RU2783866C2 - Deuterated derivatives of 2-(imidazole-4-yl)-ethanamide pentanedioic-1,5 acid - Google Patents

Abstract

FIELD: organic chemistry; pharmaceutics.

SUBSTANCE: invention relates to organic chemistry and pharmaceutics, and it is deuterated derivatives of 2-(imidazole-4-yl)-ethanamide pentanedioic-1,5 acid of the formula I, where R is H or D, provided that at least one R is D, for the treatment or prevention of diseases of the upper respiratory tract.

EFFECT: long-term average time of staying in the body, stability, and preservation of pharmacological activity, provided by a deuterated derivative of 2-(imidazole-4-yl)-ethanamide pentanedioic-1,5 acid of the formula I.

1 cl, 2 tbl, 1 ex

Description

The invention relates to pharmaceutical chemistry and represents deuterated derivatives of 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide or their pharmaceutically acceptable salts. These compounds exhibit therapeutic activity against infectious and inflammatory diseases.

Infectious diseases are the third leading cause of death in people worldwide, with viral diseases accounting for the majority. Many viruses infect the respiratory tract, nasal passages, throat, bronchi, lungs, and therefore such viral infections are collected in the group of acute respiratory viral infections (ARVI), since they also have common clinical symptoms. Influenza viruses also belong to the ARVI group, however, they are separated into a separate group due to the fact that they act systemically on the entire body. The cause of ARVI can be more than two hundred different viruses, representatives of four families of RNA viruses (orthomyxoviruses, paramyxoviruses, coronaviruses and picornaviruses) and two families of DNA viruses (adenoviruses and herpesviruses) [1, 2]. In terms of the frequency of infection, influenza is about 15% (type A - 12%, B - 3%), parainfluenza and rhinoviruses up to 50%, adenovirus up to 5%, respiratory syncytial virus (RS) - 4%, enteroviruses - about 1%, mixed infections - about 23% of cases. The high-risk group includes children in whom respiratory tract diseases account for up to 90% of all infectious pathologies and 65% of all registered diseases [3].

Despite the advances made in medicine over the past decades, in particular in the treatment of infectious diseases, SARS and influenza viruses continue to be a serious health problem for most countries of the world due to the extremely high incidence, usually in the nature of seasonal epidemics.

Influenza A and B viruses are of the greatest epidemic importance, causing annual epidemics, the economic damage from which amounts to billions of US dollars. In Russia, the annual total economic damage from influenza is estimated by experts at an amount reaching 40 billion rubles. In the world every year, 250-500 thousand people die from influenza. Numerous studies have shown a consistent relationship between influenza and acute myocardial infarction [4].

Considering that it is impossible to predict the antigenic structure of a future epidemic (pandemic) virus, it is difficult to design effective vaccines in advance, so it is important to have drugs in the arsenal for the prevention and treatment of diseases caused, among other things, by highly pathogenic strains of viruses. At the same time, as the situation with the COVID-19 pandemic around the world has shown [5], in order to provide citizens with antiviral drugs in a timely manner during a pandemic, it is advisable to create state reserves of such funds. Strategic state reserves for pandemics are subject to long-term storage and renewal after the expiration date of reserved medicines. In such a situation, it is essential to increase long-term stability to extend shelf life and reduce government costs for creating and updating strategic reserves of antivirals.

Therefore, there is a need to develop new agents and affordable therapeutic forms for the treatment and prevention of influenza and SARS.

A potentially attractive strategy for improving the metabolic properties of a drug is deuterium modification [6].

However, it is known from the prior art that modification with deuterium may reduce the activity of the drug. For example, the deuterated analog of the hormone estrogen exhibits significantly reduced activity compared to the protonated analog. It is also known that highly deuterated benzylpenicillin has a markedly reduced activity against bacteria compared to the protonated antibiotic [7]. Deuteration of compounds can affect the properties of a substance in unpredictable ways. When one atom in a molecule is replaced by its isotope, the corresponding chemical bonds change [8]. Depending on the properties and structure of the initial molecule, deuteration can lead to multidirectional actions. Thus, it is known from the prior art that the addition of a deuterium atom to the second carbon atom of 1,1-difluoro-2-2-dichloroethylmethyl ether increases the rate of decomposition of this compound compared to the non-deuterated analog [9].

The inventors of the present invention have prepared various deuterated derivatives of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid of formula (I) and have also surprisingly found that they have a longer mean residence time (MRT). time) and stability. At the same time, the presence of deuterium atoms in the compound does not in any way reduce the pharmacological activity of this substance.

(I)

(I)

where R is H or D, provided that at least one R is D.

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

Unless otherwise indicated, all technical and technical terms used in this context have the meaning generally accepted in the art.

