Derivatives of 6-aryl-5,6-dihydroimidazo [2,1-b]thiazole, or their pharmaceutically acceptable salts accession acid, or their stereochemical isomeric form, having immunostimulatory activity, the method of production thereof, derivatives of 2-aminothiazole, or their pharmaceutically acceptable salts accession acid, or their stereochemical isomeric form as intermediates for obtaining derivatives of 6-aryl-5,6 - dihydroimidazo[2,1-b]thiazole, immunostimulirutuyu composition

 

(57) Abstract:

Usage: in medicine, in particular in connection with immunostimulatory activity for creating therapeutic compositions. The essence of the invention: derivatives of 6-aryl-5,6-dihydroimidazo [2.1-b]thiazole f-ly I, where Ar is phenyl, a is not - or substituted by halogen, C1-C6alkoxy, C1-C6alkyl-, nitro-group or two Halogens, pyridinyl, thienyl, furanyl, R1and R2independent C1-C20alkyl, cyclohexyl)methyl; cyclohexyl or phenyl: one of R1and R2can be hydrogen or together form alkylphenyl radical, or their pharmaceutically acceptable salts or their stereochemical isomeric form. Derivatives of 2-imino-thiazol f-crystals II as intermediates for producing compounds of f-crystals I. how to Obtain the latest lead by cyclization of compounds of f-crystals II in an inert solvent in the presence of an activating agent. Immunostimulirutuyu composition contains in an inert medium of 0.1-500 mg per dose. The connection structure of f-crystals I and II are indicated in the text description. 4 S. p. f-crystals, 5 PL.

Known (U.S. patent N 3274209) 6-aryl-2,3,5,6-tetrahydroimidazo[2,1-b] thiazole derivatives, which were used as glista is described in U.S. patent N 4584305. Immunostimulatory properties [S]-[-]-2,3,5,6-tetrahydro-6-phenylimidazo [2,1-b]thiazole, known as levamisole were described in Immunofarmacology 1, 1979, 245-254; clin exp.Immunol, 22, 1975, 486-492; and links to these articles. The compound 5,6-dihydro-3,5,6-triphenylmethane[2,1-b] thiazole described in Gazz.Chim.Ital, 114, 1984, 201-204 (SA; 101; 211027) and the compound 5,6-dihydro-6-phenylimidazo[2,1-b] -acetic acid ethyl ester, dihydrochloride I. Heterocycl. Chem, 19, 1982 343-348. None of the compounds showed no useful pharmacological or other properties.

Compounds according to this invention differ from the known fact that the 2,3-bond is unsaturated and position 2 and/or 3 is substituted. These compounds have unexpectedly bigger potential as immunostimulatory agent in comparison with the known levamisole.

This invention relates to new derivatives of 6-aryl-5,6-dihydroimidazo[2,1-b]thiazole having a General formula I

Ar R1their pharmaceutically suitable salts accession acids and stereochemical isomers,

where AG is phenyl, optionally substituted with halogen, C1-C6-alkyloxy-FROM1-C6-alkyl-, nitro-group or two halogen atoms, pyridinyl, Tinel, R1and R2can be hydrogen; R1and R2together can form WITH3-C6-alcantarillados.

In the above definitions WITH1-C6-alkyl is a linear or branched hydrocarbon radical having from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl, etc.1-C20-alkyl means1-C6-alkyl and the higher homologues having from 7 to 20 carbon atoms, such as, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, Needell, eicosyl and their branched isomers; C3-C7-cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; C3-C6-alqadir means a divalent linear or branched hydrocarbon radicals having 3 to 6 carbon atoms, such as, for example, 1,3-PROPANEDIOL, 1,6-hexadecyl, 1,4-butandiol, 1,5-pentadien etc., halogen means fluorine, chlorine, bromine or iodine.

A subset of the substances described by formula I defined earlier in the text, includes compounds where R2the hydrogen. is by hydrogen. Interest compounds of formula I of the above-mentioned subgroups, in which Ar is phenyl, optionally substituted from 1 to 2 independently selected substituents from the group halogen, nitro, hydroxyl, C1-C6-alkyloxy-FROM1-C6-alkyl, C1-C6-alkylcarboxylic, arylcarboxamide, thienyl, furanyl or pyridinyl.

Of particular interest from the above-mentioned group of interesting compounds are compounds where R1WITH4-C10is alkyl and Ar is phenyl, partially substituted with halogen, nitro, metoxygroup or methyl.

The most interesting compounds are 6-(4-bromophenyl)-2-hexyl-5,6-dihydroimidazo[2,1-b] thiazole; 6-(4-bromophenyl)-2-pentyl-5,6-dihydroimidazo-2,1-thia - Zol; 5,6-dihydro-2-pentyl-6-phenylimidazo[2,1-b]thiazole; 2-hexyl-5,6-dihydro-6-phenylimidazo[2,1-b] thiazole; 2-heptyl-5,6 - dihydro-6-phenylimidazo[2,1-b] the thiazole; and 5,6-dihydro-2-octyl-6-phenylimidazo[2,1-b] thiazole, their pharmaceutically suitable acid salts and stereoisomers.

