DE1957769A1 - 1,2-Dihydro-1,3,5-triazine derivatives, processes for their production and their use for the production of medicinal preparations - Google Patents

Description

DR. ELISABETH JUNG. DR. VOLKER VOSSIUS, DIPL.-ING. GERHARD COLDEWEY

Patent attorneys MONKS 23. CLEMENSSTRASSE 30. TELEPHONE 345067, TELEGRAM ADDRESS: INVENT / MONCHEN. TELEX 5-2868Θ

uz _e : ε 841 (pi / j / kä) ■ ■■ ·. "";.47; Mov.i969

Case A. 303. · *

BEECHAM GROUP LTD.,
Brentford, Middlesex, England

¹¹ l, 2-dihydro-l, 3,5-triazine - I) derivatives, process for their production and their use for the production of medicinal products "

Priority: November 22, 1968, Great Britain, No. 55 428/68 March 6, 1969, Great Britain, No. 11 8,66 / 69

The invention relates to 1,2-dihydro-1,3,5-triazine derivatives, "processes for their production and their use for the production of microbicidal agents, e.g. medicinal preparations, compared to Malaria are effective.

The invention thus relates to 1,2-dihydro-1,3,5-triazine derivatives of the general formula I

R ₁ -XR ₂ -ON

(I)

χ:

R ₃ R ₄

in which R ₁ denotes an optionally substituted hydrocarbon radical or an optionally substituted heterocyclic reed, X denotes an oxygen atom, αΛβ * sulfur atom or a

ΐ- 009838/2222

NR ^ radical denotes, where R ^ is a hydrogen atom or an optionally substituted lower alkyl or aryl-CC-j ^ g-alkyl) radical, Rp denotes an optionally substituted divalent aliphatic hydrocarbon radical having 1 to 16 carbon atoms and R, a hydrogen atom or, like R., an alkyl radical j . - 4

with 1 to 4 carbon atoms or R, and R. together with the 2-carbon atom of the triazine ring to a spirocycloalkyl or lower-alkyl-spirocycloalkyl radical are associated, as well as their salts, with. with the proviso that when X is an oxygen atom, R-, no ' 4,6-diamino-1,2-dihydro-2-R., - 2-R, - (1,3, 5- * triazine-l-'ylj-radical is.

An important feature of the compounds according to the invention is the presence of the radical X, which is either a single atom or a group. If such a residue is present, possess the corresponding compounds of general formula I valuable and interesting properties, the organic R- radicals, which can have a wide variety of structures, while the likewise organic radicals Rp, R »and R. in this regard somewhat narrower limits are set.

The radical R- can be an optionally partially hydrogenated mono- or polycyclic aryl radical, a saturated or unsaturated aliphatic or cycloaliphatic radical, a heterocyclic radical Remainder or a combined consisting of several such residues Remainder with a total of 1 to 24 carbon atoms.

Specific examples of suitable radicals R- are the phenyl, Naphthyl, phenanthryl, pyrenyl, anthryl, benzyl, cinnamyl,

Tetra

Phenylethyl, phenylpropyl, tetrahydronaphthyl and / hydrophenyl group, and straight or branched alkyl radicals, such as

C) (iü839 / 2222

Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl -, n-pentyl, isopentyl or n-decyl group, cycloalkyl radicals, such as the cyclopentyl, cyclohexyl, gycloheptyl "or 'methylcyclo-, hexyl group ", alkenyl radicals, such as the vinyl, allyl or ·, butenyl group, Alkynyl radicals and heterocyclic radicals, such as the pyridyl, quinolyl, puryl or thienyl group. ·

The radical "R-, can", given a suitable structure, is very diverse Have substituents. For example, it can be substituted one or more times

be tuiert by .Alkylrest, such as methyl _: or. -ethyl groups, cycloalkyl with 3 to 8 carbon atoms, such as cyclohexyl, cyclopentyl and cycloheptyl groups, halogen atoms, such as chlorine or bromine atoms, nitro groups, halogen (lower-alkyl ) Radicals, such as mono-, di- or trichloro, fluorine or bromo (lower-alkyl) radicals, lower alkoxy radicals such as methoxy, ethoxy or propyloxy groups, lower alkoxycarbonyl radicals such as methoxycarbonyl, ethoxycarbonyl - And propyloxycarbonyl groups, aryl (lower-alkyl) radicals, such as benzyl or phenylethyl groups, carboxyl groups, oxy groups, mercapto groups, cyano groups, lower-alkyl-thio groups, such as methylthio or ethylthio groups, lower-alkyl-sulfonyl radicals, lower oxyalkyl radicals, lower -alkoxy-alkyl radicals, lower cyanoalkyl radicals, sulfonamido groups, amino groups or mono- or di- (lower alkyl) -amino groups, such as methylamino or ethylamino groups. If R ^ has more than one substituent, these can be the same or different. Unless stated otherwise, the aforementioned radicals generally contain 1 to 6 carbon atoms when they are referred to as "lower" radicals, and 1 to 24 carbon atoms when the aforementioned designation is not used.

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The radical E ₂ ^ ^s " ^{t is an} unbranched or branched, saturated or unsaturated divalent aliphatic hydrocarbon radical. Specific examples of radicals Rp are the propylene and vinylene group, as well as radicals - (CHp) -, where η is a number from 1 to 16 , e.g. the tetramethylene group.

The radical Rp can have one or more substituents, e.g. Halogen atoms, hydroxyl groups or "lower" alkoxy groups, i.e. alkoxy groups with 1 to 6 carbon atoms.

The radicals R, and R. are, for example, both methyl groups or ethyl groups or they form together with the 2-carbon atom of the triazine ring a spirocycloalkyl radical, e.g. the spirocyclohexyl or the 4-methylspiroeyclohexyl group *

If X is a radical NRf-, Rc can be a hydrogen atom or a methyl, ethyl or benzyl group which is optionally substituted by a halogen atom, preferably a chlorine atom.

Although the compounds according to the invention here by certain Formulas are characterized, the invention is not bound to the exact theoretical correctness of these formulas., The Compounds of the invention are not referred to in any particular tautomeric boundary structure by the terms and formulas used herein and not limited to any particular optical or geometric isomer. ■ '

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The general formula I also relates, for example, to the structures of the general formulas Ia and Ib '■

R ₁ -XR ₂ -O-

HK ^

• (Ib)

The compounds of the invention are conveniently in their form Addition salts with acids, since the free bases have a certain tendency to instability. For the production of the salts a wide variety of acids can be used. When the compounds according to the invention are used for the production of medicaments the acids used should of course be pharmacological be compatible, i.e. have a low toxicity, for example.

The compounds according to the invention can thus be prepared in the form of the monohydrohalides, for example the hydrobromides or hydrochlorides. However, by simply reacting the base with an acid, it is also possible to prepare other salts which are often required to adjust the properties of the product, such as toxicity, taste, physical appearance and the rate of dose to the body. The compounds of the general formula I according to the invention can, for example, be acidic in the form of their picretθ, saccharinates, acetates

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Maleinates, acid phthalates, succinates, phosphates, p-Mtrobenzoates, Stearates, almond acid salts, N-acetylglycinates, paraoates, Produce cyclohexylsulfamate, citrate, tartrate or gluco'nate.

Stable salts are generally prepared from equimolar amounts of triazine and monobasic acids (or using more than 1 mole of triazine per mole of polybasic acids). As a result of any basic radicals X or basic substituents of the radicals R ₁ , however, further acid components can combine with the triazine in some cases.

The presence of amino groups on the triazine ring of the compounds of the general formula I ensures that acyl derivatives can be prepared by reacting the aforementioned compounds with acylating agents such as acid halides, acid anhydrides or acid azides. For example, one to four acetyl groups can be found in introduce the compound of general formula I, although in some cases it is more difficult to make derivatives with such a higher one Number of acetyl groups to produce.

The invention thus also relates to compounds in general Formula I in the form of its acyl derivatives,> above see the acyl radicals preferably derived from lower aliphatic carboxylic acids, in particular from acetic acid.

The compounds of general formula I according to the invention are effective against bacteria, protozoa, parasites such as the plasmodia of malaria, fungi such as dermatophytes or candida, and in certain cases they are also effective against coccidia.

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Such an effectiveness of the compounds according to the invention was against Stapho aureus, Escherichia coli, Candida albicans, Proteus mirabilis, Pseudomonas pyocyanea and Streptococcus haemolyticus observed »

4,6-diamino-1,2-dihydro-2,2-dimethyl-l - / "3 '- (2,4,5-trichlorophenoxy) propyloxy7-1,3,5-triazine hydrobromide of formula A

e.g. is sensitive to cycloguanil and resistant to cycloguanil Plasmodium berghei strains effective in mice.

