DE1918071A1 - 2 - [(4,5,5-Trimethyl-1,3-oxazolidinylidene- (2)) amino] -5-nitro-thiazole and process for its preparation - Google Patents

Description

Oasis 5/410
10 / zö

Dr. Karl TIiomae Gntel., Biberach an der Riss

2- [(4,5,5-trimethyl-1,3-o: ca3olidinylidene- (2)) amino] - ^ - nitrotliiasol and terfolirene for its preparation.

(Zucat patent for the German federal patent (German

Patent application P 18 00 074.3).

The invention "relates to the 2 - [(4,?» 5-ü.rinG thyl-1,3-oxo.zoliäinyliden- (2)) amino] -5-nitrotliiazole of Pomel I.

x_

• ΟΧ

¹ OH

v / elches zv ^ ar under the general Pornel I of the main patent (Patent application P 1G 00 074.3) falls there, however is not expressly "described,

009842/1889

as well as its physiologically compatible acid addition salts with inorganic and organic acids and processes for their preparation.

The new compound can be according to the invention according to the following Manufacturing process:

1.) Implementation of substituted 2-methylenamino-5-nitro-thiazoles of the general formula II

II,

in which the radicals R ₁ and Rg, which can be the same or different, denote halogen atoms or radicals of the formula -SR ^, in which R * represents an alkyl, aralkyl or alkenyl group, the radicals R ₁ and R ₂ also together can be a bismercaptoalkylene group with an alkylene radical with 1,2 or 3 carbon atoms, with 2-amino-3-methyl-butanol- (3) »optionally in the presence of a heavy metal oxide which forms sparingly soluble complexes with mercaptans, for example in the presence of lead oxide (PbO).

The reaction takes place at room temperature or at elevated temperatures, expediently in the presence of a solvent, but it can also be carried out without a solvent. For example, water-containing or water-free aliphatic alcohols or ketones are suitable as solvents. Compounds of the general formula II in which one of the radicals or the two radicals R ₁ and Rg represent halogen atoms are preferably reacted in anhydrous ethers, for example in dioxane. The required temperature depends on the reactivity of the radicals R ₁ and R ₂ and is preferably

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se between 0 and 100 ° C. The addition of heavy metal oxides, for example lead oxide, is particularly advantageous if the radicals R and / or R ₂ in the compounds of the formula II to be converted are radicals of low-volatility mercaptans.

2.) Reaction of 2-amino-5-nitrothiazole with a mercapto-4-, 5,5-trimethyl - ^ - oxazoline of the formula III

.N-

III, CH ₅ CH,

in which R * denotes an alkyl, aralkyl or alkenyl radical,

The reaction is expediently carried out in solvents with heating to temperatures "up to 100 C, be carried out without solvents.

Heating to temperatures "up to 100 ⁰ C, but it can also

3.) Nitration of 2- / C4,5,5-trimethyl-2-oxazolidinylidene) -amino7-thiazole. A mixture of concentrated sulfuric acid and nitric acid up to 70% is particularly suitable for nitrating this compound. The nitration is advantageously carried out at temperatures between ⁰ ° C. and room temperature.

The 2- / r4,5 »5-trimethyl-2-oxazolidinylidene) -amino7-5" -nitro-, thiazole can be converted into its acid addition salts with inorganic or organic acids in a manner known per se convict. Examples of acids are hydrochloric acid and hydrogen bromide acid, sulfuric acid or acetic acid.

The compounds of formula II used as starting materials, in which the radicals R ₁ and R ₂ be substituted mercapto indicate "can be in the following manner, for example, manufacturing

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place:

From 2-amino-5-nitro-thiazole with carbon disulfide in Presence of a base in a polar solvent, the corresponding salt of 2- (bismercapto-methylenamino) -5-nitrothiazole prepared, which then to a compound of formula II, optionally in stages, for example with alkyl, Aralkyl or alkenyl halides. The production of this starting substance is also in the German federal patent (German patent application P 16 95 911.8).

Compounds of the formula II in which one of the radicals R. or w Rr represents a halogen atom can be prepared from 2- / TBisalkylnercaptomethylene) -amino7-5-nitro-thiazoles by the action of a halogen with heating in the presence of a halogenated solvent, such as, for example Carbon tetrachloride obtained. After the reaction has ended, the solvent is removed and the mostly oily residue is crystallized, preferably with ether. If the second radical R- or Rp in the compound of formula II obtained in this way is also to be replaced by a halogen atom, this is done under the action of a stronger halogenating agent, for example a phosphorus pentahalide, at elevated temperatures (see also German Federal Patent / German Patent application P 16 95 910.7 /).

