Derivatives of 3-(2-substituted phenyl)-2-(substituted imino)- thiazolidines or their pharmaceutically acceptable salts and pharmaceutical composition having antianginal and/or anti-neuralgic effect

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds as substances with antianginal or antineuralgic effect. The inventive product-derived 3-(2-substituted phenyl)-2-(substituted imino)-thiazolidine f-ly I with certain values radicals. The composition having the specified activities, contains an effective amount of compound 1. 2 S. and 1 C.p. f-crystals, 2 tab. Connection structure of f-crystals I:

The invention relates to new derivatives of 2-(imino-substituted)thiazolidine, method of production thereof, pharmaceutical remedies that contain these substances, use of specified derivatives of 2-(imino-substituted) thiazolidine for the treatment of various diseases, and pharmaceutical compositions based on them, used to treat.

The object of the present invention is new derivatives of 2-(imino-substituted)thiazolidine General formula (1)

(I)

where R1and R2-halogen, nitro, C1-4-alkoxy or C1-4is alkyl, hydrogen, the latter may have one or more halogen substituents,

R3and R4-halogen or C1-4-alkyl,

Z color the5is hydrogen, C1-4-alkyl, C1-4-alkylthio or group with the formula-NH-R, where R is C1-6is alkyl, aryl, aralkyl or C1-6alkenyl, sometimes with a halogen-or di-(C1-4-alkyl)-amino-Deputy or Z and R5together trivalent nitrogen atom, provided that Z-substituted imino group, R5C1-4-alkylthio, and, in the case when R5C1-4-alkylthio, Z-substituted aminogroup, and then if Z is sulfur, R5not hydrogen or C1-4-alkyl, and pharmaceuticals salt.

Compounds according to the present invention possess valuable antianginal and analgesic properties.

The term "alkyl group" used in accordance with the specification, includes straight or branched saturated hydrocarbon aliphatic series containing from 1 to 4 C-atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, tert.-butyl and so on, the Term "alkoxy group" refers to groups alilovic esters containing 1-4 C-atoms, i.e., methoxy, ethoxy, tert. -butoxy, etc. as a "2-6-alkariagroup considered straight or branched alkenilovyh group, for example, vinyl, allyl, 2-methylallyl, 1-propenyl, 1-butenyl, 2-butenyl, 2-hexenyl, etc., Di-C1-4-alkyl-amino-gr is ethylamino, diisopropylamino and so on). The term "halogen atom" refers to all four halogen atoms (fluorine, chlorine, bromine and iodine). The term "alkylthio group" refers to groups such as methylthio, ethylthio, n-propylthio. The term "aryl group" refers to aromatic groups such as phenyl or naphthyl. Under "Uralkalij groups" should be understood alkyl group with a phenyl - or naphthyl-substituents, e.g. benzyl or-venilation.

Compounds of General formula (1), where R5-alkylthio or group with the formula NH-R in which R is C1-6is alkyl, aryl, aralkyl or C1-6alkenyl, substituted di(C1-4-alkyl)-amino group, then the compounds of General formula (1), where Z and R5together trivalent nitrogen atom that is in the interaction with the acid may form a salt of the acid of accession. These salts are compounds with the General formula (1) used in the pharmaceutical industry, can be obtained by the reaction with inorganic or organic acids. In the example used in the pharmaceutical salts of acid accession should be called chlorides, bromides, econsultancy, tartarate, maleate and citrate.

The most preferred compounds of General formula I can be considered with the'-chloro-2'-nitrophenyl)-thiazolidin,

2 acetylamino-3-(4'-chloro-2'-nitrophenyl)-thiazolidin,

and their use in pharmaceutical salt.

In addition the subject of the present invention is a method of obtaining derivatives of 2-imino-substituted of thiazolidine General formula (1) and their use in pharmaceutical salts, comprising the following stages:

a) to obtain compounds of General formula (I), where Z is oxygen, and R5is hydrogen or C1-4-alkyl, 2-aminothiazoline General formula (II)

(II) where R1, R2, R3and R4have the above meaning, interact with allermuir agent of General formula (III)

(III)

where X is halogen or acyloxy, Z is oxygen, R5oxygen or C1-4-alkyl, and provided that when X is halogen, R5C1-4-alkyl; or

b) to obtain compounds of General formula (I), where Z is oxygen or sulfur, and R5the group with the formula NH-R, where R has the above significance, 2-aminothiazoline General formula (II) in which R1, R2, R2and R4have the above meaning, interact with isocyanates or isothioscyanates General formula (IV)

Z C N-R (IV)

where Z is oxygen or sulfur, and R has the above significance, or

to obtain with the crystals I, where Z is sulfur, and R5-the group with the General formula NH-R in which R is C1-6-alkyl or C1-6alkenyl, interacting with alkylhalogenide with the General formula (V),

Ala. -- X (V)

where ALK. C1-4-alkyl and X is halogen; or

g) to obtain compounds with the General formula (I), where Z and R5together trivalent nitrogen atom, 2-aminothiazoline General formula (II), where R1, R2, R3and R4have the above meaning, interact with cyanoguanidine with the General formula (VI)

(VI)

where X is halogen,

and also, if necessary and desired, the compound of General formula (I) is converted to its use in the pharmaceutical salt or the base of the General formula (I) of this salt, or the salt, acid attach to the base of the General formula (I) in other salts.

In accordance with variant a) of the method according to the object of the present invention, compounds of General formula (I), where Z is oxygen, and R5is hydrogen or C1-4-alkyl, are obtained by acylation of 2-aminothiazoline General formula (II). As Alliluyeva agent can be used carboxyaldehyde, carboxyanhydride or mixture of anhydrides (for example, acetyl is applied carboxylated, the reaction is carried out in the presence of an agent that binds acid. For this purpose it is preferable to use triethylamine or pyridine. The acylation of appropriate conduct in a proton or an aprotic solvent such as chloroform or acetic acid, at elevated temperature, preferably at the boiling temperature of the solvent. The duration of the reaction is 0.5 to 2 hours. The reaction mixture is treated with known methods by evaporation and crystallization to obtain the above product.

In accordance with variant b) method provided by the present invention, compounds of General formula (I), where Z is oxygen or sulfur, and R5substituted amino group, produced by the interaction of the compounds of General formula (II) with isocyanates or cyanate General formula (IV). The reaction is carried out mainly in a dipolar aprotic solvent, e.g. acetonitrile, at elevated temperature. The optimum can be considered a carry out reaction at the boiling temperature of the solvent. The duration of reaction is 2-10 hours. The compound of General formula (I) produced during the reaction, is released in the form of a base or salt, the resulting acid to recognize what the procedure, presented by the present invention, are compounds of General formula (I), where Z is substituted by aminogroup, and R5C1-4-alkylthio. As the starting compound used compound of General formula (I), where Z is sulfur, and R5- substituted amino group containing as a substituent C1-6-alkyl or C1-6alkenyl, which can be obtained by variant b). The specified starting material S-alkiliruya alkylhalogenide. The reaction should be carried out in proton solvents, preferably in a lower alcohol, at elevated temperatures, mainly at the boiling temperature of the reaction mixture. The resulting product is recovered from the reaction mixture by evaporation or by adding a solvent (such as ether).

In accordance with option g) obtain compounds of General formula (I), where Z and R5together trivalent nitrogen atom. To do this, hold the reaction of interaction of 2-aminothiazoline General formula (II) with changelogname General formula (VI), preferably with bromine cyan. The reaction should be carried out in a dipolar aprotic solvent, optimally in acetonitrile, at elevated temperature, preferably at a temperature boil lizovyvatj from the reaction mixture in the form of a free base or salt of the product of the merger acid by cooling or by adding a solvent for example, ether.

Compounds of General formula (I), where R5C1-4-alkylthio or group with the formula NH-R in which R is C1-6is alkyl, aryl or C1-6alkenyl substituted by di-(C1-4-alkyl)-amino group, and compounds with the General formula (I), where R5together trivalent nitrogen atom that can react with organic and inorganic acids, with formation of the corresponding salts. On the other hand, the free base of General formula (I) may be released from their acid salts of joining and salt in turn may be converted to other salts, the addition products of acids. Reactions can proceed by themselves by known methods.

