N-piperidinylmethyl)-[4H][1,4]-benzoxazine-2-acetonitrile. Hydrochloride salt

2,3-Dihydro-4-formyl-7-(N-piperidinylmethyl)[1,4]benzoxazine-2-acetonitrile (50mg) was stirred in methanol (5ml) containing 1N HCI (0.2ml) at ambient temperature for 4 days. The solvent was 20 evaporated and the residue subjected to column chromatography on silica using chloroform/ methanol mixtures as eluant, to afford 20 mg of the title compound as an oily product.

omax (CHCy 3400, 3000-2300, 2230, 1620, 1590 cm 1

5 1.45-1.56 (2H, m); 1.73-1.83 (4H, m); 2.60-2.72 (4H, m); 2.80 (2H, d, J 6Hz); 3.25-3.58 (2H, m); 3.63 (2H, s), 4.43-4.53 (1H, m); 6.63 and 6.91 (2H, ABq, J 9Hz); 7.84 (1H, s). 25 m/e 271 (nV)

EXAMPLE 22

2,3-Dihydro-7-formyl[ 1,4]benzodioxin-2-acetic acid 2,3-Dihydro-7-formyl[1,4]benzodioxin-2-acetic acid methyl ester (5.9g) was heated! at reflux in 30 10% HCI solution (40ml) for 2 hours. The reaction mixture was subsequently basified, extracted with chloroform and the aqueous phase reacidified and extracted with ether. The organic phase was separated, washed with brine, dried (MgS04) and evaporated to afford 3.08g of the title compound as a yellow solid, m.p. 158-161°C.

8 2.71-2.96 (2H, m); 4.07-4.14 (1H, m); 4.38-4.47 (1H, m); 4.65-4.75 (1H, m); 7.04 (1H, d, 35 J 9Hz); 7.45-7.51 (2H, m); 9.85 (1H, s).

EXAMPLE 23

2-Aminomethyl-2,3-dihydro-7-formyl[ 1,4]benzodioxin t-butyl carbamate A mixture of 2,3-dihydro-7-formyl[1,4]benzodioxin-2-acetic acid (0.5g), triethylamine (0.32ml) 40 and diphenylphosphoryl azide (0.48ml) in dry f-butanol was heated at reflux for 24 hours. The volatile material was removed by evaporation and the residue taken up in ethyl acetate. The ethyl acetate solution was washed successively with 5% citric acid solution, water, saturated sodium bicarbonate solution, and brine, dried (MgSO„) and evaporated to give a yellow oil. Column chromatography on silica using chloroform as eluant afforded 250 mg of the title 45 compound.

8 1.49 (9H, s); 3.40-3.60 (2H, m); 4.02-4.12 (1H, m); 4.25-4.36 (1H, m); 4.38-4.46 (1H, m); 4.95-5.10 (1H, broad s); 7.05 (1H, d, J 9Hz); 7.45-7.50 (2H, m); 9.90 (1H, s).

EXAMPLE 24

50 2-Aminomethyl-2,3-dihydro-7-{N-piperidinylmethyl)[ 1,4]benzodioxin t-butyl carbamate

2-Aminomethyl-2,3-dihydro-7-formyl[1,4]benzodioxin t-butyl carbamate (081g) was dissolved in methylene chloride (10 ml) to which was added sequentially piperidine (1.64ml) and glacial acetic acid (2ml). Borane-pyridine complex (0.3ml) was added and the mixture was stirred at ambient temperature for 18 hours. The solution was basified with 2.5M NaOH solution and extracted 55 twice with ethyl acetate. The combined organic extracts were washed with brine, dried (MgS04), and evaporated to give a yellow oil. Column chromatography on silica with chloroform/methanol mixtures as eluant afforded 0.78g of the title compound as a yellow oil, which showed as a single spot on TLC using chloroform/methanol (3.1) as solvent.

8 1.30-1.50 (6H, m); 1.36 (9H, s); 2.30-2.40 (4H, m); 3.27 (2H, s); 3.30-3.40 (2H, m); 60 3.80-3.90 (1H, m); 4.10-4.22 (2H, m); 5.17 (1H, broad s); 6.70-6.80 (3H, m).

EXAMPLE 25

2-(2-Aminoethyl)-2,3-dihydro-5-(N-piperidinylmethyl)[1,4]benzodioxin Method A

65 2-(2-Azidoethyl)-2,3-dihydro-5-(N-piperidinyImethyl)[1,4]benzodioxin (2.1g) im methanol (50ml)

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GB2174705A 15

was hydrogenated over 10% palladium/charcoal (0.5g) at about 200 kPa (30 psi) for 2 hours. The catalyst was removed and the solvent evaporated to afford 1.8g of the title compound as a colourless oil.