"Stability" is the ability of the medicinal product to maintain properties and quality characteristics within the specified limits during its shelf life (shelf life) and the period of use, subject to established storage conditions. The stability of the medicinal product is a necessary condition for ensuring its therapeutic effect or the absence of adverse reactions. Depending on the preserved properties and quality characteristics, the following types of drug stability are distinguished:

- chemical stability, which maintains the chemical integrity and activity of the active substance within the limits specified in the specification. Including includes photostability;

- physical stability, in which the original physical properties of the medicinal product are preserved, including appearance, taste, uniformity, solubility, suspendability, etc.;

- microbiological stability, at which sterility is maintained, or microbiological purity of the medicinal product in accordance with the specified requirements, or the effectiveness of its constituent antimicrobial preservatives within the specified limits;

- toxicological stability, in which there is no noticeable increase in the toxicity of the medicinal product;

- therapeutic stability, in which the therapeutic effect of the medicinal product remains unchanged.

"Mean residence time (MRT, mean residence time)" - a parameter that determines the average residence time of a drug molecule in the human body.

"Drug (preparation)" - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, syrups, injections, ointments and other prepared forms that come into contact with the human body, penetrate into the organs, tissues of the human body, used for the prevention, diagnosis, treatment of the disease.

"Pharmaceutical composition" means a composition comprising a compound of general formula I or a pharmaceutically acceptable salt thereof and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliaries, distributing agents, delivery vehicles such as preservatives, stabilizers, fillers, disintegrants, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavoring agents, flavoring agents, antibacterial agents, fungicides, lubricants, delayed delivery regulators, the choice and ratio of which depends on their nature , method of administration of the composition 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 other pharmaceutically acceptable surfactants, and mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, such as benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, chlorobutanol, sorbic acid, parabens, alkylpyridinium, benzethonium and their pharmaceutically acceptable salts and the like. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided by agents that slow down the absorption of the active principle, such as, for example, hydrophilic polymeric release retardants, for example, cellulose derivatives, polyethylene oxide, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, alginates, carbomers, hydrophobic release retarders, such as glyceryl behenate, aluminum monostearate. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, buffer solutions and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, microcrystalline cellulose, sodium citrate, calcium carbonate, calcium phosphate and the like. Various organic and inorganic acids can be used to adjust the pH, such as malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids. Examples of dispersing agents and spreading agents are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, colloidal silicon dioxide, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in standard form of administration, as a mixture with conventional pharmaceutical carriers. Suitable unit administration forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions, elixirs or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous , intranasal or intraocular forms of administration and rectal forms of administration.

"Pharmaceutical 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 compounds, or obtained specially. In particular, base salts can be prepared specifically from 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 [10]. Salts of the claimed acids can also be specifically prepared by reacting a purified acid with a suitable base, whereby 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 derived are sodium hydroxide, carbonate, 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 have sufficient basicity to form a stable salt and are suitable for medical use (in particular, they must 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 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.

Pharmaceutical compositions may include pharmaceutically acceptable carriers. By pharmaceutically acceptable carriers are meant diluents, auxiliary agents and/or excipients used in the pharmaceutical field. The pharmaceutical composition, along with the active substance of the present invention or its pharmaceutically acceptable salt, may include other active substances, including those with activity, provided that they do not cause undesirable effects.

The term "effective amount" means an amount of an active ingredient that (1) treats or prevents a particular disease, condition, or disorder, (2) relieves, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (3) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as set forth herein.

The term “pharmaceutically acceptable” means that the substance or composition to which the term is applied must be chemically and/or toxicologically compatible with the other ingredients in the formulation and safe for the person being treated with the substance or composition.

The terms "comprising", "comprises" means that the specified combinations, compositions and kits include the listed components, but do not exclude the inclusion of other components.

Disclosure of the essence of the invention

The present invention is a Compound of General Formula I or a pharmaceutically acceptable salt thereof

where R is H or D, provided that at least one R is D.

The subject of the present invention is also a pharmaceutical composition for the treatment or prevention of diseases of the upper respiratory tract, containing an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

In one of the preferred embodiments, a pharmaceutical composition for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases are selected from the group consisting of SARS and influenza.

More preferred is a pharmaceutical composition for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases of the respiratory tract are caused by a viral infection.

More preferred is a pharmaceutical composition for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases are selected from the group consisting of rhinitis, sinusitis, rhinosinusitis, pharyngitis, nasopharyngitis, tonsillitis, diseases of the vocal folds and larynx, vasomotor and allergic rhinitis, bronchitis, bronchiolitis, pneumonia, bronchial asthma, chronic obstructive pulmonary disease, cystic fibrosis.

More preferred is a pharmaceutical composition for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases are caused by a virus selected from the group consisting of rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, including influenza A, B, C and D, adenovirus, noravirus, metapneumovirus, coronavirus, hantavirus, bocavirus, coxsackievirus, ECHO group viruses, enterovirus, rotavirus, herpes virus.

The subject of the present invention is also a medicinal product for the treatment or prevention of diseases of the upper respiratory tract in the form of tablets or capsules placed in a pharmaceutically acceptable package, and the said product contains in an effective amount a compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing an effective amount of the compound formula I or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier.

In one of the preferred embodiments, a drug for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases are selected from the group consisting of SARS and influenza.

More preferred is a drug for the treatment or prevention of upper respiratory diseases, characterized in that the respiratory diseases are caused by a viral infection.