Compounds of General formula (II) used as starting compounds, are well known. The retrieval method presented in the patent Hungary N 191408. Compounds of General formula (III), (IV), (V) and (VI) are widely available in the market or can be obtained using known methods.

Compounds according to the object of the present invention are characterized by high biological activity, and have antianginal and analgesic properties. The activity of the compounds provided by the present invention, shows were performed on rats or using the method of E. Sisulizer Opendiary K. and Hoffmann, I. (Azzneimittel Forschung, 5, 680 (1955).

Male rats weighing 180 to 220 g enter florales-urethanes in the amount of 70 to 700 mg/kg, subcutaneously. Using needle electrode was removed electrocardiogram. Using vasopressin caused coronary insufficiency [1NE (kg), intravenous] Measured the height of the wave T ECG before and after injection of vasopressin in the control and experimental groups. Compound was administered intravenously over 2 minutes before the injection of vasopressin. The results are given in the following table 1.

As shown by the data above, the most effective compounds according to the object of the present invention, have an analgesic effect is much higher than the corresponding effect of prenilamin.

2. "Writhing test for acetic acid, carried out on mice (analgesic effect).

Method: Newbould, Brit. J. Pharmacol. 35, 487 (1969).

Tests were carried out according to the method Nabila on white mice, given the fact that the amount of acetic acid injected intraperitoneally changed. A large part of the response was obtained using a concentration of 0.75% at the dose of 20 mg/kg and 20 mg/kg In the period between the 5th and 10th motogo, and also recorded the total number of reactions (from 5 minutes)

expressed as a percentage of the values obtained for the control group of animals. Mice were treated with investigational compound and a carrier, respectively, for 1 hour (orally) prior to the introduction of acetic acid. One dose taken 12 animals. The results are shown in table.2.

As the data reveal, the toxicity of the most effective compounds is much lower than the comparative toxicity of the compounds used in therapy.

In addition, the subject of the present invention is the inventive pharmaceutical composition containing as an active ingredient at least one compound of General formula (I) or its suitable for pharmaceutical use salt-product accession acid in a mixture with suitable inert solid or liquid carrier.

The pharmaceutical composition corresponding to the subject of the present invention may be obtained in a known manner by mixing the active ingredient with suitable inert solid or liquid carriers to give a mixture of galenical forms.

The pharmaceutical composition corresponding to predm is, the rage, hard or soft gelatin capsules, emulsions or suspensions (parenteral) for example, solutions for injection (or rectal (suppositories) applications.

As a carrier for receiving tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn and potato starch, talc, magnesium carbonate, magnesium stearate, calcium carbonate, stearic acid or its salts. The role of the media in soft gelatin capsules can perform vegetable oil, fat, wax or polyol suitable consistency. As carriers for solutions or syrups can be applied, for example, water, polyol esters (polyethylene glycol), sucrose or glucose. Injectable solutions may contain water, alcohols, glycols, glycerin or vegetable oil as a carrier. Candles can be made with the use of oils, waxes, fats or polyethylene glycols of suitable consistency.

In addition, the pharmaceutical compositions may contain commonly used in the pharmaceutical industry food additives, such as wetting and podsushiwauschee components, flavorings, salt, causing the change of osmotic the options.

Compounds of General formula (1) is better to produce for oral administration in the form of tablets or capsules. Thus tablets or capsules should contain about 50 mg of active substance.

A daily dose of the compounds of General formula (1) can vary widely depending on various factors such as the activity of the effective component, condition and age of the patient, intensity of treatment, etc. Oral dose is usually 10 to 1000 mg/day, preferably 50-500 mg/day. It should be emphasized that these data for doses are only informative character, and enter the dose should always be determined only by the physical condition of the person under the supervision of a physician.

In addition, the object of the present invention includes the use of compounds with the General formula (1) or pharmaceuticals salts to obtain pharmaceutical compositions that have protivooksidantnoj and/or analgesic activity.

Additionally, in accordance with the present invention proposes a method of treatment based on protivooksidantnoj and analgesic activity, consisting in the introduction to a patient compounds of General formula (1) (mean efficiency is edowski examples which are unlimited in nature:

Example 1.

2-(N-butyldiethanolamine)-3-(5'-chloro-2'-nitrophenyl) -thiazolidin.

1.3 g (5 mmol) of 2-imino-3'(5'-chloro-2'-nitrophenyl)-thiazolidine and 2.1 g (10 mmol) utilizationand was boiled in 20 acetonitrile for 4 hours. The solution was filtered and evaporated under vacuum. Oily residue was led from methanol.

Yield: 1.1 g (59%) of yellowish white crystals.

So pl. 150 151o(Meon)

Chromatographic analysis: cyclohexane/ethyl acetate 1/2 Rf0,6

The formula of the compound in accordance with data analysis:

C14H17ClN4S2O2(372,9)

Calculated: Cl 9,52% S 17,19%

Found: Cl 9,38% S 17,13%

IR (KBr): NH3380, NO21530, 1360/cm

Example 2.

3-(4'-bromo-2'-nitrophenyl)-2-(N-propyl-carbamoylating)-thiazolidin.

1 g (3 mmole) of 3-(4'-bromo-2'-nitrophenyl)-2-aminothiazoline and 0.52 g (6 mmol) propositionthe boiled in 30 ml of acetonitrile for 3 hours. The solution was filtered and evaporated under vacuum. The crystalline residue was recrystallized from a mixture of ethyl acetate and hexane.

Output: 0,8 (68.9% of the yellowish-green crystals.

So pl. 136-138o(From a mix atilia according to that analysis: C13H15BrN4O3S (387,3).

Calculated: Br 20,64% S 8,28%

Found: Br 20,58% S OF 8.25%

IR (KBr): NH = 3430, amide 1 1630, NO21350/cm

Example 3.

2-(N-allylthiourea)-3-(4'-bromo-2'-nitrophenyl) -thiazolidin

0.6 g (2 mmole) of 3-(4'-bromo-2'-nitrophenyl)-2-aminothiazoline and 0.3 g (3 mmole) of allylisothiocyanate was boiled in 20 ml of acetonitrile for 6 hours. Then the solution was filtered and evaporated under vacuum. The resulting yellow oil was led from methanol.

Output: 0,6 (74,6%) yellowish-white crystalline powder.

So pl. 115-116o(Meon);

Chromatographic analysis: cyclohexane/ethyl acetate 1/2 Rf0,5

The formula of the compound according to the results of the analysis of C13H13BrN4O2S2(410,3)

Calculated: Br Of 19.91 S 15,98%

Found: Br 19,98% S 15,94%

IR (KBr): NH 3365, NO21520, 1340/see

Example 4.

2-(N-methylthiocarbamate)-3-(5'-chloro-2'-nitrophenyl)thiazolidin

2.1 g (8 mmol) of 2-imino-3-(5'-chloro-2'-nitrophenyl)-thiazolidine and 1.1 g (12 mmol) ethylisothiocyanate was boiled in 20 ml of acetonitrile for 6 hours. After this, the solution was filtered and evaporated under vacuum. The resulting crystalline residue re the

So PL 163 165oC (ethanol/HE).

Chromatographic analysis: cyclohexane/ethyl acetate 3/2 Rf0,5

The formula of the compound according to the results of the analysis: C12H13ClN4O2S2(344,8).

Calculated: Cl 10,29% S 18,59%

Found: Cl 10,37 S 18,54%

IR (KBr): NH 3395, NO21 1540, 1330/cm

Example 5.

2-[(N-benzelstierna)-imino]-3 (4-chloro-2-nitrophenyl)-thiazolidin

1.3 g (5 mmol) of 2-imino-3-(4-chloro-2-nitrophenyl)-thiazolidine and 1.8 g (13 mmole) benzylisothiocyanate boiled in 30 ml of acetonitrile for 3 hours. Then the solution was filtered and evaporated under vacuum. The resulting yellow oil was recrystallized from methanol.