It has been found that some types of the compounds according to the invention are optimally effective when the radical R _{1 is} an aryl radical linked directly to the radical X (cf. formula I). It is also advantageous if the radical X is an oxygen atom and / or the radical Ro is a ReSt- (CH ₂ ) - with η = 2 to 8.

The invention also relates to a process for the preparation of the compounds of the formula I, which is characterized in that a substituted diguanide of the general formula II

R ₆ -NH -C-NH-C-NH ₂ (H) '

Il Il

NH NH
in Rg a radical of the general formula III

R ₁ -XR ₂ -O- (III)

in which R ₁ , R ₂ and X have the meaning given in front of the symbol,

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or means a radical which is in a radical of the general

Formula III is convertible with the help of a carbonyl compound of the general "Formula IV " ^J '■' ■ ·

R ₃ - CO - R ₄ '"■ / ■

in the R * and R. the above. have given meaning,

in the presence of an acidic catalyst to a compound of

general formula V

converts and, if necessary, the remainder Rg to a remainder of the general Formula III converts, and optionally produces the corresponding salt. '.

The acid used as catalyst in the process of the invention is preferably a strong acid, such as hydrochloric or formic acid. At least 1 mole of acid is used per mole of starting compounds. Implementation can be done in some cases be carried out without the addition of solvents or thinners, however, it is preferred to add an inert solvent such as a lower aliphatic alcohol such as methanol.

If R ^ is a radical of the general formula III

R ₁ -XR ₂ -O-. (III)

is, the diguanide of the general formula II corresponds to the more specific general formula II a

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₁₂ ONH- C-NH- C-NH ₂ (Ha)

'Il Il

M NH ...

Accordingly, the invention also relates to the compounds of formula Ha ällgemei- NEN used in the aforementioned methods as precursors. These are prepared, for example, by reacting a bromide of the general formula R- ^ XR ₂ Br with benzhydroxamic acid, converting the reaction product by treatment with acids to give an oxyamine of the general formula R-, XR ₂ 0NH ₂ and further reacting this oxamine with dicyandiamide. .. · -

According to the invention, diguanides of the general formula II can also be used as starting compounds whose radical Rr is a radical which can be converted into a radical of the general formula III. Rr can be, for example, a radical R ₇ O- which can be converted into a hydroxyl group by replacing R _{7 with a hydrogen atom.} A triazine which is substituted by a radical R ₇ O N can thus be prepared from an appropriately substituted diguanide and this can then be produced by replacing R ₇ with a hydrogen atom in an oxytriazine of the general formula X.

Ho - ww ( ^X '

R '

convict.

Der.Rest R ₇ is, for example, an optionally substituted benzyl or naphthylmethyl group. The replacement of this radical by a hydrogen atom can be carried out with the aid of hydrogen in the presence of a

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Palladium catalyst can be carried out.

The oxytriazine of the general formula X can - according to the most varied known method for the desired substituted tria-

zin of the general formula I are implemented ". · ·

It can also be seen that the side chain of the general formula III either before or after the conversion of the substituted Diguanids of the general formula II also gradually build up or incorporate into the substituted triazine of the general formula V can lead. In general, however, in order to achieve optimum yields and for practical reasons, the smallest possible number such stages applied.

It is thus possible to use methods known per se for the production of ether to introduce the side chain into the triazine Oxygen atom can previously be located either on the side chain or on the triazine. Specific examples of such procedures are '

1) the reaction of a halide with a hydroxyl compound, optionally in the presence of alkalis, and

2) the implementation of a reactive ester, such as ein.s SuI-, fonsäureesters, with a hydroxyl compound.

Analogous reactions can be used to introduce the radical R- into a partial side chain which contains the radical R ₂ , where the radical (the atom) X may previously have belonged to either the radical R- or the radical R ₂ .

You can the inventive end products in the form of addition salts with acids in the course of the aforementioned reaction without

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a separate process stage of salt formation obtained, however, if necessary, such an additional process stage, i.e. one Reaction of the free base with an acid to form a salt. The free bases can be obtained from the salts again by treatment with alkalis, such as potassium hydroxide, ϊπ freedom set and then converted into other desired salts by known processes. '

Another general embodiment of the method for producing

«Position of the compounds according to the invention is that

a) first a triazine of the general formula VI

(VI)

in which Y _{2 is} a reactive radical, produces, and

b) this triazine then with a compound of the general Formula VII

R ₈ Y ₁ '. (VII)

in which Y- represents a radical which ensures the convertibility of the compound of the general formula VII with Y ₂ to form a radical R ^, preferably a radical of the general formula III, and optionally further converts it

c) the compound obtained is converted into a salt.

The radicals Y 1 and Y ₂ are preferably hydroxyl groups (cf. formula X) or their derivatives which are capable of reacting with one another to form an oxygen bridge, at least one

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the radicals Y-, and Yp should thus lead to such bridging have suitable oxygen atom. The radical Yp is preferred an OH group or an -OM radical, where 'M is a metal atom such as a sodium, potassium or lithium atom. Of the The radical Y- is preferably a chlorine, bromine or iodine atom. 3eispie-Ie for other reactive derivatives of hydroxyl groups are radicals derived from sulfonic acids.

In a preferred embodiment of the method, the invention becomes a compound of the general formula R-, XRpZ, in the Z a Is chlorine, or bromine, with the oxytriazine of the general formula X brought to reaction in an inert solvent or diluent. Specific examples of suitable solvents are dimethyl sulfoxide, dimethylformamide and ethanol «,

The oxytriazines of the general formula X are in general Form of their addition salts with acids, e.g. as hydrochlorides. From these salts the free bases can be replaced by 1 equivalent of a base, such as an alkali hydroxide, e.g. potassium hydroxide, or set free from sodium methylate or ethylate. 'The mixture can then be evaporated and in a suitable Solvents such as dimethylformamide or dimethyl sulfoxide. to the Implementation. Preferably no further base is added, since when using 2 equivalents of lithium alcoholate e.g. receives a less pure product.

In a modified procedure, which is generally poorer, Yields, the hydrochloride of oxytriazine is the general Formula X in dimethylformamide or dimethyl sulfoxide with

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1 equivalent of aqueous potassium hydroxide solution containing as little water as possible, brought to implementation. The resulting mixture becomes to a tfiazine hydrohalide further implemented.

'The triazine N-substituted by a radical Yp der'allgemeine Formula VI can, as described above, from an appropriately substituted diguanide or according to another expedient Process are produced.

The side chain of the general formula III can, as mentioned, in be introduced in various ways. You can either through a single implementation or phased in. For example, a compound of the general formula XI

R ₁ - X - R ₂ - CH = CH ₂ (XI)

in which R ^f ₂ deni radical R ₂ corresponds to the general formula I, but has 2 fewer carbon atoms, with the oxytriazine of the general

X-nen formula ^ to be brought into implementation. In a modified one The compounds according to the invention can be prepared by processes be by the oxytriazine of formula X in the presence of Hydrochloric acid with formaldehyde to form a compound of the general formula XII ·.;

Cl - CH ₂ - 0 - N.

implements and this connection continues with a connection of the general formula. XIII

R ₁ -X- R » ₂ Y ₁ . '(XIII)

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in which R " ₂ corresponds to the radical R _{2 of} the general formula I, but has 1 carbon atom less, to a compound of the general formula XIV -.- · ...

R ₁ -X- R » ₂ - CH ₂ - O - ^w ' ^w · ■ ^(XIV)

implements.

In a further modified process, certain oxy-substituted Compounds of the invention are prepared by an appropriately substituted ethylene oxide with the Oxytriazine of the formula X according to equation 1

R ₁ X - CH ₂ - CH -QH ₂ + HOTr-JJR ₁ X - CH ₂ CH - CH ₂ OTr (1)

O OH

converts, where Tr is a radical of the general formula XV

- N N "· (XV)

Similarly, certain oxy-substituted compounds of the invention can be prepared by reacting epichlorohydrin or a corresponding derivative with the oxytriazine of the general Formula X is converted into a chloro-oxy-substituted ether and the intermediate product obtained with a correspondingly substituted one Compound which has a hydroxyl group or its reactive derivative, according to equation 2

009838/2222 omGi _NAL inspected

Cl CHg - CH - CH Cl CH ₀ -CH-

2 + HO Tr

O Tr

CHo - CH - CH ₂ O Tr

, XH

R ₁ X CHg - CH - CHg O Tr. ;

OH -

brings to implementation.

