NZ198159A - Guanidine derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 98159 1 98 15 9 Priority Ba'lc{s): ;tn! ?jn: ConrspS; ri^v Co~iC-\ OA «C»«OOOOBBO»_ PubJicetioR Date: P/0. Jcisr.ic!, Ko: SM. ,j] u ■ d a a • • So-^-so 0 3 C 0 B 0 0 F 9 NOV 1984 Ifttt.....

NEW ZEALAND PATENTS ACT,1953 No.: Divided from No. 193890 Date: 30 May 198 0 COMPLETE SPECIFICATION Under the provisions of Regl#-tatien 23 (f) the Spcci;lca:;i3;)i-^sn snte-dated tO ..._ >£© SrUUj 19 <££)_; '•W \ \ - »l n \ ■■ \ vJf * ;SUBSTITUTED AROMATIC COMPOUNDS ;P9We> THE WELLCOME FOUNDATION LIMITED of 183-193 Euston Road, London, N.W.1., England, a company incorporated in England, ;hereby declare the invention for which K/ we pra.y that a patent may be granted to roe/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - ;- 1 - ;The present invention relates to a group of novel compounds which are useful as intermediates in the preparation of compounds useful in the treatment of CNS disorders, such as epilepsy. ;It has been disclosed in our New Zealand Patent Specification No. 193890 that a group of novel 3,5-diamino-6-(substituted phenyl)-1,2,4-triazines are active in the treatment of CNS disorders, such as psychiatric and neurological disorders, and are particularly useful as anticonvulsants, for example in the treatment of epilepsy. Furthermore, these triazines are believed to be nondepressant at likely therapeutic dose levels and therefore are advantageous as compared with depressant anti-epileptics such as phenobarbitone. ;These 3,5-diamino-6-(substituted phenyl)-1,2,4-triazines are compounds of the formula (III) : ;11 10 ;R ;R ;( HI ) ;- 3 - ;m 1 ;and acid addition salts thereof, ;wherein is chlorine, bromine, iodine, alkyl or ;7 ;trifluoromethyl; R is hydrogen, halogen, ^ alkyl or ;6 7 ;trifluoromethyl or R and. R form a -CH=CH-CH=CH- group optionally substituted by a halogen atom or a C-^_^ alkyl or trifluoromethyl group, ;g ;R is hydrogen, bromine, iodine, alkyl or trifluoro ;9 ;methyl, R is hydrogen, halogen, alkyl or trifluoro methyl, R"^ is hydrogen, methyl, or fluorine and R^ ;is an amino or C^_2.0 acylamino group or a di-substituted aminomethyleneamino group wherein the substituents are alkyl groups or a - (CF^) ^ (Ct^)n_ 9rouP wherein X ;is 0, S, NH or CH2 group and n is the integer 1 or 2; ;7 10 ;provided that, at most, only two of R -R are other ;7 10 ;than hydrogen and that R -R are not all hydrogen when R^ is chlorine. ;Preferred compounds of the formula (III) include: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine 3,5-diamino-6-(2,5-dichlorophenyl)-1,2,4-triazine 3,5-diamino-6-(4-bromo-2-chlorophenyl)-1,2,4-triazine 3,5-diamino-6-(5-bromo-2-chlorophenyl)-1,2,4-triazine 3,5-diamino-6-(2,3,5-trichlorophenyl)-1,2,4-triazine 3,5-diamino-6-(2-chloro-6-fluorophenyl)-1,2,4-triazine 3,5-diamino-6-(2-methylphenyl)-1,2,4-triazine 3,5-diamino-6-(2-trifluoromethylphenyl)-1,2,4-triazine 3,5-diamino-6-(2-bromophenyl)-1,2,4-triazine 3,5-diamino-6-(2-iodophenyl)-1,2,4-triazine 3,5-diamino-6-(2-bromo-5-chlorophenyl)-1,2,4-triazine 3,5-diamino-6-(1-naphthyl)-1,2,4-triazine ;1 98 1 ;- 4 - ;5-acetamido-3-amino-6-(2,3-dichlorophenyl)-1,2,4-triazine 3-amino-6-(2,3-dichlorophenyl)-5-dimethylaminomethylene- ;amino-1,2,4-triazine 3,5-diamino-6-(2-methyl-l-naphthyl)-1,2,4-triazine 3,5-diamino-6-(3-chloro-l-naphthyl)-1,2,4-triazine. ;New Zealand Patent Specification No. 193890 also provides a process for the preparation of compounds of the formula (III) which comprises the cyclisation of a compound of the formula (IV): ;( IV ) ;wherein R^-R"^ are as hereinbefore defined; and thereafter, where desired substituting the amino group adjacent to the phenyl ring to give a group R"*"^ wherein R"^ is as hereinbefore defined other than amino, by conventional methods.

