RU2417218C2 - N-alkylcarbonylaminoacid ethers and n-alkylcarbonylaminolactons and application thereof - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to certain N-alkylcarbonylaminoacid esters of formula

where R₁ independently represents hydrogen or methyl; R₂ independently represents alkyl C₁-C₂ and R₃ independently represents alkyl C₁-C₄, offered in the present invention, as well as to compositions and therapies with using the declared compounds.

EFFECT: preparing new compounds which effect on sensory processes.

27 cl, 7 tbl, 2 dwg

Description

RELATED APPLICATIONS

This application is related to:

U.S. provisional patent application No. 60/667166, filed March 29, 2005;

U.S. provisional patent application No. 60/683384, filed May 20, 2005;

U.S. provisional patent application No. 60/702505, filed July 26, 2005;

U.S. provisional patent application No. 11/203728, filed August 13, 2005; and

U.S. provisional patent application No. 60/772374, filed February 9, 2006;

the contents of each of which is incorporated into this application by reference in its entirety.

FIELD OF TECHNOLOGY

The present invention generally relates to refreshing, soothing and cooling compounds that affect sensory processes. More specifically, this invention relates to certain esters of N-alkylcarbonylamino acids and N-alkylcarbonylaminolactones, compositions and products containing these compounds, and methods of treatment, for example, methods for reducing irritation, itching and skin pains, irritation of the mucous membranes of the oral cavity and upper respiratory tract, for example, methods of treating cough and / or asthma.

BACKGROUND

In this section, references are made to a number of patents and publications for a more complete description and disclosure of the present invention and the state of the art in the field to which the invention relates. Each of these literature references is hereby incorporated by reference in its entirety, as if the inclusion of each individual reference was specifically and individually specified in this section.

It should be understood that throughout the description of the invention, including the following claims, unless otherwise provided by the context, the term “comprise” and its derivatives, such as “comprises” and “comprising”, means the inclusion of the indicated integer or step or group of integers numbers or steps in the scope of the definition, not the exclusion of any other integer or step or group of integers or steps in the scope of the definition.

It should be noted that the singular forms, in the form in which they are used in the description of the invention and the attached claims, include many objects of reference, unless otherwise explicitly out of context. For example, reference to the term “pharmaceutical carrier” includes a mixture of two or more such carriers, and the like.

The ranges of variation of values in the present description are often expressed as from “about” one particular value to “about” another specific value. When ranges of variation of values are expressed in this manner, another embodiment of the invention includes a range from one specific value and / or to another specific value. Similarly, when values are given as approximate values using the preceding word “about,” it should be understood that a particular value provides another embodiment of the invention.

Menthol and menthol-like substances are used in hygiene products, in the manufacture of confectionery, food products and over-the-counter medications, as ingredients for imparting freshness, cooling, taste, anti-irritant and analgesic effects to the skin and mucous membranes of the mouth and upper respiratory ways. However, the use of menthol to alleviate sensory discomfort is limited due to the short duration of its action and the multimodality of its effects on sensory processes, including smell, pungent taste and irritation. The unpleasant effect of menthol can be easily seen, for example, when applying ointments containing menthol in the area around the eyes. Menthol vapor causes eye pain and lacrimation. Similarly, menthol can relieve nasal congestion and eliminate coughing, but the effect, especially with regard to coughing, is short-lived, and the mucous membranes' tendency to irritation limits the use of higher doses.

Modern methods of treating damaged skin include rinsing with cold water or compresses, the use of ointments containing local anesthetics (for example, Emla®) or non-steroidal painkillers anti-inflammatory drugs (NSAIDs). Currently, dextrorphan, codeine and menthol are used to treat cough. These methods and compounds have moderate efficacy and ease of use.

Therefore, compounds like menthol are required, which have a refreshing, cooling and soothing effect on the skin and, at the same time, are free from deficiencies in the form of smell, irritant effect and, most importantly, short duration of action. To treat unpleasant skin sensations that are medically significant, such as itchy eczema or prolonged cough and asthmatic shortness of breath, it is important to have compounds that last for a much longer time than menthol.

The menthol molecule has three chiral centers. For menthol, all eight optical isomers are known. Below is the most common optical isomer, which is designated as (-) - menthol (or 1R- (1α-2β-5α) -5-methyl-2- (1-methylethyl) cyclohexanol).

About thirty years ago, a group of scientists synthesized more than 1200 compounds in an attempt to obtain cooling agents with better properties than menthol. The results of their work are presented in the article (Watson et al., "New compounds with the menthol cooling effect," J. Soc. Cosmet. Chem., 29: 185-200, 1978). As a result of their research, N-alkyl-cycloalkyl- and N-alkyl-alkylcarboxamides were marketed under the trade names WS-3 and WS-23, which are used as additives in the manufacture of confectionery, food products (for example, sweets, chewing gum) and hygiene products.

U.S. Pat. No. 4,178,459 dated December 11, 1979 Watson et al. Described the cooling properties of certain N-alkoxycarbonylalkyl-substituted p-menthanecarboxamides. The ethyl ether of the alanine derivative shown below is presented in the table in columns 5 and 6. The stereoisomerism of neither the menthan nor the alanine fragments is shown in the structure presented.

Other cooling menthol-like compounds that have found commercial use as agents for application to the skin and mucous membranes include, for example, mentillactate (Frescolat® ML) and mentholpropanediol (Coolant 10).

Current ideas about topical cooling agents are reflected in a review by MB Erman ("Cooling agents and skin care applications," Cosmetics & Toiletries, 120: 105-118, May 2005; "Progress in physiological cooling agents," Perfumer & Flavorist, 29: 34-50, 2004) and P. Jacobs and W. Johncock ("Some like it cool," Parfumerie und Kosmetik, 80: 26-31, 1999).

The glycine ethyl ester compound presented below is known as WS-5 and is shown in Figure F-11 on page 42 of the Herman review article mentioned above. There are no methyl or ethyl groups in the α position in this compound.

This compound (WS-5) and its optical isomers are also disclosed in U.S. Pat. 2005/0222256 A1 of October 6, 2005

However, at the moment, none of the compounds known from the prior art has activity or a duration of action that makes it suitable for the treatment of severe skin disorders such as itchy eczema or diseases of the upper respiratory tract, such as like asthma.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there are provided some esters of N-alkylcarbonylamino acids and some N-alkylcarbonylaminolactones, as described in the present invention.

According to another aspect of the present invention, there is provided a composition comprising such a compound and a delivery vehicle (for example, for delivering the compound to humans).

In one embodiment, the delivery vehicle is a pharmaceutically acceptable carrier or diluent.

In one embodiment, the delivery vehicle is suitable for delivering said compound to human skin.

In one embodiment, the delivery vehicle is a tissue.

In one embodiment, the delivery vehicle is suitable for delivering the compound to the oral cavity and / or upper respiratory tract of a person.

In one embodiment, the compound is presented in the form of a composition containing from 1 to 10 mg of the compound, for example, in the form of a tablet.

In one embodiment, the compound is presented in the form of a composition containing from 0.01 to 2% by weight. or about. the specified connection.

In one embodiment, the composition further comprises a polyhydric alcohol.

In one embodiment, the composition further comprises a mucoadhesive polymer.

Another aspect of the present invention relates to methods for treating a person’s skin, mouth or upper respiratory tract, including:

contacting a composition containing such a compound and a delivery vehicle with a person’s skin, oral cavity or upper respiratory tract, and thus delivering an effective amount of the compound to a person’s skin or mucous membranes.

Another aspect of the present invention relates to methods for treating a condition, including:

contacting a composition comprising a compound according to any one of claims 1 to 24 of the claims, and a delivery device, with the skin, oral cavity or upper respiratory tract of a person,

the delivery, therefore, of a therapeutically effective amount of a compound for the treatment (eg, relief) of this condition.

Another aspect of the present invention relates to such a compound intended for use in a method of treating a human or animal organism through therapy.

Another aspect of the present invention relates to the use of such a compound in the manufacture of a medicament for use in a method of treatment.

In one embodiment, treatment is understood to mean treating (e.g., alleviating) skin irritation, itching and / or pain (e.g., contacting to deliver an amount of a compound that is therapeutically effective to alleviate skin irritation, itching and / or pain).

In one embodiment, treatment refers to the treatment (eg, relief) of a cough and / or sensation of irritation and / or obstruction of the upper respiratory tract (for example, in which contacting delivers an amount of a compound that is therapeutically effective to relieve cough and / or sensation irritation and / or obstruction of the upper respiratory tract).

In one embodiment, treatment refers to the treatment (eg, alleviation) of the symptoms and signs of asthma, chronic obstructive pulmonary disease or other upper respiratory tract disease (for example, in which contacting delivers an amount of a compound that is therapeutically effective to alleviate the symptoms and signs asthma, chronic obstructive pulmonary disease or other upper respiratory tract disease).

In one embodiment, the treatment refers to the treatment of a cough (for example, in which contacting delivers an amount of a compound that is therapeutically effective for treating a cough).

In one embodiment, the treatment refers to the treatment of asthma (for example, in which contacting delivers an amount of a compound that is therapeutically effective for treating asthma).

In one embodiment, treatment is understood to mean smoking cessation therapy (for example, in which contacting delivers an amount of a compound that is effective in smoking cessation therapy).

In one embodiment, treatment is understood to mean treatment aimed at reducing the spread of an infectious microorganism in a host (for example, in which contacting delivers an amount of a compound that is effective to reduce the spread of an infectious microorganism in a host).

In one embodiment, treatment refers to treatment aimed at preventing cough and airborne transmission of infectious microorganisms (for example, in which contacting delivers an amount of a compound that is effective in preventing coughing and airborne transmission of infectious microorganisms).

In one embodiment, treatment refers to treatment aimed at increasing attention or reducing nausea, appetite, fatigue, fever or fever (for example, in which contacting delivers an amount of the compound that is effective to increase attention or to reduce nausea, appetite fatigue, fever, or fever).

One skilled in the art will appreciate that the features and preferred embodiments of one aspect of the invention also apply to another aspect of the invention.

Other advantages and aspects of the invention are disclosed in the following detailed description and the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a graph of the dependence of cooling intensity on time (hours) from the time of application for six compounds: WS-3 (filled circles), (-) menthol (open circles), WS-5 (filled triangles), D-Hsl ( unfilled triangles), D-Ala-OMe (filled squares) and D-Ala-OEt (unfilled squares).

Figure 2 is a bar graph showing the cooling duration (hours) for eight compounds (in order): D-Ala-OEt, D-Ala-OMe, D-Hsl, Sar-OEt, WS-5, WS-12, WS-3 and (-) - menthol.

DETAILED DESCRIPTION OF THE INVENTION

A class of compounds has been discovered that are suitable for use as active ingredients in preparations (eg, pharmaceuticals) intended for application to the skin, lips and mucous membranes of the oral cavity and upper respiratory tract.

These compounds are suitable for use, for example, as therapeutic agents to reduce discomfort, such as itching and pain, and also as additives for food, confectionery, cosmetics, and hygiene products.

These compounds have one or more of the following properties:

(i) a refreshing, calming and cooling effect on the surface of the skin, mouth, and / or throat and, in pathological conditions, anti-irritant, antipruritic, antitussive and / or anti-nociceptive effects;

(ii) minimal irritating effect on the eyes when applying the compound to the skin of the face in the area around or around the eyes, for example, when applying to the skin of the cheekbones or skin around the eyes (which is also a good indicator of safety), for example, when applying to the skin at a concentration of 40 mm or less, which is equivalent to a mixture with a concentration of 1% wt./about. for a molecule weighing 250 daltons;

(iii) a rapid onset of action of less than 5 minutes (e.g., from 0.5 to 5 minutes), preferably less than 3 minutes (e.g., from 0.5 to 3 minutes), preferably less than about 1 minute (e.g., from 0.5 to 1 minute ), for example, when applied to the skin at a concentration of 40 mM or less, which is equivalent to a mixture with a concentration of 1% w / v. for a molecule weighing 250 daltons;

(iv) a duration of action exceeding 1 hour, for example, when applied to the skin at a concentration of 40 mM or less, which is equivalent to a mixture with a concentration of 1% w / v, for a molecule with a mass of 250 daltons;

(v) their repeated application does not lead to a change in sensitivity to subsequent stimulation; and

(vi) strong sensations of coolness, relief of irritation and freshness that occur when it enters the oral cavity, counteracting irritating stimuli in the mouth and upper respiratory tract, causing coughing and wheezing.

These compounds can be assigned to the esters or lactones of N-alkylcarbonyl- and N-alkyl-N-alkylcarbonyl- D-, L-, or DL-amino acids, or "NACE compounds".

