UA73094C2 - Arylpiperazines, method for obtaining thereof and pharmaceutical composition for inhibition of metalloproteinases - Google Patents

Abstract

Arylpiperazines of formula (I) useful as metalloproteinase inhibitors, especially as inhibitors of MMP 13. (1)

Description

Description of the invention

The present invention relates to compounds that can be used to inhibit metalloproteinases, and, in particular, to 2 pharmaceutical compositions containing them, as well as to their use.

The compounds of the present invention are inhibitors of one or more metalloproteinase enzymes.

Metalloproteinases are a superfamily of proteinases (enzymes), the number of which has increased dramatically in recent years. Based on the structural and functional features of these enzymes, they were divided into families and subfamilies, as described in M.M. Norreg (1994) REV5Z I eyege 354:1-6. Examples of metalloproteinases include 70 matrix metalloproteinases (MMPs), such as collagenases (MMRI, MMP8, MMRI13), gelatinases (MMP2, MMRO), stromelysins (MMP3, MMP1O, MMRI1), matrilysin (MMP7), metalloelastase (MMP12), enamelisin (MMP 19),

MT-MMP (MMP1I14, MMP15, MMRI16, MMP17); reprolysin or adamalisin, or the MOS family, which includes secretases and shedases, such as TNF-converting enzymes (ABAM 10 and TACE); the astacin family, which includes enzymes such as procollagen-processing proteinase (PCP); and other metalloproteinases, such as the aggrecanase 12-converting eudothelin family of enzymes and the angiotensin-converting family of enzymes.

Metalloproteinases are believed to play an important role in a variety of physiological disease processes that include tissue remodeling, such as embryonic development, bone formation, and changes in the uterus during menstruation. This is based on the ability of metalloproteinases to cleave a wide range of matrix substrates, such as collagen, proteoglycan and fibronectin. It is also believed that metalloproteinases play an important role in the processing or secretion of biologically important cellular mediators, such as tumor necrosis factor (TNF); and post-translational processing of proteolysis, or shelling, of biologically important membrane proteins, such as the low-affinity IDE receptor CO23 (for more complete information, see M.M. Nooregei a/., (1997) Biospet U 321:265-279).

Metalloproteinases are associated with many disease states. Inhibiting the activity of one or more of the c metalloproteinases can be beneficial for such disease states as, for example, various inflammatory or allergic diseases, such as joint inflammation (especially in the case of rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract ( especially intestinal inflammation, ulcerative colitis and gastritis), skin inflammation (especially psoriasis, eczema, dermatitis); tumor metastases or neoplasms; in diseases associated with the degradation of extracellular matrices, which is not controlled, such as osteoarthritis, in M resorptive bone diseases (such as osteoporosis or Patchet's disease (Radeig5)); in diseases, Ge") associated with aberrant angiogenesis; with increased collagen changes associated with diabetes, periodontal diseases (such as gingivitis), corneal ulceration, skin ulcers, postoperative conditions (such as rectal anastomosis) and skin wound healing; with demyelinating diseases of the central and peripheral nervous system (such as multiple sclerosis), with Alzheimer's disease; and changes in extracellular matrices observed in cardiovascular diseases, such as restenosis and atherosclerosis.

A number of metalloproteinase inhibitors are known; different classes of compounds can have different degrees of efficiency and selectivity in terms of inhibiting metalloproteinases. The authors discovered a new class of compounds that inhibit "metalloproteinases" and are of particular interest in inhibiting MMP-13 as well as MMP-9. Of the 50 Compounds of the present invention have good efficacy and/or pharmacokinetic characteristics. c MMRI3, or collagenase 3, was originally cloned from a cDNA library obtained from a breast tumor

From" M. M. R. Rgeie ei aiYi. (1994) dotsgpa! of Viioiodisai Spetivigu 269(24): 16766-16773)|. RSC-CMA analysis of RNA from a wide range of tissues shows that MMP1Z expression is restricted to breast carcinomas, as it was not detected in breast fibroadenomas, normal or quiescent, mammary gland, placenta, liver, ovary, uterus, prostate or thyroid gland or in breast and gland cancer cell lines (T147-Y0, MSE-7 and 2K75-1). After such observations, MMP1Z were detected in transformed epidermal keratinocytes (|M. Oopapezzop eia)., (1997) Se Stop OiSheg. 812u243-250), squamous cell carcinomas of IM. dopapvevop ei ai., (1997) At. .-). Heaven 151(2);499-508) and in epidermal tumors of the IK. Aigoia ei ai., (1997) 9. Ipmevi. YuOeptaiio!. 109(2):225-231|. These results suggest that MMRIZ (Te) 20 is secreted by transformed epithelial cells and may be involved in the degradation of extracellular matrices and in cell-matrix interactions associated with metastasis, particularly as observed in invasive

T" lesions of breast cancer and malignant epithelial growth during skin carcinogenesis.

The results presented in recent publications provide grounds for predicting that MMRIZ play a role in the transformation of other connective tissues. For example, in accordance with the specificity of the MMRIZ substrate and 29 the advantage of collagen type I degradation R. p. Myisneyi ei ai.,, (1996) U. Siip. Ipmevi 97 (3):761-768; M.

GF) Kpashreg ei ai., (1996) Tpe Viospetisa! doigpa! 271:1544-1550), it was hypothesized that MMRIZ play a role during primary ossification and changes in the skeleton (M. e(ape-Vaskaan!i ei ai., (1997) Ihar. Ipmevi. 76(5) o 717 -728; M. dopapzzop ei ai., (1997) YuOem. YuOup.. 208(35:387-397), in destructive joint diseases, such as rheumatoid arthritis and osteoarthritis | O. UUegpiske ei ai., (1996) 9 Kneshtaiyo!. 23:590-595; R. b. 60 Misney ei a). (1996) U. Sp. Ipmevi 97(3):761-768. 0. Ipadu eg am (1997) Agiyiv Kpect 40(8 ): 1391-1399) and during aseptic loosening of hip displacement |Z. Itai ei ai., (1998) U. Vope doipi Zygo. Hg. 89(4)3: 701-710). MMP13 was found to be involved in chronic periodontitis in adults, as they are localized in the epithelium of chronically inflamed gingival tissues of the human mucosa |M. U.O., (1998) At. IN). Rayo! 152(6) 1489-1499) and in the reconstruction of collagen matrices of unhealed wounds |M. Maaiato ei ai., bo (1997) 3. Ipmevi. Oegtayo!. 109(1):96-1011.

MMRAO (Seiipase B; 92kOa TureM SoiIIadepase; 92kOa Seiyapase) is a secreted protein that was first isolated, cloned and sequenced in 1989 (5.M. UMiNei!t eii a! (1989) u. Vioi Spet. 264 ( 29): 17213-17221. Rybriznea egtaisht ip 9. Vioi Spet. (1990) 265 (36): 22570). A recent MMRO review provides an excellent source of detailed information and references regarding this protease: T.N. We 5 7. MUegr (1998) (Ip: Maih

MegiaIorgoieipazez. 1998. Ediiey Bu MU.S. Ragke 5 K.R. Mespat rriI5-148. Asadetis Rhevzv. IBM 0-12-545090-7).

The following points are taken from this review by T.N. We are 52. Meg (1998).

MMRO expression is normally restricted to several cell types, including trophoblasts, osteoclasts, neutrophils, and macrophages. However, their expression can be induced in the same cells and in cells of other 7/0 types by some mediators, including exposure of the cells to growth factors or cytokines. These are the same mediators that are often associated with the initiation of an inflammatory response. As for other secreted MMPs, MMPR is released as an inactive proenzyme, which is then cleaved to form an enzymatically active enzyme. The proteases required for this ip mimo activation are not known. The balance of active MMROU relative to the inactive enzyme is further regulated by the interaction with TIMP-1 (Tissue inhibitor /5 metalloproteinase-1), a natural protein. TIMP-1 binds to the C-terminal region of MMRO, which leads to the inhibition of the catalytic domain of MMRO. The balance of induced expression of pro-MMRO, cleavage of pro-MMRO for activation and the presence of TIMP-1 is necessary to determine the amount of catalytically active MMRO that is present in the local site. Proteolytically active MMROs attack substrates that include gelatin, elastin, and natural type IM and type M collagenases; they are not active against native type I collagen, 2o proteoglycans, or lamins.

At this time, there is a growing body of data indicating the role of MMRAO in various physiological and pathological processes. The physiological role includes the invasion of embryonic trophoblasts through the uterine epithelium during the early stages of embryo implantation; some role in bone growth and development; and the migration of inflammatory cells from the vascular system into the tissues. The increased expression of IMROU is observed in some pathological conditions, which implies the participation of sch

MMRZ in disease processes such as arthritis, tumor metastases, Alzheimer's disease, multiple sclerosis and plaque formation in atherosclerosis leading to acute coronary conditions such as myocardial infarction. and)

In the first aspect, the present invention relates to compounds of formula I: ATX and

Vl. her

Vive Fo where ring B is a monocyclic or bicyclic alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ring, including up to 12 ring atoms, and containing one or more of heteroatoms, o independently selected from M, O and 5; alternatively, ring B may be biphenyl; ring B can be optionally connected to ring A by a C1-4 alkyl or C1-4 alkoxy chain connecting the 2-position of the ring

Zo B with a carbon atom in the alpha position relative to X2; i- each KZ is independently selected from hydrogen, halogen, MO2, SOOK, where K is hydrogen or C1-6 alkyl, CM,

SEZ, C1-6 alkyl, -5-C1-6 alkyl, -50-C1-6 alkyl, -502-C1-6 alkyl, C1-6 alkoxy and up to C10 aryloxy, n-1, 2 or 3; "

P is -(CPo)n where n is 0, 1,2, or P is an alkene or alkyne chain containing six carbon atoms; where X2 represents C, P can represent -Nei-, -"SNIBb|Y)p-He-, -Nek(kSN|IVb1|)p-or C c -He-(SNIKOVI)p-Nee, where Nei is chosen from -СО-, -5-, 5О-, -502-, -МКб-or -О-, where n-1 or 2, or P can be chosen "» from -СО-М(Кб)-, -МЩ( K6)-CO-, -502-M(K6)-and -M(K6)-502-, and Kb is hydrogen, C1-6 alkyl, up to C10 aralkyl " or up to CO heteroalkyl;

Ring A is a 5-7 membered aliphatic ring, and may be optionally mono- or di-substituted with optionally substituted C1-6 alkyl, or C1-6 alkoxy; and each of the substituents is optionally selected from halogen, C1-6 alkyl or an oxo group; 2) X1 and X2 are independently selected from M and C, where the ring substituent on ring A is an oxo group, and the substituent is preferably located next to the ring nitrogen atom; o XM is chosen from -502-i -CO-, со 20 7 is SOMNON, U is -CO-a ОО is chosen from -С(К6ХК7)-, -С(Кб6Ч7)-СН2-, -М(Кб) -and -М(Кб6)-СН2-, where Кб has the values indicated above, and only in relation to С), as defined here, Кб can also

T" represents up to C10 aryl and up to CO heteroaryl, and K7 represents H, C1-6 alkyl, or together with Kb forms a carbocyclic or heterocyclic spiro 5, 6, or 7 membered ring, and the latter contains at least one heteroatom , selected from M, O and 5; 59 7 represents -SOMNON, U represents -502 and CO) selected from -"С(К6ХК7)-, and - С(К6Х7)-СН2-;

F! or 7 is -Especially and O is selected from -CH(K6)-, -CH(K6)-CH2-, and -Х(К6)-CH2-;

K1 is H, C1-6 alkyl, C5-7 cycloalkyl, up to C10 aryl, up to C10 heteroaryl, up to C12 aralkyl, where or up to C12 heteroarylalkyl, all optionally substituted with up to three groups, independently selected with

MO2, SEZ, halogen, C1-4 alkyl, carboxy(C1-4) alkyl, up to Cb cycloalkyl, -OK4, -5K4, C1-4 alkyl, 60 substituted -OKA, KA (and their oxidized analogs), ME4, M-U-K4, or C1-4 alkyl-U-MV4, provided that if K1 represents -OH, -OK4, -54K4, or MK4, or М-М-К4, then 7 is not -ШЧОН) CHO, or K1 is 2, 3, 4, 5, b-pentafluorophenyl;

C4 is hydrogen, C1-6 alkyl, up to C10 aryl or up to C10 heteroaryl or up to C9 aralkyl, each independently optionally substituted with halogen, MO2, CM, SEZ, C1-6 alkyl, -5-C1- 6 alkyl, because -850-C1-6 alkyl, -502-C1-6 alkyl or C1-6 - alkoxy;

K2 is H, C1-6 alkyl, or together with K1 will form a carbocyclic or heterocyclic spiro 5, 6 or 7 membered ring, the latter containing at least one heteroatom selected from M, O, and 5;

In addition, the O group can be connected to either K1 or K2 to form a 5-, 6-, or 7-membered alkyl or heteroalkyl ring that includes one or more C0, 5, and M.

Any of the above alkyl groups can be linear or branched.

Suitable values for the aforementioned groups include: ring A is a 5-6 membered aliphatic ring, such as a piperazine ring, and may optionally be mono- or di-substituted with optionally substituted C1-6 alkyl or C1-6 alkoxy, wherein each of the substituents /o is independently selected from halogen, C1-6 alkyl or an oxo group;

KZ represents hydrogen, halogen, MO2, SEZ, C1-4 alkyl, and C1-4 alkoxy, n represents 1 or 2, for example, 4-fluoro, SEZ, 4-chloro, and 3,4-dichloro; ring B is a monocyclic or bicyclic aryl, aralkyl or heteroaryl containing up to 10 ring atoms, especially a monocyclic aryl, aralkyl or heteroaryl containing up to 7 ring atoms, especially a monocyclic aryl or heteroaryl containing up to 6 ring atoms, such as a phenyl or pyridyl ring;

P is -(CH2)n-where n is 0 or 1, or -0-, or -CO-M(Kb)-; one or both of X2 and X1 is M, or X1 is M, or X2 is C;

U represents -502-, U represents -CO-;

O is -CH(Kb)-, -CH (Kb) -CH2-, and -Х(Кб6)-СН2-, where Kb is hydrogen or C1-6 alkyl; also, if C) is connected with CI! or K2 with the formation of a C5-7 alkyl or heteroalkyl ring, such as a cyclohexyl ring;

K1 is hydrogen, C1-6 alkyl, C5-7 cycloalkyl, up to C12 aralkyl, up to C11 heteroarylalkyl, up to

C10 aryl or heteroaryl, such as up to Cb aryl; moreover, all of them are optionally substituted up to three atoms of halogen or SEZ;

K2 represents hydrogen, or together with K1 represents a carbocyclic or heterocyclic spiro 5- or 6-membered i) ring, such as a tetrahydropyran ring;

CA is up to C10 aryl, optionally substituted by halogen, MO2-, CM, SEZ, C1-6 alkyl, -5-C1-6 alkyl, -50-C1-6 alkyl, -502-C1-6 alkyl or C1-6 alkoxy; "r zo 7 represents -SOMNON-, 7 represents -SHMONISNO.

Preferred values for the above groups include the following: b»

KZ is hydrogen, a halogen such as chlorine, bromine or fluorine, MO2, SEZ, methyl, ethyl, methoxy, ethoxy, or especially methoxy or fluorine; ring B is a monocyclic aryl, aralkyl or heteroaryl ring containing up to 7 atoms in the ring B, such as phenyl, biphenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, especially phenyl, y-pyridyl and pyrimidyl, more preferably phenyl, 2-pyridyl and 2,4-pyrimidyl;

P is a simple bond; both X2 and X1 represent M;

U represents -502-; C) represents -СН2-; "

WHO! is phenyl, 4-trifluoromethylphenyl, phenethyl, phenpropyl, isobutyl, cyclopentyl, c benzyloxymethyl, C3,4-dichlorophenyl, pyridyl, thiophenylpropyl, bromothiophenyl, pyrimidinylethyl, pyrimidinylpropyl, pyridylethyl, pyridylpropyl, or together with K2 is spirocyclohexane or spiro- 4-pyran; K2 is hydrogen; 7 represents -EVERYTHING.

More preferred values of KZ include halogen, wherein the substituent is preferably in the meta or -I para position to the bond of the ring, wherein ring B is an aryl or heteroaryl ring, wherein ring B is phenyl, then especially 4-fluoro, and where ring B is pyridyl, then 3- or 4-chloro; o O represents -СН2-. o Preferred combinations of rings B and A include phenyl and piperazinyl; pyridyl and piperazinyl, and pyrimidine and piperazinyl, respectively. Specific alicyclic, fused, and heterocyclic rings for ring B include any of:

F) name) 60 b5 su so o- sl - " so b bu

M M su

Mo "b x S r S l M. m 19. M Mo M no

M Me y: o M ooo y 20 o o o o, s hi pe - Z - iZnn

Y a o t / "Y Zh pennny; sch 25 shk p o

Specific rings for ring A include any of: -- 0-0 -usn nut ИЙ зо кч) - Fu and their corresponding seven-membered analogs.