The reactions of the aforesaid type can readily be carried out using either the oxytriazine of Formula X or a triazine can be carried out with an already existing partial side chain as the starting compound, although in some cases one a partial side chain having triazine initially from 'the Oxytriazine can be produced.

For example, a compound of the general formula IX '

(IX)

in which Y. is a reactive radical, with a compound of the general formula R ^ Y ,, in which Y, is a reactive radical ensuring the reaction of the compound R] ^ with Ya to form a radical R-, X, to form a compound of the general formula I implement.

A more specific product can be a compound of general formula XVI

R ₁ OR ₂ OTr

(XVI)

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prepare by a compound R-, Z, where Z is a bromine or Is chlorine atom, with a compound of the general formula XVII

'HOR ₂ OTr "'·""·'·· (XVII) brings about implementation.''" ..-, "'

Finally, the invention relates to the use of those according to the invention Compounds for the production of medicinal preparations which are effective against malaria and in addition to the inventive Active ingredients a pharmacologically compatible carrier material contain.

The compounds according to the invention can be used, for example, as active ingredients use for the treatment or prophylaxis of malaria in human medicine. '*

The compounds of the invention can be administered orally, parenterally, or in the form of suppositories; the oral route is preferred. ■ _t

The water solubility of the hydrochlorides of the compounds according to the invention and most of the other salts is low. The hydrochloride are not hygroscopic. If solutions are required, one must therefore incorporate solubilizers into the water, Use non-aqueous solvents, use more soluble salts or prepare very dilute solutions.

Specific examples of orally administrable preparations that are preferred, taking into account the above requirements for solutions, are tablets, coated tablets, capsules, sachets, granules, Powders, chewing gums, suspensions, emulsions and solutions. Particularly preferred oral preparations are tablets and capsules.

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If this is possible and necessary, the preparations can also contain diluents, binders, dispersants, surface-active agents Means, lubricants, coating agents, 'flavoring agents, Colorants, solvents, thickeners, suspending agents, sweeteners, or any other pharmacologically acceptable Contain additives such as gelatin, milk sugar, starch, talc, magnesium stearate, hydrogenated oils, polyglycols or syrups. In the case of tablets or capsules, for example, the preparations as specified individual doses, in the case / of e.g. granules * - thes, powders or suspensions either as such given individual dosages or also in packs with several units, from which the appropriate single dose can be taken, be placed on the market. '

Injection preparations can be aqueous or non-aqueous solutions, suspensions or emulsions in pharmacologically acceptable form Liquids, such as sterile, pyrogen-free water or parenterally compatible oils, or. Mixing several liquids be the bacteriostatics, antioxidants or other preservatives, buffers (preferably with the physiological pjr range 6.5 to 7.0), solutes to isotonicity to prepare the solution with the blood, contain thickeners, suspending agents or other pharmacologically acceptable additives can. Such injection preparations are given in single doses, such as ampoules or disposable syringes, or in several units, such as bottling, from which the appropriate dose can be taken, or as solid preparations or concentrates, which can be used to quickly manufacture injection preparations

00983872222

preferably sterilized. Su'ppositorien that make the connections

of the invention also contain suitable carrier materials, e.g. cocoa butter or polyglycols. ·

The medicinal preparations obtained from the compounds according to the invention can be produced, optionally contain in addition to the usual pharmaceutical additives other therapeutic agents, in particular anti-malarials, such as sulfonamides.

The examples illustrate the invention. ·.

example 1

4,6-diamino ^ l, 2-dihydro-2,2-dimethyl-l- / ~ 3 '- (2,4,5-trichlorophenoxy) -propyloxy_7-l, 3, 5-triazine-hydrobromide A mixture of 18 , 98 g of 2,4,5-trichlorophenol, 3.85 g of sodium hydroxide, 15.5 ml of water and 39.3 g of 1,3-dibromopropane are refluxed for 60 to 90 minutes, then with 25 ml of 14 $ -iger aqueous sodium hydroxide solution is added and the mixture is then heated ^{to 50 to 70 ° C. for a further 30 minutes.} After extraction with ether and evaporation of the dried ether layer 150 obtained by distillation of 16.4 g of 3- (2,4,5- trichlorophenoxy) propyl bromide of boiling point. To 154 ° C / O, 7 Torr (mainly 150 ⁰ C) and of m.p. 34 to 35 ° C, 2.4 g of higher boiling material (b.p. 154 to 164 ° C / O, 7 Torr) and a first run of 1.74 g of oil.

A solution of 5.5 g of potassium hydroxide in 100 ml of methanol is made With 15.23 g of 4,6-diamino-1,2-dihydro-2,2-dimethyl-l-oxy-1,3,5-triazine hydrochloride for 10 to 30 minutes heated under reflux. · The mixture is then evaporated and the hinterbleiben.de solid residue is mixed with 25 g of the bromide prepared above in 100 ml of dimethylformamide for 3 to 24 hours

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stirred at room temperature. Then the mixture is filtered, the resulting piltrate was evaporated and the solid residue that remained was stirred with acetone. 23.7 "g of product are obtained from which after washing with water and ether 19.12 g of the desired "compound of m.p. 178 to 181 ° C. , '

Example 2

4 , 6-diamino-l, 2-flihydro-2,2-dimethy1-1- / 2 '- (p-chlorophenylthio) -ethoxy_7-l, 3,5-triazine-hydrobromide -

A solution of 14.5 g (0.1 mol) of p-chlorothiophenol in methanolic Sodium hydroxide solution (4 g of NaOH in 200 ml of methanol) is treated with 37.6 g (2.0 mol) of dibromoethane, and the resulting mixture is Boiled for 90 minutes with stirring and under reflux, then cooled and then freed from a small amount of insoluble material by filtration. Then that becomes the solvent removed under reduced pressure, and the oil obtained is separated from the inorganic salts, washed with water, dried and distilled. 11.9 g of 1- (p-chlorophenyl) -2-bromoethyl sulfide are obtained of bp 116 ° C / 2 Torr.

3.87 g of 4,6-diamino-1,2-dihydro-2,2-dimethy1-1-oxy-1,3,5-triazine hydrochloride are then reacted in the form of a solution in methanol with 1.4 g of potassium hydroxide, the methanol is evaporated, and the residue obtained is suspended in dimethylformamide and cooled to -10 ⁰ C. Then 5.05 g of the abovementioned bromide are added and the resulting mixture is stirred for several hours, the temperature being allowed to rise gradually to 20 ^° C. As soon as a clear solution is obtained, the solvent is evaporated and the remaining gummy substance is rubbed with acetone. 4.9 g of a white solid substance are obtained which

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after thorough washing with water and drying, 2.52 g of a solid compound with a melting point of 193 ° to 195 ° C. are obtained. After recrystallization from ethanol, the pure compound melts at 202 ^° C .; it is the connection you want. '·'

Example 3 "

4,6-diamino-1,2-dihydro-2,2-dimethyl-1- / 2 '- (2-naphthoxy) ethoxy7-1 , 3,5-triazine hydrobromide

In a manner similar to that given in Example 1, 2- (2-naphthoxy) ethyl bromide is prepared using 2-naphthol and 1,2-dibromoethane as starting compounds. After recrystallization it has a melting point of 90 to 91 ^° C. ·.

Then 3.67 g of 4,6-diamino-1,2-dihydro-2,2-dimethy1-1-oxyl, 3 »5-triazine hydrochloride are reacted in the form of a solution in methanol with 1.4 g of potassium hydroxide Methanol is then used. removed, and the residue obtained is suspended in dimethylformamide and stirred for 2 hours at room temperature with 5> 0 g of 2- (2-naphthoxy) ethyl bromide. After working up in the conventional manner to obtain 195 g of a 3.4 white solid, mp. 197 ° C after recrystallization from ethanol melts the pure desired compound at 196 ⁰ C,

Example 4

4,6-diamino-1,2-dihydro-2,2-dimethyl-1,2-Z3 '- (p-nitrophenoxy) propyloxy / - !, 3,5-triazine-hydrobromide

It is as described in a similar manner, in Example 1, unter'Verwendung of p-nitrophenol and 1,3-dibromopropane as starting compounds 3- (p-nitrophenoxy) propyl bromide, mp. 50 to 52 ⁰ C.

