Aminopropylidene derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an aminopropylidene derivative presented by formula wherein R1 and R2, which may be identical or different, represent hydrogen or a substitute specified in the following (a)-(c), provided the case of both representing hydrogen is excluded: (a) carbonyl substituted with hydroxy, alkoxy or hydroxy alkylamino, (b) carbonylalkyl substituted by hydroxy or alkoxy, and (c) acrylic acid including its alkyl ester, R3 and R4, which may be identical or different, represent hydrogen, alkyl which may be substituted by phenyl or cycloalkyl, or R3 and R4, which together form a heterocyclic ring with a nitrogen atom bound thereto, represent pyrrolidino, piperidino, which may be substituted by oxo or piperidino, piperazinyl substituted by alkyl or penyl, morpholino or thiomorpholino; A means oxo or is absento, B represents canbon or oxygen; one of X and Y represents carbon, while the other one represents sulphur, a part represented by a dash line represents a single bond or a double bond, and a wavy line represents a cys-form and/or a transform. Also, the invention refers to a pharmaceutical composition exhibiting histamine receptor antagonist activity on the basis of said compounds.

EFFECT: there are produced new compounds and pharmaceutical compositions thereof, which can be used in medicine for treating asthma, allergic rhinitis, pollen allergy, hives and atopic dermatitis.

10 cl, 12 tbl, 58 ex

 

The scope of the invention

The present invention relates to aminopropiophenone derivative or its salt, or hydrate, which are pharmaceutically acceptable, which are useful as pharmaceutical compositions, in particular, active ingredients such as antihistamines.

Background of the invention

Histamines are representative of chemical mediators that induce allergic reaction, histamines are excreted from cells such as mast cells and basophils when substances that cause allergies, enter the body. Released histamines are associated with protein histamine receptor type 1 (H1 receptor), showing pharmacological effects, such as hypotension, vascular hyperproliferate, smooth muscle contraction, vasodilatation or hypersecretion glands, and are involved in allergic reactions and inflammation. As described above, the histamines are associated with various human diseases, and allergic diseases and inflammation can be prevented or cured, controlling their actions. Means for controlling the release of histamines and means for inhibiting the binding of histamines with receptors (antihistamines) are commercially available in large quantities, and such tools are used when the fence is evania, such as bronchial asthma, allergic rhinitis, hay fever, urticaria and atopic dermatitis.

However, antihistamines, as it is well known, show some undesirable side effects, such as sedation, sleepiness, dizziness and malaise, based on the actions on the Central nervous system; and dry mouth, dry mucous membranes and poor vision, based on anticholinergic actions; therefore, there are limitations to their application, such as the prohibition of taking antihistamines before you get behind the wheel of the vehicle, which, in turn, causes the inconvenience of the use of such funds. For these reasons, antihistamines that do not have such problems and have excellent effects are demand as patients and medical institutions. The authors of the present invention was found aminopropiophenone derivative of the present invention, which has fewer side effects on the Central nervous system and strong antihistamine effect.

As for aminopropiophenone derivatives containing thiabendazole skeleton, non-patent publication 1 discloses compounds containing thiophene ring or benzene ring, substituted with halogen, methoxy or dimethylaminomethylene what Ruppel. However, this publication only describes that these compounds are synthesized, and are not specifically indicates that these compounds have pharmacological actions such as antihistamine actions.

The publication, known from the prior art

Non-patent publication(s)

Non-patent publication 1: Helvetica Chimica Acta, 49, No. 26, (1966), 214-234 (see pages 220-221, table 3).

Brief description of the invention

The problems solved by the present invention

The aim of the present invention is to provide a pharmaceutical composition, which has fewer side effects on the Central nervous system, such as drowsiness, and excellent action, particularly useful compounds as the active ingredient, such as an antihistamine.

Means of solving problems

As a result of extensive research antihistaminic compounds having the characteristics mentioned above, the authors of the present invention, it was found that aminopropiophenone derivative represented by structural formula (I), shown below, is a compound useful as a drug, which has excellent antigistaminny effect and reduces side effects on the Central nervous system, such as drowsiness. Thus was established the present invention.

The effects on the present inventions

Aminopropiophenone derivative of the present invention has an excellent antagonistic activity against histamine receptors and shows a low transfer to the brain even in the test binding to brain receptors, where the mice orally administered the compound, and therefore demonstrates the effect of reducing the side effects on the Central nervous system, such as drowsiness. So aminopropiophenone derivative has the properties desired for the active ingredients of pharmaceutical compositions, such as antihistamines, and is extremely useful.

Ways of carrying out the invention

The present invention relates to aminopropiophenone derivative or its salt, or hydrate, which are pharmaceutically acceptable and are useful as medicines such as antihistamines, where aminopropiophenone derivative represented by the following General formula (I):

where R1and R2that may be the same or different from each other, represent hydrogen or Deputy, selected from the following (a)-(c), provided that the case where both represent hydrogen, excluded:

(a) carbonyl, substituted hydroxy, alkoxy, hydroxyalkyl the Mino,

(b) carbonylethyl, substituted hydroxy or alkoxy, and

(c) acrylic acid, including its alkilany ether,

R3and R4that may be the same or different from each other, represent hydrogen, alkyl which may be substituted by phenyl, or cycloalkyl, or

R3and R4, which together form a heterocyclic ring with the nitrogen atom associated with them, are pyrrolidino, piperidino, which may be substituted by oxo or piperidino, piperazinil, substituted alkyl or phenyl, morpholino or thiomorpholine,

A denotes unsubstituted or oxo, represents a carbon or oxygen, one of X and Y is carbon and the other is a sulfur, a portion represented by a dashed line, represents a simple bond or double bond, and the wavy line represents a CIS-form and/or TRANS-form.

In the above General formula (I) alkyl (including "alkyl" in the above-described substituents, such as carbonylethyl, alkilany ester of acrylic acid, hydroxyethylamino or alkylpiperazine) represents a linear or branched alkyl group containing from 1 to 6 carbon atoms, such alkyl group preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fluorine-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl or similar.

Alkoxy is a linear or branched alkoxygroup containing from 1 to 6 carbon atoms, and alkoxygroup preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, fluorine-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy or similar.

Cycloalkyl represents a cyclic alkyl containing 3 to 6 carbon atoms, and cycloalkyl preferably represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Halogen represents fluorine, chlorine, bromine, iodine or the like.

Of the compounds of the present invention, the preferred compounds are as follows.

Hydrochloride ethyl (E,Z)-3-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acrylate [Compound 1]

Hydrochloride ethyl (E,Z)-4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-carboxylate [Compound 3]

(E,Z)-4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-carboxylic acid [Compound 4]

Hydrochloride (E)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acetic acid [Compound 5]

Hydrochloride ethyl (E,Z)-3-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acrylate [Compound 6]

(E,Z)-3-[4-(3-Dimethylaminopropylamine)-9,10-is hydro-4H-1-tiebens[f]azulene-2-yl]acrylic acid [Compound 7]

(E,Z)-4-(3-Dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-carboxylic acid [Compound 8]

(2-Hydroxyethyl)amide (E,Z)-4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylic acid hydrochloride [Compound 9]

(E,Z)-3-[4-(3-Dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acrylic acid [Compound 11]

(2-Hydroxyethyl)amide (E)-4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-carboxylic acid [Compound 12]

Hydrochloride ethyl (E,Z)-3-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acrylate [Compound 13]

(E,Z)-3-[4-(3-Dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acrylic acid [Compound 14]

(E)-[4-(3-Dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid [Compound 15]

(Z)-[4-(3-Dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid [Compound 16]

Hydrochloride (E)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acetic acid [Compound 17]

Hydrochloride (Z)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acetic acid [Compound 18]

(E)-[4-(3-Dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 19]

(Z)-[4-(3-Dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic who Isleta [Compound 20]

Hydrochloride ethyl (E,Z)-2-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]-2-methylpropionate [Compound 21]

(E,Z)-2-[4-(3-Dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]-2-methylpropionate acid [Compound 22]

(E,Z)-2-[4-(3-Dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]-2-methylpropionate acid [Compound 23]

Hydrochloride ethyl (E)Z)-2-[4-(3-dimethylaminopropyl)-10-oxo-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]-2-methylpropionate [Compound 24]

(E)-{2-Methyl-2-[4-(3-methylaminopropyl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]}propionic acid [Compound 25]

(E)-{4-[3-(Pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 26]

(Z)-{4-[3-(Pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 27]

(Z)-[4-(3-Dimethylaminopropylamine)-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl]acetic acid [Compound 28]

(E)-[4-(3-Dimethylaminopropylamine)-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl]acetic acid [Compound 29]

(E)-[4-(3-Ethylethylenediamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 30]

(Z)-[4-(3-Ethylethylenediamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 31]

(E)-{4-[3-(Morpholine-4-yl)propylidene]-4,10-dihydro-9-oxa-3-t is ebenso[f]azulene-6-yl}acetic acid [Compound 32]

(Z)-{4-[3-(Morpholine-4-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 33]

(E)-{4-[3-(piperidine-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 34]

(Z)-{4-[3-(piperidine-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 35]

(E)-4-{4-[3-(Pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}butyric acid [Compound 36]

(Z)-4-{4-[3-(Pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}butyric acid [Compound 37]

(E)-[4-(3-Ethylenepropylene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 38]

(Z)-[4-(3-Ethylenepropylene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 39]

(E)-[4-(3-Benzylaminopurine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 40]

(Z)-[4-(3-Benzylaminopurine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 41]

(E)-[4-(3-Benzylaminopurine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 42]

(Z)-[4-(3-Benzylaminopurine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 43]

(E)-[4-(3-Cyclopentylpropionyl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 44]

(Z)-[4-(3-Cyclopentyl propylidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 45]

(E)-[4-(3-Isopropylaminomethyl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 46]

(Z)-[4-(3-Isopropylaminomethyl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 47]

(E)-3-[4-(3-Dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionic acid [Compound 48]

(Z)-3-[4-(3-Dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionic acid [Compound 49]

(E)-{4-[3-(4-Methylpiperazin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 50]

(Z)-{4-[3-(4-Methylpiperazin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 51]

(E)-3-{4-[3-(Pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}propionic acid [Compound 52]

(Z)-3-{4-[3-(Pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}propionic acid [Compound 53]

(E)-{4-[3-(4-Phenylpiperazin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 54]

(Z)-{4-[3-(4-Phenylpiperazin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 55]

Hydrochloride (E)-3-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl]propionic acid [Compound 56]

Hydrochloride (Z)-3-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-1-thia is Enzo[f]azulene-6-yl]propionic acid [Compound 57]

(E)-3-{4-[3-(Pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl}propionic acid [Compound 58]

(Z)-3-{4-[3-(Pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl}propionic acid [Compound 59]

(E)-4-[4-(3-Dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]butyric acid [Compound 60]

(Z)-4-[4-(3-Dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]butyric acid [Compound 61]

(E)-{4-[3-(4-Oxopiperidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 62]

(Z)-{4-[3-(4-Oxopiperidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 63]

(E)-[4-(3-Dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-6-yl]acetic acid [Compound 64]

Hydrochloride (Z)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-6-yl]acetic acid [Compound 65]

Deformat (E)-{4-[3-([1,4']bipiperidine-1'-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 66]

Deformat (Z)-{4-[3-([1,4']bipiperidine-1'-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 67]

(E,Z)-{4-[3-(Thiomorpholine-4-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 68]

(E,Z)-2-Methyl-2-{4-[3-(pyrrolidin-1-yl)propylidene]-9,10-dihydro-4H-1-tiebens[f]is sulan-2-yl}propionic acid [Compound 69]

Hydrochloride (E)-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 70]

Hydrochloride (Z)-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 71]

Of the above compounds of the present invention, more preferred compounds include the compounds listed in Tables 9 and 10 below. In addition, the compounds listed in Table 12, with excellent antihistaminic activity and low migration in the brain, are particularly preferred.

General method for obtaining compounds of the present invention are presented below. The compound of the present invention represented by the above General formula (I)can be obtained in accordance with the method described below. In this regard, the experts in this field should be obvious that the specific ways that you can use for certain compounds, can vary depending on the chemical structures of the compounds.

Of the above compounds of the present invention represented by the General formula (I), 4-(aminopropylene)-9,10-dihydro-4H-1-tiebens[f]Aslanova connection can be obtained in accordance with methods described in Helvetica Chimica Acta, 49, Fasc. Emile Cherbuliez, No. 26, 214-233 (1966) or Collect. zech. Chem. Commum. 59, 667-674 (1994), 4-(aminopropylene)-9,10-dihydro-4H-3-tiebens[f]Aslanova connection can be obtained in accordance with methods described in Helvetica Chimica Acta, 54, Fasc. 1, 277-282 (1971), 4-(aminopropylene)-4H-1-tiebens[f]Aslanova connection and 4-(aminopropylene)-4H-3-tiebens[f]Aslanova connection can be obtained in accordance with methods described in Helvetica Chimica Acta, 49, Fasc. Emile Cherbuliez No. 26, 214-233 (1966), 4-(aminopropane)-4,10-dihydro-9-oxa-1-tiebens[f]Aslanova connection and 4-(aminopropylene)-4,10-dihydro-9-oxa-3-tiebens[f]Aslanova connection can be obtained in accordance with methods described in Japanese laid patent application No. Sho 63-10784 or WO 2005/003131, and 4-(aminopropylene)-10-oxo-9,10-dihydro-4H-1-tiebens[f]Aslanova connection can be obtained in accordance with the methods described in Helvetica Chimica Acta, 59, Fasc. 3, 866-877 (1976). Here the introduction of the substituents carried by the choice of initial substances, previously containing any of the substituents in the position that corresponds to it.

The compound of General formula (I) can be obtained by reaction of the Wittig reaction the Wittig-Horner reaction of the Mac-Murri compounds of General formula (II). For example, when using the Wittig reaction, obtaining can be carried out in accordance with the method described in J. Org. Chem. 44, 22, 3760-3765 (1979), J. Med. Chem. 35, 2074-2084 (1992), or similar methods. In other words, the connection is their General formula (I) can be obtained by reacting compounds of General formula (II) with the corresponding 3-aminopropylphosphonic salt or like substance, in the presence of a base, such as n-utility or piperonyl potassium, in a nonaqueous solvent such as THF (tetrahydrofuran), toluene, diethyl ether or CPME (cyclopentylmethyl ether), at a suitable temperature, preferably in the range from 0°C to the boiling point of the solvent.

In addition, the compound of General formula (II) can be converted to a compound of General formula (I), subjecting the compound represented by the General formula (III), formed after the Grignard reaction, the reaction degidrirovaniya. This method of obtaining can be carried out in accordance with the method described in Helvetica Chimica Acta, 54, Fasc. 1, 277-283 (1971). For example, the Grignard reaction is carried out by treatment of compounds of General formula (II) corresponding Grignard reagent such as 3-aminopropyldimethylamine, in a nonaqueous solvent such as THF, toluene, diethyl ether or CPME, at a suitable temperature from the melting temperature to the boiling temperature of the solvent. Subsequent reaction of degidrirovaniya can be carried out using hydrochloric acid triperoxonane acid, thionyl chloride or the like, in the absence of solvent or in a suitable solvent such as water, ethanol or dichloromethane, at the optimum reaction temperature from the melting temperature to a temperature boil the solvent.