5 Method B

2,3-Dihydro-5-(N-piperidinylmethyl)[1,4]benzodioxin-2-acetonitrile (0.38g) was taken up in am-moniacal methanol (50ml) and hydrogenated over 5% rhodium/carbon (0.3g) at about 235 kPa (35psi) for 3 hours. Chloroform (50ml) was added, the catalyst removed by filtration and the filtrate evaporate to afford 0.25g of the title compound as a colourless oil identical with the 10 material obtained by Method A.

omax 3500-3100 (broad), 1570, 750 cm"1

8 1.40-1.54 (2H, m); 1.65-1.78 (4H, m); 1.78-1.92 (2H, m); 2.55-2.65 (4H, m); 3.00-3.20 (4H, m); 3.64-3.80 (2H, m); 3.90-4.00 (1H, m); 4.25-4.40 (2H, m); 6.85-7.05 (3H, m).

15 EXAMPLE 26

2-(2-Aminoethyl)-2,3-dihydro-7-(N-piperidinylmethyl)[1,4]benzodioxin

The title compound was obtained from 2-(2-azidoethyl)-2,3-dihydro-7-(N-piperidinylmethyl)[1,4]-benzodioxin by a procedure analogous to that described in Example 25, Method A, and from 2,3-dihydro-7-(N-piperidinylmethyl)[1,4]benzodioxin-2-acetonitrile by a procedure analogous to that 20 described in Example 25, Method B.

8 1.36-1.48 (2H, m); 1.48-1.55 (4H, m); 1.55-1.90 (4H, m); 2.35-2.46 (2H, m); 2.95-3.05 (2H, m); 3.44 (2H, s); 3.90-4.00 (1H, m); 4.22-4.52 (2H, m); 6.80-6.95 (3H, m).

EXAMPLE 27

25 2-(2-Aminomethyl)-2,3-dihydro-8-(N-piperidinylmethyl)[1,4]benzodioxin

The title compound was obtained as a colourless oil from 2-(2-azidomethyl)-2,3-dihydro-8-(N-piperidinylmethyl)[1,4]benzodioxin by a procedure analogous to that described in Example 25, Method A.

(DMS0-d6) 8 1.38-1.50 (2H, m); 1.50-1.65 (4H, m); 2.55-2.65 (4H, m); 2.90-3.25 (2H, m); 30 3.50-3.85 (2H, m); 4.08-4.15 (1H, m); 4.36-4.45 (1H, m); 4.50-4.60 (1H, m); 6.85-7.00 (3H, m).

EXAMPLE 28

2-(2-Aminomethyl)-2,3-dihydro-6-(N-piperidinylmethyl)[1,4]benzodioxin

35 The title compound was obtained from 2-(2-azidomethyl)-2,3-dihydro-6-(N-piperidinylmethy-l)[1,4]benzodioxin by a procedure analogous to that described in Example 25, Method A. The product was a colourless oil b.p. 170-180°C, 0.8 mmHg

EXAMPLE 29

40 2-(2-Aminomethyl)-2,3-dihydro-7-(N-piperidinylmethyl)[1,4]benzodioxin

A solution of 2-aminomethyl-2,3-dihydro-7-(N-piperidinylmethyl)[1,4]benzodioxin f-butyl carbamate (0.77g) in 5M HCI (5ml) was stirred at ambient temperature for 18 hours. The reaction mixture was basified with potassium hydroxide pellets and extracted with ethyl acetate. The organic phase was separated and dried (MgSO„) and evaporated to give 0.37g of a colourless 45 oil, which appeared as a single spot on TLC using chloroform/methanol (3:1) as solvent.

8 1.35-1.42 (2H, m); 1.42-1.54 (4H, m); 1.60-1.70 (2H, broad s); 2.30-2.40 (4H, m); 2.97 (2H, d, J 6Hz); 3.37 (2H, s); 3.94-4.30 (3H, m); 6.75-6.88 (3H, m).

EXAMPLE 30

50 2-(2-Aminoethyl)-7-(N-piperidinylmethyl)-2,3-dihydro[4H][ 1,4]benzoxazine. Hydrochloride salt 2,3-Dihydro-7-(N-piperidinylmethyl)[4H][1,4]benzoxazin-2-acetonitrile hydrochloride (200 mg) was taken up in methanol (30ml) and hydrogenated over 5% rhodium/carbon (400mg) on a Parr (Trade Mark) apparatus at about 345 kPa (50psi) for 18 hours. The reaction mixture was filtered and the solvent evaporated to afford the title compound as a yellow oil (116mg).

