Piperidine derivative

FIELD: chemistry.

SUBSTANCE: present invention relates to a piperidine derivative of general formula (I)

,

where R1 denotes hydrogen or a substitute selected from the following (b)-(i): b) acrylic acid (including alkyl ester and hydroxyalkyl amide), (c) ureide, (d) alkenyl, (e) aminoalkyl which can be substituted with alkyl carbonyl or aminocarbonyl, (f) carbonyl alkyl, substituted with hydroxy, alkoxy or hydroxyalkylamino, (g) carbonyl, substituted with hydroxy, morpholino, alkoxy, hydroxyalkyl aminoalkoxy or cyclohexyloxy carbonyloxyalkoxy, (h) carbonylamino, substituted with alkyl or alkoxy, (i) aminocarbonyl which can be substituted with one or two substitutes selected from amino, hydroxy, alkoxy, alkenyl and alkyl (which can be substituted with halogen, thiol, piperidino, amino, alkoxy, alkoxycarbonyl, aminocarbonyl or one or two hydroxy); R2 denotes hydrogen or a substitute selected from the following (j)-(r): (j) cyano, (k) acrylic acid, (l) alkyl, substituted with hydroxy or piperidino, (m) carbonyl alkyl, substituted with hydroxy, alkoxy (which can be substituted with cyclohexyloxy carbonyloxy) or hydroxyalkylamino, (n) carbonyl, substituted with hydroxy or alkoxy, (o) carbonyl alkoxy, substituted with alkoxy, (p) carbonyl alkyl sulphanyl, substituted with hydroxy or alkoxy, (q) alkoxy, (r) halogen; and R3 denotes hydrogen or a substitute selected from the following (s)-(w): (s) alkyl which can be substituted with carboxy, cyano, pyrrolidyl, piperidino, alkoxy, alkyl sulphanyl or one or two hydroxy, (t) carbonyl, substituted with alkyl or alkoxy, (u) carbonyl alkoxyalkyl, substituted with hydroxy or alkoxy, (v) carbonyl alkyl, substituted with alkyl, alkoxy or alkylphenyl, (w) aminoalkyl, substituted with aminocarbonyl or alkane sulphonyl, where one of said R1 and R2 denotes a substitute other than hydrogen, A is unsubstituted or is an oxo, B denotes carbon or oxygen, one of X and Y denotes carbon and the other denotes sulphur, the dotted line denotes a single bond or a double bond, under the condition that when R2 denotes halogen or alkoxy, A is unsubstituted, R1 denotes a substitute other than hydrogen and B denotes oxygen. The invention also relates to an antihistamine which contains a compound of formula I and use of the described compound for treatment and production of a medicinal agent.

EFFECT: novel compounds having antagonistic action on histamine receptors are obtained and described and can be suitable as active ingredients of a pharmaceutical composition, especially an antihistamine composition.

17 cl, 40 ex, 21 tbl

 

The technical FIELD

The present invention relates to a derivative of piperidine and its pharmaceutically acceptable salt and hydrate, which are suitable as pharmaceutical compositions, in particular of active ingredients such as antihistamines.

The LEVEL of TECHNOLOGY

Histamines are representative of chemical mediators that induce allergic reaction, histamines are released from cells such as mast cells and basophils when substances that cause allergies, penetrate into the body. Released histamines contact with a protein receptor for histamine type 1 (H1-receptor), while pharmacological effects, such as hypotension, increased vascular permeability, smooth muscle contraction, vasodilatation or hypersecretion glands, and are involved in allergic reactions and inflammation. As described above, histamines are released in various human diseases, and allergic diseases and inflammation can be prevented or treated by controlling their actions. Means for controlling the release of histamine and means for inhibiting the binding of histamines with receptors (antihistamines) commercially available in large quantities, and these funds are used for diseases such as bronchial asthma, allergic Rini is, hay fever, urticaria and atopic dermatitis.

However, antihistamines, as you know, have some undesirable side effects, such as sedation, sleepiness, dizziness and discomfort, based on the actions in the Central nervous system; and dry mouth, dryness of mucous membranes and impaired vision, based on anticholinergic actions; thus, there are certain restrictions apply, such as the prohibition of taking antihistamines prior to driving cars, which, in turn, lead to inconvenience in use. For these reasons, patients and medical institutions are required antihistamines that do not have such problems and have excellent effects. The authors of the present invention found a piperidine derivative of the present invention, have fewer side effects in the Central nervous system and strong antihistamine effect.

Derivatives of piperidine with thiabendazole frame described in patent publications 1-13, among which are the derivatives of piperidine, which are described in patent publications 1 to 7, are compounds which differ from the compounds according to the present invention by the fact that R1and R2the following General formula (I) are hydrogen. Chrome is also in patent publication 8 describes the connection, where R1the following General formula (I) represents an alkyl which may be substituted by acyl or hydroxy, and R2represents a hydrogen or chlorine. In patent publications 9-13 described compounds, where R1represents hydrogen and R2represents halogen, alkyl or alkoxy in the following General formula (I). However, in patent publication 8 describes that the compound has a sedative effect, and in patent publication 9 is described that the compound has an antagonistic action against ptosis and catalepsy and suppressive actions against abnormal drop in body temperature and tremor, respectively. In addition, the compounds described in patent publications 10-13, have antihistamine effect, but they are not described mitigation, as in the case of compounds of the present invention, side effects in the Central nervous system, such as drowsiness, which is a side reaction of the common antihistamines. For example, ketotifen fumarate, is described in patent publication 10, is widely used as an antihistamine of the second generation, in its application, there are side reactions that induce drowsiness. As described above, hitherto not been described production is derivative of piperidine, having thiobenzophenone frame, with fewer side effects in the Central nervous system and strong antihistaminic action, as the compounds of the present invention.

Patent publication 1: Japan Patent published under No. Hei-3-294277

Patent publication 2: Unexamined patent publication Japan No. 2001-519789

Patent publication 3: Unexamined patent publication Japan No. Hei-6-504992

Patent publication 4: Japan patent published under No. Hei-1-104069

Patent publication 5: Japan patent published under No. Sho-57-77673

Patent publication 6: examined patent publication Japan No. Sho-57-60351

Patent publication 7: Unexamined patent publication Japan No. Hei-3-504855

Patent publication 8: Japan patent published under No. Sho-49-69677

Patent publication 9: Japan patent published under No. Sho-51-110572

Patent publication 10: Examined patent publication Japan No. Sho-52-17030

Patent publication 11: Examined patent publication Japan No. Sho-55-8984

Patent publication 12: Japan patent published under No. Sho-48-81869

Patent publication 13: French patent No. 1437412

Description of the INVENTION

PROBLEMS to be SOLVED by the INVENTION of

The present invention is the provision of pharmaceutical is eskay composition, which has fewer side effects in the Central nervous system, such as drowsiness, and excellent action, in particular as an active ingredient, such as an antihistamine.

MEANS FOR SOLVING PROBLEMS

As a result of extensive research antihistamine compounds with the characteristics mentioned above, the authors of the present invention found that the piperidine derivative represented by structural formula (I), below, is a compound suitable as a medicinal product, which has excellent antihistaminic effect and softens side effects in the Central nervous system, such as drowsiness. Thus, the present invention is an improvement.

The EFFECTS of the INVENTION

A derivative of piperidine according to the present invention has an excellent antagonistic action on the receptors of histamine and shows the low passage into the brain even in the test binding receptors of the brain, where the mice orally administered compound, and therefore, it has the effect of mitigating the side effects in the Central nervous system, such as drowsiness. Thus, a derivative of piperidine has the properties desired for the active ingredients of the pharmaceutical composition is, such as antihistamines, and is highly useful.

The BEST WAYS of carrying out the INVENTION

The present invention relates to a derivative of piperidine and its pharmaceutically-priemlimymi salt and hydrate, where the piperidine derivative corresponds to the following General formula (I):

where R1means hydrogen or Deputy, selected from the following (a)to(j):

(a) halogen,

(b) cyano,

(c) an acrylic acid (including alkilany ester and hydroxyalkylated),

(d) ureido,

(e) alkenyl

(f) aminoalkyl, which can be substituted by alkylcarboxylic or aminocarbonyl,

(g) carbonylethyl, substituted hydroxy, alkoxy or hydroxyethylamino,

(h) carbonyl, substituted hydroxy, morpholino, alkoxy, hydroxyalkyloxy or cyclohexyloxycarbonyloxy,

(i) carbylamine substituted by alkyl or alkoxy,

(j) aminocarbonyl, which may be substituted by one or two substituents selected from amino, hydroxy, alkoxy, alkenyl and alkyl (which may be substituted with halogen, thiol, piperidino, amino, alkoxy, alkoxycarbonyl, aminocarbonyl, or one or two hydroxy);

R2means hydrogen or Deputy, selected from the following (k)-(s):

(k) cyano,

(l) an acrylic acid (including alkilany ester and hydroxyalkylated),

(m) alkyl which may be substituted by hydroxy or piperidino,

(n) carbonylethyl, substituted hydroxy, alkoxy (which may be substituted, cyclohexyloxycarbonyloxy), piperidino or hydroxyethylamino,

(o) carbonyl, substituted hydroxy, alkoxy, or hydroxyethylamino,

(p) carbonyloxy, substituted hydroxy or alkoxy,

(q) carbonylmethyl, substituted hydroxy or alkoxy,

(r) alkoxy,

(s) halogen; and

R3means hydrogen or Deputy, selected from the following (t)-(x):

(t) alkyl which may be substituted by carboxy, cyano, pyrrolidino, piperidino, alkoxy, alkylsulfanyl, or one or two hydroxy,

(u) a carbonyl substituted by alkyl or alkoxy,

(v) carbonyloxy, substituted hydroxy or alkoxy,

(w) carbonylethyl, substituted alkyl, alkoxy or alkylphenyl,

(x) aminoalkyl, replaced by aminocarbonyl or alkanesulfonyl,

where one of the above R1and R2means the Deputy, other than hydrogen, A is unsubstituted or represents oxo, means carbon or oxygen, one of X and Y represents a carbon, and other means sulfur, the dotted line means a single bond or double bond, provided that when R2means halogen or alkoxy, A is unsubstituted. R1means the Deputy is, different from hydrogen, and means oxygen.

In the above General formula (I), the term "alkyl" (including "alkyl" in Akilova complex ether, alkylvinyl, hydroxyalkylated, hydroxyethylamino, alkylcarboxylic, aminoalkyl, carbonylative, hydroxyalkyloxy, hydroxyethylamino, carbonylmethyl, alkylsulfanyl and carbonylchloride) means a linear or branched alkyl group having 1-6 carbon atoms, and preferably an alkyl group represents, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, or isohexyl similar to them. Also, albanova group alkanesulfonyl represents a saturated hydrocarbon corresponding to the above alkyl.

The term "alkoxy" (including "alkoxy" in hydroxyalkyloxy, alkoxycarbonyl, carbonyloxy, carbonylmethyl, cyclohexyloxycarbonyloxy) means a linear or branched alkoxygroup having 1-6 carbon atoms, and preferably alkoxygroup represents, for example, methoxy, ethoxy, N.-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy or similar.

The term "alkenyl" means a linear or branched alkenylphenol g is the SCP, having 2-4 carbon atoms, and preferably Alchemilla group represents, for example, vinyl, allyl, propenyl, Isopropenyl, 1-butenyl, 2-butenyl or similar. The term "halogen" means fluorine, chlorine, bromine, iodine or similar.

Aminoalkyl (f) R1can be replaced by alkylcarboxylic or aminocarbonyl, or aminoalkyl (x) in R3replaced by aminocarbonyl or alkanesulfonyl, and each Deputy substituted in part of amino groups in aminoalkyl.

Among the compounds of the present invention, preferred are the following compounds.

Hydrochloride of 2-cyano-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene [compound 1]

The hydrobromide of 2-bromo-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene [compound 2]

Ethyl-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylate [compound 3]

Hydrochloride [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid [compound 4]

Hydrochloride [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]carboxylic acid [compound 5]

Hydrochloride ethyl-3-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acrylate [compound 6]

Hydrochloride 3-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acrylic acid [compound 7]

2-Br the m-4-(1-methylpiperidin-4-ilidene)-4H-1-tiebens[f]azulene [compound 8]

2-Cyano-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene [compound 9]

2-Tert-butoxycarbonylamino-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene [compound 10]

2-Acetylamino-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene [compound 11]

The dihydrochloride of 2-aminomethyl-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene [compound 12]

Hydrochloride 2-acetamidomethyl-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene [compound 13]

2 Ureido-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene [compound 14]

3-[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acrylic acid [compound 15]

2-Tert-butoxycarbonylamino-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene [compound 16]

2-Acetylamino-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene [compound 17]

2 Ureido-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene [compound 18]

The dihydrochloride of 2-aminomethyl-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene [compound 19]

Hydrochloride 2-acetamidomethyl-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene [compound 20]

Ethyl-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]carboxylate [compound 21]

Ethyl-3-[4-(1-methylpiperidin-4-ilide is)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acrylate [compound 22]

Hydrochloride ethyl-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acetate [compound 23]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acetic acid [compound 24]

6-Cyano-4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene [compound 25]

[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]carboxylic acid [compound 26]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(2-hydroxyethyl)amide (IUPAC: N-(2-hydroxyethyl)-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxamide) [compound 27]

Hydrochloride [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N,N-bis(2-hydroxyethyl)amide (IUPAC: hydrochloride of N,N-bis(2-hydroxyethyl)-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxamide) [compound 28]

The dihydrochloride of 2-(2-hydroxyethylamino)ethyl-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylate [compound 29]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(3-hydroxypropyl)amide (IUPAC: N-(3-hydroxypropyl)-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxamide) [connection 30]

Amide [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carb is new acid (IUPAC: [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxamide) [compound 31]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acetic acid [compound 32]

The dihydrochloride [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-[2-(piperidine-1-yl)ethyl]amide (IUPAC: dihydrochloride of N-(2-piperidine-1-retil)-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxamide) [compound 33]

Hydrochloride ethyl-3-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acrylate [connection 34]

3-[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acrylic acid [compound 35]

Hydrochloride ethyl-3-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]acrylate [connection 36]

3-[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]acrylic acid [compound 37]

Hydrochloride [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(2-methoxyethyl)amide (IUPAC: hydrochloride N-(2-methoxyethyl)-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxamide) [compound 38]

The dihydrochloride [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(2-amino-ethyl)amide (IUPAC: dihydrochloride of N-(2-amino-ethyl)-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxamide) [compound 39]

Hydrochloride [4-(1-meth is piperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-methoxyamine (IUPAC: hydrochloride of N-methoxy-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxamide) [compound 40]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(carbarnoyl)methylamide (IUPAC: N-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carbonyl}aminoacetate) [connection 41]

Hydrochloride methyl amide of ester [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-acetic acid (IUPAC: hydrochloride methyl-N-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carbonyl}aminoacetate) [connection 42]

Hydrochloride morphodynamic [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid (IUPAC: hydrochloride of 1-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carbonyl}of the research) [compound 43]

Hydrochloride ethyl-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]carboxylate [compound 44]

[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]carboxylic acid [compound 45]

3-[4-(1-Methylpiperidin-4-ilidene)-4H-3-tiebens[f]azulene-2-yl]acrylic acid [compound 46]

Ethyl-3-[4-(1-methylpiperidin-4-ilidene)-10-oxo-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acrylate [connection 47]

3-[4-(1-Methylpiperidin-4-ilidene)-10-oxo-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acrylic acid [compound 48]

2-Freedomites-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens the[f]azulene [compound 49]

Ethyl [4-(1-methylpiperidin-4-ilidene)-10-oxo-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylate [compound 50]

[4-(1-Methylpiperidin-4-ilidene)-10-oxo-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid [compound 51]

3-[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acrylic acid-N-(2-hydroxyethyl)amide (IUPAC: N-(2-hydroxyethyl)-3-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acrylamide) [connection 52]

[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]carboxylic acid-N-(2-hydroxyethyl)amide (IUPAC: N-(2-hydroxyethyl)-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]carboxamide) [connection 53]

Hydrochloride [4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [compound 54]

[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3 - tiebens[f]azulene-2-yl]carboxylic acid-N-(2-hydroxyethyl)amide (IUPAC: N-(2-hydroxyethyl)-{[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]}carboxamide) [connection 55]

Hydrochloride of 2-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]propionic acid [compound 56]

Hydrochloride of 2-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionic acid [compound 57]

Hydrochloride [4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens the[f]azulene-2-yl]acetic acid [compound 58]

Hydrochloride [4-(1-methylpiperidin-4-ilidene)-4H-1-tiebens[f]azulene-2-yl]acetic acid [compound 59]

Hydrochloride of 2-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]propionic acid [compound 60]

Ethyl-[4-(1-ethoxycarbonylpyrimidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylate [compound 61]

Ethyl-[4-(piperidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylate [compound 62]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acetic acid-N-(2-hydroxyethyl)amide (IUPAC: N-(2-hydroxyethyl)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}ndimethylacetamide) [connection 63]

2-[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionic acid-N-(2-hydroxyethyl)amide (IUPAC: N-(2-hydroxyethyl)-{2-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]}propionamide) [connection 64]

2-Methyl-2-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]propionic acid [compound 65]

3-[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acrylic acid-N-(2-hydroxyethyl)amide (IUPAC: N-(2-hydroxyethyl)-{3-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]}acrylamide) [connection 66]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]carboxylic acid-N-(2-hydroxyethyl)amide (UPAC: N-(2-hydroxyethyl)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]}carboxamide) [connection 67]

2-Methyl-2-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionic acid [compound 68]

Hydrochloride [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(2-hydroxyethyl)-N-methylamide (IUPAC: hydrochloride of N-(2-hydroxyethyl)-N-methyl-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [compound 69]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(2-hydroxypropyl)amide (IUPAC: N-(2-hydroxypropyl)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 70]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(1-hydroxyprop-2-yl)amide (IUPAC: N-(1-hydroxyprop-2-yl)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 71]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(1,2-dihydroxypropyl)amide (IUPAC: N-(1,2-dihydroxypropyl)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 72]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(1,3-dihydroxypropyl-2-yl)amide (IUPAC: N-(1,3-dihydroxypropyl-2-yl)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 73]

[4-(1-Metile uridin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-hydroxy-N-methylamide (IUPAC: N-hydroxy-N-methyl-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 74]

2 Ethoxycarbonyl-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene [compound 75]

2 Isopropoxycarbonyl-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene [compound 76]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(2-foradil)amide (IUPAC: N-(2-foradil)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 77]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-hydroxyamide (IUPAC: N-hydroxy-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 78]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(2,2,2-triptorelin)amide (IUPAC: N-(2,2,2-triptorelin)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 79]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(2-methyl-1-hydroxyprop-2-yl)amide (IUPAC: N-(2-methyl-1-hydroxyprop-2-yl)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 80]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(3,3,3,2,2-pentafluoropropyl)amide (IUPAC: N-(3,3,3,2,2-pentafluoropropyl)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [with the unity 81]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-(2-mercaptoethyl)amide (IUPAC: N-(2-mercaptoethyl)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 82]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-amino-N-(2-hydroxyethyl)amide (IUPAC: N-amino-N-(2-hydroxyethyl)-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 83]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-methyl-N-methoxime (IUPAC: N-methyl-N-methoxy-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 84]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-propylamide (IUPAC: N-propyl-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 85]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid-N-arylamide (IUPAC: N-allyl-{[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]}carboxamide) [connection 86]

[4-(1-Methylpiperidin-4-ilidene)-10-oxo-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acetic acid [compound 87]

[4-(1-Ethoxycarbonylpyrimidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid [compound 88]

[4-(1-Metile ridin-4-ilidene)-4H-3-tiebens[f]azulene-2-yl]carboxylic acid [compound 89]

Ethyl-[4-(1-acetylpiperidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylate [compound 90]

[4-(1-Acetylpiperidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid [compound 91]

Ethyl-{4-[1-(2-carboxyethyl)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl}carboxylate [compound 92]

3-[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]propionic acid [compound 93]

{4-[1-(2-Cyanoethyl)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl}carboxylic acid [compound 94]

Ethyl-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-6-yl]carboxylate [compound 95]

[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-6-yl]carboxylic acid [compound 96]

Ethyl-3-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]propionate [compound 97]

3-[4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]propionic acid [compound 98]

Hydrochloride piperidylamine 3-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionic acid (IUPAC: hydrochloride of 1-{3-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionyl}piperidine) [connection 99]

3-[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionic acid [compound 100]

The dihydrochloride ethyl-{4-[1-(3-pyrrole ylpropyl)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl}carboxylate [compound 101]

{4-[1-(3-Pyrrolidinyl)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl}carboxylic acid [compound 102]

Hydrochloride ethyl-[4-(1-ethylpiperazin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylate [compound 103]

6-(2-Hydroxymethyl)-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene [compound 104]

Ethyl-{4-[1-(2-hydroxyethyl)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl}carboxylate [compound 105]

Hydrochloride ethyl-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-6-yl]acetate [compound 106]

Hydrochloride {4-[1-(2-hydroxyethyl)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl}carboxylic acid [compound 107]

Hydrochloride [4-(1-ethylpiperazin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylic acid [compound 108]

Ethyl-{4-{1-[4-(4-tert-butylphenyl)-4-oxobutyl]piperidine-4-ilidene}-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl}carboxylate [compound 109]

Hydrochloride ethyl-{4-[1-(2-ethoxycarbonylmethoxy)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl}carboxylate [compound 110]

Ethyl-{4-[1-(2-carboxymethoxy)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl}carboxylate [compound 111]

2-Vinyl-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene [compound 112]

Hydrochloride ethyl-(4-piperidine-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]is sulan-6-yl)acetate [compound 113]

(4-piperidine-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acetic acid [compound 114]

Ethyl-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-6-carboxylate [compound 115]

Hydrochloride methyl-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl]acetate [compound 116]

[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-1-tiebens[f]azulene-6-yl]acetic acid [compound 117]

Hydrochloride methyl-{4-[1-(2-hydroxyethyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate [compound 118]

{4-[1-(2-Hydroxyethyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 119]

4-[1-(4-Hydroxybutyl)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylic acid [compound 120]

4-(1-Methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-6-carboxylic acid [compound 121]

2-{4-[1-(2-Hydroxyethyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}ethanol [compound 122]

Hydrochloride methyl-4-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]butyrate [connection 123]

4-[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]butyric acid [compound 124]

3-[4-(6-Carboxymethyl-10H-9-oxa-3-tiebens[f]azulene-4-ilidene)piperidine-1-yl]propionic acid [compound 125]

Hydrochloride methyl-(4-PI is uridin-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acetate [compound 126]

Hydrochloride methyl-[4-(1-ethylpiperazin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetate [compound 127]

[4-(1-Ethylpiperazin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [compound 128]

Hydrochloride methyl-[4-(1-propylpiperidine-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetate [compound 129]

[4-(1-Propylpiperidine-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [compound 130]

Hydrochloride methyl-[4-(1-isopropylpiperazine-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetate [compound 131]

[4-(1-Isopropylpiperazine-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetic acid [compound 132]

Hydrochloride ethyl-4-(1-propylpiperidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylate [compound 133]

The hydrochloride of 4-(1-propylpiperidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylic acid [compound 134]

Hydrochloride methyl-4-(4-piperidine-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)butyrate [connection 135]

The hydrochloride of 4-(4-piperidine-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)butyric acid [compound 136]

Hydrochloride propyl-(4-piperidine-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acetate [compound 137]

Hydrochloride methyl-{4-[1-(3-hydroxypropyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}ACET is the [connection 138]

{4-[1-(3-Hydroxypropyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 139]

Hydrochloride ethyl-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]acetate [compound 140]

Hydrochloride methyl-4-[4-(1-ethylpiperazin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]butyrate [connection 141]

4-[4-(1-Ethylpiperazin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]butyric acid [compound 142]

Hydrochloride ethyl-3-(4-piperidine-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acrylate [connection 143]

3-(4-piperidine-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acrylic acid [compound 144]

Hydrochloride ethyl-3-(4-piperidine-4-ilidene-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl)acrylate [connection 145]

3-(4-piperidine-4-ilidene-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl)acrylic acid [compound 146]

Hydrochloride ethyl-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-6-yl]acetate [compound 147]

