Polycyclic compounds, their derivatives, pharmaceutical preparations as amplifiers and treatment of mental disorders

 

(57) Abstract:

Describes the new polycyclic compounds of the formula I or their pharmaceutically suitable salts, where a is an aromatic or heteroaromatic ring selected from the group comprising a, b, C, aromatic or heteroaromatic ring selected from the group including a group d, Z means a bond, -C(=O)- O-, -S(=O) - or-SO2R signifies phenyl, R2means - H , -l, -R4, -OR4, - OH, - COOR4- -(CH2),-(CH2)nCCR5, - (CH2)nNR6COR4or-NR6R6a, R3means - N or - OR4, R2ameans H, C1-C4-alkyl or phenyl, R4- C1-C4-alkyl, R5, R6and R6aeach independently denotes H or C1-C4-alkyl, n = 0 or 1, R is selected from the group comprising - H, -(CH2)n-(Het-2) or (CH2)n- Y, Het-1 and Het-2 are each independently mean a heterocycle selected from f, where X is H, Cl, F, Br or or4, n is 1, 2 or 4, Y represents-OR6-CO2R6, -CN or CONHR6provided that when a represents six-membered aromatic or heteroaromatic ring, Het-1 and Het-2 both are not f, where X is N. The compounds of formula I usilie are experiencing reduced its content, such as Alzheimer's disease and other conditions, including learning and thinking. Also described their derivatives, pharmaceutical preparations based compounds (I) and a method of treatment of disorders of mental activity. 8 C. and 5 C.p. f-crystals, 2 ill., table 4.

< / BR>
< / BR>

The invention relates to disubstituted polycyclic compounds, their derivatives, pharmaceutical preparations and methods of use in treating mammals disorders mental and/or neurological dysfunction and/or depressions such as diseases associated with degeneration of the nervous system, and not only them. In addition, these compounds can be used as reagents in the study of biochemical mechanisms caused by neurotransmitter diseases.

The need for effective treatment of disorders of the nervous system and neurological failure grows. Many of these disorders are associated with aging due to degenerative changes in the nervous system. Although in the early stages of some diseases, some systems are affected rather specific (e.g., cholinergic system in Alzheimer's disease and Myasthenia Gravis, dopaminergic system in epinephrin, serotonin) are usually detected at a later stage for diseases such as senile dementia, dementia with extensive infarction, Huntington's disease, mental retardation and so on. This explains the observed usually multiple symptomatology, which includes mental, neurological and effective/psychotic features (see Geof fries, Psychopharmacol, (1985), 86:245). It is believed that the failure of the synthesis and excretion of acetylcholine in the brain is associated with deterioration of mental activity (see Francis, et al., N. Engl.J.Med., (1985) 7:313), while neurological disorders (for example, the symptoms of Parkinson's disease), depression, and mental changes can be caused by damage to dopaminergic and serotonergically systems, respectively. Other neurological disorders (eg, Myasthenia Gravis) are associated with cholinergic deficiency in the peripheral nervous system. Still used treatment strategy include vasoactive funds, as vincamine and pentoxifylline; accelerators metabolism, such as ergoloid the mesylates; piracetam, and naftidrofuryl; precursors of neurotransmitters, such as 1-DOPA, choline and 5-hydroxytryptamine; transmitter, metabolizing inhibitors is inu peptides. With the exception of L-DOPA to treat Parkinson's disease and cholinesterase inhibitor treatment for Myasthenia Gravis these treatments usually cannot increase the residual function of the affected system strengthening caused by the stimulus secretion of neurotransmitters. Theoretically, such an enhancement would be to improve the signal-to-noise ratio during the chemical transmission of information, thereby reducing the failure in the processes associated with mental activity, neurological function and regulation of mood.

DeNoble, et al., Pharmacol. Biochem. Behavior, (1990) 36:957; Cook, et al., Pharmacol. Biochem. Behavior, (1990) 19:301; Nickolson, et al., Pharmacol. Biochem. Behavior, (1990) 19:285; and US patent 4760083 (1988) showed in vitro experiments that the compound 3,3-bis-(4-pyridinylmethyl)-1-phenylindolin-2-it is also used in the treatment of dysfunction mental activity.

Patent US 5173489, issued December 22, 1992, describes - disubstituted aromatic or heteroaromatic compounds of the formula

< / BR>
or their salts;

where X and Y are connected, forming a saturated ring or unsaturated first Carbo - or heterocycle, and the specified carbon atom in the ring is connected with at least one aromatic or heteroaromatic ring, kondensirovannye, and the other is selected from the series

(a) a 2-, 3 - or 4-pyridinyl

(b) a 2-, 4 - or 5-pyrimidinyl

(c) 2-pyrazinyl

(d) 3 - or 4-pyridazinyl

(e) 3 - or 4-pyrazolyl

(f) 2 - or 3-tetrahydrofuranyl and

(g) 3-thienyl,

applicable as amplifiers mental activity. All of the above sources talk about the need for two additional heteroaryl groups for the activity.

European Patent application, WO 93/14085, published on July 22, 1993, describes compounds of the formula

< / BR>
where Q

< / BR>
which is suitable amplifiers secretion of neurotransmitters.

European Patent application, WO 93/14092, published on July 22, 1993, describes compounds of the formula

< / BR>
where Q

< / BR>
applicable as amplifiers secretion of neurotransmitters.

None of the above sources not specified and it is not available compounds, which are the subject of this invention, the condensed polycyclic system type 6-5-5, where A is six-membered aromatic system; B - membered heterocyclic system and C is a five-membered ring between cycles A and B. Further, it is shown that some compounds that are the subject of this invention, especially those of them, shows a marked increase in the level of acetylcholine in the brain. Demonstrated ability to increase acetylcholine levels, measured directly in the brain represents a clear and unexpected advantage over the compounds described in the literature.

The invention

It was discovered that certain polycyclic compounds increase caused by the stimulus secretion of neurotransmitters, especially acetylcholine in nervous tissues; thus, improving the processes that make learning and memorization tasks active avoidance. Further evidence of this effect is characterized by measured increases levels of the neurotransmitter acetylcholine in the brain.

Accordingly, this invention relates to novel polycyclic compounds represented by the formula (I)

< / BR>
or their pharmaceutically suitable salts,

where A is an aromatic or heteroaromatic ring selected from the group including

< / BR>
B is an aromatic or heteroaromatic ring selected from the group including

< / BR>
Z means a bond, -C(=O)- O-, -S(=O)- or-SO2-;

P is phenyl;

R2means-H, -I, -R4, -OR4, -OH, -COOR4, -(CH2)nCCR5, -(CH2)nNR6COR4Kil or phenyl;

R4- C1-C4alkyl;

R5, R6and R6aeach, independently denotes H or C1-C6alkyl;

n is 0 or 1;

R is selected from the group including

-H,-(CH2)n,-(Het-2) or -(CH2)n,-Y;

Het-1 and Het-2 each independently represent a heterocycle selected from

< / BR>
where X is H, Cl, F, Br or or4;

n' is 1, 2 or 4;

Y means-OR6, -CO2R6, -CN or-CONHR6;

provided that when A mean six-membered aromatic or heteroaromatic ring,

Het-1 and Het-2 both are not

< / BR>
where X is H.

Preferred are compounds where In denotes an aromatic or heteroaromatic ring selected from the group including

< / BR>
Further preferred are compounds where R is selected from the group comprising-H, -CH2-(Het-2), -CH2CO2Et, -(CH2)4OCOCH3, - (CH2)4CONH2, -(CH2)4OH, and -(CH2)4-CN.

More preferred are compounds where

R2means-H, -I, -R4, -CCH, -OR4, -NR6R6a, - COOR4or -(CH2)nNR6COR6;

R3means hydrogen;

R)4CONH2, -(CH2)4OH, and -(CH2)4-CN.

Most preferred are compounds where A denotes the six-membered aromatic or heteroaromatic ring, selected from

< / BR>
R2means-H, -I, -R4, -CCH, -OR4, -NR6R6a, -COOR4or -(CH2)nNR6COR4;

R3means H;

X represents H, F, Cl, Br or or4;

R is selected from the group comprising-H, -CH2-(Het-2), -CH2CO2Et, -(CH2)4OCOCH3, -(CH2)4CONH2, -(CH2)4OH, and -(CH2)4-CN.

Particularly preferred compounds of the present invention, selected from the group including:

4-(4-pyridinylmethyl)-4H-indeno[1,2-b]thiophene;

4-(4-pyridinylmethyl)-4H-indeno[1,2-b]thiophene-4-pentane-nitrile, hydrobromide hydrate;

ethyl ester of 4-(4-pyridinylmethyl)-4H-indeno[1,2-b] thiophene-4 - acetic acid, hydrochloride;

4-(4-pyridinylmethyl)-4H-indeno[1,2-b] thiophene-4-pentanolide hydrate hydrochloride;

2-fluoro-4-[4-(4-pyridinylmethyl)-4H-indeno[1,2-b] thiophene-4-ylmethyl] pyridine;

4-[4-(phenyl)-4H-indeno[1,2-b]thiophene-4-ylmethyl]pyridine;

4-(4-pyridinylmethyl)-4H-indeno[1,2-b]thiophene-4-butanol;

4-(4-pyridinylmethyl)-4H-thieno[2'3':3,4]qi is;

2,4-dihydro-2-phenyl-4,4-bis (4-pyridinylmethyl)pyrazolo-[4,3-b] pyrrolizine;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-2-hydroxy-9H-fluoren;

5-[(2-fluoro-4-pyridinyl)methyl]-5-(4-pyridinylmethyl)-5H-indeno [1,2-b]pyridine;

5- [(2-fluoro-4-pyridinyl)methyl] -5-(4-pyridinylmethyl)-5H-indeno [2,1-b] pyridine;

10,10-bis [(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracene;

9-[(2-fluoro-4-pyridinyl)methyl]-9-(4-pyridinylmethyl)-9H-xanthene;

10-[(2-fluoro-4-pyridinyl)methyl]-10-(4-pyridinylmethyl)-9(10)- anthracene;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-4-asasantin;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-5H-indeno[1,2-b]pyridine;

4,4-bis[(2-fluoro-4-pyridinyl)methyl]-4H-thieno[3',2':4,5] cyclopent[1,2-b] pyridine;

9-[(2-fluoro-4-pyridinyl)methyl]-9-(4-pyridinylmethyl)-4-asasantin;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-2-methoxyfuran;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-7-methoxy-4-asasantin;