The preferred compounds are 2-hexyl-5,6-dihydro-6-phenylimidazo[2,1-b] thiazole; [S] -[-] -2-hexyl-5,6 - dihydro-6-phenylimidazo[2,1-b] thiazole; [R]-[+]-2-hexyl-5,6-dihydro-6-phenylimidazo [2, 1-b]thiazole; all mixtures in the latter Anantara, the compounds of formula I have several asymmetric carbon atoms. Except where otherwise indicated, the chemical name of the compound is a mixture of all possible stereoisomers mentioned mixtures contain diastereoisomers and enantiomers of the basic molecules. The exact configuration of each chiral center may be different stereochemical pointers R and s

This invention also covers stereochemical isomers of compounds of formula I.

The compounds of formula I having basic properties may be converted into a therapeutically active non-toxic salt accession acids by treatment with appropriate acids, such as, for example, inorganic acids, hydrochloric, Hydrobromic, etc., sulfuric, nitric, phosphoric, etc., or organic acids, such as, for example, acetic, propanoic, oxiana, 2-oxopropanal, 2-oxopropanal, tanginoa, proportionaly, batandjieva, [Z] -2-potentionaly, [E]-2-potentionaly, 2-oxibutinina, 2,3-dioxine - tendineae, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzosulfonate, 4-methylbenzoyl background, cyclohexanesulfamic, 2-oxybenzone, etc. Education is egodnya salt" also includes a solvate, which can form the compounds of formula I and the above-mentioned solvate covered by the invention. Examples of such solvate serve, for example, hydrates, alcoholate, etc.,

The compounds of formula I can be obtained by cyclization of the intermediate substances of the formula II in the presence of an appropriate reagent, optionally in a suitable inert solvent

ArR1ArR1< / BR>
Appropriate activating reagents include reagents that can turn a hydroxyl group in the reaction residual group W, as, for example, inorganic and organic acids, halogen acids, sulfuric, phosphoric, polyphosphoric, ethyl ester of polyphosphoric acid, acetic acid, etc., acid halogenation reagents, for example, thionyl chloride, trichloride phosphorus, phosphorylchloride, zinc chloride and the like halogenation reagents; sulfonylurea reagents, for example, methanesulfonyl chloride, methylbenzenesulfonamide etc. alleluya reagents, for example, acetic, propanoic acid, benzamide, acetyl, propionyl and benzoylchloride; dehydrating reagents, for example, dicyclohexylcarbodiimide, etc. Mentioned residual group W in the intermediate substance II is, benzoyl, etc., or sulfonyloxy, i.e. sulfonylation, methylsulfonylbenzoyl, etc. Suitable inert solvents are, for example, aromatic hydrocarbons, i.e., benzene, methylbenzol, xylene, etc., kaleidophone hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, etc., ethers, e.g. tetrahydrofuran, 1,1'-oxybisethane, 1,4-dioxane, etc., acetic anhydride, etc., or a mixture of such solvents. In some cases conduct the cyclization of the intermediate substances III in the presence of bases, such as, for example, carbonates of alkaline or alkaline earth metals or hydrogen carbonates, e.g. sodium carbonate, potassium carbonate, etc., or organic bases, such as, for example, tertiary amines, i.e. N, N-diethylethanamine, N,N-di(1-methylethyl)ethanamine, etc. Mentioned cyclization reaction can be conducted at room temperature, although in some cases it would be valuable to a small heater.

The compounds of formula I can also be obtained by reacting the imidazoline of the formula IV or equivalent fotometricheskogo of thiol, with a reagent of formula R1-CH[W1]-C[=O]-R2(V).

Ar + (I)

In the formula V and below W1is udhayakumar, 4-methylsulfonylbenzoyl, etc. Mentioned cyclization reaction can be performed by mixing, if necessary by heating the reactants in a reaction-inert solvent, sometimes in the presence of a suitable base. Suitable solvents are, for example, alkanols include methanol, ethanol, etc., ketones: 2-propanone, 4-methyl-2-pentanone, etc., carboxylic acids, acetic, propanoic, etc. acids; aromatic hydrocarbons: benzene, methylbenzol etc. kaleidophone hydrocarbons: dichloromethane, trichloromethane, carbon tetrachloride, etc., ethers: 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, etc., bipolar aprotic solvent: N,N-formamide, N, N-dimethylacetamide, pyridine, etc. or a mixture of these solvents. Suitable bases are, for example, inorganic bases include carbonates of alkali and alkaline earth metals, carbonates, oxides or hydroxides include sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc., sodium hydride; or an organic base, such as, for example, alkoxides of alkali metals: sodium methoxide, ethoxide sodium tert.piperonyl, etc. amines: N-(1-methylethyl)-2-propanamine, N,N-diethylethanamine, 1,8-diazabicyclo[5,4,0] undec-7-ene, etc., the basis is some cases it is possible to conduct the reaction between imidazoline (IV) with a protected derivative of a reagent of the formula V, specifically acetal (VII): dimethyl-, diethyl-, ethandiyl or preponderately, thus obtaining the intermediate substance of the formula VI.

Ar + RO ___ Ar ___ (I)

Mentioned intermediate compound (VI) can be further cyclosiloxane in the compound of formula I by treatment with an appropriate acid, such as, for example, hydrochloric, sulfuric, etc., carboxylic acid: acetic, propanoic, trichloroacetic, triperoxonane, etc. acids, in a suitable reaction-inert solvent, which was defined earlier.

Some of the intermediate and initial substances, referred to hereinafter, are known and can be obtained by known methods of obtaining mentioned or similar intermediate or starting substances, and a certain number of intermediate compounds are new. Some methods of obtaining these new intermediates will be described in detail in the text.