More preferred is a drug for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases are selected from the group consisting of rhinitis, sinusitis, rhinosinusitis, pharyngitis, nasopharyngitis, tonsillitis, diseases of the vocal folds and larynx, vasomotor and allergic rhinitis, bronchitis, bronchiolitis, pneumonia, bronchial asthma, chronic obstructive pulmonary disease, cystic fibrosis.

More preferred is a drug for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases are caused by a virus selected from the group consisting of rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, including influenza A, B, C and D, adenovirus, noravirus, metapneumovirus, coronavirus, hantavirus, bocavirus, coxsackievirus, ECHO group viruses, enterovirus, rotavirus, herpes virus.

Also a subject of the present invention is the use of a compound of general formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases of the upper respiratory tract.

In one preferred embodiment, a compound of general formula I or a pharmaceutically acceptable salt thereof is used for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases are selected from the group consisting of SARS and influenza.

More preferred is the use of a compound of general formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases are selected from the group consisting of SARS and influenza.

More preferred is the use of a compound of general formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases are selected from the group consisting of rhinitis, sinusitis, rhinosinusitis, pharyngitis, nasopharyngitis, tonsillitis, diseases of the vocal folds and larynx , vasomotor and allergic rhinitis, bronchitis, bronchiolitis, pneumonia, bronchial asthma, chronic obstructive pulmonary disease, cystic fibrosis.

More preferred is the use of a compound of general formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases of the upper respiratory tract, characterized in that the diseases are caused by a virus selected from the group consisting of rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, in including influenza A, B, C and D, adenovirus, noravirus, metapneumovirus, coronavirus, hantavirus, bocavirus, Coxsackie virus, ECHO group viruses, enterovirus, rotavirus, herpes virus.

The subject of the present invention is also the use of a pharmaceutical composition containing an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases of the upper respiratory tract.

In one preferred embodiment, the use of a pharmaceutical composition containing an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof is characterized in that the diseases are selected from the group consisting of SARS and influenza.

More preferred is the use of a pharmaceutical composition containing an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof, characterized in that the respiratory diseases are caused by a viral infection.

More preferred is the use of a pharmaceutical composition containing an effective amount of a compound of general formula I or a pharmaceutically acceptable thereof, characterized in that the diseases are selected from the group consisting of rhinitis, sinusitis, rhinosinusitis, pharyngitis, nasopharyngitis, tonsillitis, diseases of the vocal folds and larynx, vasomotor and allergic rhinitis, bronchitis, bronchiolitis, pneumonia, bronchial asthma, chronic obstructive pulmonary disease, cystic fibrosis.

More preferred is the use of a pharmaceutical composition containing an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof, characterized in that the diseases are caused by a virus selected from the group consisting of rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, including influenza A, B, C and D, adenovirus, noravirus, metapneumovirus, coronavirus, hantavirus, bocavirus, Coxsackie virus, ECHO group viruses, enterovirus, rotavirus, herpes virus.

The subject of the present invention is also the use of a compound of general formula I or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition containing an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof, or a medicament containing an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof for treatment or prevention of upper respiratory diseases.

The following are examples of the invention, which illustrate, but do not limit the invention.

Example 1. Synthesis of deuterated derivatives of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid.

1. Obtaining 3-d-pentanedioic acid.

The starting acid was added to NaOD-D ₂ O with vigorous stirring, the reaction mixture was heated ^to 50° C. The catalyst, Cu-Al alloy, was gradually added. The reaction was carried out for an hour under stirring in a nitrogen atmosphere, the temperature was maintained at a constant level [11].

After completion of the reaction, the mixture was cooled to room temperature, the catalyst was filtered off, the mixture was washed with a small amount of water. The filtrate was acidified with concentrated hydrochloric acid to pH=1 on cooling and extracted with benzene. The extract was dried over MgSO ₄ and evaporated in vacuo. The precipitate was treated with hexane, followed by recrystallization from a mixture of benzene and petroleum ether.

The product 3-d-pentanedioic acid (A1) is a crystal.

(А1)

(A1)

2. Obtaining 2,3,3,4-d ₄ -pentanedioic acid.

2,3-Pentadienedioic acid was used as a reagent.

The acid was dissolved in benzene. Palladium on carbon (Pd/C) and also NaBD ₄ were used as a catalyst. Afterwards, deuterated acetic acid (CH ₃ COOD) was added to the reaction mixture. The mixture was stirred for about 20 hours at room temperature. Then again added CH ₃ COOD, stirred for 20 hours at room temperature. After completion of the reaction, D ₂ O was added. The mixture was filtered, the filtrate was added to water and extracted with methylene chloride (CH ₂ Cl ₂ ). The organic phase was dried and concentrated. The product was isolated by column chromatography; CH2Cl2 was used as _the eluent [ ₁₂ ].