Hydrochloride [4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-6-yl]acetic acid [compound 148]

Hydrochloride ethyl-4-(1-isopropylpiperazine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylate [compound 149]

4-(1-Isopropylpiperazine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylic acid [compound 150]

[4-(1-Methylpiperidin-4-ylides is n)-9,10-dihydro-4H-1-tiebens[f]azulene-6-yl]acetic acid [compound 151]

Hydrochloride ethyl-2-methyl-2-(4-piperidine-4-ilidene-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl)propionate [compound 152]

Hydrochloride of 2-methyl-2-(4-piperidine-4-ilidene-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl)propionic acid [compound 153]

Hydrochloride ethyl-2-[4-(1-ethylpiperazin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]-2-methylpropionate [connection 154]

2-[4-(1-Ethylpiperazin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]-2-methylpropionate acid [compound 155]

Hydrochloride methyl-5-[4-(1-methylpiperidin-4-ilidene)-4,l0-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]valerate [connection 156]

5-[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]valeric acid [compound 157]

Ethyl-3-[4-(1-ethylpiperazin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acrylate [connection 158]

Hydrochloride 3-[4-(1-ethylpiperazin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acrylic acid [compound 159]

Ethyl-4-(1-ethylpiperazin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-6-carboxylate [compound 160]

4-(1-Ethylpiperazin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-6-carboxylic acid [compound 161]

5-(4-piperidine-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)valeric acid [compound 162]

The dihydrochloride methyl-{4-[1-(3-piperidine-1-ylpropyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate [compound 163

{4-[1-(3-piperidine-1-ylpropyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 164]

Hydrochloride methyl-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yloxy]acetate [compound 165]

[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yloxy]acetic acid [compound 166]

Hydrochloride methyl-{4-[1-(2-oxopropyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate [compound 167]

{4-[1-(2-Oxopropyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 168]

Hydrochloride methyl-{4-[1-(4-oxobutyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate [compound 169]

{4-[1-(4-Oxobutyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 170]

Hydrochloride methyl-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]acetate [compound 171]

[4-(1-Methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]acetic acid [compound 172]

Hydrochloride ethyl-3-[4-(6-methoxycarbonylmethyl-10H-9-oxa-3-tiebens[f]azulene-4-ilidene)piperidine-1-yl]propionate [compound 173]

Methyl-{4-[1-(2-areideal)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate [compound 174]

{4-[1-(2-Areideal)piperidine-4-yl) - Rev. den]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 175]

Hydrochloride of 1-cyclohexyloxycarbonyloxy-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylate [compound 176]

Hydrochloride methyl-{4-[1-(2-methanesulfonylaminoethyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate [compound 177]

{4-[1-(2-Methanesulfonylaminoethyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 178]

Tert-butyl 4-(6-carboxymethyl-10H-9-oxa-3-tiebens[f)azulene-4-ilidene)piperidine-1-carboxylate [compound 179]

Hydrochloride of 1-cyclohexyloxycarbonyloxy-(4-piperidine-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acetate [compound 180]

Hydrochloride ethyl-4-[1-(2-ethoxyethyl)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f)azulene-2-carboxylate [compound 181]

4-[1-(2-Ethoxyethyl)piperidine-4-ilidene]-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylic acid [compound 182]

The dihydrochloride of 1-methyl-4-[6-(2-piperidine-1-retil)-10H-9-oxa-3-tiebens[f]azulene-4-ilidene]piperidine [connection 183]

Hydrochloride methyl-4-{4-[1-(2,3-dihydroxypropyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}butyrate [connection 184]

4-{4-[1-(2,3-Dihydroxypropyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}butyric acid [compound 185]

3-{4-[6-(2-piperidine-1-retil)-10H-9-oxa-3-tiebens[f]azulene-4-ilidene]piperidine-1-yl}prop is about acid [compound 186]

Hydrochloride methyl-4-{4-[1-(4-oxobutyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}butyrate [connection 187]

4-{4-[1-(4-Oxobutyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}butyric acid [compound 188]

Hydrochloride methyl 2-methyl-2-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]propionate [compound 189]

Hydrochloride of 2-methyl-2-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]propionic acid [compound 190]

Hydrochloride methyl-{4-[1-(3-oxobutyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate [compound 191]

{4-[1-(3-Oxobutyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 192]

Hydrochloride methyl-{4-[1-(3-methanesulfonylaminoethyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate [compound 193]

{4-[1-(3-Methanesulfonylaminoethyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 194]

Hydrochloride methyl-3-{4-[1-(2-methanesulfonylaminoethyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}propionate [compound 195]

3-{4-[1-(2-Methanesulfonylaminoethyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}propionic acid [compound 196]

Hydrochloride methyl-(4-piperidine-4-ylides is n-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl)acetate [compound 197]

Hydrochloride methyl-{4-[1-(3-methylsulfinylpropyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate [compound 198]

{4-[1-(3-Methylsulfinylpropyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 199]

Hydrochloride methyl-{4-[1-(2-methylsulfonylamino)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate [compound 200]

{4-[1-(2-Methylsulfonylamino)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid [compound 201]

Hydrochloride of 2-methyl-2-[4-(1-propylpiperidine-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]propionic acid [compound 202]

3-(4-piperidine-4-ilidene-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl)acrylic acid [compound 203]

[6-Fluoro-4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]acetic acid [compound 204]

[6-Chloro-4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]acetic acid [compound 205]

2-[6-Chloro-4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]-2-methylpropionate acid [compound 206]

[6-Methoxy-4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]acetic acid [compound 207]

[6-Methyl-4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]acetic acid [compound 208]

3-(4-Pipa is one-4-ilidene-4H-1-tiebens[f]azulene-2-yl)propionic acid [compound 209]

3-(4-piperidine-4-ilidene-4H-3-tiebens[f]azulene-2-yl)propionic acid [compound 210]

4-piperidine-4-ilidene-9,10-dihydro-4H-3-tiebens[f]azulene-6-carboxylic acid [compound 211]

4-(2-Bromo-9,10-dihydro-1-tiebens[f]azulene-4-ilidene)-1-methylpiperidin [connection 212]

Among the compounds of the present invention, in the above General formula (I), preferred is a compound in which one of R1and R2means hydrogen, and more preferred compounds include compounds shown in tables 18 and 19 below. In addition, especially preferred are the compounds shown in table 21, with excellent antihistaminic activity and low passage into the brain.

General method of preparing compounds of the present invention herein below. The compound of the present invention corresponding to the above formula (I)can be obtained by the method described below. Here the person skilled in the art it is obvious that the exact methods that are suitable for the production of these compounds can vary, depending on their chemical structures.

Among the above compounds of the present invention corresponding to the above General formula (I), the compound 4-(piperidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene you can get is a procedure, described in Japan patent published under No. Sho-49-69677; compound 4-(piperidine-4-ilidene)-4H-1-tiebens[f]azulene can be obtained by the methods described in Japan patent published under No. Sho-49-69677 andHelvetica Chimica Acta,49,Fasc. Emile Cherbuliez (1966) No. 26, 214-234; compound 4-(piperidine-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene can be obtained by the method described inHelvetica Chimica Acta,54,Fasc. 1 (1971), 277-282; compound 4-(piperidine-4-ilidene)-4H-3-tiebens[f]azulene can be obtained by the methods described in Japan patent published under No. Sho-49-69677,Helvetica Chimica Acta,49,Fasc. Emile Cherbuliez (1966) No. 26, 214-234, andHelvetica Chimica Acta,54,Fasc. 1 (1971), 277-282; compound 4-(piperidine-4-ilidene)-10-oxo-9,10-dihydro-4H-1-tiebens[f]azulene can be obtained by the method described inHelvetica Chimica Acta,59,Fasc. 3 (1976), 866-877; and the compound 4-(piperidine-4-ilidene)-4,10-dihydro-9-oxa-1-tiebens[f]azulene and the compound 4-(piperidine-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene can be obtained by methods described in WO 2005/003131.

The formation of functional groups on the aromatic ring can be synthesized by bromine or NBS (N-bromosuccinimide), the reaction of formation of lithium using reagent-based alkylate, the reaction of acylation Friedel -, reaction formirovaniya of Vilsmeier or similar. In addition, brominated compound can be subjected to react and carbonyl the Heck reaction, the reaction cyanidation reaction formirovaniya, the Ullman reaction, the reaction combinations Suzuki or similar, properly using a catalyst based on a transition metal, such as palladium, for making the desired functional group. Alternative compounds can be synthesized by selecting the source material, in advance, with any substituent in the position that corresponds to him.

(1) the Case when A is unsubstituted

General methods for obtaining compounds of 4-(piperidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene, the compounds 4-(piperidine-4-ilidene)-4H-1-tiebens[f]azulene, the compounds 4-(piperidine-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene, the compounds 4-(piperidine-4-ilidene)-4H-3-tiebens[f]azulene, the compounds 4-(piperidine-4-ilidene)-4,10-dihydro-9-oxa-1-tiebens[f]azulene and connections 4-(piperidine-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene, each of which has the General formula (II)herein below. Compounds corresponding to General formula (II)are obtained by alkylation reaction, the reaction Ullman or Michael reaction of compounds corresponding to General formula (III). For example, the alkylation reaction is carried out with alkylhalogenide or similar in a solvent such as acetone, benzene or DMF (dimethylformamide) at a suitable temperature between room temperature is Oh and the boiling point of the solvent, in the presence of a base such as potassium carbonate, sodium hydride or piperonyl potassium.

The compound corresponding to General formula (III), get alkaline hydrolysis, cleavage of Hydrobromic acid or by reduction of compounds corresponding to General formula (IV). For example, the reaction of the alkaline hydrolysis is carried out by boiling under reflux by heating in a solvent such as butanol or isopropanol, in the presence of a strong base such as sodium hydroxide or potassium hydroxide.

The compound corresponding to General formula (IV)can be synthesized by the reaction of carbonyl compounds corresponding to General formula (V). For example, the reaction is carried out by boiling under reflux by heating in a solvent such as benzene or dichloromethane, in the presence of ethylchloride or 2,2,2-trichlorethylphosphate.

The compound corresponding to General formula (V)can be obtained by subjecting the compound corresponding to General formula (VI), cyanation reaction, carbonylation reaction, the Heck reaction, alkylation reaction or reactions formirovaniya, properly using a palladium catalyst or, alternatively, making the connection that corresponds to the plans of General formula (VI), in connection boric acid and subjecting this compound is the reaction of a combination of Suzuki. For example, the cyanation reaction can be carried out with ligand such as DPPF (1,1'-bis(diphenylphosphino)ferrocene), PPh3(triphenylphosphine), P(o-tol)3(Tris(2-were)phosphine), P(t-Bu)3(three-tert-butylphosphine) or chloride N,N'-(2,6-diisopropylphenyl)dihydroimidazole, using copper cyanide, cyanide zinc, ferric ferrocyanide or sodium cyanide, in the presence of 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)). The reaction can be carried out in miscible solvent, such as DMF, water, acetone, acetonitrile, toluene, THF (tetrahydrofuran) or a mixture thereof, at a suitable temperature, preferably at a temperature between room temperature and the boiling temperature of the solvent.

The compound corresponding to General formula (VI), obtained by bromirovanii compounds corresponding to General formula (VII). As agent for the synthesized can be used bromine, NBS, or similar. The reaction can be carried out in miscible solvent, such as acetic acid, chloroform, carbon tetrachloride, ethyl acetate, methanol or a mixture when the sentence is Noah temperature, preferably at temperatures between 0°C and boiling point of the solvent.

The compound corresponding to General formula (VII)receive, subjecting the reaction product of a Grignard reagent with a compound corresponding to the General formula (VIII), the reaction of dehydration or the mcmurry reaction. For example, the Grignard reaction is conducted by treating compound corresponding to the General formula (VIII), the Grignard reagent derived from magnesium and 4-chloro-N-methylpiperidine, in a nonaqueous solvent such as THF or toluene at a suitable temperature from the melting temperature to the boiling temperature of the solvent. The subsequent dehydration reaction can be carried out with hydrochloric acid, triperoxonane acid, thionyl chloride or similar, 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 the boiling temperature of the solvent. The compound corresponding to General formula (VIII)can be synthesized by methods described in Japan patent published under No. Sho-49-69677,Helvetica Chimica Acta,54,Fasc. 1 (1971), 277-282, and WO 2005/003131.

(2) Case, where a represents an oxo

The compound 4-(piperidine-4-ilidene)-10-oxo-9,10-dihydro-4H-1-tiebens[f]azulene corresponding to obatala (IX), receive, simultaneously subjecting the compound corresponding to General formula (X), hydrolysis of the methyl enol ether and the reaction of dehydration of alcohol. This reaction can be carried out with an inorganic acid, such as hydrochloric acid or organic acid in a water-containing solvent, such as water or ethanol, at temperatures between room temperature and boiling point.

The compound corresponding to General formula (X)can be obtained by subjecting the compound corresponding to General formula (XI), cyanation reaction, carbonylation reaction, the Heck reaction, alkylation reaction or reactions formirovaniya, properly using a palladium catalyst, or converting the compound corresponding to General formula (XI), a compound of boric acid and subjecting the compound of combination reaction Suzuki. For example, the cyanation reaction can be carried out with ligand such as DPPF, PPh3, P(o-tol)3P(t-Bu)3or chloride N,N'-(2,6-diisopropylphenyl)dihydroimidazole, using copper cyanide, cyanide zinc, ferric ferrocyanide or sodium cyanide, in the presence of Pd(dba)2Pd2(dba)3Pd(OAc)2or Pd(PPh3)4. The reaction can be carried out in miscible solvent, such as DMF, water, acetone, acetonitrile, toluene, THF sludge is a mixture, under suitable temperature, preferably at a temperature between room temperature and the boiling temperature of the solvent.

The compound corresponding to General formula (XI), get subjecting the compound corresponding to General formula (XII), the Grignard reaction or similar. For example, the Grignard reaction can be performed, treating the compound corresponding to General formula (XII), the Grignard reagent derived from magnesium and 4-chloro-N-methylpiperidine, in a nonaqueous solvent such as THF or toluene, at a suitable temperature from the melting temperature to the boiling temperature of the solvent.

The compound corresponding to General formula (XII)can be obtained by reaction of β-off or similar, which is carried out after the cleavage reaction with methanol compounds corresponding to General formula (XIII). For example, the decomposition of methanol is carried out by boiling under reflux by heating in methanol. The reaction of β-off can be performed with a base such as DBU (1,8-diazabicyclo[5,4,0]und-7-ene, triethylamine or piperonyl potassium in a solvent such as THF, benzene, toluene or methanol, at a suitable temperature from room temperature to the boiling temperature of the solvent.

The connection correspond to the its General formula (XIII), synthesize, subjecting the compound corresponding to General formula (XIV), the reaction of synthesized or similar using NBS or similar. For example, the reaction of the synthesized carried out by boiling under reflux by heating with the use of benzoyl peroxide or similar as an initiating agent in a small amount of an appropriate solvent, such as chloroform, carbon tetrachloride, dichloroethane or toluene.

The compound corresponding to General formula (XIV), synthesize, subjecting the compound corresponding to General formula (XV), bromirovanii or similar to it with bromine. Bromination is carried out in a solvent such as chloroform, acetic acid or methanol, at a suitable temperature from the melting temperature to the boiling temperature of the solvent.

The compound corresponding to General formula (XV), synthesize, subjecting the compound corresponding to General formula (XVI), intramolecular reactions Friedel-or similar. For example, the intramolecular reaction of the Friedel-can be performed directly exposing carboxylic acid or its product after the conversion of the acid into the acid chloride or mixed anhydride of the acid, the reaction in the presence of, if necessary, the Lewis acid in the quality of the ve polyphosphoric acid, aluminium chloride, titanium chloride, tin chloride or BF3·OEt2(the complex of boron TRIFLUORIDE·diethyl ether), appropriate solvent, such as THF, dichloromethane, chloroform, dichloroethane, carbon disulfide or nitrobenzene, at the optimum temperature of the melting point of the solvent up to 300°C.

The compound corresponding to General formula (XVI)can be synthesized by exposing a compound corresponding to the General formula (XVII), aldol reaction, the reaction of the Wittig reaction the Wittig-Horner, reaction Peterson or similar. For example, when using the Wittig reaction, the compound corresponding to General formula (XVII), treated with NBS for the synthesized methyl group, and then treated with triphenylphosphine with the formation of phosphonium salts of. At this time carry out the reaction synthesized by boiling under reflux by heating with the use of benzoyl peroxide or similar as the initiating agent reactions in a small amount, in a solvent such as carbon tetrachloride or dichloroethane. The reaction benzylbromide, obtained by the reaction of the synthesized with triphenylphosphine, carried out by heating in a solvent such as benzene, toluene or dichloroethane. Obtained phosphonium salt can be converted into compound (s) which corresponds to the formula (XVI), processing phosphonium salts of a base, such as butokukai or sodium hydride, with the formation of ylides, condensation ilide totenlieder, and finally, the restoration of the double bond of the condensate. At the same time spend processing phosphonium salts of totenlieder in a solvent such as THF, acetonitrile, benzene or toluene, at a suitable temperature from the melting temperature to the boiling temperature of the solvent. The restoration of the double bond of the product of the Wittig reaction is carried out by contact of the recovery, by the reaction of catalytic migration of hydrogen or recovery of hydrazine using a palladium catalyst or a complex of Wilkinson.

Compounds corresponding to General formula (I)above, the cover, when present, their pharmaceutically acceptable salts, various types of salts, and 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 or nitric acid. In addition, salts of carboxyl groups of the compounds include suitable salt of an alkali metal, which represents a sodium, potassium, calcium, and similar to them. Those with whom it can be obtained from each of the compounds in free form, or reversible transform, in a known manner. In addition, in the case where the compounds are present in the state of steric isomers, such as CIS-TRANS-isomer, optical isomer or coordination isomer, or a hydrate of the compound or its complex with the metal, the present invention relates to any steric isomers, hydrates and complex connections.

The compound of the present invention can be combined with a suitable pharmaceutical carrier or diluent with obtaining the drug. The connection can be made in the form of drugs by conventional means, and connections can be made in the form of oral formulations of input means, such as a tablet, a capsule, a fine powder or liquid, or parenteral input means for subcutaneous injection, intramuscular injection, intrarectal injection or intranasal. The purpose of the connection of the present invention can be used in the form of its pharmaceutically acceptable salts, and compounds can be used singly or in proper combination, and, in addition, mixing the product with other pharmaceutically active ingredient.

Orally administered drug can be used directly or in a suitable combination with a suitable additive, for example, with conventional excipient is m, such as lactose, mannitol, corn starch or potato starch, together with a binder, such as crystalline cellulose, a derivative of cellulose, gum Arabic, corn starch or gelatin, dezintegriruetsja substance, such as corn starch, potato starch, potassium carboxymethylcellulose, a lubricating substance, such as talc or magnesium stearate, and other additive such as a filler, a wetting agent, buffer, preservative or perfume, and similar to them with the receipt of 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, inhalation means, aerosols, syrups, instillation and ointments, etc.

The desired dose of a compound of the present invention may vary depending on subject of administration, dosage form, route of administration, the time period of introduction, etc. To achieve the desired effect of the compound of the present invention can primarily oral to enter in the amount of from 0.5 to 1000 mg, and preferably from 1 to 500 mg, per adult for once or a few individual in whom edeni per day. In the case of parenteral administration (e.g. injection), the daily dose is preferably from one-third to one-tenth of the dose level for each of the above-mentioned doses.

EXAMPLES

Further, the present invention is specifically described using examples, but they are not intended to limit the scope of the present invention.

The melting point was determined by placing the sample in a glass capillary tube and using an instrument to measure the melting temperature Yamato Scientific, model MP-21 (trim thermometer did not). MS spectrum was measured using POLARIS Q (Thermo Quest).1H-NMR was measured using the analyzer nuclear magnetic resonance (Bruker, Model ARX500, in which the chemical shift was expressed in ppm using TMS, added as an internal standard (δ=0 ppm). Column chromatography on silica gel was performed using silica gel BW-127ZH for chromatography (FUJI SILYSIA CHEMICAL LTD.). Thin-layer chromatography was performed using silica gel F254 (Merck, No. 5715) and in this case, the detection was performed using a UV lamp and 5% reagent for the degree of color development on the basis of phosphomolybdenum acid-ethanol.

Example 1

Getting 4-(2-bromo-9,10-dihydro-1-tiebens[f]azulene-4-ilidene)-1-methylpiperidine [connection 212]

To a solution of 4-(9,10-dihydro-1-tiebens[f]azulene-4-ilidene)-1-m is tipepidine (USD 5.76 g, a 19.5 mmol) in chloroform (50 ml) was added dropwise bromine (1.0 ml, of 19.5 mmol) at 0°C and the mixture was stirred at room temperature for 2 hours. Then to the mixture was added saturated aqueous sodium bicarbonate solution and the organic layer was separated. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and the residue was purified column chromatography (chloroform-methanol = 9:1) to give 5.6 g (91%) indicated in the title compound in the form of white crystals.

TPL 141-142°C. MC (EI): m/z 375 [M++2], 373 [M+].1H-NMR (DMSO-d6) δ: 1,90-and 2.79 (m, 13H), 3,18-up 3.22 (m, 2H), 6,85 (c, 1H), 6,98-7,30 (m, 4H).

Example 2

Obtain hydrochloride of 4-(2-cyano-9,10-dihydro-1-tiebens[f]azulene-4-ilidene)-1-methylpiperidine [compound 1]

To a solution of the compound obtained in example 1 (5.0 g, 14.7 mmol)in DMF (25 ml) was added Zn(CN)2(0,94 g, 8,8 mmol), Pd2(dba)3(0,61 g of 0.74 mmol) and DPPF (0,89 g, 1.8 mmol) in an argon atmosphere and the mixture was stirred over night at 80°C. the Insoluble matter was filtered, then the filtrate was added a saturated solution of sodium chloride (50 ml) and product was extracted with ethyl acetate. Solvents drove away under reduced pressure, then the residue was purified column chromatography on silica gel (chloroform-methanol = 9:1) and the floor is built oily product was treated with a mixture of 4 mol/l hydrochloric acid-dioxane to obtain 1.9 g (40%) specified in the connection header in the form of crystals.

Example 3

Obtain hydrochloride of 4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylic acid [compound 4]

To a solution of compound 1 (1.5 g, 4.2 mmol) in ethanol (10 ml) was added an aqueous solution of sodium hydroxide at a concentration of 2 mol/l (20 ml) and the mixture was stirred over night while boiling under reflux and heating. Ethanol drove under reduced pressure and the obtained precipitate was added 6 mol/l hydrochloric acid. Precipitated crystals were collected by filtration and washed with plenty of water. The crystals were dried over phosphorus pentoxide at 50°C under reduced pressure to obtain 0.96 g (67%) specified in the connection header.

Example 4

Getting ethyl-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylate [connection3]

Ethanol (10 ml) was cooled to 0°C and to it was added dropwise thionyl chloride (0,24 ml, 0.32 mmol). To the solution was added compound 4 (100 mg, 0.29 mmol) and the mixture was stirred for 30 minutes and then boiled under reflux under heating for 2 hours. Then the mixture after boiling under reflux, allowed to cool in air, solvents drove away under reduced pressure, and precipitated crystals were separated by filtration and dried to obtain 107 mg (100%) specified in the header is soedineniya in the form of white crystals.

Example 5

Getting ethyl-[4-(1-ethoxycarbonylpyrimidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylate [compound 61]

To a solution of compound 3 (22,0 g to 59.9 mmol) in dichloroethane (140 ml) was added ethylchloride (57 ml, 599 mmol) and the mixture was stirred over night while boiling under reflux and heating. The solvent is kept under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform) to obtain the 26,3 g (100%) specified in the connection header.

Example 6

Getting ethyl-[4-piperidine-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylate [compound 62]

To a solution of compound 61 (10.5 g, to 24.7 mmol) in acetic acid (90 ml) was added a solution of 33% hydrochloric acid-acetic acid (23 ml, 133,2 mmol) and the mixture was boiled under reflux under heating for 5 hours. Then the mixture was allowed to cool in air, and solvents drove away under reduced pressure, and precipitated crystals were separated by filtration and dried to obtain 8.8 g (82%) specified in the connection header.