In addition, as an alternative, you can use the method described in Collect. Czech. Chem. Commum. 59, 667-674 (1994). In other words, the compound of General formula (II) is treated with a Grignard reagent derived from magnesium and bromocyclopropane, or the like, in a nonaqueous solvent such as THF, toluene or CPME, at a suitable temperature ranging from the melting temperature to the boiling point of the solvent to obtain the compound represented by the General formula (IV). Then, the compound obtained is subjected to a halogenation reaction with Hydrobromic acid, trimethylsilylmethyl, thionyl chloride or similar substance in a suitable solvent such as water, acetic acid, dichloromethane, chloroform or 1,4-dioxane, at a suitable temperature ranging from 0°C to the boiling point of the solvent, converting, thus, the connection in the connection represented by the General formula (V). Then, the resulting halogenated product can be treated aminoven compound in a solvent such as acetone, methanol, ethanol, THF, 1,4-dioxane or acetonitrile, at a suitable temperature, preferably in the range from room temperature to the boiling point of the solvent, whereby it is possible to obtain the compound (I). In this reaction, amination potassium carbonate, sodium hydroxide, three is tillin or similar substances can be used as appropriate as the basis, as needed.

The compound of formula (II) can be obtained in accordance with the method described in Japanese laid patent application No. Sho-49-69677, Helvetica Chimica Acta, 54, Fasc. 1, 214-233 (1996), Helvetica Chimica Acta, 54, Fasc. 1, 277-282 (1971), WO 2005/003131, Japanese patent application No. 2008-019121 etc.

The formation of functional groups on the aromatic ring can be performed by subjecting the compound of General formula (I), the compound of General formula (II) or the compound of General formula (III) or (IV)synthesized by using a Grignard reagent, as specified above, the reaction of liceobramante with alkyllithium reagent, the reaction of acylation Friedel -, reaction formirovaniya of Vilsmeier or similar. In addition, the compound containing brominated aromatic ring, are chosen as the starting material and subjected to a carbonylation reaction, the Heck reaction, the reaction cyanidation reaction formirovaniya, the Ullman reaction, the reaction mix according to the method of Suzuki or the like, with or without a catalyst based on a transition metal, such as palladium, whereby the aromatic ring can be converted so that it contains the desired functional group. In this type of reaction can also use the method described in J. Am. Chem. Soc., 124, 12557-12565 (2002), Tetrahedron Lett., 40, 8193-8195 (1991), or similar.

For example, the reaction is alkilirovanija can be accomplished by treating compounds containing brominated aromatic ring, using ester derivative such as ethyl acetate, tert-butyl acetate or ethyl isobutyrate, bases, such as piperonyl potassium, potassium hydride, LiHMDS (hexamethyldisilazide lithium) or LiNCy2(dicyclohexylamine lithium), and a ligand such as DPPF (1,1'-bis(diphenylphosphino)ferrocene), PPh3(triphenylphosphine), P(o-Tol)3(Tris(2-were)phosphine), P(t-Bu)3(tri-tert-butylphosphine) or N,N'-(2,6-diisopropylphenyl)dihydroimidazolium, in the presence of a catalyst based on a transition metal, such as Pd(dba)2(palladium(0) bis(dibenzylideneacetone)), Pd2(dba)3(dipalladium(0) Tris(dibenzylideneacetone)), Pd(OAc)2(palladium(II) acetate) or Pd(PPh3)4(palladium(0)tetrakis(triphenylphosphine)). This reaction can be performed in a solvent such as toluene, benzene, pentane, cyclohexane or a mixture of such solvents, at a suitable temperature, preferably in the range from room temperature to the boiling temperature of the solvent.

The above compound of General formula (I) also includesCIS-TRANSisomeric mixture of this compound, and these isomers can be divided using liquid chromatography or by selective crystallization with or without a suitable counterion. For example, in the case to the da using high-performance liquid chromatography, the separation is performed with the use of the mixture, suitably formulated with an organic solvent, such as methanol or acetonitrile and water solution, to which was added formic acid or triperoxonane acid, as required for a specific case, as eluent.

The connection represented by the General formula (I)above includes, in the case where there is its pharmaceutically acceptable salt, various types of salts of such compounds include, for example, additive salts with an acid, such as hydrochloric acid, oxalic acid, fumaric acid, p-toluensulfonate acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, nitric acid or formic acid. Salts of carboxyl groups of the compounds may also include suitable alkali metal salts of sodium, potassium, calcium, etc. These salts can be obtained from each of the compounds in free form or by converting a reversible manner, in accordance with the known method. In addition, when the compounds are present in the form of spatial isomer, such asCIS-TRANSisomer, optical isomer or coordination isomer, or a hydrate or complex with the metal, the present invention encompasses any of the space, Breakfast is the only isomers, hydrates and complex compounds.

The compound of the present invention can be combined with a suitable pharmaceutical carrier or diluent with obtaining the drug. The connection can be obtained in the form of any drugs traditionally used method and compounds can be obtained in the form of compositions as a vehicle for oral administration, such as a tablet, a capsule, a fine powder or liquid, or as a vehicle for parenteral injection for subcutaneous injection, intramuscular injection, intrathecal injection or intranasal. According to the recipe, the compound of the present invention can be used in the form of its pharmaceutically acceptable salts and compounds can be used alone or in a suitable combination and, moreover, in a mixture with other pharmaceutically active ingredient.

The preparation for oral administration can be used directly or in a suitable combination with a suitable additive, for example, traditional excipients, such as lactose, mannitol, corn starch or potato starch, together with binders such as crystalline cellulose, a derivative of cellulose, Arabic gum, corn starch or gelatin, baking powder, such as corn starch, potato starch, ka is Ieva carboxymethyl cellulose, lubricant, such as talc or magnesium stearate, and other additive such as a filler, a wetting agent, buffer, preservative or perfume and the like, with taking tablets, powder, granules or capsules.

In addition, the connection can be obtained in the form of drugs in dosage form other than the above, which is optimal for treatment, depending on the type of disease and patients, including, for example, topical applications, such as injections, suppositories, inhalations, aerosols, syrups, instillation and ointments and the like.

The desired dose for the compounds of the present invention varies depending on the entity to which it is administered, dosage form, route of administration, the period of time during which carry out the introduction and similar factors. To obtain the desired effect the connection of the present invention, can generally be administered orally in an amount of from 0.5 to 1000 mg and preferably from 1 to 500 per adult in a single dose or as multiple doses per day. In the case of parenteral administration (e.g. injection), the daily dose is preferably from one-third to one-tenth the dose for each of the above doses.

EXAMPLES

Hereinafter the present invention will be specifically described by the introduction examples without intent to limit their scope of the present invention.

The melting point was determined by placing the sample in a glass capillary tube and using a device for determining the melting temperature Yamato Scientific, Model MP-21. Haven't used any compensation on the error of thermometer. MS spectrum was measured using a POLARIS Q (Thermo Quest).1H-NMR was measured using the analyzer nuclear magnetic resonance Model ARX500 (Bruker)with the chemical shift measured in deuterated organic solvent expressed in ppm using TMS as internal standard (δ=0 ppm). Also, when measured in deuterated water was used, the peak corresponding to water at 4,67 ppm as internal standard. Column chromatography on silica gel was performed using silica gel PSQ 100B or NH-DM1020 for chromatography (FUJI SILYSIA CHEMICAL LTD.). Thin-layer chromatography was performed using silica gel F254 (Merck, No. 5715) or TLC plate NH (FUJI SILYSIA CHEMICAL LTD.) and detection was performed using UV lamp and reagent for the degree of color development 5% phosphomolybdenum acid-ethanol. The separation of geometric isomers was carried out by high-performance liquid chromatography, using 880-PU (Nippon Bunko) as a pump to supply liquid 875-UV (Nippon Bunko) as detector and STR PREP-ODS (20 m the e × 250 mm) (Shinwa Kako) as a preparative column.

Example 1

Obtain ethyl 3-(4-oxo-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl)acrylate

The triethylamine (34 ml), acrylate (27.5 ml), palladium acetate (0.4 g) and P(o-Tol)3(1.5 g) was added to DMF (50 ml) solution of 2-bromo-9,10-dihydro-3-tiebens[f]azulene-4-it (7,00 g) and the mixture was stirred over night at 80°C in argon atmosphere. To the reaction mixture were added saturated aqueous solution of ammonium chloride, the mixture was extracted with ethyl acetate and the organic layer is then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was purified using column chromatography on silica gel (chloroform-methanol = 9:1) to obtain the 6,39 g (85%) indicated in the title compound as amorphous solid.

1H-NMR (DMSO-d6) δ: 1.26 in (t, J=7,1 Hz, 3H), 3,10-3,19 (m, 4H), 4,19 (sq, J=7,1 Hz, 2H), 6,55 (d, J=16.1 Hz, 1H), 7,40-7,44 (m, 2H), 7,55-to 7.59 (m, 2H), 7,80-of 7.82 (m, 1H), 8,59 (s, 1H).

Example 2

Obtain hydrochloride of ethyl (E,Z)-3-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acrylate [Compound 1]

1.6 mol/l solution of n-utility in hexane (42 ml) was added to THF (100 ml) solution of the hydrobromide dimethylaminopropiophenone (23,5 g) under ice cooling, and the mixed solution was stirred at room Tempe is the atur for 1 hour. THF (100 ml) solution of the compound obtained in Example 1 (6.11 g)was added to this solution and the mixture continued to stir overnight. The solvent is kept under reduced pressure, to the residue was added a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The residue was purified using column chromatography on silica gel (chloroform-methanol = 9:1), the obtained purified product was dissolved in 1,4-dioxane (20 ml)was added 4 mol/l solution of hydrogen chloride-dioxane (1.1 ml) and the mixture was stirred at room temperature for 1 hour. Solvents drove away under reduced pressure, and precipitated crystals were filtered and dried to obtain 0.51 g (6%) indicated in the title compounds as a mixture of E-form and Z-form.

Example 3

Obtain tert-butyl (E,Z)-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetate

A solution of 1.6 mol/l n-utility-hexane (14 ml) was added dropwise to hexamethyldisilazane (3,53 g) in an argon atmosphere under ice cooling. To this solution was added dropwise tert-butyl acetate (1.2 ml) and was stirred for 30 minutes. Was added Pd(dba)2(of 0.30 g), N,N'-(2,6 - diisopropylphenyl is)dihydroimidazolium (0,22 g) and (E,Z)-[3-(6-bromo-10H-9-oxo-3-tiebens[f]azulene-4-ilidene)propyl]dimethylamine (2,01 g) and the mixture was heated to room temperature and was stirred overnight. To the reaction mixture were added saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was purified using column chromatography on silica gel (hexane-ethyl acetate = 19:1) to obtain 0,80 g (36%) indicated in the title compound as an oily product, which is a mixture of E-form and Z-form.

MS (EI): m/z 400 [M++1].1H-NMR (DMSO-d6) δ: 1,35-of 1.42 (m, 9H), 2,07-of 2.66 (m, 10H), 3,51-3,55 (m, 2H), of 5.05-5,12 (m, 2H), of 5.84-the 6.06 (m, 1H), 6,77-7,53 (m, 5H).

Example 4

Receive (E,Z)-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid

Triperoxonane acid (2.0 ml) was gradually added to the compound obtained in Example 3 (1,53 g)and the mixture was stirred at room temperature for 2 hours. Triperoxonane acid drove away under reduced pressure, to the residue was added 5% aqueous potassium carbonate solution, the pH of the solution is then brought to 7 using dilute hydrochloric acid and the solution was extracted with chloroform. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solvent drove under reduced is the t to obtain 1.20 g (91%) indicated in the title compound as an oily product, representing a mixture of E-form and Z-form.

Example 5

Obtaining (E)-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 19] and (Z)-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 20]

The compound obtained in Example 4 (1.20 g)was dissolved in 30 ml of a mixed solution of 0.2% aqueous solution of formic acid/methanol and the sample solution, filtered through 0.45 µm membrane filter, was isolated and purified by high-performance liquid chromatography (eluent: a mixed solution, which represents a 0.2% solution of formic acid/methanol (3:2)). The flow rate was 6.5 ml/min, and the wavelength measurement was 254 nm. Compound 19 was suirable in the interval of 20 minutes 24 minutes and compound 20 was suirable in the range of 15 minutes to 18 minutes. The solvent of each of the collected eluates drove away under reduced pressure, and precipitated white crystals were filtered and dried to obtain 00,0,53 g (44%) and 0.28 g (23%) of compound 19 and compound 20, respectively.

Example 6

Obtain methyl (4-cyclopropyl-4-hydroxy-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acetate

Anhydrous THF (50 ml) solution of bromocyclopropane (8,3 ml) was added dropwise to the metal magnesium (2.5 g) under heating. When you are finished adding on kapl the m to the mixture was added anhydrous THF (20 ml) and the mixture was subjected to heating up to the boiling temperature under reflux for 2 hours. Then the reaction mixture was left in air for cooling and the solution was added dropwise to anhydrous THF (30 ml) solution of methyl (4-oxo-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acetate (10.0 g), pre-cooled in an ice bath. After stirring the mixture for 30 minutes to the reaction mixture were added saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and the obtained residue was purified using column chromatography on silica gel (hexane-ethyl acetate = 5:1) to give 9.0 g (79%) indicated in the title compound as an oily product.

1H-NMR (DMSO-d6) δ: 0,16-0,18 (m, 1H), 0.29 to 0.31 in (m, 1H), 0,44 of 0.47 (m, 1H), 0.60 and of 0.62 (m, 1H), 1,74-of 1.78 (m, 1H), 3,60-the 3.65 (m, 5H), 4,78 (d, J=to 15.4 Hz, 1H), are 5.36 (d, J=to 15.4 Hz, 1H), 6,10 (s, 1H), 6,72-of 6.73 (m, 1H), 7,07-7,51 (m, 4H).

Example 7

Obtain methyl (E,Z)-[4-(3-bromopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acetate

Dichloromethane (20 ml) solution of trimethylsilylpropyne (3.6 ml) was added dropwise to a dichloromethane (100 ml) solution of the compound obtained in Example 6 (9.0 g)at room temperature for implementation of the response of synthesized. After stirring the mixture for 1 hour was added saturated waters of the initial solution of sodium bicarbonate and the organic layer was allowed to separate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and then the resulting residue was purified using column chromatography on silica gel (hexane-ethyl acetate = 9:1) to give 9.3 g (87%) indicated in the title compound as an oily product, which is a mixture of E-form and Z-form.

1H-NMR (DMSO-d6) δ: was 2.76-3,10 (m, 2H), 3,60-with 3.79 (m, 7H), 5,06-5,14 (m, 2H), of 5.83-the 6.06 (m, 1H), 6,79-7,56 (m, 5H).

