DE2132028A1 - Biologically active substituted amidines - Google Patents

Description

DR. BERG DIPL.-ING. STAPF

PATENTANWÄLTE 8 MÜNCHEN 8O, MAUERKIRCHERSTR. 45 2132028

Dr. Berg Dipl.-Ing. Stapf, 8 Munich 80, Mauerkircherstraße 45 Your letter Our sign date £, Ol UUf) I 1971

Lawyer sect 21 192
Be / Be

Addendum to patent

(Patent application 1668843.0-42) Attorney's file 16 376

THE WELLCOME FOUNDATION LIMITED London / Great Britain

"Biologically active substituted amidines" *

During the past 40 years a number of safe and highly potent synthetic compounds have been developed for use against malaria infections in humans. These compounds include chloroquine (7-chloro-4- (4-diethyl-amino-1-methylbutylamino) -quinoline), progua

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nil (1- (p-chlorophenyl) -5-isQpropylbiguanid), primaquine- (8- (4-amino-1 -me thylbutylamino) -6-methoxyehinoline) and Pyrimethamine (2 ^ -amino-S-ip-ohlophenylI-o-ethylpyrimidine). All of these compounds are currently used to treat various forms of infection, however not a single synthetic antimalarial drug for the treatment and prophylaxis of all malaria infections ideal". Reports of the occurrence of opposite these Resistant malaria pathogens were an incentive for research, the doctor to the existing even more, to provide new types of antimalarials.

1- (35f «-Alkylamidino) -3-phenylureas are a class of synthetic compounds which have been examined for their antimalarial activity and found to be worthy of further investigation (Curd, SeHeS, and others, J. Chem. Soc., ( in 1949, 1732). Furthermore, were i-amidino-3-phenylureas examined by TIrbanski 1960 who demonstrated that, from the w large class of 1-amidino-3- (monosubst · phenyl) the highest activity against the malaria parasite Plasmodium ureas gallinaceum was achieved in chicken chicks with 1-amidino-3- (4-nitrophenyl) urea (Skowronska-Serafin, B.ür.banski,!., Tetrahedron, 10, 12-25 <1960).

It has now been found that amidinoureas of the formula (I) and their acid addition salts were also effective against various malaria parasites, as in

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Screening with standard infections in laboratory animals was produced.

These amidinoureas have the following general formula (I)

NH.CO.NHoC ' (I)

-KH,

wherein Y is a halogen or trihalomethyl substituent, Y is a cyano or halogen substituent and Y- * is a halogen substituent is, ■

The halogen atoms can be chlorine, bromine, fluorine or iodine, but chlorine, bromine and fluorine and especially chlorine are preferred. The preferred irihalomethyl group is irifluoromethyl. · \

The compounds of formula (i) include 1-amidino-3- (3.4.5-trichlorophenyl) urea, 1-amidino-3- (3 «4.5-tribromophenyl) urea, 1-amidino-3- (3 * 5-dichloro-4-cyanophenyl) urea, 1-amidino-3- (3o5-dibromo-4-chlorophenyl) urea, 1-Amidino-3- (4-bromo-3 "5-dichlorophenyl) urea, 1-Amidino-3- (3-bromo-4,5-dichlorophenyl) urea and their acid addition salts.

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The amidinoureas of the formula (I) and their acid addition salts are effective against Pogallinaceum in chicken chicks and PoVinckei and Poberghei in mice Some of the compounds of formula (I) also have activity against other protozoal infections _o

The activity of the above compounds is based on the base and the acid in the acid addition salts is therefore of less importance, although it must preferably be pharmacologically and pharmaceutically acceptable. For example, the acid can be hydrochloric acid, isethionic acid, sulfuric acid, toluene-p-sulfonic acid, p-chlorobenzenesulfonic acid, maleic acid or tartaric acid _o Ethanesulfonic acid, isethionic acid and methanesulfonic acids are preferred because their salts have a higher solubility than most other salts.

The compounds of formula (I) can be prepared by any process which is suitable for the formation of compounds analogous chemical structure, although some processes are suitable because of their ease of manufacture and applicability to a larger area, are preferred.

A first method by which the connections of 109883/1983 " ⁵ "

Formula (I) can be prepared consists of the one leadership of the oxygen atom of the carbonyl group, instead the Z group into a compound of the formula (II)

(II)

wherein Z is a reactive group such as an imino group, ' or a reactive derivative thereof, or a reactive derivative of a thio group, such as an -S-alkyl- or S-aralkyl group.

As an example of such a type of process, a biguanide of the formula (II), in which Z is an amino group, can be converted into a compound of the formula (i) by reaction with an excess of nitrous acid, preferably at 0 to 20 ° C., or by hydrolysis with a strong , aqueous acid, i

, are preferably converted between about 20 and 90 ⁰ C, for example Ithansulfonsäure, isethionic acid, methanesulfonic acid or hydrochloric acid 3äure. The biguanide starting materials can be prepared by a number of processes described in the literature (see, for example, "Chemistry of Carbon Compounds", Id.B »H. Rodd, 1st edition, Volume III, Part A 1954, page 198 follow). So you can duroh the reaction of dicyandiamide with a primary, aromatic

109883/1983

AminhydrοChlorid, either in a solvent or duroh melt. They can also be prepared by removing hydrogen sulfide constituents from a suitably substituted guanidine or isothiourea or from a suitably substituted amidinothiourea or dithiobiuret.

As a further example of this type of process, an S-substβ-1-amidino-3-Csubst "phenyl) -isothiourea of the formula (II) (in which Z is, for example, an S-alkyl or S-aralkyl group, can be converted into a compound of the formula ( I) _{5 are} preferably oxidized using a peroxide, for example hydrogen peroxide, as the oxidizing agent.The S-substituted isothiourea starting material can be prepared from the corresponding 1-amidino-3- (substβphenyl) thiourea, which in turn is produced by the reaction of suitable isothiocyanates accessible with guanidine, is »

Another procedure for the preparation of amidinoureas of formula (I) consists in that guanidine is substituted with a reactive derivative of a Bhenyloarbamic acid of the formula (III)

(III)

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for example an isocyanate (the internal anhydride), an acyl halide, a urea (the amide) or an N-subst "Urea (the N-substeamide), for example an N-alkyl urea, in which the alkyl group is, for example, methyl or ethyl" Further reactive derivatives which can be used are esters, for example an alkyl ester (urethane), in which preferably the alkyl group is a methyl or ethyl group, which are preferably reacted with an aqueous solution of a guanidine base. A Ν, Ν-disubsto urea (the N, N-disubstoAmid) can also be used, for example the melt of a Ν, Ν-dialkylurea, in which the alkyl groups are, for example, methyl or ethyl groups, with a guanidine base a compound of the formula (I) can provide _e It is of course to be noted that also other reactive derivatives of carbamic acid of formula (ill) in place of, the above-mentioned compounds can be used.