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The free base obtained from 2.96 g of 4,6-diaraino-l, 2-dihydro-2,2-dimethyl-l-oxy-l, 3,5-triazine hydrochloride is now suspended in dimethylformamide and at room temperature with Treated 4.0 g of the aforementioned bromide. After working up in the conventional manner, 4.25 g of the desired compound with a mp. 216 to 217 ° G are obtained. ^:

Example 5

4,6-diamino- _{1,2-dihydro-2 1} 2-dimethyl ~ 1- / 3 '- (2,4-dlnitroanilino - propyloxy7-1,3,5-triazine hydrochloride * * _ _. Using From 2,4-dinitrochlorobenzene and n-propanolamine as starting compounds, which are in the form of a methanol solution containing sodium acetate, 3- (2,4-dinitroanilino) propan-1-ol is produced, which is recrystallized from methanol to give yellow needles from pp. 72 ⁰ C.

10 g of the above compound are dissolved in 15 ml of chloroform and 8 ml

Dissolved dimethylaniline, and the resulting solution is under resting. Ren gradually mixed with a solution of 5 ml of thionyl chloride in 10 ml of chloroform. When the addition is complete, the mixture is carefully refluxed for 5 minutes, then cooled and then poured onto a mixture of ice and 100 ml of 1 HCl. A precipitate of 5.84 g of a yellow solid is obtained. Substance which is the required 3- (2,4-dinitroanilino) propyl chloride and has a pp. Of 82 ° C.

2.6 g of the abovementioned chloride are then added in portions of a ^{suspension, cooled to 0} ° C., of 1.57 g of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine In. Dimethylformamide incorporated, the resulting mixture is cooled to room temperature ge

1 ^ 1938/2222

leave and then stirred for 3 hours. When working up in the conventional manner, 0.7 g of 416-diamino-1,2-dihydro-2,2-dimethyl-1-oxy-1,3,5-triazine hydrochloride is obtained as the first fraction and a second fraction solid compound ',''which after washing with water weighs 1.03 g and is the desired compound from pp. 220 to 224 ^° C.

. Example 6

4 ₁ 6-Diamino-l, 2-dihydro-2,2-dimethyl-l- / 2 - ( 'n-butyloxy) -äthoxy_7-1 1 3 , 5-triazine hydrochloride

It becomes 2- (n-butyloxy) ethyl chloride by reacting thionyl chloride with 2- (n-butyloxy) ethanol ("butylcellosolve"). Bp 60 ° C / 1.5 Torr.

Now a solution of 7.7 g of 4,6-diamino-l, 2-dihydro-2,2-dimethyl-l-oxy-l, 3,5-triazine hydrochloride in methanol with a solution of 2.8 g of potassium hydroxide in methanol to the above Treated wisely. The "oxytriazine base" obtained is in dimethylformamide suspended and treated with 6, ο g η-butyloxyethyl chloride. The resulting mixture is heated on a steam bath with stirring for 5 hours. After processing in the conventional way " 2.5 g of the desired compound of pp. 208 C are obtained.

Example 7

416-diamino-1,2-dihydro-2,2-dimethyl-l-hydroxy-1,3 »5-triazine hydrochloride (mixture IMS: 95 # ethanol and 5 # methanol) a) A with a stirrer, dropping funnel and A condenser equipped flask is charged with 137 g (1.0 mol) of benzhydroxamic acid and 1.4 liters of IMS mixture and the resulting mixture is stirred until completely dissolved. Then it will be

009S31 / 2222

a solution of 40 g (1.0 mol) of sodium hydroxide in 100 ml of water added while the mixture is stirred thoroughly. to At this point the sodium salt of benzhydroxamic acid can precipitate.

170 g (120 ml) of benzyl bromide are now added dropwise over the course of 45 minutes, the mixture gradually becoming clear • is and after which only a small amount of inorganic material remained undissolved Stand the reaction mixture for 3 days at room temperature. Boiling under reflux for 1 to 2 hours achieves something lower yields.

The solvent is then removed under reduced pressure and the oily residue is dissolved in ethyl acetate and repeatedly washed with water. The solvent extract is dried over magnesium sulfate, filtered and reduced under reduced pressure Pressure evaporated to dryness.

The solid residue is rubbed with ether and to the; wanted benzylbenzhydroxamate (CgH ₅ CONHOCH ^ CgH ₅ ) from melting point 100 to 102 ⁰ C worked up »·.

b) 170 g of benzylbenzhydroxamate are dissolved in 500 ml of methanol and 165 ml of concentrated hydrochloric acid are added. The received The mixture is refluxed for 3 hours, filtered hot and crystallized. The through Filtra, The solid substance obtained is washed thoroughly with ether until no. More recognizable smell of methyl benzoate is.

009838/2222

Yield of amino-oxymethylbenzol hydrochloride: 120 g first fraction, mp 227 to ₀ ⁰ 2 John C (sealed tube melting); after concentration of the mother liquors and treatment with ether, a further fraction · / (20 g) with a melting point of 220 to 225 ° C. (closed melting tube) is obtained. The total yield is 140 g (about 90 % of theory).

c) 97.5 g of amino-oxymethyl-benzene hydrochloride and 51.4 g of dicyandiamide are stirred and heated in 300 .ral mixture I.M.S. solved. The resulting mixture is left for 3 hours boiled under reflux, filtered if necessary and then evaporated under reduced pressure. The oily one The residue is dissolved in water and treated with about 6 η aqueous NaOH while stirring. The diguanide base which separates out solidifies on cooling and is separated, washed with water and dried.

The yield of benzyloxydiguanide base is 95 to, 100 g (80 $> of theory); M.p. 98 to 100 ^° C.

d) 52 g of benzyloxydiguanide base are added to 200 ml of I.M.S.

dissolved and mixed successively with 43 ml of concentrated hydrochloric acid and 200 ml of acetone. The reaction mixture is preferably allowed to stand at room temperature for 3 days, obtained by refluxing for 2 to 3 hours However, you only get slightly lower yields. In general, a certain amount of triazine separates out, which is filtered off, washed with water and dried.

00 9838/2222

The mother liquors are evaporated to dryness and the residue is triturated with acetone to give a solid white substance "This, substance is isolated, washed ¹ with water and dried. . '''

The total yield of 4,6-diamino-1,2-dihydro-2,2-dimethyl-. 1-benzyloxy-1,3,5-tri.azine hydrochloride is 61 g '(80 $> of theory); Pp. 204 to .206 ⁰ C..

e) A solution of 41 parts by weight of 4,6-diamino-1,2-dihydro-2,2-di-

• ■ -

methyl-l-benzyloxy-l ^^ - triazine hydrochloride in 320 parts by weight of ethanol and 220 parts by weight of water is at room temperature and under atmospheric pressure so long with hydrogen and 0.25 to 1.0 part by weight of a 10 $ palladium-charcoal catalyst was shaken, is more added until no hydrogen. The aforementioned catalyst consists of 90 parts by weight of active charcoal washed with acid and containing 10 parts by weight of finely divided metallic palladium in adsorbed form. The catalyst is then filtered off and the piltrate is evaporated to dryness. 24.5 parts by weight of the desired compound of mp 234 ° to 235 ° C. (decomposition) are obtained. After recrystallization of the compound from ethanol, needles with a melting point of 237 ° C. (decomposition) are obtained. The reduction described in this example can be carried out using a platinum catalyst as follows.

A solution of 11 parts by weight of 4 »6-diamino-1,2-dihydro-2,2-dimethyl-1-benzyloxy-1,3,5-triazine hydrochloride in 200 parts by weight of methanol and 100 parts by weight of water is at room temperature

0098 38/2222

temperature and atmospheric pressure are shaken with steam and platinum (IV) oxide until 10 $ more hydrogen has been absorbed than theoretically calculated Evaporated dry. The solid residue is triturated with acetone and the desired compound is isolated with theoretical yield; Pp ₀ 234 ° C (decomposition) *,

Example 8,.

4,6-diamino-1,2-dihydro-2,2-dimethy1-1- / 3 '- (2,4t 5-trichlo.rphen-

oxy) propyloxy7-1,3 »5-triazine hydrobromide ;

a) 3- (2 _t 4,5-trichlorophenoxy) propyl bromide A solution of 39.5 g (1 mol) 2,4,5-trichlorophenol in 33 ml 25% sodium hydroxide solution is mixed with 81 g (2 mol) 1 , 3-Dibromopropane is added, and the mixture obtained is heated to a gentle boil for 2 hours with stirring and under reflux. After the heating has ceased, 51 ml of 14% sodium hydroxide solution are added, and the mixture is then heated to 50 to 70 ° C. for 30 minutes. It is then cooled, and the lower layer is separated off and washed five times with water. The oil obtained is distilled under a pressure of 1 torr and yields

A) Kp 30 to 6O ⁰ C: 25 g of first fraction (NJP = 1.5230). dibromopropane and water are obtained.

