HRP980062A2

HRP980062A2 - N-hydroxy-beta-sulfonyl-propionamide derivatives

Info

Publication number: HRP980062A2
Application number: HR60/037,402A
Authority: HR
Inventors: Ralph Pelton Robinson
Original assignee: Ralph Pelton Robinson
Priority date: 1997-02-07
Filing date: 1998-02-06
Publication date: 1998-12-31
Also published as: AR011116A1; AP9801169A0; PA8446001A1; TNSN98022A1; EP0966438A1; MA26472A1; WO1998034915A1; ZA98970B; BR9807824A; CA2279863A1; AU5493598A; JP2000507975A

Description

Osnove izuma Basics of invention

Ovaj izum odnosi se na derivate arilsulfonilaminohidroksam kiseline koji su inhibitori matriks metaloproteinaza ili produkcije tumorskog faktora nekroze (TNF) i, kao takvi su korisni pri liječenju stanja kao što su artritis, osteoporoza, rak, nastajanje tkivnih čireva, restenoza, periodontalna bolest, epidermološka buloza, skleritis, i ostalih bolesti kojima je karakteristična aktivnost matriks metaloproteinaza, kao što su AIDS, sepsa, ili septički šok, kao i ostalih bolesti koje imaju za posljedicu stvaranje TNF-a. Nadalje, spojevi ovog izuma mogu se koristiti u kombiniranoj terapiji sa standardnim nesteroidnim lijekovima protiv upala (dalje navedeni kao NSAID'S) i analgeticima za tretman artritisa, i u kombinaciji sa citotoksičnim lijekovima kao što su adriamicin, daunomicin, cis-platinum, etoposid, taxol, taxoter i alkaloidima, kao što su vinkristin, u liječenju raka. This invention relates to arylsulfonylaminohydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or tumor necrosis factor (TNF) production and, as such, are useful in the treatment of conditions such as arthritis, osteoporosis, cancer, tissue ulceration, restenosis, periodontal disease, epidermological bullous , scleritis, and other diseases that are characterized by the activity of matrix metalloproteinases, such as AIDS, sepsis, or septic shock, as well as other diseases that result in the production of TNF. Furthermore, the compounds of this invention can be used in combination therapy with standard nonsteroidal anti-inflammatory drugs (hereinafter referred to as NSAIDs) and analgesics for the treatment of arthritis, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, in the treatment of cancer.

Ovaj izum se također odnosi na metodu korištenja takvih spojeva u liječenju gore navedenih bolesti u sisavaca, osobito u ljudi, kao i farmaceutske pripravke koji se koriste u te svrhe. This invention also relates to a method of using such compounds in the treatment of the above-mentioned diseases in mammals, especially in humans, as well as pharmaceutical preparations used for these purposes.

Postoji više enzima koji potiču razgradnju strukturnih proteina i koji su strukturno srodne metaloproteaze. Metaloproteinaze koji razgrađuju matriks, kao što su gelatinaza, stromelisin i kolagenaza, sudjeluju u degradaciji matriksa tkiva (na primjer: razgradnja kolagena) i prisutni su u mnogo patoloških stanja obuhvaćajući abnormalni metabolizam veznih tkiva i matriksa bazne membrane, kao što su artritis (npr. osteoartritis i reumatski artritis), tkivni vrijed (npr. vrijed na epidermi, rožnici i u probavnom sustavu), abnormalno zacjeljivanje rana, periodontalna bolest, bolest kostiju (npr. Pagetova bolest i osteoporoza), metastaza ili invazija tumora, kao i infekcija virusom HIV-a ("J. Leuk. Biol.", 52 (2), 244-248, (1992.)). There are several enzymes that promote the degradation of structural proteins and are structurally related to metalloproteases. Matrix-degrading metalloproteinases, such as gelatinase, stromelysin and collagenase, are involved in the degradation of tissue matrix (for example: collagen breakdown) and are present in many pathological conditions involving abnormal metabolism of connective tissues and basement membrane matrix, such as arthritis (eg, osteoarthritis and rheumatoid arthritis), tissue ulcer (e.g. ulcer on the epidermis, cornea and digestive system), abnormal wound healing, periodontal disease, bone disease (e.g. Paget's disease and osteoporosis), tumor metastasis or invasion, as well as HIV infection a ("J. Leuk. Biol.", 52 (2), 244-248, (1992)).

Faktor nekroze tumora je dokazano obuhvaćen u puno infekcijskih i bolesti imunološkog sustava (W. Fiers: "FEBS Letters", 285, 199, (1991.)). Nadalje, dokazano je da je TNF najjači posrednik pri odgovoru upalnim procesima viđenima u sepsi i septičkom šoku (C. E. Spooner i dr.: "Clinical Immunology and Immunopathology", 62 S11, (1992.)). Tumor necrosis factor has been shown to be involved in many infectious and immune system diseases (W. Fiers: "FEBS Letters", 285, 199, (1991)). Furthermore, TNF has been shown to be the most potent mediator of the inflammatory response seen in sepsis and septic shock (C.E. Spooner et al.: "Clinical Immunology and Immunopathology", 62 S11, (1992)).

Kratki opis izuma Brief description of the invention

Ovaj izum odnosi se na spoj formule This invention relates to a compound of the formula

[image] [image]

gdje je R1 vodik, hidroksi, (C6-C10)aril(C1-C6)alkoksi, (C1-C6) alkoksi, (C1-C6)alkil(C=O)O-, (C1-C6)alkoksi(C=O)O-, (C6-C10)aril(C=O)O-, (C6-C10)ariloksi(C=O)O-, (C6-C10)aril(C1-C6)alkil(C=O)O- ili (C6-C10)aril(C1-C6) alkoksi(C=O)O-; gdje je spomenuti aril u spomenutom (C6-C10)aril(C1-C6)alkoksi, (C6-C10)aril(C=O)O-, (C6-C10) ariloksi(C=O)O-, (C6-C10)aril(C1-C6)alkil(C=O)O- ili (C6-C10)aril(C1-C6)alkoksi(C=O)O- gdje se arilna jedinica tih svih grupa opcionalno zamjenjuje s jednim ili više supstituenata (preferirano jedan do tri supstituenata) neovisno izabranih od fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi; where R1 is hydrogen, hydroxy, (C6-C10)aryl(C1-C6) alkoxy, (C1-C6) alkoxy, (C1-C6) alkyl(C=O)O-, (C1-C6) alkoxy(C= O)O-, (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-, (C6-C10)aryl(C1-C6)alkyl(C=O) O- or (C6-C10)aryl(C1-C6) alkoxy(C=O)O-; wherein said aryl in said is (C6-C10)aryl(C1-C6)alkoxy, (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-, (C6- C10)aryl(C1-C6)alkyl(C=O)O- or (C6-C10)aryl(C1-C6)alkoxy(C=O)O- where the aryl unit of all these groups is optionally replaced by one or more substituents (preferably one to three substituents) independently selected from fluoro, chloro, bromo, (C1-C6) alkyl, (C1-C6) alkoxy, perfluoro(C1-C3) alkyl perfluoro(C1-C3) alkoxy and (C6-C10) aryloxy;

R2 je vodik ili (C1-C6)alkil; R 2 is hydrogen or (C 1 -C 6 )alkyl;

R3 i R4 se neovisno biraju iz grupe koja se sastoji od vodika, (C1-C6)alkil, trifluorometil, trifluorometil(C1-C6)alkil, (C1-C6)alkil(difluorometilen), (C1-C3)alkil(difluorometilen)(C1-C3)alkil, (C6-C10)aril, (C2-C9)heteroaril, (C6-C10)aril (C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkil, (C6-C10)aril(C6-C10)aril, (C6-C10)aril(C6-C10)aril(C1-C6)alkil, hidroksi(C1-C6)alkil, (C1-C6)alkil(C=O)O-(C1-C6)alkil, (C1-C6)alkoksi(C=O)O-(C1-C6)alkil, (C6-C10)aril(C=O)O-(C1-C6) alkil, (C6-C10)ariloksi(C=O)O-(C1-C6)alkil, (C6-C10)aril(C1-C6)alkil(C=O)O-(C1-C6)alkil, (C6-C10)aril(C1-C6) alkoksi(C=O)O-(C1-C6)alkil, (C1-C6)alkoksi(C1-C6)alkil, (C6-C10)ariloksi(C1-C6)alkil, (C6-C10)aril(C1-C6)alkoksi(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkoksi(C1-C6)alkil, amino(C1-C6)alkil, (C1-C6)alkilamino(C1-C6)alkil, [(C1-C6) alkil]2amino(C1-C6)alkil, (C1-C6)alkil(C=O)NH(C1-C6)alkil, (C1-C6)alkoksi(C=O)NH(C1-C6)alkil, (C6-C10)aril (C=O)NH(C1-C6)alkil, (C6-C10)ariloksi(C=O)NH(C1-C6)alkil, (C6-C10)aril(C1-C6)alkil(C=O)NH(C1-C6)alkil, (C6-C10) aril(C1-C6)alkoksi(C=O)NH(C1-C6)alkil, (C1-C6)alkilsulfonil(C1-C6)alkil, (C6-C10)arilsulfonil(C1-C6)alkil, R5CO(C1-C6)alkil ili R8(C1-C6)alkil; ili R3 i R4 mogu biti uzeti zajedno s ugljikovim atomom na kojeg su vezani kako bi stvorili (C3-C6)cikloalkil ili benzo(C3-C6)cikloalkil prsten ili grupu formule R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, (C1-C6)alkyl(difluoromethylene), (C1-C3)alkyl(difluoromethylene) (C1-C3)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl (C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C6- C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkyl(C=O)O- (C1-C6)alkyl, (C1-C6)Alkoxy(C=O)O-(C1-C6)alkyl, (C6-C10)aryl(C=O)O-(C1-C6)alkyl, (C6- C10)aryloxy(C=O)O-(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl(C=O)O-(C1-C6)alkyl, (C6-C10)aryl( C1-C6) Alkoxy(C=O)O-(C1-C6)alkyl, (C1-C6)Alkoxy(C1-C6)Alkyl, (C6-C10)Aryloxy(C1-C6)Alkyl, (C6-C10) Aryl(C1-C6)Alkoxy(C1-C6)Alkyl, (C2-C9)Heteroaryl(C1-C6)Alkoxy(C1-C6)Alkyl, Amino(C1-C6)Alkyl, (C1-C6)Alkylamino(C1- C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, (C1-C6)alkyl(C=O)NH(C1-C6)alkyl, (C1-C6)Alkoxy(C=O) NH(C1-C6)alkyl, (C6-C10)aryl (C=O)NH(C1-C6)alkyl, (C6-C10)aryloxy(C=O)NH(C1-C6)alkyl, (C6-C10 )aryl(C1-C6)alkyl(C=O) NH(C1-C6)alkyl, (C6-C10) Aryl(C1-C6)Alkoxy(C=O)NH(C1-C6)Alkyl, (C1-C6)Alkylsulfonyl(C1-C6)Alkyl, (C6-C10 )arylsulfonyl(C1-C6)alkyl, R5CO(C1-C6)alkyl or R8(C1-C6)alkyl; or R3 and R4 may be taken together with the carbon atom to which they are attached to form a (C3-C6)cycloalkyl or benzo(C3-C6)cycloalkyl ring or group of the formula

[image] [image]

gdje je atom ugljika obilježen zvjezdicom ugljik na koji su vezani R3 i R4, "n" i "m" se neovisno biraju od brojeva 1 i 2, a X je CF2, O, SO2, ili NR9 gdje je R9 vodik, (C1-C6)alkil, (C6-C10)aril, (C2-C9)heteroaril, (C6-C10)aril(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkil, (C1-C6)alkilsulfonil, (C6-C10)arilsulfonil, (C1-C6)alkil(C=O)-, (C1-C6)alkoksi(C=O)-, (C6-C10)aril(C=O)-, (C6-C10)ariloksi(C=O)-, (C6-C10)aril(C1-C6)alkil(C=O)- ili (C6-C10)aril(C1-C6)alkoksi(C=O)-; gdje je svaki od navedenih (C6-C10)aril, (C2-C9)heteroaril ili (C3-C6)cikloalkil jedinica gdje se svaka od navedenih (C6-C10)aril, (C2-C9)heteroaril, (C6-C10)aril(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkil, (C6-C10)aril(C6-C10)aril, (C6-C10)aril(C6-C10)aril(C1-C6)alkil, (C6-C10)aril(C=O)O-(C1-C6)alkil, (C6-C10)aril(C1-C6)alkil(C=O)O-(C1-C6)alkil, (C6-C10)aril(C1-C6)alkoksi(C=O)O-(C1-C6)alkil, (C6-C10)ariloksi-(C1-C6)alkil, (C6-C10)aril(C1-C6)alkoksi(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkoksi(C1-C6)alkil, (C6-C10)aril(C=O)NH(C1-C6)alkil, (C6-C10)aril(C1-C6)alkil(C=O)NH(C1-C6)alkil, (C6-C10)aril(C1-C6)alkoksi(C=O)NH(C1-C6)alkil, (C6-C10)arilsulfonil, (C6-C10)arilsulfonil(C1-C6)alkil, (C6-C10)aril(C=O)-, (C6-C10)aril(C1-C6)alkil(C=O)-, (C6-C10)aril(C1-C6)alkoksi(C=O)-, (C3-C6)cikloalkil ili benzo-(C3-C6)cikloalkil prsten može po volji biti zamijenjen na bilo kojem atomu prstena koji je sposoban formirati dodatnu vezu pomoću supstituenta (po mogućnosti jedan do tri supstituenta po prstenu) neovisno odabranog iz grupe fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, perfluoro(C1-C3)alkoksi i (C6-C10) ariloksi; where the asterisked carbon atom is the carbon to which R3 and R4 are attached, "n" and "m" are independently selected from 1 and 2, and X is CF2, O, SO2, or NR9 where R9 is hydrogen, (C1- C6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C1-C6)alkylsulfonyl , (C6-C10)arylsulfonyl, (C1-C6)alkyl(C=O)-, (C1-C6)alkoxy(C=O)-, (C6-C10)aryl(C=O)-, (C6- C10)aryloxy(C=O)-, (C6-C10)aryl(C1-C6)alkyl(C=O)- or (C6-C10)aryl(C1-C6)alkoxy(C=O)-; where each of said (C6-C10)aryl, (C2-C9)heteroaryl or (C3-C6)cycloalkyl units where each of said (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10) aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6 )alkyl, (C6-C10)aryl(C=O)O-(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl(C=O)O-(C1-C6)alkyl, ( C6-C10)aryl(C1-C6)Alkoxy(C=O)O-(C1-C6)alkyl, (C6-C10)aryloxy-(C1-C6)alkyl, (C6-C10)aryl(C1-C6) Alkoxy(C1-C6)alkyl, (C2-C9)Heteroaryl(C1-C6)Alkoxy(C1-C6)Alkyl, (C6-C10)Aryl(C=O)NH(C1-C6)Alkyl, (C6-C10 )aryl(C1-C6)alkyl(C=O)NH(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C=O)NH(C1-C6)alkyl, (C6-C10 )arylsulfonyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, (C6-C10)aryl(C=O)-, (C6-C10)aryl(C1-C6)alkyl(C=O)-, (C6 The -C10)aryl(C1-C6)alkoxy(C=O)-, (C3-C6)cycloalkyl or benzo-(C3-C6)cycloalkyl ring may optionally be substituted on any ring atom capable of forming an additional bond by of substituents (preferably one to three substituents per ring u) independently selected from the group of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy;

ili kad su R3 i R4 uzeti zajedno s atomom ugljika na kojeg su spojeni čineći grupu formule or when R 3 and R 4 are taken together with the carbon atom to which they are attached to form a group of the formula

[image] [image]

tada bilo koji atom ugljika gore navedenog prstena, koji je sposoban stvarati dodatnu vezu, može biti po volji zamijenjen supstiuentom (po mogućnosti od nula do tri supstituenta) neovisno odabranim iz grupe koja sadrži fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi; then any carbon atom of the above ring, which is capable of forming an additional bond, may be optionally replaced by a substituent (preferably from zero to three substituents) independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 3 )alkyl, perfluoro(C 1 -C 3 )alkoxy and (C 6 -C 10 )aryloxy;

R5 je R6O ili R6R7N gdje su R6 i R7 svaki neovisno odabrani iz grupe vodik, (C1-C6)alkil, (C6-C10)aril(C1-C6)alkil ili (C2-C9)heteroaril(C1-C6)alkil; gdje je svaki od rečenih (C6-C10)aril i (C2-C9)heteroaril jedinka rečenog (C6-C10) aril(C1-C6)alkil ili (C2-C9)heteroaril(C1-C6)alkil grupe mogu biti po volji zamijenjene sa jednim ili više supstituenata neovisno odabranim iz grupe koja sadrži fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi; R 5 is R 6 O or R 6 R 7 N where R 6 and R 7 are each independently selected from the group hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein each of said (C6-C10)aryl and (C2-C9)heteroaryl units of said (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl groups may be optional substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 3 )alkyl, perfluoro (C 1 -C 3 ) alkoxy and (C 6 -C10)aryloxy;

ili R6 i R7 uzeti zajedno s atomom dušika za kojeg su vezani formiraju opcionalno supstituirane heterocikličke spojeve kao npr. piperazinil, (C1-C6)alkilpiperazinil, (C6-C10)arilpiperazinil, (C2-C9)heteroarilpiperazinil, (C6-C10) aril(C1-C6)alkilpiperazinil, (C2-C9)heteroaril(C1-C6)alkilpiperazinil; (C1-C6)alkil(C=O)-piperazinil, (C1-C6)alkoksi (C=O)-piperazinil, (C6-C10)aril(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkil(C=O)-piperazinil, (C6-C10)aril(C1-C6) alkoksi(C=O)-piperazinil, morfolinil, piperidinil, pirrolidinil ili azetidinil; gdje je svaki od rečenih piperazinil, (C1-C6)alkilpiperazinil, (C6-C10)arilpiperazinil, (C2-C9)heteroarilpiperazinil, (C6-C10)aril(C1-C6)alkilpiperazinil, (C2-C9)heteroaril(C1-C6)alkilpiperazinil; (C1-C6)alkil(C=O)-piperazinil, (C1-C6)alkoksi(C=O)-piperazinil, (C6-C10) aril(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkil(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkoksi(C=O)-piperazinil, morfolinil, piperidinil, pirolidinil ili azetidinil mogu biti po volji zamijenjeni na bilo koji atom prstena ugljika, koji je sposoban stvarati dodatnu vezu, sa supstiuentom (po mogućnosti jedan do tri supstituenta po prstenu) neovisno odabranim iz grupe koja sadrži fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, ili perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi.; or R6 and R7 taken together with the nitrogen atom to which they are attached form optionally substituted heterocyclic compounds such as piperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (C6-C10)aryl (C1-C6)alkylpiperazinyl, (C2-C9)heteroaryl(C1-C6)alkylpiperazinyl; (C1-C6)Alkyl(C=O)-piperazinyl, (C1-C6)Alkoxy (C=O)-piperazinyl, (C6-C10)aryl(C=O)-piperazinyl, (C6-C10)aryl(C1 -C6)alkyl(C=O)-piperazinyl, (C6-C10)aryl(C1-C6) alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl; wherein each of said piperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (C6-C10)aryl(C1-C6)alkylpiperazinyl, (C2-C9)heteroaryl(C1- C6)alkylpiperazinyl; (C1-C6)Alkyl(C=O)-piperazinyl, (C1-C6)Alkoxy(C=O)-piperazinyl, (C6-C10) aryl(C=O)-piperazinyl, (C6-C10)aryl(C1 -C6)alkyl(C=O)-piperazinyl, (C6-C10)aryl(C1-C6)alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl can be optionally substituted at any carbon ring atom , which is capable of forming an additional bond, with a substituent (preferably one to three substituents per ring) independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, perfluoro(C1- C3)alkyl, or perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy.;