Example 8

Obtain methyl (E,Z)-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate

Pyrrolidine (0.4 ml), sodium carbonate (0.7 g) and potassium iodide (0.9 g) was added to THF (20 ml) solution of the compound obtained in Example 7 (1,00 g)and the mixture was subjected to heating up to the boiling temperature under reflux overnight. The mixture was left in the air to cool, then was added a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and then the resulting residue was purified using column chromatography on silica gel (hexane-ethyl acetate = 5:1) to give 0.50 g (51%) specified in the header connect the Oia in the form of an oily product, representing a mixture of E-form and Z-form.

MS (EI): m/z 383 [M+],1H-NMR (DMSO-d6) δ: 1,63-to 1.67 (m, 4H), 2,35-of 2.58 (m, 8H), 3,60 at 3.69 (m, 5H), of 5.05-5,12 (m, 2H), 5,80-6,09 (m, 1H), 6,78-7,53 (m, 5H).

Example 9

Receive (E,Z)-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid

1 mol/l sodium hydroxide (22 ml) was added to ethanol (30 ml) solution of the compound obtained in Example 8 (2,80 g)and the mixture was stirred at room temperature for 2 hours. The solvent drove away, then to the residue was added water and the aqueous solution was brought to pH 7 using dilute hydrochloric acid and the mixture was extracted with chloroform. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and the resulting oily product was converted into the solid from diethyl ether obtaining of 2.21 g (82%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 10

Obtaining (E)-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 26] and (Z)-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 27]

Was carried out by the same procedure as in Example 5, d is I the implementation of the separation and purification using a mixture of E-form and Z-form, obtained in Example 9 (1,99 g), with the receipt of 1.09 g (55%) and 0.31 g (16%) of compound 26 and compound 27, respectively, in the form of white crystals.

Example 11

Obtaining hydrochloride (E,Z)-[3-(6-bromo-10H-9-oxa-3-tiebens[f]azulene-4-ilidene)propyl]amine [Compound 2]

Was carried out by the same procedure as in Examples 6 and 7, in that order, using 6-bromo-10H-9-oxa-3-tiebens[f]azulene-4-it (5.10 g) to obtain the connection, and carried out the same procedure as in Example 8, using the compounds and 50% aqueous dimethylamine with getting 3,62 g (58%) [3-(6-bromo-10H-9-oxa-3-tiebens[f]azulene-4-ilidene)propyl]amine as an oily product, which is a mixture of E-form and Z-form. The obtained isomeric mixture (1.0 g) was dissolved in 1,4-dioxane (10 ml) and to the solution was added a solution of 4 mol/l hydrogen chloride-dioxane (3.0 ml) and the mixture was stirred at room temperature for 1 hour. Solvents drove away under reduced pressure, and then the precipitated crystals were filtered and dried to obtain 0,85 g (77%) indicated in the title compound, which is represented hydrochloride a mixture of E-form and Z-form.

Example 12

Receive (E,Z)-[6-cyano-4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene]

Cyanide zinc (2,27 g), Pd2(dba)3(1,14 g) and DPPF (3,47 g) was added to DMF (150 ml) rastvoryeniya 2 (11.6 g) and the mixture was stirred overnight at 120°C in argon atmosphere. The mixture was left in air for cooling, then the reaction mixture was added water, insoluble substances were filtered off and the filtrate was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and then the resulting residue was purified using column chromatography on silica gel (hexane-ethyl acetate = 9:1) to give 1.70 g (17%) indicated in the title compound as an oily product, which is a mixture of E-form and Z-form.

MS (EI): m/z 311 [M++1].1H-NMR (DMSO-d6) δ: is 2.09 and 2.13 (m, 6H), 2,31-of 2.58 (m, 4H), 5,16-5,23 (m, 2H), 6,13-6,16 (m, 1H), for 6.81-of 7.96 (m, 5H).

Example 13

Receive (E,Z)-4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-carboxylic acid [Compound 4]

1 mol/l sodium hydroxide (27 ml) was added to ethanol (25 ml) solution of the compound obtained in Example 12 (1.70 g)and the mixture was subjected to heating up to the boiling point under reflux for 6 hours. Then the reaction mixture was subjected to the same handling procedures as in Example 9, to obtain 1.26 g (70%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 14

Obtain hydrochloride of ethyl (E,Z)-4-(3-dimethylaminopropylamine)-4,10-d the hydro-9-oxa-3-tiebens[f]azulene-6-carboxylate [Compound 3]

Ethanol (50 ml) solution of compound 4 (0.50 g) was cooled in an ice bath, then added thionyl chloride (1.1 ml) and the mixture was stirred over night at 80°C. the Reaction mixture was left in air for cooling, the solvents then drove away under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The washed mixture was dried over anhydrous sodium sulfate, the solvent then drove away under reduced pressure and the residue was purified using column chromatography on silica gel (hexane-ethyl acetate = 9:1) to obtain specified in the connection header in the free state in the form of an oily product which is a mixture of E-form and Z-form. Then carried out the same procedures as in the method of obtaining hydrochloride in Example 11, with the receipt of 0.37 g (64%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 15

Obtaining hydrochloride (E)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acetic acid [Compound 5]

Was carried out by the same procedure as in Example 3, using (E,Z)-[3-(2-bromo-9,10-dihydro-3-tiebens[f]azulene-4-ilidene)propyl]amine (2.00 g), which was obtained by the same procedures as in PR is least 11, from 2-bromo-9,10-dihydro-3-tiebens[f]azulene-4-it, with the receipt of 0.30 g (20%) [4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acetic acid as an oily product, which is a mixture of E-form and Z-form. Then carried out the same procedures as in the method of obtaining hydrochloride in Example 11, to obtain 0.15 g (45%) indicated in the title compound as white crystals.

Example 16

Obtain hydrochloride of ethyl (E,Z)-3-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acrylate [Compound 6]

To a DMF (60 ml) solution of (E,Z)-[3-(2-bromo-9,10-dihydro-1-tiebens[f]azulene-4-ilidene)propyl]dimethylamine (2,82 g) in the free state, which was obtained by the same procedures as in Example 11 from 2-bromo-9,10-dihydro-1-tiebens[f]azulene-4-it was added to the acrylate (8.5 ml), triethylamine (11 ml), palladium acetate (0.14 g) and P(o-Tol)3(0,47 g) in an argon atmosphere and the mixture was stirred over night at 80°C. the Mixture was left in air for cooling, then the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and then the resulting residue was purified using column chromatography on silica gel (hexane-etelaat is = 9:1) getting to 2.29 g (77%) specified in the connection header in the free state in the form of an oily product, representing a mixture of E-form and Z-form. Was carried out by the same procedures as in the method of obtaining hydrochloride in Example 11, using this isomeric mixture (0,76 g) obtaining 0,57 g (68%) indicated in the title compounds as a mixture of E-form and Z-form.

Example 17

Receive (E,Z)-3-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acrylic acid [Compound 7]

Was carried out by the same procedure as in Example 9 using the compound in a free state, obtained in Example 16 (1,53 g), with 0,94 g (66%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 18

Receive (E,Z)-4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-carboxylic acid [Compound 8]

Was carried out by the same procedures as in Examples 12 and 13, in that order, using the (E,Z)-[3-(2-bromo-9,10-dihydro-3-tiebens[f]azulene-4-ilidene)propyl]dimethylamine (6,33 g), which was obtained by the same procedures as in Example 11 from 2-bromo-9,10-dihydro-3-tiebens[f]azulene-4-it, with getting 2,12 g (37%) specified in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 19

Receive (2-hydroxyethyl)amide (E,Z)-4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylic acid, hydrochl the reed [Compound 9]

Dichloromethane (20 ml) solution of (E,Z)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid (0,70 g), a mixture of E-form and Z-form, which was obtained by the same procedures as in Example 18, from 2-bromo-9,10-dihydro-1-tiebens[f]azulene-4-it, N-hydroxysuccinimide (0.25 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0,41 g) was stirred over night at room temperature. The reaction mixture was washed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and the solvent drove away under reduced pressure. The residue was dissolved in dichloromethane (20 ml), was added 2-hydroxyethylamine (0,13 ml) and the mixture was stirred over night at room temperature. The reaction mixture was washed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and the solvent drove away under reduced pressure. The obtained residue was purified using column chromatography on silica gel (chloroform-methanol=19:1) to give 0.50 g (56%) specified in the connection header in the free state in the form of an oily product which is a mixture of E-form and Z-form. Then carried out the same procedures as in the method of obtaining hydrochloride is in Example 11, with the receipt of 0.29 g (34%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 20

Obtaining hydrochloride (E,Z)-2-bromo-4-(3-dimethylaminopropylamine)-4,9-dihydro-1-tiebens[f]azulene-10-she [Compound 10]

Was carried out by the same procedure as in Example 11, using 2-bromo-10-methoxy-1-tiebens[f]azulene-4-it (2,04 g) to give 1.31 g (50%) specified in the connection header in the form of crystals, which is a mixture of E-form and Z-form.

Example 21

Receive (E,Z)-3-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acrylic acid [Compound 11]

Was carried out by the same procedure as in Example 9 using compound 1 obtained in Example 2 (0,99 g), with the receipt of 0.60 g (71%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 22

Receive (2-hydroxyethyl)amide (E)-4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-2-carboxylic acid [Compound 12]

Was carried out by the same procedures as in Example 19, using compound 8 obtained in Example 18 (0.50 g), to obtain 0.14 g (25%) indicated in the title compound as white crystals.

Example 23

Obtain hydrochloride of ethyl (E,Z)-3-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acrylate [the Association 13]

Was carried out by the same procedure as in Example 16, using compound 2 obtained in Example 11 (3,05 g), to obtain 3.03 g (86%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 24

Receive (E,Z)-3-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acrylic acid [Compound 14]

Was carried out by the same procedure as in Example 9 using compound 13 (1.92 g) to obtain 1.25 g (77%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 25

Obtaining (E)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid [Compound 15] and (Z)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid [Compound 16]

The mixture of E-form and Z-form specified in the title compound (1.20 g), which was obtained by the same procedures as in Example 11, 12 and 13, in this order from 2-bromo-9,10-dihydro-1-tiebens[f]azulene-4-she was separated and purified by the same procedures as in Example 5, with the receipt of 0.53 g (44%) and 0.28 g (23%) of compound 15 and compound 16, respectively, in the form of white crystals.

Example 26

Obtaining hydrochloride (E)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acetic acid [Soy is inania 17] hydrochloride and (Z)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acetic acid [Compound 18]

The oily product, a mixture of E-form or Z-form specified in the header of the compounds in the free state, which was obtained by the same procedures as in Examples 3 and 4, in that order, using the (E,Z)-[3-(2-bromo-9,10-dihydro-1-tiebens[f]azulene-4-ilidene)propyl]amine (6.0 g)was converted into the solid form of diethyl ether. The mixture of E-form and Z-form recrystallized from a mixed solution of ethyl acetate-ethanol to obtain 1,02 g (18%) (E)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acetic acid. The residue that was obtained by distillation of the solvent from the filtrate after recrystallization, was separated and purified by the same procedures as in Example 5, to obtain 0.25 g (4%) of (Z)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acetic acid as an oily product. Then carried out the same procedures as in the method of obtaining hydrochloride in Example 11, using each of the isolated and purified compounds with getting 0,80 g (73%) and 0.21 g (75%) of compound 17 and compound 18, respectively, in the form of white crystals.

Example 27

Obtain hydrochloride of ethyl (E,Z)-2-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]-2-methylpropionate [Compound 21]

Dicyclohexylamine (1.45 g) was cooled in an ice bar is the sphere of argon was added dropwise a 1.6 mol/l solution of n-utility in hexane (5.0 ml). To the solution was added dropwise utilizabilitate (0.9 ml) and the mixture was stirred for 30 minutes. Was added Pd(dba)2(0.26 g), 10% solution P(t-Bu)3-hexane (1.0 ml) and (E,Z)-[3-(6-bromo-10H-9-oxo-3-tiebens[f]azulene-4-ilidene)propyl]dimethylamine (1.60 g), the mixture was heated to room temperature and was stirred overnight. To the reaction mixture were added saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and the obtained residue was purified using column chromatography on silica gel (hexane-ethyl acetate = 19:1). Then carried out the same procedures as in the method of obtaining hydrochloride in Example 11, to obtain 1.24 g (65%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 28

Receive (E,Z)-2-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]-2-methylpropionic acid [Compound 22]

Was carried out by the same procedure as in Example 9 using compound 21 (0,98 g) to obtain 0.32 g (39%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 29

Receive (E,Z)-2-[4-(3-dimethylaminopropylamine)-9,10-dig the DRO-4H-1-tiebens[f]azulene-2-yl]-2-methylpropionic acid [Compound 23]

Was carried out by the same procedure as in Example 9, using ethyl (E,Z)-2-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]-2-methylpropionate (1,03 g), which was obtained by using the reaction using a palladium catalyst was carried out by the same procedures as in Example 27, from (E,Z)-[3-(2-bromo-9,10-dihydro-1-tiebens [f]azulene-4-ilidene)propyl]amine, to obtain 0.32 g (33%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 30

Obtain hydrochloride of ethyl (E,Z)-2-[4-(3-dimethylaminopropyl)-10-oxo-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]-2-methylpropionate [Compound 24]

Was carried out by the same procedures as in Example 27 using 2-bromo-4-cyclopropyl-10-methoxy-4H-1-tiebens[f]azulene-4-ol (3,20 g), which was obtained by the same procedures as in Example 6, from 2-bromo-10-methoxy-1-tiebens[f]azulene-4-it, to obtain 1.78 g (50%) of ethyl (2-cyclopropyl-4-hydroxy-10-methoxy-4H-1 tiebens[f]azulene-2-yl)-2-methylpropionate in the form of an oily product which is a mixture of E-form and Z-form. Then carried out the same procedures as in the method of obtaining hydrochloride in Example 11, with the receipt of 0.67 g (33%) indicated in the title compound as an amorphous solid which is a mixture of E-form and Z-form.

Example 31

Obtaining (E)-{2-methyl-2-[4-(3-methylaminopropyl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]}propionic acid [Compound 25]

Was carried out by the same procedure as in Example 9, to handle the connection, which was obtained by the same procedures as in Example 27 (2,74 g), (E,Z)-[3-(6-bromo-10H-9-oxa-3-tiebens[f]azulene-4-ilidene)propyl]methylamine, to obtain 1.68 g (66%) indicated in the title compounds as a mixture of E-form and Z-form. This isomeric mixture was used and was subjected to separation and purification, carrying out the same procedures as in Example 5, with the receipt of 0.60 g (34%) specified in the connection header.

Example 32

Obtain (Z)-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl]acetic acid [Compound 28] and (E)-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl]acetic acid [Compound 29]

The mixture of E-form and Z-form specified in the title compound (1.63 g), which was obtained by the same procedures as in Examples 11 and 9, in that order, from methyl (4-oxo-4,10-dihydro-9-1-tiebens[f]azulene-6-yl)acetate was separated and purified by the same procedures as in Example 5, to obtain 0.39 g (23%) and of 0.58 g (36%) of compound 28 and compound 29, respectively, in the form of white crystals.

