DE1445597A1 - New amidines - Google Patents

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Today for the printing of 'the disclosure p-specific application documents - US. Sign: 20 148-BR / ro -

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND)

Case 5133 / I-3.
Germany

New documents

New amidines

The invention relates to N- [5-nitrothiazolyl- (2)! - amidines the general formula

where R is a hydrogen atom or an alkyl radical, R and R for hydrogen atoms, alkyl radicals or optionally by lower alkoxy groups, methylenedioxy groups,

. lower alkyl groups, nitro groups, amino groups, halogen atoms ^af0B ^ '■; 809812/1300

or trifluofmethyl groups substituted phenyl or Phenylalkyl radicals or together for an alkylene radical with

4 to 7 chain links or an oxaalkylene radical

5 to 6 chain links and R _x denotes an alkyl radical or, in particular, a hydrogen atom, and their salts.

Alkyl radicals are primarily lower alkyl radicals, e.g. methyl, ethyl, propyl, isopropyl, straight or branched ^ Butyl, pentyl, hexyl or heptyl radicals connected in any position.

Phenylalkyl radicals are, in particular, phenyl lower alkyl radicals, such as benzyl, phenylethyl, phenylpropyl or phenylbutyl radicals. Lower alkoxy groups are e.g. Methoxy, ethoxy, propoxy or butoxy groups. Halogen atoms are in particular fluorine, chlorine or bromine.

Alkylenreste.mit. 4 to 7 chain links and oxp

Methylene radicals with .5 to β chain members are _: in particular butylene- (1,4) ~, butylene- (l _f 5) -i hexylene ^ -UiS) - * hexylene- (1,6) -, (2 # 5) -, Heptylene- (1,7) -, heptylene '- (2,7) -i Hepfeylene-6) -, 3-OxApentylen- (1,5) - or 3-Oxahtxyltn- (1,6) - radicals . The amino group of the formula

is in particular a mono- or di-lower alkyl! amino groups like a methylamino, dimethylaminp, ethylamino or

¹ ORIGINAL BATHROOM

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Diethylan? Group, a phenyl-lower alkyl-amino group, such as a phenyl-methylamino group, or a pyrrolidino, Piperidino or morpholino group.

The process products have valuable pharmacological, especially anti-parasitic properties. In experiments on hamsters, for example, they show chickens and mice have an effect against protozoa and worms, e.g. Amebas and Coccidules, as well as Schistosomes. You can accordingly be used as anti-parasitic agents. The new compounds are also valuable intermediates for the production of other useful substances.

The products of the process are known compounds Same effect as the following experiments demonstrate" .

Hamsters are 'infected' in the liver with a virulent amoeba culture in such a way that within two to five days an amoeba abscess, which occupies large parts of the liver, develops. »The test substance was administered twice. da; s first time 24 hours after infection, second time # 8. Hours after infection. ¹ On the 5th day after infection, the animals were dissected. That was the presence of abscesses ^; Effect criterion. The dose was determined which cured 50% of the animals (BD ^ ₀ ), and the LDc ₀ (dose which kills 50% of the animals) aaa of the mouse was determined. In this experimental set-up, N- [5-sitrothiazolyl- (2)] - N ', N ¹ -dimethylformamidine has a therapeutic index when administered peporally

q: ^ld cq) of 1: 8, while the emetine when administered in this way is only about 1: 4 to 1: 6 and that of chloroquine when administered orally is even only 1: <2. ..

Particularly noteworthy are the compounds of the formula

O ₂ IMl> -Ν = α-Ν

wherein R is hydrogen or a lower alkyl radical and R, and Rp represent hydrogen or lower alkyl radicals or R, and Rg together with the nitrogen atom a pyrrolidino, Form piperidino oder.Morpholino radical, and in particular the [N- (5-nitro-thiazolyl-2) -N ', N'-dimethylformamidine.

