Piperidine derivatives and agent comprising piperidine derivative as active component

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (I): or their nontoxic salts wherein R1 represents hydrogen atom, cyano-group; each R2 and R3 represents (C1-C8)-alkyl, (C3-C7)-cycloalkyl and others; each R4 and R5 represents hydrogen atom, (C1-C8)-alkyl and others; R6 represents hydroxyl group, (C1-C8)-alkoxy-group and others; m represents 0 or a whole number 1-4. Compounds of the formula (I) possess inhibitory activity with respect to PDE4 and can be used in medicine in treatment of inflammatory, diabetic, allergic and other diseases.

EFFECT: valuable medicinal properties of compounds.

10 cl, 11 tbl, 111 ex

 

The technical field

The present invention relates to derivatives of piperidine. More specifically, the present invention relates to

(1) a piperidine derivative represented by the formula (I)

(where all the symbols have the same meanings specified below)

or their non-toxic salts,

(2) the way they are received and

(3) means containing them as active ingredient.

Prior

Cyclic adenosine 3',5'-monophosphate (camp) and cyclic guanosine 3',5'-monophosphate (cGMP) as the molecules of the intracellular signal transduction (secondary messengers) are decomposed by the group of hydrolases, usually called phosphodiesterase (PDE), inactive 5'AMR and 5'-GMP, respectively.

PDE isoenzymes that inactivate them unevenly present in vivo, but distributed in vivo have a specific localization in organs and behave differently, for example, in the distribution of cells and distribution in the tissues.

Today confirmed the presence of 11 families PDE1-PDE11 (see Current Opinion in Cell Biology, 12, 174-179 (2000)).

From among the above PDE, PDE4 is present in various cells, such as cells of the smooth muscles of the respiratory tract, epithelial cells, inflammatory cells (macrophages, neutrophils and eosinophils and T-lymphocytes, and controls cell options the s by regulating the intracellular level of camp in these cells. On the other hand, for example, in platelets, the cells of the heart muscle and the smooth muscle cells of blood vessels there are other PDE such as PDE5, which take part in the management of the system of bodies of blood circulation by regulating the intracellular level of cGMP or camp.

Thus, it is known that inhibitors of PDE4 have a bronchodilator activity, antiinflammatory activity, inhibitory activity against the release of mediators, immune activity, etc. because they cause the accumulation of intracellular camp by inhibiting the degradation of camp, carried out by PDE4.

Accordingly, it is assumed that the funds specifically inhibiting PDE4, do not show inhibitory activities against other PDE such as PDE5, in the circulatory system and are suitable for the prophylaxis and/or treatment of various diseases, such as inflammatory diseases (e.g., asthma, obstructive pulmonary disease, sepsis, sarcoidosis, nephritis, hepatitis, enteritis etc), diabetic diseases, allergic diseases (e.g. allergic rhinitis, allergic conjunctivitis, seasonal conjunctivitis, atopic dermatitis, etc.), autoimmune diseases (e.g. ulcerative colitis, Crohn's disease, rheumatism, psoriasis, multiple sclerosis, collagen disease, and so on), about theophoros, fracture, obesity, depression, Parkinson's disease, dementia, impaired reperfusion ischemia, leukemia and AIDS (AIDS) (Exp. Opin. Invest. Drugs, 8, 1301-1325 (1999)).

In the description of JP-T-8-509731 as PDE4 inhibitors is indicated compound represented by formula (A)

(where R1Arepresents H or C1-alkyl; R2Arepresents C3-alkyl, C3-cycloalkyl etc.; R3Ais COR4A, COCOR4Aetc.; R4Arepresents N, OR5A, NHOH, etc. R5Arepresents H, C1-alkyl etc.; XAndis About, etc. and YAis About and so on),

or its pharmaceutically acceptable salt, which have inhibitory activity against PDE4 (necessary parts taken from the description of groups).

In the description of WO 93/19747 also indicates that the compound represented by the formula (In)

(where R1Bis -(CR4BR5B)rBR6B; rB is 1-6; each of R4Band R5Bindependently represents a hydrogen atom or C1-alkiline group; R6Brepresents a hydrogen atom, C3-cycloalkyl group, etc.; XBrepresents the YBR2Betc.; YBis About, etc.; R2Brepresents methyl, ethyl, etc.; X2Bis About and so on; X3Brepresents a hydrogen atom, etc. that sB is 0-4; R3Bto depict the place of a hydrogen atom, CN etc.; X5Vrepresents a hydrogen atom, etc.; ZBis CR8BR8BC(O)OR14B, CR8BR8BC(Y B)NR10BR14Betc.; R8Brepresents a hydrogen atom, etc.; R10Brepresents a hydrogen atom, OR8Betc. and R14Brepresents a hydrogen atom etc.), or its pharmaceutically acceptable salt has inhibitory activity against PDE4 (necessary parts taken from the description of groups).

In addition, in the description of WO 93/19749 indicates that the compound represented by formula (C)

(where R1Cis -(CR4CR5C)rCR6Cetc.; rC is 1-6; each of R4Cand R5Cindependently represents a hydrogen atom or C1-alkiline group; R6Crepresents a hydrogen atom, C3-cycloalkyl group, etc.; XWithrepresents the YCR2Cetc.; YCis About, etc.; R2Crepresents methyl, ethyl, etc.; X2Cis About and so on; X3Srepresents a hydrogen atom, etc.; X4Sis

etc.; R3Crepresents a hydrogen atom, CN, etc.; X5Srepresents a hydrogen atom, etc.; sC is 0-4; ZCrepresents C(O)OR14CWith(Y'With)NR10CR14Cetc.; R10Crepresents a hydrogen atom, OR8Cetc. R8 is represents a hydrogen atom, etc. and R14Crepresents a hydrogen atom etc.), or its pharmaceutically acceptable salt has inhibitory activity against PDE4 (necessary parts taken from the description of groups).

Description of the invention

To find compounds with inhibitory activity against PDE4, the inventors of the present invention have conducted intensive studies and found that tasks can be executed derivatives of piperidine derivatives represented by the formula (I), and thus was established the present invention.

The present invention relates to

(1) a piperidine derivative represented by the formula (I)

(where R1represents 1) a hydrogen atom or 2) a cyano;

each of R2and R3independently represents 1) a C1-alkiline group, 2) C3-cycloalkyl group, 3) C1-alkiline group, substituted C3-cycloalkyl group, 4) C1-alkiline group substituted by 1 to 3 atom(s) halogen, 5) a hydrogen atom, 6) C1-alkiline group, substituted phenyl group, 7) C1-alkiline group, substituted C1-alkoxygroup, or

(in which n represents the number 1-5);

each of R4and R5independently represents (1) hydrogen atom or (2) C1-alkiline group or

R4R 5taken together with the linking carbon atom, represent C3-7 saturated carbocyclic ring;

R6represents 1) a hydroxyl group, 2) C1-alkoxygroup, 3) -NHOH or (4) C1-alkoxygroup, substituted phenyl group, and

m is zero or an integer of 1-4),

or their non-toxic salts,

(2) the way they are received and

(3) means containing them as active ingredient.

Detailed description of the invention

In the formula (I) C1-alcalina group includes methyl, ethyl, through boutelou, pentelow, hexeline, heptylene and octillo groups and their isomers.

In the formula (I) C1-alkoxygroup includes methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy and aktionsgruppe and their isomers.

In the present invention, the halogen atom means an atom of chlorine, bromine, fluorine or iodine.

In the formula (I) C3-cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptyl and cyclooctyl group.

In the formula (I) C3-7 saturated carbocyclic ring represented by R4and R5taken together with the linking carbon atom, includes C3-cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo, cycloheptyl and cyclooctyl group.

Unless stated otherwise,the present invention includes all isomers. For example, an alkyl group, alkoxygroup and Allenova group include a group with straight chain and branched chain. In addition, in the present invention included the isomers with the double bond, cyclic, condensed cyclic (E-, Z-, CIS-, TRANS-isomer), isomers due to the presence of asymmetric atom(s) carbon, etc. (R-, S-isomer, α-, β-isomer, enantiomer, diastereoisomer), optically active isomers having optical rotation (D-, L-, d-, l-isomer), polar compounds separated by chromatography (high-polar compound, iskopaemoe compound), equilibrium compounds, mixtures thereof at an arbitrary ratio, and a racemic mixture.

In accordance with the present invention, unless stated otherwise, and as apparent to experts in this field,

indicates that it is associated with the opposite side of the plane (i.e. α-configuration), symbol

indicates that it is associated with the front side of the plane (i.e. β-configuration), symbol

indicates that it is α-, βor their mixture, and the symbol

indicates that it is a mixture of αconfiguration β-configuration.

Connection, provided the formula (I), can be turned well-known methods in a non-toxic salt.

In the present description, the expression "non-toxic salt" includes salts of alkali metals, salts of alkaline earth metals, ammonium salts, amine salts, additive, acid salts and similar compounds.

Salt preferably is non-toxic and water soluble. Suitable salts include salts of alkali metals (e.g. potassium, sodium, etc.), salts of alkaline earth metals (e.g. calcium, magnesium etc), ammonium salts and pharmaceutically acceptable organic amines (for example, Tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine etc).

Additive salt of the acid preferably is non-toxic and water soluble. The corresponding additive salt of the acid include inorganic salts such as hydrochloride, Hydrobromic, hydroiodic, sulfate, phosphate and nitrate, and organic acid salts such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, aconsultant, bansilalpet, toluensulfonate, isethionate, glucuronate and gluconate.

In addition, the compound of the present invention represented by the formula (I)or its salt can be converted famous the techniques in the MES.

MES preferably is non-toxic and water soluble. Suitable solvate include solvate, as aqueous or alcoholic solvent (e.g. ethanol, etc).

In the formula (I) R' preferably represents cyano.

In the formula (I) R2preferably represents C1-alkiline group, C3-cycloalkyl group or C1-alkiline group, substituted C3-cycloalkyl group, and more preferably methyl group, ethyl group, isopropyl group, 2-methylpropyloxy group, cyclobutyl group, cyclopentyl group or cyclopropylmethyl group.

In the formula (I) R3preferably represents C1-alkiline group or C1-alkiline group substituted by 1 to 3 atom(s) halogen, and more preferably methyl group, ethyl group, isopropyl group, 2-methylpropyloxy group or deformational group.

In the formula (I) R4and R5preferably represent hydrogen atoms.

In the formula (I) R6preferably represents a hydroxyl group or-NHOH, and more preferably-NHOH.

From among the compounds of the present invention represented by the formula (I), preferred compounds are compounds represented by formula (I-A)

(where all the symbols have the same meanings that the decree is HN above)

compounds represented by formula (I-B)

(where all the symbols have the same meanings as above),

compounds represented by formula (I-C)

(where all the symbols have the same meanings as above),

compounds represented by formula (I-D)

(where all the symbols have the same meanings as above),

compounds represented by the formula (1-E)

(where all the symbols have the same meanings as above),

compounds represented by the formula (1-F)

(where all the symbols have the same meanings as above),

compounds represented by the formula (1-G)

(where all the symbols have the same meanings as above),

compounds represented by the formula (1-H)

(where all the symbols have the same meanings as above),

compounds represented by the formula (1-J)

(where all the symbols have the same meanings as above),

compounds represented by the formula (1-K)

(where all characters have the same values to the categories listed above).

Specific compounds of the present invention include compounds shown in tables 1-10, the compounds described in the examples, and their non-toxic salts, additive acid salt and solvate. In addition, in each table, Me represents a methyl group; Et represents an ethyl group; i-Pr represents an isopropyl group; CH2with Pr is cyclopropylmethyl group; CH2-s-Pen is cyclopentylmethyl group;-Bu represents cyclobutyl group; s-Pen is cyclopentyloxy group; CHF2is deformational group, and other symbols have the same meanings as above.

Table 1
No.R2R3No.R2R3
1MeMe33CH2c-PenMe
2MeEt34CH2c-PenEt
3Mei-Pr35CH2c-Peni-Pr
4MeCH2-c-Pr36 CH2c-PenCH2-c-Pr
5MeCH2c-Pen37CH2c-PenCH2c-Pen
6Mec-Bu38CH2c-Penc-Bu
7Mec-Pen39CH2c-Penc-Pen
8MeCHF240CH2c-PenCHF2
9EtMe41c-BuMe
10EtEt42c-BuEt
11Eti-Pr43c-Bui-Pr
12EtCH2-c-Pr44c-BuCH2-c-Pr
13EtCH2c-Pen45c-BuCH2c-Pen
14Etc-Bu46c-Buc-Bu
15Etc-Pen47c-Buc-Pen
16EtCHF2 48c-BuCHF2
17i-PrMe49c-PenMe
18i-PrEt50c-PenEt
19i-Pri-Pr51c-Peni-Pr
20i-PrCH2-c-Pr52c-PenCH2-c-Pr
21i-PrCH2c-Pen53c-PenCH2c-Pen
22i-Prc-Bu54c-Penc-Bu
23i-Prc-Pen55c-Penc-Pen
24i-PrCHF256c-PenCHF2
25CH2-c-PrMe57CHF2Me
26CH2-c-PrEt58CHF2Et
27CH2-c-Pri-Pr59CHF2i-Pr
28CH2-c-Pr60CHF2CH2-c-Pr
29CH2-c-PrCH2c-Pen61CHF2CH2c-Pen
30CH2-c-Prc-Bu62CHF2c-Bu
31CH2-c-Prc-Pen63CHF2c-Pen
32CH2-c-PrCHF264CHF2CHF2

Table 2
No.R2R3No.R2R3
1MeMe33CH2c-PenMe
2MeEt34CH2c-PenEt
3Mei-Pr35CH2c-Peni-Pr
4MeCH2-c-Pr36 CH2c-PenCH2-c-Pr
5MeCH2c-Pen37CH2c-PenCH2c-Pen
6Mec-Bu38CH2c-Penc-Bu
7Mec-Pen39CH2c-Penc-Pen
8MeCHF240CH2c-PenCHF2
9EtMe41c-BuMe
10EtEt42c-BuEt
11Eti-Pr43c-Bui-Pr
12EtCH2-c-Pr44c-BuCH2-c-Pr
13EtCH2c-Pen45c-BuCH2c-Pen
14Etc-Bu46c-Buc-Bu
15Etc-Pen47c-Buc-Pen
16EtCHF2 48c-BuCHF2
17i-PrMe49c-PenMe
18i-PrEt50c-PenEt
19i-Pri-Pr51c-Peni-Pr
20i-PrCH2-c-Pr52c-PenCH2-c-Pr
21i-PrCH2c-Pen53c-PenCH2c-Pen
22i-Prc-Bu54c-Penc-Bu
23i-Prc-Pen55c-Penc-Pen
24i-PrCHF256c-PenCHF2
25CH2-c-PrMe57CHF2Me
26CH2-c-PrEt58CHF2Et
27CH2-c-Pri-Pr59CHF2i-Pr
28CH2-c-Pr60CHF2CH2-c-Pr
29CH2-c-PrCH2c-Pen61CHF2CH2c-Pen
30CH2-c-Prc-Bu62CHF2c-Bu
31CH2-c-Prc-Pen63CHF2c-Pen
32CH2-c-PrCHF264CHF2CHF2

Table 3
No.R2R3No.R2R3
1MeMe33CH2c-PenMe
2MeEt34CH2c-PenEt
3Mei-Pr35CH2c-Peni-Pr
4MeCH2-c-Pr36 CH2c-PenCH2-c-Pr
5MeCH2c-Pen37CH2c-PenCH2c-Pen
6Mec-Bu38CH2c-Penc-Bu
7Mec-Pen39CH2c-Penc-Pen
8MeCHF240CH2c-PenCHF2
9EtMe41c-BuMe
10EtEt42c-BuEt
11Eti-Pr43c-Bui-Pr
12EtCH2-c-Pr44c-BuCH2-c-Pr
13EtCH2c-Pen45c-BuCH2c-Pen
14Etc-Bu46c-Buc-Bu
15Etc-Pen47c-Buc-Pen
16EtCHF2 48c-BuCHF2
17i-PrMe49c-PenMe
18i-PrEt50c-PenEt
19i-Pri-Pr51c-Peni-Pr
20i-PrCH2-c-Pr52c-PenCH2-c-Pr
21i-PrCH2c-Pen53c-PenCH2c-Pen
22i-Prc-Bu54c-Penc-Bu
23i-Prc-Pen55c-Penc-Pen
24i-PrCHF256c-PenCHF2
25CH2-c-PrMe57CHF2Me
26CH2-c-PrEt58CHF2Et
27CH2-c-Pri-Pr59CHF2i-Pr
28CH2-c-Pr60CHF2CH2-c-Pr
29CH2-c-PrCH2c-Pen61CHF2CH2c-Pen
30CH2-c-Prc-Bu62CHF2c-Bu
31CH2-c-Prc-Pen63CHF2c-Pen
32CH2-c-PrCHF264CHF2CHF2

Table 4
No.R2R3No.R2R3
1MeMe33CH2c-PenMe
2MeEt34CH2c-PenEt
3Mei-Pr35CH2c-Peni-Pr
4MeCH2-c-Pr36 CH2c-PenCH2-c-Pr
5MeCH2c-Pen37CH2c-PenCH2c-Pen
6Mec-Bu38CH2c-Penc-Bu
7Mec-Pen39CH2c-Penc-Pen
8MeCHF240CH2c-PenCHF2
9EtMe41c-BuMe
10EtEt42c-BuEt
11Eti-Pr43c-Bui-Pr
12EtCH2-c-Pr44c-BuCH2-c-Pr
13EtCH2c-Pen45c-BuCH2c-Pen
14Etc-Bu46c-Buc-Bu
15Etc-Pen47c-Buc-Pen
16EtCHF2 48c-BuCHF2
17i-PrMe49c-PenMe
18i-PrEt50c-PenEt
19i-Pri-Pr51c-Peni-Pr
20i-PrCH2-c-Pr52c-PenCH2-c-Pr
21i-PrCH2c-Pen53c-PenCH2c-Pen
22i-Prc-Bu54c-Penc-Bu
23i-Prc-Pen55c-Penc-Pen
24i-PrCHF256c-PenCHF2
25CH2-c-PrMe57CHF2Me
26CH2-c-PrEt58CHF2Et
27CH2-c-Pri-Pr59CHF2i-Pr
28CH2-c-Pr60CHF2CH2-c-Pr
29CH2-c-PrCH2c-Pen61CHF2CH2c-Pen
30CH2-c-Prc-Bu62CHF2c-Bu
31CH2-c-Prc-Pen63CHF2c-Pen
32CH2-c-PrCHF264CHF2CHF2

Table 5
No.R2R3No.R2R3
1MeMe33CH2c-PenMe
2MeEt34CH2c-PenEt
3Mei-Pr35CH2c-Peni-Pr
4MeCH2-c-Pr36 CH2c-PenCH2-c-Pr
5MeCH2c-Pen37CH2c-PenCH2c-Pen
6Mec-Bu38CH2c-Penc-Bu
7Mec-Pen39CH2c-Penc-Pen
8MeCHF240CH2c-PenCHF2
9EtMe41c-BuMe
10EtEt42c-BuEt
11Eti-Pr43c-Bui-Pr
12EtCH2-c-Pr44c-BuCH2-c-Pr
13EtCH2c-Pen45c-BuCH2c-Pen
14Etc-Bu46c-Buc-Bu
15Etc-Pen47c-Buc-Pen
16EtCHF2 48c-BuCHF2
17i-PrMe49c-PenMe
18i-PrEt50c-PenEt
19i-Pri-Pr51c-Peni-Pr
20i-PrCH2-c-Pr52c-PenCH2-c-Pr
21i-PrCH2c-Pen53c-PenCH2c-Pen
22i-Prc-Bu54c-Penc-Bu
23i-Prc-Pen55c-Penc-Pen
24i-PrCHF256c-PenCHF2
25CH2-c-PrMe57CHF2Me
26CH2-c-PrEt58CHF2Et
27CH2-c-Pri-Pr59CHF2i-Pr
28CH2-c-Pr60CHF2CH2-c-Pr
29CH2-c-PrCH2c-Pen61CHF2CH2c-Pen
30CH2-c-Prc-Bu62CHF2c-Bu
31CH2-c-Prc-Pen63CHF2c-Pen
32CH2-c-PrCHF264CHF2CHF2