It should be borne in mind that the specific substituents and the number of substituents in rings A and B are chosen in such a way as to avoid sterically undesirable combinations. This also applies to the rings that can be formed by K1 and : I so

O, 210, as well as Kb and K7. 35 If there are optically active centers in the compounds of formula I, the authors disclose all individual optically active forms and their combinations as separate specific embodiments of the invention, as well as their corresponding racemates.

Specific compounds include: ; 2 1 sus AH « 40 se Z . and I . with M/X My (E5R) 438 . and? A o, Ku y s go - Ya ki M/ya M (EbR-K) 455 (95) («in) o 50 s»

F) ime) 60 b5 a a "-7u- o y

MA-th Fr

M

Ba o M M (BERU) 487 c. at. - what is what? MM (E5Rya) 454 - 9 o / y Another A - sha ah ho

СХ M/ ma (255) 420

Academy of Sciences

Si I with I

M MN (EBRU 4 o v h o -OUn y s sch: ML Mi (E5RU) Ge) ---3 7 - e livi p; o-k y zo M/t, Ma (BR) 438 t a se (o)

ANA and

Ha kv, o h si i zo

I ze M/7 Ma (E5RYU) 496 o o, A -

AD ry "KAM A - y M/F M (EBRZH) " " s - o s : " y dna

E M/o i s g - M/2 Ma (B5R) 528 pt o (95) a i o shk "a i o z Ve (Se) M/X MA (E5RAU ZI h . her sho o o ya ry in TO si I" '

GF! i M/7 MI (E5RN 470 ime) bo b5 in i : - ml we (E5R-) 495 is si o i uUn

Hot Me g 70 o - MM (E5РХ) 495 . . о и - ко - КИ и и- и

M/w MA (E5RK) 455 o with -Uh eto uh - i

WHAT! "M/F Ma (EBR-) 468

AND

And in U and i! k s SHI Y . and

M/Y MA (E5RYU) 15 o

And about

AND

(From kt - M / Y 9 73 days

Mate,

M/H My (EBR) 427 ii a o ii « du kh ii z m AL p (ze) y ke | and

M/75 MA (ER) 456

U i shk Z p i Mo k-- u oo z

Y o-M z» ) o : -I : and F (95) and 9 07 Shk («c) Y ; (Se) 50 a

N o

Chl» : gd M dy ; And x-/ : r 7, and ! 5 name) because b5 o u lyly: M si M Sho tu ny a V she 70 | with - о я- и «-0 Ук х-5 ж ш-М и ЦИ о - о Й

H

M--- still with

Di aa (oh)

A o o " zo "

Ge) ai lo o s / With them sh-4 and --shchi and M o o them in! o z U h "KO A ? God bless you ohm

Who -And (95) (av) so 50

I"

Ф) ko bo b5 o yah y hi 5 .

M

GA. . M -

And. o I o M waves in kerosene and DI

M and sho

M step

And psch-- / z y s Ah y: o zi s

Her, Fr

And I am J

ShMoO00-

AK h-

Kk (22) where K is phenyl or phenethyl, and o 7 o Gze) -Y- M-87 M and Ou, and

Kk where K is an isobutyl or spiro-4-pyran ring.

As mentioned above, the compounds of the present invention are metalloproteinase inhibitors, in particular, they are "MMRI13 inhibitors." Each of the above indications for compounds of the formula | represents an independent and specific variant of the invention. Although the authors did not wish to be bound by theoretical considerations, they believe that, if the compounds of the present invention exhibit selective inhibition for any of the above variants and relative to any MMRI inhibitory activity, in non-limiting examples they may demonstrate "" 100-1000 fold selectivity for any MMP1 inhibitory activity.

In addition, the authors found that compounds of formula 1, in which ring B is represented by a phenyl, pyridyl (such as 2-pyridyl or 3-pyridyl, especially 2-pyridyl) ring, are not necessarily mono- or di-substituted, -and preferably a monosubstituted halogen (for example, chlorine), P is a simple bond; ring A is a piperazinyl or piperidinyl ring, Y is -502-, and C) is a C1-4 alkylene (for example, -CH2-), especially -CH2-; K1 has the value indicated for formula 1, and is, in particular, (α) 2-phenylpropyl, 2-(2-pyridyl)propyl, 2-(3-pyridyl)propyl, 2-(4-pyridyl)propyl, phenyl, benzyloxymethyl, c 50 4-phenylbutyl, 2-phenylbutyl, or 2-(2-thienyl)upropyl; and 7 is M(OH)CHO. Especially suitable for use as aggrecanase inhibitors, i.e. inhibitors of aggrecan decomposition. It is especially necessary to note the compounds of formula I, in which B is a phenyl, 3-methylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl or 3, 4-dichlorophenyl ring or 5-chloro-2-pyridyl; P is a simple bond; ring A is piperidinyl or piperazinyl, in particular, piperazinyl, XU is 502, 0 is -CH2-, 7 is -M(OH)CHO, and KI is phenyl, phenyl butylene, phenylisopropylene, 2-pyridylethylene, 2 -pyridylisopropylene, 3-pyridylisopropylene, 4-pyridylisopropylene or 4-chlorophenyloxydimethylmethylene. It is also necessary to mention the compounds of formula I, in which ring B is phenyl, monosubstituted by chlorine or fluorine, i.e.) in particular, 4-chlorophenyl and 4-fluorophenyl; P is a simple bond; ring A is piperidinyl, U is 502, 0) is -CH2-, 7 is -SOMNON, and KI! is hydrogen, isobutyl or 60 spirotetrahydropyranyl. Specific compounds include: 72 tk b5 in 1 7x (51981 i 1

A-E-RA RIR 802 SsNng |ISNOSN(SNZ)RA vn as | т (voz|rne|resnosnosnosna vn) vet 0 РРО vozsnorisnyusto YAN act | in (Vozono gpridipsnisnuyueno yan act | how RRO vozsnoosnvysnasno YAN yavy | viRO (ozsnoRysnsvoyuna vn and what RRO vozsnoavRStSNIENYA YAN

GoayaRy 1 RIO |6O2 sno 2.Pyrazinlonusnasno |VNI where PIR means piperazinil

KH means the reverse hydroxamate group and K2 is hydrogen

The compounds of the present invention can be presented in the form of pharmaceutically acceptable salts. These include addition salts of acids such as hydrochloride, hydrobromide, citrate, and maleate, and salts formed with phosphoric and sulfuric acids. On the other hand, suitable salts are basic salts, such as alkali metal salts, for example sodium or potassium salts, alkaline earth metal salts, for example calcium or magnesium, or Ga salts of organic amines, for example triethylamine.

The compounds of the present invention may also be presented as hydrolyzable esters. They are i) a pharmaceutically acceptable complex ester, which is hydrolyzed in the human body, forming a generic compound. Such an ester can be determined by, for example, injecting the test animal intravenously with the test compound and then examining the body fluids of the test animal. A suitable hydrolyzing ester for carboxy includes methoxymethyl and for hydroxy includes formyl and acetyl, especially acetyl. at

In order to use a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a hydrolyzed ester thereof for therapeutic use (including prophylactic use) in mammals, including humans, it is usually prepared in accordance with standard pharmaceutical practice in in the form of a pharmaceutical composition. h-

Therefore, in another aspect of this invention, a pharmaceutical composition is proposed, which includes a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a hydrolyzed ester thereof and a pharmaceutically acceptable carrier. "

The pharmaceutical compositions of the present invention can be administered by standard methods appropriate to the disease states to be treated, for example, orally, externally, parenterally, buccally, nasally, vaginally or rectally, or by inhalation. For these purposes, the compounds of the present invention can be prepared by methods known to specialists in the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral administration (including intravenous,

(Intramuscular injections and infusions) in the form of sterile aqueous or oily solutions or suspensions or sterile emulsions.

In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain, or may be administered together (simultaneously or sequentially) with one or more of a) pharmacological agents relevant to the treatment of one or more of the above painful conditions. Pharmaceutical compositions according to the present invention are usually administered to patients in such a way that they "g" receive, for example, a daily dose in the amount of 0.5-75 mg/kg of body weight (and preferably from 0.5 to 30 mg/kg of body weight) . This daily dose can be administered if necessary in divided doses, and the exact amount of compound administered and the method of administration depend on the weight, age, and sex of the patient to be treated, as well as on the specific disease state to be treated according to methods known to those skilled in the art.

Typically, a standard dosage form contains from about 1 mg to 500 mg of a compound of the present invention. Therefore, in a further aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable co salt thereof or a hydrolysed ester thereof for use in a method of therapeutic treatment of humans or animals. In yet another aspect, the present invention relates to a method of treating metalloproteinase-mediated disease states, which comprises administering to a warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a hydrolyzed ester thereof intravenously.

In the next aspect, the present invention relates to a method for obtaining a compound of formula (I), or a pharmaceutically acceptable salt thereof, or its hydrolyzed ester, which includes: 65 a) the interaction of a compound of formula (II) or its pharmaceutically acceptable salt or its hydrolyzed ester of an ester with a compound of the formula (IP):

AND

!

I am about - YOU

TR where X/" means X or a precursor of X (either by modification or substitution) or an activated form of X suitable for interaction with Y;

Mi means M, a precursor of M, or an activated form of U, suitable for interaction with X 47; as a non-limiting example, if X is C, then X 4 can be modified to include a precursor X for reaction with a compound of formula Y, wherein Y 4 is a precursor to Y; 7" means a protected form 7, a precursor of 7 (either by modification or by substitution of 77) or an activated form 7; and where O represents -"CH2)(Kb)-, followed by the interaction of a compound of formula IX with a corresponding compound of formula К1-СО-К2 to obtain an alkene of the formula X, which is then converted into a compound of the formula Xi, where 7" is a hydroxylamine precursor of group 7, and further conversion of 7" into group 7 in accordance with the following scheme: | ve

Kh I so in- about 80,- SN, 2 tons of them

WITH

In | se 25 (8) in

In Al t- PZ 50.7 i x 4 2 cho SYA chI zo ВХ "c) b

Anya and - p- 5 - 50

SIL, hi i- or

B) interaction of the compound of the formula (IM) or its pharmaceutically acceptable salt or its hydrolyzed ester with the compound of the formula (M): 40. GAS. w-v 2 x-i x s ANYA h m . and? ki Kg (95) in, What (av) where B' represents a corresponding ring group or a group that substitutes for the reaction with P "7"; 7! has the values specified above with 50; and

P" represents the corresponding activated form of the linker P for reaction with B" and" or, if X2-M, then P1 can be faster on the A ring than on the B ring or, if necessary, the P linker can be obtained by the corresponding reaction of the precursor groups P" and P", which are on the rings B and A, respectively, or vice versa. 59 The compound of the formula (II) is usually obtained by reacting the compound of the formula (MI) with the compound

GF) formulas (MY) and

M in

And MI

CA

65 where B' represents a corresponding ring group or substituent, Xo" means X or a precursor of X (either due to modification or substitution), or an activated form of X suitable for reaction with B' and Xo! in the interaction of one with one will form a linker P between ring A and ring B in a compound of formula (I).As a non-limiting example, if Xo is M, then ring B can conveniently be modified to introduce the linker P via

B", and if X"o is C, then both rings B and A can be conveniently modified, obtaining the linker P as a result of the reaction of B" with Xo.

It should be noted that many of the appropriate starting materials are commercially available. In addition, the table below presents aldehyde precursors and their corresponding registration numbers in

Spetis! Arzigasiv with and 2 cm thick about -

F o

Fo zv m h 4 Z s. and?

Aldehydes that do not have Mo registration numbers in Spetis! Abvzigasiv 3-(2-pyridyl)propionaldehyde. To a solution of 2-bromopyrimidine (7.95g, 0.05M) in acetonitrile (1500ml) add -I propargyl alcohol (4.2g, 0.075M), bis(triphenylphosphine)-palladium (II) chloride (75Omg, 1mMM), iodide copper (10Omg,

0.5MM) and triethylamine (25ml, 0.25M), and the resulting mixture is stirred and heated at 7092C for 2 hours. o Then, an additional amount of propargyl alcohol (2.1 g, 0.038 M), o bis(triphenylphosine)-palladium (I) chloride (375 mg, O.bTi) and copper iodide (5Omg, 0.25 Ti) are added to the reaction mixture, and the reaction the mixture of 5p is stirred and heated at 702С for another 1 hour. o The reaction mixture is evaporated to dryness, and the residue, which is previously adsorbed on silica gel, is treated

GT" chromatographically. Elution with ethyl acetate gave 3-(2-pyrimidyl)prop-2-yn-3-ol as a yellow solid, 4.45 g (66905). "H NMR (SOS): 2.9 (1H, t), 4.5 (2H, d), 7.3 (1H, d), 8.8 (2H, t), Mass spectrum: MH" 135. 3-(2-pyrimidyl)prop-2-yn-1-ol (4.45g, 0.033M) is dissolved in ethyl acetate (140ml), 1095 Ra/C (890OmgHg) is added, and the resulting mixture is stirred in a hydrogen atmosphere within 6 hours. The reaction mixture was filtered through celite, and the resulting filtrate was evaporated to give 3-(2-pyrimidyl)propan-1-ol as a yellow oil, 4.15 g of (9195). H NMR (SOSI): 2.1 (2H, m), 3.2 (2H, t), 3.8 (2H, t), 7.2 (1H, t), 8.7 (2H, d ). Mass spectrum: MH" 139. 3-(2-pyrimidyl)upropan-1-ol is oxidized to give 3-(2-pyrimidyl)propionaldehyde, which is obtained as a yellow oil using the Swern (Zmet) oxidation described in this patent. "N

NMR (SOSI): 3.0 (2H, t), 3.4 (2H, t), 7.1 (1H, t), 8.7 (2H, d), 9.9 (1H, s) .

Using the procedure described above, the following aldehydes are obtained: 4-(2-pyrimidyl)butyraldehyde, using 3-butyn-1-ol instead of propargyl alcohol. "H NMR (SOSI"): 2.2 (2Н, m), 2.5 (2Н, m), 3.0 (2Н, m), 7.15 (1Н, m), 8.6 (2Н, m), 9.8 (1Н, с). for 4-(5-pyrimidyl)butyraldehyde, using 3-butyn-1-ol instead of propargyl alcohol and 5-bromopyrimidine instead of 2-bromopyrimidine. IN NMR (SOCI"): 2.0 (2H, m), 2.55 (2H, t), 2.7 (2H, t), 8.6 (2H, s), 91 (1H, s), 9.8 (1H, s). 4 -(2-pyridyl)butyraldehyde, using 3-butyn-1-ol instead of propargyl alcohol and 2-bromopyridine instead of 2-bromopyrimidine.IN NMR (SOS): 2.0 (2H, m), 2.55 (2H, t ), 2.8 (2H, t), 7.1 (2H, m), 7.6 (1H, m), 8.6 (1H, d), 9.8 (1H, s).

Compounds of the present invention can be evaluated, for example, using the following assays:

Analysis of selected enzymes

A family of matrix metalloproteinases, including, for example, MMP 13.

Recombinant human pro-MMRIZ can be expressed and purified by the Kpasreg method. (M.Kpaimregei 70 a, (1996) Tpe Viospetisa! docsgpa! 271:1544-1550 (1996). The purified enzyme can be used to monitor activity inhibitors as follows: purified pro-MMP1Z is activated using 1mM aminophenyl mercuric acid (ARMA ), 20 hours at 212C; activated MMP13Z (11.25 ng per experiment) is incubated for 4-5 hours at 352C in an analytical buffer (0.1M Ttiv-HCl, pH 7.5, containing 0.1M Masi, 20mM Sas» . 12 Rto. Hetz. su. And ei.M-3-(2,4-dinirophenyl)-I-2,3-diaminopropionyl. Ah Agu.MNo in the presence of inhibitors or without them. The activity is determined by measuring the fluorescence on the Z28nM sample and the ZUZnM sample. The percentage of inhibition is calculated as follows: 95 inhibition is equal to |(Fluorescence plus inhibitor "Fluorescence background) divided by |Fluorescence minus inhibitor - Background fluorescence).

A similar scheme can be used for other expressed and purified pro-MMPs, using conditions, substrates and buffers optimal for a specific MMP, for example, as described by S. Ogapat Kpidni ei a!., (1992) REVZ

Hey hey 296 (3):263-266.

The adamalisin family, including, for example, TNF convertase

The ability of the compounds to inhibit the pro-TNF convertase enzyme can be assessed using the analysis of a partially purified isolated enzyme, and the enzyme is obtained from TNR-1 membranes, according to the method of K.M. The activity of the purified enzyme and the degree of its inhibition are determined by incubating the partially purified enzyme in the presence or absence of the tested compounds, using 4,5-dimethoxy-fluoresceinyl Zeg.RhoHeits.AiPa.SiIp.AIa.Ma|.Agud.Zeg as a substrate .Zeg.Zeg.Agu.Suv (4-(3-succinimid-1-yl)-fluorescein)-MH2 in an analytical buffer (5 mM Ttiv HC, pH 7.4, containing 0.195 (w/v) Tgyop X -100 and 2 mM Sasi"), at 2623 for 18 hours. The degree of inhibition is determined in the same way as for "MMRI3", except that they use ogzbud 49Onm and ogdosl 5ZOnm. The substrate is synthesized as follows. do

The peptide part of the substrate is collected on Etos-MN-Kipk-MVNA-polystyrene resin, either manually or on an automatic peptide synthesizer by standard methods, including the use of Etos-amino acids and o

O-benzotriazol-i-yl-M,M,M',M'-tetramethyluronium texafluorophosphate (NVT) as a cross-linking agent, at least with a 4- or 5-fold excess of Ethos-amino acid and NVT. Ze"!1 and Pgo2 are double cross-linked. The following side chain protection strategy is used; Zeg'"Vy"), Sip? (Tu), Agdb/2 (Rts or RYU, beg?7b11 (Tu), -

SuzZ(Ttyu|). After assembly, the M-terminal Ethos protecting group is removed by treating the Ethos peptidyl resin with DMF.