B) Kp 130 to 160 ⁰ C: g second fraction 50 (NJP = 1.5838). the • desired bromide gradually solidifies; M.p. 34 to 35 ° C.

(309838/2222

r * ■ ■

b) 3- (2,4,5-trichlorophenoxy) propyl benzhydroxamate

A solution of 22.5 g of benzhydroxamic acid in 300 ml of methanol is mixed with a solution of 4.8 g of üJaOH-in 15 ml of water while stirring. 37 g of 3 ~ (2,4,5 "-rtrichlorophenoxy) propyl bromide are then added, the mixture is refluxed for 1 hour and then left to stand for several days. The solution is then evaporated under reduced pressure and the remaining gummy Residue ¹ is dissolved in ether, a small amount of inorganic material is filtered off, the ether extract solidifies on evaporation, and the solid substance is recrystallized from a mixture of ligroin (bp 40 to 60 ° C.) and ethyl acetate Total amount of 30 g of benzhydroxamate, melting point 73 to 75 ° C. (in two partial fractions). A sample recrystallized from the aforementioned solvent mixture melts at 76 to

c) 3- (2,4,5-trichlorophenoxy) propyloxyamine hydrochloride

32.7 g of the benzhydroxamate (b) are treated with a mixture of 18.5 ml of concentrated hydrochloric acid and 300 ml of methanol, and the resulting mixture is refluxed for 3 hours. The oil obtained after evaporation of the solvent is cooled and ether is added. The precipitated solid substance is isolated, washed with ether and dried. 21 g of the desired compound (c) of melting point 134 to 136 ^° C. are obtained '-

d) 3 '- (2,4 »5 ~ trichlorophenoxy) propyloxy diguanide

61.4 g of compound (c) are dissolved in 1 liter of ethanol, and 25.2 g of dicyandiamide are added to the resulting solution.

9838/2222

The mixture is stirred and refluxed for 3 hours boiled, after which the solvent is evaporated under reduced pressure. ,

»· / The residue obtained is dissolved in about 300 ml of water, and the solution obtained is washed with strong aqueous sodium bicarbonate. lye made alkaline. An oil separates out, which soon solidifies. The solid substance is filtered off, washed successively with water and petroleum ether and finally dried at 60.degree. This gives 4,9,5 g * "of a pale pink colored solid substance of mp. 107 to 110 ⁰ C.

After recrystallization from ethyl acetate gave the analytical sample melts at 125 to 126 ⁰ C.

e) 4,6-diamino ~ 1,2-dihydro-2 _t 2-dimethyl-l- / 3 '- (2,4,5-trichlorophenoxy) ~ propyloxy7-l _t 3t 5-triazine hydrobromide ^: ·· .,. A solution of 45 g of diguanide (d) in 200 ml of methanol is mixed with a mixture of 25 ml of concentrated hydrochloric acid and 300 ml of acetone. The reaction mixture is left to stand for 3 days at room temperature. The solvent is then evaporated off under reduced pressure and the remaining gummy substance is rubbed with acetone. The desired triazine (23.5 g) of melting point 187 to 189 ^° C. and a small amount of a second fraction (indeterminate weight) of melting point 181 to 186 ^° C. are obtained. The first product proves to be analytically pure without further recrystallization .

00.983 8/2222

Example 9 *

4,6-diamino-1,2-dihydro-2 ₁ 2-dimethy1-1- / 2- (2-naphthoxy) ethyl oxy.7-1.31 5-triazine hydrochloride

a) 2- (2-Naphthoxy) -äth.yl-benzhydroxamat <·>

A solution of 21.4 g of 2- (2-naphthoxy) ethyl bromide (melting point 90 to 91 ° C.; see Example 3) in 50 ml of methanol is slowly added to a solution of 15.05 g of sodium benzhydroxamate in 100 ml of methanol . The resulting mixture is heated to vigorous boiling under reflux for 6 hours. Inorganic solid material is filtered off and the solvent is evaporated off under reduced pressure. The remaining gummy substance> is dissolved in ethyl acetate and washed several times with water. The solvent layer is dried over magnesium sulfate, filtered and evaporated. The behind residual gum is triturated with ligroin (bp. 60 to 80 ⁰ C) and the Benzhydroxamat required is brought "to crystallize. This gives 50.6 g of product, mp. 93 ° C. After recrystallization. Schmilzt'die from ethyl acetate Analysis sample at 100 to 101 ⁰ C.

b) 2- (2-naphthoxy) ethyloxyamine hydrochloride A solution of 7.5 g of 2- (2-naphthoxy) ethyl benzhydroxamate in 30 ml of methanol is treated with 10 ml of concentrated hydrochloric acid, and the resulting mixture is 3 hours boiled under reflux for a long time. After 2 hours a solid substance begins to separate out, after which the reaction mixture is cooled and filtered. 4.6 g of the desired oxyamine with a melting point of 192 ° to 194 ° C. are obtained. After recrystallization from methanol ₍ the analysis sample melts at 195 ^° C.

'009838/2222

Evaporation of the mother liquors and treatment of the residue with ether gives a further 0.9 g of a product which has only a slightly lower degree of purity.

c) 2- (2-naphthoxy) ethyloxydiguanide

A solution of 7.8 g of 2- (2-naphthoxy) ethyloxyamine hydrochloride in 100 ml of ethanol is mixed with 4.1 g of dicyandiamide, and the resulting mixture is then 3! Refluxed for hours, filtered and evaporated in vacuo. The remaining gummy substance is dissolved in water while warming and the solution obtained is made alkaline with strong sodium hydroxide solution. An oil separates out that slowly becomes crystalline. After washing the solid substance with water and ligroin (bp. 60 to 80 ⁰ C) 135 is obtained 8.1 g of a solid substance from Pp. To 137 ⁰ C. After ümkristallisation from ethyl acetate schmilzt'die analytical sample (the desired biguanide) at 139 to 140 ⁰ C.

d) 4,6-diamino-1,2-dih.ydro-2 _t 2-dimeth.yl-1- / 2- (2-naphthoxy) - ■ - sthyloxy ^ -l, 3,5-triazine hydrochloride

8 ml of concentrated hydrochloric acid and 75 ml of acetone are added to a solution of 8.0 g of 2- (2-naphthoxy) ethyloxydiguanide in 50 ml of methanol, and the resulting mixture is left to stand at room temperature for 3 days. The solvent is then evaporated off under reduced pressure and the residue obtained is triturated with acetone. This gives 5.4 g of the desired triazines of mp. 190-193 ⁰ C. after recrystallization from ethanol melts the analysis sample at 195-196 ⁰ C (see. Example 3).

0098 3 8/2222

Example 10

4.6-diamino-1,2-dihydro-2,2-dimethyl-l- / 3 '- (cycloheptyloxy) - propyloxy_7-1,315-triazine hydrochloride

a) A mixture of 43.3 g of cycloheptanone, 250 ml of benzene and 0.5 g of p-toluenesulfonic acid is refluxed for a few minutes and then allowed to distill off until 50 ml of a mixture of solvent and water are collected. 29.4 g of 1,3-propanediol are then added to the reaction mixture, and the resulting mixture is refluxed for 5 hours. The compound in the reaction in liberty "water is collected in a Dean-Stark trap until the 7 ml HPO contains. The solvent is then evaporated and the residue distilled under a pressure of 12 Torr. The at 127-132 ⁰ C. The boiling fraction (23.5 g; n ^ ⁵ 1.4791) is the desired product, i.e. 1,5-dioxaspiro- (5,6 -) - dodecane.

b) One equipped with a stirrer, cooler and dropping funnel 1 liter three-necked flask is put through a filter with a solution of 14 g of anhydrous aluminum chloride in 100 ml of anhydrous Ether charged. Then a solution of 1.5 g of lithium aluminum hydride in 100 ml of anhydrous ether is added dropwise at room temperature, after which the mixture is stirred for 30 minutes. The mixture is then mixed with a solution of 7.3 g 1,5-Dioxaspiro- (5 »6) -dodecane (a) in ether with such Shifted speed so that low boiling takes place under reflux. The reaction is then carried out with stirring carried out for a further 2 hours at room temperature