55 8 (CD3OD) 1.60-1.70 (2H, m); 1.75-1.95 (4H, m); 1.95-2.08 (2H, m); 3.05-3.50 (8H, m); 4.10 (2H, s); 4.15-4.25 (1H, m); 6.66 and 6.86 (2H, ABq, J 9Hz); 6.96 (1H, s).

EXAMPLE 31

3-[(6-(N-Piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)methylamino]-4-methyl-5-[4-methylphe-60 noxy]-1,2,4,6-thiatriazine 1,1-dioxide

To a stirred solution of 4-methyl-3,5-bis(tolyloxy)-1,2,4,6-thiatriazine 1,1-dioxide (1.4g) in a 1:1 mixture of acetonitrile and chloroform (50ml) was added 2-aminomethyl-2,3-dibydro-6-(N-piperidi-nylmethyl)-2,3-dihydro[1,4]benzodioxin (1.14g). The resulting homogeneous solution was stirred at ambient temperature for 96 hours, evaporated to dryness and the residue chromatographed 65 on silica. Elution with chloroform/methanol/ammonia mixtures gave the title compound as a gum

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d.6g).

(DMSO-de) 8 1.30-1.40 (2H, m); 1.40-1.54 (4H, m); 2.25-2.35 (2H, m); 2.32 (3H, s); 3.34 (2H, d, J 6Hz); 3.48 (3H, s); 3.48-3.60 (2H, m); 4.00-4.10 (1H, m); 4.36-4.44 (2H, m); 6.76-6.88 (3H, m); 7.16 and 7.31 (4H, ABq, J 9Hz), 8.25 (1H, broad s).

5

EXAMPLE 32

3-[(8-(N-Piperidinylmethylj-2,3-dihydro[ 1,4]benzodioxin-2-yl)methylamino]-4-methyl-5-[4-methylphe-noxy]-1,2,4,6-thiatriazine 1,1-dioxide The title compound was obtained by a procedure analogous to that described in Example 31 10 from the corresponding 8-{N-piperidinylmethyl) benzodioxin isomer.

(DMS0-d6) 8 1.40-1.60 (2H, m); 1.60-1.80 (4H, m); 2.36 (3H, s); 2.70-3.00 (4H, m); 3.56 (3H, s); 3.60-3.68 (2H, m); 4.00-4.60 (3H, m); 6.90-7.05 (3H, m); 7.16 and 7.33 (4H, ABq, J 9Hz); 8.50 (1H, broad s).

15 EXAMPLE 33

3-[(7-(N-Piperidinyimethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)methylamino]-4-methyl-5-[4-methylphe-noxy]-1,2,4,6-thiatriazine 1,1-dioxide

The title compound was obtained by a procedure analogous to that described in Example 31 from the corresponding 7-(N-piperidinylmethyl) benzodioxin isomer.

20

EXAMPLE 34

3-[(7-(N-Piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yi)-2-(ethylamino)]-4-methyl-5-[4-methyl-phenoxy]-1,2,4,6-thiatriazine 1,1-dioxide The title compound was obtained by a procedure analogous to that described in Example 31 25 from 2-(2-aminoethyl)-2,3-dihydro-7-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin.

EXAMPLE 35

3-[(5-(N-Piperidinyimethyi)-2,3-dihydro[1,4]benzodioxin-2-yl)-2-(ethyiamino]-4-methyl-5-[4-methyl-phenoxy]-1,2,4,6-thiatriazine 1,1-dioxide 30 The title compound was obtained by a procedure analogous to that described in Example 31 from 2-(2-aminoethyl)-2,3-dihydro-5-(N-piperidinylmethyl)-2,3-dihydro[ 1,4]benzodioxin.

EXAMPLE 36

3-[(7-(N-Piperidinylmethyi)[4H]-2,3-dihydro[1,4]benzoxazin-2-yi)-2-(ethylamino)]-4-methyi-5-[4-me-35 thylphenoxy]-1,2,4-6-thiatriazine 1,1-dioxide

The title compound was obtained by a procedure analogous to that described in Example 31 from 2-(2-aminoethyl)-2,3-dihydro-7-(N-piperidinylmethyl)[4H]-2,3-dihydro[1,4]benzoxazine.

(CD3OD) 8 1.50-1.80 (6H, m); 1.90-2.02 (2H, m); 2.34 (3H, s); 2.90-3.00 (4H, m); 3.06-3.16 (1H, m); 3.28-3.40 (1H, m); 3.50 (3H, s); 3.60-4.20 (5H, m); 6.62 and 6.75 (2H, ABq, J 9Hz), 40 6.82 (1H, s); 7.04-7.30 (4H, m).