R8 je piperazinil, (C1-C6)alkilpiperazinil, (C6-C10)arilpiperazinil, (C2-C9)heteroarilpiperazinil, (C6-C10)aril(C1-C6) alkilpiperazinil, (C2-C9)heteroaril(C1-C6)alkilpiperazinil; (C1-C6)alkil(C=O)-piperazinil, (C1-C6)alkoksi(C=O)-piperazinil, (C6-C10)aril(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkil(C=O)-piperazinil, (C6-C10)aril(C1-C6) alkoksi(C=O)-piperazinil, morfolinil, piperidinil, pirolidinil, azetidinil, piperidil, (C1-C6)alkilpiperidil, (C6-C10) arilpiperidil, (C2-C9)heteroarilpiperidil, (C6-C10)aril(C1-C6)alkilpiperidil, (C2-C9)heteroaril(C1-C6)alkilpiperidil; (C1-C6)alkil(C=O)-piperidil, (C1-C6)alkoksi(C=O)-piperidil, (C6-C10)aril(C=O)-piperidi, (C6-C10)aril(C1-C6) alkil(C=O)-piperidil ili (C6-C10)aril(C1-C6)alkoksi(C=O)-piperidil, gdje je svaki od rečenih piperazinil, (C1-C6) alkilpiperazinil, (C6-C10)arilpiperazinil, (C2-C9)heteroarilpiperazinil, (C6-C10)aril(C1-C6)alkilpiperazinil, (C2-C9) heteroaril(C1-C6) alkil piperazinil, (C1-C6)alkil(C=O)-piperazinil, (C1-C6)alkoksi(C=O)-piperazinil, (C6-C10) aril(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkil(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkoksi(C=O)-piperazinil, morfolinil, piperidinil, pirolidinil, azetidinil, piperidil, (C1-C6)alkilpiperidil, (C6-C10)arilpiperidil, (C2-C9) heteroarilpiperidil, (C6-C10)aril(C1-C6)alkilpiperidil, (C2-C9)heteroaril(C1-C6)alkilpiperidil; (C1-C6)alkil(C=O)-piperidil, (C1-C6)alkoksi(C=O)-piperidil, (C6-C10)aril(C=O)-piperidil, (C6-C10)aril(C1-C6)alkil(C=O)-piperidil i (C6-C10)aril(C1-C6)alkoksi(C=O)-piperidil mogu biti po volji zamijenjeni na bilo koji atom prstena ugljika, koji je sposoban stvarati dodatnu vezu, sa supstiuentom (po mogućnosti jedan do tri supstituenta po prstenu) neovisno odabranim iz grupe koja sadrži fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil ili perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi.; R8 is piperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (C6-C10)aryl(C1-C6)alkylpiperazinyl, (C2-C9)heteroaryl(C1-C6)alkylpiperazinyl ; (C1-C6)Alkyl(C=O)-piperazinyl, (C1-C6)Alkoxy(C=O)-piperazinyl, (C6-C10)aryl(C=O)-piperazinyl, (C6-C10)aryl(C1 -C6)alkyl(C=O)-piperazinyl, (C6-C10)aryl(C1-C6) alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperidyl, (C1-C6)alkylpiperidyl, ( C6-C10) arylpiperidyl, (C2-C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C2-C9)heteroaryl(C1-C6)alkylpiperidyl; (C1-C6)alkyl(C=O)-piperidyl, (C1-C6)alkoxy(C=O)-piperidyl, (C6-C10)aryl(C=O)-piperidyl, (C6-C10)aryl(C1 -C6) alkyl(C=O)-piperidyl or (C6-C10)aryl(C1-C6)alkoxy(C=O)-piperidyl, wherein each of said piperazinyl, (C1-C6) alkylpiperazinyl, (C6-C10 )arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (C6-C10)aryl(C1-C6)alkylpiperazinyl, (C2-C9)heteroaryl(C1-C6)alkyl piperazinyl, (C1-C6)alkyl(C=O)-piperazinyl , (C1-C6)Alkoxy(C=O)-piperazinyl, (C6-C10) aryl(C=O)-piperazinyl, (C6-C10)aryl(C1-C6)alkyl(C=O)-piperazinyl, ( C6-C10)aryl(C1-C6)alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C2-C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C2-C9)heteroaryl(C1-C6)alkylpiperidyl; (C1-C6)alkyl(C=O)-piperidyl, (C1-C6)alkoxy(C=O)-piperidyl, (C6-C10)aryl(C=O)-piperidyl, (C6-C10)aryl(C1 -C6)alkyl(C=O)-piperidyl and (C6-C10)aryl(C1-C6)alkoxy(C=O)-piperidyl can be optionally substituted on any carbon ring atom, which is capable of forming an additional bond, with a substituent (preferably one to three substituents per ring) independently selected from the group consisting of fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, perfluoro(C 1 -C 3 )alkyl or perfluoro(C 1 - C3) alkoxy and (C6-C10) aryloxy.;

Q je (C1-C6)alkil, (C6-C10)aril, (C6-C10)ariloksi(C6-C10)aril, (C6-C10)aril(C6-C10)aril, (C6-C10)aril(C6-C10)aril(C1-C6) alkil, (C6-C10)ariloksi(C2-C9)heteroaril, (C2-C9)heteroaril, (C2-C9)heteroaril(C2-C9)heteroaril, (C1-C6)alkil(C6-C10)aril, (C1-C6)alkoksi(C6-C10)aril, (C6-C10)aril(C1-C6)alkoksi(C6-C10)aril, (C6-C10)aril(C1-C6)alkoksi(C1-C6)alkil, (C2-C9) heteroariloksi(C6-C10)aril, (C1-C6)alkil(C2-C9)heteroaril, (C1-C6)alkoksi(C2-C9)heteroaril, (C6-C10)aril(C1-C6) alkoksi(C2-C9)heteroaril, (C2-C9)heteroariloksi(C2-C9)heteroaril, (C6-C10)ariloksi(C1-C6)alkil, (C2-C9) heteroariloksi(C1-C6)alkil, (C1-C6)alkil(C6-C10)ariloksi(C6-C10)aril, (C1-C6)alkil(C2-C9)heteroariloksi(C6-C10)aril, (C1-C6)alkil(C6-C10) (C2-C9)heteroaril, (C1-C6)alkoksi(C6-C10)ariloksi(C6-C10)aril, (C1-C6)alkoksi(C2-C9) heteroariloksi(C6-C10)aril ili (C1-C6)alkoksi(C6-C10)ariloksi(C2-C9)heteroaril gdje svaka (C6-C10)aril ili (C2-C9) heteroaril jedinica navedenih (C6-C10)aril, (C6-C10)ariloksi(C6-C10)aril, (C6-C10)aril(C6-C10)aril, (C6-C10)aril(C6-C10) aril(C1-C6)alkil, (C6-C10)ariloksi(C2-C9)heteroaril, (C2-C9)heteroaril, (C1-C6)alkil(C6-C10)aril, (C1-C6) alkoksi(C6-C10) aril, (C6-C10)aril(C1-C6)alkoksi(C6-C10)aril, (C6-C10)aril(C1-C6)alkoksi(C1-C6)alkil, (C2-C9) heteroariloksi(C6-C10)aril, (C1-C6)alkil(C2-C9)heteroaril, (C1-C6)alkoksi(C2-C9)heteroaril, (C6-C10)aril(C1-C6) alkoksi(C2-C9)heteroaril(C2-C9) heteroariloksi(C2-C9)heteroaril, (C6-C10)ariloksi(C1-C6)alkil, (C2-C9) heteroariloksi(C1-C6)alkil, (C1-C6)alkil(C6-C10) ariloksi(C6-C10)aril, (C1-C6)alkil(C2-C9)heteroariloksi(C6-C10)aril, (C1-C6)alkil(C6-C10) (C2-C9)heteroaril, (C1-C6) alkoksi(C6-C10)ariloksi(C6-C10)aril, (C1-C6)alkoksi(C2-C9) heteroariloksi(C6-C10)aril ili (C1-C6)alkoksi(C6-C10) ariloksi(C2-C9)heteroarila supstituirana na svakom atomu ugljika u prstenu koji je sposoban da stvori dodatnu vezu s jednim ili više supstituenata (preferirano jedan do tri supstituenta) neovisno odabranih između fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi; Q is (C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6 -C10)aryl(C1-C6)alkyl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C1-C6)alkyl (C6-C10)Aryl, (C1-C6)Alkoxy(C6-C10)Aryl, (C6-C10)Aryl(C1-C6)Alkoxy(C6-C10)Aryl, (C6-C10)Aryl(C1-C6) Alkoxy(C1-C6)alkyl, (C2-C9) Heteroaryloxy(C6-C10)aryl, (C1-C6)Alkyl(C2-C9)Heteroaryl, (C1-C6)Alkoxy(C2-C9)Heteroaryl, (C6- C10)Aryl(C1-C6)Alkoxy(C2-C9)Heteroaryl, (C2-C9)Heteroaryloxy(C2-C9)Heteroaryl, (C6-C10)Aryloxy(C1-C6)Alkyl, (C2-C9)Heteroaryloxy(C1 -C6)alkyl, (C1-C6)alkyl(C6-C10)aryloxy(C6-C10)aryl, (C1-C6)alkyl(C2-C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl( C6-C10) (C2-C9)heteroaryl, (C1-C6)Alkoxy(C6-C10)aryloxy(C6-C10)aryl, (C1-C6)Alkoxy(C2-C9)Heteroaryloxy(C6-C10)aryl or ( C1-C6)Alkoxy(C6-C10)aryloxy(C2-C9)heteroaryl wherein each (C6-C10)aryl or (C2-C9)heteroaryl unit of said (C6-C10)aryl, (C6-C10)aryloxy(C6- C10)aryl, (C6-C10)aryl (C6-C10)aryl, (C6-C10)aryl(C6-C10) aryl(C1-C6)alkyl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C1-C6 )alkyl(C6-C10)aryl, (C1-C6) alkoxy(C6-C10) aryl, (C6-C10)aryl(C1-C6) alkoxy(C6-C10)aryl, (C6-C10)aryl(C1- C6)Alkoxy(C1-C6)Alkyl, (C2-C9)Heteroaryloxy(C6-C10)Aryl, (C1-C6)Alkyl(C2-C9)Heteroaryl, (C1-C6)Alkoxy(C2-C9)Heteroaryl, ( C6-C10)Aryl(C1-C6)Alkoxy(C2-C9)Heteroaryl(C2-C9)Heteroaryloxy(C2-C9)Heteroaryl, (C6-C10)Aryloxy(C1-C6)Alkyl, (C2-C9)Heteroaryloxy( C1-C6)alkyl, (C1-C6)alkyl(C6-C10) aryloxy(C6-C10)aryl, (C1-C6)alkyl(C2-C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl (C6-C10) (C2-C9)heteroaryl, (C1-C6)Alkoxy(C6-C10)aryloxy(C6-C10)aryl, (C1-C6)Alkoxy(C2-C9)Heteroaryloxy(C6-C10)aryl or (C1-C6)Alkoxy(C6-C10)aryloxy(C2-C9)heteroaryl substituted at each ring carbon atom capable of forming an additional bond with one or more substituents (preferably one to three substituents) independently selected from fluoro, chloro , bromo, (C1-C6)alkyl, (C1-C6 )Alkoxy, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)Alkoxy and (C6-C10)aryloxy;

uzevši u obzir da ako su R3 ili R4 vodici, ili su oba R3 i R4 vodici, onda R1 i R2 ne mogu oba biti vodici, ili R1 mora biti hidroksi, (C1-C6)alkoksi, (C6-C10)aril(C1-C6)alkoksi, (C1-C6)alkil(C=O)O-(C1-C6)alkil, (C1-C6)alkoksi (C=O)O-(C1-C6)alkil, (C6-C10)aril(C=O)O-(C1-C6)alkil, (C6-C10)ariloksi(C=O)O- (C6-C10)arilalkil(C=O)O-(C1-C6) alkil ili (C6-C10)arilalkoksi(C=O)O-(C1-C6)alkil; provided that if R 3 or R 4 is hydrogen, or both R 3 and R 4 are hydrogen, then R 1 and R 2 cannot both be hydrogen, or R 1 must be hydroxy, (C 1 -C 6 ) alkoxy, (C 6 -C 10 )aryl(C 1 -C6)Alkoxy, (C1-C6)Alkyl(C=O)O-(C1-C6)Alkyl, (C1-C6)Alkoxy (C=O)O-(C1-C6)Alkyl, (C6-C10) aryl(C=O)O-(C1-C6)alkyl, (C6-C10)aryloxy(C=O)O-(C6-C10)arylalkyl(C=O)O-(C1-C6) alkyl or (C6 -C 10 ) arylalkoxy (C=O) O -(C 1 -C 6 ) alkyl;

ili njihova farmaceutski prihvatljiva sol. or a pharmaceutically acceptable salt thereof.

Ovaj se izum također odnosi i na farmakološki prihvatljive kisele adicijske soli spojeva formule I. Kiseline koje se koriste za pripremu farmakološki prihvatljivih kiselih soli prije spomenutih baznih spojeva ovog izuma su one koje formiraju netoksične kisele soli, tj. soli koje sadrže farmakološki prihvatljive anione, kao što su hidroklorid, hidrobromid, hidrojodid, nitrat, sulfat, bisulfat, fosfat, hidrogenfosfat, acetat, laktat, citrati, hidrogencitrat, tatrat, bitartrat, sukcinate, maleat, fumarat, glukonat, glukarat, benzoat, metansulfonat, etansulfonat, benzensulfonat, p-toluensulfonat i pamoat [tj. 1,1'-metilen-bis-(2-hidroksi-3-naftoat)]. This invention also relates to pharmacologically acceptable acid addition salts of compounds of formula I. The acids used for the preparation of pharmacologically acceptable acid salts of the previously mentioned base compounds of this invention are those that form non-toxic acid salts, i.e. salts containing pharmacologically acceptable anions, such as which are hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, hydrogenphosphate, acetate, lactate, citrates, hydrogencitrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, glucorate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate [i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)].

Izum se također odnosi na bazni dodatak soli formule I. Kemijske baze koje mogu biti korištene kao reagenti za pripremu farmakološki prihvatljivih baznih soli spojeva formule I koji su kiseli po prirodi su one koji tvore netoksične bazne soli sa takvim spojevima. Takve netoksične bazne soli uključuju, ali nisu ograničene na one izvedene iz takvih farmakološki prihvatljivih kationa kao što su kationi alkalnih metala (primjerice, kalij i natrij) i kationa zemnoalkalnih metala (primjerice kalcij i magnezij), amonijaka ili amonijevih soli topljivih u vodi kao što su N-metilglukamin-(meglumin), trimetilamin ili dietilamin i soli nižih aminoalkohola kao što su tris-(hidroksimetil)-metilamin i ostale bazne soli farmaceutski prihvatljivih organskih amina. The invention also relates to the base addition of salts of formula I. Chemical bases that can be used as reagents for the preparation of pharmacologically acceptable base salts of compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), ammonia, or water-soluble ammonium salts such as are N-methylglucamine-(meglumine), trimethylamine or diethylamine and salts of lower amino alcohols such as tris-(hydroxymethyl)-methylamine and other base salts of pharmaceutically acceptable organic amines.

Pojam "alkil" korišten ovdje, ako nije naznačeno drugačije, sadrži zasićene monovalentne ugljikovodične radikale koji imaju ravne, razgranate ili ciklične jedinke ili kombinacije istih. The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic units or combinations thereof.

Pojam "aloksi" korišten ovdje, sadrži O-alkilne grupe (gore definirani pojam “alkil”). The term "aloxy" used herein includes O-alkyl groups (the term "alkyl" is defined above).

Pojam "aril" korišten ovdje, ako nije naznačeno drugačije, sadrži organski radikal izveden iz aromatskog ugljikovodika izdvajanjem jednog vodika, kao što su fenil ili naftil. The term "aryl" as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.

Pojam "heteroaril" korišten ovdje, ako nije naznačeno drugačije, sadrži organski radikal izveden iz aromatskog heterocikličkog spoja izdvajanjem jednog vodika, kao što su piridil, furil, pirolil, tienil, izotiazolil, imidazolil, benzimidazolil, tetrazolil, pirazinil, pirimidinil, kinolil, izokinolil, benzofuril, izobenzofuril, benzotienil, pirazolil, indolil, izoindolil, purinil, karbazolil, izoksazolil, tiazolil, oksazolil, benztiazolil ili benzoksazolil. The term "heteroaryl" as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by the removal of one hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl , benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl.

Pojam "acil" korišten ovdje, ako nije naznačeno drugačije, sadrži radikal opće formule RCO, gdje je R alkil, alkoksi, aril, arilalkil ili arilalkoksi, a pojmovi "alkil" i "aril" su gore definirani. The term "acyl" as used herein, unless otherwise indicated, includes a radical of the general formula RCO, where R is alkyl, alkoxy, aryl, arylalkyl, or arylalkoxy, and the terms "alkyl" and "aryl" are as defined above.

Termin "alkoksi" korišten ovdje, sadrži O-acil gupe, dok je pojam "acil" gore definiran. The term "alkoxy" as used herein includes O-acyl groups, while the term "acyl" is defined above.

Spoj formule I može imati kiralne centre i tako postojati u različitim diasteroizomernim ili enantiomernim oblicima. Ovaj izum odnosi se na sve optičke izomere i stereoizomere spojeva formule I i daljnjih spojeva. The compound of formula I can have chiral centers and thus exist in different diastereoisomeric or enantiomeric forms. This invention relates to all optical isomers and stereoisomers of compounds of formula I and further compounds.

Preferirani spojevi formule I obuhvaćaju i one gdje je R1 OH, i R2 je vodik. Preferred compounds of formula I include those where R1 is OH, and R2 is hydrogen.