In one embodiment, the compound is selected from compounds of formula (1):

Where:

R ₁ independently represents hydrogen or methyl;

R ₂ independently represents alkyl C ₁ -C ₂ and

R ₃ independently represents C ₁ -C ₄ alkyl.

The mentyl group (i.e., 5-methyl-2- (1-methylethyl) cyclohex-1-yl group) has the same stereochemistry as (-) - menthol.

The α-carbon atom located between the —NR ₁ group and the —C (= O) OR ₃ group has the same stereochemistry as D-alanine. It is also known as the R-configuration, according to the Cahn-lngold-Prelog nomenclature system. With the exception of glycine, all α-amino acids have a chiral center in the form of an α-carbon atom. Although amino acids in the D-configuration are found in some antibiotics and cell membranes of microorganisms, amino acids in proteins are almost always in the L (or S) configuration.

In one embodiment, R ₁ independently represents hydrogen.

In one embodiment, R _{1 is} independently methyl.

In one embodiment, R _{2 is} independently methyl.

In one embodiment, R _{2 is} independently ethyl.

In one embodiment, R _{3 is} independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl.

In one embodiment, R _{3 is} independently methyl or ethyl.

In one embodiment, R _{3 is} independently methyl.

In one embodiment, R _{3 is} independently ethyl.

The present invention includes any possible combination of the embodiments described above, as if all of these combinations were listed separately.

The combination of R ₂ and D configuration has a stronger and longer lasting effect, and also creates a selective effect of refreshing coolness without causing tissue irritation.

In a preferred embodiment, R ₁ is hydrogen, R ₂ is methyl and R ₃ is methyl or ethyl (forming the corresponding methyl ether or methyl ethyl ether of D-alanine derivatives).

D-alanine (R) -2-amino-propionic acid

D-alanine methyl ester (R) -2-amino-propionic acid methyl ester

D-alanine ethyl ester (R) -2-amino-propionic acid ethyl ester

Examples of some preferred compounds include the following:

one (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid methyl ester

2 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexyl carbonyl) amino] propionic acid ethyl ester

3 n-propyl ester of (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid

four Isopropyl ester of (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid

5 (R) -2 n-butyl ether - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid

6 (R) -2 sec-butyl ester - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid

7 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid isobutyl ester

8 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid tert-butyl ester

Additional examples of some preferred compounds include the following:

one (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] propionic acid methyl ester 2 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] propionic acid ethyl ester 3 (R) -2 n-propyl ester - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] propionic acid four (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] propionic acid isopropyl ester 5 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] propionic acid n-butyl ester 6 (R) -2 sec-butyl ester - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] propionic acid 7 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] propionic acid isobutyl ester 8 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] propionic acid tert-butyl ester

Additional examples of some preferred compounds include the following:

one (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] -butanoic acid methyl ester 2 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] -butanoic acid ethyl ester 3 n-propyl ester of (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] butanoic acid four (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] -butanoic acid isopropyl ester 5 (R) -2 n-butyl ether - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] butanoic acid 6 (R) -2 sec-butyl ester - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] butanoic acid 7 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] -butanoic acid isobutyl ester 8 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] -butanoic acid tert-butyl ester

Additional examples of some preferred compounds include the following:

one (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] -butanoic acid methyl ester 2 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] -butanoic acid ethyl ester 3 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] -butanoic acid n-propyl ester four (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] -butanoic acid isopropyl ester 5 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] -butanoic acid n-butyl ester 6 (R) -2 sec-butyl ether - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] -butanoic acid 7 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] -butanoic acid isobutyl ester 8 (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) methyl-amino] -butanoic acid tert-butyl ester

In one embodiment, the compound is selected from the group of compounds of formula (2):

Where:

n independently represents 1, 2, or 3; and

R ₁ independently represents hydrogen or methyl.

In addition, the mental group (i.e., 5-methyl-2- (1-methylethyl) cyclohex-1-yl group) has the same stereochemistry as (-) - menthol.

In one embodiment, n independently represents 1.

In one embodiment, n is independently 2.

In one embodiment, n is independently 3.

In one embodiment, R ₁ independently represents hydrogen.

In one embodiment, R _{1 is} independently methyl.

In one embodiment, the α-carbon atom is in the (R) configuration.

In one embodiment, the α-carbon atom is in the (S) configuration

The present invention includes any possible combination of the embodiments described above, as if all of these combinations were listed separately.

Compounds of formula (2) are similar to compounds of formula (1), except that the groups R ₂ and R ₃ in Formula (1) form together an alkylene chain (for example, - (CH ₂ ) _n -), and together with atoms, to which they are attached, form a five-, six- or seven-membered lactone cycle.

For compounds of formula (2), the α-carbon atom can be independently in the D-configuration of the amino acid (i.e., (R) configuration) or the L-configuration of the amino acid (i.e., (S) -configuration). Both enantiomers and their mixtures (for example, racemic) are approximately equivalent in biological action (see below). The chiral center of the lactone is such that there may be no significant energy barriers in the formation of any of the active configurations. Therefore, a racemic mixture of lactone may also be useful.

Homoserin (Hse) can cyclize to form a five-membered lactone cycle (γ-lactone cycle) called homoserine lactone (Hsl). Accordingly, compounds of formula (2), where n is 1, are referred to in the present invention as D-Hsl, L-Hsl and DL-Hsl analogues.

Examples of some preferred compounds include the following:

one ((S) -2-oxo-tetrahydrofuran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid

2 ((R) -2-oxo-tetrahydrofuran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid

3 (2-oxo-tetrahydrofuran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid

Additional examples of some preferred compounds include the following:

one Methyl - ((S) -2-oxo-tetrahydropyran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid 2 Methyl - ((R) -2-oxo-tetrahydropyran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid 3 Methyl- (2-oxo-tetrahydropyran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid

Additional examples of some preferred compounds include the following:

one ((S) -2-oxo-tetrahydropyran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid 2 ((R) -2-oxo-tetrahydropyran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid 3 (2-oxo-tetrahydropyran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid four Methyl - ((S) -2-oxo-tetrahydropyran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid 5 Methyl - ((R) -2-oxo-tetrahydropyran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid 6 Methyl- (2-oxo-tetrahydropyran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid

Additional examples of some preferred compounds include the following:

one ((S) -2-oxo-tetrahydrooxepan-3-yl) -amide of isopropyl-5-methyl-cyclohexylcarboxylic acid (1R, 2S, 5R) -2- 2 ((R) -2-oxo-tetrahydrooxepan-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid 3 (2-oxo-tetrahydrooxepan-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid four Methyl - ((S) -2-oxo-tetrahydrooxepan-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid 5 Methyl - ((R) -2-oxo-tetrahydrooxepan-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid 6 Methyl- (2-oxo-tetrahydrooxepan-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarboxylic acid

In one embodiment, the compound is in a substantially purified form and / or a form substantially free of impurities.

In one embodiment, the substantially purified form is at least 50% by weight, for example at least 60% by weight, for example at least 70% by weight, for example, at least 80% by weight, for example at least 90% by weight, for example at least 95% by weight, for example at least 97% by weight, for example, at least 98% by weight, for example, at least 99% by weight

Unless otherwise indicated separately, the term “substantially purified form” refers to a compound in any of the stereoisomeric or enantiomeric forms. For example, in one embodiment, the term “substantially purified form” refers to a mixture of stereoisomers, i.e. the form is purified in relation to other compounds. In one embodiment, the term “substantially purified form” refers to one of the stereoisomers, for example, an optically pure stereoisomer. In one embodiment, the term “substantially purified form” refers to a mixture of enantiomers. In one embodiment, the term “substantially purified form” refers to an equimolar mixture of enantiomers (ie, racemic mixture, racemate). In one embodiment, the term “substantially purified form” refers to one of the enantiomers, for example, an optically pure enantiomer.

In one embodiment, the impurities comprise not more than 50 wt.%, For example, not more than 40 wt.%, For example, not more than 30 wt.%, For example, not more than 20 wt.%, For example, not more than 10 wt. for example, not more than 5% of the mass., for example, not more than 3% of the mass., for example, not more than 2% of the mass., for example, not more than 1% of the mass.

Unless otherwise indicated separately, the term "impurities" refers to the rest of the compounds, that is, to all compounds except stereoisomers or enantiomers. In one embodiment, the term “impurities” refers to other compounds and other stereoisomers. In one embodiment, the term “impurities” refers to other compounds and another enantiomer.

In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, based on the molar content, is the desired stereoisomer or enantiomer, and 40% is the secondary stereoisomer or enantiomer), for example, at least 70% optically pure, for example at least 80% optically pure, for example at least 90% optically pure, for example at least 95% optically pure, for example at least 97% optically pure for example at least 98% optical and pure, for example at least 99% optically pure.

Preferred among these NACE compounds are "long-acting" NACE compounds, which when applied to the skin or mucous membranes create a feeling of freshness, alleviate irritation and coolness without causing skin irritation, and cause minimal eye irritation, and the duration of action of which on the skin lasts more than 1 hour when applied at a concentration of 40 mm or less, and the duration of action on the lining of the oral cavity and upper respiratory tract lasts more than 30 minutes. (A concentration of 40 mM corresponds to 1% w / v, or 10 mg / 100 ml for a compound with a molecular weight of 250 daltons).

Long-acting NACE compounds differ from other esters of N-alkylcarbonyl amino acids (for example, WS-5 and WS-31; see Table 2) and N-alkyl substituted carboxamides (for example, WS-3, WS-12, WS-23; see Table 5, where WS-23 is N-2,3-trimethyl-2-isopropylbutanamide), which are known to have cooling properties and two of which (WS-3 and WS-23) are used commercially in food production products, confectionery and hygiene products.

As shown in the examples, WS-3, WS-5, WS-12, WS-23 and WS-31 have a short duration of action (less than 1 hour) at a concentration of 40 mm or a slow onset of action (more than 5 minutes). In addition, some of these compounds do not cause significant cooling, but rather cause skin sensations such as pinching, burning and irritation - effects similar to the effects of (-) - menthol, a compound with a multimodal effect on sensory processes. It should be noted that (-) - menthol is one of the eight stereoisomers of menthol; it has the most powerful cooling effect and is the only stereoisomer of menthol that has found commercial application.

Preferred long-acting NACE compounds, in contrast, provide a perfect cooling effect in combination with a quick onset of action, a long-lasting effect and minimal irritation to the skin or eyes, which was not previously known.

Moreover, the introduction of a methyl group in ethyl ether of N-p-menthanecarbonylglycine (WS-5) both at the nitrogen atom and at the α-carbon atom increases the duration of action by at least 50%.

Moreover, the efficacy, duration and selectivity (absence of irritation) of exposure increase for an alanine derivative having an α-carbon atom in the D configuration.

In addition, the cyclization of the α-carbon atom of an amino acid with a short circuit on the alkyl group of the ester with the formation of a 5-membered γ-lactone cycle leads to the formation of compounds with the desired biological activity.

Due to their prolonged action, these compounds, compositions and products can be used for therapeutic purposes, for example, to reduce the discomfort associated with the pathophysiological manifestations of damage and inflammation of the skin and the surface of the upper digestive tract and upper respiratory tract.

These compounds can be used on the skin or in the oral cavity to counteract irritation, itching and pain in therapeutic cases where long-term relief of sensory discomfort is required, such as, for example, severe itchy eczema and strong prolonged coughing and wheezing.

These compounds suppress the sensation of itching, pain and discomfort that occurs in the skin and mucous membranes of the oral cavity and upper respiratory tract and, thus, can be used to suppress sensory disturbances in these tissues.

These compounds (for example, in the form of a tablet or liquid with standard doses up to 10 mg) are characterized by a rapid onset of action (less than 1 minute), relieve sore throat, and have a strong antitussive effect that lasts for several hours without irritating the mouth or respiratory tract.

These compounds are odorless, do not cause pain or burning of the skin of the face or mouth.

These compounds may be used alone and / or in formulations additionally containing a delivery vehicle, for example, a delivery vehicle for delivering the compound to the skin. In one embodiment, the compound is applied to a tissue adapted for delivery or having a structure that is suitable in its structure for delivering to the skin a dermatologically effective amount of the compound.

Prolonging the action allows the use of options for the implementation of long-acting NACE compounds in therapeutic cases when the discomfort of the skin or mucous membranes lasts at least one day, for example, after photodynamic or laser surgery of the skin of the face, dermatitis of the skin of the face or even after severe insect bites.