This cyclisation reaction is normally carried out by refluxing in an alkanol, preferably a alkanol such as methanol or ethanol, in the presence of a strong base such as potassium hydroxide.

The compounds of the formula (IV) are novel intermediates .

Accordingly the present invention provides compounds of the formula (IV): 1 93 1 i (IV) 6 wherein R is chlorine, bromine, iodine, alkyl or 7 trifluoromethyl; R is hydrogen, halogen, alkyl or 6 7 trifluoromethyl or R and R form a -CH=CH-CH=CH- group optionally substituted by a halogen atom or a alkyl or trifluoromethyl group, 8 R is hydrogen, bromine, iodine, alkyl or trifluoro- 9 methyl, R is hydrogen, halogen, alkyl or trifluoro methyl, and R"^ is hydrogen, methyl, or fluorine, provided 7 10 that at most only two of R -R are other than hydrogen and that R^-R"^ are not all hydrogen when R^ is chlorine.

Suitably the alkyl group is a methyl group.

Suitably R^ is a chlorine or bromine atom or a methyl or 7 trifluoromethyl group or is linked to R to form a -CH= 6 CH-CH=CH- group and preferably R is a chlorine or 7 bromine atom or linked to R to form a -CH=CH-CH=CH- group. 7 9 Preferably R and R are each hydrogen, chlorine or bromine atoms. 8 Preferably R is a hydrogen or bromine atom. 6 X 0 When three of the substituents R -R are other than 8 10 hydrogen, it is preferred that R and R are hydrogen 6 7 9 and that R , R and R are those halogen atoms previously defined and in particular chlorine atoms.

The preparation of the compounds of the formula (IV) _6_ 198159 is analogous to that described in the literature, i.e. U.S, Patent No. 3,637,688, for structurally related compounds.

Thus, the compounds of the formula (IV) may be prepared by the reaction of the appropriately substituted benzoyl cyanide with amino-guanidine in the presence of a strong acid. The.reaction is suitably carried out in a solvent, particularly a dipolar aprotic solvent. Particularly strong acids are mineral acids for example nitric acid or~sulphuric acid.

The following examples illustrate the preparation of the compounds of the invention and the corresponding 3,5-diamino-6-(substituted phenyl)-1,2,4-triazine.

EXAMPLE 1 Preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine. 2,3-Dichlorobenzoic Acid A solution of 2,3-dichloroiodobenzene (37.3g, 0.14M) in sodium dried ether (300 mis) was added dropwise to magnesium turnings (3.65 g, 0.15gm Atm) and a crystal of iodine with warming so as to form a Grignard reagent.

The mixture was stirred and refluxed for 2 hours then cooled and transferred dropwise, under nitrogen, into a stirred mixture of sodium dried ether (250 mis) containing solid carbon dioxide (ca. lOOg). The mixture was stirred for 2 hours, left overnight to warm to room temperature, then treated with ice (ca. 150g) and 2N aqueous hydrochloric acid (75 mis), and the product extracted with ether (200, 100 and 50 mis). The combined ether extracts were washed with water (2 x 40 mis) then repeatedly extracted with 2N aqueous sodium hydroxide 1(100, "50 and 50 mis) . These basic solutions were combined, stirred with activated charcoal (3 g) for 10 minutes, filtered and the cooled filtrate was acidified with i 98 i concentrated hydrochloric acid (25 mis) at 10°C. The resultant solid was filtered off, washed with water (2 x 20 mis) and dried in vacuo. Yield 20.76' g (77 .6%) , m.p. 167-169°C (uncorrected). 2,3-Dichlorobenzoyl Chloride A mixture of 2,3-dichlorobenzoic acid (39.4g 0.2M) and thionyl chloride (100 mis) was heated to reflux for 2% hours. The cooled solution was evaporated down in vacuo and distilled under nitrogen. Yield 35.5g (85%), b.p. 146-148°C at 31mm of mercury pressure. 2,3-Dichlorobenzoyl Cyanide' A mixture of cuprous cyanide (36.9g, 0.41 M), potassium iodide (68.5g, 0.41 M) and xylene (400 mis) was refluxed in an atmosphere of nitrogen under a Dean and Stark trap for 24 hours so as to remove all trace of water.