Intermediate substances of the formula II are new and can be prepared by oxidation of an intermediate ketone of formula VII.

ArR1____ ArR1< / BR>
The said oxidation is carried out by treatment of the intermediate ketone (VIII) in a suitable reaction-inert , preferably sodium borohydride, cyanoborohydride sodium, trimethoxyborohydride sodium bis-(2-methoxyethoxy) aluminum hydride, sociallyengaged, trialcialis lithium, etc. oxidants. Suitable solvents are, for example, water, alkanols, methanol, ethanol, 1-propanol, 2-propanol, etc., for example, 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, 2,2'-oxybisethane, 1,2-dimethoxyethane, 1,1'-oxybis(2-methoxyethane), etc., aromatic hydrocarbons: benzene, methylbenzol, xylene, etc. or mixtures of these solvents.

Another way to obtain the intermediate compounds of the formula II is the reaction between the epoxide of formula IX and diazolinum formula X

ArO + ____ (II)

The above reaction can be carried out by heating, sometimes with heating the reactants in a reaction-inert solvent, sometimes in the presence of the appropriate acid. A suitable solvent is aromatic hydrocarbons: benzene, methylbenzol etc. kaleidophone hydrocarbons: dichloromethane, trichloromethane, carbon tetrachloride, etc., ethers: 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, etc., bipolar aprotic solvents: N, N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, etc., or mixtures of these solvents. the I acid, etc.

Intermediate substances of the formula VIII can be obtained by N-alkylation of thiazoline formula X with a reagent of formula XI, where W is the residual reactive group, which was previously defined

Ar W +____(VIII)< / BR>
The above reaction of N-alkylation may be carried out by mixing, sometimes heated, agents in a reaction-inert solvent. As a reaction-inert solvents are: methanol, ethanol, 2-propanol, 1-butanol, etc., ketones: 2-propanone, 4-methyl-2-pentanone, etc., aromatic hydrocarbons: benzene, methylbenzol etc. kaleidophone hydrocarbons: dichloromethane, trichloromethane, carbon tetrachloride, etc., ethers: 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, etc., esters include ethyl acetate, etc., bipolar solvents: N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc., or mixtures of these solvents. In some cases, can be used the addition of alkali metal iodide such as sodium iodide.

Intermediate substance of the formula IV can be obtained by cyclization of the diamine of formula XII with a reagent of formula L-C[=S]-L (XIII), where L represents a suitable residual group

AR + L-L____ Ar

As typical examples of reagents X is Gasol], etc. the reagents.

Said cyclization reaction may be conducted by stirring and, if necessary, heated reagent in a reaction inert solvent such as, for example, aromatic hydrocarbons: benzene, methylbenzol, xylene, etc., golozhabernyi hydrocarbons: trichlormethane, tetrachlorobenzene, chlorobenzene, etc., ethers: 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, etc., dipolar aprotic solvents: N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, methylpyridin, dimethylpyridin, 1,1-dioxide, tetrahydrothiophene, etc., or mixtures of these solvents. In some cases, however, it is preferable to carry out the reaction with heating in the absence of solvent. Sometimes you want to add to the reaction mixture a base, such as, for example, amines: N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 4-methylmorpholine, etc. amines. In the case of use as a reagent of formula XIII disulphide reaction can also be performed in water or alkanol, such as, for example, methanol, ethanol, propanol, etc., in the presence of bases like potassium hydroxide, sodium, etc. Or otherwise this reaction can be conducted in the primary solvent, such as, for example the mules XIII in General receive and dissolved as described in article Ann.Chem. 1932, 494, 143 and in the references to this article. Another way you can also get the diamines of the formula XII: the reaction of the corresponding aldehyde Ar-CHO with an alkali metal cyanide: cyanide sodium or potassium, etc., in the presence of ammonia or an acid salt type ammonium hydrochloride, etc. thus Obtained aminonitriles can then be oxidized to the diamine (XII) according to the known methods of oxidation, for example, by hydrogenation with palladium, platinum, Nickel, etc., catalysts in a suitable solvent, for example, in alkanol: methanol, ethanol, 2-propanol, etc. in the air: 1,1'-oxybisethane, 2,2'-oxybisethane, tetrahydrofuran, 1,4-dioxane; aromatic hydrocarbons: benzene, methylbenzol, etc. in the presence of a suitable acid, such as hydrochloric, Hydrobromic, acetic, etc.

Intermediate substances of the formula X, in turn, can be obtained by the reaction of intermediate substances of the formula V with thiourea XIV

H2N H2____ H2NR1< / BR>
The above reaction can be carried out according to the method of obtaining compounds of formula I of the intermediates IV and V, as described earlier.

Another way to obtain the intermediate compounds of the formula X also serves reaccelerating substances XV c using the appropriate acid, as described in the case of preparing compounds of formula I of the intermediates IV, VII

< / BR>
Pure stereochemical isomers of compounds of formula I can be obtained by the application of known methods. Diastereoisomer can be separated by physical methods, such as, for example, selective crystallization and chromatography: a counter-current separation, liquid chromatography, etc., enantiomers can be separated by selective crystallization of their diastereomeric salts with optically active acids or preferably by chromatography: liquid chromatography using as a chiral stationary phase suitable derivative of cellulose, for example, three(dimethylcarbamoyl) cellulose (Chiroal OD), etc. Pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomers of suitable starting substances, provided that the reaction is stereospecific.