The new compounds are obtained by known methods, for example if you either in a manner known per se

a) a compound of the general formula

wherein R and R, 'have the meanings given and X has a esterified or etherified hydroxyl group or a mercapto group means with a compound of the formula

Ν- ¹

14455S7

wherein H ₁ and R _{2 have} the meanings given, converts

b) a compound of the general formula

¹ V- *

where R, <ti # has the given meaning, with a Mitril of the formula R-CV, with a thioarid of the formula

B ₂ .

or with tinem enteprtchencien thioiminoMther, with one Bnolttther (Iminoether), Enolester (Im ^ noeeter) or Aoetal • a carboxylic acid amideB of the formula

0 HI ₁

or with a salt of these compounds, or with an addition product of a Lewis acid, such as boron trifluoride _f with a carboxamide of the formula above, where R, R, and R ₂ .dl * have the meanings given, umietitol or c) a compound of the formula

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wherein. R, R ₁ , H ₂ and R, the meanings given, are nitrided

and, if desired, compounds obtained in which H « i *

and / or H, hydrogen atoms mean with reactive Esters of alcohols of the formula R, OH, where A has the meanings given, with the exception of a hydrogen atom, converts and / or in compounds obtained tertiary amino groups -N ^ _B by Uwset ** n with a primary amin of the formula -NHR ₁ biw. with aaaonia converts into secondary or primary amino groups and / οφΐΓ obtained free bases in their salts or obtained strings in the free bases. - _: - ■

An etherified hydroxy group is 2.B. eiiü through, an aliphatic or araliphatic * O & tenw * se «** toffrest« substituted hydroxyl groups such as an alkoxy group, e.g., a lower alkoxy group such as an ethoxy group or methoxy group, or an optionally substituted Aralkxy group such as benzyloxy group.

_t Esterified hydroxy groups, for example with the eleventh carboxylic acid, for example an aliphatic carboxylic acid such as ChIorameisensäure or Chlorcarbonylameisensäure, or

'i SAD ORiG ¹ NAL

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~ ⁷ ~ '1445G97

an aromatic carboxylic acid, such as a benzoic acid, esterified hydroxyl groups or, preferably, hydroxyl groups esterified with a strong inorganic or organic acid, such as with a hydrohalic acid, for example chlorine ^{; ": 5} baths hydrobromic acid, a sulfonic acid such as an arylsulfonic acid, wie'Benzol- or toluenesulfonic acid, chlorosulfonic acid or Chlorsulfinsäure, or halogehierten * acid of phosphorus, such as diChlorphosphoriger acid, or Dichlorpftoisphorsäure tetrachloride phosphoric acid, or gegebeheiifälls corresponding bromine compounds i esterified hydroxyl groups..

A mercapto group is primarily a free or etherified mercapto group, e.g. one of those mentioned above etherified hydroxy groups corresponding to etherified Mercapto group. .

As enol ethers in particular those in imprint come as above for the etherified hydroxyl groups described, contain aliphatic or aromatic hydrocarbon radicals. The enol esters are in particular those in question that have an acid residue one of the above for the esterified hydroxyl groups contain acids, such as imide chlorides or amine chlorides. As acetals particularly those in question are those in which the. Alcohol component is a lower alkanol or alkandiql, such as

e.g., dimethylformamide dimethyl acetal.

'I I

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The nitration takes place in a manner known per se, of course under conditions in which the amidine moiety is not attacked, as by reaction with the mixed anhydride of nitric acid and a carboxylic acid such as acetic acid.

The end products obtained can be converted into one another. For example, compounds in which the amino group -N τ is primary or secondary can be alkylated. The alkylation is carried out in a manner known per se, for example by reacting with reactive esters of alcohols, such as lower alkanols or aralkanols, such as lower alkyl or aralkyl halide sulfates, or corresponding esters of sulfonic acids such as methyl, ethyl, n- ^: or i-propyl-. or benzyl chloride, bromide. or iodide, dimethyl or diethyl sulfate, methane, ethane or p-toluenesulfonic acid methyl

or ethyl ester.

i <

In compounds obtained in which the amino group -N ^ _{R is} tertiary, this can be converted into a secondary acid or primary amino group. This conversion takes place in the usual way, for example by reaction with ammonia or a primary amine.