09 8 38/2222

The reaction mixture is then cooled vigorously and slowly with 10 $ aqueous sulfuric acid added until the entire precipitated solid substance is dissolved. Thereupon separates '"you remove the ether layer and wash it with water, neutral. '' The solvent layer is dried over magnesium sulfate

net, filtered and evaporated. The remaining 3-cyclo- "heptyloxypropanol is a colorless mobile oil, which in the gas chromatographic analysis shows only a single maximum and according to the thin-layer chromatography only one color spot . > -.... · .- ■

It is therefore brominated without a further purification stage. c) The 3-cycloheptyl obtained after the aforementioned reaction

Oxypropanol is dissolved in benzene and the solution obtained is cooled to -10.degree. 3 ml of phosphorus tribromide in 15 ml of benzene are added dropwise to this solution while stirring. The temperature is then allowed to rise to about 20 ^° C., the mixture is then heated to 50 ° C. for 1 hour, cooled and washed successively with water, sodium bicarbonate and again with water. The solvent layer is dried over magnesium sulfate and the solvent is then removed. 5.3 g of 3-cycloheptyloxypropyl bromide are obtained in the form of a colorless oil which, according to gas or thin-layer chromatography, is homogeneous.

d) The bromide (c.) is in dimethylformamide at -10 ⁰ C with the 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-oxy-1 obtained from 3.9 g of the hydrochloride, 3,5-triazine base implemented. To

009838/2222

Working up in the conventional manner gives 7.5 g of a white solid substance ^{with a melting point of HO 0} C. This solid substance is washed with water and recrystallized from ethanol. 5.6 g of the pure desired compound are obtained ₍ from melting point to 135 ° C. · '. ·· ■' ■ * ...

Example 11

4,6-diamino-1,2-dihydro-2,2-dimethyl-1- / 3 '- (4-cyclohexyl phenoxy) propyloxy7-1.3 _t 5-triazin-hydrobrom.id

Following a procedure similar to that described in Example 1 was, 4-cyclohexylphenoxypi * opylbromid using 4-cyclohexylphenol and dibromopropane as starting compounds in Presence of NaOH produced.

The bromide (bp 150 to 160 ° C / 2 Torr. N ^ ° 1.5468) 45 ⁰ solidifies slowly to a white waxy substance, mp, C

The free oxytriazine base is obtained by reacting 3.87 g of 4,6-diamino-l , 2-dihydro-2,2-dimethyl-1-oxy-1,3,5-triazine hydrochloride prepared with a solution of 1.4 g of KOH in methanol. The residue obtained after evaporation of the solvent is dissolved in dimethylformamide suspended and stirred for 2 days at room temperature with 5.94 g of 4-cyclohexylphenoxypropyl bromide. The reaction mixture is then filtered and evaporated under reduced pressure. The residue obtained is rubbed with acetone, and

the solid substance is filtered off and washed with water

and dried. The product (5.48 g) is the desired compound of bp 204-2O7 ° C. . !

00 9838/2222

1957763

Example 12 '

4-, 6-diamino-l ₁ 2-dihydro-2 ₁ 2-dimethyl-l- / 3 '- (4-chl or-2-cyclo hexylphenox.y) propyloxy7-l _t 3 _t 5-triazine hydrobromide In a manner similar to that described in Example 1, 4-chloro-2-cyclohexylphenoxypropyl bromide is prepared; Kp. 165

to 175 ^° C /]. ', 5 torr; n £ ° 1.5530.

6.63 g of the aforementioned bromide are according to Example 11 with the obtained from 3.87 g of oxytriazine hydrochloride in dimethylformamide suspended free base implemented. The reaction mixture is stirred for 24 hours at room temperature, filtered and concentrated Evaporated dry.

The residue obtained is stirred with acetone. filtered, and the solid substance is washed with water and dried. The crude triazine has a pp. Of 220 to 222 ⁰ C and is recrystallized from ethanol. This gives 5.35 g of the desired compound with a pp. 225 ^° C

Example 13

Diacetyl derivative of 4 t 6-diamino-l, 2-dihydro-2 ₁ 2-dimethyl- »l - / 3 '- (2,4,5-trichlorophenoxy) -propyloxy7-l, 3,5-triazine (M) 5 g of the above free base (M) are heated for 5 minutes with 25 ml of repeatedly distilled acetic anhydride on a steam bath, and the reaction mixture is then evaporated to dryness under reduced pressure, then extracted with ethyl acetate, washed with water, crystallized and removed Recrystallized ethanol. The diacetyl derivative is obtained in the form of small white needles, Pp. 171-172 ⁰ C.

009838/2222

Example 14

Tablets of 4,6-diamino-l _t 2-dihydro-2 _t 2'-dimethyl-l - / '3'-'2,4t 5-trichlorophenoxyj-propyloxy / - !, 3 , 5-triazine-hydrobromide One tablet contains 10 mg of active ingredient. '· ·'.

Approach to the production of 100'QOO tablets (about 15 kg)

Active ingredient

Corn starch (maximum 6 to 9
Humidity)

Gum arabic milk sugar powdered sugar talc

Magnesium stearate

1,000 g

21 α υ. ι oi et

water

Theoretical yield

"50Og-. 8 000 g '4 500 g"''"'

200 g

• 100 g

15 g

about 1 liter of 100,000 tablets

Manufacturing process

(1) granulation

1.) The starch is dried in a hot air oven at 40 ^° C. to a moisture content of 6 to 9 wt .- ^.

2.) The individual powders are sifted separately through a sieve with a mesh size of 0.317 mm (40 mesh).

3.) The active ingredient is placed in a planetary stirrer and gradually mixed with the milk sugar while stirring continuously offset.

4i) The icing sugar, the starch and the gum arabic * added, mixing for about 5 minutes after each addition and then mixing the whole thing for another 20 minutes,

5 ·) Sufficient water is added with constant stirring until a suitable granulation consistency is achieved (approx. 1 liter). 009838/2 222

6.) The moist granulate is passed through a rotary granulator, which is provided with a sieve with a mesh size of 1.27 mm (10 mesh). '. ·

7.) The granulate is sieved at approx. 50 C dried.

(2) Press mixture

1.) The dried granulate is passed through a sieve with a clear Mesh size of 0.792 mm (16 mesh) happened.

2.) Through a sieve with a mesh size of 0.317 mm (40 mesh) a sufficient amount of the dried granules is sieved to obtain about 500 g of fines. :

3.) the Peinstoffen paraffinum liquidum are mixed, and the whole passed through a sieve with a mesh size of 0.635 π ™ (20 mesh).

4.) The talc and magnesium stearate are passed through a sieve with a clear mesh size of 0.635 mm (20 mesh) "

5.) The bulk of the granulate will be in the planetary mixer the lubricated fines are added, whereupon the talc and magnesium stearate are added. Mix thoroughly for at least 10 minutes after each addition. At the end it is mixed for another 20 minutes.

(3) tabletting . ;

The tablets are made on a rotary press using specific punches and adhering to the thickness limits - pressed. The weight of the tablets is checked (10 tablets = 1.5 g). The tablets can be coated with special coating varnishes be spray coated.

009838/2222

The compounds listed in Table I are prepared by procedures similar to that described in Example 1.

Using the terminology used in the discussion of the general formula I, the radical R _{2 is} here a radical - (CHp) - »while the radicals R and R are methyl groups, unless otherwise stated.

