Retinoid compounds, method for their preparing (variants), pharmaceutical composition based on thereof and method for treatment of respiratory way obstructive disease, cancer or dermatological disturbance of disorder

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: improved treatment method, valuable medicinal properties of compounds and composition.

28 cl, 10 tbl, 16 ex

 

The present invention relates to new heterocyclic retinoid compounds and methods for their synthesis. The present invention also relates to methods of using these heterocyclic retinoid compounds and to pharmaceutical compositions comprising these compounds. In particular, the invention relates to compounds of formula (I)

or their pharmaceutically acceptable salts, solvate or hydrate,

where n means an integer from 0 to 2;

And represents aryl or heteroaryl;

In represents O, S or NR6;

R6represents hydrogen or alkyl;

Y represents-OR7, -SR7or-NR8R9;

R7represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or cycloalkenyl;

R8and R9independently represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or cycloalkenyl, or together with the nitrogen atom to which they are attached, form heterocyclimamines ring system;

Z represents-C(R101)2O, -R102C=CR102-, -C≡C-, -CR103-, -C(O)O - or-C(O)NR10-;

each of R10, R101, R102and R103independently represents hydrogen or alkyl;

R1and R2independently represent hydrogen or alkyl;

R3 represents hydrogen or alkyl and

R4and R5independently represent hydrogen, (C1-C8)alkyl or arylalkyl.

Retinoids are structural analogues of vitamin a and include both natural and synthetic compounds. Retinoid compounds, such as all isomeric TRANS-retinoic acid (ATRA). "all trans-retinoic acid), 9-CIS-retinoic acid, TRANS-3,4-didehydroretinal acid, 4-axaramedia acid, 13-CIS-retinoic acid and retinol are pleiotropic regulatory compounds that affect a large number of prone to inflammation, immune and structural cells.

For example, retinoids are modulators of proliferation of epithelial cells, morphogenesis in the lung and differentiation, with the participation of a number of nuclear hormone receptors, which belong to the subfamily of steroid/thyroid receptors. Retinoid receptors are divided into the retinoic acid receptors (RAR). retinoic acid receptor and retinoid X receptors (RXR - from the English. retinoid X receptor), which consist of three separate subtypes (α, β and γ).

ATRA is a natural ligand of retinoic acid receptors and binds with similar affinity, α-, β- and γ-subtypes. For a number of synthetic α-, β- and γ-retinoid of agonistica RAR defined quantitative characteristics according to the structure - the activity, which allow to explain the basic electronic and structural characteristics that provide selectivity of binding for each subtype receptors RAR (Douget et al. Quant. Struct. Act. Relat, 1999, v.18, p.107).

ATRA does not attach to the receptor RXR, in relation to which 9-CIS-retinoic acid is a natural ligand. A number of synthetic α-, β- and γ-retinoid agonists of receptors RXR and RAR are known from the prior art (see, for example, U.S. patent No. 5962508 (Billoni et al.); application WO 01/30326 published 03.05.2001 (Belloni et al.), U.S. patent No. 5986131 (Klaus et al.) and the application WO 92/06948 published 30.04.1992 (Bernardon et al.)). Other patents relating to retinoids include U.S. patent No. 5716624 (Bernadon) and U.S. patent No. 6046220 (Bernadon).

In tissues other than the lungs, retinoids tend to be anti-inflammatory effect, can alter the sequence of differentiation of epithelial cells, and can inhibit matrix producing stromal cells. These biological effects of retinoids has led to the development of many tools for local use in case of dermatological diseases such as psoriasis, acne and hypertrophic scars on the skin. Retinoids are also used in the treatment of age-related skin damage and skin damage caused by exposure to light, to heal wounds, poyavivhsijsya, for example, surgery or burns (Mustoe et al., 1987, Science, v.237, p.1333; Sprugel et al., J. Pathol., 1987, v.129, p.601; Boyd, Am. J. Med., 1989, v.86, p.568), as well as anti-inflammatory agents for the treatment of arthritis. Other types of medical applications of retinoids include management of acute promyelocytic leukemia, adenocarcinoma and squamous cell carcinoma, and liver fibrosis. Retinoids are also widely used for the treatment of precancerous lesions of the epithelium and malignant tumors (carcinomas) epithelial nature (Bollag et al., U.S. patent No. 5248071; Sporn et al., Fed. Proc. 1976, 1332; Hong et al., "Retinoids and Human Cancer", in Proc.: The Retinoids: Biology, Chemistry and Medicine, M.B. Sporn, A.B. Roberts and D.S. Goodman (eds.) Raven Press, New York, 1994, 597-630). However, many known retinoids do not have the selectivity and consequently cause adverse pleiotropic effects, which when used in therapeutically effective amounts can cause death of the patient. Thus, the use of retinoids in the case of diseases other than cancer, limited toxic side effects. Overview of retinoids can be found in Goodman & Gilman''s "The Pharmacological Basis of Therapeutics", Chapters 63-64, 9thedition, 1996, McGraw-Hill.

The term "chronic obstructive pulmonary disease" (COPD) refers to a large group of lung diseases that interfere with normal breathing. Approximately 11% of the U.S. population, the country is up from chronic obstructive lung diseases, and the available data allow to conclude that the incidence of chronic obstructive pulmonary disease increases. Currently, COPD is the fourth leading cause of death in the USA.

COPD is a disease in which the lungs are obstructed due to the presence of at least one disease selected from the group comprising asthma, emphysema and chronic bronchitis. The term COPD was introduced due to the fact that these diseases often occur simultaneously and in a particular case can be difficult to determine which disease was the cause of obstruction light (1987, Merck Manual). Clinically COPD is diagnosed by reduced expiratory flow from the lungs, which is not changed in several months, and in the case of chronic bronchitis remains so for two or more consecutive years. The most severe manifestations of COPD usually include symptoms characteristic of emphysema.

Emphysema is a condition in which the dissolved gas exchange patterns of the lung (e.g., the alveoli), which leads to the insufficient oxygen, which can cause disability and death. Anatomically emphysema determined by unchanging hypertrophy of the respiratory tract towards the periphery of the terminal bronchioles (for example the EP, breathing tubes), emphysema characterized by reduced elasticity of the lung, reduced the surface of the alveoli and reduced gas exchange, as well as the destruction of the alveoli, which leads to difficulty breathing. Thus, the characteristic physiological changes in emphysema are reduced gas exchange and expiratory gas flow.

Cigarette Smoking is the most common cause of emphysema, although other toxins - products of pollution can also contribute to the destruction of the alveoli. Harmful substances present in these aggressive agents that can activate the destructive processes that include, for example, the release of excessive amounts of proteases that suppress the normal protective mechanisms, since protease inhibitors are present in the lungs. The imbalance between proteases and protease inhibitors present in the lungs, can lead to the destruction of the elastin matrix, decreased elasticity, tissue damage and permanent loss of activity of the lung. The rate of destruction of the lung can be reduced by lowering the content of toxins in the lung (i.e. when to quit). However, the damaged alveolar structures are not restored, and the activity light is not restored. Described at least four of them is, in accordance with their location in the side lobes: panorama emphysema, centrilobular emphysema, peripheral lobular emphysema and parabola emphysema.

The main symptom of emphysema is a chronic shortness of breath. Other important symptoms of emphysema include, but are not limited to specified, chronic cough, the coloration of the skin caused by lack of oxygen, shortness of breath with minimal exertion and wheezing. Additional symptoms that may be associated with emphysema include, but are not limited to specified, blurred vision, dizziness, temporary cessation of breathing, swelling, fatigue, insomnia and memory loss. Emphysema is usually diagnosed during a medical examination, if sounds when breathing quieter or unusual, and if there is wheezing and prolonged exhalation. In the case of emphysema for confirmation of the diagnosis can be used to test the functional activity of the lungs, establishing a reduced content of oxygen in the blood and chest x-ray.

From the prior art are not aware of any existing effective recovery methods clinical indicators characteristic of emphysema. In some cases, medications such as bronchodilators ven the rata βagonists, Tefillin, anticholinergics, diuretics and corticosteroids that are injected into the lungs using an inhaler or nebulizer, can improve breathing, weakened due to emphysema. The oxygen treatment is often used in such situations, when the lungs are so severely disturbed that the necessary amount of oxygen cannot be absorbed from the air. Therapy aimed at restoring the normal condition of the lung, can be used to treat patients with severe emphysema. In this case, the damaged areas of the lung are removed, which allows normal functioning part of the lung to expand more fully and allows you to gain an advantage at the expense of increasing the degree of aeration. In conclusion, a lung transplant is another surgical alternative available to individuals with emphysema, which thus can improve the quality of life, but the life expectancy to increase slightly.

The alveoli are formed in the process of development by separating the bags, which constitute the gas exchange elements of the immature lung. The true mechanisms that control the formation of partitions and their location in primates, it is still not known. Retinoids such as ATRA, which is a multifunctional modulator of the mi behavior of cells, modifying how the extracellular matrix metabolism and normal differentiation of epithelial cells, play an important regulatory role in mammals, such as rats. For example, ATRA is a modulator of the important aspects of differentiation of lung cells, by binding with specific receptors retinoic acid, which is expressed with selective temporal and spatial characteristics. Coordinated activation of different subtypes of receptors retinoic acid is associated with lung branching, the formation of alveoli/sacs and gene activation tropoelastin in newborn rats.

During the formation of the alveoli of the sacs in fibroblastoid mesenchyme surrounding walls of the alveoli, increasing the granules of which accumulated retinoic acid (Liu et al., Am. J. Physiol. 1993, v.265, L430; McGowan et al., Am. J. Physiol., 1995, v.269, L463), and expression of retinoic acid receptors in the lung reaches its maximum (Ong et al., Proc. Natl. Acad. of Sci., 1976, 73, 3976; Grummer et al., Pediatr. Pulm., 1994, 17, 234). Pick new elastin matrix and the formation of septa runs parallel to the depletion of these granules, which accumulated retinoic acid. As shown, postnatal introduction retinoic acid increases the number of alveoli in rats, which confirms the concept, according to which an increase in the number is TBA ATRA and other retinoids can induce the formation of alveoli (Massaro et al., Am, J. PhysioL, 270, L305, 1996). Treatment of newborn rats with dexamethasone, a glucocorticosteroid, prevents the formation of partitions and reduces the expression of some subtypes of retinoic acid receptors. As shown, an additional amount of ATRA prevent inhibition by dexamethasone formation of alveoli. In addition, ATRA decreases the expression of receptors of the retinoic acid under the action of dexamethasone and the effects of dexamethasone on the subsequent formation of the walls of the alveoli in the developing rat lung.

It was reported that ATRA induces the formation of new alveoli and helps to restore the elasticity of the lung to approximately normal values in models of emphysema in animals (Massaro et al., Nature Med., 1997, v.3, p.675; "Strategies to Augment Alveolization", National Heart, Lung, and Blood Institute, RFA: HL-98-011, 1998; U.S. patent No. 5998486 (Massaro et al.)). However, the mechanism of action of ATRA in these studies remains uncertain, although Massaro (Massaro) reported that ATRA promotes generation of new alveoli. More importantly, when using ATRA there was some toxicity associated with some unwanted effects.

Thus, it needs new retinoid agonists, which may be useful for the treatment of dermatological disorders, disorders of the lung, such as COPD, emphysema, and cancer, without p is oblama toxicity, inherent in the use of ATRA or other retinoids.

The present invention provides for the receipt of new heterocyclic retinoid compounds, the creation of new methods of treatment or prevention of disorders or disorders of the activity of the lung, such as chronic obstructive Airways disease, cancer and dermatological disorders, obtaining pharmaceutical compositions suitable for the treatment and prevention of such diseases or disorders, and methods of delivery of compositions of new heterocyclic retinoid compounds in the lung of a mammal suffering from such diseases or disorders.

The present invention provides the use of compounds according to the present invention for the treatment or prevention of certain chronic obstructive respiratory diseases, particularly chronic obstructive pulmonary disease, including chronic bronchitis, emphysema and asthma in mammals, particularly in people who smoke cigarettes. In accordance with a preferred embodiment the present invention relates to the treatment or prevention panoramoi emphysema, centrilobular emphysema or peripheral lobular emphysema in a mammal using non-toxic and therapeutically effective doses with the of dinani according to the present invention.

The present invention also relates to the use of compounds which are the subject of the invention, for treating or preventing cancer or dermatological disorders or disorders. In addition, the present invention provides the use of pharmaceutical compositions of the compounds of the subject invention, for the treatment or prevention of chronic obstructive respiratory diseases, cancer or dermatological disorders or disorders. In addition, the present invention allows the use of electrohydrodynamic device to retrieve aerosol and sprays for delivery of compositions comprising compounds according to the present invention, in the lung of a mammal suffering from such disease or susceptible to risk of developing chronic obstructive airway disease or cancer.

The present invention also allows the system application, as well as local application connections that are the subject of the present invention, and the combination of these uses. Separately or together, these applications can be implemented through oral, mucosal or parenteral routes of administration. As mentioned above, the means of delivery of the compounds according to the present invention directly to the lung by means of a spray, inhaler or other known devices for delivery are determined by the invention. A method of treating chronic obstructive disorders of the respiratory tract, cancer or dermatological disorders by combining compounds that are the subject of the present invention, and one or more additional treatment is also provided by this invention.

When used in the text of this application, the term "compound according to the present invention" means a compound of General formula (I), including, but not limited to, the specific compounds falling under formula given in the text of the application. Compounds according to the present invention are identified in the proposal according to their chemical structural formula and/or chemical name. In the case when the connection is given as a chemical structural formula and chemical name and chemical structure does not match the chemical name, decisive for the identification of compounds is a chemical structural formula. Compounds according to the present invention can contain one or more chiral centers and/or one or more double bonds and, therefore, may exist as stereoisomers, such as position isomers of double bonds (i.e., geometric isomers), enantio is ture or diastereomers. In accordance with the invention, the chemical structure is described in the proposal, and, thus, the compounds according to the present invention include all relevant enantiomers and stereometry connection, i.e. stereoisomers pure form (for example, a pure geometric isomer, the pure enantiomer or pure diastereoisomer), and mixtures of enantiomers or stereoisomers. Mixture of enantiomers, or stereoisomers can be separated into its constituent components - enantiomers using either of the methods of separation, or stereospecific methods of synthesis known to a person skilled in the technical field.

"Acyl" means a radical-C(O)R, in which R represents hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl or arylalkyl, in which alkyl, cycloalkyl, cycloalkenyl, aryl and arylalkyl are as defined in the proposal. Typical examples include, but are not limited to, groups such as formyl, acetyl, cyclohexylcarbonyl, cyclohexylcarbonyl, benzoyl, benzylcarbamoyl and similar groups.