Was obtained 1.1 g (54%) of yellow crystals in the form of needles with so pl. 179 - 180o(Meon).

Chromatographic analysis: chloroform/ethyl acetate 3/2 Rf0,8

The formula of the compound according to that analysis: C17H15ClN4O2S2(406,9)

Calculated Cl 8,72% N 13,77% S 15,76%

Found: Cl 8,71% N 13,92% S 15,85%

C17H15ClN4O2S2(406,9)

IR (KBr): NH 3230, NO21515 1340/cm

Example 6

2-(N-benzyldimethylamine)-3-(5'-chloro-2'-nitrophenyl)-thiazolidin.

1.3 g (5 mmol) of 2-imino-3-(5'-chloro-2'-nitrogen the R was filtered and evaporated under vacuum. The crystalline residue was recrystallized from methanol.

Output: 1,7 (84% ) of a yellow crystalline powder with so pl. 175o(Meon).

Chromatographic analysis: cyclohexane/ethyl acetate 3/2 Rf0,6

The formula of the compound according to that analysis: C17H15ClN4O2S2(406,9)

Calculated: Cl 8,72% S 15,7%

Found: Cl 8,72% S 15,86%

IR (KBr): NH 3250, NO21530, 1350/see

Example 7.

2-(N-butylcarbamoyl)-3-(4'-chloro-2'-nitrophenyl)-thiazolidin.

1.3 g (5 mmol) of 2-imino-3-(4'-chloro-2'-nitrophenyl)-thiazolidine and 2 g (10 mmole) utilizationof was boiled in 20 ml of acetonitrile for 6 hours. The solution was filtered and evaporated under vacuum. The rest, has the form of a yellowish oil was dissolved in ethyl acetate, the solution was filtered and again evaporated to obtain the final product by crystallization from hexane.

Output: 1,05 g (59%) of a yellowish-white crystalline powder with so pl. 73 74oWith (EtOAc hexane)

Chromatographic analysis: cyclohexane/ethyl acetate 1/2 Rf0,6

The formula of the compound according to that analysis: C14H17ClN4O2S (356,9)

Calculated: Cl 9,94 S 8,98%

Found: Cl 9,82% S 8,67%

IR (KBr): NH 3410, azalides.

1.3 g (5 mmol) of 2-imino-3-(5-chloro-2'-nitrophenyl)-thiazolidine and 2.0 g (10 mmol) utilizationof was boiled in 20 ml of acetonitrile for 10 hours. Then the solution was filtered, evaporated under vacuum and the oily residue was vykristallizovyvalas from methanol. Received 0,86 g (48%) of pale yellow crystalline powder with so pl. 122 123o(Meon).

Chromatographic analysis: cyclohexane/ethyl acetate 1/2 Rf0,5

The formula of the compound according to that analysis: C13H17ClN4O3S (356,9)

Calculated: Cl 9,94% S 8,98%

Found: Cl Cl 9,89% S 9.28 ARE%

IR (KBr): NH 3430, amide-1 1650, NO21510, 1370/see

Example 9

2-(N-propellerlike)-3-(4'-chloro-2'-nitrophenyl)-thiazolidin.

1.3 g (5 mmol) of 2-imino-3-(4'-chloro-2'-nitrophenyl)-thiazolidine and 0.85 grams (10 mmol) propositionthe was boiled in 20 ml of acetonitrile for 6 hours. The solution was filtered and evaporated under vacuum. The residue was vykristallizovyvalas of a small amount of ethanol. Was obtained 1.1 g (64%) of pale yellow crystalline powder with so pl. 150 151oWith EE.IT).

Chromatographic analysis: cyclohexane/ethyl acetate 1/2 Rf0,6

The formula of the compound according to that analysis: C13H15ClN4O3S (342,9) Example 10

2-(N-propellerlike)-3-(5'-chloro-2'-nitrophenyl)-thiazolidin

1.3 g (5 mmol) of 2-imino-3-(5'-chloro-2'-nitrophenyl)-thiazolidine and 0.85 grams (10 mmol) propositionthe was boiled in 20 ml of acetonitrile for 10 hours. After this, the solution was filtered and evaporated under vacuum. The residue was vykristallizovyvalas of a mixture of acetate and hexane.

Was obtained 0.9 g (52%) of a yellowish-white powder in the form of crystals.

So pl. 124 125oWith EE.OAU-hexane)

Chromatographic analysis: cyclohexane/ethyl acetate 1/2 Rf0,5

The claims according to the analysis: C13H15ClN4O3S (342,9)

Calculated: Cl 10,35% S 9,35%

Found: Cl 10,20% S 9,50%

IR (KBr): NH 3460, amide-1 1670, NO21530, 1370/cm

Example 11

2-N'(3-dimethylaminopropyl-thiocarbamoyl)-imino-3-(2'- nitrophenyl)-thiazolidine hydrochloride.

1.1 g (5 mmol) of 2-imino-3-(2'-nitrophenyl)-thiazolidine and 1.2 g (8 mmol) of 3-dimethylaminopropylamine was boiled in 20 ml of acetonitrile for 8 hours. Then the solution was filtered and evaporated under vacuum. The oily residue was mixed with methanol and saturated with gaseous hydrogen chloride for 1 hour. The solution is evaporated under vacuum; the residue was vykristallizovyvalas from a mixture at">

Chromatographic analysis: MeOH Rf0,3

The claims according to the analysis: C15H26ClN<52S2(408)

Calculated: Cl 8,70% N 17,17% S 15,72%

Found: Cl 8,86% N 16,96% S OF 15.75%

IR (KBr): NO21520, 1340, NH 3270, 1340/see

Example 12.

2-(N'-allylthiourea)-3-(2'-nitrophenyl)-thiazolidin.

1.7 g (5 mmol) of 2-imino-3-(2'-nitrophenyl)-thiazolidine and 0.75 g (7.5 mmol) of allylisothiocyanate was boiled in 20 ml of acetonitrile for 5 hours. Then the solution was filtered and evaporated under vacuum. The resulting yellow oil was vykristallizovyvalas from methanol.

Yield: 0.9 g (56%) of a yellow crystalline powder with so pl. 102 - 103o(Meon)

Chromatographic analysis: cyclohexane/ethyl acetate 1/2 Rf0,8

The claims according to the analysis: C13H14N4O2S2(322,4)

Calculated: N 17,38% S fall of 19.88%

Found: N 17,21% S 20,17%

IR (KBr): NH 3460, NO21530, 1370=CH21630, 950/see

Example 13.

2-(N'-allylthiourea)-3-(5'-methoxy-2-nitrophenyl)-thiazolidin.

1.7 g (5 mmol) of 2-imino-3-(5'-methoxy-2'-nitrophenyl)-thiazolidin-hydrobromide suspended in 20 ml of ethanol under stirring. The basis of the identified ima 0.75 mg allylisothiocyanate and the mixture is boiled for 4 hours. After filtration the solution is evaporated under vacuum and the resulting yellow oil was vykristallizovyvalas of n-propanol.

Received: 1.1 g (62%) of a yellow crystalline powder.

So pl. 114 115oWith (n-prop. IT)

Chromatographic analysis: cyclohexane/ethyl acetate 3/2 Rf0,4

The claims according to the analysis: C14H16N4O3S2(352,4)

Calculated: N 15,90% S 18,20%

Found: N 16,15% S 18,03%

IR (KBr): NH 3370, NO21520, 1359 CH21620, 910/cm

Example 14

2-(N'-allylthiourea)-3-(4'-chloro-2'-nitrophenyl)-thiazolidin.

1.3 g (5 mmol) of 2-imino-3-(4'-chloro-2'-nitrophenyl)-thiazolidine and 0.75 g (7.5 mmole) of allylisothiocyanate boiled for 5 hours in 30 ml of acetonitrile. The solution was filtered and evaporated under vacuum. The solid precipitate was vykristallizovyvalas from methanol. Received 1.1 N. (61%) of a yellow crystalline powder. So pl. 111 113o(Meon).