Ostali preferirani spojevi formule I obuhvaćaju one gdje su i R3 i R4 (C1-C6)alkil ili R3 i R4 uzeti zajedno formiraju po želji zamijenjen (C3-C6)cikloalkilni prsten ili benzo-(C3-C6)cikloalkilni prsten ili grupu formule Other preferred compounds of formula I include those where both R 3 and R 4 are (C 1 -C 6 )alkyl or R 3 and R 4 taken together form an optionally substituted (C 3 -C 6 )cycloalkyl ring or benzo-(C 3 -C 6 )cycloalkyl ring or a group of the formula

[image] [image]

gdje je atom ugljika sa zvjezdicom onaj ugljik na kojeg su R3 i R4 vezani, "n" i "m" su nezavisno izabrani između cijelih brojeva 1 i 2, i X je CF2, O, SO2 ili NR9, gdje je R9 vodik, (C1-C6)alkil, (C6-C10)aril, (C2-C9)heteroalkil, (C6-C10)aril(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkil, (C1-C6)alkilsulfonil, (C6-C10)arilsulfonil, (C1-C6) alkil(C=O)-, (C1-C6)alkoksi(C=O)O-, (C6-C10)aril(C=O)O-, (C6-C10)aril(C1-C6)alkil(C=O)O-, ili (C6-C10)aril(C1-C6)alkoksi (C=O)O-; gdje svaka od navedenih (C6-C10)aril i (C2-C9)heteroaril jedinki iz navedenih (C6-C10)aril, (C2-C9) heteroalkil, (C6-C10)aril(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkil, (C6-C10)arilsulfonil, (C6-C10) aril(C=O)O-, (C6-C10)aril(C1-C6)alkil(C=O)O-, i (C6-C10)aril(C1-C6)alkoksi(C=O)O- grupe mogu biti opcionalno neovisno zamijenjene sa jednim ili više supstituenata (preferirano jedan do tri supstituenta) neovisno odabranih iz grupe fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, perfluoro(C1-C3)alkoksi i (C6-C10) ariloksi. where the asterisked carbon atom is the carbon to which R3 and R4 are attached, "n" and "m" are independently selected from the integers 1 and 2, and X is CF2, O, SO2 or NR9, where R9 is hydrogen, ( C1-C6)alkyl, (C6-C10)aryl, (C2-C9)heteroalkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C1-C6 )alkylsulfonyl, (C6-C10)arylsulfonyl, (C1-C6) alkyl(C=O)-, (C1-C6) alkoxy(C=O)O-, (C6-C10)aryl(C=O)O- , (C6-C10)aryl(C1-C6)alkyl(C=O)O-, or (C6-C10)aryl(C1-C6)alkoxy (C=O)O-; where each of said (C6-C10)aryl and (C2-C9)heteroaryl units from said (C6-C10)aryl, (C2-C9) heteroalkyl, (C6-C10)aryl(C1-C6)alkyl, (C2- C9)heteroaryl(C1-C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)aryl(C=O)O-, (C6-C10)aryl(C1-C6)alkyl(C=O)O- , and (C6-C10)aryl(C1-C6)alkoxy(C=O)O- groups may be optionally independently substituted with one or more substituents (preferably one to three substituents) independently selected from the group of fluoro, chloro, bromo, ( C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 3 )alkyl, perfluoro (C 1 -C 3 ) alkoxy and (C 6 -C 10 )aryloxy.

Preferirani spojevi formule I uključuju one kod kojih R3 i R4 zajedno čine opcionalno supstituirani (C3-C6) cikloalkilni prsten. Preferred compounds of formula I include those in which R 3 and R 4 together form an optionally substituted (C 3 -C 6 ) cycloalkyl ring.

Drugi preferirani spojevi formule I uključuju one kod kojih je R1 hidroksi skupina. Other preferred compounds of formula I include those wherein R 1 is a hydroxy group.

Drugi preferirani spojevi formule I uključuju one kod kojih je Q (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril, gdje se svaka (C6-C10)aril jedinica navedenih (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril grupa može opcionalno zamijeniti s jednim ili više supstituenata neovisno odabranih iz grupe fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6) alkoksi ili perfluoro(C1-C3)alkil. Other preferred compounds of formula I include those wherein Q is (C6-C10)aryl or (C6-C10)aryloxy(C6-C10)aryl, wherein each (C6-C10)aryl unit of said (C6-C10)aryl or ( The C6-C10)aryloxy(C6-C10)aryl group may be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6) alkoxy or perfluoro(C1-C3) alkyl.

Drugi preferirani spojevi formule I uključuju one kod kojih je Q fenil ili fenoksifenil opcionalno supstituiran jednim ili više supstituenata neovisno odabranih između fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi ili perfluoro(C1-C3)alkil, još su preferiraniji oni kod kojih su supstituenti odabrani između fluoro, kloro, bromo, (C1-C6)alkoksi ili (C1-C6)alkil, pri čemu je najbolje da supstituent bude u položaju 4. Other preferred compounds of formula I include those in which Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy or perfluoro(C1-C3)alkyl , those in which the substituents are selected from fluoro, chloro, bromo, (C1-C6) alkoxy or (C1-C6) alkyl are even more preferred, wherein it is best for the substituent to be in position 4.

Posebno preferirani spojevi formule I uključuju: Particularly preferred compounds of formula I include:

(2S)-2,N-dihidroksi-3-(4-metoksibenzensulfonil)propionamid; (2S)-2,N-dihydroxy-3-(4-methoxybenzenesulfonyl)propionamide;

3-[4-(4-fluorofenoksi)fenilsulfonil]2,N-dihidroksipropionamid; 3-[4-(4-fluorophenoxy)phenylsulfonyl]2,N-dihydroxypropionamide;

2,N-dihidroksi-2-[1-(4-metoksibenzensulfonil)ciklobutil]acetamid; 2,N-dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclobutyl]acetamide;

2,N-dihidroksi-2-[1-(4-metoksibenzensulfonil)ciklopentil]acetamid; 2,N-dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclopentyl]acetamide;

2-[1-(4-ciklobutoksibenzensulfonil)ciklobutil]-2,N-dihidroksiacetamid; 2-[1-(4-cyclobutoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide;

2-[1-(4-butoksibenzensulfonil)ciklobutil]-2,N-dihidroksiacetamid; 2-[1-(4-butoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide;

2-{1-[4-(4-fluorofenoksi)benzensulfonil]ciklobutil}-2,N-dihidroksiacetamid; ili 2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclobutyl}-2,N-dihydroxyacetamide; or

2-{1-[4-(4-fluorofenoksi)benzensulfonil]ciklopentil}-2,N-dihidroksiacetamid. 2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclopentyl}-2,N-dihydroxyacetamide.

Ostali spojevi formule I uključuju slijedeće: Other compounds of formula I include the following:

2,N-dihidroksi-2-[1-(4-fenoksibenzensulfonil)ciklopentil]acetamid; 2,N-dihydroxy-2-[1-(4-phenoxybenzenesulfonyl)cyclopentyl]acetamide;

2,N-dihidroksi-2-[1-(4-fenoksibenzensulfonil)ciklobutil]acetamid; 2,N-dihydroxy-2-[1-(4-phenoxybenzenesulfonyl)cyclobutyl]acetamide;

metilni ester {1-[4-(4-fluorofenoksi)benzensulfonil]ciklopentil} hidroksikarbamoil octene kiseline; {1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclopentyl}hydroxycarbamoyl acetic acid methyl ester;

metilni ester {1-[4-(4-fluorofenoksi)benzensulfonil]ciklobutil} hidroksikarbamoil octene kiseline; {1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclobutyl}hydroxycarbamoyl acetic acid methyl ester;

2-{1-[4-(4-fluorofenoksi)benzensulfonil]ciklopentil}-N-hidroksi-2-metoksiacetamid; 2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclopentyl}-N-hydroxy-2-methoxyacetamide;

2-{1-[4-(4-fluorofenoksi)benzensulfonil]ciklobutil}-N-hidroksi-2-metoksi-acetamid; 2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclobutyl}-N-hydroxy-2-methoxy-acetamide;

2-[1-(4-butoksibenzensulfonil)cikloheksil]-2,N-dihidroksiacetamid; 2-[1-(4-butoxybenzenesulfonyl)cyclohexyl]-2,N-dihydroxyacetamide;

2-[1-(4-butoksibenzensulfonil)ciklopentil]-2,N-dihidroksiacetamid; ili 2-[1-(4-butoxybenzenesulfonyl)cyclopentyl]-2,N-dihydroxyacetamide; or

2-[1-(4-butoksibenzensulfonil)ciklobutil]-2,N-dihidroksiacetamid. 2-[1-(4-butoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide.

Ovaj se izum također odnosi na farmaceutski pripravak za: (a) tretman stanja odabranih iz grupe koja sadrži artritis, osteoporozu, rak, sinergiju sa citotoksičnim antikancerogenim agensima, tkivni vrijed, makularnu degradaciju, restenozu, periodontalnu bolest, epidermolizis bullosa, skleritis, u kombinaciji sa standardnim NSAID'S i analgeticima i u ostalim bolestima karakteriziranim matriks metaloproteaznom aktivnošću, AIDS, sepsa, septički šok i ostale bolesti koje uključuju proizvodnju faktora nekroze tumora (TNF); ili (b) inhibiciju matriks metaloproteinaze ili proizvodnje faktora nekroze tumora (TNF) u sisavaca, uključujući čovjeka, a koji sadrži određenu količinu spoja formule I ili njegove farmaceutski prihvatljivu sol djelotvornog za takav tretman i farmaceutski prihvatljiv nosač. This invention also relates to a pharmaceutical composition for: (a) treatment of conditions selected from the group consisting of arthritis, osteoporosis, cancer, synergy with cytotoxic anticancer agents, tissue ulcer, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, in combination with standard NSAIDs and analgesics and in other diseases characterized by matrix metalloprotease activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF); or (b) inhibition of matrix metalloproteinase or tumor necrosis factor (TNF) production in mammals, including humans, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective for such treatment and a pharmaceutically acceptable carrier.

Ovaj se izum također odnosi na metodu inhibicije: (a) matriks metaloproteinaze; ili (b) proizvodnju faktora nekroze tumora (TNF) u sisavaca, uključujući čovjeka, koja se sastoji u tretiranju navedenog sisavca djelotvornom količinom spoja formule I ili njegove farmaceutski prihvatljive soli. This invention also relates to a method of inhibiting: (a) matrix metalloproteinase; or (b) producing tumor necrosis factor (TNF) in a mammal, including a human, comprising treating said mammal with an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Ovaj se izum također odnosi na metodu tretiranja stanja odabranih iz grupe koja sadrži artritis, osteoporozu, rak, tkivni vrijed, makularnu degradaciju, restenozu, periodontalnu bolest, epidremolizis bullosa, skleritis, spojevi formule I mogu se koristiti u kombinaciji sa standardnim NSAID'S i analgesticima u kombinaciji s citotoksičnim antitumorskim agensima, i kod ostalih bolesti karakteriziranih aktivnošću matriks metaloproteinaze, AIDS, sepsu, septički šok i ostale bolesti koje uključuju proizvodnju faktora nekroze tumora (TNF) u sisavaca, uključujući čovjeka, a koji koja se sastoji u tretiranju navedenog sisavca djelotvornom količinom spoja formule I ili njegove farmaceutski prihvatljive soli djelotvornog u tretmanu takvog stanja. This invention also relates to a method of treating conditions selected from the group consisting of arthritis, osteoporosis, cancer, tissue ulcer, macular degeneration, restenosis, periodontal disease, epidremolisis bullosa, scleritis, the compounds of formula I can be used in combination with standard NSAIDs and analgesics in in combination with cytotoxic antitumor agents, and in other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in mammals, including humans, which consists in treating said mammal with an effective amount a compound of formula I or a pharmaceutically acceptable salt thereof effective in the treatment of such a condition.

Detaljni opis izuma Detailed description of the invention

Sljedeće sheme reakcija ilustriraju pripravu spojeva ovog izuma. Ako nije drukčije navedeno n,m,R1, R2, R3, R4, R5, R6, R7, R8, Q i X u shemama reakcija i diskusiji koja slijedi definirani su kao gore. The following reaction schemes illustrate the preparation of the compounds of this invention. Unless otherwise noted, n, m, R1, R2, R3, R4, R5, R6, R7, R8, Q and X in the reaction schemes and discussion that follows are defined as above.

Shema 1 Scheme 1

[image] [image]

Shema 2 Scheme 2

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Shema 3 Scheme 3

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Shema 4 Scheme 4

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Shema 1 odnosi se na pripremu spojeva formule I, gdje su R3 i R4 vodik. Na shemi 1, spoj formule I je pripravljen iz spoja formule II hidrogenolizom u atmosferi vodika u prisutnosti katalizatora u inertnom otapalu. Prikladni katalizatori sadrže 5 % paladija na barijevom sulfatu ili 5 % paladija na ugljiku, po mogućnosti 5 % paladija na barijevom sulfatu. Prikladna otapala uključuju alkohol kao što su etanol, metanol ili izopropanol, po mogućnosti metanol. Prije spomenuta reakcija može biti izvedena pod tlakom od oko 1 do oko 5 bara, po mogućnosti oko 3 bara. Prikladne temperature za gore navedenu reakciju su od oko 20 °C (sobna temperatura) do oko 60 °C, po mogućnosti da je temperatura između 20 °C i 25 °C (tj. sobna temperatura). Reakcija je gotova unutar oko 30 minuta do oko 5 sati, najbolje oko 3 sata. Scheme 1 relates to the preparation of compounds of formula I, where R3 and R4 are hydrogen. In scheme 1, the compound of formula I is prepared from the compound of formula II by hydrogenolysis in a hydrogen atmosphere in the presence of a catalyst in an inert solvent. Suitable catalysts contain 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol. The aforementioned reaction can be carried out under a pressure of about 1 to about 5 bar, preferably about 3 bar. Suitable temperatures for the above reaction are from about 20°C (room temperature) to about 60°C, preferably between 20°C and 25°C (ie room temperature). The reaction is complete within about 30 minutes to about 5 hours, preferably about 3 hours.

Spoj formule II je pripravljen iz spoja formule III reakcijom sa O-benzilhidroksilamin hidrokloridom, aktivirajućim agensom, i bazom u inertnom otapalu. Prikladni aktivirajući agensi uključuju (benzotriazol-1-iloksi)tris (dimetilamino)fosfonium heksafluorofosfat ili 1-(3-(dimetilaminopropil)-3-etilkarbodiimid hidroklorid, po mogućnosti (benzotriazol-1-iloksi)tris(dimetilamino)fosfonium heksafluorofosfat. Prikladne baze uključuju tercijarne amine kao što su trietilamin, diizopropiletilamin ili 4-N,N-dimetilaminopiridin, po mogućnosti trietilamin. Temperatura gore navedene reakcije može biti između oko 0 °C do oko 60 °C, najbolje oko 20 °C (sobna temperatura). Prikladna otapala uključuju halogena otapala kao što su metilenklorid ili kloroform, ili eteri kao THF ili dietileter, po mogućnost da je otapalo metilenklorid. Reakcija je završena za otprilike 4 sata do otprilike 48 sati, najbolje oko 16 sati. The compound of formula II is prepared from the compound of formula III by reaction with O-benzylhydroxylamine hydrochloride, an activating agent, and a base in an inert solvent. Suitable activating agents include (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate or 1-(3-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), preferably (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate. include tertiary amines such as triethylamine, diisopropylethylamine or 4-N,N-dimethylaminopyridine, preferably triethylamine.The temperature of the above reaction may be between about 0°C to about 60°C, preferably about 20°C (room temperature). solvents include halogen solvents such as methylene chloride or chloroform, or ethers such as THF or diethyl ether, optionally the solvent is methylene chloride.The reaction is complete in about 4 hours to about 48 hours, preferably about 16 hours.

Spoj formule III je pripravljen iz spoja formule IV hidrogenolizom u atmosferi vodika u prisutnosti katalizatora u inertnom otapalu. Prikladni katalizatori sadrže paladij ili 5-10 % paladija na aktivnom ugljenu, po mogućnosti 10 % paladija na aktivnom ugljenu. Prikladna otapala uključuju octenu kiselinu, alkohole kao što su etanol, metanol ili izopropanol, po mogućnosti etanol. Gore spomenuta reakcija može biti izvedena pod tlakom od oko 1 do oko 5 bara, po mogućnosti oko 3 bara. Prikladne temperature za gore navedenu reakciju su od oko 20 °C (sobna temperatura) do oko 60 °C, po mogućnosti da je temperatura između 20 °C i 25 °C (tj. sobna temperatura). Reakcija je gotova unutar oko 30 minuta do oko 24 sata, po mogućnosti oko 3 sata. The compound of formula III was prepared from the compound of formula IV by hydrogenolysis in a hydrogen atmosphere in the presence of a catalyst in an inert solvent. Suitable catalysts contain palladium or 5-10% palladium on activated carbon, preferably 10% palladium on activated carbon. Suitable solvents include acetic acid, alcohols such as ethanol, methanol or isopropanol, preferably ethanol. The above-mentioned reaction can be carried out under a pressure of about 1 to about 5 bar, preferably about 3 bar. Suitable temperatures for the above reaction are from about 20°C (room temperature) to about 60°C, preferably between 20°C and 25°C (ie room temperature). The reaction is complete within about 30 minutes to about 24 hours, preferably about 3 hours.

Spojevi formule IV mogu biti pripravljeni iz spojeva formule V reakcijom s oksidansom u inertnom otapalu. Prikladni oksidansi uključuju metakloroperbenzojevu kiselinu, vodikov peroksid ili natrijev perborat, po mogućnosti metakloroperbenzojevu kiselinu. Prikladna otapala uključuju halogena otapala kao što su metilenklorid ili kloroform, po mogućnosti metilenklorid. Prikladne temperature za gore navedenu reakciju su od oko 20 °C (sobna temperatura) do oko 60 °C, po mogućnosti da je temperatura između 20 °C i 25 °C (tj. sobna temperatura). Reakcija je gotova unutar oko 30 minuta do oko 24 sata, po mogućnosti oko 3 sata. Compounds of formula IV can be prepared from compounds of formula V by reaction with an oxidant in an inert solvent. Suitable oxidants include metachloroperbenzoic acid, hydrogen peroxide or sodium perborate, preferably metachloroperbenzoic acid. Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. Suitable temperatures for the above reaction are from about 20°C (room temperature) to about 60°C, preferably between 20°C and 25°C (ie room temperature). The reaction is complete within about 30 minutes to about 24 hours, preferably about 3 hours.