The aminopeptidyl resin obtained in this way is oxidized by treating for 1.5-2 hours at 70 9 with 1.5-2 equivalents of 4",5'dimethoxyfluorescein-4(5)-carboxylic acid | (Kpappa 8: ShPtap, (1980) Apa ! Viospet. " 108:156-161), which is activated in advance with diisopropylcarbodiimide and 1-hydroxybenzotriazole in DMF. Then the protective groups are simultaneously removed from the dimethoxyfluorescein oleptide and the resins are cleaved from it by treatment with trifluoroacetic acid containing 590 g of water and 590 g of triethylsilane. is isolated by evaporation, thorough trituration with diethyl ether, and filtration. The isolated peptide is reacted with 4-((M-maleimido)-fluorescein in DMF containing diisopropylethylamine, the resulting product is purified by reverse-phase HPLC, and finally -I is isolated, freeze-drying from aqueous acetic acid. The product is characterized using the MA mass spectrum! 0I-TOE and analysis of amino acids. and Natural substrates o The activity of compounds according to the present invention as inhibitors of aggrecan degradation can be analyzed,

Using, for example, the methods disclosed by E. S. Agpeg ei ai.,, (1998) Ovieoagiiigiyiz apa SapiPade se) 6:214-228; (1999) dotsgpa! oi Viioiodisai Speptivigh, 274 (10), 6594-6601 and the antibodies described there. Efficiency

T" compounds as collagenase inhibitors can be determined by the method of T. Samusiop apa A. Vaitek (1979) Apai. ViosNeia. 99:340-345.

Inhibition of metalloproteinase activity in cells/tissues based on activity assay as an agent to inhibit membrane shedases such as TNF convertase

The ability of compounds according to the present invention to inhibit cellular processing of TNF production can be evaluated in

F) TNR-1 cells, using EEG IZA to determine the release of TNF practically according to the method of K. M. Mopieg eyi a|., ka (1994) Maitsge 370:218-220. In a similar way, processing or shedding of other membrane molecules, such as those described by M.M. Nooregei ai., (1997) Viospet. 9. 321:265-279, can be tested using the appropriate 60 cell lines and appropriate antibodies to determine the shed protein.

Testing as an agent that inhibits invasion at the cellular level

The ability of the compounds according to the present invention to inhibit cell migration in the invasion assay can be determined by the method of A. Ayirbipi ei ai., (1987) Sapseg Kezeagsi 47:3239-3245.

Testing as an Agent for Inhibiting TNF Shedase Activity of Whole Blood 65 The ability of the compounds according to the present invention to inhibit the production of TNFα is evaluated in the analysis of human whole blood, where RB5 is used to stimulate the release of TNF p. Heparinized (10 Units/ml) human blood,

obtained from volunteers, dissolved in a ratio of 1:5 with medium (KRMI1640-bicarbonate, penicillin, streptomycin and glutamine), and incubated (16bOmcl) with 20μl of the compound under investigation (three repetitions) in DMSO or a suitable carrier for 30 min. at 372C in an incubator with a humid environment (5956 СО2/9595 air), before adding 20 μl of RHZ (E. soii. 0111: B4; final concentration 1Omkg/ml). Each assay includes a diluted blood control incubated in only one medium (b cells per plate) or a known TNFα inhibitor as a standard. Then the plates are incubated for 2 hours at 37 oC (incubator with a humid environment), centrifuged (2000 rpm for 1 hour; 42C), plasma is collected (50-100 μl) and stored on 96 cell plates at -702C before further analysis of TNFα concentration according to with the help of EI IZA.

Testing as an agent inhibiting ip may cartilage degradation

The ability of the compounds according to the present invention to inhibit the degradation of aggrecan or collagen components of cartilage can be assessed practically according to the method of K. M. Voyotieu, (1997) Viospet.). 323:483-488.

Pharmacodynamic test

To evaluate the cleansing properties and bioavailability of the compounds according to the present invention, the ex mimo test 75 of pharmacodynamics is used, in which the above-mentioned analyzes of the synthetic substrate are used, or in another variant

HPLC or mass spectrometric analysis. It is a general test that can be used to assess the rate of clearance of compounds for a wide range of species. Animals (e.g., rats, monkeys) are administered intravenously or orally doses of a soluble composition of the compound (e.g., 2095 w/v DMSO, 6095 w/v PES400), and at successive time points (e.g., 5, 15, 30 , 60, 120, 240, 480, 720, 1220 min.) take blood samples from the appropriate vessel in 10) heparin. After centrifugation, plasma fractions are obtained, and plasma proteins are precipitated with acetonitrile (final concentration 8095 w/v). Through ЗОхв. at -209C, plasma proteins are sedimented by centrifugation, and the supernatant fractions are evaporated to dryness using Zamapi zreead mass. The precipitate is diluted in an analytical buffer and then analyzed for compound content using a synthetic substrate assay. Namely, they build a compound concentration-response curve for the compounds to be evaluated. with

Evaluating the activity of serial dilutions of reconstituted plasma extracts, the amount of compound present in the initial plasma sample is calculated using a concentration-response curve taking into account the dilution factor of whole plasma.

Estimates of ip mimo

Testing as an anti-TNF agent "I

The effectiveness of the compounds according to the present invention as ex mimo TNF inhibitors is evaluated in experiments on rats. Specifically, groups of male rats of the UMiziag strain from AIdegieu Ragk (AR) (180-210g) were administered the compounds (6 rats) or the drug carrier (10 rats) by an appropriate method, for example, orally (p.o.), intraperitoneally (in .o.), o subcutaneously (p.sh.). After 90 minutes, rats are euthanized using increasing CO concentrations and blood is drawn from the posterior vena cava in bod sodium heparin/ml blood. Blood samples are immediately placed on

On ice and centrifuged at 2000 rpm for 10 minutes. at 42C, and the collected plasma samples are frozen at -202C for further analysis of their influence on the production of TNF in due to I Re-stimulated human blood. Rat plasma samples are thawed and 175 μl of each sample is added to a set of 96) cell plates. Then 500 μl of heparinized human blood is added to each cell, mixed, and the plate is incubated for 30 minutes at 372C (incubator with a moist environment). I RZ (25 μl; final concentration 1 Ω/ml) is added to C 10 cells, and incubation is continued for another 5.5 hours. Control cells are incubated only with 25 μl of medium. Then the plates are centrifuged for 7 hours. at 2000 rpm, and 200 μl of supernatant liquids are transferred to a 96-well plate and frozen at -202C for further determination of TNF concentrations using EGISA.

The obtained results are analyzed using special programs for each compound/dose test. 75 Percentage of inhibition - FNPa- Mean FNIPzhkkont role- mean FN Pedoobroblenkhx10 mean FNIPakcontroli io Testing as an anti-arthritic agent (аv) The activity of the compound as an anti-arthritic agent is tested on collagen-induced arthritis (SIA), according to the so 50 method of OO. E. Tgepiy.at ei ai., (1977) U. Ehr. May 146857. In this model, acid-soluble natural type II collagen induces polyarthritis in rats when administered in incomplete Freund's adjuvant. Analogous

I" conditions can be used to induce arthritis in mice and primates.

Testing as an anticancer agent

The activity of the compound as an anticancer agent can be evaluated practically in accordance with the method described in 1). Riadaig (1978) Meijodz ip Sapseg Kezeagspj 15:399-439, using, for example, the cell line B16

Gee! (described by V. Nibpeg ei a!.. Abzigashi 283 p75 1017 MSI-EOVTS Zutrovicht, Atviegdat pe 16-19 1998).

Further, this invention will be illustrated by the following examples, which in no way limit the scope of the invention. o EXAMPLES

Example 1 60 1-(2-(M-formyl-M-hydroxyamino)-2-phenylethanesulfonyl1|-4-(4-fluorophenyl)piperazine given in note (c) 65 To a solution of 1-(2-(hydroxyamino)-2- phenylethanesulfonyl|-4-(4-fluorophenyl) piperazine (338 mg, 0.89 mmol) in THF (bml) and formic acid (2 ml) was added to a previously prepared mixture of formic acid (2 ml) and acetic anhydride (0.5 ml). This mixture was stirred. at room temperature for 1 hour. The mixture was evaporated in vacuo, and toluene (2 x 5 mL) was added and evaporated in vacuo. The residue was taken up in a mixture of CH2SiO2-methanol (bml, 9:1) and silicon dioxide (1 g) was added. This mixture was stirred for 18 hours. The silicon dioxide is filtered off and washed with a mixture of CH2Cl2-methanol (9:11). The residue is purified on silica gel (eluent CHCl2-MeOH 496), obtaining the title compound as a light orange solid (22Omg, 61905). "YAN YAMR (SOSIVv): 8.45 and 8.15 (s, 1H), 7.39 (m, 5H), 6.97 (m, 2H), 6.88 (m, 2H), 5.89 and 5.35 (m, 1H), 4.05 and 3.85 (m, 1H), 3.30-3.53 (m, 5H), 3.20-3.10 (m, 4H); Mass spectrum (E5I E5I): 408 (MH"), 430 (MMa"). Elemental analysis: calculated for С.9Но2ЕМаО,5: С 56.01, Н 5.44, M 10.31, 5 7.87. Found: C 56.01, H 5.52, M 10.04, 70 57.39.

The starting material is obtained as follows: i) Methanesulfonyl chloride (20ml, 258mmol) is added dropwise to a solution of 1-(4-fluorophenyl)piperazine (35g, 194mmol) and pyridine (17.5ml) in dry dichloromethane (200ml) at 02. This mixture was stirred for 3 hours at room temperature. The mixture was washed with water and extracted with dichloromethane (2x100 ml). The organic layer 75 was dried over magnesium sulfate and evaporated in vacuo. The residue was carefully triturated with methanol to obtain 1--4-fluorophenyl)-4-(methanesulfonyl)piperazine (39.35 g) as white crystals.

T"H NMR (SOSIZ): 7.00 (m, 2H), 6.90 (m, 2H), 3.40 (m, 4H), 3.20 (m, 4H), 2.83 (s, ZH).i) To a solution of I0A (|8.bmmol; obtained by slowly adding n-butyllithium (3.5ml, 8.5mmol, 2.5M in hexane) to a solution of diisopropylamine (8bOmg, 8.5mmol) in dry THF ( bBml) at -782С) at 789 add dropwise a solution of 1-(4-fluorophenyl)-4-(methanesulfonyl)piperazine (1g, 3.87mmol) in THF (25ml). The resulting mixture is stirred at -782С7 for 1 hour, and a solution of diethylchlorophosphate (67Omg, 3.87mmol) in THF (3ml) was added.The mixture was stirred at -782C for 1 hour and benzaldehyde (45Omg, 4.24mmol) in THF (3ml) was added.

This mixture is gently heated to room temperature and stirred for 18 hours.

The mixture is washed with aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were washed with water, with 29 saturated saline solution and dried over magnesium sulfate. As a result of purification of the residue on silica gel (eluent dichloromethane), 1-(4-fluorophenyl)-4-(trans-p-styrenesulfonyl)piperazine was obtained as a white powder (621 mg, 4690). "YAN NMR (SOSIv): 7.50 (m, ЗН), 7.43 (m, ЗН), 6.97 (m, 2Н), 6.89 (m, 2Н), 6.71 (d, 1Н , uU-15.4 Hz), 3.37 (m, "

AN), 3.19 (m, 4H). ii) To a solution of 1-(4-fluorophenyl)-4-(trans-pD-styrenesulfonyl)piperazine (620 mg, 1 µmol) in THF (20 ml) (e) add hydroxylamine (3 ml, 5095 aqueous solution). This mixture is stirred for 18 hours. The solvent is evaporated. The residue is dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate to give 1-(2-(hydroxyamino)||-2-phenylethanesulfonyl)|-4-(4-fluorophenyl)piperazine (7ZOmgHg). i) "YAN YMR (SOSIV): 7.4-7.1 (m, 5H), 6.97 (m, 2H), 6.87 (m, 2H), 5.95 (width c, 1H), 4.74 (s, 1H), 4.60 (dd, che 1H, 9-4Hz, -8.8Hz), 3.56 (dd, 1H, U-8.8Hz, U-14.3Hz), 3 .40 (m, 4H), 3.19 (dd, 1H, 1-4Hz, U-14.3Hz), 3.12 (m, 4H).

Example 2

In a similar way, the following compounds are obtained:

NN of note M5 (E5P): 400 (МН), 421 - . o (mMa) /-l-- o s o On, (av) note M5 (E5I): 476 (MI, SI) ; 498 so 50 ik y (mMMa7 C)

T" Oh; m M5 (E5P): 422 (MM no I 5 Example Z

M-hydroxy-3-I(4-(4-fluorophenyl)piperazine-1-sulfonyl|propionamide

F): in DI

M-5 - legal

To a solution of 60 0/0 M-(2,4-dimethoxybenzyloxy)-M-(2,4,6-trimethoxybenzyl)-3-(4-(4-fluorophenyl)piperazine-1-sulfonyl| propionamide (125 mg, 0, 19mmol) in dichloromethane (2ml) was added triethylsilane (100ml, 0.42mmol) and trifluoroacetic acid (1500ml). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo.

The residue is purified by chromatography on silica gel (eluent: dichloromethane, then ethyl acetate, then dichloromethane -1095 MeOH), obtaining 35 mg of the title compound. "H NMR (DMSO a-6 - SEZSOOB): 7.16 (m, 4H), 3.36 bo (m, 6vH), 3.25 (m, AN), 2.45 (t, 2H, U- 1.4 Hz); Mass spectrum (E5I): 332 (MM), 354 (MMa")

The starting material is obtained as follows:

Her) A solution of 3-mercaptopropionic acid (2.0g, 145mmol) in a mixture of acetic acid (150ml) - water (30ml) at 02С is reacted with gaseous chlorine (mainly condensed at -782С, 20ml). After the chlorine is driven off, the solvents are evaporated in a vacuum; add toluene and evaporate to give 1,2-oxathiolan-5-one 2-dioxide (36.12g). "IN NMR (DMSO a-6): 2.70 (t, 2H, 9-7.2Hz), 2.50 (t, 2H, 9-7.2Hz). i) Solution of 1,2-oxathiolane-5 -one 2-dioxide (3.8g, 28mmol) in thionyl chloride (2Oml) and DMF (5 drops) was stirred at room temperature for 18h. This mixture was heated at 402C for 1h. 70 The solvents were evaporated, toluene was added and evaporated in vacuo , receiving crude

C-chlorosulfonylpropionyl chloride (purity according to NMR data: 7095 3.58g). "H NMR (SOCIv8): 4.02 (t, 2Н,

U-7.2GuC), 3.63 (t, 2H, 9-7.2Hz). her) To a solution of 3-chlorosulfonylpropionyl chloride (500mg, 1.83mmol, 7090 purity) and diisopropylethylamine (75μl) in dichloromethane (Bml) at -1896, a solution of 75 O-dimethoxybenzyl-M-trimethoxybenzylhydroxy (bba4mg, 1.83mmol) is added dropwise and of diisopropylethylamine (32µL, 1.83mMmol) in dichloromethane (bml) for 2 hours. After 30 minutes, a solution of 1-(4-fluorophenyl)piperazine (30 mg, 1.8 mmol) and diisopropylethylamine (320 μl, 1.83 mmol) in dichloromethane (5 ml) was added to the reaction mixture.

The solution is heated to room temperature and stirred for 2 hours. The solution is partitioned between dichloromethane and hydrochloric acid. The organic layers are washed with saturated saline and dried over magnesium sulfate. Chromatographic treatment of the residue on silica gel (eluent: ethyl acetate-petroleum ether: gradient from 50/50 to 80/20) gives

IM-(2,4-dimethoxybenzyloxy)-M-(2,4,6-trimethoxybenzyl)-3-I4-(4-fluorophenyl)piperazine-1-sulfonyl|propionamide 26Omg). Mass spectrum (electron impact): 661 (M).