Example 7

Getting ethyl-{4-(1-[4-(4-tert-butylphenyl)-4-oxobutyl]piperidine-4-ilidene}-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]carboxylate [compound 109]

To a solution of compound 62 (3.0 g, 6,9 mmol) in DMF (75 ml) was added triethylamine and 2.1 ml, 15.1 mmol) and 1-(4-tert-butylphenyl)-4-chlorobutane-1-he (1.98 g, 8.3 mmol) and the mixture was stirred at 80°C for 21 hours. Solvents drove away under reduced pressure, then to the precipitate was added water and the product was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and then the residue was purified column chromatography on silica gel (hexane-ethyl acetate) to obtain 0.9 g (23%) specified in the connection header.

Example 8

Getting the hydrobromide of 2-bromo-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene [compound 2]

To a solution of 4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene (3.0 g, 10.2 mmol) in chloroform (30 ml) was added dropwise bromine (0,52 ml, 10.2 mmol) at 0°C. the Mixture was stirred at room temperature for 2 days and then thereto was added a saturated aqueous solution of sodium bicarbonate to ensure separation of the organic layer. The organic layer was washed with a saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and the residue was then purified column chromatography (chloroform-methanol = 9:1) to obtain 3.8 g (100%) specified in the connection header in the form of white crystals.

u> Example 9

Getting ethyl-3-[4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-3-tiebens[f]azulene-2-yl]acrylate [compound 22]

To a solution of compound 2 (9,2 g, 24.5 mmol) in DMF (160 ml) was added triethylamine (35,5 ml, 255 mmol), acrylate (26,8 ml, 246 mmol), palladium acetate (0.4 g, 1.8 mmol) and three(toluyl)phosphine (1.5 g, 5.0 mmol) 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 product was extracted with ethyl acetate and then the organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. Solvents drove away under reduced pressure, and then the obtained residue was purified column chromatography (chloroform-methanol = 9:1) to give 7.6 g (79%) indicated in the title compound in the form of white crystals.

Example 10

Getting 4-(6-bromo-10H-9-oxa-3-tiebens[f]azulene-4-ilidene)-1-methylpiperidine

To the Grignard reagent derived from 4-chloro-N-methylpiperidine (20 ml, 150 mmol), magnesium metal (3.6 g, 150 mmol), dibromoethane (0.1 ml) and THF (200 ml), was added 6-bromo-10H-9-oxa-3-tiebens[f]azulene-4-one (of 21.6 g, 100 mmol). The reaction mixture was stirred at room temperature for 2 hours, to the solution was added a saturated aqueous solution of ammonium chloride to stop the reaction, and then the product was extracted with what acetate. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. Solvents drove away under reduced pressure, the obtained residue was dissolved in dichloromethane (300 ml), were added triperoxonane acid (77 ml, 1.0 mol) and the mixture was stirred over night. Solvents drove under reduced pressure and to the precipitate was added a saturated aqueous solution of sodium bicarbonate. The product was extracted with ethyl acetate and the extract was washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate. Solvents drove away under reduced pressure, and then the obtained residue was purified column chromatography (hexane-ethyl acetate = 3:2) to give 16.2 g (81%) specified in the connection header.

MC (EI): m/z 378,0 [M++1].1H-NMR (DMSO-d6) δ: 2,09-2,77 (m, 11H), is 4.85 (d, J=15,5 Hz, 1H), 5,42 (d, J=15,5 Hz, 1H), for 6.81 was 7.45 (m, 5H).

Example 11

Obtain hydrochloride of 2-[4-(1-methylpiperidin-4-ylidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl]propionic acid [compound 57]

Hexamethyldisilazane (5.0 ml, and 31.2 mmol) was cooled on ice in an argon atmosphere, and thereto was added dropwise a solution of 1.6 mol/l utility-hexane (19,5 ml, and 31.2 mmol). After stirring the mixture for 30 minutes to the solution was added dropwise tert-butylphosphonate (2.1 g, 16,1 mmol) and was stirred for 30 minutes. Chrome is also to it was added Pd(dba)2(0.45 g, 0.8 mmol) and chloride N,N'-(2,6-diisopropylphenyl)dihydroimidazole (0.34 g, 0.8 mmol), the mixture was stirred for 10 minutes, and then thereto was added dropwise a solution of 4-(6-bromo-10H-9-oxa-3 - tiebens[f]azulene-4-ilidene)-1-methylpiperidine (3.0 g, 8.0 mmol) in toluene (25 ml). The mixture was stirred over night at room temperature, then the reaction mixture was added water and the product was extracted with ethyl acetate. The solvent in the organic layer is kept under reduced pressure and the residue was purified column chromatography on silica gel (hexane-ethyl acetate). The purified compound was dissolved in dioxane (10 ml), to the solution was added a solution of 4 mol/l hydrochloric acid-dioxane (12.5 ml, 50 mmol) and the mixture was stirred over night. Solvents drove away under reduced pressure, and precipitated crystals were collected by filtration to obtain 1.5 g (69%) specified in the connection header.

Example 12

Obtain 2-bromo-9,10-dihydro-1-tiebens[f]azulene-4-it

To a solution of 9,10-dihydro-1-tiebens[f]azulene-4-it (23,2 g, 108 mmol) in chloroform (300 ml) was added dropwise bromine (8.5 ml, 165 mmol) and the mixture was stirred for 4 hours. To the reaction mixture was added water, the product was extracted with ethyl acetate, then the organic layer was washed saturated aqueous sodium bicarbonate and saturated Rast is the PR of sodium chloride and dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and the residue was purified by chromatography on silica gel (hexane-ethyl acetate) to obtain 22,0 g (69%) specified in the connection header.

MC (EI): m/z 294 [M++2], 292 [M+],1H-NMR (DMSO-d6) δ: 3,19 (c, 4H), 7,38-7,42 (m, 2H), 7,52-of 7.55 (m, 2H), 7,78-7,79 (m, 1H).

Example 13

Getting 2,9,10-tribrom-9,10-dihydro-1-tiebens[f]azulene-4-it

To a solution of the compound obtained in example 12 (53,9 g, 184 mmol)in dichloroethane (500 ml) was added NBS (65,4 g, 367 mmol) and benzoyl peroxide (0.1 g, 0.5 mmol) and the mixture was boiled under reflux under heating for 4 hours. The reaction mixture was allowed to cool in air and thereto was added a saturated solution of potassium carbonate to provide separation of the organic layer. Next, the organic layer was washed with saturated potassium carbonate solution and saturated sodium chloride solution and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and the residue was purified column chromatography on silica gel (hexane-ethyl acetate) to obtain with 76.8 g (93%) specified in the connection header.

1H-NMR (DMSO-d6) δ: 5,96 (d, J=5.3 Hz, 1H), from 6.22 (d, J=5.3 Hz, 1H), to 7.67-7,74 (m, 4H), 8,03-with 8.05 (m, 1H).

Example 14

Obtain 2-bromo-10-methoxy-1-tiebens[f]azulene-4-it

A solution of the compound obtained in example 13 (90,2 g, 200 mmol), methane is e (1100 ml) was boiled under reflux by heating during the night. Then the mixture was allowed to cool in air, and then thereto was added DBU (63,4 g, 417 mmol) and the mixture is boiled under reflux with heating for the next night. The reaction mixture was allowed to cool in air, precipitated crystals were separated by filtration and dried to obtain specified in the connection header in the number of 55.7 g, 173 mmol (stage 2, 87%).

MS (EI): m/z 322 [M++2], 320 [M+].1H-NMR (DMSO-d6) δ: was 4.02 (s, 3H), 6,98 (s, 1H), to 7.61 to 7.62 (m, 1H), to 7.77-7,80 (m, 1H), of 7.90-of 7.96 (m, 2H), 8,46-of 8.47 (m, 1H).

Example 15

Obtain 2-bromo-10-methoxy-4-(1-methylpiperidin-4-yl)-4H-1-thiazolino[f]azulene-4-ol

The compound obtained in example 14 (4,27 g, 13.3 mmol)was added to the Grignard reagent derived from 4-chloro-N-methylpiperidine (2.7 ml, 20 mmol), magnesium metal (0,49 g, 21 mmol), dibromoethane (0.2 ml) and THF (20 ml). The reaction mixture was stirred at room temperature for 2 hours and the solution was added a saturated aqueous solution of ammonium chloride to stop the reaction, then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane-ethyl acetate) to obtain 2.8 g (50%) specified in the connection header.

<> MS (EI): m/z 422 [M++3], 420 [M++1],1H-NMR (DMSO-d6) δ: 0,41-0,43 (m, 1H), of 0.77-0.87 (m, 2H), 1,18-of 1.52 (m, 3H), 1,83-of 1.92 (m, 1H), 1,99 (s, 3H), 2,50 is 2.55 (m, 1H), 2,64-of 2.66 (m, 1H), of 5.83 (s, 1H), 6,40 (s, 1H), 7,22-7,26 (m, 2H), 7,31-7,34 (m, 1H), 7,38-7,39 (m, 1H), 7,72-7,73 (m, 1H).

Example 16

Getting ethyl-[4-hydroxy-10-methoxy-4-(1-methylpiperidin-4-yl)-4H-1-tiebens[f]azulene-2-yl]acetate

Hexamethyldisilazane (16,8 g, 104 mmol) was cooled on ice in an argon atmosphere, and thereto was added dropwise a solution of 1.6 mol/l utility-hexane (65 ml, 104 mmol). After stirring the mixture for 30 minutes to the solution was added dropwise ethyl acetate (5 ml, 51 mmol) and the mixture was stirred for 30 minutes. Then to the mixture was added Pd(dba)2(1.5 g, 2.6 mmol) and chloride N,N'-(2,6-diisopropylphenyl)dihydroimidazole (1.1 g, 2.6 mmol), the mixture was stirred for 10 minutes, and then thereto was added dropwise a solution of the compound obtained in example 15 (5.0 g, 12 mmol) in toluene (100 ml). Then the mixture was stirred at room temperature overnight, the reaction mixture was added water and the product was extracted with ethyl acetate. The solvent in the organic layer is kept under reduced pressure and the residue was purified column chromatography on silica gel (hexane-ethyl acetate) to obtain 3.1 g (60%) specified in the connection header.

MS (EI): m/z 428 [M++1].1H-NMR (DMSO-d6) δ: 0,41-0,78 (m, 2H), of 1.18 (t, J=7,1 Hz, 3H), 1.30 and 1.83 m, 5H), 1,99 (c, 3H), 2,50 2.63 in (m, 2H), 3,84-to 3.92 (m, 5H), 4,08 (kV, J=7,1 Hz, 2H), 5,68 (c, 1H), 6,33 (c, 1H), 7,10 (c, 1H), 7,20-7,74 (m, 4H).

Example 17

Obtain [4-(1-methylpiperidin-4-ilidene)-10-oxo-9,10-dihydro-4H-1-tiebens[f]azulene-2-yl]acetic acid [compound 87]

To a solution of the compound obtained in example 16 (2.0 g, 4.7 mmol)in ethanol (24 ml) was added hydrochloric acid (8 ml) and the mixture is boiled under reflux by heating during the night. Solvents drove away, then to the precipitate was added water (20 ml) and sodium hydroxide (0.8 g, 20 mmol) and the mixture was stirred at room temperature overnight. The solution was brought to pH 6.5 with hydrochloric acid, the precipitated crystals were separated by filtration and dried to obtain 0.68 g (39%) specified in the connection header.

Example 18

Getting ethyl-(4-hydroxyphenylethyl)acetate

To a solution of 4-mercaptoethanol (23.1 g, 183 mmol) in DMF (450 ml) was added ethylbromoacetate (21,5 ml, 194 mmol) and potassium carbonate (50,7 g, 367 mmol) and the mixture was stirred at room temperature overnight. Solvents drove away under reduced pressure, to the precipitate was added water and the product was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate and the solvents drove away under reduced pressure. The residue was purified column of HRO what ecografia on silica gel (hexane:ethyl acetate = 5:1) obtaining of 30.3 g (78%) specified in the connection header.

MS (EI): m/z 212 [M+],1H-NMR (DMSO-d6) δ: 1,11 (t, J=7,1 Hz, 3H), 3,60 (c, 2H), 4,03 (kV, J=7,1 Hz, 2H), 6,72-6,74 (m, 2H), 7,25-7,27 (m, 2H), for 9.64 (c, 1H).

Example 19

Obtain methyl 3-(4-ethoxycarbonylmethylene)thiophene-2-carboxylate

To a solution of the compound obtained in example 18 (28,1 g, 132 mmol)in DMF (300 ml) was added methyl-3-brometalia-2-carboxylate (28,2 ml, 120 mmol) and potassium carbonate (36,6 g, 264 mmol), the mixture was stirred over night at room temperature. Solvents drove away under reduced pressure, to the precipitate was added water and the product was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate and the solvents drove away under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 5:1) to obtain 35.1 g (80%) specified in the connection header.

1H-NMR (DMSO-d6) δ: 1,11 (t, J=7,1 Hz, 3H), 3,70 (c, 2H), 3,83 (c, 3H), Android 4.04 (q, J=7,1 Hz, 2H), 5,41 (c, 2H), of 6.96-7,38 (m, 5H), 7,89-of 7.90 (m, 1H).

Example 20

Obtaining 3-(4-carboxymethylaminomethyl)thiophene-2-carboxylic acid

To a solution of the compound obtained in example 19 (35.1 g, 96 mmol)in methanol (250 ml) was added an aqueous solution of sodium hydroxide (19.2 g, 480 mmol) and the mixture was boiled under reflux under heating for 2 hours. With whom thou art allowed to cool in air, solvents drove under reduced pressure and to the precipitate was added water. The solution neutralize hydrochloric acid, precipitated crystals were separated by filtration and dried to obtain 30.0 g (97%) specified in the connection header.

1H-NMR (DMSO-d6) δ: 3,64 (c, 2H), 5,41 (c, 2H), 6,94 and 7.36 (m, 5H), 7,79-7,80 (m, 1H), 13,04 (users, 2H).

Example 21

Receive (4-oxo-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-alsultaniyyah acid

To a solution of the compound obtained in example 20 (29.0 g, 89 mmol)in dichloroethane (300 ml) was added anhydride triperoxonane acid (28,0 ml, 201 mmol) and the mixture was stirred over night at 60°C. the Solvents drove under reduced pressure and to the precipitate was added water. Precipitated crystals were separated by filtration and dried to obtain 26.7 g (98%) specified in the connection header.

MS (EI): m/z 307 [M++1].1H-NMR (DMSO-d6) δ: 3,81 (c, 2H), 5,31 (c, 2H), 7,20-8,10 (m, 5H), 12,78 (users, 1H).

Example 22

Obtaining methyl-(4-oxo-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphanilamide

To a solution of the compound obtained in example 21 (26,1 g, 85 mmol)was added methyliodide (6.5 ml, 104 mmol) and potassium bicarbonate (17.0 g, 170 mmol) and the mixture was stirred at room temperature overnight. Solvents drove away under reduced pressure, to the precipitate was added water and the product was extracted with what dilatatum. The organic layer was washed with a saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate and the solvents drove away under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=5:1) obtaining of 24.0 g (88%) specified in the connection header.

MS (EI): m/z 320 [M+].1H-NMR (DMSO-d6) δ: 3,64 (c, 3H), 3,91 (c, 2H), 5,31 (c, 2H), 7,20-7,27 (m, 2H), 7,63-7,66 (m, 1H), 7,97-8,10 (m, 2H).

Example 23

Obtaining methyl-[4-hydroxy-4-(1-methylpiperidin-4-yl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]acetate

The Grignard reagent derived from magnesium (2.8 g, 116 mmol), 4-chloro-1-methylpiperidine (15,5 ml, 116 mmol) and THF (180 ml), cooled on ice, and thereto was added dropwise a solution of the compound obtained in example 22 (18.5 g, 58 mmol)in THF (120 ml). Then the mixture was allowed to react for 30 minutes, and thereto was added a saturated solution of ammonium chloride and the product was extracted with ethyl acetate. Then the organic layer was washed with a saturated solution of ammonium chloride and a saturated solution of sodium chloride, then dried over anhydrous sodium sulfate and the solvents drove away under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:2) to obtain 4.4 g (18%) specified in the connection header.

1H-NMR (DMSO-d6) δ: 0,78-0,80 (m, 1H), 1,34-of 1.64 (m, 5H), 2.05 is c, 3H), 2.26 and-to 2.29 (m, 1H), 2,63 is 2.75 (m, 2H), 3,61 (c, 3H), 3,80-a 3.87 (m, 2H), 4,74 (d, J=15,5 Hz, 1H), 5,38 (d, J=15,5 Hz, 1H), 6,06 (c, 1H), 6,70-of 6.71 (m, 1H), 7,09-of 7.48 (m, 4H).

Example 24

Obtaining methyl-[4-(1-methylpiperidin-4-yl)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]acetate

To a solution of the compound obtained in example 23 (5.7 g, 14 mmol)in dichloromethane was added triperoxonane acid (10 ml) and the mixture was stirred at room temperature overnight. Solvents drove away and the residue was purified column chromatography on silica gel (hexane:ethyl acetate = 3:2) to obtain the free connection. Then thereto was added a mixture of 4 mol/l hydrochloric acid-dioxane (8.0 ml, 32 mmol) and the mixture was stirred for 1 hour. Solvents drove under reduced pressure and to the precipitate was added a simple ether to provide crystallization. Precipitated crystals were separated by filtration and dried to obtain 4.1 g (69%) specified in the connection header. TPL 210-212°C.1H-NMR (DMSO-d6) δ: 2,36-of 3.60 (m, 11H), 3,60 (c, 3H), 3,81-3,93 (m, 2H), 4,87 (d, J=15.3 Hz, 1H), the 5.45 (d, J=15.3 Hz, 1H), 6,85-7,53 (m, 5H), 10,67 (users, 1H).

Example 25

Obtain [4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]acetic acid [compound 172]

To a solution of the compound obtained in example 24 (2.9 g, 6.7 mmol)in ethanol (40 ml) was added an aqueous solution of sodium hydroxide (1.4 g, 680 mm is l) and the mixture was boiled under reflux under heating for 2 hours. The mixture was allowed to cool in air, and then the solvents drove away under reduced pressure, to the precipitate was added water and the mixture neutralize hydrochloric acid. Precipitated crystals were separated by filtration and dried to obtain 1.3 g (50%) specified in the connection header.

Example 26

Getting hydrochloride 1-cyclohexyloxycarbonyloxy-4-(1-methylpiperidin-4-ilidene)-9,10-dihydro-4H-1-tiebens[f]azulene-2-carboxylate [compound 176]

To a solution of compound 4 (3.0 g, 8,84 mmol) in DMF (50 ml) was added triethylamine (6.2 ml, a 44.2 mmol), potassium iodide (4.4 g, of 26.5 mmol) and 1-chlorotestosterone (2.2 g, 10.6 mmol) and the mixture was stirred at 80°C during the night. Solvents drove away under reduced pressure, to the precipitate was added water and the product was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate and the solvents drove away under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 5:1). Received free amino acids was dissolved in dioxane (20 ml), thereto was added a mixture of 4 mol/l hydrochloric acid-dioxane and the mixture was stirred for 1 hour. Solvents drove under reduced pressure and added a simple broadcast to ensure crystallization of the hydrochloride. Cree is of Tallaght was separated by filtration and dried to obtain 1.8 g (stage 2, 37%) specified in the connection header.

Example 27

Getting 4-(2-bromo-10H-9-oxa-3-tiebens[f]azulene-4-ilidene)-1-methylpiperidine

To a solution of 1-methyl-4-(10H-9-oxa-3-tiebens[f]azulene-4-ilidene)piperidine (19.3 g, 65,0 mmol) in chloroform (300 ml) was added dropwise bromine (5 ml, 98 mmol) at 0°C. the Mixture was stirred at 0°C for 2 hours, and then thereto was added a saturated aqueous solution of sodium bicarbonate to ensure separation of the organic layer. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate, then the solvent drove under reduced pressure and the residue was purified column chromatography (chloroform:methanol = 9:1). From the petroleum ether was obtained crystals to obtain 11.2 g (46%) specified in the connection header.

TPL 101-103°C.1H-NMR (CDCl3) 2,10-a 2.71 (m, 11H), was 4.76 (d, J=to 15.4 Hz, 1H), are 5.36 (d, J=to 15.4 Hz, 1H), 6,93 (c, 1H), 7,08 for 7.12 (m, 3H), 7,26-7,29 (m, 1H).

Example 28

Obtain tert-butyl[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]acetate

Hexamethyldisilazane (of $ 11.97 g, to 74.2 mmol) was cooled on ice in an argon atmosphere, and thereto was added dropwise a solution of 1.6 mol/l n-utility-hexane (46.6 ml, 74,6 mmol). To the solution was added dropwise tert-butyl acetate (4.9 ml of 36.7 mmol) and the mixture was stirred for 30 minutes. To it was added Pd(dba)2(1,05 g, 1,mmol), chloride N,N'-(2,6-diisopropylphenyl)dihydroimidazole (0,80 g, 1.9 mmol) and the compound obtained in example 27 (7.0 g, to 18.6 mmol), the mixture was heated to room temperature and was stirred overnight. To the reaction mixture was added water, the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic layer is kept under reduced pressure and the residue was purified column chromatography (hexane:ethyl acetate = 9:1) to obtain 3,30 g (43%) indicated in the title compound in the form of an oily product.

MS (EI): m/z 412 [M++1].1H-NMR (DMSO-d6) δ: 1,40 (c, 9H), 2,11-of 2.28 (m, 6H), 2,39-to 2.57 (m, 3H), 2,68-to 2.74 (m, 2H), 3,70 (c, 2H), amounts to 4.76 (d, J=to 15.4 Hz, 1H), are 5.36 (d, J=to 15.4 Hz, 1H), 6,58 (c, 1H), 7,05-7,10 (m, 3H), 7,25 (DD, J=2,3, 8.5 Hz, 1H).

Example 29

Getting hydrochloride [4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]acetic acid [compound 58]

To a solution of the compound obtained in example 28 (2,21 g, 5.4 mmol)in dioxane (30 ml) solution was added 4 mol/l hydrochloric acid-dioxane (10 ml, equivalent to 40 mmol of hydrochloric acid) and the mixture was stirred at 40°C for 8 hours. Solvents drove away under reduced pressure, and precipitated crystals were collected by filtration to obtain 1.70 g (81%) indicated in the title compound in the form of crystals containing 0.5 equivalents of dioxane.

Example 30

P is torching methyl-{4-[1-(4-oxobutyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetate

To a solution of methyl-(4-piperidine-4-ilidene-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acetate (2.50 g, 7.0 mmol) in DMF (50 ml), anhydrous potassium carbonate (2.15 g, 15.6 mmol) and potassium iodide (1,41 g, 8.5 mmol) was added 5-chloro-2-pentanon (2.4 ml, of 20.9 mmol) and the mixture was stirred over night at 80°C. the Solvents drove away under reduced pressure, to the precipitate was added water and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then the solvent drove away under reduced pressure. The residue was purified column chromatography (chloroform:methanol = 19:1) obtaining of 2.40 g (78%) indicated in the title compound in the form of an oily product.

MS (EI): m/z 439 [M+].1H-NMR (DMSO-d6) δ: 1,63 (TT, J=7,1, 7,1 Hz, 2H), 2,09 (c, 3H), 2,17 is 2.33 (m, 5H), 2,36-2,47 (m, 3H), 2,49-2,61 (m, 2H), 2,65-of 2.72 (m, 2H), 3,59 (c, 3H), 3,61 and the 3.65 (ABq, J=15.7 Hz, 2H), 4,82 (d, J=15.3 Hz, 1H), of 5.40 (d, J=15,3 Hz, 1H), 6,79 (d, J=5,2 Hz, 1H), 7,00 (d, J=2.0 Hz, 1H), 7,03 (d, J=8,2 Hz, 1H), 7,13 (DD, J=2.0 a, 8,2 Hz, 1H), 7,42 (d, J=5,2 Hz, 1H).