10,10-bis[(2-fluoro-4-pyridinyl)methyl]-3-hydroxy-9(10)anthracene;

10,10-bis[(2-fluoro-4-pyridinyl)methyl]-2,6-dimethoxy-9(10H) -anthracene;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-cyclopent[1,2-b:3,4-b] dipyridine;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-2-phenyl-5H-indeno-[1,2-d] pyrimidine,

10,10-bis[(2-fluoro-4-pyridinyl)methyl]-3-methoxy-9(10H)-anthracene;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-9H-indeno[2,1-b]pyridine;
5,5-bis[(2-fluoro-4-pyridinyl)methyl]-5H-indeno[1,2-d]pyrimidine;

5,5-bis[(2-bromo-4-pyridinyl)methyl]-5H-indeno[1,2-b]pyridine;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-2-[(N-methyl-N-acetylamino) methyl]fluoren;

10,10-bis[(2-bromo-4-pyridinyl)methyl]-9(10H)-anthracene;

5,5-bis[(2-chloro-4-pyridinyl)methyl]-5H-indeno[1,2-b]pyridine;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-2-methyl-5H-indeno[1,2-d] pyrimidine;

5,5-bis[(2-methoxy-4-pyridinyl)methyl]-5H-indeno[1, 2-b]pyridine;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-7-(ethyl)-5H-indeno-[1,2-b] pyridine;

5,5-bis[(2-chloro-6-methyl-4-pyridinyl)methyl]-5H-indeno[1,2-b] pyridine;

5,5-bis[(2-methyl-4-pyridinyl)methyl]-5H-indeno[1,2-b]pyridine;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-7-iodine-5H-indeno[1,2-b] pyridine;

methyl ether of 9,9-bis[(2-fluoro-4-pyridinyl)methyl]-9H-fluoren-1 - carboxylic acid;

methyl ester of 9-[(2-fluoro-4-pyridinyl)methyl]-9-(4-pyridinylmethyl)- 9H-fluoren-1-carboxylic acid, racemate;

5,5-bis[(2-fluoro-4-pyridinyl)methyl] -5H-cyclopent[2,1-b: 3,4-b'] dipyridine,

methyl ester 5-[(2-fluoro-4-pyridinyl)methyl]-5-(4-pyridinylmethyl)- 5H-cyclopent[2,1-b: 3,4-b'] dipyridine-4-carboxylic acid dihydrochloride (racemate);

methyl ester 5-[(2-fluoro-4-pyridinyl)methyl]-5-(4-pyridinylmethyl)- 5H-cyclopent[2,1-b:3,4-b] piperidin-4-carboxylic sour is 3,4-b'] dipyridine-4-carboxylic acid, hydrochloride, (+)-isomer;

5,5-bis-[(6-fluoro-3-pyridinyl)methyl] -5H-cyclopent[2,1-b:3,4-b'] dipyridine;

5-[(6-fluoro-2-pyridinyl)methyl]-5-(4-pyridinylmethyl)-5H-cyclopent [2,1-b: 3,4-b'] dipyridine;

5,5-bis-[(6-fluoro-2-pyridinyl)methyl] -5H-cyclopent[2,1-b:3,4-b'] dipyridine;

5,5-bis-[(3-methyl-4-pyridinyl)methyl] -5H-cyclopent[2,1-b: 3,4-b'] dipyridine, trihydrochloride;

2-fluoro-4-[(9-(4-pyridinylmethyl)-9H-fluoren-9-yl)methyl] pyridine, hydrochloride;

5-[(2-fluoro-4-pyridinyl)methyl]-5-(4-pyridinylmethyl)-5H-cyclopent [2,1-b: 3,4-b'] dipyridine;

5,5-bis-[(2-fluoro-4-pyridinyl)methyl]thioxanthen-10,10-dioxide;

5,5-bis-[(2-fluoro-4-pyridinyl)methyl]thioxanthen-10-oxide.

In addition, the method of treatment of violations of intellectual activity and/or failure neurological function and/or depression and mental disorders in patients suffering from nervous system disorders, such as Alzheimer's disease, Parkinson's disease, senile dementia, dementia with extensive infarction, Huntington's disease, mental deficiency, Myasthenia gravis, and so on introduction to the recipients suffering from these diseases, therapeutically effective amounts of compounds of formula (I). These compounds may have asymmetric centers. All hiramaru olefins, C=N double bonds and the like may also be present among the compounds described herein, and all stable isomers are considered in the present invention.

When any determination (e.g., R1to R6, m, n, P, W, Y, A, B, and so on) occurs more than once in any group or in the formula (I), its value in each case depends on its value in any other case. Furthermore, the combination of the substituents and/or definitions are valid only in the combinations, giving a stable connection.

Here and in the claims "*" means the place of attachment of ring A and B, to more clearly show the possible spatial isomers.

Here and in the claims, "alkyl" includes both branched and unbranched, saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group with the specified number of carbon atoms linked through an oxygen bridge.

The term "substituted" is used here and in the claims to denote that one or more hydrogen atoms from a suitable atom replaced by the indicated group, provided that the normal valency of the new compound" or "stable structure" is meant here a compound, which can be isolated from the reaction mixture suitable purity and transformed into an effective therapeutic agent.

Both here and in the claims "pharmaceutically suitable salts" refer to derivatives of the above compounds that are modified by the transformation in acidic or basic salts. Examples include, but are not limited to, mineral or organic acid salts or basic groups such as amines; alkali or organic salts of acidic radicals, such as carboxylic acids; acetyl, formyl and benzoline derivatives of alcohols and amines, and so forth.

Pharmaceutically suitable salts of the compounds of the subject invention can be obtained by the interaction of the free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or mixtures thereof; usually prefer non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile. A list of suitable salts is Remington''s Pharmaceutical Sciences, 17 th ed. Mack Publishing Company, Easton, PA, (1985), p. 1418, here we provide links.

The term "therapeutically effective" both here and in the function of the affected system strengthening caused by the stimulus secretion of neurotransmitter, thereby reducing the failure processes related to mental, neurological function and regulation of mood.

"Therapeutically effective amount" here and in the claims refers to the amount suitable for the treatment of disturbances of mental activity and/or failure neurological function and/or depression and mental disorders in patients suffering from such disorders of the nervous system like Alzheimer's disease, Parkinson's disease, senile dementia, dementia with extensive infarction, Huntington's disease, mental retardation, Myasthenia gravis, and so forth. In addition, these compounds can be used as reagents in the study of the biochemical mechanism of diseases caused by neurotransmitter.

Detailed description of the invention

The compounds of this invention can be described as consisting of two parts: a "core" represents a tricyclic system, formed by A and B and the Central five - or six-membered ring (C); and "side groups", which consist of 'CH2-Het-1' and 'R'.

Kernel (base) can be synthesized by the methods described below and the links that are listed here: Zascht2: 303; Massa, S. et al., J. Heterocyclic Chem., (1990) 27:1805; and Shen J-K, and Katayama, H.; Chem Lett., (1992) 451.

An additional group of "core", suitable for the synthesis of compounds of the present invention, can be obtained in accordance with the methods described in the literature links below or similarly described methods.

< / BR>
< / BR>
< / BR>
< / BR>
<1> Chem. Ber 1971, 104, 2975-83;

<2> J. Med. Chem 1978, 21, 623-8;

<3> Obtained by analogy with <2> using azaindole instead indanone. Isomers with a different position of the nitrogen is also acceptable.

<4> Farmaco, Ed.Sci 1985, 40, 979-86;

<5> Farmaco, Ed. Sci 1979, 34, 72-80;

<6> Obtained by analogy with <5> using azaindole instead indanone. Other nitrogen isomers position is also acceptable.

<7> Rend Accad Sci Fis Mat, Naples 1983, 50, 353-6;

<8> Tetrahedron 1991, 47, 6851-6886

<9> Obtained by analogy with the above using azaindole instead indanone. Other isomers of the position of the nitrogen atom is also acceptable; see Heterocycles 1991, 32, 41-72.

<10> J Med Chem 1975, 18, 1-8 and Yakugaku Zasshi 1976, 96, 99-109;

<11> Obtained by analogy with <10>;

<12> J Org Chem 1986, 51, 2011-21;

<13> Heterocycles 1988, 27, 2643-50.

Recovery of anthraquinones in antrona can be performed with the use of thiosulfate on the Sabbath. -7:

Synthesis of

The compounds of formula I where R is-CH2-(Het-2), and Het-1=Het-2, can be obtained from the corresponding "core", as shown in scheme I.

< / BR>
Base applicable for the formation of the anion include, but are not limited to, sodium hydroxide or potassium hydroxide, sodium amide, diisopropylamide lithium (LDA), sodium hydride, tert-butyl potassium, sodium alcoholate, potassium alcoholate, potassium hydride, 2,2,6,6 - tetramethylpiperidine lithium utility, second-utility, tert - utility, hexamethyldisilazide lithium, sodium or potassium. The reaction can be carried out in an aprotic solvent, typically an ether, such as (but not limited to, tetrahydrofuran (THF), dioxane, glyme, diglyme or diethyl ether (Et2O); or benzene or toluene.

Furthermore, the reaction can be carried out in dimethylformamide (DMF) or dimethylacetamide (DMAC). However, if the reagents are soluble in non-polar solvent, the reaction can be carried out in a hydrocarbon solvent, such as hexane, heptane, cyclohexane, methylcyclohexane, benzene or toluene.

If the reagents are compatible with water, the reaction may be conducted in a solvent system containing water and any of the above organic solvents.

Depending on the strength of what about the connection, such as (II) bis-alkiliruya, giving (Ia) by reaction (II) under conditions of phase transfer catalysis (IFC). Suspension methylene-active compounds (II) in a mixture of 50% caustic soda and toluene containing catalytic amount of a catalyst IFC, such as tetrabutylammonium or bromide process, adding dropwise, for example, 4-picolylamine hydrochloride (2.2 equivalent), while receiving Ia.

The compounds of formula I where R is-CH2-(Het-2) or Het-1 = Het-2, can be synthesized by the equation shown in scheme II.