Quite unexpectedly, it turned out that the proposed substances have much more opportunities as immunostimulatory drugs compared to the previously known [S]-[-]-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b] the thiazole, in U.S. patents NN 3274209 and Alt when measuring the degree of inclusion of3H-thymidine in concavalin And stimulated in thymocytes of mice [in Conconavalin A-stimulated murine thymocytes] in the presence of micromolar amounts of the proposed substances.

When [S] -[-]-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole(levamisole) shows its maximum stimulating effect is only about 100 M (Immunopharma - cology, 1979, 1, 246): "the introduction of3H-thymidine maximum at a concentration of 50 mg/ml (-200 M))" offered substances show the maximum stimulating effect at a concentration of 0.1-1.0 M Thus, the proposed substances are the most active at concentrations 100-1000 times lower than concentrations previously known substances.

Quite unexpectedly, that intermediate substances of the formula II and VIII also have immune-stimulating properties that can be shown by using the described method of analysis.

With regard to enhanced immunostimulatory properties of the compounds of formula I and intermediate substances of the formulae II and VIII are useful in the treatment of humans and warm-blooded animals suffering from diseases in which the immune system is weakened or suppressed. Typical examples of such diseases are, for example, bacterial, viral infections, for example, verrucal, herpes simplex, viral hepatitis, With the clusters as a subsidiary of drugs in the treatment of neoplastic diseases.

Such use includes the treatment of the patient by the compounds of formula I or intermediate compounds of the formula I or VIII in conjunction with anti-tumor therapy as well as patients who have a risk of recurrence after cancer treatment. The term "antitumor treatment" is defined as the methods commonly used for the treatment of patients suffering from malignant diseases, for example, surgery, radiotherapy and especially chemotherapy. From the point of view of usefulness of the pharmacological properties of these compounds and intermediate compounds can be applied in various forms.

To obtain a pharmaceutical preparation according to the invention the required quantity of a particular compound or intermediate substance in the form of salts are acidic or basic form is mixed with a pharmaceutically suitable carrier, so you can get different patterns depending on the way of application of medicines. It is advisable to get these pharmaceutical compositions in a single dose, preferably suitable for the following applications: by mouth, rectal, subcutaneous or parenteral injection. For example, when the preparation for the use of the p. for the case of liquid compositions, such as suspensions, syrups, elixirs and solutions; or solid carriers such as starch, sugar, kaolin, lubricating oils, binders, disintegrating agents, etc., in the case of powders, pills, capsules and tablets. Tablets and capsules that use solid pharmaceutical carrier, the most convenient due to the ease of their application. For parenteral compositions, the carrier typically includes distilled water, at least more than other ingredients, for example, to improve solubility. Injectable solutions, for example, can be prepared using carriers including saline solutions, glucose solutions or mixtures thereof. Suspension for injection can also be obtained using suitable liquid carriers, suspendida agents, etc.

For formulations for subcutaneous administration, the media enables the agent to accelerate the introduction and/or a suitable wetting agent, sometimes mixed with small amounts of suitable additives, these additives should not adversely impact on the skin. Mentioned additives promote drug and/or may be useful in the preparation of the desired compounds. These shutochnye substances of the formulae II and VIII because of its higher solubility in water, compared with the basic forms, obviously more convenient to obtain an aqueous composition.

It is especially important to make the aforementioned pharmaceutical compositions in the form of single doses for ease of use and uniformity of distribution of substances in the dose. Are physically separate doses for single use, each dose contains pre-calculated amount of active ingredient to obtain the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such doses are tablets (ordinary or in the shell), capsules, pills, sachets of powder, wafers, injectable solutions or suspensions, teaspoons and tablespoons, etc. are divided among themselves. The amount of active ingredient per dose is in the range of 0.1 to 500 mg, more specifically 0.5 to 100 mg, preferably 2-40 mg

From the point of view of the useful properties of these compounds and intermediates as Immunostimulants, the invention provides a method of treatment of humans and warm-blooded animals suffering from disorders and/or diseases in which a weakened immune system, the said method includes the use of immunostimulating effective amount of the compounds of formula the isomers, in a mixture with a pharmaceutical carrier. Specialists in the treatment of disorders and/or diseases related to the weakening of the immune system, can easily determine an effective immunostimulating amount of the compounds of formula I and intermediates II and VIII of the experimental results presented later in the text. In the General case it is assumed that the effective daily dose of the compounds of formula I or intermediates of formulas II and VIII is 0.01-5.0 mg/kg body weight, preferably 0.04 to 2.5 mg/kg of body weight per day. In some cases, the required dose should be taken in a trick or two, or three, or four, or more doses at appropriate intervals throughout the day. Reduced doses may be prepared in the form of single forms. It is obvious that the effective daily dose depends on the condition, the patient's response to treatment, severity of disease, evaluation by the attending physician of these compounds, i.e., an effective amount may be correspondingly reduced or increased. The range of effective amounts is only General direction and does not limit the use of the invention.