Chromatographic analysis: cyclohexane/ethyl acetate 3/2, Rf0,5

The claims according to the analysis: C13H13ClN4O2S2(356,9)

Calculated: Cl 9,94% N 15,70% S 17,96%

Found: Cl 10,26% N 15,40% S 18,20%

IR (KBr): NH 3380, NO21540, 1370 CH21630, 950/see

2.6 g (10 mmol) of 2-imino-3-(4'-chloro-2'-nitrophenyl)-thiazolidine and 2.3 g (16 mmol) of 3-dimethylaminopropyl-isothiocyanate was boiled in 50 ml of acetonitrile for 14 hours. The solution was filtered and evaporated. The remainder in the form of a yellow oil was boiled for 1 hour in 20 ml of methanol saturated with gaseous hydrogen chloride. The solution is evaporated under vacuum and the solid residue was vykristallizovyvalas from isopropanol.

Received: 3,9 g (89%)

So pl. 207 208oC (isopropanol)

Chromatographic analysis: benzene/methanol 1/3 Rf0,4

The claims according to the analysis: C15H21Cl2N5O2S

Calculated: Cl 16,50% S 14,620

Found: Cl 15,98% S 15,05%

IR (KBr): NO21530, 1350, NH 3260, 2620/see

Example 16

2-N'-(3-dimethylaminopropyl)-thiocarbamoyl-imino)-3-(5' -chloro-2'-nitrophenyl)-thiazolidin.

1.8 g (7 mmol) of 2-imino-3-(5'=chloro-2'-nitrophenyl)-thiazolidine and 1.6 g (11 mmol) of 3-dimethylaminopropylamine was boiled in 20 ml of acetonitrile for 12 hours. The solution was filtered, evaporated and the resulting oily residue was vykristallizovyvalas from 20 ml of ethanol.

Received 2.0 g (71% ) of a yellow crystalline powder with so pl. 135 - 136oC (from ethanol).

Chalisa: C15H20ClN5O2S2(402,0)

Calculated: Cl 8,83% S 15,96%

Found: Cl cent to 8.85% S 16,46%

IR (KBr): NO21530, 1350, NH 3450, 3100/see

Example 17

2-(N'-allylthiourea)-3-(2'-nitro-4'-trifluoromethyl - phenyl)-thiazolidin.

2.9 g (10 mmol) of 2-imino-3-(2'-nitro-4'-trifluoromethyl-phenyl)-thiazolidine in 2 ml (2 g, 20 mmol) allylisothiocyanate boiled in 30 ml of acetonitrile for 4 hours. The solution is evaporated under vacuum and the residue was treated with (rubbed) hexane.

Was obtained 2.3 g (59%) of pale yellow crystalline powder.

So pl. 140 141o(Meon).

The claims according to the analysis: C14H13F3N4O2S2(RUR 390.4)

Calculated: N 14,35% S 16,42%

Found: N 14,35% S 16,69%

IR (KBr): NH 3370, C(=S)N 1490/cm

910, 830/cm

Example 18

2-(N-methylcarbamoyl)-3-(5'-chloro-2'-nitrophenyl)-thiazolidin

2.6 g (10 mmol) of 2-imino-3-(5'-chloro-2'-nitrophenyl)-thiazolidine and 1.8 g (25 mmol) methylisothiocyanate boiled in 30 ml of acetonitrile for 5 hours. Then the solution was filtered, evaporated under vacuum and the resulting oil was vykristallizovyvalas from isopropanol. Was obtained 2.2 g (66,5%) yellowish-white crystalline powder. So pl. 158 159oWith 2(330,9)

Calculated: Cl Of 10.72% S 16,99%

Found: Cl 10,63% S 16,96%

IR (KBr): nNH 3220, C(=S)N 1490/cm

IH-NMR: , 3,35 m (2H), 4,05 m (2H)

(COCl3) 6,5 S (NH), 7,2-8,0 m (3H).

Example 19

2-[(N-methylcarbamoyl)-imino]-3-(5-chloro-2-nitrophenyl)-thiazolidin

2,6 (10 mmol) of 2-imino-3-(5-chloro-2-nitrophenyl)-thiazolidine and 1.14 g of methyl isocyanate was heated in acetonitrile for 2 hours. After that, the mixture was cooled, isolated crystalline mass was filtered and washed with hexane.

Received 2.7 g (66%) of yellowish white crystals.

So pl. 218 220oC (isopropanol).

Chromatographic analysis: chloroform/ethyl acetate 1/2 Rf0,5

The claims according to the analysis of compound C11H1ClN4O3S (314,8)

Calculated: Cl 11,27% S 10,18%

Found: Cl 11,09% S 10,30%

IR (KBr): nNH 3200, amide-1 1620, NO21510, 1340/see

Example 20.

2-(N'-allylthiourea)-3-(5'-chloro-2'-nitrophenyl)-thiazolidin.

2.6 g (10 mmol) of 2-imino-3-(5'-chloro-2'-nitrophenyl)-thiazolidine and 1.5 ml (1.5 g, 15 mmol) allylisothiocyanate boiled in 40 ml of acetonitrile for 4 hours. The solution is evaporated under vacuum and the resulting oil was led by processing a small amount (isopropanol).

The formula of the compound according to that analysis: C13H13ClN4O2S2(356,9)

Calculated: Cl 9,94% S 17,90%

Found: Cl 10,07% S 18,20%

IR (KBr): NH 3300, C(=S)N 1490/see

Example 21.

2-(N'-methylthiocarbamate)-3-(2'-nitro-4'-triptoreline)-thiazolidin.

2.9 g (10 mmol) of 2-imino-3-(2'-nitro-4-4'-trifluoromethyl-phenyl)-thiazolidine and 1.2 g (16.5 mmol) methylisothiocyanate boiled in 30 ml of acetonitrile for 4 hours. The solution is evaporated under vacuum and the crystalline residue was vykristallizovyvalas from methanol. Received 1.8 g (53%) of a yellowish-white crystalline powder with so pl. 169 171o(Meon).

The formula of the compound according to the results of the analysis: C12H11F3N4S2O2(340,4)

Calculated: N 16,48% S 18,84%

Found: N 16,18% S 18,38%

IR (KBr): NH 3170, C(=S)N 1500, C=1140 S/cm

IN-R(CDCl3): 3,1 d (3H), 3,3 t (2H), 4,1 t (2H)

6,6 S (NH), 7,25 to 8.1 m (3H)

Example 22.

2-[(N-3-chlorpheniramol)-imino] -3-(2-nitro-4 - triptoreline)-thiazolidin

2.9 g (10 mmole) of 2-imino-3-(2-nitro-4-trifluoromethyl-phenyl)-thiazolidine and 1.85 g (12 mmol) of 3-chlorophenylalanine boiled in 30 ml of acetonitrile for 1 hour. The mixture is then cooled, eye-catching crystals were washed propanol).

Hromatografische analysis: cyclohexane/ethyl acetate 1/2 Rf0,6.

The formula of the compound according to the results of the analysis: C17H12ClF3N4O3(444,8)

Calculated: N 12,60% S 7,20%

Found: N 12,59% S 7.65% OF

IR (KBr): NH 3210, amide-1 1630, NO21510, 1340/see

Example 23.

2/(N-phenylthiocarbamoyl)-amino/-3-(2-nitro-4-triptoreline)-thiazolidin.

2.9 g (10 mmol) of 2-imino-3-(2-nitro-4-trifluoromethyl-phenyl)-thiazolidine and 1.3 ml (1.5 g, 11 mmol) phenylisothiocyanate boiled in 30 ml of acetonitrile for 4 hours. The mixture is then cooled, the formed crystals were filtered and washed with zantanon. Received 3.5 g (89%) slightly yellow-white crystalline powder with so pl. 168 169oC (isopropanol). Chromatographic analysis: cyclohexane/ethyl acetate 3/2 Rf0,7.