EXAMPLE 37

3-[(6-(N-Piperidinyimethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)methylamino]-4-methyl-5-amino-1,2,4,6-thiatriazine 1,1-dioxide 45 A solution of 3-[(6-(N-piperidinylmethyl)-2,3-dihydrobenzodioxin-2-yl)methylamino]-4-methyl-5-[4-methylphenoxy]-1,2,4,6-thiatriazine 1,1-dioxide (0.4g) in ammoniacal methanol (160ml) was stirred at ambient temperature for 72 hours. The solvent was evaporated and the residue triturated with ether to affor 0.32g of the title compound as a colourless solid, m.p. 243-245°C. (DMSO-d6) 8 1.30-1.55 (6H, m); 2.24-2.45 (4H, m); 3.28 (3H, s); 3.98-4.08 (1H, m); 50 4.35-4.45 (2H, m); 6.76-6.92 (3H, m); 7.44 (2H, broad s); 7.80 (1H, broad t).

EXAMPLE 38

3-[(8-(N-Piperidinyimethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)methylamino]-4-methyl-5-amino-1,2,4,6-thiatriazine 1,1-dioxide 55 The title compound was obtained as a colourless solid from 3-[(8-(N-piperidinylmethyl)-2,3-dihydro[ 1,4]benzodioxin-2-yl)methylamino]-4-methyl-5-[4-methylphenoxy]-1,2,4,6-thiatriazine 1,1-dioxide by a procedure analogous to that described in Example 37. (m.p. 204-206°C.)

(DMSO-d6) <5 1.40-1.70 (6H, m); 2.48-2.58 (4H, m); 3.28 (3H, s); 3.95-4.55 (4H, m); 6.88-7.04 (3H, m); 7.48 (2H, broad s); 8.02 (1H, broad s).

60

EXAMPLE 39

3-[(7-(N-Piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yi)methylamino]-4-methyl-5-amino-1,2,4,6-thiatriazine 1,1-dioxide The title compound was obtained as a colourless solid from 3-[(7-(N-piperidinylmethyl)-2,3-65 dihydro[ 1,4]benzodioxin-2-yl) methylamino]-4-methyl-5-[4-methylphenoxy]-1,2,4,6-thiatriazine 1,1-

5

10

15

20

25

30

35

40

45

50

55

60

65

17

GB2174705A 17

dioxide by a procedure analogous to that described in Example 37. (m.p. 257-260°C.) (DMSO-d6) d 1.32-1.56 (6H, m); 2.20-2.50 (4H, m); 3.28 (3H, s); 3.98-4.08 (1H, m); 4.30-4.44 (2H, m); 6.60-6.85 (3H, s); 7.40 (2H, broad s); 7.74 (1H, broad t).

5 EXAMPLE 40

3-[(7-(N-Piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)-2-ethylamino]-4~methyl-5-amino-1,2,4,6-thiatriazine 1,1-dioxide

The title compound was obtained as a colourless solid (m.p. 219-223°C.) from 3-[(7-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)-2-ethylamino]-4-methyl-5-[4-methylphenoxy]-10 1,2,4,6-thiatriazine 1,1-dioxide by a procedure analogous to that described in Example 37. (DMSO-d6) 8 1.32-1.55 (6H, m); 1.78-1.92 (2H, m); 2.25-2.45 (4H, m); 3.22 (3H, s); 3.86-3.96 (1H, m); 4.22-4.38 (2H, m); 6.74-6.88 (3H, m); 7.36 (2H, broad s); 7.56 (1H, broad s).

15 EXAMPLE 41

3-[(5-(N-Piperidinylmethyi)-2,3-dihydro[ 1,4]benzodioxin-2-yl)-2-ethylamino]-4-methyi-5-amino-1,2,4,6-thiatriazine 1,1-dioxide The title compound was obtained from 3-[(5-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-

2-yl)-2-ethylamino]-4-methyl-5-[4-methylphenoxy]-1,2,4,6-thiatriazine 1,1-dioxide by a procedure 20 analogous to that described in Example 37.

(DMSO-d6) S 1.32-1.60 (6H, m); 1.80-1.95 (2H, m); 2.30-2.55 (4H, m); 3.26 (3H, s); 3.78-4.45 (3H, m); 6.78-6.95 (3H, m); 7.40 (2H, broad s), 7.60 (1H, broad s).

EXAMPLE 42

25 3-[(7-(N-Piperidinylmethyl)-2,3-dihydro[4H][1,4]benzoxazin-2-yl)-2-ethylamino]-4-methyl-5-amino-1,2,4,6-thiatriazine 1,1-dioxide

The title compound was obtained from 3-[(7-(N-piperidinylmethyl)-2,3-dihydro[4H][1,4]benzo-dioxin-2-yl)-2-ethylamino]-4-methyl-5-[4-methylphenoxy]-1,2,4,6-thiatriazine 1,1-dioxide by a procedure analogous to that described in Example 37.