A solution of 2,3-dichlorobenzoyl chloride (35.5g, 0.17M) in sodium dried xylene (130 mis) was added dropwise to the above mixture of dry cuprous cyanide and xylene. The resulting, mixture was stirred and heated to reflux for a further 7 2 hours. The cooled mixture was filtered and the solid washed well with sodium dried xylene (200 mis). The filtrate and washings were combined and evaporated down in vacuo to give an oil. Yield 32g (94%) . 2,3-Dichlorobenzoyl Cyanide Amidino Hydrazone, nitric acid salt A solution of 2,3-dichlorobenzoyl cyanide (32g, 0.16M) in dimethylsulphoxide (80 mis) was added dropwise to a stirred suspension of aminoguanidine bicarbonate (81.67g, 0.6M) which had been treated with 8N aqueous nitric acid 198159 (40 0 mis) at a temperature of ca 25°C. The mixture was stirred for 3 hours, then left to stand at room temperature for 7 days. The cooled mixture was stirred and basified with 0.880 aqueous ammonia (400 mis) at 20°C, then stirred with ice cooling for 30 minutes, filtered and the resulting solid washed thoroughly with water and finally dried in vacuo. ^' 5-Diamino-6- { 2, 3-dichloropheny 1) -1, 2 , 4~-triazine The above solid was added to a 10% solution of potassium hydroxide pellets in methanol (400 mis) and the solution heated to refluxed for 1h hours. When cool the solution was evaporated down in vacuo, treated with ice water (800 mis) then stirred for 30 minutes and filtered. The residue was dried and recrystallised from isopropanol to give 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine. Yield 6.8g (15.6%), m.p. 216-218°C (uncorrected).

EXAMPLE 2 By a method analogous to that described in Example 1 the compounds listed in Tables 1 and 2 were prepared:- t Table 1 fj.J. i i 14SEP1982 I _ bBECBVED 1 98 15 9 V; R m.p. ( uncorrected ) 96Yield ( from acid ) 2,5-Cl2 228-230°C 2 2-Cl^-Br 223-225°C 6 . 2-Cl,5-Br 238-240°C 2 2-CF3 177-178°C O.f .

I2-C1.S-F 226-228°C l'f .5 2-Me 181-183°C . 2-3r 'f-207°C 3f 2-1 219-222°C 7 2-Br,5-Cl 255-256°c 1.2 Table 2 (VI) % VI; R m.p. ( uncorrected ) 96Yield ( from acid ) H 21.5-216°C 7.5 2-Me 131-13<f°C 0.3 3-C1 285-2S6°C 1.0 1 9a 159 EXAMPLE 3 Preparation of 3,5-diamino-6-(2,3,5-trichlorophenyl)-1, 2,4-triazine. 2,3,5-Trichlorobenzoic Acid Powered sodium nitrite (37.Og, 0.54M) was added portionwise to concentrated sulphuric acid (27 0 ml) which was stirred under an atmosphere of nitrogen. The temperature of the mixture was not allowed to rise about 70°. Meanwhile 3-amino-2,5-dichlorobenzoic acid (lOOg, 0.45M) was dissolved in hot glacial acetic acid (1,200 ml), the resultant solution was cooled rapidly to room temperature and added dropwise to the above stirred and cooled nitrous acid mixture so that the internal temperature did not rise above 30°. The solution formed after the addition was left at room temperature for 2 hours then was slowly added to a stirred solution of cuprous chloride (97g, 0.97M) in concentrated hydrochloric acid (97 0 ml). The resultant mixture was stirred until the nitrogen evolution had ceased and was then left overnight. The solid was filtered off, washed well with water and dried in vacuo. Yield 90.lg (89%) m.p. 164-165°C (uncorrected). 2 ,3,5-Trichlorobenzoyl Chloride A mixture of 2,3,5-trichlorobenzoic acid (90g, 0.4M) and dimethylformamide (1 ml) in thionyl chloride (200 ml) was heated to reflux for 2 hours. The cooled solution was evaporated down in vacuo and the residue distilled under nitrogen. Yield 89.2g (90%), b.p. 158^160°C at the pressure of 30 mm of mercury. 11 Ifiisf t t t t 2,3,5-Trichlorobenzoyl Cyanide A mixture of cuprous cyanide (89 g, 0.9M), potassium iodide (150.5 g, 0.9M) and xylene (800 ml) was heated to reflux in an atmosphere of nitrogen under a Dean and Stark trap for 24 hours.