Example 4 with 29,000 M-tihydroxy-3-|(4-benzylpiperazine-1-sulfonyl|propionamide He) o - iy : MA SI on -

By a method similar to the method of example 3, from 4-benzylpiperazine and 3-chlorosulfonylpropionyl chloride, the compound specified in the title is obtained. "H NMR (DMSO 4-6 - SEZSOOB): 7.50 (m, 5H), 4.41 (s, 2H), 3.78 (m, F 2H), 3.41 (m, 4H), 3 ,18 (m, 2H), 2.43 (t, 2H, 9U-7.1Gu); Mass spectrum (E5I): 328 (MH") | "in)

Example 5 p

M-hydroxy-3-I(4-(4-fluorophenyl)piperazine-1-sulfonyl/|-2-isobutylpropionamide and - t. TU 0 H o, (c)

Trifluoroacetic acid (200 μl) and triethylsilane are added to a solution of /M-(2,4-dimethoxybenzyloxy)-3-(4-(4-fluorophenyl)piperazine-1-sulfonyl|-2-isobutylpropionamide (220 mg) in dichloromethane (4 mL) (145 μl). This mixture C is stirred at room temperature for 15 minutes, evaporated in vacuo, and the residue is purified on silica gel c (eluent: dichloromethane-ether-methanol (80:20:0.55 to dichloromethane-methanol (80:20) ), resulting

From" the title compound is obtained (88mg, 5690).

The starting material is obtained as follows: "H NMR (DMSO-a6): 10.72 (s, 1H), 7.08 (m, 2H), 6.99 (m, 2H), 3.37 (dd, IN, U-8.4Hz, 7 -14.3Hz), 3.27 (m, -1 15 4H), 3.15 (m, 4H), 3.00 (dd, 1H, 9U-4Gu, U-14, 3HC), 2.62 (m, 71Н), 1.6-1.2 (m, ZN), 0.89 (d, ZN, 9U-6.6Gu), 0.85 (d, ZN, U- 6.6 Hz). Mass spectrum (E5I): 388 (MH), 410 (MMa U. o The starting material is obtained as follows: o Her) A solution of 3-acetylthio-2-isobutylpropionic acid (obtained in the addition reaction, according to Mikael, 50 thioacetic acid and 2-isobutylacrylic acid) (7g, 34.3mmol), benzyl bromide (4.29ml, Zbmmol) and OVO se) (5B2ml, Zbmmol) in toluene (5bml) were stirred for 18 hours at room temperature. Solvent

T" is evaporated in a vacuum. The residue is partitioned between ethyl acetate and 595 sodium bicarbonate. The organic layer is washed with saturated saline and dried over magnesium sulfate. As a result of chromatographic purification of the residue on silica gel (eluent: dichloromethane-ether (9:1)), benzyl 5B 3-acetylthio-2-isobutylpropionate (8.4 g) was obtained. Mass spectrum (ESI): 317 (MMa"). i) A solution of benzyl 3-acetylthio-2-isobutylpropionate (588mg, 2mmol) in a mixture of acetic acid (12ml) - water (F; (1.b6ml) at 02C is subjected to interaction with gaseous chlorine (predominantly condensed at -782C, 1.9ml). After the chlorine is driven off, the solvents are evaporated in vacuo to give crude benzyl

Z-chlorosulfonyl-2-isobutylpropionate (b3Omg). Mass spectrum (electron impact): 318 (MU. 60 her) A solution of benzyl 3-chlorosulfonyl-2-isobutylpropionate (63Omg, 2mmol), 1-(4-fluorobenzyl)piperazine (378mg, 2.mmol) and triethylamine (34Oml, 2.4 mmol) in dichloromethane (15 ml) was stirred at 02 for 18 hours. After evaporation of the solvents, the residue is partitioned between ethyl acetate and water. The organic layer is washed with saturated saline and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was purified by chromatography on silica gel (eluent: dichloromethane-ether (9:1)), obtaining benzyl 65 3-I4-(4-fluorophenyl)piperazine-1-sulfonyl)|-2-isobutylpropionate (640 mg). Mass spectrum (EI-electron impact): 462 (MU,

them) A solution of benzyl 3-(4-(4-fluorophenyl)piperazine-1-sulfonyl|-2-isobutylpropionate (63Omg) in methanol (1Oml) is hydrogenated at a pressure of 4 Org (2.812 kg/cm") for 18 hours in the presence of palladium- on coal (bZmg, 10965).

The catalyst was filtered off and the solvents were removed in vacuo to give 3-(4-(4-fluorophenyl)-piperazine-1-sulfonyl/|-2-isobutylpropionic acid (4600 mg). Mass spectrum (E5BI): 373 (MH, 395 (MMa ") m) To a solution of 3-(4-(4-fluorophenyl)piperazine-1-sulfonyl|-2-isobutylpropionic acid (23mg, 0.62mmol), 2,4-dimethoxybenzylhydroxylamine Y2PI (124mg, 0.6v8mmol), OMAR (75mg, 0.b2mmol) in DMF (1ml) is added

M-ethyl-M'-(3-dimethylaminopropyl)carbodiimide hydrochloride (152mg, 0.bmmol). This mixture is stirred at 70 room temperature for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate.

The organic layer is washed with 595 sodium bicarbonate, saturated saline solution and dried over magnesium sulfate. Purification of the residue on silica gel (eluent: dichloromethane-ether: gradient from 9/1 to 8/2) gives M-(2,4-dimethoxybenzyloxy)-3-(4-(4-fluorophenyl)piperazine-1-sulfonyl-| -2-isobutylpropionamide (158mg).

TN NMR (SOSIV): 8.21 (s, 1H), 7.30 (m, 1), 6.97 (m, 2), 6.88 (m, 2H), 6.46 (m, 2H) , 4.95 (m, 2H), 3.82 (s, 6H), 3.50 (dd, 1H, 9-9Hz, -14.2Hz), 3.37 (m, 4H), 3.14 ( m, 4H), 2.84 (dd, 1H, 9U-142Hz, U-2Gu), 2.60 (m, 1H), 1.7-1.2 (m, ЗН), 0.90 (m, 6H).

Example 6 4-I4-(4-fluorophenyl)piperazine-1-sulfonylmethyl|utetrahydropyran-4-(M-hydroxycarboxamide) on day 5

Oxalyl chloride (700 mg, 5.bmmol) and DMF (18 μl ). This mixture is heated at 3523 for 1 hour. After evaporation of the solvents, crude hydrogen chloride dissolved in dichloromethane (i9) (dml) is added to an ice-cooled solution of hydroxylamine (44µl, 50956 aqueous solution) in THF (ml). This mixture is stirred for 90 minutes at room temperature. After evaporation of the solvents, the residue is thoroughly triturated in a mixture of dichloromethane-ether-methanol (80:20:53. The obtained solid product is washed with water and ethyl acetate, and dried, obtaining the compound indicated in the title in the form of white crystals o (22) (230 mg, 47 9b). "YAN NMR (DMSO 4-6): 10.56 (s broad, 1H), 8.74 (s broad, 1H), 7.07 (m, 2H), 6.99 (m, 2H ), 3.66 (m, 2H), 3.47 "F (m, 2H), 3.40 (s, 2H), 3.25 (m, 4H), 3.16 (m, 4H), 1 .99 (m, 2H), 1.72 (m, 2H); Mass spectrum (E5I): 402 (MH", 424 (MMa").

Initial materials are obtained as follows:

Zo () Thioacetic acid (7 μM, 1 μM) and tributylphosphine (2.5 ml, 1 μM) in DMF (5 ml) are added in a dropwise manner. dropwise to an ice-cooled suspension of sodium hydride (53Omg, 60 95 in oil, 1Zmmol) in DMF (1.5 mL) under an argon atmosphere. The resulting mixture is stirred at 02C for 30 minutes. To the above solution was added 2,7-dioxaspiro|Z,5|nonan-1-ONINegI (1.4g, 10mmol) in DMF (10ml). This mixture is stirred at 09°C for 30 minutes, and at room temperature for 18 hours. The reaction mixture is diluted with ether. The precipitate - about 79 is filtered and dried, obtaining the sodium salt of 4-(acetylthiomethyl)tetrahydropyran-4-carboxylic acid. "H NMR s (DMSO a-6): 3.65-3.40 (m, 4H), 2.99 (s, 2H), 2.27 (s, ЗН), 1.86 (m, 2H) . of the sodium salt of 4-(acetylthiomethyl)tetrahydropyran-4-carboxylic acid, 4-I4-(4-fluorophenyl)piperazine-1-sulfonylmethyl/itetrahydropyran-4-carboxylic acid (490 mg) is obtained. (acetylthiomethyl)tetrahydropyran-4-carboxylic acid benzyl ester): Mass spectrum (EI): 331 (MMa"); 4-(chlorosulfonylmethyl)tetrahydropyran-4-("carboxylic acid benzyl ester): Mass spectrum (ESI: 354 (MMa"); 4-I4-(4-fluorophenyl)piperazine-1-sulfonylmethylyltetrahydropyran-4-carboxylic acid "in benzyl ester: Mass spectrum (ESI): 477 (MmMa", 499 (MmMa"); c 50 А-(4--4-fluorophenyl)piperazine-1-sulfonylmethyltetrahydropyran-4-carboxylic acid: Mass spectrum (E5I): 387 (MN), 409 (MMa 7).

I" Cap: V. Vagiaa|y, A. Natop, M. Matsaei; Teigapedgop I hey; 1998, 39, 7865

Keys: R. Neutapp-i a Kospe, Adotsgop Rpagt.; Eshig. Ra Arry. ER 780386.

Example 7 1-(2-(M-formyl-M-hydroxyamino)-2-phenylethanesulfonyl|-4-phenylpiperazine e. g. borax o gu 60 Fi y

A previously obtained mixture of formic acid (0.58 ml) and acetic anhydride (0 , 29 ml).

The solution is stirred at room temperature for 18 hours. The mixture is evaporated under vacuum, diluted with db/dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and evaporated. The residue is purified chromatographically, eluting with 195 methanol in dichloromethane, and obtaining

1-phenyl-(4-trans-bB-styrenesulfonyl)piperazine (42mg) as foam (105mg). "H NMR (DMSO-46 at 373K): 9.60 (s, 1H), 8.25 (s, 1H), 7.40 (m, 2H), 7.30 (m, ЗН), 7.20 (m, 2H), 6.90 (d, 2H), 6.75 (m, 1H), 5.60 (m, 1H), 3.85 (dd, 1H), 360 (dd, 1H), 3 .30 (m, 4H); 3.15 (m, 4H) t/2: 390 (M.n1).

The starting material is obtained as follows:

A solution of phenylpiperazine (487 mg) in dichloromethane (bml) containing triethylamine (0.6 ml) was added dropwise over 5 minutes to trans-b-styrenesulfonyl chloride (638 mg) in dichloromethane (4 ml). The solution is stirred at room temperature for 18 hours. The solution is diluted with dichloromethane and washed with water, dried over sodium sulfate and evaporated. The residue was purified by chromatography, eluting 195 with methanol in dichloromethane to give 70 1-phenyl-(4-trans-b-styrenesulfonyl)piperazine (420 mg) as a solid. H NMR (dMoO-ab): 7.75 (m, 2H), 7.40 (m, 4H), 7.30 (d, 1H), 7.20 (dd, 2H), 6.90 (d , 2H), 6.80 (dd, 1H), 3.20 (s, 8H) t/2 329 (M'-1).

Hydroxylamine (0.45 ml, 50 95 aqueous solution) was added to a solution of 1-phenyl-4-(trans-b-styrenesulfonyl)piperazine (108 mg) in THF (3 ml). This mixture is stirred at room temperature for 18 hours. Solvent 75 was removed in vacuo and the residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate and evaporated to give the product 1-(2-(hydroxyamino)-2-phenylethanesulfonyl|-4-phenylpiperazine) as a foam (120mg).

TN nMR (DMSO-a6): 7.50 (m, 1H), 7.40 (m, 2H), 7.30 (m, 5H), 6.90 (d, 2H), 6.80 (dd, 1H), 5.90 (m, 1H), 4.20 (m, 1H), 3.60 (dd, 1H), 3.40 (dd, 1H), 3.20 (m, 4H); 3.10 (m, 4H) t/2 362 (Mya1).

Example 8 1-22-(M-formyl-M-hydroxyamino)-2-(quinolin-4-yl)ethane-1-sulfonyl|-4-(4-fluorophenyl)piperazine and-C

OO su s no i Go)

To the suspension /1-(2-(M-hydroxyamino)-2-(quinolin-4-yl)ethane-1-sulfonyl|-4-(4-fluorophenyl)piperazine (148 mg,

0.Za4mmol) in a mixture of THF (2ml) -SNHCl" (2ml) add B-methyl-3-formyl-1,3,4-thiadiazole-2(ZH)-thione"). (14Omg,

Oh, 87 mmol). This mixture is stirred for 3 hours. After adding methanol (2ml) and silicon dioxide (1g), this mixture was stirred for 18 hours. The solid part is filtered. The filtrate is washed with a saturated sodium bicarbonate solution and a saturated saline solution. As a result of the evaporation of the solvents followed by thorough trituration in the mixture of acetonitrile-CH»oSiO», the starting material (bOmg) is obtained. After chromatographic treatment of the mother liquor with a mixture of acetonitrile-CHNOCl (1:11), the title compound (20 mg, 1395) is obtained. "H NMR (SOSIv): 8.97 (m, 1H), 8.21 (m, 2H), 8.01 (s, 1H), 7.8-7.65 (m, ЗН), about 6, 97 (m, 2H). 6.86 (m, 2H), 5.66 (m, 1H), 3.55-3.1 (m, 1OH); Mass spectrum (E5I): 459 (MMa U. -

The starting material is obtained from quinoline-4-carboxaldehyde and 1-(fluorophenyl)-4-methanesulfonyl)piperazine according to the method of example 1: 188mg: Mass spectrum (E5I): 431 (MH); HPLC (Column TZKadei ! zireg O05 2mm 4.bmmx5cm, methanol/water gradient 20 to 10095 in 5 min., flow rate: 1.4 ml/min): 3.43 min. " (1) Hagama, N.; So, 5. Teigapedgop I ey, 1985, 26, 3703

Example 9 - c 1-(1-N-formyl-N-hydroxyamino)-1-(3,4-dichlorophenyl)pentane-2-sulfonyl)|-4-(4-fluorophenyl)piperazine. ; Analogously to the method of example 1, diastereoisomers of 1-(1-(M-hydroxyamino)-1-(3,4-dichlorophenyl)pentane-2-sulfonyl|-4-(4- fluorophenyl) of piperazine is converted into the title compound (as 2 diastereoisomers): o-diastereoisomer 1 from less polar hydroxylamine: Zbmg, 7090; "IN NMR (SOCI3,): 8.45 and 8.10 (s, 1H), so 20 7.6-7.2 (m, ЗН), 7.0-6.8 (m, 2H), 5.96 and 5.18 (m, 1H), 3.8-3.4 (m, 5H), 2.9-3.15 (m, 4H), 2.0-1.0 (m, 4H), he 0.88 and 0.76 (t, ЗН, U-7Hz); Mass spectrum (EBI): 540 (MIZ5CI, 33Ma"), 542 (MZS, З5СИМа "y. -diastereoisomer 2 from more polar hydroxylamine: 49mg, 6395; "H NMR (SOSIv): 8.28 and 8.13 (s, 1Н ), 7.6-7.2 (m, ЗН), 7.0-6.85 (m, 2H), 5.54 and 5.02 (m, 1H), 3.45-3.9 (m , 5H), 3.15 (m, 4H), 1.7-1.2 (m, 4H), 0.76 (t, ЗН, 9-7Hz); Mass spectrum (EI): 540 (M/ З5СИ, 353Ма"), 542 (MI СИ, 5СИМа").

The starting material is obtained as follows: (F) According to the method of example 1, it is obtained from 1-(4-fluorophenyl)piperazine and 1-butanesulfonyl chloride

GI 1-(4-fluorophenyl)-4-(butane-1-sulfonyl)piperazine (1.84 g); according to the method of example 1 iii), it is subjected to interaction with 3,4-dichlorobenzaldehyde, obtaining 4-(4-fluorophenyl)-1-(1-(3,4-dichlorophenyl)pent-1-ene-2-sulfonyl|-piperazine bo In the form of a mixture of 2/E isomers (33Omg, 2296): Mass spectrum (EBI): 457 (MI 5С1,353Н7), 459 (MI/С1,55С13Н"); according to the method of example 1 and it) except that the mixture is refluxed for 3 days, it is converted into 1-|(1-(M-hydroxyamino)-1-(3,4-dichlorophenyl)-pentane-2-sulfonyl/|-4-(4-fluorophenyl) )piperazine in the form of vup and apium diastereoisomers.

Less polar isomer: (5Omg, 1595) (TLC: eluent EUAs -CH Si»-petroleum ether (15-45-50); "H NMR 65 (SOSIa): 7.53 (d, 1H, 9U-2.2Hz ), 7.46 (d, 1H, 9U-7.4HZ), 7.27 (m, 1H), 6.97 (m, 2H), 6.88 (m, 2H), 4.63 (m, 1H), 3.55 (m, 4H), 3.16 (m, 5H), 1.75 (m, 2H), 1.4 (m, 1H), 1.2 (m, 1H), 0, 77 (t, ZN, 9-7, 4 Hz).