Table I.

at η ν game 2 15th 2 0 16 2 0 17th 2 0 18th CVl 0 19th 3 0 20th 3 0 21 3 0 22nd 3 0 23 3 0 24 ■ 3 0 25th 3 0 26th 3 0 27 3 0 28 4th 0 29 3 0 30th . 5 0 31 6th 0 32 7th 0 33 8th 0 34 9 0 35 10 0 36 3 0 37 0

salt

Pp., ' ⁰ C

η-butyl

3,5-dimethyl-4-chlorophenyl 3-methyl-4-chlorophenyl 3-trifluoromethylphenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl. 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl

2,4,5-trichlorophenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl. 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl 2,4,5-trichlorophenyl

2,4,5-trichlorophenyl ((CH ^)

HBr 184 186-188 HBr 185-186 186 HBr 183-184 180 HBr 210 140 HBr 223-225 about 85 Saccharinate 208 178-179 Citrate 150 Maleat 201-204 acetate 190-193 Embonate 191-192 Gluconate .128-132 Cyclohe- ■
xyl-
sulfamate 185-186 1/2 pamoate 174-175 HCl Ϊ84-185 HBr 149-150 phosphate 180-181 HBr " 193-197 HBr HBr - HBr HBr HBr HBr

009838/2222

L. 2 X R ₁ . : salt M.p., ⁰ ° C • 170-172 38. 2 0 4-nitrophenyl '■ HBr 207 180 39., 3 .0 2,4-dichlorophenyl · ··. ·. · HBr ·. . ■ 200-202 187 40 4th 0 . 2,4-dichlorophenyl HBr. 209-210 41 2 0 2,4-D i chi ο rph, e ny 1 HBr 196-197 42 ■ 3 Ό 3,4-dichlorophenyl. HBr 198-200 43 4th 0 3,4-dichlorophenyl _s HBr "208-210 44 3 0 3,4-dichlorophenyl HBr ; 190-191 45 3 0 3,5-dimethylphenyl HBr 197-198 46 2 0 2-naphthyl HBr '. · 192-193 47 _: 2 0 4-benzylphenyl HBr ,. 171 48. 2 S. 2,5-dichloro-3-thienylmethyl HBr 175 49 3 NH Phenyl HBr ■ 175 50 3 S. 4-chlorophenyl. · < HCl . · 149 51 3 0 4-chlorophenyl HBr .205 52 2 . 0 , 2-methoxycarbonylphenyl HBr .135 53 3 0 4-methoxyphenyl HBr 193 54 2 0 4-tert-butylphenyl HBr 180 55 4th 0 3,5-diraethylphenyl HBr ■ ..... 207 56 2 0 3-trifluoromethylphenyl HBr 157 57 " 2 0 4-chlorophenyl HBr 191 58 2 0 4-benzylphenyl HBr • 217 59 - 3 NC ₂ H ₅ Ethyl ■ HCl 183-185 60 2 NC ₂ H ₅ ethyl . HCl 200 61 2 NCH ₃ methyl HCl 192 62 NC H ₅ Ethyl (R ₃ R ₄ -CH ₂ - HCl 207 2 -CH ₂ CH (CH ₃ ) CH ₂ CH ₂ -) 63 2 NC ₂ H ₅ Ethyl (R ₃ R ₄ -.- (CH ₂ J ₅ -) HCl 165-167 64 NCH ₃ . Methyl (R ₃ R ₄ -CH ₂ - HCl • '182 2 -CH ₂ CH (CH ₃ ) CH ₂ CH ₂ -) 65 3 NCH ₃ Methyl (R ₃ R ₄ - (CH ₂ ) ₅ -) HCl 218 66 NC ₂ H ₅ Ethyl (R ₃ R ₄ -CH ₂ - HCl 191 3 -CH ₂ CH (CH ₃ ) CH ₂ CH ₂ -) 67 3 NC ₂ H ₅ Ethyl (R ₃ R ₄ - (CHg) ₅ -) HCl 68 3 0 o-bromophenyl HBr 59. 0 p-bromophenyl HBr

mphenyl 0098 38/222 2

Zl χ - 39 - SaXz 1957769 game 4th 0 .H ₁ ... '. HBr / M.p. ", ° C 7θ ' 2 0 • p-chlorophenyl ', ■ "■' ■ ν HBr 165 71 0 p-chlorobenzyl · .- ·. ,,. HBr ,: \ 211 72. 3 0 3,4-dichlorophenyl HBr '• lasi-193 73
^4th
75 4th * 0 2,4,6-trichlorophenyI HBr '198 76 4th 0 2,4,6-trichlorophenyl. .HBr 168-170 77 4th 0 Phenyl, ■ ■ HBr ■, 161-163 78 3 0 2,3-dimethylphenyl HBr 178-180 79 4th 0 3,4-dimethylphenyl HBr ■ 206-210 .80 4th 0 3,4-dimethylphenyl • HBr about 90 81 4th 0 3,5-dimethylphenyl HBr 183-185 82 4th 0 3-methyl-4-chlorophenyl HBr '". 182 83 3 0 2-0yclohexyl-4-chloropheny1 HBr 180 84 3 S. Pentachlorophenyl HBr • 187 85 2 NH • - ■ - ■. .
Pentachlorophenyl HBr 193-196 86 3 NH p-chlorophenyl '■ HBr 178-180 87 2 NH p-chlorophenyl . HBr , 183-185 88 3 NH 2,4-dichlorophenyl HBr, . 200 89 · 3 NH 2,4-dichlorophenyl HBr 192. . 90 2 NH 2,6-Dinitro-4-methylphenyl HBr ' . '■' 207 2 N - p-chlorobenzyl ■ .-. HBr 165-167 91. (p-chlorobenzyl) ", 184 92 2. C. p-chlorobenzyl HBr "93 3 0 1-naphthyl ' HBr 218 94 4th 0 1-naphthyl, '. " HBr ' 191; 95 6th 0 1-naphthyl HBr ' 170-172 96 4th 0 1-naphthyl HBr '180 97 6th 0 2-naphthyl HBr 187 98 CM 0 2-naphthyl HBr 165 99 3 0 4-chloro-1-naphthyl HBr 211 . 100 6th ο · 4-chloro-1-naphthyl HBr ■ 191-193 101 2 0 4-chloro-1-naphthyl HBr 198> 102 3 0 5,6,7,8-tetrahydro-2-naphthyl HBr '168-170 103 6th 0 5,6,7,8-tetrahydro-2-naphthyl HBr 161-163 3 0 5,6,7,8-tetrahydro-2-naphthyl HBr 178-180 1-naphthyl (R ₃ R ₄ - (CH ₂ J ₅ -) 2O6-2I0

009838/2222

example

salt

• Pp.,

104 · 3 105 · .- ■ 3 106 -. 3 107 3 108 2 109 2

0 cyclohexyl

NH Cyclohexyl · "'

0x2-chloro-4,5-dimethylphenyl

0 2-isopropyl-5-methylphenyl

0 'CH ₂ = CH-CH ₂ -

0 CH ₂ Cl-CHCl-CH ₂ -

HBr HBr HBr

HBr

HBr HBr

180

160 179

The links below are also made in a similar manner, as stated in example 1, manufactured and determined *

Example 110 , · '.

4-, 6-diamino-l _f 2-dihydro-2 _t 2-dimethyl-lA- (2 _t 4.5-trichloro- phenoxy) -but-2-enyloxy_7-l , 3 »5-triazine-hydrobromide . '· ■

Cl

JL - // VV-

OCH ₂ -CH = CH-CH ₂ -O-:

Cl

(B)

pp. 197 to 198 ^W C.

Example 111

4.6-diamino-l. 2-dihydro-2.2-dimethyl-LA- (2 ₁ 4.5-trichlor phenoxy) -2 ₁ 3-dichlorobutyloxy7-1,315-triazine hydrobromide

. ClHf Vy-OCH ₂ -CHCl-CHCl-CH ₂ -OI Cl '. . CI

.HBr 3

(C)

2p, 191 C.

0098 3 8/2222

Example 112 * -

4,6-diamino-1,2-dihydro-2,2-dimethyl-l-Z ^ - (p-chlorpherioxy) - 2,2-dimeth.yläthyloxy7 ~ l _t 3 _t 5 ~ triazine hydrobromide

Pp. 252 ⁰ C.

CH <7 CH · »CHt

Example 113 "..,.

A mixture of 2 g of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-. (2,4-dichlorobenzyloxypropyloxy) -l, 3,5-triazine base and 10 ml of repeatedly distilled acetic anhydride are heated in a steam bath for i> minutes and then evaporated under reduced pressure. After uracrystallization of the solid residue from a mixture of ethyl acetate and ligroin, 1.7 g are obtained. a product from Pp. 154 to 156 ⁰ C. By further recrystallization to obtain the desired diacetyl derivative of triazines having a Pp. 154-155 ⁰ C. ■.

Example 114 '.

A mixture of the triazine base from Example 113, 10 ml of repeatedly distilled acetic anhydride and 5 ml of triethylamine is stirred for 72 hours at room temperature, poured onto ice, white. tere stirred for 30 minutes and extracted with ethyl acetate, finally. After washing with water, the solution is dried, treated with charcoal, concentrated and then ligroin is added. 0.7 g of the desired tetraacetyl derivative is obtained. The melting point (124 to 125 ⁰ C) does not change with further recrystallization

00983872222

Example 115

In a manner similar to that given in Example 114, 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-Z3 '- (2,4,5-tri chlorophenoxy) -propyloxy_7-1, 3,5-triazine base converted into its tetraacetyl derivative, which has a melting point of 117 to 118 ^° C. after recrystallization from a mixture of ethanol and ligroin.