< / BR>
< / BR>
Methyl compound II in the aldol condensation with the appropriate substituted aldehyde pyridine or pyrimidine series gives (III), which can be restored by detribalized, Pd/c and formic acid, and hydrogen in the presence of dissolved metal, such as zinc in acetic acid gives (IV). The intermediate compound (IV) is dissolved in dry THF, cooled to 0oC, treated with 1.1 equivalent hexamethyldisilazide sodium or potassium and the crown ether is mixed 10-60 min in the atmosphere of inert gas thereto dropwise added a solution of the alkylating agent R-X in dry THF, where X is a leaving group such as halogen, until, until there is no longer the original connection (chromatography). The reaction mixture pariveda in vacuum and the residue is extracted from the water and methylene chloride. The organic layer is washed with water and brine, dried with anhydrous magnesium sulfate, filtered and pariveda in vacuum. Depending on the purity of the compounds of the present invention can be in the form of oil, resin and amorphous precipitate; or precrystallization from the appropriate solvent system; or further purified by chromatography, sublimation or distillation. The compounds may also exist in the form of free bases or as salts of the acids formed by adding a pharmaceutically suitable acid. In addition, the compounds of formula (I) can be in the form of racemates, mixtures of diastereoisomers or optically active isomers.

Further, the compounds of this invention where X is not equal to H, can be synthesized and incorporated into the compounds of the present invention with the use of the intermediate compounds represented below. These connections being handled by the methods described above or other methods used in organic synthesis, into the compounds of formula (I).

Source substituted pyridyloxy substituted methylpyridine presented in scheme III.

< / BR>
Reagents:

a) NaNO2, HX, CuX2b) H2Pd/c or SnCl2; (c) H2O2; H2SO4; d) HNO3H2SO4; (e) CF3I, Cu, HMPT; (f) (1) MCPBA, 2) KCN.

In addition, if receiving a substituted and unsubstituted glomerulonephritides of the present invention is not described in the literature, they were synthesized from the source or intermediate compounds according to scheme IV.

< / BR>
Reagents:

a) CBr4, PPh3b) NCS or NBS; (c) NaBH4; MeOH; (d) (1) SOCl2, 2) MeOH; (e) PCC, f) NaBH4g) I2/DMSO; (h) DIBAL-H.

The compounds of formula I where Het-1 and Het-2 - substituted pyrimidines, derived from substituted pyrimidines, industrially produced or described in the literature, such as those presented in table. IB.

Other compounds of formula I can be obtained by transformations of functional groups of the compounds presented in this invention, using standard methods of organic synthesis. Some examples of such transformations shown in scheme V.

< / BR>
A number of other compounds of the present invention can be synthesized similarly by using conventional methods of organic synthesis, for example, the transformation of R2, R3the corresponding acid (CO2H); or an alcohol (OH) can be further transformed into a simple ether (OR5or in "reverse ester" (O-COR5). In this case, the ester by saponification converted to the acid (CO2H), which can be restored to alcohol. Or ester can be directly restored to alcohol. Another way of turning into a "reverse ester" (-OC(=O)R5may be done on the basis of a complex ether, which is reduced to alcohol, then alleroed halogenerator or anhydride or alcohol condensed with an acid in the presence of N,N-dicyclohexylcarbodiimide, diaminotoluene or any other dehydrating agent, known in preparative organic chemistry. The nitrile is converted to the corresponding amide by the method proposed by Nellera, Org Syn Coll. Vol. 11: p 586. The same amide can be obtained from the corresponding complex ester hydrolysis, activation of carboxyl and reaction with ammonia. Replacement of ammonia, primary and secondary amines can get other amides of the present invention. The restoration of the amides are obtained the corresponding amines.

The compounds of this invention and their synthesis is further illustrated by the following examples. All temperatures are given in degrees CE is ml; 1,0 M Et2O) and cooled to 0oC. From the dropping funnel within 30 minutes, add a solution of 2-titillate (75 ml; 1.0 M in THF). A two-phase system is stirred for further one hour, then poured through a tube to a solution of methyl 2-iodobenzoate (13,1, r, 0.05 mol) and tetrakis(triphenylphosphine)-palladium (2.9 g, 0,0025 mol) in THF (120 ml). The reaction is allowed to mix at room temperature over night. Add 500 ml of water and the resulting emulsion was filtered through celite. The organic layer is separated and the aqueous is extracted with EtOAc (h ml 2x250 ml). The combined EtOAc extracts washed with brine, dried with Na2SO4, filtered, then dried MgSO4. The resulting subsequent filtration and evaporation the crude ether immediately omelet KOH (5.61 g, 5.10 mol), water (16.5 ml) and EtOH (65 ml) at boiling for one hour. The reaction mixture is evaporated at 30oC, diluted with water (200 ml), washed with EtOAc(3x50 ml), Et2O and filtered through celite. The aqueous solution acidified with conc. HCl and extracted with EtOAc (g ml). The organic layer was washed with brine, dried with MgSO4, filtered, evaporated and distilled azeotropic distillation with benzene. The resulting brown oil is cooled during the night and get acid (10 g) with a quantitative yield. Untreated is 3 mol) (catalyst DMF). After stirring for 1 hour the reaction mixture is evaporated in vacuum. The residue is dissolved in benzene (113 ml) at 4oC and add 5.7 ml (0.053 mol) of tin tetrachloride. Stirred for 15 min (or until completion of the reaction, what is judged by TLC), diluted with water and 1N HCl until smooth and extracted with Et2O. the Ether extracts are treated in the usual way and the crude product is purified on silica gel (eluent hexane/ether = 5: 1), giving depicted product (5.8 g) with a yield of 58%; melting point 99-100oC. Variations of this method include the use of 2-thiophene-trimethylurea instead of 2-titillate and thionyl chloride instead of oxalicacid for the formation of carboxylic acids.

Method 2

< / BR>
The solution of the original ketone in method 1 (1.28 g) and heat at 160oC diethylene glycol, add hydrazine (13,9 ml) and raise the temperature to 200oC for 40 minutes After cooling and dilution with water and subsequent extraction with ether quantitative yield was highlighted brown solid; melting point 62-64oC.

Getting 2-fluoro-4-chloromethylpyridine

In odnogolosy round bottom flask 1000 ml, equipped with a magnetic stirrer, reflux condenser and agrevate is soil (1.5 g). The reaction mixture is boiled for 6 hours, add 1.5 g of benzoyl peroxide and warm until morning. Monitoring by TLC (1:1 toluene/methylene chloride). (At high concentrations produce more dichloropropyl). The reaction mixture is cooled to or below room temperature, filtered through celite and the precipitate washed yet CCl4. The organic solution was washed with a saturated solution of sodium thiosulfate (Na2S2O3), a saturated solution of NaHCO3, water and brine. Dried with magnesium sulfate, the filtrate evaporated, receiving oil; determine the ratio of products by NMR. This crude mixture of products can be used for the next stage without further purification (of the two portions was obtained 32,94 g of a mixture of products containing 60% of the desired product, 16% dichlorsilane and 24% of the initial connection).

Example 1.

< / BR>
4-(4-Pyridinylmethyl)-4H-indeno[1,2-B]thiophene

The solution methylene compounds (method 2) (1,87 g to 0.011 mol) results in the interaction with the 4-pyridinecarboxamide (1.05 ml, 0.011 mol), KOtBu-t (1.35 g 0,012 mol) in THF (40 ml) for 5 minutes. The reaction mixture was diluted with a saturated solution of NH4Cl (100 ml) and extracted with CH2Cl2(G ml). United CH2C2 crude red oil reacts with zinc (11.0 g) in ACOH (50 ml) at boiling. Conventional neutralization and extraction get a named connection in the form of solid substances with 75% yield; melting point 91-93oC (hexane/ethyl acetate).

Method 3

General method for the alkylation

< / BR>
To a solution of example 1 (1 equiv.) and 18-crown-6 (0.1 equiv.) in THF (50 ml, 2 mmol) at 0oC add hexamethyldisilazide potassium (1 equiv.) and stirred for 45 minutes Add the electrophile (R-Br) [always bromide] (1 equiv.) in THF (10 ml) and left overnight at room temperature. The reaction mixture was diluted with CHCl3/NH4Clthe feast upon.(50 ml each). Extracted with CHCl3United CHCl3the extract was washed with brine, dried with MgSO4, filtered and evaporated. The crude residue purified liquid chromatography on a column of silica gel (eluent MeOH/CHCl3), obtaining the free base. Characteristics usually are for hydrochloridw or hydrobromides; however, in some cases, the free base is preferable.

Example 2

< / BR>
3-[4-(4-Pyridinylmethyl)-4H-indeno[1,2-B] thiophene-4 - ylmethyl-benzonitrile hydrobromide hydrate

Based on 3-cyanobenzaldehyde (method 3) this compound (C25H18N2S HBr H2O) get off exit 92%; the temperature of the hydrobromide hydrate

The above compound is obtained from 5-bangaloreindia by method 3 to yield 33%; melting point 136oC (decomp). (C22H20N2S HBr H2O).

Example 4

< / BR>
Ethyl ester of 4-(4-pyridinylmethyl)-4H-indeno[1,2-b] thiophene-4-acetic acid hydrochloride

The above-mentioned compound (C21H19N2OS HCl) is obtained from ethyl ether 2-bromocatechol acid according to method 3 with 75% yield; melting point 183-187oC.

Example 5

< / BR>
4-(4-Pyridinylmethyl)-4H-indeno[1,2-B]thiophene-4-butanolate hydrochloride

The above compound (C23H23N2S HCl) is obtained from 4-bromoethylamine by method 3 to yield 69%; melting point 186 to 190oC.

Example 6.

< / BR>
4-(4-Pyridinylmethyl)-4H-indeno[1,2-B] thiophene-4-pentanone hydrochloride hydrate

Using the method described Noller, Org. Syn Coll, Vol. 11, p. 586, nitrile from example 3 is transformed into the corresponding amide (C22H22N2OS HCl H2O) to yield 65%; melting point 187-190oC.

Example 7

< / BR>
2-Fluoro-4-[4-(4-pyridinylmethyl)-4H-indeno[1,2-B]thienylmethyl]-pyridine

The above compound is obtained from 2-fluoro-4-picolylamine on methods is[4-(phenyl)-4H-indeno[1,2-B]thiophene-4-ylmethyl]-pyridine

By using benzylbromide according to method 3 receives the above-mentioned compound (C24H19NS) with a yield of 20%; melting point 88-92oC.

Example 9

< / BR>
4-(4-Pyridinylmethyl)-4H-indeno[1,2-B]thiophene-4-butanol

The above connection get alkaline hydrolysis of the product from example 5 in the form of an oil in quantitative yield; C21H21NOS, M. C. 335,45 mass spectrum 336 (M+1).

