RU2607630C1 - Aromatic derivatives of sulfanilamides carbonic anhydrase ii (ca ii) inhibitors, methods for production and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to novel aromatic sulphonamide derivatives, general formula 1 and pharmaceutically acceptable salts thereof, which are selective inhibitors of carbonic anhydrase II (CA II). Substituted sulphonamides correspond to general formula 1

,

where A is phenyl or thiophene; R₁ is C₁-C₅alkyl, C_-3C₆cycloalkyl, -C(O)R₃; provided that R₁ is not methyl, when A is phenyl, R₂ represents hydrogen; R₃ is a 5-6 member heterocyclyl with one or two heteroatoms, selected from nitrogen or oxygen atoms; R₂ is C₁-C₃alkyl, C₁-C₃alkoxy. Invention also relates to a method of producing compounds of general formula 1. Method involves two stages: a) sulphochlorination of corresponding oxazole derivative of general formula 5 (a-o) or 6 (a-j) with a mixture chlorosulphonic acid and thionyl chloride to produce intermediate sulphochlorides of formula 7 (a-o) or 8 (a-j), respectively, and b) with subsequent conversion of obtained sulphochlorides into primary sulphamides of formula 9 (b-o) or 10 (a-j) by reacting with ammonia according to following scheme

,

where

,

where R₁ is C₁-C₅alkyl, C₃-C₆cycloalkyl; NR'Rʺ is a morpholine or pyrrolidine.

EFFECT: compounds can be used for treating glaucoma, in particular, open-angle glaucoma, and other diseases caused by high intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathy mediated by activity of carbonic anhydrase II.

11 cl, 2 dwg, 2 tbl, 57 ex

Description

The present invention relates to new aromatic derivatives of sulfonamides local inhibitors of carbonic anhydrase II (CA II), their use as a tool for the local inhibition of carbonic anhydrase II (CA II), and the treatment of glaucoma and diseases caused by high intraocular pressure.

These compounds are carbonic anhydrase II (CA II) inhibitors, and can be used as local inhibitors of carbonic anhydrase II (CA II), for the treatment of glaucoma, increased intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathy.

Glaucoma is a disease in which the optic nerve of the eye is damaged, which leads to rapidly progressive loss of vision and its occurrence is associated with high intraocular pressure. In Russia, there are 800,000 people with glaucoma, and in the world 14 million people. Glaucoma ranks third in the world among diseases that cause blindness. The cause of glaucoma is an imbalance between the volume of intraocular fluid produced and the volume of fluid removed from the eye, which increases intraocular pressure and causes compression of the eye organs. It is known that an increase in intraocular pressure can be regulated by administering medications - beta adrenoreceptor antagonists or muscarinic receptor agonists. Treatment with drugs that lower intraocular pressure also produces a noticeable effect. Another treatment option is the systemic administration of carbonic anhydrase inhibitors. What is described in US patents: U.S. Pat. 5,679,670; U.S. Pat. 4,797,413; U.S. Pat. 4,847,289 describing dosages for topical application of thiophene sulfonamides, which lower the level of intraocular pressure by inhibiting carbonic anhydrase.

Carbonic anhydrase is an enzyme that is present in many tissues of the body (including in the tissues of the eye) and is involved in the process of hydration of carbon dioxide and dehydration of carbonic acid. In humans, this enzyme is represented by various isoenzymes, the most active of which is carbonic anhydrase II (CA-II), originally found in red blood cells and then in cells of other tissues. Inhibition of carbonic anhydrase of the ciliary body of the eye leads to a decrease in the secretion of intraocular fluid (mainly due to a decrease in the formation of bicarbonate ions with a subsequent decrease in the transport of sodium and liquid ions).

Non-selective inhibitors (CA-II) are known, such as Acetazolamide, US 2554816, May 29, 1951, Metazolamide, GB 781418 Aug. 21, 1957, Dorzolamide, EP 296879, Dec 28.1988, Brinzolamide, WO 9115486, Oct 17, 1991.

which are pan-inhibitors of all types of human carbonic anhydrase (which is 16 known isoforms).

In this regard, the search for new highly effective carbonic anhydrase II inhibitors is one of the main directions for creating new pharmacological agents for the treatment of glaucoma, increased intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathy.

The following are definitions of terms that are used in the description of this invention.

“Azaheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" (C ₁ -C ₆ ) alkyl substituents. Preferred alkyl groups are (C ₁ -C ₆ ) alkyl, even more preferred (C ₁ -C ₃ ) alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropylmethyl , cyclobutylmethyl, cyclopentylmethyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, cyclohexyl. Alkyl may have substituents.

“Cycloalkyl” means a saturated or partially saturated, monocyclic or polycyclic hydrocarbon ring containing from 3 to 14 carbon atoms.

“Alkoxy” means a (C ₁ -C ₃ ) alkyl-O-group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

“Amino group” means an R ₁ R ₂ N group optionally substituted or unsubstituted with the same substituents R ₁ and R ₂ . An amino group may have substituents.

“Aryl” means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, more preferably phenyl, naphthyl. Aryl may contain one or more “cyclic system substituents”, which may be the same or different.

“Aromatic cycle” (aromatic system) means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system, which, according to the Hückel rule, includes (4n + 2) π-electrons (n is a non-negative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, and the like. In the case of “heteroaromatic cycles”, π-electrons and p-electrons of heteroatoms participate in the conjugation system; their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like. An aromatic ring may have one or more “ring system substituents” and may be annelated with a non-aromatic ring, heteroaromatic or heterocyclic ring.

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).

“Heteroaryl” (hetaryl) means an aromatic monocyclic or polycyclic system comprising from 3 to 14 carbon atoms, preferably from 3 to 10, in which one or more carbon atoms are replaced by heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in the heteroaryl can be oxidized to an N-oxide. Heteroaryl may have one or more “ring system substituents”, which may be the same or different.

“Heterocyclyl” means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 3 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur phosphorus. The prefix "aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclyl may have one or more substituents, which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of heterocyclyl are piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxan-2-yl, tetrahydrofuryl, tetrahydrothienyl, oxazolinyl, thiophenyl, etc.

"Substituents of the cyclic system" may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle. Preferred cyclic system substituents are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted C ₁ -C ₅ alkyl, optionally substituted cycloC ₁ -C ₅ alkyl, C ₁ -C ₅ alkene, hydroxy group, C ₁ -C ₅ alkyloxy group ( methoxy, ethoxy, propoxy, ethyleneglycol diester s, methanediol diester), cyano, C ₁ -C ₅ alkyloxycarbonyl (methyl, ethyl), alkylthio (methylthio), carboxy, aminocarbonyl.

“Substituent” means a chemical radical that is attached to a molecular skeleton (scaffold, fragment), for example, “substituent alkyl”, “substituent of amino group”, “substituent of carbamoyl”, “substituent of cyclic system”, the meanings of which are defined in this section.

“Heterocycle substituents” may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle. Preferred cyclic system substituents are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted C ₁ -C ₅ alkyl, optionally substituted cycloC ₁ -C ₅ alkyl, C ₁ -C ₅ alkene, hydroxy group, C ₁ -C ₅ alkyloxy group ( methoxy, ethoxy, propoxy, ethylene glycol diester).

“Medicinal product (preparation)” - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.

"Pharmaceutical composition" means a composition comprising a compound of formula I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving agents, agents delivery, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal such as ointments and creams, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (Detailed description of the properties of such salts is given in Berge SM, et al., Pharmaceutical Salts J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

An object of the present invention is to provide novel selective carbonic anhydrase II inhibitors.

This goal is achieved by new selective carbonic anhydrase II inhibitors, which are aromatic derivatives of sulfonamides of the general formula 1 or their pharmaceutically acceptable salts.

The compounds of the present invention are aromatic derivatives of sulfonamides which inhibit the activity of carbonic anhydrase II and can be used to lower the level of intraocular pressure and treat glaucoma without causing significant systemic side effects when applied topically. The sulfonamide group in these compounds is functionally responsible for the enzymatic prosthetics of the metal ion (which is mainly Zn ²⁺ for all known types of carbonic anhydrase) and is therefore called zinc - linked group.

The subject of this invention is new aromatic derivatives of sulfonamides of the general formula 1, their pharmaceutically acceptable salts.

where A represents phenyl or thiophene;

R ₁ represents C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, —C (O) R ₃ ;

R ₃ represents a 5-6 membered heterocyclyl, with one or two heteroatoms selected from a nitrogen or oxygen atom.

R ₂ represents C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy.

More preferred are compounds that are aromatic derivatives of sulfonamides of the general formulas 1.1, 1.2, 1.3, 1.4, their pharmaceutically acceptable salts

where R ₁ and R ₂ take the values indicated above.

More preferred aromatic derivatives of sulfonamides are compounds of formulas 9a-9o, 10a-10j:

4- (2-Methyl-1,3-oxazol-5-yl) benzenesulfonamide (9a);

4- (2-Cyclopropyl-1,3-oxazol-5-yl) benzenesulfonamide (9b);

4- (2-Cyclobutyl-1,3-oxazol-5-yl) benzenesulfonamide (9c);

2-Methyl-5- (2-methyl-1,3-oxazol-5-yl) benzenesulfonamide (9d);

5- (2-Cyclopropyl-1,3-oxazol-5-yl) -2-methylbenzenesulfonamide (9e);

5- (2-Cyclobutyl-1,3-oxazol-5-yl) -2-methylbenzenesulfonamide (9f);

2-Methoxy-5- (2-methyl-1,3-oxazol-5-yl) benzenesulfonamide (9g);

5- (2-Cyclopropyl-1,3-oxazol-5-yl) -2-methoxybenzenesulfonamide (9h);

5- (2-Cyclobutyl-1,3-oxazol-5-yl) -2-methoxybenzenesulfonamide (9i);

5- (2-Methyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9j);

5- (2-Cyclopropyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9k);

5- (2-Cyclobutyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9I);

4- (2-Methyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9m);

4- (2-Cyclopropyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9n);

4- (2-Cyclobutyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9 °);

4- [2- (Pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10a);

4- [2- (Morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10b);

2-Methyl-5- [2- (pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10c);

2-Methyl-5- [2- (morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10d);

2-Methoxy-5- [2- (pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10e);

2-Methoxy-5- [2- (morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10f);

5- [2- (Pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10g);

5- [2- (Morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10h);

4- [2- (Pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10i);

4- [2- (Morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10j).

The subject of this invention is a method for producing compounds of general formula 1, general formulas 1.1, 1.2, 1.3, 1.4, compounds 9 (ao), 10 (aj) of their pharmaceutically acceptable salts, which comprises reacting the starting oxazoles of compounds of general formulas 5 (ao) or 6 (aj) with chlorosulfonic acid and thionyl chloride followed by the preparation of intermediate sulfochlorides of compounds 7 (ao) and 8 (aj), respectively, and the preparation of sulfamides 9 (ao) and 10 (aj), respectively, in two stages by sulfochlorination and conversion to sulfamides, as shown in Schemes 1

The subject of this invention is a method of inhibiting carbonic anhydrase II by contacting carbonic anhydrase II with compounds of the general formula 1 or of the general formulas 1.1, 1.2, 1.3, 1.4 and compounds 9 (a-o), 10 (a-j), their pharmaceutically acceptable salts.

The subject of this invention is an active component having the properties of selective carbonic anhydrase II inhibitors, which are aromatic derivatives of sulfonamides of general formula 1 or general formulas 1.1, 1.2, 1.3, 1.4, compounds 9 (ao), 10 (aj), as well as their pharmaceutically acceptable salts, for pharmaceutical compositions and medicines intended for the treatment of glaucoma, high intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertension implicit retinopathy and retinal vasculopathy.