"Acylamino" means a radical-NR'r C(O)R, in which R' represents hydrogen or alkyl, and R represents hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl or arylalkyl, where the alkyl, cycloalkyl, cycloalkenyl, aryl and arylalkyl are as defined is prohibited in the text of the application. Typical examples include, but are not limited to, groups such as formylamino, acetylamino, cyclohexylcarbodiimide, cyclohexyldimethylamine, benzoylamine, benzylmorphine and similar groups.

"Alkoxy" means a radical-OR where R represents an alkyl group, as defined in the proposal, for example methoxy, ethoxy, propoxy, butoxy and similar groups.

"Alkoxycarbonyl" means the radical-C(O)-alkoxy, where alkoxygroup is the same as defined in the proposal.

"Alkyl" means a linear saturated monovalent hydrocarbon radical containing from one to eight carbon atoms, or branched saturated monovalent hydrocarbon radical containing from three to eight carbon atoms, for example methyl, ethyl, propyl, 2-propyl, n-butyl, ISO-butyl, tert-butyl, pentyl and similar groups.

"Alkylamino" means the radical other, where R represents an alkyl group, cycloalkyl or cycloalkenyl that are defined in the text of the application. Typical examples include, but are not limited to, groups such as methylamino, ethylamino, isopropylamino, cyclohexylamino and similar groups.

"Alkylene" means a linear saturated divalently hydrocarbon radical containing from one to ten carbon atoms, or razvetvlenno the th rich divalently hydrocarbon radical, containing from three to ten carbon atoms, for example methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropene, butylene, pentile and similar groups.

"Alkylsulfonyl" means the radical-S(O)2R, in which R represents an alkyl group, cycloalkyl or cycloalkenyl, as defined in the proposal, for example methylsulphonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and similar groups.

"Alkylsulfonyl" means the radical-S(O)R, in which R represents an alkyl group, cycloalkyl or cycloalkenyl, as defined in the proposal, such as methylsulfinyl, ethylsulfinyl, propylsulfonyl, butylsulfonyl and similar groups.

"Alkylthio" means a radical-SR where R is an alkyl group, cycloalkyl or cycloalkenyl, as defined in the proposal, for example methylthio, ethylthio, propylthio, butylthio and similar groups.

"Aryl" means a monocyclic or bicyclic aromatic hydrocarbon radical, preferably phenyl, which is optionally substituted by one or more substituents, preferably one, two or three substituents, the substituents preferably selected from the group consisting of acyl, alkyl, acylamino, alkoxycarbonyl, alkylamino, alkylsulfonyl, alkylsulfonyl, alkylthio, alkoxy, amino, carbamoyl cyano, dialkylamino, Ethylenedioxy, halogen, halogenoalkane, heteroalkyl, hydroxyl, hydroxyalkyl, methylenedioxy, nitro, and thio, more preferably from hydroxy, alkoxy, alkyl, halogenoalkane or halogen, even more preferably from halogen. More specifically, the term "aryl" includes, but is not limited to the above, phenyl, chlorophenyl, forfinal, methoxyphenyl, 1-naphthyl, 2-naphthyl and derivatives thereof.

"Arylalkyl" refers to an alkyl radical as defined in the proposal, in which the alkyl is one of hydrogen atoms substituted aryl group. Typical examples of the groups arylalkyl include, but are not limited to, benzyl, 2-Penilaian-1-yl, naphthylmethyl, 2-Nettleton-1-yl, naphthalenyl, 2-naphthenate-1-yl and the like groups.

"Aryloxy" means the group-O-aryl, where aryl is defined in the text of the application.

"Arylalkyl" means the group-O-arylalkyl, where the group arylalkyl defined in the proposal.

"Carbarnoyl" means the radical-C(O)N(R)2in which each group R independently represents hydrogen or alkyl, as defined in the proposal.

"Carboxy" means the radical-C(O)HE.

"Cyano" means the radical-CN.

"Cycloalkyl" means a saturated monovalent cyclic hydrocarbon radical containing from three to seven carbon atoms in the ring, such as cyclopropyl, cyclobutyl, the CEC shall hexil, 4-methylcyclohexyl and similar radicals.

"Cycloalkenyl" means a radical-RaRbin which Rarepresents a group of alkylene, a Rbrepresents a group of cycloalkyl, as defined in the proposal, such as cyclohexylmethyl and similar radicals.

"Dialkylamino" means a radical-NRR'where R and R' independently represent alkyl groups, cycloalkyl or cycloalkenyl, as defined in the proposal. Typical examples include, but are not limited to specified, dimethylamino, methylethylamine, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)amino, (cyclohexylmethyl)(ethyl)amino and the like groups.

"Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

"Halogenated" means an alkyl group substituted by one or more halogen atoms, equal or different, for example, -CH2Cl-CF3, -CH2CF3, -CH2CCl3and similar groups.

"Heteroalkyl" means an alkyl radical, which is defined in the proposal, this radical one or more hydrogen atoms replaced by the Deputy, is independently selected from the group consisting of-ORa, -NRbRcand-S(O)nRd(where n means 0, 1 or 2), assuming that p is soedinenie of radical heteroalkyl occurs through a carbon atom, in this case, the substituent Rarepresents hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl; Rband Rcindependently of one another represent hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl and in the case when n is 0, Rdrepresents hydrogen, alkyl, cycloalkyl or cycloalkenyl, and in the case when n is 1 or 2, Rdrepresents alkyl, cycloalkyl, cycloalkenyl, amino, acylamino, alkylamino or dialkylamino. Typical examples include, but are not limited to specified, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydroxypropyl, 1-hydroxymethylation, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-amino-ethyl, 3-aminopropyl, 2-methylsulfonylmethyl, aminocarbonylmethyl, aminosulfonyl, aminosulfonyl, methylaminoethanol, methylaminomethyl, methylaminoethanol and similar groups.

"Heteroaryl" means a monocyclic or bicyclic radical, comprising from 5 to 12 atoms in the ring system, containing at least one aromatic ring containing one, two or three heteroatoms in the ring selected from N, O or S and the remaining atoms in the ring are C, provided that interconnection point or heteroaryl radical is located in the aromatic ring is. Heteroaryl ring optionally substituted independently by one or more substituents, preferably one or two substituents selected from alkyl, halogenoalkane, heteroalkyl, halogen, hydroxy, alkoxy, nitro, cyano, cycloalkyl, cycloalkenyl, -COR (where R represents alkyl or optionally substituted phenyl, -(CR'R")n-COOR (where n is an integer from 0 to 5, R' and R" independently represent hydrogen or alkyl, and R represents hydrogen, alkyl, cycloalkyl or cycloalkenyl) or(CR'R")n-CONRaRb(where n is an integer from 0 to 5, R' and R" independently denote hydrogen or alkyl and Raand Rbindependently of one another represent hydrogen, alkyl, cycloalkyl or cycloalkenyl or Raand Rbtogether with the nitrogen atom to which they are attached, form a heterocyclic ring). More specifically, the term "heteroaryl" includes, but is not limited to the above, pyridyl, furanyl, thienyl, thiazolyl, isothiazolin, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrofuranyl, isobenzofuranyl, benzothiazolyl, benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, hinely, tetrahydroquinoline, ethanolic, benzimidazolyl, benzisoxazole or benzothiazyl and their production is adnie.

"Heterocyclimamines" means a saturated monovalent cyclic group containing 4 to 8 atoms in the ring, in which at least one atom is a N atom and which optionally contains one additional ring heteroatom selected from the group consisting of atoms N, O or S(O)n(where n is 0, 1 or 2), and the remaining atoms in the ring are atoms C. the Ring - heterocyclyl may be optionally independently substituted one, two or three substituents selected from alkyl, halogenoalkane, heteroalkyl, acyl, halogen, nitro, carboxy, cyano, cyanoalanine, hydroxy, alkoxy, amino, alkylamino or dialkylamino. More specifically, the term "heterocyclyl" includes, but is not limited to the above, piperidino, N-methylpiperidin-3-yl, piperazine derivatives, N-methylpyrrolidine-3-yl, 3-pyrrolidino, morpholino, thiomorpholine, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide and derivatives thereof.

"Hydroxyalkyl" means an alkyl radical as defined in the proposal, substituted by one or more hydroxy-group, provided that one and the same carbon atom is substituted by no more than one hydroxy-group. Typical examples include, but are not limited to specified, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl. In line with this, in the text of this application, the term "hydroxyalkyl" is used to denote the subgroup heteroalkyl groups.

The term "tsepliaeva group" has the meaning traditionally inherent in synthetic organic chemistry, that is, means an atom or group which can be substituted by a nucleophile and includes halogen (such as chlorine, bromine and iodine), alkanesulfonyl, arenesulfonyl, alkylcarboxylic (for example, acetoxy), arylcarboxylic, mesilate, tosyloxy, tripterocalyx, aryloxy (for example, 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamine and similar groups.

The term "pharmaceutically acceptable excipient" means an excipient that is suitable for the manufacture of pharmaceutical compositions, in General, safe, non-toxic and such, which is not unsuitable neither biological, nor in any other respect, the term includes a filler which is suitable for veterinary use as well as for use in the manufacture of medicinal products intended for men. The term "pharmaceutically acceptable excipient", EIT is the situation, in which it is used in the present description and in the claims includes both one and more than one such excipient.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the necessary pharmacological activity of the parent compound. Such salts include : (1) salt - addition products of acids formed with inorganic acids such as chloromethane acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like acids; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonate acid, 4-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]Oct-2-ene-1-carboxylic acid is one glucoheptonate acid, 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and the like acids, or (2) salts formed when a proton acid present in the initial compound, substituted or metal ion, for example an alkali metal ion, alkali earth metal ion or an aluminum ion, or forms a coordination compound with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and similar bases.

The terms "Pro-drug" and "prodrug" in the text of this application interchangeably and refer to any compound which can release the active source of the medication corresponding to the structural formula (I)in vivo when such prodrug administered to the mammal. Prodrugs of the compounds of structural formula (I), obtained by modification of one or more functional groups present in the compound of structural formula (I), so that the modifier fragment can be derived in vivo to release the source connection. Prodrugs include compounds structurally the formula (I), in which the group hydroxy, amino or sulfhydryl included in the compound of structural formula (I), associated with any group that can be split in vivo to release this free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to specified, esters (for example, derivatives - acetate, formate and benzoate), carbamates (for example, N,N-dimethylaminoethyl) functional hydroxy groups of the compounds of structural formula (I) and similar derivatives.

"Protective group" refers to a grouping of atoms, which in the case of accession to the reactive group of a molecule masks, reduces reactivity or prevent the manifestation of such reactivity. Examples of protective groups can be found in .W. Green and .G. Wuts, "Protective Groups in Organic Chemistry" (Wiley, 2nded., 1991)and Harrison et al., "Compendium of Synthetic Organic Methods", vols.1-8 (John Wiley and Sons, 1971-1996). Typical protective groups for amino groups include, but are not limited to, formyl, acetyl, TRIFLUOROACETYL, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilylethynyl (SES), trichilia and substituted triteleia group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC), nitroferricyanide (NVOC) and similar groups. Typical protective group for g is proxygroup include, but are not limited to specified such group, where the hydroxy-group or acelerou or alkylate, namely groups such as benzyl, trifilova a simple ether, and group alilovic ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

When used in the text of this application, the term "mammal" includes humans. The terms "man" and "patient" in the text of the application are used interchangeably.

The term "treating" chronic obstructive lung disease, emphysema, cancer or dermatological disorders or disorders includes the prevention of disease (i.e. allows to develop in a mammal at least one clinical symptom of the disease, to the appearance or manifestation of which predisposes to the disease, but which as yet has not developed or has not manifested as a symptom of illness), suppression of disease development (i.e. suspension or delay development of the disease or at least one clinical symptom) or weakening of the disease (i.e. regression of the disease or at least one clinical symptom). For the prevention or warning of the introduction is carried out prior to the manifestation of diseases, disorders or disorders.

"therapeutically effective the effective amount" means the amount of coupling, which when administered to a mammal for the treatment of the disease is sufficient to produce such treatment of the disease. "Therapeutically effective amount" will vary depending on the compound, the disease and the severity of its symptoms, as well as age, weight, etc. of a mammal, which is subjected to the treatment.

Next will be described in detail preferred embodiments of the invention. While the invention will be illustrated by describing the preferred embodiments, it is necessary to understand that the scope of the invention should not be limited to these preferred variant embodiment of the invention. On the contrary, it is assumed that the scope of the invention includes alternatives, modifications and equivalents that correspond to the essence of the invention, which is defined as represented by the claims.

The present invention aims to provide new compounds and the use of these new compounds for the effective treatment of chronic obstructive lung disease, such as emphysema, cancer and dermatological disorders or disorders. The present invention is directed to the treatment of chronic obstructive lung disease and associated disorders, cancer and dermatological disorders with reduced or without the tender is athelny effects inherent natural and synthetic retinoids in the case when they are used in therapeutically effective doses. Unwanted effects associated with retinoids used in a therapeutic quantity, include, but are not limited to the above, the toxic effects of hypervitaminosis A, such as headache, fever, fever, dry skin and membranes, bone pain, nausea and vomiting, psychiatric disorders and gastrointestinal disorders.

More specifically, the present invention relates to compounds of formula (I)

or pharmaceutically acceptable salts, solvate or hydrates of these compounds,

where n means an integer from 0 to 2;

And represents aryl or heteroaryl;

In represents O, S or NR6;

R6represents hydrogen or alkyl;

Y represents-OR7, -SR7or-NR8R9;

R7represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or cycloalkenyl;

R8and R9independently represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or cycloalkenyl or together with the nitrogen atom to which they are attached, form heterocyclimamines ring system;

Z represents-C(R101)2O-, -R102C=CR102-, -C≡C-, -C(R 103)2S-, -C(O)O - or-C(O)NR10-;

each of R10, R101, R102and R103independently represents hydrogen or alkyl;

R1and R2independently represent hydrogen or alkyl;

R3represents hydrogen or alkyl and

R4and R5independently represent hydrogen, (C1-C8)alkyl or arylalkyl.

According to a preferred variant embodiment of the invention And corresponds to structural formula (II)

in which R11and R12independently represent hydrogen, acyl, acylamino, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylsulfonyl, alkylsulfanyl, alkylthio, carbarnoyl, carboxy, cyano, dialkylamino, halogen, halogenated, hydroxy, hydroxyalkyl or nitro. In some preferred versions of the invention, R11and R12independently represent hydroxy, alkoxy, alkyl, halogenated, halogen or hydrogen. Compounds in which R11and R12independently denote a halogen or hydrogen, are preferred. Preferably R11and R12mean hydrogen or in other preferred embodiments of the invention R11and R12are different and are either fluorine or hydrogen. Connections in the cat is where R 11means hydrogen and R12means fluorine, or R11means fluorine, and R12means hydrogen, are also preferred.