Example 31

Obtain {4-[1-(4-oxobutyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl)acetic acid [compound 170]

To a solution of the compound obtained in example 30 (2,40 g, 5.5 mmol), in ethanol (20 ml) was added an aqueous solution of 2 mol/l sodium hydroxide (5 ml, equivalent to 10 mmol of sodium hydroxide and the mixture was stirred at room temperature for 2 hours. Dissolve and drove away, then to the precipitate was added water and the aqueous solution was brought to pH 7 with diluted hydrochloric acid. Precipitated crystals were separated by filtration and dried to obtain 1.30 grams (56%) specified in the connection header.

Example 32

Obtain hydrochloride of 2-methyl-2-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]propionic acid [compound 190]

To a solution of the hydrochloride of methyl 2-methyl-2-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]propionate [compound 189] (0.88 g, 1.8 mmol) in ethanol (20 ml) was added an aqueous solution (10 ml) of sodium hydroxide (0,82 g, 20,6 mol) and the mixture was boiled under reflux under heating for 6 hours. Solvents drove away under reduced pressure, then the residue was dissolved in water, neutralize the solution with diluted hydrochloric acid, the precipitated crystals were separated by filtration and dried to obtain 0,67 g (72%) indicated in the title compound in the form of crystals.

Example 33

Getting ethyl-4-(2-bromo-9,10-dihydro-1-tiebens[f]azulene-4-ilidene)piperidine-1-carboxylate

To a solution of the compound obtained in example 1 (21,0 g, 56 mmol)in toluene (200 ml) was added ethylchloride (32 ml, 336 mmol) and the mixture was boiled under reflux under heating for 6 hours. The mixture was allowed the OHL is occurring in the air and the reaction mixture was added to saturated aqueous solution of sodium bicarbonate to ensure separation of the organic layer. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate, then the solvent drove under reduced pressure and the residue was purified column chromatography (hexane:ethyl acetate=19:1) to give 15.0 g (62%) indicated in the title compound in the form of an oily product.

MS (EI): m/z 433 [M++2], 431 [M+].1H-NMR (DMSO-d6) δ: 1,17 (t, J=7,1 Hz, 3H), 2,10-of 2.23 (m, 2H), 2,38-2,48 (m, 2H), 2,68-and 2.83 (m, 2H), 2,92-3,26 (m, 4H), 3,52-of 3.78 (m, 2H), Android 4.04 (q, J=7,1 Hz, 2H), 6.90 to (c, 1H), 7,02-7,13 (m, 1H), 7,16 and 7.36 (m, 3H).

Example 34

Getting ethyl-4-[2-(2-ethoxycarbonylphenyl)-9,10-dihydro-1-tiebens[f]azulene-4-ilidene)piperidine-1-carboxylate

To a solution of the compound obtained in example 33 (8,80 g of 17.0 mmol)in DMF (50 ml) was added to the acrylate (18.5 ml, 170 mmol), triethylamine (24 ml, 170 mmol), palladium acetate (0.3 g, 1.3 mmol) and three(o-toluyl)phosphine (2.0 g, 6.6 mmol) in a stream of gaseous argon and the mixture was stirred over night at 80°C. the Mixture was allowed to cool in air, and then the reaction mixture was added water, the product was extracted with ethyl acetate and the organic layer was washed with saturated a solution of sodium chloride, and then dried over anhydrous sodium sulfate. Solvents drove under reduced pressure and the residue was purified column chromatography (hexane-ethyl acetate = 9:1) obtaining of 6.1 g (79%) specified in the header joint is in the form of an oily product.

1H-NMR (DMSO-d6) δ: of 1.18 (t, J=7.0 Hz, 3H), of 1.23 (t, J=7.0 Hz, 3H), 2,11-of 2.16 (m, 1H), 2,20-of 2.28 (m, 1H), 2,38-2,48 (m, 2H), 2,78-of 2.86 (m, 2H), 2,96-3,14 (m, 1H), 3,20-of 3.32 (m, 3H), 3,55-3,61 (m, 1H), 3,68-3,74 (m, 1H), 4.04 the (kV, J=7,0 Hz, 2H), 4,15 (m, 2H), the 6.06 (d, J=15.7 Hz, 1H), 7,03 (d, J=7.2 Hz, 1H), 7,16-7,24 (m, 2H), 7,27 (c, 1H), 7,31 (d, J=8.0 Hz, 1H), 7,72 (d, J=15.7 Hz, 1H).

Example 35

Obtain tert-butyl 4-[2-(2-ethoxycarbonylethyl)-1-tiebens[f]azulene-4-ilidene]piperidine-1-carboxylate

To a solution of the compound obtained in example 34 (6,10 g, 13.5 mmol)in acetic acid (50 ml) was added a 30% solution of hydrogen bromide-acetic acid (3.8 ml, equivalent to 67.5 mmol hydrobromide) and the mixture was stirred at 120°C for 4 hours. The reaction mixture was allowed to cool in air to room temperature, the precipitate obtained from the distillation of the solvents under reduced pressure, was dissolved in ethanol (50 ml), the solution was added 2 mol/l aqueous sodium hydroxide solution (14 ml, equivalent to 28 mmol of sodium hydroxide and the mixture was stirred at room temperature for 3 hours. Solvents drove away, then to the precipitate was added to water, the aqueous solution was brought to pH 7 with diluted hydrochloric acid and the product was extracted with chloroform. The organic layer was washed with a saturated solution of sodium chloride, solvents drove away under reduced pressure, then the solution of the residue in dichloromethane (50 ml) was added di-tert-butyl is carbonate (3.0 g, 13.7 mmol) and the mixture was stirred at room temperature for 3 hours. To the mixture was added water, the organic layer was allowed to separate and was dried with anhydrous sodium sulfate and then the solvent drove away under reduced pressure. To a solution of the residue in DMF (50 ml) was added potassium bicarbonate (4.0 g, 40,5 mmol) and ethyliodide (1.1 ml, 13.5 mmol) and the mixture was stirred over night at room temperature. To the reaction mixture was added water, the product was extracted with ethyl acetate, the organic layer was washed with a saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate and the solvents drove away under reduced pressure. The residue was purified column chromatography (hexane:ethyl acetate = 19:1) to obtain 2.9 g (45%) indicated in the title compound in the form of an oily product.

1H-NMR (CDCl3) δ: 1,24 (t, J=7,1 Hz, 3H), 1,45 (c, 9H), 2,08 with 2.14 (m, 1H), 2,20-28 (m, 1H), 2,30-of 2.36 (m, 2H), 2,65 (t, J=7,6 Hz, 2H), 2,84-a 3.01 (m, 1H), to 3.02 (m, 1H), 3,12 (t, J=7,6 Hz, 1H), 3,56-3,70 (m, 2H), 4,14 (kV, J=7,1 Hz, 1H), 6,59 (c, 1H), 6,76 (d, J=11.5 Hz, 1H), at 6.84 (d, J=11.5 Hz, 1H), 7,10 (d, J=7,6 Hz, 1H), 7.23 percent-7,28 (m, 1H), 7,31 and 7.36 (m, 2H).

Example 36

Getting ethyl-3-(4-piperidine-4-ilidene-4H-1-tiebens[f]azulene-2-yl)propionate

To a solution of the compound obtained in example 35 (2.9 g, 6.0 mmol)in dioxane (30 ml) was added a mixture of hydrochloric acid-dioxane (7.5 ml, equivalent to 30 mmol hydrochloric key is lots) and the mixture was stirred at room temperature for 5 hours. Solvents drove under reduced pressure and the residue was purified column chromatography (chloroform-methanol = 19:1) to give 2.0 g (88%) indicated in the title compound in the form of an oily product.

1H-NMR (DMSO-d6) δ: 1,15 (t, J=7,1 Hz, 3H), 1,82-1,89 (m, 1H), 2,03 is 2.10 (m, 1H), 2,11-to 2.18 (m, 1H), 2.26 and of-2.32 (m, 1H), 2,44-of 2.58 (m, 1H) 2,60 of 2.68 (m, 2H), 2,70-2,82 (m, 1H), to 3.02 (t, J=7,3 Hz, 2H), 3,44-to 3.52 (m, 1H), 3,65-3,74 (m, 1H), Android 4.04 (q, J=7,1 Hz, 2H), 6,67 (c, 1H), 6,85 (d, J=11.5 Hz, 1H), 6.89 in (d, J=11.5 Hz, 1H), to 7.09 (d, J=7.5 Hz, 1H), 7,25-7,30 (m, 1H), 7,34-7,38 (m, 2H).

Example 37

Obtaining 3-(4-piperidine-4-ilidene-4H-1-tiebens[f]azulene-2-yl)propionic acid [compound 209]

To a solution of the compound obtained in example 36 (2.0 g, 5.3 mmol)in ethanol (30 ml) was added 2 mol/l aqueous solution of sodium hydroxide (10 ml, equivalent to 20 mmol of sodium hydroxide and the mixture was stirred at room temperature for 2 hours. Solvents drove away, then to the precipitate was added water and the mixture is brought to pH 7 with diluted hydrochloric acid. Precipitated crystals were separated by filtration and dried to obtain 1.1 g (59%) specified in the connection header.

Compounds of the present invention, different from the compounds mentioned above, was obtained in the same manner in accordance with the General methods of preparation, above, and the methods described in the Examples, using an appropriate source mA is Arial instead of starting material in the examples. Data about the properties of the compounds of the present invention, thus obtained, are presented in tables 1-17.

Table 1
No. of connectionsProperties
Connection 1TPL 138°C (decomp.). MS (EI): m/z 321 [M+].1H-NMR (DMSO-d6) δ: 1,92-to 2.85 (m, 13H), 3,18-is 3.21 (m, 1H), 3,35-3,37 (m, 1H), 7,02-7,58 (m, 5H).
Connection 2TPL 164-168°C. MS (EI): m/z 375 [M++2]. 373 [M+].1H-NMR (DMSO-d6) δ: 1,99-3,17 (m, 15H), 6,85 (s, 1H), 7,00-7,31 (m, 4H).
Connection 3TPL 135-137°C.1H-NMR (DMSO-d6) δ: 1,24-of 1.27 (m, 3H), 1.91 a-2,85 (m, 13H), 3,23-to 3.38 (m, 2H), 4,20-to 4.28 (m, 2H), 7.03 is-7,41 (m, 5H).
Connection 4TPL 212°C (decomp.). MS (EI): m/z 340 [M+].1H-NMR (DMSO-d6) δ: 2.21 are to 2.85 (m, 12H), 3,17-3,39 (m, 3H), 7.03 is-7,31 (m, 5H).
Connection 5TPL 243°C (decomp.). MS (EI): m/z 339 [M+].1H-NMR (DMSO-d6) δ: 2,61 is 3.40 (m, 15H), 7,09-7,40 (m, 5H), 10,42-10,98 (user., 1H), 12,78-13,08 (user., 1H).
Connection 6TPL 229°C (decomp.).1H-NMR (DMSO-d6) δ: 1,22 (t, J=7 Hz, 3H), 1,99-3,19 (m, 15H), 4,14 (kV, J=7,1 Hz, 2H), 6,01 (d, J=16.1 Hz, 1H), 7,01-7,31 (m, 5H), 7,63 (d, J=16.1 Hz, 1H).
Connection 7TPL 252°C (decomp.).1H-NMR (DMSO-d6) δ: 2,38-to 2.85 (m, 13H), 3,20 is-3.45 (m, 2H), 6,01 (d, J=15.7 Hz, 1H),? 7.04 baby mortality-7,34 (m, 5H), the 7.65 (d, J=15.7 Hz, 1H), 11,00 (users, 1H), of 12.33 (users, 1H).
Compound 8TPL 153°C (decomp.). MS (EI): m/z 373 [M++1].1H-NMR (DMSO-d6) δ: 1,89-to 2.55 (m, 11H), 6,87 (d, J=11,6 Hz, 1H), 6,98 (d, J=11,6 Hz, 1H), 7,06 (s, 1H), 7,12-7,13 (m, 1H), 7,30-7,33 (m, 1H), 7,41-7,44 (m, 2H).
Connection 9TPL 190-193°C. MS (EI): m/z 320 [M+].1H-NMR (DMSO-d6) δ: 2.00 in 2,89 (m, 13H), 3,16-3,19 (m, 2H),? 7.04 baby mortality-7,33 (m, 4H), to 7.61 (s, 1H).
Connection 10TPL 230°C (decomp.). MS (EI): m/z 410 [M+].1H-NMR (DMSO-d6) δ: the 1.44 (s, 9H), 2,01-3,17 (m, 15H), 6,10 (s, 1H), of 6.96-7,26 (m, 4H), 10,20-10,23 (m, 1H).
Connection 11TPL 223°C (decomp.).1H-NMR (DMSO-d6) δ: 2,00-3,17 (m, 18H), 6,21 (s, 1H), 6,97-7,27 (m, 4H), 10,94 (s, 1H).
Connection 12TPL 239°C (decomp.). MS (EI): m/z 324 [M+].1H-NMR (DMSO-d6) δ: 2,33-3,61 (m, 15H), 4,01-is 4.21 (m, 2H), 6.89 in (s, 1H), 7,05-7,33 (m, 4H), 8,29-to 8.34 (m, 3H), br11.01-11,12 (m, 1H).
Connection 13TPL 15°C (decomp.). MS (EI): m/z 366 [M+].1H-NMR (DMSO-d6) δ: 2,04 of 3.28 (m, 18H), 4,40-a 4.53 (m, 2H), 5,74 (users, 1H), 6,60 (s, 1H), 7,01-7,26 (m, 4H).
The connection 14TPL 156°C (decomp.). MS (EI): m/z 353 [M+].1H-NMR (DMSO-d6) δ: 1,98-3,18 (m, 15H), 5,94-6,00 (m, 3H), 6,95-7,26 (m, 4H), of 9.30 (users, 1H).

Table 2
No. of connectionsProperties
The connection 15TPL 225°C (decomp.).1H-NMR (DMSO-d6) δ: 2,08-3,37 (m, 15H), 6,00 (d, J=16.1 Hz, 1H), 6,95-7,31 (m, 5H), 7,58 (d, J=16.1 Hz, 1H), 11,85-12,47 (user., 1H).
The connection 16TPL 215°C (decomp.).1H-NMR (DMSO-d6) δ: USD 1.43 (s, 9H), 1,95-3,20 (m, 15H), 6,20 (c, 1H), 6,97-7,27 (m, 4H), 10,13 (users, 1H).
Connection 17TPL 225°C (decomp.).1H-NMR (DMSO-d6) δ: 1,98 is 2.80 (m, 16H), 3,12-is 3.21 (m, 2H), 6,29 (c, 1H), 6,98-7,28 (m, 4H), 10,89 (c, 1H).
The connection 18TPL 115°C (decomp.). MS (EI): m/z 353 [M+].1H-NMR (DMSO-d6) δ: 1,93-is 3.21 (m, 15H), 5,96 (users, 2H), 6,06 (c, 1H), of 6.96-7,27 (m, 4H), 9,45 (users, 1H).
Connection 19TPL 230°C (decomp.).1H-NMR (DMSO-d6) δ: 227-3,38 (m, 15H), 4.09 to-4,10 (m, 2H), 6,97-7,33 (m, 5H), 8,40-8,51 (m, 3H), 10,92-11,12 (m, 1H).
The connection 20TPL 118°C (decomp.)1H-NMR (DMSO-d6) δ: 1,79 is 2.80 (m, 16H), 3,18-up 3.22 (m, 2H), 4,22-4,30 (m, 2H), 6,60 (c, 1H), 6,97-7,28 (m, 4H), 8,32-of 8.33 (m, 1H).
Connection 21TPL 134-136°C.1H-NMR (DMSO-d6) δ: 1,25 (t, J=7,1 Hz, 3H), 2,01-and 2.79 (m, 13H), 3,15-3,18 (m, 2H), 4,23 (kV, J=7,1 Hz, 2H), 7,02-to 7.32 (m, 4H), 7,44 (c, 1H).
The connection 22TPL 93-96°C. MS (EI): m/z 393 [M+].1H-NMR (DMSO-d6) δ: 1,22 (t, J=7,1 Hz, 3H), 1,99-3,19 (m, 15H), 4,14 (kV, J=7,1 Hz, 2H), 6,09 (d, J=16.1 Hz, 1H), 7,01-7,31 (m, 5H), 7,63 (d, J=16.1 Hz, 1H).
The connection 23TPL 138°C (decomp.). MS (EI): m/z 380 [M+].1H-NMR (DMSO-d6) δ: 1,17 (t, J=7,1 Hz, 3H), 2,00-2,75 (m, 13H), 3.04 from-3,18 (m, 2H), 3.75 to (c, 2H), 4,06 (kV, J=7,1 Hz, 2H), 6,56 (s, 1H), 6,98-7,29 (m, 4H).
Connection 24TPL 174°C (decomp.).1H-NMR (DMSO-d6) δ: 2,08-and 2.79 (m, 13H), 3.04 from-3,17 (m, 2H), 3,62 (c, 2H), of 6.52 (s, 1H), 6,98-7,29 (m, 4H).
The connection 25TPL 154-156°C. MS (EI): m/z 323 [M++1].1H-NMR (DMSO-d6) δ: 2.06 to 2,73 (m, 11H), 4,99 (d, J=15,5 Hz, 1H), 5,49 (d, J=15,5 Hz, 1H), 6,94-of 7.70 (m, 5H).
The connection 26TPL 208°C (decomp.). MS (EI): m/z 342 [M++1]. H-NMR (DMSO-d6) δ: 1.32 to is 2.37 (m, 11H), 4,36 (d, J=15,5 Hz, 1H), 5,97 (d, J=15,5 Hz, 1H), 6,14-6,16 (m, 1H), 6,66-6,69 (m, 2H), 7,39-to 7.50 (m, 2H).
Connection 27TPL 111°C (decomp.). MS (EI): m/z 382 [M+].1H-NMR (DMSO-d6) δ: 1,97-and 2.83 (m, 13H), 3,19-of 3.48 (m, 6H), 4,69-4,71 (m, 1H), 6,98-6,99 (m, 1H), 7,16-7,21 (m, 2H), 7,29-7,30 (m, 1H), 7,47 (c, 1H), at 8.36-8,39 (m, 1H).
The connection 28TPL 120°C (decomp.). MS (EI): m/z 426 [M+].1H-NMR (DMSO-d6) δ: 1,97-to 3.58 (m, 23H), 4,79 to 4.92 (user., 2H), 7,02-7,03 (m, 1H), 7,16-7,21 (m, 2H), 7,24 (c, 1H), 7,29-7,31 (m, 1H).

Table 3
No. of connectionsProperties
The connection 29TPL 111°C (decomp.). MS (EI): m/z 426 [M+].1H-NMR (DMSO-d6) δ: 1,82-to 2.85 (m, 18H), 3,25-3,44 (m, 4H), 4,20-4.26 deaths (m, 2H), of 4.44-to 4.46 (m, 1H), 7.03 is? 7.04 baby mortality (m, 1H), 7,16-7,22 (m, 2H), 7,30-7,31 (m, 1H), 7,43 (s, 1H).
The connection 30TPL 106°C (decomp.). MS (EI): m/z 396 [M+].1H-NMR (DMSO-d6) δ: 1,62-of 1.64 (m, 2H), 1,96-and 2.83 (m, 13H), 3,19 is-3.45 (m, 6H), 4,43-4,45 (m, 1H), 6,99-7,00 (m, 1H), 7,16-7,21 (m, 2H), 7,29-7,30 (m, 1H), 7,44 (s, 1H), 8,33-8,35 (m, 1H).
The connection 31TPL 220°C (decomp.).1H-NMR (DMSO-d6) δ: 1,97-and 2.83 (m, 13H), 3,22-3,29 (m, 2H), 6,9-7,00 (m, 1H), 7,16-7,31 (m, 4H), 7,45 (s, 1H), 7,87 (users, 1H).
The connection 32TPL 244°C (decomp.). MS (EI): m/z 353 [M+].1H-NMR (DMSO-d6) δ: 1,94-2,84 (m, 13H), 3,19-of 3.42 (m, 4H), 6,59 (s, 1H), 6,98-6,99 (m, 1H), 7,14-7,19 (m, 2H), 7,27-7,29 (m, 1H).
The connection 33TPL 195°C (decomp.) MS (EI): m/z 450 [M++1].1H-NMR (DMSO-d6) δ: of 1.33 to 1.37 (m, 2H), of 1.46 to 1.47 (m, 4H), 1,96-and 2.83 (m, 17H), 3,19-3,44 (m, 4H), 6.89 in-7,00 (m, 1H), 7,16-7,21 (m, 2H), 7,29-7,30 (m, 1H), 7,43 (s, 1H), 8,29-8,31 (m, 1H).
The connection 34TPL 176°C (decomp.).1H-NMR (DMSO-d6) δ: 1,25 (t, J=7,1 Hz, 3H), 2,08-a 2.71 (m, 11H), 4,16 (kV, J=7,1 Hz, 2H), 4,90 (d, J=12.1 Hz, 1H), the 5.45 (d, J=12.1 Hz, 1H), of 6.52 (d, J=16.1 Hz, 1H), 6,86-7,63 (m, 6H).
The connection 35TPL 193°C (decomp.). MS (EI): m/z 368 [M++1].1H-NMR (DMSO-d6) δ: 1,28-a 2.71 (m, 11H), 4,25 (d, J=12.1 Hz, 1H), around 4.85 (d, J=12.1 Hz, 1H), equal to 6.05 (d, J=16.1 Hz, 1H), 6,47-6,99 (m, 6H).
The connection 36TPL 179°C (decomp.).1H-NMR (DMSO-d6) δ: of 1.23 (t, J=7,1 Hz, 3H), 2,12-to 2.74 (m, 11H), 4,15 (kV, J=7,1 Hz, 2H), 4,80 (d, J=12.1 Hz, 1H), of 5.40 (d, J=12.1 Hz, 1H), 6,16 (d, J=16.1 Hz, 1H), 7,09-7,29 (m, 5H), 7,66 (d, J=16.1 Hz, 1H).
The connection 37TPL 229°C (decomp.).1H-NMR (DMSO-d6) δ: 2,12-to 2.74 (m, 11H), 4,80 (d, J=12.1 Hz, 1H), of 5.40 (d, J=12.1 Hz, 1H), 6,07 (d, J=16.1 Hz, 1H), 7,09-7,29 (m, 5H), and 7.6 (d, J=16.1 Hz, 1H), 12,14 (user., 1H).
Compound 38TPL 113°C (decomp.). MS (EI): m/z 396 [M+].1H-NMR (DMSO-d6) δ: 1,94-and 2.83 (m, 15H), 3,23 is 3.40 (m, 7H), 6.89 in-7,00 (m, 1H), 7.23 percent-7,30 (m, 3H), 7,47 (s, 1H), 8,45-8,46 (m, 1H).
Connection 39TPL 140°C (decomp.).1H-NMR (DMSO-d6) δ: 2,28-3,71 (m, 19H), 7,01-7,11 (m, 1H), 7,19-7,25 (m, 2H), 7,33-7,34 (m, 1H), 7,66-to 7.77 (m, 1H), 8.07-a 8,21 (m, 3H), 8,84 is 9.15 (m, 1H), 11,12 (users, 1H).