A solution of 2,3,5-trichlorobenzoyl chloride (89 g, 0.36M) in sodium dried xylene (100 ml) was added to the above suspension. The resulting mixture was stirred and heated to reflux for a further 72 hours. The cooled mixture was filtered and the solid was washed well with sodium dried xylene (200 ml). The filtrate and washings were combined and evaporated in vacuo to give an oil.

Yield 76 g (96%) . ...... 2,3,5-Tr ichlorobenzoy1 Cyanide Amidino Hydrazcne, nitric acid salt A solution of 2,3,5-trichlorobenzoyl cyanide (38.5 g, 0.16M) in dimethylsulphoxide (80 ml) was added dropwise to a stirred suspension of aminoguanidine bicarbonate (65.76 g, 0.32M) which had been treated with 8N aqueous nitric acid (560 ml). The mixture was stirred for 3 hours and then was left to stand at room temperature for 21 days. The solid was filtered off, washed with water (2 x 100 ml) and dried in vacuo.j 3,5-Diamino-6- (2,3,5-trichlorophenyl)-l; 2,4-triazine A suspension of the dried solid in a 10% solution of potassium hydroxide pellets in methanol (320 ml) was heated to reflux for 1 hour, the mixture was cooled and evaporated down in vacuo. The residue was treated with ice/water (200 ml), the resultant solid was filtered off and dried was put on top of 1 98 1 5 a dry column (25 mm diameter, 200 g of MFC silica gel) and eluted with a solution of ethyl acetate/methanol/acetic acid (90:2.5:2.5). Fractions 50 to 80 (900 drops per fraction) were collected, combined and evaporated down in vacuo. The resultant solid was recrystallised from ispropanol to give 3,5-diamino-6-(2,3,5-trichlorophenyl)-1,2,4-triazine. Yield 0.77 g (1.6%), m.p. 232-235°C (uncorrected). 1 98 1 5

Claims (6)

1. WHAT WE CLAIM IS:
2. !• A compound of the formula (IV):
3. wherein is chlorine, bromine, iodine, alkyl or trifluoro-
4. 7
5. methyl; R is hydrogen, halogen, alkyl or trifluoro-
6. 6 7

   methyl or R and R form a -CH=CH-CH=CH- group optionally substituted by a halogen atom or a G-^_^ alkyl or trifluoro-

   8

   methyl group; R is hydrogen, bromine, iodine, alkyl

   9

   or trifluoromethyl; R is hydrogen, halogen, alkyl or trif luoromethyl; and R"*"0 is hydrogen, methyl or;7 10;fluorine, provided that at most only two of R -R . are;7 10;other than hydrogen and that R -R are not all hydrogen when R^ is chlorine.;2. A compound of the formula (IV), as claimed in;£;claim 1 herein, wherein R is a chlorine or bromine atom,;7 6;R is a hydrogen, chlorine or bromine.atom or R is linked;7 9;to R to form a -CH=CH-CH-CH- group, R is a hydrogen,;8;chlorine or bromine atom, and R is a hydrogen or bromine atom.;1931 [>9;- 14 -;3. A compound of the formula (IV), as claimed;7 9;in claim 1 herein, wherein R and R are each hydrogen, chlorine, bromine, iodine, C^-4 alkyl or trifluoromethyl;;g;R is hydrogen, bromine, iodine, C^_^ alkyl or trifluoromethyl; and R"^ is hydrogen or fluorine, provided that at most only one of R^-R"^ is other than hydrogen and that R^-R"*"^ are not all hydrogen when R^ is chlorine.

   DATED THIS DAY OF I?

   A. J. PARK & SON PER

   AGENTS FOR THE APPLICANTS