The 2-amino-3-methyl-butanol- (3) is known from the literature and can after ¥. Pfleiderer and H. Zondler, Chem .. .Ber. 99, page 3014 (1966).

The compounds of the general formula III can, starting from 2-amino-3-methyl-butanol- (3), analogously to the process of

/ 5 009842/1889

H.C. Clapp, Bisset and long, υ.Heterocycl. Chen. 5_, page 107 - T08 (1968) and U.S. U.S. Patent 2,856,227.

The 2-ΖΓ4,5,5, -trimethyl-2-oxazolidinylidene) amino / thiazole, which is used as the starting compound for process 3, can be prepared according to process 2 by reacting 2-aminothiazole with 2-methylmercapto-4,5 , 5-trimethyl- ^A 2 ~ oxazoline represent.

The never compound has valuable pharmacological properties. It has an antimicrobial effect and is particularly effective against trichomonads.

The antitrichoiaonaden effect was determined in male KMRI mice checked which vrarden previously infected with Trichomonas fetus; A thioglycolate broth served as the nutrient medium for Trichomonas fetus with 10 $ horse serum and added antibiotics (500 IU penicillin / ml and 0.2 mg streptomycin / ml) at pH 7.0. The incubation period of Trichomonas fetus in this nutrient medium was 24 hours at 37 ° C.

From this solution, which was diluted in such a way that approx. 8 to 10 germs could be seen in the field of view of the microscope at 320-fold magnification, 0.5 ml each were administered ip to groups of 6 mice each. The infected animals received 50 mg / kg of active substance twice daily for 3 days, for the first time 2 hours after infection, orally. Eg the number of surviving animals was determined after an observation period of 28 days. Untreated control animals died after 4-5 days. It was found that with a dose of 50 ml / kg after oral application 6 out of 6 animals survived after 28 days.

The acute toxicity was determined in groups of 10 male ITMRI mice per dose. The mice had an average body weight of 18-20 g. It was found that the active substance is non-toxic, its LD is ₅₀

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^BATH

over 4 g / kg when administered orally.

The following examples are intended to explain the invention in more detail:

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Example 1

24.9 g (0.1 KdI) 2- (bismethylmercapto-methylenamino) -5-nitrothiazole are dissolved in 700 ml hot n-butanol and 10.3 g (0.1 mol) 2-amino-3-methyl- butanol- (3) added. The mixture is refluxed for 4 hours. After cooling, the Kriatalle are sucked off and recrystallized from ethanol. Melting point: 210 ⁰ C;
Yield: 17 g ($ 62 of theory).

Example 2

9.9 g (0.04 mol) of 2- (5-nitro-2-thlazolyaiiino) -1,3-cLithiacyclopentane and 13.5 g (0.06 mol) of lead oxide (PbO) are slurried in 500 ml of ethanol, 4 g (0.04 mol) of 2 ~ amino-3-methyl-butanol- (3) added and boiled with stirring and reflux for 3 hours. The approach is still hot from the resulting lead salt Sucked off 1,2-ethylene dithiol and evaporated the filtrate in a vacuum. The crude product is recrystallized several times from the ethanol.

Melting point: 218 ° C;
Yield: 4.1 g (40 % of theory)

Example 3

6.15 g (0.03 mol) 2- / CChlor-methylmereaptQ-methylene), - amino7 ~ 5-nitro-thiazole are dissolved in 30 ml anhydrous dioxane and 3 g (0.03 mol) 2-amino- 3-methyl-butanol- (3) was added dropwise. It is allowed to come to room temperature and stand for a further 5 hours. Finally, the solution is heated on the Viasser bath for another 1/2 hour. After evaporation, a dark brown Sehmier is obtained, which partially crystallizes on trituration with ethyl acetate. The crude product is recrystallized from ethanol.
Melting point: 217 ° C.