Method 4

< / BR>
For obtaining this compound was applied method is similar to method 1, but instead of methyl-2-iodobenzoate taken methyl - 2-bromonicotinate.

Example 10

< / BR>
4-(4-Pyridinylmethyl)-4H-thieno[2',3':3,4] cyclopent[1,2-B] pyridine

The introduction of the product from method 4 in methods 2 and 3 receive the above-mentioned compound (C16H12N2S) with the release of 45%; melting point 178-181oC.

Example 11

< / BR>
4-[(2-Fluoro-4-pyridinyl)methyl] -4-(4-pyridinylmethyl)-4H-thieno [3',2':4,5] cyclopent[1,2-b]pyridine

Taking the original product from example 10 and using 2-fluoro-4-picolylamine according to method 3 receives the above-mentioned compound (C22H16FN3S) with exit 92%; melting point 192-193oC.

Example 12

< / BR>
This monobike the who synthesized according to the method, proposed Mazzola, V. J.,et al.; J. Org.Chem, (1967) 32: 486.

Example 13

< / BR>
9-(4-Pyridinylmethyl)9-((2-fluoro-4-pyridinylmethyl)-9H - pyrrolo[1,2-A]indol

The above compound is obtained according to the method used for example 11, example 12, is taken as the source.

Example 14

< / BR>
1,4-Dihydro-1-(phenylmethyl)-4,4-bis(4-pyridinylmethyl) indeno[1,2-C] pyrazole

To a mixture of KOBu-tert. (1.44 g, 12.8 mmol) in 20 ml of DMSO/Et2O (1:1) with stirring in an atmosphere of dry nitrogen and 10oC was added dropwise a solution of N-benzylpyridine (6.1 mmol) in 10 ml of DMSO. Then to the mixture are added dropwise over 30 min a solution of 4-picolylamine (free base) (14.6 mmol) in 30 ml Et2O. the Mixture is stirred at room temperature for 16 h and poured into 100 ml of water. Extracted with 100 ml of Et2O. the Extract was washed with water and brine, dried with MgSO4, filtered and evaporated in vacuum, get 1.8 g of product as a foam. Foam chromatographic on silica gel (CH2Cl2- eluent). The appropriate fractions are combined and evaporated in vacuum. The residue is recrystallized from a mixture of EtOAc/hexane. Get above the connection with the yield 74%; melting point 154-155oC; Calculated for C29H24N4in %: C 81.28; H, 5.65; N ricinulei)-pyrazolo[4,3-B] pyrrolizine

To a solution of 2,4-dihydro-2-phenylpyrazole[4,3-b] pyrrolizine (6.1 mmol) and 18-crown-6 (6.1 mmol) in tetrahydrofuran at 0oadd hexamethyldisilazide potassium, then 4-picolylamine (14.6 mmol, free base in toluene) and the reaction left overnight at room temperature. Conventional extraction and purification receive the above compound in the form of a solid substance with a yield of 4%; melting point 169-170oC; Analysis: calculated for C26H21N5in %; C, 77.40; H, 5.25; N, 17.36. Found,%: C 77.01; H, 5.12; N 17,18. Mass spectrum m/e 404 (M+1).

In table. 1 shows the substances obtained by the methods illustrated in the above examples.

Using the methods illustrated by the above examples, have the following connections.

Example 61

< / BR>
9,9-Bis((2-fluoro-4-pyridinyl)methyl)-2-hydroxy-9H-fluoren

Melting point 200-201oC. Mass spectrum (NH3/Cl) m/e 401(M+H);

Analysis: Calculated for C25H18F2N2O0.25H2O in %: C, 74.15; H, 4.61; N 6,92; F 9.38. Found %: C, 73.91; H, 5.10; N 6,39; F 8.94.

Yield 49%.

Example 62

< / BR>
5-(2-fluoro-4-pyridinyl)methyl)-5-(4-pyridinylmethyl)-5H-indeno [1.2-b] pyridine

Melting point 164-5oC. Mass spec C, 77.63; H 4.85; N 11,20.

Yield 22%.

Example 63.

< / BR>
5-(2-Fluoro-4-pyridinyl)methyl)-5-(4-pyridinylmethyl)-5H - indeno[2.1-b] pyridine

Melting point 163-4oC. Mass spectrum (NH3/Cl) m/e 368(M+H);

Analysis: Calculated for C24H18FN3in %: C 78.44; H, 4.94; N, 11.11 IS

Found %: C, 78.10; H, 4.78; N 11,36.

Yield 22%.

Example 64

< / BR>
10,10-Bis((2-fluoro-4-pyridinyl)methyl)-9(10H)-anthracene

Melting point 156-157oC. Mass spectrum (NH3/Cl) m/e 413 (M+H);

Analysis: Calculated for C26H18F2N2O 0.25 H2O in %: C 75.72; H, 4.40; N 6,70; F 9.21. Found %: C, 75.54; H, 4.38; N 6,76; F 9.27%.

Yield 44%.

Example 65

< / BR>
9-((2-Fluoro-4-pyridinyl)methyl)-9-(4-pyridinylmethyl)-9H-xanthene

Melting point 180-1oC. Mass spectrum (NH3-Cl) m/e 383(M+H);

Analysis: Calculated for C25H19FN2O 0.25 H2O in %: C 77.60; H 5.08; N 7,24. Found,%: C 77.94; H, 4.97; N 7,25.

Output 3%.

Example 66

< / BR>
9-((2-Fluoro-4-pyridinyl)methyl-9-(4-pyridinylmethyl)-9H-xanthene

Melting point 199-201oC. Mass spectrum (NH3-Cl) m/e 395(M+H);

Analysis: Calculated for C26H19FN2O in %: C 79.17; H, 4.86; N 7,10. Found %: c, 78.84; H, 4.80; N 7,13.

Exit 129oC. Mass spectrum (NH3-Cl) m/e 402(M+H);

Analysis: Calculated for C24H17N3F2O in %: C, 71.81; H, 4.27; N 10,47. Found %: C, 71.50; H, 4.25; N 10,28.

Output 10%.

Example 68

< / BR>
5, 5-Bis((2-fluoro-4-pyridinyl)methyl)-5H-indeno[1,2-b]pyridine

Melting point 137-140oC. Mass spectrum (Cl/NH3) m/e 386(M+H);

Analysis: Calculated for C24H17N3F2in %: C, 74.79; H, 4.45; N 10,90; F 9.86. Found %: C, 74.39; H, 4.51; N 10,91; F 9.91.

Yield 46%.

Example 69

< / BR>
4,4-Bis((2-fluoro-4-pyridinyl)methyl)-4H-thieno[3',2':4,5]cyclopent [1,2-b] pyridine.

Melting point 157-9oC. Mass spectrum (Cl/NH3) m/e 392(M+H);

Analysis: Calculated for C22H15F2N3S in %: C, 67.50; H 10.73; S 8,19. Found %: C, 67.11; H, 3.88; N 10,69; S, 8.34.

Yield 55%.

Example 70.

< / BR>
9-((2-Fluoro-4-pyridinyl)methyl)-9-(4-pyridinylmethyl)-4-asasantin

Melting point 206-208oC. Mass spectrum (NH3-Cl) m/e 384(M+H);

Analysis: Calculated for C24H18FN3O0,25H2O in %: C, 74.31; H, 4.81; N 10,83. Found %: C, 74.17; H, 4.69; N 10,67%.

Yield 12%.

Example 71

< / BR>
9,9-Bis((2-fluoro-4-pyridinyl)methyl)-2-methoxyflurane

Melting point 143-146oC. Mass-speno in %: C, 75.33; H 4.78; N 6,67.

Yield 54%.

Example 72

< / BR>
9,9-Bis((2-fluoro-4-pyridinyl)methyl-7-methoxy-4-asasantin

Melting point 196-197oC. Mass spectrum (NH3-Cl) m/e 432(M+H);

Analysis: Calculated for C25H19F2N3O2in %: C, 69.60; H, 4.44; N 9,74. Found: C, 69.55; H, 4.37; N 9,74.

Yield 8%.

Example 73

< / BR>
10,10-Bis((2-fluoro-4-pyridinyl)methyl)-3-hydroxy-9(10H)-anthracene

Melting point 219-221oC. Mass spectrum (NH3-Cl) m/e 429(M+H);

Analysis: Calculated for C26H18F2N2O2in %: C at 72.89; H, 4.23; N 6,54. Found %: C, 72.97; H, 4.19; N, 6.48 in.

Yield 26%.

Example 74

< / BR>
10,10-Bis((2-fluoro-4-pyridinyl)methyl)-2,6-dimethoxy-9(10H)-anthracene

Melting point 151-2oC. Mass spectrum (Cl/NH3) m/e 473(M+H);

Analysis: Calculated for C28H22F2N2O2in %: C, 71.17; H, 4.69; N To 5.93; F 8.04. Found %: C, 70.76; H, 4.86; N 5,90; F 7.91.

Yield 12%.

Example 75

< / BR>
9,9-Bis((2-fluoro-4-pyridinyl)methyl)-cyclopent[1.2-b:3,4-b']dipyridine

Melting point 134-5oC. Mass spectrum (Cl/NH3) m/e 387(M+H);

Analysis: Calculated for C23H16F2N4in %: C, 71.49; H, 4.17; N 14,50; F 9.83. Found %: C, 71.08; H, 4.00; N 14,29; F 9.96.


Melting point 213-5oC. Mass spectrum (Cl/NH3) m/e 463(M+H);

Analysis: Calculated for C29H20F2N4in %: C, 75.31; H, 4.36; N 12,11; F 8.22. Found %: C, 74.98; H, 4.31; N 12,01; F 8.36.

A 30% yield.

Example 77

< / BR>
10,10-Bis((2-fluoro-4-pyridinyl)methyl)-3-methoxy-9-(10H)-anthracene

Melting point 155-7oC. Mass spectrum (Cl/NH3) m/e 443(M+H);

Analysis: Calculated for C27H20F2N2O2in %: C, 73.29; H, 4.56; N 6,33; F 8.59%. Found %: C, 72.90; H, 4.54; N 6,24; F 8.55%.

The output is 27%.

Example 78

< / BR>
9,9-Bis((2-fluoro-4-pyridinyl)methyl)-9H-indeno-[2,1-b]pyridine

Melting point 128-130oC. Mass spectrum (Cl/NH3) m/e 386(M+H);

Analysis: Calculated for C24H17F2N3in %: C, 74.79; H, 4.45; N 10,90; F 9.86. Found %: C, 74.50; H, 4.24; N 10,75; F 9.87.