(A2)

(A2)

3. Obtaining 2,4-d ₂ -pentanedioic acid, 3,3-d ₂ -pentanedioic acid, 2,2,4,4-d ₄ -pentanedioic acid.

To obtain 2,4-d ₂ -pentanedioic acid, 2,4-dichloropentanoic acid was used as a reagent, for 3,3-d ₂ -pentanedioic acid - 3,3-dichloropentanoic acid, for 2,2,4,4-d ₄ -pentanedioic acid - 2,2,4,4-tetrachloropentanedioic acid.

The starting acid was added to NaOD-D ₂ O with vigorous stirring, the reaction mixture was heated ^to 50° C. The Cu-Al alloy catalyst was gradually added. The reaction was carried out for one hour with stirring under nitrogen atmosphere, the temperature was maintained at a constant level.

After completion of the reaction, the mixture was cooled to room temperature, the catalyst was filtered off, the mixture was washed with a small amount of water. The filtrate was acidified with concentrated hydrochloric acid to pH=1 on cooling and extracted with benzene. The extract was dried over MgSO ₄ and evaporated in vacuo. The precipitate was treated with hexane, followed by recrystallization from a mixture of benzene and petroleum ether [11].

The product 2,4-d ₂ -pentanedioic acid (A3) is a crystal.

(A3)

(A3)

The product 3,3-d ₂ -pentanedioic acid (A4) is a crystal.

(A4)

(A4)

The product 2,2,4,4-d ₄ -pentanedioic acid (A5) is a crystal.

(А5)

(A5)

4. Obtaining 2,2,3,3,4,4-d ₆ -pentanedioic acid.

Pentandioic acid was used as a reagent. The reaction was carried out in the solvent system propan-2-ol-d ₈ /D ₂ O at a temperature of 120 ^about C with stirring for 24 hours. After completion of the reaction, the product was filtered, washed with methanol. The remaining solvent was removed on a rotary evaporator. The precipitate was recrystallized from a mixture of benzene and petroleum ether [13].

The product 2,2,3,3,4,4-d ₆ -pentanedioic acid (A6) is a crystal.

(A6)

(A6)

5. Preparation of 2-(1H-imidazol-4-yl)-2-d-ethanamine, 2-(1H-imidazol-4-yl)-2,2-d ₂ -ethanamine.

1-Aminomethyl-1H-imidazole-4 acetic acid was used as the starting material. N-methylpyrrolidone (NMP) and deuterium oxide were added to the acid. The resulting mixture was stirred for 10 minutes at a temperature of 110 ^about C in a nitrogen atmosphere. D ₂ O was then added twice, followed by a 10 minute nitrogen purge. After the mixture was heated to 170 ^about C for 16 hours. After completion of the reaction, the mixture was added to water and extracted with diethyl ether, washed with an aqueous solution of NaHCO ₃ , dried over MgSO ₄ and filtered. The final product was separated by column chromatography [14].

The reaction product 2-(1H-imidazol-4yl)-2-d ₁ -ethanamine (B1) is a crystal.

(B1)

(B1)

2-(1H-imidazol-4yl)-2-d-ethanamine obtained at the previous stage was used as the initial reagent.

The reagent was dissolved in deuterated acetone (acetone-d ₆ ), which acts as a source of deuterium. Tris(pentafluorophenyl)borane (B(C ₆ F ₅ ) ₃ ) was used as a catalyst. All components were dissolved in toluene. The reaction was carried out at 150 ^about C, with stirring for one hour. After the completion of the reaction, the mixture was concentrated in a vacuum, the remaining solvent was removed on a rotary evaporator [15].

The reaction product 2-(1H-imidazol-4yl)-2,2-d ₂ -ethanamine (B2) is a crystal.

(B2)

(B2)

6. Obtaining 2-(1H-2,5-d ₂ -imidazol-4-yl)-ethanamine, 2-(1H-2,5-d ₂ -imidazol-4-yl) -2-d-ethanamine, 2 -(1H-2,5-d ₂ -imidazol-4-yl) -2,2-d ₂ -ethanamine.

2-(1H-imidazol-4-yl)-ethanamine was dissolved in ice-cold deuterated trifluoromethanesulfonic acid (CF ₃ SO ₃ D). The solution was gradually heated to 130 ^° C. The reaction was carried out for 5 days. The mixture was filtered, the filtrate was added to water and extracted with methylene chloride (CH ₂ Cl ₂ ). The organic phase was dried and concentrated [16].

The product 2-(1H-2,5-d ₂ -imidazol-4-yl)-ethanamine (B3) is a crystal.

(B3)

(B3)

2-(1H-2,5-d ₂ -imidazol-4-yl)-2-d-ethanamine, 2-(1H-2,5-d ₂ -imidazol-4-yl)-2,2- d ₂ -ethanamine. 2-(1H-imidazol-4yl)-2-d-ethanamine and 2-(1H-imidazol-4yl)-2,2-d2- _ethanamine , respectively, were used as initial reagents.

The product 2-(1H-2,5-d ₂ -imidazol-4-yl)-2-d-ethanamine (B4) is a crystal.

(B4)

(B4)

The product 2-(1H-2,5-d ₂ -imidazol-4-yl)-2,2-d ₂ -ethanamine (B5) is a crystal.