Table 6
No.R2R3No.R2R3
1MeMe33CH2c-PenMe
2MeEt34CH2c-PenEt
3Mei-Pr35CH2c-Peni-Pr
4MeCH2-c-Pr36 CH2c-PenCH2-c-Pr
5MeCH2c-Pen37CH2c-PenCH2c-Pen
6Mec-Bu38CH2c-Penc-Bu
7Mec-Pen39CH2c-Penc-Pen
8MeCHF240CH2c-PenCHF2
9EtMe41c-BuMe
10EtEt42c-BuEt
11Eti-Pr43c-Bui-Pr
12EtCH2-c-Pr44c-BuCH2-c-Pr
13EtCH2c-Pen45c-BuCH2c-Pen
14Etc-Bu46c-Buc-Bu
15Etc-Pen47c-Buc-Pen
16EtCHF2 48c-BuCHF2
17i-PrMe49c-PenMe
18i-PrEt50c-PenEt
19i-Pri-Pr51c-Peni-Pr
20i-PrCH2-c-Pr52c-PenCH2-c-Pr
21i-PrCH2c-Pen53c-PenCH2c-Pen
22i-Prc-Bu54c-Penc-Bu
23i-Prc-Pen55c-Penc-Pen
24i-PrCHF256c-PenCHF2
25CH2-c-PrMe57CHF2Me
26CH2-c-PrEt58CHF2Et
27CH2-c-Pri-Pr59CHF2i-Pr
28CH2-c-Pr60CHF2CH2-c-Pr
29CH2-c-PrCH2c-Pen61CHF2CH2c-Pen
30CH2-c-Prc-Bu62CHF2c-Bu
31CH2-c-Prc-Pen63CHF2c-Pen
32CH2-c-PrCHF264CHF2CHF2

Table 7
No.R2R3No.R2R3
1MeMe33CH2c-PenMe
2MeEt34CH2c-PenEt
3Mei-Pr35CH2c-Peni-Pr
4MeCH2-c-Pr36 CH2c-PenCH2-c-Pr
5MeCH2c-Pen37CH2c-PenCH2c-Pen
6Mec-Bu38CH2c-Penc-Bu
7Mec-Pen39CH2c-Penc-Pen
8MeCHF240CH2c-PenCHF2
9EtMe41c-BuMe
10EtEt42c-BuEt
11Eti-Pr43c-Bui-Pr
12EtCH2-c-Pr44c-BuCH2-c-Pr
13EtCH2c-Pen45c-BuCH2c-Pen
14Etc-Bu46c-Buc-Bu
15Etc-Pen47c-Buc-Pen
16EtCHF2 48c-BuCHF2
17i-PrMe49c-PenMe
18i-PrEt50c-PenEt
19i-Pri-Pr51c-Peni-Pr
20i-PrCH2-c-Pr52c-PenCH2-c-Pr
21i-PrCH2c-Pen53c-PenCH2c-Pen
22i-Prc-Bu54c-Penc-Bu
23i-Prc-Pen55c-Penc-Pen
24i-PrCHF256c-PenCHF2
25CH2-c-PrMe57CHF2Me
26CH2-c-PrEt58CHF2Et
27CH2-c-Pri-Pr59CHF2i-Pr
28CH2-c-Pr60CHF2CH2-c-Pr
29CH2-c-PrCH2c-Pen61CHF2CH2c-Pen
30CH2-c-Prc-Bu62CHF2c-Bu
31CH2-c-Prc-Pen63CHF2c-Pen
32CH2-c-PrCHF264CHF2CHF2

Table 8
No.R2R3No.R2R3
1MeMe33CH2c-PenMe
2MeEt34CH2c-PenEt
3Mei-Pr35CH2c-Peni-Pr
4MeCH2-c-Pr36 CH2c-PenCH2-c-Pr
5MeCH2c-Pen37CH2c-PenCH2c-Pen
6Mec-Bu38CH2c-Penc-Bu
7Mec-Pen39CH2c-Penc-Pen
8MeCHF240CH2c-PenCHF2
9EtMe41c-BuMe
10EtEt42c-BuEt
11Eti-Pr43c-Bui-Pr
12EtCH2-c-Pr44c-BuCH2-c-Pr
13EtCH2c-Pen45c-BuCH2c-Pen
14Etc-Bu46c-Buc-Bu
15Etc-Pen47c-Buc-Pen
16EtCHF2 48c-BuCHF2
17i-PrMe49c-PenMe
18i-PrEt50c-PenEt
19i-Pri-Pr51c-Peni-Pr
20i-PrCH2-c-Pr52c-PenCH2-c-Pr
21i-PrCH2c-Pen53c-PenCH2c-Pen
22i-Prc-Bu54c-Penc-Bu
23i-Prc-Pen55c-Penc-Pen
24i-PrCHF256c-PenCHF2
25CH2-c-PrMe57CHF2Me
26CH2-c-PrEt58CHF2Et
27CH2-c-Pri-Pr59CHF2i-Pr
28CH2-c-Pr60CHF2CH2-c-Pr
29CH2-c-PrCH2c-Pen61CHF2CH2c-Pen
30CH2-c-Prc-Bu62CHF2c-Bu
31CH2-c-Prc-Pen63CHF2c-Pen
32CH2-c-PrCHF264CHF2CHF2

Table 9
No.R2R3No.R2R3
1MeMe33CH2c-PenMe
2MeEt34CH2c-PenEt
3Mei-Pr35CH2c-Peni-Pr
4MeCH2-c-Pr36 CH2c-PenCH2-c-Pr
5MeCH2c-Pen37CH2c-PenCH2c-Pen
6Mec-Bu38CH2c-Penc-Bu
7Mec-Pen39CH2c-Penc-Pen
8MeCHF240CH2c-PenCHF2
9EtMe41c-BuMe
10EtEt42c-BuEt
11Eti-Pr43c-Bui-Pr
12EtCH2-c-Pr44c-BuCH2-c-Pr
13EtCH2c-Pen45c-BuCH2c-Pen
14Etc-Bu46c-Buc-Bu
15Etc-Pen47c-Buc-Pen
16EtCHF2 48c-BuCHF2
17i-PrMe49c-PenMe
18i-PrEt50c-PenEt
19i-Pri-Pr51c-Peni-Pr
20i-PrCH2-c-Pr52c-PenCH2-c-Pr
21i-PrCH2c-Pen53c-PenCH2c-Pen
22i-Prc-Bu54c-Penc-Bu
23i-Prc-Pen55c-Penc-Pen
24i-PrCHF256c-PenCHF2
25CH2-c-PrMe57CHF2Me
26CH2-c-PrEt58CHF2Et
27CH2-c-Pri-Pr59CHF2i-Pr
28CH2-c-Pr60CHF2CH2-c-Pr
29CH2-c-PrCH2c-Pen61CHF2CH2c-Pen
30CH2-c-Prc-Bu62CHF2c-Bu
31CH2-c-Prc-Pen63CHF2c-Pen
32CH2-c-PrCHF264CHF2CHF2

Table 10
No.R2R3No.R2R3
1MeMe33CH2c-PenMe
2MeEt34CH2c-PenEt
3Mei-Pr35CH2c-Peni-Pr
4MeCH2-c-Pr36 CH2c-PenCH2-c-Pr
5MeCH2c-Pen37CH2c-PenCH2c-Pen
6Mec-Bu38CH2c-Penc-Bu
7Mec-Pen39CH2c-Penc-Pen
8MeCHF240CH2c-PenCHF2
9EtMe41c-BuMe
10EtEt42c-BuEt
11Eti-Pr43c-Bui-Pr
12EtCH2-c-Pr44c-BuCH2-c-Pr
13EtCH2c-Pen45c-BuCH2c-Pen
14Etc-Bu46c-Buc-Bu
15Etc-Pen47c-Buc-Pen
16EtCHF2 48c-BuCHF2
17i-PrMe49c-PenMe
18i-PrEt50c-PenEt
19i-Pri-Pr51c-Peni-Pr
20i-PrCH2-c-Pr52c-PenCH2-c-Pr
21i-PrCH2c-Pen53c-PenCH2c-Pen
22i-Prc-Bu54c-Penc-Bu
23i-Prc-Pen55c-Penc-Pen
24i-PrCHF256c-PenCHF2
25CH2-c-PrMe57CHF2Me
26CH2-c-PrEt58CHF2Et
27CH2-c-Pri-Pr59CHF2i-Pr
28CH2-c-Pr60CHF2CH2-c-Pr
29CH2-c-PrCH2c-Pen61CHF2CH2c-Pen
30CH2-c-Prc-Bu62CHF2c-Bu
31CH2-c-Prc-Pen63CHF2c-Pen
32CH2-c-PrCHF264CHF2CHF2

The method of obtaining the compounds of the present invention

The compound of the present invention represented by the formula (I)can be obtained by the following methods or by methods described in the examples.

[1] From among the compounds of the present invention represented by the formula (I), the following methods a)to C) can be obtained compound in which R6represents C1-alkoxygroup or C1-alkiline group, substituted phenyl group, and-OR2and-OR3do not represent a hydroxyl group, i.e. the compound represented by formula (IA)

(where R6-1represents C1-alkoxygroup or C1-alkiline group, substituted phenyl GRU who sing; -OR2-1and-OR3-1have the same value, OR2and-OR3provided that they do not represent a hydroxyl group; the other symbols have the same meanings as above).

a) Compound represented by formula (IA)can be obtained by the interaction of the compounds represented by formula (II-1)

(where all the symbols have the same meanings as above),

with the compound represented by formula (III-1)

(where R7is the group that you want (for example, a halogen atom, triftormetilfullerenov, methyloxirane or tosyloxy), and other symbols have the same meanings as above).

The reaction of the compound represented by formula (II-1), with the compound represented by formula (III-1)are known. For example, it is carried out at 0-100°in an inert organic solvent (e.g. dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, etc. in the presence of a base (e.g. potassium carbonate, calcium carbonate, sodium carbonate, cesium carbonate, triethylamine, pyridine, 2,6-lutidine, and so on).

b) the Compound represented by formula (IA)can be obtained by the interaction of the compounds represented by Faure who Ulai (II-2)

(where all the symbols have the same meanings as above),

with the compound represented by formula (III-2):

(where all the symbols have the same meanings as above).

The reaction of the compound represented by formula (II-2), with the compound represented by formula (III-2)are known. For example, it is carried out in a mixture of inert organic solvents (e.g. dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, dichloroethane, diethyl ether, tetrahydrofuran, acetonitrile, etc.) with acetic acid in the presence of a reducing agent (for example, triacetoxyborohydride sodium (NaBH(OAc)3), cyanoborohydride sodium (NaBH3CN), etc.) at 0-100°C.

c) among the compounds represented by formula (IA), the compound in which m is 1 and each R4and R5represents a hydrogen atom, i.e. a compound represented by formula (IA-1)

(where all the symbols have the same meanings as above),

can be obtained by the interaction of the compounds represented by formula (II-1), with the compound represented by formula (IV)

(where all the symbols have the same meanings as above).

The reaction of the compound represented what armoloy (II-1), with the compound represented by formula (IV)are known. For example, it is carried out in an inert organic solvent (e.g. dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, etc. in the presence of a base (e.g. potassium carbonate, calcium carbonate, sodium carbonate, cesium carbonate, triethylamine, pyridine, 2,6-lutidine, etc.) at 0-100°C.

[2] From among the compounds of the present invention represented by the formula (I), a compound in which at least one of COR6, -OR2and-OR3represents carboxyl group or hydroxyl group, i.e. the compound represented by formula (IB)

(COR6-2, -OR2-2and-OR3-2have the same meanings as-COR6, -OR2and-OR3provided that at least one of them represents a carboxyl group or hydroxyl group, and other symbols have the same meanings as above), can be obtained by the reaction of removing the protective group from the compound among the compounds of formula (IA)obtained by the above methods, in which-COR6-1, -OR2-1or3-1represents carboxyl group or a hydroxyl group protected by a protective group, i.e. compounds represented by FD is moloi (IA-2)

(COR6-3, -OR2-3and-OR3-3have the same meanings as-COR6, -OR2and-OR3provided that at least one of them represents a carboxyl group or a hydroxyl group protected by a protective group, and other symbols have the values specified above).

Examples of protective groups for the carboxyl group include methyl group, ethyl group, tert-boutelou group and benzyl group.

Examples of protective groups for the hydroxyl group include methoxymethyl group, 2-tetrahydropyranyloxy group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group and benzyl group.

The protective group for carboxyl group and hydroxyl group in particular is not limited by the above groups and can also be used by other groups as long as they can be easily and selectively removed. So, for example, can be used protective groups, which are indicated by T.W. Greene in Protective Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999.

The reaction of removal of these protective groups for carboxyl groups and hydroxyl groups are known and its examples include:

(1) the reaction of removing protection in an alkaline medium,

(2) the reaction of removing protection in acidic medium,

(3) reaction unprotect gidrol the way,

(4) the reaction of removal of the silyl group and the like reactions.

These methods are specifically described below.

(1) the Reaction of removing protection in alkaline medium is carried out, for example, in an organic solvent (e.g. methanol, tetrahydrofuran, dioxane, dimethylformamide and so on) using a hydroxide of an alkali metal (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide of alkaline earth metal (such as barium hydroxide, calcium hydroxide and so on) or a carbonate (e.g. sodium carbonate, potassium carbonate, etc.), organic amine (e.g. triethylamine, diisopropylethylamine, piperazine, etc.) or Quaternary ammonium salt (e.g. tetrabutylammonium fluoride and etc), or their aqueous solution, or a mixture thereof at a temperature of 0-40°C.

(2) the Reaction of removing protection in acidic medium is carried out, for example, in an organic solvent (e.g. methylene chloride, chloroform, dioxane, ethyl acetate, anisole etc) using organic acid (e.g. acetic acid, triperoxonane acid, methanesulfonic acid etc), inorganic acids (e.g. hydrochloric acid, sulfuric acid, etc. or their mixtures (for example, a mixture of Hydrobromic acid/acetic acid etc) at 0-100°C.

(3) Reaction unprotect the hydrolysis is carried out,for example, in a solvent such as a system on the basis of simple ether (e.g. tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), system-based alcohol (e.g. methanol or ethanol), a system based on benzene (for example, benzene, toluene and so on), the system on the basis of a ketone (e.g. acetone, methyl ethyl ketone and so on), the system on the basis of a nitrile (e.g. acetonitrile etc), system-based amide (e.g. dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixture of two or more of these solvents, in the presence of a catalyst (e.g. palladium on carbon, palladium mobiles, palladium hydroxide, platinum oxide, Raney-Nickel etc) under normal or increased pressure in the atmosphere of hydrogen or in the presence of ammonium formate at a temperature of 0-200°C.

(4) the Reaction of removal of the silyl groups are, for example, in an organic solvent miscible with water (e.g., tetrahydrofuran, acetonitrile, etc.) using tetrabutylammonium fluoride at a temperature of 0-40°C.

As specialists in this field, the target compound of the present invention can be easily obtained using these methods remove the protection.

[3] From among the compounds of the present invention represented by the formula (I), the compound in which R6is-NHO, and-OR2and-OR3do not represent a hydroxyl group, i.e. the compound represented by formula (IC)

(where all the symbols have the same meanings as above),

can be obtained by removing protection from a compound represented by the formula (V)

(where R8represents a protective group for hydroxamic acids and other symbols have the same meanings as above).

The protective group for hydroxamic acids include tert-boutelou group, -C(CH3)2-Och3, benzyl group, tert-butyldimethylsilyloxy group and tetrahydropyran-1-ilen group, but without any particular restrictions can also be used for other groups as long as they can be easily and selectively removed. So, for example, can be used protective groups specified by T.W. Greene in Protective Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999.

The reaction of removal of these protective groups for hydroxamic acids are known and examples include:

(1) the reaction of removing protection in an alkaline medium,

(2) the reaction of removing protection in acidic medium,

(3) reaction unprotect hydrolysis,

(4) the reaction of removal of the silyl group and the like reactions.

These reactions can implement the above methods.

[4] among connected to the second present invention, represented by formula (I), the compound in which R6is-NHOH, and at least one of-OR2and-OR3represents a hydroxyl group, i.e. the compound represented by formula (ID)

(OR2-4and-OR3-4have the same value, OR2and-OR3provided that at least one group represents a hydroxyl group, and other symbols have the same meanings as above),

can be obtained by the reaction of removing the protective group from the compound among the compounds of formula (IC), obtained above, in which-OR2-1or3-1represents a hydroxyl group protected by a protective group, i.e. compounds represented by formula (IC-1)

(OR2-5and-OR3-5have the same value, OR2and-OR3provided that at least one is a hydroxyl group protected by a protective group, and other symbols have the same meanings as above).

The reaction of removing the protective group can implement the above methods.

Compounds represented by formulas (II-1), (II-2), (III-1), (III-2), (IV) and (V)are known compounds or can be easily obtained by known methods.

So, for example, connect the tion, represented by formulas (II-1), (II-2), and (V)can be obtained by methods shown in the following reaction schemes 1-3.

In the reaction schemes IU represents a methyl group; Et represents an ethyl group; BOC is tert-butoxycarbonyl group; Ms is mesyl group; LiHMDS is hexamethyldisilazane lithium; TFU is triperoxonane acid and other symbols have the same meanings as above.

In reaction schemes 1 and 3 compounds used as starting compounds represented by formulas (VI), (X), (XIII) and (XVII)are known compounds or can be easily obtained by known methods.

In each presented in this description of the reaction, the reaction product can be purified by conventional methods of purification, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing and recrystallization. Cleaning can be performed in each reaction or after completion of several reactions.

[Pharmacological effects]

Inhibiting activity of the compounds of infusion is his invention, represented by formula (I)in respect of PDE4 was confirmed by the following tests.

Analysis of the enzyme in vitro

Test methods

In the environment PRMI 1640 containing 10% fetal calf serum, cultured U937 cells (originating from human monocytes). The U937 cells were collected and homogenized in 20 mm buffer Tris-HCl [pH 8.0, containing PMSF (1 mm), leupeptin (1 μg/ml) and pepstatin A (1 μg/ml). After centrifugation (15,000 rpm for 10 minutes) the supernatant was removed and filtered through 0.45 µm filter. The sample was placed on a MonoQ column (c strong anion-exchange resin, manufactured by Pharmacia) and was suirable NaCl when the density gradient from 0 to 0.8 M was Extracted fraction in which the activity of PDE disappeared under the effect of 10 μm of rolipram (inhibitor, selectively acting on PDE4) and used as the enzyme solution to determine the inhibitory activity against PDE4.