Another type of process for making the compounds of formula (I) consists in using an appropriately substituted aniline or a reactive derivative thereof with a reactive derivative of a guanidine carboxylic acid of the formula (IV)

NH

¹¹ (IV)

A.NH.C - NH

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"for example the nitrile, amide or ester In this way, dicyandiamide of the formula (IV), the inner Anhydride of the acid amide, in which A is a -GN group with the suitably substituted aniline in the presence of at least twice the equivalent amount of strong, aqueous acid, based on dicyandiamide, with the formation of an amidinoureas of the formula (I). The acid can be a strong, aqueous acid such as hydrochloric acid, isethionic acid, ethanesulfonic acid, methanesulfonic acid or an acid be of similar strength. It should be noted that the amidinourea is formed via the corresponding biguanide is / which is converted in situ by the excess acid to the amidinourea «. However, if it is, for example If it is desired for labeling or purification, the biguanide can first be isolated (e.g. using an equimolecular equivalent of acid in the reaction) and then to the amidinourea, as already described, being transformed. You can also, for example, carry out this type of procedure in such a way that one the suitable-subst »aniline or its acid addition salt with a nitrourea of the formula (IV) (in which A NOpoNH.CO-) or an alkoxyoarbonylguanidine (wherein A, for example ΟΗ, Ο, ΟΟ- is implemented), or that one is a Grignard derivative of aniline with an alkoxycarbonylguanidine react to

An amidine urea of formula (I) can also be prepared 109803/1983

are produced by ammonolysis of a methyl enurea Formula (T)

where R is the amino group and R is an alkoxy, alkylthio, Is thio, aryloxy or aralkoxy group. If R is an alkoxy or alkylthio group, it can have one to four carbon atoms and are the preferred groups correspondingly one methoxy and one methyl thio group

The amidinoureas of the formula (i) can also thereby be obtained by initially using a 1-N-substituted amidinourea of formula (VI)

N- 00.R

NH.CO.NH.O (VI)

NH-A

wherein the radicals Y ^, Y ^4- and Y ^ have the meaning given above and R is a hydrogen atom or an aryl or alkyl group and A is a hydrogen atom or the CO.B-f group, in which B is an aryl group or forms an acid addition salt thereof and then this or this au

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ORIGINAL INSPECTED

hydrolyzed an amidinourea of the formula (I), which can then be isolated as the base or as an acid addition salt thereof with the 3-Y -, 4-Y -, 5-Ϊ -PhenylisoByanat, which in turn, if desired, can be prepared in situ from the corresponding azide. The preparation of these 1-N-subst »amidinoureas of the formula (VI) is facilitated by the solubility of the subst _β guanidine derivatives in non-protonic solvents, in contrast to the very low solubility of the guanidine itself. The formation of the compounds of the formula (VI) is therefore preferably effected by reaction in a non-protonic medium, for example an aromatic hydrocarbon such as benzene or a polyhalogenated, aliphatic hydrocarbon such as chloroform.

Among the aoylamidino derivatives of the formula (VI) that are used include the formyl, acetyl, propionyl and butyryl derivatives (i.e. those compounds in which B is a hydrogen atom or a methyl, ethyl or propyl group is) and belong to suitable aroyl derivatives those compounds in which B and / or B (if A is the ÖO.B group) is a phenyl or an aubet.Phenylgrupp « such as a tolyl group · is. The I-N.N'-dibenzoylamidino derivatives (in which B is a phenyl and A is the CO.B group, in which B is also phenyl) are particularly useful for obtaining the

10988371883 mrm ' ¹¹ '

ORIGINAL! HSPECTED

Amidinoureas of the formula (I) are valuable.

The hydrolysis of the 1-N-substituted amidinoureas of the formula (YI) to the amidinoureas of the formula (i) becomes easy at low temperatures, preferably below 100 C, in The presence of an aqueous base effected acid hydrolysis can also be used to remove an acyl group and a dilute mineral acid such as aqueous hydrochloric acid is one suitable for this purpose Reagent. Nevertheless, an aqueous solution of an alkali metal hydroxide, for example sodium hydroxide, is preferred optionally to be used in the presence of a polar solvent other than water. This second solvent can be a lower alkanol, for example ethanol or Methanol, acetone or a mixture of these solvents can be. Aqueous sodium hydroxide, preferably in a mixture with Ethanol has been found to be a suitable hydrolyzing agent. The amidinoureas of the formula (I) can be used as Base can be isolated by diluting the reaction mixture with water and thus precipitating the amidinourea base. You can also use an amidinourea of formula (I) as isolate an acid addition salt by adding the reaction mixture treated with an excess of an acid

Amidinoureas of the formula (I) can also be selected from the corresponding Amino compound by diazotization and subsequent reaction with an oyanide or halide one

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109883/1983

Alkali metal or a copper salt can be produced, as provided by the Sandmeyer, Korner-Contardi, G-att ermann and Angeli processes. (See "Marne Index of Organic Reactions", Gowan JE u _o Wheeler T ₀ S ₀ , 1960, Longmans)

The product formed by means of any of the reactions described can be a 1-amidino-3- (subst ₀ phenyl) -urea in the form of the base or an acid addition salt thereof and can then, depending on suitability, be converted into an acid addition salt, a salt of another acid or the base can be converted by reaction with an acid, a salt thereof or a base, for example in solution or in an ion exchange column. Such a reaction of an acid addition salt with an alkali such as sodium hydroxide gives the 1-amidino-3- (subst _e phenyl) urea base.