More polar isomer: (7bmg, 23905) "IN nMR (SOS): 7.52 (d, 1H, 9U-2Hsh), 7.45 (d, 1H, 9U-8Hts), 7.27 (m, 1H) , 6.99 (m, 2H), 6.89 (m, 2H), 4.42 (m, 71H), 3.55 (m, 4H), 3.41 (m, 1H), 3.14 ( m, 4H), 1.6 (m, 2H), 1.25 (m, 2H), 0.76 (t, ЗН, U-7.43Hz).

Example 10 16)

ОО х- о|: po osno 70 Trans 1-(2-(M-formyl-M-hydroxyamino)cyclohexane-1-sulfonyl 1|-4-(4-fluorophenyl)piperazine

According to the method of example 1, from trans 1-(2-(M-hydroxyamino)-cyclohexane-1-sulfonyl/|-4-(4-fluorophenyl)piperazine, the title compound (b8mg, 2390) is obtained. ): 8.39 and 8.02 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.40 and 3.92 (m, 1H), 3.35- 3.55 (m, 5H), 3.15 (m, 4H), 2.35 (m, 1H), 2.0-1.8 (m, ZN), 1.2-1.6 (m, 4H); Mass spectrum (E5I): 408 (MMa").

The starting material is obtained as follows: i) To a solution of PA (51 mmol, obtained as a result of the slow addition of n-butyllithium (20.4 ml, 2.5 M in hexane, 5 mmol) to a solution of diisopropylamine (5.1 bg, 5 bimol) in THF (30 ml) at -782C) at -789C7 add a solution of 1-(4-fluorophenyl)-4-(methanesulfonyl)-piperazine (bg, 23.2 mmol) in THF (150 ml). The mixture is stirred for 1 hour at -782C. A solution of 5-chlorovaleryl chloride (4 g, 25.8 mmol) in THF (20 ml) was added dropwise. The mixture is stirred at -782C for 1 hour and at room temperature for 18 hours. The solution is diluted

EtOAc and washed with saturated MNACI and saturated saline solution and dried over magnesium sulfate.

As a result of chromatographic processing of the residue on silica gel (eluent: EtOAc -CHNOCl -petroleum ether (15:35:50)) 1-(6b-chloro-2-hexanone-1-sulfonyl)-4-(4-rtorphenyl)piperazine ( 5.22g, bObo) in the form of white crystals: Mass spectrum (E5I): 399 (MMa" ). c i) A mixture of this compound (5.22g, 13.bmmol) and Ma! (42g) in acetone (9Oml ) refluxed for 5 h. After cooling and partitioning between EtOAc and water, the organic layer was washed with 10 9 NaHb5Oz and saturated brine, and dried over magnesium sulfate to give 1-(6-iodo-2-hexanone- 1-sulfonyl)-4-(4-fluorophenyl)piperazine (6.13 g, quantitative) in the form of yellow crystals. "H NMR (SOCIv): 6.98 (m, 2H), 6.88 (m, 2) , 4.00 (s, 2H), 3.46 (t, 4H, 29-4.8Hz), 3.19 (t, 2H, M uznv,, bGu), 3.16 (t, 4H, 2U- 4.8Hz), 2.79 (t, 2H, U-6.6Hz), 1.85 (m, 2H), 1.74 (m, 2H). A mixture of this compound (1.27g, 4.85mmol) and cesium carbonate (8g, 24.5mmol) in NaCl (90ml) was stirred at room temperature for 4 hours. Water and 2N HCl to pH-7 are slowly added to this mixture. The mixture is extracted SNSI". The organic layer is dried over magnesium sulfate. Chromatographic treatment on silica gel (eluent: EtOAc - petroleum ether (4:6)) gave 1-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (88mg, 5395). "H NMR (SOSIv): 6.97 (m, 2H), 6.88 - (m, 2H), 3.83 (m, 1H), 3.48 (m, 4H), 3.12 (m, 4H), 2.81 (m, 1H), 2.54 (m, 1H), 2.46 (m, 1), 2.2-2.0 (m, ЗН), 1.75 (m, 2H ); mass spectrum (E5I): 363 (MMa"). 14: 1716.

As a result of further elution (EuOAc petroleum ether (6:4)), 1-Ktetrahydropyran-2-yl)methylidenesulfonyl|-4-(4-fluorophenyl)piperazine (b3Omg, 38 95) is obtained; "H NMR (SOSIv): 6.98 v s (m, 2), 6.87 (m, 2H), 5.21 (s, 1H), 4.14. (t, 2H, 9-52GSH), 3.32 (m, 4H), 3.15 (m, 4H), 2.35 (t, 2H, and U-6.6Hz), 1.82 (m, 4H); Mass spectrum (E5I); 363 (MMa U. "» them) To a solution of 1-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl) piperazine (284 mg, 0.8 mmol) in a methanol-THF mixture (1 bml, 3:1) at 09С add sodium borohydride (3.7 mg, thymole). The mixture is stirred at 09C for 30 minutes and at room temperature for 1 hour 30 minutes. Solvents evaporate. Add a saturated solution of MNASI and water. The precipitate was filtered off, washed with water and dried to give this 1-(2-cyclohexanol-1-sulfonyl)-4-(4-fluorophenyl)piperazine (25mg, 8895): Mass spectrum (ESI): 343 (MH). m) Triphenylphosphine (1.18 g; 4 .5 mmol) and OEAO (712 μl, 4.5 mmol). The mixture is stirred at 50°C room temperature for 18 hours. After evaporation of solvents and chromatographic purification on silica gel (eluent: EtOAc-petroleum ether, gradient from 2:8 to 3:7) 1-(1-cyclohexene-1-sulfonyl)|-4-(4-fluorophenyl)piperazine is obtained (285mg, 9895): Mass spectrum (EBI): 325 (MN). mi) According to the method of example 1 iiiiii) except that the reaction mixture is heated at 659C for 30 hours, with 1-(1-cyclohexene-1-sulfonyl)-4-(4-fluorophenyl)piperazine (280 mg, 0.8 bmg) trans 1-I(2-(M-hydroxyamino)cyclohexane-1-sulfonyl)|-4-(4-fluorophenyl)piperazine (27 Ω, 8895) was obtained: "H NMR (SOCIv): 6.98

HF) (m, 2H), 6.88 (m, 2H), 3.54 (m, 4H), 3.34 (m, 2H), 3.14 (m, 4H), 2.30 (m, 71H), 2.17 (m, 1H), 2.05 (m, tn), 7 1.9-1.2 (m, 5H); Mass spectrum (E51I): 358 (MN).

Example 11 in Cis /1-(2-("M-formyl-M-hydroxyamino)cyclohexane-1-sulfonyl|-4-(4-fluorophenyl)-piperazine.

I'm Masha, but it's a dream

According to the method of example 71, from cis 1-(2-(M-hydroxyamino)-cyclohexane-1-sulfonyl|-4-(4-fluorophenyl)piperazine 65, the title compound (18 mg, 1895) is obtained: "H NMR (SOCIv) : 8.39 and 8.07 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.77 and 4.25 (m, 1H), 3.48 (m , 5H), 3.13 (m, 4H), 2.25-1.3 (m, 8H); Mass spectrum (EI): 408 (MMa").

The starting material is obtained as follows: i) A mixture of 1-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)-piperazine (5mg, 0.14mmol), hydroxylamine hydrochloride (51mg, 0.7mmol) and potassium acetate (72mg, 0.7 mmol) in methanol (5 ml) is heated at 0 709C for 4 hours. Solvents evaporate. After separation between EtOAc and water, the organic layer is washed with saturated saline and dried over magnesium sulfate to give

I-(2-(M-Hydroxyimino)cyclohexane-1-sulfonyl/|-4-(4-fluorophenyl)piperazine as a white solid (48mg, 9496); Mass spectrum (E5I): 356 (MH). i) To this compound (210mg, 0.bmmol) in a mixture of THF-acetic acid (7ml, 1:11) is added 70. sodium cyanoborohydride (27bmg, 4.4mmol). The mixture is stirred at room temperature for 18 hours. Water is added, and the pH is adjusted to 9. The mixture is extracted with E(OAc). The organic layer is washed with saturated saline solution and dried over magnesium sulfate. As a result of chromatographic treatment on silica gel (eluent: E(OAc-petroleum ether, gradient from 111 to 8:2) cis 1-(2-(M-hydroxyamino)cyclohexane-1-sulfonyl-4-(4-fluorophenyl)-piperazine (97 mg, 4595) was obtained: "H NMR (SOCIv8): 6.98 75 (m, 2H), 6.89 (m, 2H), 3.63 (m, 1H), 3.52 (m, 4H), 3.24 (dt, 1H, 9U4-10.6Hz, U,-3.5Hz), 3 .15 (m, 4H), 2.2-1.2 (m, 8H); and I

Mass spectrum (E5I): 358 (MN).

Example 12

The following compounds are obtained using the method described in example 1: o Ex. 1 « EM-n

K2 is hydrogen

PIR-piperazinil

ВНе-reverse hydroxamate p

A: carboxylic acid. at

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Mass spectrum for S.47NaEMz3O55 (MAN), calculated 402, found 402 F

BUT 2 mo o s c)

Aryl/heteroarylpiperazines and piperidines used as starting materials are commercially available in or described in the literature, for example, 4-(4-fluorophenyl)-piperidine, CA5 number 37656-48-7,

Piperazine, 1-(/1,1"-biphenyl|-4-yl-(180698-19-5) «

Piperazine, 1-(/1,1"-biphenyl|-3-yl-(115761-61-0)

Piperazine, 1-(2-naphthalenyl)-(57536-91-1) o) c Piperazinone, 1-phenyl-(90917-86-5) "» 1H-1,4-Diazepine, 1-(4chlorophenyl)hexahydro- (41885-98-7) " Quinoline, 4-methyl-2-(1-piperazinyl)-(50693-78-2)

Piperazine, 1-(4-phenoxyphenyl)-52755-61-7

Piperazine, 1-(3-chlorophenyl)-2-methyl-4-(4-fluorophenyl)-piperazine, used as starting material, is obtained as follows: sodium tert-butoxide (4.1 g) is added to a solution of tritolylphosphine (0.638g) and palladium acetate (0.319g) in toluene (250ml) under argon and the mixture was stirred for 20 minutes. 4-Fluoro-bromobenzene o (5g) and 2-methylpiperazine (2.85g) are added, and this mixture is heated at 11092 for 7 hours, then left

Ge) 20 to cool to room temperature, and kept at this temperature for 20 hours. The reaction mixture is filtered through Seille?, the filter cake is washed twice with dichloromethane (2X25 ml), and the resulting filtrate is evaporated to dryness. The residue is processed chromatographically on silica gel, eluting first with dichloromethane and then with a mixture of dichloromethane-dethanol and ammonium hydroxide (100:5:1), obtaining 2-methyl-4-(4-fluorophenyl)-piperazine, 2.5 g.

Using the same method and 2,6-dimethylpiperazine as a starting material, is obtained

HF) 2,6-dimethyl-4-4-(fluorophenyl)-piperazine.

Piperazine, 1-11,1-biphenyl-4-fluoro|-4-yl hydrochloride tert-butoxycarbonylpiperazine, and 1-11,1-biphenyl-4-fluoro|-4-yl (0.712g) are stirred in a mixture of dichloromethane (1Oml ) and trifluoroacetic acid (1.Oml) for 18 hours at room temperature, evaporated in vacuo to give a gray 60 solid, which was used without further purification. / tert-butoxycarbonylpiperazine, 1-11,1-biphenyl-4-fluoro)|-4-yl, used as starting material, is obtained as follows:

Sodium tert-butoxide (1.35g) is added to a solution of 5-(-)-2,2'-bis(diphenyl.phosphino)-1,1-binaphthyl (-0.046g) and bis-(dibenzylideneacetone)ipalladium (0.023 d) in toluene (25ml) in an argon atmosphere, and then 4-bromo-4-fluorobiphenyl (2.51g) and 1-tert-butoxycarbonylpiperazine (2.2g) are added and this mixture is heated at 802C for 5 hours. The reaction mixture is filtered, the filtrate is evaporated in vacuo to give a yellow solid, which is thoroughly triturated and then filtered with diethyl ether (2Oml) to give tert-butoxycarbonylpiperazine, 1-(1,1'-,biphenyl-4-fluoro|-4 -yl (2.67 g), M.p. 165-166 "S. H NMR (DMSO-46) 1.42 (s,

OH), 3.15 (m, 4H), 3.48 (m, 4H, 7.02 -(d, 2H), 7.22 (m, 2H), 7.51 (d, 2H), 7, 63 (m, 2H); t/2, 357 (M--1).

Example 13 a lx v si (J ke o 70) Acetic anhydride (0.23 ml) is added directly to formic acid (0.9 ml). The solution is stirred at room temperature for 3 minutes, and then the solution is added

IM-(2-Х4-(-6-chloropyrimidin-4-yl)|(tetrahydropyrazin-1-yl|sulfonyl)-1-(3,4-dichlorophenyl)(ethylhydroxylamine (0.227g) in tetrahydrofuran (5ml). The solution is stirred at room temperature for 18 hours.

IM-(2-Х4-(b-chloropyridin-4-yl)|(piperazino|sulfonyl)-1-(3,4-dichlorophenyl-ethyl)|-M-hydroxyformamide (0.178 g), 98-10126.

NMR (DMSO-ab, 3732K): 3.31 (m, 4H), 3.70 (dd, 1H), 3.75 (m, 4H), 3.95 (dd, 1H), 5.61 (pt width c, 1H), 6.89 (c, 1H), 7.43 (dd, 1H), 7.60 (d, 1H), 7.70 (d, 1H), 8.29 (s, 1H) , 8.36 (c, 1H); t/2 494 (M'-t1). ho si

Go (c)

Acetic anhydride (0.6 ml) is added directly to formic acid (42.48 ml). The solution is stirred at room temperature for 30 minutes, and then a solution of 29 M-2-C4-(B-chloropyridin-2-yl)|(piperazino|sulfonyl)-1-(3,4-dichlorophenyl)ethylhydroxylamine (0, 61 g) in tetrahydrofuran (1 Oml). The solution is stirred at room temperature for 3 hours, and then diluted with ethyl acetate, the pH is adjusted to neutral with saturated aqueous sodium bicarbonate. The ethyl acetate layer is separated, dried over sodium sulfate and evaporated to dryness. The precipitate is purified chromatographically, using 10 g of silicon dioxide, eluting with a mixture of 1095 ethyl acetate/hexane-8095 ethyl acetate/hexane, then evaporated to dryness. The obtained white solid is filtered from diethyl ether, obtaining b

M-42-C4-(5-chloropyridin-2-yl)-piperazino|sulfonyl)-1-(3,4-dichlorophenyl)-ethyl|-M-hydroxyformamide (0.431 g), 211-212e6. at

NMR (DMSO-ab, 3732K): 3.30 (m, 4H), 3.80 (m, 4H), 3.85 (dd, 1H), 3.95 (dd, 1H), 5.58 (pt width c, 1H), so 6.85 (d, 1H), 7.43 (m, 1H), 7.58 (m, 2H), 7.85 (m, 1H), 8.10 (d, 1H ), 8.13 (s, 1H); t/2493(M 1). m o

S. on rock with Y

Acetic anhydride (0.48 ml) is added directly to formic acid (1.9 ml). The solution is stirred at room temperature for 30 minutes, and then a solution of 770 M-(2-(benzyloxy)-1-(4-pyridin-2-ylpiperazine)-sulfonyl|methyl)ethyl)hydroxylamine (0.42 g) is added in with tetrahydrofuran (ml). The solution is stirred at room temperature for 3 hours, and then diluted with ethyl acetate, the pH value is brought to neutral with a saturated aqueous solution of sodium bicarbonate. The ethyl acetate layer is separated, dried over sodium sulfate and evaporated to dryness. As a result of chromatographic purification of the residue on silica gel (10 g) , eluting with a mixture of CHSi» 595 methanol/-CHNoSi» 75 obtain /-M-(2-(benzyloxy)-1-(4-pyridin-2-ylpiperazino)sulfonyl|methylethyl)-M-hydroxyformamide 40.233G), ev. 70-7596. (95) NMR (DMSO-a6, 3732K): 3.25 (dd, 1H), 3.31 (m, 4H), 3.48 (dd, 1H), 3.65 (m, 4H ), 3.66 (dd, 1H), 3.70 o (dd, 1H), 4.55 (point width s, 1H), 4.55 (s, 2H), 6.70 (m, 1H), 6.85 (d, 1H), 7.28 (m, H), 7.32 (m, 4H), 7.56 (m, 1H), 8.17 (m, 2H), 9.45 (width s, 1H); t/2 435 (M.-1). o 50 t-ov

Shield

Acetic anhydride (0.48 ml) is added directly to formic acid (1.9 ml). The solution is stirred at room temperature for 30 minutes, and then a solution of N-(3-pyridin-2-yl-1-(4-pyridin-2-ylpiperazino)-sulfonyl|methyl)propyl)hydroxylamine (0.152 g) in tetrahydrofuran (ml). The solution is stirred at room temperature for 3 hours, and then diluted with ethyl acetate, the pH value is brought to neutral with a saturated aqueous solution of sodium bicarbonate. The ethyl acetate layer is separated, dried over sodium sulfate and evaporated to dryness. As a result of 60 chromatographic purification of the residue on silica gel (10 g), eluting with a mixture of CHCl» 595 methanol/CHClCl», M-hydroxy-M-(3-pyridin-2-yl-1-((4-pyridin-2-ylpiperazino)sulfonyl) is obtained |methyl)ipropyl)formamide (0.039g), 80-8496.

