DE1965941A1 - Substituted diguanides and processes for their preparation and their use for the preparation of triazine derivatives - Google Patents

Description

"Substituted Biguanides and Process for Their Preparation and-their use for the production of triazine derivatives "

Priority: January 1st, 1969, Great Britain. -Ur. 102/69

The invention relates to substituted biguanides and a method to. their manufacture. .

The invention thus relates to substituted diguanides

; 1

general formula I -

R ₁ R ₉ ONH - C - NH - C - NH NH

Il

NH

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in the R ^ is an optionally substituted aromatic or heterocyclic Hest or non-aromatic carbocyclic C * Q hydrocarbon radical, and R ₉ is an optionally substituted divalent aliphatic C _2- I6 ^K ok ^{"Le: aWasser} '~ substance radical, with the proviso that when R _{9 is} an unsubstituted radical, R _{1 is} not a non-substituted phenyl

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group, and that when Rp is an ethylene group, R _{1 is} not a l-methyl-2-naphthyl group.

V The radical E ₁ can be an optionally partially hydrogenated mono- or polycyclic aryl radical, a saturated or unsaturated: cycloaliphatic radical or a heteroyclic radical.

Specific examples of suitable radicals R are phenyl, naphthyl, phenanthryl, pyrenyl, anthryl, tetrahydronaphthyl ψ and Tetrahydrophenylgruppe, Cyeloalkylreste how the cyclopentyl

Cyclohexyl, cycloheptyl or methylcyelohexyl group, cycloalkenyl radicals, like the Cyelohexeny! group, heterocyclic residues, like the pyridyl, pyrrolidinyl, piperazinyl, iraidazol'yl, Benzimidazolyl, phthalimido, quinolyl, Fury1 or thienyl ' group. -.

With a suitable structure, the radical R- can be very diverse Have substituents. For example, it can be substituted one or more times by aromatic hydrocarbon radicals, such as aryl or aryloxy radicals, aliphatic hydrocarbon radicals, such as alkyl radicals, e.g. methyl or ethyl groups, cycloalkyl radicals with 3 to 8 carbon atoms, such as cyclohexyl, cyelopentyl or cyclohepty] groups, halogen atoms, such as chlorine or bromine atoms, nitro groups, halogen (lower-alkyl) radicals, such as mono-, di- or trichloro, -bromo or fluorine (lower-alkyl) radicals, lower alkoxy radicals, such as methoxy, ethoxy or propyloxy groups, lower alkoxycarbony1 radicals, such as methoxycarbonyl, ethoxycarbonyl or propyloxycarbonyl groups, Aryl (lower-alkyl) radicals, such as benzyl or phenyl ethyl groups, carboxyl groups, oxy groups, mercapto groups, cyano groups, lower alkyl thio radicals, such as methylthio or ethylthio

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groups, di-lower-alkyl-sulfonyl radicals, alkoxysulfonylalkyl radicals, oxy-lower-alkyl radicals, such as 2-oxyethyl groups, lower-alkoxyalkyl radicals, cyano-lower-alkyl radicals, sulfonamido groups, amino groups or mono- or "di- ( lower-alkyl) -amino radicals, such as methylamino or ethyl amino groups, if R _{1 has} more than one substituent, these can be the same or different.Unless otherwise stated, the aforementioned radicals generally contain 1 to 6 carbon atoms , if they are referred to as "lower" radicals, and 1 to 24 C atoms, if the abovementioned designation is not used.

The radical R ₂ ″ is an unbranched or branched, saturated or unsaturated divalent aliphatic hydrocarbon _{radical. Specific examples of radicals R 2} are the propylene and vinylene group, as well as radicals - (CH ₂ ) _n -, where n is an integer from 2 to 16 is, for example, the tetramethylene group or 3-methylpropylene group.

The radical R ^ can have one or more substituents, e.g. Halogen atoms, hydroxyl groups or "lower" alkoxy groups, i. Alkoxy radicals with ί to 6 carbon atoms.

Preferred compounds of the general formula I have phenyl or naphthyl groups substituted by one or more halogen, in particular chlorine atoms, _{as radicals R 1} and saturated aliphatic C2_Q hydrocarbon _{radicals as radicals R 2.}

The invention also relates to a method for producing the Compounds of the general formula I, which is characterized in that a bromide of the general formula II

R ₁ R ^ Br. (II)

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in which R- and R _{2 have} the aforementioned meaning, converted with benzhydroxanoic acid, the product obtained by treatment with an acid to form an oxyamine of the general formula III

R ₁ R ₂ OWH ₂ (III) = -

converts and this oxyamine with dicyandiamide for implementation "brings.

The invention finally relates to the use of the compounds of the general formula I for the preparation of

ψ 1,2-Dihydro-1,3,5-triazine derivatives that can be used in pharmaceuticals.