For the treatment or prophylaxis of malaria, the compounds of the formula W encryption can (i) with a suitable carrier as pharmaceutical preparations are presented "The carrier must, of course, be" appropriate "in the sense that acceptable ermit the other ingredients of the formulation and not deleterious is for the recipient of the preparation. The carrier can be a solid or a liquid and is ¹ with a compound of formula (I), rezeptierto as a unit dose, for example as a tablet Other pharmacologically active substances can also

109883/1983

be present in the preparations of the present compounds. The amidinoureas of the formula (I) can be added to the preparations be incorporated either in the form of their base or their acid addition salt and according to one of the The preparation formulated in well-known pharmacy techniques preferably consists as a base of a mixture the components of the preparation "

For oral administration, fine powders or granules of the compounds diluting, dispersing and above may contain ι surfactants and non-aqueous in a potion in water or in a syrup, in capsules or Kaschetten in dry state or in an aqueous or Suspension, which can also contain a suspending agent, as tablets, preferably made from granules of the active ingredient with an extender, by pressing with binders and lubricants, or as a suspension in water, a syrup or in an oil or in a water / oil emulsion, flavoring agents, preservatives, suspending agents, thickening agents and emulsifying agents "can also be added. The granules or the tablets can be provided with a coating and the tablets with graduation marks. For parenteral administration, the compounds can be in unit dose or multi-dose containers in aqueous or non-aqueous injection solutions which A ntioxidants, buffers, bacteriostats and solutes that bind the compounds with the

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109883/1983

Blood isotonic, making, may contain or in aqueous or non-aqueous suspension, with suspending and thickening agents may be included or as mixed injection solutions and suspensions as required are presented, which are made of sterile powders, granules or tablets, which are diluting, dispersing and surface active, Binders and lubricants can contain, can be produced.

The preferred preparations of the invention described above are those which can be used orally, and the preferred mode of administration for compounds of formula (I) is oral administration _{or the like}

From experiments using the compounds of formula (I) for the treatment of experimental malaria infections in laboratory animals it has been found that a dose of 1 to 100 mg of a compound of the formula (i) or a Acid addition salt thereof, calculated as base per kg of body weight, is a suitable therapeutic or prophylactic one Human dose is recommended, and preferably a dose of 5 to 25 mg per kg of body weight will. When a compound of the formula (I) is administered in the form of a dosage unit, for example as tablets or cassettes, each unit can contain 50 to 7000 mg of one Compound and preferably from 100 to 500 mg, calculated as base, contain

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109883/1983

The present invention therefore discloses compounds of Formula (I), their acid addition salts and their preparation, as well as the preparations described above which contain a compound of the formula (I) and a carrier compatible therefor, furthermore the manufacturing process for such Preparations available by mixing the components. The present invention further provides A method for the treatment or prophylaxis of malaria in warm-blooded animals, including a compound of formula (i), preferably administered in an amount in the dosage range of 1 to 100 mg / kg to the host or possible carrier of infection.

The following examples explain the invention, with temperatures being given in ⁰ C.

example 1

3.4.5-trichloroaniline (4.9 g), dicyandiamide (4.2 g) and 4N hydrochloric acid (12-5 ml) are refluxed. A clear solution was obtained after a few minutes, after which the product was separated off. After cooling the product was 1- (3.4 »5-trichlorophenyl) -biguanidhydrochlorid collected, and was obtained after tJmkristallisierung thereof from water white needles (7.15 g), melting point 264 ⁰ C with decomposition" A solution of this salt in water was made alkaline made and the base precipitated as white platelets of the monohydrate \ melting point 184 ° C under vigorous

Effervescence.

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10 9 8 8 3/1983, c; ;

A solution of the vorausbezeiehneten biguanide (4 »5 g) i Ä'thansulfonsäure (45 nil normal aqueous Lösimg) was heated for two hours at 9O ⁰ C. 1-Amidino-3- (3 <> 4o5-trichlorophenyl) urea ethane sulfonate was separated off and, after cooling, collected and washed with water. This salt had a melting point of 245 to 246 0, which was not increased after recrystallization from methanol.

The aqueous solution of the salt was made alkaline and the base separated off W as a crystalline solid, which was recrystallized from aqueous alcohol to give white needles in prism shape of the basic hydrate, melting point 193 ⁰ C

Example 2

3.4o5-trichlorophenyl isocyanate (2.22 g) and Ν, Ν'-dibenzoylguanidine (2.67 g) were refluxed in dry benzene (60 ml). After a few minutes a crystalline contaminant began to separate and after 30 minutes the reaction mixture was cooled. The solid was collected, washed with benzene and then with hot ethanol. The residue (4.45 g) of 1-N, N'-Dibenzoylamidino-3- (3,4,5-trichlorophenyl) urea was in the form white needles, melting point 209-210 ⁰ C with decomposition and was chromatographically pure.

This compound (0.98 g) was refluxed for 2 hours with a solution of sodium hydroxide (0.24 g) in water (1 ml)

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and ethanol (20 ml) heated. The reaction mixture was filtered off from a small residue of unreacted dibenzoyl compound. The filtrate was diluted with water and the alcohol evaporated. The product 1-amidino-3- (3o4 _e 5-trichlorophenyl) urea was then separated off as a white, crystalline solid, the white prismatic needles of the hydrate after recrystallization from aqueous alcohol yielded a melting point of 192 ⁰ C ₀

Example 3 ^{

4 «Bromo-3,5-dichloroaniline (2.41 g), dicyandiamide (2.52 g), 4N hydrochloric acid (7» 5 ml) and ethanol (7.5 ml) were heated to reflux. The hydrochloride of the amine that separated first quickly dissolved and after a few minutes white needles began to separate. After 30 minutes, the reaction mixture was cooled and filtered, the residue was washed with alcohol and then weighed (2.5 g) and had yielded a melting point 266-267 ⁰ C with decomposition · Crystallization from water white, glänzen- ä de needles unchanged melting point This hydrochloride was dissolved in hot water and the solution made alkaline, whereby 1- (4-bromo-3,5-dichlorophenyl) -biguanide precipitated, melting point 191 ⁰ O with effervescence. This base formed colorless prisms after recrystallization from alcohol of the same melting point

This biguanide (1.5 g) was dissolved in normal aqueous ethanesulfonic acid (15 ml) and the solution for 2 hours

109883/1983

Held 9O ⁰ C. 1-Amidino-5- (4-bromo-3,5-dichlorophenyl) -ureaethanesulfonate separated from the hot liquid as white prismatic needles, which were collected and washed with water; Melting point 245 ° C with some disintegration.