The reactions mentioned are carried out in a manner known per se, in the presence or absence of diluents and / or condensation agents, at low, ordinary or elevated temperature in the open or in the closed Vessel carried out under pressure.

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Depending on the process conditions and starting materials, the end products are obtained in free form or in the form of their salts also included in the invention. For example, basic, neutral, acidic or mixed salts, optionally also hemi-, mono-, sesqui- or polyhydrates thereof, can be obtained. The salts the end products can be converted into the free bases in a manner known per se, e.g. with alkalis or ion exchangers will. Of the latter, by reaction with organic or inorganic acids, in particular those which are suitable for the formation of therapeutically useful salts win salts. As such acids are for example: hydrohalic acids, Sulfuric acids, phosphoric acids, nitric acid, perchloric acid; aliphatic, alicyclic, aromatic or heterocj-r cyclic carboxylic or sulfonic acids, such as formic, vinegar, propionic, amber, glycol, milk, apple, wine, Citric, ascorbic, maleic, hydroxymaleic or pyruvic acid; Phenylacetic, benzoic, p-aminobenzoic, anthranil, p-hydroxy-benzoic, salicylic or p-aminosalicylic acid, Embona acid, methanesulfonic, ethanesulfonic, Hydroxyethane sulfonic acid, ethylene sulfonic acid; Halobenzene

sulfone - ** toluenesulfonic, naphthalenesulfonic acids or suI

■■ ■ ■ i

fani! acid; Methionine, tryptophan, lysine or arginine.

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These or other salts of the new compounds, such as, B * the picrates, can also be used to purify the obtained Bases serve by converting the bases into salts, separates these and in turn frees the bases from the salts. Due to the close relationship between the bases in free form and in the form of their salts are in advance and in the following under the free bases analogously and according to purpose possibly also to understand the corresponding salts.

In procedures a) and b), the enol ethers and enol esters of the carboxamides, or the Form condensation products with Lewis acids under the reaction conditions. You can e.g. the acid amide in question with the corresponding amine in the presence of an acid

implement halides or a Lewis acid.

For the reactions according to the invention, those starting materials are mainly used which are those above give preferred compounds mentioned.

The starting materials are known or can be used according to methods known per se can be obtained.

The new compounds can be used as medicaments, for example in the form pharmazeutisoher preparations find use ^v, welohe them or their salts in Miaohung with an example for enteral or paronterale application suitable pharmaceutical organic or inorganic, include solid odor liquid carrier material. For the formation of the same

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such substances come into question with the new compounds do not react, such as water, gelatin, lactose, starch, Stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohol, rubber, propylene glycol, polyalkylene glycols, Petroleum jelly, cholesterol, or other known excipients. The pharmaceutical preparations can be, for example, as Tablets, dragees, capsules or in liquid form as solutions, suspensions or emulsions. Possibly are they sterilized and / or contain auxiliary materials, such as preservatives, stabilizers, wetting agents or emulsifiers, Solubilizers or salts to change the osmotic pressure or buffers. You can have others too Contain therapeutically valuable substances. The pharmaceutical Preparations are obtained using the usual methods.

The new compounds can also be used in animal

ι ·

medicine, e.g. in one of the forms mentioned above or in the form of feed or additives for animal feed be used. For example, the usual diluents and thinners or feed are used.

The invention is described in more detail in the following examples. The temperatures are given in degrees Celsius *

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Example 1: ι.