Enzymatic activity was measured by the following method. Mixed with 80 ál of diluted enzyme solution in phosphate buffer (pH 7.4)containing 0.1 mg/kg bovine serum albumin), 10 μl of a solution of the compound of the present invention (in 10% DMSO) and 10 μl of3H-camp (20000 counts/min, 10 μm) [in imidazole buffer (100 mm, pH 7.5)containing MgSO4(100 mm) and bovine serum albumin (1 mg/ml)] and incubated at room temperature t is within 30 minutes. The reaction was stopped by treatment of the reaction solution in the microwave for 2.5 minutes. After centrifugation (at 2000 rpm for 1 minute) was added to 10 μl of snake venom (1 mg/ml, manufactured by Sigma, trade name V7000) and incubated at room temperature for 30 minutes. On a column of aluminum oxide (100 μl) were placed 50 μl of the supernatant was suirable 80 μl of 0.005 N. hydrochloric acid and measured the radioactivity of the eluate.

The degree of inhibitory activity of compounds of the present invention in respect of PDE4 was calculated in accordance with the following equation:

The degree of inhibitory activity against PDE4 (%) = (1-radioactivity in the presence of compounds of the present invention/the radioactivity in the absence of compounds of the present invention) x 100.

To calculate the value of the IC50for each connection, as the concentration of the compounds of the present invention, which inhibits 50% of the activity of PDE4.

The test results presented in table 11.

Inhibitory activity against the production of TNF-α

Sample heparinization blood collected from a healthy person, were distributed in 96-well plate, 180 µl/well. Distributed solution of the compound of the present invention (the final concentration of DMSO: 0.1% or less) in an amount of 10 μl, and the plate was given the possibility the ü to stand at 37° C for 30 minutes in an incubator with 5% CO2. The reaction was initiated by adding 10 μl of LPS solution. After 6 hours incubation with CO2(5% CO2moistened) plate was shaken and centrifuged at 300×g for 5 minutes to extract 50 μl of the supernatant (plasma). The amount of TNF-α in the supernatant was measured using ELISA kit for TNF-α person (DIACLONE Cat. No. 850090096) in accordance with the applied method. In the result, it was found that the compound of the present invention shows a dose-dependent inhibitory activity.

[Toxicity]

The toxicity of the compounds of the present invention represented by the formula (I)is very low, so it is believed that the compound is relatively safe when used as a pharmaceutical preparation.

Industrial applicability

[Application in pharmacy]

Because the connection of the present invention has inhibitory activity against PDE4, it is assumed that it is useful for prevention and/or treatment of various diseases, such as inflammatory diseases (e.g., asthma, obstructive pulmonary disease, sepsis, sarcoidosis, nephritis, hepatitis, enteritis etc), diabetic diseases, allergic diseases (e.g. allergic rhinitis, allergic situation is ivit, seasonal conjunctivitis, atopic dermatitis, etc.), autoimmune diseases (e.g. ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriasis, multiple sclerosis, collagen disease, etc.), osteoporosis, bone fracture, obesity, depression, Parkinson's disease, dementia, impaired reperfusion ischemia, leukemia and AIDS.

The compound of the present invention represented by the formula (I), its non-toxic salt or its hydrate is usually administered systemically or topically and orally or parenterally, when they are used for such purposes.

Dose depending on the age, body weight, symptoms, therapeutic effect, the route of administration, duration of treatment, and similar factors. Usual adult administered orally from one to seven times a day from 1 to 1000 mg or administered parenterally, preferably intravenously) from one to seven times a day from 1 to 100 mg, or continuously injected through a vein in the course of time from 1 to 24 hours.

Because the dose varies depending on various conditions mentioned above, there are cases in which can be used to lower or higher doses than the dose in the above ranges.

The compound of the present invention represented by the formula (I)may be introduced in the form of solid compositions, liquid kompoziziii other compositions, intended for oral administration, injections, liniments, suppositories, eye drops, inhalation, etc. intended for parenteral administration.

Solid compositions for oral administration include tablets, pills, capsules, dispersible powders, granules and similar drugs.

Capsules include hard capsules and soft capsules.

In these solid compositions one or more active compounds are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or aluminum metasilicate magnesium. The composition can also contain additional additives other than the inert diluent, for example, lubricants such as magnesium stearate, a disintegrator such as picosatellites, stabilizers such as lactose, and a means of facilitating dissolution, such as glutamic acid and aspartic acid. If necessary, tablets or pills may be coated with a film soluble in the stomach or intersolubility means, such as sugar, gelatin, hydroxypropylcellulose and phthalate of hydroxypropylcellulose, or covered by two or more films. Moreover, to include capsules of absorbable material, such as chelation is N.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and similar drugs. In these liquid compositions, one or more active compounds contained in a generally used inert diluent (for example, purified water, alcohol). In addition, these compositions may also contain adjuvants, such as moisturizers or suspendresume tools, sweeteners, corrigentov and preservatives.

Other compositions for oral administration include sprays containing one or more active compounds, which get well-known methods. Such compositions, in addition to inert diluents may contain stabilizers, such as sodium bisulfate, buffers for isotonicity of the solution, isotonic solutions, such as sodium chloride, sodium citrate or citric acid. The method of preparation of aerosols is described in U.S. patent No. 2868691 and 3095355.

Injections for parenteral administration in the present invention include sterile aqueous or nonaqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include distilled water for injection and physiological saline. Non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols, that is their as ethanol, POLYSORBATE 80 (registered trademark), etc. Sterile aqueous and non-aqueous solutions, suspensions and emulsions can be used in the form of a mixture. Such compositions may additionally contain preservatives, humectants, emulsifiers, dispersing agents, stabilizers (e.g., lactose), auxiliary additives, such as solubilization (for example, glutamic acid, aspartic acid). They can be sterilized by filtration through bacteroidaceae filter, by incorporation of sterilizing agent or irradiation. For example, they can also produce in the form of sterile solid compositions which can be dissolved in distilled water or other sterile diluent, suitable for injection prior to use of liofilizirovannogo product.

Dosage form, liquid dosage forms, input drops intended for parenteral administration includes eye drops, eye drops in the form of suspensions, eye drops in the form of emulsions, eye drops, dissolved in their use, and liquid eye ointment.

These liquid medicines introduced drops, made known methods. For example, eye drops can be obtained, if necessary, by appropriate choice of isotonic means (e.g., sodium phosphate, ACET is that sodium and so on), surfactants (e.g. POLYSORBATE 80 (product name), polyoxy 40 stearate, castor oil, hydrogenated on polyoxyethylene, etc), solubilizers funds (sodium citrate, edetate sodium, etc.), preservatives (for example, benzylaniline, parabens etc) and similar substances. They are sterilized in the final stage or receive aseptic processing.

Means for inhalation for parenteral administration include aerosols, powders for inhalation and liquid for inhalation, the liquid for inhalation may be in the form that when using dissolved or suspended in water or in an appropriate environment.

These funds for inhalation can be obtained in accordance with known methods.

For example, a liquid for inhalation can be obtained if necessary by appropriate choice of preservatives (for example, benzylaniline, parabens etc), dyes, buffers (e.g., sodium phosphate, sodium acetate, etc.), isotonic means (e.g., sodium chloride, concentrated glycerin, etc.), thickeners (for example, carboxyvinyl polymer and so on), means that contribute to the absorption, and the like.

Powders for inhalation can be obtained if necessary by appropriate choice of lubricants (e.g. stearic acid is you, its salts, etc.), binders (e.g. starch, dextrin, etc.), excipients (e.g. lactose, cellulose, etc.), dyes, preservatives (for example, benzylaniline, parabens etc), tools that contribute to the absorption, and the like.

With the introduction of liquid for inhalation usually use the spray (e.g., spray, inhaler). When used for inhalation powders commonly used device for administration by inhalation powder tools.

Other compositions for parenteral administration include liquids for external use, liniments for percutaneous injection, ointments, suppositories for vnutribruchinnogo introduction, pessaries for intravaginal administration and similar products containing one or more active compounds, which can be obtained by known methods.

The best option of carrying out the invention

The present invention is explained in more detail below on the basis of the reference examples and examples; however the present invention is not limited.

The solvents in parentheses show the solvents for the manifestation or the elution ratio of the used solvents in% vol. when the chromatographic separations or TLC. The solvents in parentheses in the NMR spectrum shows the solvents for the dimension.

Reference the example 1

(tert-Butoxy)-N,N-bis(2-hydroxyethyl)carboxamide

To a solution in methylene chloride (200 ml) bis(2-hydroxyethyl)amine (20,0 g) at 0°C was added dropwise a solution of methylene chloride (50 ml) di-tert-BUTYLCARBAMATE (45.6 g), then stirred at 0°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 2:1 → 1:2 → only ethyl acetate), the result has been specified in the header connection (41,0 g)having the following physical properties.

TLC: Rf of 0.56 (chloroform:methanol = 10:1).

NMR (CDCl3): δ of 3.80 (s, 4H), 3.43 points (s, 4H), of 3.60 3.00 for (width, 2H), 1,47 (s, 9H).

Reference example 2

(tert-Butoxy)-N,N-bis(2-(methylsulfonylamino)ethyl)carboxamide

To a solution in methylene chloride (80 ml) of the compound (a 7.85 g)obtained in reference example 1, at -78° (C) was added by drop wise addition of triethylamine (16.0 ml) and methylchloride (8,89 ml). The reaction mixture was stirred at -78°C for 10 minutes and added to her water, then heated to room temperature. The reaction mixture was extracted with ethyl acetate (twice). The extract was washed with a saturated solution of salt. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, as a result received the decree is Noah in the title compound (13,2 g), having the following physical properties.

TLC: Rf of 0.64 (ethyl acetate).

NMR (CDCl3): δ 4,40-of 4.25 (m, 4H), 3,62 (shirt, J = 5.4 Hz, 4H), 3.04 from (s, 6H), to 1.48 (s,9H).

Reference example 3

tert-Butyl ester 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-icarbonell acid

To an anhydrous solution in tetrahydrofuran (30 ml) nitrile 2-(3-cyclopentyloxy-4-methoxyphenyl)ethane (2.50 g) at -78°C was added dropwise a 1.0 M hexamethyldisilazane lithium (LiHMDS, 24,0 ml in THF), then was stirred at -78°C for 20 minutes. To the reaction mixture was added dropwise a solution of tetrahydrofuran (10 ml) of the compound (2.17 g)obtained in reference example 2, and then heated to room temperature and was stirred for 2 hours. The reaction mixture was diluted with ice water and saturated salt solution and was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:diethyl ether = 2:1 → 1:2 → only diethyl ether), was obtained is listed in the title compound (1.78 g)having the following physical properties.

TLC: Rf of 0.56 (hexane:ethyl acetate = 2:1).

Reference example 4

The hydrochloride of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-lanap is peridine

To a solution in methylene chloride (10 ml) of the compound (1.68 g)obtained in reference example 3 at room temperature was added methyldibenzo (5 ml) and triperoxonane acid (5 ml), then stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with methylene chloride (twice). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added a 4 n solution of hydrogen chloride-ethyl acetate (1 ml) and the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate and filtered the precipitated solid substance in the received specified in the title compound (510 mg)having the following physical properties.

TLC: Rf of 0.33 (chloroform:methanol = 10:1).

NMR (CDCl3): δ 10,02 (Sirs, 2H), 7,10-7,00 (m, 2H), to 6.88 (d, J = 9.0 Hz, 1H), 4,82 (m, 1H), 3,86 (s, 3H), 3,80-of 3.60 (m, 2H), 3,50-3,30 (m, 2H), 2,80-2,60 (m, 2H), 2,40-of 2.20 (m, 2H), 2,10 and 1.80 (m, 6H), 1,80-to 1.60 (m, 2H,).

Example 1

Ethyl ester of 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

A mixture of the compound (300 mg)obtained in reference example 4, potassium carbonate (246 mg), dimethylformamide (4 ml) and ethyl ester of 2-bromoxynil acid (0.15 ml) was stirred at room temperature for 20 hours. The reaction mixture rasb ulali with ethyl acetate, washed with water and saturated saline solution in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 2:1 → 1:1 → only ethyl acetate), the result has been specified in the title compound (341 mg)having the following physical properties.

TLC: Rf 0.36 and (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,10-to 6.95 (m, 2H), 6,86 (d, J=8,8 Hz, 1H), 4,79 (m, 1H), 4,22 (kV, J=7,0 Hz, 2H), 3,85 (s, 3H), and 3.31 (s, 2H), 3,15-3,00 (m, 2H), 2,75-to 2.55 (m, 2H), 2,30-2,05 (m, 2H), 2,20-2,00 (m, 2H), 2,00-1,80 (m, 6H), 1,80 of 1.50 (m, 2H), of 1.30 (t, J=7.0 Hz, 3H).

Examples 1(1) - 1(14)

The following compounds of the present invention was obtained in the same manner as in example 1 using the compound obtained in reference example 4 or the corresponding amine derivative and ethyl ester of 2-bromoxynil acid or a corresponding halogen derivative.

Example 1(1)

Ethyl ester of 2-(4-(3,4-acid)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.33 (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,06 (DD, J=8,4, 2.4 Hz, 1H), 6,99 (d, J=2.4 Hz, 1H), 6.87 in (d, J=8,4 Hz, 1H), 4,22 (kV, J=7,4 Hz, 2H), 3,90 (s, 3H), with 3.89 (s, 3H), and 3.31 (s, 2H), 3,15-3,00 (m, 2H), 2,75-2,60 (m, 2H), 2,30-of 2.15 (m, 2H), 2,15-2,00 (m, 2H), of 1.30 (t, J=7.4 Hz, 3H).

Example 1(2)

Ethyl ester of 2-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic is sloty

TLC: Rf of 0.50 (ethyl acetate).

NMR (CDCl3): δ 7,30-to 6.95 (m, 2H), 6.87 in (d, J=8,4 Hz, 1H), 4,22 (kV, J=7.2 Hz, 2H), 4,10 (kV, J=7.2 Hz, 2H), 3,88 (s, 3H), and 3.31 (s, 2H), 3,13 was 3.05 (m, 2H), 2,73-2,60 (m, 2H), 2.26 and-of 2.15 (m, 2H), 2,12-2,05 (m, 2H), of 1.47 (t, J=7.2 Hz, 3H), of 1.30 (t, J=7.2 Hz, 3H).

Example 1(3)

Ethyl ester of 2-(4-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf 0.36 and (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,05 (DD, J=8,7, 2.7 Hz, 1H), 6,99 (d, J=2.7 Hz, 1H), 6.87 in (d, J=8.7 Hz, 1H), 4,22 (kV, J=7.2 Hz, 2H), 3,88 (s, 3H), 3,86 (d, J=6,9 Hz, 2H), 3,30 (s, 2H), 3,15-3,00 (m, 2H), 2,75-2,60 (m, 2H), 2,25-2,10 (m, 2H), 2,15-2,00 (m, 2H), of 1.30 (t, J=7.2 Hz, 3H), 1,40-1,20 (m, 1H), 0.70 to to 0.60 (m, 2H), 0,40-0,30 (m, 2H).

Example 1(4)

Ethyl ester of 2-(4-(3-isopropoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.34 (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,10-7,00 (m, 2H), 6.87 in (d, J=8,4 Hz, 1H), 4,54 (Sept, J=6.0 Hz, 1H), 4,22 (kV, J=7.2 Hz, 2H), 3,85 (s, 3H), 3,30 (s, 2H), 3,20-3,00 (m, 2H), 2,75-2,60 (m, 2H), 2,25-2,10 (m, 2H), 2,15-2,00 (m, 2H), to 1.37 (d, J=6.0 Hz, 6H), of 1.30 (t, J=7.2 Hz, 3H).

Example 1(5)

Ethyl ester of 2-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf 0.95 (chloroform:methanol = 9:1).

NMR (CDCl3): δ 7,02-7,00 (m, 1H), 6.90 to-to 6.80 (m, 2H), 4,67 (Quint, J=7.2 Hz, 1H), 4,22 (kV, J=7.2 Hz, 2H), a 3.87 (s, 3H), and 3.31 (s, 2H), 3,12 was 3.05 (m, 2H), 2,73-2,60 (m, 2H), 2,55 is 2.43 (m, 2H), 2,33 is 2.00 (m, 6H), 1.93 and-of 1.78 (m, 1H) 1,76 is 1.60 (m, 1H), 1,30 (t, J=7.2 Hz, 3H).

Example 1(6)

Ethyl ester of 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

TLC: Rf and 0.46 (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,05-to 6.95 (m, 2H), 6,85 (d, J=8.7 Hz, 1H), 4,79 (m, 1H), 4,30-to 4.15 (m, 2H), of 3.84 (s, 3H), 3,37 (kV, J=7,4 Hz, 1H), 3,10-2,95 (m, 2H), 2,90-to 2.65 (m, 2H), 2,20-2,00 (m, 4H), from 2.00 and 1.80 (m, 6H), 1,75-1,50 (m, 2H), 1,35 (d, J=7,4 Hz, 3H), 1,32 (t, J=7.2 Hz, 3H).

Example 1(7)

Ethyl ester of 4-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)butane acid

TLC: Rf of 0.48 (hexane:ethyl acetate = 2:3).

NMR (CDCl3): δ 7,02-6,98 (m, 2H), 6.87 in-6,84 (m, 1H), a 4.83 was 4.76 (m, 1H), 4,15 (kV, J=7.2 Hz, 2H), 3,85 (s, 3H), 3,05-of 2.97 (m, 2H), 2,52 is 2.43 (m, 4H), of 2.36 (t, J=7.2 Hz, 2H), 2,12-2,03 (m, 4H), 2,01 to 1.76 (m, 8H), 1,68-of 1.55 (m, 2H), 1.27mm (t, J=7.2 Hz, 3H).

Example 1(8)

Ethyl ester of 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)butane acid

TLC: Rf of 0.55 (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,02-6,98 (m, 2H), 6,88-6,83 (m, 1H), a 4.83 was 4.76 (m, 1H), 4,24 (kV, J=7,4 Hz, 2H), of 3.84 (s, 3H), 3,16-3,10 (m, 1H), 3,05-2,95 (m, 2H), 2.95 and-2,84 (m, 1H), 2,79-2,69 (m, 1H), 2.13 and is 2.01 (m, 4H), 2.00 in 1,54 (m, 10H), of 1.26 (t, J=7,1 Hz, 3H), of 0.95 (t, J=7.4 Hz, 3H).

Example 1(9)

Ethyl ester of 2-(4-(3-cyclopentyloxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.20 (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,16 (d, J=8,4 Hz, 1H), ,10 (d, J=2.4 Hz, 1H), 7,03 (DD, J=8,4, 2.4 Hz, 1H), 6,54 (t, J=75,3 Hz, 1H), a 4.83 (m, 1H), 4,22 (kV, J=7.2 Hz, 2H), and 3.31 (s, 2H), 3,20-3,00 (m, 2H), 2,80-2,60 (m, 2H), 2,30 is 2.10 (m,2H), 2,15-2,00 (m, 2H), 2,00-1,70 (m, 6H), 1.70 to 1.55V (m, 2H), of 1.30 (t, J=7.2 Hz, 3H).

Example 1(10)

Ethyl ester of 2-(4-(3-cyclopentyloxy-4-ethoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf to 0.80 (chloroform:methanol = 10:1).