Table 4
No. of connectionsProperties
The connection 40TPL 194°C (decomp.). MS (EI): m/z 368 [M+].1H-NMR (DMSO-d6) δ: 2,03-to 2.85 (m, 13H), 3,20-3,44 (m, 2H), to 3.67 (s, 3H), 6,99-7,01 (m, 1H), 7,16-7,25 (m, 2H), 7,29-7,33 (m, 2H), 11,63 (users, 1H).
The connection 41TPL 136°C (decomp.). MS (EI): m/z 395 [M+].1H-NMR (DMSO-d6) δ: 2.00 in 2,84 (m, 13H), 3,21-3,26 (m, 2H), 3,75 (DQC, J=16,4, 6,0 Hz, 2H), 7,00-7,01 (m, 2H), 7,16-7,21 (m, 2H), 7,29-7,33 (m, 2H), 7,50 (s, 1H), 8,60-8,63 (m, 1H).
The connection 42TPL 167°C (decomp.). MS (EI): m/z 410 [M+].1H-NMR (DMSO-d6) δ: 2,05-of 2.86 (m, 13H), 3,22-to 3.34 (m, 2H), to 3.64 (s, 3H), 3,90-4,01 (m, 2H), 7,00-7,02 (m, 1H), 7,21-7,24 (m, 2H), 7,29-7,30 (m, 1H), 7,50 (s, 1H), 8,86-8,88 (m, 1H).
The connection 43TPL 138°C (decomp.). MS (EI): m/z 408 [M+].1H-NMR (DMSO-d6) δ: 1,89-2,84 (m, 13H), 3,24-to 3.64 (m, 10H), 7,01? 7.04 baby mortality (m, 2H), 7,14-7,31 (m, 3H).
The connection 44TPL 246°C (decomp.).1H-NMR (DMSO-d6) δ: 1.25 or of 1.28 (m, 3H), 2,42-3,63 (m, 11H), 4,24-to 4.28 (m, 2H), 4,88-4,91 (m, 1H), 5,45-of 5.48 (m, 1H), 7,12-EUR 7.57 (m, 5H), 10,99 (users, 1H).
The connection 45TPL 209°-212°C.1H-NMR (DMSO-d6) δ: 2,28-2,78 (m, 11H), 4,84 (d, J=15,5 Hz, 1H), 5,41 (d, J=15,5 Hz, 1H), 7,07-7,29 (m, 4H), 7,34 (s, 1H).
The connection 46TPL 180°-184°C.1H-NMR (DMSO-d6) δ: 2,08-to 2.57 (m, 11H), 6,38 (d, J=15,9 Hz, 1H), 7,02-the 7.43 (m, 6H), EUR 7.57 (d, J=15,9 Hz, 1H), 8,07 (s, 1H), 12,19 (user., 1H).
Connection 47TPL 139°-141°C. MS (EI): m/z 407 [M+].1H-NMR (DMSO-d6) δ: 1,25 (t, J=7,1 Hz, 3H), 2.06 to 2,70 (m, 11H), to 3.73 (d, J=13,6 Hz, 1H), 4,16-to 4.23 (m, 3H), 6,51 (d, J=15,9 Hz, 1H), 7,17-7,27 (m, 3H), 7,37-7,39 (m, 1H), 7.62mm (s, 1H), 7,79 (d, J=15,9 Hz, 1H).
The connection 48TPL 207°C (decomp.). MS (EI): m/z 379 [M+].1H-NMR (DMSO-d6) δ: 2,12-of 2.75 (m, 11H), and 3.72 (d, J=13,6 Hz, 1H), 4,23 (d, J=13,6 Hz, 1H), 6,41 (d, J=15,8 Hz, 1H), 7.18 in-7,39 (m, 4H), EUR 7.57 (s, 1H), of 7.70 (d, J=15,8 Hz, 1H).
The connection 49TPL 138°C (decomp.). MS (EI): m/z 368 [M++1].1H-NMR (who MCO-d 6) δ: 2,02 is 2.80 (m, 13H), 3,19 is 3.23 (m, 2H), 4,19 (d, J=5,9 Hz, 2H), 5,49 (s, 2H), 6,36 (t, J=5,9 Hz, 1H), return of 6.58 (s, 1H), 6,97-6,99 (m, 1H), 7,14-7,19 (m, 2H), 7,27-7,28 (m, 1H).
The connection 50TPL 138-139°C. MS (EI): m/z 381 [M+].1H-NMR (DMSO-d6) δ: of 1.29 (t, J=7,1 Hz, 3H), 2.00 in a 2.71 (m, 11H), of 3.77 (d, J=13,7 Hz, 1H), 4,24 is 4.36 (m, 3H), 7,21-7,40 (m, 4H), 7,89 (s, 1H).
The connection 51TPL 280-283°C. MS (EI): m/z 353 [M+].1H-NMR (DMSO-d6) δ: 2,36-of 3.07 (m, 11H), 3,70 (d, J=13,7 Hz, 1H), 4,30 (d, J=13,7 Hz, 1H), 7,21-7,40 (m, 5H).

Table 5
No. of connectionsProperties
The connection 52TPL 111-113°C.1H-NMR (DMSO-d6) δ: 2,02-of 3.43 (m, 19H), 4,69 (t, J=5.4 Hz, 1H), 6,29 (d, J=15,5 Hz, 1H), 6,97 (s, 1H), 7,01-7,31 (m, 4H), 7,34 (d, J=15,5 Hz, 1H), 8,07 (t, J=5.7 Hz, 1H).
The connection 53TPL 114°C (decomp.). MS(EI): m/z 385 [M++1].1H-NMR (DMSO-d6) δ: 2,13-of 2.72 (m, 11H), 3,23 is-3.45 (m, 4H), 4,70-4,74 (m, 1H), 4,82 (d, J=to 15.4 Hz, 1H), 5,42 (d, J=to 15.4 Hz, 1H), 7,07-7,29 (m, 4H), 7,44 (s, 1H), 8,39 (t, J=5.7 Hz, 1H).
The connection 54TPL 264°C (decomp.). MS (EI): m/z 355 [M++1].1H-NMR (DMSO-d6) δ: 2,36-3,63 (m, 11H), a 4.86 (d, J=15.3 Hz, 1H), 5,44 (d, J=15.3 Hz, 1H), 683-7,51 (m, 5H), 10,83-10,91 (user., 1H), 12,32 (s, 1H).
The connection 55TPL 105°C (decomp.). MS (EI): m/z 384 [M+].1H-NMR (DMSO-d6) δ: 2,10-of 2.72 (m, 11H), 3,26-to 3.50 (m, 4H), and 4.68 (t, J=5.7 Hz, 1H), 4,90 (d, J=14,9 Hz, 1H), 5,46 (d, J=14,9 Hz, 1H), 6,86-7,76 (m, 5H), to 8.34 (t, J=5.5 Hz, 1H).
The connection 56TPL 206°C (decomp.). MS (EI): m/z 367 [M+].1H-NMR (DMSO-d6) δ: 1,04-of 1.07 (m, 3H), 2,48-of 3.43 (m, 15H), 3,85-a 3.87 (m, 1H), 6,66 is 6.67 (m, 1H), 7,02-to 7.32 (m, 4H), 10,78 (user., 1H), 12,55 (users, 1H).
Connection 57TPL 179°C (decomp.). MS (EI): m/z 370 [M++1].1H-NMR (DMSO-d6) δ: 1.32 to about 1.36 (m, 3H), 2,36-to 3.67 (m, 12H), 4,84-4,88 (m, 1H), 5.40 to-the 5.45 (m, 1H), 6,84-7,51 (m, 5H), 10,63-10,76 (m, 1H), 12,31 (users, 1H).
The connection 58TPL 149°C (decomp.). MS (EI): m/z 356 [M++1].1H-NMR (DMSO-d6) δ: 2,36-a 3.87 (m, 13H), 4,78-to 4.81 (m, 1H), lower than the 5.37-5.40 to (m, 1H), 6,65-7,31 (m, 5H), 10,69 (users, 1H), 12,60 (users, 1H).
Connection 59TPL 244°C (decomp.). MS (EI): m/z 352 [M++1].1H-NMR (DMSO-d6) δ: 2,18-3,10 (m, 13H), of 6.96-7,66 (m, 7H), 10,70 (user., 1H), to 12.44 (users, 1H).
The connection 60TPL 212°C (decomp.). MS (EI): m/z 367 [M+].1H-NMR (DMSO-d6) δ: 1,36 (t, J=6.4 Hz, 3H), 2,50 is-3.45 (m, 15H), 3,82-of 3.85 (m, 1H), is 6.61 (s, 1H), 7.03 is-to 7.32 (m, 4H), a 10.74-br11.01 (user., 1H), 12,56 (ush the D.C, 1H).
The connection 61MS (EI): m/z 425 [M+].1H-NMR (DMSO-d6) δ: of 1.18 (t, J=6,7 Hz, 3H), of 1.26 (t, J=7,1 Hz, 3H), 2,17-of 2.23 (m, 2H), 2,42 at 2.45 (m, 1H), 2,82-to 3.36 (m, 7H), 3,61-3,63 (m, 1H), 3,74-of 3.77 (m, 1H), Android 4.04 (q, J=7,1 Hz, 2H), 4,24 (kV, J=6,7 Hz, 2H),? 7.04 baby mortality-7,05 (m, 1H), 7.18 in-of 7.23 (m, 2H), 7,31-7,32 (m, 1H), 7,45 (s, 1H).
The connection 62TPL 155°-159°C. MS (EI): m/z 353 [M+].1H-NMR (DMSO-d6) δ: 1.26 in (t, J=6.8 Hz, 3H), 2,09 of 2.92 (m, 11H), 3,26-3,37 (m, 2H), 4.26 deaths (kV, J=6,8 Hz, 2H), 7,02? 7.04 baby mortality (m, 1H), 7,16-7,21 (m, 2H), 7,29-7,31 (m, 1H), 7,40 (s, 1H).

TPL 115°C (decomp.).1H-NMR (DMSO-d6) δ: 1,97-of 3.60 (m, 20H), 4,51-4,56 (m, 1H), 4,74-4,78 (m, 1H), 6,99 is 7.50 (m, 5H), 8,24-of 8.37 (m, 1H).
Table 6
No. of connectionsProperties
Connection 63MS (EI): m/z 396 [M+].1H-NMR (DMSO-d6) δ: 1,95-3,39 (m, 19H), 3,49 (s, 2H), of 4.66 (t, J=5.3 Hz, 1H), 6,55 (s, 1H), 6,97-6,99 (m, 1H), 7,14-7,19 (m, 2H), 7,27-7,28 (m, 1H), 8,02-of 8.04 (m, 1H).
The connection 64TPL 86°C (decomp.). MS (EI): m/z 413 [M++1].1H-NMR (DMSO-d6) δ: 1.25 or of 1.28 (m, 3H), 2,18-to 3.58 (m, 16H), br4.61 with 4.64 (m, 1H), 4,81 (d, J=15.3 Hz, 1H), 5,39 (d, J=15.3 Hz, 1H), 6,78-7,42 (m, 5H), 7,88-of 7.97 (m, 1H).
The connection 65TPL 251°C (decomp.). MS (EI): m/z 381 [M+].1H-NMR (DMSO-d6) δ: 1,45 of 1.46 (m, 6H), 1,99 is 3.23 (m, 15H), to 6.58 (s, 1H), 6,99-7,29 (m, 4H).
Compound 66TPL 122°C (decomp.). MS (EI): m/z 411 [M++1].1H-NMR (DMSO-d6) δ: 2,16-a 2.71 (m, 11H), 3,22-3,24 (m, 2H), 3,43-3,47 (m, 2H), 4,74 (t, J=5.5 Hz, 1H), 4,89 (d, J=to 15.0 Hz, 1H), 5,44 (d, J=to 15.0 Hz, 1H), 6,59 (d, J=15,8 Hz, 1H), 6,85-to 7.09 (m, 2H), 7,34 (s, 1H), 7,35 (d, J=to 15.8 Hz, 1H), 7,42 was 7.45 (m, 2H), 8,03 (t, J=5.5 Hz, 1H).
Connection 67TPL 198-200°C. MS (EI): m/z 382 [M+].1H-NMR (DMSO-d6) δ: 2,01 is-3.45 (m, 19H), 4,70 (t, J=5.6 Hz, 1H), 7,01-7,03 (m, 1H), 7,16-of 7.23 (m, 2H), 7,30-7,31 (m, 1H), 7,38 (s, 1H), 8.30 to-8,32 (m, 1H).
The connection 68TPL 247-250°C.1H-NMR (DMSO-d6) δ: of 1.42 (s, 3H), USD 1.43 (s, 3H), 2,20-by 2.73 (m, 11H), 4,84 (d, J=15.3 Hz, 1H), of 5.40 (d, J=15.3 Hz, 1H), 6,80-the 7.43 (m, 5H).
Connection 69TPL 151°C (decomp.). MS (EI): m/z 396 [M+].1H-NMR (DMSO-d6) δ: 2,45-3,70 (m, 22H), 4,43-4,48 (user., 1H), 7,05-7,33 (m, 5H), 10,75-11,04 (user., 1H).
The connection 70TPL 186-188°C. MS (EI): m/z 396 [M+].1H-NMR (DMSO-d6) δ: of 1.03 (d, J=6,1 Hz, 3H), 1,96-3,74 (m, 18H), 4,71 (d, J=4,7 Hz, 1H), 6,98-7,49 (m, 5H), 8,35-at 8.36 (m, 1H).
Connection 71TPL 226-229°C.1H-NMR (DMSO-d6) δ: 1,07-1,11 (m, 3H), 1,91-of 3.42 (m, 17H), 3,89-3,93 (m, 1H), 4,70 (dt, J=21,9, 5.8 Hz, 1H), 6,97-7,52 (m, 5H), 8,02 (d, J=7.9 Hz, 1H).
The connection 72
Connection 731H-NMR (DMSO-d6) δ: 1,91-3,50 (m, 19H), 3,85-a 3.87 (m, 1H), 4,60-of 4.67 (m, 2H), 6,97-7,53 (m, 5H), 7,94 (d, J=8,1 Hz, 1H).
The connection 74TPL 112°C (decomp.). MS (EI): m/z 368 [M+].1H-NMR (DMSO-d6) δ: 1,98 is 3.23 (m, 18H), 7,03-of 7.48 (m, 5H), 10,46 (users, 1H).

Table 7
No. of connectionsProperties
Connection 75TPL 228°C (decomp.). MS (EI): m/z 382 [M+].1H-NMR (DMSO-d6) δ: 1,21 (t, J=7,1 Hz, 3H), 1,95-3,20 (m, 15H), 4,10 (kV, J=7,1 Hz, 2H), 6,23 (s, 1H), 6,97-7,28 (m, 4H), 10,35 (users, 1H).
The connection 76TPL 143-146°C. MS (EI): m/z 396 [M+].1H-NMR (DMSO-d6) δ: 1,21-of 1.23 (m, 6H), 1,95-3,20 (m, 15H), 4,82-to 4.87 (m, 1H), from 6.22 (s, 1H), 6,97-7,28 (m, 4H), 10,31 (users, 1H).
Connection 77TPL 191-192°C. MS (EI): m/z 384 [M+].1H-NMR (DMSO-d6) δ: 1,97-3,50 (m, 17H), of 4.44-4,56 (m, 2H), 6,99 is 7.50 (m, 5H), 8,63 (t, J=5.6 Hz, 1H).
The connection 78TPL 166°C (decomp.). M is (EI): m/z 354 [M +].1H-NMR (DMSO-d6) δ: 2,02-to 3.33 (m, 15H), 7,00-7,30 (m, 5H), 9,06 (user., 1H), 11.11 is (user, 1H).
Connection 79TPL 195-197°C. MS (EI): m/z 420 [M+].1H-NMR (DMSO-d6) δ: 1,97-to 3.33 (m, 15H), 3,97-4,08 (m, 2H), 7,00-7,31 (m, 4H), to 7.59 (s, 1H), 8,99-9,01 (m, 1H).
The connection 80TPL 220-222°C.1H-NMR (DMSO-d6) δ: 1,24-of 1.26 (m, 6H), 1,87-of 3.31 (m, 15H), of 3.46 (d, J=5,9 Hz, 2H), 4,84 (t, J=5,9 Hz, 1H), 6,97-7,31 (m, 4H), 7,45 (s, 1H), 7,52 (s, 1H).
Connection 81TPL 188-191°C. MS (EI): m/z 470 [M+].1H-NMR (DMSO-d6) δ: 1,97-to 3.33 (m, 15H), 3,99-4,18 (m, 2H), 7,00-7,31 (m, 4H), to 7.59 (s, 1H), 8,98 (t, J=6.2 Hz, 1H).
The connection 82TPL 175°C (decomp.). MS (EI): m/z 398 [M+].1H-NMR (DMSO-d6) δ: 1,96-3,51 (m, 20H), of 6.96-of 7.48 (m, 5H), 8,51-8,61 (m, 1H).
Connection 83TPL 110°C (decomp.). MS (EI): m/z 397 [M+].1H-NMR (DMSO-d6) δ: 1,98-3,66 (m, 19H), 4,77 (users, 1H), 4,96-5,02 (m, 2H), 7,02-7,53 (m, 5H).
The connection 84TPL 144-146°C. MS (EI): m/z 382 [M+].1H-NMR (DMSO-d6) δ: 2,00-3,39 (m, 18H), and 3.72 (s, 3H), 7.03 is-7,31 (m, 4H), of 7.48 (s, 1H).
Connection 85TPL 180-183°C.1H-NMR (DMSO-d6) δ: 0,86 (d, J=7,4 Hz, 3), 1,47-is 1.51 (m, 2H), 1,95-to 3.35 (m, 17H), 6,99-7,30 (m, 4H), 7,45 (s, 1H), at 8.36 (t, J=5.6 Hz, 1H).
Connection 86TPL 185-187°C.1H-NMR (DMSO-d6) δ: 1,98-to 3.33 (m, 15H), 3,79-a 3.87 (m, 2H), 5,08 (d, J=10,2 Hz, 1H), 5,15 (d, J=17.3 Hz, 1H), 5,81-of 5.89 (m, 1H), 6,99-7,30 (m, 4H), to 7.50 (s, 1H), 8,58 (t, J=5.6 Hz, 1H).
Connection 87TPL 194-197°C. MS (EI): m/z 367 [M+].1H-NMR (DMSO-d6) δ: 2,12 was 2.76 (m, 11H), the 3.65 (d, J=13.5 Hz, 1H), 3,81 (s, 2H), 4,19 (d, J=13.5 Hz, 1H), 7,00 (s, 1H), 7,16-7,37 (m, 4H).
The connection 88TPL 160°C (decomp.). MS (EI): m/z 397 [M+].1H-NMR (DMSO-d6) δ: 1,18 (m, 3H), 2,23-of 4.05 (m, 14H),? 7.04 baby mortality-to 7.32 (m, 5H).

Table 8
No. of connectionsProperties
Connection 89TPL >280°C. MS (EI): m/z 337 [M+].1H-NMR (DMSO-d6) δ: 2,10 at 2.59 (m, 11H), 7,02 (d, J=11,9 Hz, 1H), 7,15-7,41 (m, 4H), of 7.48 (d, J=11,9 Hz, 1H), 8,23 (s, 1H).
Connection 90MS (EI): m/z 395 [M+].1H-NMR (DMSO-d6) δ: 1,24 of 1.28 (m, 3H), 2.00 in 4.26 deaths (m, 17H), 7,05 was 7.45 (m, 5H).
Connection 91TPL 176°C (decomp.). MS (EI): m/z 367 [M+].1H-NMR (DMSO-d sub> 6) δ: 1,94-3,93 (m, 15H), 7,05 was 7.45 (m, 5H).
The connection 92TPL 169-173°C. MS (EI): m/z 425 [M+].1H-NMR (DMSO-d6) δ: 1,23-of 1.27 (m, 3H), 2,10-to 3.38 (m, 16H), 4,21-to 4.28 (m, 2H), 7.03 is-7,44 (m, 5H).
Connection 93TPL 136-140°C. MS (EI): m/z 367 [M+].1H-NMR (DMSO-d6) δ: 1,99-3,17 (m, 19H), of 6.45 (s, 1H), 6,97-7,27 (m, 4H).
Connection 94TPL 119°C (decomp.). MS (EI): m/z 378 [M+].1H-NMR (DMSO-d6) δ: 2,14-of 3.46 (m, 16H), 7,03-to 7.35 (m, 5H).
Connection 95TPL 109-111°C.1H-NMR (DMSO-d6) δ: of 1.18 (t, J=7,1 Hz, 3H), 1,94-2,95 (m, 13H), 3.27 to to 3.36 (m, 2H), 4,29 (kV, J=7,1 Hz, 2H), for 6.81-PC 6.82 (m, 1H), 7,29-7,30 (m, 1H), 7,45-7,47 (m, 1H), 7,56-EUR 7.57 (m, 1H), 7,78-7,81 (m, 1H).
Connection 96TPL >280°C.1H-NMR (DMSO-d6) δ: 2,16-of 2.93 (m, 13H), 3,28-to 3.35 (m, 2H), for 6.81-PC 6.82 (m, 1H), 7,30-7,31 (m, 1H), 7,42-the 7.43 (m, 1H), EUR 7.57-7,58 (m, 1H), to 7.77-7,79 (m, 1H).
Connection 97TPL 88-92°C. MS (EI): m/z 395 [M+].1H-NMR (DMSO-d6) δ: 1,15 (t, J=7,1 Hz, 3H), 1,94-is 3.21 (m, 19H), Android 4.04 (q, J=7,1 Hz, 2H), 6,50 (s, 1H), of 6.96-7,28 (m, 4H).
Connection 98TPL 207-212°C. MS (EI): m/z 367 [M+].1H-NMR (DMSO-d6) δ: 1,95-up 3.22 (m, 19H), of 6.45 (s, 1H), 6,97-7,28 (m, 4H).
Connection 99TPL 109°C (decomp.).1H-NMR (DMSO-d6) δ: 1.26 in to 1.47 (m, 6H), 2,37-5,43 (m, 27H), for 6.81-to 7.50 (m, 5H), 10,84-10,92 (m, 1H).
Connection 100TPL 98°C (decomp.). MS (EI): m/z 370 [M++1].1H-NMR (DMSO-d6) δ: 2,30-to 3.33 (m, 15H), 4,82 (d, J=15,5 Hz, 1H), of 5.40 (d, J=15,5 Hz, 1H), 6,80-for 6.81 (m, 1H), 6,99 (s, 1H), 7,02-7,14 (m, 2H), 7,46-7,47 (m, 1H).
Connection 101TPL >280°C. MS (EI): m/z 464 [M+].1H-NMR (DMSO-d6) δ: 1,24 of 1.28 (m, 3H), 1,87 is 3.57 (m, 26H), 4,23-the 4.29 (m, 2H), 7,07-7,52 (m, 5H), 10,94-11,34 (m, 2H).
Connection 102TPL 161°C (decomp.). MS (EI): m/z 436 [M+].1H-NMR (DMSO-d6) δ: 1,83-of 3.25 (m, 26H), 6,99-7,30 (m, 5H).
Connection 103TPL 185°C (decomp.). MS (EI): m/z 381 [M+].1H-NMR (DMSO-d6) δ: 1,21 (t, J=7,3 Hz, 3H), of 1.25 to 1.31 (m, 3H), 2,25-the 3.65 (m, 14H), 4,22-4,27 (m, 2H), 7,07-7,52 (m, 5H), 10,42 (user., 1H).