The subject of this invention is a pharmaceutical composition for the treatment of glaucoma, increased intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathy, which has selective inhibitory activity against carbonic anhydrase II, containing pharmaceutically acceptable excipients component is a pharmaceutically effective amount of a compound of general formula 1 or general pho mule 1.1, 1.2, 1.3, 1.4, or a compound selected from 9, (a-o), 10 (a-j) or a pharmaceutically acceptable salt thereof, placed in farmatsevicheski acceptable packing.

The subject of this invention is a pharmaceutical composition for treating glaucoma, increased intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathy, containing pharmaceutically acceptable excipients and containing as a active ingredient a pharmaceutically effective amount of a compound of general formula 1 or general formulas 1.1, 1.2, 1.3, 1.4 or a compound selected from 9 (ao), 10 (aj), in the form of an ophthalmic p solution or emulsion.

The subject of this invention is a pharmaceutical composition for treating open-angle glaucoma containing pharmaceutically acceptable excipients and containing as active ingredient a pharmaceutically effective amount of a compound of general formula 1 or general formulas 1.1, 1.2, 1.3, 1.4, or a compound selected from 9 (ao), 10 ( aj) in the form of an ophthalmic solution or emulsion.

Pharmaceutical compositions may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, excipients (agents) and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with the active ingredient, which is a compound of general formula 1 or general formulas 1.1, 1.2, 1.3, 1.4 or a compound selected from 9 (ao), 10 (aj) of the present invention, may include other active ingredients, provided that they do not cause undesirable effects, for example, allergic reactions.

Preferably, the pharmaceutical composition is a 0.5-3% ophthalmic solution. Excipients in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical industry to obtain ophthalmic forms, including solvents, diluents, stabilizers, suspending agents, colorless agents, antiseptic agents, in ophthalmic solutions and suspensions. Excipients of the present invention are: salts of quaternary ammonium bases (benzalkonium chloride, cetylpyridinium chloride, dodecyldimethylbenzylammonium chloride) at a concentration of 1: 10000, P-phenylethyl alcohol - 0.3-0.5%, gasoline alcohol - 0.9%, nipagin - 0.05-0.23%, nipazole - 0.03-0.08%, ethanol mercuric chloride 0.01%, merthiolate 0.005%, disodium edetate, sodium chloride, monosubstituted sodium phosphate, disubstituted sodium phosphate, sodium tetraborate , sodium thiosulfate, sodium sulfacyl, hyloxapol, mannitol, carbomer (974P), ascorbic acid, thiamine bromide, riboflavin, boric acid in a concentration of 1.9-2% with a pH of ~ 5.0, sodium hydroxide and / or concentrated hydrochloric acid (to adjust the pH of the solution to 4.5-9.0), sorbic acid (pH = 3, 0-4.0) in a concentration of 0.05-0.2%, purified water.

The subject of the present invention is also a method for producing a pharmaceutical composition in the form of a 0.5-3% ophthalmic solution which consists of mixing with carriers selected from: quaternary ammonium salts (benzalkonium chloride, cetylpyridinium chloride, dodecyldimethylbenzylammonium chloride) at a concentration of 1: 10000, alcohol P-phenylethyl - 0.3-0.5%, benzyl alcohol - 0.9%, nipagin - 0.05-0.23%, nipazole - 0.03-0.08%, ethanol mercuric chloride 0.01 %, merthiolate 0.005%, disodium edetate, sodium chloride, monosubstituted sodium phosphate, disubstituted phosphate sodium, sodium tetraborate, sodium thiosulfate, sodium sulfacyl, hyloxapol, mannitol, carbomer (974Р), ascorbic acid, thiamine bromide, riboflavin, boric acid at a concentration of 1.9-2% with a pH of ~ 5.0, sodium hydroxide and / or concentrated hydrochloric acid (to adjust the pH of the solution 4.5-9.0), sorbic acid (pH = 3.0-4.0) at a concentration of 0.05-0.2%, purified water, at least at least one active component of general formula 1 or general formulas 1.1, 1.2, 1.3, 1.4 or a compound selected from 9 (ao), 10 (aj) or a pharmaceutically acceptable salt thereof.

The subject of this invention is also a medicinal product in the form of a 0.5-3% ophthalmic solution, placed in a pharmaceutically acceptable package comprising the active component comprising a compound of general formula 1 or general formulas 1.1, 1.2, 1.3, 1.4 or a compound selected from 9 (ao), 10 (aj) or an active ingredient or pharmaceutical composition for the treatment of glaucoma, increased intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic ret nopatii, hypertensive retinopathy and retinal vasculopathy.

The subject of the present invention is also a method for treating glaucoma, increased intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathy by topical administration (to the affected eye) of a pharmacologically effective amount of a compound of general formula 1 or general formulas 1.1, 1.2 , 1.3, 1.4 or a compound selected from 9 (ao), 10 (aj) or a pharmaceutically acceptable salt or drug or pharmaceutical composition thereof ii, or the active component.

The clinical dosage of a pharmaceutical composition or medicine containing, as an active principle, a compound of general formula 1 or, of general formulas 1.1, 1.2, 1.3, 1.4 or a compound selected from 9 (ao), 10 (aj) in patients may be adjusted depending on: therapeutic the effectiveness and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, as well as depending on the age, sex and stage of the patient’s disease, while the daily dose in adults is usually 5-10 ml per affected eye.

The invention is illustrated by drawings.

FIG. 1. Concentration dependences of lowering intraocular pressure with compound 10a and Pilocarpine.

FIG. 2. Concentration dependences of lowering the intraocular pressure with compound 10a and Indomethacin.

The invention is illustrated, but not limited to the following examples.

Example 1. General procedure 1 for the synthesis of compounds of formulas 5 (a-f) and 5 (j-o).

A suitable starting acylamino derivative (13.0 mmol) is added to 94% sulfuric acid. The reaction mixture was heated to 80 ° C for 1.5 hours, then cooled to room temperature and poured into ice water (100 ml). The solution was neutralized with 28% aqueous ammonia and extracted with ethyl acetate (150 ml). The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. Analytically pure oxazoles 5 (a-f) and 5 (j-o) are obtained.

Example 2. General procedure 2 for the synthesis of compounds of General formula 5g-i.

A suitable starting acylamino derivative (10.0 mM) is added to phosphorus (V) oxychloride (130 mM). The reaction mixture was heated to 80 ° C for 1.5 hours, then cooled to room temperature and poured into crushed ice. The precipitate formed is filtered off, washed with water, dried in air and recrystallized from acetonitrile. Analytically pure oxazoles 5g-i are obtained.

Example 3. Obtaining 2-Methyl-5-phenyl-1,3-oxazole (5A).

Receive by the General method 1 in the form of a yellow oil, t _pl. = 126-128 ° C,

Yield (82%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.21 (s, 1 N, H _oxazole ), 7.80 (d, J = 7.2 Hz, 2H, 2.6-H _Ar ), 7.43 (t, J = 7.2 Hz, 2H, 3.5-H _Ar ), 7.40 (t, J = 7.2 Hz, 1H, 4-H _Ar ), 2.47 (s, 3H, CH ₃ ); MS m / z 159 (M ⁺ , 100), 118 (15), 117 (68), 116 (38), 105 (47), 89 (46), 90 (50), 76 (36), 77 (42 ), 78 (22), 63 (34), 43 (29), 39 (42), 32 (12); 159 (M ⁺ , 100), 118 (15), 117 (68), 116 (38), 105 (47), 89 (46), 90 (50), 76 (36), 77 (42), 78 ( 22), 63 (34), 43 (29), 39 (42), 32 (12); ELEMENT ANALYSIS DATA: calculated for C ₁₀ H ₉ NO (159.19): C, 75.45; H, 5.70; N, 8.80; C, 75.31; H, 5.60; N, 8.83; found C, 75.31; H, 5.60; N, 8.83.

Example 4. Obtaining 2-Cyclopropyl-5-phenyl-1,3-oxazole (5b).

Receive according to the General method in the form of a yellow oil, t _PL. = 123-125 ° C,

Yield (79%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.64 (d, J = 7.2 Hz, 2H, 2,6-H _Ar ), 7.49 (s, 1H, H _oxazole ), 7.43 (t, J = 7.2 Hz , 2H, 3,5-H _Ar ), 7.32 (t, J = 7.2 Hz, 1H, 4-H _Ar ), 2.16 (m, 1H, CH _cyclopropyl ), 1.05 (m, 2H, H _cyclopropyl ), 1.00 ( m, 2H, H _cyclopropyl ); 185 (M ⁺ , 100), 118 (15), 117 (42), 116 (23), 105 (62), 89 (60), 90 (73), 76 (12), 77 (62), 78 ( 23), 63 (14), 62 (23), 51 (45), 50 (42), 43 (26), 39 (42), 32 (32); ELEMENT ANALYSIS DATA calculated for C ₁₂ H ₁₁ NO (185.23): C, 77.81; H, 5.99; N, 7.56; found C, 77.73; H, 6.08; N, 7.53.

Example 5. Obtaining 2-Cyclobutyl-5-phenyl-1,3-oxazole (5c).

Receive according to the General method in the form of a yellow oil, t _PL. = 105-107 ° C,

Yield (73%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (d, J = 7.2 Hz, 2H, 2,6-H _Ar ), 7.56 (s, 1H, H _oxazole ), 7.44 (t, J = 7.2 Hz , 2H, 3,5-H _Ar ), 7.34 (t, J = 7.2 Hz, 1H, 4-H _Ar ), 3.69 (m, 1H, CH _cyclobutyl ), 2.36 (m, 2H, H _cyclobutyl ), 2.33 ( m, 2H, H _cyclobutyl ), 2.07 (m, 1H, H _cyclobutyl ), 1.92 (m, 1H, H _cyclobutyl ); 199 (M ⁺ , 100), 145 (12), 118 (75), 89 (35), 90 (75), 76 (47), 77 (86), 78 (24), 63 (35), 62 ( 43), 51 (47), 50 (62), 43 (33), 39 (39), 32 (21); ELEMENT ANALYSIS DATA: calculated for C ₁₃ H ₁₃ NO (199.25): C, 78.36; H, 6.58; N, 7.03; Found: C, 78.30; H, 6.53; N, 7.05.

Example 6. Obtaining 2-Methyl-5- (4-methylphenyl) -1,3-oxazole (5d).

Receive according to the General method in the form of a yellow oil, t _PL. = 110-112 ° C,

Yield (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.90 (s, 1H, H _oxazole ), 7.69 (d, J = 8.2 Hz, 2H, H _Ar ), 7.29 (d, J = 8.2 Hz, 2H, H _Ar ) 2.34 (s, 3H, CH ₃ ), 1.33 (s, 3H, CH ₃ ); 173 (M ⁺ , 100), 131 (30), 130 (54), 119 (42), 132 (62), 116 (42), 115 (35), 104 (42), 103 (48), 77 ( 58), 77 (41), 67 (32), 65 (32), 43 (42), 39 (34), 32 (42); ELEMENT ANALYSIS DATA: calculated for C ₁₁ H ₁₁ NO (173.22): C, 76.27; H, 6.40; N, 8.09; Found: C, 76.19; H, 6.41; N, 8.11.

Example 7. Obtaining 2-Cyclopropyl-5- (4-methylphenyl) -1,3-oxazole (5e).