Example 33

Obtaining (E)-[4-(3-ethylethylenediamine)-4,10-digit the-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 30] and (Z)-[4-(3-ethylethylenediamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 31]

The mixture of E-form and Z-form specified in the title compounds (1,00 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, from the compound obtained in Example 7, and N-ethylmethylamine, was separated and purified by the same procedures as in Example 5, to obtain 0.21 g (21%) and 0.09 g (9%) of compound 30 and the connection 31, respectively, in the form of white crystals.

Example 34

Obtaining (E)-{4-[3-(morpholine-4-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 32] and (Z)-{4-[3-(morpholine-4-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 33]

The mixture of E-form and Z-form specified in the title compound (1.52 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, from the compound obtained in Example 7, and the research was separated and purified by the same procedures as in Example 5, with the receipt of 0.42 g (28%) and 0.15 g (10%) of compound 32 compound 33, respectively, in the form of white crystals.

Example 35

Obtaining (E)-{4-[3-(piperidine-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 34] and (Z)-{4-[3-(piperidine-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 35]

The mixture of E-form and Z-form specified in the header of the compounds of 1.25 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, from the compound obtained in Example 7, and piperidine were separated and purified by the same procedures as in Example 5, to obtain 0,70 g (56%) and 0.08 g (6%) of compound 34, compound 35, respectively, in the form of white crystals.

Example 36

Obtaining (E)-4-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}butyric acid [Compound 36] and (Z)-4-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}butyric acid [Compound 37]

The mixture of E-form and Z-form specified in the title compound (1.31 g), which was obtained by the same procedures as in Examples 6, 7, 8 and 9, in that order, from methyl 4-(4-oxo-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)butyrate, was separated and purified by the same procedures as in Example 5, with the receipt of 0.60 g (46%) and 0.16 g (12%) compounds 36 and connection 37, respectively, in the form of an amorphous solid.

Example 37

Obtaining (E)-[4-(3-ethylenepropylene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 38] and (Z)-[4-(3-ethylenepropylene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 39]

The mixture of E-form and Z-form specified in the title compound (0.66 g), which was obtained by the implementation of the Aceh same procedures, as in Examples 8 and 9, in that order, from the compound obtained in Example 7, and etilamingidrokhlorida, was separated and purified by the same procedures as in Example 5, to obtain the 0,46 g (70%) and 0.08 g (12%) of compound 38 and connection 39, respectively, in the form of white crystals.

Example 38

Obtaining (E)-[4-(3-benzylaminopurine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 40] and (Z)-[4-(3-benzylaminopurine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 41]

The mixture of E-form and Z-form specified in the title compound (1.54 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, from the compound obtained in Example 7, and n-benzylmethylamine, was separated and purified by the same procedures as in Example 5, to obtain 0.65 g (42%) and 0.10 g (6%) of compound 40 and the connection 41, respectively, in the form of white crystals.

Example 39

Obtaining (E)-[4-(3-benzylaminopurine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 42] and (Z)-[4-(3-benzylaminopurine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 43]

The mixture of E-form and Z-form specified in the title compound (1.51 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, and the connection obtained in Example 7, and benzylamine, was separated and purified by the same procedures as in Example 5, with the receipt of 0.62 g (41%) of compound 42 in the form of amorphous solids and 0.23 g (15%) of compound 43 in the form of white crystals.

Example 40

Obtaining (E)-[4-(3-cyclopentylpropionyl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 44] and (Z)-[4-(3-cyclopentylpropionyl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 45]

The mixture of E-form and Z-form specified in the title compounds (1,00 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, from the compound obtained in Example 7, and cyclopentylamine, was separated and purified by the same procedures as in Example 5, to obtain 0.54 g (54%) and 0.10 g (10%) of compound 44 and the connection 45, respectively, in the form of white crystals.

Example 41

Obtaining (E)-[4-(3-isopropylaminomethyl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 46] and (Z)-[4-(3-isopropylaminomethyl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [Compound 47]

The mixture of E-form and Z-form specified in the title compounds (2,02 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, from the compound obtained in Example 7, and isop is operamini, was separated and purified by the same procedures as in Example 5, with the receipt of 0.38 g (19%) and 0.05 g (2%) of compound 46 and connection 47, respectively, in the form of white crystals.

Example 42

Obtaining (E)-3-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionic acid [Compound 48] and (Z)-3-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionic acid [Compound 49]

Was carried out by the same procedure as in Examples 6 and 7, on the basis of methyl 3-(4-oxo-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)propionate, to obtain methyl (E,Z)-3-[4-(3-bromopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)propionate. Was carried out by the same procedures as in Examples 8 and 9, in that order, using the mixture of E-form and Z-form and dimethylaminohydrolase, obtaining a mixture of E-form and Z-form specified in the title compounds (1,32 g) and the resulting mixture was separated and purified by the same procedures as in Example 5, to obtain 0.33 g (25%) of compound 48 in the form of amorphous solids and 0.06 g (5%) of compound 49 in the form of white crystals.

Example 43

Obtaining (E)-{4-[3-(4-methylpiperazin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 50] and (Z)-{4-[3-(4-methylpiperazin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Conn is 51%]

The mixture of E-form and Z-form specified in the title compounds (0,61 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, from the compound obtained in Example 7 and 1-methylpiperazine, was separated and purified by the same procedures as in Example 5, to obtain 0.25 g (41%) and 0.03 g (5%) of compound 50 compound 51, respectively, in the form of white crystals.

Example 44

Obtaining (E)-3-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}propionic acid [Compound 52] and (Z)-3-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}propionic acid [Compound 53]

The mixture of E-form and Z-form specified in the title compounds (1,21 g), which was obtained by the same procedures as in Examples 6, 7, 8 and 9, in that order, from methyl 3-(4-oxo-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)propionate was separated and purified by the same procedures as in Example 5, to obtain 0.33 g (27%) of compound 52 in the form of white crystals and 0.06 g (5%) of compound 53 in the form of an amorphous solid.

Example 45

Obtaining (E)-{4-[3-(4-phenylpiperazin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 54] and (Z)-{4-[3-(4-phenylpiperazin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Joint the 55]

The mixture of E-form and Z-form specified in the title compound (1.08 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, from the compound obtained in Example 7 and 1-phenylpiperazine, was separated and purified by the same procedures as in Example 5, to obtain 0.11 g (10%) and 0.05 g (5%) of compound 54 compound 55, respectively, in the form of white crystals.

Example 46

Obtaining hydrochloride (E)-3-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl]propionic acid [Compound 56] hydrochloride and (Z)-3-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl]propionic acid [Compound 57]

Was carried out by the same procedure as in Examples 6 and 7, on the basis of methyl 3-(4-oxo-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl)propionate, to obtain methyl (E,Z)-3-[4-(3-bromopropylamine)-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl)propionate. The mixture of E-form and Z-form specified in the title compounds (0,89 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, from the mixture of E-form and Z-form and dimethylaminohydrolase, was separated and purified by the same procedures as in Example 5, to obtain the compounds 56 and connection 57, which consisted of amorphous solids, in the free state. Then made the conduct the same procedure, as in the way to obtain hydrochloride of Example 11, to obtain 0.10 g (11%) and 0.08 g (9%) of compound 56 and connection 57, respectively, in the form of white crystals.

Example 47

Obtaining (E)-3-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl}propionic acid [Compound 58] and (Z)-3-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl}propionic acid [Compound 59]

The mixture of E-form and Z-form specified in the title compound (1.20 g), which was obtained by the same procedures as in Examples 6, 7, 8 and 9, in that order, from methyl 3-(4-oxo-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl)propionate was separated and purified by the same procedures as in Example 5, with the receipt of 0.37 g (31%) and 0.22 g (18%) connection 58 and the connection 59, respectively, in the form of amorphous solids.

Example 48

Obtaining (E)-4-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]butyric acid [Compound 60] and (Z)-4-[4-(3-dimethylaminopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]butyric acid [Compound 61]

Was carried out by the same procedure as in Examples 6 and 7, on the basis of methyl 4-(4-oxo-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)butyrate, to obtain methyl (E,Z)-4-[4-(3-bromopropylamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)butyrate. Was carried out by the same procedure as in the Use of the Ah 8 and 9, in this order, using the mixture of E-form and Z-form and dimethylaminohydrolase obtaining a mixture of E-form and Z-form specified in the title compound (1.52 g) and the resulting mixture was separated and purified by the same procedures as in Example 5, to obtain 0.33 g (22%) of compound 60 in the form of white crystals and 0.09 g (6%) of compound 61 in the form of an amorphous solid.

Example 49

Obtaining (E)-{4-[3-(4-oxopiperidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 62] and (Z)-{4-[3-(4-oxopiperidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 63]

The mixture of E-form and Z-form specified in the title compounds (0,60 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, from the compound obtained in Example 7 and 4-piperidone, was separated and purified by the same procedures as in Example 5, to obtain 0.28 g (47%) and 0.10 g (17%) of compound 62 and connection 63, respectively, in the form of white crystals.

Example 50

Obtaining (E)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-6-yl]acetic acid [Compound 64] hydrochloride and (Z)-[4-(3-dimethylaminopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-6-yl]acetic acid [Compound 65]

Was carried out by the same procedure as in Examples 6 and 7, IP is odya of ethyl (4-oxo-9,10-dihydro-4H-3-tiebens[f]azulene-6-yl)acetate, to obtain ethyl (E,Z)-[4-(3-bromopropylamine)-9,10-dihydro-4H-3-tiebens[f]azulene-6-yl]acetate. The mixture of E-form and Z-form specified in the title compounds (0,91 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, using the mixture of E-form and Z-form and 50% aqueous dimethylamine was separated and purified by the same procedures as in Example 5, to obtain 0.35 g (38%) of compound 64 in the form of white crystals and 0.20 g (22%) of compound 65 in the free state in the form of amorphous solids. Was carried out by the same procedures as in the method of obtaining a hydrochloride of Example 11, treatment of compound 65 in the free state to obtain 0.15 g (68%) indicated in the title compound 65 in the form of white crystals.

Example 51

Getting diformate (E)-{4-[3-([1,4']bipiperidine-1'-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 66] and diformate (Z)-{4-[3-([1,4']bipiperidine-1'-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Connection 67]

The mixture of E-form and Z-form specified in the title compounds (0,83 g), which was obtained by the same procedures as in Examples 8 and 9, in that order, using the compound obtained in Example 7 and 4-piperidinylidene, was separated and purified by implementing such W the procedures as in Example 5, with the receipt of 0.44 g (53%) and 0.14 g (16%) of compound 66 and connection 67, respectively, in the form of amorphous solids.

Example 52

Receive (E,Z)-{4-[3-(thiomorpholine-4-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 68]

Was carried out by the same procedures as in Examples 8 and 9, in that order, proceeding from the compound obtained in Example 7 (2.00 g) and thiomorpholine, obtaining 0,83 g (37%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 53

Receive (E,Z)-2-methyl-2-{4-[3-(pyrrolidin-1-yl)propylidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl}propionic acid [Compound 69]

Was carried out by the same procedures as in Examples 27 and 9, in that order, using the (E,Z)-1-[3-(6-bromo-9,10-dihydro-3-tiebens[f]azulene-4-ilidene)propyl]pyrrolidine (3,01 g), which was obtained by the same procedures as in Examples 6, 7 and 8, in that order, from 6-bromo-9,10-dihydro-3-tiebens[f]azulene-4-it, with the receipt of 1.53 g (51%) indicated in the title compound in the form of crystals, which is a mixture of E-form and Z-form.

Example 54

Obtaining hydrochloride (E)-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 70]

Was carried out by the same procedures as in the method of obtaining hydrochlori is and Example 11, using compound 26 (1,09 g)obtained in Example 10, to obtain 1.10 g (92%) indicated in the title compound as white crystals.

Example 55

Obtaining hydrochloride (Z)-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [Compound 71]

Was carried out by the same procedures as in the method of obtaining a hydrochloride of Example 11 using compound 27 (0.31 g)obtained in Example 10, to obtain 0.31 g (90%) indicated in the title compound as white crystals.

The performance properties of the compounds of the present invention obtained in the Examples described above, are presented in Tables 1-8.

Table. 1-8
Connection # Properties
Connection 1TPL 108°C (decomp.).1H-NMR (DMSO-d6) δ: 1,16-1,25 (m, 3H), 1,99-of 2.66 (m, 10H), 2,94-to 3.02 (m, 4H), was 4.02-4,18 (m, 2H), 5,73-6,12 (m, 1H), 6,38-of 6.45 (m, 1H), 7,12-of 7.48 (m, 6H).
Connection 21H-NMR (DMSO-d6) δ: 2,63-2,95 (m, 8H), 3,20-of 3.27 (m, 2H), 5,10-5,17 (m, 2H), of 5.92-6,05 (m, 1H), for 6.81-to 7.61 (m, 5H), 10,18-10,49 (m, 1H).
Connection 31H-NMR (DMSO-d6) δ: of 1.30 to 1.34 (m, 3H), 2,64-only 2.91 (m, 8H), 3,203,28 (m, 2H), 4,28-4,34 (m, 2H), 5,17-5,24 (m, 2H), 6,03-between 6.08 (m, 1H), 6,83-to 7.99 (m, 5H), 10,16-10,35 (m, 1H).
Connection 41H-NMR (DMSO-d6) δ: 2,13-2,19 (m, 6H), 2,35-2,63 (m, 4H), 5,13-to 5.21 (m, 2H), 6,04-6,12 (m, 1H), 6,80-to $ 7.91 (m, 5H).
Connection 5TPL 220°C (decomp.). MS (EI): m/z 342 [M++1].1H-NMR (DMSO-d6) δ: 2,50 is-3.45 (m, 14H), 5,50-of 5.92 (m, 1H), 6,83-6,86 (m, 1H), 7,15-7,33 (m, 4H), 10,17 (user., 1H), 12,53 (users, 1H).
Connection 61H-NMR (DMSO-d6) δ: 1-22-1,25 (m, 3H), 2,50-of 3.25 (m, 14H), 4,14-4,18 (m, 2H), 5,59-6,14 (m, 2H), 7.18 in-7,51 (m, 5H), 7.68 per-7,79 (m, 1H), 10,10 (users, 1H).
Connection 71H-NMR (DMSO-d6) δ: 2,02-up 3.22 (m, 14H), 5,65-6,04 (m, 2H), 7,14-to 7.68 (m, 6H).
Compound 81H-NMR (DMSO-d6) δ: 2,09-of 2.20 (m, 6H), 2,30-of 3.12 (m, 8H), 5,72-the 6.06 (m, 1H), 7,12-7,33 (m, 4H), 7,98-to 8.14 (m, 1H).