Example 4

504.5-tribromaniline (3.3 g) was dissolved in hot alcohol (7.5 ml) and dicyandiamide (2.52 g) and 4N hydrochloric acid (7.5 ml) were added to the solution. 3e4o5 was immediately separated off -Tribromaniline hydrochloride, which, however, was redissolved after warming, followed by separation of 1- (3.4 «5-tribromophenyl) -biguanidhydrochlorido. After the mixture was refluxed for minutes, it was cooled and filtered Hydrochloride remained as white, dull needles (3.73 g), melting point 2.75.5 ° O with disintegration. The Umkristall! Zation of a large volume of water raised the melting point is not the _o by treating a hot aqueous solution of this salt base obtained with alkali had a melting point of 193 ⁰ O with effervescence.

1- (3.4.5-tribromophenyl) -biguanide (2.2 g) was dissolved in normal aqueous Xthansulfonsäure (22 ml) and the solution kept at 90 ⁰ C for 2 hours. It crystallized 1-Amidino-3- (3.4.5-tribromophenyl) -urea äthansulfona t as white prisms, which are further purified by recrystallization from methanol and then have a melting point of

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241 ⁰ G with decay. A hot aqueous solution of this salt, which was only sparingly soluble in water, was made alkaline and provided the base as white needles after recrystallisation from aqueous alcohol a melting point of 180 ⁰ C with effervescence to Teilsehmelze at about 120 ⁰ C under Loss of water of crystallization and subsequent renewed solidification had _β

Example 5

tablets of 1-amidino-3- (3o4.5-trichlorophenyI) -urea were made from the following components:

1. 1-Amidino-3- (3o4.5-trichlorophenyl) urea 200 mg

2. Strength B.P. 30 mg 3 · lactose Β «Ρ · 75 mg

4. Gelatin B.P. 6 mg

5. Magnesium stearate B ₀ Pe 4 mg

Products 1, 2 and 3 were mixed with a solution of 4 in 5 The above, aqueous ethanol granulated product 5 was the dried granules are added and the mixture is compressed to form tablets

Example 6

In the same manner as in Example 5, tablets were made from the following compounds, each tablet made with 200 mg of active ingredient ι

1-Amidino-3 '- (3 »4« 5-tribromophenyl) urea 1-Amidino-3- (4-bromo-3 · 5-dichlorophenyl) -urea »

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Example 7

An oral suspension of 1-amidino- ^ - (3.4.5-trichlorophenyl) -urea was made from the following components:

1. 1-Amidino-3- (3o4o5-trichloro-

phenyl) urea 100 mg 2.0 # wt. / vol.

2. tragacanth B _{0 0} P 12 mg 0.24 wt $ _e / Vol. 3 · Acacia B ₀ P ₀ 15 mg 0.3 # w / v. 4ο Glycerin B _O P. 300 mg 6.0 # wt. / Vol. 5. Sorbitol BPC ₀ 2.25 g of 45 $> ₀ wt / vol _e 6 "B Sucrose ₆ P. 2.0 g of 40% by weight _o / Vol. 7 ο Best. Water B ₀ P. to 5.0 ml to 100 $

A carrier for the active ingredient was made up of the ingredients 2 »3,4» 5 »6 and 7 according to an established pharmaceutical Method Manufactured «$ 15 of the carrier were used to manufacture a homogeneous suspension of compound 1 is used, which is then diluted with the rest of the carrier prepared became,

Example 8

1. 1-Amidino-3- (3o4o5-trichloro-

phenyl) urea 100. mg

2ο water for injection Β, Ρο to 2 ml.

Under aseptic conditions, a suspension of the finely ground and stabilized compound 1 in sterilized Injection water produced. The suspension was then distributed into vials, which were made under aseptic conditions were locked.

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Example 9

3,5-dibromo-4-chloronitrobenzene (10 g), iron powder (10 g), water (100 ml) and two drops of acetic acid were refluxed for 2 hours. The reaction mixture was cooled and filtered. The solid was dried and then extracted with ethanol; after evaporation of the extract gave 3 »5-dibromo-4-chloroaniline, m.p. 120 ⁰ O.

This amine (2.85 g) was dissolved in hot alcohol (7 »5 ml) and to the solution were added dicyandiamide (2.25 g) and ^ -hydrochloric acid (6.6 ml) * Immediate separation of 3,5-Dibromo-4-chloroaniline hydrochloride, but this was redissolved on heating, after which 1- (3 β 5-dibromo-4-chlorophenyl) -biguanide hydrochloride was separated β After refluxing for 30 minutes, the reaction mixture was cooled and filtered "the product was washed with alcohol and recrystallized from water to give the hydrochloride as white, silky needles, melting point 277 ° C and the disintegration of the corresponding base formed white prisms of the hydrate from aqueous alcohol, melting point 185 ⁰ C with effervescence.

1- (3 »5-dibromo-4-chlorophenyl) -biguanide (3.6 g) and Na \ thansulfonaäure (36 ml) were heated for 2 hours at 90 0, during which time the solution crystals of 1-amldino- 3- (3 · 5-dibromo-4- "chlorophenyl) -urst of fäthansulfonat deposited. Recrystallization of this salt from methanol gave white needles, melting point 252 ⁰ C with disintegration

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Base crystallized from alcohol as white needles, melting point 193 to 194 ^° C

Example 10

Dry hydrogen chloride was bubbled into a solution of 3,5-dichloro-4-oyanoaniline (5.6 g) in toluene (150 ml) and then phosgene was bubbled through for 2 hours. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure to give crystalline 3,5-diehlor-4-cyanophenyl isocyanate (4.5 g). A hot solution of this product in benzene (150 ml) was extracted with N, N'-Dibenzoylguanidine (5.6 g) and heated to reflux for 30 minutes * After cooling, the solid product was collected and washed with hot alcohol to give a residue (8 g) of 1-N, N ^f -dibenzoylamidino -3- (3e5-dichloro-4-cyanophenyl) urea received} decay
at approx. 210 ⁰ C.