Receive according to the General method in the form of a yellow oil, t _PL. = 122-124 ° C,

Yield (48%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.52 (d, J = 8.2 Hz, 2H, H _Ar ), 7.41 (s, 1H, H _oxazole ), 7.24 (d, J = 8.2 Hz, 2H, H _Ar ) 2.32 (s, 3H, CH ₃ ), 2.14 (m, 1H, CH _cyclopropyl ), 1.05 (m, 2H, H _cyclopropyl ), 1.00 (m, 1H, H _cyclopropyl ); 199 (M ⁺ , 100), 131 (21), 130 (42), 119 (45), 117 (23), 116 (45), 115 (62), 104 (41), 103 (42), 77 ( 41), 77 (32), 67 (12), 65 (42), 43 (45), 39 (62), 32 (62); ELEMENTAL ANALYSIS DATA: calculated for C ₁₃ H ₁₃ NO (199.25): C, 78.37; H, 6.58; N, 7.03; Found: C, 78.28; H, 6.58; N, 7.00.

Example 8. Obtaining 2-Cyclobutyl-5- (4-methylphenyl) -1,3-oxazole (5f).

Receive according to the General method in the form of a yellow oil, t _PL. = 82-84 ° C,

Yield (56%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.56 (d, J = 8.2 Hz, 2H, H _Ar ), 7.48 (s, 1H, H _oxazole ), 7.26 (d, J = 8.2 Hz, 2H, H _Ar ), 3.68 (m, 1H, CH _cyclobutyl ), 3.32 (s, 3H, CH ₃ ), 2.35 (m, 2H, H _cyclobutyl ), 2.33 (m, 2H, H _cyclobutyl ), 2.05 (m, 1H, H _cyclobutyl ), 1.93 (m, 1H, H _cyclobutyl ); 213 (M ⁺ , 100), 159 (57), 131 (35), 130 (46), 119 (47), 117 (86), 116 (36), 115 (75), 104 (37), 77 ( 24), 67 (13), 65 (53), 43 (59), 39 (64), 32 (50); ELEMENT ANALYSIS DATA: calculated for C ₁₄ H ₁₅ NO (213.28): C, 78.84; H, 7.09; N, 6.57; Found: C, 78.80; H, 7.20; N, 6.56.

Example 9. Obtaining 5- (4-Methoxyphenyl) -2-methyl-1,3-oxazole (5g).

Receive according to the General method in the form of a yellow oil, t _PL. = 115-117 ° C,

Yield (83%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (s, 1H, H _oxazole ), 7.57 (d, J = 8.9 Hz, 2H, H _Ar ), 7.03 (d, J = 8.9 Hz, 2H, H _Ar ) 3.79 (s, 3H, OCH ₃ ), 2.45 (s, 3H, CH ₃ ); 189 (M ⁺ , 100), 160 (53), 146 (24), 135 (86), 133 (24), 132 (67), 77 (24), 76 (54), 39 (54), 32 ( 24); ELEMENT ANALYSIS DATA: calculated for C ₁₁ H ₁₁ NO ₂ (189.22): C, 69.82; H, 5.86; N, 7.40; found: C, 69.88; H, 5.91; N, 7.41.

Example 10. Obtaining 2-Cyclopropyl-5- (4-methoxyphenyl) -1,3-oxazole (5h).

Receive according to the General method in the form of a yellow oil, t _PL. = 102-104 ° C,

Yield (75%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.55 (d, J = 8.9 Hz, 2H, H _Ar ), 7.41 (s, 1H, H _oxazole ), 7.01 (d, J = 8.9 Hz, 2H, H _Ar ) 3.70 (s, 3H, OCH ₃ ), 2.13 (m, 1H, CH _cyclopropyl ), 1.05 (m, 2H, H _cyclopropyl ), 1.00 (m, 2H, H _cyclopropyl ); 215 (M ⁺ , 100), 160 (35), 146 (42), 135 (16), 133 (76), 132 (83), 104 (28), 103 (29), 91 (31), 77 ( 21), 76 (23), 39 (27), 32 (41); ELEMENTAL ANALYSIS DATA: calculated for C ₁₃ H ₁₃ NO ₂ (215.25): C, 72.54; H, 6.09; N, 6.51; Found: C, 72.53; H, 6.02; N, 6.47.

Example 11. Obtaining 2-Cyclobutyl-5- (4-methoxyphenyl) -1,3-oxazole (5i).

Receive according to the General method in the form of a yellow oil, t _PL. = 113-115 ° C,

Yield (72%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.58 (d, J = 8.9 Hz, 2H, H _Ar ), 7.41 (s, 1H, H _oxazole ), 7.11 (d, J = 8.9 Hz, 2H, H _Ar ), 3.60 (s, 3H, OCH ₃ ), 3.65 (m, 1H, CH _cyclobutyl ), 2.34 (m, 2H, H _cyclobutyl ), 2.32 (m, 2H, H _cyclobutyl ), 2.07 (m, 1H, H _cyclobutyl ), 1.92 (m, 1H, H _cyclobutyl ); 229 (M ⁺ , 100), 175 (41), 160 (24), 146 (41), 135 (15), 133 (52), 132 (25), 104 (31), 103 (25), 91 ( 42), 77 (24), 76 (63), 65 (57), 43 (12), 39 (54), 32 (12); ELEMENTAL ANALYSIS DATA: calculated for C ₁₄ H ₁₅ NO ₂ (229.28): C, 73.34; H, 6.59; N, 6.11; Found: C, 73.30; H, 6.55; N, 6.01.

Example 12. Obtaining 2-Methyl-5- (thiophen-2-yl) -1,3-oxazole (5j).

Receive according to the General method in the form of a brown solid, t _PL. = 98-100 ° C,

Yield (64%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.61 (dd, J _3-4 = 4.9 Hz, J _3-5 = 1.3 Hz, 1H, 3-H _thiophene ), 7.39 (dd, J _4-5 = 3.6 HZ, J _3-5 = 1.3 Hz, 1H, 5-H _thiophene ), 7.33 (s, 1H, H _oxazole ), 7.14 (dd, J _3-4 = 4.9 Hz, J _4-5 = 3.6 Hz, 1H 4-H _thiophene ), 2.45 (s, 3H, CH ₃ ); 165 (M ⁺ , 100), 123 (32), 122 (42), 111 (56), 109 (21), 108 (6), 97 (15), 70 (16), 69 (42), 58 ( 17), 57 (18), 45 (42), 39 (62), 38 (32), 32 (42), 30 (32); ELEMENT ANALYSIS DATA: calculated for C ₈ H ₇ NOS (165.22): C, 58.16; H, 4.27; N, 8.48; Found: C, 58.02; H, 4.23; N, 8.45.

Example 13. Obtaining 2-Cyclopropyl-5- (thiophen-2-yl) -1,3-oxazole (5k).

Receive according to the General method in the form of a brown solid, t _PL. = 99-102 ° C,

Yield (73%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.60 (dd, J _3-4 = 4.9 Hz, J _3-5 = 1.3 Hz, 1H, 3-H _thiophene ), 7.36 (dd, J _4-5 = 3.6 HZ, J _3-5 = 1.3 Hz, 1H, 5-H _thiophene ), 7.30 (s, 1H, H _oxazole ), 7.13 (dd, J _3-4 = 4.9 Hz, J _4-5 = 3.6 Hz, 1H, 4-H _thiophene ), 2.14 (m, 1H, CH _cyclopropyl ), 1.05 (m, 2H, H _cyclopropyl ), 0.97 (m, 2H, H _cyclopropyl ); 191 (M ⁺ , 100), 151 (52), 123 (12), 109 (39), 108 (46), 97 (35), 96 (53), 70 (12), 69 (35), 45 ( 76), 39 (34), 38 (97), 32 (65), 30 (45); ELEMENT ANALYSIS DATA: calculated for C ₁₀ H ₉ NOS (191.25): C, 62.80; H, 4.74; N, 7.32; Found: C, 62.71; H, 4.80; N, 7.35.

Example 14. Obtaining 2-Cyclobutyl-5- (thiophen-2-yl) -1,3-oxazole (5l).

Receive according to the General method in the form of a brown solid, t _PL. = 92-105 ° C,

Yield (74%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.61 (dd, J _3-4 = 4.9 Hz, J _3-5 = 1.3 Hz, 1H, 3-H _thiophene ), 7.40 (dd, J _4-5 = 3.6 Hz, J _3-5 = 1.3 Hz, 1H, 5-N _thiophene ), 7.37 (s, 1H, H _oxazole ), 7.14 (dd, J _3-4 = 4.9 Hz, J _4-5 = 3.6 Hz, 1H , 4-H _thiophene ), 3.66 (m, 1H, CH _cyclobutyl ), 2.34 (m, 2H, H _cyclobutyl ), 2.32 (m, 2H, H _cyclobutyl ), 2.05 (m, 1H, H _cyclobutyl ), 1.90 (m , 1H, H _cyclobutyl ); 205 (M ⁺ , 100), 151 (36), 123 (56), 122 (76), 111 (69), 109 (40), 69 (35), 58 (97), 57 (59), 45 ( 36), 39 (28), 38 (42), 32 (47), 30 (53); ELEMENT ANALYSIS DATA: calculated for C ₁₁ H ₁₁ NOS (205.28): C, 64.37; H, 5.40; N, 6.82; Found: C, 64.32; H, 5.33; N, 6.85.

Example 15. Obtaining 2-Methyl-5- (thiophen-3-yl) -1,3-oxazole (5m).

Receive according to the General method in the form of a brown solid, t _PL. = 100-102 ° C,

Yield (68%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (d, J _2-4 = 2.4 Hz, 1H, 2-H _thiophene ), 7.67 (dd, J _2-4 = 5.1 Hz, J _4-5 = 2.4 Hz, 1H, 4-H _thiophene ), 7.41 (d, J _4-5 = 2.4 Hz, 1H, 5-H _thiophene ), 7.32 (s, 1H, H _oxazole ), 2.45 (s, 3H, CH ₃ ) ; 165 (M ⁺ , 100), 123 (42), 122 (41), 111 (23), 109 (21), 108 (42), 97 (16), 83 (22), 84 (23), 70 ( 41), 69 (23), 45 (41), 39 (69), 38 (15), 32 (41), 30 (15); ELEMENT ANALYSIS DATA calculated for C ₈ H ₇ NOS (165.22): C, 58.16; H, 4.27; N, 8.48; Found: C, 58.09; H, 4.22; N, 8.47.

Example 16. Obtaining 2-Cyclopropyl-5- (thiophen-3-yl) -1,3-oxazole (5n).

Receive according to the General method in the form of a brown solid, t _PL. = 78-80 ° C,

Yield (67%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (dd, J _2-4 = 3.0 Hz, J _2-5 = 1.2 Hz, 1H, 2-H _thiophene ), 7.62 (dd, J _2-4 = 5.0 Hz, J _4-5 = 3.0 Hz, 1H, 4-N _thiophene ), 7.40 (dd, J _4-5 = 5.0 Hz, J _2-5 = 1.2 Hz, 1H, 5-N _thiophene ), 7.29 (s , 1H, H _oxazole ), 2.13 (m, 1H, CH _cyclopropyl ), 1.04 (m, 2H, H _cyclopropyl ), 0.98 (m, 2H, H _cyclopropyl ), 191 (M ⁺ , 100), 151 (35), 123 (35), 108 (83), 97 (13), 83 (45), 84 (64), 70 (34), 69 (75), 45 (35), 39 (65), 32 (44), 30 (35); ELEMENT ANALYSIS DATA: calculated for C ₁₀ H ₉ NOS (191.25): C, 62.80; H, 4.74; N, 7.32; Found: C, 62.65; H, 4.79; N, 7.26.

Example 17 Preparation of 2-Cyclobutyl-5- (thiophen-3-yl) -1,3-oxazole (5 °).