The formula of the compound according to the results of the analysis to connect WITH17H13F3N4O2S2(394,4)

Calculated: N 13,14% S 15,04%

Found: N 13,04% S 15,36%

IR (KBr): NH 3160, NO21510, 1302/see

Example 24

2 acetylamino-3-(4'-chloro-2'-nitrophenyl)-thiazolidin.

a) 2.6 g (10 mmol) of 2-imino-3-(4'-chloro-2'-nitrophenyl)-thiazolidine boiled in a mixture of 5 ml of acetic acid and 5 ml of dioxide is lsua each time with 20 ml dichloromethane. The organic phase was combined and washed three times, using each time with 20 ml of 5% aqueous sodium carbonate solution and water. Then the solution was dried and evaporated. The oily residue was vykristallizovyvalas of ethyl acetate.

Was obtained 2.3 g (77%) of yellowish-white crystals in the form of needles.

So pl. 127 128oWith (ethyl acetate).

Chromatographic analysis (thin layer chromatography):

cyclohexane/ethyl acetate 3/2 Rf0,3

The claims according to the results of the analysis: C11H10ClN3O3S (TO 299.7)

Calculated: Cl 11,84% N 14,02% S 10,70%

Found: Cl 11,64% N 13,80% S 10,69%

IR (KBr): AMD-1 1630, NO21520, 1350/see

b) 0.52 g (2 mmole) of 2-imino-3-(4'-chloro-2-nitrophenyl)-thiazolidine was dissolved in 20 ml of anhydrous chloroform. 0.24 g (of 0.21 ml, 3 mmole) acetylchloride and 0.4 mmole (0.3 g, 3 mmole) of triethylamine was added to the solution and boiled in the last 30 minutes. Then the solution is evaporated under vacuum, the oily residue was dissolved in 30 ml of dichloromethane, and was extracted twice, using each time 10 ml of a saturated aqueous solution of sodium chloride. The resulting solution was dried and evaporated, the oily residue was led from ethyl acetate.

Received 0.4 g (67% the way the product is a connection, the corresponding option a).

Example 25

L-acetylamino-3-(2-nitrophenyl)-thiazolidin

7.5 g (a 33.6 mmole) of 2-imino-3-(2-nitrophenyl)-thiazolidine boiled in a mixture of 15 ml of acetanhydride and 20 ml of acetic acid, in the presence of 0.2 g of powdered zinc in for 30 minutes. The mixture is then evaporated under vacuum, the crystalline residue was dissolved in 50 ml of dry ethyl acetate and was filtered while it was still hot. Then cooled, isolated crystals were also filtered hot and washed twice using each time 10 ml of ether. Received 6.8 g (76,3%) of the product so pl. 173 174oWith (ethyl acetate).

The claims according to the results of the analysis: C11H11N3O3(265,3)

Calculated: N 15,83% S 12,08%

Found: N 15,47% S 12,58%

Example 26

2-acetylamino-3-(4'-trifluoromethyl-2'-nitrophenyl)-thiazolidin

2.9 g (10 mmol) of 2-imino-3-(4'-trifluoromethyl-2'-nitrophenyl)-thiazolidine boiled in a mixture of 5 ml of acetanhydride and 5 ml of acetic acid for 1 hour. The solution was poured into 30 ml of ice water, the resulting crystals were filtered off and washed with water.

Was obtained 2.9 g (87%) of a yellowish-white crystalline powder.

So pl. 144 145oWith (ethyl acetate/hexane)

Danese data analysis: C12H10F3N3O3S (TO 333.3)

Calculated: N 12,60% S 9,62%

Found: N KZT 12.39% S 9,45%

IR (KBr): amide-1 1630, NO21520, 1340/see

Example 27

2 formylamino-3-(4'-chloro-2'-nitrophenyl)-thiazolidin.

0.52 g (2 mmole) of 2-imino-3-(4'-chloro-2-nitrophenyl)-thiazolidine and 0.9 g (10 mmol) of a mixture of anhydrides of acetic and formic acid was boiled in 10 ml of anhydrous chloroform for 30 minutes. Then the solution is evaporated under vacuum and the oily residue was vykristallizovyvalas from methanol. Received 0.45 g (79%) of a yellowish-white crystalline powder. So pl. 128 129oC (methanol).

The results of the analysis by the method of thin-layer chromographic: cyclohexane/ethyl acetate 3/2 Rf0,3.

The claims according to the analysis: C10H8ClN3O3(235,8)

Calculated: Cl 12,42% S 11,22%

Found: Cl 12,67% S 11,38%

IR (KBr): nCH 2900, amide-1, 1634, NO21530, 1355/see

Example 28.

2-[(N-allylthiourea)-imino]-3-(2'-chloro-6'-nitrophenyl)-thiazolidin.

1.04 g (4 mmole) of 2-imino-3-(2'-chloro-6'-nitrophenyl)-thiazolidine and 0.8 ml (0,81 g, 8 mmol) of allylisothiocyanate was boiled in 20 ml of acetonitrile for 5 hours. Then the solution was filtered and evaporated under vacuum. Formed from the powder.

So pl. 110 112oC (methanol)

The claims according to the analysis: C13H13ClN4O2S2(356,9)

Calculated: Cl 9,95% S 17,97%

Found: Cl 9,99% S 17,49%

IR (KBr): NH 3280, NO21520, 1340 cm

Example 29

3-(2'-chloro-6'-nitrophenyl)-2-[(N-propellerblades)-imino]-thiazolidin.

0,98 g (3.6 mmol) of 2-imino-3-(2'-chloro-6'-nitrophenyl)-thiazolidine and 0.6 ml (0.5 g, 6 mmol) propositionthe was boiled in 20 ml of acetonitrile for 3 hours. The crystalline residue was recrystallized from a mixture of ethyl acetate/hexane.

Was obtained 0.9 g (72,9%) yellowish-white crystalline powder with so pl. 132 134oWith (ethyl acetate/hexane) 1/2 Rf0,6.

The formula of the compound according to that analysis: C13H15ClN4O3S (342,9)

Calculated: Cl 10,35% S 9,35%

Found: Cl 10,41% S 9,01%

IR (KBr): NH 3420, amide-1, 1620, NO21520, 1350/cm

Example 30

3-(3'-chloro-2'-nitrophenyl)-2-[(N-propyl-carbarnoyl)-imino]-thiazolidin.

0.31 g (1.2 mmole of 2-imino-2-(3'-chloro-2'-nitrophenyl)-thiazolidine and 0.2 ml (0.17 g, 2 mmole) propositionthe boiled in 15 ml of acetonitrile for 1.5 hours. Then the solution was filtered and evaporated under vacuum. The resulting oily crystals were washed with ether.

The formula of the compound according to that analysis: C13H15ClN4O3S (342,9)

Calculated: Cl 10,35% S 9,35%

Found: Cl At 10.64% S 9.51%

IR (KBr): NH 3380, amide-1 1620, NO21530, 1355/see

Example 31

2-[(N-allylthiourea)-imino]-3-(2'-chloro-4'-nitrophenyl)-thiazolidin.

1.52 g (2 mmole) of 2-imino-3-(2'-chloro-4'-nitrophenyl)-thiazolidine and 0.4 ml (0.4 g, 4 mmole) of allylisothiocyanate boiled in 15 ml of acetonitrile for 6 hours. The solution was filtered and evaporated under vacuum. The crystalline residue was precrystallization from methanol.

Obtain 0.6 g (84%) of a yellowish-white crystalline powder with so pl. 154 155oC (methanol).

The formula of the compound according to that analysis: C13H13ClN4O2S2(356,9)

Calculated: Cl 9,95% S 17,97%

Found: Cl 9,48% S 17,82%

IR (KBr): NH 3260, NO21525, 1350/cm

Example 32

3-(2'-chloro-4'-nitrophenyl)-2-[(N-propyl-carbarnoyl)-imino]-thiazolidin.