30 (CD3OD) <5 1.55-1.70 (2H, m); 1.70-1.88 (4H, m); 1.88-2.00 (2H, m); 2.90-4.70 (11H, m); 4.02 (2H, s); 4.05-4.15 (1H, m); 6.62 and 6.78 (2H, ABq, J 9Hz), 6.84 (1H, s).

EXAMPLE 43

3-[(6-(N-Piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yi)methylamino]-4-methyl-5-(2-propyny-35 l)amino-1,2,4,6-thiatriazine 1,1 -dioxide

2-Propynylamine (propargylamine) (1ml) was added in one portion to a solution of 3-[(6-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)methylamino]-4-methyl-5-(4-methylphenoxy)-1,2,4,6-thiatriazine 1,1-dioxide (0.4ml) in a mixture of methanol (10ml) and chloroform (50ml) at ambient temperature. The resulting homogeneous solution was stirred for 72 hours, after which 40 time TLC showed the reaction to be complete. The solvent was evaporated and the residue triturated with ether to afford 0.33g of the title compound as a colourless solid.

(DMSO-d6) <5 1.35-1.55 (6H, m); 2.24-2.38 (4H, m); 3.20-3.60 (7H, m); 3.90-4.10 (4H, m); 4.35-4.45 (2H, m); 6.78-6.92 (3H, m); 7.80-8.20 (2H, broad s).

45 EXAMPLE 44

3-[(8-(N-Piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)methylamino]-4-methyl-5-(2-propyny-l)amino-1,2,4,6-thiatriazine 1,1-dioxide

The title compound was obtained from 3-[(6-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)methylamino]-4-methyl-5-(4-methylphenoxy)-1,2,4,6-thiatriazine 1,1-dioxide by a procedure 50 analogous tothat described in Example 43.

(DMSO-d6) 5 1.35-1.65 (6H, m); 2.60-2.75 (4H, m); 3.95-4.50 (6H, m); 6.65-7.04 (3H, m); 8.00 and 8.10 (2H, each broad s).

EXAMPLE 45

55 3-[(7-(N-Piperidinyimethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)-2-ethylamino]-4-methyi-5-(2-propyny-i)amino-1,2,4,6-thiatriazine 1,1 -dioxide The title compound was obtained from 3-[(7-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-

2-yl)-2-ethylamino]-4-methyl-5-(4-methylphenoxy)-1,2,4,6-thiatriazine 1,1-dioxide by a procedure analogous to that described in Example 43.

60 (DMSO-d6) S 1.30-1.56 (6H, m); 1.80-1.95 (2H, m); 2.20 (1H, s); 2.24-2.40 (4H, m); 3.86-4.40 (6H, m); 6.70-6.90 (3H, m); 7.65 (1H, broad s); 8.05 (1H, broad s).

EXAMPLE 46

3-[(5-(N-Piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yi)-2-ethylamino]-4-methyl-5-(2-propyny-65 l)amino-1,2,4,6-thiatriazine 1,1-dioxide

5

10

15

20

25

30

35

40

45

50

55

60

65

18

GB2174705A 18

The title compound was obtained from 3-[(5-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)ethylamino]-4-methyI-5-(4-methyIphenoxy)-1,2,4,6-thiatriazine 1,1-dioxide by a procedure analogous to that described in Example 43.

(DMSO-d6) 8 1.30-1.58 (6H, m); 1.80-1.94 (2H, m); 2.30-2.40 (4H, m); 3.25 (3H, s); 5 3.85-4.45 (5H, m); 6.76-6.92 (3H, m).

EXAMPLE 47

1-Methyl-3-amino-5-[(6-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)methylamino] 1,2,4-triazole

10 A mixture of N-cyano-1-methyl-2-(phenylmethylene)hydrazine-carboximidothioc acid, methyl ester (GB 2 023 133B) (0.84g) and 2-(aminoethyl)-2,3-dihydro-6-(N-piperidinylmethyl)[1,4]benzo-dioxin (1.0g) was heated at 70°C. under vacuum for 3 hours. The oily residue was taken up in acetone (30ml), 2M HCI (10ml) was added and the resulting homogenous solution was stirred at ambient temperature for 16 hours. The mixture was extracted with ether, the pH of the aqueous 15 phase adjusted to 10 with 1N NaOH solution, and re-extracted with ethyl acetate. The extract was dried (MgS04) and evaporated to afford 0.78g of the title compound as a colourless solid on trituration with ether.