A solution of 10 g of 2-amino-5-nitro-thiazole and 12 g of p-toluenesulfonyl chloride in 100 cm ^ dimethylformamide is heated to 140 for 2 hours. After cooling, water is added and the precipitate which has separated out is recrystallized from alcohol. N- [5-nitro-thiazolyl-2] -N ¹ , N ¹ -dimethylformamidine of the formula is obtained

in yellow crystals from F. I56 - 157 °. ' ^::

The hydrochloride of this compound, · produced with the calculated amount of alcoholic -Chlorwasserstoffsäure, melts at I88 - 190 ^0;

! 'Example 2:

In a solution of 10 g of 2-amino-5-nitro-thiazole

in 75 g of N-methyl-formanilide one passes for two hours a phosgene with stirring at room temperature. That

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The reaction mixture is then poured into 500 cnr ice water. A precipitate separates out, which is filtered off, dried and, for purification, from Chloraform petroleum ether recrystallized. The N- [5-nitro-thiazolyl- (Hjl-N'-njethyl-N'-phenyl-formamidine) is obtained the formula

Hi = OH-F

in yellow crystals with a temperature of 164 - 165 °,

Example 3 ^:

12 g of p-toluenesulfonyl chloride and 10 g of 2-amino-4-methyl-5-nitrothiazole are added to 100 cc of dimethylformamide and the mixture is heated to 140 ° for 2 hours. The dimethylformamide is then distilled off in vacuo. The residue; water is added and the precipitate which has separated out is filtered off. After recrystallization from methanol, the N- [4-methyl-5-nitro-thiazolyl- (2)] -N ¹ , N ¹ -dimethylformamidine of the formula melts

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at 110 - 112 °. ·· ·· '■

In an analogous manner, N- [5-nitrothlazolyl- ^ l-NSN'-diethylformamidine and N- [5-nitrothiazolyl- (2)} - N ^r , N'-dimethyl-acetamidine (P. 96 ° ) obtain. *

"Example 4: ■

9 S dimethylformamide dimethylacetal is added to a solution of 10 g of 2-amino-4-methyl-5-nitrothiazole in 75 cm ^ ^{1 of benzene and the mixture is refluxed for 2 hours.} The solution is then evaporated in vacuo. The residue is recrystallized from methanol. This gives N- [4-methyl-5-nitro-thiazolyl- (2)] - N ¹ , K * -dimethylformamidine of the formula

CH,

I I

CH

in crystals from P. 110 - 112 °.

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Example ^:

^{10 g of N- [thiazolyl- (2) 3-N l} , N ^f -dimethylformamidine are introduced into a mixture of 50 cm of acetic anhydride and 10 g of nitric acid while stirring at 0 °, and the mixture is stirred at 0 ° for 1 hour. The reaction mixture is poured onto ice and made neutral by adding sodium hydroxide solution. The deposited precipitate is purified by recrystallization from alcohol. The N- [5-nitro-thiazolyl- (2)] - N ^l , N ^l dimethylformamidine of the formula is obtained

0 y

-N = OH-U

2 \ α / \

CH

in crystals from P. 156 - 157 °.

The N- [thiazolyl- (2)] - N ^! , N ^l -dimethyl-formamidine can be prepared as follows:

10 g of 2-amino-thiazole are added to 18 g of dimethylformamide dimethylacetal and the mixture is heated to 50 ° for 2 hours. The excess dimethylformamide dimethylacetal is distilled off. A crystalline residue remains, which is dissolved in benzene and filtered through an aluminum oxide column. After the solvent has been distilled off, N- [thiazolyl- (2) JN ¹ , N ¹ -dimethylformamidine with a melting point of 35 ° -38 ° remains.

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Example 6

The new compounds can be used in the form of pharmaceutical preparations, the daily dose in humans being 75-30 ° ^m S. Administration can take place, for example, in the form of capsules which contain 25-100 mg of the active compound, especially N- [5-nitrothiazolyl- (2) IN ^ N'-dimethylformamidine.

As an additive to animal feed, e.g. poultry feed, the new compounds, in particular N- [5-nitrothiazolyl- (2)] - N ¹ , N ¹ -dimethylformamidine, can be mixed with cerelose, for example (content of active compound e.g. 0, 1-1 $, preferably 0.5 $) · This premix can then be added to the feed in the usual way, expediently in such a way that the content of nitrothiazolamidine derivative is approx. 0.001 $.