Connection 9MS (EI): m/z 371 [M++1].1H-NMR (DMSO-d6) δ: 2,30-3,51 (m, 18H), 4,69 of 4.83 (user., 1H), 5,57-6,00 (m, 1H), 7,14-7,34 (m, 4H), 7,79-7,83 (m, 1H), 8,39-8,72 (m, 1H), 9,99 of 10.05 (m, 1H).
Connection 101H-NMR (DMSO-d6) δ: 2,52-of 3.25 (m, 10H), 3,69-to 4.28 (m, 2H), 5,97-6,44 (m, 1H), 7,29-7,44 (m, 4H), EUR 7.57-to 7.59 (m, 1H),10,34 (users, 1H).
Connection 111H-NMR (DMSO-d6) δ: 2,08-2,19 (m, 6H), 2,22 is 3.40 (m, 8H), 6,02 to 6.35 (m, 2H), 7,14-7,42 (m, 5H), the 7.85-with 8.05 (m, 1H).
Connection 12MS (EI): m/z 371 [M++1].1H-NMR (DMSO-d6) δ: 2,03 (s, 6H), 2.13 and to 2.35 (m, 4H), 2,50-up 3.22 (m, 6H), 3,42-of 3.46 (m, 2H)and 4.65 (t, J=5.6 Hz, 1H), 6,01-6,04 (m, 1H), 7,15-to 7.32 (m, 4H), a 7.62 (s, 1H), 8,03-of 8.06 (m, 1H).
Connection 131H-NMR (DMSO-d6) δ: 1,24-of 1.27 (m, 3H), 2,66-3,39 (m, 10H), 4,16-is 4.21 (m, 2H), 5,13-5,20 (m, 2H), 6,02-6,05 (m, 1H), 6,60-7,81 (m, 7H), 10,12-10,53 (m, 1H).
The connection 141H-NMR (DMSO-d6) δ: 2,20 was 2.25 (m, 6H), 2,41 of 2.68 (m, 4H), 5,11-5,17 (m, 2H), 6,01-6,09 (m, 1H), 6,46-6,53 (m, 1H), 6,80-7,72 (m, 6H).
The connection 15TPL 154-156°C.1H-NMR (DMSO-d6) δ: 2,32 to 2.35 (m, 8H), 2,83-3,20 (m, 6H), equal to 6.05 (t, J=7,3 Hz, 1H), 7,15 and 7.36 (m, 5H).

The connection 16TPL 160-163°C. MS (EI): m/z 328 [M++1].1H-NMR (DMSO-d6) δ: 2,46-to 3.09 (m, 14H), 5,52-of 5.55 (m, 1H), 7,14-7,29 (m, 5H).
Connection 17TPL 218°C (decomp.). MS (EI): m/z 342 [M++1].1H-NMR (DMSO-d6) δ: 2,36-3,70 (m, 16H), 5,88-of 5.92 (m, 1H), 6,84 (s, 1H), 7,15-7,34 (m, 4H), 10,18 (user., 1H), 12,55 (OSiR.the, 1H).
The connection 18TPL 242°C (decomp.). MS (EI): m/z 342 [M++1].1H-NMR (DMSO-d6) δ: 2,71-to 2.74 (m, 8H), 3.00 and-up 3.22 (m, 6H), 3,76 (s, 2H), of 5.53 (t, J=7.2 Hz, 1H), 6,84 (s, 1H), 7,14-7,29 (m, 4H), 10,31 (users, 1H), 12,56 (users, 1H).
Connection 19TPL 182-184°C. MS (EI): m/z 344 [M++1].1H-NMR (DMSO-d6) δ: 2,12 (s, 6H), 2,35-2,39 (m, 4H), 3,55 (s, 2H), of 5.05 (s, 2H), 6,03-the 6.06 (m, 1H), 6,77-of 6.78 (m, 1H), 7,09-7,11 (m, 1H), 7,19-to 7.32 (m, 3H).
The connection 20TPL 188-190°C. MS (EI): m/z 344 [M++1].1H-NMR (DMSO-d6) δ: 2,19 (s, 6H), 2,46 of 2.68 (m, 4H), 3,53 (s, 2H), 5,12 (s, 2H), 5,85 (t, J=7,3 Hz, 1H), 6.89 in-6,98 (m, 2H), 7,13-to 7.15 (m, 2H), 7,52-7,53 (m, 1H).

Connection 21MS (EI): m/z 400 [M++1].1H-NMR (DMSO-d6) δ: 1,11-of 1.15 (m, 3H), 1,49-of 1.52 (m, 6H), 2,63-of 3.27 (m, 10H), 4,05-4,10 (m, 2H), 5.08 to further 5.15 (m, 2H), 5,80-6,03 (m, 1H), 6,80-to 7.61 (m, 5H), 10,33-10,52 (m, 1H).
The connection 22MS (EI): m/z 372 [M++1].1H-NMR (DMSO-d6) δ: 1,44 of 1.46 (m, 6H), 2,22-to 2.67 (m, 10H), 5,06-5,12 (m, 2H), of 5.82-the 6.06 (m, 1H), 6,78-7,53 (m, 5H).
The connection 23MS (EI): m/z 370 [M++1].1H-NMR (DMSO-d6) δ: 1,48-of 1.52 (m, 6H), 2.05 is-is 3.08 (m, 14H), 5,56-5,96 (m, 1H), 6,98-6,77 (m, 1H), 7,11-7,29 (m, 4H).
Connection 24MS (EI): m/z 412 [M++1].1H-NMR (DMSO-d6) δ: 1,14-1,19 (m, 3H), 1,59-of 1.62 (m, 6H), 2,50-3,39 (m, 10H), 3,66-and 3.72 (m, 1H), 4,07-4,11 (m, 2H), to 4.23-4.26 deaths (m, 1H), 5,93-6,34 (m, 1H), 7,20-the 7.43 (m, 5H), 9,87-to 9.93 (m, 1H).
The connection 25TPL 218°C (decomp.). MS (EI): m/z 357 [M+].1H-NMR (DMSO-d6) δ: to 1.38 (s, 6H), 2,36-to 2.42 (m, 2H), 2.91 in-2,95 (m, 2H), is 5.06 (s, 2H), 6,01 (t, J=8.0 Hz, 1H), for 6.81-PC 6.82 (m, 1H), 7,06-7,37 (m, 4H).
The connection 26TPL 225-227°C. MS (EI) : m/z 370 [M++1].1H-NMR (DMSO-d6) δ: 1,15-1,19 (m, 4H), 2,39 at 2.59 (m, 8H), of 3.54 (s, 2H), of 5.05 (s, 2H), 6,03-6,07 (m, 1H), 6,77-6,69 (m, 1H), 7,09-to 7.32 (m, 4H).

Connection 27TPL 203-205°C. MS (EI) :m/z 370 [M++1].1H-NMR (DMSO-d6) δ: 1,6 was 1.69 (m, 4H), 2,49-a 2.71 (m, 8H), of 3.60 (s, 2H), 5,12 (s, 2H), of 5.84-5,88 (m, 1H), 6.89 in-7,16 (m, 4H), 7,52-rate of 7.54 (m, 1H).
The connection 28TPL 168-170°C.1H-NMR (DMSO-d6) δ: 2,12 (s, 6H), 2,34-2,39 (m, 4H), of 3.54 (s, 2H), 5,17 (s, 2H), 6,07 (t, J=7,1 Hz, 1H), 7,07-7,19 (m, 4H), 7,39-7,41 (m, 1H).
The connection 29TPL 176-179°C.1H-NMR (DMSO-d6) δ: 2,17 (s, 6H), 2.40 a is 2.46 (m, 4H), 3,50 (s, 2H), 5,24 (s, 2H), 5,88-5,91 (m, 1H), 6,84-6,86 (m, 1H), 7,08-7,17 (m, 3H), 7,49-to 7.50 (m, 1H).
The connection 30 TPL 179-180°C.1H-NMR (DMSO-d6) δ: of 0.96 (t, J=7.2 Hz, 3H), 2,12 (s, 3H), 2,35-2,39 (m, 4H), 2,45-of 2.50 (m, 2H), 3,55 (s, 2H), of 5.05 (s, 2H), 6,04-6,07 (m, 1H), 6,77-of 6.78 (m, 1H), 7,09-to 7.32 (m, 4H).
The connection 31TPL 181-182°C.1H-NMR (DMSO-d6) δ: 0,98 (t, J=7.2 Hz, 3H), 2,17 (s, 3H), 2,39 (sq, J=7,1 Hz, 2H), 2,50-to 2.67 (m, 4H), 3,52 (s, 2H), 5,12 (s, 2H), 5,85 (t, J=7.2 Hz, 1H), 6.89 in-to 7.15 (m, 4H), 7,52-7,53 (m, 1H).
The connection 32TPL 172-174°C.1H-NMR (DMSO-d6) δ: 2,30-to 2.40 (m, 8H), 3,52-to 3.58 (m, 6H), of 5.05 (s, 2H), 6,05-6,07 (m, 1H), 6,77-of 6.78 (m, 1H), 7,10-to 7.32 (m, 4H).

The connection 33TPL 193-194°C.1H-NMR (DMSO-d6) δ: 2,37-2,70 (m, 8H), 3,53 is 3.57 (m, 6H), 5,12 (s, 2H), 5,86 (t, J=7,4 Hz, 1H), 6.89 in-7,16 (m, 4H), 7,52-7,53 (m, 1H).
The connection 34TPL 138-140°C.1H-NMR (DMSO-d6) δ: 1,35 of 1.50 (m, 6H), 2,38-of 2.50 (m, 8H), 3,55 (s, 2H), of 5.05 (s, 2H), 6,01-6,05 (m, 1H), 6,77-6,79 (m, 1H), 7,09-to 7.32 (m, 4H).
The connection 35TPL 180-181°C.1H-NMR (DMSO-d6) δ: 1,36-1,49 (m, 6H), 2,37-2,69 (m, 8H), 3,52 (s, 2H), 5,12 (s, 2H), of 5.84 (t, J=7,4 Hz, 1H), 6.89 in-to 7.15 (m, 4H), 7,52-7,53 (m, 1H).
The connection 361H-NMR (DMSO-d6) δ: 1,70-1,80 (m, 6H), 2,13-of 2.16 (m, 2H), 2,41-a 2.71 (m, 10H), 5,04 (s, 2H), 6,03 (t, J=7.5 Hz, 1H), 6,77-of 6.78 (m, 1H), 7,08-7,32 (who, 4H).
The connection 371H-NMR (DMSO-d6) δ: 1,65-of 1.78 (m, 6H), 2,20-2,22 (m, 2H), 2,49-a 2.71 (m, 10H), 5,11 (s, 2H), 5,85-5,88 (m, 1H), 6,88-to 7.09 (m, 4H), 7,52-7,53 (m, 1H).
Compound 38TPL 200-202°C.1H-NMR (DMSO-d6) δ of 1.12 (t, J=7.2 Hz, 3H), 2,43-of 2.50 (m, 2H), 2,80 (sq, J=7.2 Hz, 2H), 2,90-to 2.94 (m, 2H), 3,41 (s, 2H), of 5.05 (s, 2H), 6,03 (t, J=7.7 Hz, 1H), 6,79-for 6.81 (m, 1H),? 7.04 baby mortality-7,35 (m, 4H).

Connection 39TPL 256-258°C.1H-NMR (DMSO-d6) δ: of 1.03 (t, J=7.2 Hz, 3H), 2,50-and 2.79 (m, 6H), 3,50 (s, 2H), 5,12 (s, 2H), 5,85-5,88 (m, 1H), 6,88-to 7.18 (m, 4H), 7,52-rate of 7.54 (m, 1H).
The connection 40TPL 92-94°C.1H-NMR (DMSO-d6) δ: 2,10 (s, 3H), 2,36-of 2.50 (m, 4H), 3,47 (s, 2H), only 3.57 (s, 2H), is 5.06 (s, 2H), 6,07 (t, J=7,1 Hz, 1H), 6,77-6,79 (m, 1H), 7,10-7,33 (m, 9H).
The connection 41TPL 98-99°C.1H-NMR (DMSO-d6) δ: 2,19 (s, 3H), 2,63-of 2.72 (m, 4H), 3,52-of 3.54 (m, 4H), 5,11 (s, 2H), 5,86 (t, J=7.2 Hz, 1H), 6,88-of 6.99 (m, 2H), 7,14-7,31 (m, 7H), 7,51-7,52 (m, 1H).
The connection 421H-NMR (DMSO-d6) δ: 2,38-of 2.45 (m, 2H), 2,69 (t, J=7,0 Hz, 2H), 3,52 (s, 2H), 3,74 (s, 2H), of 5.05 (s, 2H), between 6.08 (t, J=7,4 Hz, 1H), 6,79 (d, J=5,1 Hz, 1H), 7,10 (d, J=7.9 Hz, 1H), 7.18 in-7,7,26 (m, 3H), 7,27-7,26 (m, 5H).
The connection 43 TPL 221°C (decomp.).1H-NMR (DMSO-d6) δ: 2,62 was 2.76 (m, 4H), 3,50 (s, 2H), of 3.73 (s, 2H), 5,10 (s, 2H), 5,88 (t, J=6,6 Hz, 1H), to 6.88 (d, J=5.0 Hz, 1H), of 6.96 (d, J=8.0 Hz, 1H), 7,14 (d, J=8.0 Hz, 1H), 7,17 (s, 1H), 7,18 and 7.36 (m, 5H), 7,51 (d, J=5.0 Hz, 1H).

The connection 441H-NMR (DMSO-d6) δ: 1,48-of 1.53 (m, 4H), 1,63 by 1.68 (m, 1H), 1.85 to to 1.87 (m, 1H), 2,49-2,52 (m, 2H), 2,93-2,96 (m, 2H), 3,29-of 3.31 (m, 1H), 3,47 (s, 2H), is 5.06 (s, 2H), 6,04 (t, J=7,3 Hz, 1H), 6,79 (d, J=5,2 Hz, 1H), was 7.08 (d, J=8.0 Hz, 1H), 7.18 in-7,22 (m, 2H), 7,34 (d, J=5,2 Hz, 1H).
The connection 451H-NMR (DMSO-d6) δ: is 1.31 and 1.33 (m, 2H), 1,44-of 1.45 (m, 2H), 1,58 is 1.60 (m, 2H), 1,71-of 1.74 (m, 2H), 2,64-by 2.73 (m, 4H), 3.04 from-of 3.07 (m, 1H), 3,48 (s, 2H), 5,12 (m, 2H), 5,86 (t, J=7,1 Hz, 1H), to 6.88 (d, J=5,2 Hz, 1H), of 6.96 (d, J=8,1 Hz, 1H), 7,12-7,17 (m, 2H), 7,52 (d, J=5,2 Hz, 1H).
The connection 461H-NMR (DMSO-d6) δ: 1.14 in (d, J=6.2 Hz, 1H), 2,38 at 2.45 (m, 2H), 2,89 (t, J=8.0 Hz, 2H), 3,01-is 3.08 (m, 1H), 3,36 (s, 2H), of 5.05 (s, 2H), 6,04 (d, J=7.7 Hz, 1H), 6,80 (d, J=5,1 Hz, 1H), 7,02-7,14 (m, 2H), 7,24 (s, 1H), 7,35 (d, J=5,1 Hz, 1H).
Connection 471H-NMR (DMSO-d6) δ: 1,05 (d, J=6.2 Hz, 6H), 2,63 are 2.98 (m, 5H), 3,49 (s, 2H), 5,12 (s, 2H), 5,85 (t, J=7.2 Hz, 1H), make 6.90 (d, J=5,2 Hz, 1H), 6,97 (d, J=8,2 Hz, 1H), 7,12-7,19 (m, 2H), 7,55 (d, J=5.0 Hz, 1H).