Table 9
No. of connectionsProperties
The connection 104TPL 197°-200°C.1H-NMR (DMSO-d6) δ: 1,93-of 2.81 (m, 13H), 3,19-of 3.32 (m, 2H), 4,42-4,43 (m, 2H), 5,06 (user., 1H), 6,76-6,77 (m, 1H), of 6.96-6,97(m, 1H), 7,10-7,11 (m, 1H), 7,22-7,26 (m, 2H).
Connection 105TPL 123°-125°C. MS (EI): m/z 398 [M++1].1H-NMR (DMSO-d6) δ: 1.26 in (t, J=7,1 Hz, 3H), 2,07-3,50 (m, 16H), 4,22-4.26 deaths (m, 2H), 4,37 (t, J=5.4 Hz, 1H), 7,02-7,31 (m, 4H), 7,41 (s, 1H).
The connection 106TPL 123°C (decomp.). MS (EI): m/z 381 [M+].1H-NMR (DMSO-d6) δ: 1,17 (t, J=7,1 Hz, 3H), 2,46-the 3.65 (m, 17H), 4,06 (kV, J=7,1 Hz, 2H), 6,83-7,39 (m, 5H).
Connection 107TPL 252°C (decomp.).1H-NMR (DMSO-d6) δ: 2,32-and 3.72 (m, 16H), 5,33 (s, 1H), 7,08-7,42 (m, 5H), of 10.05 (user., 1H), 13,02 (users, 1H).
The connection 108TPL >280°C. MS (EI): m/z 353 [M+].1H-NMR (DMSO-d6) δ: 1,17-of 1.35 (m, 3H), 2,30 is 3.57 (m, 14H), 7,09-the 7.43 (m, 5H), 10,30-10,43 (user., 1H), 13,01 (users, 1H).
Connection 109TPL 123-124°C. MS (EI): m/z 555 [M+].1H-NMR (DMSO-d6) δ: 1.26 in (t, J=7,1 Hz, 3H), of 1.31 (s, 9H), 1.77 in-3,37 (m, 18H), 4,21-to 4.28 (m, 2H), 7,00-7,30 (m, 4H), 7,38 (s, 1H), 7,53-to $ 7.91 (m, 4H).
The connection 110TPL 85-89°C. MS (EI): m/z 484 [M++1),1H-NMR (DMSO-d6) δ: 1.18 to to 1.23 (m, 3H), of 1.27 (t, J=7,1 Hz, 3H), 2,36-3,82 (m, 16H), 4,11-4,27 (m, 6H), 7,06 is 7.50 (m, 5H), 10,42 (users, 1H).
Connection 111TPL 135°C (decomp.). MS (I): m/z 456 [M ++1].1H-NMR (DMSO-d6) δ: 1.26 in (t, J=7,1 Hz, 3H), 2,28-3,39 (m, 14H), to 3.67 (t, J=5,1 Hz, 2H), 3,86 (s, 2H), 4,22-4.26 deaths (m, 2H), 7,07-to 7.32 (m, 4H), 7,46 (s, 1H).
The connection 112TPL 157-159°C. MS (EI): m/z 321 [M+].1H-NMR (DMSO-d6) δ: 1,97-of 2.86 (m, 13H), 3,26-3,30 (m, 2H), 5,09-5,11 (m, 1H), are 5.36 of 5.39 (m, 1H), 6,78-6,84 (m, 2H), 7,02? 7.04 baby mortality (m, 1H), 7,20-of 7.23 (m, 2H), 7,33-7,34 (m, 1H).
Connection 1131H-NMR (DMSO-d6) δ: 1,17 (t, J=7,1 Hz, 3H), 2,66-2,70 (m, 1H), 2,94-of 3.07 (m, 4H), 3,22-3,37 (m, 3H), 3,59-3,66 (m, 2H), 4.04 the-4,08 (m, 2H), around 4.85 (d, J=to 15.4 Hz, 1H), 5,44 (d, J=to 15.4 Hz, 1H), 6,83-6,85 (m, 1H), 7,05-was 7.08 (m, 2H,), 7,15-7,17 (m, 1H), of 7.48-to 7.50 (m, 1H), 9,10 (users, 1H), to 9.32 (users, 1H).
The connection 114TPL 202°C (decomp.)1H-NMR (DMSO-d6) δ: 2,20-to 2.94 (m, 8H), 3,38-3,47 (m, 2H), 4,82 (d, J=to 15.4 Hz, 1H), of 5.40 (d, J=to 15.4 Hz, 1H), 6,78-6,79 (m, 1H), 6,98-to 7.09 (m, 3H), 7,41-the 7.43 (m, 1H).
Connection 115TPL 118-120°C.1H-NMR (DMSO-d6) δ: of 1.30 (t, J=7,1 Hz, 3H), 1,99-of 3.31 (m, 15H), 4,28 (kV, J=7,1 Hz, 2H), 6,74-7,81 (m, 5H).
The connection 116TPL 199-203°C. MS (EI): m/z 370, [M++1).1H-NMR (DMSO-d6) δ: 2,36-of 3.78 (m, 16H), 4,98-5,04 (m, 1H), of 5.53-5,62 (m, 1H), 6,95-7,13 (m, 4H), of 7.48-7,56 (m, 1H), at 10.64-a 10.74 (m, 1H).

Table 10
No. of connectionsProperties
Connection 117TPL 240-245°C. MS (EI): m/z 356 [M++1].1H-NMR (DMSO-d6) δ: 2,13-of 2.58 (m, 1H), 3.46 in-to 3.52 (m, 2H), equal to 4.97 (d, J=to 15.0 Hz, 1H), of 5.53 (d, J=to 15.0 Hz, 1H), 6,91-6,97 (m, 3H), 7,06-to 7.09 (m, 1H), 7,42-the 7.43 (m, 1H).
The connection 118TPL 156-158°C. MS (EI): m/z 400 [M++1].1H-NMR (DMSO-d6) δ: 2,36-3,81 (m, 17H), a 4.83-4,88 (m, 1H), 5,31-5,46 (m, 2H), 6,84-to 7.18 (m, 4H), of 7.48-7,52 (m, 1H), 10,28-10,41 (m, 1H).
Connection 119TPL 242°C (decomp.). MS (EI): m/z 386 [M++1].1H-NMR (DMSO-d6) δ: 2,28-a 2.71 (m, 10H), 3,49-3,51 (m, 4H), 4,82 (d, J=to 15.4 Hz, 1H), of 5.40 (d, J=to 15.4 Hz, 1H), 6,78-6,79 (m, 1H), 6,98-7,03 (m, 2H), 7,10-7,13 (m, 1H), 7,41-7,42 (m, 1H).
Connection 120TPL 174°C (decomp.). MS (EI): m/z 397 [M+].1H-NMR (DMSO-d6) δ: of 1.41 to 1.48 (m, 5H), 2,16-and 2.83 (m, 12H), 3,30 is 3.40 (m, 4H), 7,02? 7.04 baby mortality (m, 1H), 7,16-7,22 (m, 2H), 7,29-7,30 (m, 2H).
Connection 121TPL 258°C (decomp.).1H-NMR (DMSO-d6) δ: 2,18-3,24 (m, 15H), 6,74-7,79 (m, 5H).
The connection 122MS (EI): m/z 371 [M+].1H-NMR (DMSO-d6) δ: 2,28-2,70 (m, 12H), 3,48 is 3.57 (m, 4H), 4,35-4,39 (m, 1H), 4,56-4,58 (m, 1H), 4,78-of 5.40 (m, 2H), 6,77-7,41 (m, 5H).
Connection 123 TPL 174-177°C. MS (EI): m/z 397 [M+].1H-NMR (DMSO-d6) δ: of 1.76 and 1.80 (m, 2H), 2,27-3,70 (m, 18H), 4,82-a 4.86 (m, 1H), 5.40 to-5,44 (m, 1H), 6,82-6,83 (m, 1H), of 6.96-7,11 (m, 3H), of 7.48-to 7.50 (m, 1H), 11,00-11,08 (m, 1H).
The connection 124TPL 114-118°C. MS (EI): m/z 383 [M+].1H-NMR (DMSO-d6) δ: 1,72-to 1.77 (m, 2H), 2,18-of 2.72 (m, 15H), to 4.81 (d, J=to 15.4 Hz, 1H), 5,39 (d, J=to 15.4 Hz, 1H), 6,77-of 6.78 (m, 1H), 6.89 in-7,07 (m, 3H), 7,40-7,42 (m, 1H).
Connection 125TPL 238°C (decomp.).1H-NMR (DMSO-d6) δ: 2,31-of 2.72 (m, 12H), 3,50-3,55 (m, 2H), a 4.83 (d, J=15.1 Hz, 1H), 5,41 (d, J=15.1 Hz, 1H), 6,79-to 6.80 (m, 1H), 7,00-7,14 (m, 3H), 7,42-7,44 (m, 1H).
Connection 1261H-NMR (DMSO-d6) δ: 2,65-a 2.71 (m, 1H), 2,92-of 3.07 (m, 4H), 3,22-3,37 (m, 3H), of 3.60 (s, 3H), of 3.65 (s, 2H), around 4.85 (d, J=to 15.4 Hz, 1H), 5,44 (d, J=to 15.4 Hz, 1H), 6,83-6,85 (m, 1H), 7,05-was 7.08 (m, 2H), 7,15-to 7.18 (m, 1H), of 7.48-7,50 (m, 1H), 9,15 (users, 1H), 9,39 (users, 1H).
Connection 127TPL 227-231°C.1H-NMR (DMSO-d6) δ: 1,17-of 1.32 (m, 3H), 2,35-3,66 (m, 15H), a 4.83-4,88 (m, 1H), 5.40 to-5,46 (m, 1H), 6,83-6,85 (m, 1H), 7,05-7,20 (m, 3H), 7,50-7,52 (m, 1H), 10,52-10,76 (m, 1H).
Connection 128TPL 255-259°C. MS (EI): m/z 369 [M+].1H-NMR (DMSO-d6) δ: 1,01 (t, J=6.9 Hz, 3H), 2,25-a 2.71 (m, 10H), 3,49-free 5.01 (m, 2H), 4,82 (d, J=to 15.4 Hz, 1H), 5,41 (d, J=to 15.4 Hz, 1H), 6,78-to 6.80 (m, 1H), 6,99-7,13 (m, 3H), 7,41-7,42 (m, 1H).

Table 11
No. of connectionsProperties
Connection 129TPL 221-224°C.1H-NMR (DMSO-d6) δ: 0,87-to 0.96 (m, 3H), 1,67-1,72 (m, 2H), 2,35-3,66 (m, 15H), a 4.83-4,88 (m, 1H), 5.40 to-5,46 (m, 1H), 6,82-6,85 (m, 1H), 7,05-7,19 (m, 3H), 7,49-7,52 (m, 1H), 10,51-of 10.73 (m, 1H).
The connection 130TPL 203-206°C.1H-NMR (DMSO-d6) δ: 0,86 (t, J=7.4 Hz, 3H), of 1.41 to 1.47 (m, 2H), 2,24-a 2.71 (m, 10H), 3,51-3,55 (m, 2H), 4,82 (d, J=to 15.4 Hz, 1H), 5,41 (d, J=to 15.4 Hz, 1H), 6,78-6,79 (m, 1H), 6,99-7,13 (m, 3H), 7,41-7,42 (m, 1H).
Connection 131TPL 236°C (decomp.).1H-NMR (DMSO-d6) δ: of 1.23 to 1.34 (m, 6H), 2,42-3,66 (m, 14H), a 4.83-4,88 (m, 1H), 5.40 to-5,47 (m, 1H), 6,82-6,86 (m, 1H), 7,05-to 7.18 (m, 3H), 7,49-7,52 (m, 1H), of 10.21-10,48 (m, 1H).
Connection 132TPL 249-253°C.1H-NMR (DMSO-d6) δ: 0,96-0,98 (m, 6H), 2,24-to 2.74 (m, 9H), 3,51-of 3.54 (m, 2H), 4,82 (d, J=to 15.4 Hz, 1H), 5,41 (d, J=to 15.4 Hz, 1H), 6,78-6,79 (m, 1H), 6,99-7,13 (m, 3H), 7,41-7,42 (m, 1H).
Connection 133TPL 223°C (decomp.).1H-NMR (DMSO-d6) δ: 0,87-to 0.96 (m, 3H), of 1.26 (t, J=7,1 Hz, 3H), 1,64 was 1.69 (m, 2H), 2,30-of 3.48 (m, 14H), 4,24-or 4.31 (m, 2H), 7,06 for 7.12 (m, 1H), 7,19-7,35 (m, 3H), of 7.48-7,51 (m, 1H), 10,43-10,49 (m, 1H).
Connection 134TPL >280°C.1H-NMR(DMSO-d 6) δ: from 0.88 to 0.94 (m, 3H), of 1.66 to 1.76 (m, 2H), 2,30-was 4.02 (m, 14H), 7,07-7,41 (m, 5H), 10,47-of 10.58 (m, 1H), 13,03 (users, 1H).
Connection 135TPL 208-210°C.1H-NMR (DMSO-d6) δ: 1,77-of 1.81 (m, 2H), 2,27-2,31 (m, 2H), 2,50-to 2.67 (m, 4H), 2,94-of 3.32 (m, 6H), of 3.56 (s, 3H), of 4.83 (d, J=15,5 Hz, 1H), 5,42 (d, J=15,5 Hz, 1H), for 6.81-6,83 (m, 1H), 6,98-7,11 (m, 3H), of 7.48-7,49 (m, 1H), 9,05-9,37 (m, 2H).
Connection 136TPL 243°C (decomp.).1H-NMR (DMSO-d6) δ: 1,75-of 1.78 (m, 2H), 2,18-2,22 (m, 2H), 2,49-to 2.67 (m, 4H), 2,93-of 3.32 (m, 6H), of 4.83 (d, J=15,5 Hz, 1H), 5,42 (d, J=15,5 Hz, 1H), for 6.81-6,83 (m, 1H), 6,98 for 7.12 (m, 3H), of 7.48-7,49 (m, 1H), 8,97-9,13 (m, 2H), 12,01-12,12 (m, 1H).
Connection 1371H-NMR (DMSO-d6) δ: 0,82-of 0.90 (m, 3H), 1,52-to 1.61 (m, 2H), 2,68 is 3.23 (m, 8H), to 3.64 (s, 2H), 3,92-was 4.02 (m, 2H), 4,84 (d, J=15,5 Hz, 1H), 5,43 (d, J=15,5 Hz, 1H), 6,83 is 7.50 (m, 5H), 9,07-9,36 (m, 2H).
Connection 138TPL 148-151°C.1H-NMR (DMSO-d6) δ: 1,82 of 1.99 (m, 2H), 2,36 of 3.75 (m, 19H), 4,76-4,88 (m, 2H), 5.40 to-5,46 (m, 1H), 6,84-6,86 (m, 1H), 7,05-to 7.18 (m, 3H), 7,50-7,52 (m, 1H), of 10.21-10,43 (m, 1H).
Connection 139TPL 229°C (decomp.). MS (EI): m/z 399 [M+].1H-NMR (DMSO-d6) δ: 1,57-to 1.60 (m, 2H), 2,22-2,70 (m, 10H), 3,42-3,51 (m, 4H), 4,82 (d, J=to 15.4 Hz, 1H), of 5.40 (d, J=to 15.4 Hz, 1H), 6,78-6,79 (m, 1H), 6,99 for 7.12 (m, 3H), 7,41-7,42 (m, 1H).

table 12
No. of connectionsProperties
The connection 140TPL 144-145°C.1H-NMR (DMSO-d6) δ: 1,16-1,19 (m, 3H), 2,36-3,63 (m, 13H), was 4.02-4,4,08 (m, 2H), 4,85-4,88 (m, 1H), 5,42-5,46 (m, 1H), 6,84-6,85 (m, 1H), 7,08-to 7.18 (m, 3H), 7,50-7,52 (m, 1H), 10,56-of 10.21 (m, 1H).
Connection 141TPL 214°-216°C.1H-NMR (DMSO-d6) δ: 1,15-of 1.32 (m, 3H), 1.77 in-is 1.81 (m, 2H), 2,28-3,70 (m, 17H), 4,81-a 4.86 (m, 1H), 5,38-4,55 (m, 1H), for 6.81-7,11 (m, 4H), 7,49-to 7.50 (m, 1H), 10,51-10,69 (m, 1H).
Connection 1421H-NMR (DMSO-d6) δ: 1.00 and was 1.04 (m, 3H), 1,73-to 1.77 (m, 2H), 2,17-by 2.73 (m, 14H), to 4.81 (d, J=to 15.4 Hz, 1H), 5,39 (d, J=to 15.4 Hz, 1H), 6,77-of 6.78 (m, 1H), 6.90 to-7,07 (m, 3H), 7,41-7,42 (m, 1H).
Connection 1431H-NMR (DMSO-d6) δ: 1,09 (t, J=7,1 Hz, 3H), of 2.51-of 3.31 (m, 8H), 4,17 (kV, J=7,1 Hz, 2H), is 4.93 (d, J=14,9 Hz, 1H), 5,49 (d, J=14,9 Hz, 1H), to 6.57 (d, J=16.0 Hz, 1H), 6.90 to-6,91 (m, 1H), 7,08-7,10 (m, 1H), 7,49-the 7.65 (m, 4H), 9,07-9,24 (m, 2H).
Connection 144TPL 217°C (decomp.). MS (EI): m/z 353 [M+].1H-NMR (DMSO-d6) δ: 2.26 and-to 2.94 (m, 9H), of 4.90 (d, J=14,8 Hz, 1H), the 5.45 (d, J=14,8 Hz, 1H), 6,39-to 6.43 (m, 1H), 6,85-6,86 (m, 1H),? 7.04 baby mortality-7,06 (m, 1H), was 7.36-of 7.55 (m, 4H).
Connection 1451H-NMR (DMSO-d6) δ: of 1.23 (t, J=7,1 Hz, 3H), 2,42-of 3.27 (m, 12H), 4,16 (kV, J=7,1 Hz, 2H), 6,09 (d, J15,6 Hz, 1H), 7,07-7,33 (m, 5H), 7,71 (d, J=15.6 Hz, 1H), 9,03-remaining 9.08 (user. 1H).
Connection 146TPL 264°C (decomp.).1H-NMR (DMSO-d6) δ: 2,07 is 2.44 (m, 5H), 2.57 m) of 2.92 (m, 5H), 3,21-3,47 (m, 2H), 5,94-5,97 (m, 1H), 6,83-7,30 (m, 6H).
Connection 147TPL 191-193°C.1H-NMR (DMSO-d6) δ: 1,15 (t, J=7,1 Hz, 3H), 1,99-of 3.31 (m, 17H), 4,08 (kV, J=7,1 Hz, 2H), 6,74-7,40 (m, 5H), 10,83 (users, 1H).
Connection 148TPL 171-174°C.1H-NMR (DMSO-d6) δ: 2,64-to 3.49 (m, 17H), 6,77-7,40 (m, 5H), a 10.74 (users, 1H), 12,27 (users, 1H).
Connection 149TPL 250°C (decomp.). MS (EI): m/z 395 [M+].1H-NMR (DMSO-d6) δ: 1,22-of 1.34 (m, 9H), 2,30 is 3.57 (m, 13H), 4,22-4,27 (m, 2H), 7,06-to 7.61 (m, 5H), 10,36 (m, 1H).
Connection 150TPL >280°C.1H-NMR (DMSO-d6) δ: 0,94-0,96 (m, 6H), 2.13 and is 3.23 (m, 13H), 6,95-7,28 (m, 5H).
Connection 151TPL 149°C (decomp.).1H-NMR (DMSO-d6) δ: 1,99-3,29 (m, 15H), of 3.48 (s, 2H), 6,76-7,27 (m, 5H).
Connection 152TPL 186°C (decomp.).1H-NMR (DMSO-d6) δ: 1.14 in (t, J=7,1 Hz, 3H), 1,49-is 1.51 (m, 6H), 2,30-3,30 (m, 13H), of 4.05 (q, J=7,1 Hz, 2H), 6,61-only 6.64 (m, 1H),? 7.04 baby mortality-7,31 (m, 4H), 8,87-of 9.02 (m, 2H).

Table 13
No. of connectionsProperties
Connection 153TPL >280°C.1H-NMR (DMSO-d6) δ: to 1.48 (s, 6H), 2,31-3,30 (m, 12H), 6,61-only 6.64 (m, 1H),? 7.04 baby mortality-7,31 (m, 4H), 8,95-9,06 (m, 2H), to 12.52 (users, 1H).
Connection 154TPL 247°C (decomp.).1H-NMR (DMSO-d6) δ: of 1.13 to 1.31 (m, 6H), of 1.50 (s, 6H), 2.26 and-to 3.58 (m, 14H), a 4.03-4,07 (m, 2H), 6,64-of 6.65 (m, 1H), 7,02-to 7.32 (m, 4H), 10,32-10,86 (m, 1H).
Connection 155TPL 255°C (decomp.).1H-NMR (DMSO-d6) δ: 0,95-1,01 (m, 3H), 1,45-is 1.51 (m, 6H), 2,08 is 3.23 (m, 14H), 6,58-of 7.24 (m, 5H).
Connection 156TPL 164-166°C.1H-NMR (DMSO-d6) δ: of 1.76 and 1.80 (m, 2H), 2,27-3,70 (m, 18H), 4,82-a 4.86 (m, 1H), 5.40 to-5,44 (m, 1H), 6,82-6,83 (m, 1H), of 6.96-7,11 (m, 3H), of 7.48-to 7.50 (m, 1H), 11,00-11,08 (m, 1H).
Connection 157TPL 121-123°C. MS (EI): m/z 397 [M+].1H-NMR (DMSO-d6) δ: 1,47-of 1.53 (m, 4H), 2,14 is 2.55 (m, 15H), 4,80 (d, J=to 15.4 Hz, 1H), 5,39 (d, J=to 15.4 Hz, 1H), 6,77-of 6.78 (m, 1H), 6.89 in-7,07 (m, 3H), 7,40-7,42 (m, 1H).
Connection 158TPL 114-117°C. MS (EI): m/z 407 [M+].1H-NMR (DMSO-d6) δ: 0,99 (t, J=7.2 Hz, 3H), of 1.23 (t, J=7,1 Hz, 3H), 1,99 be 3.29 (m, 14H), 4,12-4,16 (m, 2H), equal to 6.05 (d, J=15.7 Hz, 1H), 7,01-7,02 (m, 1H), 7,15-,20 (m, 2H), 7,25 (s, 1H), 7,29-7,31 (m, 1H), 7,72 (d, J=15.7 Hz, 1H).
Connection 159TPL 223°C (decomp.). MS (EI): m/z 379 [M+].1H-NMR (DMSO-d6) δ: 1,92-of 1.30 (m, 3H), 2,20-3,62 (m, 14H), 6,01 (d, J=15.7 Hz, 1H),? 7.04 baby mortality-to 7.68 (m, 6H), 9,99-10,41 (m, 1H), 12,35 (users, 1H).
The connection 160TPL 123°-124°C. MS (EI): m/z 381 [M+].1H-NMR (DMSO-d6) δ: 0,99 (t, J=7,1 Hz, 3H), of 1.30 (t, J=7,1 Hz, 3H), 2.05 is-to 3.33 (m, 14H), 4,25-4,32 (m, 2H), 6.73 x to 6.75 (m, 1H), 7,34-of 7.55 (m, 3H), 7,79-7,81 (m, 1H).
Connection 161TPL 219°-222°C. MS (EI): m/z 353 [M+].1H-NMR (DMSO-d6) δ: 1,02 (t, J=7,1 Hz, 3H), 2,18-of 3.32 (m, 14H), 6,74 to 6.75 (m, 1H), 7,35-of 7.55 (m, 3H), to 7.77-7,79 (m, 1H).
Connection 162TPL 156-158°C.1H-NMR (DMSO-d6) δ: 1,47-of 1.53 (m, 3H), 2,16-2,87 (m, 17H), 4,80 (d, J=to 15.4 Hz, 1H), 5,39 (d, J=to 15.4 Hz, 1H), 6,76-of 6.78 (m, 1H), 6.89 in-7,06 (m, 3H), 7,39-7,40 (m, 1H).
Connection 163TPL 233°C (decomp.). MS (EI): m/z 480 [M+].1H-NMR (DMSO-d6) δ: 1,39-of 2.23 (m, 8H), 2,50-3,66 (m, 21H), a 4.83-4,89 (m, 1H), 5,41-5,46 (m, 1H), 6,83-6,86 (m, 1H), 7,07-7,20 (m, 3H), 7,50-7,52 (m, 1H), 10,27-10,50 (m, 1H), 11,06-of 11.26 (m, 1H).
Connection 164TPL 123°C (decomp.). MS (EI): m/z 466 [M+].1H-NMR (DMSO-d6) δ: 1,40 was 1.69 (m, 8H), 2,31-of 2.72 (m, 16H), 3,44-to 3.52 (m, 2H), 4,82 (d, J=to 15.4 Hz, 1H), of 5.40 (d, J=to 15.4 Hz, 1H), ,78-6,79 (m, 1H), 6,98-7,02 (m, 2H), 7,10 for 7.12 (m, 1H), 7,41-7,42 (m, 1H).