(DMS0-d6) 8 1.30-1.55 (6H, m); 2.25-2.35 (4H, m); 2.35 (3H, s); 2.30-2.55 (4H, m); 3.88-4.08 (1H, m); 4.30-4.42 (2H, m); 4.90 (2H, s); 6.54 (1H, t, J 6Hz); 6.75-6.90 (3H, m).

20

EXAMPLE 48

1-Methyl-3-amino-5-[(8-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)methylamino]-1,2,4-triazole

The title compound was obtained from 2-(aminomethyl)-2,3-dihydro-8-(N-piperidinylmethyl)[1,4]-25 benzodioxin by a procedure analogous to that described in Example 47. (DMSO-d6) 8 1.30-1.55 (6H, m); 2.30-2.42 (4H, m); 2.32 (3H, s); 3.96-4.06 (1H, m); 4.28-4.45 (2H, m); 4.85 (2H, s); 6.50 (1H, t, J 6Hz); 6.75-6.92 (3H, m).

EXAMPLE 49

30 1-Methyl-3-amino-5-[(7-(N-piperidinylmethyl)-2,3-dihydro[ 1,4]benzodioxin-2-yl)methylannino]-1,2,4-triazole

A solution of N-cyano-1-methyl-2-(phenylmethylene)hydrazine-carboximidothioc acid, methyl ester (GB 2 023 133B) (0.82g) and 2-(aminomethyl)-2,3-dihydro-7-(N-piperidinylmethyl)[1,4]ben-zodioxin (0.93g) in acetonitrile (20ml) was heated under reflux for 72 hours. The solvent was 35 evaporated and the residue chromatographed on a column of silica using chloroform/methanol mixtures as eluant to give a yellow oil (1.57g). This material was dissolved in acetone (10ml), 2M HCI (15ml) was added and the resulting mixture was stirred at ambient temperature for 3 hours. The mixture was washed with ethyl acetate, basified with sodium hydroxide, and re-extracted with ethyl acetate. The extract was dried (MgS04) and evaporated to afford 0.83g of 40 the title compound as a yellow gum, which showed as a single spot on TLC using chloroform/-methanol (3:1) as solvent.

8 1.35-1.48 (2H, m); 1.48-1.60 (4H, m); 2.30-2.40 (4H, m); 3.35 (2H, s); 3.42 (3H, s); 3.45-3.75 (2H, m); 3.90-4.50 (6H, m); 6.78-6.86 (3H, m).

45 EXAMPLE 50

1-Methyl-3-amino-5-[(5-{N-piperidinylmethyl)-2,3-dihydro[ 1,4]benzodioxin-2-yl)-2-ethylamino]-1,2,4-triazole. Hemioxalate salt

The title compound was obtained from 2-(2-aminoethyl)-2,3-dihydro-7-(N-piperidinylmethy-l)[1,4]benzodioxin by a procedure analogous to that described in Example 49.

50 (D20) 8 1.30-2.00 (8H, m); 2.85-3.02 (2H, m); 2.40 (3H, s); 3.40-3.50 (4H, m); 3.50-3.60 (2H, m); 4.00-4.42 (3H, m); 6.94 (3H, s).

EXAMPLE 51

1-Methyl-3-amino-5-[(7-(N-piperidinylmethyl)-2,3-dihydro[1,4]benzodioxin-2-yl)-2-ethylamino]-1,2,4-55 triazole

8 1.36-1.50 (2H, m); 1.50-1.62 (4H, m); 1.80-2.10 (2H, m); 2.30-2.42 (4H, m); 3.36 (2H s); 3.42 (3H, s); 3.55-3.66 (2H, m); 3.85-4.35 (4H, m); 6.75-6.90 (3H, m). m/e 372 (nrr)

60

Claims

CLAIMS 1. A compound of formula I

5

10

15

20

25

30

35

40

45

50

55

60

19

GB 2 174 705A

19

R1 \

N - (CH2)

(i)

(CH2)n - NHR

in which formula

R1 and R2, which may be the same or different, each represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms or, together with the nitrogen 10 atom to which they are attached, R1 and R2 form a 4 to 8-membered ring which may contain an 10 oxygen atom or another nitrogen atom, which nitrogen atom may have an alkyl group having from 1 to 4 carbon atoms as substituent,

X represents an oxygen atom or a group NR4 in which R4 represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms, a phenyl group or a 15 phenalkyl group, the alkyl moiety of which has a straight or branched chain and from 1 to 4 15

carbon atoms,

an alkyl, phenyl or phenalkyl group being unsubstituted or substituted by one or more substituents, which may be the same or different, for example, by one or two substituents, especially by one substituent, selected from halogen atoms, straight and branched chain alkyl groups 20 having from 1 to 4 carbon atoms, straight and branched chain alkoxy groups having from 1 to 4 20 carbon atoms, nitro and trifluoromethyl groups,

or R4 represents a nitrogen protecting group;

m represents an integer of from 1 to 4;

n represents the integer 1 or 2; and 25 R3 represents a group of formula II, III, IV, V or VI 25

NCN

NO.