The connection 481/sup> H-NMR (DMSO-d6) δ: 2,35 is 2.44 (m, 10H), 2,72 is 2.75 (m, 2H), 2,80-of 2.81 (m, 2H), to 5.03 (s, 2H), 5,96 (t, J=7.8 Hz, 1H), 6,77 (d, J=5.3 Hz, 1H), 7,07 (d, J=7.8 Hz, 1H), 7,15-7,17 (m, 2H), 7,31 (d, J=5.3 Hz, 1H), 8,17 (s, 1H).
The connection 491H-NMR (DMSO-d6) δ: 2,20 (s, 6H), 2,47-to 4.52 (m, 4H), 2,64-2,69 (m, 2H), was 2.76-and 2.79 (m, 2H), 5,10 (s, 2H), of 5.84 (t, J=7,1 Hz, 1H), 6.87 in (d, J=5,1 Hz, 1H), 6,94 (d, J=8.5 Hz, 1H), 7,11-7,14 (m, 2H), 7,51 (d, J=5,1 Hz, 1H).
The connection 501H-NMR (DMSO-d6) δ: 1,99 (s, 3H), 2,17-to 2.41 (m, 12H), of 3.57 (s, 2H), of 5.05 (s, 2H), 6,04 (t, J=7.5 Hz, 1H), 6,77 (d, J=4.9 Hz, 1H), 7,10 for 7.12 (m, 1H), 7,20-7,22 (m, 2H), 7,31-7,32 (m, 1H).
The connection 511H-NMR (DMSO-d6) δ: 2,15 (s, 3H), 2,30-2,49 (m, 10H), 2,65-of 2.66 (m, 2H), 3,53 (s, 2H), 5,12 (s, 2H), of 5.82-to 5.85 (m, 1H), 6.89 in (d, J=4,6 Hz, 1H), 6,97 (d, J=7,6 Hz, 1H), 7,10-to 7.15 (m, 2H), 7,52 (d, J=4,6 Hz, 1H).,
The connection 521H-NMR (DMSO-d6) δ: 1.70 to to 1.83 (m, 4H), 2,22-of 2.30 (m, 2H), 2,41-of 2.50 (m, 2H), 2,75 is 2.80 (m, 2H), 2,84-3,00 (m, 6H), 5,02 (s, 2H), 5,94 (t, J=8.0 Hz, 1H), 6,78 (d, J=5.0 Hz, 1H), 7,07 (d, J=8.0 Hz, 1H), 7,15 (d, J=8.0 Hz, 1H), 7,18 (s, 1H), 7,33 (d, J=5.0 Hz, 1H).

The connection 531H-NMR (DMSO-d6) δ: 1,62-of 1.75 (m, 4H), 2,50 is 2.80 (m, 12H), 5,10 (s, 2H), 5,86 (t, J=6,6 Hz, 1H), to 6.88 (d, J=5.0 Hz, 1H), 6,91 (d, J=8.0 Hz, 1H), 7,10-to 7.15 (m, 2H), 7,52 (d, J=5.0 Hz, 1H).
The connection 541H-NMR (DMSO-d6) δ: 2,39-to 2.55 (m, 8H), 3,06-of 3.12 (m, 4H)and 3.59 (s, 2H), is 5.06 (s, 2H), between 6.08 (t, J=7.2 Hz, 1H), 6.73 x-6,79 (m, 2H), make 6.90 (d, J=8.1 Hz, 2H), 7,12 (d, J=8.5 Hz, 1H), 7,16-7,24 (m, 4H), 7,32 (d, J=5,2 Hz, 1H).
The connection 551H-NMR (DMSO-d6) δ: 2,50 was 2.76 (m, 8H), is 3.08-3,14 (m, 4H), 3,53 (s, 2H), 5,13 (s, 2H), 5,88 (t, J=7,3 Hz, 1H), 6,76 (DD, J=7,2, 7.2 Hz, 1H), 6.90 to-6,92 (m, 3H), 6,97 (d, J=8.0 Hz, 1H), 7,13-7,25 (m, 4H), 7,54 (d, J=5.0 Hz, 1H).
The connection 561H-NMR (DMSO-d6) δ: 2,50-only 2.91 (m, 12H), 3,16-is 3.21 (m, 2H), 5,17 (s, 2H), 6,02-between 6.08 (m, 1H), 7,08-7,22 (m, 4H), 7,41-7,47 (m, 1H), 10,02 (users, 1H), 12,13 (s, 1H).
Connection 571H-NMR (DMSO-d6) δ: 2,50-of 2.54 (m, 2H), 2,62-2,77 (m, 10H), 3,18-3,26 (m, 2H, in), 5.25 (s, 2H), 5,86 (t, J=7,0 Hz, 1H), 6,85 (d, J=8,2 Hz, 1H), 7,05-7,20 (m, 3H), 7,53 (d, J=5.0 Hz, 1H), of 10.25 (users, 1H), 12,12 (s, 1H).

The connection 581H-NMR (DMSO-d6) δ: 1,75-to 1.86 (m, 4H), 2,20-2,315 (m, 2H), 2,42-of 2.50 (m, 2H), 2,70-of 2.81 (m, 2H), 2.93 which is 3.00 (m, 6H), 5,14 (s, 2H), 5,98 (t, J=8.0 Hz, 1H), 7,02-7,21 (m, 4H), 7,41 (d, J=5.0 Hz, 1H).
Connection 591H-NMR (DMSO-d6) δ: 1,63-of 1.75 (m, 4H), 2,45-2,70 (m, 6H), 2,72-2,78 (m, 4H), with 5.22 (s, 2H), 5,91 (t, J=7,3 Hz, 1H), for 6.81-6,83 (m, 1H),? 7.04 baby mortality-7,22 (m, 3H), 7,49 (d, J=5.0 Hz, 1H).
Connection 60 1H-NMR (DMSO-d6) δ: 1,71-to 1.82 (m, 2H), 2,16 was 2.25 (m, 8H), 2,39 (d, J=7,0 Hz, 2H), 2,42 is 2.55 (m, 2H), 2,60 (t, J=7.5 Hz, 2H), 5,04 (s, 2H), 6,03 (t, J=7.2 Hz, 1H), 6,77 (d, J=5.0 Hz, 1H), 7,07-7,13 (m, 2H), 7,16 (d, J=8,2 Hz, 1H), 7,31 (d, J=5.0 Hz, 1H).
The connection 611H-NMR (DMSO-d6) δ: 1,73-of 1.80 (m, 2H), 2,14-of 2.23 (m, 8H), 2,41-of 2.50 (m, 2H), 2,52-of 2.56 (m, 2H), to 2.67 (t, J=7.2 Hz, 2H), 5,11 (s, 2H), of 5.84 (t, J=7.2 Hz, 1H), to 6.88 (d, J=5.0 Hz, 1H), of 6.96 (d, J=7.8 Hz, 1H), 7,07-7,10 (m, 2H), 7,52 (d, J=5.0 Hz, 1H).
The connection 621H-NMR (DMSO-d6) δ: 2,28-of 2.30 (m, 4H), 2,41 at 2.45 (m, 3H), 2,55-of 2.58 (m, 2H), 2,63-of 2.66 (m, 3H), to 3.58 (s, 2H), is 5.06 (s, 2H), 6,09 (t, J=7,4 Hz, 1H), 6,78 (d, J=5,2 Hz, 1H), 7,12 (t, J=4,2 Hz, 1H), 7,22 (s, 2H), 7,32 (d, J=5,1 Hz, 1H).

Connection 631H-NMR (DMSO-d6) δ: 2,31-of 2.38 (m, 4H), 2,65-of 2.72 (m, 8H), 3,53 (s, 2H), 5,13 (s, 2H), 5,88-the ceiling of 5.60 (m, 1H), 6.89 in-6,91 (m, 1H), 6,97-6,98 (m, 1H), 7,12-7,17 (m, 2H), 7,52-7,53 (m, 1H).
The connection 641H-NMR (DMSO-d6) δ: 2,07 (s, 6H), 2,11-to 2.42 (m, 4H), 2,50-up 3.22 (m, 4H), 3,51 (s, 2H), of 5.99 (t, J=6,6 Hz, 1H), 6.75 in (d, J=5.0 Hz, 1H), and 7.1 (s, 1H), 7,12 (d, J=7.5 Hz, 1H), 7,20-7,26 (m, 2H).
The connection 651H-NMR (DMSO-d6) δ: 2,75 (s, 6H), 2,85-a 3.01 (m, 4H), 3.25 to to 3.52 (m, 4H), 3,53 (s, 2H), 5,58-5,67 (m, 1H), 6,80-6,83 (m, 1H), 7,0-7,25 (m, 3H), 7,42-to 7.61 (m, 1H), 10,19 (users, 1), 12,31 (s, 1H).
Compound 661H-NMR (DMSO-d6) δ: 1.41 to 1.55V (m, 8H), 1,69-of 1.74 (m, 2H), 1,91-of 1.95 (m, 2H), 2,37-2,39 (m, 4H), 2,58 of 2.68 (m, 4H), 2,88-2,90 (m, 2H), 3,54 (s, 2H), of 5.05 (s, 2H), 6,03 (t, J=7.2 Hz, 1H), 6,77 (d, J=5,2 Hz, 1H), 7,10 (d, J=8,1 Hz, 1H), 7,19-7,21 (m, 2H), 7,30 (d, J=5,2 Hz, 1H), 8,23 (users, 2H).
Connection 671H-NMR (D2O) δ: 1.41 to a 2.01 (m, 8H), 2,31 is 2.33 (m, 2H), 2,82-of 3.25 (m, 8H), 3.40 in at 3.69 (m, 7H), 5,09 (s, 2H), 5,75-5,79 (m, 1H), 6,79-for 6.81 (m, 1H), 7,02-7,03 (m, 1H), 7,11-7,19 (m, 2H), 7,39-7,41 (m, 1H), 8,63 (users, 2H).

The connection 681H-NMR (DMSO-d6) δ: 2,32 of 2.68 (m, 12H), 5,03-5,14 (m, 2H), 5,78-6,03 (m, 1H), 6,76-of 7.82 (m, 5H).
Connection 691H-NMR (DMSO-d6) δ: of 1.46 (s, 6H), 1,61 was 1.69 (m, 4H), 2,22-3,19 (m, 12H), 5,56-5,94 (m, 1H), 6,66-of 6.78 (m, 1H), 7,10-7,29 (m, 4H).
The connection 701H-NMR (DMSO-d6) δ: 1,82-2,00 (m, 4H), 2,58-of 2.66 (m, 2H), 3,12-3,18 (m, 4H), 3.15 and is 3.23 (m, 2H), 3,62 (s, 2H), 5,07 (s, 2H), 6,01 (t, J=7,4 Hz, 1H), 6,80 (d, J=5,2 Hz, 1H), 7,13 (d, J=8.0 Hz, 1H), 7,20-7,58 (m, 2H), was 7.36 (d, J=5,2 Hz, 1H).
Connection 711H-NMR (DMSO-d6) δ: 1,82-2,02 (m, 4H), 2,93 totaling 3.04 (m, 4H), 3,29-to 3.38 (m, 2H), 3,52-3,55 (m, 4H), of 5.15 (s, 2H), of 5.82 (t, J=7.2 Hz, 1H), 6,93 (d, J=5,2 Hz, 1H), 7,00 (d, J=8,2 Hz, 1H), 7,17-7,22 (m, 2H), 7,60 (d, J=5,2 G is, 1H), 10,56 (users, 1H), of 12.33 (s, 1H).

Example 56

Experiment to determine the binding of the human histamine H1 receptor in vitro

The plasmids containing recombinant human histamine receptor H1 (manufacturer company Invitrogen)was transfusional in HEK293A cells using lipofectamine 2000 (Invitrogen). Cells stably expressing the human histamine H1 receptor, was skanirovali using geneticin (Invitrogen). Cells continued to cultivate using the modified Dulbecco eagle medium containing 10% fetal bovine serum, 0.1 mmol/l MEM solution, nonessential amino acids, 2 mmol/l L-glutamine and 0.7 mg/ml geneticin, 5% CO2incubator at 37°C. Cells stably expressing the human histamine H1 receptor, prepared using 50 mmol/l Tris-HCl (pH 7.5) (hereinafter indicated as a buffer), containing 0.1% bovine serum albumin to obtain a concentration of 3×106cells/ml, with a drug sample cells. Fifty microliters buffer, 50 μl of a solution of the test substance in various concentrations and 50 μl of a solution of [3H]pyrilamine (final concentration: 3 nmol/l) was added to each well of 96-hole tablet and stirred, then added 100 μl of the preparation of the sample cells (at a concentration of 3×105cells/well) and is ichinomiya reaction.

Cells were incubated at room temperature for 60 minutes and then filtered on a filter plate UniFilter GF/C (Packard) when immersed in 0.5% polyethylenimine using harvester cells (IH-110, INNOTECH CORPORATION) to stop the reaction and the plate was rinsed with buffer. After washing the tablet was dried sufficiently and was added 20 μl of scintillation fluid (MaxiLight, manufacturer Hidex) and determined the number of pulses per minute (cpm) using a counter for microplates with different labels (Plate Chameleo II, Hidex). Nonspecific binding was determined in the cpm when added 30 µmol/l pyrilamine. The experiments were carried out with n=3 and repeated at least 3 times.

One example of the results is presented in Table 9. Compounds of the present invention showed a very high level of activity in the experiment the binding of the human histamine H1 receptor in vitro.

Connection 19
Table 9
Connection # IR50(nmol/l)
Connection 322,2
Connection 955,7
Connection 1332,4
56,9
Connection 2174,7
The connection 2260,0
The connection 2374,6
Connection 2413,2
The connection 2619,2
Connection 27to 70.2
The connection 2843,4
The connection 2970,7
The connection 3057,6
The connection 34of 31.4
The connection 4019,1
The connection 4299,8
The connection 50of 89.1
The connection 5410,9
The connection 5519,6
The connection 5629,0
Connection 57 56,3
The connection 5823,0
Connection 5936,0
The connection 62of 60.5
The connection 648,56
The connection 6514,0
Compound 6631,2
The connection 6845,2
Connection 6953,8
The connection 7014,3
Connection 7163,4

Example 57

Histamine-induced vascular reaction hyperproliferate in rats (in vivo antihistamine effect)

The SD rat (SPF)male, weighing 180 g pre-fed for one week or more, providing access to solid feed and tap waterad libitumin the conditions of a temperature of 22°C, humidity of 55% and artificial light for 12 hours per day (the period of coverage from 8 a.m. to 8 p.m.), and the rat was hungry within the night, so it can be used in the experiment. Used the Geest is in•dihydrochloride (hereinafter indicated as histamine) and Evans blue by dissolving each in physiological saline using. The test substance was dissolved in water for injection or suspended in 0.5% sodium-carboxymethylcellulose and rat oral injected with a solution or suspension (volume dose: 5 ml/kg body weight). Within 1 hour after injection was administered physiological saline and the solution of histamine by intradermal injection in two places (20 μg/0.05 ml/introduction), with each injection site was in the back of the rat, and in this area the hair was removed with electric clippers hair under ether anesthesia. Physiological saline containing 0.5% Evans blue was administered by injection into the tail vein of rats (1 ml/200 g body weight) immediately prior to intradermal injection of histamine.