Yield 35%.

Example 79

< / BR>
5,5-Bis((2-fluoro-4-pyridinyl)methyl)-7-(ethinyl)-5H-indeno- [2,2-b]pyridine

Melting point 139-40oC. Mass spectrum (Cl/NH3) m/e 410(M+H);

Analysis: Calculated for C26H17F2N3in %: C, 76.27; H, 4.19; N 10,26; F 9.28. Found %: C, 75.95; H, 4.14; N To 10.09; F 9.18.

Yield 43%.

Example 80

< / BR>
9,9-Bis((2-Fluoro-4-pyridinyl)methyl)-9H-indeno-[1,2-b]pyrazin

The is F2N2in %: C, 71.49; H, 4.17; N 14,50; F 9.83. Found %: C, 71.28; H, 4.12; N 14,47; F 9.73.

Yield 68%.

Example 81

< / BR>
5,5-Bis((2-fluoro-4-pyridinyl)methyl)-5H-indeno-[1,2-d]pyrimidine

Melting point 171-4oC. Mass spectrum (Cl/NH3) m/e 387(M+H);

Analysis: Calculated for C23H16F2N4in %: C, 71.49; H, 4.17; N 14,50; F 9.83. Found %: C, 71.30; H, 4.09; N 14,40; F 9.96.

Yield 64%.

Example 82

< / BR>
5,5-Bis((2-bromo-4-pyridinyl)methyl)-5H-indeno-[1,2-b]pyridine

Melting point 190oC. Mass spectrum (Cl/NH3) m/e 508(M+H);

Analysis: Calculated for C24H17Br2N3in %: C, 56.83; H, 3.38; N 8,28; Br 31.51. Found %: C, 57.20; H, 3.43; N 8,20; Br 31.12%.

Yield 63%.

Example 83

< / BR>
9,9-Bis((2-fluoro-4-pyridinyl)methyl-2-((N-methylamino)methyl)fluoren

Melting point 130-4oC. Mass spectrum (Cl/NH3) m/e 428(M+H);

Yield 92%.

Example 84

< / BR>
9,9-Bis((2-fluoro-4-pyridinyl)methyl)-2-((N-methyl-N - methoxycarbonylamino)methyl)fluoren

Oil. Mass spectrum (Cl/NH3) m/e 486 (M+H);

Analysis: Calculated for C29H25F2N3O20.5 H2O in %: C, 70.43; H, 5.30; N 8,50. Found %: C, 70.65; H, 5.08; N 8,53.

Yield 85%.

Example 85

< / BR>
9,9-Bis((2-fluoro-4-p is3) m/e 470(M+H);

Analysis: Calculated for C29H25F2N3O 0,25 H2O in %: C, 73.48; H, 5.42; N 8,86. Found %: C, 73.30; H, 5.34; N 8,67.

Yield 79%.

Example 86

< / BR>
10.10-Bis(2-bromo-4-pyridinyl)methyl)-9(10H)-anthracene

Melting point 182-3oC. Mass spectrum (Cl/NH3) m/e 535(M+H);

Analysis: Calculated for C26H18Br2N2O in %: C, 58.45; H, 3.40; N 5,24; Br 29.91. Found: C, 58.69; H, 3.26; N 5,22; Br 29.68.

Yield 54%.

Example 87

< / BR>
5,5-Bis((2-chloro-4-pyridinyl)methyl)-5H-indeno-[1,2-b]pyridine

Melting point 188-90oC. Mass spectrum (Cl/NH3) m/e 418(M+H);

Analysis: Calculated for C24H17Cl2N3in %: C, 68.91; H, 4.10; N 10,04; 16.95 Cl. Found %: C, 68.70; H, 3.99; N 9,95; Cl 16.76.

Yield 48%.

Example 88

< / BR>
5,5-Bis((2-fluoro-4-pyridinyl)methyl)-2-methyl-5H-indeno-[1, 2 - d] pyrimidine

Melting point 114-5oC. Mass spectrum (Cl/NH3) m/e 401(M+H);

Analysis: Calculated for C24H18F2N4in %: C, 71.99; H, 4.53; N 13,99; F 9.49. Found %: C, 71.88; H, 4.52; N-13; F 9.87.

Yield 31%.

Example 89

< / BR>
5,5-Bis((2-methoxy-4-pyridinyl)methyl)-5H-indeno-[1,2-b]pyridine

Melting point 138-40oC. Mass spectrum (Cl/NH3) m/e 410(M+H);

the>The yield is 50%.

Example 90

< / BR>
5,5-Bis((2-fluoro-4-pyridinyl)methyl)-7-(ethyl)-5H-indeno [1,2-b]pyridine

Oil. Mass spectrum (Cl/NH3) m/e 414(M+H);

Analysis: Calculated for C26H21F2N3in %: C, 75.53; H, 5.12; N, 10,16. Found,%: C 75; H, 5.36; N 9,95%.

Output 90%.

Example 91.

< / BR>
5,5-Bis((2-chloro-6-methyl-4-pyridinyl)methyl)-5H-indeno[1,2-b]pyridine

Melting point 159-60oC. Mass spectrum (Cl/NH3) m/e 446(M+H);

Analysis: Calculated for C26H21Cl2N3in %: C, 69.96; H, 4.68; N 9,41, Cl 15.88. Found,%: C 70,00; H, 4.74; N 9,31, Cl 15.82.

Exit 14%.

Example 92

< / BR>
5,5-Bis((2-methyl-4-pyridinyl)methyl)-5H-indeno[1,2-b]pyridine

Melting point 177-9oC. Mass spectrum (Cl/NH3) m/e 378(M+H);

Analysis: Calculated for C26H23N3in %: C, 82.73; H 6,14; N 11,13 Found %: C 82,54; H, 6.12; N 11,10.

Output 90%.

Example 93

< / BR>
5,5-Bis((2-fluoro-4-pyridinyl)methyl)-7-(iodine)-5H-indeno[1,2-b]pyridine

Melting point 158-61oC. Mass spectrum (Cl/NH3) m/e 512(M+H);

Analysis: Calculated for C24H16F2IN3in %: C, 56.38; H, 3.15; F 7.43; N by 8.22. Found,%: C 56,83; H, 3.17; F 7.58; N, 8.1% OF

The output 25%.

Example 94

< / BR>
9,9-Bis((2-fluoro-4-pyridinyl)Mr (NH3/Cl) m/e 443(M+H);

Analysis: Calculated for C27H20F2N2O2in %: C, 73.29; H, 4.56; N 6,33; F 8,59. Found %: C, 72.99; H, 4.56; N 6,24; F 8,59.

Yield 49%.

Example 95

< / BR>
9-((2-Fluoro-4-pyridinyl)methyl)-9-(4-pyridinylmethyl)-9H-fluoren - 1-carboxylic acid methyl ester, racemate

Melting point 144-6oC. Mass spectrum (NH3/Cl) m/e 425(M+H);

Analysis: Calculated for C27H21FN2O20,25 H2O in %: C, 75.60; H, 5.05; N 6,53; F 4.43. Found,%: C 75,69; H, 4.85; N, 6.42 Per; F 4.26.

Yield 55%.

Example 96

< / BR>
9,9-Bis((2-fluoro-4-pyridinyl)methyl)-9H-fluoren-1-amine

Melting point 182-4oC. Mass spectrum (NH3/Cl) m/e 400(M+H);

Analysis: Calculated for C25H19F2N30.25 H2O in %: C at 74.34; H, 4.87; N The 10.40; F 9,41. Found,%: C 74,43; H, 4.68; N accounted for 10.39; F 9.39.

The output 25%.

Example 97

< / BR>
5,5-Bis((2-fluoro-4-pyridinyl)methyl)-5H-cyclopent[1,2-b:3.4-b'] dipyridine

Melting point 239-241oC. Mass spectrum (NH3/Cl) m/e 387(M+H);

Analysis: Calculated for C23H16F2N40,25 H2O in %: C, 70.67; H, 4.25; N 14,33; F 9.72. Found,%: C 70,95; H, 4.05; N, 14.24 From; F 9.37.

Yield 44%.

Example 98

< / BR>
5-((2-Fluoro-4-pyridinyl)methyl)-5-(4-pyridinylmethyl) - the melting 181-9oC. Mass spectrum (NH3-Cl) m/e 427(M+H);

Analysis: Calculated for C25H19FN4O22HClH2O in %: C, 58.04; H, 4.48; N 10,83; Cl 13.70. Found,%: C 58,45; H, 4.30; N 10,76; Cl 13,73.

Yield 79%.

Example 99

< / BR>
5-((2-Fluoro-4-pyridinyl)methyl)-5-(4-pyridinylmethyl)-5H - cyclopent[2,1-b: 3.4-b'] dipyridine-4-carboxylic acid methyl ester hydrochloride, (-)-isomer

The melting point is hygroscopic. []2D5= -14.95o(C=0.6, CHCl3). Mass spectrum (NH3-Cl) m/e 427(M+H);

Analysis: Calculated for C25H19FN4O2HCl0,5H2O in %: C, 63.43; H, 4.49; N, 11.87 Per; Cl 7,51. Found %: C, 63.47 per; H, 4.06; N 11,73; Cl 7,26.

The yield was 73%.

Example 100

< / BR>
5-((2-Fluoro-4-pyridinyl)methyl)-5-(4-pyridinylmethyl)-5H-cyclopent [2,1-b: 3.4-b'] dipyridine-4-carboxylic acid methyl ester, hydrochloride. (+)-isomer

The melting point is hygroscopic. []2D5= +14.95o(C=0.6, CHCl3). Mass spectrum (NH3-Cl) m/e 427(M+H);

Analysis: Calculated for C25H19FN4O2HCl0,5H2O in %: C, 63.63; H, 4.49; N, 11.87 Per; Cl 7.51. Found %: C, 63.60; H, 4.03; N 11,80; Cl 7.01.

Output 90%.

Example 101

< / BR>
5-((2-Fluoro-4-pyridinyl)methyl)-5-(4-pyridinylmethyl)-5H-cyclopent [2.1-b: 3.4-b'] dipyridine-4-Tr (NH3-Cl) m/e 387(M+H);

Analysis: Calculated for C23H16N4F20,25 H2O in %: C, 70.67; H, 4.25; N 14,33; F 9.72. Found,%: C 70,81; H, 4.08; N 14,26; F 9.70.