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Example 4

2- / rDichloromethylene) -amino7-5-nitro-thiazole is dissolved in an inert solvent, for example dioxane, and the “calculated amount of 2-amino-3-methyl-butanol- (3), dissolved in dioxane, is added dropwise while cooling with ice . Man melting point "can be 5 hours at room temperature and are not heated to 6O ° C evaporation gives a crude product which is recrystallized from ethanol:.. 217 ⁰ C

Example 5

1.6 g (0.01 mol) of 4,5,5-trimethyl-2-methylmercapto- ^ 2-oxazoline are mixed with 1.45 g (0.01 mol) of 2-amino-5-nitrothiazole in 20 ml of n- Butanol refluxed for 5 hours with stirring. The ■ reaction mixture is concentrated, the residue is filtered off with suction and recrystallized from ethanol.
Melting point: 218 ⁰ C.

Example 6

2.1 g (0.01 mol) of 2- / T4,5,5-trimethyl-1,3-oxazolidinylidene- (2)) ~ amino7-thiazole are dissolved in 20 ml of concentrated sulfuric acid and, while cooling, with ice / salt Mixture 1.03 g (0.011 mol) of 67 # nitric acid was added dropwise. The mixture is stirred for a further 1 hour while cooling and left to stand for about 5-6 hours at room temperature. The mixture is poured onto ice and neutralized with ammonia while cooling. The crude product is filtered off with suction, washed with water, dried and recrystallized from ethanol at 40 ⁰ G.
Melting point: 218 ⁰ G.

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Example 7

2- / Γ4,5,5-trimethyl-1,3-oxazolidinylidene- (2)) -amino7-5-nitrothiazole hydrochloride.

1.2 g of 2- / Γ4 »5,5-trimethyl-1,3-oxazolidinylidene- (2)) -amino7-5-nitrothiazole are dissolved in 60 ml of methylene chloride. An excess of dry hydrogen chloride is passed into the solution while cooling with ice and stirring. The solution is concentrated at 2O ⁰ C in vacuo, and the precipitated crystals filtered off with suction. The crude product is washed with warm methylene chloride. Melting point: 135 ^° C. (decomposition).

The compound of the formula I can be used for pharmaceutical purposes optionally in combination with other antibacterial, antiprotozootic and / or anthelmintic compounds incorporate into the usual pharmaceutical preparations. The single dose for adults is 20 - 4-00 mg, preferably 50-250 mg. The following examples describe the production of some pharmaceutical preparation forms.

2/1839

Example I.

Tablets with 100 mg 2- / C4,5,5-trimethyl-1,3-oxazolidinylidene- (2) 5 araino7-5-iitrothiazole

1 tablet contains:

2- / Γ4> 5,5-trimethyl-1,3-oxazolidinylidene

(2)) - amino7-5-nitrothiazole. 100.0 mg

Milk sugar ■ 50.0 mg

Potato starch 42.0 mg

Polyvinylpyrrolidone 6.0 mg

Cellulose microcrystalline 20.0 mg

Magnesium stearate 2.0 mg

220.0 mg

Production method;

The active substance is mixed with lactose and potato starch and granulated with a 12.5 mm $ strength by weight ethanolic solution of the polyvinylpyrrolidone through a sieve of mesh width 1.5, "dried again rubbed mm at 40 ⁰ G and through a sieve of mesh width 1.0. The granules obtained in this way are mixed with cellulose and magnesium stearate and pressed into tablets.

Tablet weight: 220.0 mg

Stamp: 9 mm

Example II

Dragfees 1 with 00 mg of 2- / Γ4, 5, 5-trimethyl-1, 3-oxazolidinyliden- (2)) - aminoZ-S-nitrothiazole

The tablets prepared according to Example I are coated by a known method with a shell consisting essentially of sugar and talc . The finished coated tablets are polished with the help of beeswax.

Dragee ge v / i cht: 300.0 mg

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HI

Oolaten-Xapselii with 200 mg 2- / C4,5,5-trimethyl-1,3-oxazolidiny-

liden- (2)) -arjinc> 7-5-2iitro thiazole 1 cachet contains:

2- / Γ4,5,5-? Riaethyl-1,3-oxazolidinylidene-

(2)) - anino7-5-nitrothiazole 200.0 mg

Corn starch 50.0 mg

250.0 mg Horntoli un ^ r-vorf nlircm:

The "l '/ irkoubctans is mixed intensively with the corn starch and filled in cachets of suitable size. Capsule filling: 250.0 mg

Example IY

Dragees with 150 ng 2- / T4,5,5-trimethyl-1,3-oxazolidinyiiden- (2)) amino7-5-nitrothiazole
1 dragee contains:

2- / Γ4,5,5-trimethyl-1,3-oxazolidinylidene

(2 ~)) - amino7-5-nitrothiazole Cornstarch gelatin

Carboxymethyl cellulose highly viscous

Magne s iumste arat

Production method:

The mixture of active ingredient and maize starch is v with a 1Obigen / ässrigen gelatin solution then granulated through a sieve of mesh width 1.5, dried at 45 ⁰ C. and again rubbed through a sieve of mesh width 1.0 mm. The granules are mixed with carboxymethyl cellulose and with magnesium stearate and the mixture is compressed to form Bragee cores.