A method of treating patients suffering from neoplastic diseases. The proposed m is about with anti-tumour treatment, such as, surgery, radiation and especially chemotherapy. As an example of anticancer drugs that can be used in chemotherapy, it should be noted ancitabine (cycloxydim), azathioprine, bleomycin, busulfan, calusterone, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, doxorubicin (adriamycin), dromostanolone propinate, epitiostanol (epitiostanol), estramustine phosphate, etoposide, fluorouracil, diethylstilbestrol diphosphate, oxytocin, lomustin, melengestrol, melphalan, 6-mercaptopurine, methotrexate, mitobronitol, mitomycin With, metabolized, mitotane, mycophenolic acid, nimustine, pipobroman, piposulfan, prednimustine, procarbazine, razoxane, tegafur, teniposide, testolactone, triethylenephosphoramide, tioguanin, triaziquone, trofosfamide, uramustine, vinblastine, vincristine, etc., antitumor drugs.

An effective amount of the antineoplastic drug, especially one or more of the drugs given to the patient simultaneously, separately or sequentially with an effective immunostimulating amount of a compound of formula I or intermediates of formulas II or VIII. In General it is believed that effective the th number of immunostimulating compounds of formula I or intermediates of formulas II or VIII will be in the following range of 0.01-5 mg/kg body weight, preferably 0.04 to 2.5 mg/kg body weight.

The following examples illustrate the invention but do not limit its creatures. Except where otherwise noted, all quantities of substances are expressed in weight.h.

Experimental part

A. Obtaining intermediates.

P R I m e R 1. To a stirred solution of 21 hours of octadecanol 65 hours of dichloromethane and 50 hours of 1,4-dioxane is added drop by drop to 34.1 hours of bromine. After stirring for 4 h at room temperature the reaction mixture was poured into 250 hours of water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated to yield 28 h (95% ) 2-bromooctadecane (intermediate substance 1).

A mixture of 6.7 h thiourea, 28 hours intermediate substance 1 and 80 h of ethanol was stirred for 1 h at a temperature of phlegmy. The reaction mixture was evaporated, and the residue was washed with NaOH (aq.). The product was extracted with dichloromethane, the extract was dried, filtered and evaporated to yield 11.8 hours (45%) 5-hexadecyl-2-thiazoline (intermediate substance 2).

P R I m m e R 2. A mixture of 6 h 5-heptyl-2-thiazoline (obtained as an intermediate substance 2), 6 o'clock 2-bromo-1-phenylethanone and 120 hours of acetonitrile was stirred overnight at whom the foreign Ministry 2-(5-heptyl-2,3-dihydro-2-imino-3-thiazolyl)-1-phenylethanone (intermediate substance 3).

P R I m e R 3. To a stirred and cooled (ice bath) mixture of 10 o'clock intermediate substance 3 in 120 hours of methanol in small portions was added 1 tsp of tetrahydroborate sodium. After stirring for 2 h at room temperature the reaction mixture was diluted with 100 hours of water and then was carried out by evaporation. The residue was ground into powder in water, filtered and dissolved in trichloromethane. This solution was dried, filtered and evaporated. The residue was led from 2-propanol with the release of 5.3 hours 5-heptyl-2,3-dihydro-2-imino-phenyl-3-thiazoleethanol; similar to 123.5about(Intermediate substance 4). Intermediate substances that are listed in the table. 1 and 2, obtained in the same way.

P R I m e R 4. A mixture of 51 h 2-bromo-1-(2-thienyl)ethanone, 28,5 h 5-ethyl-2-thiazoline and 240 hours of acetonitrile was stirred for 1 hour while heating on a water bath. After cooling, the precipitate was filtered, washed with ethanol and dried under vacuum to yield 54 PM hydrobromide 2-(2,3-dihydro-2-imino-5-methyl-3-thiazolyl) -1-(2-thienyl)ethanone; so pl. 207,5-208about(Intermediate substance 56).

The mixture 38 PM intermediate substance 56,19 including acetic anhydride, 19 hours of pyridine and 300 hours of trichloromethane was heated for 6 h on the steam bath. After cooling arali. The residue was recrystallized from methylbenzol with the release of 20 hours N-[2,3-dihydro-3-[2-oxo-2-(2-thienyl)ethyl]-5-methyl-2-thiazolidin]-aceta - Mead; so pl. 187-188,5about(Intermediate substance 57).

To a stirred suspension of 7 hours intermediate substance 57 100 hours of methanol drop was added to 0.95 g tetrahydroborate sodium. After stirring for 1 h at room temperature the solvent was evaporated. The residue was placed in the water and was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was recrystallized from hot methylbenzol exit 6 o'clock N-[2,3-dihydro-3-[2-hydroxy-2-(2-thienyl)ethyl] -5-methyl-2-thiazo - Liden]-ndimethylacetamide; so pl. 114-115about(Intermediate substance 55).

Similarly obtained N-[2,3-dihydro-3-[2-hydroxy-2(2-thienyl)ethyl]-4-methyl-2-thiazolidin] ndimethylacetamide; so pl. of 105.5-107about(Intermediate substance 59).

B. Obtain the target compounds.

P R I m e R 5. A mixture of 4 h intermediate substance 4 and 36 hours of sulfuric acid was stirred for 0.5 h at 0aboutWith and for 1.5 h at room temperature. The reaction mixture was poured in a container of crushed ice, which was added NH4OH (aq.). The product was extracted with dichloromethane and the extract was dried, filter 3 hours 2-heptyl-5,6-dihydro-6-phenylimidazo[2,1-b]thiazole-ethane-dioate; so pl. 108,7about(Compound 34).