In yet another embodiment of the invention Y is a OR7and R7means hydrogen or alkyl, preferably hydrogen or methyl, more preferably hydrogen.

In yet another embodiment of the invention n is 1 and R3means hydrogen. Compounds in which n is 1 are preferred. Compounds in which R3means hydrogen, are also preferred.

According to another variant embodiment of the invention R1and R2mean alkyl. Preferably R1and R2means methyl.

According to preferred variants of the invention, Z represents-C(R101)2O-, -R102C=R102-, -C(R103)2S-, -C(O)O - or-C(O)NR10-, and R101, R102and R103mean hydrogen. Preferred are those compounds in which Z represents-C(R101)2O-, -R102C=CR102-, -C(R103)2S-, -C(O)O - or-C(O)NR10-, and R101, R102and R103mean hydrogen, and R10represents hydrogen or alkyl. More preferably Z represents-CH2O - or TRANS-CH=CH-.

According to another variant implementation of the ia of the invention means In NR 6. More preferably R6represents hydrogen, methyl or ethyl. According to another preferred variant of the invention, the means In NR6and Z represents-CH2O-, TRANS-HC=CH -,- ≡ -,- C(O)O - or-C(O)NR10-.

According to another variant embodiment of the invention R4means hydrogen. In accordance with a preferred embodiment of the invention R4means hydrogen, and R5means (C1-C8)alkyl or arylalkyl. Such compounds in which R5means (C1-C8)alkyl or arylalkyl, are preferred, and those in which R5means (C1-C8)alkyl or benzyl, are particularly preferred. Preferably R5represents ethyl, pentyl, octyl or benzyl. More preferably R5means of pencil.

The connections defined, as described above, in which means Of that relate to a preferred variant implementation of the present invention. Other preferred compounds are those in which the means In S. in Addition, the connection, which means NR6and R6means hydrogen or alkyl, are preferred, and compounds in which R6means hydrogen, methyl or ethyl are particularly preferred.

With the according to one of preferred embodiments of the invention In means and Z denotes-CH 2O - or TRANS-HC=CH-. According to another preferred variant of the invention, the means In S and Z denotes-CH2O-, TRANS-HC=CH-, -C(O)O - or-C(O)NR10-.

According to another preferred variant of the invention, n is 1, Y represents OR7, R1and R2mean alkyl, R3means hydrogen, R4means hydrogen, R5means alkyl or arylalkyl, R7means hydrogen, R11means a hydrogen or halogen and R12means hydrogen. According to a more specific variant of carrying out the invention means NR6Z denotes-CH2O-, TRANS-HC=CH - or-C≡ -, R5means alkyl, a R6means hydrogen, methyl or ethyl.

Preferred are compounds selected from the group which consists of the following:

4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptyloxy]benzoic acid,

4-[2-(4,4-dimethylthiochroman-7-yl)heptyloxy]benzoic acid,

4-[3-(4,4-DIMETHYLPROPANE-7-yl)Oct-1-enyl]benzoic acid,

4-[3-(4,4-dimethylthiochroman-7-yl)Oct-1-enyl]benzoic acid,

4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid,

4-[3-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid,

4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Penta-1-enyl]benzoic acid,

4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-yl)undec-1-enyl]benzoic acid,

4-[4-phenyl-3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)but-1-enyl]benzoic acid,

4-[3-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid,

3-fluoro-4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid,

4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptyloxy]benzoic acid,

4-[2-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptyloxy]benzoic acid,

4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid,

4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid and

4-[3-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-inyl]benzoic acid.

Preferred compounds according to the present invention are presented in table 1.

/tr>
Table 1
ExampleStructureMass spectrumtPL
191,5-93,3°C
2123,0-123,5°C
3(M--1) 391
4(M--1) 407
5(M++1) 405
6(M++1) 421
7(M++1) 364

ExampleStructureMass spectrumtPL
8
9
10(M++1) 392
11(M++1) 423
12(M++1) 410
13(M++1) 424

ExampleWith ructure Mass spectrumtPL
14
15M-408
16M-388

According to another variant embodiment of the invention the present invention relates to a method for producing the compounds defined above, the method includes:

a) interaction of the compounds of formula (IV)

with a compound HO-A-COY, in which R1, R2, R3, R4, R5A , b, Y and n are as defined above, and T means-SH or-HE, or

b) interaction of the compounds of formula (V)

connection (EtO)3RSN2-A-COY, in which R1, R2, R3, R4, R5A , b, Y and n are as defined above, or

C) the interaction of the compounds of formula (VI)

to connect the observed X-A-COY, in which R1, R2, R3, R4, R5A , b, Y and n are as defined above and X is halogen, or

g) the interaction of the compounds of formula (VII)

connection M-A-COY, in which M means HE or other10and R1, R2, R3, R4, R5, R10A , b, Y and n are as defined above.

In addition, the present invention relates to compounds of formula (I), defined above, are obtained by the process defined above.

The compounds of formula (I) can be obtained by the methods provided below, by the methods described in the examples or by analogous methods. Suitable reaction conditions for each particular stage of the reaction known to a person skilled in the art. Source materials are either commercially available or can be obtained by methods similar to the methods presented below or in the examples or by methods known from the prior art.

Compounds according to the present invention can be obtained by applying the methodology of the synthesis shown in schemes 1-6. Source materials required for producing compounds according to the present invention and the corresponding intermediate compounds are commercially available or can be obtained using the two well-known methods of synthesis. Methods of synthesis of compounds according to the present invention, different from that presented in figures 1-6, there will be immediately obvious to a person skilled in the art. Accordingly, the sequence of reactions for the synthesis presented in figures 1-6 are illustrative rather than exhaustive. Also in the present description by reference entirely included simultaneously filed patent application U.S. USSN 09/840486, filed April 23, 2001.

Specialists in the art will know that the key intermediate compound in the synthesis of the compounds of formula (I) is an alcohol of the formula (III)below, in which n, A, R1, R2, R3, R4and R5are the same as in the formula (I).

Scheme 1 illustrates a method of producing alcohols of the formula (III) in the case when means either oxygen or sulfur. Commercially available phenol or thiophenol 33 in turn alkene 35 or the equivalent of alkene (for example, a tertiary alcohol) via alkylation or accession by Michael (Michael). Intramolecular cyclization of Friedel-(for example, using AlCl3allows you to get indan 37. Education organometallics derived indana (for example, using n-utility) with PEFC is blowing the completion of the reaction using amide Weinrebe (Weinreb) allows to obtain a ketone, which can be transformed by the Wittig reaction (for example, with the use of halide methyltriphenylphosphonium and base) in the alkene 39. Conventional oxidation-hydroporinae (for example, using DIBORANE, hydrogen peroxide) results of alcohol 41 (=O or S).

Scheme 1

Figure 2 shows the derivation of the alcohols of the formula (III) in the case when means nitrogen, for example alcohols - derivatives of quinoline, 51. Commercially available 3-nitrophenylazo acid is subjected to esterification (for example, the esterification Fisher) and alkylate (for example, using cesium carbonate, alkylhalogenide), while receiving complex nitroethyl 45. Restore the nitrogroup (for example, using a metal catalyst and hydrogen) and carry out the acylation, while receiving alkanolamide 47, which after processing using the catalyst of the Friedel-(such as AlCl3) undergoes intramolecular cyclization with the formation of the alcohol 51 after recovery as ester and amide groups (for example, using lithium aluminum hydride). It should be noted that alcohol 51 can be turned into N-alkyl derivatives NR6by alkylation or reductive alkylation or otherwise, can be C sishen (for example, using urethane group, thioamide group and so on), if it is necessary for the subsequent conversion into the compound of formula (I).

Scheme 2

It should be noted that in schemes 3-6 values of n, a, b, Y, R1, R2, R3, R4and R5are as defined in formula (I), or a relevant protected predecessors. Usually compounds in which Y means SR7or NR8R9receive from acid-predecessor (Y=OH) by activation of the acid and the substitution of the appropriate nucleophile containing sulfur or nitrogen.

Figure 3 presents the transformation of alcohol 53 in the compound of formula (I), in which the linking group Z is an alkene. Preferably in the case when V=NR6and R6means hydrogen, the nitrogen atom is protected, before performing the above-described sequence of stages, and after the formation of the olefin protection removed (see, for example, Green et al., "Protective Groups in Organic Chemistry" (Wiley, 2nded., 1991)). Alcohol 53 oxidized to the aldehyde 55 (for example, using chloramine pyridinium or oxidation will Roll (Swern)), the obtained aldehyde interacts with phosphonate derivative 57 (for example, obtained by known methods, such as the substitution of halogen by trialkylphosphates) in the presence of a base with what rucenim directly derived 59.

Scheme 3

Figure 4 presents the transformation of alcohol 53 (=NR6, S, or O) in the compound of formula (I), in which the linking group Z is an ester (-C(O)O-) or amide (-C(O)NR10) group. As before, in the case when R6represents hydrogen, the nitrogen atom is protected, before performing the above-described sequence of stages, and remove the protection after the formation of ester or amide. Alcohol 53 oxidize to carboxylic acid 61 (for example, using pyridinium dichromate), which then activate (for example, using dicyclohexylcarbodiimide, dimethylaminopyridine) and result in interaction with compound 63 (M represents HE or other10), while receiving amide or ester 65 (X represents O or NR10).

Scheme 4

Figure 5 presents the transformation of alcohol 53 (=NR6, S, or O) in the compound of formula (I), in which the linking group Z is an alkyne (- ≡ -). As before, in the case when V=NR6and R6means hydrogen, the nitrogen atom is protected, before performing the above-described sequence of stages, and after the formation of the alkyne protection is removed. Alcohol 53 oxidized to the aldehyde 55, which communicates with ridom dibromethane 67 with about what adowanie this dibromodecane 69. Dibromsalan then turn to alkyne, which are then subjected to interaction with arylhalides or heteroarylboronic 71 to obtain the desired alkyne 73.

Scheme 5

Figure 6 illustrates the conversion of alcohol 53 (=NR6, S, or O) in the compound of formula (I), in which the linking group, Z represents an ether (-CH2O-) or thioester group (-CH2S-). As before, in the case when V=NR6and R6represents hydrogen, the nitrogen atom is protected, before performing the above-described sequence of stages, and remove the protection after the formation of the simple ester or simple tiefer. Alcohol 53 communicates with hydroxy 75 under the reaction conditions Mitsunobu (Mitsonobu) (for example, using triphenylphosphine and diethylazodicarboxylate) education directly ether 77. Alternatively, the alcohol 53 can be converted into a thiol 79 (for example, using thiourea, grounds and then hydrolysis with subsequent interaction with hydroxy 75 under the reaction conditions Mitsunobu with getting tiefer 79.

Scheme 6

As described above, the compounds of formula (I) according to the present invention can be used as drugs for treatment and/or prevention of obstructive disorders or disorders of the respiratory tract, cancer or dermatological disorders or disorders. The preferred violation or disorder of the respiratory tract is a chronic obstructive pulmonary disease, more preferably emphysema.

Thus, the present invention also relates to pharmaceutical compositions comprising the compound, which is described above, and a pharmaceutically acceptable carrier and/or excipient.

In addition, the present invention relates to compounds, which are described above, intended for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prevention of obstructive disorders or disorders of the respiratory tract, cancer or dermatological disorders or disorders.

In accordance with another embodiment the present invention relates to a method of treatment and/or prevention of obstructive disorders or disorders of the respiratory tract, cancer or dermatological disorders or disorder, the method includes introducing the compound, as defined above, a person or an animal.

The present invention also relates to the use of compounds as defined above for the treatment and/or prevention of obstructive disorders or disorders of the respiratory tract, cancer liedermaching disorders or disorders.

In addition, the present invention relates to the use of compounds as defined above, to obtain drugs for the treatment and/or prevention of obstructive disorders or disorders of the respiratory tract, cancer or dermatological disorders or disorders. Such drugs include connection, which is defined above.

Selective agonist of the receptor of retinoic acid compounds according to the present invention can be determined by analysis of the binding of ligands known to the person skilled in the art (Apfel et al., Proc. Natl. Acad. Sci., 1992, v.89, p.7129; Teng et al., J. Med. Chem., 1997, v.40, p.2445; U.S. patent No. 5807900 (Bryce et al.), these information sources included in the text of the application as references). Processing of RAR agonists, in particular RAR γ-agonists may promote restoration of alveolar matrix and forming the walls of the alveoli, which is important in the treatment of emphysema. It should be noted that RAR agonists, which are not γ-selective, can be effective in the treatment of emphysema.

Transactivation, which represents the ability of the retinoid to activate transcription of a gene, in the case where gene transcription is initiated by binding of a ligand to a specific receptor retinoic acid, which is subjected to the study, can be the ü determined using methods known from the prior art (Apfel et al., Proc. Natl. Acad. Sci., 1992, v.89, R; Bernard et al., Biochem. and Biophys. Res. Comm., 1992, v.186, p.977 included in the text of the application as a reference).

The use of compounds according to the present invention for the treatment of dermatological disorders and disorders caused by exposure to radiation or age-related changes, and to accelerate wound healing can be assessed using methods known from the prior art (Mustoe et al., Science, 1987, v.237, p.1333; Sprugel et al., J. Pathol., 1987, v.129, p.601 included in the text of the application as references). Methods known from the prior art, can be used to assess the potential use of compounds according to the present invention for the treatment of dermatological disorders and disorders, such as acne and psoriasis (Boyd, Am. J. Med., 1989, v.86, p.568, and references in this article, and Doran et al., Methods in Enzymology, 1990, v.190, p.34 included in the text of the application as references). In conclusion, the use of compounds according to the present invention for the treatment of cancer can also be determined using methods known from the prior art (Sporn et al., Fed. Proc., 1976, 1332; Hong et al., "Retinoids and Human Cancer" in: The Retinoids: Biology, Chemistry and Medicine, M.B.Sporn, A.B.Roberts and D.S.Goodman (eds.) Raven Press, New York, 1994, 597-630 included in the text of the application in the CA is este links).

Compounds according to the present invention, described in the text of the application can be used as promoters repair damaged alveoli and forming the walls of the alveoli. Thus, methods that are the subject of the present invention can be used to treat lung diseases such as emphysema. Methods of treatment, according to which use connections that are the subject of the present invention and described in the text of the application can also be used for the treatment of cancer and dermatological disorders and disorders.