(B5)

(B5)

7. Obtaining 2-(1H-2,5-d ₂ -imidazol-4-yl) -1,1-d ₂ -ethanamine, 2-(1H-2,5-d ₂ -imidazol-4-yl) - 1,1,2-d ₃ -ethanamine, 2-(1H-2,5-d ₂ -imidazol-4-yl)-1,1,2,2-d ₄ -ethanamine.

To 2-(1H-2,5-d ₂ -imidazol-4-yl)-ethanamine under nitrogen atmosphere was added the catalyst dichloro (p-cymol) ruthenium (II) dimer and deuterium oxide (D ₂ O). The reaction was carried out with stirring and 135 ^about C for 24 hours. The mixture was filtered, the filtrate was added to water and extracted with methylene chloride (CH ₂ Cl ₂ ). The organic phase was dried over sodium sulfate. Solvent residues were removed under reduced pressure [17].

The product 2-(1H-2,5-d ₂ -imidazol-4-yl)-1,1-d ₂ -ethanamine (B6) is a crystal.

(B6)

(B6)

Similarly, 2-(1H-2,5-d ₂ -imidazol-4-yl)-1,1,2-d ₃ -ethanamine, 2-(1H-2,5-d ₂ -imidazol-4-yl) was obtained -1,1,2,2-d ₄ -ethanamine. 2-(1H-imidazol-4yl)-2-d-ethanamine and 2-(1H-imidazol-4yl)-2,2-d2- _ethanamine , respectively, were used as initial reagents.

The product 2-(1H-2,5-d ₂ -imidazol-4-yl)-1,1,2-d ₃ -ethanamine (B7) is a crystal.

(B7)

(B7)

The product 2-(1H-2,5-d ₂ -imidazol-4-yl)-1,1,2,2-d ₄ -ethanamine (B8) is a crystal.

(B8)

(B8)

8. The final product was obtained by the reaction of the intermediates obtained earlier.

The reagents were dissolved in DMF-d ₇ . The reaction mixture was stirred for 3 hours, then left for 20 hours at room temperature. The formed precipitate was filtered off, the remaining solvent was removed in a vacuum. The product was recrystallized from methylene chloride [18].

Where R is H or D, provided that at least one R is D.

The degree of saturation with deuterium for compounds (Table 1) is at least 88%, for most reactions 92-96%, for some reactions 99%.

¹ H NMR and High Resolution Mass Spectrometry (HRMS-ESI) were used to confirm the structures of the obtained compounds.

The NMR method allows you to confirm the position and number of remaining protons in the studied molecules.

The high-resolution mass spectrometry method provides information on the exact mass of the molecule, which confirms the elemental composition, including the exact number of protons and deuterium atoms.

Table 1. Data ^one H NMR and mass spectrometry of compounds according to the invention.

Compounds 1-62 were prepared according to steps 1-8 of Example 1.

No. Reagents Product ^one H NMR (400 MHz, D ₂ O) HRMS-ESI (m/z) one A1+B1

δ 2.1 (m, 1H), 2.6 (m, 4H), 3.3 (m, 1H), 3.7 (m, 2H), 7.5 (s, 1H), 8.8 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₃ D ₂ N ₃ O ₃ 228.1312, experimental 228.1304 2 A1+B2

δ 2.0 (m, 1H), 2.5 (m, 4H), 3.6 (m, 2H), 7.4 (s, 1H), 8.7 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₂ D ₃ N ₃ O ₃ 229.1374, experimental 229.1382 3 A1+B3

δ 2.1 (m, 1Н), 2.6 (m, 4Н), 3.5 (t, J = 7.0 Hz, 2Н), 3.8 (t, J = 7.0 Hz, 2Н) [M+H] ⁺ calculated for С ₁₀ H ₁₂ D ₃ N ₃ O ₃ 229.1374, experimental 229.1362 four A1+B4

δ 2.0 (m, 1H), 2.6 (m, 4H), 3.3 (m, 1H), 3.7 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₁₁ D ₄ N ₃ O ₃ 230.1437, experimental 230.1429 5 A1+B5

δ 2.1 (m, 1H), 2.6 (m, 4H), 3.8 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₁₀ D ₅ N ₃ O ₃ 231.1500, experimental 231.1511 6 A1+B6

δ 2.0 (m, 1H), 2.6 (m, 4H), 3.6 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₁₀ D ₅ N ₃ O ₃ 231.1500, experimental 231.1491 7 A1+B7

δ 2.0 (m, 1H), 2.6 (m, 4H), 3.5 (m, 1H) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 232.1563, experimental 232.1555 eight A1+B8

δ 2.1 (m, 1H), 2.6 (m, 4H) [M+H] ⁺ calculated for С ₁₀ H ₈ D ₇ N ₃ O ₃ 233.1626, experimental 233.1616 9 A2+B1

δ 2.3 (m, 2H), 3.4 (m, 1H), 3.8 (m, 2H), 7.5 (s, 1H), 8.8 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₀ D ₅ N ₃ O ₃ 231.1500, experimental 231.1493 ten A2+B2