^ The dibenzoyl compound (7.2 g) was refluxed with
Ethanol (150 ml.) And a solution of sodium hydroxide
(1.8 g) heated in water (7.5 nil). A small amount of insoluble matter was filtered off from the reaction mixture, and the piltrate was diluted with an equal volume of water and evaporated under reduced pressure to remove the alcohol. That with advancing
Evaporation of crystallized product 1-amidino-3- (3 »5-dichloro-4-cyanophenyl) urea had fawn-colored needles

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and was collected and washed with water. After recrystallizing the product from alcohol, small, fawn-brown prisms which ^{did not melt at 300 °} C. were obtained.

The hydrochloride was obtained as white, silky needles (from water) with decomposition at approx »27O ⁰ C.

Example 11

A solution of 3,5-dibromo-4-chloroaniline (5 »1 g) in toluene (100 ml) was saturated with hydrogen chloride and then refluxed while phosgene 1 1/2 hours was passed long _o Reaktionsgemisoh was cooled, a slight precipitate was filtered off and then to dryness under reduced pressure and the residue evaporated (5g) of 3 »5-dibromo-4-ehlorphenylisocyanat (crystallized) had a melting point of 58-60 ⁰ C. The isocyanate was dissolved in benzene (30 ml) and added dropwise to a refluxed solution of Ν, Ν'-dibenzoylguanidine (6.31 g) in benzene (100 ml). The product 1-N, N'-Dibenzoylamidino-3- (3 '5-dibromo-4-chloro-phenyl) -urea was separated at once as white needles (8.8 g), melting point 215-216 ⁰ C. This product (2.4 g), ethanol (50 ml) and a solution of sodium hydroxide (0.6 g) in water (3 ml) was refluxed for 1 hour and then a slight residue was filtered off. The piltrate was diluted with water and evaporated under reduced pressure to remove alcohol. The crystalline precipitation of "crude 1-amidino-3- (3 · 5-dibromo-4-chlorophenyl) urea was

109883/1983 °

collects, dried and recrystallized from benzene-ethyl acetate. It formed white needles, melting point 194 ⁰ G, the product being identical in every respect to that of Example 9 »

Example 12

A solution of 3.4 ° 5-trichlorophenyl isocyanate (2.23 g) in chloroform (30 ml) was refluxed to one solution of benzoylguanidine (1.63 g) in chloroform was added, after one hour the chloroform was distilled off and the residue crystallized from alcohol gave a first crop (1 g) of colorless prisms, Melting point 213-215 ° C. with a strong effervescence. These Substance 1 == Bensoylamidino-3- (3o4.5-trichlorophenyl) -urea was refluxed for 15 minutes with alcohol (10 ml) and a solution of sodium hydroxide (0.2 g) in Water (1 ml) heated alcohol was removed by evaporation, and the residue diluted with water gave a

fc Precipitation of 1-amidino-3- (3 β 4 »5-trichlorophenyl) urea, which after recrystallization from benzene-ethyl acetate had a melting point of 192 ⁰ O, at which the product was identical to that of Example 2 _e

Example 15

Its suspension of 2j6 ~ dibromo-4-nitroaniline (29.6 g) in Glacial acetic acid (100 ml) was added portionwise with stirring to a solution of sodium nitrate (7.8 g) in concentrated Sulfuric acid (55 ml) added at 10 to 15 ° C after 2

109883/1983

Hours of stirring at 20 C, the reaction mixture was filtered and slowly added with stirring to a solution of nickel disgusting • chloride hexahydrate (17 g) »anhydrous sodium carbonate (95 g) , potassium cyanide (35 g) in water (500 ml). After one hour the solid was collected, washed with water, dried and extracted with benzene. The benzene extract was evaporated and the residue was recrystallized from alcohol to give 3o5-dibromo-4-cyanonitrobenzene (19.1 g) ; Melting point 188 to 190 ⁰ O. The reduction of this nitro compound with bison powder and water gave 3 »5-dibromo-4-cyanoanilinj fawn-brown crystals from alcohol, not melted at 300 ⁰ C.

The procedures of Example 10 were used, this compound to convert successively · 5-dibromo-4-cyanophenyl isocyanate in 3, 1-N, LT ^l -Dibenzoylamidino-3- (3e5-dibromo-4-cyanophenyl) urea, melting point 210 ⁰ G with decay and 1-amidino-3- (3 ο5-dibromo-4-cyanophenyl) urea, whitish prism needles, unmelted at 300 ⁰ O.

Example 14

The reduction of 3-bromo-4o5-dichloronitrobenzene with bison and water gives 3-bromo-4o5-dichloroaniline, which is obtained as whitish flakes, melting point 107 to 108 ⁰ O after recrystallization from cyclohexane «4N hydrochloric acid (8.5 ml) was a refluxed solution of this amine (2.74 g) 'and dicyandiamide (2.87 g) in alcohol (8.5 ml) to-

-26-

109883/1983

given. Later 1- (3-bromo-4o5-dichlorophenyl) -biguanide hydrochloride was separated off, and after 30 minutes the reaction mixture was cooled and diluted with water o The salt (3> 2 g) was collected and recrystallized from water to form white, silky needles Melting point 270 ⁰ O with disintegration The base crystallized from aqueous, alcoholic solution long in the form of white prisms, melting point 176 ⁰ O Tor.

A solution of the biguanide (3 »3 g) in normal aqueous ethanesulfonic acid (33 ml) was kept at 95 ° 0 for 3 hours. After cooling, crystals of 1-amidino-3- (3-bromo-4 <> 5-dichlorophenyl) urea ethane sulfonate were collected and washed successively with water and hot alcohol? Melting point 250 ° C with disintegration. The salt was converted into 1-amidino-3- (3-bromo-4β5-dichlorophenyl) urea, which was crystallized from benzene-ethyl acetate as white needles? Melting point 193 ⁰ G.