After 30 minutes, the animal was decapitated and released the blood and the skin was removed to measure the amount of leaked pigment dyed blue part. The measurement of the amount of leaked pigment was carried out as follows. Cut in two places skin at the site where leaked pigment was placed in a test tube was added 1 ml of 2 mol/l aqueous potassium hydroxide solution and the tube was left overnight at 37°C to dissolve. Then to the solution was added 6 ml of 1:3 mixed solution of 0.67 mol/l phosphoric acid and acetone and the mixture was intensively shaken for 10 minutes. Then the mixture was filtered and measured the POG is odaudu the ability of the filtrate at 620 nm. Absorptive capacity obtained for two locations of the injection of physiological saline, as a control value used for compensation. The number of leaked pigment was calculated from a standard curve of Evans blue at 620 nm.

One example of the results is presented in Table 10. The compound of the present invention showed a very strong antagonistic activity in histamine-induced responses in vascular hyperprolinemia a rat.

Table 10
Connection # ED50(mg/kg)
The connection 160,299
The connection 180,063
Connection 190,24
The connection 200,45
The connection 22Approximately 1
Connection 24Approximately 1
The connection 255,70
The connection 260,156
Connection 270,226
The connection 28<0,1
The connection 29<0,1
The connection 30Approximately 0.3
The connection 31Approximately 1
The connection 33Approximately 0.3
The connection 34Approximately 0.3
The connection 35Approximately 0.1
The connection 431,31
The connection 50of 1.34
Connection 57Approximately 0.1
The connection 58Approximately 0.1
Connection 59Approximately 0.3
The connection 700,42
Connection 710,83
Ketotifen0,54

58

The rate of cerebral H1 receptor mouse (ex vivo)

Mouse ICR, male, age 6 weeks pre-fed for one week or more, providing access to solid feed and tap waterad libitumin the conditions of a temperature of 22°C, humidity of 55% and artificial light for 12 hours per day, and the mouse was hungry within the night, so it can be used in the experiment. The test substance was dissolved in water for injection or suspended in 0.5% solution of carboxymethylcellulose and mouse oral injected with a solution or suspension (volume dose: 0.1 ml/10 g body weight). Within 1 hour after oral administration, the animal was decapitated and the whole brain excluding cerebellum and medulla oblongata, quickly cut out. Cut the fabric brain homogenized using a transmitter station (Kinematica) in 50 mmol/l ice a phosphate buffer saline solution (pH of 7.4, 100 mg/1.9 ml).

In a test tube for reaction (TPX-Tube) was added to 180 μl of brain homogenate and 10 μl of solution3H-pyrilamine (final concentration: 2 nmol/l) and 10 μl of a solution of unlabeled pyrilamine (final concentration: 200 umol/l) or 50 mmol/l phosphate-buffer saline and the mixture is incubated at room temperature for 45 minutes and then was added to 2.0 ml ice 50 mmol/l FOS is atno-buffer saline solution to stop the reaction. The reaction mixture was filtered using a GF/B filter (ADVANTEC), and the filtrate was placed in a test tube and dried overnight at a temperature of 60 degrees. After drying, the product was added to 10 ml scintillation fluid (AL-1, based on toluene, DOJINDO LABORATORIES) and determined the number of disintegrations per minute (dpm) using a scintillation counter (Packard, U.S.A., TRI-CARB 2700TR) (5 minutes/vial).

One example of the results is presented in Table 11. In this experiment requires a high concentration of compounds of the present invention for practicing receptor in the brain, and this indicates a low level of migration in the brain. The presented results show that the compounds of the present invention showed peripheral-selective antihistamine effect, without migrating to the brain, thus, connections can alleviate the side effects on the Central nervous system, such as drowsiness.

Table 11
Connection # ID50(mg/kg)
The connection 1645,8
The connection 182,1
Connection 19
The connection 20109,3
The connection 2218,7
Connection 24174,0
The connection 25>200
The connection 2680,9
Connection 27>200
The connection 285,85
The connection 2923,7
The connection 3095,0
The connection 31>200
The connection 3321,1
The connection 3434,8
The connection 3565,7
The connection 43>80
The connection 50>80
Connection 57>80
The connection 58110,2
Connection 59>200
The connection 7051,4
Connection 71>80
Ketotifen0,51

Based on the results of Examples 57 and 58, above, the value obtained by dividing ID50(Table 11) testing the binding of cerebral receptor on the ED50(Table 10) tests histamine-induced responses in vascular hyperprolinemia presented in Table 12. The higher the value ID50(Table 11) testing the binding of cerebral receptor, the less migration in the brain, i.e. fewer side effects on the Central nervous system, such as drowsiness; and the smaller the value of the ED50(Table 10) in histamine-induced responses in vascular hyperprolinemia, the stronger antihistamine effect. Therefore, the value calculated as ID50/ED50may serve as an index showing that more than the calculated value, the stronger antihistamine effect and less side effects on the Central nervous system, such as drowsiness. As shown in Table 12, the connection of the present invention shows a high value, rasschitannoj is how ID 50/ED50compared to existing antihistaminic drug by ketotifen. Therefore, we can say that the compound of the present invention has the desired properties in the form of pharmaceutical compositions, in particular, as an active ingredient antihistamine, which has a strong antihistamine effect and fewer side effects on the Central nervous system, such as drowsiness.

Table 12
Connection # ID50(mg/kg)/ED50(mg/kg)
The connection 16153,2
The connection 1833,3
Connection 19to 25.3
The connection 20242,9
The connection 2218,7
Connection 24174,0
The connection 25>35,1
The connection 26518,6
Connection 27 >885
The connection 28>58,5
The connection 29>237
The connection 30316,7
The connection 31>200
The connection 3370,3
The connection 34116,0
The connection 35657,0
The connection 43>61,1
The connection 50>59,7
Connection 57>800
The connection 58110,2
Connection 59>666,7
The connection 70122,4
Connection 71>96,4
Ketotifen0,9

Industrial applicability

Aminopropiophenone derivative of the present invention has a high ability to bind histamine is the first H1 receptor, as shown in Table 9, and showed strong antagonistic activity against histamine receptors in histamine-induced responses in vascular hyperproliferate in rats, as shown in Table 10. In addition, Table 11 shows that aminopropiophenone derivative shows a low transfer to the brain, even in the test binding with cerebral receptor, where the mice orally administered the compound, thus, aminopropiophenone derivative of the present invention is preferred from the viewpoint of reducing the side effects on the Central nervous system, such as drowsiness. From the Table 12 values for the joint assessment of antagonistic activity against histamine receptor and transfer to the brain shows that aminopropiophenone derivative of the present invention is a strong antagonist of histamine receptor and has fewer side effects on the Central nervous system, such as drowsiness; therefore aminopropiophenone derivative has properties suitable for the active ingredient of the pharmaceutical composition, as desired antihistamine, so aminopropiophenone derived is extremely useful.

1. Aminopropiophenone derivative or pharmaceutical is Ki acceptable salt or hydrate, where aminopropiophenone derivative represented by the following General formula (I):

where R1and R2that may be the same or different from each other, represent hydrogen or Deputy, selected from the following (a)-(C), provided that the case where both represent hydrogen, excluded:
(a) carbonyl, substituted hydroxy, alkoxy or hydroxyethylamino,
(b) carbonylethyl, substituted hydroxy or alkoxy, and
(c) acrylic acid, including its alkilany ester,
R3and R4that may be the same or different from each other, represent hydrogen, alkyl which may be substituted by phenyl, or cycloalkyl, or
R3and R4, which together form a heterocyclic ring with the nitrogen atom associated with them, are pyrrolidino, piperidino, which may be substituted by oxo or piperidino, piperazinil, substituted alkyl or phenyl, morpholino or thiomorpholine,
And means oxo or absent, represents a carbon or oxygen, one of X and Y is carbon and the other is a sulfur, a portion represented by a dashed line, represents a simple bond or double bond, and the wavy line represents a CIS-form and/or TRANS-form.

2. Aminopropiophenone about svodnoe or its pharmaceutically acceptable salt or hydrate according to claim 1, where a is missing.

3. Aminopropiophenone derivative or its pharmaceutically acceptable salt or hydrate according to claim 2, where In represents the oxygen.

4. Aminopropiophenone derivative or its pharmaceutically acceptable salt or hydrate according to claim 3, where R2represents hydrogen.

5. Aminopropiophenone derivative or its pharmaceutically acceptable salt or hydrate according to claim 4, where X is a carbon and Y is sulfur.

6. Aminopropiophenone derivative or its pharmaceutically acceptable salt or hydrate according to claim 5, where R1is carbonylethyl, substituted hydroxy.

7. Aminopropiophenone derivative or its pharmaceutically acceptable salt or hydrate according to claim 1, where aminopropiophenone derivative represented by the General formula (I)is a compound selected from (E)-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl} acetic acid,
(Z)-{4-[3-(pyrrolidin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid,
(E)-[4-(3-ethylethylenediamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid,
(Z)-[4-(3-ethylethylenediamine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid,
(E)-{4-[3-(piperidine-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid,
(Z)-{4-[3-(piperid the n-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid,
(Z)-[4-(3-benzylaminopurine)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid and
(E)-{4-[3-(4-methylpiperazin-1-yl)propylidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid.

8. Pharmaceutical composition having antagonistic activity against histamine receptor, comprising at least one of aminopropiophenone derivatives, its pharmaceutically acceptable salts and hydrates defined in any one of claims 1 to 7, and a pharmaceutically acceptable carrier or diluent.

9. Antihistamine, including at least one of aminopropiophenone derivatives, its pharmaceutically acceptable salts and hydrates defined in any one of claims 1 to 7.

10. Application aminopropiophenone derivative or its pharmaceutically acceptable salt or hydrate defined in any one of claims 1 to 7, in getting medicines for treating at least one disease selected from asthma, allergic rhinitis, pollinosis, allergic rash and atopic dermatitis.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula: , wherein Y represents -CO2H; A represents -(CH2)n-Ar-(CH2)o-, wherein Ar represents thiophenyl; total m and o is equal to 3, and wherein 1 group -CH2- may be substituted by O; G and G' represents -H; and B represents phenyl containing 1 to 2 substitutes independently specified in -F, -Cl and -Br. The invention also refers to a composition on the basis of the mentioned compounds.

EFFECT: there are produced new compounds and pharmaceutical composition on their basis which can find application in medicine for treating glaucoma or ocular hypertension.

10 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

,

where X is O, NH or N-Rx, and Rx, Ra, Rb, R10a, R11a, R2, R3, R4 are selected from hydrogen, different aliphatic, alicyclic, aromatic, heteroaromatic and functional groups which can be optionally substituted, wherein R4 together with R2 can form a C1-C5alkylene or C3-C5alkenylene fragment. Said compounds are positive modulators of metabotropic glutamate receptor 2 and can be used in medicine.

EFFECT: novel biologically active compounds are efficient when treating a range of diseases of the nervous system which are mediated by the dysfunction of the glutamate receptor.

23 cl, 590 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new derivatives of ((phenyl)imidazolyl)methylheteroaryl of formula wherein A represents pyridyl or thienyl having 0 or 1 substitute; B represents phenyl having 0, 1 or 2 substitutes; wherein each substitute independently represents alkyl having 1 to 8 carbon atoms, -F, -Cl, -Br or -CF3. Also, the invention refers to the use of the declared compounds for the purpose of preparing a therapeutic agent, a pharmaceutical composition on the basis of the declared compounds, and to a kit containing the pharmaceutical composition above.

EFFECT: there are prepared new derivatives of ((phenyl)imidazolyl)methylheteroaryl effective in pain management.

10 cl, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts wherein r represents 1; Ar is specified in and , R1 is specified in -COOR1a, -NHSO2R1b, -SO2NHR1d, -SO2OH, -O-CH(R1e)-COOH and tetrazol-5-yl, R1a represents H, -C1-6alkyl, -C1-3alkylenaryl, -C1-3alkyleneheteroaryl, - C3-7cycloalkyl, -CH(C1-4alkyl)OC(O)R1aa, or R1aa represents -O-C1-6alkyl or -O-C3-7cycloalkyl; R1b represents R1c; R1d represents -C1-6alkyl or -C0-4alkylenaryl; R1d represents -C(O)R1c or -C(O)NHR1c; R1e represents -C1-4alkyl; Y represents -C(R3)-, Z represents -N-, Q represents -C(R2)-, and W represents a bond; Y represents -N-, Z represents -C(R3)-, Q represents -C(R2)-, and W represents a bond; Y represents -C(R3)-, Z represents -N-, Q represents -N-, and W represents a bond; or Y represents -C(R3)-, Z represents -CH-, Q represents -C(R2)-, and W represents -C(O)-; R2 is specified in H, halogen, -C1-6alkyl, -C3-6dicloalkyl, and -C0-5alkylene-OR2b; wherein R2b is specified in H and -C1-6alkyl; R3 is specified in -C1-10alkyl and -C0-5alkylene-O-C0-5alkylene-R3b; and R3b represents -C1-6alkyl; X represents -C1-12alkylene-, where at least one group -CH2- in alkylene is substituted by the group -NR4a-C(O)- or -C(O)-NR4a-, wherein R4a is specified in H, -OH, and -C1-4aalkyl; R5 is specified in -C0-3 alkylene-SR5a, -C0-3alkylene-C(O)NR5bR5c, -C0-3alkylene-NR5b-C(O)R5d, -NH-C0-1alkylene-P(O)(OR5e)2, -C0-2alkylene-CHR5g-COOH and -C0-3alkylene-C(O)NR5h-CHR5i-COOH; R5a represents H or -C(O)-R5aa; R5aa represents -C1-6alkyl, -C0-6alkylene-C3-7cycoalkyl, -C0-6alkylenaryl, or -C0-6alkylenemorpholine; R5b represents -OH, -OC(O)R5ba, -CH2COOH or -OC(S)NR5bbR5bc; R5ba represents -C1-6alkyl, -OCH2-aryl or -CH2O-aryl; R5bb and R5bc independently represents -C1-4alkyl; R5c represents H; R5d represents H; R5e represents H; R5g represents H or -CH2-O-(CH2)2-O-CH3; R5h represents H; R5i represents -C0-3alkylenaryl; R6 is specified in -C1-6alkyl, -C0-3alkylenaryl, -C0-3alkyleneheteroaryl and -C0-3alkylene-C3-7cycloalkyl; and R7 represents H or together with R6 to form -C3-7cycloalkyl; where each ring in Ar and each aryl and heteroaryl in R1-3 and R5-6 are optionally substituted by 1-3 substitutes optionally specified in -C1-6alkyl, -CN, halogen, -O-C1-6alkyl, -phenyl, -NO2, wherein each alkyl is optionally substituted by 1-5 fluorine atoms; each carbon atom in X is optionally substituted by one or more groups R4b, and one group -CH2- in X may be substituted by -C4-8cycloalkylene- and -CH=CR4d-; where R4b is specified in -C0-5alkylene-COOR4c and benzene, where R4c represents H; and R4d represents -CH2-thiophen; each alkyl and each aryl in R1-3, R4a-4d and R5-6 are optionally substituted by 1-7 fluorine atoms; where aryl represents monovalent aromatic hydrocarbon having one ring or condensed rings, and contains 6-10 carbon atoms in the ring; and heteroaryl represents a monovalent aromatic group having one ring or two condensed rings, and having 5-10 atoms in large in the ring with one atom of the ring represents a heteroatom specified in nitrogen, oxygen and sulphur. Besides, the invention refers to a pharmaceutical composition based on the compound of formula

,

to a method for preparing the compound of formula (I), to intermediate compounds used in synthesis of the compound of formula (I), to the use of the compounds of formula (I).