Core weight: 220.0 mg

Stamp: 9 mm, domed

The drag fair cores produced in this way are

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150.0 mg 60.0 mg 4.0 mg 4.0 mg 2.0 mg 220.0 mg

drive covered with a shell that, essentially, looks like Consists of sugar and talc. The finished coated tablets v / erden ^ i-; Polished with the help of beeswax.

Drag fee weight .: '300.0 mg

Example 7

Gelatin capsules with 100 mg 2- / T4,5,5-trimethyl-1,3-oxazolidinylidene- (2)) -amino7-5-nitrothiazole

To π α mm c η r < e t Zunp ;:

1 gelatino capoel contains:

2- / Pi> 5,5-trimethyl-1,3-oxazolidinylidene- (2)) -aniino7-5-nitrothiazole 100.0 mg

Aerosil R 972® 1.0 mg

101.0 mg

Production method:

The active substance is mixed intensively with Aerosil and filled into gelatine capsules of a suitable size.

Capsule filling: 101.0mg

Example YI

Tablets with 200 mg 2- / T4,5,5-trimethyl-1,3-oxazolidinylidene- (2)) -anino7-5 ~ nitrothiazole

Composition:

W 1 tablet contains:

2- / Γ4,5,5-trimethyl-1,3-oxazolidinylidene

(2)) - amino7-5-nitrothiazole x 200.0 mg

• Milk sugar 110.0 mg

Potato starch 70.0 mg

Polyvinylpyrrolidone 10.0 x mg

Aerosil ^ 5.0 mg

Magnesium stearate 5 »0 mg

400.0 mg

Production method:

The active ingredient mixed with milk sugar and potato starch is mixed with a 1Obigen ethanolic solution of polyvinylpyrro-

009842/1889 _BAD0RIG1NAt .

lidons granulated through a sieve with a mesh size of 1.5 mm, "at 45 ° C dried and rubbed through the above sieve again. The granules obtained in this way are nit Aerosil and magnesium stearate mixed. The mixture is compressed into tablets.

Tablet weight: 400.0 mg

Stamp: 11 mm, flat

BeiGTiiol VII-

Vacinal tablets with 100 mg 2- / C4,5,5-trimethyl-1,3-oxazolidinylidene- (2)) - araino7-5-nitrothiazole
To G ο rriaono et

1 tablet contains:

2- / R, 5,5-trimethyl -1,3-oxazolidinylidene

- (2)) - amino7-5-nitrothiazole 100.0 mg

Dextrose 240.0 mg

Milk sugar 505.0 mg

Corn starch 200.0 mg

Polyethylene Glycol 6000 33.0 mg

Polyethylene sorbitan monostearate (Tween 61) 10.0 mg

Aerosil® 5.0 mg

Magnesium stearate 7.0 mg

1 100.0 mg

Production method:

The mixture of the virksubstanz with grape sugar, lactose and corn starch is moistened uniformly with a 15% aqueous solution of polyethylene glycol, which also contains Tween 61, granulated through a sieve with a mesh size of 1.5 mm and dried ^{at 45 ° C.} The granulate is again beaten through a sieve with a mesh size of 1 mm, mixed with the remaining excipients and compressed to form vaginal tablets.

Tablet weight: 1.1 g

The tablets are coated with a sliding layer of polyethylene glycol 1500 using a suitable process.

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Example VIII

Ointment with 1 £ 2- / C4,5,5-trimethyl-1,3-oxazolidinylidene- (2)> -

amino / -5-nitrothiazole 1.0 g Composition: 20.0 g 2- / Γ4,5,5-triethyl-1,3-oxazolidinylidene 15.0 g (2)) - amino7-5-nitrothiazole, ground 1.0 g vaseline 2.0 g Cetiol V 4.0 ^ g Cetyl alcohol 0.1 g Wool wax alcohol 0.2 g Sorbitan monooleate (Span 80) 56.7 g methyl p-oxybenzoate 100.0 g Perfume Distilled water Production method:

In the heated to 65 ⁰ C melt of Vaseline, Cetiol, cetyl alcohol, wool wax alcohol and Span 80, the p-oxybenzoate is dissolved and then emulsified in the heated to the same temperature water. It is cooled to room temperature with slow stirring and the perfume is added. The active substance is rubbed with part of the ointment and the trituration is then distributed evenly in the rest of the base.