NMR (CDCl3): δ 7,05-to 6.95 (m, 2H), 6,86 (d, J=9.0 Hz, 1H), 4,78 (m, 1H), 4,22 (kV, J=7.2 Hz, 2H), 4,06 (kV, J=7.2 Hz, 2H), 3,30 (s, 2H), 3,10-3,00 (m, 2H), 2,75-2,60 (m, 2H), 2,25-2,10 (m, 2H), 2,15-2,00 (m, 2H), 1,95 is 1.75 (m, 6H), 1.70 to 1.55V (m, 2H), 1,42 (t, J=7.2 Hz, 3H), of 1.30 (t, J=7.2 Hz, 3H).

Example 1(11)

Ethyl ester of 2-(4-(3-cyclopentyloxy-4-ethoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

TLC: Rf 0,41 (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,05-to 6.95 (m, 2H), 6,86 (d, J=9.0 Hz, 1H), 4,78 (m, 1H), 4,30-to 4.15 (m, 2H), 4,05 (kV, J=6,9 Hz, 2H), 3,36 (kV, J=6,9 Hz, 1H), 3,10-2,95 (m, 2H), 2,90-to 2.65 (m, 2H), 2,20-2,00 (m, 4H), from 2.00 and 1.80 (m, 6H), 1.70 to 1,50 (m, 2H), 1,42 (t, J=6.9 Hz, 3H), of 1.34 (d, J=6.9 Hz, 3H), 1,32 (t, J=6.9 Hz, 3H).

Example 1(12)

Ethyl ester of 2-(4-(3-cyclopentyloxy-4-isopropoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf 0,87 (chloroform:methanol = 9:1).

NMR (CDCl3): δ 7,01-6,97 (m, 2H), 6.89 in (d, J=7.8 Hz, 1H), 4.80 to 4,74 (m, 1H), 4,42 (Sept, J=6.0 Hz, 1H), 4,22 (kV, J=7,0 Hz, 2H), 3,30 (s, 2H), 3,12-to 3.02 (m, 2H), 2,72-2,61 (m, 2H), 2.26 and with 2.14 (m, 2H), 2,12-2,05 (m, 2H), 1,90 is 1.75 (m, 2H), 1,65 of 1.50 (m, 6H), is 1.31 (d, J=6.0 Hz, 6H), of 1.28 (t, J=7.0 Hz, 3H).

Example 1(1)

Ethyl ester of 2-(4-(3-isopropoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf to 0.63 (hexane:ethyl acetate = 1:3).

NMR (CDCl3): δ 7,17 (d, J=8,4 Hz, 1H), 7,11 (d, J=2.3 Hz, 1H), 7,05 (DD, J=8,4, 2.3 Hz, 1H), to 6.57 (t, J=75,5 Hz, 1H), 4,58 (Sept, J=6,1 Hz, 1H), 4,22 (kV, J=7.2 Hz, 2H), and 3.31 (s, 2H), 3,14-of 3.06 (m, 2H), 2,73-2,63 (m, 2H), 2.26 and-of 2.15 (m, 2H), 2.21 are 2,04 (m, 2H), 1,37 (d, J=6,1 Hz, 6H), of 1.30 (t, J=7.2 Hz, 3H).

Example 1(14)

Ethyl ester of 2-(4-(3-cyclohexyloxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.53 (hexane:ethyl acetate = 1:1).

NMR (CDCl3): δ 7,17 (d, J=8.6 Hz, 1H), 7,11 (d, J=2.3 Hz, 1H), 7,06 (DD, J=8,6, and 2.3 Hz, 1H), return of 6.58 (t, J=75,5 Hz, 1H), or 4.31 (m, 1H), 4,22 (kV, J=7.2 Hz, 2H), and 3.31 (s, 2H), 3,13-of 3.06 (m, 2H), 2,72 2.63 in (m, 2H), 2,25-of 2.15 (m, 2H), 2,12-2,03 (m, 2H), 1,99-1,89 (m, 2H), 1.85 to 1,72 (m, 2H), 1,66 of 1.50 (m, 2H), 1,50 is 1.23 (m, 4H), of 1.28 (t, J = 7.2 Hz, 3H).

Example 2

2-(4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

A mixture of compound (330 mg)obtained in example 1, ethanol (5 ml) and 2 N. aqueous sodium hydroxide solution (0,86 ml) was stirred at room temperature for 35 minutes. The reaction mixture was neutralized 2 N. hydrochloric acid (0,86 ml) and subjected to azeotropic distillation with toluene. The residue was purified column chromatography on silica gel (chloroform:methanol:water = 10:2:0,1), floor is Ali compound of the present invention (278 mg), having the following physical properties.

TLC: Rf is 0.22 (chloroform:methanol:acetic acid= 10:1:0,2).

NMR (CDCl3): δ 7,10-7,00 (m, 2H), to 6.88 (d, J=9.0 Hz, 1H), a 4.83 (m, 1H), 4,30-4,00 (width, 1H), 3,85 (s, 3H), 3,56 (sird, J=12,6 Hz, 2H), 3.46 in (s, 2H), 2,99 (shirt, J=12,6 Hz, 2H), of 2.51 (shirt, J=12,6 Hz, 2H), 2,19 (sird, J=12,6 Hz, 2H), 2.05 is is 1.75 (m, 6H), 1.70 to 1.55V (m, 2H).

Examples 2(1) - 2(14)

The following compounds of the present invention was obtained in the same manner as in example 2, using the compounds obtained in examples 1(1)-1(14)instead of the compound obtained in example 1.

Example 2(1)

2-(4-(3,4-Acid)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.38 (chloroform:methanol:acetic acid= 10:2:1).

NMR (DMSO-d6): δ 7,10-7,00 (m, 2H), 6,97 (d, J=9,3 Hz, 1H), of 3.78 (s, 3H), of 3.75 (s, 3H), 4,00 3.00 for (width, 1H), 3,23 (s, 2H), 3,05-2,95 (m, 2H), 2,65-of 2.50 (m, 2H), 2,20-of 1.95 (m, 4H).

Example 2(2)

2-(4-(3-Ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.30 (chloroform:methanol = 9:1).

NMR (CDCl3): δ 7,10-7,05 (m, 2H), 6,95-6,85 (m, 1H), 4,15 (kV, J=6,9 Hz, 2H), 3,88 (s, 3H), 3,50 is 3.40 (m, 4H), 3,10-2,95 (m, 2H), 2,60-to 2.40 (m, 3H), 2,25-of 2.15 (m, 2H), 1,49 (t = 6.9 Hz, 3H).

Example 2(3)

2-(4-(3-Cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf is 0.59 (chloroform:methanol:acetic acid= 10:2:1).

NMR (DMSO-d6): δ 7,05-to 6.95 (m, 3H), and 3.8 (d, J=6,9 Hz, 2H), 3,76 (s, 3H), 3,60-2,90 (width, 1H), 3.27 to (s, 2H), 3,05-2,95 (m, 2H), 2,70-of 2.50 (m, 2H), 2,20-of 1.95 (m, 4H), 1,20 (m, 1H), 0,65 is 0.55 (m, 2H), 0,40-0,25 (m, 2H).

Example 2(4)

2-(4-(3-Isopropoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.10 (ethyl acetate).

NMR (CDCl3): δ 7,15-7,00 (m, 2H), 6,95-6,85 (m, 1H), 4,59 (Sept, J=6.0 Hz, 1H), 3,86 (s, 3H), 3,60-to 3.50 (m, 2H), 3.46 in (s, 2H), 3,05-of 2.93 (m, 2H), 2,85-2,60 (m, 1H), 2,60-to 2.40 (m, 2H), 2,24-2,12 (m, 2H), 1,37 (d, J=6,0 Hz, 6H).

Example 2(5)

2-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.10 (ethyl acetate).

NMR (CDCl3): δ 7,10-7,00 (m, 1H), 6,95-6,85 (m, 2H), 4,71 (Quint, J=7.5 Hz, 1H), a 3.87 (s, 3H), 3,70 is 3.40 (m, 2H), 3,49 (s, 2H), 3,10-2,95 (m, 2H), 2.70 height is 2.00 (m, 9H), from 2.00 and 1.80 (m, 1H), 1,80-to 1.60 (m, 1H).

Example 2(6)

2-(4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

TLC: Rf of 0.67 (chloroform:methanol:acetic acid= 15:2:1).

NMR (DMSO-d6) 7,03-6,94 (m, 3H), 4,88-4,80 (m, 1H), of 3.73 (s, 3H), 3,30 (kV, J=7,1 Hz, 1H), 4,00-2,70 (width, 1H), 3.00 and-2,90 (m, 2H), 2,78 of 2.68 (m, 1H), 2,66-of 2.56 (m, 1H), 2,13-2,04 (m, 2H), 2,02 and 1.80 (m, 4H), 1,76-to 1.63 (m, 4H), 1,63 of 1.50 (m, 2H), 1,19 (d, J=7,1 Hz, 3H).

Example 2(7)

4-(4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)butane acid

TLC: Rf of 0.55 (chloroform:methanol = 8:1).

NMR (DMSO-d6): δ 7,03-6,94 (m, 3H), 4,87-to 4.81 (m, 1H), 3,74 (s, 3H), 3,31 (width, 1H), 3,01-2,96 (m, 2H), 2,44-of 2.38(m, 2H), 2,33-of 2.21 (m, 4H), 2,13-of 2.08 (m, 2H), 2.00 in was 1.94 (m, 2H), 1,92 of-1.83 (m, 2H), 1,76-to 1.63 (m, 6H), 1,62-and 1.54 (m, 2H).

Example 2(8)

2-(4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)butane acid

TLC: Rf value of 0.52 (chloroform:methanol = 9:1).

NMR (DMSO-d6): δ 7,02-6,93 (m, 3H), 4,87-4,80 (m, 1H), and 3.72 (s, 3H), 3,31 (width, 1H), 3,05 (t, J=7,4 Hz, 1H), 2,97-of 2.86 (m, 2H), 2,81-2,70 (m, 1H), 2,64-of 2.54 (m, 1H), 2,13-2,04 (m, 2H), 1,99 and 1.80 (m, 4H), 1,75-to 1.63 (m, 6H), 1,63-is 1.51 (m, 2H), 0,87 (t, J=7.4 Hz, 3H).

Example 2(9)

2-(4-(3-Cyclopentyloxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.35 (chloroform:methanol:acetic acid= 10:1:0,2).

NMR (DMSO-d6): δ 7,25-to 7.15 (m, 2H), to 7.09 (DD, J=8,1, 2.1 Hz, 1H), 7,01 (t, J=75,0 Hz, 1H), to 4.98 (m, 1H), 3,60-3,00 (width, 1H), 3,26 (s, 2H), 3,10-2,95 (m, 2H), 2,70-of 2.50 (m, 2H), 2,20-2,00 (m, 4H), from 2.00 and 1.80 (m, 2H), 1,80-to 1.60 (m, 4H), 1,65 of 1.50 (m,2H).

Example 2(10)

2-(4-(3-Cyclopentyloxy-4-ethoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf to 0.39 (chloroform:methanol:acetic acid= 10:1:0,2).

NMR (DMSO-d6): δ 7,05-of 6.90 (m, 3H), of 4.83 (m, 1H), 4.00 points (kV, J=6,9 Hz, 2H), 4,00 3.00 for (width, 1H), 3,23 (s, 2H), 3,05-2,95 (m, 2H), 2,65-of 2.50 (m, 2H), 2,15-1,90 (m, 4H), 1,95-of 1.80 (m, 2H), 1,80-to 1.60 (m, 4H), 1,65 of 1.50 (m, 2H), 1,29 (t, J=6.9 Hz, 3H).

Example 2(11)

2-(4-(3-Cyclopentyloxy-4-ethoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

TLC: Rf of 0.47 (chloroform:methanol:acetic acid= 10:1:0,2).

NMR (DMSO-d6): δ 7,05-of 6.90 (m, 3H), of 4.83 (m, 1H), 3,99 (kV, J=6,9 Hz, 2H), 3,90-3,00 (width, 1H), and 3.31 (q, J=6,9 Hz, 1H), 3,05-to 2.85 (m, 2H), 2,73 (m, 1H), 2,61 (m, 1H), 2,15-2,00 (m, 2H), 2.05 is and 1.80 (m, 4H), 1,80-to 1.60 (m, 4H), 1,65 of 1.50 (m, 2H), 1,29 (t, J=6.9 Hz, 3H), 1,19 (d, J=6.9 Hz, 3H).

Example 2(12)

2-(4-(3-Cyclopentyloxy-4-isopropoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.20 (chloroform:methanol = 9:1).

NMR (CDCl3): δ? 7.04 baby mortality (d, J=2.1 Hz, 1H), 7,00 (DD, J=8,4, and 2.1 Hz, 1H), 6,91 (d, J=8,4 Hz, 1H), 4,84-4,78 (m, 1H), of 4.44 (Sept, J=6.0 Hz, 1H), 3,48-to 3.34 (m, 4H), 3,02-2,90 (m, 2H), 2,48-of 2.30 (m, 2H), 2,20-of 1.75 (m, 9H), 1,70-to 1.60 (m, 2H), 1,32 (d, J=6.0 Hz, 6H).

Example 2(13)

2-(4-(3-Isopropoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.35 (chloroform:methanol:acetic acid= 10:2:1).

NMR (DMSO-d6): δ to 7.25 (d, J=2.2 Hz, 1H), 7,21 (d, J=8,4 Hz, 1H), 7,11 (DD, J=8,4, 2.2 Hz, 1H),? 7.04 baby mortality (t, J=74,6 Hz, 1H), 4,74 (Sept, J=5,9 Hz, 1H), 3,31 (width, 1H), 3,23 (s, 2H), 3,05 are 2.98 (m, 2H), 2,63 of $ 2.53 (m, 2H), 2,14-to 1.98 (m, 4H), of 1.28 (d, J=5,9 Hz, 6H).

Example 2(14)

2-(4-(3-Cyclohexyloxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.50 (chloroform:methanol:acetic acid= 10:2:1).

NMR (DMSO-d6): δ 7,26 (d, J=2.1 Hz, 1H), 7,21 (d, J=8.5 Hz, 1H), 7,10 (DD, J=8,5, and 2.1 Hz, 1H), 7,03 (t, J=74,6 Hz, 1H), to 4.52 (m, 1H), 3.33 and (width, 1H), 3,19 (s, 2H), 3,06-of 2.97 (m, 2H), 2,61-of 2.50 (m, 2H), 2,15-to 1.98 (m, 4H), 1.93 and-to 1.82 (m, 2H), 1,75-of 1.64 (m, 2H), 1.55V is 1.25 (m, 6H).

Reference example 5

N-(1-M the Teal-1-methoxyethyl)-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)ndimethylacetamide

The compound (239 mg)obtained in example 2, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 192 mg), 1-hydroxybenzotriazole (HOBt, 135 mg), dimethylformamide (4 ml) and (1-methoxy-1-methylethyl)Xiamen (0.35 ml) was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water (twice), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 1:1 → only ethyl acetate), the result has been specified in the title compound (289 mg)having the following physical properties.

TLC: Rf 0.26 (ethyl acetate).

NMR (CDCl3): δ 8,94 (Sirs, 1H), 7,05-of 6.90 (m, 2H), 6.87 in (d, J=8,4 Hz, 1H), to 4.81 (m, 1H), 3,86 (s, 3H), on 3.36 (s, 3H), 3,23 (s, 2H), 3,10-3,00 (m, 2H), 2,80-to 2.65 (m, 2H), 2,20-2,00 (m, 2H), 2,10-of 1.75 (m, 8H), 1.70 to of 1.55 (m, 2H), 1,46 (s, 6H).

Example 3

The hydrochloride of N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)ndimethylacetamide

A mixture of compound (280 mg)obtained in reference example 5, methanol (3 ml) and 2 N. hydrochloric acid (0.35 ml) was stirred at room temperature for 1 hour. The reaction mixture was subjected to azeotropic distillation with toluene. The residue was ground and filtered with a simple isopropyl ether and a small amount of methanol, R is the result of the received connection of the present invention (189 mg), having the following physical properties.

TLC: Rf of 0.38 (chloroform: methanol = 10:1).

NMR (pyridine-d5+CDCl3): δ to 7.09 (d, J=2.4 Hz, 1H), 6,99 (DD, J=8,4, 2.4 Hz, 1H), to 6.88 (d, J=8,4 Hz, 1H), between 6.08 (Sirs, 3H), and 4.75 (m, 1H), and 3.72 (s, 3H), 3,30 (s, 2H), 3,02 (sird, J=14,4 Hz, 2H), 2,75-2,60 (m, 2H), 2,20-of 1.95 (m, 4H), 2,00-of 1.65 (m, 6H), 1.60-to of 1.40 (m, 2H).

Examples 4-4(11)

The following compounds of the present invention was obtained in the same manner as in reference example 5, → example 3 using the compound obtained in the examples 2(1) - 2(12), instead of the compound obtained in example 2.

Example 4

The hydrochloride of N-hydroxy-2-(4-(3,4-acid)-4-cyanopiperidine-1-yl)ndimethylacetamide

TLC: Rf 0.21 in (chloroform:methanol = 10:1).

NMR (pyridine-d5+CDCl3): δ 7,05-to 6.95 (m, 2H), 6,85 (d, J=9.0 Hz, 1H), 6,80-6,00 (width, 3H in), 3.75 (s, 6H), of 3.28 (s, 2H), 3,05-2,95 (m, 2H), 2,70 is 2.55 (m, 2H), 2,20-1,90 (m,4H).

Example 4(1)

The hydrochloride of N-hydroxy-2-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)ndimethylacetamide

TLC: Rf of 0.15 (ethyl acetate).

NMR (pyridine-d5+CDCl3): δ 8,30-7,00 (m, 5H), 6,93-6,87 (m, 1H), 3,95 (kV, J=6,9 Hz, 2H), 3,74 (s, 3H), 3,34 (s, 2H), 3,10-3,00 (m, 2H), 2,75-2,60 (m, 2H), 2,15-of 1.95 (m, 4H), of 1.33 (t, J=6.9 Hz, 3H).

Example 4(2)

The hydrochloride of N-hydroxy-2-(4-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)ndimethylacetamide

TLC: Rf 0.31 in (chloroform: methanol = 10:1).

NMR (pyridi the-d 5+CDCl3): δ 8,80-7,50 (width, 3H), was 7.08 (d, J=2.4 Hz, 1H), 7,02 (DD, J=8,4, 2.4 Hz, 1H), 6.87 in (d, J=8,4 Hz, 1H), 3,83 (d, J=6,9 Hz, 2H), of 3.73 (s, 3H), 3,30 (s, 2H), 3,10-2,90 (m, 2H), 2,70 is 2.55 (m, 2H), 2,15-of 1.95 (m, 4H), 1.26 in (m, 1H), 0.55 to 0.45 in (m, 2H), 0.35 to 0.25 in (m, 2H).

Example 4(3)

The hydrochloride of N-hydroxy-2-(4-(3-isopropoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)ndimethylacetamide

TLC: Rf is 0.22 (ethyl acetate).

NMR (pyridine-d5+CDCl3): δ 7,10 (d, J=2.1 Hz, 1H), 7,02 (DD, J=6,0, 2.1 Hz, 1H), to 6.88 (d, J=6.0 Hz, 1H), 6,25-of 5.50 (m, 3H), 4,51 (Sept, J=6.0 Hz, 1H), of 3.73 (s, 3H), of 3.28 (s, 2H), 3,05-2,95 (m, 2H), 2,75-to 2.55 (m, 2H), 2,15-1,95 (m, 4H), of 1.28 (d, J=6.0 Hz, 6H).

Example 4(4)

The hydrochloride of N-hydroxy-2-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl)ndimethylacetamide

TLC: Rf of 0.20 (ethyl acetate).