Example 15

A solution of 1- (3.4 »5-trichlorophenyl) -biguanide (2 g) in normal aqueous isethionic acid (20 ml) was kept for 2 hours at 90 ⁰ G. 1-Amidino-3- (3 »4.5-trichlorophenyl) urea isethionate crystallized out and was collected after cooling and washed first with water and then with alcohol. The salt was recrystallized from water or methanol and formed white flakes, melting point

200 ⁰ C. -27-

109883/198 3

Example 16

A solution of 3.4-0 5-trichlorophenyl isocyanate (5.9 g) in dry dioxane (25 ml) was treated dropwise with stirring with a solution of diethylamine (1.96 g) in dioxane (10 ml). A crystalline solid separated and was collected after 30 minutes. This product (6g) of 1- (3,4,5-Triohlorphenyl) -3.3-diäthylharnstoff was recrystallized from alcohol and formed white flakes, mp 15O ⁰ C. It (2.7 g) was added to guanidine, prepared from the hydrochloride (0, 95 g) were added and the mixture was heated to 145 ° C., with a violent effervescence due to the escape of diethylamine. The mixture was kept at HO ⁰ G for 45 minutes, then cooled and extracted with dilute, aqueous isethionic acid, a residue of unchanged urea remained. After cooling the acid extract, 1-amidino-3- (3 · 4 ·· 5-trichlorophenyl) urea isethionate deposited, which after recrystallization from methanol showed white flakes, melting point 20O ⁰ C, the product in every respect with that of Example I5 was identical.

Example 17

2-Bromo-6-fluoro-4-nitroaniline, melting point 136 ^° C. (10.3 g) in glacial acetic acid (100 ml) was diazotized by a solution of sodium nitrite (3.29 g) in concentrated sulfuric acid (25 ml). The diazonium solution was stirred into a solution of copper (I) chloride (4.33 g) in concentrated

-28- 1 09883/1983

Hydrochloric acid (50 ml) was added. A precipitate of 3-bromo-4-chloro-5-fluoronitrobenzene (9 »3 g) was formed and purified by recrystallization from alcohol to give fawn needles (7 g), melting point 64 ° C. After reduction of the nitro compound using iron and water, 3-bromo-4-chloro-5-fluoroaniline, melting point 72 ° C. after recrystallization from cyclohexane _{or the like, was obtained}

3-Bromo-4-chloro-5-fluoroaniline (3.36 g), dicyandiamide (3.78 g) W and 4N hydrochloric acid (11.25 ml) were heated to reflux for 30 minutes. Crystals of 1- (3-bromo-4-chloro-5-fluorophenyl) biguanide hydrochloride separated while cooling. The salt was collected and washed sequentially with water and ether. Recrystallization from water gave white needles (3.9 g), melting point 246 to 247 ° C. The corresponding base gave white prisms from alcohol, melting point 195 ° C. A solution of this base (3.7 g) in a normal aqueous solution A "thansulfonsäure (37 ml) was added 2 fc hours at 9O ⁰ C. After about I5 minutes, 1-amidino-3- began (3-bfom-4-chloro-5-fluorophenyl) -harnstoffäthansulfonat separate. The salt was collected and washed successively with water and alcohol? melting point 241.5 C "by recrystallization from methanol gave white needles of -umgeändertem melting point, the base received one, crystallized from Xthylacetat-benzene as white flakes or from toluene as white prism-melting point 162 ⁰ C,

109883/1983 ~ ²⁹ "

Example 18

A suspension of thiophosgene (3 »8 ml) in water (35 ml) was stirred while a solution of 3.4 <> 5-trichloroaniline (7 * 37 g) and in chloroform (40 ml) was added dropwise. After stirring for 30 minutes, the chloroform layer was separated, dried (CaCl ₂ ) and distilled: boiling point 186 to 188 ° / 25 mm. The distillate (6.5 g) of 3,405-Trichlorphenylisothiocyanat solidified and was (40 to 6O ⁰ C boiling point) crystallized from light petroleum to give a white Nadelnj melting point of 68 ⁰ C.

Guanidine thiocyanate (6.62 g) and 3.40 5-trichlorophenyl isothiocyanate (7 »1 g) were added successively to a solution of sodium (0.9 g) in acetone (25 ml). The resulting solution was kept at 40 ° C. for 30 minutes and then poured into water «. The solid, which separated, crude 1-amidino-3- (3e4e5-trichlorophenyl) thiourea was collected and crystallized from aqueous alcohol \ melting point 178-179 ° 0 (3.4 g).

A solution of this thiourea (4 »6 g) in methanol (80 ml) and methyl iodide (2 ml) was heated at reflux for 30 minutes and then evaporated to dryness The residual resin was heated with aqueous sodium hydroxide _f and the solid thus obtained was recrystallized from Methanol crystallized out to give white needles (4g) of

1-Amidino-3- (3.4.5-tri ohlophenyl) -2-methyliso thiourine- 109883/1983 -50-

substance, melting point 189 ⁰ O.

This substance (0.4 g) was converted to hydrogen peroxide (4 ml 100 YoIo) added. After 24 hours the solid became collected and dissolved in boiling water. After the addition of alkali, crude 1-alaidino-3- (3.4 < > 5 - trichlorophenyl) urea, which after recrystallization in every respect was identical to the product of Example 2

Example 19

2T chloro-6-fluoro-4-nitroaniline (4.76 g) was diazotized in glacial acetic acid-sulfuric acid solution and then disintegrated by means of copper (I) chloride according to the method described in Example 17. The oily product was separated off with iter, over sodium sulfate dried and distilled. 3e4-Diohlor-5-fluoronitrobenzene was ^{collected at 128 to 132 0} C (25 Torr), (2.75 g) n | ⁵ 1.5660.

This nitro compound was reduced by means of iron and water. The product 3o4 ~ ^{I) icIllor} ~ 5 ~ ^{fluoroaniline} was extracted with ether and recrystallized from cyclohexane. It formed fawn Prismennadelnj melting point of 71 ⁰ C

3.4-dichloro-5-fluoroaniline (1.8 g), dicyandiamide (1.68 g) and 4N hydrochloric acid (5 ml) were heated to reflux for 30 minutes. The hot solution was filtered free of traces of contamination and, after cooling, yielded whitish needles. These were collected (2.5 g) and washed with water. Recrystallization from water (charcoal) yielded 109883/1983 -51-

White, silky needles of 1- (3.4-Diohlor-5-fluorophenyl) -biguanide hydrochloride, melting point 239 to 24-O ⁰ C. The corresponding base, crystallized from aqueous alcohol, was present as white flakes, melting point 187 ° C.