Example "7

Tablets containing 100 mg of N- [5-Nltrothiazolyl- (2)] - N ', N'-dimethylformamidine can e.g. be produced in the following composition:

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N- [5-nitrothiazolyl- (2)] - N ^l , N'-dimethylformamidine

Lactose wheat starch

Colloidal silica with hydrolyzed starch

Maranta starch stearic acid « . Talk

100.0 mg 90.0 mg 50.0 mg 15.0 mg 25.0 mg 6.0 mg 14.0 mg 300.0 mg
SSSBBSS3

Manufacturing:

N- [5-Nitrothiazolyl- (2)] - N ', N ¹ -dimethylformamidine is mixed homogeneously with Milohzuoker and wheat starch and forced through a sieve with a width of 0.5 mm. This powder mixture is moistened with water and kneaded until it becomes plastic, while colloidal silica with hydrolyzed starch is added in portions

Mass originated 1st. This is through a sieve of 3 mm Masohen-wide soles, dried at 45 ° and covered with soles driven through a sieve of 1.5 mm mesh size. The granules obtained in this way are maranta starch, Stearic acid and talc added in finely sieved form. This mixture is made into tablets of ordinary wheat 300 mg fluted and pressed 9 rom diameter.

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Claims (2)

Claims Compounds of the general formula. where R is a hydrogen atom or an alkyl radical, R, and Rg for hydrogen atoms, alkyl radicals or optionally by lower alkoxy groups, methylenedioxy groups, lower alkyl groups, nitro groups, amino groups, halogen atoms or trifluoromethyl groups substituted phenyl or Phenylalkyl radicals or 'together for an alkylene radical with 4 to 7 chain links or a Qxaalkylenrest with 5 to Chain links are and R, an alkyl radical or a hydrogen atom means and its salts. 2.. N- (5-Nitro-thia2olyl-2> -N ^l _i N ^l -dimethylformamidine and its salts 3. Pharmaceutical preparations characterized by a content of one of the compounds named in claims 1 or 2. 8 0 9812/1300 New documents (Article 7, Paragraph 1, Paragraph 1, Sentence 3 of the amendment of September 4, 2019 ) 4. Animal feed characterized in that it contains one of the compounds mentioned in claims 1 or 2. 5 · Process for the preparation of compounds of the general formula R. where R is a hydrogen atom or an alkyl radical, R, and Rp for hydrogen atoms, alkyl radicals or optionally by lower alkoxy groups, methylenedioxy groups, lower alkyl groups, nitro groups, amino groups, halogen atoms or trifluoromethyl groups substituted phenyl or Phenylalkyl radicals or together for an alkylene radical with 4 to 7 chain links or an oxaalkylene radical with 5 Ms Chain links are and R-, an alkyl radical or a hydrogen atom means, and its salts, characterized in that iuan in a manner known per se either a) a compound of the general formula .809812 / 1300 -so- 1Λ45597. wherein R and R have the meanings given and X has a means esterified or etherified hydroxyl group or a mercapto group, with a compound of the formula HN wherein R, and R have the meanings given, converts or b) a compound of the general formula in which R, has the meaning given, with a nitrile of the formula R-CN, with a thioamide of the formula // RG \ or with a corresponding thioimino ether, with a Enol ethers (imino ethers), enol esters (imino esters) or acetal of a carboxamide of the formula RG R ₁ IT 809812/1300 or with a salt of these compounds, or with an addition product of a Lewis acid such as boron trifluoride with a carboxamide of the formula above, where R, R, and R have the meanings given, or c) a compound of the formula wherein R, R ,, R _p and R have the meanings given, nitrated and, if desired, compounds obtained in which Rp and / or R are hydrogen atoms, with reactive esters of alcohols of the formula R ^ OH, where R _{1 has} the meanings given, with the exception of a hydrogen atom, and / or in compounds obtained ter- / ^R l
tiary amino groups -N by reacting with a primary ₂
Amine of the formula -NHR, or converted with ammonia into secondary or primary amino groups and / or obtained free bases converted into their salts or obtained salts converted into the free bases. 809812/1300