Currently, there are no local painkillers approved for use as such for the therapeutic relief of skin discomfort, although there is a need for such compounds. The potent derivatives of D-Ala and Hsl, which, among other things, have selective cooling and refreshing effects, expand the range of agents that can be used in the oral cavity and upper respiratory tract and can be incorporated into medicines such as antitussive and anti-asthma compounds.

The characteristic structural features of the molecules, which provide the required properties in the form of increased activity and the presence of refreshing cooling in the absence of irritation, are unforeseen and unknown from the prior art.

The term "treatment" in the sense in which it is used in the present invention in the context of the treatment of a condition generally refers to treatment and therapy in which some desired therapeutic effect is achieved, for example, slowing down progression and including reducing the rate of progression, stopping progression, relief of symptoms, improvement and cure. The term “treatment” also includes treatment as a preventive measure (ie, prevention). For example, the treatment of patients who have not yet developed the condition, but who are at risk of developing the condition, is also indicated by the term "treatment".

The term "effective amount", in the sense in which it is used in the present invention, refers to that amount of the active compound or material, composition or dosage form containing the active compound, which is effective to achieve some desired therapeutic effect, commensurate with the appropriate ratio benefit / risk in the appointment in accordance with the selected treatment regimen.

Pharmacology and mechanisms of action of esters and lactones of N-alkylcarbonyl- and N-alkyl-N-alkylcarbonylamino acids

It is believed that harmful impulses are transmitted from the skin with the help of C-group non-myelin nerve fibers and A-delta thin myelin nerve fibers. From a functional point of view, these fibers are also called polymodal, and they can contain neuropeptides within one group, such as a peptide associated with the calcitonin gene, and substance P, or in another group, phosphatases and binding sites for isolectin B4. These sensory fibers also contain various receptors, including the transient potential receptor (TRP), a family of receptors that are responsible for heat sensitivity and pain. Afferent signals initiating coughing come from detectors on the surface of the trachea and larynx and are transmitted through the laryngeal branch of the vagus nerve. These fibers of the A-delta group are formed by neurons of the nodose ganglion and contain rapidly adaptive receptors. Sensitivity to cough irritants is separately enhanced by group C fibers with protons, inflammation, and TRPV1 vanilloid receptor antagonists such as capsaicin, but there is currently no precise description of the group C fiber detector and transducer (see, for example, Canning et al. J. Physiol. 557: 643-548, 2004).

There are many conditions that cause discomfort to the skin and mucous membranes of the mouth and upper respiratory tract - discomforts that are alleviated by cooling (see below). Cooling of the skin of the face and mucous membranes is recorded by many primary sensory afferents having receptors on the nerve endings. Such sensory fibers produce a rhythmic continuous discharge at normal temperatures, which increases in response to a decrease in skin temperature (a sequential decrease from 33 to 23 ° C) and is suppressed by heating. Dynamic information propagates along axons in the form of successive peaks at a speed of about 20 to 40 impulses / s to central neurons, which in humans leads to a feeling of cold. This type of sensation is similar to skin perception of air or water with a temperature of 15 to 22 ° C. The primary afferents of the facial skin end with the surface layer of the caudal nucleus of the trigeminal nerve, where they represent more than 95% of the thermoceptive input signal (see, for example, Hutchinson et al., J. Neurophysiol., 77: 3252-3266, 1997). Cooling signals from the nasopharynx and oral part of the pharynx are transmitted through the glossopharyngeal nerve.

The input signals of temperature detection from the face and lips are extremely important for modeling behavior, since this surface is densely innervated, as shown in the diagrams of the model of human perception in psychology textbooks. This fact is fully confirmed if we pay attention that the temperature easily changes from sensations on our face, but to a much lesser extent from perception by other parts of the body. Three branches of the trigeminal nerve - the ophthalmic, maxillary and mandibular - send afferent information about the perception of temperature from the skin of the face, head, scalp, lips, pharyngeal membranes and the dorsal surface of the tongue to the surface of the core of the brain stem. These thermoceptive regions of the trigeminal nerve dynamically respond to surface temperature differences and are inhibited by heat. Pulses from cold receptors dominate the thermal perception of the facial region, while heat recording is not tonic active.

The cooling signals coming from the oral cavity are more complex, since the exact identification of the signal can be complicated by the action of various factors (secretion of saliva, taste impulses transmitted by the facial and glossopharyngeal nerves), which differ from the input signals from the trigeminal nerve. Sensory signals from the oral cavity, trachea and pharynx come from detectors at the nerve endings of the branches of the trigeminal nerve, lingual nerve, sublingual nerve and upper laryngeal nerve of the vagus nerve.

The exact mechanisms underlying the beneficial effect of refreshing coolness on sensory discomfort have not been fully understood, although this effect is used in normal practice. Sensations can be “confused” when a chemical compound acts on more than one sensory modality. This is especially true for (-) - menthol. also known as L-menthol, (1R) -mentol and (1R, 2S, 5R) -mentol. (-) - Menthol is widely used as a cooling agent, but at the same time it has a multimodal effect on sensory processes. For example, in the upper respiratory tract and oral cavity (-) - menthol can cause somatic sensations (coolness, irritation, pinching), olfactory sensation (mint smell) and taste sensation (bitterness). As an anti-irritant (-), menthol can reduce irritation of the buccal-pharyngeal and pharyngeal membranes (for example, strong mint caramel or toothpaste) and have analgesic effects on the muscles (for example, BenGay® ointment). Multimodalities can additionally overlap with each other with the formation of complex sensations of irritation (burning, tingling), especially in the area around the eyes, temperature effects (cooling, heating) and tactile effects (itching, tingling, tickling, numbness). In the nose and oral cavity, the predominant way of recording the action of (-) - menthol is the sense of smell (see, for example, Nagata et al., J. Exptl. Psychol., 31: 101-109, 2005).

It is still unclear whether the antinociceptive effect of (-) - menthol is transmitted to peripheral structures, such as nociceptors, directly or indirectly through activation of cold receptors on cold nerve endings. In the latter case, the suppression of nociception occurs through the central "gate" of incoming harmful and irritating impulses. The peripheral receptor, which senses the coolness of (-) - menthol, is believed to be a protein called TRP-M8. However, it was found that the activity of compounds activating TRP-M8 does not correlate with the cooling effect (see, for example, AK-.Vogt-Eisele, D.Viga, H.Matt, and ETWei. N-Alkylcarboxamide Cooling Agents : Activities on Skin and Cells with TRPM8 and TRPA1 Receptors. 3rd Annual Workshop on the Study of Itch, September 25 to 27, 2005 in Heidelberg, Germany. Acta Dermato-Venereological 85: pg.468, 2005). Moreover, TRP-M8 is activated by mustard oil and an acute wasabi flavoring agent. Thus, the compounds of the present invention should not be construed as acting exclusively through TRP-M8 receptors.

The multimodal effect of (-) - menthol and related agents on sensory processes is used in compositions used in food products, confectionery products, flavorings, chewing gums, lipsticks and other products placed in the mouth, drinks, tobacco products, hygiene products, pharmaceutical formulations over-the-counter drugs for the treatment of nasal symptoms and signs of respiratory disease, gastrointestinal distress, and as an anti-irritant to relieve discomfort ozhi, muscles, mucous membranes of the mouth and throat. Although menthol preparations, such as confectionery, have a stimulating effect on the central nervous system, menthol compositions cannot be applied to facial skin in concentrations that are effective for stimulation, as this causes eye irritation (burning, tearing and pain).

Thus, it seems appropriate to find an agent that does not cause irritation to the surface of the eyes and can be applied to the skin for an exciting effect. In addition, such an agent can be applied to the skin around the eyes to refresh and reduce skin irritation, itching and pain.

Cosmetic menthol-like cooling compounds that have found commercial application for topical application to the skin mainly include mentillactate (Frescolat® ML), menthol glycerol acetal (Frescolat® MGA) and mentholpropanediol (Coolant 10). These agents, when applied to the skin, last no more than 30 minutes. Two other agents, WS-3 and WS-23, are primarily used in confectionery, chewing gums and hygiene products (mouthwashes, aftershave, shampoos, deodorants and toothpastes). A recent review of information on cooling agents used for application to the skin was made by M.B. Erman (Cooling agents and skin care applications. Cosmetics & Toiletries 120: 105-118, May 2005; Progress in physiological cooling agents. Perfumer & Flavorist 29 : 34-50, 2004) and by P. Jacobs and W. Johncock (Some like it cool. Parfumerie und Kosmetik 80: 26-31.1999).

None of the agents in this group meets the criteria for therapeutic use on the skin, since (a) in the pharmaceutical preparation, as a rule, there should be only one active ingredient and (b) none of the currently known cooling agents has a sufficient duration of action for being therapeutically useful.

In order to cure skin discomfort, the compound must have an effect for at least an hour and preferably longer, otherwise the patient will be forced to reapply the drug to achieve relief. To provide an anti-irritant and antitussive effect in the respiratory tract, an ideal agent should have a quick onset of action, a calming effect and the ability to alleviate discomfort over a long time, for example, several hours.

Non-technical description of the concept of the invention

The signals of cold and heat entering the brain (see Hutchinson et al. Above) were converted into audio signals using the discharge electrodes. Neurons of “cold” create the sound of frequent light tapping, like the sound of raindrops falling on the roof. These neurons are tonically active at room temperature. Further cooling, for example, when placing ice cubes near the receiving surface, increases the volume and frequency of the sound of tapping to the noise of heavy rain, but not to the noise of a shower or stream of discharges. Conversely, heat / pain neurons are silent until the heat source heats the skin to about 43.3 ° C. After that, these neurons are discharged with a hum that resembles the noise of high waves or tides. The tapping of cold neurons and the hum of heat neurons are modally specific and do not occur when pressed or touched. It is believed that the long-acting NACE compounds proposed in the present invention adjusts the transmission of “cold” neurons in such a way that the brain perceives the ambient temperature in the range of about 15 to 18 ° C. Activating these neurons is similar to turning on a powerful air conditioner in a hot room. The normal subject perceives this sensory strip as an invigorating, refreshing effect and coolness. In the present description, this condition is referred to as "perfect coolness." In pathological conditions, the presence of NACE compounds and perfect coolness blocks the penetration of harmful signals into the spinal cord and / or brain. Thus, a soothing nociceptive (anti-irritant, antipruritic and antitussive) effect with a therapeutic effect is achieved.

The present inventor has discovered molecules with a strong and lasting activation of a feeling of perfect coolness. These molecules are qualitatively and quantitatively unlike (-) - menthol and WS-3, which last less than 20 minutes. In some cases of itching and coughing, it was also observed that NACE compounds have a long antinociceptive effect, while the feeling of perfect coolness is no longer perceived on a conscious level, and that repeated use of NACE compounds can muffle and extinguish nociception. These results suggest that a feeling of perfect coolness can further regulate and weaken the flexibility of nociception processes.

Long-acting NACE compounds are active at a single dose of 1 to 10 mg and a concentration of 10 mg / ml or less when applied topically on the surface of the body. By "local" application is meant application to the surface of the body in contact with air, which includes the skin of the face, eyelids, lips, upper and lower respiratory tract, entry and exit of the gastrointestinal tract, namely the oral cavity and rectum.

Long-acting NACE compounds also have a fast onset of action (from about 0.5 to about 3 minutes) compared to other compounds (see, for example, Figures 1 and 2 and Examples). The onset and termination of these compounds was first detected when they were tested on the facial skin of subjects and subsequently when placed in the oral cavity.

Determination of the biological activity of esters and lactones of N-alkylcarbonyl- and N-alkyl-N-alkylcarbonyl-amino acids

Mental phenomena such as refreshment, calming, cooling, irritation, itching and pain cannot be verbally expressed by animals (animals cannot say “cold”, “ah!” Or “itches”). Therefore, the sensory effects of chemical compounds on animals should be interpreted according to indirect data. As a model of sensory processes, a receptor analysis based on the use of cells transfected with genes of proteins associated with heat sensitivity (for example, TRP-M8, TRP-A1, TRP-V1) can be used. Receptor analysis provides quantitative information. However, this analysis does not provide information on the onset and termination of action or on the quality of sensations caused by compounds in humans. Moreover, activity measured using the average effective concentration (EC ₅₀ ) in the receptor assay may not correlate with antinociceptive or cooling effects. Thus, the most complete information on the pharmacological properties of chemical compounds is obtained in direct human trials.