NMR (DMSO-ab, 3732K): 2.10 (m, 2H), 2.80 (m, 2H), 3.25 (dd, 1H), 3.30 (m, 4H), 3.50 (dd , 1H), 3.60 (m, 4H), 4.42 (m, 1H), 5.70 (m, 71H), 6.85 (d, 1H), 7.19 (m, 1H) . .45 (m, 1H), 9.50 (point width s, 1H); t/2420(M-1).

Example 14

M-11-(44-(5-chloropyridin-2-yl)oxy))(piperidino)sulfonyl)methyl/|-3-pyridin-3-ylpropyl)-M-hydroxyformamide o. y ' ZO o-k - X-o

To a solution of 1-M-(2-(hydroxyamino)-2-(3-pyridinyl)butanesulfonyl)-4-0-(5-chloro-2-pyridinyl)piperidine 121g, 4.1bmmol) in THF (Zbml) is added in advance the obtained mixture of formic acid (9.0 ml) and acetic anhydride (2.25 ml). This mixture is stirred at room temperature for 18 hours. The reaction mixture is neutralized using saturated aqueous MnSO" before extracting the EtOAc solution (x2). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue is stirred in Meon at room temperature for 20 hours to remove bisformyl. The residue was crystallized from EYN, obtaining a white solid (0.898 g). T.pl. 130-14026.

TN nMR (DMSO-1002C): 9.50 (bt c, 1H), 8.43 (d, 1H), 8.39 (dd, 1H), 8.15 (d, 1H), 8.13 (bt s, 1H), 7.74 (dd, 1H), 7.60 (m, 1), 7.27 (m, 1H), 6.83 (d, 1H), 5.12 (m, 1H), 4.32 (width c, 1H), 3.42 (m, ЗН), 3.1-6 (m, ЗН), 2.68-2.54 (m, 2Н), 2.06-1.93 (m, 4H), 1.76 (m, 2H); Mass spectrum (EbBzh): 469.2 (MH), 491.1 (MMa");

Elemental analysis: Calculated for С 20Но5СИМаОвБ5: С 51.22, Н 5.37, СИ 7.56, М 11.95, 5 6.84, Found: С 50.92, Н 5.30, СИ 7.55, M11.90, 5 6.75.

The starting material is obtained as follows: i) Mann (2.88 g, 6-bmmol, 5595 dispersion in mineral oil) is stirred in dry DME (200 ml) under an argon atmosphere. A mixture of 2,5-dichloropyridine (8.87g, bOmmol) and 4-hydroxypiperidine (6.67g, bbmmol) dissolved in dry DME (200ml) was added dropwise to the Mann suspension over 30 minutes. After the addition is complete, the reaction mixture is heated at 822 for 48 hours, maintaining an argon atmosphere. Reaction c is slowly quenched with water before most of the THF is removed. The aqueous layer is extracted by OSM (x3). The organic layers were dried over sodium sulfate and evaporated in vacuo to give 2-(4-piperidinyloxy)-5-chloropyridine as a yellow oil (12.7 g, quantitative). "H NMR (DMSO): 8.17 (d, 1H), 7.76 (dd, 1H), 6.81 (d, 1H), 4.96 (m, 1H), 2.93 (m, 2H ), 2.53 (m, 2H), 1.91 (m, 2H), 1.46 (m, 2H); Mass spectrum (EB): 213.3 (MH), 225.3 (MMa") . i) To a solution of 2-(4-piperidinyloxy)-5-chloropyridine (12.9 g, 0.02 mol) and E6BM (254 ml, 0182 mol) in dry 3 dichloromethane (4000 ml) under 02 and in an argon atmosphere, dropwise add methanesulfonyl chloride ( 5.3 ml, 0.067 (o) mol) in dry dichloromethane (100 ml). This mixture is stirred for 20 hours at room temperature. at

The mixture is diluted with dichloromethane (250 ml), then washed with water (x3), then with saturated saline solution. The organic layers were dried over sodium sulfate and evaporated in vacuo. The residue is thoroughly triturated (9 and washed with diethyl ether, obtaining 2-(M-methanesulfonyl-4-piperidinyloxy)-5-chloropyridine (15.1 g) in the form of a pale yellow solid. "H NMR (DMSO) 8.20 ( d, 1H), 7.81 (dd, 1H), 6.87 (d, 1H), 5.09 (m, 1H), 3.32 (m, 2H), 3.11 (m, 2H), 2.90 (s, ZN), 2.02 (m., 2H), 1.75 (1H, 2H); Mass spectrum (EB'zh): 291.2 (MNU), 313.2 (Mma" ).« her) 2-(M-methanesulfenyl-4-piperidinyloxy)-5-chloropyridine (2.0g, b6.869mmol) was placed in anhydrous THF 40. (100ml) under an argon atmosphere, then cooled to -782С before adding I and (TM5A) (13.8 ml of a 1.0 M solution in THF, - with 13.8 mmol). This mixture is stirred at -782C for 20 minutes, and a solution of diethylchlorophosphate (1.0 bml, 7.2 mmol) is added. This mixture was stirred at -789C for one hour before addition of N-pyridinylpropanal (1.12g, 8.27mmol), then stirred at -782C for another hour. The mixture is left to warm to room temperature, then washed with aqueous ammonium chloride and extracted with ethyl acetate.

The organic layers are washed with water, saturated saline and dried over sodium sulfate. As a result, purification of the residue on silica gel (eluent: a gradient of rom-29o0 meonlosm) yielded oo 2-IM-(E/27-4(3-pyridyl)-but-1-enyl|isulfonyl)4-piperidinyloxy)-5-chloropyridine in in the form of yellow oil (2.09 g). "H NMR (DMSO): 8.45 (m, 1H), 8.37 (m, 1H), 8.19 (m, 1H), 7.82 (m, 1H), 7.64 (m, 1H )), 7.30 (m, 1H), o 6.85 (m, 71H), 6.88-6.27 (m, 2H, E/7 isomers), 5.00 (m, 1H), 3 ,15 (m, 2H), 2.83 (m, 5H), 2.61 (m, 1H), 1.85 (Ce) 50 (m, 2H), 1.70 (m, 2H); spectrum (Ebh): 408.1 (MH), 430.2 (MMa").

I» them) To a solution of /-2-1MCh-IE/2-4(3-pyridyl)-but-1-enyl|-sulfonyl)-4-piperidinyloxy)-5-chloropyridine (2.09g, 5.mmol) add hydroxylamine (3.4 ml, 5095 aqueous solution) to THF (20 ml). This mixture is stirred for 18 hours. The solvent is evaporated. The residue is dissolved in E(Ac) and washed with water (x4). The organic layer is dried over sodium sulfate and evaporated in vacuo to give 2-(4-piperidinyloxy)-5-chloropyridine 25 1-H-I2-(hydroxyamino)-2-( 3-pyridinyl)butanesulfonyl|-4-O-(5-chloro-2-pyridinyl)piperidine (73Omg). But NMR (F) (DMSO): 8.43 (d, 1H), 8.37 (dd, 1H ), 8.18 (d, 1H), 7.78 (dd, 1H), 7.61 (m, 1H), 7.36 (s, 1H), 7.29 (m, tn),

He 7.85 (d, 1H), 5.70 (s, 1H), 5.08 (m, 1H), 3.35 (m, ЗН), 3.16-3.00 (width m, 4H) , 2.80-2.60 (width m, 2H), 1.98 (m, 2H), 1.84 (m, 2H), 1.69 (m, 2H); Mass spectrum (Eb): 441.2 (MH"), 463.2 (MMa 7). 60 Using a method similar to the method of example X, aryl-4-O-piperidine is reacted with the corresponding aldehyde to obtain the compounds listed below. o) in TEZ

І uUskon ko Vi b5

You are VZ MV |MS (EVZYU Fr

The following aryl-4-O-piperidines were previously disclosed:

Piperidine, 4-(3-chlorophenoxy)-(9C1), SAZ (97840-40-9)

Piperidine, 4-(4-chlorophenoxy)-(9C1), CA5 (97839-99-1)

Pyridine, 2-(4-piperidagnyloxy)-(9C1), C AZ (127806-46-6)

Piperidine, 4-(3,4-dichlorophenoxy)-(9C1) was synthesized by the following alternative method: 1) To a solution of 4-hydroxypiperidine (3.5 g, O0.035 mol) stirred in dry methanol (5 Oml) at 02С, add dropwise di-tert-butyl decaroonate (9.2 ml, 0.042 mol) in dry methanol (5 bml). This mixture is stirred for 20 hours at room temperature. Methanol is removed, the remaining solution is placed in EBO, then it is washed with citric acid (x3) and water (x3). The combined aqueous extracts are extracted with EBO, dried over sodium sulfate and evaporated in vacuo. As a result of cleaning the residue on Ha 2; silica gel (eluent: gradient OSM-3096 Meon/OosMm), M-BOC-4-hydroxypiperidine is obtained as a yellow oil (6.4 g). IN NMR (DMSO): 4.05 (m, 2H), 3.70-3.52 (width m, ЗН), 2.92 (m, 2H), 1.66 (m, 2H), 1.40 (c, 9H), 1.33-1.18 (width m, 2H); Mass spectrum (Eq): 201.3 (MH), 219.4 (MMH, 7). 2) To a stirred solution of M-BO5-4-hydroxypiperidine (2.0 g, 0.0 mol), triphenylphosphine (3.68 g, 0.014 mol), and 3,4-dichlorophenol (1.96 g, 0.012 mol) in dry toluene (75 ml) (with molecular sieves, at 09C and - in an argon atmosphere) add diethyl azodicarboxylate (2.52 ml, 0.01 bmol) dropwise. This mixture is stirred F) for 1.5 hours at 02С. The solution is filtered, and the toluene is removed before intensively stirring isohexane (100 ml), and the resulting suspension is filtered. This filtrate is washed with 2M aqueous Mahon (x8), dried over sodium sulfate and evaporated in vacuo. As a result of chromatographic purification of the residue on silica gel (eluent: 20956 EtOAc/isohexane), M-Bos-piperidine, 4-(3,4-dichlorophenoxy)-(9C1) was obtained as a yellow solid (1.96 gHg). IN nMR (DMSO): 7.52 (d, 1), 7.91 (d, 1H), 7.01 (ai, tn), 4.62 (m, 1H), - 3.65 (m, 2H ), 3.15 (m, 2H), 1.88 (m, 2H), 1.53 (m, 2H), 1.40 (c, 9H); Mass spectrum (EB Kc): 346.3 (MNK). 368.4 (MMa").

C) 5095 aqueous trifluoroacetic acid (13ml) was added to a stirred solution of M-Boc-piperidine, 4-(3,4-dichlorophenoxy)-(9C1) (1.96g, 5.6bmmol). After 3.5 hours, toluene is added and evaporated in vacuo, and this is repeated twice. Then the residue is transferred to E(Ac, washed with saturated aqueous MansCoO with uc (x3), dried over sodium sulfate and evaporated in vacuo to obtain piperidine, and 4-(3,4-dichlorophenoxy)-(9C1) as a white solid (1.3g). "H NMR (DMSO): 7.54 (d, 1H), 7.35 (d, 1H), ,» 7.04 (dd, 1H), 4.70 (m, 1H) , 3.31 (m, 2H), 3.09 (m, 2H), 2.08 (m, 2H), 1.80 (m, 2H); Mass spectrum (E5K): 2.26.3 ( MN).

Then, piperidine, 4-(3,4-dichlorophenoxy)-(9C1) is treated according to the stages ii-im presented above.

Example 15 - I 1-Mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine 1-Mesylpiperazine hydrochloride (4.24g) is added to a solution of methyl b-chloronicotinate (1.7g) and o M,M-diisopropylethylamine (6b .3ml) in dimethylacetamide (2Oml), and this mixture is heated at 1202 for 2 hours. (ав) This mixture is allowed to cool to room temperature and poured onto a mixture of crushed ice and 50% water (5 Bbml) until a yellow-brown solid precipitates. This solid was collected by filtration and dried at 80 9C for 18 hours in a vacuum thermostat to give 1-mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine (2.05 g), T. pl. 205-20720. "H NMR (DMSO-a6): 2.90 (s, ЗН), 3.20 (m, 4Н), 3.78 (m, ЗН), 3.80 (s, ЗН), 6.92 (d , 1H), 8.00 (dd, 1H), 8.67 (d, 1H); t/2 300 (M'-1).

Using a similar method, 1-mesylpiperazine hydrochloride, SAZ (161357-89-7), is reacted with the corresponding chloropyridine 22 to obtain the following compounds.

F. Hl -M OO M-5-SN, ich) k/ in bo 80000 mvimiaemnu b5 5-SM-2-pyridyl 266 267

Bvgolridy 10 zoovog 1-(6-chloropyrimidin-4-yl)-4-mesylpiperazine

A mixture of 4,6-dichloropyrimidine (39.4g), 1-mesylpiperazine hydrochloride (55.7g) and triethylamine (11bml) in ethanol (500ml) was stirred at reflux for 4 hours. This mixture is then stirred at room temperature for 12 hours. The separated solid was collected by filtration, the suspension was washed with ethanol (2x800ml, 1b0ml) then with diethyl ether (150ml), and dried to give 1-(b-chloropyrimidin-4-yl)-4-mesylpiperazine as a cream-colored solid ( 71.9 Gh). T. pl. 200-2022С "H NMR (DMSO-ab): 2.88 (s, 3H), 3.18 (m, 4H), 3.80 (m, 4H), 7.04 (s, 1H), 8, 38 (m, 1H), t/2 277.3 (M.-1).

Using a similar procedure, 1-mesylpiperazine hydrochloride, SAB (161357-89-7), is reacted with the corresponding chloropyrimidine or chloropyridazine to give the following compounds. no dream

IN

(in

Sk mvrnyamnu 2 (b-methoxytyrimidineachl | otv

Example 16

NOI sch 25 hundred (o) what she

Acetic anhydride (19ml) is added directly to formic acid (7bml). This solution is stirred at t 30 room temperature for 3 minutes. A solution of Ge) 1-(6b-chloropyrimidin-4-yl)-4-12-(hydroxyamino)-4-phenylbutyl|sulfonyl)ipiperazine (17.2 g) in tetrahydrofuran (8 bml) is added in portions to the solution obtained above at 272C for 25 minutes The solution is stirred at room temperature for one hour. The solution is evaporated (temperature of the water bath ЗО 2), and the resin that remains 95 is dissolved in ethyl acetate (500 ml). The resulting solution is treated with a saturated aqueous solution of M sodium bicarbonate (20000 ml), and this mixture (pH 8) is stirred at room temperature for 16 hours.

The ethyl acetate layer is separated, washed with saturated saline solution (100 ml), dried over sodium sulfate and evaporated to dryness. The remaining foam is dissolved in ethanol, the solid part is separated, and this mixture is stirred for 2 days. The solid product is collected by filtration, the suspension is washed with diethyl ether (POOMl), and dried to give

IM-(1-444-(b-chloropyrimidin-4-yl)|(piperazino|-sulfonyl)methyl)-3-phenylpropyl|-M-hydroxyformamide as a colorless solid (12.8 g). T, square 155-157960, :z» Found C, 50.29, H, 5.29, SI, 7.82, M, 15.31, and 5, 6.82 96. St9No«SIM5O,5 calculated C, 50, 27, H, 5.33, SI, 7.81, M, 15.43, and 5, 7.06 95. "H NMR (DMSO-46 3732K): 1.93 (m, 1H), 2.03 (m, 1H), 2.57 (m, 1H), 2.65 (m, 1H), 450 3.20 (dd, 1H), 3.26 (t, 4H), 3.48 (dd, 1H ), 3.74 (t, 4H), 4.3 (point width, 1H), 6.90 (s, 1H), 7.19 (m, ЗН), 7.27 (m, 2H), 8.1 (width 1H), 8.38 (s, 1H), 9.5 (s, 1H); t/2 454.2 (M.-1). , i o AD h M u OS

I«e) -E

T» Acetic anhydride (31.5ml) is added directly to formic acid (12bml). The solution is stirred at room temperature for 30 minutes.

A solution of 1-(3-benzyloxy-2-(hydroxyamino)|(|propyl|Isulfonyl)-4-(b-chloropyrimidin-4-yl)piperazine / (29.5 g) in tetrahydrofuran (15 Oml) and formic acid (25 ml ), is added portionwise to the above solution at 25920 over 25 minutes. The solution is stirred at room temperature for one hour. The solution is evaporated (F) (water bath temperature 302) and the remaining resin is dissolved in ethyl acetate (5000ml). This solution is treated with saturated aqueous solution of sodium bicarbonate (2x250 ml) and this mixture (pH 8) is stirred at room temperature for 16 hours. The ethyl acetate layer is separated, washed with saturated saline and Vozchin (100 ml), dried over sodium sulfate and evaporated to dryness. The remaining foam is dissolved in of methanol (70 mL), and the solution was stirred for 16 h. The solution was evaporated to dryness (water bath temperature 3022). The remaining foam was stirred in ethanol (2500 mL), the solid was separated, and the mixture was stirred for 18 h. The solid product was collected by filtration, the suspension is washed with diethyl ether (10 Oml), and dried, obtaining b0 M-(2-(benzyloxy)-1-(14-(b-chloropyrimidin-4-yl)-piperazino|sulfonyl)methyl)ethyl|-M -hydroxyformamide (25.5 g).