Yield 88%.

Example 102

< / BR>
5-((6-fluoro-2-pyridinyl)methyl)-5-(4-pyridinylmethyl)-5H - cyclopent[2,1-b: 3.4-b']dipyridine

Melting point 180-182oC. Mass spectrum (NH3-Cl] m/e 369(M+H);

Analysis: Calculated for C23H17N3F 0,25 H2O in %: C, 74.08; H, 4.73; N 15,02; F 5.09. Found,%: C 73,94; H, 4.53; N 14,93; F 4.84.

Yield 81%.

Example 103

< / BR>
5,5-Bis((6-fluoro-2-pyridinyl)methyl)-5H-cyclopent[2,1-b:3.4-b] piperidin

Melting point 221-225oC. Mass spectrum (NH3-Cl) m/e 387(M+H);

Analysis: Calculated for C23H16N4F20,33 H2O in %: C, 70.40; H, 4.28; N Of 14.28; F 9.68. Found,%: C 70,71; H, 4.04; N 14,30; F 9.53.

Yield 81%.

Example 104

< / BR>
5,5-Bis((3-methyl-4-pyridinyl)methyl)-5H-cyclopent[2,1-b: 3.4-b'] dipyridine, trihydrochloride

Melting point 301oC(decomp.). Mass spectrum (NH3-Cl) m/e 379(M+H);

Analysis: Calculated for C25H22N43HCl 2H2O in %: C, 57.32; H, 5.58; N 10,69; Cl 20.30. Found,%: C 57,68; H, 5.41; N 9,96; Cl 20.76.

A 71% yield.

Example 105

< / BR>
2-Fluoro-4-((9-pyridinylmethyl)-9H-fluoren-9->Analysis: Calculated for C25H21N2F1,2HCl 0.5 H2O in %: C, 71.63; H, 5.10; N 6,68; F 4.53; Cl 10.15. Found,%: C 71,40; H, 4.86; N 6,54; F 4.14; Cl 10.55.

Exit 13%.

Example 106

< / BR>
5-((2-Fluoro-4-pyridinyl)methyl)-5-(4-pyridinylmethyl)-5H-cyclopent [2,1-b: 3.4-b']dipyridine

Melting point 228-230oC. Mass spectrum (Cl/NH3) m/e 369(M+H);

Analysis: Calculated for C23H17FN40,25 H2O in %: C, 74.08; H, 4.73; N 15,02. Found,%: C sampled at 74.25; H, 4.53; N 15,11%.

Yield 69%.

Example 107

< / BR>
5,5-Bis(2-herperidin-4-ylmethyl)thioxanthene-10,10-dioxide

The mixture thioxanthene-10,10-dioxide (1,00 g, 4.3 mmol), 4 - chloromethyl-2-herperidin (1.45 g, 9.6 mmol), benzyltriethylammonium (90 mg, 0.4 mmol) and 50% aqueous NaOH solution (2.5 ml) in toluene (60 ml) was stirred at 50-60oC (temperature in the reaction flask) 18 hours After cooling to room temperature the reaction mixture was poured into water (100 ml) and extracted three times with ethyl acetate. The combined organic extracts dried over MgSO4, filtered and evaporated in vacuum. Chromatography on a column (ether:hexane=1:1) receive the above named product (0.68 g, Rf0.2): melting point > 200oC.

1H NMR (300 MHz, CDCl3): 8,3 (d, 2H, J=7), 7.9 (d, 2H, J=7), 7.6 (t, 2H, J= 7), 7.45 (>O2S: 449,1135 (M+H): Found: 449.1150

Example 108

< / BR>
5,5-Bis- (2-herperidin-4-ylmethyl) thioxanthen-10-oxide

The mixture thioxanthen-10-oxide (1.00 g, 4.7 mmol), 4-chloromethyl-2-herperidin (1.73 g, 10.3 mmol),

benzyltriethylammonium (90 mg, 0.4 mmol) and 50% aqueous NaOH solution (2.5 mol) in 60 ml of toluene was stirred at 50-60oC (the temperature inside the flask) 18 hours after being cooled to room temperature, the reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The combined organic extracts dried over MgSO4, filtered and evaporated in vacuum. Chromatography on a column (ether: hexane (III) and subsequent preparative TLC receive the above named product (mixed with 5,5-bis-(2-herperidin-4-ylmethyl)-thioxanthene-10,10-dioxide).

(0.12 g, Rf0.1): melting point > 200oC.1H NMR (300 MHz, CDCl3): 8,3 (d, 1H, J=7), 8.2 (d, 2H, J=7), 7.9 (d, 1H, J=7), 7.85 (d, 2H, J=7), 7.6 (t, 2H, J=7), 7.5 (t, 1H, J=7), 7.45 (t, 1H, J=7), 7.35 (t, 2H, J= 7), 7.25 (d, 1H, J=7), 7.15 (d, 2H, J=7), 6.45-6.35 (m, 2H), 6.2 (s,2H), 3.9 (s,2H); 3.8 (s, 2H), 3.15 in (s, 2H), Cl - mass spectrometry: 433(M+H).

Example 109

< / BR>
2,6-Dimethyl-4-((9-(4-pyridinylmethyl)-9H-fluoren-9-yl)methyl) pyridine, dihydrochloride

Melting point 180oC. Mass spectrum (Cl/NH3) m/e 372(M+H for the free base);

is yhod 91% (for free base).

Example 110

< / BR>
5-((2,6-Dimethyl-4-pyridinyl)methyl)-5-(4-pyridinylmethyl) -5H-cyclopent[2,1-b:3.4-b']dipyridine

Melting point >240oC. Mass spectrum (Cl/NH3) m/e 378(M+H);

Analysis: Calculated for C25H22N40,25 H2O in %: C, 78.40; H, 5.92; N 14,63. Found,%: C 78,05; H, 5.58; N 14,32.

The yield was 73%.

Example 111

< / BR>
5,5-Bis((2,6-dimethyl-4-pyridinyl)methyl)-5H-cyclopent[2,1-b: 3.4-b'] dipyridine, E-2-fumarate

Melting point 98-101oC(decomp). Mass spectrum (NH3-Cl) m/e 407(M+H);

Analysis: Calculated for C27H26N4C4H4O41,2 H2O in %: C, 67.74; H, 6.05; N 10,19. Found,%: C 67,64; H, 6.48; N 8,71.

The yield is 50%.

Example 112

< / BR>
5,5-Bis((2-fluoro-4-pyridinyl)methyl)-5H-indeno[1,2-C]pyridazin

Melting point 219-20oC(decomp). Mass spectrum (Cl/NH3) m/e 387(M+H), 278 (M+H-C6H4NF); 169 (M+H)-2(C6H4NF);

Analysis: Calculated for C23H16F2N4in %: C, 71.49; H, 4.17; N 14,50; F 9.83. Found,%: C 71,21; H, 4.13; N accounted for 14.45; F 9.80.

Yield 22%.

Although this invention is described very specific connections, this does not mean that part, the elements of these compounds should be the same. Various equivalents, changes, modify the such equivalent connections are also part of this invention.

The compounds of formula (I) stimulate the secretion of neurotransmitters and effective in cases of memory impairment. Therefore, compounds of this invention find application in the treatment of disturbances of mental activity and/or failure neurological function and/or depression and mental disorders in patients with neurological disorders such as Alzheimer's disease, Parkinson's disease, senile dementia, dementia with extensive infarction, Huntington's disease, mental retardation, Myasthenia Gravis, and so forth.

The activity of compounds of this invention in relation to the secretion of neurotransmitters were determined using standard methods of biochemical analysis, for example, the analysis of neurotransmitter secretion, as described below. The ability of the compounds of the present invention effectively reduce memory impairment demonstrated the standard behavioral tests, such as the model of passive prophylaxis (PA) caused by hypoxia amnesia in rats, as described below.

Analysis of neurotransmitter secretion

The effectiveness of compounds of this invention in relation to section neurotransmitter (ACh) was determined by the method described Nickolson, et al. Dru male Wistar rats (Charies River) weighing 175-200 g Rats obezglavlivayuschii and the brain is opened immediately. Prepare slices (0.3 mm thick) of the parietal lobe of the cerebral cortex (wet weight of approximately 100 mg) and placed in 10 ml of culture medium Krebs Ringer (KR) containing NaCl (116 mm), KCl (3 mm), CaCl2(1-3 mm), MgCl2(1.2 mm), KH2PO4(1-2 mm), Na2SO4(1-2 mm), NaHCO3(25.0 mm) and glucose (11.0 mm), which is added to 10 uCi 3H-choline (specific activity approximately 35 Ci/mm; NEN), 10 ml of unlabeled choline, so that the final concentration is 1 micromoles. Drugs brain thermostatic 30 min at 37owhen DC 95% O2/5%CO2. Under these conditions, part of the radioactive choline, absorbed drug is transformed into radioactive acetylcholine (ACh) in cholinergic nerve endings contained in synaptic vesicles, and released upon depolarization under the action of a nutrient medium containing a high concentration of potassium ion (K+).

After ACh marked, the samples are washed three times with non-radioactive environment KR and transferred to the apparatus for a continuous washing for measuring the impact of drugs on Acetylcholine secretion. Apparatus for the continuous washing consists of 10 temperature-controlled glass columns giamanco).

Washing is carried out in KR-medium (0.3 ml/min) containing 10 mm gemilina-3 (HC-3). HC-3 prevents re-absorption of choline generated during washing of phospholipids and released ACh, which turns into unlabeled. ACh and provided mainly in comparison with the previously formed labeled ACh. Nutrient medium is supplied through a 25-channel pulsatile pump (Brinkmann firm Ismatec) and heated to 37oC in a thermostatic coil stainless steel before serving in the wash column. Each column is equipped with 4-way valve (devices Beckmann), which allows you to quickly change from low to high K+/KR-Wednesday, and two 10-channel 3-way valves to change from not containing up containing drugs low and high K+/KR protection. After a 15 minute wash is not specifically bound radioactivity start to collect 4 min faction. After three 4-minute fractions of the initial culture medium is changed to kR - environment in which the KCl concentration was increased to 25 mm (high-K+environment) (S1I). Caused by depolarization stimulation allocation using high-K+/KR protection lasts 4 minutes Free from drugs low and highly concentrated K-environments and washing lasts three 4-minute portions of dilute K+/KR protection, one 4-minute portion of the highly concentrated K+/KR-medium (S2), and two 4-minute portions of dilute K+/KR protection.