NMR (pyridine-d5+CDCl3): δ 7,05-7,00 (m, 2H), 6,95-to 6.88 (m, 1H), 6,80-of 6.20 (m, 3H)and 4.65 (Quint, J=6.9 Hz, 1H, in), 3.75 (s, 3H), 3,36 (s, 2H), 3,10-3,00 (m, 2H), 2,75-to 2.65 (m, 2H), 2.40 a-2,30 (m, 2H), 2,20-1,90 (m, 6H), 1,75-1,40 m, 2H).

Example 4(5)

The hydrochloride of N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanamide

TLC: Rf of 0.44 (chloroform:methanol = 10:1).

NMR (pyridine-d5+CDCl3): δ then 7.20 (d, J=2.3 Hz, 1H), to 7.09 (DD, J=8,3, 2.3 Hz, 1H), 6,94 (d, J=8,3 Hz, 1H), 6,45 (width, 3H), 4,82-of 4.75 (m, 1H), 3,74 (s, 3H), 3,53 (kV, J=6,9 Hz, 1H), 3,23-to 3.02 (m, 3H), 2,93-2,82 (m, 1H), 2.26 and is 2.10 (m, 4H), 1,95-of 1.65 (m, 6H), 1,53-of 1.41 (m, 2H), 1,47 (d, J=6.9 Hz, 3H).

Example 4(6)

The hydrochloride of N-hydroxy-4-(4-(3-cyclopent is loxi-4-methoxyphenyl)-4-cyanopiperidine-1-yl)butanamide

TLC: Rf to 0.63 (chloroform:methanol = 9:1).

NMR (pyridine-d5+CDCl3): δ 7,29 (d, J=2.6 Hz, 1H), 7,17 (DD, J=8,7, and 2.6 Hz, 1H), 6.87 in (d, J=8.7 Hz, 1H), 6,04 (width, 3H), 4,89 of 4.83 (m, 1H), and 3.72 (s, 3H), 3,32 of 3.28 (m, 2H), 2,90 2.63 in (m, 6H), 2,46 (t, J=6.9 Hz, 2H), 2.26 and with 2.14 (m, 4H), 1,92-of 1.85 (m, 4H), 1,80-of 1.66 (m, 2H), 1.56 to a 1.45 (m, 2H).

Example 4(7)

The hydrochloride of N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)butanamide

TLC: Rf of 0.54 (chloroform:methanol = 9:1).

NMR (pyridine-d5+CDCl3): δ then 7.20 (d, J=2.4 Hz, 1H), 7,10 (DD, J=8,5, 2.4 Hz, 1H), 6,92 (d, J=8.5 Hz, 1H), 6.35mm (width, 3H), a 4.83 was 4.76 (m, 1H), and 3.72 (s, 3H), 3,34 is 3.15 (m, 4H), 3,06-2,96 (m, 1H), 2,27-2,00 (m, 5H), 1,95-1, 62 (m, 7H), 1,54-of 1.39 (m, 2H), 0,99 (t, J=7.2 Hz, 3H).

Example 4(8)

The hydrochloride of N-hydroxy-2-(4-(3-cyclopentyloxy-4-deformational)-4-cyanopiperidine-1-yl)ndimethylacetamide

TLC: Rf of 0.36 (chloroform:methanol = 10:1).

NMR (pyridine-d5+CDCl3): δ of 7.23 (d, J=8,4 Hz, 1H), 7,18 (d, J=1.8 Hz, 1H), 6,97 (DD, J=8,4, 1.8 Hz, 1H), 6,97 (t, J=75,0 Hz, 1H), 6,60-the ceiling of 5.60 (width, 3H), 4,74 (m, 1H), and 3.31 (s, 2H), 3,10-3,00 (m, 2H), 2,70-2,60 (m, 2H), 2,20-2,00 (m, 4H), 1.85 to to 1.60 (m, 6H), 1.60-to of 1.40 (m, 2H).

Example 4(9)

The hydrochloride of N-hydroxy-2-(4-(3-cyclopentyloxy-4-ethoxyphenyl)-4-cyanopiperidine-1-yl)ndimethylacetamide

TLC: Rf of 0.36 (chloroform:methanol = 10:1).

NMR (pyridine-d5+CDCl3): δ 8,10-7,20 (width, 3H), 7,10 (d, J=2.1 Hz, 1H), 7,00 (DD, J=8,4, and 2.1 Hz, 1H), make 6.90 (d, J=8,4 Hz, 1H), amounts to 4.76(m, 1H), 3,97 (kV, J=6,9 Hz, 2H), and 3.31 (s, 2H), 3,10-2,95 (m, 2H), 2,75-2,60 (m, 2H), 2,20-of 1.95 (m, 4H), 2.00 in of 1.65 (m, 6H), 1.60-to of 1.40 (m, 2H), 1,31 (t, J=6.9 Hz, 3H).

Example 4(10)

The hydrochloride of N-hydroxy-2-(4-(3-cyclopentyloxy-4-ethoxyphenyl)-4-cyanopiperidine-1-yl)propanamide

TLC: Rf of 0.37 (chloroform:methanol = 10:1).

NMR (pyridine-d5+CDCl3): δ 7,14 (Sirs, 1H), 7,03 (sird, J=8,4 Hz, 1H), make 6.90 (d, J=8,4 Hz, 1H), 7,30-6,60 (width, 3H), of 4.77 (m, 1H), 3,97 (kV, J=7.2 Hz, 2H), 3,42 (m, 1H), 3,15-3,00 (m, 2H), 2,96 (m, 1H), 2,77 (m, 1H), 2,20-2,00 (m, 4H), 2.00 in to 1.60 (m, 6H), 1.60-to of 1.40 (m, 2H), 1,42 (d, J=6.6 Hz, 3H), of 1.31 (t, J=7.2 Hz, 3H).

Example 4(11)

The hydrochloride of N-hydroxy-2-(4-(3-cyclopentyloxy-4-isopropoxyphenyl)-4-cyanopiperidine-1-yl)ndimethylacetamide

TLC: Rf of 0.40 (chloroform:methanol = 9:1).

NMR (pyridine-d5+CDCl3): δ 7,15-7,10 (m, 1H), 7,05-of 6.90 (m, 2H), 5,80 to 5.35 (m, 3H), 4,78-4,72 (m, 1H), 4,46 (Sept, J=6.0 Hz, 1H), or 3.28 (s, 2H), 3.04 from-2,96 (m, 2H), 2,68-of 2.58 (m, 2H), 2,15-of 1.95 (m, 4H), 1,95-of 1.65 (m, 6H), 1,58-1,45 (m, 2H), 1,28 (d, J=6.0 Hz, 6H).

Example 5

Methyl ester of 3-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

To a solution in tetrahydrofuran (5 ml) of the compound (0.45 g)obtained in reference example 4, was added triethylamine (0,37 ml) and methyl acrylate (0,36 ml), then the mixture was stirred at 45°C for 1 day. The reaction mixture was cooled to room temperature, poured into water and was extracted with utilized the volume. The extract was washed with water and saturated saline solution in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 1:1), resulting in the received connection of the present invention (0,4505 g)having the following physical properties.

TLC: Rf is 0.42 (hexane:ethyl acetate = 2:3).

NMR (CDCl3): δ 7,02-6,97 (m, 2H), 6.87 in-6,83 (m, 1H), a 4.83 was 4.76 (m, 1H), 3,85 (s, 3H), 3,70 (s, 3H), 3,05-2,96 (m, 2H), of 2.81 (t, J=7.2 Hz, 2H), 2,59-2,49 (m, 2H), by 2.55 (t, J=7.2 Hz, 2H), 2,12-2,02 (m, 4H), 2,02-to 1.76 (m, 6H), 1.70 to 1,50 (m, 2H).

Example 6

Methyl ester of (2R)-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

(S)-(-)-Metallated (0,34 ml) was dissolved at 0°in methylene chloride (3 ml) in an argon atmosphere was added anhydrous triftormetilfullerenov acid (0,661 ml) and 2,6-lutidine (0,457 ml), then stirred at room temperature for 30 minutes. To the reaction mixture solution was added in methylene chloride (2.5 ml) of the compound (400 mg)obtained in reference example 4, and triethylamine (0,358 ml) in that order, after which it was stirred at room temperature for 18 hours. To the reaction mixture were added water (5 ml) to separate the liquids. The aqueous layer was extracted with ethyl acetate (5 ml x 3 times). The extract was mixed with organizes the m layer, was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 3:1), in the received connection of the present invention (492 mg)having the following physical properties.

TLC: Rf 0,90 (chloroform:methanol = 9:1).

NMR (CDCl3): δ 7,05-6,97 (m, 2H), 6.87 in-6,83 (m, 1H), 4,85-of 4.75 (m, 1H), 3,84 (s, 3H), 3,76 (s, 3H), 3,39 (kV, J=7,0 Hz, 1H), 3,10-2,95 (m, 2H), 2,85 of 2.68 (m, 2H), 2,15-2,05 (m, 4H), 2.00 in a 1.75 (m, 6H), 1,65-1,45 m, 2H), 1,35 (d, J=7,0 Hz, 3H).

Example 6(1)

Methyl ester (2S)-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

The compound of the present invention having the following physical properties was obtained in the same manner as in example 6, using (R)-(+)-metallichica instead of (S)-(-)-metallichica.

TLC: Rf 0,90 (chloroform:methanol = 9:1).

NMR (CDCl3): δ 7,05-6,97 (m, 2H), 6.87 in-6,83 (m, 1H), 4,85-of 4.75 (m, 1H), 3,84 (s, 3H), 3,76 (s, 3H), 3,39 (kV, J=7,0 Hz, 1H), 3,10-2,95 (m, 2H), 2,85 of 2.68 (m, 2H), 2,15-2,05 (m, 4H), 2.00 in a 1.75 (m, 6H), 1,65-1,45 m, 2H), 1,35 (d, J=7,0 Hz, 3H).

Examples 7 - 7(2)

The following compounds of the present invention was obtained in the same manner as in example 2 using the compound obtained in example 5, example 6 or example 6(1), instead of the compound obtained in example 1.

Example 7

3-(4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanol the I acid

TLC: Rf of 0.43 (chloroform:methanol = 9:1).

NMR (DMSO-d6): δ 7,03-to 6.95 (m, 3H), 4,87-4,80 (m, 1H), 3,74 (s, 3H), 3,31 (width, 1H), 3,24-3,19 (m, 2H), 2,96-to 2.85 (m, 2H), 2,66 of $ 2.53 (m, 4H), 2,27-of 2.20 (m, 2H), 2,16-2,05 (m, 2H), 1,96 and 1.80 (m, 2H), 1,75-to 1.63 (m, 4 H), 1,63 is 1.48 (m, 2H).

Example 7(1)

(2R)-2-(4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

TLC: Rf of 0.20 (chloroform:methanol = 9:1).

NMR (CDCl3): δ 7,10-7,00 (m, 2H), 6.90 to-6,85 (m, 1H), 4,88-4,80 (m, 1H), 3,85 (s, 3H), 3,50 (chircu, J=7,0 Hz, 1H), 3,28 totaling 3.04 (m, 3H), 3.00 and-2,90 (m, 1H), 2,50-of 2.15 (m, 5H), 2.05 is and 1.80 (m, 6H), 1.70 to 1.55V (m, 2H), 1,48 (sird, J=7,0 Hz, 3H).

[α]D= +10,69 (0,305, DMSO).

Example 7(2)

(2S)-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

TLC: Rf of 0.20 (chloroform:methanol = 9:1).

NMR (CDCl3): δ 7,10-7,00 (m, 2H), 6.90 to-to 6.80 (m, 1H), 4,86-4,58 (m, 1H), 3,84 (s, 3H), 3,54-3,44 (m, 1H), 3,34-3,20 (m, 2H), 3,14-to 3.02 (m, 1H), 3.00 and-of 2.86 (m, 1H), 2,50 is 1.75 (m, 11H), 1,75-of 1.55 (m, 2H), 1,45 (sird, J=7,0 Hz, 3H).

[α]D= -10,40 (0,245, DMSO).

Examples 8 - 8(2)

The following compounds of the present invention was obtained in the same manner as in reference example 5, → example 3, using the compounds obtained in examples 7 - 7(2), instead of the compound obtained in example 2.

Example 8

The hydrochloride of N-hydroxy-3-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanamide

TLC: Rf value of 0.52 (chloroform:methanol = 9:1).

NMR (pyridine-d5+CDCl3): δ of 7.23 (d, J=2.2 Hz, 1H), 7,11 (DD, J = 8,5, 2.2 Hz, 1H), to 6.88 (d, J = 8.5 Hz, 1H), 6,53 (width, 3H), a 4.86-rate 4.79 (m, 1H), and 3.72 (s, 3H), 3,37 of 3.28 (m, 2H), or 3.28 (t, J = 7.2 Hz, 2H), 2,93-and 2.83 (m, 2H), 2,85 (t, J = 7.2 Hz, 2H), 2,59-2,48 (m, 2H), 2,15-2,10 (m, 2H), 1,92-of 1.84 (m, 4H), 1,80-of 1.65 (m, 2H), and 1.54-1.41 to (m, 2H).

Example 8(1)

Hydrochloride (2R)-N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanamide

TLC: Rf of 0.45 (chloroform:methanol = 9:1).

NMR (pyridine-d5+CDCl3): δ 7,08-7,00 (m, 1H), 7,00-to 6.95 (m, 1H), 6,85 (d, J=8.7 Hz, 1H), 5,95-of 5.50 (m, 3H), 4.80 to 4.72 in (m, 1H), of 3.73 (s, 3H), 3,38-of 3.25 (m, 1H), is 3.08 are 2.98 (m, 2H), 2,90 is 2.75 (m, 1H), 2,75-2,60 (m, 1H), 2,15-2,00 (m, 4H), 1,95-of 1.65 (m, 6H), 1,55-of 1.45 (m, 2H), 1,43 (sird, J=6.6 Hz, 3H).

[α]D= +8,76 (from 0.37, DMSO).

Example 8(2)

Hydrochloride, (2S)-N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanamide

TLC: Rf of 0.45 (chloroform:methanol = 9:1).

NMR (pyridine-d5+CDCl3): δ 7,11 (d, J=2.1 Hz, 1H), 7,02 (DD, J=2.1 a, 8,7 Hz, 1H), to 6.88 (d, J=8.7 Hz, 1H), 6,80-of 6.20 (m, 3H), 4.80 to 4.72 in (m, 1H), and 3.72 (s, 3H), 3,40 (chircu, J=6,9 Hz, 1H), 3,14-to 3.02 (m, 2H), 3.00 and-is 2.88 (m, 1H), 2,82-2,70 (m, 1H), 2,20-2,05 (m, 4H), 1,95-of 1.65 (m, 6H), 1,55-of 1.45 (m, 2H), 1,41 (d, J=6.9 Hz, 3H).

[α]D= -8,72 (0.15, DMSO).

Reference example (6)

1-(3-Cyclopentyloxy-4-methoxyphenyl)cyclopent-3-uncarbonated

2-(3-Cyclopentyloxy-4-methoxyphenyl)eternity is l (4.0 g) was dissolved in tetrahydrofuran (75 ml) in an argon atmosphere and the resulting solution at -78° With added dropwise tertrahydrofuran ring solution (40,4 ml) 1.0 M hexamethyldisilazane lithium, and then was stirred at -78°C for 1 hour. The reaction mixture was diluted with saturated aqueous ammonium chloride and was extracted with ethyl acetate. The extract was washed with water and saturated saline solution in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 8:1), the result has been specified in the header connection (3,05 g)having the following physical properties.

TLC: Rf to 0.39 (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,00-to 6.95 (m, 2H), PC 6.82 (d, J=8.7 Hz, 1H), of 5.82 (s, 2H), 4,78 (m, 1H), 3,84 (s, 3H), 3,35-3,20 (m, 2H), 3.00 and-to 2.85 (m, 2H), 2.00 in a 1.75 (m, 6H), 1.70 to 1.55V (m, 2H).

Reference example 7

2-(3-Cyclopentyloxy-4-methoxyphenyl)-4-oxo-2-(2-oxoethyl)Botanical

The compound (460 mg)obtained in reference example 6, was dissolved in methylene chloride (10 ml)for 25 minutes at -78°in the resulting solution was purged ozone was added triphenylphosphine (513 mg), then stirred at -78°C for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to obtain specified in the title compound (1.27 g). The compound obtained IP who was olovely without purification in the next reaction.

Example 9

Benzyl ether of 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)-2-methylpropanoic acid

To the solution in dichloroethane (10 ml) of the compound (1.27 g)obtained in reference example 7, and benzyl ether of 2-amino-2-methylpropanoic acid (374 mg) was added triacetoxyborohydride sodium (1,03 g) and acetic acid (of 0.56 ml) in that order, then stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated saline solution in this order, dried with anhydrous sulfonate sodium and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 4:1), in the received connection of the present invention (196 mg)having the following physical properties.

TLC: Rf and 0.62 (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,45-7,30 (m, 5H), 7,05-to 6.95 (m, 2H), 6,85 (d, J=9.0 Hz, 1H), 5,19 (s, 2H), 4,80 (m, 1H), 3,84 (s, 3H), 3,05-2,95 (m, 2H), 2,80-2,60 (m, 2H), 2,10-2,00 (m, 4H), 2.05 is and 1.80 (m, 6H), 1,80 of 1.50 (m, 2H,), to 1.38 (s, 6H).

Examples 10 - 10(2)

Compounds of the present invention was obtained in the same manner as in reference example 6 → reference example 7 → example 9, using 2-(3-cyclopentyloxy-4-methoxyphenyl)ethnical or the corresponding derivative is of itria and benzyl ester 1-aminocyclopropane acid instead of the benzyl ester 2-amino-2-methylpropanoic acid.

Example 10

Benzyl ester 1-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid

TLC: Rf of 0.50 (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,50-7,30 (m, 5H), 7,00 (d, J=2.1 Hz, 1H), 6,98 (DD, J=9,0, 2.1 Hz, 1H), at 6.84 (d, J=9.0 Hz, 1H), 5,19 (s, 2H), 4,80 (m, 1H), 3,84 (s, 3H), 3,65-to 3.50 (m, 2H), 3.00 and-2,90 (m, 2H), 2,10-2,00 (m, 2H), 2,00-of 1.75 (m, 8H), 1.70 to 1.55V (m, 2H), 1,40-of 1.35 (m, 2H), 1,00-of 0.95 (m, 2H).

Example 10(1)

Benzyl ester 1-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid

TLC: Rf of 0.48 (ethyl acetate:hexane = 1:3).

NMR (CDCl3): δ 7,45-7,28 (m, 5H), 7,02-6,97 (m, 2H), 6,85 (d, J=9.0 Hz, 1H), 5,20 (s, 2H), 4,12 (kV, J=7,0 Hz, 2H), a 3.87 (s, 3H), 3,62-3,51 (m, 2H), 3.00, it is only 2.91 (m, 2H), 2,08 is 2.00 (m, 2H), 1,90-to 1.79 (m, 2H), 1,47 (t, J=7.0 Hz, 3H), 1,38 is 1.34 (m, 2H), 0,99-0,94 (m, 2H).

Example 10(2)

Benzyl ester 1-(4-(3-methoxyethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid

TLC: Rf of 0.45 (ethyl acetate:hexane = 1:2).