δ 2.2 (m, 2H), 3.5 (m, 2H), 7.5 (s, 1H), 8.7 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 232.1563, experimental 232.1575 eleven A2+B3

δ 2.2 (m, 2H), 3.5 (t, J = 7.0 Hz, 2H), 3.9 (t, J = 7.0 Hz, 2H) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 232.1563, experimental 232.1557 12 A2+B4

δ 2.3 (m, 2H), 3.3 (m, 1H), 3.7 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₈ D ₇ N ₃ O ₃ 233.1626, experimental 233.1614 13 A2+B5

δ 2.2 (m, 2H), 3.8 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₇ D ₈ N ₃ O ₃ 234.1688, experimental 234.1694 fourteen A2+B6

δ 2.3 (m, 2H), 3.5 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₇ D ₈ N ₃ O ₃ 234.1688, experimental 234.1694 fifteen A2+B7

δ 2.2 (m, 2H), 3.5 (m, 1H) [M+H] ⁺ calculated for С ₁₀ H ₆ D ₉ N ₃ O ₃ 235.1751, experimental 235.1759 16 A2+B8

δ 2.3 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₅ D ₁₀ N ₃ O ₃ 236.1814, experimental 236.1823 17 A3+B1

δ 2.1 (m, 2H), 2.4 (m, 2H), 3.4 (m, 1H), 3.7 (m, 2H), 7.4 (s, 1H), 8.8 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₂ D ₃ N ₃ O ₃ 229.1374, experimental 229.1382 eighteen A3+B2

δ 2.0 (m, 2H), 2.4 (m, 2H), 3.6 (m, 2H), 7.4 (s, 1H), 8.7 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₁ D ₄ N ₃ O ₃ 230.1437, experimental 230.1445 19 A3+B3

δ 2.1 (m, 2Н), 2.4 (m, 2Н), 3.5 (t, J = 7.0 Hz, 2Н), 3.8 (t, J = 7.0 Hz, 2Н) [M+H] ⁺ calculated for С ₁₀ H ₁₁ D ₄ N ₃ O ₃ 230.1437, experimental 230.1425 twenty A3+B4

δ 2.0 (m, 2H), 2.4 (m, 2H), 3.4 (m, 1H), 3.6 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₁₀ D ₅ N ₃ O ₃ 231.1500, experimental 231.1520 21 A3+B5

δ 2.0 (m, 2H), 2.4 (m, 2H), 3.8 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 232.1563, experimental 232.1556 22 A3+B6

δ 2.1 (m, 2H), 2.4 (m, 2H), 3.5 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 232.1563, experimental 232.1571 23 A3+B7

δ 2.0 (m, 2H), 2.4 (m, 2H), 3.5 (m, 1H) [M+H] ⁺ calculated for С ₁₀ H ₈ D ₇ N ₃ O ₃ 233.1626, experimental 233.1637 24 A3+B8

δ 2.1 (m, 2H), 2.4 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₇ D ₈ N ₃ O ₃ 233.1626, experimental 233.1637 25 A4+B1

δ 2.6 (m, 4H), 3.3 (m, 1H), 3.7 (m, 2H), 7.5 (s, 1H), 8.8 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₂ D ₃ N ₃ O ₃ 229.1374, experimental 229.1366 26 A4+B2

δ 2.6 (m, 4H), 3.6 (m, 2H), 7.4 (s, 1H), 8.7 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₁ D ₄ N ₃ O ₃ 230.1437, experimental 230.1431 27 A4+B3

δ 2.7 (m, 4Н), 3.6 (t, J = 7.0 Hz, 2Н), 3.8 (t, J = 7.0 Hz, 2Н) [M+H] ⁺ calculated for С ₁₀ H ₁₁ D ₄ N ₃ O ₃ 230.1437, experimental 230.1444 28 A4+B4

δ 2.7 (m, 4H), 3.4 (m, 1H), 3.7 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₁₀ D ₅ N ₃ O ₃ 231.1500, experimental 231.1492 29 A4+B5

δ 2.7 (m, 4H), 3.8 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 232.1563, experimental 232.1571 thirty A4+B6

δ 2.6 (m, 4H), 3.6 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 232.1563, experimental 232.1574 31 A4+B7

δ 2.6 (m, 4H), 3.5 (m, 1H) [M+H] ⁺ calculated for С ₁₀ H ₈ D ₇ N ₃ O ₃ 233.1626, experimental 233.1638 32 A4+B8

δ 2.6 (m, 4H) [M+H] ⁺ calculated for С ₁₀ H ₇ D ₈ N ₃ O ₃ 234.1688, experimental 234.1682 33 A5+B1

δ 2.1 (m, 2H), 3.4 (m, 1H), 3.7 (m, 2H), 7.5 (s, 1H), 8.7 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₀ D ₅ N ₃ O ₃ 231.1500, experimental 231.1516 34 A5+B2

δ 2.0 (m, 2H), 3.6 (m, 2H), 7.5 (s, 1H), 8.7 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 232.1563, experimental 232.1577 35 A5+B3

δ 2.0 (m, 2Н), 3.5 (t, J = 7.0 Hz, 2Н), 3.7 (t, J = 7.0 Hz, 2Н) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 232.1563, experimental 232.1554 36 A5+B4