Watson et al. (US Pat. No. 4,178,459) investigated the properties of N-substituted p-menthan carboxamides on volunteers by placing filter paper (1 × 1 cm) soaked in a known amount of the compound on the dorsal surface of the test subject's tongue. After 30 seconds, the subject was asked to report the presence or absence of a cooling effect. These data were presented as the “threshold value, mcg” and are assigned to the threshold amount of the test compound, causing a feeling of coolness in a group of volunteers when applied to the tongue. The average threshold value for (-) - menthol in 6 volunteers was 0.25 μg, however, a 100-fold difference in individual sensitivity was observed. As mentioned above, “cold” signals coming from the dorsal surface of the tongue can mix due to taste, olfactory, and other components, as well as due to dilution with saliva.

It was found that when searching for a drug suitable for topical use, it is first best to examine the refreshing, cooling and sensory properties of long-acting NACE compounds by suspending or dissolving the test compound in an ointment (usually Aquaphor®, which consists of 41% petroleum jelly, and the rest is mineral oil, ceresin and lanolin alcohol) and a single application of the ointment (from 40 to 70 mg) on the surface of the skin with a plastic stick. A reliable area for local application is the skin above the upper lip (above the red border of the lips), the nasal groove, the lateral part of the nasal groove to the nasolabial folds and the lower part of the nostrils (at the junction of the nasal septum and upper lip). It is known that this region is densely innervated by cold receptors, second only to the surface of the eyeball and anogenitalia. The second region is located on the zygomatic tubercle or lower (cheekbone). The skin above the cheekbone is thicker than above the lips, and therefore has a large activation threshold value. In both of these locations, the sensations of tingling, coolness and coldness on the skin can be examined and evaluated by the time of onset of action and intensity.

The intensity of subjective skin perception is estimated as 0, 1, 2 or 3, where 0 corresponds to the absence of changes; 1 - a weak sensation of coolness, cold or tingling; 2 - a clear signal of coolness, cold, or tingling; and 3 - strong cooling or cold. The intervals for recording sensations are from 5 to 10 minutes until two zero values are obtained in a row. The results (presented in Figures 1 and 2) represent the average value of 4-6 independent experiments for one subject. The data are represented as graph points using SigmaPlot® (Systat Software, Point Richmond CA), and a smooth negative exponential function of negative exponentially weighted smoothing was used to analyze and statistically process the results. Studies confirming the cooling effect of long-acting NACE compounds were carried out on 2-4 subjects, but some of them were not quantified due to the large number of evaluated chemical compounds.

For the onset of the action of the medicine, it is taken the time to reach 2 units of the intensity of the sensation of coolness, and the termination of the action is the time during which the intensity of the sensation of coolness falls below 2, after having previously reached a value exceeding 2 units. The duration of the cooling effect is defined as the time of termination of action minus the time of onset of action. An inactive compound is defined as a compound whose cooling intensity does not reach 2 units within 5 minutes after application. The quality of the sensation is noted, for example, as pure refreshing coolness or as a sensation accompanied by irritation (burning). The quality of the sensation is not evaluated by intensity.

The ointment is also applied to the skin around the eyes (on the upper and lower eyelids and on the skin near the lateral angle of the palpebral fissure) to examine the irritating effect near the eyes, while the subject was asked if there was irritation or not. The intensity of eye sensation is not evaluated.

The sensory information described above cannot be obtained in a receptor analysis. Therefore, for a local agent, the most reliable results are primarily obtained by direct skin tests. The next object of study are the receptors of the oral cavity and upper respiratory tract. Taste thresholds are difficult to quantify in the tongue because of the dynamic fluid state in the oral cavity and the presence of taste and adaptation factors that affect the heat sensitivity of the tongue. The oral cavity is extremely high and low temperatures, which are unacceptable to the skin. For example, hot drinks, such as coffee, are carried in the mouth at temperatures that are considered painful and burning on the skin. In addition, ice drinks can be refreshing in the mouth, but a piece of ice on the skin quickly causes discomfort.

It has been established that the most effective method for testing the action of a compound in the oral cavity is to place 1 to 5 mg of a sample on the dorsal surface of the tongue, 2/3 of the tip and on the midline. Volunteers are asked to close their mouths and keep the connection in their mouths for at least 10 seconds without swallowing. Then, descriptions of sensation are recorded at five minute intervals.

Qualitative aspects of the intensity of sensations of coolness and cold.

Static and dynamic skin temperatures lead to sensations that are qualitatively different. Normal skin temperature is from 32 to 34 ° C, and when water is applied to the skin, it is considered slightly warm at a temperature of 27 to 32 ° C; cool at a temperature between 18 and 27 ° C, cold at a temperature of 13 to 18 ° C, and very cold at a temperature below 13 ° C. The critical range of room temperatures for a feeling of coolness and cold is from 18 to 22 ° C. For example, a lightly dressed still person will often have a desire to turn on a thermostat when the room temperature drops one or two degrees below 20 ° C (68 ° F). In gambling establishments, the air temperature is deliberately kept at a level of 18 to 20 ° C in order to cause excitement, increase activity and activate gambling activity. In the open air, inhaling cool air with a temperature of 15 to 21 ° C has a refreshing, firming and invigorating effect, and an emotional reaction can be positive and bring joy. However, at an ambient or skin temperature of 15 ° C (55 ° F) or lower, the feeling of cold becomes painful, causes a feeling of disgust and is accompanied by affect - that is, a person considers these feelings of cold to be unpleasant, tries to change the environment and can become angry, hostile or irritable if the cold cannot be avoided.

The long-acting NACE compounds described in the present invention are useful as topical agents to alleviate skin discomfort and have an effect similar to cold running water on damaged skin. The “nominal” temperature of the external surface of the skin, imitated by a cooling agent, lies in the range from 15 to 22 ° C. The effect can also be simulated by applying a towel moistened with water at room temperature. The feeling of coolness from a wet towel will quickly dissipate (this effect is called adaptation), even if the cooling stimulus is still on the skin. On the other hand, if a chemical agent is applied to the skin of the face, this stimulus is present more constantly. Accurate physiological sensations to be copied by the compounds of the present invention include sensations of freshness, soothing coolness, with minimal sensation of irritation or burning, or lack thereof and lack of excessive cold.

As shown in the Examples, preferred long-acting NACE compounds tested at a concentration of 40 mM, creating a feeling of coolness on the skin of the face, have a fast onset of action (less than 5 minutes) and a slow termination of action (more than 1 hour). On the contrary, various compounds of similar structure were either inactive or had a short duration of action, as shown by comparative data in Figures 1 and 2 and in the Examples.

The long duration of action of some preferred NACE compounds was unexpected and surprising. It was found that some of the NACE compounds, especially the D-amino acid derivative of alanine and Hsl analogues, have a cooling effect for several hours, which is a striking and unforeseen effect.

In the language of the average test subject, the action of the NACE compound can cause an initial tickle from 1 to 3 seconds, then a sensation of a strong and refreshing coolness can be noted. Typically, at a dose of a NACE compound, such as D-Ala-OMe or D-Ala-OEt analogues, from 1 to 2 mg, a feeling of coolness lasts for about 30 minutes. Unexpectedly, volunteers with coughing or irritating stimuli originating in the throat experienced a rapid (within 1 minute) relaxation of sensory discomfort and cessation of coughing. It was also surprising and unexpected that the duration of the antitussive effect was at least several hours, and that the effect was observed even when the sensations of coolness were minimal or absent altogether. This calming effect on the mouth and throat was especially beneficial for two asthmatic volunteers who had frequent coughing, chest tightness and shortness of breath.

The relationship structure - the activity of compounds that create a feeling of perfect coolness.

The idea of obtaining a chemical agent that can provide a long refreshing, calming and cooling effect with minimal irritation or burning, suggests the presence of a certain relationship of the molecule with the receptor on the nerve endings. The activity and selectivity of the action of chemical agonists on receptors are the main concepts of the action of drugs. The candidate for cold receptors, which have a great chance of success, is TRP-M8, because it is present in sensory neurons, reacts to temperature changes and the action of cooling agents, such as icilin and menthol. However, N-p-methoxyphenyl-p-menthan-carboxamide (WS-12) has a stronger effect on TRP-M8 than WS-5 (Gly Et Ester), and yet, WS-12 has less cooling. action and slower onset of action than WS-5. This observation shows that the potency of the TRP-M8 receptor is not critical to achieving a feeling of perfect coolness (see also Vogt-Eisele et al., Previously). Unexpectedly for eleven compounds, as shown in Table 5, there is also no correlation between the strength of the cooling effect on the tongue and the duration of cooling on the skin of the face.

It seems likely that to provide a feeling of perfect coolness, long-acting NACE compounds act on more than one type of receptor. Sensory neurons have a large number of receptors associated with harmful impulses (TRPA1, TRP-vanilloid receptors, peptide receptors, such as receptors for substance P and bradykinin, histamine receptors and K ⁺ channels). Some of them, for example TRP-V1, have activation binding sites (on the intracellular transmembrane loops of 2-3 receptors) that are similar to the active TRP-M8 binding site. As long as there is no understanding of harmful receptors that cause heat, heat, irritation, itching and pain, the question of the selectivity of the action of long-acting NACE compounds on the receptor cannot be resolved.

The access and location of the agonist molecule in the receptor are important characteristics for the action of the drug. A key pharmacokinetic factor in drug distribution and skin delivery is the octanol / water partition coefficient. Thus, the logarithm of the octanol / water partition coefficient (log P) in the range from 2.0 to 4.0 is considered ideal for activating cold skin receptors. However, in Examples log P for Sar Et-ester, the long-acting NACE compound is the same as for non-NACE analogs such as WS-11 in the absence of equivalent “perfect cool” for WS-11. Sar Et-ether has a duration of action five times that of WS-11, but in tests for determining a threshold in the language, it is 2.7 times less active than WS-11.

An analysis of the structure-activity relationship conducted in this study shows that the presence of one ether group, preferably methyl or ethyl ether group, in the molecule of N-substituted p-menthane-carboxamides provides the desired biological activity, but is not sufficient in itself for long-term cooling (> 1 hour). The presence of additional polar groups in the ester structure of an amino acid, for example, hydroxyl, alkoxy and / or diester groups, such as Ser or Glu (OMe), reduces activity. Replacing the hydrogen of the amino group with a methyl group with the formation of N-methyl-glycine (Sar Et-ether) increases the duration of action. The introduction of N-alkyl substituents affects the ratio of cis-trans isomers in the amide bond, reduces the relative energy of the cis-isomer, and can also inhibit the action of enzymes (e.g. amidases) that cleave the amide bond. In addition, the results show that the activity is long-lasting if the glycine α-atom has one or two alkyl substituents (2-amino-n-propanoic or 2-amino-n-butanoic acid), for example, forming an alanine ester derivative. Moreover, if the spatial orientation of the alanine α-carbon atom is a D-configuration instead of the L-configuration, or if the α-carbon atom participates in the formation of a cycle with an ether group, forming a lactone cycle, then the activity, duration and selectivity of the preferred sensory effects increase.

The advantages of alkylation of the α-carbon atom in the D-configuration and cyclization of the α-carbon atom with a short circuit on the alkyl ether with the formation of lactone, as important factors for a long-lasting sensation of refreshing coolness (in the absence of irritation), are new observations.

It has also been found that although p-menthane is the preferred cycloalkyl group, where cycloalkyl is 2-isopropyl-5-methylcyclohexyl, other cyclic structures such as alkyl-substituted cyclopentyl, cycloheptyl and cyclooctyl or alkyl-substituted bicycloheptyl and bicyclooctyl are also effective. Moreover, the cyclooctyl moiety may be substituted with a branched chain aliphatic group, such as in the WS-23 structure, with a tendency to a cooling effect.