T. pl. 118-120

Found C, 48.35, H, 5.09, SI, 7.26, M, 14.73, and 5, 6.78 905. С19Но«СИМ5О5З calculated C, 48.56, H, 5.15, SI . (dd, 1H), 3.57 (dd, 1H), 3.67 (dd, 1H), 3.72 (t, 4H), 4.50 (s, 2H), 4.50 (m, 71H) , 7.35 (m, 5H), 8.15 (width, 1H), 8.38 (s, 1H), 9.48 (width, 1H); t/2 470.2 (M--1).

Y syu g yo zi

Acetic anhydride (0.vml) was added directly to formic acid (3.2ml). The solution is stirred at room temperature for 30 minutes.

A solution of 1-(5-chloro-2-pyridyl)-4-(2-(hydroxyamino)-4-phenylbutyl|sulfonyl)piperazine (0.72g) in tetrahydrofuran (5ml) was added to the previously obtained solution at room temperature. The solution is stirred at room temperature for 2 days. The solution is evaporated (water bath temperature 492).

The residue is dissolved in 595 methanol in dichloromethane. Silicon dioxide (5 g Megsk 9385) is added to the solution and the mixture is stirred for 21 hours and evaporated to dryness. This material (previously adsorbed on silica) is purified by chromatography on silica (Vopa EEiiYishi 1Og) using 0-390 methanol in dichloromethane as eluent to give

IM-(1-414-(5-xpor-2-pyridyl)|(piperazino|sulfonyl)methyl)-3-phenylpropyl|-M-hydroxyformamide in the form of an orange foam (0.17g).

TN NMR (AMSO-a6 3732K): 1.92 (m, 1H), 2.04 (m, 1H), 2.55 (m, 1H), 2.64 (m, 1H), 3.20 (dd , 1H), 3.27 (m, 4H), 3.47 (dd, 71H), 3.58 (m, 4H), 4.35 (m, 1H), 6.88 (dd, 1H), 7.17 (m, 2H), 7.27 them, 2H), 7.57 (dd, 1H), 8.10 (s, 1H), 8.10 (width, 1H), 9.5 (s, 1H); t/2 453.3 (M--1).

Example 17 with di Y o ! and school

And Me Me Z

Acetic anhydride (7.9 ml) is added to formic acid (31.5 ml) at 02C. After 20 minutes, the mixture was added to hydroxylamine (6.10g) dissolved in THF (80ml) in formic acid (40ml), and the resulting solution was stirred overnight at room temperature. The solvent is removed under reduced pressure, and the residue (a) is dissolved in OSM (500 ml), washed with a saturated aqueous solution of sodium bicarbonate (2x50 Oml), dried and evaporated to dryness. Diethyl ether (10.00 ml) was added to the residue dissolved in OSM (10 ml), obtaining the product as a white solid (5.60 g), which was collected by filtration. T. pl, 168-170 20. N.O

NMR (DMOSO-46) a 10.2 (width s, 1H)"; 9.8 (width s, 1337; 8.7 (width s, 1H)"; 8.6 (width s, 1)"; 8 .5 (d, 1H); 8.3 (m, 1); 8.1 (d, 71); 7.9-7.8 (m, 1H); 7.6 (dd, 1H); 7, 4 (dd, 1H); 6.9 (d, 1); 58 (m, 138); 5.5 (m, PU; 4.1-3.6 (m, 2H); 3.6 (m, 4H); 3.2 (m, 4H). Elemental analysis: calculated for С47Но0СИМ5О.5: С, 48.0; Н, 4.7;

SI, 8.3, M, 16.5; 5, 7.5, found: C, 47.9; H, 4.7; C1, 8.4; M, 16.3; 5, 7.5. Mass spectrum for S.7NooSIM5O,Z (MAN) calculated 426, found 426. t s x rotation signals ts Stage A is» on | then

MU y, day I OK Ho -i ! Kk (95) shi

The oxime (31.05g) (|(Geiapedgoop Ieyege 1994, 35, 1011|) is dissolved in OSM (500ml) and 3-pyridinecarboxaldehyde (12.09g) is added, followed by anhydrous magnesium sulfate (13.6g). After 2 days of stirring magnesium sulfate (13.6 g) is added at room temperature of 250 °C and stirring is continued for another 3 days. The mixture is then filtered, the solvent is evaporated, and the residue is thoroughly triturated with diethyl ether, obtaining the product (36.34 g) as a white solid color. T. pl. 174-17520. "H NMR (SOCI5): a 9.0 (s, 1H); 8.9 (d, 1NU 8.7 (d, 1H); 7.7 (s, 1H ); 7.4 (dd, 1H); 5.6 (c, 1H); 5.3 (d, 1H); 4.9 (dd, 1H); 4.6 (dd, 1H); 4.4 (ddd 1H); 4.2 (dd, 1H); 3.7 (dd, 1H); 1.5 (s, ЗН); 1.4 (s, ЗН); 1.4 (s, ЗН); 1.3 (c, ZN). 29 Stage V still still (0) TK

Methylsulfonamide (14.30g) was dissolved in THF (500ml) and cooled to -10 9C when lithium hexamethyldisilazide (78ml, 1.0M in THF) was added. After 30 minutes, the solution is cooled to -782C, and niron bo (18.00 g) dissolved in THF (ZBOml) is added, maintaining the temperature below -659C. The resulting solution is stirred for 3 hours at -782С, after which it is quenched by adding a saturated saline solution (500ml), and the aqueous layer is extracted with ethyl acetate (3x50Oml). The combined organic layers were dried and evaporated to give a yellow solid which was thoroughly triturated with ethyl acetate/isohexane (4:1) and then purified by flash chromatography eluting with dichloromethane/methanol (97:3) to give compound 1 (16.40 g) as a white solid. T.pl. 209-2112C (with folding). "H NMR (SOSIV): a 8.6 (c, 1); 8.4 (d, 1H); 8.1 (d, 1H); 7.8 (d, 18); 7.5 (width c , 1H); 7.4 (dd, 1H); 7.3 (dd, 1H); 6.6 (d, 1H); 4.9 (d, 1); 4.8 (c, 1); 4 ,7-4.6 (m, 2H); 4.2-4.1 (m, 3H); 3.8 (dd, 1H); 3.6 (dd, 1H); 35-34 (m, 5H ); 3.3-3.2 (m, 4H); 1.4 (s, ЗН); 1.3 (s, ЗН); 1.3 (s, ЗН); 1.3 (s, ЗН) 70 It shows: that s, s o 1

KUA ooo 75 and Zh u, and Won and ha

Ge 0)

Water (220 ml) is added to a solution of hydroxylamine 2 (14.90 g) in ethanol (30 ml), and then

O-benzylhydroxylamine hydrochloride (13.91g) and sodium bicarbonate (6.95g). As a result of heating, a solution is obtained, which is stirred overnight at 80 C. Ethanol is removed under reduced pressure, and the residue is partitioned between water (500 ml) and ethyl acetate (500 ml). The aqueous layer was washed with ethyl acetate (2 x 50 mL), and the combined organic layers were dried and evaporated to give a residue which was thoroughly triturated with dichloromethane (100 mL) to give compound C (6.10 g) as a white solid. The mother liquor was purified by flash chromatography, eluting with ethyl acetate, and then with a mixture of EM dichloromethane/methanol (96:4), obtaining compound C (0.85 g). T. pl, 170-1732S. "H NMR (DMSO-46) a 8.6 (s, 1H); o 8.5 (d, 1); 8.1 (d, 71); 7.8 (d, 1H); 7.6 ( dd, 1H); 7.6 (s, 1H); 7.3 (dd, 1H); 6.9 (d, 1H); 6.1 (width c, 1H); 4.3 (width c, 1H ); 3.7-3.4 (1H, 6H); 3.2-3.1 (m, 4H).

Example 18

The following compounds are obtained using the method of example 7: - x z

And 1 av!

TtlnyunarttlvyuoyumnI 81 A |х|19| i 5 o zv 0 zhwatnsyu 0000 (poeridenvoz sna, tkovn, m

With vvgansa 00000 peredyanavoz sno Riv koy 000000 peridenvoz sno, tk jan « 2 with sot RRvossn wn sh 1 oamyutyu 00001 RO vozsn, kov ; With vvamoyuya 0010111 RR vozsn vn 1 as 0001 RO vozsn, kov 4? pi PI t zn NT ENN C) by car 00101011 RR vozsn vn s 0 vevovi 001001 vRoovozsn, kov 1 zvzsvi 0010101 RR vozsn vn o 0 waye 011101 vRoovozsn, kov

By truck 00101011 RR vozsn 1 vzadkotu 00001 РRO vozsn і" 1 vasvyuvyu 0001 РО (vozsn, tkoyan o yaotyuso 00101011 RRooovozsn 1 zazhtvoi 0001 РО vozsn, kov 1 (in vmooopridya 0 РRO vozsn в

F. 111100 dmvaiisnosyud/ 0 RR ovoo sna; вн ю 0 vmozneamlvoi 000veovozsyu) tv

S tatu РРоовозсн вн и 1 веолрамня 001 РРО возсн, тк ян

Due to 0000010 RR vozsn vn 1 in tsivoyut 0 PRO (ozone, tk yan took RRovyu syu. vn

S yavasvyo 00101011 RR vozstov vn dv 0 fatigue 01010010 (vozsyu) vn 440 2-Naphthyl RIR 802 sno RA vn

S rvvrnyayut 00001 ee (waxy 1 (mvoapreronyaeni 00 PRO vozsn wn 0 zvoalrekutdenon) PRO (ozone, tkovn | 50 hmesttyu 0 (Pperidinlivog sno, vin, 0 vvapvdya 00001 PRO (ozone, tk yan

С вееватт 000010 Ри; vozsn wn two ato 0000010 RIP vossna) ovo vN 0 watt (zoyuovrovozsnt tov o 1 (esoomelryadya PRO vossn wn 1 vioolvidadnso 0 (Pperidinl vo? sno zi disTRA yan, (vvvayupridylnoo Poeridiny 502 sno zadistti kn 1000000 dvmoasiRnmso 0 Pisno VN zadinil osi? , 1711111 vooirimso 0 (Piperidinl in

K2-evodenium

RIP - "piperazinil".

KNe-reverse hydroxamate

The starting material is obtained as follows:

Addition of hydroxylamine to 1-trans-p-styrenesulfonylpiperidine-4-(M-phenylcarboxamide) and further formulation of the product is carried out according to the method of example 7.

Dimethylformamide (2 drops) was added to a suspension of i-trans-D-styrenesulfonylpiperidine-4-carboxylic acid (0.75 g) and oxalyl chloride (0.2 mL) in dichloromethane (1 mL) and stirred for 2 hours. The reaction mixture was evaporated to dryness, redissolved in dichloromethane (1 Oml) and evaporated again to dryness. The obtained residue is dissolved in dichloromethane (4 ml), and a mixture of aniline (0.2 ml) and triethylamine (0.35 ml) is added dropwise. This mixture is stirred for 20 hours, and washed with diluted 2M hydrochloric acid, water, saturated aqueous bicarbonate solution sodium and water, and dry. After removing the solvent, 1-trans-D-styrenesulfonylpiperidine-4-(M-phenylcarboxamide), 0.89 g, is obtained. AND

Using the method described above, the following compounds du-i-trans-p-styrenesulfonylpiperidine-4-carboxamides are obtained:

Ges Vo o vod Os 438 | zum-) so - i-

YAMU O 439 | 44 million)

I (Mi s Y po s. s Zo " voSh Oh che 473 | "72(M-i) shsh s GO, ;" " prrt ia, us. 42 9 s

A solution of ethyl piperidine-4-carboxylate (3.99g) in a mixture of THF (30ml) and methanol (bml) is treated with an aqueous (95) solution of sodium hydroxide (2Oml of 2M Mahon), and the resulting mixture is stirred for 3 hours, evaporated to a small volume it and acidify to pH 5 with diluted 2M hydrochloric acid. The obtained mixture is extracted with ethyl acetate (2x25 ml), the ethyl acetate extracts are washed with water, dried and evaporated to dryness, (Ce) 50 obtaining 1-trans-P-styrenesulfonylpiperidine-4-carboxylic acid, 2.64 g.

T» A solution of ethyl piperidine-4-carboxylate (3.0ml) and triethylamine (2.7ml) in dichloromethane (10ml) was added dropwise to a cooled (ice bath) solution of trans-P-styrenesulfonyl chloride (3.95g) in dichloromethane ( 1 Oml). The reaction mixture is allowed to warm to room temperature, and stirring is continued for 20 hours. The reaction mixture is evaporated to dryness, the residue is diluted with water and extracted with ethyl acetate (2x25 ml). The combined ethyl acetate extracts were washed with saturated saline solution and dried (F) over magnesium sulfate, obtaining ethyl-(1-trans-b-styrenesulfonyl)-piperidine-4-carbokoylate, 5.76 g, MAN-324.

Ge You can use an alternative method of obtaining 1-trans-p-3,4-dichlorostyrenesulfonylpiperidine-4-carboxylic acid. 60 2 M sodium hydroxide (11 ml) was added to a solution of 1-trans-D-3,4-dichlorostyrenesulfonyl chloride (2.7 g) and isonipecotinic acid (1.41 g) in acetonitrile (15 ml) and stirred at room temperature for 1 hour. The reaction mixture is acidified to pH with 2M hydrochloric acid and extracted with ethyl acetate (2 x 15 ml), the ethyl acetate extracts are dried over sodium sulfate, filtered and evaporated, obtaining 1-trans-rD-3,4-dichlorostyrenesulfonylpiperidine-4-carboxylate (2.67 g), t /2 364 (M'1). 65 Example 19

The following compounds are obtained:

- Mr

IN

PIR-piperazinyl 2-reverse hydroxamate group

K2-hydrogen ma| in (А|х1а|. я 15) a o bzhttie vo sno prot (VN, zvo de RIRIR VOgsNEetil VNI zvo DERIRR 802 SNO Sprostenit YAN. ovovy ERI BO sno yalMmeaRy (VN, me act Oz snoyasRt VN iv zav at RIR VO sno Trekkuty (VN. me act Oz snasti VN zva KERy Riv vo smo yati VN, zv KER RIR God sno zadkomeRy (VN. po Osno VN ho zve vogsnootoi N zvovy ototy N zm RAV VO sleep live JAN. in which fire nym VN networks tu zum VN sch zov aERIRR VO sno sSnosnovsnya YAN o zv MARY RIR BO sn vovutt (VN. beer ERIRR VO2 SN ya Vgotofenya JAN. zvvVY ERI RR VO sno zvy (VN, yav KER RIR VO sno ona (VN. - zo ze ERI) RIR BO? sno zatorenya AN.

God RIR BO? Art. 245-2-SgRRIsuryl VN. zvo ERIRR VO sno SNosN(sNUyuy YAN. ovIVY ER VIR BOR SN aPierony (VN, « y o avRure vozsnoziosnovkyut yan -

S etvvieevozsno asno (VN. sh o etnvieevozsnozssttt (VN,

From the deteidera faith in Og|sno|svkv vni

Example 20 -1 75 It gives formulas and NMR data for the following compounds: 6 -t o NU («c) d (DMSO) 9.6 (IN, s), 8.5 (IN, m), 84 and 7 .9 (1H, s), 7.7 (IN, m), 7.2 (2H, M), 7.1 (2H, m), 7.0 (2H, m), ise) 4,714.2 ( 1N, width m), 3.4 (1N, m), 3.3 (5N. m), 3.1 (4N, m). 2.7 (2N. m), 2.1 (2N, m). at

Chl» x I sa 5B (DMSO) 9.81 9.5 (IN, width s), 8.3 1 8.0 (IN, s), 81 (IN, d), 7.6 (1H, dd) , 7.2 (5H, m), 6.9 (1H, d), 4.7 and 4.1 (1P, width, m), 3.6 (4H, m), 3.4 (1H, m ), 3.3 (1H, m), 3.3 (4H, m), 2.6 (2H, m), 1.6 (AN, m). o A) tui sh ko Ot Y M is o 50 (DMSO) 9.6 (IN, width s), 84 (IN, m), 8.3 and 7.9 (IN, s), 8.1 (IN , d), 7.6 (2Н, m), 7.2 (1Н, d), 7.1 (1Н, m), 6.9 (1Н, d), 4.7 and 4.1 (1Н, width, m), 3.6 (4H, m), 3.4 (1H, m), 3.3 (1H, m), 3.2 (4H, m), 2.7 (2H, m), 2.0 (2H, m). with

Say

LY: 1 lo 1 M 65 I! (DMSO) 9.7 (IN, width s), 8.5 (1IN, m), 8.4 (IN, m), 8.1 and 7.9 (IN, s), 7.6 (1IN, m), 7.2 (2Н, m), 7.0 (1Н,

m), 4.614.1 (1H, width, m), 3.7 (4H, m), 3.4 (1H, m), 3.3 (5H, m), 2.7 (2H, m), 2.0 (2H, m).