P R I m e R 6. To a stirred solution of 9.8 hours intermediate substance 6 in 75 hours of trichlormethane drop was added 5 hours of titillated. After stirring for 1 h at 50aboutTo the reaction mixture was evaporated and the residue was placed in an aqueous solution of 100 hours Na2CO32N. This solution was stirred for 1 h at 90aboutWith, cooled and extracted with trichloromethane. The extract was dried, inteletravel and evaporated. The residue was led from a mixture of methylbenzene and petroleum ether with a yield of 3.5 hours 6-(4-bromophenyl)-2-ethyl-5,6-dihydroimidazo-[2,1-b]-thiazole; so pl. 74,8about(Compound 2).

P R I m e R 7. To a stirred and cooled (0aboutC) 16 hours of thionyl chloride were added in small portions 5,6 including intermediate substance 58, and the temperature was maintained below 10aboutC. After stirring for 2 hours at room temperature was added 50 hours of acetanhydride at temperatures below 20aboutC. the Resulting acetylchloride distilled (136aboutC) and the residue was evaporated. Bottom the residue was dissolved in a mixture of water and hydrochloric acid. After filtration of this solution was added NH4OH and extragere Salt was filtered, washed with 2-propanone and dried to yield 1.5 h ()-5,6-dihydro-2-methyl-6-(2-thienyl)imidazo-[1,2-b]-TIA - evils-of ethanoate; so pl. 170-171,5about(Compound 56).

P R I m e R 8. To a solution of 5.3 h (S)-(+)-1-mercapto-4-phenyl-2-imidazoline (U.S. patent N 3274209) in 63 hours of acetic acid was added to 6.2 h 2-bromoacetaldehyde. After stirring for 1.5 hours at a temperature of phlegmy solvent evaporated. The residue was placed in water and was added NH4OH. The free base was extracted with methylbenzol and the extract was dried, filtered and evaporated. The residue was converted into echandia in 2-propanol. Salt was filtered and dried to yield 3.1 hours (27,4%) of product; so pl. 132,7aboutC. the mother liquor was evaporated, and the residue was treated with NH4OH. The product was extracted with dichloromethane, the extract was dried, filtered and evaporated. The residue was purified through column chromatography (silica gel; CH2Cl2(CH3OH)NH3(97,5:2,5). Eluent of the desired fraction was evaporated and the residue was converted into tandikat as before, with the release of 1.6 hours (14,2%) of product; so pl. 136,3aboutC. Total yield: up to 4.7 hours (Se,6% ) (S)-(-)-2-hexyl-5,6-dihydro-6-phenylimidazo-[2,1-b] -thiazolidinedione (1:1) (compound 50).

[]D20(fraction 2)=-32,40about(conc.1% CH3

The connection 52 prepared in a similar manner, driving for 17 h in methanol in the first stage, then replacing the solvent for acetic acid, distilled for 15 am

P R I m e R 9. A mixture of 1.78 h 2-mercapto-4-phenyl-2-imidazoline, 44,5 h, tetrahydrofuran and 0.92'clock dispersion of sodium hydride in mineral oil (50% ) was stirred for 45 min at room temperature. Then add 1.5 to 2 hours of chlorocyclohexanone and continued to stir for 2 hours, the Reaction mixture was diluted with water, then evaporated. The residue was stirred in HCl 2 N. for 15 min, then was added NH4OH. The product was extracted with dichloromethane, the extract was dried, filtered and evaporated. The residue was twice purified through column chromatography [silica gel; CH2Cl(CH3OH 95:5; CH2Cl2(CH3OH)CH3OH(NH3) 97: 2:1] Eluent of the desired fraction was evaporated and the residue was converted into echandia in tetrahydrofuran. Salt was filtered and dried with a yield of 1.6 hours (46,2%) 2,3,5,6,7,8-hexahydro-2-phenylimidazo [2,1-b]benzothiazolium - oate (1:1); so pl. 146,2about(Compound 53).

P R I m e R 10. 3,8 including connection 33 is divided into R - and S-isomers by preparative chromatography (Chiracel OD ): hexanol (2-C3H7aboutC; []D20= +32,23about(conc. 1% CH3HE) (compound 54). Evaporation of eluent (S)-(-)-fraction and the same processing as that for (S)-(-)-2-hexyl-5,6-dihydro-6-phenylimidazo-[2,1-b] thiazole-ethanoate (1: 1); so pl. 142,2aboutC; []D20=-32,34about(conc.1% CH3HE) (compound 50).

Similar compounds listed in table.3 and 4, were obtained by methods similar to the methods specified in the examples.

C. Pharmacological examples.

Immunostimulatory properties of the compounds according to the invention can be illustrated by the following examples.

P R I m e R 11. Co-stimulatory effect on the implementation of3H-thymidine in murine thymocytes stimulated Concanavalin As described in Int.I=Immunopharm, 1979, 1, 233-237).

The culture medium consists of EarLe environment with the addition of 100 u/ml penicillin, 100 mg/ml streptomycin and 2 mm L-glutamine (GIBCO, Grand Osland, N-Y) together with 5% of fetal serum (FCS).

The culture procedure.