δ 2.1 (m, 2H), 3.4 (m, 1H), 3.7 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₈ D ₇ N ₃ O ₃ 233.1626, experimental 233.1614 37 A5+B5

δ 2.0 (m, 2H), 3.7 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₇ D ₈ N ₃ O ₃ 234.1688, experimental 234.1673 38 A5+B6

δ 2.0 (m, 2H), 3.5 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₇ D ₈ N ₃ O ₃ 234.1688, experimental 234.1699 39 A5+B7

δ 2.1 (m, 2H), 3.5 (m, 1H) [M+H] ⁺ calculated for С ₁₀ H ₆ D ₉ N ₃ O ₃ 235.1751, experimental 235.1766 40 A5+B8

δ 2.0 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₅ D ₁₀ N ₃ O ₃ 236.1814, experimental 236.1809 41 A6+B1

δ 3.3 (m, 1H), 3.8 (m, 2H), 7.5 (s, 1H), 8.8 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₈ D ₇ N ₃ O ₃ 233.1626, experimental 233.1633 42 A6+B2

δ 3.5 (m, 2H), 7.5 (s, 1H), 8.7 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₇ D ₈ N ₃ O ₃ 234.1688, experimental 234.1690 43 A6+B3

δ 3.5 (t, J = 7.0 Hz, 2H), 3.9 (t, J = 7.0 Hz, 2H) [M+H] ⁺ calculated for С ₁₀ H ₇ D ₈ N ₃ O ₃ 234.1688, experimental 234.1676 44 A6+B4

δ 3.4 (m, 1H), 3.7 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₆ D ₉ N ₃ O ₃ 235.1751, experimental 235.1747 45 A6+B5

δ 3.8 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₅ D ₁₀ N ₃ O ₃ 236.1814, experimental 236.1808 46 A6+B6

δ 3.6 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₅ D ₁₀ N ₃ O ₃ 236.1814, experimental 236.1821 47 A6+B7

δ 3.5 (m, 1H) [M+H] ⁺ calculated for С ₁₀ H ₄ D ₁₁ N ₃ O ₃ 237.1877, experimental 237.1870 48 A6+B8

The fully deuterated structure was confirmed by HRMS-ESI due to the absence of proton signals in the ¹ H NMR spectrum. [M+H] ⁺ calculated for С ₁₀ H ₃ D ₁₂ N ₃ O ₃ 238.1939, experimental 238.1944 49 A0+B1

δ 1.9 (m, 2H), 2.4 (t, J = 6.6 Hz, 4H) 3.4 (m, 1H), 3.7 (m, 2H), 7.5 (s, 1H), 8.8 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₄ DN ₃ O ₃ 227.1249, experimental 227.1237 fifty A0+B2

δ 2.0 (m, 2H), 2.4 (t, J = 6.6 Hz, 4H), 3.6 (m, 2H), 7.5 (s, 1H), 8.7 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₃ D ₂ N ₃ O ₃ 228.1312, experimental 228.1305 51 A0+B3

δ 2.0 (m, 2H), 2.4 (t, J = 6.6 Hz, 4H), 3.4 (t, J = 7.0 Hz, 2H), 3.8 (t, J = 7.0 Hz, 2H) [M+H] ⁺ calculated for С ₁₀ H ₁₃ D ₂ N ₃ O ₃ 228.1312, experimental 228.1316 52 A0+B4

δ 1.9 (m, 2H), 2.4 (t, J = 6.6 Hz, 4H), 3.4 (m, 1H), 3.7 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₁₂ D ₃ N ₃ O ₃ 229.1374, experimental 229.1361 53 A0+B5

δ 1.9 (m, 2H), 2.4 (t, J = 6.6 Hz, 4H), 3.8 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₁₁ D ₄ N ₃ O ₃ 230.1437, experimental 230.1429 54 A0+B6

δ 1.9 (m, 2H), 2.4 (t, J = 6.6 Hz, 4H), 3.5 (m, 2H) [M+H] ⁺ calculated for С ₁₀ H ₁₁ D ₄ N ₃ O ₃ 230.1437, experimental 230.1448 55 A0+B7

δ 1.9 (m, 2H), 2.4 (t, J = 6.6 Hz, 4H), 3.5 (m, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₀ D ₅ N ₃ O ₃ 231.1500, experimental 231.1520 56 A0+B8

δ 1.9 (m, 2H), 2.5 (t, J = 6.6 Hz, 4H) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 231.1500, experimental 231.1520 57 A1+B0

δ 2.1 (m, 1Н), 2.6 (m, 4Н), 3.4 (t, J = 7.0 Hz, 2Н), 3.8 (t, J = 7.0 Hz, 2Н), 7.5 (s, 1Н), 8.8 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₄ DN ₃ O ₃ 227.1249, experimental 227.1254 58 A2+B0

δ 2.3 (m, 2H), 3.4 (t, J = 7.0 Hz, 2H), 3.8 (t, J = 7.0 Hz, 2H), 7.5 (s, 1H), 8.8 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₁ D ₄ N ₃ O ₃ 230.1437, experimental 230.1441 59 A3+B0