Drugs are introduced into the environment after 100-fold dilution of the applied concentrations of the drugs (0.9% saline) low - or high-concentrated K+/KR environments. For even skipped also linopirdine.

All leaching fractions are collected in vials with scintillation counters. After washing, the slices are removed from the wash column and extracted 1.0 ml of 0.1 N HCl. To proryvnym fractions and extracts add 12 ml liquid scintillation counter (NEN), and the samples counted on a liquid scintillation counter Packard Tricarb. On dilution correction is not done.

The ratio S2/S1 (compared to the control samples, where no drugs during S2) is a measure of the ability of drugs to increase or decrease caused by the stimulus secretion of acetylcholine.

For certain compounds of this invention was the analysis of neurotransmitter secretion and revealed their effectiveness when called Lekar table. II.

Passive prophylaxis (PEP) amnesia in rats induced by hypoxia.

Neolodge male SD rats weighing 165-210 g train on the PP apparatus as follows: rats placed on the light side of the camera, consisting of two compartments, and give 90 to enter the dark compartment. 10 seconds after the rat is in the dark half, within 3 served with pulse (1.0 mA) on the grid floor, then through 10 with another 3-second pulse. The retention is checked after 4 hours the Rats given 300 with the fact that they entered the dark compartment; time is seen. Memory impairment is caused by a mixture of oxygen (6.5%) and nitrogen, the effect of which is subjected to rats for 30 min before performing the PP tests. Doses of the test compounds are assigned (0.1 ml/100 g; SC) in accordance with PP time tests.

Individual compounds of this invention were tested in a model of passive habituation (PP) rats at amnesia caused by hypoxia, and was effective for the reduction of memory impairment caused by hypoxia (unlike filler, Mann-Whitney and test). Results the average time saving of the latent state is shown in table. II and III.

The methodology were synthesized

Male Wistar rats whiskers the minimum recovery period of 72 h, probes for dialysis (0.5 mm diameter, 4.0 mm length from BAS) are injected into the hippocampus through the guide cannula. The probes are washed at the rate of 2 μl/min with artificial cerebrospinal fluid containing 100 μm of physostigmine (cholinesterase inhibitor). Rats allowed to acclimate for 2 hours before starting to collect the samples. Sample dialysate collected every 20 min (40 μl) and immediately injected into a high performance liquid chromatograph, fitted for electrochemical detection (HPLC-EC) acetylcholine (ACh). After collecting 3 servings source of fluid injected drugs or fillers from the calculation of 0.01 ml/g body weight, and sample dialysate going another 3 hours with peaks ACh of the 3 samples before drug is averaged to determine the initial level of ACh. Height ACh - peaks after drug measure and determine (in percent) change in the level of ACh in comparison with the initial, at the end of the experiment, the injection probe is checked histologically.

HPLC-EC analysis of acetylcholine

ACh stands out by chromatography on reverse phase (Hamilton PRP-1 column h.5 mm) and converted into the acetate, betaine and hydrogen peroxide in a column with a fixed enzyme as a reactor (BAS). The hydrogen peroxide is then defined e the pH is brought to 8.0 with phosphoric acid and 50 ml of Kathon CG (ESA), added to 1 liter of mobile phase to retard the growth of bacteria.

Results.

Fig. 1, 2 (A and B) show the effect of the presence of fluorine in pairs of substituents in the series antrona and azafluorene on the ability of the compound to increase the level of ACh in the hippocampus of rats in vivo. Compound was administered in an amount of 5 mg/kg, with the exception of example N 64, which was introduced in quantities of 1 mg/kg of the Compound was administered orally, with the exception of example N 611 in US patent 5137489, which i was introduced.p.

Example N 611 in U.S. patent 5137489 not affect the level of ACh in comparison with filler (A). This was observed even in the case when the connection is introduced in this way (i.p.), which provides greater bioavailability than the oral route. Example 68 of the present invention, dipterology similar example 611 of the American patent 5137489, on the other hand, leads to a twofold increase in ACh level that persists for more than 1 h (A). Derived antrona example N 440 American patent 5137489 at the dose of 5 mg/kg leads to the maximum content of ACh in excess of the original 72% (B). Example N 64 of the present invention Giverny similar example N 440 American patent 5137489, at the dose of 1 mg/kg, leads to slow the trust with the observed effect of the example 400 (U.S. patent 5137489) increase level of ACh after the introduction of for example 64 of the present invention was maintained throughout the test time (3 h). All data were synthesized are shown in table. IV.

Area % under the curve (from the graphical Fig. 7) maximum - the maximum % increase-ACh secretion compared to the original @ minutes after injection.

Duration minutes secretion above.

There are no specific points.

The compounds of this invention can also be used as reagents or standards for biochemical analysis of neurological function, dysfunction and disease.

Dosage and method of application

The compounds of this invention can be used to treat disorders of mental activity and/or failure neurological function and/or depression and mental disorders in any way, in which occurs the contact of the active agent at the action part of the body of a mammal or patient. The compounds may be introduced by any convenient method, suitable for use in combination with a pharmaceutical or individual therapeutic agent or combination of therapeutic agents. They can be administered alone, but are usually prescribed in the form of pharmaceutical compositions comprising the compounds and a pharmaceutical carrier selected depending on the awns from the use and known factors, such as the pharmacodynamic nature of individual agents and their mode and route of administration; the age of the recipient, weight and health; the nature and strength of symptoms; kind of concurrent treatment; frequency of treatment; the desired effect. For use in the treatment of the aforementioned diseases or conditions compounds of this invention can be administered orally daily in the amount of active ingredient 0.001-100 mg/kg body weight. The usual dose is 0.01-10 mg/kg/day divided 1 to 4 servings per day, or in the form of prolonged action is effective to achieve the desired pharmacological action. Release forms (pharmaceutical compositions) suitable for administration contain ~1-100 mg of the active ingredient per unit. In these pharmaceutical compositions the active ingredient is usually by weight, from 0.5 to 95% by weight of the composition.

The active ingredient may be administered orally in solid dosage forms such as capsules, tablets and powders; or in liquid forms, such as elixirs, syrups, and/or suspension. The compounds of this invention can also be administered parenterally, in sterile liquid forms.

To store the active ingredient can be used in gelatin capsules, and kacestvenoje and so on. Such diluents can be used for tabletting. As tablets and capsules can be manufactured in the form of prolonged action, which provides long-lasting medication. Tablets may be coated with sugar or film to mask an unpleasant taste or to protect the active ingredients from the weather or to provide selective splitting of tablets in the gastrointestinal tract.

Liquid forms for oral administration can contain dyes and corrigentov for better perception of the patient.

In General, water, farmatsevticheskii suitable oil, saline, aqueous dextrose (glucose) and similar sugars, glycols, such as propylene glycol or polyethylene glycol, is useful as carriers in parenteral solutions. Solutions for parenteral administration mainly contain an aqueous solution of salt of the active ingredient, suitable stabilizing agents, and if necessary oil. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid alone or in combination are a good stabilizing agents. Also used citric acid and its salts and EDTA. the palparan or chlorbutanol.

Used pharmaceutical carriers are described in "Remington''s Pharmaceutical Sciences"., A. Osol.(and references therein).

Convenient pharmaceutical dosage form of the compounds of this invention can be illustrated by the following examples.

Capsules

A large number of unit capsules are prepared by filling standard two-part gelatin capsules, each 100 mg of powdered active ingredient, 150 mg of galactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules.

Prepare a mixture of active ingredient in a digestible oil such as soybean, cottonseed or olive, and accurate method of substitution under pressure injected into gelatin, getting soft gelatin capsules containing 100 mg of active ingredient. The capsules are washed and dried.

Tablets

A large number of tablets are prepared convenient method, so that a single dose of 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. You can cover the tablet corresponding shell to improve the taste or decrease the absorption.

Injection

Parenteral is containing a series of 10% by volume propylene glycol in water. The solution is sterilized in a customary manner.

Suspension

Aqueous suspension is prepared for oral administration so that 5 ml contains 25 mg melkorazdroblennyh active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 grestore sorbitol, U. S. P, and 0.025 ml of vanillin.

Nose drops

An aqueous solution is prepared so that 1 ml contains 10 mg of active ingredient, 1.8 mg methylparaben, 0.2 mg of propyl paraben and 10 mg of methylcellulose. The solution is poured into ml vials.

Inhaler

Homogeneous mixture of the active ingredient in the Polysorbate 80 is prepared so that the final concentration of the active ingredient is 10 mg on the tank and the final concentration of Polysorbate 80 in the tank is 1% by weight. The mixture is poured into containers, the containers are strengthened valves and pressure is added dichlorotetrafluoroethane.

The preceding information is required in order to practice the claimed compounds. As cited applications can contain additional useful information, these cited materials are presented in the references.

1. Polycyclic compounds of the formula I

< / BR>
the Il group, including

< / BR>
< / BR>
< / BR>
B is an aromatic or heteroaromatic ring selected from the group including

< / BR>
< / BR>
< / BR>
< / BR>
Z means a bond, -C(=O)- O-, -S(=O)- or-SO2;

P is phenyl;

R2means-H, -I, -R4, -OR4, -OH, -COOR4, -(CH2)nCCR5, -(CH2)nNR6COR4or-NR6R6a;

R3means-H or-OR4;

R2ameans H, C1-C4-alkyl or phenyl;

R4-C1-C4-alkyl;

R5, R6and R6aeach independently denote H or C1-C6-alkyl;

n is 0 or 1;

R is selected from the group comprising-H, -(CH2)n-(Het-2) or -(CH2)n-Y

Het-1 and Het-2 each independently represent a heterocycle selected from

< / BR>
or

< / BR>
where X is H, Cl, F, Br or or4;

n' is 1, 2 or 4;

Y means-OR6, -CO2R6, -CN or-CONHR6;

provided that when A mean six-membered aromatic or heteroaromatic ring, Het-1 and Het-2 both are not

< / BR>
where X is H.

2. Connection on p. 1, wherein B stands for an aromatic or heteroaromatic ring, selected from the group VK is B>2-(Het-2), -CH2CO2Et, -(CH2)4OCOCH3, -(CH2)4CONH2, -(CH2)4OH, and -(CH2)4-CN.

4. Connection on p. 3, wherein R2means-H, -I, -R4, -CCH,, -OR4, -NR6R6a, -COOR4or -(CH2)nNR6COR4; R3means hydrogen; R is selected from the group comprising: -H, -CH2-(Het-2), -(CH2)CO2Et, -(CH2)4OCOCH3, -(CH2)4CONH2, -(CH2)4OH, and -(CH2)4-CN.