Example IX

Vaginal gel with 1 ~ £ 2- / C4,5,5-trimethyl-1,3-oxazolidinylidene- (2)) -amino / -5-nitrothiazole
Composition:

2- / Γ4 »5> 5-trimethyl-1,3-oxazolidinylidene

(2)) - amino7-5-nitrothiazole, ground 1.0 g

Carboxymethyl cellulose high viscosity 2.2 g

Polyoxyethylene sorbitan monooleate (Tween 80) I ₁ Og

methyl p-oxybenzoate 0.1 g

Propyl p-oxybenzoate 0.2 g

Lactic acid 0.2 g

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- ι ς -

Glycerin. 10, floor

Distilled water 85.4 g

100.0 g Manufacturing process:

Dist. Water v / ith at 8O ⁰ C heated -and the p-Oxyberizoesäurees'ter and Tween 80, and lactic acid dissolved. The active substance is suspended in the solution cooled to room temperature and the suspension of the carboxymethyl cellulose in glycerol is then stirred in. Stirring is continued until the carboxymethyl cellulose is completely dissolved.

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Claims (5)

1913071 t e η t a η c ρ r ü c h e 1.) AIZ ii ^ uo Voroindurc 2 - / [ "4,5,5-Tri: N-ethyl-1, 3-oxazcIidinyllden- (2) 5c> .iinr ₁ 7-5 ~ ^ itrotl-iiazol and its Säureadditionssälzc r. -it ar.orf ;. ulöohon or organic GJ-I 2.) Yut £; \. "\:; \ I, u. ' li.jrijtolluiv ·; clul, new 2- ^ 4,5. »^ - ΐζΊ-ί v, .iyl-1 _? 5-c; r.iiJoii.ui: iyliden- (2)) amino7-5-nitrothiazoles der .s ^ ra Ο, .ΙΪ —1 _c . J N = C ' ■ ° - ^ CH 3 H. dadurcli marked that a) a 2-Kexhylenainino-5-nitro-thiazole of the general Formula II = ^c in which the radicals R ₁ and R ₂ , which are identical or different, denote calogen atoms or radicals 4er Jev ^ l -SR, ", in which R _{5 represents} an alkyl, aralkyl or al, nyl group or in which the radicals R- and R ₂ together form a bismercaptoalkylene group with a - "ilcylenrest with 1, 2 or 3 carbon atoms, sit 2-amino-3-methyl-" butanol- (3) reacted or Λ; 009842/1889 BATH ORIGINAL 117 iii d.-r ^; billon alkyl- , Λι-alkyl- or alkenyl J -'- ^ 'be ^ UvV ¹ L, i "iit 2-amino-5-riitrpthiazole" at Teia ^ craLLir ^ n 1 ·; av. lOO'O un ^ esetat or c) clr.j 2- _t {""<-,5> 5-Ti \ ir ^ 3thyl-2-o; i: uaolidinylidene) - aaiiiC-7 "iiol nitrated \ / ird ur ^ d dio ao obtained before "binu" i ^. _w c, e "..ur.jchteniallü subsequently by means of inorganic : -l? .r organic acids in their acid addition salt. ü ". ·. ¹ vfuhrt v / ird ,. 3.) Veriahr. ^ N £ &: wJ. & An ^^ rucli 2a, thereby gol'eiinzeichnel, · 1λ £ the liuair ^ iön- in Αη-, / jJunriDit uinoj Schwerinotalloxidj., '.Ar.ljhe-I-Iorc ^ ptano: i scLv / erlöcilicho Zomplexe "forms ,, diirchjexiu ^, t will. ■ · 4.) V ^ rfa.rren goaiüß Anspruca 2a, 2b and 3, thereby g ntit that the! reactions in a solvent s 5.) Method according to xXnspruch 2c, thereby gelcennzölehnet, L&B the nitration by means of nitric acid in the presence of ύο ~ Zctws feisäure at temperatures between ^{0 0} C and the Ziaunerteaperatur takes place.