0.31 g (1.2 mmole) of 2-imino-3-(2'-chloro-4'-nitrophenyl)-thiazolidine and 0.2 ml (0.17 g, 2 mmole) propositionthe boiled in 15 ml of acetonitrile for 2.5 hours. Then the solution is evaporated under vacuum and the oily residue was vykristallizovyvalas from a mixture of ethyl acetate and hexan).

Data analysis using thin layer chromatography: benzene/acetone 1/1 Rf0,8

The formula of the compound according to that analysis: C13H15ClN4O3S (342,9)

Calculated: Cl 10,35% S 9,35%

Found: Cl 10,38% S 9,20%

IR (KBr): NH 3470, amide-1 1650, NO21510, 1340 cm

Example 33

(R, S)-3-(4'-chloro-2'-nitrophenyl)-5-methyl-2-[(N - propellerblades)-imino] -thiazolidin.

2.7 g (10 mmol) of 2-imino-3-(4'-chloro-2'-nitrophenyl)-5-methylthiazolidine and 2 ml (1.7 g, 19 mmol) propositionthe was boiled in 20 ml of acetonitrile for 4 hours. Then the solution is evaporated under vacuum and the crystalline residue was recrystallized from ethyl acetate.

Was obtained 3.1 g (87%) of pale yellow crystalline powder. So pl. 168

170oWith (ethyl acetate).

Analysis by the method of thin-layer chromatography: benzene/acetone 1/1 Rf0,8.

The formula of the compound according to that analysis: C14H17ClN4O3S (356,9)

Calculated: Cl 9,94% S 8,98%

Found: Cl 9,95% S 9,07%

IR (KBr): NH 3460, amide-1 1640, NO21530, 1350/see

Example 34

-2-[(N-allylthiourea)-imino] -4-ethyl-3-(4'-chloro-2'- nitrophenyl)-thiazolidin.

0,57 g (2 mmole) -4-ethyl-2-imino-3-(4'-chloro-2'-nitrophenyl)-thiazolidine and 0.4 ml (0.4 Aravali under vacuum. Yellowish oily residue triturated with hexane.

Received 0,69 g (89%) of pale yellow crystalline powder.

So pl. 140oC (methanol).

Analysis using the method of thin-layer chromatography: cyclohexane/ethyl acetate 1/2 Rf0,8.

The formula of the compound according to that analysis: C15H17ClN4O2S2(384,9)

Calculated: Cl Which 9.22% S 16,66%

Found: Cl 9,42% S 16,55%

IR (KBr): NH 3240, NO21530, 1350/see

Example 35

(R, S)-2-[(N-allylthiourea)-imino] -3-(4'-chloro-2'- nitrophenyl)-5-methyl-thiazolidin.

of 1.36 g (5 mmol) of (R, S)-2-imino-3-(4'-chloro-2'-nitrophenyl)-5-methyl-thiazolidine and 1 ml of 1.02 g, 10 mmol) allylisothiocyanate boiled in 15 ml of acetonitrile for 3 hours. Then the solution is evaporated under vacuum. The resulting yellowish oily crystals were washed with hexane.

Was obtained 1.1 g (59,5%) of pale yellow crystalline powder with so pl. 110oC (methanol).

Analysis using the method of thin-layer chromatography: cyclohexane-ethyl acetate 1/2 Rf0,6.

The formula of the compound according to that analysis: C14H15ClN4S2O2(370,9)

Calculated: Cl To 9.57% S 17,29%

Found: Cl 9,54% enyl)-thiazolidin.

1.3 g (5 mmol) of 2-imino-3-(4-chloro-2-nitrophenyl)-thiazolidine and 1 g (14 mmol) utilizationof boiled in 30 ml of acetonitrile for 3 hours. Then the solution was filtered, evaporated under vacuum and the crystalline residue was precrystallization from methanol.

Received 0,85 g (52%) of a yellowish-white crystalline powder.

So pl. 162 164oC (methanol).

Analysis using the method of thin-layer chromatography: cyclohexane-ethyl acetate 1/2 Rf0,6. The formula of the compound according to that analysis: C12H13ClN4O3S (328,8)

Calculated: Cl 10,79% S 9,75%

Found: Cl 10,61% S 9,72%

IR (KBr): NH 3370,, amide-1 1620, NO21515, 1345/cm

Example 37

3-(5'-chloro-2'-nitrophenyl)-2-[(N-isopropyl-carbarnoyl)-imino]-thiazolidin.

1.3 g (5 mmole) of 2-imino-3-[(5'-chloro-2'-nitrophenyl)-imino]-thiazolidine and 1 g (12 mmol) Isopropylamine boiled in 30 ml of acetonitrile for 2 hours. After this, the solution was filtered and evaporated under vacuum. The resulting oil was vykristallizovyvalas from a mixture of ethyl acetate and hexane.

Was obtained 0.9 g (63%) of light yellow crystalline powder with so pl. 145 146oWith (ethyl acetate/hexane).

Analysis by the method of thin-layer chromatography: qi is ClN4O3S (342,8)

Calculated: Cl 10,34% S 9,36%

Found: Cl there is a 10.03% S 9,51%

IR (KBr): NH 3450, amide-1 1640, NO21520, 1360/see

Example 38

2-[(N-ethylcarbamate)-imino]-3-(4'-chloro-2'-nitrophenyl)-thiazolidin

1.3 g (5 mmol) of 2-imino-3-(4'-chloro-2-nitrophenyl)-thiazolidine and 1 g (14 mmol) utilizationof boiled in 30 ml of acetonitrile for 4 hours. Then the solution was filtered, evaporated under vacuum and the resulting crystalline residue was recrystallize from methanol.

Was obtained 0.9 g (55%) of a yellowish-white crystalline powder.

So pl. 174 175oC (methanol).

Analysis by the method of thin-layer chromatography: cyclohexane/ethyl acetate 1/2 Rf0,7.

The formula of the compound according to that analysis: C12H13ClN4O3S (328,8)

Calculated: Cl 10,79% S 9,75%

Found: Cl 10,88% S 9,89%

IR (KBr): NH 3350, amide-1 1625, NO21535, 1365/see

Example 39

3-(4'-chloro-2'-nitrophenyl)-2-[(N-isopropyl-carbarnoyl)-imino]-thiazolidin.

1.3 g (5 mmol) Isopropylamine boiled in 30 ml of acetonitrile for 3 hours. Then the solution was filtered, evaporated under vacuum and the resulting crystalline residue was recrystallized from methanol.

Got a 1.2 what Ecodom thin-layer chromatography: cyclohexane/ethyl acetate 1/2 Rf0,6. The formula of the compound according to the results of the analysis: C13H15ClN4O3S (342,8)

Calculated: Cl 10,34% S 9,36%

Found: Cl The 10.40% S 9,38%

IR (KBr): NH 3210, amide-1 1645, NO21530, 1360/see

Example 40

2-[(N-etildiocolmain)-imino]-2-(4'-chloro-2'-nitrophenyl)-thiazolidin

1.3 g (5 mmol) of 2-imino-3-(4'-chloro-2'-nitrophenyl)-thiazolidine and of 1.65 g (20 mmol) utilizationof boiled in 30 ml of acetonitrile for 8 hours. Then the solution was filtered, evaporated under vacuum, and the resulting crystalline residue was precrystallization from acetonitrile.

Received of 0.95% (55%) of pale yellow crystalline powder with so pl. 170 171oC (methanol).

Analysis by thin-layer chromatography: cyclohexane/ethyl acetate 1/2 Rf0,8.

The formula of the compound according to the results of the analysis: C12H13ClN4O2S2(344,8)

Calculated: Cl 10,29% S 18,39%

Found: Cl 10,15% S 18,39%

IR (KBr): NH 338, NO21530, 1365/see

Example 41

2-[(N-butylthioethyl)-imino]-3-(4'-chloro-2'-nitrophenyl)-thiazolidin.