This relationship structure - activity allows us to determine the following class of compounds with the property of perfect coolness; these are mainly the compounds described by Formula (3), as well as the salts and solvates of these compounds:

Where

each of R and R ′ independently is C ₁ -C ₇ alkyl; and

R "independently represents hydrogen or C ₁ -C ₅ alkyl;

provided that:

(1) R, R ′ and R ″ together contain at least 5 carbon atoms, preferably from 7 to 13 carbon atoms; and

(2) if R ″ is hydrogen, then: R must contain at least 2 carbon atoms and R ′ must contain at least 3 carbon atoms, and at least one of R and R ′ must be a branched alkyl a group (preferably with branching at the α or β position with respect to the C — CO — N group); and

(3) if R ″ is hydrogen, it is preferred that at least one of R and R ″ is isopropyl or sec-butyl;

or:

R and R 'together with the carbon to which they are attached form an alkyl-substituted cycloalkyl group selected from the following: cyclopentyl, cycloheptyl, cyclooctyl, [3.1.1] bicycloheptane, [2.2.1] bicycloheptane, and [2.2.2] bicyclooctane, and further comprise an unsaturated ethylene moiety (preferably a menthol group found in (-) - menthol);

and

R "represents hydrogen or a linear or branched alkyl C ₁ -C ₅ ; provided that:

(i) an alkyl-substituted cycloalkyl ring contains a total of 7 to 14 carbon atoms (and preferably a total of 8 to 12 carbon atoms); and

(ii) an alkyl-substituted cycloalkyl ring contains from 1 to 3 linear or branched alkyl substituents C ₁ -C ₅ ; and

(iii) if R ″ is hydrogen, then: at position 2 or 3 of the cycloalkyl ring (preferably at position 2) a C ₁ -C ₅ linear or branched alkyl substituent is present (preferably said alkyl substituent is branched at the α or β position in relation to the ring) (preferably the aforementioned alkyl substituent is isopropyl or sec-butyl);

and where:

R ₁ represents hydrogen or methyl;

Y represents a divalent alkylidene group selected from —CHR ₂ -, —CH ₂ CHR ₂ -, and —CHR ₂ CH ₂ -, where R ₂ is hydrogen or C ₁ -C ₂ alkyl; and

R ₃ represents a linear or branched alkyl C ₁ -C ₄ ; provided that:

(a) additionally, R ₂ and R ₃ , together with the atoms to which they are attached, can form a 5-, 6- or 7-membered lactone ring; and

(b) additionally, R ₁ and R ₃ , together with the atoms to which they are attached, can form a 5-, 6- or 7-membered saturated 3'-oxo-1 ', 4'-oxo ring; and

(c) additionally, R ₁ and R ₂ , together with the atoms to which they are attached, can be closed to form a 5-, 6-, or 7- saturated nitrogen-containing heterocycle with an alkoxycarbonyl substituent in position 2 'or 3' and may additionally contain as substituents, one or more alkyl groups C ₁ -C ₂ .

These compounds (i.e., selected from the compounds of Formula (3), salts and solvates of these compounds) can also be used in the methods described in the present invention, and, in particular, in methods of preventing coughing and transmission of infectious microorganisms by airborne droplets , as well as in methods of reducing the spread of infectious microorganisms in the host.

The use of long-acting NACE compounds on the face and other surfaces

In a preferred application, one or more long-acting NACE compounds is applied topically to relieve irritation, itching and / or pain in the inflamed skin and / or inflamed tissues of the oral cavity and / or upper respiratory tract.

Other intended uses include prolonged refreshment of the face, as well as invigorating and energizing.

Considered methods of non-therapeutic use include the use as components of food products (for example, in chewing gums, mouthwashes, anti-gingivitis products, toothpastes), cosmetics, lipsticks, flavors, tobacco additives, confectionery or hygiene products.

The term "topical" means applying to the surface of the body in contact with air, which includes the skin, surface of the eyes, lips, upper (nose) and lower respiratory tract, as well as the entrance and exit of the gastrointestinal tract, i.e. oral cavity and rectum. Particularly preferred areas for application are the superficial tissues of the face and head innervated by the trigeminal nerve, which include the skin, scalp and lining of the eye socket, lips, nose and mouth. Another preferred area is the nerve endings of the glossopharyngeal nerve in the nasopharynx and oropharynx.

By the term “oral administration” is meant the delivery of the active component in the form of a solid, liquid substance or aerosol to the oral cavity, preferably as part of a delivery vehicle.

The pharmaceutical composition for topical application of the NACE long-acting compound is preferably formulated so that it has a fast onset of action and a slow cessation of action.

Preferably, the compound does not cause burning or irritation when applied to the face near the eyes and gives more refreshing coolness than cold.

Some of the applications can be further classified as:

Therapeutic: A long-acting NACE compound can, for example, be used as a local analgesic when applied to inflamed skin or as an antipruritic drug. It can also be taken orally as an antitussive or anti-irritant drug for treating asthma.

Anti-irritant: A long-acting NACE compound may form part of a skin care product containing irritating compounds such as retinoids or α- or ω-fatty acids.

Excitatory: In the case of normal, healthy people, long-acting NACE compounds can be used to provide freshness and energy, to resist fatigue and rehabilitation after heat stroke, with irritation in the nose and eyes and breathing difficulties. Thanks to their refreshing properties, they can be used to enhance attention and alertness. They can be useful for athletes training in high-temperature environments, such as baseball players in Arizona during spring training or soccer players in Spain or South America.

Cleansing: A long-acting NACE compound can be included in makeup remover wipes, especially mascaras around the eyes.

Food and personal care products: To give a fresh feeling, the NACE long-acting compound can be included in food products (for example, chewing gums, toothpastes), cosmetics, lipsticks, flavors, confectionery, tobacco, drinks or hygiene products.

Therapeutic uses of one or more long-acting NACE compounds in the form of a wipe, lotion, cream, ointment or oral formulations or inhalations, including the possibility of using:

(a) to relieve irritation, itching and / or pain caused by various forms of dermatitis (atopic, contact and irritating),

(b) for pain from burnt, injured or irritated skin (for example, after laser surgery), as well as for pain associated with surgical treatment of a wound,

(c) with itching and discomfort associated with skin infections, insect bites, sunburn, photodynamic treatment of the skin (e.g. actinic keratosis, basal cell carcinoma),

(d) for pruritus due to xerosis,

(e) with inflammation of the mucous membranes and stomatitis, for example, with an ulcer or chemotherapy of tumors, with inflammation of the lips or itching on the lips with herpes simplex and gingivitis,

(e) with anal itching, hemorrhoidal discomfort, pain with anal fissures, pain or itching with fistula of the rectum, pain with excision of hemorrhoids, inflammation of the perineum, inflammation of the skin of anogenitalia and discomfort due to various local causes such as incontinence, diaper rash inflammation of the perineum

(g) with itching and pain of the female genital organs (for example, with candidiasis or itching and pain of unknown origin, such as vulvar vestibulitis or vulvodynia), with dyspareunia, anogenital infections, including warts and sexually transmitted diseases, viral infections of the skin (mainly in the case of immunocompromised patients),

(h) with nostril and nasal discomfort or discomfort of the upper respiratory tract with difficulty breathing, for example, with rhinitis, asthma, bronchitis, emphysema and chronic obstructive pulmonary diseases, shortness of breath, sleep apnea syndrome and snoring, and

(i) with conjunctivitis, irritation of the ocular surface, pain with corneal scratches and pain associated with surgery.

Since sensory processes also have a significant effect in hollow internal organs, long-acting NACE compounds can be delivered orally, or by inhalation, or as capsules for systemic or local delivery to the gastrointestinal tract, bladder, and respiratory tract. In the case of the gastrointestinal tract, the NACE long-acting compound can be used to alleviate heartburn, stomach pain and discomfort due to irritation of the intestines and inflammatory intestinal diseases. Enteric-coated capsules may be the preferred method of delivery to the lower gastrointestinal tract. Alternatively, a long-acting NACE compound, such as an analogue of Sar Et-ether, which exists as an oil at body temperature, can be delivered to the surface of the digestive tract using a controlled release device such as an osmotic mini-pump. An oral pharmaceutical composition with a long-acting NACE compound can be used to eliminate discomfort in the bladder with interstitial cystitis and to alleviate the symptoms of an overactive bladder. A long-acting NACE compound inhaled into the upper respiratory tract or delivered as an aerosol or spray can mimic (-) - menthol and alleviate congestion, relax the smooth muscles of the bronchi and symptomatically ease the sensation of suffocation during shortness of breath.

The use of long-acting NACE compounds in anti-aging applications

With age, people feel the need for therapeutic procedures that can help them cope with skin aging. With age, wrinkles appear, the color, development and texture of the skin change. In such skin conditions, various carboxylic acids, for example, hydroxy acids and retinoic acid, are applied topically. These agents act by exfoliating the upper layers of the skin. Another method of rejuvenating aging skin is the application of mechanical, chemical, photodynamic or laser (temperature) energy. Such cleansing of the skin surface leads to skin wounds and associated skin discomfort. Long-acting NACE compounds can be used to alleviate discomfort in case of skin damage due to anti-aging procedures and therapy.

With age, the skin loses its ability to retain a sufficient amount of moisture. This condition, known as elderly xerosis, appears as itchy, dry, and cracked skin with tearing and peeling. In some cases, xerosis is similar to cracked porcelain. The skin is cracked due to loss of water and, if deeper, the destruction of capillaries and due to bleeding. Itching leads to scratches and roughness, conditions that exacerbate pathological processes and cause a skin condition called lichenification. The factor causing xerosis is cold, dry weather, for example, in winter or when air conditioning. In a study conducted in private hospitals, xerosis and eczema were diagnosed in 29% and 37% of patients, respectively. Therapy includes frequent application of moisturizers and steroid ointments, but as an aid to alleviate skin discomfort, it is possible to use long-acting NACE formulations delivered as part of ointments. Thus, similar skin disorders observed with simple ichthyosis and psoriasis can be treated.

The use of long-acting NACE compounds for coughing, irritation and obstruction of the upper respiratory tract

The sensation of stimuli initiating cough and the physical act of coughing represent the body's response to irritation and obstruction of the upper respiratory tract. Causes of irritation and obstruction of the upper respiratory tract are multifactorial and in the case of acute cough, bacterial or viral infections of the upper respiratory tract, nasopharyngeal discharge, allergies, airway inflammation, pharyngitis, laryngitis, and, in the case of chronic cough, conditions such as asthma, chronic obstructive pulmonary disease, gastroesophageal reflux, lung cancer, pneumonia, nocturnal apnea, snoring, pulmonary edema, congestive heart failure and shortness of breath. It has been found that NACE compounds regulate and eliminate signals of irritation and obstruction of the upper respiratory tract and, thus, reduce the sensations of stimuli that cause discomfort in the throat, for example, with pharyngitis (sore throat) and laryngitis (hoarseness and loss of voice). Thus, the desire to cough is dulled and the frequency of coughing is reduced. However, this does not affect the sensation of airway obstruction, and intentional coughing may be caused to eliminate it.

Description of action of a long-acting NACE-compound when coughing can be classified as an “anti-cough” rather than an “inhibitory cough” because the patient’s ability to cough is not suppressed. Instead, the NACE compound relieves the sensation of irritation that triggers an involuntary cough. The actions of NACE compounds are qualitatively more powerful, penetrating, refreshing and cooling than menthol tablets containing 10 mg (-) - menthol - the maximum content for conventional over-the-counter drugs. The most likely area of action of the NACE compound is the sensory nerve endings of the glossopharyngeal nerve in the oropharynx. Then the afferent impulses entering the brain stem regulate or cancel the annoying cough impulses coming from afferents of the laryngeal branch of the vagus nerve. The final effect is that cough impulses are no longer perceived as irritation and do not cause a cough reflex. Other possible mechanisms of action of NACE compounds on the upper respiratory tract are direct relaxation of the smooth muscles of the bronchi and / or a decrease in airway hyperresponsiveness or an increased reaction to inflammatory mediators.

When a long-acting NACE compound is used in asthma or chronic obstructive pulmonary diseases, it can be administered in combination with a β-adrenergic agonist, such as formoterol, or an anti-inflammatory glucocorticosteroid, such as betamethasone, or a muscarinic receptor antagonist, such as ipratropium or tiotropium.

The use of long-acting NACE compounds to limit the transmission of the virus in an influenza epidemic

Methods for controlling the flu epidemic are limited to strategies such as vaccines, isolation of infected individuals (quarantine), and the use of neuraminidase inhibitors. Viruses are transmitted from the infected host by expectoration of large particles, drops, as well as materials whose sizes allow them to be inhaled. Sneezing is not a common symptom of influenza, but coughing is often a flu symptom. Sore throat and cough often begin 3 days after infection, and coughing can continue for 3 weeks.

In a quantitative model for assessing the risk of infection by inhaled pathogens, Nicas et al. (J. Occupational and Environmental Hygiene 2: 143-154) showed that the possibility of infection by airborne pathogens directly correlates with the frequency of coughing. It is established that one person who is in a confined space for 4.5 hours can infect 72% of those around them with flu (M.V. Gregg. The epidemiology of influenza in humans, Ann. NYAcad. Sciences, 353: 45-53, 1980) . This unhealthy person was described as having a “dry, metallic cough”.

The use of potent NACE compounds as cough suppressants to reduce the spread of the virus and the transmission of the flu epidemic is a new idea. This can be especially useful for protecting healthcare providers treating infected patients. Cough suppression can be considered as a general method of limiting viral infections that can be observed, for example, in schools, hospitals or other crowded places. This method of limiting the transmission and spread of infection can also be applied to pathogenic respiratory viruses, such as respiratory syncytial virus, rhinovirus and coronaviruses.