Spojevi formule V, gdje je R1 hidroksi, mogu biti pripravljeni iz spojeva formule VI reakcijom sa Grignardovim reagensom i tiolom formule QSH u inertnom otapalu. Prikladni Grignardovi reagensi uključuju etil- magnezijev bromid ili fenilmagnezijev bromid, po mogućnosti etil- magnezijev bromid. Prikladna otapala uključuju etere kao što su dietileter, tetrahidrofuran ili 1,2-dimetoksietan, po mogućnosti da je otapalo smjesa tetrahidrofurana i dietiletera. Prikladne temperature za gore navedenu reakciju su od oko -78 °C do oko 50 °C, po mogućnosti da je temperatura između 0 °C i 25 °C (tj. sobna temperatura). Reakcija je gotova unutar oko 1 sat do oko 24 sata, po mogućnosti oko 3 sata. Compounds of formula V, where R1 is hydroxy, can be prepared from compounds of formula VI by reaction with a Grignard reagent and a thiol of formula QSH in an inert solvent. Suitable Grignard reagents include ethylmagnesium bromide or phenylmagnesium bromide, preferably ethylmagnesium bromide. Suitable solvents include ethers such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, preferably a mixture of tetrahydrofuran and diethyl ether. Suitable temperatures for the above reaction are from about -78°C to about 50°C, preferably between 0°C and 25°C (ie, room temperature). The reaction is complete within about 1 hour to about 24 hours, preferably about 3 hours.

Spojevi formule V, gdje je R1 (C6-C10)aril(C1-C6)alkoksi ili (C1-C6)alkoksi, mogu biti pripravljeni iz spojeva formule V gdje je R1 hidroksi, reakcijom sa spojem formule R1aL, gdje je L grupa koja odlazi, a R1a je (C6-C10) aril(C1-C6)alkil ili (C1-C6)alkil, u prisutnosti jake baze u aprotičkom polarnom otapalu. Prikladne grupe koje odlaze uključuju kloro, fluoro, bromo, mesilat, triflat ili tosilat. mogućnosti grupa koja odlazi je jodo. Prikladne baze uključuju natrijev hidrid, litijeve dialkilamide kao što su litijev N-izopropil-N-cikloheksilamid ili litijev diizopropilamid, kalijev t-butoksid, natrijev amid, ili kalijev hidrid, po mogućnosti natrijev hidrid. Prikladna otapala uključuju etere (kao što su THF, dietileter ili 1,2- dimetoksietan), po mogućnosti THF. Gore navedena reakcija izvodi se pri oko -78 °C do oko 0 °C, po mogućnosti oko 0 °C. Compounds of formula V, where R 1 is (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy or (C 1 -C 6 )alkoxy, can be prepared from compounds of formula V where R 1 is hydroxy, by reaction with a compound of formula R 1aL , where L is a group which leaves, and R1a is (C6-C10) aryl(C1-C6)alkyl or (C1-C6)alkyl, in the presence of a strong base in an aprotic polar solvent. Suitable leaving groups include chloro, fluoro, bromo, mesylate, triflate or tosylate. the possibilities of the group leaving is iodo. Suitable bases include sodium hydride, lithium dialkylamides such as lithium N-isopropyl-N-cyclohexylamide or lithium diisopropylamide, potassium t-butoxide, sodium amide, or potassium hydride, preferably sodium hydride. Suitable solvents include ethers (such as THF, diethyl ether or 1,2-dimethoxyethane), preferably THF. The above reaction is carried out at about -78 °C to about 0 °C, preferably about 0 °C.

Spojevi formule V, gdje je R1 (C1-C6)alkil(C=O)O-, (C1-C6)alkoksi-(C=O)O-, (C6-C10)aril(C=O)O-, (C6-C10) ariloksi(C=O)O-, (C6-C10)aril(C1-C6)alkil(C=O)O- ili (C6-C10)aril(C1-C6)alkoksi(C=O)O-, mogu biti pripravljeni od spojeva formule formule V gdje je R1 hidroksi, reakcijom sa spojem formule R1bL, gdje je L grupa koja odlazi, a R1b je (C1-C6)alkil(C=O)-, (C1-C6)alkoksi(C=O)-, (C6-C10)aril(C=O)-, (C6-C10)ariloksi(C=O)-, (C6-C10)aril(C1-C6) alkil(C=O)- ili (C6-C10)aril(C1-C6)alkoksi(C=O)-, u prisustvu baze u inertnom otapalu. . Prikladne grupe koje odlaze uključuju kloro, fluoro, bromo, ili R1bO (tj. anhidrid). mogućnosti grupa koja odlazi je kloro. Prikladne baze uključuju tercijarne amine kao što su trietilamin, piridin ili 4-dimetilaminopiridin, najbolje trietilamin. Temperatura gore navedene reakcije je od oko 0 °C do oko 30 °C, po mogućnosti od oko 20 °C do oko 25 °C (tj. sobna temperatura). Prikladna otapala uključuju halogena otapala kao što su metilenklorid ili kloroform, po mogućnosti metilenklorid. Reakcija traje od oko 1 sat do oko 24 sata, najbolje oko 2 sata. Compounds of the formula V, where R1 is (C1-C6)alkyl(C=O)O-, (C1-C6)alkoxy-(C=O)O-, (C6-C10)aryl(C=O)O-, (C6-C10) aryloxy(C=O)O-, (C6-C10)aryl(C1-C6)alkyl(C=O)O- or (C6-C10)aryl(C1-C6)alkoxy(C=O )O-, can be prepared from compounds of the formula V where R1 is hydroxy, by reaction with a compound of the formula R1bL, where L is a leaving group, and R1b is (C1-C6)alkyl(C=O)-, (C1-C6 )Alkoxy(C=O)-, (C6-C10)aryl(C=O)-, (C6-C10)aryloxy(C=O)-, (C6-C10)aryl(C1-C6) alkyl(C= O)- or (C6-C10)aryl(C1-C6)alkoxy(C=O)-, in the presence of a base in an inert solvent. . Suitable leaving groups include chloro, fluoro, bromo, or R1bO (ie, anhydride). the possibilities of the group leaving is chloro. Suitable bases include tertiary amines such as triethylamine, pyridine or 4-dimethylaminopyridine, preferably triethylamine. The temperature of the above reaction is from about 0 °C to about 30 °C, preferably from about 20 °C to about 25 °C (ie, room temperature). Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. The reaction lasts from about 1 hour to about 24 hours, preferably about 2 hours.

Spojevi formule VI mogu se pripremiti metodama dobro znanim osobama prosječne vještine. Spojevi formule VI mogu se također pripremiti oksidacijom perkiselinama (npr. meta-klorberbenzojeva kiselina) pripadajućih �,�-nezasićenih benzil estera kako opisano u Jerry March, Advanced Organic Chemistry, 735 (3. izdanje 1985). Pripadajući �,�-nezasićeni benzil esteri mogu biti pripravljeni Knovenagelovom kondenzacijom između monobenzil estera maleinske kiseline i paraformaldeheida u prisutnosti piperidina kako je opisano u H.O. House: "Modern Synthetic Reactions", 2.izdanje, 649-65, W. A. Benjamin, Menlo Park, Kalifornija, (1972.). Compounds of formula VI can be prepared by methods well known to those of ordinary skill. Compounds of formula VI may also be prepared by oxidation with peracids (eg, meta-chloroberbenzoic acid) of the corresponding ,,-unsaturated benzyl esters as described in Jerry March, Advanced Organic Chemistry, 735 (3rd ed. 1985). The corresponding �,�-unsaturated benzyl esters can be prepared by Knovenagel condensation between maleic acid monobenzyl ester and paraformaldehyde in the presence of piperidine as described in H.O. House: "Modern Synthetic Reactions", 2nd ed., 649-65, W. A. Benjamin, Menlo Park, CA, (1972).

Spojevi formule VI, gdje je R2 vodik, mogu također biti pripremljeni u racemičnom ili enantiomerno čistom obliku konverzijom L-, D-, ili D,L-serina kao što su opisali W. Roush i B. Brown: u "J. Org. Chem.", 47, 3387, (1992.). Compounds of formula VI, wherein R 2 is hydrogen, may also be prepared in racemic or enantiomerically pure form by conversion of L-, D-, or D,L-serine as described by W. Roush and B. Brown: in "J. Org. Chem.", 47, 3387, (1992).

Shema 2 odnosi se na pripravu spojeva formule I, gdje je R2 vodik a R1 je OH. Prema shemi 2, spojevi formule I mogu se pripraviti iz spojeva formule VII hidriranjem u atmosferi vodika uz prisustvo katalizatora u inertnom otapalu. Prikladni katalizatori uključuju 5 % paladija na barijevom sulfatu ili 5 % paladija na ugljiku, preferirano 5 % paladija na barijevom sulfatu. Prikladna otapala uključuju alkohole kao što su etanol, metanol ili izopropanol, preferirano metanol. Navedena reakcija može se provesti pod tlakom od 1 do oko 5 bara, preferirano oko 3 bara. Pogodne temperature za navedenu reakciju kreću se od oko 20 °C (sobna temperatura) do oko 60 °C, preferirano temperatura se može kretati od oko 20 ° do oko 25 °C (tj. sobna temperatura). Reakcija je dovršena za oko 30 minuta do 5 sati, preferirano za 3 sata. Scheme 2 refers to the preparation of compounds of formula I, where R2 is hydrogen and R1 is OH. According to scheme 2, compounds of formula I can be prepared from compounds of formula VII by hydrogenation in a hydrogen atmosphere with the presence of a catalyst in an inert solvent. Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include alcohols such as ethanol, methanol or isopropanol, preferably methanol. Said reaction can be carried out under a pressure of 1 to about 5 bar, preferably about 3 bar. Suitable temperatures for said reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature can range from about 20° to about 25°C (ie room temperature). The reaction is complete in about 30 minutes to 5 hours, preferably 3 hours.

Spojevi formule VII mogu se pripraviti iz spojeva formule VIII reakcijom s hidroksidom alkalnih metala u polarnom otapalu. Prikladni hidroksidi alkalnih metala uključuju litijev hidroksid, natrijev hidroksid ili kalijev hidroksid, preferirano litijev hidroksid, najbolje oko 5 molova (ekvivalenata) hidroksida alkalnog metala. Navedena reakcija može se provesti pri temperaturi od oko 0 °C do oko 60 °C, preferirano od oko 20 °C do oko 25 °C (tj. pri sobnoj temperaturi). Prikladna otapala uključuju smjesu vode i alkohola kao što su metanol i etanol i po potrebi etera topljivog u vodi, kao što su tetrahidrofuran ili 1,2-dimetoksietan. Preferirani sustav otapala je metanol/voda/tetrahidrofuran. Reakcija se provodi od oko 1 do oko 72 sata, preferirano oko 24 sata. Compounds of formula VII can be prepared from compounds of formula VIII by reaction with alkali metal hydroxide in a polar solvent. Suitable alkali metal hydroxides include lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide, preferably about 5 moles (equivalents) of the alkali metal hydroxide. Said reaction can be carried out at a temperature of from about 0 °C to about 60 °C, preferably from about 20 °C to about 25 °C (ie at room temperature). Suitable solvents include mixtures of water and alcohols such as methanol and ethanol and optionally water-soluble ethers such as tetrahydrofuran or 1,2-dimethoxyethane. The preferred solvent system is methanol/water/tetrahydrofuran. The reaction is carried out for about 1 to about 72 hours, preferably about 24 hours.

Spoj formule VIII pripravlja se iz spoja formule IX reakcijom s O-benzilhidroksilamin hidrokloridom u prisustvu katalizatora i baze u inertnom otapalu. Prikladni katalizatori uključuju (benzotriazol-1-iloksi)tris(dimetilamino) fosfonium heksaklorofosfat ili 1-(3-(dimetilaminopropil)-3-etilkarbodiimid hidroklorid, preferirano (benzotriazol-1-iloksi)tris(dimetilamino)fosfonium heksaklorofosfat. Prikladne baze uključuju tercijarne amine kao što su trietilamin, diizopropiletilamin ili dimetilaminopiridin, preferirano trietilamin. Temperatura navedene reakcije je od oko 0 °C do oko 60 °C, preferirano od oko 20 °C do oko 25 °C (tj. sobna temperatura). Prikladna otapala uključuju halogena otapala kao što su metilenklorid i kloroform, preferirano metilenklorid. Reakcija se provodi od oko 4 do oko 48 sati, preferirano oko 16 sati. The compound of formula VIII is prepared from the compound of formula IX by reaction with O-benzylhydroxylamine hydrochloride in the presence of a catalyst and a base in an inert solvent. Suitable catalysts include (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexachlorophosphate or 1-(3-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, preferably (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexachlorophosphate. Suitable bases include tertiary amines such as triethylamine, diisopropylethylamine or dimethylaminopyridine, preferably triethylamine. The temperature of said reaction is from about 0°C to about 60°C, preferably from about 20°C to about 25°C (ie, room temperature). Suitable solvents include halogen solvents such as methylene chloride and chloroform, preferably methylene chloride The reaction is carried out from about 4 to about 48 hours, preferably about 16 hours.

Spoj formule IX pripravlja se iz spoja formule X reakcijom sa suviškom natrijevog perjodata u prisustvu rutenij triklorid hidrata kao katalizatora. Navedena reakcija provodi se pri temperaturi od oko 0 °C do oko 35 °C, preferirano od oko 20 °C do oko 25 °C (tj. sobna temperatura). Prikladna otapala uključuju aceton ili smjesu acetonitrila, ugljikovog tetraklorida i vode, preferirano smjesu acetonitrila, ugljikovog tetraklorida i vode u omjeru 1:1:2. Reakcija se provodi od oko 30 minuta do oko 2 sata, preferirano oko 75 minuta. The compound of formula IX is prepared from the compound of formula X by reaction with an excess of sodium periodate in the presence of ruthenium trichloride hydrate as a catalyst. Said reaction is carried out at a temperature of from about 0 °C to about 35 °C, preferably from about 20 °C to about 25 °C (ie room temperature). Suitable solvents include acetone or a mixture of acetonitrile, carbon tetrachloride and water, preferably a mixture of acetonitrile, carbon tetrachloride and water in a ratio of 1:1:2. The reaction is carried out from about 30 minutes to about 2 hours, preferably about 75 minutes.

Spoj formule X, gdje je “P” pivaloil, acetil ili benzoil, pripravlja se iz spoja formule XI uz reagens za zaštitu grupa u prisustvu baze u inertnom otapalu. Prikladni reagensi za zaštitu grupa uključuju pivaloil- klorid, anhidrid pivalinske kiseline, acetilklorid, anhidrid octene kiseline, benzoilklorid ili anhidrid benzojeve kiseline, preferirano anhidrid octene kiseline. Prikladne baze uključuju tercijarne amine kao što su piridin ili 4-N,N-dimetilaminopiridin, preferirano 4-N,N-dimetilaminopiridin. Temperatura navedene reakcije je od oko 0 °C do oko 30 °C, preferirano od oko 20 °C do oko 25 °C (tj. sobna temperatura). Prikladna otapala uključuju halogena otapala kao što su metilenklorid i kloroform, preferirano metilenklorid. Reakcija se provodi od oko 1 do oko 24 sata, preferirano oko 2 sata. A compound of formula X, where "P" is pivaloyl, acetyl or benzoyl, is prepared from a compound of formula XI with a group-protecting reagent in the presence of a base in an inert solvent. Suitable protecting group reagents include pivaloyl chloride, pivalic anhydride, acetyl chloride, acetic anhydride, benzoyl chloride or benzoic anhydride, preferably acetic anhydride. Suitable bases include tertiary amines such as pyridine or 4-N,N-dimethylaminopyridine, preferably 4-N,N-dimethylaminopyridine. The temperature of said reaction is from about 0 °C to about 30 °C, preferably from about 20 °C to about 25 °C (ie, room temperature). Suitable solvents include halogenated solvents such as methylene chloride and chloroform, preferably methylene chloride. The reaction is carried out for about 1 to about 24 hours, preferably about 2 hours.

Spoj formule XI pripravlja se iz spoja formule XII reakcijom s 2-furaldehidom i jakom bazom u polarnom aprotičnom otapalu. Prikladne baze uključuju kalijev terc-butoksid, litijev diizopropilamid i butil-litij, preferirano 2.5 M n-butil-litij u heksanu. Temperatura navedene reakcije je od oko -78 °C do oko 0 °C, preferirano oko -78 °C. Prikladna otapala uključuju dietileter, tetrahidrofuran ili 1,2-dimetoksietan, preferirano tetrahidrofuran. Reakcija se provodi od oko 15 minuta do oko 6 sati, preferirano oko 20 minuta. The compound of formula XI is prepared from the compound of formula XII by reaction with 2-furaldehyde and a strong base in a polar aprotic solvent. Suitable bases include potassium tert-butoxide, lithium diisopropylamide and butyllithium, preferably 2.5 M n-butyllithium in hexane. The temperature of said reaction is from about -78 °C to about 0 °C, preferably about -78 °C. Suitable solvents include diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, preferably tetrahydrofuran. The reaction is carried out from about 15 minutes to about 6 hours, preferably about 20 minutes.

Spoj formule XII pripravlja se iz spoja formule XIII reakcijom s oksidansom u inertnom otapalu. Prikladni oksidansi uključuju metaklor-perbenzojevu kiselinu, vodikov peroksid ili natrijev perborat, preferirano metaklor-perbenzojeva kiselina. Prikladna otapala uključuju halogena otapala kao što su metilenklorid i kloroform, preferirano metilenklorid. Pogodne temperature za navedenu reakciju kreću se od oko 0 °C do oko 60 °C, preferirano od oko 20 °C do oko 25 °C (tj. sobna temperatura). Reakcija je dovršena za oko 30 minuta do 24 sata, preferirano za oko 3 sata. The compound of formula XII is prepared from the compound of formula XIII by reaction with an oxidant in an inert solvent. Suitable oxidants include metachloro-perbenzoic acid, hydrogen peroxide or sodium perborate, preferably metachloro-perbenzoic acid. Suitable solvents include halogenated solvents such as methylene chloride and chloroform, preferably methylene chloride. Suitable temperatures for said reaction range from about 0°C to about 60°C, preferably from about 20°C to about 25°C (ie, room temperature). The reaction is complete in about 30 minutes to 24 hours, preferably in about 3 hours.