NMR (CDCl3): δ 7,45-7,29 (m, 5H), 7,22 (d, J=2.4 Hz, 1H), 7,14 (DD, J=8,4 Hz, 2.4 Hz, 1H), to 6.88 (d, J=8,4 Hz, 1H), 5,23 (s, 2H), 5,19 (s, 2H), 3,88 (s, 3H), 3,61-to 3.50 (m, 2H), 3,53 (s, 3H), 3.00 and of 2.92 (m, 2H), 2,08 is 2.00 (m, 2H), 1,89-of 1.78 (m, 2H), 1,38 is 1.34 (m, 2H), 1,00-of 0.95 (m, 2H).

Example 11

Hydrochloride benzyl ester 1-(4-(3-hydroxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid

To a solution of methyl is chloride (10 ml) of the compound (1.8 g), obtained in example 10(2), was added a 4 n solution of hydrogen chloride-ethyl acetate (10 ml) and then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate, the obtained compound of the present invention (1.51 g)having the following physical properties.

TLC: Rf of 0.38 (ethyl acetate:hexane = 1:2).

NMR (CDCl3): δ 7,42-to 7.32 (m, 5H), 7,19 (d, J=2.7 Hz, 1H), 7,07 (DD, J=8,4 Hz, 2.7 Hz, 1H), 6,86 (d, J=8,4 Hz, 1H), 5,90-of 5.83 (Sirs, 1H), 5,22 (s, 2H), 4,50 is 4.36 (m, 2H), with 3.89 (s, 3H), 3,56-3,47 (m, 2H), 3.27 to 3,09 (m, 2H), 2,30-of 2.23 (m, 2H), 2,22-2,12 (m, 2H), 1,72-of 1.65 (m, 2H), 1.70 to 1,50 (width, 1H).

Example 12

Benzyl ester 1-(4-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid

To a solution in dimethylformamide (5 ml) of the compound (664 mg)obtained in example 11, at room temperature was added cyclopropylamine (0,22 ml) and potassium carbonate (518 mg) in that order and then the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and was extracted with ethyl acetate. The extract is washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline solution in this order, dried with anhydrous sodium sulfate and concentrated under reduced pressure. OS is atok was purified column chromatography on silica gel (hexane:ethyl acetate = 2:1), the result has been the connection of the present invention (763 mg)having the following physical properties.

TLC: Rf of 0.57 (ethyl acetate:hexane = 1:2).

NMR (CDCl3): δ 7,45-7,28 (m, 5H), 7,02-of 6.96 (m, 2H), 6.87 in-PC 6.82 (m, 1H), 5,19 (s, 2H), 3,88-a-3.84 (m, 5H), 3,61-to 3.49 (m, 2H), 3.00 and-2,90 (m, 2H), 2,08 of 1.99 (m, 2H), 1,90-to 1.77 (m, 2H), 1,38-of 1.32 (m, 2H), 0,98-to 0.96 (m, 2H), 0,69-and 0.61 (m, 2H), 0,40-0,33 (m, 3H).

Example 13

Benzyl ester 1-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid

To a suspension in tetrahydrofuran (5 ml) of the compound (664 mg)obtained in example 11, at room temperature was added triethylamine (0,21 ml), cyclobutanol (0,18 ml), triphenylphosphine (787 mg) and diethylcarbamoyl (0,47 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was purified column chromatography on silica gel (hexane:ethyl acetate = 7:2), in the received connection of the present invention (683 mg)having the following physical properties.

TLC: Rf value of 0.52 (ethyl acetate:hexane = 1:2).

NMR (CDCl3): δ 7,45-7,29 (m, 5H), 6,97 (DD, J=8,4 Hz, 2.4 Hz, 1H), 6.87 in (d, J=2.4 Hz, 1H), at 6.84 (d, J=8,4 Hz, 1H), 5,19 (s, 2H), 4,69 (Quint, J=7,0 Hz, 1H), 3,86 (s, 3H), 3,61-to 3.50 (m, 2H), 3.00 and-2,90 (m, 2H), 2,55-2,43 (m, 2H), 2,33-to 2.18 (m, 2H), 2,08 of 1.99 (m, 2H), 1,89 is 1.60 (m, 4H), 1,38 is 1.34 (m, 2H), 0,99-0,94 (m, 2H).

Example 14

2-(4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)-2-methylpropanoate acid

The compound (180 mg)obtained in example 9, was dissolved in methanol (4 ml) and tetrahydrofuran (4 ml), was added 10% palladium on carbon (20 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 1.5 hours. The reaction mixture was filtered using celite and the filtrate was concentrated. The residue was purified column chromatography on silica gel (chloroform:methanol:water = 10:2:0,1), in the received connection of the present invention (140 mg)having the following physical properties.

TLC: Rf of 0.34 (chloroform:methanol = 10:1).

NMR (DMSO-d6): δ 7,05-of 6.90 (m, 3H), 4,84 (m, 1H), 3,74 (s, 3H), 3,80-3,00 (width, 1H), 3,15-3,00 (m, 2H), 2,65-of 2.50 (m, 2H), 2,20-2,05 (m, 2H), 2,10-of 1.95 (m, 2H), from 2.00 and 1.80 (m, 2H), 1,80-to 1.60 (m, 4H), 1,65-of 1.55 (m, 2H), 1,25 (s, 6H).

Examples 14(1) - 14(4)

The following compounds of the present invention was obtained in the same manner as in example 14, by using the compound obtained in example 10, example 10(1), example 12 or example 13 instead of the compound obtained in example 9.

Example 14(1)

1-(4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid

TLC: Rf of 0.45 (chloroform:methanol = 10:1).

NMR (DMSO-d6): δ 12,29 (Sirs, 1H), 7,05-of 6.90 (m, 3H), 4,82 (m, 1H), of 3.73 (s, 3H), 3,45-3,30 (m, 2H), 2.95 and-to 2.85 (m, 2H), 2,10-of 1.95 (m, 2H), 2.00 in to 1.60 (m, 8H), 1,65 of 1.50 (m, 2H), 1,25-1,10 (m, 2H), 0,95-0,80 (m, 2H).

Example 14(2)

1-(4-(3-Ethoxy-4-methox is phenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid

TLC: Rf of 0.38 (dichloromethane:methanol = 9:1).

NMR (DMSO-d6): δ 12,45-12,15 (width, 1H), 7.03 is-6,93 (m, 3H), Android 4.04 (q, J=6.9 Hz, 2H, in), 3.75 (s, 3H), 3.45 points-to 3.35 (m, 2H), 2.95 and-of 2.86 (m, 2H), 2,09-to 1.98 (m, 2H), 1,86-1,72 (m, 2H), 1,32 (t, J=6.9 Hz, 3H), 1,21-of 1.16 (m, 2H), 0,92 is 0.86 (m, 2H).

Example 14(3)

1-(4-(3-Cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid

TLC: Rf of 0.35 (ethyl acetate:hexane = 1:1).

NMR (DMSO-d6): δ the 12,5 12,0 (width, 1H),? 7.04 baby mortality-6,93 (m, 3H), 3,82 (d, J=7.2 Hz, 2H), of 3.77 (s, 3H), 3.46 in-to 3.36 (m, 2H), 2,94-of 2.86 (m, 2H), 2,07-of 1.97 (m, 2H), 1.85 to 1,71 (m, 2H), 1,26-to 1.14 (m, 3H), 0,91-of 0.85 (m, 2H), 0.60 and of 0.53 (m, 2H), 0.35 to 0.28 in (m, 2H).

Example 14(4)

1-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid

TLC: Rf 0.36 and (dichloromethane:methanol = 19:1).

NMR (DMSO-d6): δ 12,5-12,1 (width, 1H), 7,01-6,93 (m, 2H), at 6.84 (d, J=1.8 Hz, 1H), 4,73 (Quint, J=7.5 Hz, 1H, in), 3.75 (s, 3H), 3,44-to 3.36 (m, 2H), 2.95 and-of 2.86 (m, 2H), 2,46 is 2.33 (m, 2H), 2,11 is 1.96 (m, 4H), 1,83-of 1.55 (m, 4H), 1,21-of 1.15 (m, 2H), 0,92-0,86 (m, 2H).

Examples 15 - 15(4)

The following compounds of the present invention was obtained in the same manner as in reference example 5, → example 3, using the compounds obtained in examples 14 - 14(4), instead of the compound obtained in example 2.

Example 15

The hydrochloride of N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)-2-methylpropanamide

TLC: Rf of 0.38 (chloroform:methanol = 10:1).

NMR (pyridine-d5+CDCl3): δ 7,14 (d, J=2.1 Hz, 1H), 6,99 (DD, J=8,4, and 2.1 Hz, 1H), 6,91 (d, J=8,4 Hz, 1H), 5,95 (Sirs, 3H), 4.72 in (m, 1H), of 3.73 (s, 3H), 3,10-3,00 (m, 2H), 2,80-to 2.65 (m, 2H), 2,20-2,00 (m, 4H), 2.00 in to 1.70 (m, 6H), 1,60-of 1.40 (m, 2H), 1.39 in (s, 6H).

Example 15(1)

The hydrochloride of N-hydroxy-1-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarboxamide

TLC: Rf of 0.45 (chloroform:methanol = 10:1).

NMR (pyridine-d5+CDCl3): δ for 7.12 (d, J=2.4 Hz, 1H), 6,99 (DD, J=8,4, 2.4 Hz, 1H), 6.87 in (d, J=8,4 Hz, 1H), 6.90 to-6,00 (width, 3H), and 4.75 (m, 1H), of 3.73 (s, 3H), 3.00 and-2,90 (m, 2H), 2,90-2,70 (m, 2H), 2,20-2,00 (m, 4H), 2.00 in to 1.60 (m, 6H), 1.60-to of 1.40 (m, 2H), 1,35-1,25 (m, 2H), 1,10-1,00 (m, 2H).

Example 15(2)

The hydrochloride of N-hydroxy-1-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarboxamide

TLC: Rf 0,42 (dichloromethane:methanol = 9:1).

NMR (pyridine-d5+CDCl3): δ 8,00-7,20 (width, 3H), to 7.09 (d, J=1.8 Hz, 1H),? 7.04 baby mortality (DD, J=8,4, 1.8 Hz, 1H), 6.89 in (d, J=8,4 Hz, 1H), 3,91 (kV, J=6,9 Hz, 2H), 3,74 (s, 3H), 2,99-and 2.79 (m, 4H), 2,19 is 2.10 (m, 4H), 1,37-of 1.27 (m, 5H), 1,09-of 1.03 (m, 2H).

Example 15(3)

The hydrochloride of N-hydroxy-1-(4-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarboxamide

TLC: Rf 0,60 (dichloromethane:methanol = 9:1).

NMR (pyridine-d5+CDCl3): δ 8,60-6,80 (width, 3H), 7,15 (d, J=2.0 Hz, 1H), 7,05 (DD, J=9,0, 2.0 Hz, 1H), 6,91 (d, J=9.0 Hz, 1H), 3,81 (d, J=6,9 Hz, 2H), of 3.73 (s, 3H), 2,9-and 2.79 (m, 4H), 2,20-2,02 (m, 4H), 1,37 to 1.31 (m, 2H), 1,31-1,20 (m, 1H), 1,08-of 1.03 (m, 2H), 0,55 of 0.47 (m, 2H), 0,32-0,26 (m, 2H).

Example 15(4)

The hydrochloride of N-hydroxy-1-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarboxamide

TLC: Rf of 0.64 (dichloromethane:methanol = 9:1).

NMR (pyridine-d5+CDCl3): δ 8,00-7,10 (width, 3H),? 7.04 baby mortality (d, J=2.1 Hz, 1H), 7,00 (DD, J=8,4, and 2.1 Hz, 1H), make 6.90 (d, J=8,4 Hz, 1H), to 4.62 (Quint, J=7.5 Hz, 1H, in), 3.75 (s, 3H), 3.00 and is 2.80 (m, 4H), 2,42-of 2.30 (m, 2H), 2.23 to-2,02 (m, 6H), 1,74 is 1.60 (m, 1H), 1,58-1,40 (m, 1H), 1,38-of 1.32 (m, 2H), 1,09-of 1.03 (m, 2H).

Examples 16 - 16(1)

The following compounds of the present invention was obtained in the same manner as in reference example 6 → reference example 7 → example 9, using the appropriate derived nitrile instead of 2-(3-cyclopentyloxy-4-methoxyphenyl)ethnical and using a corresponding derivative instead of the benzyl ester 2-amino-2-methylpropanoic acid.

Example 16

Ethyl ester of 2-(4-(3-benzyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf 0.31 in (hexane:ethyl acetate = 2:1).

NMR (CDCl3): δ 7,50-7,40 (m, 2H), 7,45-7,25 (m, 3H), 7,10-7,00 (m, 2H), 6.89 in (d, J=8.7 Hz, 1H), further 5.15 (s, 2H), 4,22 (kV, J=7.2 Hz, 2H), 3,88 (s, 3H), 3,30 (s, 2H), 3,15-3,00 (m, 2H), 2,70 is 2.55 (m, 2H), 2,20-2,05 (m, 2H), 2,15-of 1.95 (m, 2H), of 1.30 (t, J=7.2 Hz, 3H).

Example 16(1)

Methyl ester of 2-(4-(3-benzyloxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid is you

TLC: Rf 0.31 in (hexane:ethyl acetate = 1:1).

NMR (CDCl3): δ 7,42-7,30 (m, 5H), 7,20 (d, J=8,1 Hz, 1H), 7,18 (d, J=2.4 Hz, 1H), 7,07 (DD, J=8,1, 2.4 Hz, 1H), return of 6.58 (t, J=75,0 Hz, 1H), further 5.15 (s, 2H), 3,76 (s, 3H), of 3.32 (s, 2H), is 3.08 (dt, J=12,0, 2.7 Hz, 2H), of 2.66 (dt, J=12,0, 2.7 Hz, 2H), 2,18 (TD, J=12,0, 3,9 Hz, 2H), 2,09 is 2.01 (m, 2H).

Examples 17 - 17(1)

The following compounds of the present invention was obtained in the same manner as in example 14, by using the compound obtained in example 16 or example 16(1), instead of the compound obtained in example 9.

Example 17

Ethyl ester of 2-(4-(3-hydroxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.43 (hexane:ethyl acetate = 1:2).

NMR (CDCl3): δ 7,06 (d, J=2.4 Hz, 1H), 7,00 (DD, J=8,1, 2.4 Hz, 1H), 6,85 (d, J=8,1 Hz, 1H), 5,66 (width, 1H), 4,22 (kV, J=7.2 Hz, 2H), 3,90 (s, 3H), 3,30 (s, 2H), 3,11-3,03 (m, 2H), 2,72-2,62 (m, 2H), 2,20-2,04 (m, 4H), of 1.30 (t, J=7.2 Hz, 3H).

Example 17(1)

Methyl ester of 2-(4-(3-hydroxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.55 (chloroform:methanol = 9:1).

NMR (CDCl3): δ 7,16 (d, J=2.4 Hz, 1H), 7,13 (d, J=8,4 Hz, 1H), 7,02 (DD, J=8,4, 2.4 Hz, 1H), 6,54 (t, J=73,5 Hz, 1H), 3,76 (s, 3H), of 3.32 (s, 2H), of 3.07 (d, J=12.0 Hz, 2H), 2,66 (TD, J=12,0, 2.7 Hz, 2H), 2,16 (TD, J=13,5, 3,9 Hz, 2H), 2,12-2,03 (m, 3H).

Examples 18 - 18(2)

The following compounds of the present invention was obtained in the same manner as in example 13, using connect the tion, obtained in example 17 and example 17(1), instead of the compound obtained in example 11 and using cyclobutylamine alcohol or the corresponding alcohol.

Example 18

Ethyl ester of 2-(4-(3-(indan-2-yloxy)-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf and 0.62 (hexane:ethyl acetate = 1:2).

NMR (CDCl3): δ 7,26-7,16 (m, 4H), 7,09-7,05 (m, 2H), 6.90 to-6,86 (m, 1H), 5,20 (m, 1H), 4,22 (kV, J=7.2 Hz, 2H), 3,82 (s, 3H), 3,44-to 3.35 (m, 2H), and 3.31 (s, 2H), 3.27 to 3,19 (m, 2H), 3,14 was 3.05 (m, 2H), 2,73-2,63 (m, 2H,), and 2.26-of 2.16 (m, 2H), 2,15-to 2.06 (m, 2H), of 1.30 (t, J=7.2 Hz, 3H).

Example 18(1)

Methyl ester of 2-(4-(3-CYCLOBUTANE-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.54 (ethyl acetate:toluene = 1:1).

NMR (CDCl3): δ 7,17 (d, J=8,1 Hz, 1H), 7,02 (DD, J=8,1, 2.1 Hz, 1H), 6,97 (d, J=2.1 Hz, 1H), return of 6.58 (t, J=75,0 Hz, 1H), 4,69 (m, 1H), 3,76 (s, 3H), 3.33 and (s, 2H), to 3.09 (dt, J=12,3, 2.7 Hz, 2H), 2,66 (TD, J=12,3, 2,7 Hz, 2H), 2,54 is 2.43 (m, 2H), 2,29-to 2.13 (m, 4H), 2,11-2,02 (m, 2H), 1,89 (m, 1H), 1,72 (m, 1H).

Example 18(2)

Methyl ester of 2-(4-(3-(indan-2-yloxy)-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.29 (hexane:ethyl acetate = 1:1).

NMR (CDCl3): δ 7,27-7,16 (m, 6H), 7,07 (DD, J=8,1, 2.4 Hz, 1H), 6,38 (t, J=75,3 Hz, 1H), 5,26-5,20 (m, 1H), 3,76 (s, 3H), 3,41 (DD, J=16.5, and 6.3 Hz, 2H), 3,34 (s, 2H), 3,20 (DD, J=16.5, and 3,3 Hz, 2H), 3,11 (d, J=12.0 Hz, 2H), 2,69 (dt, J=12,0, 2.4 Hz, 2H), 2,28-2,19 (m, 2H), 2,14-2,04 (m, 2H).

Examples 19 - 19(5)

Following the connection of the present invention was obtained in the same way, as in example 12, using the compound obtained in example 17(1), instead of the compound obtained in example 11 and using cyclopropanemethylamine or corresponding halogen derivative.

Example 19

Methyl ester of 2-(4-(3-cyclopropylmethoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf to 0.80 (chloroform:methanol = 9:1).

NMR (CDCl3): δ to 7.18 (d, J=8,1 Hz, 1H), to 7.09-7.03 is (m, 2H), 6,63 (t, J=75,6 Hz, 1H), 3,88 (d, J=6,9 Hz, 2H), 3,76 (s, 3H), of 3.32 (s, 2H), is 3.08 (dt, J=12,0, 2.7 Hz, 2H), 2,66 (TD, J=12,0, 2.7 Hz, 2H), 2,27-of 2.15 (m, 2H,), 2,12-2,05 (m, 2H), 1.28 (in m, 1 H), 0,69 to 0.63 (m, 2H), 0,40-0,33 (m, 2H).

Example 19(1)

Methyl ester of 2-(4-(3-cyclobutylmethyl-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf 0.84 (chloroform:methanol = 9:1).

NMR (CDCl3): δ 7,17 (d, J=8,4 Hz, 1H), to 7.09 (d, J=2.1 Hz, 1H), 7,05 (DD, J=8,4, and 2.1 Hz, 1H), to 6.57 (t, J=75,3 Hz, 1H), 3,99 (d, J=6.6 Hz, 2H), 3,76 (s, 3H), 3.33 and (s, 2H), to 3.09 (dt, J=11,7, 2.4 Hz, 2H), 2,81 (m, 1H), to 2.67 (dt, J=11,7, 2.4 Hz, 2H), 2,28-to 1.82 (m, 10H).