Receive according to the General method in the form of a brown solid, t _PL. = 92-105 ° C,

Yield (81%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.76 (dd, J _2-4 = 3.0 Hz, J _2-5 = 1.2 Hz, 1H, 2-H _thiophene ), 7.67 (dd, J _2-4 = 5.0 Hz, J _4-5 = 3.0 Hz, 1H, 4-N _thiophene ), 7.43 (dd, J _4-5 = 5.0 Hz, J _2-5 = 1.2 Hz, 1H, 5-H _thiophene ), 7.36 (s , 1H, H _oxazole ), 4.61 (M, 1H, CH _cyclobutyl ), 2.34 (m, 4H, H _cyclobutyl ), 2.03 (m, 1H, H _cyclobutyl ), 1-92 (m, 1H, H _cyclobutyl ); 205 (M ⁺ , 100), 151 (53), 123 (35), 122 (53), 111 (24), 84 (35), 70 (36), 69 (46), 45 (64), 39 ( 83), 38 (14), 32 (46), 30 (68); ELEMENT ANALYSIS DATA: calculated for C ₁₁ H ₁₁ NOS (205.28): C, 64.36; H, 5.40; N, 6.82; Found: C, 64.20; H, 5.32; N, 6.79.

Table 1 presents data on the percentage yield of compounds of general formula 5 (a-t) according to Scheme 1.

where R ₁ takes the above values.

Example 18. General procedure 3 for the synthesis of compounds of formulas 6 (a-j).

The cyclodehydration step is carried out as described in General Procedure 2. 1,3-Oxazoles 5 (p-t) are mixed with pyrrolidine or morpholine (100 mmol). The reaction mixture was heated at 50 ° C for 2.5 hours, then cooled to room temperature and water (150 ml) was added. The precipitate formed is filtered off, washed with water, dried in air and recrystallized from isopropanol. Analytically pure oxazoles 6 (a-j) are obtained.

Example 19. Obtaining (5-Phenyl-1,3-oxazol-2-yl) (pyrrolidin-1-yl) methanone (6a).

Receive according to the General method in the form of a brown solid, t _PL. = 127-130 ° C,

Yield (85%) at the amidation step.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (s, 1H, H _oxazole ), 7.79 (d, J = 7.2 Hz, 2H, 2,6-H _Ar ), 7.49 (t, J = 7.2 Hz , 2H, 3,5-H _Ar ), 7.41 (t, J = 7.2 Hz, 1H, 4-H _Ar ), 3.96 (t, J = 6.7 Hz, 2H, H _pyrrolidine ), 3.55 (t, J = 6.7 Hz, 2H, H _pyrrolidine ), 1.94 (t, J = 6.7 Hz, 4H, H _pyrrolidine ); 242 (M ⁺ , 28), 116 (31), 105 (14), 102 (30), 98 (17), 89 (19), 77 (28), 70 (100), 56 (33), 55 ( 40), 42 (33), 41 (38), 39 (25), 29 (11); ELEMENT ANALYSIS DATA: calculated for C ₁₄ H ₁₄ N ₂ O ₂ (242.28): C, 69.40; H, 5.82; N, 11.56; Found: C, 69.36; H, 5.76; N, 11.49.

Example 20. Obtaining Morpholin-4-yl (5-phenyl-1,3-oxazol-2-yl) methanone (6b).

Receive according to the General method in the form of a brown solid, t _PL. = 93-96 ° C,

Yield (79%) at the amidation stage.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (s, 1H, H _oxazole ), 7.79 (d, J = 12 Hz, 2H, 2.6-H _Ar ), 7.50 (t, J = 12 Hz , 2H, 3,5-H _A ), 7.42 (t, J = 12 Hz, 1H, 4-H _Ar ), 4.12 (m, 2H, H _morpholine ), 3.69 (m, 6H, H _morpholine ); 258 (M ⁺ , 18), 172 (31), 171 (25), 116 (57), 114 (12), 105 (19), 102 (30), 89 (23), 86 (100), 77 ( 35), 70 (30), 63 (12), 56 (57), 42 (42), 41 (12), 39 (13), 30 (16), 29 (38); ELEMENT ANALYSIS DATA: calculated for C ₁₄ H ₁₄ N ₂ O ₃ (258.28): C, 65.11; H, 5.46; N, 10.85; Found: C, 65.01; H, 5.46; N, 10.87.

Example 21. Obtaining [5- (4-Methylphenyl) -1,3-oxazol-2-yl] (pyrrolidin-1-yl) methanone (6c).

Receive according to the General method in the form of a yellow oil, t _PL. = 168-170 ° C,

Yield (82%) at the amidation stage.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (s, 1H, H _oxazole ), 7.68 (d, J = 8.2 Hz, 2H, H _Ar ), 7.32 (d, J = 8.2 Hz, 2H, H _Ar ), 3.91 (m, 2H, H _pyrrolidine ), 3.51 (m, 2H, H _pyrrolidine ), 2.35 (s, 3H, CH ₃ ), 1.89 (m, 4H, H _pyrrolidine ); 256 (M ⁺ , 10), 130 (20), 119 (8), 116 (15), 115 (12), 98 (11), 91 (15), 77 (10), 70 (100), 56 ( 24), 55 (27), 42 (40), 41 (42), 39 (22), 29 (7); ELEMENT ANALYSIS DATA: calculated for C ₁₅ H ₁₆ N ₂ O ₂ (256.31): C, 70.29; H, 6.29; N, 10.93; Found: C, 70.20; H, 6.35; N, 10.94.

Example 22. Obtaining [5- (4-Methylphenyl) -1,3-oxazol-2-yl] (morpholin-4-yl) methanone (6d).

Receive according to the General method in the form of a yellow oil, t _PL. = 157-159 ° C,

Yield (83%) at the amidation stage.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (s, 1H, H _oxazole ), 7.68 (d, J = 7.9 Hz, 2H, H _Ar ), 7.33 (d, J = 8.2 Hz, 2H, H _Ar ), 4.07 (m, 2H, H _morpholine ), 3.67 (m, 6H, H _morpholine ), 2.35 (s, 3H, CH ₃ ); 272 (M ⁺ , 10), 186 (34), 185 (34), 130 (60), 119 (17), 116 (33), 103 (19), 89 (9), 86 (100), 77 ( 17), 70 (32), 63 (9), 56 (49), 42 (40), 41 (12), 39 (13), 30 (13), 29 (28); ELEMENT ANALYSIS DATA: calculated for C ₁₅ H ₁₆ N ₂ O ₂ (272.31): C, 66.16; H, 5.92; N, 10.29; Found: C, 66.08; H, 5.97; N, 10.28.

Example 23. Obtaining [5- (4-Methoxyphenyl) -1,3-oxazol-2-yl] (pyrrolidin-1-yl) methanone (6e).

Receive according to the General method in the form of a yellow oil, t _PL. = 110-112 ° C,

Yield (79%) at the amidation stage.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (d, J = 8.5 Hz, 2H, H _Ar ), 7.64 (s, 1H, H _oxazole ), 7.03 (d, J = 8.5 Hz, 2H, H _Ar ), 3.95 (m, 2H, H _pyrrolidine ), 3.83 (s, 3H, OCH ₃ ), 3.54 (m, 2H, H _pyrrolidine ), 1.94 (m, 4H, H _pyrrolidine ); 272 (M ⁺ , 21), 146 (15), 132 (15), 98 (13), 77 (6), 70 (100), 56 (19), 55 (25), 42 (23), 41 ( 22), 39 (10), 29 (7); ELEMENT ANALYSIS DATA: calculated for C ₁₅ H ₁₆ N ₂ O ₃ (272.31): C, 66.16; H, 5.92; N, 10.29; Found: C, 65.99; H, 5.92; N, 10.32.

Example 24. Obtaining [5- (4-Methoxyphenyl) -1,3-oxazol-2-yl] (morpholin-4-yl) methatone (6f).

Receive according to the General method in the form of a yellow oil, t _PL. = 88-90 ° C,

Yield (79%) at the amidation stage.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (d, J = 8.5 Hz, 2H, H _Ar ), 7.67 (s, 1H, H _oxazole ), 7.04 (d, J = 8.5 Hz, 2H, H _Ar ) 4.13 (m, 2H, H _morpholine ), 3.89 (s, 3H, OCH ₃ ), 3.68 (m, 6H, H _morpholine ); 288 (M ⁺ , 28), 202 (14), 201 (18), 145 (39), 135 (11), 132 (29), 114 (11), 89 (7), 86 (100), 77 ( 11), 70 (31), 63 (6), 56 (47), 42 (28), 41 (7), 32 (16), 30 (9), 29 (26); ELEMENT ANALYSIS DATA: calculated for C ₁₅ H ₁₆ N ₂ O ₄ (288.31): C, 62.49; H, 5.59; N, 9.72; Found: C, 62.43; H, 5.63; N, 9.75.

Example 25. Preparation of Pyrrolidin-1-yl [5- (thiophen-2-yl) -1,3-oxazol-2-yl] methanone (6g).

Receive according to the General method in the form of a brown solid, t _PL. = 121-123 ° C,

Yield (80%) at the amidation stage.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (dd, J _3-4 = 4.9 Hz, J _3-5 = 1.0 Hz, 1H, 3-H _thiophene ), 7.72 (s, 1H, H _oxazole ) 7.58 (dd, J _4-5 = 3.6 Hz, J _3-5 = 1.0 Hz, 1H, 5-H _thiophene ), 7.21 (dd, J _3-4 = 4.9 Hz, J _4-5 = 3.6 Hz, 1H , 4-H _thiophene ), 3.90 (m, 2H, H _pyrrolidine ), 3.50 (m, 2H, H _pyrrolidine ), 1.88 (m, 4H, H _pyrrolidine ); 248 (M ⁺ , 21), 122 (30), 111 (15), 108 (15), 98 (19), 70 (100), 56 (38), 55 (39), 45 (18), 42 ( 52), 41 (58), 39 (42), 29 (12); ELEMENT ANALYSIS DATA: calculated for C ₁₂ H ₁₂ N ₂ O ₂ S (248.31): C, 58.05; H, 4.87; N, 11.28; Found: C, 57.97; H, 4.92; N, 11.30.

Example 26. Preparation of Morpholin-4-yl [5- (thiophen-2-yl) -1,3-oxazol-2-yl] methanone (6h).

Receive according to the General method in the form of a brown solid, t _PL. = 60-70 ° C,

The yield (73%) at the amidation stage

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (dd, J _3-4 = 4.9 Hz, J _3-5 = 1.0 Hz, 1H, 3-H _thiophene ), 7.72 (s, 1H, H _oxazole ) 7.59 (dd, J _4-5 = 3.6 Hz, J _3-5 = 1.0 Hz, 1H, 5- _thiophene ), 7.21 (dd, J _3-4 = 4.9 Hz, J _4-5 = 3.6 Hz, 1H 4-H _thiophene ), 4.06 (m, 2H, H _morpholine ), 3.66 (m, 6H, H _morpholine ); 264 (M ⁺ , 19), 178 (21), 177 (21), 122 (69), 114 (18), 111 (22), 108 (26), 95 (13), 86 (100), 70 ( 51), 69 (23), 58 (15), 57 (12), 56 (82), 45 (34), 42 (62), 41 (20), 39 (25), 30 (23), 29 ( 55); ELEMENT ANALYSIS DATA: calculated for C ₁₂ H ₁₂ N ₂ O ₃ S (264.31): C, 54.53; H, 4.58; N, 10.60; Found: C, 54.41; H, 4.65; N, 10.53.

Example 27. Preparation of Pyrrolidin-1-yl [5- (thiophen-3-yl) -1,3-oxazol-2-yl] methanone (6i).