Spoj formule XIII pripravlja se iz spoja formule XIV reakcijom s tiolom formule QSH u prisustvu baze i aprotičnog otapala. Prikladne baze uključuju natrijev hidrid, etilmagnezijev bromid, litijev diizopropilamid, kalijev hidrid ili natrijev metoksid, preferirano natrijev hidrid. Temperatura navedene reakcije je od oko 0 °C do oko 60 °C, preferirano od oko 20 °C do oko 25 °C (tj. sobna temperatura). Prikladna otapala uključuju aprotička otapala kao što su metilenklorid, tetrahidrofuran ili N,N-dimetilformamid, preferirano N,N-dimetilformamid. Reakcija se provodi od oko 1 do oko 48 sati, preferirano oko 16 sati. The compound of the formula XIII is prepared from the compound of the formula XIV by reaction with a thiol of the formula QSH in the presence of a base and an aprotic solvent. Suitable bases include sodium hydride, ethylmagnesium bromide, lithium diisopropylamide, potassium hydride or sodium methoxide, preferably sodium hydride. The temperature of said reaction is from about 0 °C to about 60 °C, preferably from about 20 °C to about 25 °C (ie, room temperature). Suitable solvents include aprotic solvents such as methylene chloride, tetrahydrofuran or N,N-dimethylformamide, preferably N,N-dimethylformamide. The reaction is carried out from about 1 to about 48 hours, preferably about 16 hours.

Spojevi formule XIV ili QSH su komercijalno dostupni ili se mogu pripraviti metodama koje su dobro poznate svakom koji vlada uobičajenim vještinama struke. Spojevi formule QSH mogu se također prirediti reakcijom alkil ili aril halogenida s natrijevim sulfhidridom kao što je opisano u Jerry March: "Advanced Organic Chemistry", 3. izdaje, str. 360 i 589, (1985.). Alternativno, spojevi formule QSH mogu se također prirediti reakcijom arildiazonijeve soli s natrijevim hidrogensulfidom, kao što je opisano u March id. 601. Alternativno, spojevi formule QSH mogu se također prirediti reakcijom Grignardovog reagensa sa sumporom, kako je opisano u u March id. 550. Alternativno, spojevi formule QSH mogu se također prirediti redukcijom sulfonil klorida, sulfonske kiseline ili disulfida, kako je opisano u u March id. 1107 i 1110. Compounds of formula XIV or QSH are commercially available or can be prepared by methods well known to one of ordinary skill in the art. Compounds of formula QSH can also be prepared by reacting an alkyl or aryl halide with sodium sulfhydride as described in Jerry March: "Advanced Organic Chemistry", 3rd ed., p. 360 and 589, (1985). Alternatively, compounds of formula QSH can also be prepared by reacting the aryldiazonium salt with sodium hydrogen sulfide, as described in March id. 601. Alternatively, compounds of formula QSH can also be prepared by reacting a Grignard reagent with sulfur, as described in March id. 550. Alternatively, compounds of formula QSH may also be prepared by reduction of sulfonyl chloride, sulfonic acid, or disulfide, as described in March id. 1107 and 1110.

Shema 3 odnosi se na pripravu spojeva formule I, gdje je R1 različit od hidroksi, a R2 je vodik. Scheme 3 relates to the preparation of compounds of formula I, where R1 is different from hydroxy and R2 is hydrogen.

Prema shemi 3, spojevi formule I pripravljaju se iz spojeva formule XVII hidrogenolizom prema metodama analognim onima opisanim za konverziju spojeva formule VII u spojeve formule I u shemi 2. According to scheme 3, compounds of formula I are prepared from compounds of formula XVII by hydrogenolysis according to methods analogous to those described for the conversion of compounds of formula VII to compounds of formula I in scheme 2.

Spojevi formule XVII pripravljaju se iz spojeva formule XVI reakcijom s O-benzilhidroksiamin-hidrokloridom u prisustvu katalizatora i baze u inertnom otapalu prema metodama analognim konverziji spojeva formule IX u spojeve formule VIII, kako je gore opisano u shemi 2. Compounds of formula XVII are prepared from compounds of formula XVI by reaction with O-benzylhydroxyamine hydrochloride in the presence of a catalyst and a base in an inert solvent according to methods analogous to the conversion of compounds of formula IX into compounds of formula VIII, as described above in scheme 2.

Spojevi formule XVI pripravljaju se iz spojeva formule XV reakcijom s viškom natrijevog perjodata u prisustvu katalizatora prema metodama analognim onima koje se upotrebljavaju za konverziju spojeva formule X u spojeve formule IX, kako je gore opisano u shemi 2. Compounds of formula XVI are prepared from compounds of formula XV by reaction with an excess of sodium periodate in the presence of a catalyst according to methods analogous to those used for the conversion of compounds of formula X into compounds of formula IX, as described above in scheme 2.

Spojevi formule XV, gdje je R1 (C6-C10)aril(C1-C6)alkoksi ili (C1-C6)alkoksi, mogu se pripraviti iz spojeva formule XI reakcijom sa spojem formule R1aL, gdje je L grupa koja odlazi, a R1a je (C6-C10)aril(C1-C6)alkil ili (C1-C6)alkil, u prisustvu jake baze u aprotičkom polarnom otapalu. Prikladne grupe koje odlaze uključuju kloro, fluoro, bromo, mesilat triflat ili tosilat. Grupa koja odlazi preferirano je jodo. Prikladne baze uključuju litijeve dialkilamide kao što su litijev N-izopropil-N-cikloheksilamid ili litijev diizopropilamid, kalijev t-butoksid, natrijev amid, kalijev hidrid ili natrijev hidrid, preferirano natrijev hidrid. Prikladna otapala uključuju etere (kao THF, dietileter ili 1,2-dimetoksietan), preferirano THF. Navedena se reakcija provodi kod temperature od oko -78 °C do oko 0 °C, preferirano oko 0 °C. Compounds of formula XV, where R 1 is (C 6 -C 10 )aryl(C 1 -C 6 )alkyloxy or (C 1 -C 6 )alkoxy, can be prepared from compounds of formula XI by reaction with a compound of formula R 1aL , where L is a leaving group and R 1a is (C6-C10)aryl(C1-C6)alkyl or (C1-C6)alkyl, in the presence of a strong base in an aprotic polar solvent. Suitable leaving groups include chloro, fluoro, bromo, mesylate triflate or tosylate. The group that leaves is preferred iodo. Suitable bases include lithium dialkylamides such as lithium N-isopropyl-N-cyclohexylamide or lithium diisopropylamide, potassium t-butoxide, sodium amide, potassium hydride or sodium hydride, preferably sodium hydride. Suitable solvents include ethers (such as THF, diethyl ether or 1,2-dimethoxyethane), preferably THF. Said reaction is carried out at a temperature of about -78 °C to about 0 °C, preferably about 0 °C.

Spojevi formule XV, gdje je R1 (C1-C6)alkil(C=O)O-, (C1-C6)alkoksi(C=O)O-, (C6-C10)aril(C=O)O-, (C6-C10) ariloksi(C=O)O-, (C6-C10)aril(C1-C6)alkil(C=O)O- ili (C6-C10)aril(C1-C6)alkoksi(C=O)O-, mogu se pripraviti iz spojeva formule XI reakcijom sa spojem formule R1bL, gdje je L grupa koja odlazi a R1b je (C1-C6)alkil(C=O)-, (C1-C6)alkoksi(C=O)-, (C6-C10)aril(C=O)-, (C6-C10)ariloksi(C=O)O-, (C6-C10)aril(C1-C6)alkil(C=O)- ili (C6-C10) aril(C1-C6)alkoksi(C=O)-, u prisustvu baze u inertnom otapalu. Prikladne grupe koje odlaze uključuju kloro, fluoro, bromo ili (R1b)O- (tj. anhidrid) Preferirano, grupa koja odlazi je kloro. Prikladne baze uključuju tercijarne amine, kao što su trietilamin, piridin ili 4-dimetilaminopiridin, preferirano trietilamin. Temperatura navedene reakcije je od oko 0 °C do oko 30 °C, preferirano od oko 20 °C do oko 25 °C (tj. sobna temperatura). Prikladna otapala uključuju halogena otapala kao što su metilenklorid i kloroform, preferirano metilenklorid. Reakcija se provodi od oko 1 do oko 24 sata, preferirano oko 2 sata. Compounds of formula XV, where R 1 is (C 1 -C 6 )alkyl(C=O)O-, (C 1 -C 6 )alkoxy(C=O)O-, (C 6 -C 10 )aryl(C=O)O-, ( C6-C10) aryloxy(C=O)O-, (C6-C10)aryl(C1-C6)alkyl(C=O)O- or (C6-C10)aryl(C1-C6)alkoxy(C=O) O-, can be prepared from compounds of the formula XI by reaction with a compound of the formula R1bL, where L is a leaving group and R1b is (C1-C6)alkyl(C=O)-, (C1-C6)alkoxy(C=O)- , (C6-C10)aryl(C=O)-, (C6-C10)aryloxy(C=O)O-, (C6-C10)aryl(C1-C6)alkyl(C=O)- or (C6- C10) aryl(C1-C6)alkoxy(C=O)-, in the presence of a base in an inert solvent. Suitable leaving groups include chloro, fluoro, bromo or (R1b)O- (ie, anhydride) Preferably, the leaving group is chloro. Suitable bases include tertiary amines, such as triethylamine, pyridine or 4-dimethylaminopyridine, preferably triethylamine. The temperature of said reaction is from about 0 °C to about 30 °C, preferably from about 20 °C to about 25 °C (ie, room temperature). Suitable solvents include halogenated solvents such as methylene chloride and chloroform, preferably methylene chloride. The reaction is carried out for about 1 to about 24 hours, preferably about 2 hours.

Spojevi formule XI mogu se prirediti metodama iz sheme 2. Compounds of formula XI can be prepared by the methods of scheme 2.

Shema 4 odnosi se na pripravu spojeva formule I, gdje su R2 R3 i R4 različiti od vodika. Scheme 4 relates to the preparation of compounds of formula I, where R2, R3 and R4 are other than hydrogen.

Prema shemi 4, spojevi formule I pripravljaju se iz spojeva formule XXIII hidrogenolizom u atmosferi vodika u prisustvu katalizatora u inertnom otapalu. Prikladni katalizatori uključuju 5 % paladija na barijevom sulfatu ili 5 % paladija na ugljiku, preferirano 5 % paladija na barijevom sulfatu. Prikladna otapala uključuju alkohole kao što su etanol, metanol ili izopropanol, preferirano metanol. Navedena reakcija može se provesti pod tlakom od 1 do oko 5 bara, preferirano oko 3 bara. Pogodne temperature za navedenu reakciju kreću se od oko 20 °C (sobna temperatura). do oko 60 °C, preferirano temperatura se može kretati od oko 20 °C do oko 25 °C (tj. sobna temperatura). Reakcija je dovršena za oko 30 minuta do 5 sati, preferirano za 3 oko sata. According to scheme 4, compounds of formula I are prepared from compounds of formula XXIII by hydrogenolysis in a hydrogen atmosphere in the presence of a catalyst in an inert solvent. Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include alcohols such as ethanol, methanol or isopropanol, preferably methanol. Said reaction can be carried out under a pressure of 1 to about 5 bar, preferably about 3 bar. Suitable temperatures for this reaction range from about 20 °C (room temperature). to about 60 °C, preferably the temperature can range from about 20 °C to about 25 °C (ie, room temperature). The reaction is complete in about 30 minutes to 5 hours, preferably in about 3 hours.

Spoj formule XXIII pripravlja se iz spoja formule XXII reakcijom s O-benzilhidroksilamin hidrokloridom u prisustvu katalizatora i baze u inertnom otapalu. Prikladni katalizatori uključuju (benzotriazol-1-iloksi) tris(dimetilamino) fosfonium heksafluorofosfat ili 1-(3-(dimetilaminopropil)-3-etilkarbodiimid hidroklorid, preferirano (benzotriazol-1-iloksi)tris(dimetilamino)fosfonium heksaklorofosfat. Prikladne baza uključuju tercijarne amine kao što su trietilamin, diizopropiletilamin ili dimetilaminopiridin, preferirano trietilamin. Temperatura navedene reakcije je od oko 0 °C do oko 60 °C, preferirano od oko 20 °C do oko 25 °C (tj. sobna temperatura). Prikladna otapala uključuju halogena otapala kao što su metilenklorid i kloroform, preferirano metilenklorid. Reakcija se provodi od oko 4 do oko 48 sati, preferirano oko 16 sati. The compound of formula XXIII is prepared from the compound of formula XXII by reaction with O-benzylhydroxylamine hydrochloride in the presence of a catalyst and a base in an inert solvent. Suitable catalysts include (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate or 1-(3-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, preferably (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexachlorophosphate. Suitable bases include tertiary amines such as triethylamine, diisopropylethylamine or dimethylaminopyridine, preferably triethylamine. The temperature of said reaction is from about 0°C to about 60°C, preferably from about 20°C to about 25°C (ie, room temperature). Suitable solvents include halogen solvents such as methylene chloride and chloroform, preferably methylene chloride The reaction is carried out from about 4 to about 48 hours, preferably about 16 hours.

Spoj formule XXII može se prirediti uklanjanjem zaštite sa spoja formule XXI reakcijom s hidroksidom alkalnog metala u polarnom otapalu. Prikladni hidroksidi alkalnih metala uključuju litijev hidroksid, natrijev hidroksid ili kalijev hidroksid, preferirano litijev hidroksid, najbolje oko 5 molova (ekvivalenata) hidroksida alkalnog metala. Navedena reakcija može se provesti pri temperaturi od oko 0 °C do oko 60 °C, preferirano od oko 20 °C do oko 25 °C (tj. pri sobnoj temperaturi). Prikladna otapala uključuju smjesu vode i alkohola kao što su metanol ili etanol i po potrebi etera topljivog u vodi, kao sto su tetrahidrofuran ili 1,2-dimetoksietan. Preferirani sustav otapala je metanol/ voda/tetrahidrofuran. Reakcija se provodi od oko 1 do oko 72 sata, preferirano oko 24 sata. A compound of formula XXII can be prepared by deprotection of a compound of formula XXI by reaction with an alkali metal hydroxide in a polar solvent. Suitable alkali metal hydroxides include lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide, preferably about 5 moles (equivalents) of the alkali metal hydroxide. Said reaction can be carried out at a temperature of from about 0 °C to about 60 °C, preferably from about 20 °C to about 25 °C (ie at room temperature). Suitable solvents include a mixture of water and an alcohol such as methanol or ethanol and optionally a water-soluble ether such as tetrahydrofuran or 1,2-dimethoxyethane. The preferred solvent system is methanol/water/tetrahydrofuran. The reaction is carried out for about 1 to about 72 hours, preferably about 24 hours.

Spojevi formule XXI mogu se pripraviti iz spojeva formule XII reakcijom sa spojevima formule Compounds of formula XXI can be prepared from compounds of formula XII by reaction with compounds of formula

[image] [image]

gdje je P' metil, etil ili benzil, i jake baze u polarnom aprotičkom otapalu. Prikladne baze uključuju natrijev hidrid (NaH), kalij-terc.-butoksid, litijev diizporopilamid, i butil-litij, po mogućnosti 2,5 M n-butil-litija u heksanu. Temperatura navedene reakcije je od oko -78 °C do oko 0 °C, preferirano oko -78 °C. Prikladna otapala uklučuju dietileter, tetrahidrofuran, ili 1,2.dimetoksietan, preferirano otapalo je tetrahidrofuran. Reakcija se provodi od oko 15 minuta do oko 6 sati, po mogućnosti oko 20 minuta. where P' is methyl, ethyl or benzyl, and strong bases in a polar aprotic solvent. Suitable bases include sodium hydride (NaH), potassium tert.-butoxide, lithium diisotropylamide, and butyllithium, preferably 2.5 M n-butyllithium in hexane. The temperature of said reaction is from about -78 °C to about 0 °C, preferably about -78 °C. Suitable solvents include diethyl ether, tetrahydrofuran, or 1,2-dimethoxyethane, the preferred solvent being tetrahydrofuran. The reaction is carried out from about 15 minutes to about 6 hours, preferably about 20 minutes.

izboru, spojevi formule I, gdje R1 nije hidroksi, R2 nije vodik i R3 i R4 nisu vodik, mogu biti pripremljeni od spojeva formule XXV metodama analognim konverziji spojeva formule XXII ka spojevima formule I, kao je gore prikazano u shemi 4. optionally, compounds of formula I, where R1 is not hydroxy, R2 is not hydrogen and R3 and R4 are not hydrogen, may be prepared from compounds of formula XXV by methods analogous to the conversion of compounds of formula XXII to compounds of formula I, as shown above in scheme 4.

Spojevi formule XXV mogu biti pripravljeni od spojeva formule XXIV, gdje je P' benzil, hidrogenolizom pod atmosferom vodika u prisutnosti katalizatora u inertnom otapalu. Prikladni katalizatori uključuju paladij ili 5-10 % paladij na aktivnom ugljenu, po mogućnosti 10 % paladija na aktivnom ugljenu. Prikladna otapala su octena kiselina, alkoholi kao što su etanol, metanol ili izopropanol, preferirano etanol. Navedena reakcija može biti provedena pri tlaku od oko 1 do oko 5 bara, po mogućnosti oko 3 bara. Prikladne temperature za navedenu reakciju su od oko 20 °C do oko 60 °C, po mogućnosti između 20 °C i 25 °C (tj. sobna temperatura). Reakcija je gotova unutar oko 30 minuta do oko 24 sata, preferirano oko 3 sata. Compounds of formula XXV can be prepared from compounds of formula XXIV, where P' is benzyl, by hydrogenolysis under a hydrogen atmosphere in the presence of a catalyst in an inert solvent. Suitable catalysts include palladium or 5-10% palladium on activated carbon, preferably 10% palladium on activated carbon. Suitable solvents are acetic acid, alcohols such as ethanol, methanol or isopropanol, preferably ethanol. Said reaction can be carried out at a pressure of about 1 to about 5 bar, preferably about 3 bar. Suitable temperatures for said reaction are from about 20°C to about 60°C, preferably between 20°C and 25°C (ie room temperature). The reaction is complete within about 30 minutes to about 24 hours, preferably about 3 hours.

Spojevi formule XXIV, gdje je R1 (C6-C10)aril(C1-C6)alkoksi, (C1-C6)alkoksi, mogu biti pripravljeni od spojeva formule XXI reakcijom sa arilalkil- ili alkil-halogenidom u prisutnistibaze u aprotičkom otapalu. Prikladne baze uključuju natrijev hidrid, etilmagnezijev bromid, litijdiizpropilamid, kalijev hidrid, ili natrijev metoksid, po mogućnosti natrijev hidrid. Temperatura navedene reakcije je od oko 0 °C do oko 60 °C, po mogućnosti 20 °C do oko 25 °C (tj. sobna temperatura). Prikladna otapala uključuju aprotička otapala kao što su metilenklorid, tetrahidrofuran ili N,N-dimetilformamid, preferirano N,N-dimetilformamid. Reakcija se provodi oko 1 sat do oko 48 sati, po mogućnosti oko 16 sati. Compounds of formula XXIV, where R 1 is (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy, can be prepared from compounds of formula XXI by reaction with an arylalkyl- or alkyl-halide in the presence of a base in an aprotic solvent. Suitable bases include sodium hydride, ethylmagnesium bromide, lithium diisopropylamide, potassium hydride, or sodium methoxide, preferably sodium hydride. The temperature of said reaction is from about 0 °C to about 60 °C, preferably 20 °C to about 25 °C (ie room temperature). Suitable solvents include aprotic solvents such as methylene chloride, tetrahydrofuran or N,N-dimethylformamide, preferably N,N-dimethylformamide. The reaction is carried out for about 1 hour to about 48 hours, preferably about 16 hours.