Example 19(2)

Methyl ester of 2-(4-(3-ethoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC Rf of 0.33 (hexane:ethyl acetate = 1:2).

NMR (CDCl3): δ 7,17 (d, J=8,4 Hz, 1H), to 7.09 (d, J=2.1 Hz, 1H),? 7.04 baby mortality (DD, J=8,4, and 2.1 Hz, 1H), to 6.57 (t, J=75,3 Hz, 1H), 4,11 (kV, J=6,9 Hz, 2H, in), 3.75 (s, 3H), of 3.32 (s, 2H), is 3.08 (d, J=12.0 Hz, 2H), 2,66 (dt, J=12,0, 2.7 Hz, 2H), 2.26 and-of 2.16 (m, 2H), 2,10-2,05 (m, 2H), and 46 (t, J=6.9 Hz, 3H).

Example 19(3)

Methyl ester of 2-(4-(3-butoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.57 (hexane:ethyl acetate = 1:1).

NMR (CDCl3): δ 7,17 (d, J=8.5 Hz, 1H), to 7.09 (d, J=2.2 Hz, 1H), 7,05 (DD, J=8,5, 2.2 Hz, 1H), 6,56 (t, J=75,0 Hz, 1H), a 4.03 (t, J=6.5 Hz, 2H), 3,76 (s, 3H), 3.33 and (s, 2H), 3,13 was 3.05 (m, 2H), 2,72-2,62 (m, 2H), 2,27-2,17 (m, 2H), 2,11-2,04 (m, 2H), 1,86 to 1.76 (m, 2H), 1.60-to a 1.45 (m, 2H), 0,99 (t, J=7.4 Hz, 3H).

Example 19(4)

Methyl ester of 2-(4-(3-propoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.56 (hexane:ethyl acetate = 1:1).

NMR (CDCl3): δ to 7.18 (d, J=8,1 Hz, 1H), 7,10 (d, J=2.4 Hz, 1H), 7,05 (DD, J=8,1, 2.4 Hz, 1H), to 6.57 (t, J=75,0 Hz, 1H), 3,99 (t, J=7,0 Hz, 2H), 3,76 (s, 3H), 3.33 and (s, 2H), 3,15-3,00 (m, 2H), 2,75-2,60 (m, 2H), 2,30-of 2.15 (m, 2H), 2,15-2,00 (m, 2H), 1,86 (Sextus, J=7,0 Hz, 2H), 1.06 a (t, J=7.0 Hz, 3H).

Example 19(5)

Methyl ester of 2-(4-(3-(2-methylpropoxy)-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.40 (hexane:ethyl acetate = 1:1).

NMR (CDCl3): δ to 7.18 (d, J=7.8 Hz, 1H), 7,10-7,00 (m, 2H), 6,56 (t, J=75,3 Hz, 1H), 3,78 (d, J=6.6 Hz, 2H), 3,76 (s, 3H), 3.33 and (s, 2H), 3,20-3,00 (m, 2H), 2,80-2,60 (m, 2H), 2,30-of 2.15 (m, 2H), 2,25-2,00 (m, 1H), 2,20-2,00 (m, 2H), of 1.05 (d, J=6.6 Hz, 6H).

Examples 20 - 20(8)

The following compounds of the present invention was obtained in the same manner as in example 2, using the compounds obtained in examples 18 - 18(2) or examples 19 - 19(5, instead of the compound obtained in example 1.

In addition, the compound in example 20(3) was converted into the hydrochloride by a known method.

Example 20

2-(4-(3-(Indan-2-yloxy)-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.68 (chloroform:methanol:acetic acid= 30:2:1).

NMR (DMSO-d6): δ 7,28-of 7.23 (m, 2H), 7,19-7,13 (m, 2H), 7,10 (d, J=1.8 Hz, 1H), 7,06 (DD, J=8,6, 1.8 Hz, 1H), 6,98 (d, J=8.6 Hz, 1H), 5,28 (m, 1H), 3,69 (s, 3H), 3,80-2,60 (width, 1H), 3,39-3,30 (m, 2H), 3,25 (s, 2H), 3,16 are 2.98 (m, 4H), 2,66 of $ 2.53 (m, 2H), 2,15-of 1.97 (m, 4H).

Example 20(1)

2-(4-(3-CYCLOBUTANE-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.67 (chloroform:methanol = 3:1).

NMR (DMSO-d6): δ 7,21 (d, J=8,1 Hz, 1H), 7,10 (DD, J=8,1, 2.1 Hz, 1H), was 7.08 (t, J=74,4 Hz, 1H), 7,06 (d, J=2.1 Hz, 1H), around 4.85 (m, 1H), 4,25-2,60 (Sirs, 1H), 3,24 (s, 2H), 3,01 (sird, J=12.0 Hz, 2H), 2,58 (shirt, J=12.0 Hz, 2H), 2,48-of 2.34 (m, 2H), 2,16-of 1.94 (m, 6H), 1.77 in (m, 1H), 1,62 (m, 1H).

Example 20(2)

2-(4-(3-(Indan-2-yloxy)-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf is 0.24 (chloroform:methanol:acetic acid= 9:1:0,1).

NMR (DMSO-d6): δ 7,32-7,14 (m, 7H), 6,91 (t, J=74,4 Hz, 1H), 5,43 lower than the 5.37 (m, 1H), 4,00-2,60 (width, 1H), 3,39 (DD, J=16,8, 6,0 Hz, 2H), 3,24 (s, 2H), 3,07-3,00 (m, 4H), 2,60 (dt, J=11,7, 3.0 Hz, 2H), 2,17-2,03 (m, 4H).

Example 20(3)

Hydrochloride of 2-(4-(3-cyclopropylmethoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic to the slots

TLC: Rf and 0.61 (chloroform:methanol = 2:1).

NMR (DMSO-d6): δ 7,21-7,14 (m, 2H), 7,02 (t, J=74,4 Hz, 1H), 7,01 (DD, J=8,7, and 2.1 Hz, 1H), 4,12 (s, 2H), 3.95 to 2,95 (Sirs, 2H), 3,85 (d, J=6,9 Hz, 2H), to 3.58 (sird, J=12.0 Hz, 2H), 3,23 (shirt, J=12.0 Hz, 2H), 2,54-2,31 (m, 4H), to 1.14 (m, 1H), 0,47 (m, 2H), 0,24 (m, 2H).

Example 20(4)

2-(4-(3-Cyclobutylmethyl-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.53 (chloroform:methanol = 3:1).

NMR (DMSO-d6): δ to 7.25 (d, J=2.4 Hz, 1H), 7,21 (d, J=8,4 Hz, 1H), 7,11 (DD, J=8,4, 2.4 Hz, 1H), 7,03 (t, J=74,4 Hz, 1H), 4,06 (d, J=6.6 Hz, 2H), 4,00-2,80 (Sirs, 1H), 3,24 (s, 2H), 3,02 (sird, J=12.0 Hz, 2H), 2,72 (m, 1H), 2,59 (TD, J=12,0, 2.7 Hz, 2H), 2,17-of 1.95 (m, 6H), 2.00 in a 1.75 (m, 4H).

Example 20(5)

2-(4-(3-Ethoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.15 (chloroform:methanol:acetic acid= 9:1:0,1).

NMR (DMSO-d6): δ 7,22-7,19 (m, 2H), to 7.09 (DD, J=8,4, and 2.1 Hz, 1H), 7,06 (t, J=74,4 Hz, 1H), 4,13 (kV, J=6,9 Hz, 2H), 4,00 3.00 for (width, 1H), 3,21 (s, 2H), 3,01 (d, J=12.0 Hz, 2H), 2.57 m (dt, J=11,7, 3.0 Hz, 2H), 2.13 and of 1.99 (m, 4H), 1,32 (t, J=6.9 Hz, 3H).

Example 20(6)

2-(4-(3-Butoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.56 (chloroform:methanol:acetic acid= 10:2:1).

NMR (CDCl3+ DMSO-d6): δ 7,17 (d, J=8,1 Hz, 1H), to 7.09 (DD, J=8,1, 2.1 Hz, 1H),? 7.04 baby mortality (d, J=2.1 Hz, 1H), to 6.57 (t, J=75,2 Hz, 1H), a 4.03 (t, J=6.5 Hz, 2H), 3,57 (width, 1H), 3,29 (s, 2H), 3,20-3,10 (m,2H), 2,72-2,61 (m, 2H), 2,30-2,19 (m, 2H), 2,13-2,05 (m, 2H), 1,86 to 1.76 (m, 2H), 1,58-of 1.44 (m, 2H), 0,99 (t, J=7.5 Hz, 3H).

Example 20(7)

2-(4-(3-Propoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf of 0.60 (chloroform:methanol:acetic acid= 10:2:1).

NMR (DMSO-d6): δ 12,40-11,00 (width, 1H), 7,30-to 7.15 (m, 2H), 7,11 (DD, J=8,7, 2.7 Hz, 1H), 7,05 (t, J=74,4 Hz, 1H), Android 4.04 (t, J=6.6 Hz, 2H), 3,23 (s, 2H), 3,10-2,95 (m, 2H), 2,70-of 2.50 (m, 2H), 2,20-2,00 (m, 4H), 1,74 (Sextus, J=6,6 Hz, 2H), and 0.98 (t, J=6.6 Hz, 3H).

Example 20(8)

2-(4-(3-(2-Methylpropoxy)-4-deformational)-4-cyanopiperidine-1-yl)acetic acid

TLC: Rf to 0.63 (chloroform:methanol:acetic acid= 10:2:1).

NMR (DMSO-d6): δ 12,20-10,80 (width, 1H), 7,25-7,20 (m, 2H), 7,11 (DD, J=8,7, 2.4 Hz, 1H),? 7.04 baby mortality (t, J=74,4 Hz, 1H), 3,86 (d, J=6.3 Hz, 2H), 3,23 (s, 2H), 3,10-2,95 (m, 2H), 2,65-of 2.50 (m, 2H), 2,20-2,00 (m, 5H), and 0.98 (d, J=6.6 Hz, 6H).

Reference example 8

3-(3-Cyclopentyloxy-4-methoxyphenyl)-2,4-bis(etoxycarbonyl)-5-hydroxy-5-methylcyclohexane-1-he

3 Cyclopentyloxy-4-methoxybenzaldehyde (30 g) and ethylacetoacetate (33,36 ml) was dissolved in ethanol (7 ml) was added piperidine (4 ml), then the reaction mixture was stirred at room temperature overnight. To the reaction mixture were added ethanol and after grinding solids were filtered. The filtrate was washed with ethanol to obtain when this is specified in the header connection to 37.1 g), having the following physical properties.

TLC: Rf of 0.55 (hexane:ethyl acetate = 1:1).

NMR (DMSO-d6): δ 6,87 (d, J=1.8 Hz, 1H), for 6.81 (d, J=8,4 Hz, 1H), 6.75 in (DD, J=8,4, 1.8 Hz, 1H), a 4.83 (s, 1H), 4.75 V-4,69 (m, 1H), 3.95 to 3,70 (m, 6H), to 3.67 (s, 3H), 3,26 (d, J=12.0 Hz, 1H), 2,90 (d, J=13.5 Hz, 1H), 2,31 (d, J=13.5 Hz, 1H), 1,90-of 1.78 (m, 2H), 1,78-to 1.63 (m, 4H), 1,63-of 1.53 (m, 2H), 1,23 (s, 3H), of 0.96 (t, J=7.2 Hz, 3H), of 0.87 (t, J=7.2 Hz, 3H).

Reference example 9

3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-carboxymethylamino acid

Connection (37,1 g)obtained in reference example 8, was dissolved in ethanol (370 ml) and tetrahydrofuran (200 ml) and the resulting mixture was added sodium hydroxide (200 g) and water (200 ml), then boiled under reflux for 5 hours. The reaction mixture was cooled to room temperature and under reduced pressure evaporated ethanol. The reaction mixture was neutralized with concentrated hydrochloric acid (410 ml) while cooling on ice and was extracted with ethyl acetate. The extract was washed with water and saturated saline solution in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to get this specified in the connection header (26,28 g)having the following physical properties. The compound obtained was used without purification in subsequent reactions.

TLC: Rf of 0.58 (chloroform:methanol = 5:1).

NMR (DMSO-d6): 4 12,01 (width, 2H), 6,83-6,79 (m, 2H), 6,72 (DD, J=8,3, 2.0 Hz, 1H), 4,77-4,71 (m, 1H), 3,68 (s, 3H), 3,38-3,30 (m, 1H), 2,59 (DD, J=15,6, 6.3 Hz, 2H), 2,46 (DD, J=15,6, and 8.4 Hz, 2H), 1,92-of 1.78 (m, 2H), 1,76-of 1.62 (m, 4H), 1,62-1,46 (m, 2H).

Reference example 10

4-(3-Cyclopentyloxy-4-methoxyphenyl)piperidine-2,6-dione

To the compound (26,28 g)obtained in reference example 9, was added urea (14.5 g) and then stirred at 165°C for 4 hours. The reaction mixture was cooled to room temperature and to it was added dichloromethane (150 ml). Insoluble substances were filtered off. The filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate and the residue was crushed, and then recrystallized. The obtained crystals were filtered and dried to obtain specified in the connection header (14,02 g)having the following physical properties.

TLC: Rf 0,77 (chloroform:methanol = 5:1).

NMR (DMSO-d6): δ 10,79 (s, 1H), 6.89 in-6,85 (m, 2H), 6.75 in (DD, J=8,4, and 2.1 Hz, 1H), amounts to 4.76 (m, 1H), 3,70 (s, 3H), at 3.35 (m, 1H), 2,77 (DD, J=16,8, to 10.8 Hz, 2H), 2,61 (DD, J=16,8, 4,7 Hz, 2H), 1,95-of 1.80 (m, 2H), 1,78-to 1.61 (m, 4H), 1,61 of 1.50 (m, 2H).

Reference example 11

The hydrochloride of 4-(3-cyclopentyloxy-4-methoxyphenyl)piperidine

Alumoweld lithium (7.0 g) suspended in tetrahydrofuran (150 ml) and the formed mixture was added dropwise a solution in tetrahydrofuran (150 ml) of the compound (7 g)obtained in referential in the ore 10, when the internal temperature of 30°s or less under ice cooling, and then stirred at room temperature for 3 hours. The reaction mixture was cooled with ice, and thereto was added dropwise a saturated aqueous solution of sodium sulfate (30 ml) at an internal temperature of 30°s or less, then stirred at room temperature for 1 hour. To the reaction mixture was added a simple ether (200 ml) and anhydrous magnesium sulfate, and then was stirred at room temperature for 2 hours. The reaction mixture was filtered using celite and the filtrate was concentrated under reduced pressure. To the residue was added a 4 n solution of hydrogen chloride-ethyl acetate (6 ml) and the mixture was stirred and then concentrated under reduced pressure to obtain specified in the title compound (7.2 g)having the following physical properties.

TLC: Rf of 0.15 (chloroform:methanol = 9:1).

NMR (DMSO-d6): δ 6,83 (d, J=8,1 Hz, 1H), 6,74 (d, J=1.9 Hz, 1H), of 6.68 (DD, J=8,1, 1.9 Hz, 1H), and 4.75 (m, 1H), 3,68 (s, 3H), 3,36 (m, 1H), 3,31 (width, 2H), 3,02-to 2.94 (m, 2H), 2,58-2,52 (m, 2H), 1,94-of 1.39 (m, 12H).

Example 21

Ethyl ester of 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)piperidine-1-yl)acetic acid

The compound of the present invention having the following physical properties was obtained in the same manner as in example 1, using the connection, the floor is built in reference example 11, instead of the compound obtained in reference example 4.

TLC: Rf and 0.61 (hexane:ethyl acetate = 1:1).

NMR (CDCl3): δ 6,82-of 6.71 (m, 3H), and 4.75 (m, 1H), 4,21 (kV, J=7.2 Hz, 2H), 3,82 (s, 3H), of 3.25 (s, 2H), 3,10-to 3.02 (m, 2H), 2,43 (m, 1H), 2,33-of 2.23 (m, 2H), 1,95 is 1.75 (m, 10H), 1.70 to 1,50 (m, 2H), 1,29 (t, J=7.2 Hz, 3H).

Example 22

2-(4-(3-Cyclopentyloxy-4-methoxyphenyl)piperidine-1-yl)acetic acid

The compound of the present invention having the following physical properties was obtained in the same manner as in example 2 using the compound obtained in example 21 instead of the compound obtained in example 1.

TLC: Rf of 0.44 (chloroform:methanol = 5:1).

NMR (DMSO-d6): δ to 6.88 (d, J=8,1 Hz, 1H), 6,79 (d, J=1.8 Hz, 1H), 6.73 x (DD, J=8,1, 1.8 Hz, 1H), 4,79-4,72 (m, 1H), 4,11 (s, 2H), 3,70 (s, 3H), 3,59-to 3.49 (m, 2H), 3,32 (width, 1H), 3,18 was 3.05 (m, 2H), 2,74 of 2.68 (m, 1H), 2,04 and 1.80 (m, 6H), 1.77 in-and 1.63 (m, 4H), 1,63 of 1.50 (m, 2H).

Example 1 obtaining a composition

The following components were mixed traditional method and was knocked out by a punch to obtain 100 tablets each containing 50 mg of active ingredient.

The hydrochloride of N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)ndimethylacetamide5.0 g
Calcixerollic (disintegrator)0.2 g
Magnesium stearate (lubricating agent)01 g
Microcrystalline cellulose4.7 grams

Example 2 obtaining a composition

The following components were mixed traditional method and the solution sterilized by the conventional method, was placed 5 ml in each vial and dried by freezing the traditional method to obtain 100 ampoules each containing 20 mg of active ingredient.

The hydrochloride of N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)ndimethylacetamide2.0 g
Mannitol20 g
Distilled water1000 ml

Table 11
Indicators PDE4 inhibitory activity (in vitro) compounds of formula (I)
Compound of example No.StructureIC50(nm)
266
30,03
4(5)0,41
1534
14(1) 46%

(at 1 μm)
15(1)4,6
2067
2(9)65
4(8)0,051
2(3)39%

(at 0.3 microns)
4(2)0,29

1. A derivative of piperidine derivatives represented by the formula (I)

where R1represents: 1) a hydrogen atom or 2) a cyano;

each R2and R3independently represents: 1) C1-alkiline group, 2) C3-7 cycloalkyl group, 3) C1-alkiline group, substituted C3-7 cycloalkyl group, 4) C1-alkiline group substituted by 1-3 halogen atoms, (5) a hydrogen atom, 6) C1-alkiline group, substituted phenyl group, 7) C1-alkiline group, substituted C1-8 alkoxygroup, or

in which n represents the number of 1-5;

each of R4and R5independently represents: 1) hydrogen atom or (2) C1-alkiline group, or

R4and R5

R6represents: 1) a hydroxyl group, 2) C1-alkoxygroup, 3) -NHOH or (4) C1-alkoxygroup, substituted phenyl group; and

m represents 0 or an integer 1-4,

or its non-toxic salt.

2. A derivative of piperidine according to claim 1, where the compound represented by formula (I)has the formula (I')

where R6'represents: 1) a hydroxyl group, 2) C1-alkoxygroup or (4) C1-alkoxygroup, substituted phenyl group; and other symbols have the same meaning, which is defined in claim 1, or its non-toxic salt.