Table 14
No. of connectionsProperties
Connection 165TPL 200°-203°C.1H-NMR (DMSO-d6) δ: 2,31-of 3.69 (m, 14H), 4,73 of 4.83 (m, 3H), are 5.36-5,41 (m, 1H), 6,72-to 6.88 (m, 3H), 7,07-7,10 (m, 1H), 7,50-7,52 (m, 1H), or 10.60-10,80 (m, 1H).
The connection 166TPL 262°C (decomp.). MS (EI): m/z 372 [M++1].1H-NMR (DMSO-d6) δ: 2,29-of 2.81 (m, 11H), a 4.53 (s, 2H), 4,77 (d, J=15.7 Hz, 1H), lower than the 5.37 (d, J=15.7 Hz, 1H), 6,57 return of 6.58 (m, 1H), 6.75 in-is 6.78 (m, 2H), 7,02-7,05 (m, 1H), 7,42-7,44 (m, 1H).
Connection 167MS (EI): m/z 412 [M++1].1H-NMR (DMSO-d6) δ: 2,17-of 2.23 (m, 3H), 2,68-the 3.65 (m, 11H), 4,32-to 4.46 (m, 2H), 4,85-4,88 (m, 1H), 5,42-of 5.45 (m, 1H), 6,84-7,51 (m, 5H), 10,27-10,38 (m, 1H).
Connection 168TPL 183°C (decomp.). MS (EI): m/z 398 [M++1].1H-NMR (DMSO-d6) δ: 2,09 (s, 3H), 2,28-to 2.74 (m, 8H), 3,19 (s, 2H), 3,47-of 3.54 (m, 2H), 4,82 (d, J=to 15.4 Hz, 1H), 5,41 (d, J=to 15.4 Hz, 1H), 6,78-to 6.80 (m, 1H), 6,98-7,03 (m, 2H), 7,10 for 7.12 (m, 1H), 7,41-the 7.43 (m, 1H).
Connection 169TPL 183°-187°C.1H-NMR (DMSO-d6) δ: 1,17-1,90 (m, 5H), 2,22-to 3.73 (m, 17H), a 4.83-4,88 (m, 1H), 5.40 to-5,46 (m, 1H), 6,82 is 7.50 (m, 5H), 10,33-10,50 (m, 1H).
Connection 170TPL 108°C (decomp.). MS (EI): m/z 425 [M4].1H-NMR (DMSO-d6) δ: 1,61-of 1.64 (m, 2H), 2,09 (s, 3H), 2.23 to-2,70 (m, 14H), 3,50-3,51 (m, 2H), 4,82 (d, J=to 15.4 Hz, 1H), of 5.40 (d, J=to 15.4 Hz, 1H), 6,78-6,79 (m, 1H), 6,98-7,03 (m, 2H), 7,10-7,13 (m, 1H), 7,41-7,42 (m, 1H).
Connection 171TPL 210-212°C.1H-NMR (DMSO-d6) δ: 2,36-of 3.60 (m, 11H), of 3.60 (s, 3H), 3,81-3,93 (m, 2H), 4,87 (d, J=15.3 Hz, 1H), the 5.45 (d, J=15.3 Hz, 1H), 6,85-7,53 (m, 5H), 10,67 (users, 1H).
Connection 172TPL 143-146°C.1H-NMR (DMSO-d6) δ: 2,09-2,70 (m, 11H), 3,64-to 3.73 (m, 2H), a 4.83 (d, J=14,9 Hz, 1H), 5,41 (d, J=14,9 Hz, 1H), for 6.81-7,44 (m, 5H).
Connection 173TPL 216°C (decomp.).1H-NMR (DMSO-d6) δ: 1,18 (m, 3H), 2,25-3,75 (m, 17H), 4,07-to 4.15 (m, 2H), a 4.83-4,88 (m, 1H), 5.40 to-5,46 (m, 1H), 6,85-7,51 (m, 5H), 10,70-10,95 (m, 1H).
Connection 174MS (EI): m/z 441 [M++1].1H-NMR (DMSO-d6) δ: 2,28-by 2.73 (m, 10H), 3,06-3,11 (m, 2H), 3,59-to 3.67 (m, 5H), of 4.83 (d, J=to 15.4 Hz, 1H), 5,41 (d, J=to 15.4 Hz, 1H), 5,46 (s, 2H), of 5.82 (s, 1H), 6,78-to 6.80 (m, 1H), 7,00-7,14 (m, 3H), 7,42-the 7.43 (m, 1H).
Connection 175TPL 161-164°C. MS (EI): m/z 429 [M++2].1H-NMR (DMSO-d6) δ: 2,28-to 3.52 (m, 14H), 4,82 (d, J=to 15.4 Hz, 1H), 5,41 (d, J=to 15.4 Hz, 1H), vs. 5.47 (s, 2H), of 5.84 (s, 1H), 6,78-6,79 (m, 1H), 6,99-7,13 (m, 3H), 7,41-the 7.43 (m, 1H), of 12.26 (user., 1H).
Connect the imposition of the 176 TPL 116°C (decomp.). MS (EI): m/z 509 [M+].1H-NMR (DMSO-d6) δ: 1,24-of 1.81 (m, 12H), 2,68-is 2.88 (m, 8H), 3,34-to 3.41 (m, 8H), 4,53-of 4.57 (m, 1H), 6,77-EUR 7.57 (m, 6H), 10,91 (users, 1H).

Table 15
No. of connectionsProperties
Connection 177MS (EI): m/z 477 [M++1].1H-NMR (DMSO-d6) δ: 2,41-3,81 (m, 20H), a 4.83-4,89 (m, 1H), 5.40 to-5,46 (m, 1H), 6,83-6,86 (m, 1H), 7,06-to 7.18 (m, 3H), 7,50-7,52 (m, 2H), 10,50-10,67 (m, 1H).
Connection 178TPL 163-165°C. MS (EI): m/z 462 [M*+1].1H-NMR (DMSO-d6) δ: 2,28-3,55 (m, 17H), 4,82 (d, J=15.3 Hz, 1H), 5,41 (d, J=15.3 Hz, 1H), 6,78-to 6.80 (m, 1H), 6.87 in (s, 1H), 6,99-7,03 (m, 2H), 7,11-7,13 (m, 1H), 7,41-the 7.43 (m, 1H).
Connection 179TPL 149°C (decomp.).1H-NMR (DMSO-d6) δ: of 1.41 (s, 9H), 2,24-of 3.53 (m, 10H), 4,82-5,43 (m, 2H), 6,80 was 7.45 (m, 5H), 12,36 (users, 1H).
Connection 1801H-NMR (DMSO-d6) δ: 1,24-to 1.79 (m, 13H), 2,49-is 3.21 (m, 8H), 3,69 of 3.75 (m, 2H), a 4.83-5,46 (m, 2H), 6,62 is 7.50 (m, 6H), 9.28 are (users, 1H), 9,54 (users, 1H).
Compound 181TPL 237°C (decomp.).1H-NMR (DMSO-d6) δ: 1.10 is of 1.28 (m, 6H), 2,41-of 3.80 (m, 18H), 4,23-4,27 (m, 2H), 7,06-7,10 (m, 1H), 7,21-7,35 (m, 3H), 7,47-7,0 (m, 1H), of 10.58-10,59 (m, 1H).
Connection 182TPL >280°C. MS (EI): m/z 397 [M+].1H-NMR (DMSO-d6) δ: 1,13 (t, J=6,7 Hz, 3H), 2,39-and 3.72 (m, 18H), 7,07-to 7.09 (m, 1H), 7,19-7,26 (m, 2H), 7,32-7,34 (m, 1H), 7,42 (s, 1H).
Connection 183TPL 126°C (decomp.).1H-NMR (DMSO-d6) δ: 1,38-of 1.78 (m, 6H), 2,50-3,62 (m, 19H), is 4.85 (d, J=15.2 Hz, 1H), 5,44 (d, J=15.2 Hz, 1H), 6,84-7,51 (m, 5H), 10,35-10,67 (m, 1H), 10,99-11,20 (m, 1H).
Connection 184TPL 131°C (decomp.).1H-NMR (DMSO-d6) δ: 1,77-of 1.81 (m, 2H), 2,28-3,93 (m, 20H), 4.80 to 4,96 (m, 2H), 5,38 is 5.54 (m, 2H), 6,80-7,11 (m, 4H), of 7.48-to 7.50 (m, 1H), 9,75-9,89 (m, 1H).
Connection 185TPL 130-133°C. MS (EI): m/z 443 [M+].1H-NMR (DMSO-d6) δ: 1,74-of 1.75 (m, 2H), 2,17-2,70 (m, 17H), 3,61-6,62 (m, 1H), 4,30-to 4.38 (m, 1H), 4,81 (d, J=to 15.4 Hz, 1H), 5,39 (d, J=to 15.4 Hz, 1H), 6,77-of 6.78 (m, 1H), 6.90 to-7,07 (m, 3H), 7,40-7,41 (m, 1H).
Connection 186TPL 124°C (decomp.). MS (EI): m/z 467 [M+-1].1H-NMR (DMSO-d6) δ: of 1.37 to 1.47 (m, 6H), 2,27-2,70 (m, 20H), 4,79 (d, J=to 15.4 Hz, 1H), 5,39 (d, J=to 15.4 Hz, 1H), 6,77-to 7.09 (m, 4H), 7,41-7,42 (m, 1H).
Compound 187TPL 152-154°C.1H-NMR (DMSO-d6) δ: 1,77-of 1.84 (m, 4H), 2,08-2,12 (m, 3H), 2,27-2,31 (m, 2H), 2,46-3,70 (m, 17H), 4,81-a 4.86 (m, 1H), of 5.83-5,44 (m, 1H), for 6.81-6,84 (m, 1H), of 6.96-7,11 (m, 3H), of 7.48-to 7.50 (m, 1H), 10,45-to 10.62 (m, 1H).
Connection 188MS (EI): m/z 453 [M+].1H-NMR (DMSO-d6) δ: 1,62-of 1.65 (m, 2H), total 1.74 to 1.76 (m, 2H), 2,09 (s, 3H), 2,17-2,70 (m, 16H), 4,80 (d, J=to 15.4 Hz, 1H), 5,39 (d, J=to 15.4 Hz, 1H), 6,77-of 6.78 (m, 1H), 6.90 to-7,07 (m, 3H), 7,41 was 7.45 (m, 1H), 11,95-12,05 (user., 1H).

Table 16
No. of connectionsProperties
Compound 189TPL 242°C (decomp.).1H-NMR (DMSO-d6) δ: 1,38-of 1.42 (m, 6H), 2,43 of 3.56 (m, 14H), 4,93-4,96 (m, 1H), 5,48-the 5.51 (m, 1H), 6,91-7,52 (m, 5H), of 10.72 (users, 1H).
Connection 190TPL 182-185°C.1H-NMR (DMSO-d6) δ: of 1.35-1.39 (m, 6H), 2,37-3,55 (m, 11H), to 4.92 (d, J=14,8 Hz, 1H), 5,48 (d, J=14,8 Hz, 1H), 6.90 to-7,52 (m, 5H), 10,88 (user., 1H), 12,59 (user., 1H).
Connection 191TPL 162°C (decomp.).1H-NMR (DMSO-d6) δ: 2.06 to 3,79 (m, 20H), a 4.83-4,88 (m, 1H), 5.40 to-5,46 (m, 1H), 6,82-6,86 (m, 1H), 7,05-to 7.18 (m, 3H), 7,50-7,52 (m, 1H), 10,17-10,48 (m, 1H).
Connection 192TPL 166°C (decomp.). MS (EI): m/z 411 [M+].1H-NMR (DMSO-d6) δ: 2,09-3,50 (m, 17H), 4,82 (d, J=to 15.4 Hz, 1H), of 5.40 (d, J=to 15.4 Hz, 1H), 6,78-6,79 (m, 1H), 6,98 for 7.12 (m, 3H), 7,41-7,42 (m, 1H).
Connection 193TPL 113-115°C.1H-NMR (DMSO-d6 ) δ: 1,79 of 1.99 (m, 2H), 2,36-3,66 (m, 22H), a 4.83-4,89 (m, 1H), 5.40 to-5,46 (m, 1H), 6,83-6,86 (m, 1H), 7,05-7,20 (m, 4H), 7,50-7,52 (m, 1H), 10,06-10,43 (m, 1H).
Connection 194TPL 181-183°C.1H-NMR (DMSO-d6) δ: 1.60-to of 1.64 (m, 2H), 2,22-3,11 (m, 15H), 3,48-3,55 (m, 2H), 4,82 (d, J=to 15.4 Hz, 1H), 5,41 (d, J=to 15.4 Hz, 1H), 6,787-6,79 (m, 1H), 6,99-7,03 (m, 3H), 7,11-7,13 (m, 1H), 7,41-the 7.43 (m, 1H).
Connection 195TPL 102-105°C.1H-NMR (DMSO-d6) δ: 2,36 is 3.57 (m, 22H), 4.80 to a 4.86 (m, 1H), 5.40 to-5,44 (m, 1H), for 6.81-6,84 (m, 1H), 7,01-to 7.15 (m, 3H), 7,37-7,51 (m, 2H), 9,88-10,51 (m, 1H).
Connection 196TPL 121°C (decomp.). MS (EI): m/z 477 [M++1].1H-NMR (DMSO-d6) δ: 2,27-3,39 (m, 19H), 4,79 (d, J=to 15.4 Hz, 1H), 5,38 (d, J=15,41 Hz, 1H), 6,76-6,77 (m, 1H), 6.89 in-to 7.09 (m, 4H), 7,40-7,42 (m, 1H).
Connection 197TPL 208-210°C.1H-NMR (DMSO-d6) δ: 2,46-2,69 (m, 2H), 2.91 in-to 3.09 (m, 4H), 3,21-of 3.27 (m, 2H), 3,60 (s, 3H), 3,82 (d, J=15.7 Hz, 1H), 3,91 (d, J=15.7 Hz, 1H), a 4.86 (d, J=15.3 Hz, 1H), the 5.45 (d, J=15.3 Hz, 1H), 6,85-7,51 (m, 5H), 9,12-of 9.30 (m, 2H).
Connection 198TPL 221°C (decomp.).1H-NMR (DMSO-d6) δ: 1,93-3,66 (m, 22H), a 4.83-4,89 (m, 1H), 5.40 to-5,46 (m, 1H), 6,83-6,86 (m, 1H), 7,05-7,20 (m, 3H), 7,50-7,52 (m, 1H), 10,14-10,32 (m, 1H).
Compound 199TPL 127°C (decomp.). MS (EI): m/z 429 [M+].1H-NMR (DMSO-d6) δ: 1,67-1,71 (m, 2H), 2,03(s, 3H), 2,22-2,70 (m, 14H), 3,48-3,55 (m, 2H), 4,82 (d, J=to 15.4 Hz, 1H), 5,41 (d, J=to 15.4 Hz, 1H), 6,78-6,79 (m, 1H), 6,98-7,13 (m, 3H), 7,41-7,42 (m, 1H).
The connection 200TPL 257°C (decomp.).1H-NMR (DMSO-d6) δ: 2,10-of 2.16 (m, 3H), 2,36-3,74 (m, 17H), a 4.83-4,89 (m, 1H), 5.40 to-5,46 (m, 1H), 6,83-6,86 (m, 1H), 7,06-7,19 (m, 3H), 7,50-7,42 (m, 1H), 10,42-10,61 (m, 1H).

Table 17
No. of connectionsProperties
Connection 201TPL 204-206°C.1H-NMR (DMSO-d6) δ: 2,07 (s, 3H), 2,28-2,70 (m, 12H), 3,51-3,55 (m, 2H), 4,82 (d, J=to 15.4 Hz, 1H), 5,41 (d, J=to 15.4 Hz, 1H), 6,78-6,79 (m, 1H), 6,99-7,13 (m, 3H), 7,41-the 7.43 (m, 1H).
The connection 202TPL 193°C (decomp.).1H-NMR (DMSO-d6) δ: from 0.90 (m, 3H), of 1.35-1.39 (m, 6H), of 1.66 (m, 2H), 2,50-3,39 (m, 10H)to 4.92 (d, J=to 15.0 Hz, 1H), vs. 5.47 (d, J=to 15.0 Hz, 1H), 6.89 in-7,51 (m, 5H), 10,45 (m, 1H), 12,51 (m, 1H).
Connection 203TPL 279°C (decomp.).1H-NMR (DMSO-d6) δ: 2,19-up 3.22 (m, 13H), of 6.02 (d, J=15.6 Hz, 1H),? 7.04 baby mortality-to 7.32 (m, 5H), 7,52 (d, J=15.6 Hz, 1H).
Connection 204TPL 265°C (decomp.). MS (EI): m/z 373 [M+].1H-NMR (DMSO-d6) δ: 2,13-and 2.79 (m, 11H), of 3.69 (s, 2H), and 4.75 (d, J=15.6 Hz, 1H), of 5.34 (d, J=15.6 Hz, 1H), to 6.57 (s, 1H), 6.89 in-7,16 (m, 3H).
Connection 205TPL 248°C (decomp.). MS (EI): m/z 389 [M+].1H-NMR (DMSO-d6) δ: 2,13-and 2.79 (m, 11H), 3,70 (s, 2H), 4,78 (d, J=15.6 Hz, 1H), are 5.36 (d, J=15.6 Hz, 1H), 6,60 (s, 1H), 7,09-7,31 (m, 3H).
The connection 206TPL 245°C (decomp.). MS (EI): m/z 417 [M+].1H-NMR (DMSO-d6) δ: 1,06 is 1.48 (m, 6H), 2,12-to 3.38 (m, 11H), 4,74-rate 4.79 (m, 1H), 5,33 is 5.38 (m, 1H), 6,52-of 6.65 (m, 1H), 7,08-7,13 (m, 2H), 7,28-7,31 (m, 1H).
Connection 207TPL 260-262°C. MS (EI): m/z 385 [M+].1H-NMR (DMSO-d6) δ: 2,19-of 2.97 (m, 11H), 3,60-3,81 (m, 5H), 4,69 (d, J=15.6 Hz, 1H), from 5.29 (d, J=15.6 Hz, 1H), 6,54-6,59 (m, 2H), 6,79-to 6.80 (m, 1H), 7.03 is-7,05 (m, 1H).
Connection 208TPL 274-275°C.1H-NMR (DMSO-d6) δ: 2,20-and 2.79 (m, 14H), to 3.67 (s, 2H), 4,70 (d, J=15.6 Hz, 1H), 5,32 (d, J=15.6 Hz, 1H), 6,56 (s, 1H), 6,85 (s, 1H), 6,97-7,05 (m, 2H).
Connection 209TPL 244°C (decomp.).1H-NMR (DMSO-d6) δ: 1,92-2,99 (m, 12H), 6,69 (s, 1H), 6,83 (d, J=11.5 Hz, 1H), to 6.88 (d, J=11.5 Hz, 1H), 7,10-7,39 (m, 4H).
Connection 210TPL >280°C.1H-NMR (DMSO-d6) δ: 1,92-of 2.86 (m, 13H), at 6.84 (d, J=11.5 Hz, 1H), 6,97 (d, J=11.5 Hz, 1H), 7,10-7,40 (m, 5H).
Connection 211TPL 245°C (decomp.).1H-NMR (DMSO-d6) δ: 2,18-3,26 (m, 13H), 6.73 x to 6.75 (m, 1H), 7,34-7,35 (m, 2H), 7,54 (s, 1), 7,73 to 7.75 (m, 1H).
The connection 212TPL 141°-142°C. MS (EI): m/z 375 [M++2]. 373 [M+].1H-NMR (DMSO-d6) δ: 1,90-and 2.79 (m, 13H), 3,18-up 3.22 (m, 2H), 6,85 (s, 1H), 6,98-7,30 (m, 4H).

Example 38

Experimentthe binding of H1-receptorperson for histaminein vitro

The recombinant plasmid with H1-receptor for histamine (obtained from Invitrogen) was transfusional in HEK293A cells using Lipofectamine 2000 (manufactured by Invitrogen). Cells stably expressing H1-receptor for histamine were subjected to screening using geneticin (manufactured by Invitrogen). Cells continued to cultivate using a modified method of Dulbecco eagle medium containing 10% fetal calf serum, 0.1 mmol/l solution of MEM nonessential amino acids, 2 mmol/l L-glutamine and 0.7 mg/ml geneticin in an incubator with 5% CO2at 37°C. Cells stably expressing H1-receptor for histamine, were prepared using 50 mmol/l Tris-HCl (pH 7.5) (hereinafter in this document called buffer)containing 0.1% bovine serum albumin, so that the concentration was 3×106cells/ml with sample cell preparation. In each well of 96-hole tablet was added fifty microliters buffer, 50 μl of a solution fathers-in-law who has been created substances at various concentrations and 50 μl of a solution of [ 3H]pyrilamine (final concentration: 3 nmol/l) and stirred, and then was added 100 μl of the sample cell of the drug (at a concentration of 3×105cells/well) to start the reaction.

Cells were incubated at room temperature for 60 minutes and then was filtered on a tablet UniFilter GF/C (manufactured by Packard), was immersed in 0.5% polyethylenimine using the device for collecting cells (IH-110, manufactured by INNOTECH CORPORATION), for stopping the reaction, the tablet was rinsed with buffer. The tablet after washing sufficiently dried, to it was added 20 ml of scintillator (MaxiLight made Hidex) and determined the number of pulses per minute (cpm) using reader microplate with multiple labels (Plate Chameleo II, made Hidex). Nonspecific binding was a cpm, when added 30 µmol/l pyrilamine. The experiments were conducted with n=3 and repeated at least 3 times.

One example of the results is presented in table 18. Compounds of the present invention showed very high activity in the experiment the binding of H1-receptor for histaminein vitro.

Table 18
No. of connectionsIC50(nmol/l)IC50(nmol/l)
Connection 1088,5The connection 11823,6
The connection 1526,8Connection 12194,7
The connection 2015,2The connection 122the 13.4
The connection 233,5Connection 1233,12
Connection 2752,8The connection 12446,7
The connection 3116,4Connection 1278,20
Compound 3870,8Connection 12922,7
The connection 4052,1The connection 13078,4
The connection 4419,2 Connection 13132,3
Connection 4729,3Connection 133of 17.0
The connection 4932,5Connection 13826,0
The connection 5016,9The connection 140the 10.1
Connection 5770,1Connection 1416,77
The connection 5869,3Connection 14290,9
The connection 6059,1Connection 14568,6
Connection 6342,0Connection 1474,04
The connection 6448,6Connection 15193,6
The connection 7093,3Soy is inania 154 25,6
Connection 7162,0Connection 1569,66
The connection 7470,9Connection 15790,5
Connection 7574,8Connection 15847,0
Connection 77of 37.8The connection 1605,58
The connection 7865,1Connection 16390,8
Connection 7928,2Connection 16511,8
The connection 8069,9Connection 1698,32
The connection 8438,4Connection 1714,16
Connection 8527,5Connection 172 22,2
Connection 86of 21.2Connection 1731,26
Connection 9469,0Connection 17411,0
Connection 9514,9Connection 17672,7
Connection 9716,9Connection 1777,12
Connection 10335,4Compound 18113,0
The connection 1044,8Compound 1878,76
Connection 10550,2Connection 1914,72
The connection 106? 7.04 baby mortalityConnection 19313,1
The connection 11023,4Connection 195117
The connection 1121,94Connection 19780,9
Connection 11516,6Connection 1980,59
The connection 1163,95The connection 2007,83

Example 39

Induced by histamine in rats reaction increased vascular permeability(antihistamine effectin vivo)

Male SD rats (SPF) weight 180 g pre-fed for one week or more, allowing the rat to take solid food and tap water without restrictions,in ambient conditions temperature 22°C, humidity of 55% and artificial light for 12 hours per day (light phase from 8:00 to 20:00), for use in the experiment rats were subjected to fasting throughout the night. Histamine·dihydrochloride (hereafter in this document referred to as histamine), and Evans Blue was used by dissolving each of them in saline solution during application. The substance to be tested was dissolved in water for injection or suspended in 0.5% sodium-carboxymethylcellulose and rats orally introduced rest the R or suspension (volume dose: 5 ml/kg body weight). Within 1 hour after administration of each of the saline solution and the solution of histamine was intradermally injected with in two areas (20 μg/0.05 ml/area) in each case in the side of the rat, the hair which had been shaved off electrostically device during anaesthesia simple ether. Saline solution containing 0.5% Evans Blue was injected with intravenously in the tail of the rats (1 ml/200 g body weight) immediately prior to intradermal injection of histamine.

After 30 minutes the animals were deceptional left for fatal bleeding and removed the skin to measure the amount of leaked pigment dyed blue part. The measurement of the amount of leaked pigment was carried out as follows. The skin area with leaked pigment was cut in two areas, to it was added 1 ml of 2 mol/l aqueous solution of potassium hydroxide in a test tube for testing and the test tube for testing was allowed to stand over night 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 to the solution was added acetone, the mixture was vigorously shaken for 10 minutes. Then the mixture was filtered and measured the absorbance of the filtrate at 620 nm. Were used for comparison the absorption obtained from the two sections of the areas that were injected with saline as empty values education is CA. The number of leaked pigment was calculated using the calibration curve for Evans Blue at 620 nm.