Mouse timony aseptically removed using forceps were placed in the culture of the cold environment and filtered through nylon mesh. Counting glue the bone size h mm plastic tubes. Culture contained 106 thymocytes. CON a (2 mg) and the test compound in the amount of 1.0 ml Tubes were incubated in 5% CO2-the atmosphere. After incubation for 64 h at 37aboutWith cells were subjected to pulses Were pulsed) by adding 1 Ci3H-thymidine. After this culture were washed once with 2 ml of 0.9% NaCl and twice with 1 ml of 5% trichloroacetic acid. The precipitate was dissolved in 0.3 ml of 0.5 N. hydroxide of Na, translated in obschenie capacity and added 10 ml of Instagel. Implementation was measured using a Packard Tri-Carp liquid scintillation spectrometer. Co-stimulating effect of the tested substances were defined as follows.

Different concentrations of the test substances of formula I calculated the ratio between the number of cpm/culture in the presence of concanavalin And (2 mg/ml) and the test compound, and the number of cpm/culture in the presence of concanavalin And (2 mg/ml) separately. In table.5 shows the concentration (μm) of the test substance at the maximum co-stimulatory effect, i.e. the maximum of the calculated ratio, the introduction of 3H-thymidine.

, Typical forms of pharmaceutical compounds in dosages suitable for systemic use for warm-blooded animals according to image rmaceuticals it suitable acid salt or its stereochemical isomers.

P R I m e R 12. Drops for oral administration.

500 g AI was dissolved in 0.5 l of 2-oxopropanoic acid and 1.5 glycol at 60-80aboutC. After cooling to 30-40aboutWith added 35 l of polyethylene glycol, and the mixture was well stirred. Then was added a solution of 1750 g of Na saccharin in 2.5 l of purified water and while stirring was added 2.5 liters of coconut filling and the polyethylene glycol to a volume of 50 l, obtaining the solution drops oral administration containing 10 mg/ml AI. The resulting solution was poured into a suitable container.

P R I m e p 13. Solutions for oral administration.

9 g of methyl 4-oxybenzoates and 1 g of propyl-4-oxybenzoates was dissolved in 4 l of boiling purified water. In 3 l of this solution were dissolved first 10 g of 2,3-dioxaborinane acid and then 20 g AI. The last solution was decanted from the remaining part of the previous solution and 12 l 1,2,3-propantriol and added 3 l of 70% aqueous solution of sorbitol. 40 g of Na saccharin was dissolved in 0.5 l of water was added 2 ml of raspberry and 2 ml essences gooseberry. The last solution was decanted from the previous and diluted with water to a volume of 20 l, obtaining a solution for oral administration containing 5 mg AI per 1 teaspoon (5 ml). The resulting solution was poured into a suitable container.

P R I m silicon and 1.2 g of magnesium stearate were thoroughly stirred. The resulting mixture was poured into 1000 suitable hard gelatin capsules, each of which contained 20 mg of AI.

P R I m e R 15. Coated tablet.

Preparation of the inner part (core).

A mixture of 100 g AI, 570 g lactose and 200 g starch is well mixed, was moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon-K90) in 200 ml of water. The wet powder was sieved, dried and re-sieved. Then was added 100 g microcrystalline cellulose (Avicel) and 15 g hydrogenated vegetable oil (Sterotex). All is well mixed. He opressively 10,000 tablets, each containing 10 mg of AI.

Shell.

To a solution of 10 g of methyl cellulose (Methocel 60 HG) in 75 ml of denatured ethanol was added 5 g of ethyl cellulose (Ehhocel 22 eps) in 150 ml of dichloromethane. Then added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol was melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the previous, and then added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colour suspension (Opaspray K-1-2109) and homogenized. The core tablets were coated in a mixture.

P R is the present water for injection. After cooling to 50aboutWith stirring, was added 4 g lactic acid, 0.05 grams propylene glycol and 4 g of AI. The solution was cooled to room temperature and diluted with water to a volume of 1 l, the resulting solution contained 4 mg of IA/ml. the Solution was sterilized by filtration (U. S. P. XVII p. 811) and poured into sterile ampoules.

P R I m e R 17. The candles.

3 g AI was dissolved in a solution of 3 g of 2,3-dioxaborinane acid in 25 ml of polyethylene glycol 400. 12 g of surfactant (SPAN) and triglyceride (Witepsol 555) was added to 300 g and all melted. The mixture was well mixed with the previous solution. Thus obtained mixture was poured into moulds at 37-38aboutC. 100 candles, each of which contained 30 mg of AI.

1. Derivatives of 6-aryl-5,6-dihydroimidazo[2,1 thiazole of General formula I

< / BR>
where Ar is phenyl, optionally substituted with halogen, C1- C6-alkyloxy-, C1C6-alkyl-, nitro-group or two halogen atoms, pyridinyl, thienyl or furanyl;

R1and R2each independently C1C20-alkyl, (cyclohexyl)methyl, cyclohexyl or phenyl, one of R1and R2can also be hydrogen or R1and R2taken together form a Cand their stereochemical isomeric forms, having immunostimulatory activity.