1.3 g (5 mmol) of 2-imino-3-(4'-chloro-2'-nitrophenyl)-tizaidine and 1.7 g (15 mmol) utilizationand boiled in 30 ml of acetonitrile for 10 hours. Then a solution of Phil.

Received 1.2 g (66%) of a yellowish-white crystalline powder with so pl. 130oC (from methanol).

Analysis by the method of thin-layer chromatography: cyclohexane/ethyl acetate 1/2 Rf0,8.

The claims according to the results of the analysis: C14H17ClN4O2S2(372,9)

Calculated: Cl 9,52% S 17,19%

Found: Cl To 9.93, S 16.88 IN%

IR (KBr): NH 3380, NO21530, 1355/see

Example 42

2-[(N-tert-butylthiophenol)-imino] -3(4'-chloro-2'-nitrophenyl)-thiazolidin.

1.3 g (5 mmol) of 2-imino-3-(4'-chloro-2'-nitrophenyl)-thiazolidine and 1.7 g (15 mmol) of tert.-utilizationand boiled in 30 ml of acetonitrile for 12 hours. Then the solution was filtered and evaporated. Then the yellow crystalline residue was precrystallization from ethanol.

Received: 0.7 g (38%) yellowish-white crystalline powder.

So pl. 168 170oC (ethanol).

Analysis by the method of thin-layer chromatography: cyclohexane/ethyl acetate 3/2 Rf0,8.

The claims according to the results of the analysis: C14H16ClN4O2S2(372,9)

Calculated: Cl 9,52% S 17,19%

Found: Cl 9,38% S 17,49%

IR (KBr): NH 3220, NO21530, 1350/see

Example 43

2-[(N-tert-bgolden and 1.7 g (15 mmol) of tert.-utilizationand boiled in 30 ml of acetonitrile for 15 hours. Then the solution was filtered and evaporated. The resulting yellow crystalline residue was precrystallization from ethanol.

Was obtained 0.9 g (48%) of yellowish-white crystalline powder with so pl. 181 182oC (methanol).

Analysis by the method of thin-layer chromatography: cyclohexane/ethyl acetate 3/2 Rf0,6.

The claims according to the results of the analysis: C14H17ClN4O2S2(372,9)

Calculated: Cl 9,52% S 17,19%

Found: Cl 9,74% S 17,23%

IR (KBr): NH 3330, O21525, 1350/see

Example 44

2-[(N-ethyl-S-methyl-isotianil)-imino]-3(5'-chloro-2' -nitrophenyl)-thiazolidin-hydroiodide.

1.7 g (5 mmol) of 2-[(N-etildiocolmain)-imino]-3-(5'- chloro-2'-nitrophenyl)-thiazolidine and 1.5 ml (3.4 g, 25 mmol) methyliodide was boiled in 20 ml of anhydrous methanol for 1.5 hours. Then the solution was filtered and evaporated under vacuum. The resulting crystalline residue was precrystallization from ethanol. Received 1.8 g (740) a yellow crystalline powder with so pl. 194 196oC.

Analysis by the method of thin-layer chromatography: cyclohexane/ethyl acetate 3/2 Rf0,5.

The claims according to the results of the analysis: C13H16ClN4O2S 45

2-[(N'-allyl-S-methyl-isotianil)-imino] -3-(5'-chloro -2'-nitrophenyl)-thiazolidin.

1.8 g (5 mmol) of 2-(N-allylthiourea-imino)-3-(5'-chloro-2'-nitrophenyl)-thiazolidine and 1.5 ml (3.4 g, 25 mmol) methyliodide boiled in 40 ml of anhydrous methanol for 1.5 hours. Then the solution was filtered and osvetleni, evaporated and cooled. Selected crystals were filtered off and washed with ether. Received 2,2 (88%) of a yellowish-white crystalline powder with so pl. 184o(ISO-propanol).

Analysis by the method of thin-layer chromatography: cyclohexane/ethyl acetate 3/2 Rf0,6.

The claims according to the results of the analysis: C14H16ClN4O2S2(498,8)

Calculated: N 11,23% S IS 12.85%

Found: N 11,20$, S 13,28%

IR (KBr): NO21530, 1350,CH2, 920/cm

Example 46

2 cyanimide-3-(5'-chloro-2'-nitrophenyl)-thiazolidin.

2.6 g (10 mmol) of 2-imino-3-(5'-chloro-2'-nitrophenyl)-thiazolidine and 1.5 g (14 mmol) of bromine cyan boiled in 50 ml of acetonitrile for 3 hours until they begin to stand out crystals. The mixture was cooled, the selected crystals were filtered off and washed with ether. Was obtained 2.6 g (92%) of a yellowish-white crystalline powder.

So pl. 202oC (acetonitrile).


Found: Cl 12,36% S 11,83%

Example 47

2 cyanimide-3-(2'-nitro-4'-trifluoromethyl-phenyl)-thiazolidin-hydrobromide.

2.9 g (10 mmol) of 2-imino-3-(2'-nitro-4'-trifluoromethyl-phenyl)-thiazolidine and 1.5 g (14 mmol) of bromine cyan boiled in 50 ml of acetonitrile for 3 hours. Then the solution was cooled, the selected crystals were filtered off and washed with ether. Got 2.8 g (71%) of a yellowish-white crystalline powder with so pl. 263 264o(Glacial acetic acid-ether).

The formula of the compound according to the results of the analysis: C11H8BF3N4O2S (397,2)

Calculated: Br 20,13% S 8,07%

Found: Br 20,05% S 8,14%

IR (KBr): C N inactive

IH-NMR: DMSO-d6: 3,7 t (2H), 4,3 t (2H)

7,7 8,4 m (3H), 9,8 S (NH).

Example 48

Tablet containing 25 mg of active ingredient.

Composition one tablet is as follows:

active ingredient (the compound of example 46) 25.0 mg

corn starch 97,0 mg

polyvinylpyrrolidone 175,0 mg

magnesium stearate 3.0 mg 300,0 mg

Tablets prepared as follows:

Mix the active ingredient and the corn starch, then moisten 10-15% aqueous solution of polyvinylpyrrolidone and granularit mixture, then dried at temperatures of 40-50 the tablets.

The weight of one tablet of 300.0 mg

Example 49

Tablet containing 250 mg of active ingredient.

Composition one tablet is as follows:

active ingredient (the compound of example 46) 250.0 mg

lactose, 270.0 mg

corn starch 75,0 mg

magnesium stearate 5.0 mg

Moisten and mix the active ingredient, lactose and corn starch, granularit and dried at a temperature of 40-50oC. the Dried granules are forced through a sieve, as described above, is mixed with magnesium stearate and talc, then form tablets.

The weight of one tablet of 600.0 mg

Example 50

Tablets containing 25 mg of active ingredient.

The kernel of one bean is:

active ingredient (compound of example 20) 25.0 mg

corn starch 245,0 mg

talc 18,0 mg

gelatin 8.0 mg

magnesium stearate 4.0 mg

Mix the active ingredient and the corn starch, moistened with 10% aqueous solution of gelatin, the moist mixture into pellets, dried at a temperature of 40-50oC. the Dried granules are forced through a sieve, homogenized with talc and magnesium stearate and pressed from a mixture of core tablets 300,0 mg

Example 51

Pills, y ingredient (compound of example 20) 50.0 mg

lactose 97,0 mg

polyvinylpyrrolidone 2.0 mg

magnesium stearate 1 mg

Prepare granules, as described above. The mass of the nucleus pills is 150,0 mg

The dragee cores are covered with a layer containing sugar and talc by well-known methods. Thus obtained coated tablets paint non-toxic food dye of the desired color and polished with beeswax.

Example 52

Gelatin capsule containing 5.0 mg of the active ingredient.

The composition of the gelatine capsule is as follows:

active ingredient (compound of example 26) 5.0 mg

corn starch 40,0 mg

Aerosil 3.0 mg

magnesium stearate 2.0 mg

The ingredients are homogenized and filled with a mixture of gelatin capsules of suitable size.