Long-acting NACE compounds for smoking cessation therapy

Trademarks for menthol-containing cigarettes make up about 25% of the total number of cigarettes sold in the United States. In some countries, such as the Philippines, this value can reach 60%. In the United States, 69% of African-Americans and 22% of white-skinned people smoke menthol cigarettes. The ethnic difference in menthol preference is attributed to carefully thought-out cigarette sales to subpopulations with the idea that menthol-containing cigarettes are: (a) healthy and healthy, (b) cool, cleansing, revitalizing, fresh and refreshing, (c) associated with youth, stupidity and fun, and (d) ethnically special.

One of the goals of pharmaceutical therapies for quitting smoking is to deliver the sensations caused by a cigarette in a non-inhalation way, thereby avoiding the toxic effects of tar and carbon monoxide contained in cigarette smoke. The compounds described herein can replace menthol sensations of menthol-containing cigarettes by creating a lasting sensation of freshness in the oral cavity and upper respiratory tract. In addition, the compounds of this invention can be combined with nicotine, lobelin, or other nicotinic receptor agonists to form a product designed to reduce the hard taste of nicotine and, at the same time, mimic the effects of cooling and the main stimulatory effect of a menthol-containing cigarette. Delivery methods may include a tablet, chewing gum, spray, aerosol, syrup, liquid, mouthwash, film or lollipop, designed both to cool the mucous membranes of the mouth and oropharynx, and to absorb nicotine in the mouth.

Long-acting NACE compounds for nausea, difficulty swallowing, and discomfort

To date, it is known that some seasonings with specific tastes can suppress nausea, difficulty swallowing, bulimia, and malaise in various diseases. For example, ginger-flavored drinks or candies can in some cases resist nausea in motion sickness. NACE compounds can also be used in these cases and to suppress appetite.

The use of long-acting NACE compounds with heat load and elevated body temperature

Thermal stress is defined as any combination of work, air flow, humidity, air temperature, thermal radiation or the internal conditions of the body, which lead to the state that the body strains to adapt to temperature. When heat production prevails over its removal, the body temperature rises, while the temperature in the mouth or in the rectum and ears rises above 37.8 ° C and 38.3 ° C, respectively. When stress exceeds the body’s ability to adapt to temperature, heat stress can reduce performance, morale, mental activity, increase the risk of accidents and lead to diseases associated with overheating. It has been established that oral doses of NACE compounds, typically in excess of 5 mg, will give a feeling of coolness in the upper chest. These effects can be caused by temperature sensors in the upper digestive tract. Thus, the delivery of NACE compounds to the body and to thermoreceptors for cooling can be considered as a way to overcome and alleviate difficulties at elevated body temperature and thermal stress.

Delivery to the facility and the benefits of esters of N-alkylcarbonylamino acids

In topical and oral pharmaceutical formulations, the NACE long-acting compound can be combined with a base which may be inert or contain other active ingredients.

Suitable formulations, for example, include compositions such as liquids, aerosols, powders, pastes, lotions, liniments, creams and ointments, and cosmetics. A variety of bases can be used as appropriate, depending on the particular active component, for example, solid, liquid bases, emulsions, foams and gels. Typical bases include oils and fats, for example, liquid petroleum products, polyhydric alcohols, calcium or magnesium stearates, fatty acid esters, higher alcohols and silicone oils; finely divided solids, for example, starch or talc; low boiling hydrocarbons; gums and natural or synthetic resins.

Suitable formulations for the oral cavity and throat, for example, include liquids, powders, tablets, films or pastes. Tablets (also called cough lozenges, lozenges or lozenges) are the dosage form used to treat the tissues of the mouth and throat. A typical tablet contains a substantially inert base, carrier or diluent. The drug is distributed in this carrier. The tablet dissolves in the oral cavity, releasing the drug so that it can come into contact with the tissues of the mouth and pharynx. A typical diluent, carrier or base may be referred to by the term “polyhydric alcohol”, which may be construed as the following compounds: xylitol, mannitol, sorbitol, maltitol, isomaltitol, maltotriitol, lactitol and β-linked glucopyranosido-sorbitol. Flavoring agents such as sugar substitutes, aspartame, sucralose or alitam can be added to hide any tastes. The mixture is granulated into a uniformly distributed mixture into which dispersants, anti-caking and dusting agents can be added; then the mixture is compressed into tablets for oral administration. Alternatively, the active ingredient may be part of the chewing gum. These methods are familiar to those skilled in the art and are described, for example, in US Pat. 5,322,694 (David Sixsmith, Pharmaceutical Lozenges) and US Pat. 5,846,557 (Eisenstadt et al. Chewing gum containing cough suppressing agent).

The duration of action of the active drug can be further increased and limited by the area of its action (for example, the oropharynx) due to the introduction of a mucoadhesive or bioadhesive agent. These include, for example, mucoadhesives or bioadhesives described in US Pat. 6,638,521 (D.J.Dobrozsi: Oral liquid mucoadhesive compositions) and US Pat. 6,562,363 (J. Mantelle et al., Bioadhesive compositions and methods for topical administration of active agents). Typical adhesive molecules include polymers of sugars, alcohols, vinylpyrrolidone, cellulose, and the like. Dissolution of the solid active components in the oral cavity can sometimes be complicated by chewing or swallowing the tablet, or by the level of salivation, so a liquid delivery formulation may be preferred. NACE compounds are readily soluble (sometimes after heating) in aqueous solutions containing polyhydric alcohols, cyclodextrins, sugars, etc. Preservatives, flavors, and solvents can be added to these liquids after sterilizing filtration, after which the liquids are poured into collector-type packaging containers (for example, plastic packaging with a dropper in a lid) or in a commercially available single-dose packaging. For example, Unicep Corporation in Sandpoint, Idaho, USA, provides single-dose packaging from 0.3 to 0.5 ml per order. An ideal single dose option for these delivery volumes would be from 2 to 20 mg / ml NACE compound. Alternatively, the NACE connection can be delivered with a nebulizer, mouth spray or hand pump, as with a broncho-inhaler, which is well known to those skilled in the art.

In practice, long-acting NACE compounds can be applied to the skin with a tissue that has a structure suitable for delivering the NACE compound to the skin. Thus, for contact with a tissue, the desired NACE compound is suspended, dissolved and / or dispersed. Suitable wipes are woven or nonwoven pads, usually in a dispenser. Rubbing the skin with a napkin or pad ensures the delivery of the dermatologically active component (s) to the skin, which means that the skin is substantially saturated with the drug. Other medications, medical and cosmetic products, herbal medicines, traditional medicine and active cosmetic components suitable for topical application in humans can also be applied to the napkin.

It is believed that a long-acting NACE compound can be part of a wipes for treating aging skin: for treating discomfort from acne, sunburn, fever, hyperthermia, fungal infections, yeast infections, rosacea, photo-damage to the skin; to reduce the discomfort associated with the treatment of skin hyperpigmentation, eczema, allergic or contact dermatitis, seborrheic dermatitis, inflammation of the mucous membrane, erythema or psoriasis; and for combining with other dermatological agents such as carboxylic acids, antibiotics, keratolytic agents, or a combination thereof. To achieve a prolonged sensation of perfect coolness, a long-acting NACE compound can be combined with icilin, a cooling agent, acting in an area other than menthol. Preferably, the compositions are prepared with synthetic compounds, which according to standard analytical homogeneity tests show at least 95-99% purity.

The ability of a long-acting NACE compound to provide a cooling and refreshing effect of a wipe without burning or irritation (especially in the eye area) is an achievement in modern technology of cooling agents. Currently known wipes often contain SD alcohol (specially denatured alcohol, typically ethanol, isopropyl alcohol or methanol), which is a solvent or cooling agent. Alcohol creates a cooling sensation when heat is removed by evaporation. The disadvantage of using lower alcohols in such formulations is that alcohol drains the tissues and causes irritation. When such a napkin is used near the eyeball, alcohol vapors irritate the surface of the eye. Similarly, menthol, camphor, eucalyptol and other components of napkins, added to give flavor and cooling, also irritate the skin and eyes.

In one embodiment, a long-acting NACE compound is delivered using a tissue, which, for example, when applied to the face, will mainly have the advantage of counteracting fatigue and increasing alertness and attention; for example, to combat fatigue from prolonged driving or working in high ambient temperatures.

Summary of biological activity test results

The main results of experiments conducted on the skin are summarized in Table 1. Useful properties of long-acting NACE compounds have a longer duration of action in the absence of significant eye irritation.

Table 1 Final Comparison of the Unique Properties of Long-acting NACE Compounds with Other Compounds Chemical compound class Tongue cooling Cooling on the skin of the face The test is "perfect" cool Eye irritation Action> 1 hour at 40 mM Long-acting NACE Connections Yes Yes Yes no Yes non-nace carboxamides Yes varies no Yes no (-)-menthol Yes Yes no Yes no SD alcohol no Yes Yes Yes no

Chemical synthesis

Synthesis of esters of N-alkylcarbonylamino acids

The synthesis of NACE compounds can be carried out by the reaction of a free amine with a chloride of a suitable acid, typically in the presence of a suitable hydrogen chloride acceptor, which may be an excess of a free amine or other base, for example triethylamine.

The reaction usually takes place in a suitable organic solvent, but depending on the reactivity of the acid chloride, it can also be carried out in a water / organic solvent system; in the latter case, sodium bicarbonate is a suitable base.

The synthesis begins with the reaction of carbonyl chloride with the corresponding derivative of an amino acid ester. Acid chloride, or carbonyl chloride, can be prepared by many methods known in the art. As an example, (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-carbonyl chloride is prepared from (-) - menthol as follows: first, a reaction with zinc chloride in hydrochloric acid is carried out to form 2-isopropyl-5-methylcyclohexyl chloride ; Grignard reagent is then prepared and carboxylated to form 2-isopropyl-5-methylcyclohexyl carboxylic acid; and the final reaction with thionyl chloride gives carbonyl chloride.

In order to avoid difficulties in cleaning the NACE compound, it is advisable that the thionyl chloride used in the preparation of the acid chloride be preliminarily double distilled. In addition, depending on the reactivity of the NACE compound, it may be appropriate to carry out the reaction with a slight excess of acid chloride or at an elevated temperature so that no trace amounts of free amine remain in the final product.

Such methods of controlling the course of the reaction to facilitate the conversion and / or to prevent the formation of certain impurities are well known to specialists in this field of technology.

From commercial sources such as Sigma-Aldrich Corp., St. Louis, MO, USA, many substituted amino acid esters can be obtained. For example, sarcosine ethyl ester, β-alanine ethyl ester, R- or S-amino-butyrolactone and L- or D-alanine methyl ester are presented in the Aldrich catalog for 2003-2004. The precursor, D-alanine ethyl ester, is available from Indofine Chemicals, Co., Hillsborough, NJ. The acid chloride reacts with a suitable amino acid ester to form a NACE compound.

Synthesis of 2-Isopropyl-5-methyl-cyclohexylcarbonyl-L-Hsl (also known as (S) - (2-oxo-tetrahydrofuran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-6-methyl β-cyclohexylcarboxylic acid):

The (S) -α-amino-γ-butyrolactone hydrochloride obtained from Aldrich Chemical Co., in an amount of 500 mg, was dissolved in 18 ml of diethyl ether and 1.5 ml of bidistilled water. A catalytic amount of diaminopyrimidine was added. Then 0.68 ml of p-menthyl chloride was added dropwise and 1.02 ml of triethylamine was added. The reaction mixture was stirred at room temperature overnight. The precipitate was dissolved in ethyl acetate, washed with bidistilled water and dried over sodium sulfate. The organic phase was evaporated in vacuo to give the final product, which crystallized at room temperature. The estimated molecular weight was confirmed by mass spectrometry, and the absorption spectrum by nuclear magnetic resonance.

Synthesis of 2-Isopropyl-5-methyl-cyclohexylcarbonyl-D-Ala methyl ester (also known as (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino ] -propionic acid):

D-Ala methyl ester hydrochloride obtained from Aldrich Chemical Co., in an amount of 1.0 g, was dissolved in 28 ml of diethyl ether and 1 ml of double-distilled water and cooled to 0 ° C. A catalytic amount of diaminopyrimidine was added. Then, 1.62 ml of p-menthyl chloride was added dropwise and 2 ml of triethylamine was added. After stirring the reaction mixture at room temperature overnight, lumps of white precipitate formed. The precipitate was dissolved in ethyl acetate, washed with double-distilled water and dried over sodium sulfate. The organic phase was evaporated in vacuo to give 2 g of the final product, which crystallized at room temperature. The expected molecular weight was confirmed by mass spectrometry, and the absorption spectrum by nuclear magnetic resonance.