2. The method of obtaining derivatives of 6-aryl-5,6-dihydroimidazo[2,1-b]thiazole of General formula I

< / BR>
where Ar is phenyl, optionally substituted with halogen, C1- C6-alkyloxy-, C1C6alkyl-, nitro-group or two halogen atoms, pyridinyl, thienyl or furanyl;

R1and R2each independently C1C20-alkyl, (cyclohexyl)methyl, cyclohexyl or phenyl;

R1and R2one may also be hydrogen or R1and R2taken together form a C3C6-ascandilwy radical,

or their pharmaceutically acceptable salts accession acids, or their stereochemical isomeric forms, wherein the derivatives of 2-aminothiazole General formula II

< / BR>
where Ar is phenyl, optionally substituted with halogen, C1- C6-alkyloxy, C1C6-alkyl-, nitro-group or two halogen atoms, pyridinyl, thienyl or furanyl;

R1and R2each independently C1C20-alkyl, (cyclohexyl)methyl, cyclohexyl or phenyl;

R1and R2one may also be hydrogen or R1and R2taken together, can also form a C3-C

3. Derivatives of 2-aminothiazole General formula II

< / BR>
where Ar is phenyl, optionally substituted with halogen, C1- C6-alkyloxy-, C1C6-alkyl-, nitro-group or two halogen atoms, pyridinyl, thienyl or furanyl;

R1and R2each independently C1C20-alkyl, (cyclohexyl)methyl, cyclohexyl or phenyl;

R1and R2one may also be hydrogen or R1and R2taken together, can also form a C3- C6-ascandilwy radical,

or their pharmaceutically acceptable salts accession acid, or their stereochemical isomeric form as intermediates for obtaining derivatives of 6-aryl-5,6-dihydroimidazo-[2,1-b] is trichomania fact, as the active ingredient it contains derivatives of 6-aryl-5,6-dihydroimidazo[2,1 b] thiazole of General formula I

< / BR>
where Ar is phenyl, optionally substituted with halogen, C1C6alkyloxy-,C1C6-alkyl-, nitro-group or two halogen atoms, pyridinyl, thienyl, or furanyl;

R1and R2each independently C1C20-alkyl, (cyclohexyl)methyl, cyclohexyl or phenyl, R1and R2one may also be hydrogen or R1and R2taken together, can also form a C3C6ascandilwy radical,

or their pharmaceutically acceptable salts accession acid, or their stereochemical isomeric form in an amount of 0.1 to 500 mg per dose.

 

Same patents:

The invention relates to new cephalosporins, namely to derive 1-zetia-diazaphosphorines General formula 1:

(I)

where the wavy line represents a CIS - or TRANS-configuration; R1-C1-C4alkyl, if necessary, replaced by carboxypropyl;

R2-tetrazol-5-yl, if necessary, replaced by stands, methylthiourea or dihydroxyphenylethylamine, thiadiazole-2-yl, if necessary, replaced by stands, methylthio-, amino-, pyridylcarbonyl-, 3,4-diacetoxybiphenyl - carbonylmethyl - or 1-methylprednisolone - amino group of the purine-6-yl, 1,2,3-triazole-5-yl, 1,2,4-triazolyl, if necessary, replaced by stands and trifluoromethyl, thiazolo (5,4-C) pyridin-2-yl or 5,6-dioxo-1,2,4-triazinyl, replaced by chlorpropamide, cooa group COOH or R2-1 methylpyridine, sooa-radical soo-that may find application as antibacterial substances in medicine

The invention relates to new biologically active chemical compounds, specifically to derived dihydropyrimidine formula I

where R1- C1-C6-alkoxy or phenylaminopropyl,

R2- C1-C6-alkyl or phenyl,

R3is a hydrogen atom or a C1-C6-alkyl,

R4- C1-C6-alkyl or phenyl which may be substituted by one or more identical or different substituents from the group halogen, nitro, C1-C6-dialkylamino,1-C6-alkyl, C1-C6-alkoxy and hydroxy-group, or their therapeutically acceptable salts accession acid with protivominniy and anti-inflammatory activity

The invention relates to the first new derivatives of 1,2,5-thiadiazolo[3,4-h] quinoline General formula 1

NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity

The invention relates to new azetidinone derived isothiazol-pyridone: 2,3,4,9-tetrahydroindazole[5,4-b]China - in-3,4-dione, 2,3,4,9-tetrahydrothieno [5,4-b] [1,8]-naphthiridine-3,4-dione, 1,2,8,9-tetrahydro-7H-isothiazol-[4',5',5,6]pyrido [1,2,3-de]benzoxazine-7,8-dione and its salts

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective
The invention relates to medicine and used to replenish the Arsenal of normalizing the immune status of the organism

The invention relates to medicine and can be used to enhance antibacterial activity and expansion of the spectrum of antibacterial action

The invention relates to medicine, in particular to the surgery and the result they have proved

The invention relates to 7-examinerlawrence heterocyclic Amida - analogues of prostaglandins, which are receptor antagonists AND thromboxane a2(THA2or combined receptor antagonists AND thromboxane a2(thromboxane synthetase inhibitors, and are used, for example, in the treatment of thrombotic disease and/or vascular spasm: have a long duration of action

The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/УZ;

Y represents a single bond, 0, NR7or; Z represents hydrogen, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6that may be the same or different, represent hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

R8, R9, R10, R11which may be the same or different, represent hydrogen, lower alkyl or benzyloxycarbonyl, or their N-alkyl

The invention relates to methods of producing substituted imidazole derivatives and their non-toxic pharmaceutically acceptable acid additive salts

The invention relates to the synthesis of new biologically active chemical compounds, specifically to N-2-(I-R1-5-R2-6-R3-benzimidazolyl)-Succinimidyl acids of General formula I

where (a) R1=n-C4H9, R2=R3=H;

b) R1= CH3, R2= R3=Br, which have neuroleptic, antihypoxic and antiarrhythmic activity, and can find application in medicine
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