EFFECT: there are prepared new compounds possessing activity of a type 1 angiotensin II (AT1) receptor antagonist and activity of neprilysin inhibition.

38 cl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula in which: X denotes S, N-R5 or O; R denotes H; alkyl; heteroaryl, which is a thienyl optionally substituted with alkyl; R1 denotes alkyl; aryl, optionally substituted with a halogen; heteroaryl which is a thienyl optionally substituted with an alkyl, a a halogen, a methoxy group; R2 denotes heteroaryl which is 2-, 3- or 4-pyridyl; R3 denotes H; aryl, optionally substituted with a halogen, a methoxy group; heteroaryl, which is a thienyl optionally substituted with a halogen; alkyl, optionally substituted with oxytetrahydropyranyl; R4 denotes H; R5 denotes H; alkyl; or salt thereof.

EFFECT: invention also relates to a method of producing said compounds, which can be used as antifungal agents for crops, as well as agents against other pests, such as insects or mites and weeds which can harm crops.

10 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing α,ω-bis-[2-(N,N-dimethylamino)thien-5-yl]alkanes, which involves reaction of α,ω-bis-[2-(N,N-dimethylaminomethyl)ethynyl]alkane, where (alkane = propyl, butyl, hexyl), with excess elementary sulphur (S8) in the presence of a three-component catalyst consisting of cobalt acetylacetonate Co(acac)2, triphenylphosphine Ph3P and triethylaluminium Et3Al, taken in molar ratio α,ω-bis-[2-(N,N-dimethylaminomethyl)ethynyl]alkane:S8:Co(acac)2:Ph3P:Et3Al=10:(40-60):(0.3-0.7):(0.6-1.4):(0.9-2.1), preferably 10:50:0.5:1.0:1.5, at temperature 125-135°C and atmospheric pressure for 5-7 hours.

EFFECT: obtaining novel compounds which can be used as biologically active compounds, additives to oil and process lubricants and in fine organic synthesis.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazoline derivatives of formula (I), where n equals 0 or 1, R1 denotes a saturated branched or straight unsubstituted C1-C4alkyl, saturated unsubstituted C3-C8cycloalkyl or unsubstituted phenyl bonded through a C1-C3alkyl chain, R2 denotes an unsubstituted or halogen atom-monosubstituted phenyl or thiophenyl, or unsubstituted phenyl bonded through a C1-C3alkyl chain, R3 denotes a saturated branched or straight C1-C8alkyl which is not substituted or contains one substitute selected from a group comprising -COO-methyl, thiomethyl or thiobenzyl, or a phenyl which is mono-substituted with a halogen atom and bonded through a C1-C3alkyl chain, R4 denotes a C1-C4alkyl, R5 and R6 independently denote a saturated branched or straight C1-C6alkyl, in form of a racemate, enantiomers, diastereomers, mixture of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method for synthesis of the compound of formula (I), intermediate compounds of formula B , a medicinal agent based on the compound of formula (I) or formula B and use of compounds of formula (I) or formula B to prepare a medicinal agent.

EFFECT: novel derivatives of imidazoline and substituted aldehyde of formula B, having µ-opiate receptor affinity, are obtained.

16 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula 1a:

, wherein: A means CH=CH orS; R23 means hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkyloxy or (C1-C4)-alkyl-S-; R24 means hydrogen or halogen when A means CH=CH or hydrogen, halogen, (C1-C4)-alkyl when A means S; X means N(H)C=O, N(H)S(O)2, C=ON(H) or S(O)2N(H); Y means C(R12)=C(R13), N=C(R14) or C(R15)=N, or condensed optionally substituted 5-7-member carbocyclyl; R12 means hydrogen, halogen, (C1-C10)-alkyl, (C2-C10)-alkenyl, (C3-C6)-cycloalkyloxy, (C3-C10)-cycloalkenyloxy, (C3-C6)-cycloalkyl, (C3-C10)-cycloalkenyl, (C3-C6)-cycloalkyl[(C1-C4)-alkyl or (C2-C4)-alkenyl], (C3-C6)-cycloalkyl (C1-C4)-alkyloxy, (C1-C10)-alkyloxy, (C3-C10)-alkenyloxy, (C1-C10)-alkyl-S-, cyano, (C1-C10)-alkylcarbonyl- or phenyl; R13 means hydrogen, halogen or (C1)-alkyl; R14 means hydrogen or (C1-C3)-alkyl-S(O)m; R15 means hydrogen, halogen, (C1-C10)-alkyl, amino, [(C1-C10)-alkyl or (C2-C10)-alkenyl] amino, [(C1-C10)-alkyl or (C2-C10)-alkenyl]((C1-C10)-alkyl)amino or nitro; R21 means hydrogen; R22 means hydrogen, halogen, (C1)-alkyl, while Y means C(R12)=C(R13), N=C(R14) or C(R15)=N; R51 means COOH or CONH(R53); R53 means R55-SO2- or tetrazolyl; R55 means (C1-C4)-alkly; and m is equal to 0; wherein all specified phenyl groups may be independently substituted by one or more halogen atoms; wherein all specified alkyl groups may be independently substituted by one or more fluorine atoms; or its stereoisomer form, a mixture of stereoisomer forms in any ratio or its physiologically acceptable salt, provided the following compounds are excluded: 2-benzoylamino-2,3-dihydro-2-indencarboxylic acid; 2-(naphthalin-2-ylsulphonylamino)indane-2-carboxylic acid. Also, the invention refers to a pharmaceutical composition possessing CXCR5 receptor inhibitory activity on the basis of the compounds described above, as well as a method of treating a patient, involving introducing said compounds into the patient.

EFFECT: there are prepared and described the new compounds which possess CXCR5 inhibitory action and may be used for treating and preventing various inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, lupus, and Crohn's disease.

17 cl, 397 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel aminoindane derivatives of formula (Ia) or pharmaceutically acceptable salts thereof, which have NMDA receptor antagonist effect, and can be used to prepare a medicinal agent for treating dementia. In formula (Ia):

,

R1 is a lower alkyl, C5-C6 cycloalkyl, phenyl which can be substituted with OH, lower alkyl, halogen atom, O-alkyl, C5-C6 heteroaryl containing a S atom as a heteroatom, or lower alkyl substituted with one or more halogen atoms, R2 and R3 are identical or different, each denoting alkyl or phenyl, R4 and R5 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-lower alkyl, -lower alkylene-OH or -lower alkylene-O-lower alkyl, R6-R9 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-lower alkyl, halogen atom, lower alkyl substituted with one or more halogen atoms, OH, CN, lower alkenyl or nitrogen-containing C5-C6 heterocyclic group, R10 and R11 are identical or different and each denotes a hydrogen atom or lower alkyl. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: improved properties of the derivative.

6 cl, 15 tbl, 130 ex

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing exo-tricyclo[4.2.1.02.5]nonane-3-spiro-1'-(3'-thia)cyclopentane, which involves reaction of 3-methylene-exo-tricyclo[4.2.1.02.5]nonane with triethylaluminium in the presence of a zirconocene dichloride catalyst (Cp2ZrCl2) in an argon atmosphere at room temperature and atmospheric pressure in hexane for 4 hours and then addition of elementary sulphur (S8) to the reaction mass, taken in amount equimolar to AlEt3 and stirring at temperature 80°C for 5-7 hours.

EFFECT: design of a method for synthesis of a novel compound which can be used in fine organic synthesis, production of highly efficient antiscoring and antiwear oil additives, biologically active substances.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 1,2,3,4,5,6,7,9,10,11,12,13,14,15-tetradecahydrocyclonone[b,d]thiophene of general formula (1): , characterised by that cyclonone-1,2-diene reacts with ethylaluminium dichloride (EtAlCl2) in the presence of Mg (powder) and a zirconocene dichloride (Cp2ZrCl2) catalyst in molar ratio cyclonone-1,2-diene : EtAlCl2 : Mg : Cp2ZrCl2 = 20:(11-13):20:(1.0-1.4), preferably 20:12:20:1.2, in an argon atmosphere at room temperature (20-22°C) and atmospheric pressure for 6-8 hours in tetrahydrofuran, and subsequent addition of an amount of elementary sulphur S8 which is equimolar to EtAlCl2, benzene as a solvent and heating the reaction mass for 6 hours at approximately 80°C and the reaction mass is kept at approximately 140°C for 1 hour after evaporation of light solvents.

EFFECT: method for synthesis of a novel compound which can be used in fine organic synthesis and synthesis of biologically active heterocyclic compounds.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 3,4,5,6,7,8,9,10-octahydro-2H-cyclonone-[b]thiophene of general formula (I): , characterised by that cyclonone-1,2-diene reacts with triethylaluminium (Et3Al) in the presence of a zirconocene dichloride (Cp2ZrCl2) catalyst in molar ratio cyclonone-1,2-diene : Et3Al : Cp2ZrCl2 = 10:(10-14):(0.4-0.6) in an argon atmosphere at normal pressure in hexane for 8-12 hours and then addition of elementary sulphur S8 in an amount equimolar to Et3Al and heating the reaction mass for 4 hours at temperature of 80°C in benzene.

EFFECT: design of a method for synthesis of a novel compound which can be used in fine organic synthesis, production of highly efficient antiscoring and antiwear oil additives, biologically active substances.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method for synthesis of 1,2,3,4,5,6,10,11,12,13,14,15,15a,15b-tetradecahydro-dicyclonone[b,d]thiophene of general formula (1): characterised by that cyclonone-1,2-diene is reacted with ethylmagnesium bromide (EtMgBr/ether) in the presence of Mg (powder) and a titanocene dichloride (Cp2TiCl2) catalyst taken in molar ratio cyclonone-1,2-diene : EtMgBr : Mg : Cp2TiCl2 = 20:(22-26):20:(1.0-1.4), preferably 20:24:20:1.2, in an argon atmosphere at room temperature (20-22°C) and atmospheric pressure for 6-8 hours in diethyl ether, with subsequent addition of an amount of elementary sulphur S8 which is equimolar to k EtMgBr, benzole as a solvent and heating the reaction mass for 5 hours at temperature of approximately 40°C.

EFFECT: design of a method of obtaining a new compound 1,2,3,4,5,6,10,11,12,13,14,15,15a,15b- tetradecahydro-dicyclonone[b,d]thiophene which can be used in fine organic synthesis, as well as for synthesis of biologically active heterocyclic compounds.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new biologically active substances and specifically to 4-(methylphenyl)-4-oxo-2-[3-ethoxycarbonyl-4,5-R2,R1-thiophen-2-ylamino]but-2-enoic acid of general formula: R1,R2=CH3 R1+R2=(CH2)3.

EFFECT: obtaining new compounds having anti-inflammatory and analgesic activity, as well as low toxicity, which can be used as medicinal agents.

1 cl, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: described are novel thiophene derivatives of formula (1) and pharmaceutically acceptable salts thereof, where A is -CH2CH2-, -NH-CH2-, -CH2-O or -CH2NH-, R1 is hydrogen or alkyl, when X is C-R4, R1 additionally represents halogen, and when A is -CH2-CH2- or -CH2NH, R1 additionally represents alkoxy, R2 is hydrogen, alkoxy, fluoralkoxy, hydroxyalkoxy, hydroxyalkyl, di-(hydroxy)alkoxy, pyridinyl-3-methoxy, pyridinyl-4-methoxy, R3 is hydrogen, alkyl, trifluoromethyl, and when X is C-R4, R3 additionally represents halogen, and when A is -CH2-CH2-, R3 additionally represents alkoxy, X is N or C-R4, R4 is hydrogen, alkyl, alkoxy or halogen, R5 is methyl or ethyl. Also described are isomers of the said compounds, an initial compound for synthesis of formula (1) compound, which has agonistic effect on S1P1/EDG1 receptors, as well as a pharmaceutical composition based on formula (1) compound and use of formula (1) compound.

EFFECT: obtaining a pharmaceutical composition for preventing or treating diseases or disorders associated with activated immune system.

19 cl, 2 tbl, 167 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-alkyl-5,6,7,8,9,10-hexahydro-4H-cyclonone[b]thiophenes of general formula : (1), where R=n-C5H11, n-C7H15, n-C9H19, characterised by that the mixture of cyclonone-1,2-diene and alka-1,2-diene (octa-1,2-diene, deca-1,2-diene, dodeca-1,2-diene) is reacted with ethylmagnesium bromide (EtMgBr/ether) in the presence of Mg (powder) and titanocene dichloride (Cp2TiCl2) catalyst, taken in molar ratio cyclonone-1,2-diene : alka-1,2-diene : EtMgBr : Mg : Cp2TiCl2= 10:10:(22-26):20:(1.0-1.4), preferably 10:10:24:20:1.2, in an argon atomosphere at room temperature (20-22°C) and atmospheric pressure for 6-8 hours and diethyl ether, with subsequent addition of an amount of elementary sulphur S8 which is equimolar to EtMgBr, benzene as a solvent and heating the reaction mass for 6 hours at temperature of approximately 40°C, then after evaporation of light solvents, the reaction mass is kept for 1 hour at temperature of approximately 140°C.

EFFECT: compounds can be used in the food industry as components of flavour boosters, biologically active compounds, dyes, oil additives and hydraulic liquids.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new method for the chemical synthesis of asymmetrically or symmetrically substituted β-(1→6)-bound glucosamine disaccharide of formula (1), as well as to a method for purifying it. The invention declared the intermediate compounds referred to the given method.

EFFECT: invention refers to a pharmaceutical composition comprising the mentioned compounds, and to the use of the compounds in treating the disorders affected by immune system activity modulation, including the inhibition or activation of the immune system, such as a disorder selected from immune disorders and/or cancer.

26 cl, 8 ex, 26 dwg

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