Po želji, spojevi formule XXIV, gdje je R1 (C1-C6)alkil(C=O)O-, (C1-C6)alkoksi(C=O)O-, (C6-C10)aril(C=O)O-, (C6-C10)ariloksi(C=O)O-, (C6-C10)aril(C1-C6)alkil(C=O)O- ili (C6-C10)aril(C1-C6)alkoksi(C=O)O-, mogu biti pripravljeni od spojeva formule XXI reakcijom sa arilacil ili acil halidom u prisutnosti baze u aprotičnom otapalu. Prikladne baze su tercijarni amini kao trietilamin, diizopropiletilamin ili 4-N,N-dimetilaminopiridin, preferirano trietilamin. Temperatura navedene reakcije može se kretati od oko 0 °C do oko 60 °C, preferirano oko 20° (sobna temperatura). Prikladna otapala uključuju halogena otapala kao što su metilenklorid ili kloroform, ili etere kao što su THF ili dietileter, preferirano otapalo je metilenklorid. Reakcija se provodi od oko 4 do oko 48 sati, preferirano oko 16 sati. Optionally, compounds of formula XXIV, wherein R 1 is (C 1 -C 6 )alkyl(C=O)O-, (C 1 -C 6 )alkoxy(C=O)O-, (C 6 -C 10 )aryl(C=O)O -, (C6-C10)aryloxy(C=O)O-, (C6-C10)aryl(C1-C6)alkyl(C=O)O- or (C6-C10)aryl(C1-C6)alkoxy(C =O)O-, can be prepared from compounds of formula XXI by reaction with an aryl acyl or acyl halide in the presence of a base in an aprotic solvent. Suitable bases are tertiary amines such as triethylamine, diisopropylethylamine or 4-N,N-dimethylaminopyridine, preferably triethylamine. The temperature of said reaction can range from about 0°C to about 60°C, preferably about 20° (room temperature). Suitable solvents include halogenated solvents such as methylene chloride or chloroform, or ethers such as THF or diethyl ether, the preferred solvent being methylene chloride. The reaction is carried out from about 4 to about 48 hours, preferably about 16 hours.

Spojevi formule I, koji su po prirodi bazični sposobni su za tvorbu mnogo različitih soli s različitim anorganskim ili organskim kiselinama. Iako ovakve soli moraju biti farmakološki prihvatljive, kako bi se primijenile na životinjama, često je poželjno izolirati spoj formule I iz reakcijske smjese u obliku farmakološki neprihvatljive soli, i onda ga jednostavno prevesti u slobodnu bazu djelovanjem alkalnog reagensa, te zatim prevesti slobodnu bazu u farmaceutski prihvatljivu sol dobivenu kiselom adicijom. Kisele adicijske soli baznog spoja koji je predmet ovog izuma mogu se jednostavno prirediti tretiranjem baznog spoja s ekvivalentnom količinom odabrane mineralne ili organske kiseline u vodi ili prikladnom organskom otapalu kao što je metanol ili etanol. Nakon pažljivog isparavanja otapala, dobiva se željena kruta sol. The compounds of formula I, which are basic in nature, are capable of forming many different salts with different inorganic or organic acids. Although such salts must be pharmacologically acceptable, in order to be used on animals, it is often desirable to isolate the compound of formula I from the reaction mixture in the form of a pharmacologically unacceptable salt, and then simply convert it into a free base by the action of an alkaline reagent, and then convert the free base into a pharmaceutical acceptable salt obtained by acid addition. Acid addition salts of the base compound of the present invention can be simply prepared by treating the base compound with an equivalent amount of a selected mineral or organic acid in water or a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is obtained.

Kiseline koje se upotrebljavaju za pripravu farmaceutski prihvatljivih kiselih soli baze koja je predmetom ovog izuma su one koje tvore netoksične kisele soli, tj. soli koje sadrže farmakološki prihvatljive anione, kao što su hidroklorid, hidrobromid, hidrojodid, nitrat, sulfat ili bisulfat, fosfat ili kiseli fosfat, acetat, laktat, citrat ili kiseli citrat, tartarat ili bitartarat, sukcinat, maleat, fumarat, glukonat, glukarat, benzoat, metansulfonat i pamoat [tj. 1,1'-metilen-bis-(2-hidroksi-3-naftoat)]. The acids that are used for the preparation of pharmaceutically acceptable acid salts of the base that is the subject of this invention are those that form non-toxic acid salts, i.e. salts that contain pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, glucorate, benzoate, methanesulfonate and pamoate [i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)].

Spojevi formule I koji su po prirodi kiseli, mogu tvoriti bazne soli s različitim farmakološki prihvatljivim kationima. Primjeri ovakvih soli uključuju soli alkalnih i zemnoalkalnih metala a posebno soli natrija i kalija. Sve se ove soli pripravljaju uobičajenim tehnikama. Kemijske baze koje se upotrebljavaju kao reagensi za pripravu farmakološki prihvatljivih baznih soli spojeva iz ovog izuma su one koje tvore netoksične bazične soli ovdje opisanih kiselih spojeva formule I. Ove netoksične bazične soli uključuju one dobivene iz farmakološki prihvatljivih kationa kao što su natrij, kalij, kalcij, magnezij itd. Ove se soli mogu lako pripraviti tretiranjem odgovarajućih kiselih spojeva vodenom otopinom koja sadrži željene farmakološki prihvatljive katione, a zatim isparavanjem dobivene otopine do suha, preferirano pod sniženim tlakom. Alternativno, ove se soli mogu prirediti miješanjem otopine kiselog spoja u nižim alkanima s alkoksidom željenog alkalnog metala, te zatim isparavanjem dobivene otopine na način opisan ranije. U oba slučaja treba upotrijebiti stehiometrijske odnose reaktanata, kako bi se osiguralo dovršenje reakcije i maksimalni prinos. Compounds of formula I, which are acidic in nature, can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali and alkaline earth metal salts, and especially sodium and potassium salts. All these salts are prepared using the usual techniques. The chemical bases used as reagents for the preparation of pharmacologically acceptable base salts of the compounds of this invention are those that form non-toxic base salts of the acid compounds of formula I described herein. These non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium , magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, these salts can be prepared by mixing a solution of the acidic compound in lower alkanes with an alkoxide of the desired alkali metal, and then evaporating the resulting solution in the manner described earlier. In both cases, stoichiometric ratios of reactants should be used to ensure completion of the reaction and maximum yield.

Sposobnost spojeva formule I ili njihovih farmakološki prihvatljivih soli (koje ćemo od sada također smatrati predmetom ovog izuma) da inhibiraju matriks metaloproteinaze ili stvaranje faktora nekroze tumora (TNF) i da prema tome efikasno djeluju na bolesti karakterizirane matriks proteinazom ili stvaranjem faktora nekroze tumora, pokazana je slijedećim in vitro pokusima. The ability of the compounds of formula I or their pharmacologically acceptable salts (which we will henceforth also consider to be the subject of this invention) to inhibit matrix metalloproteinases or the formation of tumor necrosis factor (TNF) and to therefore effectively act on diseases characterized by matrix proteinase or the formation of tumor necrosis factor, demonstrated is the following in vitro experiments.

BIOLOŠKO ODREĐIVANJE BIOLOGICAL DETERMINATION

Inhibicija humane kolagenaze (MMP-1) Inhibition of human collagenase (MMP-1)

Humana rekombinantna kolagenaza se aktivira tripsinom u slijedećem omjeru: 10 mg tripsina na 100 mg kolagenaze. Tripsin i kolagenaza se inkubiraju pri sobnoj temperaturi 10 minuta, a zatim se doda peterostruki suvišak (50 mg na 10 mg tripsina) soja tripsin inhibitora. Human recombinant collagenase is activated by trypsin in the following ratio: 10 mg of trypsin per 100 mg of collagenase. Trypsin and collagenase are incubated at room temperature for 10 minutes, and then a fivefold excess (50 mg per 10 mg of trypsin) of trypsin inhibitor strain is added.

10 mM otopine inhibitora dopuni se dimetilsulfoksidom i zatim razrijedi prema slijedećoj shemi: 10 mM inhibitor solution is supplemented with dimethylsulfoxide and then diluted according to the following scheme:

10 mM -> 120 µM -> 12 µM -> 1,2 µM -> 0,12 µM 10 mM -> 120 µM -> 12 µM -> 1.2 µM -> 0.12 µM

Dvadeset pet mikrolitara svake koncentracije zatim se doda u triplikatu u odgovarajuća okna mikrofluorimetrijske ploće s 96 okana. Završna koncentracija inhibitora biti će razrijeđenje 1:4, nakon što se dodaju enzim i supstrat. Pozitivna kontrola (enzim, bez inhibitora) stave se u okna D1 - D6, a slijepe probe (bez enzima, bez inhibitora) u okna D7 - D12. Twenty-five microliters of each concentration is then added in triplicate to the appropriate wells of a 96-well microfluorimetric plate. The final inhibitor concentration will be a 1:4 dilution, after enzyme and substrate are added. Positive control (enzyme, no inhibitor) is placed in columns D1 - D6, and blank samples (no enzyme, no inhibitor) in columns D7 - D12.

Kolagenaza se razrijedi do 400 ng/ml i 25 ml se zatim doda u odgovarajuća okna mikrofluorimetrijske ploče. Završna koncentracija kolagenaze u ovom određivanju je 100 ng/ml. Collagenase is diluted to 400 ng/ml and 25 ml is then added to the appropriate wells of the microfluorimetric plate. The final collagenase concentration in this assay is 100 ng/ml.

Supstrat (DNP-Pro-Cha-Gly-Cys-(Me)-His-Ala-Lys(NMA)-NH2) pripravlja se kao standardna 5mM otopina u dimetilsulfoksidu i zatim razrjeđuje na 20 mM puferom. Određivanje započinje dodatkom 50 ml supstrata u svako okno ploće za mikrofluorimetriju, što daje završnu koncentraciju od 10 mM. The substrate (DNP-Pro-Cha-Gly-Cys-(Me)-His-Ala-Lys(NMA)-NH2) is prepared as a standard 5mM solution in dimethylsulfoxide and then diluted to 20mM with buffer. The determination is initiated by the addition of 50 ml of substrate to each well of the microfluorimetry plate, giving a final concentration of 10 mM.

Fluorescencija (360 nm ekscitacija, 460 nm emisija) se mjeri u vremenu 0 i zatim u intervalima od po 20 minuta. Određivanje se provodi na sobnoj temperaturi, a tipično vrijeme određivanja je 3 sata. Fluorescence (360 nm excitation, 460 nm emission) is measured at time 0 and then at 20 minute intervals. The determination is carried out at room temperature, and the typical determination time is 3 hours.

Zatim se ucrtava ovisnost fluorescencije o vremenu za slijepu probu i uzorke koji sadrže kolagenazu (uzimaju se prosječni podaci tri mjerenja). Za određivanje IC50 vrijednosti biraju se točke koje daju dobar signal (slijepa proba) i koje su na linearnom dijelu krivulje (obično oko 120 minuta). Nulto vrijeme upotrebljava se kao slijepa proba za svaki spoj u svakoj koncentraciji i te se vrijednosti odbijaju od podatka za 120 minuta. Podaci se nanose na grafikon kao koncentracija inhibitora prema % kontrole (fluorescencija inhibitora podijeljena s fluorescencijom same kolagenaze × 100). IC50 se određuju iz koncentracije inhibitora koja daje signal koji je 50 % kontrole. Then the dependence of fluorescence on time is plotted for blank and samples containing collagenase (average data of three measurements are taken). To determine the IC50 value, the points that give a good signal (blank test) and are on the linear part of the curve (usually around 120 minutes) are chosen. Zero time is used as a blank for each compound at each concentration and these values are subtracted from the 120 minute data. Data are plotted as inhibitor concentration vs. % of control (inhibitor fluorescence divided by collagenase fluorescence alone × 100). IC50s are determined from the inhibitor concentration that gives a signal that is 50% of the control.

Ako su IC50 > 0,03 mM, inhibitori se određuju u koncentracijama od 0,3 mM, 0,03 mM i 0,003 mM. If IC50 > 0.03 mM, inhibitors are determined at concentrations of 0.3 mM, 0.03 mM and 0.003 mM.

Inhibicija gelatinaze (MMP-2) Inhibition of gelatinase (MMP-2)

Inhibicija aktivnosti gelatinaze se određuje korištenjem DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2 supstrata (10mM) pod istim uvjetima kao i inhibicija humane kolagenaze (MMP-1). Inhibition of gelatinase activity is determined using DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2 substrate (10mM) under the same conditions as inhibition of human collagenase (MMP-1).

72kD gelatinaza aktivira se sa 1 mM APMA (p-aminofenilživin acetat) kroz 15 sati na 4 °C i razrijedi da bi se dobila završna koncentracija određivanja od 100 mg/ml. Inhibitori se razrjeđuju kao i kod određivanja humane kolagenaze (MMP-1) kako bi dali završne koncentracije pri određivanju od 30 mM, 3 mM, 0,3 mM i 0,03 mM. Svaka se koncentracija radi u triplikatu. The 72kD gelatinase was activated with 1 mM APMA (p-aminophenylmercuric acetate) for 15 hours at 4 °C and diluted to give a final assay concentration of 100 mg/ml. Inhibitors are diluted as in the human collagenase (MMP-1) assay to give final assay concentrations of 30 mM, 3 mM, 0.3 mM, and 0.03 mM. Each concentration is done in triplicate.

Fluorescencija (360 nm ekscitacija, 460 nm emisija) se mjeri u vremenu 0 zatim u intervalima od 20 minuta, tijekom 4 sata. Fluorescence (360 nm excitation, 460 nm emission) is measured at time 0 and then at 20 minute intervals for 4 hours.

IC50 se određuju kao kod određivanja inhibicije humane kolagenaze (MMP-1). Ako su IC50 > 0,03 mM, inhibitori se određuju u koncentracijama od 0,3 mM, 0,03 mM i 0,003 mM. IC50s are determined as in the human collagenase (MMP-1) inhibition assay. If IC50 > 0.03 mM, inhibitors are determined at concentrations of 0.3 mM, 0.03 mM and 0.003 mM.

Inhibicija aktivnosti stromelizina (MMP-2) Inhibition of stromelysin (MMP-2) activity

Inhibicija aktivnosti stromelizina bazira se na modificiranom spektrofotometrijskom određivanju koje su opisali Weingarten H. i Feder J.: "Spektrofotometrijsko određivanje kolagenaze vertebrata, Anal. Biochem.", 147, 437-440, (1985)). Hidroliza tiopeptidnog supstrata [Ac-Pro-Leu-Gly SCH(Ch2CH(CH3)2CO-Leu-Gly-OCH2H5] tvori merkaptanski fragment koji se može pratiti u prisustvu Ellmanovog reagensa. Inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingarten H. and Feder J.: "Spectrophotometric determination of vertebrate collagenase, Anal. Biochem.", 147, 437-440, (1985)). Hydrolysis of the thiopeptide substrate [Ac-Pro-Leu-Gly SCH(Ch2CH(CH3)2CO-Leu-Gly-OCH2H5] forms a mercaptan fragment that can be monitored in the presence of Ellman's reagent.

Humani rekombinantni prostromelizin aktivira se tripsinom u odnosu 1 ml 10 mg/ml tripsin standardne otopine na 26 mg stromelizina. Tripsin i stromelizin inkubiraju se na 37 °C tokom 15 minuta, a zatim još 10 minuta na 37 °C uz 10 ml 10 mg/ml soja tripsin inhibitora, kako bi se zaustavila aktivnost tripsina. Human recombinant prostromelysin is activated by trypsin in the ratio of 1 ml of 10 mg/ml trypsin standard solution to 26 mg of stromelysin. Trypsin and stromelysin are incubated at 37 °C for 15 minutes, and then for another 10 minutes at 37 °C with 10 ml of 10 mg/ml soy trypsin inhibitor, to stop trypsin activity.

Određivanje se provodi u ukupnom volumenu od 250 ml pufera (200 mM natrijevog klorida, 50 mM MES i 10 mM kalcijevog klorida, pH 6,0) na mikrolitarskoj ploći s 96 okana. Aktivirani stromelizin se razrijedi puferom na 25 mg/ml. Ellmanov reagens (3-karboksi-4-nitrofenil disulfid) priredi se kao 1M standardna otopina u dimetilformamidu i razrjeđuje se puferom na 5 mM kako bi s 50 ml po oknu dao završnu koncentraciju od 1 mM. The determination is carried out in a total volume of 250 ml of buffer (200 mM sodium chloride, 50 mM MES and 10 mM calcium chloride, pH 6.0) in a 96-well microliter plate. Activated stromelysin is diluted with buffer to 25 mg/ml. Ellman's reagent (3-carboxy-4-nitrophenyl disulfide) is prepared as a 1M standard solution in dimethylformamide and diluted to 5 mM with buffer to give a final concentration of 1 mM with 50 ml per well.

Priredi se 10 mM standardna otopine inhibitora u dimetilsulfoksidu i serijski razrijedi puferom na taj način da dodatak 50 ml u odgovarajuće okno daje završnu koncentraciju od 3 mM, 0,3 mM, 0,003 mM i 0,0003 mM. Svaka se koncentracija radi u triplikatu. A 10 mM standard inhibitor solution in dimethylsulfoxide is prepared and serially diluted with buffer in such a way that the addition of 50 ml to the corresponding well gives a final concentration of 3 mM, 0.3 mM, 0.003 mM and 0.0003 mM. Each concentration is done in triplicate.

300 mM standardna otopina peptidnog supstrata u dimetilsulfoksidu se razrijedi puferom na 15 mM i određivanje započne dodatkom 50 ml u svako okno, kako bi se dobila završna koncentracija supstrata od 3 mM. Slijepe se probe sastoje od peptidnog supstrata i Ellmanovog reagensa bez enzima. Stvaranje produkta prati se na 405 nm pomoću Molecular Devices UVmax čitača ploča. A 300 mM standard solution of peptide substrate in dimethylsulfoxide is diluted to 15 mM with buffer and the assay is started by adding 50 ml to each well, to give a final substrate concentration of 3 mM. Blanks consist of peptide substrate and Ellman's reagent without enzyme. Product formation was monitored at 405 nm using a Molecular Devices UVmax plate reader.

IC50 vrijednosti određuju se na isti način kao za kolagenazu. IC50 values are determined in the same way as for collagenase.