30

35

NHR

(II)

NHR5

(IV)

CH3 N N

(V)

A

N ^NHR

V

N N

(VI)

NHR

30

35

ch3

40 in which formulae 40

R5 represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms; and

R6 represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkenyl group having from 2 to 4 carbon atoms, or a 45 straight or branched chain alkynyl group having 3 or 4 carbon atoms. 45

2. A compound as claimed in claim 1, wherein n is 2.

3. A compound as claimed in claim 1 or claim 2, wherein the group

R1

50 \

/

N-(CH2L-

R2

50

55 is in the 7-position. 55

4. A compound as claimed in any one of claims 1 to 3, wherein when X represents an oxygen atom, R3 represents a group of formula V or VI.

5. A compound as claimed in claim 4, wherein in formula VI R6 represents a hydrogen atom or a propargyl group.

60 6. A compound as claimed in any one of claims 1 to 3, wherein X represents a group NH, 60 and R3 represents a group of formula VI.

7. A compound as claimed in claim 6, wherein the formula VI R6 represents a hydrogen atom.

8. A compound as claimed in any one of claims 1 to 7, wherein R1, R2 and the nitrogen

65 atom to which they are attached form a pyrrolidine, morpholine or N-methylpiperazine ring. 65

20

GB 2 174 705A 20

9. A compound as claimed in any one of claims 1 to 7, wherein R1, R2 and the nitrogen atom to which they are attached form a piperidine ring.

10. A compound as claimed in claim 1, wherein R\ R2 and the nitrogen atom to which they are attached form a piperidine ring, m is 1, X is oxygen, n is 2, and R3 represents a 3-amino-1-

5 methyl-1,2,4-triazol-5-yl group, that is to say, 3-amino-1-methyl-5-[2-(7-(N-piperidinylmethyl)-2,3- 5 dihydro[ 1,4]benzodioxin-2-yl)ethylamino]-1,2,4-triazole.

11. A compound as claimed in claim 1, wherein R1, R2 and the nitrogen atom to which they are attached form a piperidine ring, m is 1, X is oxygen, n is 2, and R3 represents a 3-amino-4-methyl-1,2,4,6-thiatriazin-5-yl 1,1-dioxide group, that is to say, 3-amino-4-methyl-5-[2-(7-(N-piper-

10 idinylmethyl)-2,3-dihydro[ 1,4]benzodioxin-2-yl)ethylamino]-1,2,4,6-thiatriazine 1,1 -dioxide. 10

12. A compound as claimed in claim 1, wherein R1, R2 and the nitrogen atom to which they are attached form a piperidine ring, m is 1, X is oxygen, n is 2, and R3 represents a 4-methyl-5-propargylamino-1,2,4,6-thiatriazin-3-yl 1,1-dioxide group, that is to say, 4-methyl-3-[2-(7-(N-piper-idinylmethyl)-2,3-dihydro[ 1,4]benzodioxin-2-yl)ethylamino]-5-propargylamino-1,2,4,6-thiatriazine

15 1,1-dioxide. 15

13. A compound as claimed in claim 1, wherein R1, R2 and the nitrogen atom to which they are attached form a piperidine ring, m is 1, X is -NH-, n is 2, and R3 represents a 3-amino-4-methyl-1,2,4,6-thiatriazin-5-yl 1,1-dioxide group, that is to say, 3-amino-4-methyl-5-[2-(7-(N-piper-idinylmethyl)-2,3-dihydro[4H][ 1,4]benzoxazin-2-yl)ethylamino]-1,2,4,6-thiatriazine 1,1 -dioxide.