Synthesis of 2-isopropyl-5-methyl-cyclohexylcarbonyl-D-Ala ethyl ester (also known as (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino ] -propionic acid):

D-Ala Ethyl Hydrochloride was obtained on request from Indofine Chemical Co. To a stirred suspension of HCl · HD-Ala-OEt (11.6 g; 71.6 mmol) in 100 ml of dry EtOAc was added 21.14 ml (143.2 mmol) of Et ₃ N and the reaction mixture was cooled to 0 ° C. Then 13.2 g (65.14 mmol) of p-menthyl chloride was added and the solution was stirred for 1 hour at 0 ° C and an additional 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate to 300 ml, washed with 1 N. HCl, 5% NaHCO ₃ , and water, after which it was dried (Na ₂ SO ₄ ). The solvent was removed, and the residue was crystallized from a mixture of Et ₂ O - hexane. The purity of the obtained product, established by HPLC, amounted to about 93%. For further purification, the product was dissolved in 100 ml of isopropyl alcohol and 100 ml of distilled water was added, isopropyl alcohol was evaporated, the precipitate was filtered off and dried under vacuum. The purity of the final product, established by HPLC, amounted to more than 96%. The yield was 14.2 g (76%). Melting point 99-103 ° C.

Test procedure for biological activity

Long-acting NACE compounds are most often crystalline solids at room temperature, with the exception of the Sar Et-ester derivative, which is an oily liquid at room temperature.

To test the biological activity on the skin, approximately 30 mg of the compound was mixed and dissolved in 3 g of Aquaphor® warm liquid ointment to form 40 mM (~ 1% w / v) ointment. The exact amount was selected so that the molar equivalent was approximately 35 to 40 mm. From 40 to 70 mg of chilled solid ointment was placed on the tip of a plastic stick and applied to the skin of test subjects above the upper lip, on the tray, up to the nasolabial fold, and the duration of the cooling sensation was noted.

The intensity of subjective skin sensations was evaluated as 0, 1, 2 or 3, where: 0 - no change; 1 - a weak sensation of coolness, cold or tingling; 2 - a clear signal of coolness, cold, or tingling; and 3 - strong cooling or cold. The intervals for recording sensations ranged from 5 to 10 minutes until two zero values in a row were obtained. The results (shown in Figures 1 and 2) represent the average value of 4-6 independent experiments for one subject. Data are presented as graph points using SigmaPlot® (Systat Software, Point Richmond CA); For analysis and statistical processing of the obtained results, the function of negative exponentially weighted smoothing was used.

For irritation tests near the eyes, the ointment was applied to the skin around the eyes (upper and lower eyelids and to the skin near the lateral corner of the eye cavity) and asked the subject whether there was a sensation of irritation or not. The intensity of eye sensations was not evaluated, but was noted as “present” or “absent”.

For the onset of the action of the medicine, the time was taken to reach 2 units of the intensity of the feeling of coolness, and for the termination of the action, the time at which the intensity of the feeling of coolness fell below 2, having previously reached values exceeding 2 units. The duration of the cooling effect was determined as the time of termination of action minus the time of onset of action. An inactive compound was defined as a compound whose cooling intensity does not exceed 2 units after its application. The quality of the sensation was noted as pure refreshing coolness or as a sensation accompanied by irritation (burning). The quality of the sensation in intensity was not evaluated.

Study 1

A large number of compounds were synthesized and tested, the test results are presented in Figures 1 and 2. The studied compounds were applied separately to the skin above the upper lip in a dose of 40 to 70 mg in 1% (w / v) ointment.

The duration of the cooling effect of some known agents, for example, (-) - menthol, WS-3 and WS-5 in Figure 1 is 0.3, 0.3 and 0.5 hours, respectively, and is relatively short in comparison with NACE compounds, especially in comparison with analogues D -Hsl, D-Ala-OMe and D-Ala-OEt, providing 1.3, 1.9 and 2.4 hours of cooling, respectively.

The Figure 2 presents the features of the chemical structure that affect the duration of action. So, WS-12, effective when tested on the TRP-M8 receptor, does not have a long-lasting effect on the skin. The presence of a methyl group at N-nitrogen Sar-OEt increases activity. Similarly, the lactone cycle in D-Hsl, the additional carbon atom at the α-carbon atom, and the D configuration of D-Ala-OMe and D-Ala-OEt significantly increase the duration of action.

Table 2 and Table 3 provide additional data. In Table 2 and Table 3, long-acting NACE compounds with a refreshing coolness without eye or skin irritation are indicated (*). Analogs of D-Ala and Hsl seem especially useful.

table 2

Connections R ₁ Y R ₃ Duration of action
Start-End (minutes) Gly Me-ether (WS-31) H -CH ₂ - Me 5-25 = 20 Gly Ethereal (WS-5) (*) H -CH ₂ - Et 4-37 = 33 Sar Ethereal (*) Me -CH ₂ - Et 2-65 = 63 L-Ala Ethereal H -CH (CH ₃ ) - Et 8-52 = 44 L-Ala Me-ether H -CH (CH ₃ ) - Me 1-80 = 79 D-Ala Me-ether (*) H -CH (CH ₃ ) - Me 1-115 = 114 D-Ala Et-ether (*) H -CH (CH ₃ ) - Et 1-143 = 142 β-Ala Ethereal H -CH ₂ -CH ₂ - Et 3-90 = 87 Table 3

Connections R ₁ n Duration of action
Start-End (minutes) D-Hsl (*) H one 2-80 * = 78 L-Hsl (*) H one 2-87 * = 85 racemic Hsl (*) H one 2-86 * = 84

(*) refers to compounds having a refreshing coolness in the absence of irritation to the eyes or skin after application to the skin of the face or region around the eyes; "perfect coolness."
(Gly = glycine; Sar = sarcosine; Ala = alanine; Hsl = homoserine-lactone (or α-amino-butyro-γ-lactone))

Table 4 and Table 5 provide examples of compounds that were inactive in tests on the skin of the upper lip at 40 mm. (Ser = serine; Glu = glutamic acid; Lys = lysine; Tyr = tyrosine; Val = valine; Leu = leucine.)

Table 4

Connections R ₁ R ₂ R ₃ Duration of action Start-End (minutes) Ser Ethereal -H -CH ₂ -OH Et not active Glu (OMe) Me-ether -H - (CH ₂ ) ₂ -C (= O) -OMe Me not active Lys (Z) t-Bu-ether -H - (CH ₂ ) ₄ -NH-C (= O) -O-CH ₂ -C ₆ H ₅ t-bu not active Tyr Me Live -H -CH ₂ -C ₆ H ₄ -4'-OH Me not active L-Val Me-ether -H -CH- (CH ₃ ) ₂ Me not active D-Val Me-ether -H -CH- (CH ₃ ) ₂ Me not active Leu Me Live -H - (CH ₂ ) ₂ —CH— (CH ₃ ) ₂ Me not active

Table 5 Compound Structure Duration of action
Start-End (minutes) Pro Me Live

not active

Table 6 presents examples of compounds of N-alkyl or aryl-cycloalkyl-carboxamides, which gave a short cooling effect in tests on the skin of the upper lip at a concentration of 40 mm.

Table 6

Compound Q Duration of action
Start-End (minutes) WS-3 ethyl-CH ₂ CH ₃ 5-23 = 18 WS-10 isopropyl-CH (CH ₃ ) ₂ 6-25 = 19 WS-34 sec-butyl -CH (CH ₃ ) CH ₂ CH ₃ inert WS-14 tert-butyl-C (CH ₃ ) ₃ 15-23 = 8 WS-11 1 ', 1'-dimethyl-2'-hydroxyethyl-C (CH ₃ ) ₂ CH ₂ OH 8-18 = 10 WS-12 4'-methoxyphenyl-C ₆ H ₅ -4'-OMe 13-38 = 25 CPS-309 2 ', 4'-dimethoxyphenyl-C ₅ H ₄ -2', 4'-di-OMe 13-50 = 37 CPS-306 4'-ethoxyphenyl-C ₆ H ₅ -4'-OEt inert CPS-310 4'-n-propoxyphenyl-C ₆ H ₅ -4'-n-OPr inert CPS-308 4'-n-butoxyphenyl-C ₆ H ₅ -4'-n-OBu inert

Study 2

Physical properties and cooling thresholds in the language for various compounds

For a large number of compounds, the octanol / water partition coefficients (expressed in log P units) were determined, which are presented in Table 7 together with the threshold cooling value in the tongue at 40 mM. From these data it follows that there is no correlation between the cooling in the tongue and the duration of the cooling. A longer duration of action does not correspond strictly to the values of log P.

Again, D-Ala Me-ether and Hsl analogues are of particular interest due to the absence of significant irritation to the skin or eyes.

Study 3

2-Isopropyl-5-methyl-cyclohexylcarbonyl-D-alanine methyl ester was dissolved in a warm solution of 10% propylene glycol / 90% distilled water to form a concentration of 0.1 or 0.5% (w / v) (1 or 5 mg / ml). Six to seven milliliters of the resulting solutions were placed on a paper towel (Luncheon Napkins, Kirkland Signature brand from Costco, Inc.) using a pipette. Napkins were single-layer with dimensions of 30.4 × 29.5 cm. Then each napkin was hermetically packed in a plastic envelope (Foodsaver by Tilia). In two independent cases, these wipes were sent to Los Angeles, California, USA, where the air temperature exceeded 332 ° C (90 ° F), and were used to wipe the face while playing golf. Sensations of pleasant coolness were obtained, lasting about 10 minutes for napkins with a concentration of 0.1% and about 60 minutes for napkins with a concentration of 0.5%. None of the concentrations showed eye irritation.

Study 4

A 1% preparation of 2-isopropyl-5-methyl-cyclohexylcarbonyl-D-alanine methyl ester in Aquaphor® ointment was applied bilaterally to the orbit of four volunteers. Within one minute, an onset of cooling was observed, which lasted, on average, 30 minutes. Eye irritation was not observed. Suddenly, all four volunteers noted increased alertness, the ability to focus their eyes and see more clearly. The vigilance effect lasted about an hour. This experiment was carried out again in the evening three days later on the same volunteers whose activities are related to working at the computer monitor for a whole day. It was again noted that applying ointment to the area around the eyes relieves fatigue, enhances visual activity and increases attention and focus. Feelings of freshness and mood improvement are also noted. For comparison, tests under the same conditions with other carboxamides WS-3, WS-23, WS-11 and WS-14 showed that they give significant irritation to the skin and eyes, do not increase the coolness of the skin and do not deliver satisfactory freshness.

Study 5

A twenty-year-old woman underwent treatment for acne dermatitis with Tazorak® (a local gel with tazarotene). After using this drug for several days, she complained of redness, itching and unpleasant burning sensations on the skin at the places of application of the drug. Then, 1.5% preparation of 2-isopropyl-6-methyl-cyclohexylcarbonyl-D-alanine methyl ester in Aquaphor® ointment was applied to the irritation zones. Within 5 minutes there was an onset of sensations of cooling, which lasted, on average, about 30 minutes. Discomfort from irritated skin decreased within five minutes, and the patient noted improvement in well-being.

Study 6

Safety Indicators for Active Components

Most of the preferred compounds of Formula (1) can be considered as consisting of three components: (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-carbonyl function; D-alanine; and alkyl ether.

The first component is part of WS-3, a refrigerant recognized as safe (GRAS) and approved for use in cosmetics, toiletries and confectionery. WS-3 is commercially available from Qaroma, Baytown, Texas, USA with a purity of 99.5 +%, as well as Millennium Specialty Chemicals with a purity of 99-100%. At The Flavor and Extract Manufacturer Association (FEMA) for WS-3, the GRAS code is 3455 and its safety record is fully documented.

The second component, D-alanine, is part of synthetic substitutes for aspartame and alitam sugar, therefore, it is considered safe. D-alanine is a component of the bacterial cell walls, but is not found in the human body. D-alanine, labeled with the isotope ¹⁴ C, during metabolism in rats is converted to carbon dioxide and water.

The alkyl ether group of the amino acid can be hydrolyzed to alcohol, which then decomposes into carbon dioxide and water. Thus, alkyl esters do not have toxic potential. Therefore, these molecules have a good safety indicator.