When used for treatment or prevention of emphysema or related diseases, cancer or dermatological disorders and disorders, compounds according to the present invention can be introduced or applied separately or in combination with other agents. Compounds according to the present invention can be introduced or applied separately or in combination with other pharmaceutically active agents, including other compounds that are the subject of the present invention. The connection according to the present invention can be introduced or applied by itself or in the form of pharmaceutical compositions. The composition of a particular pharmaceutical composition will depend on the method used and obvious JV is the expert in this field of technology. From prior art it is known a large number of compositions for the introduction of retinoid agonists. Any of these compositions can be used for the preparation of compositions comprising a compound according to the present invention.

Pharmaceutical compositions comprising the compound according to the present invention, can be prepared using conventional methods of mixing, dissolving, granulating, production drops, rubbing the powder in the wet state, emulsification, the manufacture of capsules, enable or lyophilization. The pharmaceutical compositions can be manufactured in conventional manner using one or more physiologically acceptable carrier, diluent, excipient or excipients, which facilitates the manufacture of compositions for potential pharmaceutical use, based on the compounds according to the present invention. A suitable composition depends on the method of administration.

For local administration of the compound according to the present invention can be included in the composition, representing a solution, gel, ointment, cream, suspension, etc., the preparation of such compositions is well known from the prior art.

Compositions for systemic injections include such compositions, which is ispolneny suitable for administration by injection or infusion, for example, by subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as such compositions, which are suitable for transdermal, transmucosal, oral administration or administration into the lung. In the composition for systemic injections can be entered an additional active agent that improves mucociliary clearance of mucus in the respiratory tract or reduces the viscosity of mucus. Such active agents include, but are not limited to specified, blockers of sodium channels, antibiotics, N-acetylcysteine, homocysteine and phospholipids.

For injection, the compound according to the present invention can be included in the composition constituting the aqueous solution, preferably in physiologically compatible buffers such as solution Hank (Hank), ringer's solution (Ringer) or saline. The solution may contain an agent that facilitates the preparation of the composition, for example suspendisse, stabilizing and/or dispersing agents. Such compositions are preferably sterile.

Alternatively, compounds according to the present invention can be in powder form for the preparation before using the composition with a suitable carrier, such as sterile, containing no programada.

For transmucosal introduction in the composition are the agents that provide permeability through the barrier, through which you must pass. Such agents, providing permeability, well known from the prior art.

For oral administration the compound according to the present invention can be easily incorporated into the composition by combining with pharmaceutically acceptable carriers that are well known from the prior art. Such media can produce the formulation of the composition containing the compound according to the present invention and presented in the form of pellets, pastilles, pills, capsules, liquid formulations, gels, syrups, pastes, suspensions and similar compositions intended for oral administration the patient being treated. Suitable fillers for the manufacture of compositions in solid form, such as powders, capsules and pills include fillers like sugar, for example lactose, sucrose, mannitol and sorbitol; preparations of cellulose, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hypromellose, sodium salt of carboxymethylcellulose and/or polyvinylpyrrolidone (PVP); Agen is s for granulating and binding. If necessary, can be added to the agents contributing to the disintegration of dosage forms, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate. If necessary, the solid dosage form using known methods may be a coating of sugar or coating soluble in the gastrointestinal tract. Methods preparation of compositions containing a retinoid analogues and intended for oral administration, known from the prior art (see, for example, the composition "Accutane®", Physicians' Desk Reference 54thEd., p.2610, 2000).

In the case of liquid preparations for oral administration such as suspensions, elixirs or solutions, suitable carriers, excipients or diluents include water, saline, alkalophile (e.g., propylene glycol), polyalkylene glycols (e.g. polyethylene glycol), oils, alcohols, acid buffers, pH 4 to 6 (for example, acetate, nitrate, ascorbate, from about 5.0 mm to about 50,0 mm), etc. may be Optionally added substances that improve the taste and smell, preservatives, tinted substance, bile agar-agar, and similar acylcarnitine their substance.

If transbukkalno the introduction of the composition can be in the form of a tab is etok, candy, etc. made in the usual way.

Compounds according to the present invention it is also possible to enter directly into the lung by inhalation for the treatment of cancer, emphysema or dermatological disorders or disorders (see, for example, published application WO 97/39745 (Tong et al.); published application WO 99/47196 (Clark et al.), included in the text of this application by reference). For administration by inhalation, the compound which is the subject of the present invention, can be easily delivered to the lung using a number of different devices. For example, can be used dosing inhaler (MDI). Metered Dose Inhaler)that uses a canister containing a suitable low-boiling compressed fluid, for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, to deliver the compounds that are the subject of the present invention, in the lung. Device type dosing inhaler (MDI) are produced by a number of suppliers, for example, such companies as "ZM Corporation, Aventis, Boehringer Ingleheim", "Forest Laboratories, Glaxo-Wellcome", "Schering-Plough" and "Vectura".

Alternatively, for introduction into the lung compounds according to the present invention can be used device-inhaler dry powder (DPI). Dry Powder Inhler) (see, for example, Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, v.40, p.397 included in the text of the application as references). In the device DPI usually use a mechanism such as this, which provides the emission gas to create a "cloud" of dry powder inside a container, which is then through inhalation is administered to the patient. The DPI device is also well known from the prior art and can be purchased from several suppliers, which include, for example, "Fisons", "Glaxo-Wellcome", "Inhale Therapeutic Systems", "ML Laboratories", "Qdose" and "Vectura". The public option is repeatedly dosing inhaler dry powder (MDDPI). multiple dose DPI), which enables the delivery of more than one therapeutic dose. System device MDDPI can be purchased from such suppliers as "AstraZeneca", "GlaxoWellcome", "IVAX", "Schbering Plough", "SkyePharma and Vectura". For example, capsules and cartridges designed for use in an inhaler or apparatus for injection may be formulated in such a way that it will contain a powder mix of the compound which is the subject of the present invention and a suitable powder base, such as lactose or starch, intended for use in such systems.

Another type of device that can be used to deliver the compounds according to present the invention in light, is a device for the supply of liquid in aerosol form, which is made, for example, the firm "Aradigm Corporation. In the supply system of the liquid in aerosol form in the outlet only use small apertures, in order to turn into an aerosol of liquid drug, which can then directly be used for inhalation lung.

In accordance with one of preferred embodiments of the present invention the device is a nebulizer is used to deliver easy connection, which is the subject of the present invention. Sprayers are used to retrieve aerosol of liquid medication, using, for example, ultrasound energy in order to obtain fine particles, which can then easily be used for inhalation (see, for example, Verschoyle et al., British J. Cancer, 1999, 80, Suppl. 2, 96, included in the text of the application as references). Examples of nebulizers include devices manufactured by firms Sheffield/Systemic Pulmonary Delivery Ltd. (see U.S. patent No. 5954047 (Armer et al.); U.S. patent No. 5950619 (van der Linden et al.); U.S. patent No. 5970974 (van der Linden et al.), included in the text of the application as references), "Aventis and Batelle Pulmonary Therapeutics".

According to another preferred variant of the invention for delivery of the compounds according to the present invention in an easy to use electr the hydrodynamic device (EHD device) to retrieve aerosol. In the EHD device to retrieve aerosol use electrical energy to convert a liquid solution or suspension of the drug in the aerosol (see, for example, U.S. patent No. 4765539 (Noakes et al.); U.S. patent No. 4962885 (Coffee); and published application WO 94/12285 (Coffee); and published application WO 94/14543 (Coffee); and published application WO 95/26234 (Coffee), published application WO 95/26235 (Coffee), published application WO 95/32807 (Coffee), which are included in the text of the application as references). In that case, when using the EHD device for aerosol electrochemical properties of the drug, based on the connection which is the subject of the present invention, can be an important parameter in the optimization process of delivery of such compounds in the lung, and this optimization can be carried out in the usual way by a person skilled in the art. The use of EHD device for receiving an aerosol can allow for more effective delivery of drugs to the lung than the existing methods of delivery. Other shipping methods in the light of the compounds according to the present invention known to the specialist in the art and are included in the scope of the present invention.

Liquid compositions suitable for use in nebulizers, the device for producing an aerosol from the liquid and in EHD devices to receive the deposits of aerosol typically include connection which is the subject of the present invention, in combination with a pharmaceutically acceptable carrier. Preferably pharmaceutically acceptable carrier is a liquid, such as alcohol, water, polyethylene glycol or perfluorocarbons. Optional can be added to another substance in order to alter some properties of the solution or suspension of the compounds that are the subject of the present invention, which affect the formation of aerosol. Preferably the substance is a liquid, such as alcohol, glycol, polyglycol or fatty acid. Other methods of preparation of liquid solutions or suspensions of drugs that are suitable for use in apparatus for producing aerosol, well-known specialist in the art (see, for example, U.S. patent No. 5112598 (Biesalski); U.S. patent No. 5556611 (Biesalski)included in the text of the application as a reference).

The connection according to the present invention can also be used to produce compositions for rectal or vaginal administration, such as suppositories or retention enemas, for example, those that contain the usual bases for suppositories, such as cocoa butter or other glycerides.

In addition to the above-described compositions of the connection according to the present invention which may be used for the manufacture of drugs slow release (drug depot). Such long acting compositions can be introduced by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. For example, the connection according to the present invention can be used to obtain a composition with suitable polymeric or hydrophobic materials (for example, in the form of an emulsion in a suitable oil) or ion exchange resins, or in the form of poorly soluble derivatives, for example in the form of a poorly soluble salt.

Alternatively can be used in other pharmaceutical delivery system. Well-known examples of media that can be used to deliver the compounds according to the present invention are liposomes and emulsions. Can also be used in some organic solvents, such as dimethylsulfoxide, although usually at a cost of increased toxicity. The connection according to the present invention can also be delivered using a system with controlled release. In one of the embodiments may be used in the pump (Sefton, CRC Crit. Ref. Biomed. Eng., 1987, v.14, p.201; Buchwald et al., Surgery, 1980, v.88, p.507; Saudek et al., N. Engl. J. Med., 1989, v.321, p.574). In accordance with another embodiment can be used polymeric materials (see Medical Applications of Controlled Release, Langer and Wise (es.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem., 1983, V.23 supported, p.61; Levy et al., Science, 1985, v.228, p.190; During et al., Ann. Neurol., 1989, v.25, p.351; Howard et al., 1989, J. Neurosurg., v.71, p.105). According to another variant of the invention, the system controlled release can be placed close to the target for compounds that are the subject of the present invention, for example in the vicinity of the lung, which then requires only a part of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp.115 (1984)). Can be used in other systems controlled release (see, for example, Langer, Science, 1990, 249, 1527).

In the case where the connection which is the subject of the present invention has an acidic nature, it can be included in the above compositions in the form of the free acid, pharmaceutically acceptable salts, prodrugs, MES or hydrate. Pharmaceutically acceptable salts mainly retain the activity of the free acid and can be obtained by the interaction with substrates. Pharmaceutically acceptable salts include any suitable salt of retinoic acid, known from the prior art and used for the introduction of mammals. Pharmaceutically acceptable salts are generally more soluble in water and other the proton solvents, than the corresponding free acid. Similarly, the connection according to the present invention can be included in any of the above compositions in the form of MES, hydrate or prodrug. Preferred prodrugs include able to undergo hydrolysis derivatives - esters, such as aromatic esters, benzyl esters and lower alkalemia esters, such as ethyl, cyclopentylamine etc. Other prodrugs of known experts in the pharmaceutical field.

The connection according to the present invention or compositions based on these compounds generally used in amounts effective for achieving a given goal. Of course, you need to understand that the amount used will depend on the method of administration.

In the case of use for the treatment or prevention of chronic obstructive lung disease, such as emphysema, cancer and dermatological disorders or disorders, compounds according to the present invention or compositions on their basis is administered or applied in a therapeutically effective amount. The establishment of therapeutically effective amounts of compounds according to the present invention, used for systemic injections, may be based on a detailed disclosure of izaberete the Oia, presents the text of the application.

The pharmacokinetic profile of the compounds according to the present invention is predictable and can be described using linear pharmacokinetic theory. It is essential that the pharmacokinetics of the compounds according to the present invention for use in the case of a person can be easily installed by an expert in the field of technology. Ordinary specialist in the art can determine the interval of standard pharmacokinetic parameters after a single dosage of the compounds according to the present invention using methods known from the prior art (see, for example, Khoo et al., J. Clin. Pharm, 1982, v.22, p.395; Colbum et al., J. Clin. Pharm, 1983, V.23 supported, p.534; Colbum et al., Eur. J. Clin. Pharm., 1983, V.23 supported, p.689). Specialist in the art can also measure these pharmacokinetic parameters after multiple oral dosing, using methods known from the prior art, in order to determine whether there under these conditions, induction or accumulation of compounds according to the present invention (Brazzel et al., Eur. J. Clin. Pharm., 1983, v.24, p.695; Lucek et al., Clin. Pharmacokinetics, 1985, v.10, p.38). Specialist in the art can assess the appropriate dose level with the systemic administration for treatment of emphysema, cancer or dermatological drug is making or disorders in a mammal (preferably, people using pharmacokinetic parameters defined according to the above methods in accordance with the data regarding the dosage received on the animal model.

Dosage and time intervals can be selected individually, in order to ensure that the content of compounds in plasma, sufficient to maintain therapeutic effect. The usual dosage for administration to the patient by injection range from 0.1 mg to about 10.0 mg, preferably from about 1.0 microgram to about 1.0 mg, more preferably from approximately 10.0 μg to about 300,0 μg, most preferably from about to 50.0 μg to about 200 μg. Therapeutically effective content in the serum can be achieved with the introduction of a single daily dose or multiple doses each day.

The number of compounds according to the present invention, of course, will depend, among other factors, whether the subject being treated, the body weight of the subject, the severity of symptoms of the disease, the route of administration and the discretion of the attending physician. For example, the required dose can be delivered in the form of pharmaceutical compositions, single administration, with repeated use or when making a slow release. D. the licensing can be repeated periodically, may be an introduction only, alone or in combination with other drugs and may continue for as long as is necessary for effective treatment of emphysema.