Receive according to the General method in the form of a brown solid, t _PL. = 134-136 ° C,

Yield (78%) at the amidation stage.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (s, 1H, H _thiophene ), 7.73 (s, 1H, H _thiophene ), 7.71 (s, 1H, H _oxazole ), 7.52 (s, 1H, H _thiophene ), 3.90 (m, 2H, H _pyrrolidine ), 3.51 (m, 2H, H _pyrrolidine ), 1.88 (m, 4H, H _pyrrolidine ); 248 (M ⁺ , 19), 122 (25), 111 (16), 108 (17), 98 (16), 70 (100), 56 (29), 55 (31), 45 (20), 42 ( 36), 41 (40), 39 (30), 29 (9); ELEMENT ANALYSIS DATA: calculated for C ₁₂ H ₁₂ N ₂ O ₂ S (248.31): C, 58.05; H, 4.87; N, 11.28; found: C, 58.00; H, 4.92; N, 11.19.

Example 28. Preparation of Morpholin-4-yl [5- (thiophen-3-yl) -1,3-oxazol-2-yl] methanone (6j)

Receive according to the General method in the form of a brown solid, t _PL. = 103-105 ° C,

Yield (80%) at the amidation stage.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H, H _thiophene ), 7.74 (s, 1H, H _thiophene ), 7.71 (s, 1H, H _oxazole ), 7.52 (s, 1H, H _thiophene ), 4.05 (m, 2H, H _morpholine ), 3.66 (m, 6H, H _morpholine ); 264 (M ⁺ , 26), 178 (32), 177 (29), 122 (57), 114 (15), 111 (23), 108 (33), 95 (8), 86 (100), 70 ( 53), 69 (9), 58 (11), 57 (7), 56 (44), 45 (37), 42 (56), 41 (11), 39 (24), 30 (13), 29 ( 27); ELEMENT ANALYSIS DATA: calculated for C ₁₂ H ₁₂ N ₂ O ₃ S (264.31): C, 54.53; H, 4.58; N, 10.60; Found: C, 54.50; H, 4.53; N, 10.66.

Example 29. General procedure 3 for the synthesis of compounds of formulas 9 (a-o) and 10 (a-j).

The starting oxazole 5 or 6 (6.0 mmol) is added in small portions to a chilled mixture of chlorosulfonic acid (60 mmol) and thionyl chloride (6.0 mmol). The resulting mixture was heated at 60 ° C for 2 hours, then cooled to room temperature and poured into crushed ice. The precipitate formed is filtered off, washed with water and dissolved in chloroform (100 ml). This solution was washed with a 5% aqueous potassium carbonate solution, dried over anhydrous calcium chloride, filtered and evaporated in vacuo. The resulting mass was chromatographed on silica gel and using a suitable gradient of ethyl acetate in hexane as eluent. Intermediate sulfonyl chlorides 7 and 8 are obtained as a viscous, slowly crystallizing oil. A part of the obtained substance (1.25 mmol) was dissolved in 1,4-dioxane (2.5 ml) and the resulting solution was treated with 25% aqueous ammonia (0.56 ml, 7.5 mmol). The resulting mixture was heated at 75 ° C for 2 hours. Volatile components are removed in vacuo and water (10 ml) is added to the residue. The precipitate formed is filtered off, washed with water, dried in air and recrystallized from isopropanol. The yield of the obtained primary sulfamides 9 and 10 is calculated in two stages (sulfochlorination and conversion to sulfamides).

Example 30. Obtaining 4- (2-Methyl-1,3-oxazol-5-yl) benzenesulfonamide (9a)

Receive according to the General method in the form of a white solid, t _PL. = 221-224 ° C (i-PrOH),

Yield (72%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (d, J = 8.8 Hz, 2H, H _Ar ), 7.84 (d, J = 8.8 Hz, 2H, H _Ar ), 7.70 (s, 1H, H _oxazole ), 7.40 (s, 2H, NH ₂ ), 2.49 (s, 3H, CH ₃ ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 162.64, 149.96, 144.04, 131.42, 127.39, 125.54, 124.71, 14.60; 238 (M ⁺ , 100), 174 (21), 158 (19), 130 (10), 120 (5), 103 (7), 77 (7), 76 (7), 63 (7), 54 ( 9), 50 (5), 43 (5), 27 (5); ELEMENT ANALYSIS DATA: calculated for C ₁₀ H ₁₀ N ₂ O ₃ S (238.27): C, 50.41; H, 4.23; N, 11.76; Found: C, 50.36; H, 4.23; N, 11.80.

Example 31. Preparation of 4- (2-Cyclopropyl-1,3-oxazol-5-yl) benzenesulfonamide (9b).

Receive according to the General method in the form of a white solid, t _PL. = 181-184 ° C (i-PrOH),

Yield (83%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (d, J = 8.8 Hz, 2H, H _Ar ), 7.84 (d, J = 8.8 Hz, 2H, H _Ar ), 7.66 (s, 1H, H _oxazole ), 7.39 (s, 2H, NH ₂ ), 2.18 (m, 1H, CH _cyclopropyl ), 1.06 (m, 4H, H _cyclopropyl ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 162.46, 150.04, 144.16, 131.48, 127.39, 125.50, 124.66, 21.10, 9.90, 9.84; 264 (M ⁺ , 100), 263 (18), 238 (12), 200 (6), 184 (11), 129 (13), 128 (9), 89 (18), 80 (14), 77 ( 5), 76 (8), 75 (5), 63 (6), 53 (11), 52 (5), 51 (5), 50 (5), 41 (7), 39 (8), 27 ( 7); ELEMENT ANALYSIS DATA: calculated for C ₁₂ H ₁₂ N ₂ O ₃ S (264.31): C, 54.53; H, 4.58; N, 10.60; Found: C, 54.48; H, 4.58; N, 10.62.

Example 32. Preparation of 4- (2-Cyclobutyl-1,3-oxazol-5-yl) benzenesulfonamide (9c).

Receive according to the General method in the form of a white solid, t _PL. = 192-195 ° C (i-PrOH),

Yield (64%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (d, J = 8.8 Hz, 2H, H _Ar ), 7.86 (d, J = 8.8 Hz, 2H, H _Ar ), 7.73 (s, 1H, H _oxazole ), 7.40 (s, 2H, NH ₂ ), 3.72 (quin, J = 8.3 Hz, 1H, CH _cyclobutyl ), 2.18 (m, 4H, H _cyclobutyl ), 2.06 (m, 1H, H _cyclobutyl ), 1.94 ( m, 1H, H _cyclobutyl ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 167.98, 149.76, 144.09, 131.48, 127.38, 125.48, 124.81, 38.30, 33.20, 27.69, 18.99; 278 (M ⁺ , 30), 252 (6), 251 (16), 250 (100), 186 (9), 170 (13), 115 (8), 89 (15), 39 (8), 27 ( 5); ELEMENT ANALYSIS DATA: calculated for C ₁₃ H ₁₄ N ₂ O ₃ S (278.33): C, 56.10; H, 5.07; N, 10.06; Found: C, 56.02; H, 5.08; N, September 10.

Example 33. Preparation of 2-Methyl-5- (2-methyl-1,3-oxazol-5-yl) benzenesulfonamide (9d).

Receive according to the General method in the form of a white solid, t _PL. = 195-198 ° C (i-PrOH),

Yield (71%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (s, 1H, XH _Ar ), 7.77 (d, J = 7.7 Hz, 1H, BH _Ar ), 7.56 (s, 1H, H _oxazole ), 7.47 ( s, 2H, NH ₂ ), 7.46 (d, J = 7.7 Hz, 1H, AH _Ar ), 2.60 (s, 3H, CH ₃ ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 161.96, 150.07, 143.74, 136.56, 133.95, 127.56, 126.52, 123.91, 122.86, 20.54, 14.54; 252 (M ⁺ , 76), 172 (27), 171 (100), 143 (10), 116 (23), 115 (21), 103 (17), 102 (25), 89 (16), 77 ( 21), 63 (11), 54 (14), 51 (10), 43 (11), 27 (9); ELEMENT ANALYSIS DATA: calculated for C ₁₁ H ₁₂ N ₂ O ₃ S (252.29): C, 52.37; H, 4.79; N, 11.10; Found: C, 52.31; H, 4.79; N, 11.12.

Example 34. Preparation of 5- (2-Cyclopropyl-1,3-oxazol-5-yl) -2-methylbenzenesulfonamide (9e).

Receive according to the General method in the form of a white solid, t _PL. = 175-177 ° C (i-PrOH),

Yield (80%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (d, J _BX = 1.1 Hz, 1H, XH _Ar ), 7.75 (dd, J _AB = 8.1 Hz, J _BX = U Hz, 1H, BH _Ar ) 7.53 (s, 1H, H _oxazole ), 7.47 (s, 2H, NH ₂ ), 7.45 (d, J _AB = 8.1 Hz, 1H, A-H _Ar ), 2.60 (s, 3 H, CH ₃ ), 2.18 (m, 1H, CH _cyclopropyl ), 1.08 (m, 2H, H _cyclopropyl ), 1.01 (m, 2H, H _cyclopropyl ); ¹³ C NMR (DMSO-d ₆ ) δ 166.32, 149.40, 143.74, 136.39, 133.92, 127.45, 126.52, 123.93, 122.74, 67.25, 20.55, 9.40, 9.04; 278 (M ⁺ , 100), 277 (10), 198 (21), 197 (91), 168 (13), 142 (13), 141 (24), 128 (15), 115 (11), 103 ( 16), 102 (19), 90 (12), 89 (26), 80 (24), 77 (26), 63 (15), 53 (26), 52 (13), 51 (14), 41 ( 20), 39 (21), 27 (19); ELEMENT ANALYSIS DATA: calculated for C ₁₃ H ₁₄ N ₂ O ₃ S (278.33): C, 56.10; H, 5.07; N, 10.06; found: C, 56.00; H, 5.07; N, 10.10.

Example 35. Preparation of 5- (2-Cyclobutyl-1,3-oxazol-5-yl) -2-methylbenzenesulfonamide (9f).

Receive according to the General method in the form of a white solid, t _PL. = 170-173 ° C (i-PrOH),

Yield (75%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.12 (d, J _BX = 1.2 Hz, 1H, XH _Ar ), 7.82 (dd, J _AB = 7.9, J _BX = 1.2 Hz, 1H, BH _Ar ), 7.63 (s, 1H, H _oxazole ), 7.51 (m, 2H, NH ₂ ), 7.48 (d, J _AB = 7.9 Hz, 1H, A-H _Ar ), 3.73 (m, 1H, CH _cyclobutyl ), 2.62 ( s, 3H, CH ₃ ), 2.38 (m, 4H, H _cyclobutyl ), 2.07 (m, 1H, H _cyclobutyl ), 1.95 (m, 1H, H _cyclobutyl ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 165.91, 149.75, 143.55, 136.59, 133.48, 127.62, 126.31, 123.94, 122.52, 33.00, 26.98, 20.55, 19.01; 292 (M ⁺ , 43), 291 (9), 266 (6), 265 (15), 264 (100), 184 (16), 183 (79), 154 (6), 128 (13), 103 ( 5), 102 (7), 89 (6), 77 (8), 39 (7); ELEMENT ANALYSIS DATA: calculated for C ₁₄ H ₁₆ N ₂ O ₃ S (292.36): C, 57.52; H, 5.52; N, 9.58; Found: C, 57.48; H, 5.52; N, 9.60.

Example 36. Preparation of 2-Methoxy-5- (2-methyl-1,3-oxazol-5-yl) benzenesulfonamide (9g).