3. A derivative of piperidine according to claim 1, where the compound represented by formula (I)has the formula (I")

where all symbols have the same meaning, which is defined in claim 1), or its non-toxic salt.

4. A derivative of piperidine according to claim 2, where R6'represents a hydroxyl group.

5. A derivative of piperidine according to claim 2, where R6'represents C1-8 alkoxygroup or C1-alkoxygroup, substituted phenyl group.

6. A derivative of piperidine according to claim 4, which is

(1) 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) acetic acid,

(2) 2-(4-(3,4-dimethoxy the Nile)-4-cyanopiperidine-1-yl)acetic acid,

(3) 2-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid,

(4) 2-(4-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid,

(5) 2-(4-(3-isopropoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) acetic acid,

(6) 2-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl) acetic acid,

(7) 2-(4-(3-cipointernet-4-methoxyphenyl)-4-cyanopiperidine-1-yl) propanoic acid

(8) 4-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) butane acid,

(9) 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) butane acid,

(10) 2-(4-(3-cipointernet-4-deformational)-4-cyanopiperidine-1-yl)acetic acid,

(11) 2-(4-(3-cyclopentyloxy-4-ethoxyphenyl)-4-cyanopiperidine-1-yl) acetic acid,

(12) 2-(4-(3-cipointernet-4-ethoxyphenyl)-4-cyanopiperidine-1-yl) propanoic acid

(13) 2-(4-(3-cyclopentyloxy-4-isopropoxyphenyl)-4-cyanopiperidine-1-yl) acetic acid,

(14) 2-(4-(3-isopropoxy-4-deformational)-4-cyanopiperidine-1-yl) acetic acid,

(15) 2-(4-(3-cyclohexyloxy-4-deformational)-4-cyanopiperidine-1-yl) acetic acid,

(16) 3-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) propanoic acid

(17) (2R)-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyano shall piperidin-1-yl) propanoic acid

(18) (2S)-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) propanoic acid

(19) 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)-2-methylpropanoyl acid,

(20) 1-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid,

(21) 1-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid,

(22) 1-(4-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) cyclopropanecarbonyl acid,

(23) 1-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarbonyl acid,

(24) 2-(4-(3-(indan-2-yloxy)-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid,

(25) 2-(4-(3-CYCLOBUTANE-4-deformational)-4-cyanopiperidine-1-yl) acetic acid,

(26) 2-(4-(3-(indan-2-yloxy)-4-deformational)-4-cyanopiperidine-1-yl) acetic acid,

(27) 2-(4-(3-cyclopropylmethoxy-4-deformational)-4-cyanopiperidine-1-yl) acetic acid,

(28) 2-(4-(3-cyclobutylmethyl-4-deformational)-4-cyanopiperidine-1-yl) acetic acid,

(29) 2-(4-(3-ethoxy-4-deformational)-4-cyanopiperidine-1-yl) acetic acid,

(30) 2-(4-(3-butoxy-4-deformational)-4-cyanopiperidine-1-yl) acetic acid,

(31) 2-(4-(3-propoxy-4-deformational)-4-cyanopiperidine-1-yl) acetic to the slot,

(32) 2-(4-(3-(2-methylpropoxy)-4-deformational)-4-cyanopiperidine-1-yl) acetic acid or

(33) 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)piperidine-1-yl) acetic acid.

7. A derivative of piperidine according to claim 5, which is

(1) ethyl ester of 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid,

(2) ethyl ester of 2-(4-(3,4-acid)-4-cyanopiperidine-1-yl)acetic acid,

(3) ethyl ester of 2-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) acetic acid,

(4) ethyl ester of 2-(4-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid,

(5) ethyl ester of 2-(4-(3-isopropoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid,

(6) ethyl ester of 2-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid,

(7) ethyl ester of 2-(4-(3-cipointernet-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

(8) ethyl ester of 4-(4-(3-cipointernet-4-methoxyphenyl)-4-cyanopiperidine-1-yl)butane acid,

(9) ethyl ester of 2-(4-(3-cipointernet-4-methoxyphenyl)-4-cyanopiperidine-1-yl)butane acid,

(10) ethyl ester of 2-(4-(3-cyclopentyloxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid,

(11) ethyl ester of 2-(4-(3-cyclopentyloxy-4-ethoxyphenyl)-4-canopy Eridan-1-yl)acetic acid,

(12) ethyl ester of 2-(4-(3-cyclopentyloxy-4-ethoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

(13) ethyl ester of 2-(4-(3-cyclopentyloxy-4-isopropoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid,

(14) ethyl ester of 2-(4-(3-isopropoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid,

(15) ethyl ester of 2-(4-(3-nikoletseas-4-deformational)-4-cyanopiperidine-1-yl)acetic acid,

(16) methyl ether 3-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

(17) methyl ester of (2R)-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

(18) methyl ester (2S)-2-(4-(3-cipointernet-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanoic acid

(19) benzyl ether of 2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)-2-methylpropanoic acid,

(20) benzyl ester 1-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarboxylic acid,

(21) benzyl ester 1-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) cyclopropanecarboxylic acid,

(22) benzyl ester 1-(4-(3-methoxyethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarboxylic acid,

(23) benzyl ester 1-(4-(3-hydroxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) cyclopropanecarbonyl key is lots

(24) benzyl ester 1-(4-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarboxylic acid,

(25) benzyl ester 1-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarboxylic acid,

(26) ethyl ester of 2-(4-(3-benzyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) acetic acid,

(27) methyl ester of 2-(4-(3-benzyloxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid,

(28) ethyl ester of 2-(4-(3-hydroxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) acetic acid,

(29) methyl ester of 2-(4-(3-hydroxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid,

(30) ethyl ester of 2-(4-(3-(indan-2-yloxy)-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetic acid,

(31) methyl ester of 2-(4-(3-CYCLOBUTANE-4-deformational)-4-cyanopiperidine-1-yl)acetic acid,

(32) methyl ester of 2-(4-(3-(indan-2-yloxy)-4-deformedarse-phenyl)-4-cyanopiperidine-1-yl)acetic acid,

(33) methyl ester of 2-(4-(3-cyclopropylmethoxy-4-deformedarse-phenyl)-4-cyanopiperidine-1-yl)acetic acid,

(34) methyl ester of 2-(4-(3-temporalelement-4-deformedarse-phenyl)-4-cyanopiperidine-1-yl)acetic acid,

(35) methyl ester of 2-(4-(3-ethoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid,

(36) methyl ester of 2-(4-3-butoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid,

(37) methyl ester of 2-(4-(3-propoxy-4-deformational)-4-cyanopiperidine-1-yl)acetic acid,

(38) methyl ester of 2-(4-(3-(2-methylpropoxy)-4-deformedarse-phenyl)-4-cyanopiperidine-1-yl)acetic acid or

(39) ethyl ester of 2-(4-(3-cyclopentyloxy-4-methoxyphenyl) piperidine-1-yl) acetic acid.

8. A derivative of piperidine according to claim 3, which is

(1) N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyano-piperidine-1-yl) acetamide", she

(2) N-hydroxy-2-(4-(3,4-acid)-4-cyanopiperidine-1-yl) acetamide", she

(3) N-hydroxy-2-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetamide", she

(4) N-hydroxy-2-(4-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-cyano-piperidine-1-yl)acetamide", she

(5) N-hydroxy-2-(4-(3-isopropoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetamide", she

(6) N-hydroxy-2-(4-(3-CYCLOBUTANE-4-methoxyphenyl)-4-cyanopiperidine-1-yl)acetamide", she

(7) N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) propanamide,

(8) N-hydroxy-4-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) butanamide,

(9) N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) butanamide,

(10) N-hydroxy-2-(4-(3-cyclopentyloxy-4-deformational)-4-cyanopiperidine-1-yl)acetamide", she

(11) N-hydroxy-2-(4-(3-cyclopentyloxy-4-amoxifen the l)-4-cyanopiperidine-1-yl) acetamide", she

(12) N-hydroxy-2-(4-(3-cyclopentyloxy-4-ethoxyphenyl)-4-cyanopiperidine-1-yl) propanamide,

(13) N-hydroxy-2-(4-(3-cipointernet-4-isopropoxyphenyl)-4-cyanopiperidine-1-yl)acetamide", she

(14) N-hydroxy-3-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) propanamide,

(15) (2R)-N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanamide,

(16) (2S)-N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)propanamide,

(17) N-hydroxy-2-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)-2-methylpropanamide,

(18) N-hydroxy-1-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl) cyclopropanecarboxamide,

(19) N-hydroxy-1-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarboxamide,

(20) N-hydroxy-1-(4-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-cyanopiperidine-1-yl)cyclopropanecarboxamide or

(21) N-hydroxy-1-(4-(3-zikopoulos-4-methoxyphenyl)-4-cyanopiperidine-1-yl) cyclopropanecarboxamide.

9. The PDE4 inhibitor containing as the active ingredient piperidine derivative represented by the formula (I) according to claim 1, or its non-toxic salt.

10. The remedy for the prevention and/or treatment of inflammatory diseases (eg, asthma, obstructive pulmonary disease, sepsis, sarcoidosis, nephritis, hepatitis, and EN is Erica), diabetic eye diseases, allergic diseases (e.g. allergic rhinitis, allergic conjunctivitis, seasonal conjunctivitis and atopic dermatitis), autoimmune diseases (e.g. ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriasis, multiple sclerosis and collagen disease), osteoporosis, bone fracture, obesity, depression, Parkinson's disease, dementia, disorders of reperfusion ischemia, leukemia and AIDS, containing as the active ingredient piperidine derivative represented by the formula (I) according to claim 1, or its non-toxic salt.

Priority on 11/08/2000 is set according to claims 1, 9 and 10 for compounds of formula (I) or their non-toxic salts with all the declared values radicals, except for the following:

R2and R3mean: 5) a hydrogen atom, 6) C1-alkiline group, substituted phenyl group, 7) C1-alkiline group, substituted C1-alkoxygroup, or

R4and R5taken together with the linking carbon atom, represent C3-7 saturated carbocyclic ring;

R6is 4) C1-alkoxygroup, substituted phenyl group.

Priority from 24.11.2000 is set according to claims 1, 9 and 10 for compounds of formula (I) or their non-toxic salts with visheizlojennie values radicals.



 

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The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to a piperidine derivative of General formula (I) where Z represents the group -(CH2)m-CH(OR3) or a carbonyl group, R1is hydrogen or (C1- C3)alkyl, R2- (C1- C3)alkyl, or R1and R2together form a chain -(CH2)n, where n is the number of 3 - 5, or -(CH2)2-O-(CH2)2-, m = 0 - 1, n = 1 - 2, R3- hydrogen or-COCH3and R4- hydrogen, -CH3, -OH or-OCH3provided that when Z represents a carbonyl group, h = 2, or their pharmaceutically acceptable salts

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new crystalline forms of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydoxybuthyl1-dymethylbenzeneacetic acid (), more particularly, to new form of A-phexophenadine having the next powder X-ray pattern (d, E): 23.11; 11.50; 8.29; 7.03; 6.67; 6.16; 6.02; 5.75; 5.43; 5.33; 5.07; 4.69; 4.63; 4.44; 4.20; 4.15; 4.07; 3.55;4.44; as well as to crystalline form of X-phexophenadine hydrochloride, having the next powder X-ray pattern (d, E): 16.05; 12.98; 8.29; 8.06; 6.25; 5.97; 5.54; 5.41; 4.89; 4.70; 4.55;4.37; 4.32; 4.15; 4.03; 3.80; 3.67; 3.57; 3.42; and to methods for production thereof. New crystalline phexophenadine forms of high purity (content of one isomer is higher than 99.5 %) are manufactured with essentially quantitative yield and are useful as antihistamine and antiallergic agents.

EFFECT: new phexophenadine forms useful as antihistamine and antiallergic agents.

18 cl, 10 dwg, 2 tbl, 5 ex

The invention relates to agriculture and veterinary medicine

The invention relates to new 4-substituted piperidines General formula (I) in which R1and R2represent aryl radicals, substituted or not substituted, which are obtained as racemic mixtures or as pure enantiomers

The invention relates to a derivative of biphenylamine General formula (1), where R1represents a hydrogen atom; L represents a direct bond or C1-4-alkylenes group; R2represents a carboxyl group;1-8-alkoxycarbonyl group; karbamoilnuyu group, and a nitrogen atom that is part of carbamoyl group, may be substituted mono - or di-C1-8is an alkyl group or may be a nitrogen atom in the amino acid; C1-8-alkylcarboxylic group; R3represents a hydrogen atom; X represents any of the groups-O-, -NH-CO-NH-, -N(R4)-, -CO-N(R5)-, -N(R5)-CO-, in which R4represents a hydrogen atom, a C1-10is an alkyl group, a C1-10-alkylcarboxylic group1-10-alkylsulfonyl group, R5represents a hydrogen atom, a C1-10is an alkyl group, Y represents a C4-8-cycloalkyl the group in which the methylene group in the C4-8-cycloalkyl may be substituted WITH1-8is an alkyl group WITH1-8-CNS group, carbamoyl group1-8-alkoxycarbonyl group, a carboxyl group, or the following 5-8-membered ring of formula I-1

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to a piperidine derivative of General formula I

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and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

The invention relates to new niftystories compounds of formula I, where R1and R2- H, -OH, -O(C1-C4alkyl), -OCOC6H5, -OCO(C1-C6alkyl), -OSO2(C4-C6alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, 1 hexamethyleneimino; intermediate compounds, which are suitable for easing symptoms of postmenopausal syndrome, including osteoporosis, hyperlipemia and estrogenzawisimy cancer, and inhibition of uterine fibroids, endometriosis and proliferation of aortic smooth muscle cells

The invention relates to new aryl-substituted derivatives of piperidine, which has antagonistic activity to the receptor NK3person, to a method for their production and to their use in pharmaceutical compositions

FIELD: pharmaceutical industry and technology.

SUBSTANCE: invention relates to a method for preparing oily extracts from vegetable raw. Method for preparing gum-tree oily extract involves drying branches with 70% of leaves, not less, to the definite moisture index and milled followed by their treatment with electric activated liquid at the definite pH value and in the definite amount of raw mass at stirring and keeping for a definite time. Then prepared mass is wetted with ethyl alcohol, dried to the definite moisture value and extraction is carried out under definite conditions and filtered. Method allows decreasing extraction time and enhancing the yield of total amount of extractive substances.

EFFECT: improved preparing method of extracts.

5 tbl, 9 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: method involves administering fluoroquinolone-series antibiotic like Ciproflaxin at a dose of 100-250 mg twice a day during 3-5 days and non-steroid anti-inflammatory preparation of Diclophenac at a dose of 75-150 mg/day during 3-7 days are sequentially introduced in preparing patient to diagnostic examination.

EFFECT: enhanced effectiveness in increasing method sensitivity.

2 tbl

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

SUBSTANCE: invention relates to methods for preparing 2-phenylamino-5-alkylphenylacetic acids of the general formula (I)

intermediate compounds for their preparing, their pharmaceutically acceptable salts and pharmaceutically acceptable prodrug esters wherein R, R1, R2, R3, R4 and R5 have corresponding values. Compound of the general formula (I) is prepared by splitting lactam of the formula (II): wherein symbols have values given in the description with a base, its precursors and methods for preparing these precursors. Abovementioned methods can comprise if necessary the temporal protection of all reaction groups showing effect followed by isolation of the prepared compound. Invention provides preparing compounds of the general formula (I) representing pharmaceutically active compounds that represent selective inhibitors of cyclooxygenase-2.

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

10 cl, 1 sch, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds able to prevent the extracellular release of inflammatory cytokines. Proposed compounds including their diastereomeric forms and their pharmaceutically acceptable salts correspond to the formula: wherein R means: (a) -O[CH2]kR3 or (b) -NR4aR4b; R3 means a substituted or unsubstituted (C1-C4)-alkyl, a substituted or unsubstituted phenyl wherein substitutes are taken among halogen atom, cyano-group, trihalidemethyl, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein R3 means hydrogen atom each among R4a and R4b means independently hydrogen atom or (C1-C4)-alkyl-CO- or benzo(1,3)dioxol; index k has a value from 0 to 5; each among R4a and R4b means independently: (a) hydrogen atom or (b) -[C(R5aR5b)2]mR6 wherein each Ra means hydrogen atom, and R5b means hydrogen atom, linear or branched (C1-C)-alkyl; R6 means vinyl, the group -OR7, -CO2R7, cyclic (C3-C)-alkyl, unsubstituted phenyl or phenyl substituted with (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein each among R3, R4a and R4b means independently hydrogen atom, or unsubstituted 6-membered nitrogen-containing heteroaryl; R7 means hydrogen atom, water-soluble cation or (C1-C4)-alkyl; index m has a value from 0 to 5. Also, invention relates to a pharmaceutical composition comprising the effective dose of compounds corresponding to abovementioned formula, and to a method for inhibition of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 sch, 6 tbl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a new compound, i. e. 3-(4-nitrobenzoylmethylene)-1H,4H-hexahydro-2-quinoxalone of the formula (I) possessing anti-inflammatory activity. Proposed compound possesses the reduced toxicity.

EFFECT: improved and valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new ortho-substituted and N-substituted indoles of the formula (α): or (β): or their pharmaceutically acceptable salts wherein Z1 represents -CR4 or nitrogen atom (N); R4 means hydrogen atom (H), (C1-C6)-alkyl comprising optionally oxygen atom (O) or nitrogen atom (N) possibly substituted with halogen atom, keto-group, 5-6-membered cycloaliphatic radical possibly comprising 1-2 oxygen atoms (O) or nitrogen atom (N); Z2 represents -CH or -CR wherein R means (C1-C6)-alkyl; R1 means compound of the formula: wherein X1 means -CO or its isostere; m = 0, 1; Y represents alkyl that can be substituted; or two Y form in common (C2-C3)-alkylene; n = 0, 1 or 2; Z3 represents -CH; X2 represents -CH, -CH2 or their isostere; Ar represents one or two phenyl groups bound with X2 wherein phenyl can be substituted; R2 represents hydrogen atom (H), (C1-C6)-alkyl or aryl wherein each aryl comprises, possibly, oxygen atom (O) or nitrogen atom (N) and can be substituted. Proposed compounds are selective inhibitors of p38α kinase.

EFFECT: valuable biochemical properties of compounds.

34 cl, 5 tbl, 23 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to composition possessing an anti-inflammatory effect and useful for oral administration in form of emulsion preliminary concentrate. Composition comprises NO-releasing nonsteroid anti-inflammatory drug, surface-active substance, oil or semisolid fat and forms in situ emulsion of type oil-in-water after contact with aqueous medium, such as gastroenteric fluid. Also, invention relates to a medicinal formulation based on thereof, oral emulsion, set based on thereof and a method for treatment of inflammation and pain. Proposed compositions possess the improved availability.

EFFECT: improved and valuable properties of composition.

40 cl, 1 tbl, 20 ex

FIELD: medicine, surgery.

SUBSTANCE: since the 2nd d after operation for 2 wk one should prescribe nimesulide per 100 mg twice daily, and on the 7th - 10th d after operation - microwave therapy onto thyroid area at the power of 2.5 W for 5 min at low-thermal mode, moreover, after hemithyroidectomy one should prescribe physiotherapy since the 7th d, after resection of isthmus - since the 8th d, after subtotal resection - since the 9th d, after total thyroidectomy - since the 10th d. The method provides enhanced secretion of thyroid hormones and compensation of hypothyroidism due to physiotherapy, that enables to get rid of hormonal substitution therapy or decrease its dosage.

EFFECT: higher efficiency.

1 ex

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