Preferably a therapeutically effective dose of a compound according to the present invention described in the proposal, will provide a therapeutic effect without causing significant toxic effect. The toxicity of the compounds according to the present invention can be determined using standard pharmaceutical procedures and may be easily installed by an expert in the field of technology. The dose ratio with toxic and therapeutic effect, represents a therapeutic index. The connection according to the present invention preferably is characterized by a particularly high therapeutic indices in treating emphysema, cancer or dermatological disorders or disorders, in comparison with other retinoid agonists. The dosage of the compounds according to the present invention, which is described in the text of the application, preferably is in the range of circulating concentrations that include the effective dose, non-toxic or low toxicity. The dosage may vary within this interval in zavisimost and used dosage form and route of administration. The specific composition, the route of administration and dosage can be selected by the physician depending on the patient's condition (see, for example, Fingi et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch.1, p.1). For example, a therapeutically effective dose of a compound according to the present invention can be administered either orally or directly into the lung.

Examples

Further, the invention is illustrated by the following examples, which are described in detail obtaining the compounds and compositions according to the present invention. Specialist in the art it will be clear that, without going beyond the scope of the invention may be implemented many modifications, both in terms of substances and methods.

Example 1: synthesis of 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptyloxy]benzoic acid (racemic mixture)

Stage 1

A solution of 3-bromophenol (10.0 g, of 57.8 mmol) in 50 ml of ethyl acrylate is treated with 0.9 ml of Triton C. the Reaction mixture is refluxed for 18 hours. The excess ethyl acrylate distilled off at atmospheric pressure. The obtained residue was diluted using 50 ml of toluene, and evaporated. The remaining product was diluted with 100 ml ether and washed with two portions of 50 ml of a solution of sodium carbonate, 50 ml of water and 50 ml saturated aqueous solution of sodium chloride. The organic phase is Assiut over MgSO 4, filtered and concentrated in vacuo to obtain this pale yellow liquid substance. This product cleans Express chromatography (SiO2with 5% ethyl acetate in hexane)to give 6,435 g of ethyl ester of 3-(3-bromophenoxy)propionic acid as colorless liquid substance.

Stage 2

A solution of ethyl ester of 3-(3-bromophenoxy)propionic acid (6,435 g, 23.6 mmol) in 50 ml of anhydrous THF at 0°treated dropwise to 23.6 ml of 3 M solution of chloride Metalmania in THF. The reaction mixture was kept at 0°C for 30 minutes, allowed to warm to room temperature for 15 hours, gently stop the reaction by adding 100 ml of a saturated aqueous solution of ammonium chloride, and then extracted with three portions of ether, 50 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain this pale yellow oily substance. The product was then purified Express chromatography (SiO2, 20% ethyl acetate in hexane)to give 5,741 g of 4-(3-bromophenoxy)-2-methylbutane-2-ol as a transparent oily substance.

Stage 3

A solution of 4-(3-bromophenoxy)-2-methylbutane-2-ol (5,741 g of 22.2 mmol) in 45 ml of nitromethane is added dropwise to a suspension of aluminium chloride (4,019 g, to 30.1 mmol) in 45 ml of nitromethane. The reaction mixture was stirred at room temperature T. the value of two hours and then poured into 300 ml of ice water. The pH value was adjusted to 2.0 with 10%aqueous HCl solution, then the product is extracted with three portions of ether, 100 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain when this oily substance violet. The product was then purified Express chromatography (SiO2, 1% ethyl acetate in hexane), while receiving 4,667 g of 7-bromo-4,4-DIMETHYLPROPANE in the form of a colorless oily substance, which contains approximately 16% 5-bromo-4,4-DIMETHYLPROPANE.

Stage 4

A solution of 7-bromo-4,4-DIMETHYLPROPANE (1.0 g, 4,15 mmol) in 20 ml of THF at -78°With handle 1,91 ml of 2.5 M solution of utility. After 30 minutes at -78°to the solution add methoxyethylamine hexanoic acid (0,726 g, 4,56 mmol) in 5 ml of THF. The reaction mixture was stirred at -78°C for 30 minutes, warmed to room temperature, stop the reaction by adding 25 ml of a saturated aqueous solution of ammonium chloride, and extracted with three portions of ether and 25 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2with 5% ethyl acetate in hexane)to give 0,516 g of 1-(4,4-DIMETHYLPROPANE-7-yl)hexane-1-it is in the form of a colorless oily substance.

One hundred of the Oia 5

A suspension of the bromide methyltriphenylphosphonium (of 1.062 g of 2.97 mmol) in 20 ml THF at 0°treated dropwise 1.2 ml of a 2.5 M solution of utility. The mixture is stirred at room temperature for 30 minutes and then cooled to 0°C. To the solution ilide add a solution of 1-(4,4-DIMETHYLPROPANE-7-yl)hexane-1-it (0,516 g of 1.98 mmol) in 5 ml of THF. The reaction mixture was stirred at room temperature for one hour, stop the reaction by adding 25 ml of water and extracted with three portions of ether and 25 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow solid. The product was then purified Express chromatography (SiO2, 2% ethyl acetate in hexane)to give 0,442 g 4,4-dimethyl-7-(1-Methylenebis)chromane in the form of a colorless oily substance.

Stage 6

A solution of 4,4-dimethyl-7-(1-Methylenebis)chromane (0,442 g, 1,71 mmol) in 8 ml of THF at 0°With handle 1,71 ml of 1 M complex NR3·THF. The reaction mixture was stirred at room temperature for three hours and then cooled to 0°C. the Mixture was sequentially treated with 0.3 ml of water, 0,34 ml of 3 M sodium hydroxide solution and 0.34 ml of 30%hydrogen peroxide solution, stirred at room temperature for two hours and then diluted with 10 ml of water. The pH value was adjusted to 4.0, COI is lsua 10%solution of HCl, and extracted with three portions of ether, 12.5 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain this pale yellow oily substance. The product was then purified Express chromatography (SiO2, 10-20% ethyl acetate in hexane)to give 0,366 g of 2-(4,4-DIMETHYLPROPANE-7-yl)heptane-1-ol as a colorless oily substance.

Stage 7

A solution of 2-(4,4-DIMETHYLPROPANE-7-yl)heptane-1-ol (0,366 g of 1.32 mmol) in 27 ml of THF is treated 0,222 g of methyl ester of 4-hydroxybenzoic acid, 0,382 g of triphenylphosphine and 0.23 ml of diethylazodicarboxylate (DEAD). The reaction mixture is refluxed for two hours, diluted with 50 ml of ether and then washed with two portions of water to 25 ml and 25 ml saturated aqueous solution of sodium chloride. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2, 7% ethyl acetate in hexane)to give 0,474 g of methyl ester 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptyloxy]benzoic acid as a pale yellow oily substance.

Stage 8

A solution of methyl ester 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptyloxy]benzoic acid (0,474 g, 1.15 mmol) in 8 ml of ethanol is treated with a solution of potassium hydroxide (1.3 g) in 5 ml of water. Add Aut THF (4 ml) and the mixture is heated to 45° C for two hours, diluted with 20 ml water and the pH adjusted to 2 using concentrated HCl. The mixture is then extracted with three portions of ethyl acetate and 20 ml combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain this pale yellow foam substance. The product was then purified by recrystallization from a mixture of acetonitrile/water, getting 0,362 g of 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptyloxy]benzoic acid (1) in the form of a white solid. TPL 91,5-93,3°C.

Example 2: synthesis of 4-[2-(4,4-dimethylthiochroman-7-yl)heptyloxy]benzoic acid (racemic mixture)

Stage 1

A solution of 3-bromothiophene (5.0 g) in 60 ml of DMF is treated with 3.75 g of powdered potassium carbonate and 3.2 ml of 3,3-dimethylacrylamide. The reaction mixture was stirred at room temperature for two hours, poured into 75 ml of ice water, acidified to pH 2.0 using a 10%HCl solution and extracted with three portions of ether (75 ml Organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified by rapid distillation (T=170°s at 950 mtorr), receiving 5,651 g of 1-bromo-3-(3-methylbut-2-animalfunny)benzene as a colorless liquid.

Stage 2

A solution of 1-bromo-3-(3-methylbut-2-animalpen the l)benzene (5,651 g, 22 mmol) in 100 ml of toluene is treated 5,433 g monohydrate para-toluensulfonate acid and refluxed for 15 hours. The mixture is diluted with 100 ml of water, neutralized with solid sodium bicarbonate and extracted with two portions of ethyl acetate, 100 ml of the Organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified by rapid distillation (T=190°when 1,08 Torr), while receiving 4,902 g of 7-bromo-4,4-dimethylthiochroman in the form of a pale yellow oily substance, which contains approximately 20% of 5-bromo-4,4-dimethylthiochroman.

Stage 3

A solution of 7-bromo-4,4-dimethylthiochroman (2.0 g, 7,78 mmol) in 45 ml of THF at -78°process of 3.9 ml of 2.5 M solution of utility. After 30 minutes at -78°add a solution of methoxyethylamine hexanoic acid (1,486 g, was 9.33 mmol) in 5 ml of THF. The reaction mixture was stirred at -78°C for 30 minutes, warmed to room temperature, stop the reaction by adding 50 ml of a saturated aqueous solution of ammonium chloride and extracted with three portions of ether, 50 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2, 3% ethyl acetate in hexa is (e), getting 1,183 g of 1-(4,4-dimethylthiochroman-7-yl)hexane-1-it is in the form of a pale yellow oily substance.

Stage 4

A suspension of the bromide methyltriphenylphosphonium (2,293 g, 6.42 per mmol) in 40 ml THF at 0°treated dropwise 2,6 ml of 2.5 M solution of utility. The mixture is stirred at room temperature for 30 minutes and then cooled to 0°C. To the solution ilide add a solution of 1-(4,4-dimethylthiochroman-7-yl)hexane-1-it (1,183 g, to 4.28 mmol) in 10 ml of THF. The reaction mixture was stirred at room temperature for one hour, stop the reaction by adding 50 ml of water and extracted with three portions of ether, 50 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow solid. The product was then purified Express chromatography (SiO2, 1% ethyl acetate in hexane)to give 0,939 g 4,4-dimethyl-7-(1-Methylenebis)thiochroman in the form of a colorless oily substance.

Stage 5

A solution of 4,4-dimethyl-7-(1-Methylenebis)thiochroman (0,939 g of 3.42 mmol) in 15 ml THF at 0°process of 3.42 ml of 1 M complex NR3·THF. The reaction mixture was stirred at room temperature for three hours and then cooled to 0°C. the Mixture was sequentially treated with a 0.59 ml of water, of 0.67 ml of 3 M sodium hydroxide and 0.67 ml of 30%hydrogen peroxide solution. React the mixture was stirred at room temperature for two hours and then diluted with 20 ml of water. The pH value was adjusted to 4.0 using 10%HCl solution and then extracted with three portions of ether and 25 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain this pale yellow oily substance. The product was then purified Express chromatography (SiO2, 10% ethyl acetate in hexane)to give 0,532 g of 2-(4,4-dimethylthiochroman-7-yl)heptane-1-ol as a colorless oily substance.

Stage 6

A solution of 2-(4,4-DIMETHYLPROPANE-7-yl)heptane-1-ol (0,532 g, 1.82 mmol) in 35 ml of THF is treated 0,304 g methyl-4-hydroxybenzoate, 0,525 g of triphenylphosphine and 0.32 ml of diethylazodicarboxylate (DEAD). The reaction mixture is refluxed for two hours, diluted with 70 ml of ether and washed with two portions of water (35 ml and 35 ml of a saturated aqueous solution of sodium chloride. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2with 5% ethyl acetate in hexane)to give 0,715 g of methyl ester 4-[2-(4,4-dimethylthiochroman-7-yl)heptyloxy]benzoic acid as a pale yellow oily substance.

Stage 7

A solution of methyl ester 4-[2-(4,4-dimethylthiochroman-7-yl)heptyloxy]benzoic acid (0,715 g, by 1.68 mmol) in 12 ml of ethanol is treated concrete is potassium hydroxide (1.9 g) in 7.5 ml of water. Add THF (5 ml) and heat the mixture to 45°C for two hours, diluted with 30 ml of water and adjusted the pH value to 2.0 using concentrated HCl. The mixture is extracted with three portions of ethyl acetate and 30 ml of the Organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain this pale yellow foam substance. The product is distilled, pounding in pentane, and get 0,617 g of 4-[2-(4,4-dimethylthiochroman-7-yl)heptyloxy]benzoic acid as a white solid. TPL 123,0-123,5°C.

Example 3: synthesis of 4-[3-(4,4-DIMETHYLPROPANE-7-yl)Oct-1-enyl]benzoic acid (racemic mixture)

Stage 1

To a solution of oxalicacid (0.15 ml) in 9 ml of dichloromethane at -78°add to 0.19 ml DMSO. The mixture was stirred at -78°C for 5 minutes and then add a solution of 2-(4,4-DIMETHYLPROPANE-7-yl)heptane-1-ol (0,22 g, of 0.79 mmol, obtained according to example 1) in 3 ml dichloromethane. The mixture was stirred at -78°C for 15 minutes, then add of 0.56 ml of triethylamine. Stirring is continued at -78°C for another 15 minutes and then at room temperature for two hours. The reaction is stopped by adding 20 ml of water, extracted with three portions of dichloromethane 20 ml and the combined organic extracts are washed with two portions of water to 20 ml and 20 ml saturated aqueous RA the creators of sodium chloride. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2, 10% ethyl acetate in hexane)to give 0.16 g of 2-(4,4-DIMETHYLPROPANE-7-yl)heptanal in the form of a colorless oily substance.

Stage 2

A solution of methyl ester 4-(diethoxyphosphoryloxy)benzoic acid (0.25 g, 0.87 mmol) in 5 ml of THF at -20°With handle 0,88 ml of 1 M solution of bis(trimethylsilyl)amide lithium in hexane. The mixture is stirred at -20°C for 20 minutes before adding a solution of 2-(4,4-DIMETHYLPROPANE-7-yl)heptanal (0.16 g, of 0.58 mmol) in 5 ml of THF. The reaction mixture was stirred at -20°C for 30 minutes at room temperature for 6 hours, stop the reaction by adding 10 ml of a saturated aqueous solution of ammonium chloride and extracted with three portions of ethyl acetate and 10 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2, 10% ethyl acetate in hexane)to give 0.1 g of methyl ester 4-[3-(4,4-DIMETHYLPROPANE-7-yl)Oct-1-enyl]benzoic acid as a colorless oily substance.

Stage 3

A solution of methyl ester 4-[3-(4,4-DIMETHYLPROPANE-7-yl)Oct-1-enyl]Ben is oinoi acid (0.1 g, 0.25 mmol) in 25 ml of a mixture of THF/methanol in the ratio of 4:1 is treated with a solution of 0.1 g of the monohydrate of lithium hydroxide in 5 ml of water. The reaction mixture was stirred at 40°C for 2 hours, concentrated in vacuo and the pH adjusted to 3-4 using 1 HCl solution. The mixture is extracted with three portions of ethyl acetate and 25 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain at that 0.06 g of 4-[3-(4,4-DIMETHYLPROPANE-7-yl)Oct-1-enyl]benzoic acid as a colourless glassy oil substance. Mass spectrum (EI): (M--1) 391.