20 14. A salt of a compound as claimed in any one of claims 1 to 13. 20

15. A physiologically tolerable salt of a compound as claimed in any one of claims 1 to 13.

16. A hydrate or solvate of a compound as claimed in any one of claims 1 to 13.

17. A process for the production of a compound of formula I as claimed in claim 1, which comprises

25 (i) reacting a compound of formula VII 25

R1

-fcA 1 CV,I)

<a,A"^ 30

in which R', R2, X, m and n are as defined in claim 1 with a compound of formula Ila or Ilia

NCN

—2

(Ilia)

(Ila)

35

35

in which L represents a leaving group, for example, a halogen atom or a group -YR7 in which Y represents an oxygen or sulphur atom, a group SO or a group S02, and R7 represents a straight 40 or branched chain alkyl group having from 1 to 4 carbon atoms, an unsubstituted or substituted 40 phenyl group, or an unsubstituted or substituted phenalkyl group having from 1 to 4 carbon atoms in the alkyl moiety, wherein a phenyl or phenalkyl group may be substituted by one or two substituents selected from alkyl, alkoxy, methylenedioxy, phenoxy, halogen, dialkylaminoal-kyl, trifluoromethyl, nitro, cyano, sulphonic acid, sulphonamide, amino, and mono- and di-alkylam-45 ino groups, an alkyl moiety having a straight or branched chain and from 1 to 4 carbon atoms; 45 and R5 is as defined in claim 1, to obtain a compound of formula I in which R3 represents a group of formula II or III respectively; or (ii) reacting a compound of formula VII as defined in (i) above with a compound of formula VIII

50 50

(VIII)

55 in which L is as defined in (i) above, and cyclising the resulting compound of formula IX 55

SO.™,.,,-

60 fca. 60

(IX)

to obtain a compound of formula I in which R3 represents a group of formula V; or

(iii) reacting a compound of formula VII as defined in (i) above with a compound of formula IVa or Via

21

GB2174705A 21

5

o o x ''

M X S V

<1Va) jf f <VI»)

I

X.

■sL CH,

in which the two groups L each represents a leaving group as defined in (i) above, the two groups L being the same of different with the proviso that the two radicals R7 can be the same or different, but the two groups Y must be the same, to give a compound of formula IVb or VIb 10 respectively, 10

(IVb)

15 vwl2'n~"n j, 15

1 J1 II (VIb)

20 ^ °^<CH2)n-«H « L 20

3

and reacting the resulting compound of formula IVb or VIb with a compound of formula Xa or Xb, respectively

25 (Xa) H,NR5 H2NRb (Xb) 25

in which R5 and R8 are as defined in (i) above, to give a compound of formula I in which R3 represents a group IV or VI, respectively.

18. A process as claimed in claim 17, wherein in a leaving group L, when Y represents a

30 sulphur atom, R' represents a lower alkyl group, and when Y represents an oxygen atom, R' 30 represents a methyl or a substituted phenyl group.

19. A process as claimed in claim 18, wherein when Y represents a sulphur atom, R'

represents a methyl group, and when Y represents an oxygen atom R' represents a tolyl group or a nitro-phenyl group.

35 20. A process as claimed in any one of claims 17 to 19, wherein a compound of formula VII 35 is produced by reducing a compound of formula XI

;>-««*>. -fOr ^ ™

" Vn ~ "3

40 O (CH-) - N, 40

in which R1, R2, m, X and n are as defined in claim 1.

21. A process as claimed in any one of claims 17 to 19, wherein a compound of formula VII is produced by reducing in the presence of a base a compound of formula XII

5 ■=>

« n in which R\ R2, m, X and n are as defined in claim 1.

50 22. A process as claimed in any one of claims 17 to 19, wherein a compound of formula VII 50 is produced by hydrolysing in the presence of an acid a compound of formula XIII

R v 2 / " "

1

(XIII)

55 R (CH2)n - NH- COOR8 55

in which R\ R2, m and n are as defined in claim 1, and Ra represents a carboxylic acid protecting group.

23. A process as claimed in claim 17, carried out substantially as described in any one of

60 Examples 37 to 51 herein. 60

24. A compound as claimed in claim 1, whenever produced by a process as claimed in any one of claims 17 to 23.

25. A compound as claimed in claim 1, substantially as described in any one of Examples 37 to 51 herein.

65 26. A pharmaceutical preparation which comprises a compound as claimed in any one of 65

22

GB 2 174 705A 22

claims 1 to 13, 24 and 25, or a physiologically tolerable salt thereof as active ingredient, in admixture or conjunction with a pharmaceutical^ suitable carrier.

27. A pharmaceutical preparations as claimed in claim 26, which comprises one or more further pharmaceutical^ active substances.

5 28. A pharmaceutical preparation as claimed in claim 27, which also comprises a histamine 5 H-1 antagonist.

29. The use of a compound of the general formula I as claimed in any one of claim 1 to 13, 24 and 25 for the manufacture of a medicament.

30. The use of a compound of the general formula I as claimed in any one of claim 1 to 13,

10 24 and 25 for the manufacture of a medicament for use as a histamine H-2 antagonist. 10

Printed in the United Kingdom for Her Majesty's Stationery Office, Dd 8818935, 1986, 4235.

Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.