With tk n. what a

Ma (DMSO) 9.9 (1H, s), 8.4 (2H, m), 8.2 (1H, d), 7.65 (2H, m), 7.3 (IN, m), 7 ,0 (IN, m), 40 and 4.2 (2Н, m), 3.6 (4Н, width, m), 3.4-3.2 (6Н, width, m), 2.0 (2Н , width, m). her

Guti il 70 Ogo about her Z ! a (DMSO) 10.0 (1H, s), 8.5 (2H, d), 8.2 (IN, width c), 7.8 (IN, width), 7.6 (1H, m), 7.4 (1H, m), 6.9 (1H, m), 3.6 (4H, width, m), 3.2 (6H, width, m). at

GO; - and A s ah Tu chi Yi

M

(DMSO) 10.0 (IN, s), 8.5 (2H, m), 8.4 and 8.0 (IN, s), 7.9 (IN, m), 7.7 (IN, m ), 7.93 (IN, m), 7.1 (IN, m), 3.7 (DN, width, m), 3.45 (2Н, m), 3.3 (4Н, width, m) , 2.75 (ЗН, m), 2.1 (2Н, m). : Z

Оуцо сч (DMSO) 100 (IN, width s), 8.6 (2Н, m), 82 (1Н, d), 72 (IN, m), 6.9 (4Н, m), 49 142 (IN , width), ZA(EN, (in m), 3.0 (VN, m), 1.9(4H, m). 4 tu it kt

M. a

CI b (DMSO) 9.8 (1H, width), 8.7 (2H, m), 8.3 Her 7.9 (1H, s), 8.1 (2H, s), 7.6 (1H , m), 7.3 (IN, m), 6.9 (IN, m), o 4.1 (1H, width, m), 3.6 (AN, m), 3.2 (6H, m ), 2.8 (2H, m), 1.8 (AN, m). - and oh yah 7" and yours - m! o (DMSO) 8.5 (1N, m), 8.1 (2N, s), 6.51 8.0 (1N, s), 7.8 (1N, m), 7.4 (IN, m ), 7.3 (2H, m), 656 (IN, m), 48142 (TN, width, m), 9.6 (4H, m), 3.2 (6H, m), 2.8 (2H , m), 1.8 (4H, m). « min

NOYU to v s i "» (DMSO) 8.5 (IN, d), 84 ii 8.2 (1Н, с), 7.7 (1Н, m), 7.2 (6Н, m), 4, 8 and 4.2 (1H, width, m), 3.6 (4H, m), 3.2 " (6H, m), 2.8 (2H, m), 1.8 (4H, m).

Example 21 - 45 The following compounds were obtained: va d) tu k2 ti o PIP-piperazinil o 20 7 reverse hydroxamate group

K2-hydrogen "g" tlyankyitlvkov mn| 08000119 as 1 ziva 0011111 vo; UN; zlridykhonsnounya Jan 99 55 456. A-E-RA 802) st /C-Hexyl-C(Me)сН2 vn (Me) o lav folav1mo av | RR vo2) sleep vpsnovsna outside them 166000 me up to 000000 Preridinil 502 sleep (vu2RASSNSNVYUUN? veya 00000 Periodnyo in sleep? (vugepsnisnasn vo pe 1zyayao up to 00110100 РРО в; sleep osrestonyut vn yav zhvRI 11 RR vom asni asniRO1111010 zorisnonyut vn v voalrd 100 РРО vo; sno oprazaonsnuunya yan g vvayatu 0010111 Reovor ono estuvsnsnyanyut yan bo 466 |3-СИ-РП RIR 802) сНн2 (832-РІСН(СНЗ)СН2 внря Bazlvidy | ee vo sno (vuzevsnsnayuno vni vni | am avt 000000 Pieridiny sno otofenisnsnuyn vn vv | up to 0000010 RR o vogsnia 0011111 15 up to 00110100 РRO in sno resnvosna vn me 45 |foyavyu in 000010 RR in snovysnovsna///- vn av voolrdiya 00 РRO vost 0 VN oprimst 0 Bceyuzlryadya |

Savko vueyuth 000100 РРО in sno olofenisnostos vn st 111111 vvnozlryda | РРО in so zpridzhsnst VN and 0 vayuzlrudy | ПРО всно опридилонносносно ян 050 ввнюогтриди | РРО in? a dream is carried forward into the air РРО осно опридылсносно ВН т вюттриды | РРО in? sleep from front VN 0 inputs 000 РРО in sleep opridylsnosno VN 20 0 viv vezpridia 000 РРО in sleep zLridylsnosno VN 1 tu vvlrvid 000 РРО in? 1110

B vevvslridy 000 РРО in sno olofenisnaso sna VN cm 5 1000000 introduced |vVeopiridylo | PP (802) sleep JAN, o 1 bavmovveolridy 000РРО in sleep опридисносносно вн 06 олрамня 00100 РРО in sleep опримидннысносносно Ян 17 ayuoopedya 0000100 РРО in sleep отоденисноснос сно ян аю олрамня 00100 РРО in sleep olophenysnosnosnona ВН with zo 1 zoovoylridnya eopleridnny vo? sno oTophenysnosnosno tn F 11 zvz Boyuliridii kolitheridnnia 02 SNO oPridylsnosnono sna KN o 1 rvvoovalvyadnu sopleridnnia vo? st zadistt VN Fo vu Boyulrvidy 00 РРО VO SNO придивеююю VN with yav | 5 | 655 vmeolprimdii PRO in? sno veonosna VN and yav, limit 0000100 РРО О sno opridylsnosno VN rya pvimdnnyi/ 11111111 5 | 85 | Is it acceptable for the RRO VO? co ZPrydisnosna VN « yu vv 10 l5500 408 BMeolpirimdzhi РРО 0802 SNO opofenlsnosnosna VA Z s i» | I |abbya vMmeolpridny RPO 802 sno 2 Primidynlsnosnosn? jan 77777171 lion (vMmeolpyrimidnny | RIR 802) sno o-Pyridylsnosnosna vn) ;"

All compounds were obtained by the method of example 1, except for those cases where ring A is 4-O-piperidinyl, and then they were obtained by the method of example 14. - 395 Example 22

It presents the formulas and NMR data for the compounds listed in example 21: О ШЧИ! c 50 M452587 - a new compound NMR (DMSO) 9.9, 9.6 (1H, width c); 8.6 (2H, m); 8.3 and 7.9 (1H, s); 8.1 (1H, dd); 7.3 (IN, m), 6.9 (1H, d); 4.7 and 4.2 (IN width, m); 3.6 (4H, m); 3.4-3.2 (6H, m); 2.8 (2H, m); 2.1 (2H, m). / iz» and sgsy I 5 more (DMSO) 9.9 and 9.6 (IN width c); 8.7 (2H, d); 8.3 and 8.0 (IN, s); 8.2 (1H, d); 7.8 (1H, dd), 7.3 (1H, m); 6.9 o (IN, d), 5.1 (IN, width, m), 4.7 and 4.2 (IN, width, m), 34 (ZN, m), 3.1 (ZN, m ), 2.9 (211, m), 2.0 (2Н, m), 1.7 (6Н, m). Example 23 of Obtaining: because b5 ih! that) about -shOo and iu about b-ky t in To - 2

Acetic anhydride (1.2 ml) is added to formic acid (4.8 ml) at 092C. After 20 minutes this is added to hydroxylamine 2 (0.68g) dissolved in THF (11ml) and formic acid (5ml) and the resulting solution is stirred 7/5 overnight at room temperature. The solvent is removed under reduced pressure, and the residue is dissolved in

OSM (100 ml), washed with a saturated solution of sodium bicarbonate (2x100 ml), dried over magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography eluting with a mixture of dichloromethane/methanol (96:4) to give the product (0.41 g) as a resin. "H NMR (SOSIV): 5 9.7 (width s, 1NU, 9.2 (width s, 1NU, 8.4 (s, 1), 8.0 (s, 1H)U 7.5-7, 2 (m, 5H), 7.0-6.8 (m, 4H), 5.7 (m, 1NU, 54 (min, 3.9-3.4 (m, 5H), 3.3 (m , 1H)", 3.2-2.9 (m, 4H), 2.8 (m, 1H3U7. Mass spectrum for SooNooEMa3Oz (MEN) calculated 372, found 372 x rotation signals

Stage A ud /th --- E she ma: from 0Оо- 007 o 1

To 1-(4-fluorophenyl)piperazine (1.00g) dissolved in OSM (10ml), cinnamoyl chloride (0.85g) in OSM (10ml) was added, followed by triethylamine (1.55ml). The solution is stirred at room temperature overnight. Him ! : : these " are separated between UOSM (15Oml) and water (100ml), the organic layer is washed with water (10Oml), dried over magnesium sulfate and evaporated to dryness, obtaining a cream-colored solid, which is carefully Ge") triturated with diethyl ether (1Oml) , obtaining compound 1 (1.20 g) as a white solid. "H NMR (SOSIv): 5 7.7 (d, 2H), 7.5 (m, 2H), 7.4 (m, ЗН), 7.0-6.9 (m, 5H), 4, 0-3.8 (m, 4H), 3.1 (m, 4H). Mass spectrum for C159H19EM2O (MAN) calculated 311, found 311. (ze)

Stage V n i - o obky chto - i Zo 1 2 «

Hydroxylamine (ml, 5095 aqueous solution) was added to the amide (2.00 g) dissolved in THF (40 ml). This solution /-) s is stirred at room temperature for 48 hours. The solvent was evaporated under reduced pressure, and toluene (50 mL) was added and evaporated again under reduced pressure. The residue was thoroughly triturated with dichloromethane/methanol (98:2) and the mother liquor was purified by flash chromatography eluting with dichloromethane/methanol (98:2) to give compound 2 (0.70 g) as a resin. "H NMR (SOSIV): 5 7.5-7.2 (m, 5H), 7.0-6.9 (m, 2H), 6.9-6.8 (m, 2H), 4.5 (dd, 1H), 3.8-3.7 (m, 2H), 3.6-3.5 (m, 2H), 3.1-2.8 (m, 5H), -I 2.7 (dd, 1H). Mass spectrum for C49Noo EMO" (MAN) calculated 344, found 344. (95) o

Claims (6)

The formula of the invention is 50 1. Arylpiperazines of formula I: Her" | | | , /ATU pishnu 4 Huonn- Y CHA ke 4 2 F) ! 0 - Po) KZ " Kk 60 where ring B is phenyl, pyridyl or pyrimidyl; each KZ is independently selected from hydrogen, halogen, MO", SOOK, where K is hydrogen or C1-6 alkyl, CM, CE3, C1- 6 alkyl, -5-C1-6 alkyl, -50-C1-6 alkyl, -505-C1-6 alkyl, C1-6 alkoxy and up to C10 aryloxy, n - 1, 2 or 3; P is a direct bond "bond; 65 ring A is piperazinyl; Hu and Ho" are M; U is from -505-; 7 represents -EVERY; O represents -СН»о-; K1 is H, C1-6 alkyl, C5-7 cycloalkyl, up to C10 aryl, up to C10 heteroaryl, up to C12 aralkyl, or up to C12 heteroarylalkyl, all optionally substituted with up to three groups independently selected from MO », CEz, halogen, C1-4 alkyl, carboxy (C1-4)alkyl, up to Сb cycloalkyl, -OK4, -С3К4, C1-4 alkyl, substituted -OK4, ZKA (and their oxidized analogs), MK4A, M -U-KA or C1-4 alkyl-U-MK4, or K1 is 2, 3, 4, 5, b-pentafluorophenyl; 70 K4 is hydrogen, C1-6 alkyl, up to C10 aryl or up to C10 heteroaryl, or up to C9 aralkyl, each independently optionally substituted with halogen, MO", CM, C3, C1-6 alkyl, -5 -C1-6 alkyl, -50-21-6 alkyl, -50-25-C1-6 alkyl or C1-6 alkoxy; K2 represents H, C1-6 alkyl, or together with K1 forms a carbocyclic or heterocyclic spiro 5-, 6- or 7-ene ring, the latter containing at least one heteroatom selected from M, O, and 5; in addition, the O y/5 group can be connected either to КИ or to К2 with the formation of a 5-, 6- or 7-membered alkyl or heteroalkyl ring, which includes one or more of O, 5 and M; and wherein any of the above alkyl groups may be linear or branched; or a pharmaceutically acceptable salt thereof, or a hydrolysed ester thereof. 2. The compound according to claim 1, where: KZ is hydrogen, halogen, MO", SEz, C1-4 alkyl and C1-4 alkoxy, n is 1 or 2; K1 represents hydrogen, C1-6 alkyl, C5-7 cycloalkyl, up to C12 aralkyl, up to C11 heteroarylalkyl, up to C10 aryl or C10 heteroaryl; moreover, all of them are optionally substituted up to three halogen or CE atoms"; K2 represents hydrogen, or together with K1 represents a carbocyclic or heterocyclic spiro 5- or b-lene ring; сч К4 is up to C10 aryl, optionally substituted with halogen, MO 5, CM, CE3, C1-6 alkyl, -5-C1-6 alkyl, -50-C1-6 alkyl, -505-C1-6 alkyl or C1-6 alkoxy; (8) or a pharmaceutically acceptable salt thereof, or a hydrolysed ester thereof. Z. The compound according to claim 1, where: KZ is hydrogen, halogen, MO», CEz, methyl, ethyl, methoxy or ethoxy; "g from KI! is phenyl, 4-trifluoromethylphenyl, phenethyl, phenpropyl, isobutyl, cyclopentyl, benzyloxymethyl, 3,4-dichlorophenyl, 2-pyridyl, 3-pyridyl, 2-pyridylethyl, 3-pyridylethyl, thiophenylpropyl, Me) bromothiophenyl, 2-pyrimidinylethyl, 2-pyrimidinylpropyl, pyridylpropyl, or together with K2 represents o spirocyclohexane or spiro-4-pyran; K2 is hydrogen; i) or a pharmaceutically acceptable salt thereof, or a hydrolyzed ester thereof. Cha 4. The compound of formula I according to claim 1, where ring B, substituted by KZ(p), is a phenyl, 3-methylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl ring or is a 5- chloro-2-pyridyl; or a pharmaceutically acceptable salt thereof, or a hydrolysed ester thereof. " 5. Compound of the formula | according to claim 1, where the group B is a phenyl, 3-methylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl ring or 5-chloro-2-pyridyl; and CT represents phenyl, phenbutylene, phenisopropylene, 2-pyridylethylene, 2-pyridylisopropylene, ;" 3-pyridylisopropylene, 4-pyridylisopropylene or 4-chlorophenyloxydimethylmethylene; or a pharmaceutically acceptable salt thereof, or a hydrolysed ester thereof. 6. A pharmaceutical composition for inhibiting at least one metalloproteinase, which includes compound -I of formula (I), according to claim 1, or its pharmaceutically acceptable salt, or its hydrolyzed complex ester and a pharmaceutically acceptable carrier. o 7. The method of obtaining the compound of formula (I) or its pharmaceutically acceptable salt, or its hydrolyzed ester, which includes the interaction of the compound of formula (II) or its pharmaceutically acceptable salt, or its hydrolyzed ester with the compound formulas (PP): і» / in Р- хХ, хи ии cups are. KZ, name) 60 and U u e! - TI 65 Kk Kk de hee! means X or a precursor of X (either by modification or by substitution) or an activated form of X suitable for interaction with Y; Well! means Y, a precursor of Y or an activated form of Y suitable for interaction with X.4!; 7! means protected 2 form 7, predecessor 7 (either by modification or substitution 7) or activated form 7; with the subsequent interaction of the compound of the formula X with the corresponding compound of the formula K1-CO-K2 to obtain the alkene of the formula X, which is further converted into the compound of the formula XI, where 7" means the hydroxylamine precursor of group 2, and the subsequent conversion of 72" into group 2 according to the following scheme: 10 od I | V. ' that KU | I R-- - 80-77 750 of them 2 15 and I K in, | what 20 I . re - stump xx 1 zv R KCh; 5; x o VZ, 2 30 : - F «c) . co. | 6 LY AH 2: и- Р-Х 7 х-80,--2К 7 m ш in 2 ХИ и т « 40 8. The method of obtaining the compound of formula (I) or its pharmaceutically acceptable salt, or its hydrolyzed ipm ester, which includes the interaction of a compound of the formula (IM) or its pharmaceutically acceptable salt, or its hydrolyzed ester with a compound of the formula (M): p m . ' AAU that - V. R- At and Fo - a -k M o ti. v2 se) r "z" | | i - I GF) r - VZ | tire in p where B" represents a suitable ring group or substituent for reaction with P"; 7! has the above values; and R! represents a correspondingly activated group for reaction with V. because the Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 6, 15.06.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. with (8) "Fo"c) so and - - with -And (95) ("c) at 50 s" F) name) 60 b5