Receive according to the General method in the form of a white solid, t _PL. = 215-217 ° C (i-PrOH),

Yield (75%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.90 (d, J _BX = 1.9 Hz, 1H, XH _Ar ), 7.83 (dd, J _AB = 8.6, Hz, J _BX = 1.9 Hz, 1H, BH _Ar ), 7.41 (s, 1H, H _oxazole ), 7.31 (d, J _AB = 8.6 Hz, 1H, А-H _Ar ), 7.17 (s, 2H, NH ₂ ), 3.94 (s, 3H, ОCH ₃ ), 2.50 (s, 3H, CH ₃ ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 165.74, 156.54, 149.38, 132.76, 129.79, 124.14, 122.00, 120.77, 114.45, 57.38, 12.46; 268 (M ⁺ , 100), 190 (5), 189 (12), 162 (6), 161 (6), 131 (7), 119 (5), 118 (6), 104 (7), 103 ( 5), 91 (5), 89 (17), 77 (6), 76 (11), 75 (6), 63 (8), 54 (8), 43 (10), 36 (7), 27 ( 5), 15 (7); ELEMENT ANALYSIS DATA: calculated for C ₁₁ H ₁₂ N ₂ O ₄ S (268.29): C, 49.25; H, 4.51; N, 10.44; Found: C, 49.15; H, 4.51; N, 10.46.

Example 37. Preparation of 5- (2-Cyclopropyl-1,3-oxazol-5-yl) -2-methoxybenzenesulfonamide (9h).

Receive according to the General method in the form of a white solid, t _PL. = 211-215 ° C (i-PrOH),

Yield (68%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.94 (d, J _BX = 1.8 Hz, 1H, XH _Ar ), 7.84 (dd, J _AB = 8.6, Hz, J _BX = 1-8 Hz, 1H, BH _Ar ), 7.45 (s, 1H, H _oxazole ), 7.29 (d, J _AB = 8.6 Hz, 1H, A-H _Ar ), 7.18 (s, 2H, NH ₂ ), 3.94 (s, 3H, OCH ₃ ), 2.17 (m, 1H, CH _cyclopropyl ), 1.06 (m, 2H, H _cyclopropyl ), 0.99 (m, 2H, H _cyclopropyl ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 165.82, 156.51,149.37, 132.72, 129.77, 123.65, 122.74, 120.71, 114.40, 67.23, 57.24, 9.37, 8.95; 294 (M ⁺ , 100), 293 (7), 279 (5), 215 (6), 129 (5), 128 (8), 115 (7), 89 (7), 80 (7), 76 ( 7), 53 (7), 41 (6), 39 (6), 27 (6); ELEMENT ANALYSIS DATA: calculated for C ₁₃ H ₁₄ N ₂ O ₄ S (294.33): C, 53.05; H, 4.79; N, 9.52; Found: C, 52.96; H, 4.80; N, 9.54.

Example 38. Preparation of 5- (2-Cyclobutyl-1,3-oxazol-5-yl) -2-methoxybenzenesulfonamide (9i).

Receive according to the General method in the form of a white solid, t _PL. = 175-177 ° C (i-PrOH),

Yield (69%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (d, J _BX = 2.0 Hz, 1H, XH _Ar ), 7.88 (dd, J _AB = 8.7, J _BX = 2.0 Hz, 1H, BH _Ar ), 7.52 (s, 1H, H _oxazole ), 7.31 (d, J _AB = 8.7 Hz, 1Н, А-H _Ar ), 7.18 (s, 2Н, NH ₂ ), 3.94 (s, 3H, ОCH ₃ ), 3.70 ( m, 1H, CH _cyclobutyl ), 2.3.5 (m, 4H, H _cyclobutyl ), 2.04 (m, 1H, H _cyclobutyl ), 1.93 (m, 1H, H _cyclobutyl ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 166.84, 156.63, 149.84, 132.70, 129.97, 123.80, 122.68, 120.72, 114.42, 57.24, 33.14, 27.69, 18.99; 308 (M ⁺ , 25), 282 (5), 281 (14), 280 (100), 225 (6), 201 (7), 115 (5), 89 (11), 76 (7), 55 ( 6), 39 (9), 27 (7); ELEMENTAL ANALYSIS DATA: calculated for C ₁₄ H ₁₆ N ₂ O ₄ S (308.36): C, 54.53; H, 5.23; N, 9.08; Found: C, 54.49; H, 5.23; N, 9.08.

Example 39. Preparation of 5- (2-Methyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9j).

Receive according to the General method in the form of a white solid, t _PL. = 154-157 ° C (i-PrOH),

Yield (76%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (s, 2H, NH ₂ ), 7.55 (s, 1H, H _oxazole ), 7.54 (d, J = 4.0 Hz, 1H, H _thiophene ), 7.38 ( d, J = 4.0 Hz, 1H, H _thiophene ), 2.48 (s, 3H, CH ₃ ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 162.26, 145.31, 134.09, 131.76, 125.03, 124.57, 14.48; 244 (M ⁺ , 100), 189 (25), 180 (12), 164 (7), 152 (16), 136 (12), 111 (6), 110 (8), 109 (59), 95 ( 37), 93 (7), 83 (6), 82 (15), 69 (12), 64 (7), 54 (20), 53 (7), 52 (5), 45 (16), 43 ( 25), 39 (6), 38 (5), 27 (11), 26 (6), 15 (5); ELEMENT ANALYSIS DATA: calculated for C ₈ H ₈ N ₂ O ₃ S ₂ (244.29): C, 39.33; H, 3.30; N, 11.47; Found: C, 39.28; H, 3.30; N, 11.45.

Example 40. Preparation of 5- (2-Cyclopropyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9k).

Receive according to the General method in the form of a white solid, t _PL. = 140-142 ° C (i-PrOH),

Yield (69%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (s, 2H, NH ₂ ), 7.55 (s, 1H, H _oxazole ), 7.53 (s, 1H, H _thiophene ), 7.45 (s, 1H, H _thiophene ), 2.16 (M, 1H, CH _cyclopropyl ), 1.08 (m, 2H, H _cyclopropyl ), 1-02 (m, 2H, H _cyclopropyl ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 162.19, 145.34, 133.97, 131.24, 125.24, 124.20, 65.83, 10.49, 10.05; 270 (M ⁺ , 100), 269 (16), 268 (16), 244 (10), 190 (19), 162 (7), 135 (55), 134 (19), 123 (5), 98 ( 7), 95 (14), 91 (10), 82 (16), 80 (21), 69 (7), 54 (5), 53 (23), 52 (9), 51 (10), 45 ( 11), 41 (16), 39 (17), 38 (10), 29 (9), 27 (23), 26 (7), 15 (7); ELEMENT ANALYSIS DATA: calculated for C ₁₀ H ₁₀ N ₂ O ₃ S ₂ (270.33): C, 44.43; H, 3.73; N, 10.36; Found: C, 44.35; H, 3.73; N, 10.32.

Example 41. Preparation of 5- (2-Cyclobutyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9l).

Receive according to the General method in the form of a white solid, t _PL. = 149-152 ° C (i-PrOH),

Yield (78%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (s, 2H, NH ₂ ), 7.59 (s, 1H, H _oxazole ), 7.54 (d, J = 4.0 Hz, 1H, H _thiophene ), 7.40 ( d, J = 4.0 Hz, 1H, H _thiophene ), 3.69 (quin, J = 8.33 Hz, 1H, CH _cyclobutyl ), 2.35 (m, 4H, H _cyclobutyl ), 2.04 (m, 1H, H _cyclobutyl ), 1.93 ( m, 1H, H _cyclobutyl ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 167.59, 145.37, 145.11, 134.12, 131.72, 124.96, 124.69, 33.02, 27.66, 18.98; 284 (M ⁺ , 33), 283 (5), 258 (12), 257 (14), 256 (100), 201 (12), 192 (5), 164 (7), 148 (7), 121 ( 18), 95 (15), 94 (5), 66 (6), 64 (5), 55 (11), 45 (7), 39 (11), 29 (6), 27 (10); ELEMENT ANALYSIS DATA: calculated for C ₁₁ H ₁₂ N ₂ O ₃ S ₂ (284.36): C, 46.46; H, 4.25; N, 9.85; Found: C, 46.43; H, 4.25; N, 9.87.

Example 42. Preparation of 4- (2-Methyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9m).

Receive according to the General method in the form of a white solid, t _PL. = 182-185 ° C (i-PrOH),

Yield (81%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.98 (d, J = 1.3 Hz, 1H, H _thiophene ), 7.84 (d, J = 1.3 Hz, 1 H, H _thiophene ), 7.76 (s, 2H, NH ₂ ), 7.47 (s, 1H, H _oxazole ), 2.46 (s, 3H, CH ₃ ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 165.80, 148.18, 146.39, 129.21, 127.57, 125.27, 123.84, 9.01; 244 (M ⁺ , 100), 216 (8), 190 (7), 189 (28), 175 (9), 173 (16), 164 (6), 136 (14), 125 (11), 123 ( 7), 110 (7), 109 (22), 108 (7), 97 (7), 95 (32), 93 (7), 83 (5), 82 (19), 81 (5), 69 ( 12), 64 (9), 54 (26), 53 (8), 52 (7), 51 (7), 50 (5), 45 (26), 43 (18), 39 (8), 38 ( 8), 27 (16), 26 (7), 15 (5); ELEMENT ANALYSIS DATA: calculated for C ₈ H ₈ N ₂ O ₃ S ₂ (244.29): C, 39.33; H, 3.30; N, 11.47; Found: C, 39.32; H, 3.30; N, 11.50.

Example 43. Preparation of 4- (2-Cyclopropyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9n).

Receive according to the General method in the form of a white solid, t _PL. = 150-153 ° C (i-PrOH),

Yield (75%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.98 (d, J = 1.2 Hz, 1H, H _thiophene ), 7.85 (d, J = 1.2 Hz, 1H, H _thiophene ), 7.79 (s, 2H, NH ₂ ), 7.46 (s, 1H, H _oxazole ), 2.17 (m, 1H, CH _cyclopropyl ), 1.08 (m, 2H, H _cyclopropyl ), 1.01 (m, 2H, H _cyclopropyl ); ¹³ C NMR (126 MHz, DMSO-40 δ 165.80, 148.18, 146.39, 129.21, 127.57, 125.27, 123.84, 67.23, 9.37, 9.01; 270 (M ⁺ , 100), 269 (16), 268 (13), 244 (11), 241 (5), 190 (14), 189 (5), 162 (6), 136 (5), 135 (41), 134 (14), 133 (6), 123 (6), 110 (5), 98 (5), 95 (18), 91 (11), 83 (5), 82 (15), 81 (5), 80 (19), 69 (12), 64 (8), 54 (11), 53 (26), 52 (14), 51 (11), 50 (7), 45 (19), 43 (6), 41 (19), 39 (25), 38 (8), 29 (11), 27 (26), 26 (6), 15 (6); ELEMENT ANALYSIS DATA: calculated for C ₁₀ H ₁₀ N ₂ O ₃ S ₂ (270.33): C, 44.43; H, 3.73; N, 10.36 ; found: C, 44.40; H, 3.73; N, 10.35.

Example 44. Preparation of 4- (2-Cyclobutyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9 °).

Receive according to the General method in the form of a white solid, t _PL. = 169-173 ° C (i-PrOH),

Yield (70%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.00 (d, J = 1.5 Hz, 1H, H _thiophene ), 7.85 (d, J = 1.5 Hz, 1H, H _thiophene ), 7.76 (s, 2H, NH ₂ ), 7.51 (s, 1H, H _oxazole ), 3.68 (m, 1H, CH _cyclobutyl ), 2.34 (m, 4H, H _cyclobutyl ), 2.04 (m, 1H, H _cyclobutyl ), 1.92 (m, 1H, H _cyclobutyl ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 166.85, 148.22, 146.85, 129.25, 127.67, 125.61, 123.77, 33.10, 27.66, 18.98; 284 (M ⁺ , 31), 283 (7), 258 (12), 257 (14), 256 (100), 228 (6), 201 (18), 148 (7), 121 (21), 95 ( 13), 82 (8), 66 (8), 64 (6), 55 (9), 53 (5), 45 (11), 41 (5), 39 (17), 29 (8), 27 ( eleven); ELEMENT ANALYSIS DATA: calculated for C ₁₁ H ₁₂ N ₂ O ₃ S ₂ (284.36): C, 46.46; H, 4.25; N, 9.85; Found: C, 46.45; H, 4.26; N, 9.84.