Study 7

Comparison of D and L compounds

L-homoserine-lactone, (S) - (2-oxo-tetrahydrofuran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-carboxylic acid (analogue of the compounds of Formula (2)), has some similarities with the family of N-acyl homoserine-lactone molecules secreted by gram-negative bacteria. These regulatory molecules of the intercellular signaling system implement one of several mechanisms by which bacteria interact with each other. Despite the fact that the structure of the L-homoserine-lactone analog for regulatory functions does not meet the requirements of strict compliance, its toxic properties are likely to be carefully studied for pharmaceutical use.

D-homoserine-lactone does not have the activity of regulatory molecules, however, the starting materials for its preparation are probably expensive to produce the final product on a large scale. Thus, the compound D-homoserine-lactone, (R) - (2-oxo-tetrahydrofuran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-carboxylic acid (analogue of the compounds of Formula ( 2)), can be used as a cough inhibitor, but it is more expensive than the compounds of Formula (1).

The compounds of Formulas (1) and (2) are white crystalline substances at room temperature. These compounds were tested as individual compounds or in a 1: 1 mixture with powdered or granulated sugar. The studied compounds in an amount of 1 to 5 mg were applied to the central point of the dorsal surface of the tongue using a metal scapula or plastic applicator. The volunteer was prescribed to keep the mouth closed with the test compound in the tongue, to allow the fluids in the mouth to mix with the test compound and to move it deeper into the mouth (into the oropharynx). Then, the presence and duration of individual perception in the mouth was recorded.

In healthy people, the effects of the compounds of D-Ala methyl and ethyl ester corresponding to Formula (1) were studied (methyl or ethyl ester (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid)). Three doses of 1, 2 or 4 mg per application were examined and compared with the same dose of the analogue of L-Ala methyl or ethyl ester (methyl or ethyl ester (S) -2 - [((1R, 2S, 5R) -2-isopropyl -5-methyl-cyclohexylcarbonyl) amino] propionic acid)). At doses of 2 or 4 mg, all compounds gave a pleasant and strong sensation of coolness on the tongue, spreading to the back of the throat and lasting about 30 minutes or more. The onset of action, as a rule, occurred within 30 seconds of application.

D-analogues were undoubtedly more active than their L-equivalent. At higher doses, sensations of cooling in the chest were also observed, most likely due to activation of receptors in the esophagus and the spread of such sensations in the chest. In cold environments, this particular sensation can cause a negative reaction. Therefore, it may be useful to mix the active ingredient with an adhesive molecule to localize the effect of the drug in the mouth.

Based on the analysis, cooling — response duration (area under the curve), the D analogues were at least three times stronger and refreshing than the L analogues. Menthol, studied under the same conditions, mainly acts in the nasopharynx and to a lesser extent in the oral cavity. The action of menthol was short-term, about 8-12 minutes. All analogues had a slightly bitter taste, similar to the taste of (-) - menthol.

D-, L-, and racemic Hsl analogs corresponding to Formula (2) ((R / S) - (2-oxo-tetrahydrofuran-3-yl) -amide (1R, 2S, 5R) -2-isopropyl-5- methyl-cyclohexylcarboxylic acid) were investigated in a dose of 2 mg. These compounds also provided strong and prolonged cooling at the posterior pharyngeal wall. These compounds had a pleasant and aromatic ether-like taste.

Under the same conditions, studies of WS-5 and the analogue of sarcosine ethyl ester, which did not have the spatial configuration of D-Ala, also had cooling properties, however, the duration of action was less than 10 minutes, and some sensory irritation was observed.

Study 8

Two 60-year-old men, heavy smokers who consume 3 to 5 cigarettes a day, often suffered from bouts of dry and jerky cough. At night, there were cases of insomnia, characterized by difficulty breathing, increased pressure in the chest and throat, and subsequent awakening from a sensation of suffocation. During the day, frequent and persistent sensations of tickling and irritation were observed at the posterior pharyngeal wall, causing a cough.

In 20 experiments, 10 experiments per volunteer, two mg of D-Ala ethyl ether powder corresponding to Formula (1) (ethyl ether (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl -cyclohexylcarbonyl) -amino] -propionic acid), with a purity of 95% +, was placed on the central point of the dorsal surface of the tongue of these two volunteers. Within 1 minute after application, both reported relief of the desire to cough. There was a feeling of great coolness at the back of the throat, lasting about 30 minutes. The use of the same amounts of powdered sugar was ineffective, but the placebo was easily distinguished from the active compound by the lack of sensations of coolness.

After applying the test compound, irritation and itching at the posterior pharyngeal wall (cough impulses) were absent for about 4-5 hours, and it was noted that the volunteers did not cough for 6-8 hours. Unexpectedly, after 4 uses by one volunteer and after 6 uses by another, with a period of 2 days, it was noted that the desire to cough disappeared for at least 5 days, despite continued smoking of cigars. This suggested that the test compound may have cough receptor suppression mechanisms and an ever-increasing threshold for cough impulses. This therapeutic effect was observed when the test compound ceased to cause a cooling sensation in the oropharynx.

Study 9

A 61-year-old woman with a history of asthma attacks for 31 years was a volunteer in the study of one of the compounds corresponding to Formula (1). She was hypersensitive to tobacco smoke, dust, pollen, odors, materials with a reduced content of wool (fluff / wool), cleaning products, pets and sudden changes in temperature, which was manifested by a sharp cough, mucous secretions, wheezing, asthma attacks and shortness of breath. During the study, for the observed conditions, she took the following drugs: theophylline, Allegra®, Advair®, Intal® and Singular®. In five experiments with an active cough, she placed one or two mg of a powder of ethyl ether D-Ala, corresponding to Formula (1) (ethyl ether (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl -cyclohexylcarbonyl) -amino] -propionic acid), with a purity of 95% +, to the central point of the dorsal surface of the tongue. She noted a feeling of soothing and coolness in her mouth and throat with a faint aftertaste similar to eucalyptus oil. After 3-5 minutes, the cough stopped and breathing was restored. She did not feel any accumulation of mucus or other side effects. In three experiments, when the compound was applied at night, she slept throughout the night, not awakening from a cough. Her husband noticed that for 30 years of marriage, this was the first time that the drug was effective. She noted that in the presence of a chemical compound, the irritating cough impulses disappear, however, she feels a mechanical accumulation of secretions in the airways and, if necessary, can arbitrarily cough out these secretions. She continues to take test compounds for asthma control, informing her doctor about it and getting his consent. Suddenly, attacks of asthmatic cough in any manifestation did not return to her for a month. This effect suggests that one of the pathophysiological signs of asthma, airway hypersensitivity, can be overcome by such treatment.

Study 10

A 74-year-old man suffered from adult asthma for 20 years. The initiators of the attacks were tobacco smoke, dust and temperature changes. He took Foradil® (formoterol fumarate) and Asmanex® (mometasone furoate) twice a day to control asthma and monitored lung function using a portable instrument for measuring peak expiratory flow rate. Every day, he observed cases of both wet and dry cough. In 5 experiments, when he felt pharyngeal irritation and a desire to cough, the use of 1 to 3 mg of ethyl ether (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] -propionic acid gave quick relief and was called a soothing and removing "compression" in the chest. The peak expiratory flow rate was improved from 320 l / min to 370 l / min. In 3 cases, when the test compound was taken during wet coughing attacks, no significant effect was observed, and the volunteer reported that he coughed up the taken compound. The individual response to the long-acting NACE compound was definitely favorable. The volunteer noted that the best time to take the NACE compound was after inhalation of crystalline Foradil®, because the inhaled drug irritated the throat. Menthol tablets were ineffective in alleviating airway discomfort, because they had an anti-irritant effect of moderate strength, and the sugar filling of the tablets interrupted appetite.

The foregoing describes the principles, preferred embodiments and modes of operation of the present invention. However, the present invention should not be construed as limited only by these implementation methods. On the contrary, the above described embodiments should be considered to be more explanatory than restrictive, and it should be recognized that those skilled in the art may make changes to these embodiments without departing from the scope of the present invention.

Claims (27)

1. The compound of formula (1)

where R ₁ independently represents hydrogen or methyl;
R ₂ independently represents an alkyl C ₁ -C ₂ and
R ₃ independently represents alkyl C ₁ -C ₄ ,
and pharmaceutically acceptable salts of this compound. 2. The compound according to claim 1, where R ₁ independently represents hydrogen or methyl. 3. The compound according to claim 1, where R ₂ independently represents methyl or ethyl. 4. The compound according to claim 1, where R ₃ independently represents methyl or ethyl. 5. The compound according to claim 1, selected from the following compounds:
(R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid methyl ester;
(R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid ethyl ester;
n-propyl ester of (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid;
isopropyl ether of (R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid;
(R) -2 n-butyl ether - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid;
(R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid sec-butyl ester;
(R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid isobutyl ester;
(R) -2 - [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexylcarbonyl) amino] propionic acid tert-butyl ester, as well as pharmaceutically acceptable salts of this compound. 6. The compound according to any one of claims 1 to 5 for use in order to alleviate sensory discomfort. 7. The compound according to any one of claims 1 to 5 for use in the manufacture of a medicament for alleviating skin irritation, skin itching and / or pain. 8. The compound according to any one of claims 1 to 5 for use in the manufacture of a medicament for the treatment or relief of cough and / or sensation of irritation of the upper respiratory tract. 9. The compound according to any one of claims 1 to 5 for use in the manufacture of a medicament for treating asthma or alleviating the symptoms and signs of asthma. 10. The compound according to any one of claims 1 to 5 for use in the manufacture of a medicament for the prevention of cough. 11. The compound according to any one of claims 1 to 5 for use in the manufacture of a medicament to increase alertness or reduce fatigue, fever or fever. 12. A pharmaceutical composition that affects sensory (nociceptive) processes, comprising a compound according to any one of claims 1 to 11 in an effective amount and a delivery vehicle that is a pharmaceutically acceptable carrier or diluent. 13. The composition of claim 12, wherein the delivery vehicle is adapted to deliver said compound to human skin. 14. The composition according to item 12, in which the delivery vehicle is a napkin. 15. The composition of claim 12, wherein the delivery vehicle is adapted to deliver the compound to the oral cavity and / or upper respiratory tract of a person. 16. The composition according to any one of paragraphs.12-15, in which the specified compound is included in the amount of from 1 to 10 mg. 17. The composition according to any one of paragraphs.12-15, in which the specified compound is included in the composition in an amount of from 0.01 to 2% wt./about. 18. The composition according to any one of paragraphs.12-15, characterized in that the composition further comprises a polyhydric alcohol. 19. The composition according to any one of paragraphs.12-15, characterized in that the composition further comprises a mucoadhesive polymer. 20. A method for treating a person’s skin, mouth, or upper respiratory tract, comprising:
contacting a composition containing a compound according to any one of claims 1 to 11 and a delivery vehicle with a person’s skin, oral cavity or upper respiratory tract,
delivering in this way an effective amount of said compound to human skin or mucous membranes. 21. A method of treating skin irritation, itching and / or pain, including:
contacting a composition containing a compound according to any one of claims 1 to 11 and a delivery vehicle with a person’s skin, oral cavity or upper respiratory tract,
thus delivering such an amount of said compound that is therapeutically effective to alleviate skin irritation, itching and / or pain. 22. A method of treating cough and / or sensation of irritation of the upper respiratory tract, including:
contacting the composition containing the compound according to any one of claims 1 to 11 and a delivery means with the oral cavity or upper respiratory tract of a person,
thus delivering such an amount of said compound that is therapeutically effective to alleviate coughing and / or sensation of upper respiratory tract irritation. 23. A method of treating or alleviating asthma or cough or symptoms and signs of asthma, such as a cough, comprising:
contacting the composition containing the compound according to any one of claims 1 to 11 and a delivery means with the oral cavity or upper respiratory tract of a person,
thus delivering such an amount of said compound that is therapeutically effective for treating or alleviating asthma or cough, or alleviating the symptoms and signs of asthma. 24. A method of preventing coughing and transmitting an infectious microorganism by airborne droplets, including:
contacting the composition containing the compound according to any one of claims 1 to 11 and a delivery means with the oral cavity or upper respiratory tract of a person,
thus delivering such an amount of said compound that is therapeutically effective to prevent coughing and transmission of the infectious microorganism by airborne droplets. 25. The method according to any one of claims 20-24, wherein said composition contains from 1 to 20 mg of said compound, wherein said composition is in the form of a tablet. 26. The method according to any one of claims 20-24, wherein said composition contains from 0.01 to 2% w / v. the specified connection. 27. The method according to any one of claims 20-24, wherein said compound is taken as a composition further comprising a compound selected from polyhydric alcohol and a mucoadhesive polymer.

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