δ 2.1 (m, 2Н), 2.4 (m, 2Н), 3.4 (t, J = 7.0 Hz, 2Н), 3.8 (t, J = 7.0 Hz, 2Н), 7.5 (s, 1Н), 8.7 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₂ D ₂ N ₃ O ₃ 228.1312, experimental 228.1322 60 A4+B0

δ 2.8 (m, 4H), 3.4 (t, J = 7.0 Hz, 2H), 3.8 (t, J = 7.0 Hz, 2H), 7.5 (s, 1H), 8.8 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₂ D ₂ N ₃ O ₃ 228.1312, experimental 228.1309 61 A5+B0

δ 2.0 (m, 2H), 3.4 (t, J = 7.0 Hz, 2H), 3.8 (t, J = 7.0 Hz, 2H), 7.5 (s, 1H), 8.7 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₁₁ D ₄ N ₃ O ₃ 230.1437, experimental 230.1444 62 A6+B0

3.4 (t, J = 7.0 Hz, 2H), 3.8 (t, J = 7.0 Hz, 2H), 7.5 (s, 1H), 8.8 (s, 1H) [M+H] ⁺ calculated for С ₁₀ H ₉ D ₆ N ₃ O ₃ 232.1563, experimental 232.1570

Example 2. Study of the anti-inflammatory activity of new compounds of general formula I in a model of carrageenan paw edema in rats.

Compounds 1 – 62 obtained according to Example 1 were used for research.

Conducted several series of experiments on rats, which were randomly divided into groups, each group of 5 animals. Control data were pooled. For research, a model of carrageenan paw edema in Wistar rats was used. Edema was caused by subplantar injection of 0.1 ml of a 1% aqueous solution of λ-carrageenan into the hind limb of the animals of the experimental and control groups. Animals of the experimental groups received the test compounds immediately after the induction of carrageenan edema orally using a probe. Compounds 1 – 62 were administered to animals at a dose of 10 mg/kg. Similarly, animals in the control group received an appropriate amount of placebo. Edema was assessed by measuring the volume of the foot using a mechanical oncometer before the administration of flagogen (λ-carrageenan), two hours after its administration, and four hours after its administration. The degree of edema was judged by the difference in volume between the edematous foot and the foot prior to the induction of inflammation. The anti-inflammatory activity of the compounds of general formula (I) was determined using the formula A=(ΔVk-ΔVe/ΔVk)·100%, where A is the anti-inflammatory activity in percent; ΔVe and ΔVk are the difference between edematous and normal feet in animals of the experimental and control groups [19, 20].

Table 2 Anti-inflammatory effects of the compounds of the present invention in a carrageenan paw edema model in rats.

Compound The degree of reduction of foot edema, the average value for the group, % In 2 hours after 4 hours Compound 1 41* 44* Compound 2 36* 41* Compound 3 45* 49* Compound 4 43* fifty* Compound 5 38* 43* Compound 6 40* 45* Compound 7 44* 48* Compound 8 36* 42* Compound 9 42* 47* Compound 10 35* 40* Compound 11 43* 46* Compound 12 40* 49* Compound 13 37* 41* Compound 14 39* 43* Compound 15 45* fifty* Compound 16 41* 45* Compound 17 43* 48* Compound 18 35* 42* Compound 19 38* 44* Compound 20 36* 41* Compound 21 44* 48* Compound 22 40* 46* Compound 23 39* 40* Compound 24 37* 41* Compound 25 43* 49* Compound 26 44* fifty* Compound 27 41* 45* Compound 28 45* 48* Compound 29 36* 40* Compound 30 40* 46* Compound 31 39* 44* Compound 32 35* 41* Compound 33 41* 47* Compound 34 43* fifty* Compound 35 38* 42* Compound 36 40* 43* Compound 37 36* 40* Compound 38 37* 42* Compound 39 45* 49* Compound 40 36* 41* Compound 41 35* 41* Compound 42 39* 43* Compound 43 44* 49* Compound 44 41* 45* Compound 45 45* 48* Compound 46 38* 42* Compound 47 42* 47* Compound 48 43* 46* Compound 49 37* 40* Compound 50 40* 48* Compound 51 36* 43* Compound 52 42* 49* Compound 53 35* 41* Compound 54 38* 45* Compound 55 43* 47* Compound 56 41* 44* Compound 57 37* 40* Compound 58 44* 46* Compound 59 39* 42* Compound 60 45* 49* Compound 61 36* 43* Compound 62 40* 48*

* significant difference in the degree of reduction in foot edema in rats of the experimental groups treated with compounds No. 1-62, from the corresponding indicators in rats treated with placebo (p<0.05).

The data presented indicate that when the novel compounds of the present invention were administered, there was a significant (p<0.05) reduction in foot edema in experimental rats compared to placebo, indicating that the novel compounds of the present invention exhibit anti-inflammatory activity.

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Claims (3)

Compound of general formula I

, where R is H or D, provided that at least one R is D.