Example 53

Gelatin capsule containing 25.0 mg of the active ingredient

The composition of the gelatine capsule is as follows:

active ingredient (compound of example 26) 25.0 mg

corn starch 265,0 mg

Aerosil 6.0 mg

magnesium stearate 4.0 mg

Homogenize the ingredients and fill with a mixture of gelatin capsules of suitable size.

Example 54

Gelatin capsule containing 50.0 mg of active ingredient.
lactose 90,0 mg

Aerosil 6.0 mg

magnesium stearate 4.0 mg

Homogenize the ingredients and fill with a mixture of a gelatin capsule of appropriate size.

Example 55

Gelatin capsule containing 25.0 mg of the active ingredient.

The composition of the gelatine capsule is as follows:

active ingredient (compound of example 26) 250.0 mg

lactose 148,0 mg

magnesium stearate 2.0 mg

Homogenize the ingredients and fill with a mixture of gelatin capsules of suitable size.

Example 56

Injection containing 25.0 mg of the active ingredient.

Composition one ampoule is as follows:

active ingredient (compound of example 25) 25.0 mg

sodium chloride 5.0 mg

dissolved in 5 ml of double-distilled water.

The active ingredient and the sodium chloride are dissolved in the required amount of double-distilled water, suitable for the preparation of the injection. This solution is filtered, filled them ampoules and sterilized.

Example 57

Injection containing 50.0 mg of active ingredient.

Composition one ampoule is as follows:

active ingredient (compound of example 25) 50.0 mg

sodium chloride 10.0 mg

Example 58

Suppositories containing 250 mg of active ingredient.

One of the suppository is as follows:

active ingredient (compound of example 24) 250.0 mg

the glycerides of the fatty acid

750,0 mg

Melt the glycerides of fatty acids, homogenize the active ingredient, then poured into the form. Weight of one suppository is 1000,0 mg, it contains 250.0 mg of the active ingredient.

Example 59

Drops containing 5% wt. the active ingredient.

active ingredient (the compound of example 46) 50.0 mg

sorbitol 340,0 mg

the glycol 100.0 mg

citric acid 1.0 mg

sodium citrate 3.0 mg

deionized water 1.0 mg

flavor 1.0 mg 505,0 mg

Dissolve sorbitol, active ingredient, citric acid and sodium citrate in an aqueous solution of propylene glycol, then after the dissolution of solid materials added flavor. Filter the solution and fill their flasks supplied to the distributor drops.

1. Derivatives of 3-(2-substituted phenyl)-2-( substituted imino)-thiazolidine General formula I

< / BR>
where R1hydrogen, halogen, nitro, C1WITH4-alkoxy or C1WITH4-alkyl, neobyazatelno or1WITH4-alkyl;

Z is oxygen, sulfur or imino, substituted C1WITH6-alkyl or C1WITH6-alkenyl;

R5hydrogen, C1WITH4-alkyl, C1- C4-alkylthio or group-other, where R1WITH6alkyl, phenyl, benzyl, or1WITH6alkenyl, which may be substituted with halogen or di(C1WITH4-alkyl)-amino group, or Z and R5together trivalent nitrogen atom, provided that Z is specified substituted aminogroup, and R5WITH1WITH4-alkylthio, and, if R5WITH1WITH4-alkylthio, and Z is substituted aminogroup, and further provided that when Z is sulfur, R5cannot be hydrogen or C1WITH4the alkyl,

or their pharmaceutically acceptable salts.

2. Derivatives under item 1, characterized in that they are 2-(N-alkyldiethanolamine)-3-(5'-chloro-2'-nitrophenyl) -thiazolidine, 2-cyanimide-3-(5'-chloro-2'-nitrophenyl)-thiazolidine, 2-acetylamino-3-(4'-chloro-2'-nitrophenyl)- thiazolidin, or their pharmaceutically acceptable salts.

3. Pharmaceutical composition having antianginal and/or anti-neuralgic effect, consisting of the active ingredient, which is Krainev mixture with a suitable inert solid or liquid pharmaceutical carrier.

 

Same patents:

The invention relates to a series of new derivatives of thiazolidinone and oxazolidinone containing nitroacetanilide group, and to methods of producing these compounds may find use of these compounds as vasodilators, for example, for the treatment and prevention of cardiovascular diseases

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

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a solid composition eliciting with an anti-ulcer activity and to a method for its preparing. Pharmaceutical composition consists of a core containing famotidine as an active component and starch, aerosil, stearic acid salt as accessory inert substances wherein a core is covered by polymeric envelope. Core comprises glucose and stearic acid as an accessory inert substance and magnesium stearate as a stearic acid salt. Polymeric envelope comprises oxypropylmethylcellulose, propylene glycol, castor oil, talc and titanium dioxide taken in the definite ratio of all components in the composition. Method for preparing pharmaceutical composition involves preparing raw, mixing therapeutically effective amount of famotidine with glucose and starch, moistening the mixture with starch paste, granulation, drying wetted granulate, repeated granulation, powdering dry granules, tableting and applying polymeric envelope containing oxypropylmethylcellulose on prepared cores with addition of titanium dioxide, propylene glycol, castor oil and talc. Invention provides enhancement of degradability, solubility and stability in storing.

EFFECT: improved method for preparing, valuable pharmaceutical properties of composition.

3 cl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: medicine, therapy, gastroenterology.

SUBSTANCE: method involves preliminary assay of the disorder type in gallbladder motor contraction and bile-excretion ways followed by prescribing thermal low-mineralized hydrocarbonate-sodium-sulfate-calcium-magnesium mineral water in the dose by 200-300 ml, 3 times per a day, 1 h before eating, tubages № 3 with mineral water, bathes and shower with mineral water every day for 10-14 days. In the hypotonic type of motor activity method involves mineral water at temperature 25-30°C, and in the hypertonic type - at temperature 38-40°C. Method provides accelerating in scars formation of ulcers and epithelization of erosions in gastroduodenal system, to prevent frequent exacerbations and to reduce activity of Chelicobacter-induced inflammation.

EFFECT: improved therapy method.

4 tbl, 2 ex

FIELD: medicine, endocrinology.

SUBSTANCE: invention relates to treatment of diabetes mellitus in mammals. Invention proposes applying inhibitors of enzyme dipeptidyl peptidase IV as an active component in manufacturing a medicinal agent, and in a method for treatment of diabetes mellitus. Invention provides enhancing the functional activity of insulin-producing cells in animal and differentiation of epithelial cells of the pancreas.

EFFECT: improved method for insulin producing and diabetes treatment.

20 cl, 5 dwg, 2 tbl, 2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: medicine.

SUBSTANCE: method involves using dipeptidyl peptidase IV (DP IV or CD 26) or DP IV-like enzyme for producing drug for treating stress or anxiety cases. Inhibitors are usable in combination with neuropeptides Y. The inhibitors are transported in physiologically compatible carriers. The inhibitors are also produced as prodrugs.

EFFECT: enhanced effectiveness of treatment.

6 cl, 11 dwg, 2 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to new polymorphous crystalline forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate of formula and stereomers thereof.

EFFECT: polymorphous crystalline forms of high stability.

12 cl, 1 tbl, 13 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of obtaining heterocycles of formula I , where X, A, R10-R17 are as defined in point 1 of the claim, while a) isothiocyanate of formula II is transformed into thiourea of formula IV by interaction with primary amine of formula III, and b) thiourea of formula IV is transformed into compound of formula I by interaction with sulfochloride R6SO2Cl in the presence of a base, where A, X, n, m and R10 to R17 in compounds of formulae II, III and IV are as defined in formula I, and R6 is (C1-C4)-alkyl, trifluoromethyl or phenyl non-sustituted or substituted by methyl, trifluoromethyl, F, CI, Br or polymer carreir. The transportation is shown by combination formulae

EFFECT: new multipurpose synthesis technique for heterocyclic compounds of the general formula I.

8 cl, 31 ex

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