Example 4: synthesis of 4-[3-(4,4-dimethylthiochroman-7-yl)Oct-1-enyl]benzoic acid (racemic mixture)

According to the method described in example 3, but replacing in stage 1 of 2-(4,4-DIMETHYLPROPANE-7-yl)heptane-1-ol for 2-(4,4-dimethylthiochroman-7-yl)heptane-1-ol (obtained according to example 2), receive a 4-[3-(4,4-dimethylthiochroman-7-yl)Oct-1-enyl]benzoic acid as a colourless glassy oil substance. Mass spectrum (EI): (M--1) 407.

Example 5: synthesis of 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid (racemic mixture)

Stage 1

A solution of 3-nitrophenylarsonic acid (12,755 g of 70.4 mmol) in 150 ml of ethanol is treated with a 3.83 ml of concentrated sulfuric to the slots. The reaction mixture is refluxed for 20 hours, concentrated in vacuo to 1/3 the original volume and diluted with using 250 ml of ethyl acetate. The organic solution is successively washed with two portions of water, 100 ml, two portions of saturated aqueous sodium bicarbonate solution, 100 ml, 100 ml water and 100 ml saturated aqueous solution of sodium chloride. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain this 14,69 g of ethyl ester of 3-nitrophenylarsonic acid in the form of a pale yellow oily substance.

Stage 2

A solution of ethyl ester of 3-nitrophenylarsonic acid (4.0 g, 19,1 mmol) in 80 ml of DMF is treated 12,46 g of cesium carbonate and 2.55 ml of pentaiodide. The reaction mixture was stirred at room temperature for 15 hours, diluted with 200 ml of water and extracted with three portions of ether in 150 ml the combined organic extracts are washed with 200 ml of water and 200 ml of a saturated aqueous solution of sodium chloride. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2with 5% ethyl acetate in hexane)to give 4,451 g of ethyl ester of 2-(3-nitrophenyl)heptane acid in the form of a pale yellow oily substance.

Stage 3

A solution of ethyl ester of 2-(3-nitrophenyl)heptane acid (4,451 g, 15.9 mmol) in 150 ml of ethyl acetate containing 1,69 g 10%palladium on carbon is exposed to hydrogen at atmospheric pressure for 15 hours. The mixture is filtered through a layer of celite/SiO2and remove volatiles in vacuum, obtaining 3,866 g of ethyl ester of 2-(3-AMINOPHENYL)heptane acid in the form of a pale yellow oily substance.

Stage 4

A solution of ethyl ester of 2-(3-AMINOPHENYL)heptane acid (3,866 g of 15.5 mmol) in 40 ml of chloroform is treated with 1.73 ml of 3,3-dimethylacrylamide. The mixture is refluxed for four hours, stop the reaction by adding 100 ml of water and extracted with three portions of chloroform, 50 ml the combined organic extracts are washed with 100 ml saturated aqueous sodium bicarbonate solution, 100 ml of water and 100 ml saturated aqueous solution of sodium chloride. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2, 15% ethyl acetate in hexane)to give 3,822 g of ethyl ester of 2-[3-(3-methylbut-2-anolamine)phenyl]heptane acid in the form of a pale yellow oily substance.

Stage 5

A solution of ethyl ester of 2-[3-(3-methylbut-2-anolamine)phenyl]heptane acid(3,822 g, 11.5 mmol) in 60 ml of dichloromethane is treated 4,613 g of aluminium chloride and refluxed for four hours. The reaction mixture is poured into 200 ml of ice water and extracted with two portions of dichloromethane, 100 ml the combined organic extracts are washed with 200 ml saturated aqueous sodium bicarbonate solution. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2, 25% ethyl acetate in hexane)to give to 3.657 g of ethyl ester of 2-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)heptane acid in the form of a pale yellow oily substance.

Stage 6

A solution of 2-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)heptane acid (to 3.657 g, 11 mmol) in 100 ml of ether is treated with 1.6 g of lithium aluminum hydride, is refluxed for four hours and then cooled to 0°C. the Reaction is stopped by the sequential addition of 1.6 ml of water, 1.6 ml of 15%sodium hydroxide solution and 4.8 ml of water and stirred at room temperature until a precipitate appears. Add MgSO4then the mixture is filtered and concentrated in vacuo, while receiving a yellow oily substance. The product was then purified Express chromatography (SiO2, 25% ethyl acetate in hexane)to give 2.1 a is 2-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptane-1-ol as a pale yellow oily substance.

Stage 7

A solution of 2-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptane-1-ol (2.1 g, 7.62 mmol) in 30 ml THF is treated with 32 ml of 1 M solution of bis(trimethylsilyl)amide sodium in THF. The reaction mixture was stirred at room temperature for 30 minutes and then add a solution of 3.5 g of di-tert-BUTYLCARBAMATE in 30 ml of THF. The mixture is stirred at room temperature for 15 hours, stop the reaction by adding 100 ml of a saturated aqueous solution of ammonium chloride and extracted with three portions of ether, 100 ml the combined organic phases are dried over MgSO4, filtered and concentrated in vacuo to obtain this orange oily substance. The residue is placed in 100 ml of methanol and treated with 10 ml of 1%aqueous potassium carbonate solution. The mixture is stirred at room temperature for two hours, concentrated in vacuo and the residue diluted with 200 ml of ether. The organic solution was washed with two portions of water 100 ml and 100 ml saturated aqueous solution of sodium chloride. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain this dark yellow oily substance. The product was then purified Express chromatography (SiO2, 10% ethyl acetate in hexane)to give 0,757 g tert-butyl ester 7-(1-hydroxymethylene)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-karbonvansty in the form of a yellow oily substance.

Stage 8

A solution of tert-butyl ester 7-(1-hydroxymethylene)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (1.27 g, to 3.38 mmol) in 10 ml of dichloromethane is added to a suspension of 1.1 g Harrogate pyridinium in 15 ml of dichloromethane. The reaction mixture was stirred at room temperature for 6 hours, diluted with 50 ml of ether and filtered through a layer of celite. Volatiles are removed under vacuum obtaining in this brown oily substance. The product was then purified Express chromatography (SiO2with 5% ethyl acetate in hexane)to give 0,91 g tert-butyl ester 7-(1-formigenes)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid as a yellow oily substance.

Stage 9

A solution of methyl ester 4-(dimethoxyphosphoryl)benzoic acid (0,94 g, 3.6 mmol) in 10 ml of THF at -20°treated with 3.7 ml of 1 M solution of bis(trimethylsilyl)amide lithium in hexane. After 20 minutes at -20°add a solution of tert-butyl ester 7-(1-formigenes)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (of 0.91 g, 2.4 mmol) in 5 ml of THF. The reaction mixture was stirred at -20°C for 30 minutes, at room temperature for 6 hours, then stop the reaction by adding 10 ml of a saturated aqueous solution of ammonium chloride and extracted with three portions of ethyl acetate and 10 ml the combined organic extracts dried the hell MgSO 4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2with 5% ethyl acetate in hexane)to give 0,98 g of tert-butyl methyl ether 7-{1-[2-(4-ethoxycarbonylphenyl)vinyl]hexyl}-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid as a pale yellow oily substance.

Stage 10

A solution of tert-butyl methyl ether 7-{1-[2-(4-ethoxycarbonylphenyl)vinyl]hexyl}-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (0,98 g) in 10 ml of dichloromethane is treated with 1.5 ml triperoxonane acid. The mixture is stirred at room temperature for four hours and then concentrated in vacuo, getting to 0.72 g of methyl ester 4-[3-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid as a yellow oily substance.

Stage 11

A solution of methyl ester 4-[3-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid (0.36 g, 0.88 mmol) in 10 ml of THF is cooled to -78°and treated With 1.1 ml of 1 M solution of bis(trimethylsilyl)amide lithium in hexane. After 30 minutes at -78°With added 0.06 ml under the conditions. The mixture is stirred at room temperature for 7 hours, stop the reaction by adding 10 ml of a saturated aqueous solution of ammonium chloride and extracted with two portions of ethyl acetate and 10 ml the combined organic is their extracts are dried over MgSO 4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2with 5% ethyl acetate in hexane)to give to 0.23 g of methyl ester 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid as a pale yellow oily substance.

Stage 12

A solution of methyl ester 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid (0,23 g, 0.5 mmol) in 10 ml of a mixture of THF/methanol in a ratio of 1:1 is treated with a solution of 0.09 g of the monohydrate of lithium hydroxide in 2.5 ml of water and stirred at 40°C for 6 hours. The mixture is diluted with 10 ml water and the pH value was adjusted to 2.0 using 2 HCl solution. The mixture is extracted with three portions of ethyl acetate and 10 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified preparative thin-layer chromatography (TLC) (SiO2, 25% ethyl acetate in hexane)to give 0,095 g of 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid as a pale yellow oily substance. Mass spectrum (EI): (M+) 405.

Example 6: synthesis of 4-[3-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid (racemic mixture)

SL is blowing technique, described in example 5.5, but replacing at stage 11 methyliodide on ethyliodide receive 4-[3-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid as a pale yellow oily substance. Mass spectrum (EI): (M+1) 421.

Example 7: synthesis of 4-[3-(1,4,4)-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Penta-1-enyl]benzoic acid (racemic mixture)

Following the method described in example 5.5, but replacing in stage 2 of pentolite on ethyliodide receive 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Penta-1-enyl]benzoic acid as a pale yellow oily substance.

Example 8: synthesis of 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)undec-1-enyl]benzoic acid (racemic mixture)

Following the procedure described in example 5, but replacing in stage 2 of pentolite on actilite receive 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)undec-1-enyl]benzoic acid as a pale yellow oily substance.

Example 9: synthesis of 4-[4-phenyl-3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)but-1-enyl]benzoic acid (racemic mixture)

Following the method described in example 5.5, but replacing in stage 2 of pentolite on benzylbromide receive 4-[4-phenyl-3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)but-1-enyl]benzoic acid is ledno-yellow oily substance.

Example 10: synthesis of 4-[3-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid (racemic mixture)

Following the method described in example 5.5, but without holding stage 11 (no N-alkylation), receive 4-[3-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid as a pale yellow oily substance. Mass spectrum (EI): (M++1) 392.

Example 11: synthesis of 3-fluoro-4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid (racemic mixture)

Following the method described in example 5.5, but replacing at stage 9 methyl ester 4-(dimethoxyphosphoryl)benzoic acid methyl ester 3-fluoro-4-(dimethoxyphosphoryl)benzoic acid, receive 3-fluoro-4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid as a pale yellow oily substance. Mass spectrum (EI): (M++1) 423.

Example 12: synthesis of 4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptyloxy]benzoic acid (racemic mixture)

Stage 1

A solution of 2-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptane-1-ol (obtained according to example 5.5, stage 6) (2,52 g, to 9.15 mmol) in 35 ml of acetonitrile cooled to 0°and process of 6.68 ml of 37%solution of formaldehyde, of 5.82 g triacetoxyborohydride and a 2.36 ml of acetic acid. The reaction mixture was stirred at 0°C for 30 minutes, then at room temperature for four hours, diluted with 50 ml of water and extracted with two portions of 50 ml. ethyl acetate the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2, 25% ethyl acetate in hexane)to give 2,39 g 2-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptane-1-ol as a pale yellow oily substance.

Stage 2

A solution of 2-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptane-1-ol (1.2 g, 4,15 mmol) in 20 ml of THF is treated 0,69 g methyl-4-hydroxybenzoate, 1.2 g of triphenylphosphine and 0.72 ml of diethylazodicarboxylate (DEAD), then refluxed for 6 hours. The mixture is diluted with 100 ml ethyl acetate and washed with two portions of water, 50 ml and 50 ml saturated aqueous solution of sodium chloride. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2, 10% ethyl acetate in hexane)to give 1.1 g of methyl ester 4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptyloxy]benzoic acid as a pale yellow oily substance.

Stage 3

Rast is the PR methyl ester 4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptyloxy]benzoic acid (1.1 g, 2.6 mmol) in 14 ml of a mixture of THF/methanol in a ratio of 1:1 is treated with a solution of 0.44 g of the monohydrate of lithium hydroxide in 5 ml of water and stirred at 40°C for 6 hours. The mixture is diluted with 20 ml water and the pH value was adjusted to 2.0 using 2 HCl solution. The mixture is extracted with three portions of ethyl acetate and 20 ml combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified preparative TLC (SiO2, 25% ethyl acetate in hexane)to give 0,875 g of 4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptyloxy]benzoic acid as a pale yellow oily substance. Mass spectrum (EI): (M++1) 410.

Example 13: synthesis of 4-[2-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptyloxy]benzoic acid (racemic mixture)

Following the procedure described in example 5.12, but replacing in stage 1 formaldehyde to acetaldehyde, receive a 4-[2-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptyloxy]benzoic acid as a pale yellow oily substance. Mass spectrum (EI): (M++1) 424.

Example 14: synthesis of 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid

Stage 1

A solution of 2-(4,4-DIMETHYLPROPANE-7-yl)heptane-1-ol (0.2 g, to 0.72 mmol), obtained according to example 5.1, tadia 6, 1.5 ml of CCl4and 2.2 ml of water containing 4 mg RuCl3handle using 628 mg (2,94 mmol) NaIO4. The mixture is stirred at room temperature for 2.5 h, diluted with 10 ml water and the pH adjusted to 2 using 10%aqueous HCl solution. The mixture is extracted with dichloromethane, concentrated to dryness and purified Express chromatography (0-20%ethyl acetate/hexane, elution with a gradient), while receiving 105 mg (50%) 2-(4,4-DIMETHYLPROPANE-7-yl)heptane acid.

Stage 2

A solution of 2-(4,4-DIMETHYLPROPANE-7-yl)heptane acid (105 mg, 0.36 mmol) in 5 ml of dichloromethane containing of 91.6 mg, 0.4 mmol of benzyl ester of 4-hydroxybenzoic acid and 44 mg, 0.36 mmol, DMAP (4-dimethylaminopyridine), cooled to 0°and treated With 83 mg, 0.4 mmol, DCC (N,N'-dicyclohexylcarbodiimide). The mixture was kept at 0°C for 15 minutes, then warmed to room temperature. After 2 hours the mixture is filtered and the resulting solution was washed with water and saturated salt solution. The solution is dried and concentrated, then purified Express chromatography (8% ethyl acetate/hexane) to obtain this 152 mg (84%) of benzyl ester 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid.