Inhibicija MMP-13 Inhibition of MMP-13

Humani rekombinantni MMP-13 aktivira se s 2 mM APMA (p-aminofenil živin acetat) tokom 90 minuta na 37 °C a zatim se razrijedi na 400 mg/ml puferom (50 mM Tris, pH 7,5, 200 mM natrijevog klorida, 5 mM kalcijevog klorida, 20 mM cinkovog klorida, 0,02 % brij). Dvadeset pet mikrolitara razrijeđenog enzima dodaje se u okna mikrofluorimetrijske ploče s 96 okana. Enzim se tada razrijedi u omjeru 1:4 dodatkom inhibitora i supstrata, kako bi se dobila završna koncentracija određivanja od 100 mg/ml. Human recombinant MMP-13 was activated with 2 mM APMA (p-aminophenyl mercuric acetate) for 90 min at 37 °C and then diluted to 400 mg/ml with buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mM calcium chloride, 20 mM zinc chloride, 0.02 % brij). Twenty-five microliters of diluted enzyme is added to the wells of a 96-well microfluorimetric plate. The enzyme is then diluted 1:4 with the addition of inhibitor and substrate to give a final assay concentration of 100 mg/ml.

Priprave se standardne 10 mM otopine inhibitora u dimetil sulfoksidu i zatim razrijede puferom prema shemi razrijeđenja za inhibiciju humane kolagenaze (MMP-1): na ploču se dodaje 25 µl svake koncentracije u triplikatu. Završne koncentracije određivanja su 30 mM, 3 mM, 0,3 mM i 0,03 mM. Standard 10 mM inhibitor solutions in dimethyl sulfoxide are prepared and then diluted with buffer according to the dilution scheme for inhibition of human collagenase (MMP-1): 25 µl of each concentration is added to the plate in triplicate. The final determination concentrations are 30 mM, 3 mM, 0.3 mM and 0.03 mM.

Supstrat (DNP-Pro-Cha-Gly-Cys(Me)-His--Lys(NMA)-NH2) se pripravi kao za inhibiciju humane kolagenaze (MMP-1) i u svako okno se doda 50 ml da bi se dobila završna koncentracija od 10 mM. Fluorescencija (360 nm ekscitacija, 460 nm emisija) se mjeri u vremenu 0 i zatim u intervalima od 5 minuta kroz 1 sat. Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His--Lys(NMA)-NH2) was prepared as for inhibition of human collagenase (MMP-1) and 50 ml was added to each well to obtain the final concentration of 10 mM. Fluorescence (360 nm excitation, 460 nm emission) is measured at time 0 and then at 5 minute intervals for 1 hour.

Pozitivnu kontrolu čine enzim i supstrat bez inhibitora, a slijepu probu sam supstrat. The positive control consists of the enzyme and the substrate without inhibitors, and the blank is the substrate itself.

IC50 se određuju kao kod određivanja inhibicije humane kolagenaze (MMP-1). Ako su IC50 > 0,03 mM, inhibitori se određuju u koncentracijama od 0,3 mM, 0,03 mM 0,003 mM i 0,0003 mM. IC50s are determined as in the human collagenase (MMP-1) inhibition assay. If IC50 > 0.03 mM, inhibitors are determined at concentrations of 0.3 mM, 0.03 mM, 0.003 mM, and 0.0003 mM.

Svi spojevi opisani izumom koji su bili ispitani na inhibiciju MMP-13 imali su IC50 manje od 50 nm. All compounds described by the invention that were tested for MMP-13 inhibition had an IC50 of less than 50 nm.

Inhibicija produkcije TNF Inhibition of TNF production

Sposobnost spojeva ili njihovih farmaceutski prihvatljivih soli da inhibiraju stvaranje TNF i prema tome efikasno djeluju na bolesti koje uključuju stvaranje faktora nekroze tumora, pokazana je slijedećim in vitro određivanjima: The ability of the compounds or their pharmaceutically acceptable salts to inhibit the formation of TNF and therefore effectively act on diseases involving the formation of tumor necrosis factor was demonstrated by the following in vitro determinations:

Ljudske mononuklearne stanice izdvojene su iz anti-koagulirane ljudske krvi upotrebom jednostupnjevne Ficoll-hypaque tehnike odvajanja. (2) Mononuklearne stanice bile su isprane tri puta u Hanksovoj balansiranoj otopini soli (HBSS) s dvovalentnim kationima i resuspendirane na gustoću od 2 × 106 /ml u HBSS koja sadrži 1 % BSA. Diferencijalna brojanja određena korištenjem Abbot Cell Dyn 3500 analizatora pokazala su da monociti broje od 17 do 24 % totalnih stanica u ovim preparatima. Human mononuclear cells were isolated from anti-coagulated human blood using a one-step Ficoll-hypaque separation technique. (2) Mononuclear cells were washed three times in Hanks' balanced salt solution (HBSS) with divalent cations and resuspended at a density of 2 × 10 6 /ml in HBSS containing 1% BSA. Differential counts determined using the Abbot Cell Dyn 3500 analyzer showed that monocytes numbered from 17 to 24% of the total cells in these preparations.

180 m stanične suspenzije podijeljeno je na ploče s 96 okana ravnog dna (Costar). Dodaci spojeva i LPS (100ng/ml završna koncentracija) dali su završni volumen od 200 ml. Sva stanja bila su izvedena u triplikatu. Nakon 4 sata inkubacije pri 37 °C u vlažnom CO2 inkubatoru, ploče su uklonjene i centrifugirane (10 minuta pri približno 250 × g) a supernatantna tekućina je izdvojena i ispitana na TNF? korištenjem R&D ELISA Kit ®. 180 m of cell suspension was divided into 96 flat bottom well plates (Costar). Additions of compounds and LPS (100 ng/ml final concentration) gave a final volume of 200 ml. All conditions were performed in triplicate. After 4 hours of incubation at 37 °C in a humidified CO2 incubator, the plates were removed and centrifuged (10 minutes at approximately 250 × g) and the supernatant liquid was separated and assayed for TNF? using the R&D ELISA Kit ® .

Za davanje sisavcima, uključujući ljude, za inhibiciju matričnih metaloproteinaza ili inhibiciju proizvodnje faktora nekroze tumora (TNF), mogu se upotrijebiti različiti uobičajeni putovi, uključujući oralnu, parenteralnu (tj. intravensku, intramuskularnu ili subkutanu), bukalnu, analnu ili topičku primjenu. Općenito, aktivna se supstanca daje u dozama od oko 0,1 do 25 mg/kg tjelesne težine tretiranog subjekta na dan, preferirano od oko 0,3 do 5 mg/kg. Aktivna se komponenta preferirano daje oralno ili parenteralno. Međutim, nužno dolazi do varijacija doze ovisno o stanju tretiranog subjekta. Osoba odgovorna za davanje će u svakom pojedinačnom slučaju odrediti odgovarajuću dozu za svaki individualni subjekt. For administration to mammals, including humans, for inhibition of matrix metalloproteinases or inhibition of tumor necrosis factor (TNF) production, a variety of common routes may be used, including oral, parenteral (ie, intravenous, intramuscular, or subcutaneous), buccal, anal, or topical administration. In general, the active substance is administered in doses of about 0.1 to 25 mg/kg body weight of the treated subject per day, preferably about 0.3 to 5 mg/kg. The active component is preferably administered orally or parenterally. However, there are necessarily dose variations depending on the condition of the treated subject. The person responsible for administration will determine the appropriate dose for each individual subject in each individual case.

Spojevi opisani ovim izumom mogu se administrirati u širokom dijapazonu farmaceutskih oblika, a općenito terapeutski efikasni spojevi opisani u izumu prisutni su u takvim oblicima u koncentracijama od oko 5,0 % do oko 70 % težinski. The compounds described in this invention can be administered in a wide range of pharmaceutical forms, and generally the therapeutically effective compounds described in the invention are present in such forms in concentrations from about 5.0% to about 70% by weight.

Za oralnu primjenu mogu se upotrijebiti tablete koje sadrže različite ekscipijente, kao što su mikrokristalinična celuloza, natrijev citrat, kalcijev karbonat, dikalcijev fosfat i glicin, zajedno s različitim dezintegrirajućim agensima, kao što su škrob (preferirano kukuruzni, krumpirov ili tapiokin), alginska kiselina i određeni kompleksni silikati, te vezivima kao što su polivinilpirolidon, saharoza, želatina i akacia. Uz to, za tabletiranje mogu često biti vrlo korisna klizna sredstva, kao što su magnezijev stearat, natrijev laurilsulfat i talk. Krute smjese sličnog tipa mogu se primijeniti i kao punila u želatinskim kapsulama; preferirani materijali za ovu primjenu obuhvaćaju laktozu ili mliječni šećer kao i polietilen glikole visokih molekularnih težina. Ako se za oralnu primjenu traže vodene suspenzije ili otopine, aktivna supstanca se može kombinirati s različitim sladilima ili aromama, bojama, i ako se želi emulgatorima ili suspendirajućim agensima, uz otapala kao što su voda, etanol, propilen glikol, glicerol i njihove različite kombinacije. U slučaju životinja, najbolje je da su sadržane u stočnoj hrani ili vodi za piće u koncentraciji od 5-5000 ppm, preferirano 25 do 500 ppm. Za parenteralnu primjenu (intramuskularnu, intraperitonealnu, subkutanu i intravensku) obično se pripravlja sterilna otopina aktivne komponente za injekcije. Mogu se primijeniti otopine supstanci opisanih izumom u sezamovom ili kikirikijevom ulju ili u vodenoj otopini propilen glikola. Vodene otopine trebaju biti prikladno podešene i ako je potrebno puferirane, preferirano na pH veći od 8, a otapalo treba prethodno učiniti izotoničnim. Ovakve vodene otopine pogodne su za intravenoznu primjenu. Uljne otopine pogodne su za intraartikularnu, intramuskularnu i supkutanu primjenu. Priprema svih ovih otopina pod sterilnim uvjetima postiže se standardnim farmaceutskim tehnikama dobro poznatima svima koji se bave ovim područjem. U slučaju životinja, spojevi se mogu primjenjivati intramuskularno ili subkutano u dozama od oko 0,1 do 50 mg/kg/dan, a najbolje 0,2 do 10 mg/kg/dan, u jednoj ili podijeljeno u tri doze. For oral administration, tablets can be used containing various excipients, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, together with various disintegrating agents, such as starch (preferably corn, potato or tapioca), alginic acid and certain complex silicates, and binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, glidants such as magnesium stearate, sodium lauryl sulfate, and talc can often be very useful for tableting. Solid mixtures of a similar type can also be used as fillers in gelatin capsules; preferred materials for this application include lactose or milk sugar as well as high molecular weight polyethylene glycols. If aqueous suspensions or solutions are required for oral administration, the active substance can be combined with various sweeteners or flavors, colors, and if desired with emulsifiers or suspending agents, with solvents such as water, ethanol, propylene glycol, glycerol and various combinations thereof. . In the case of animals, they are best contained in feed or drinking water at a concentration of 5-5000 ppm, preferably 25 to 500 ppm. For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous), a sterile solution of the active component for injections is usually prepared. Solutions of the substances described by the invention in sesame or peanut oil or in an aqueous solution of propylene glycol can be used. Aqueous solutions should be suitably adjusted and if necessary buffered, preferably to a pH higher than 8, and the solvent should be made isotonic beforehand. Such aqueous solutions are suitable for intravenous administration. Oil solutions are suitable for intra-articular, intramuscular and subcutaneous use. The preparation of all these solutions under sterile conditions is accomplished by standard pharmaceutical techniques well known to those skilled in the art. In the case of animals, the compounds may be administered intramuscularly or subcutaneously at doses of about 0.1 to 50 mg/kg/day, preferably 0.2 to 10 mg/kg/day, in one or three divided doses.

Aktivne supstance opisane izumom mogu se formulirati u rektalne oblike, kao što su supozitoriji ili retention enamas, tj. tako da sadrže konvencionalnu bazu za supozitorije kao što su kokosov maslac ili gliceridi. The active substances described by the invention can be formulated into rectal forms, such as suppositories or retention enemas, i.e. by containing a conventional base for suppositories such as coconut butter or glycerides.

Za intranazalnu primjenu ili primjenu inhalacijom, aktivna se supstanca opisana izumom uobičajeno daje u formi otopine ili suspenzije iz posude za prskanje s pumpicom koju pacijent napumpa ili stisne, ili kao aerosolni sprej iz spremnika ili nebulizatora pod tlakom uz upotrebu pogodnog potisnog sredstva, tj. diklorodifluorometana, triklorofluorometana, diklorotetrafluoroetana, ugljikovog dioksida ili drugog prikladnog plina. U slučaju aerosola pod tlakom, jedinična doza može se osigurati primjenom mjernog ventila. Spremnik pod tlakom ili nebulizator mogu sadržati otopinu ili suspenziju aktivne supstance. Kapsule i spremnici (izrađeni na primjer iz želatine) za upotrebu u inhalatorima ili insuflatorima mogu se formulirati tako da sadrže praškastu mješavinu spoja opisanog izumom i praškaste baze kao što je laktoza ili škrob. For intranasal administration or administration by inhalation, the active substance described by the invention is usually given in the form of a solution or suspension from a spray container with a pump that the patient pumps or squeezes, or as an aerosol spray from a container or nebulizer under pressure with the use of a suitable propellant, i.e. dichlorodifluoromethane , trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosols, a unit dose can be provided by using a metering valve. A pressurized container or nebulizer can contain a solution or suspension of the active substance. Capsules and containers (made for example from gelatin) for use in inhalers or insufflators can be formulated to contain a powder mixture of a compound of the invention and a powder base such as lactose or starch.

Slijedeći primjeri ilustriraju pripravu spojeva opisanih ovim izumom. Talipta nisu korigirana. NMR podaci su navedeni u dijelovima na milijun (d) i odnose se na deuterijev signal iz otopine uzorka (deuterirani kloroform ako nije drugačije navedeno). Komercijalni reagensi upotrijebljeni su bez daljnjeg pročišćavanja. THF se odnosi na tetrahidrofuran. DMF se odnosi na N,N-dimetilformamid. Kromatografija se odnosi na kolonsku kromatografiju uz upotrebu 32-63 mm silikagela i provedenom pod tlakom dušika (flash kromatografija). Sobna temperatura ili temperatura ambijenta odnosi se na 20-25 °C. Nevodene reakcije vođene su pod atmosferom dušika zbog jednostavnosti i povećanog prinosa. Isparavanje pod smanjenim tlakom znači da je upotrijebljen rotacioni isparivač. The following examples illustrate the preparation of the compounds described in this invention. Talipta are not corrected. NMR data are reported in parts per million (d) and refer to the deuterium signal from the sample solution (deuterated chloroform unless otherwise stated). Commercial reagents were used without further purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. Chromatography refers to column chromatography using 32-63 mm silica gel and carried out under nitrogen pressure (flash chromatography). Room temperature or ambient temperature refers to 20-25 °C. Non-aqueous reactions were carried out under a nitrogen atmosphere for simplicity and increased yield. Evaporation under reduced pressure means that a rotary evaporator is used.

Primjer 1 Example 1

(2S)-2,N-DIHIDROKSI-3-(4-METOKSIBENZENSULFONIL)PROPIONAMID (2S)-2,N-DIHYDROXY-3-(4-METHOXYBENZENESULFONYL)PROPIONAMIDE

(A) Benzilni ester (2S)-2hidroksi-3-(4-metoksifenilsulfanil)propionske kiseline (A) Benzyl ester of (2S)-2hydroxy-3-(4-methoxyphenylsulfanyl)propionic acid

Otopina 1M etilmagnezijevog bromida u dietileteru (16,6 ml, 16,7 mmola) razrijedi se tetrahidrofuranom (32 ml) i hladi u ledenoj kupki. Kap po kap se dodaje otopina 4-metoksibenzentiola (2,3 g, 16,7 mmola) u bezvodnom hidrofuranu (5 ml). Konačna smjesa miješa se na 0 °C 1 sat, a zatim se doda otopina benzil (2S)-glicidata (2,3 g, 12,9 mmola) u tetrahidrofuranu (5 ml). Smjesa se miješa na sobnoj temperaturi 3 sata. Nakon zaustavljanja reakcije s vodom smjesa se ekstrahira s eterom. Vodeni se sloj zakiseli do pH 5 i ponovo ekstrahira dietileterom. Kombinirani dietileter ekstrakti oprani su vodom i, osušeni nad magnezijevim sulfatom i ugušćeni do ulja. Produkt, (2S)-2-hidroksi-3-(4-metoksifenilsulfanil) benzilni ester propionske kiseline (3,6 g, 88 %) izolira se kao svjetložuto ulje kromatografijom na silikagelu uz upotrebu 1:1 smjese dietileter/heksan kao eluenta. A solution of 1M ethylmagnesium bromide in diethyl ether (16.6 ml, 16.7 mmol) was diluted with tetrahydrofuran (32 ml) and cooled in an ice bath. A solution of 4-methoxybenzenethiol (2.3 g, 16.7 mmol) in anhydrous hydrofuran (5 ml) was added dropwise. The final mixture was stirred at 0 °C for 1 h, then a solution of benzyl (2S)-glycidate (2.3 g, 12.9 mmol) in tetrahydrofuran (5 mL) was added. The mixture is stirred at room temperature for 3 hours. After stopping the reaction with water, the mixture is extracted with ether. The aqueous layer is acidified to pH 5 and extracted again with diethyl ether. The combined diethyl ether extracts were washed with water and dried over magnesium sulfate and concentrated to an oil. The product, (2S)-2-hydroxy-3-(4-methoxyphenylsulfanyl)propionic acid benzyl ester (3.6 g, 88%) was isolated as a light yellow oil by silica gel chromatography using 1:1 diethyl ether/hexane as eluent.

(B) Benzilni ester (2S)-2-Hidroksi-3-(4-metoksibenzenesulfonil)propionske kiseline (B) Benzyl ester of (2S)-2-Hydroxy-3-(4-methoxybenzenesulfonyl)propionic acid

Otopina (2S)-2-hidroksi-3-(4-metoksibenzenesulfonil) benzilnog estera propionske kiseline (3,6 grama, 11 mmola) u metilenkloridu (25ml) rashladi se u ledenoj kupelji, te se kap po kap dodaje otopina 50 % m-kloroperbenzoične kiseline (8,4 grama, 24 mmola) u metilenkloridu. Rezultirajuća smjesa miješa se pri sobnoj temperaturi 4 sata. Nakon zaustavljanja reakcije sa zasićenom vodenom otopinom natrijevog bisulfita, smjesa se ekstrahira dietileterom. Ekstrakt se pere sa zasićenom vodenom otopinom natrij bikarbonata i slanom vodom, osuši iznad magnezijevog sulfata i ispari u bijelu krutinu. Rekristalizacija iz 1:1 heksan/etil acetata dala je (2S)-2-Hidroksi-3-(4-metoksibenzenesulfonil) benzilnog estera propionske kiseline (3,2 grama, 84 %) kao bijelu kristalnu krutinu. A solution of (2S)-2-hydroxy-3-(4-methoxybenzenesulfonyl) benzyl ester of propionic acid (3.6 grams, 11 mmol) in methylene chloride (25 ml) is cooled in an ice bath, and a solution of 50% m -chloroperbenzoic acid (8.4 grams, 24 mmol) in methylene chloride. The resulting mixture was stirred at room temperature for 4 hours. After stopping the reaction with a saturated aqueous solution of sodium bisulfite, the mixture is extracted with diethyl ether. The extract is washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to a white solid. Recrystallization from 1:1 hexane/ethyl acetate gave (2S)-2-Hydroxy-3-(4-methoxybenzenesulfonyl)propionic acid benzyl ester (3.2 grams, 84%) as a white crystalline solid.