The aforementioned triazine derivatives are made from the compounds of the invention by reacting these compounds with certain carbonyl compounds in the presence of acidic catalysts obtain..'. "=

The examples illustrate the invention.

example 1

3- (3,4-Dichlorophenyl) -propyloxydlguanid A solution of 13.7 g of benzhydroxamic acid in 100 ml of methanol is mixed with a solution of 4.0 g of NaOH in 10 ml of water while stirring. Then 26.8 g of 3- (3 "4-dichlorophenyl) propyloxybromide are added dropwise with stirring, and the mixture is then boiled under reflux for 3 hours. The solvent is then evaporated off and the residue obtained is dissolved in water and then extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated. A pale yellow viscous oil is obtained in which long-

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form crystals together. The desired benzhydroxamate is isolated by triturating this oil with ether and filtration. Included one obtains a white solid substance from which the pure compound be obtained by recrystallization from ethanol can. '

16.2 g of 3 ~ (3 »4-dichlorophenyl) propylbenzhydroxamate are then refluxed for 2 hours with a mixture of 120 ml of methanol and 40 ml of concentrated hydrochloric acid. The reaction mixture is then filtered and evaporated under reduced pressure. The residue obtained is triturated with ether ·, filtered and washed well with ether ^v. 12.8 g of 3- (3j4-dichlorophenyl) propyloxyamine hydrochloride are obtained. This compound is then dissolved together with 6.3 g of dicyandiamide in 10 ml of ethanol and the mixture obtained is refluxed for 3 hours. Thereafter, the reaction mixture is evaporated to dryness under reduced pressure and the residue obtained, a gummy substance, is dissolved in water. The aqueous solution obtained is made alkaline with 4N sodium hydroxide solution, an oil separating out and slowly solidifying. The solid substance is filtered off, washed well with water and dried in a vacuum desiccator. The off-white compound is the desired 3- (3,4-diohlophenyl) propyloxydiguanide. With prolonged exposure to light, the connection turns dark. The pure compound can be obtained from the crude product by recrystallization from a mixture of ethyl acetate and gasoline.

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The example below illustrates how to make a Triazine derivative from a compound according to the invention.

Example 2

4 _} 6-diamino-1,2-dihydro-2,2-dimethyl-lZ ^ - (3,4-dichlorophenylpropyloxy) 7-1>3> 5-triazine hydrochloride 15j2 g of the pure 3- (3, 4-Dichlorophenyl) propyloxydiguanide from Example 1 is dissolved in 50 ml of methanol and 8.6 ml of concentrated hydrochloric acid and 50 ml of acetone are added one after the other. The obtained mixture is boiled for 3 hours under reflux ^, then filtered and then evaporated under reduced pressure zx dryness. The residue obtained is rubbed with acetone and is filtered. The solid white sut obtained is gvct mii; Washed water, dried and recrystallized from ethane. This gives the desired compound of Pp 235 -. 236 ⁰ C (decomposition).

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Claims (1)

Substituted diguanides of the general formula I R ₁ R ₀ OKH - G - EfH - C - NH ₀ / _T s ^x <- ir it * - - ■ Λ · ¹ - / NH HH. in which R-, an optionally substituted aromatic, ^ p the heterocyclic radical or non-aromatic carbocyclic C-zg-hydrocarbon radical, and Rg is an optionally substituted divalent aliphatic C ₂ _- * g-hydrocarbon radical, with the hatred that, if Rp is an unsubstituted radical, R- is not an unsubstituted phenyl group, and that when R _{2 is} an ethylene group, R-. is not a 1-methyl-2-naphthyl group. · 2ο connections according to claim 1, d a d u r 'c h g e k e η η ze i c h η e t that R- ^ an optionally substituted Phenyl or naphthyl group_is. 3. Compounds according to claim 1 or 2, d a du r c h g e -. indicates that R-, through at least one halogen atom, preferably chlorine atom, is substituted. 4. Compounds according to claim 1 bls ~ 3 ₅ because you rchgek e η η ζ eich η et that R ^ is a saturated aliphatic hydrocarbon _{radical, preferably an unbranched C 2-} Q -alkylene radical, · 5. 3- (3> 4-dichlorophenyl) propyloxydiguanide. 009836/2287 6. Compounds according to claim 1, dadurchgeke η η ζ eich η et that, R-, an optionally substituted heterocyclic radical, an optionally substituted Cz g -cyeloalkyl radical or an aryl radical which is substituted or in the case where Rp is substituted, substituted or unsubstituted, and Ro is a divalent, unbranched or branched aliphatic C _2- , / - hydrocarbon residue, which is optionally substituted by one or more halogen atoms and / or one or more hydroxyl groups and / or one or more methoxy groups is substituted. 7. Process for the preparation of the substituted piguanides according to Claims 1 to 6, d a d u r c h characterized, that a bromide of the general formula II R ₁ R ₂ Br (II) in which R ₁ and R _{2 have} the meaning given in claim 1 and reacts with benzhydroxamic acid, and the product obtained is converted into an oxyamine of the general formula III by treatment with an acid ¹ R ₁ R ₂ O NH ₂ (III) converts and this oxyamine with dicyandiamide for implementation brings. 8. Use of the compounds according to Claims 1 to 6 for the preparation of 1,2-dihydro-1,3 »5-triazine derivatives which can be used in medicaments. 009836 / 22ST
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