One example of the results is presented in table 19. The compound of the present invention showed a very high antagonistic activity induced by histamine in rats reactions of increased vascular permeability.

td align="center"> Approximately 0.1
Table 19
No. of connectionsED50(mg/kg)No. of connectionsED50(mg/kg)
Connection 40,69The connection 140About 0.01
The connection 150,18Connection 142Approximately 0.3
The connection 260,059Connection 1450,29
Connection 271,63Connection 151<0,1
The connection 350,28With the unity 152 1,49
The connection 480,68Connection 1532,61
The connection 49Approximately 1Connection 1550,334
The connection 540,027Connection 1650,107
The connection 580,78Connection 1670,194
The connection 650,14Connection 1680,264
The connection 680,13Connection 1690,241
The connection 1081,16Connection 1700,614
Connection 1130,072Connection 1710,073
Connection 1170,027 Connection 1720,117
The connection 1180,48Connection 1731,430
Connection 1191,10Connection 1770,302
The connection 1240,009Connection 1801,55
Connection 1260,446Connection 188Approximately 0.3
Connection 127Approximately 0.1Connection 1900,419
Connection 128Approximately 0.1Connection 1910,597
Connection 1290,088Connection 1920,312
The connection 1300,044Connection 1970,190
Connection 131Connection 198Approximately 0.3
Connection 1320,17Compound 199About 0.01
Connection 1352,33The connection 200Approximately 0.3
Connection 1370,24Connection 2090,42
Connection 1380,47Ketotifen0,54
Connection 1392,24

Example 40

Occupying the capacity of the H1-receptor brain mouse(ex vivo)

Male ICR mice aged 6 weeks pre-fed for one week or more, allowing the mouse to eat solid food and tap water without restrictions,in ambient conditions at a temperature of 22°C, humidity of 55% and artificial light for 12 hours per day, mouse for use in the experiment were subjected to starvation during the night. Substances which, to be tested was dissolved in water for injection or suspended in 0.5% solution of carboxymethyl cellulose solution or suspension oral injected mouse (volume dose: 0.1 ml/10 g body weight). Within 1 hour after oral administration, the mouse was deceptional and the whole brain excluding cerebellum and prodolgovatoe brain was rapidly removed. The extracted brain tissue homogenized using a transmitter station (manufactured by Kinematica) in ice-cold phosphate-buffered saline at a concentration of 50 mmol/l (pH of 7.4, 100 mg/1.9 ml).

In a test tube for testing reaction (TPX-Tube) was added to 180 μl of brain homogenate, 10 μl of a solution3H-pyrilamine (final concentration: 2 nmol/l) and 10 μl of unlabeled solution pyrilamine (final concentration: 200 umol/l) or 50 mmol/l phosphate-saline buffer, the mixture is incubated at room temperature for 45 minutes and then was added 2.0 ml of ice-cold phosphate-saline buffer at a concentration of 50 mmol/l to stop the reaction. The reaction mixture was filtered through GF/B filter (manufactured by ADVANTEC), the filtrate was placed into the vial and dried over night at 60°C. After drying the product was added 10 ml of scintillator (AL-1, based on toluene, manufactured by DOJINDO LABORATORIES) and measured the number of disintegrations per minute (dpm) using a liquid scintillation counter (manufactured by Packard, USA, TRI-CARB 2700TR) (5) - Rev. minutes/vial).

One example of the results is presented in table 20. In this experiment requires a high concentration of compounds of the present invention for the occupation of the receptor in the brain that indicates that the passage in the brain is low. From the results it was evident that the compounds of the present invention show selective for the peripheral antihistaminic action without passing into the brain, so that connections can mitigate adverse effects on the Central nervous system, such as drowsiness.

Table 20
No. of connectionsID50(mg/kg)No. of connectionsID50(mg/kg)
Connection 4to 43.1The connection 1403,50
The connection 155,6Connection 14211,9
The connection 264,8Connection 145>200
Connection 27551 Connection 1516,36
The connection 3528,4Connection 152199,34
The connection 4895,5Connection 153>200
The connection 4933,9Connection 15566,6
The connection 549,3Connection 16523,0
The connection 58205,2Connection 16735,1
The connection 6519,5Connection 16810,4
The connection 6814,6Connection 16912,5
The connection 108110,5Connection 17070,3
Connection 11398,7 Connection 17129,6
Connection 1174,2Connection 17228,0
The connection 11824,3Connection 17387,1
Connection 11974,5Connection 177124,6
The connection 1243,2Connection 180>200
Connection 126236,7Connection 18823,0
Connection 1279,84Connection 19073,2
Connection 1287,45Connection 19179,2
Connection 12940,5Connection 19263,8
The connection 1308,0 Connection 197>200
Connection 1319,20Connection 19822,1
Connection 13237,5Compound 1994,5
Connection 135>200The connection 20053,4
Connection 137>200Connection 209>200
Connection 13865,4Ketotifen0,51
Connection 139>200

From the results of examples 39 and 40 above, the value obtained by dividing ID50(table 20) in the test binding receptors of the brain, ED50(table 19) test-induced histamine reactions of high permeability are presented in table 21. The bigger is the ID of a50(table 20) in the test binding receptor brain, the lower is the fast passing into the brain, i.e. the lower are the side effects on the Central nervous system, such as drowsiness; and the smaller is the ED50(table 19) in the test-induced histamine reaction and increased vascular permeability, the stronger is the antihistamine effect. Thus, the value calculated as ID50÷ ED50may serve as an index, where the bigger is the calculated value, the stronger is the antihistamine action and the lower are the side effects on the Central nervous system, such as drowsiness. As shown in table 21, the connection of the present invention shows a higher value, computed as ID50÷ ED50compared to existing the antihistamine ketotifen. Thus, we can say that the compound of the present invention has desirable properties as pharmaceutical compositions, particularly as the active ingredient antihistamine, which has a strong antihistamine effect and fewer side effects on the Central nervous system, such as drowsiness.

Table 21
No. of connectionsID50(mg/kg)/ EDsub> 50(mg/kg)No. of connectionsID50(mg/kg)/ ED50(mg/kg)
Connection 462,5The connection 140350,0
The connection 1531,1Connection 14239,7
The connection 2681,4Connection 145>689,7
Connection 27to 33.8Connection 151>63,6
The connection 35101,4Connection 152133,8
The connection 48140,4Connection 153>76,6
The connection 4933,9Connection 155199,4
The connection 54to 344.4Connection 165215,0
The connection 58263,1Connection 167180,9
The connection 65139,3Connection 16839,4
The connection 68112,3Connection 16951,9
The connection 108for 95.3Connection 170114,5
Connection 1131370,8Connection 171to 405.5
Connection 117155,6Connection 172239,3

>129,0
The connection 11850,6Connection 17360,9
Connection 11967,7Connection 177412,6
The connection 124to 355.6Connection 180
Connection 126530,7Connection 18876,7
Connection 12798,4Connection 190174,7
Connection 12874,5Connection 191132,7
Connection 129460,2Connection 192204,5
The connection 130181,8Connection 197>1052,6
Connection 13192,0Connection 19873,7
Connection 132br220.6Compound 199450,0
Connection 135>85,8The connection 200178,0
Connection 137>833,3Connection 209 >476,2
Connection 138139,1Ketotifen0,9
Connection 139>89,3

INDUSTRIAL APPLICABILITY

A derivative of piperidine according to the present invention possesses a strong ability to bind H1-receptor histamine, as shown in table 18, and showed strong antagonistic activity against histamine receptor in induced histamine reactions of increased vascular permeability in rats as shown in table 19. In addition, as is evident from table 20, a derivative of piperidine shows a low pass into the brain even in the test binding receptors of the brain, where the mouse was performed oral administration, so piperidine derivative of the present invention is preferred from the viewpoint of mitigating adverse effects on the Central nervous system, such as drowsiness. As is evident from the values in table 21 for the joint evaluation of the antagonistic activity to a histamine receptor, and passing into the brain, piperidine derivative of the present invention is a strong antagonistic substance p is Ceptor histamine, and has fewer side effects on the Central nervous system, such as drowsiness; therefore, the derivative of piperidine has the properties of the active ingredient of the pharmaceutical composition, such as desirable antihistamine, so the derivative of piperidine is highly suitable.

1. A derivative of piperidine or pharmaceutically acceptable salt or hydrate, where the piperidine derivative corresponds to the following General formula (I):

where R1means hydrogen or Deputy, selected from the following (b)-(i):
(b) an acrylic acid (including alkilany ester and hydroxyalkylated),
(c) ureido,
(d) alkenyl,
(e) aminoalkyl, which can be substituted by alkylcarboxylic or aminocarbonyl,
(f) carbonylethyl, substituted hydroxy, alkoxy or hydroxyethylamino,
(g) carbonyl, substituted hydroxy, morpholino, alkoxy, hydroxyalkyloxy or cyclohexyloxycarbonyloxy,
(h) carbylamine substituted by alkyl or alkoxy,
(i) aminocarbonyl, which may be substituted by one or two substituents selected from amino, hydroxy, alkoxy, alkenyl and alkyl (which may be substituted with halogen, thiol, piperidino, amino, alkoxy, alkoxycarbonyl, aminocarbonyl or one or two hydroxy);
R2oznachaet is hydrogen or Deputy, selected from the following (j)to(r):
(j) cyano,
(k) acrylic acid,
(l) alkyl, substituted hydroxy or piperidino,
(m) carbonylethyl, substituted hydroxy, alkoxy (which may be substituted, cyclohexyloxycarbonyloxy), or hydroxyethylamino,
(n) a carbonyl, a substituted hydroxy or alkoxy,
(o) carbonyloxy, substituted alkoxy,
(p) carbonylmethyl, substituted hydroxy or alkoxy,
(q) alkoxy,
(r) halogen; and
R3means hydrogen or Deputy, selected from the following (s)-(w):
(s) alkyl which may be substituted by carboxy, cyano, pyrrolidino, piperidino, alkoxy, alkylsulfanyl or one or two hydroxy,
(t) a carbonyl substituted by alkyl or alkoxy,
(u) carbonyloxy, substituted hydroxy or alkoxy,
(v) carbonylethyl, substituted alkyl, alkoxy or alkylphenyl,
(w) aminoalkyl, replaced by aminocarbonyl or alkanesulfonyl, where one of the above R1and R2means the Deputy, other than hydrogen, And is unsubstituted or represents oxo, means carbon or oxygen, one of X and Y represents a carbon, and other means sulfur, the dotted line means a single bond or double bond, provided that when R2means halogen or alkoxy, a is unsubstituted, R1means the Deputy, other than bodoro is a, and means oxygen.

2. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 1, where a is unsubstituted.

3. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 2, where one of R1and R2is carbonylethyl, substituted hydroxy and the other represents hydrogen.

4. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 3, where R1is carbonylethyl, substituted hydroxy.

5. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 3, where R2is carbonylethyl, substituted hydroxy.

6. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 2, where a represents oxygen, R1represents hydrogen and R2is carbonylmethyl, substituted hydroxy.

7. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 4, where In is the carbon.

8. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 3, where In represents the oxygen.

9. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 1, where R3represents hydrogen.

10. A derivative of piperidine or it is pharmaceutically acceptable salt or hydrate of claim 8, where R3represents an unsubstituted alkyl.

11. A derivative of piperidine or pharmaceutically acceptable salt or hydrate of claim 8, where R3is alkylcarboxylic.

12. Derived piperidine or its pharmaceutically acceptable salt or hydrate according to claim 1, where the piperidine derivative corresponding to General formula (I)represents [4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-2-yl]acetic acid.

13. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 1, where the piperidine derivative corresponding to General formula (I)represents {4-[1-(4-oxobutyl)piperidine-4-ilidene]-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-yl}acetic acid.

14. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 1, where the piperidine derivative corresponding to General formula (I)represents 2-methyl-2-[4-(1-methylpiperidin-4-ilidene)-4,10-dihydro-9-oxa-3-tiebens[f]azulene-6-ylsulphonyl]propionic acid.

15. A derivative of piperidine or pharmaceutically acceptable salt or hydrate according to claim 1, where the piperidine derivative corresponding to General formula (I)represents a 3-(4-piperidine-4-ilidene-4H-1-tiebens[f]azulene-2-yl)propionic acid.

16. Antihistamine containing at least one representative selected from PR is svodnik piperidine, or its pharmaceutically acceptable salt or hydrate as defined in any one of claims 1 to 15.

17. The application of the piperidine derivative or its pharmaceutically acceptable salt or hydrate according to any one of claims 1 to 15 for the manufacture of a medicinal product for treating at least one disease selected from asthma, allergic rhinitis, pollinosis, urticaria and atopic dermatitis.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compound presented by Formula

or Formula ,

wherein A and B optionally represent CH2, CO; D represent S; the values R1, R2, R4, R4 are specified in cl. 1 of the patent claim, as well as to their pharmacologically acceptable salts or hydrates and methods for preparing them.

EFFECT: compounds are able to inhibit TNF-α recovering cells.

19 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A, J, R1, R4, X, Z are given in claim 1, and to a pharmaceutical composition containing such compounds, which modulate activity of store-operated calcium (SOC) channels. The present invention also describes methods of using such SOC channel modulators to treat diseases or conditions where inhibition of activity of SOC channels can be beneficial.

EFFECT: improved method.

17 cl, 5 tbl, 2 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae Ic-d , where X is O or S; R1 is selected from -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)nOR10, -C(=Y)NR10Rn, -C(-O)NR12(CR14R15)mNR10RH, -NHR12, C1-C12alkyl, C2-C8alkenyl, C3-C6heterocyclyl, which is a saturated carboxylic radical containing 3-6 ring atoms, wherein one ring atom is a heteroatom selected from nitrogen and oxygen, phenyl or a C4-C9heteroaryl, which is a univalent aromatic radical containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur; R2 is selected from H, pyrimidinyl and C1-C6alkyl; mor is a morpholine group and R3 is a monocyclic heteroaryl group, and to pharmaceutically acceptable salts thereof.

EFFECT: compounds can be used to modulate lipid kinase activity, including PI3K, and to treat lipid kinase mediated disorders such as cancer.

15 cl, 2 tbl, 468 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (S)-2-clopidogrel and salts thereof, which involves the following steps: (a) enzymatic hydrolysis of a racemic 2-chlorophenylglycine alkyl ester of formula 9 using an enzyme which is efficient for aqueous solution or aqueous phase hydrolysis to obtain an optically active compound of formula 10 ; (b) reaction of the formed optically active compound of formula 10 with a compound of formula 11 to obtain a compound of formula 12 and (c) cyclisation of the compound of formula 12 with a formulating agent in the presence of acid, where R1 denotes H, substituted or unsubstituted C1-C8-alkyl, substituted or unsubstituted C1-C8-alkenyl, benzyl or C3-C6-cycloalkyl; and X denotes a halogen atom selected from a group consisting of fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), or -OSO2R2 (where R2 denotes a substituted or unsubstituted C1-C8-alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl).

EFFECT: novel method of producing clopidogrel which does not involve use of chiral resolving agents, which reduces the cost of preparations while maintaining high output of the product.

7 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

where X is S or O, mor is a morpholine group, and R3 is a monocyclic heteroaryl group, including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, which are used to modulate lipid kinase activity, including PI3K, and for treating lipid kinase mediated disorders such as cancer.

EFFECT: obtaining compounds which are used to modulate lipid kinase activity, including PI3K, and for treating lipid kinase mediated disorders such as cancer.

27 cl, 1 tbl, 354 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are produced new diazepane substituted compounds representing various heterocyclic systems, including condensed, pharmaceutical compositions containing said compounds.

EFFECT: producing the compounds and compositions for preventing and treating neurological and mental disorders and diseases with involved orexin receptors.

13 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of indole with formula (I) or indole pharmaceutically acceptable salts: where: ring A stands for a benzene or a tiofen ring; R1 stands for a C1-.6 alkyl that may be substituted by one or several groups selected from among -OH, - O-C1-6 alkyl, an amino group that may be substituted by one or two C1-6 alkyls; -O-C1-6 alkyl; a halogen; CN; 5-6-membered cyclic amine; n is equal to 0 - 4 and to 0- 2 if ring A is a benzene or a tiofen ring accordingly; R2 stands for -H, -C1-6 alkyl; R3 stands for H, -C1-6 alkyl that may be substituted by phenyl, C3-6 cycloalkyl; R4 stands for C1-6 alkyl that may be substituted by one or several groups selected from among -OH, -O- C1-6 alkyl, an amino group that may be substituted by one or two C1-6 alkyls and 5-6-membered cyclic amine; C3-6 cycloalkyl, phenyl or-OH; X1 stands for -CH2-, -O-, -S-, -CH(R°)-; X2 stands for -C(RA)(RB)-, -O-; X3 stands for -C(RC)(RD)-; m is equal to 1 - 3; R° stands for -H, or R°, together with R4, form C3-6 alkylene; RA, RB, RC and RD are identical or different and stand for -H, C1-6 alkyl where, in case m is equal to 2 or 3, each RC and R° may be identical or different provided 1- methyl-4a-phenyl-2,3,4,4a,5,9b-hexahydro-1H-indeno [1,2-b] pyridine, 4a-phenyl-2,3,4,4a,5,9b-hexahydro-4aH-indeno [1,2-b] pyridine and 2-(1,2,3,4,5,9b-hexahydro-4aH-indeno [1,2-b] pyridine -4a-yl)-N,N-dimethylethanamine are excluded).

EFFECT: compounds possess antagonistic activity regarding NMDA receptor which enables their usage in pharmaceutical compositions for treatment of Alzheimer disease, vascular dementia, Parkinson disease, chronic depression, attention deficit hyperactivity disorder, migraines etc.

18 cl, 40 tbl, 84 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the use of compounds of formula (wherein R1, R2, X, Y and n have the values specified in the patent claim) or their pharmaceutically acceptable salts for treating the diseases related to the biological function of the trace amine associated receptors, namely depression, anxiety disorders, bipolar disorders, attention deficit/hyperactivity disorder, stress-induced disorders, schizophrenia, neurological disorders, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, addictions, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy consumption and assimilation disorders, thermal homeostasis disorders and disturbances, sleeping and circadian rhythm disorders, and cardiovascular diseases. Besides, the invention refers to compounds of formulas I-A, I-B, I-C, I-D, l-E, l-F, I-G, I-H (structural formulas of which are presented in the patent claim) and to a pharmaceutical composition based on the compounds of formula (I) for treating the diseases related to the biological function of the trace amine associated receptors.

EFFECT: use of the compounds of formula 1 in preparing the drugs for treating the diseases related to the biological function of the trace amine associated receptors.

45 cl, 9 dwg, 1 tbl, 379 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2-heteroaryl-substituted benzothiophene and benzofuran, precursors thereof and therapeutic use of said compounds, having structural formula (1a) where R1, R2, X9 and Q assume values given in the description, and pharmaceutically acceptable salts thereof, which are suitable for imaging amyloid deposits in living patients. The invention also relates to pharmaceutical compositions based on compounds of formula 1a, use and methods of producing said compounds. More specifically, the present invention relates to a method of imaging brain amyloid deposits in vivo for intravital diagnosis of Alzheimer's disease, and measuring clinical efficiency of therapeutic agents against Alzheimer's disease.

EFFECT: high efficiency of using said compounds.

15 cl, 1 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel disubstituted phenylpyrrolidines of formula , any stereoisomers thereof or any mixtures of stereoisomers thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, where Ar denotes phenyl; R1 denotes F, Cl; R2 denotes F and Cl; R3 denotes H, Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, cyclopropylmethyl, CFH2CH2CH2-, CF2HCH2CH2-, CF3CH2CH2-, allyl and CH3OCH2CH2-; X denotes F, OH; under the condition that X denotes OH, R3 does not denote H.

EFFECT: compounds are capable of increasing levels of dopamine, norepinephrine and serotonin, which enables their use in treating central nervous system disorders.

16 cl, 21 dwg, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3-alkyl(aryl)-2,2'-bithiophene-5-carboxylic acids and esters thereof of general formula I where R = C1-C10-alkyl or aryl; R1 = hydrogen atom or C1-C4 alkyl, involving reaction of 2-acyl thiophenes of general formula II with dimethyl formamide and phosphoryl chloride, and the formed 2-alkyl(aryl)-3-chloro-3-(2-thienyl)acrylaldehyde of general formula III reacts with thioglycolic ester in the presence of a base, and by hydrolysis of the obtained esters of general formula I, where R assumes values given above and R1=C1-C4 alkyl, 3-alkyl-2,2'-bithiophene-5-carboxylic acids are obtained, where R1 = hydrogen atom.

EFFECT: simpler method of producing compounds of formula I, which can be used in synthesis of solvatochromic and thermochromic dendrimers, oligothiophenes with adjustable electrical and optical properties.

1 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,3-disubstituted indoles of general formula (I): , where the method involves the following steps: a) reaction of bromine diol (i): with dialkoxyborane in the presence of a ligand, a palladium catalyst, preferably selected from Pd(OAc)2, PdCl2, PdBr2, Pd2(dba)3, Pd2(dba)3.CHCl3, [Pd(ally)Cl]2,- Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, Pd/C and encapsulated Pd and a base to obtain a compound of general formula or, alternatively, reaction of compound (i) with a magnesium compound containing 3 alkyl groups, with subsequent treatment with a borate to obtain a compound of general formula ii given above; b) reaction of the product from step (a) with R2-Hal to obtain a compound of general formula I; where: R denotes (C1-C6)alkyl; R2 denotes: , , , , ,

, , , , ;

R3 denotes cyclopentyl: X denotes carboxymethyl; Hal denotes Br or I; or pharmaceutically acceptable salt thereof.

EFFECT: higher efficiency.

12 cl, 4 dwg, 2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: described are novel 1,2,4-triazolones of general formula (I):

, where A denotes N and values of other radicals are given in the claim, which are vasopressin receptor inhibitors, synthesis method thereof and use thereof to prepare medicinal agents for treating and/or preventing diseases, particularly for treating and/or preventing cardiovascular diseases.

EFFECT: high efficiency of using said derivatives.

6 cl, 512 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (1) in free form or in form of a salt. In formula (1): X1 and X2 all independently denote halogen; A denotes a radical of formula where (R1)1-2 denotes 1-2 identical or different substitutes selected from a group comprising C1-C4-alkyl, halogen-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, R2R3N-C1-C4-alkyl, halogen, hydroxy group, C1-C4-alkoxy group, halogen-C1-C4-alkoxy group, C1-C4-alkylthio group, C1-C4-alkanoyl, C1-C4-alkanoylamino group, C1-C4-alkylsulphonylamino group, C1-C4-alkylsulphonyl, C1-C4-alkylthionyl, NR2R3 and morpholinyl; or A denotes a radical of formula where ring (a) denotes a 5-member heterocyclic ring containing 1 or 2 heteroatoms selected from a group comprising O and N, which can further be substituted with C1-C4-alkyl, and which is annelated in positions 3 and 4; and R2 and R3 all independently denote hydrogen or C1-C4-alkyl. The invention also relates to a parasite control composition containing said compounds, a parasite control method on warm-blooded animals and use of compounds of formula (1) to prepare a parasite control composition.

EFFECT: high efficiency of using said compounds.

11 cl, 7 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula A

the radicals R1, R2, R3, R4, R5, R25, R26, U, T, W, V, Y are those as specified in clause 1 of the patent claim. Also, the invention refers to a method for preparing the compound of formula A, the drug based on this compound applied for treating disorders or diseases which are at least partially mediated by vanilloid receptor VR1 /NRPV1, as well as use of this compound for preparing the drug.

EFFECT: there are prepared and described new compounds which can be effective in treating diseases which are at least partially mediated by vanilloid receptor VR1 /NRPV1.

43 cl, 367 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel complex of 5-hydroxy-6-methyluracil with sodium succinate (5-hydroxy-6-methyluracil succinate) of formula: , which exhibits antihypoxic activity. The disclosed compound widens the range of pharmacologically active compounds with low toxicity and high antihypoxic activity, which increase body resistance to certain types of hypoxia and in conditions influenced by other extreme environmental factors. The invention also relates to a method of producing the complex. The method involves mixing 5-hydroxy-6-methyluracil and sodium succinate in ratio of 1:10 in distilled water and then mixing the reaction mixture until dissolution of 5-hydroxy-6-methyluracil, removing the solvent from the reaction mixture and extracting the product.

EFFECT: output of the end product reaches 98%.

3 cl, 2 tbl, 4 ex

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