Stage 3

A solution of benzyl ester 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid (152 mg, 0.3 mmol) in 10 ml of ethyl acetate, containing the 32 mg of 10%palladium on carbon, exposed to H2at a pressure of 1 ATM. After 2 hours the mixture is filtered through celite and silica gel, concentrated under vacuum and purified Express chromatography (elution using a gradient of 10-50% ethyl acetate/hexane) to give 74 mg (59%) of 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid.

Example 15: synthesis of 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid

Stage 1

To a solution of 2-(4,4-DIMETHYLPROPANE-7-yl)heptane-1-ol (0.27 g, 0.98 mmol, obtained according to example 1, step 6) in a mixture of 2 ml of carbon tetrachloride, 2 ml of acetonitrile and 3 ml of water containing 3-5 mg of ruthenium chloride, add 0,85 g periodate sodium. The mixture is stirred at room temperature for 2 hours, diluted with 10 ml water and the pH adjusted to 2 using a 10%solution chloroethanol acid. The mixture is extracted with three portions of dichloromethane and 10 ml of the Organic phase is dried over MgSO4,filter and concentrate under vacuum, thus obtaining a dark oily substance. The product was then purified Express chromatography (SiO2, gradient from 0 to 20% ethyl acetate in hexane)to give 0.16 g of 2-(4,4-DIMETHYLPROPANE-7-yl)heptane acid in the form of a pale yellow oily substance.

Stage 2

A solution of 2-(4,4-DIMETHYLPROPANE-7-yl)heptane acid (0.16 g, 0.55 mmol) in 8 ml of d is of chloromethane treated with 1 ml of oxalicacid and 0.06 ml of DMF. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue is dissolved in 5 ml of pyridine and added 0.17 g of methyl ester of 4-aminobenzoic acid. The reaction mixture was stirred at 40°C for 18 hours, diluted with 10 ml of water and extracted with three portions of ethyl acetate and 10 ml combined extracts are washed with 10 ml of 1 n solution chloroethanol acid, 10 ml water and 10 ml of saturated salt solution. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain when this oily substance. The product was then purified Express chromatography (SiO2, 20% ethyl acetate in hexane)to give 0.15 g of methyl ester 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid as a white foam substance.

Stage 3

A solution of methyl ester 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid (0.15 g, 0.35 mmol) in 10 ml of a mixture of THF/methanol in the ratio of 4:1, is treated with a solution of 0.1 g of the monohydrate of lithium hydroxide in 2.5 ml of water and stirred at 40°C for 6 hours. The mixture is diluted with 10 ml water and the pH value was adjusted to 2.0 using 2 HCl solution. The mixture is extracted with three portions of ethyl acetate and 10 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain this yellow is th oily substance. The product was then purified Express chromatography (SiO2, 10% methanol in dichloromethane)to give 0.11 g of 4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid as a white powder. Mass spectrum (ESI - ionization electrospray): (M-) 408.

Example 16: synthesis of 4-[3-(4,4-dimethyl-1,3,3,4-tetrahydroquinolin-7-yl)Oct-1-inyl]benzoic acid

Stage 1

To a solution of tetrabromide carbon (0.32 g, 0.96 mmol) in 5 ml of dichloromethane at -20°add triphenylphosphine in 5 ml of dichloromethane. After stirring at 0°C for 15 minutes, the reaction mixture is treated with a solution of tert-butyl ester 7-(1-formigenes)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (0.18 g, 0.48 mmol, obtained according to example 5, step 8) in 2 ml of dichloromethane. The reaction mixture was stirred at room temperature for 4 hours, stop the reaction by sequential addition of 5 ml of water and 1.5 ml of saturated sodium bicarbonate solution. The phases are separated and the aqueous phase is extracted with two portions of dichloromethane and 25 ml of the Organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain this brownish viscous oily substance. The product was then purified Express chromatography (SiO2, 20% ethyl acetate in hexane)to give 0.08 g of tert-butyl EPE is 7-(3,3-dibromo-1-partially)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid as colorless oily substance.

Stage 2

A solution of tert-butyl ester 7-(3,3-dibromo-1-partially)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (0.08 g, 0.15 mmol) in 2 ml THF at -78°treated with 0.13 ml of 2.5 M solution of utility. The reaction mixture was stirred at -78°C for 1 hour, then at room temperature for 2 hours, stop the reaction by sequential addition of 5 ml water and 5 ml of a saturated aqueous solution of ammonium chloride and extracted with three portions of ether and 25 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2with 5% ethyl acetate in hexane)to give 0,049 g of tert-butyl methyl ether of 4,4-dimethyl-7-(1-intelprop-2-inyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid as colorless oily substance.

Stage 3

The mixture 0,043 g of methyl 4-iodobenzoate, 0,093 ml of triethylamine, and 4.6 mg of Pd(Ph3P)2Cl2and 2.5 mg of copper iodide (I) in 2 ml of DMF Tegaserod and treated with a solution of tert-butyl methyl ether of 4,4-dimethyl-7-(1-intelprop-2-inyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid (0,049 g, 0.13 mmol) in 1 ml DMF. The reaction mixture was stirred at room temperature for 18 hours, diluted with 10 ml of water and extracted with three portions of ethyl acetate and 10 ml of the combined organization is systematic extracts are washed with 10 ml of 1 N. HCl solution, 10 ml of water and 10 ml of saturated salt solution, dried over MgSO4, filtered and concentrated in vacuo to obtain as a yellow oily substance. The product was then purified Express chromatography (SiO2, 10% ethyl acetate in hexane)to give 0.035 g of tert-batibot ether 7-[3-(4-ethoxycarbonylphenyl)-1-intelprop-2-inyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid.

Stage 4

A solution of tert-butyl methyl ether 7-[3-(4-ethoxycarbonylphenyl)-1-intelprop-2-inyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (0.035 g, 0.07 mmol) in 5 ml of a mixture of THF/methanol in the ratio of 4:1, is treated with a solution of 0.1 g of the monohydrate of lithium hydroxide in 2 ml of water and stirred at 40°C for 2 hours. The mixture is diluted with 5 ml water and the pH adjusted to 2 using 2 HCl solution. The mixture is extracted with three portions of ethyl acetate and 10 ml the combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain at that 0.03 g of tert-bouteloua ether 7-[3-(4-carboxyphenyl)-1-intelprop-2-inyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid as a yellow oily substance.

Stage 5

A solution of tert-butyl methyl ether 7-[3-(4-carboxyphenyl)-1-intelprop-2-inyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (0.035 g, 0.07 mmol) in 2 ml of a mixture of TFU/dichloromethane, 1:1 ratio, per mesilat for 30 minutes and concentrated. The residue is dissolved in 5 ml of dichloromethane and washed with 5 ml saturated sodium bicarbonate solution, 5 ml of water and 5 ml of saturated salt solution, the organic layer is dried over MgSO4, filtered and concentrated in vacuo to obtain at that 0.02 g of 4-[3-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-inyl]benzoic acid in the form of a brown oily substance. Mass spectrum (ESI): (M-) 388.

Biological studies

Assessment of binding to retinoid receptors and the study of TRANS-activation of retinoid receptors

Selective agonist of the receptor of retinoic acid compounds according to the present invention can be determined by analysis of binding of a ligand known to the person skilled in the art (Apfel et al., Proc. Natl. Acad. Sci., 1992, v.89, p.7129; Teng et al., J. Med. Chem., 1997, v.40, p.2445; Bryce et al., U.S. patent No. 5807900 included in the text of the application as references). Treatment with agonists of receptors RAR, particularly RAR γ-agonists, promotiom restore alveolar matrix and the restoration of the walls of the alveoli, which is essential in the treatment of emphysema. It should be noted that RAR agonists, which are not γ-selective, can be effective for the treatment of emphysema.

Transactivation, which represents the ability of the retinoid to activate transcription of the gene in the second case, when the transcription of the gene is initiated by the binding of ligand to a specific receptor retinoic acid, which to be evaluated can be determined using methods known from the prior art (Apfel et al., Proc. Natl. Acad. Sci., 1992, v.89, R; Bernard et al., Biochem. And Biophys. Res. Comm., 1992, v.186, p.977 included in the text of the application as a reference).

Compounds according to the present invention are characterized by the values of the IC50located in the interval from 0.1 to 10 μm. Indicators linking of some compounds according to the present invention is given below.

ExampleStructureBinding, IC50nm

α/β/γ
13921/3162/3768
22065/3005/3226
36920/2919/3868
41579/1487/2326
51455/1938/1417
61284/1474/1000
7 3386/1053/>10000

105139/8272/6390
116287/3263/4064
123174/4146/5436
132516/3125/3603

Investigation of dermatological and anti-cancer properties

The use of compounds according to the present invention for treatment of age-related skin damage and skin damage caused by exposure to light, and to accelerate wound healing can be determined using methods known from the prior art (Mustoe et al., Science, 1987, v.237, p.1333; Sprugel et al., J. PathoL, 1987, v.129, 601, included in the text of the application as references). Methods known from the prior art, can be applied to determine whether the use of the compounds according to the present invention for the treatment of dermatological disorders or disorders, such as acne or psoriasis (Boyd, Am. J. Med., 1989, v.86, p.568, and the links provided in this article; Doran et al., Methods in Enzymology, 1990, v.190, p.34 included in the text of the application as references). In conclusion, the use connected the th according to the present invention for the treatment of cancer can be determined using techniques known from the prior art (Sporn et al., Fed. Proc., 1976, 1332; Hong et al., "Retinoids and Human Cancer" in The Retinoids: Biology, Chemistry and Medicine, M.B. Sporn, A.B. Roberts and D.S. Goodman (eds.) Raven Press, New York, 1994, 597-630 included in the text of the application as a reference).

Measuring recovery of alveoli in the lung of rats when exposed to the compounds according to the present invention

Can be measured indicators of the impact of the compounds according to the present invention for the restoration of the alveoli on the model in rats emphysema induced elastases (Massaro et al., Nature, 1997, vol.3, No.6: p.675; Massaro et al., U.S. patent No. 5998486). Preferably, the animals are divided into groups to research approximately eight animals. Inflammation of the lung and damage to the alveoli can be induced in rats-males line Sprague Dawley single infusion of approximately 2 Units/gram body mass pancreatic elastase (isolated from pigs, "Calbiochem").

Animals can be treated by the compounds according to the present invention, used in the composition with megliola ("Miglyol") using the usual dosage interval (preferably from about 10.0 to 0,0001 mg/kg), animals can be entered dosage for oral administration once a day, beginning with the 21st day after the damage. The control group provoke elastases and through 21 de the animals ü receive filler ("Miglyol") within 14 days. Animals sacrificial 24 hours after they received the last dose by exsanguination under deep anesthesia. Blood during bleeding collected for analysis.

Lungs by intratracheal injection with 10%buffered formalin at a constant speed (1 ml/g body weight/min). Easy excised and immersed in the fixer for 24 hours before processing. For preparation of standard 5 µm paraffin sections using conventional techniques. Sections stained with hematoxylin and eosin. Measurement of alveolar indicators is carried out in four areas of the lung in rats through computer-assisted morphometric analysis. The average value for the group under study can be determined by summing the average area per rat determined based on eight rats in groups exposed to processing, and the rate of recovery of damage elastases, expressed as percentage recovery relative to the group treated with the elastase and the filler, based on the following calculation results:

% recovery of alveoli:

The data for 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid, compound 9.

Dose [μg/kg], r.o. The restoration of the alveoli, %
10060,9
1054
165

EXAMPLES of COMPOSITIONS

Composition for oral administration

Table 2 shows the ingredients for the preparation of dosage forms - tablets containing compound according to the present invention.

Table 2
ComponentQuantity per tablet (mg)
The connection according to the present invention0,1-10,0
Lactose125,0
Corn starch50
Magnesium stearate0,5
Croscarmellose, sodium salt25

Active ingredient (i.e. the connection according to the present invention) is mixed with the lactose until a uniform mixture. The rest of the ingredients are thoroughly mixed with the above mixture containing lactose, and then subjected to pressing, making this tablet one notch.

Composition for oral administration

Capsules containing the compound according to the present invention is suitable for treatment of emphysema, prepared using ingred the clients, presented in table 3.

Table 3
ComponentAmount per capsule (mg)
The connection according to the present invention0,1-5,0
Lactose148
Magnesium stearate2

The above ingredients are thoroughly mixed and placed in a hard gelatin capsule.

Composition for the preparation of suspensions

Table 4
ComponentNumber
The connection according to the present invention0.1 to 1.0 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Granulated sugar25,5 g
Sorbitol (70%solution)is 12.85 g
"Veegum" (firm "Vanderbilt Co.")1.0 g
Substances that improve the taste and smella 0.035 ml
Tinted substance0.5 mg
Distilled waterThe quantity n is necessary, in order to bring the volume to 100 ml

The above ingredients listed in table 4, are mixed together to receive the suspension for oral administration.

Composition for injection

Table 5
ComponentNumber
The connection according to the present invention0.02 g-0.2 g
Buffer solution of sodium acetate, 0.4 M2.0 ml
HCl (1 BC) or NaOH (1 BC)The amount needed to reach the appropriate pH values
Distilled waterThe amount needed to bring the volume to 20 ml

The above ingredients listed in table 5 are mixed to obtain the composition for injection. Composition for injection

Table 6
ComponentQuantity (mg/ml)
The connection according to the present invention2,0-20
Citric acid0,2
Sodium citrate2,6
The benzalkonium chloride0,2
SorbitolTaurocholate or glycolate sodium10

The above ingredients are mixed to obtain the composition for injection.

Composition for nasal introduction

Table 7
ComponentNumber
The connection according to the present invention0.2 g
Buffer solution of sodium acetate, 0.4 M2.0 ml
HCl (1 BC) or NaOH (1 BC)The amount needed to bring the volume to a suitable pH
Distilled or sterile waterThe amount needed to bring the volume to 20 ml

The above ingredients are mixed together to receive the suspension for nasal administration.

Composition for inhalation

Table 8
ComponentThe percentage (by weight)
The connection according to the present invention (stable α-tocopherol)1,0
1,1,2-Trichlorotrifluoroethane26,1
40% by weight of DICHLORODIFLUOROMETHANE and 60% by weight of 1,2-dichloro-1,1,2,2-is straftaten 72,0

The connection according to the present invention thoroughly dissolved in 1,1,2-trichloro-1,2,2-triptoreline, avoiding evaporation of the solvent, and the resulting solution is filtered and stored in an airtight container. The resulting solution and liquefied gas to obtain the aerosol is introduced into a spray bottle for spraying, as a percentage, which is shown in table 8, using methods known to the person skilled in the art. To deliver the appropriate dosage of the compounds according to the present invention can be used metering valve, which is designed so that one injection was applied from 100 to 300 mcg.