5. Connection on p. 1, characterized in that A means six-membered aromatic or heteroaromatic ring, selected from

< / BR>
R2means-H, -I, -R4, -CCH,, -OR4, -NR6R6a, -COOR4or -(CH2)nNR6COR4; R3means H; X is H, F, Cl, Br or or4; R is selected from the group comprising-H, -CH2-(Het-2), -CH2CO2Et, -(CH2)4OCOCH3, -(CH2)4CONH2,

-(CH2)4OH, and -(CH2)4-CN.

6. Connection on p. 1, selected from the group including:

4-(4-pyridinylmethyl)-4H-indeno[1,2-b]thiophene;

4-(4-pyridinylmethyl)-4H-indeno[1,2-b] thiophene-4-pentenenitrile, hydrobromide hydrate;

ethyl ester of 4-(4-Hairdryer-4-pentanolide hydrate hydrochloride;

2-fluoro-4-[4-(4-pyridinylmethyl)-4H-indeno[1,2-b]thiophene-4-ylmethyl]pyridine;

4-[4-phenyl)-4H-indeno[1,2-b]thiophene-4-ylmethyl]predin;

4-(4-pyridinylmethyl)-4H-indeno[1,2-b]thiophene-4-butanol;

4-(4-pyridinylmethyl)-4H-[2'3':3,4]cyclopent[1,2-b]pyridine;

4-[(2-fluoro-4-pyridinyl)methyl] -4-(4-pyridinylmethyl)-4H-thieno[3', 2':4,5] cyclopent[1,2-b]pyridine;

2,4-dihydro-2-phenyl-4,4-bis(4-pyridinylmethyl)pyrazolo-[4,3-b]pyrrolizine;

9,9-bis-[(2-fluoro-4-pyridinyl)methyl]-2-hydroxy-9H-fluoren;

5-[(2-fluoro-4-pyridinyl)methyl]-5-(4-pyridinylmethyl)-5H-indeno[1,2-b]pyridine;

5-[(2-fluoro-4-pyridinyl)methyl]-5-(4-pyridinylmethyl)-5H-indeno[1,2-b]pyridine;

10,10-bis-[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracene;

9-[(2-fluoro-4-pyridinyl)methyl]-9-(4-pyridinylmethyl)-9H-xanthene;

10-[(2-fluoro-4-pyridinyl)methyl]-10-(4-pyridinylmethyl)-9(10)-anthracene;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-4-asasantin;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-5H-indeno[1,2-b]pyridine;

4,4-bis[(2-fluoro-4-pyridinyl)methyl] -4H-thieno[3',2':4,5]cyclopent[1,2-b] pyridine;

9-[(2-fluoro-4-pyridinyl)methyl]-9-(4-pyridinylmethyl)-4-asasantin;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-2-methoxyfuran;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-7-methoxy-4-asasantin;

10,10-bis[(2-fluoro-4-pyridinyl)methyl]-3-hydroxy-9(10)anthracene;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-2-phenyl-5H-indeno[1,2-d]pyrimidine,

10,10-bis[(2-fluoro-4-pyridinyl)methyl]-3-methoxy-9(10H)-anthracene;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-9H-indeno[2,1-b]pyridine;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-7-ethinyl-5H-indeno[2,1-b]pyridine;

9,9-bis[(2-fluoro-4-pyridinyl)methyl]-9H-indeno[1,2-b]pyrazin;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-5H-indeno[1,2-d]pyrimidine,

5,5-bis[(2-bromo-4-pyridinyl)methyl]-5H-indeno[1,2-b]pyridine;

9,9-bis[(2-fluoro-4-pyridinyl)methyl] -2-[(N-methyl-N-acetylamino) methyl] fluoren;

10,10-bis[(2-bromo-4-pyridinyl)methyl]-9-(10H)-anthracene;

5,5-bis[(2-chloro-4-pyridinyl)methyl]-5H-indeno[1,2-b]pyridine;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-2-methyl-5H-indeno[1,2-d]pyrimidine,

5,5-bis[(2-methoxy-4-pyridinyl)methyl]-5H-indeno[1,2-b]pyridine;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-7-(ethyl)-5H-indeno[1,2-b]pyridine;

5,5-bis[(2-chloro-6-methyl-4-pyridinyl)methyl]-5H-indeno[1,2-b]pyridine;

5,5-bis[(2-methyl-4-pyridinyl)methyl]-5H-indeno[1,2-b]pyridine;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]-7-iodine-5H-indeno[1,2-b]pyridine;

methyl ether of 9,9-bis[(2-fluoro-4-pyridinyl)methyl] -9H-fluoren-1-carboxylic acid;

methyl ester of 9-[(2-fluoro-4-pyridinyl)methyl] -9-(4-pyridinylmethyl)9H-fluoren-1-carboxylic acid, racemate;

5,5-bis[(2-fluoro-4-a feast who yl)-5H-cyclopent[2,1-b : 3,4-b'] dipyridine-4-carboxylic acid, the dihydrochloride (racemate),

methyl ester 5-[(2-fluoro-4-pyridinyl)methyl]-5-(4-pyridinylmethyl)-5H-cyclopent[2,1-b : 3,4-b]piperidin-4-carboxylic acid, hydrochloride, (-)-isomer;

methyl ester 5-[(2-fluoro-4-pyridinyl)methyl]-5-(4-pyridinylmethyl)-5H-cyclopent[2,1-b : 3,4-b'] dipyridine-4-carboxylic acid, hydrochloride, (+)-isomer;

5,5-bis[(6-fluoro-3-pyridinyl)methyl] -5H-cyclopent[2,1-b : 3,4-b']dipyridine;

5-[(6-fluoro-2-pyridinyl)methyl]-5-(4-pyridinylmethyl)-5H-cyclopent[2,1-b : 3,4-b']dipyridine,

5,5-bis[(6-fluoro-2-pyridinyl)methyl] -5H-cyclopent[2,1-b : 3,4-b']dipyridine;

5,5-bis[(3-methyl-4-pyridinyl)methyl]-5H-cyclopent[2,1-b : 3,4-b']dipyridine, trihydrochloride;

2-fluoro-4-[(9-(4-pyridinylmethyl)-9H-fluoren-9-yl)methyl] -pyridine, hydrochloride;

5-[(2-fluoro-4-pyridinyl)methyl]-5-(4-pyridinylmethyl)-5H-cyclopent[2,1-b : 3,4-b']dipyridine;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]thioxanthen-10,10-dioxide;

5,5-bis[(2-fluoro-4-pyridinyl)methyl]thioxanthen-10-oxide.

7. Pharmaceutical drug with stimulating the secretion of acetylcholine by hippocampal activity, containing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient contains an effective amount of the compounds under item 1.

8. ASI active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient contains an effective amount of the compounds on p. 2.

9. Pharmaceutical drug with stimulating the secretion of acetylcholine by hippocampal activity, containing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient contains an effective amount of the compounds on p. 3.

10. Pharmaceutical drug with stimulating the secretion of acetylcholine by hippocampal activity, containing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient contains an effective amount of the compounds under item 4.

11. Pharmaceutical drug with stimulating the secretion of acetylcholine by hippocampal activity, containing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient contains an effective amount of the compounds on p. 5.

12. Pharmaceutical drug with stimulating the secretion of acetylcholine by hippocampal activity, containing the active ingredient and pharmaceutically acceptable carrier, characterized in that Thu is possible violations of intellectual activity and neurological dysfunctions, including the appointment of those in need of such treatment an effective amount of the active substance that stimulates the secretion of acetylcholine by the hippocampus, characterized in that the active substance is used as a compound for PP.1 - 6.

Priorities signs:

08.04.1993: A is an aromatic or heteroaromatic ring selected from the group including:

B - heteroaromatic ring of the formula

Z represents a relationship, Het-1 means 4-pyridinylmethyl, P is phenyl, R2means-H, -R4, -OR4, -OH or-COOR4, R3means-H or-OR4, R4means-C1-C4is alkyl, R is selected from the group comprising-H, -(CH2)n-Y, 2-fluoro-4-pyridinylmethyl or 2-, 3 - or 4-pyridinylmethyl, Y means-OR6, -COOR6, -CN or-CONHR6n' is 1, 2 or 4;

28.03.1994 B - aromatic ring of the formula

Z - means-C = O; R2means-I or-CCH; R is -(CH2)-(Het-2), Het-1 and Het-2 are independently selected from 2-, 3 - or 4-pyridinylmethyl, replaced by X, where X is Cl, F or Br, with the exception of 2-fluoro-4-pyridinylmethyl; other signs are the priority filing date of this application 04.04.1994.

 

Same patents:

The invention relates to medicine, for new thienopyrimidine derivatives of the formula

where the radicals R1, R2, R3, R4, W and n are specified in paragraph 1 of the claims

The invention relates to new N-substituted azabicycloalkanes

The invention relates to new heterocyclic compounds of the formula I where ring a and ring To represent optionally substituted benzene or cycloalkane ring or optionally substituted 5 - or 6-membered aromatic heterocyclic ring containing one to two heteroatoms selected from nitrogen, sulfur and oxygen

The invention relates to new derivatives of dihydropyridines, possessing valuable pharmacological properties, in particular derived analyoung of dihydropyridines and means of selective blocking the reabsorption of cations
The invention relates to organic chemistry, in particular to a method of obtaining 2', 3', 4',5'-tetrabenzyl-5-acetyl-1,5-dihydroquinoline (benzoflavone), and can be used in pharmaceutical industry and medicine
The invention relates to organic chemistry, particularly to a process for the preparation of secondary amines from the corresponding sulfonamides

The invention relates to a derivative pyrrolopyridine or their pharmaceutically acceptable salts, with high activity, inhibiting the secretion of gastric juice; activity, protects the mucous membrane of the stomach; and high antibacterial activity against Helicobacter pylori; and antiulcer agent containing the derivative or salt as an active ingredient

The invention relates to nitroglicerine General formula A-X1-NR2or their salts, where a and X1have the meanings indicated in the claims, as well as to pharmaceutical compositions based on them

The invention relates to new heterocyclic compounds with biological activity, more specifically, to the derivatives of benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone, the pharmaceutical composition having inhibitory cell adhesion or HIV activity, method of inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it and the method of treating mammals infected with HIV
Up!