A solution of the Biguanidbase (1.3 g) in hot, normal aqueous A'thansulfonsäure (13 ml) layered white Kadeln of 1-amidino-3- (3,4-di chloro-5-fluorophenyl) -harnstoffäthansulfonat, melting point 24O ⁰ C. while the melting point was not increased duroh recrystallization from methanol · the corresponding base was recrystallized from ethyl acetate-benzene to afford white flakes, mp 178.5 ⁰ C.

Example 20

3-Trifluoromethyl-4,5-dichloroaniline (4.6 g), dicyandiamide (5.4 g) and 4N hydrochloric acid (15 ml) were heated to reflux. A solution soon ensued, but after a few minutes the very sparingly soluble product became Heating was continued on the steam bath for 30 minutes, after cooling, crude 1- (3-triefefluoromethyl-4,5-diochlorophenyl) biguanide hydrochloride was collected and washed with water. This salt (6 g) was recrystallized from water and formed white flakes, melting point 255 C. The corresponding base, crystallized from aqueous alcohol, was present as white prisms, melting point 174 ^° C.

109883/1983 ~ ³² ~

A solution of the base (2 g) in hot, normally aqueous ethanesulphonic acid (20 ml) deposited white prisms of 1-amidino-3- (3-trifluoromethyl-4 or 5-cLi chlorophenyl) urea ethanesulphonate, melting point 24.1 ⁰ C, no improvement after recrystallization from methanol.

Claim ι

-33-109883 / 1983

Claims (1)