Composition based on compounds according to the present invention, intended for inhalation

Table 9
ComponentThe percentage (by weight)
The connection according to the present invention (stable α-tocopherol)0,5
Emulsifier (for example, Cremophor RH 40")22,0
1,2-Propylene glycol2,0
Water and carrier gasThe rest (add up to 100% by weight)

"Cremaphor RH 40" can be purchased from the Irma BASF. From the prior art and other known emulsifiers or contribute to the preparation of the solution, which can be added to aqueous solution instead of the product "Cremaphor RH 40". The connection according to the present invention, the emulsifier, 1,2-propylene glycol and water are mixed, thus obtaining the solution. The above liquid composition can be used, for example, in an aerosol spray can with gas under pressure, with a suitable carrier gas such as nitrogen or carbon dioxide).

Composition for use in the EHD device

Table 10
ComponentThe percentage by weight
The connection according to the present invention (stable α-tocopherol)0,1
Emulsifier (for example, Cremophor RH 40")10,0
The polyethylene glycol3,0
Water86,9

The connection according to the present invention, the emulsifier, polyethylene glycol and water are mixed together to obtain the solution. The above liquid composition can be used in conventional EHD devices known from the prior art.

Options for the implementation of the ing the invention, described above are supposed to be only an illustration, and a specialist in the art will be able to identify or be able to install, only by ordinary experimentation, numerous equivalents to the specific procedures described in the proposal. It is assumed that all such equivalents are included in the scope of the present invention, as it is defined by the following claims.

1. Retinoid compounds according to formula (I)

or their pharmaceutically acceptable salt, solvate or hydrate, in which n means an integer from 0 to 2;

And represents optionally substituted phenyl;

In represents O, S or NR6;

R6represents hydrogen or alkyl;

Y represents-OR7;

R7represents hydrogen, alkyl, optionally substituted phenyl, arylalkyl, where the aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkenyl;

Z represents-C(R103)2O-, -R102C=CR102- ,- ≡ -,- C(R103)2S-, -C(O)O - or-C(O)NR10-;

each of R10, R101, R102and R103independently represents hydrogen or alkyl;

R1and R2independent pre whom represent hydrogen or alkyl;

R3represents hydrogen or alkyl;

R4and R5independently represent hydrogen, (C1-C8)alkyl or arylalkyl, where the aryl fragment means optionally substituted phenyl.

2. Compounds according to claim 1, in which n is 1.

3. Compounds according to claim 1, in which R1and R2mean alkyl.

4. Compounds according to claim 3 in which R1and R2means methyl.

5. Compounds according to claim 1, in which R3means hydrogen.

6. Compounds according to claim 1, in which R4means hydrogen.

7. Compounds according to claim 1, in which R5is a (C1-C8)alkyl or arylalkyl, where the aryl fragment means optionally substituted phenyl.

8. Compounds according to claims 1 to 7, in which R5represents ethyl, pentyl, octyl or benzyl.

9. Compounds according to claim 1, in which a is represented by formula (II)

in which R11and R12independently represent hydroxy, alkoxy, alkyl, halogenated, halogen or hydrogen.

10. Compounds according to claim 9, in which R11and R12independently represent a halogen or hydrogen.

11. Compounds according to claim 9, in which R11and R12mean hydrogen.

12. Connection of claim 10, in which R11means hydrogen, R12means fluorine, or R11means fluorine is R 12means hydrogen.

13. Compounds according to claim 1, in which the means Acting

14. Compounds according to claim 1, in which means S.

15. Compounds according to claim 1, in which means NR6, a R6means hydrogen or alkyl.

16. Connections § 15, in which R6means hydrogen, methyl or ethyl.

17. Compounds according to claim 1, in which Z denotes-C(R101)2O-, -R102C=CR102-, -C(R103)2S-, -C(O)O - or-C(O)NR10-, and R101, R102and R103mean hydrogen, and R10means hydrogen or alkyl.

18. Compounds according to claim 1, in which Z denotes-CH2O - or TRANS-CH=CH-.

19. Compounds according to claim 1, in which Y means OR7and R7means hydrogen or alkyl.

20. Compounds according to claim 19, in which R7means hydrogen.

21. Compounds according to claim 1, selected from the group consisting of the following compounds:

4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptyloxy]benzoic acid,

4-[2-(4,4-dimethylthiochroman-7-yl)heptyloxy]benzoic acid,

4-[3-(4,4-DIMETHYLPROPANE-7-yl)Oct-1-enyl]benzoic acid,

4-[3-(4,4-dimethylthiochroman-7-yl)Oct-1-enyl]benzoic acid,

4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid,

4-[3-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid,

4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Penta-1-enyl]be sauna acid,

4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)undec-1-enyl]benzoic acid,

4-[4-phenyl-3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)but-1-enyl]benzoic acid,

4-[3-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid,

3-fluoro-4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-enyl]benzoic acid,

4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptyloxy]benzoic acid,

4-[2-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)heptyloxy]benzoic acid,

4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid,

4-[2-(4,4-DIMETHYLPROPANE-7-yl)heptanoate]benzoic acid and

4-[3-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)Oct-1-inyl]benzoic acid.

22. Method of preparing compounds according to one of claims 1 to 21, in which Z denotes-C(R101)2O - or-C(R103)2S-including interaction of the compounds of formula (IV)

with a compound HO-A-COY, in which R1, R2, R3, R4, R5A , b, Y and n are as defined in claim 1, and T means-SH or-HE,

23. Method of preparing compounds according to one of claims 1 to 21, in which Z means R102C=CR102that includes the interaction of the compounds of formula (V)

connection (EtO)3 2-A-COY, in which R1, R2, R3, R4, R5A , b, Y and n are as defined in claim 1.

24. Method of preparing compounds according to one of claims 1 to 21, in which Z denotes-C(O)O - or-C(O)NR10that includes the interaction of the compounds of formula (VII)

connection M-A-COY, in which M means HE or other10and R1, R2, R3, R4, R5, R10A , b, Y and n are as defined in claim 1.

25. Compounds according to one of claims 1 to 21, obtained by the method according to PP, 23 or 24.

26. Pharmaceutical composition for treatment and/or prevention of obstructive airway disease, cancer or dermatological disorders or disorders, comprising a compound according to one of claims 1 to 21 and a pharmaceutically acceptable carrier and/or excipient.

27. Compounds according to one of claims 1 to 21 for use as therapeutically active substances for the treatment and/or prevention of obstructive airway disease, cancer or dermatological disorders or disorders.

28. The method of treatment and/or prevention of obstructive airway disease, cancer or dermatological disorders or disorders, where the method includes introducing the compound according to one of claims 1 to 21 human or animal.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino}-3,3-diphenylpropanoyl}-2-pyrrolidine carboxamide maleate of the formula (1): . Also, invention relates to a method for preparing this compound by interaction of free compound of the formula (1) with maleic acid in the presence of organic solvent. This salt can be used as thrombin inhibitor.

EFFECT: improved preparing method, valuable medicinal properties of compound.

4 cl, 2 tbl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

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

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

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

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry of natural compounds, medicine.

SUBSTANCE: invention relates to new taxanes with carbonate substitute at C7 of the general formula (I) given in the invention description wherein R2 means benzoyloxy group; R7 means -COO; R9 means -CO; R10 means -OH; R14 means hydrogen atom (H); X3 means (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom; X5 means -COX10, -COOX10 wherein X10 means (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom, and Ac means acetyl. Proposed compounds possess an anti-tumor activity.

EFFECT: valuable medicinal properties of compounds.

61 cl, 1 tbl, 5 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to new compounds - C7-ester-substituted taxanes of the general structural formula:

wherein R2 represents benzoyloxy-group; R7 represents R7aCOO-; R10 represents hydroxy-group; X3 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among oxygen (O), nitrogen (N) and sulfur (S) atoms; X5 represents -COX10 wherein X10 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, phenyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among O, N and S; or it (X5) represents -COOX10 wherein X10 represents (C1-C8)-alkyl or (C2-C8)-alkenyl; R7a represents (C1-C20)-alkyl or (C2-C20)-alkenyl; Ac represents acetyl group. These compounds possess an anti-tumor activity. Also, invention relates to a method for inhibition of tumor growth in mammals and to a pharmaceutical composition based on synthesized compounds. Invention provides preparing new derivatives of taxanes possessing the enhanced anti-tumor activity and reduced toxicity as compared with taxol and taxoter.

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to derivatives of taxane of the general formula (I):

wherein R2 means acyloxy-group; R7 means hydroxy-group; R9 means keto-group; R10 means carbonate; R14 means hydrogen atom; X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted optionally with nitro-group or 5-6-membered heteroaromatic group comprising heteroatoms taken among oxygen (O), nitrogen (N) or sulfur (S) atoms; X5 means -C(O)X10, -C(O)OX10 or -CONHX10 wherein X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl, furyl, pyridyl or thienyl; Ac means acetyl. Also, invention describes a pharmaceutical composition based on taxanes and a method for inhibition of a tumor growth.

EFFECT: improved inhibiting method, valuable medicinal properties of compounds.

98 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

The invention relates to new derivatives aminomethylpropanol acid formula 1

< / BR>
where Z represents (CH2)n, O or S; n is 0, 1 or 2; X represents 1-3 substituent, independently selected from hydrogen, halogen, (C1-6)alkyloxy,(C3-6)cycloalkane, (C6-12)aryloxy, (C6-12)aryl, teinila, CN, СООR6and (C1-4)alkyl, optionally substituted with halogen, or 2 substituent in adjacent positions together represent a condensed (C5-6)aryl group, or O-(CH2)m-O, where m is 1 or 2; Y is 1-3 selected from hydrogen, halogen, (C1-4)alkyloxy and (C1-4)alkyl, optionally substituted with halogen; R1represents COOR7; R2and R6are (C1-4)alkyl; R3, R4and R5independently represent hydrogen; R7, R8and R9independently represent hydrogen or (C1-4)alkyl; or pharmaceutically acceptable salts, and pharmaceutical compositions on their basis, with effect on the Central nervous system

The invention relates to new N-phenylamine and N-pyridylamine derivative of the formula I

< / BR>
in which X denotes O or S;

R1and R2which may be identical or different, denote hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl;

R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different;

Y represents halogen;

R4and R5represent hydrogen;

Ar denotes one of the following groups or WITH:

< / BR>
T represents hydrogen or (C1-C6)alkyl;

T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)allylthiourea;

R6and R7each denotes hydrogen or R6and R7together represent a bond;

Z denotes either (I) the divalent group-CHR9- in which the R11-, in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11that may be the same or different, have the meanings indicated above for R9or (III) a divalent group-CHR12-CHR13-CH2-, in which R12and R13together they form a bond, Z represents-CH=CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,

as well as their additive salts with pharmaceutically acceptable acids or bases, and method of production thereof, pharmaceutical compositions and drug manifesting gipolipedimecescoe and antiatherosclerotic action based on them

The invention relates to novim retinoid compounds of General formula I, II, III, IV with retinoid negative hormone biological activity and/or activity of antagonist retinoids, compositions based on them, a method of determining the retinoid antagonists hormones,the method of treating a pathological state in a mammal, vospriimchivosti to treatment with retinoid antagonist or negative hormone by injection of compound I or II

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to new Bermatingen compounds, the United propylenebis communication, General formula I where Ar represents a radical of formula (a) or (b), R1is-OR6or-COR7, R2represents a polyether radical, comprising 1 to 6 carbon atoms and 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar connection, R3represents lower alkyl, or R2or R3taken together form a 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur, R4represents H, linear or branched C1-C20alkyl or aryl, R5represents H or-OR8, R6represents H, R7represents H, -OR10or-N(r)r (r) r are H, lower alkyl or taken together with the nitrogen atom form a ring of morpholino, R8represents H or lower alkyl, R10represents H, linear or branched C1-C20alkyl, X represents a divalent radical, which is from right to left or Vice versa has the formula (d), R11Fri carboxylic acid and the optical and geometrical isomers of the above compounds of formula (I)

The invention relates to new heterocyclic condensed to benzoylpyridine General formula I, where R1and R2denote independently from each other H or A; X denotes CR4R5; C=Z or O, Y represents CR6R7Z denotes O or CH2, R4, R5, R6or R7denote independently from each other H, A, HE or OA, or R5and R6or R7and R8indicate link together, with each molecule may receive a maximum of only one such bond, or R4and R5indicate together O-(CH2)2-O or O-(CH2)3-O, or R8and R9denote independently from each other H or A; And denotes alkyl with 1 to 6 C-atoms; n represents 0 or 1, and their physiologically acceptable salts

The invention relates to non-steroidal anti-inflammatory drugs, particularly to substituted dihydrobenzofuran and related compounds

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention concerns to applying RARγ agonist for preparing a medicinal agent comprising one or some such agonists and designated for treatment of emphysema wherein RARγ agonist is taken among compounds of the formula (I):

wherein R1 means residue of the formula:

or , or , or ; R2 means (C2-C8)-alkanoyl, (C2-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or group -OCH2R3 wherein R3 means hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl; each among R4-R9 means independently of one another hydrogen atom or (C1-C6)-alkyl; or R8 and R9 mean in common (CRaRb)n wherein Ra and Rb mean independently of one another hydrogen atom or (C1-C6)-alkyl; n = 1, 2 or 3; R4-R7 have above given values; R10 means carboxyl, (C1-C6)-alkoxycarbonyl or mono- or di-(C1-C6)-alkylcarbamoyl; and their pharmaceutically acceptable salts; or among compounds of the formula (VI):

wherein R1 means C(O)R6 or CH2OH (wherein R6 means hydroxy-group or (C1-C6)-alkoxy-group); R2 means hydrogen atom, (C1-C15)-alkyl, (C1-C6)-alkoxy-group or cycloaliphatic group; R3 means hydrogen atom, hydroxy-group, (C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, (C1-C10)-alkoxy-group or cycloaliphatic group; R4 and R5 mean independently of one another hydrogen atom, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; or among compound of the formula (VIII):

. Invention provides applying agonists eliciting the selective effect with respect to RARγ, for preparing a medicinal agent comprising one or some such agonists designated for emphysema treatment.

EFFECT: valuable medicinal properties of compounds.

4 cl, 5 tbl, 3 ex

Up!