009838/2222

Claims (1)

Patent claims 1. 1,2-Dihydro-1,3,5-triazine derivatives of. general formula Ϊ in the R, an optionally substituted hydrocarbon. radical or an optionally substituted heterocyclic radical, X is an oxygen or sulfur atom or an Radical NRc, where Rc is a hydrogen atom or a given - optionally substituted lower alkyl or aryl (C ·, c-alkyl) - _ Is the remainder, Rp is an optionally substituted divalent * aliphatic hydrocarbon radical having 1 to 16 carbon atoms loading \ indicated and E, a "water st off atom or as R. is alkyl. '(. radical having 1 to 4 carbon atoms * or R ^, and R ^ are linked together with the 2-C atom of the triazine ring to form a spirocycloalkyl or lower · "■ alkyl-spiroeye .oalkyl radical, as well as their salts, with the proviso that when X is an oxygen atom, R, no · ' 4,6-diamino-1,2-dihydro-2-R, -2-R ₄ - (1,3,5-triazin-1-yl) radical; 2. Compounds according to claim 1, characterized in that that R-j is an optionally substituted one Is phenyl or naphthyl. 3. Compounds according to claim 1 or 2, characterized in that * I mark η et that R-, by at least one halogen * atom is substituted. ". *, QQ9838 / 2222. 4. Compounds according to claim 3, characterized in that indicates that R ^ 'is a trichlorophenyl group, preferably.' se is a 2,4,5- "or 2,4,6-trichlorophenyl group. 5 · - Compounds according to claims 1 to 4, characterized in that they are identified means that X is an oxygen atom: - ·· * 6. Compounds according to claim 1 to 5, 'dadurch- marked It means that R2 is a residue - (CHp) -, where n- ·. is an integer from 1 to 16, preferably from 2 to 8. · · '../ 7. Compounds according to claim 1 to 6, characterized in that - · ·· indicates that the radicals R, and R. are methyl groups ■ ■■ '- are. ; 8. 4,6-Diamino-1,2-dihydro-2,2-dimethyl- ^{1,2-Z3 f} - (2,4,5-trichloro- "phenoxy) -propyloxy-7-1,3,5-triazine and its salts . \ _ 9. Compounds according to claim 1, characterized marked. ' indicates that X is an oxygen or sulfur atom or '· an NH or NCH, group, R- ^ an optionally polynuclear aryl radical, an alkyl radical with 1 to 24 carbon atoms, an:' aralkyl radical with 1 to 24 carbon atoms in the alkyl moiety, a cycloalkanes 1 'radical having 3 to 8 carbon atoms, an alkenyl group mil · I to 24 carbon atoms, an aralkenyl group having 1 to 24 carbon atoms in the alkenyl' \. Nyl part or a heterocyclic radical means, with the proviso that "if R ₁ contains an aryl ring, this optionally." one or more times through: halogen atoms, nitro, carboxyl, hy- ' \ Sulfonamido alkoxy, ·. ' . ! hydroxyl, mercapto / or cyano groups or alkyl, haloalkyl, * / ^ j • ί carbalkoxy, aralkyl, alkylthio, alkylsulfonyl, oxyalkyl, ·, " Alkoxyalkyl, cyanoalkyl or alkoxysulfonylalkyl radicals are substituted 00 98 38/222 2 is tuted, where these substituents can be the same or different ·, with the proviso that, if R _{1 is} an aliphatic. Contains part, this is optionally substituted one or more times by halogen atoms, hydroxyl or amino groups or alkoxy * - '/ mono- or dialkylamino, carbalkoxy or heterocyclic radicals, these substituents being identical or different ', as well as with the proviso that if R- contains a heterocycle · see ring, this optionally one or more times by halogen atoms, nitro groups or alkoxy, carbalkoxy,' oxyalkyl, alkylsulfonylalkyl, alkoxyalkyl - Or Cyanalkylgrup- '■ pen is substituted, where these substituents can be the same or different. th or branched aliphatic hydrocarbon radical with 1 * · ; means up to 16 carbon atoms which is optionally substituted once or several times by halogen atoms or hydroxyl or methoxy groups. '·' Iert, it being possible for these substituents to be identical or different . . ' 10. Compounds according to claim 9, characterized in that the radical R _n is substituted by at least one cyclo- _: alkyl radical having 3 to 8 carbon atoms. ^! · 11. Acyl derivatives of the compounds according to Claims 1 to 10. 12 »Acyl derivatives of the compounds according to Claims 1 to 10. t , 13. A process for the preparation of the compounds according to claim 1 up to 12, characterized in that * a substituted biguanide of the general formula II - R _A - NH -C-NH-C - NH ₉ "'(II) in which Rr is a radical of the general formula III R ₁ -XR ₂ -O- (III) in which R- ^, R ₂ and X have the meaning given in claim 1, or denotes a radical which can be converted into a radical of the general formula III with the aid of a carbonyl compound of the general formula IV R ₃ -CO-R ₄ '■ "(IV) in which R 1 and R _{A have} the meaning given in claim 1, in the presence of an acidic catalyst to give a compound of the general formula V (V) converts and, if necessary, the remainder Rc to a remainder of the 'general Formula III converts, and optionally produces the corresponding salt. 14. The method according to claim 13, characterized in that that Rc denotes a radical of the general formula HI. , 15. The method according to claim 13 or 14 »characterized in that to implement a strong Acid. And an inert solvent is used. 16. The method according to claim 13, characterized in that g e k, e η η z β i c h-n e t that one 009838/2222 a) first a triazine of the general formula VI (VI) in the Yp means a reactive radical, produces, and ■ b) this triazine then with a 'compound of the general. my formula VII - · . ''' ■ R ₈ Y ₁ 'evil).: in which Y _{1 represents} a residue which is the convertibility of the '. Compound of the general formula VII with Y ₂ to form a radical. »Rc, preferably a radical of the general formula III. guaranteed, continued to implement, and if necessary c) the compound obtained is converted into a salt .. ■, Process according to claim 16, characterized in that Y ₁ and Y _{2 are} hydroxyl groups or their derivatives, with the proviso that at least one of the radicals Y ₁ and Y _{0 has} an oxygen atom capable of bridging ^. shows. 18. The method according to claim 17, characterized in that Y _{2 is} a hydroxyl group and Y _{1 is} a chlorine, bromine or iodine atom. '. 19. The method according to claim 16 to 18, characterized in g e code In that Rg in Formula VII is a remainder of the general formula R ₁ XR ^, - is preferably of the general formula \ R, ORö #. 0098 38/222 2; 20. The method according to claim '16, characterized in that one. in step (a) a compound ^{1 of} the general formula VI, in which Y _{2 is} a hydroxyl group, by first preparing a compound of the general formula VIII •. (Viii) • » and then send it through to think about this connection ^f replaces a hydrogen atom. 21. The method according to claim 20, dad ^ urchg β ke η η - < records that one _{replaces the radical R 7} by a hydrogen atom with the aid of hydrogen in the presence of a Performs palladium catalyst. · •. -r .. _v 22. The method according to "Claim 20 or 21, characterized in that" ζ e i cMi net that the remainder Ry in formula VIII an optionally substituted benzyl or naphthylmethyl group is" . " 23. The method according to claim 16, characterized in that in step (a) a compound of the general formula IX _r R3 in which Y * is a reactive radical, and this compound in step (b) with a compound of the general 009838/2222 Formula RtY-z, in which Y, is a reactive radical ensuring the reaction of the compound R-iY * with Y. to form a radical R- ^ X, ^ --— * 24. The method according to claim 13 to 23,. as a result, I show that the compounds obtained are then acylated, preferably acetylated. ·. '] 25. Use of the compounds according to claims 1 to 12; for her- ^ " production of medicinal products that are used to treat or prevent malaria. . "" '' * 26. Embodiment 231 ~ ZI1- · ~ _ ~ IJj according to claim 25, .g e - . ■ · <t characterized by the use for the preparation of pharmaceutical preparations with simultaneous use of additional ~~ '~ T-malarials, preferably from SuIfonamiden. R ₁ XR ₂ ONH - C - NH - G / ^ NH ₂ (Ha) the rest R ₁ . It J f NH. to have· NH a the : in the R ₂ up * interpretation X the specified in claim 1 28. Process for the preparation of the substituted diguanides according to claim 27, characterized in that a Brornii of the general Pornil R-XRgBr mlt.Benzhydroxamaaure reacts, the obtained product by treating with an acid in a Qxyamine of the silly inner formula R ₁ XR ₂ converts ONH ₂ , and this oxyamine ÖÖSI3S / 2222