Example 45. Preparation of 4- [2- (Pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10a).

Receive according to the General method in the form of a white solid, t _PL. = 265-267 ° C (i-PrOH),

Yield (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H, H _oxazole ), 7.99 (d, J = 8.6 Hz, 2H, H _Ar ), 7.84 (d, J = 8.6 Hz, 2H, H _Ar ), 7.46 (s, 2H, NH ₂ ), 3.93 (t, J = 6.7 Hz, 2H, H _pyrrolidine ), 3.53 (t, J = 6.7 Hz, 2H, H _pyrrolidine ), 1.93 (m, 2H, H _pyrrolidine ), 1.87 (m, 2H, H _pyrrolidine ); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 155.50, 154.24, 150.77, 144.79, 130.06, 127.10, 125.77, 125.43, 49.03, 47.38, 26.39, 23.83; 321 (M ⁺ , 22), 98 (11), 70 (100), 56 (14), 55 (20), 42 (5), 41 (5); ELEMENT ANALYSIS DATA: calculated for C ₁₄ H ₁₅ N ₃ O ₄ S (321.36): C, 52.33; H, 4.70; N, 13.08; Found: C, 52.32; H, 4.71; N, 13.10.

Example 46. Preparation of 4- [2- (Morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10b).

Receive according to the General method in the form of a white solid, t _PL. = 190-193 ° C (i-PrOH),

Yield (70%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (s, 1H, H _oxazole ), 7.98 (d, 7 = 8.8 Hz, 2H, H _Ar ), 7.94 (d, J = 8.8 Hz, 2H, H _Ar ) 7.45 (br.s., 2H, NH ₂ ), 4.05 (m, 2H, H _morpholine ), 3.67 (m, 6H, H _morpholine ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 155.58, 154.83, 151.26, 145.23, 130.35, 127.51, 125.86, 125.76, 67.19, 66.84, 47.93, 43.53; 337 (M ⁺ , 5), 251 (16), 250 (21), 181 (8), 131 (6), 115 (6), 114 (12), 87 (6), 86 (100), 72 ( 5), 70 (24), 56 (18), 42 (16), 29 (5); ELEMENT ANALYSIS DATA: calculated for C ₁₄ H ₁₅ N ₃ O ₅ S (337.36): C, 49.85; H, 4.48; N, 12.46; Found: C, 49.80; H, 4.49; N, 12.40.

Example 47. Preparation of 2-Methyl-5- [2- (pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10c)

Receive according to the General method in the form of a white solid, t _PL. = 247-250 ° C (i-PrOH),

Yield (63%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.24 (d, J _BX = 1.2 Hz, 1H, XH _Ar ), 7.98 (s, 1H, H _oxazole ), 7.94 (dd, J _AB = 7.9, Hz, J _BX = 1.2 Hz, 1H, B-H _Ar ), 7.56 (s, 2H, NH ₂ ), 7.55 (d, J _AB = 8.6 Hz, 1H, A-H _Ar ), 3.94 (t, J = 6.7 Hz , 2H, H _pyrrolidine ), 3.55 (t, J = 6.7 Hz, 2H, H _pyrrolidine ), 2.66 (s, 3H, OCH ₃ ), 1.95 (m, 2H, H _pyrrolidine ), 1.89 (m, 2H, H _pyrrolidine ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 155.73, 153.99, 151.37, 143.69, 137.81, 134.38, 128.58, 125.47, 124.16, 123.79, 49.12, 47.07, 26.56, 24.23, 20.69; 335 (M ⁺ , 23), 98 (13), 70 (100), 56 (12), 55 (20), 44 (5); ELEMENTAL ANALYSIS DATA: calculated for C ₁₅ H ₁₇ N ₃ O ₄ S (335.38): C, 53.72; H, 5.11; N, 12.53; Found: C, 53.58; H, 5.11; N, 12.55.

Example 48. Preparation of 2-Methyl-5- [2- (morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10d)

Receive according to the General method in the form of a white solid, t _PL. = 239-242 ° C (i-PrOH),

Yield (61%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.21 (d, J _BX = 1.7 Hz, 1H, XH _Ar ), 7.92 (s, 1H, H _oxazole ), 7.91 (dd, J _AB = 7.9 Hz, J _BX = 1.2 Hz, 1H, B-H _Ar ), 7.54 (d, J _AB = 8.6 Hz, 1H, A-H _Ar ), 7.53 (s, 2H, NH ₂ ), 4.07 (m, 2H, H _morpholine ) 3.67 (m, 6H, H _morpholine ); 2.63 (s, 3H, CH ₃ ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 155.58, 154.36, 151.44, 143.93, 138.07, 134.17, 128.58, 125.47, 124.38, 123.79, 67.19, 66.85, 47.93, 43.53, 20.66; 351 (M ⁺ , 19), 266 (6), 265 (24), 264 (35), 252 (6), 130 (8), 128 (6), 114 (20), 87 (5), 86 ( 100), 70 (23), 56 (13), 42 (12); ELEMENT ANALYSIS DATA: calculated for C ₁₅ H ₁₇ N ₃ O ₅ S (351.38): C, 51.27; H, 4.88; N, 11.96; Found: C, 51.25; H, 4.88; N, 11.97.

Example 49. Obtaining 2-Methoxy-5- [2- (pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10e)

Receive according to the General method in the form of a white solid, t _PL. = 275-278 ° C (i-PrOH),

Yield (69%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (s, 1H, XH _Ar ), 8.00 (d, J = 8.4 Hz, 1H, BH _Ar ), 7.89 (s, 1H, H _oxazole ), 7.38 ( d, J = 8.4 Hz, 1H, А-H _Ar ), 7.24 (br.s., 2H, NH ₂ ), 3.97 (s, 3H, ОCH ₃ ), 3.92 (t, J = 6.4 Hz, 2Н, H _pyrrolidine ), 3.52 (t, J = 6.4 Hz, 2H, H _pyrrolidine ), 1-89 (m, 4H, H _pyrrolidine ); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 157.10, 154.68, 154.29, 151.04, 132.55, 130.52, 124.34, 123.32, 119.19, 114.22, 56.95, 49.03, 47.34, 26.42, 23.82; 351 (M ⁺ , 10), 211 (6), 98 (15), 70 (100), 56 (13), 55 (25), 29 (5); ELEMENT ANALYSIS DATA: calculated for C ₁₅ H ₁₇ N ₃ O ₅ S (351.38): C, 51.27; H, 4.88; N, 11.96; Found: C, 51.21; H, 4.88; N, 11.95.

Example 50. Preparation of 2-Methoxy-5- [2- (morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10f)

Receive according to the General method in the form of a white solid, t _PL. = 198-201 ° C (i-PrOH),

Yield (72%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (d, J _BX = 2.2 Hz, 1H, XH _Ar ), 8.00 (dd, J _AB = 8.7, J _BX = 2.2 Hz, 1H, BH _Ar ), 7.89 (s, 1H, H _oxazole ), 7.38 (d, J _AB = 8.77 Hz, 1H, A-H _Ar ), 7.23 (br s, 2H, NH ₂ ), 4.08 (m, 2H, H _morpholine ), 3.97 (s, 3H, OCH ₃ ); 3.67 (m, 6H, H _morpholine ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 157.53, 155.56, 153.96, 151.52, 132.90, 130.95, 124.75, 123.30, 119.46, 114.62, 67.19, 66.87, 57.36, 47.91, 43.52; 367 (M ⁺ , 31), 282 (7), 281 (26), 280 (49), 268 (8), 254 (7), 225 (14), 211 (16), 114 (16), 87 ( 5), 86 (100), 70 (28), 56 (11), 44 (5), 42 (11); ELEMENT ANALYSIS DATA: calculated for C ₁₅ H ₁₇ N ₃ O ₆ S (367.38): C, 49.04; H, 4.66; N, 11.44; found: C, 49.00; H, 4.67; N, 11.45.

Example 51. Obtaining 5- [2- (Pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10g)

Receive according to the General method in the form of a white solid, t _PL. = 226-229 ° C (i-PrOH),

Yield (70%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.92 (s, 1 N, H _oxazole ), 7.86 (s, 2 N, NH ₂ ), 7.60 (d, J = 3.8 Hz, 1H, N _thiophene ), 7.58 (d, J = 3.8 Hz, 1H, H _thiophene ), 3.90 (t, J = 6.7 Hz, 2H, N _pyrrolidine ), 3.51 (t, J = 6.7 Hz, 2H, N _pyrrolidine ), 1.90 (m, 4H , N _pyrrolidine ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 155.27, 154.34, 147.03, 146.63, 132.82, 131.83, 126.72, 125.62, 49.45, 47.82, 26.81, 24.23; 327 (M ⁺ , 12), 98 (24), 71 (7), 70 (100), 56 (24), 55 (39), 42 (7), 41 (6); ELEMENT ANALYSIS DATA: calculated for C ₁₂ H ₁₃ N ₃ O ₄ S ₂ (327.38): C, 44.03; H, 4.00; N, 12.84; Found: C, 43.98; H, 4.01; N, 12.85.

Example 52. Obtaining 5- [2- (Morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] thiophene-2-sulfonamide (10h)

Receive according to the General method in the form of a white solid, t _PL. = 188-191 ° C (i-PrOH),

Yield (73%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.91 (s, 1 N, H _oxazole ), 7.86 (s, 2 N, NH ₂ ), 7.60 (d, J = 3.8 Hz, 1H, H _thiophene ), 7.58 (d, J = 3.8 Hz, 1H, H _thiophene ), 4.03 (m, 2H, H _morpholine ), 3.66 (m, 6H, H _morpholine ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 155.27, 154.22, 147.09, 146.70, 132.67, 131.82, 126.81, 125.19, 67.14, 66.82, 47.93, 43.53; 343 (M ⁺ , 12), 258 (6), 257 (17), 256 (30), 201 (7), 187 (11), 137 (6), 114 (22), 86 (100), 72 ( 6), 70 (40), 64 (8), 56 (21), 45 (6), 42 (25), 29 (6); ELEMENT ANALYSIS DATA: calculated for C ₁₂ H ₁₃ N ₃ O ₅ S ₂ (343.38): C, 41.97; H, 3.82; N, 12.24; Found: C, 41.95; H, 3.82; N, 12.26.

Example 53. Preparation of 4- [2- (Pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10i).

Receive according to the General method in the form of a white solid, t _PL. = 268-2710C (i-PrOH),

Yield (64%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (d, J = 1.2 Hz, 1H, H _thiophene ), 7.96 (d, J = 1.2 Hz, 1H, H _thiophene ), 7.81 (s, 1H, H _oxazole ), 7.86 (s, 2H, NH ₂ ), 3.91 (t, J = 6.7 HZ, 2H, H _pyrrolidine ), 3.51 (t, J = 6.7 Hz, 2H, H _pyrrolidine ), 1-89 (m, 4H , H _pyrodiline ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 154.94, 154.59, 148.63, 148.21, 127.94, 124.75, 49.47, 47.79), 26.82, 24.24; 327 (M ⁺ , 1), 187 (9), 98 (14), 70 (100), 56 (17), 55 (25), 42 (6), 41 (5); ELEMENT ANALYSIS DATA: calculated for C ₁₂ H ₁₃ N ₃ O ₄ S ₂ (327.38): C, 44.03; H, 4.00; N, 12.84; Found: C, 44.01; H, 4.00; N, 12.82.