Claims ί or its acid addition salt, in which Ί? is a halogen or a trihalomethyl substituent, Y ^ "is a cyano or a halogen substituent and Y ^ is a halogen substituent. 2. Amidinourea of the lormel NH.CO.NH.C NH NH or its acid addition room, in which Y is a halogen substituent, Y ^ is a cyano or a halogen substituent and Y ^ is a halogen substituent. 3. Amidinourea of the formula 10988Ci / 1981 -3-l - .NH
IiH.GO.NH.O ' or its acid addition salt, in which Y is an irihalomethyl substituent, Y is a cyano or a halogen substituent and Y ^ is a halogen substituent. 4o amidinourea or its acid addition salt according to Claim 1 or 3 characterized in that that the trihalomethyl substituent is trifluoromethyl. 5 ο amidinourea or its acid addition salt according to one of claims 1 to 4> characterized in that at least one of the halogen substituents Is chlorine. 6 «amidinourea or its acid addition salt according to one of claims 1 to 5, characterized in that at least one of the halogen substituents Bromine or fluorine is " 7. 1-Amidino-3- (3.4.5-trichlorophenyl) urea. 8 ₀ 1-amidino-3- (3.4.5-tribromophenyl) urea. 9 3 1-amidino-3- (3- »5-dichloro-4-cyanophenyl) urea <,
1 o. L-Amidino-3- (3 »5-dibromo-4-cülorFh.tiiiyl) -urea f. 1U9883 / 1983 -> r> - 11. 1-Amidino-3- (4- "bromo-3o5-diclilorp] ienyl) -haras toff. 12.1-Amidino-3- (5- "bromo-4o5-dichlorophenyl) urea. 13 x 1-Amidino-3- (3 x 5-dibromo-4-oyanophenyl) urea. 14β 1-Amidino-3- (3- "bromo-4-chloro-5-fluorophenyl) urea» 15. 1-Amidino-3- (4 β 5-dichloro-3-trifluoromethylphenyl) - urea· 16. Acid addition salt of an amidinoureas according to one of claims 7 to 15. 17c ethanesulfonic acid addition salt of an amidinourea according to any one of claims 7 to 15. 18. Isäthionsäureadditionsgtlz an amidine urea according to one of claims 7 to 15 < > 19. 1-Amidino-3- (3.4.5-trichlorophenyl) -ureaethane- sulfonato 20. 1-Amidino-3- (3 x 4.5-trichlorophenyl) urea isethionate. 21. A method for the preparation of an amidine urea or its acid addition salt according to any one of claims 1 Ms 2u, characterized in that one a biguanide of the formula / > - 9 8th NH .CNH.
Il 0
\ , NH : ι NH Υ * - 1 O 83 / 198 3 ^s NH Υ * " ν > - -36- • ζ λ C. wherein Y, Y and X ^{J are} those as defined in one of claims 1 to 20, reacted with an excess of nitrous acid or with a hydrolyzing agent and then optionally converted the product to its base or to a salt of another acid 22. The method according to claim 21, characterized in that that the hydrolyzing agent is a strong, aqueous acid " 23 ο Method according to claim 22, characterized in that the strong, aqueous acid is ethanesulphonic acid, isethionic _{acid s} methanesulphonic acid or hydrochloric acid ο Method according to one of Claims 21 to 23, characterized in that the biguanide is L · 1- (3o4 «5-T3? Chlorophenyl) biguanide _e 25 »Process for the preparation of an amidine larnea or its acid addition salt according to any one of claims 1 to 20, characterized in that the S-X-G group of a compound of the formula _Y 5 1 0 9 Ii B 3/1 9 8 3 _ _{? 7} _ wherein X is an alkyl or aralkyl group and Y, Y ^ and Y ^ can have the meanings defined in claims 1 to 20, selectively oxidized and then optionally converted the product into one of its acid addition salts 26. The method according to claim 25, characterized in that the oxidation using is carried out by hydrogen peroxide » 27. The method according to any one of claims 25 and 26, characterized in that in the starting compound Y, Y and Y ^ total chlorine substituents are, 28 »Process for the production of an amidine urea or its acid addition salt according to any one of claims 1 to 20, characterized in that a guanidine with a reactive derivative of a subst. Phenylcarbamic acid of the formula OH Ϊ , Y and Ί? who have defii.iurUm iiedoubungen in claims 1 to 20, umyefczt and «lanach gögeberion- ■. ,. ·> Ά '\ Λ , r.j'liikt, jri eiii-'ü ntün-ir;> aurwlii i Li -.> Nn3til : .e umu.xeit, iOOOBJ / i <i Π 3., .. ,. 8AD 29. The method according to claim 28, characterized in that that the derivative used is an alkyl ester of the acid » 3Oo method according to claim 28 characterized that the derivative is a Ιϊ, ϊί-dialkylamide of Acid is. 31 ο method according to one of claims 29 and 30, characterized in that used in the Derivative the alkyl groups are methyl or ethyl «, 32 ο Method according to one of claims 28 to 31, characterized in that the guanidine used in IOrm of its base. 33 ο method according to one of claims 28 to 32, characterized in that the used Derivative a derivative of 3,0405-irichlorophenylcarbamic acid is" 34. A process for the preparation of an amidine urea or its acid addition salt according to any one of claims 1 to 20, characterized in that α in aniline of the formula BAD OR wherein Y, Y and T ^ are as defined in claims 1-20 Have meanings with a dicyandiamide in the presence of at least two times the equivalent amount a strong, aqueous acid, with regard to the dicyandiamide, and optionally converts the product into it Base or converted to a salt of another acid 35 · The method according to claim 34 characterized that the strong, aqueous acid used is ethanesulfonic acid, methanesulfonic acid, hydrochloric acid or isethionic acid " 36 · Method according to one of Claims 34 and 35, characterized in that the aniline 3.4.5 is trichloroaniline. 37c Process for the preparation of an amidine urea or one of its acid addition salts according to one of the claims 1 to 20, characterized in that a compound of the formula -40- 109883/1983 R.
NH.CO. Έ = G wherein Y, Y and Y ^ are those in any one of claims 1 to 20 have a defined meaning, R is the amino group and R is an alkylthio group having 1 to 4 carbon atoms, the Subjects to ammonolysis and then, if necessary, the Pro ™ converted into one of its acid addition salts 38ο method according to claim 37 characterized that the alkylthio group is the methylthio group. 39 «Method according to one of claims 37 and 38, characterized in that used in the Compound · Y, Y and Y ^ total chlorine substituents are. 40. Process for the preparation of an amidinourea or one of its acid addition salts according to one of claims 1 to 20, characterized in that one is a 1-N-substituted amidinourea of the formula 109883/1983 N- GO.R co. NH. σ- ■■.: ■■: ■■ .- ■ - ■ ' NH-A or one of its acid addition salts, in which Y, Y ^ and Y ^ have the meaning defined in one of claims 1 to 20, R is a hydrogen atom or an alkyl or Aryl group and Ä a hydrogen atom or the CO.B group where B is an aryl group, with a hydrolyzing agent converts and then optionally the product obtained in the base, one of its acid addition salts or converted into a salt of another acid, depending on its suitability » 41. The method according to claim 40, characterized by that the group A is a hydrogen atom and the group R is also a hydrogen atom or an alkyl group is. 42ο Method according to claim 41 d a d u r ch characterized in that the hydrolyzing agent is a Mineral acid used 43. The method according to claim 40 characterized in that b that the group H is a phenyl group and the group A is the UO, B group, in which B is just ao is a phenyl group, -42- 109883/1983 44o method according to one of claims 40 »41 and 43, characterized in that the hydrolyzing agent used is an aqueous solution of a Alkali metal hydroxide is " 45 ο Method according to one of claims 40 to 44, characterized in that the Τ-ΪΙ-substo-amidinourea or its acid addition salt is a 1-N-su "bst ₀ amidino-3- (3» 4.5-trichlorophenyl) urea or its acid addition salt » 46ο Amidinourea or one of its acid addition salts according to one of claims 1 to 20, provided that it is produced by a method according to one of claims 21 to 45 is. 47 «Pharmaceutical preparation thereby, indicates that it is an amidinourea or one of its acid addition salts, according to one of the claims 1 to 20 together with a suitable carrier.,. 48ο Preparation according to claim 47, characterized in that that the carrier is a pest, 49, preparation according to claim 47, characterized in that that the carrier is a liquid ^iBt · 109883/1983 "* ⁴³ ~ 50. Preparation according to one of claims 47 to 49, characterized in that it is in the form of dosage units is available <> 51. Tablet, characterized by the content of an amidinoureas or one of its acid addition salts, according to one of claims 1 to 20 and an acceptable carrier " 52. capsule characterized by the content of an amidinourea or one of its acid addition salts, according to any one of claims 1 to 20 and an acceptable carrier. 53. A solution suitable for oral administration, characterized by the content of an amidinourea or one of its acid addition salts, according to one of claims 1 to 20, in a liquid carrier _{or the like} 54. A suspension suitable for oral administration, characterized by the content of an amidinourea or one of its acid addition salts, according to any one of claims 1 to 20, in a liquid carrier 55 · Sterile injectable liquid suitable for parenteral administration, characterized by the content of an amidinourea or one of its drinks ^! addition salts, according to any one of claims 1 to 20, in a liquid carrier * 56. Preparation according to one of claims 47 to 55, characterized in that the amidino · urea or its acid addition salt 1-amidino -;? - (3 »4ο5-trichlorophenyl) urea or one of its acid addition salts. "57. Tablet with the content of a 1-amidino-3- (3.4c5-tri- chlorophenyl) urea or one of its acid addition salts and a suitable carrier © 58o process for the manufacture of a pharmaceutical preparation, according to one of claims 47 to 57, characterized in that the Amidinourea or its acid addition salt mixed with a suitable carrier. 59β Method of making a tablet of 1-amidino-3- (3.4.5-trichlorophenyl) urea or one of its acid addition salts, characterized in that that the compound and a suitable carrier are wet granulated and then the dried granules compressed into a tablet. 60. Procedure essentially as described above, 109883/1983 -45- for the production of an amidinourea or its acid addition salt, according to one of claims 1 to 20, with particular reference to Examples 1 to 4 and 9 to 18 » 61 ο Pharmaceutical preparation essentially as above described, characterized by an amidinourea or one of your acid addition salts, according to one of claims 1 to 20 and a suitable carrier for this with particular reference to the examples 5 to 8. 62. The method essentially as described above for the production of a pharmaceutical preparation, characterized in that it has a Amidinourea or one of its acid addition salts according to one of Claims 1 to 20, and one suitable therefor Contains carrier, with particular reference to Examples 5 to 8, 63 “Biguanide of the formula NH NH. CNfU G NH HH ₂ or one of its acid addition salts, where X ^{J is} a halogen 10980 3/1983 ~ ⁴⁶ "" ORfGlNAi INSPECTED or a trihalomethyl substituent, Y is a cyano or halo substituent and Y ^ is a halogen substituent. 64. 1- (3.4.5-Trichlorophenyl) biguanide or one of its Acid addition salts. INSPECTED 9 ^ 03/1903