Example 54. Preparation of 4- [2- (Morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10j)

Receive according to the General method in the form of a white solid, t _PL. = 226-229 ° C (i-PrOH),

Yield (68%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (d, J = 1.2 Hz, 1H, H _thiophene ), 7.96 (d, J = 1.2 Hz, 1H, H _thiophene ), 7.81 (s, 1H, H _oxazole ), 7.86 (s, 2H, NH ₂ ), 4.05 (m, 2H, H _morpholine ), 3.67 (m, 6H, H _morpholine ); ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 155.50, 153.85, 148.66, 148.27, 128.11, 127.94, 124.31, 67.19, 66.85, 47.91, 43.52; 343 (M ⁺ , 8), 258 (6), 257 (21), 256 (28), 201 (16), 187 (13), 114 (14), 86 (100), 70 (33), 56 ( 18), 45 (7), 42 (21), 29 (5); ELEMENT ANALYSIS DATA: calculated for C ₁₂ H ₁₃ N ₃ O ₅ S ₂ (343.38): C, 41.97; H, 3.82; N, 12.24; Found: C, 41.92; H, 3.82; N, 12.28.

Example 55. Measurement of the inhibition of carbonic anhydrase activity by compounds of the general formula 1. The biological activity of twenty-five compounds 9 (a-o) and 10 (a-j) as carbonic anhydrase inhibitors was measured against human carbonic anhydrase (CAI, CAII, CAIX, CAXII). Cytosolic isoforms of CAI, CAII are usually not targets for membrane-binding isoforms of CAIX, CAXII. While CAI, CAII are together involved in the formation of edema (and CAII is a classic target for the treatment of glaucoma), CAIX and CAXII are targeted in studies to find new drugs for the treatment of cancer. The inhibitory activity of the compounds with respect to carbonic anhydrase was studied by the stopped flow method (R. G. Khalifah, J. Biol Chem 246 (1971) 2561-2573) using Applied Photophysics equipment. Phenol red dye (phenol red) at a concentration of 0.2 mmol / L was used as an indicator at an absorption wavelength of 557 nm, in a Tris buffer of 20 mmol / L with a pH of 8.3 containing 20 mmol / L sodium sulfate to maintain a constant ionic strength of the solution. The initial rate of carbon dioxide catalyzed by carbon dioxide hydration reaction was observed in the period of 10-100 s. Carbon dioxide concentrations ranged from 1.7-17 mmol / L to determine the kinetic parameters of the reaction and the inhibition constants. For each inhibitor, the reaction rate was measured at 5-10% in at least 6 repetitions to determine the initial rate. The rate of the non-catalyzed reaction was determined in the same way and subtracted from the observed total reaction rate. Initial inhibitor solutions at a concentration of 0.1 mMol / L were prepared using distilled and deionized water and diluted with successive dilutions with a buffer solution to a concentration of 0.005 nMol / L. The enzyme and inhibitor solutions were preincubated at room temperature for 15 minutes to ensure the formation of the enzyme complex with the inhibitor. Inhibition constants were determined from the curves of the concentration dependence of the reaction rate constructed by the least square method using the PRISM 3 software and the Cheng-Prusov equation. The values obtained are average values, determined in at least three repetitions of each experiment.

The results of the inhibition of carbonic anhydrase activity by compounds of the general formula 1 are shown in Table 2.

Table 2. Inhibition of carbonic anhydrase activity by compounds of the general formula 1.

The studied compounds showed high activity as carbonic anhydrase II inhibitors. Several compounds that showed very good results, as carbonic anhydrase II inhibitors, can be isolated as leader compounds, these are compounds 9a, 10a, 10e, 10h, 10i.

Example 56. Test for hypotensive effect (lowering of intraocular pressure).

For compound 10a, an experiment was conducted in which the ability of the compound to lower the experimentally induced intraocular pressure in rabbit models was determined.

The experiment was conducted on New Zealand white rabbits of both sexes weighing 1.5-2.0 kg, kept at a temperature of 22 ± 2 C, humidity 55 ± 5% and a 12/12 hour light cycle, access to food and water was provided without restrictions.

Description of the experiment.

For rabbits weighing 1.5 to 2.0 kg, diazepam was administered as a sedative (1 mg / kg intravenously). Freshly prepared alpha-chymotrypsin (50 units) was dissolved in 0.1 ml of sterile saline and the posterior wall of the eye was irrigated with a cannula. Particles of tissue blocked the outflow of fluid in the trabecular network, which caused intraocular hypertension. To determine the effect of test compound 10a on intraocular pressure, 6 rabbits with glaucoma were selected and used. After achieving a stable increase in intraocular pressure caused by the introduction of drugs into the left eye of the animal, while the right eye was left as a control, the values of intraocular pressure were measured using a tonometer at appropriate time intervals before the introduction of eye drops. A 1% solution of Indomethacin (a prostaglandin inhibitor) was introduced into the left eye in the form of drops. The right eye served as a control. 45 minutes after the administration of Indomethacin, a 1% solution of the test compound 10a was locally injected (instilled). Changes in intraocular pressure were measured at appropriate times using a tonometer. In the next step, Indomethacin was replaced by Pilocarpine to study the interaction with test compound 10a. The compound was first used for intraocular administration and showed no side effects. Student's test was used to determine the statistical curve for most data with a probability level of 95%. As a result of the experiment, data were obtained that showed that the highest rise in intraocular pressure is up to 35-40 mmHg. observed with intravenous administration of 5% dextrose solution (15 ml / kg). Preliminary administration of compound 10a and Pilocarpine reduced intraocular pressure from 32.13 to 22, 53 mm Hg and from 28.07 to 17.10 mm Hg. respectively (the result is shown in Fig. 1). In the case of the interaction of Indomethacin in the form of 1% solution and compound 10a in the form of 1% solution, Indomethacin slowed down the decrease in the intraocular pressure caused by compound 10a (the result is shown in Fig. 2), however, preliminary administration of Polycarpin with subsequent administration of compound 10a caused further decrease in intraocular pressure. Test compound 10a showed good results as a drug for reducing intraocular pressure.

Example 57. Obtaining a pharmaceutical composition in the form of an ophthalmic solution. An ophthalmic solution was prepared by dissolving riboflavin in freshly boiled purified water while heating, followed by adding boric acid to the hot solution until the solution reaches pH 4.5-9 and the compound of general formula 1 or general formulas 1.1, 1.2, 1.3, 1.4 or a compound selected from 9 ( ao), 10 (aj) and ascorbic acid at a solution temperature of 20-25 ° C and sterilization in the following ratio of components, wt. %:

Riboflavin 0.01-0.02 Vitamin C 0.01-0.60 Boric acid 1.0-2.0 Nipagin 0.01-0.05

Compounds of general formula 1 or general formulas 1.1, 1.2, 1.3, 1.4 or a compound selected from 9 (a-o), 10 (a-j) 1.0-2.53

Purified freshly boiled water 97.88-94.80.

Claims (49)

1. Substituted sulfonamides of the general formula 1 and their pharmaceutically acceptable salts

where a represents phenyl or thiophene; R ₁ represents C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, —C (O) R ₃ ; with the proviso that R _{1 is} not methyl, when A is phenyl, R ₂ is hydrogen; R ₃ represents a 5-6 membered heterocyclyl, with one or two heteroatoms selected from a nitrogen or oxygen atom; R ₂ represents C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy. 2. The compounds according to claim 1, which are sulfonamides of the general formulas 1.1, 1.3, 1.4, their pharmaceutically acceptable salts,

where R ₁ and R ₂ take the values indicated above. 3. The compounds according to claim 1, selected from a number of compounds 9b-9o, 10a-10j 4- (2-Cyclopropyl-1,3-oxazol-5-yl) benzenesulfonamide (9b); 4- (2-Cyclobutyl-1,3-oxazol-5-yl) benzenesulfonamide (9c); 2-Methyl-5- (2-methyl-1,3-oxazol-5-yl) benzenesulfonamide (9d); 5- (2-Cyclopropyl-1,3-oxazol-5-yl) -2-methylbenzenesulfonamide (9e); 5- (2-Cyclobutyl-1,3-oxazol-5-yl) -2-methylbenzenesulfonamide (9f); 2-Methoxy-5- (2-methyl-1,3-oxazol-5-yl) benzenesulfonamide (9g); 5- (2-Cyclopropyl-1,3-oxazol-5-yl) -2-methoxybenzenesulfonamide (9h); 5- (2-Cyclobutyl-1,3-oxazol-5-yl) -2-methoxybenzenesulfonamide (9i); 5- (2-Methyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9j); 5- (2-Cyclopropyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9k); 5- (2-Cyclobutyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9l); 4- (2-Methyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9m); 4- (2-Cyclopropyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9n); 4- (2-Cyclobutyl-1,3-oxazol-5-yl) thiophen-2-sulfonamide (9 °); 4- [2- (Pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10a); 4- [2- (Morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10b); 2-Methyl-5- [2- (pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10c); 2-Methyl-5- [2- (morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10d); 2-Methoxy-5- [2- (pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10e); 2-Methoxy-5- [2- (morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] benzenesulfonamide (10f); 5- [2- (Pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10g); 5- [2- (Morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10h); 4- [2- (Pyrrolidin-1-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10i); 4- [2- (Morpholin-4-ylcarbonyl) -1,3-oxazol-5-yl] thiophen-2-sulfonamide (10j). 4. A method of obtaining compounds of General formula 1 according to paragraphs. 1-3, consisting in two stages a) sulfochlorination of the corresponding oxazole derivative of the general formula 5 (a-o) or 6 (a-j) with a mixture of chlorosulfonic acid and thionyl chloride to obtain intermediate sulfonyl chlorides of the formula 7 (a-o) or 8 (a-j), respectively, b) with the subsequent conversion of the obtained sulfochlorides to primary sulfamides of the formula 9 (b-o) or 10 (a-j) by reaction with ammonia according to the following scheme

Where

where R ₁ represents C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl; NR'Rʺ is morpholine or pyrrolidine. 5. A method of inhibiting carbonic anhydrase II, which consists in contacting carbonic anhydrase II with a compound of general formula 1 according to claims. 1-3 and / or its pharmaceutically acceptable salt in an effective amount. 6. The active component having the properties of a selective carbonic anhydrase II inhibitor, which is a compound of general formula 1 according to claims. 1-3 or its pharmaceutically acceptable salts. 7. A pharmaceutical composition comprising a compound of general formula 1 according to claims. 1-3 or a pharmaceutically acceptable salt or active ingredient thereof according to claim 6 in a therapeutically effective amount, suitable for use for the treatment of glaucoma, in particular open angle glaucoma, increased intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathy mediated by activity of carbonic anhydrase II. 8. The pharmaceutical composition according to claim 7 in the form of an ophthalmic solution or emulsion. 9. A method of obtaining a pharmaceutical composition by mixing with an inert excipient and / or solvent of at least one compound of general formula 1 according to claims. 1-3 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount. 10. The drug in the form of an ophthalmic solution, placed in a pharmaceutically acceptable package containing a compound of General formula 1 according to paragraphs. 1-3 and / or its pharmaceutically acceptable salt as an active ingredient or pharmaceutical composition according to claim 7 in a therapeutically effective amount, intended for use for the treatment of glaucoma, in particular open-angle glaucoma, increased intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathy. 11. A method of treating a disease mediated by the activity of carbonic anhydrase II selected from glaucoma, in particular open-angle glaucoma, increased intraocular pressure, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathy, consisting in local administration (to the affected eye) in a therapeutically effective amount of the active ingredient according to claim 6, or a pharmaceutical composition according to claims. 7, 8, or a medicament according to claim 10.

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