(C) (2S)-2-Hidroksi-3-(4-metoksibenzenesulfonil)propionska kiselina (C) (2S)-2-Hydroxy-3-(4-methoxybenzenesulfonyl)propionic acid

Otopina (2S)-2-hidroksi-3-(4-metoksibenzenesulfonil)benzilnog estera propionske kiseline (1,0 grama, 2,8 mmola) u metanolu (70 ml) tretirana je s 10 % paladija na aktivnom ugljenu (100 mg) i hidrogenira se pri tlaku od 3 bara tokom 3 sata u Parrovoj tresilici. Katalizator se odvaja filtracijom kroz dijatomejsku zemlju a filtrat je isparen kako bi dao (2S)-2-Hidroksi-3-(4-metoksibenzenesulfonil) propionsku kiselinu kao bijelu pjenu (729 mg, 100 %) A solution of propionic acid (2S)-2-hydroxy-3-(4-methoxybenzenesulfonyl)benzyl ester (1.0 grams, 2.8 mmol) in methanol (70 mL) was treated with 10% palladium on charcoal (100 mg) and is hydrogenated at a pressure of 3 bar for 3 hours in a Parr shaker. The catalyst was separated by filtration through diatomaceous earth and the filtrate was evaporated to give (2S)-2-Hydroxy-3-(4-methoxybenzenesulfonyl)propionic acid as a white foam (729 mg, 100 %)

(D) (2S)-N-Benziloksi-2-hidroksi-3-(4-metoksibenzenesulfonil)propionamid (D) (2S)-N-Benzyloxy-2-hydroxy-3-(4-methoxybenzenesulfonyl)propionamide

Otopini (2S)-2-Hidroksi-3-(4-metoksibenzenesulfonil) propionske kiseline (800 mg, 3 mmola), O-benzilhidroksilamin hidroklorida (526 mg, 3,3 mmola) i trietilamina (1,2ml, 9,0 mmola) u metilenkloridu (80 ml) dodan je (benzotriazol-1-iloksi)tris(dimetilamino)fosfonium heksafluorofosfat (1,4 grama, 3,3 mmola). Reakciona smjesa miješa se pri sobnoj temperaturi 16 sati i onda se razrijedi metilenkloridom. Otopina se za redom ispire zasićenom vodnom otopinom natrij bikarbonata, vodom, 0,5 M vodenom otopinom klorovodične kiseline i zasićenom otopinom natrijevog klorida. Poslije sušenja na magnezijevom sulfatu, otopina se isparava kako bi dala ulje. Željeni produkt, (2S)-N-benziloksi-2-hidroksi-3-(4-metoksibenzenesulfonil)propionamid (400 mg, 36 %) izolira se flash kromatografijom na silikagelu, a eluira se redom s kloroformom, 1 % metanolom u kloroformu i 2 % metanolom u kloroformu. Solutions of (2S)-2-Hydroxy-3-(4-methoxybenzenesulfonyl) propionic acid (800 mg, 3 mmol), O-benzylhydroxylamine hydrochloride (526 mg, 3.3 mmol) and triethylamine (1.2 ml, 9.0 mmol) ) in methylene chloride (80 ml) was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.4 grams, 3.3 mmol). The reaction mixture is stirred at room temperature for 16 hours and then diluted with methylene chloride. The solution is washed successively with saturated aqueous sodium bicarbonate solution, water, 0.5 M aqueous hydrochloric acid solution and saturated sodium chloride solution. After drying over magnesium sulfate, the solution is evaporated to give an oil. The desired product, (2S)-N-benzyloxy-2-hydroxy-3-(4-methoxybenzenesulfonyl)propionamide (400 mg, 36%) was isolated by flash chromatography on silica gel, eluting with chloroform, 1% methanol in chloroform and 2% methanol in chloroform.

(E) (2S)-2,N-dihidroksi-3-(4-metoksibenzensulfonil)propionamid (E) (2S)-2,N-dihydroxy-3-(4-methoxybenzenesulfonyl)propionamide

Otopina (2S)-N-benziloksi-2-hidroksi-3-(4-metoksibenzeneonil)propionamida (400 mg, 1,0 mmola) u metanolu (30ml) je tretirana s 5 % paladija na barijevom sulfatu (200 mg) i hidrogenira se pri tlaku od 3 bara tokom 4 sata u Parrovoj tresilici. Katalizator se izdvaja prolaskom kroz 0,45 µm najlonski filter i filtrat se koncentrira. Željeni produkt, (2S)-N-dihidroksi-3-(4-metoksibenzensulfonil)propionamid (180 mg, 65 %) izolira se flash kromatografijom na silikagelu, a eluira se s 5 % metanola u kloroformu popraćeno rekristalizacijom iz kloroform/metanola. A solution of (2S)-N-benzyloxy-2-hydroxy-3-(4-methoxybenzeneonyl)propionamide (400 mg, 1.0 mmol) in methanol (30 ml) was treated with 5% palladium on barium sulfate (200 mg) and hydrogenated at a pressure of 3 bar for 4 hours in a Parr shaker. The catalyst is separated by passing through a 0.45 µm nylon filter and the filtrate is concentrated. The desired product, (2S)-N-dihydroxy-3-(4-methoxybenzenesulfonyl)propionamide (180 mg, 65%) was isolated by flash chromatography on silica gel, eluting with 5% methanol in chloroform followed by recrystallization from chloroform/methanol.

Točka taljenja 138-144 °C; MS m/z 276 (M+1). Melting point 138-144 °C; MS m/z 276 (M+1).

Analizom izračunato za C10H13NO6S: C 43,63; H 4,76; N 5,09. Calculated by analysis for C10H13NO6S: C 43.63; H 4.76; N 5.09.

Nađeno: C 43,51; H 4,68; N 4,95. Found: C 43.51; H 4.68; N 4.95.

Primjer 2 Example 2

3-[4-(4-FLUOROFENOKSI)FENILSULFONIL]-2,N-DIHIDROKSIPROPIONAMID 3-[4-(4-FLUOROPHENOXY)PHENYLSULFONYL]-2,N-DIHYDROXYPROPIONAMIDE

3-[4-(4-fluorofenoksi)fenilsulfonil]-2,N-dihidroksipropionamid pripravlja se metodom analognom onoj opisanoj u primjeru 1, upotrebom (4-fluorofenksi)fenilitiola kao početnog materijala. Rekristalizira se iz kloroforma. 3-[4-(4-fluorophenoxy)phenylsulfonyl]-2,N-dihydroxypropionamide is prepared by a method analogous to that described in example 1, using (4-fluorophenoxy)phenylthiol as starting material. It is recrystallized from chloroform.

Točka taljenja 129-130 °C; MS m/z 356 (M+1). Melting point 129-130 °C; MS m/z 356 (M+1).

Analizom izračunato za C15H14FNO6S.0,75H2O: C 48,84; H 4,24; N 3,80. Calculated by analysis for C15H14FNO6S.0.75H2O: C 48.84; H 4.24; N 3.80.

Nađeno: C 49,03; H 4,06; N 3,86. Found: C 49.03; H 4.06; N 3.86.

Primjer 3 Example 3

2,N-DIHIDROKSI-2-[1-(4-METOKSIBENZENSULFONIL)CIKLOBUTIL] ACETAMID 2,N-DIHYDROXY-2-[1-(4-METHOXYBENZENESULFONYL)CYCLOBUTYL] ACETAMIDE

(A) 1-Ciklobutilsulfanil-4-metoksibenzen (A) 1-Cyclobutylsulfanyl-4-methoxybenzene

4-Metoksibenzentiol (5,7 g, 40,7 mmola) dodaje se suspenziji natrijevog hidrida (1,17 grama, 49 mmola) u suhom N,N-dimetilformamidu (50 ml). Nakon mješanja tokom 1 sata, dodaje se ciklobutilbromid (6,0 grama, 4,44 mmola). Reakciona smjesa se miješa 16 sati i reakcija se prekida dodavanjem zasićene vodene otopine amonijevog klorida. Otapala se ispare. Ostatak se otopi u dietileteru i pere redom sa 0,5 M(N) vodenom otopinom klorovodične kiseline, vodom i otopinom natrijevog klorida. Nakon sušenja na magnezijevom sulfatu, dietileter je isparen kako bi dao 1-ciklobutilsulfanil-4-metoksibenzen u obliku ulja (7,9 grama, 100 %). 4-Methoxybenzenethiol (5.7 g, 40.7 mmol) was added to a suspension of sodium hydride (1.17 grams, 49 mmol) in dry N,N-dimethylformamide (50 mL). After stirring for 1 hour, cyclobutyl bromide (6.0 grams, 4.44 mmol) was added. The reaction mixture was stirred for 16 hours and the reaction was terminated by adding a saturated aqueous solution of ammonium chloride. The solvent evaporates. The residue is dissolved in diethyl ether and washed successively with 0.5 M(N) aqueous hydrochloric acid solution, water and sodium chloride solution. After drying over magnesium sulfate, the diethyl ether was evaporated to give 1-cyclobutylsulfanyl-4-methoxybenzene as an oil (7.9 grams, 100%).

(B) 1-Ciklobutilsulfonil-4-metoksibenzen (B) 1-Cyclobutylsulfonyl-4-methoxybenzene

Otopina 1-ciklobutilsulfanil-4-metoksibenzena (7,9 grama, 40,7 mmola) u metilenkloridu (50 ml) ohladi se u ledenoj kupelji i kap po kap se dodaje otopina 57 % m-kloroperbenzoične kiseline (28 grama, 92 mmola) u metilenkloridu (100 ml). Dobivena smjesa miješa se na sobnoj temperaturi 7 dana. Nakon prekida reakcije sa zasićenom vodenom otopinom natrijevbog bisulfita, smjesa se filtrira kako bi se uklonio bijeli talog i ekstrahira s metilenkloridom. Ekstrakt je opran redom zasićenom otopinom natrijevog bikarbonata, vodom i otopinom natrijevog klorida. Nakon sušenja iznad magnezijevog sulfata otopina se ispari do bijele krutine. Rekristalizacija iz etilacetata dala je 1-ciklobutilsulfonil-4-metoksibenzen (7,28 g, 79 %) u obliku bijelih kristala. A solution of 1-cyclobutylsulfanyl-4-methoxybenzene (7.9 grams, 40.7 mmol) in methylene chloride (50 mL) was cooled in an ice bath and a solution of 57% m-chloroperbenzoic acid (28 grams, 92 mmol) was added dropwise. in methylene chloride (100 ml). The resulting mixture is stirred at room temperature for 7 days. After quenching with saturated aqueous sodium bisulfite, the mixture was filtered to remove the white precipitate and extracted with methylene chloride. The extract was washed successively with saturated sodium bicarbonate solution, water and sodium chloride solution. After drying over magnesium sulfate, the solution was evaporated to a white solid. Recrystallization from ethyl acetate gave 1-cyclobutylsulfonyl-4-methoxybenzene (7.28 g, 79%) as white crystals.

(C) Furan-2-[1-(4-metoksibenzensulfonil)ciklobutil]metanol (C) Furan-2-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methanol

Otopina 1-ciklobutilsulfonil-4-metoksibenzena (4,0 g, 17,7 mmol) u suhom tetrahidrofuranu (80 ml) ohlađena je na -78 °C, a zatim joj je dodana 2,5 M otopina n-butillitija u heksanu. Dopušteno je da se smjesa zagrije na -50 °C, a zatim je opet ohlađena na -78 °C. Zatim je dodan 2-furaldehid (4 ml,48 mmol). Nakon miješanja tokom 20 minuta pri temperaturi od -78 °C, reakcija je zaustavljena dodavanjem zasićene vodene otopine amonijevog klorida. Dobivena smjesa je ekstrahirana etilacetatom. Organski ekstrakt opran je vodom i otopinom natrijevog klorida i sušen iznad magnezijevog sulfata. Isparavanjem otapala dobiveno je ulje, iz kojeg je izoliran furan-2-[1-(4-metoksibenzensulfonil)ciklobutil]metanol (4,3 g, 75 %) flash kromatografijom na silikagelu uz eluiranje sa smjesom 1:3 etil acetat/heksan. A solution of 1-cyclobutylsulfonyl-4-methoxybenzene (4.0 g, 17.7 mmol) in dry tetrahydrofuran (80 mL) was cooled to -78 °C and then a 2.5 M solution of n-butyllithium in hexane was added. The mixture was allowed to warm to -50 °C and then cooled again to -78 °C. Then 2-furaldehyde (4 ml, 48 mmol) was added. After stirring for 20 minutes at a temperature of -78 °C, the reaction was stopped by adding a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent gave an oil, from which furan-2-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methanol (4.3 g, 75 %) was isolated by flash chromatography on silica gel eluting with a mixture of 1:3 ethyl acetate/hexane.

(D) Furan-2-[1-(4-metoksibenzensulfonil)ciklobutil]metilni ester 2,2-dimetilpropionske kiseline (D) Furan-2-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methyl ester of 2,2-dimethylpropionic acid

Otopina furan-2-[1-(4-metoksibenzensulfonil)ciklobutil]metanola (1,57 g, 4,9 mmol) i A solution of furan-2-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methanol (1.57 g, 4.9 mmol) and

4-dimetilaminopiridina (0,89 g, 7,3 mmol) u metilenkloridu (50 ml) ohlađena je u ledu. Dodan je pivaloilklorid (0,66 ml, 5,4 mmol). Smjesa je miješana 2 sata na 0 °C, razrijeđena metilenkloridom i ekstrahirana prvo 0,5 M(N) klorovodičnom kiselinom i zatim otopinom natrijevog klorida.. Nakon sušenja iznad magnezijevog sulfata otapalo je ispareno, a iz preostalog ulja željeni produkt, furan-2-il-[1-(4–metoksibenzen- sulfonil)ciklobutil]metilni ester 2,2-dimetilpropionske kiseline (1,60 g, 81 %) izoliran je flash kromatografijom uz 16 % etil acetat u heksanu kao eluent. 4-Dimethylaminopyridine (0.89 g, 7.3 mmol) in methylene chloride (50 mL) was cooled in ice. Pivaloyl chloride (0.66 mL, 5.4 mmol) was added. The mixture was stirred for 2 hours at 0 °C, diluted with methylene chloride and extracted first with 0.5 M(N) hydrochloric acid and then with sodium chloride solution. After drying over magnesium sulfate, the solvent was evaporated, and the desired product, furan-2, was obtained from the remaining oil. -yl-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methyl ester of 2,2-dimethylpropionic acid (1.60 g, 81%) was isolated by flash chromatography with 16% ethyl acetate in hexane as eluent.

(E) Karboksi-[1-(4-metoksibenzensulfonil)ciklobutil]metilni ester 2,2-dimetilpropionske kiseline (E) Carboxy-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methyl ester of 2,2-dimethylpropionic acid

Otopini furan-2-il-[1-(4-metoksibenzensulfonil)ciklobutil]metilnog estera 2,2-dimetilpropionske kiseline (1,6 grama, 3,94mmola) u acetonitrilu (12 ml), ugljikovom tetrakloridu (12 ml) i vodi (22 ml) pri sobnoj temperaturi dodani su redom natrijev perjodat (6,73 grama, 31 mmol) i rutenij(III)kloridhidrat. Smjesa je miješana pri sobnoj temperaturi 75 minuta, a onda je razrijeđena vodom i etilacetatom. Vodeni sloj je odvojen i ekstrahiran etilacetatom. Kombinirane organske frakcije osušene su iznad magnezij sulfata da bi se dobio sirovi produkt karboksi-[1-(4-metoksibenzensulfonil)ciklobutil]metilni ester 2,2-dimetilpropionske kiseline u obliku ulja. Solutions of 2,2-dimethylpropionic acid furan-2-yl-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methyl ester (1.6 grams, 3.94 mmol) in acetonitrile (12 ml), carbon tetrachloride (12 ml) and water (22 ml) at room temperature, sodium periodate (6.73 grams, 31 mmol) and ruthenium(III) chloride hydrate were added respectively. The mixture was stirred at room temperature for 75 minutes and then diluted with water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate to give the crude product carboxy-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methyl ester 2,2-dimethylpropionic acid as an oil.

(F) Benziloksikarbamoil-[1-(4-metoksibenzensulfonil)ciklobutil]metilni ester 2,2-dimetilpropionske kiseline (F) Benzyloxycarbamoyl-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methyl ester of 2,2-dimethylpropionic acid

Cijeli neprerađeni uzorak karboksi-[1-(4-metoksibenzensulfonil)ciklobutil]metilnog estera Whole crude sample of carboxy-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methyl ester

2,2-dimetilpropionske kiseline dobiven u koraku E otopljen je u metilenkloridu (60 ml). Zatim su u nizu dodani O-benzilhidroksilamin hidroklorid (0,69 grama, 4,3 mmola), trietilamin (1,6 ml, 11,5 mmola) i (benzotriazol-1-iloksi)tris(dimetilamino)fosfonium heksafluorofosfat (1,91 grama, 4,3 mmola). smjesa je miješana pri sobnoj temperaturi 16 sati i onda je isparena pod vakuumom. Ostatak je otopljen u etil acetatu, a otopina je redom oprana s 0,5 M vodenom otopinom klorovodične kiseline, zasićenom vodenom otopinom natrij bikarbonata i otopinom natrijevog klorida. Nakon sušenja nad magnezijevim sulfatom, otopina je isparena kako bi dala ulje. Željeni produkt, benziloksikarbamoil-[1-(4-metoksibenzensulfonil)ciklobutil] metilni ester 2,2-dimetilpropionske kiseline (0.87 grama, 46 %) izoliran je flash kromatografijom na silikagelu eluiranjem s 30 % etil acetata u heksanu. The 2,2-dimethylpropionic acid obtained in step E was dissolved in methylene chloride (60 ml). Then, O-benzylhydroxylamine hydrochloride (0.69 grams, 4.3 mmol), triethylamine (1.6 mL, 11.5 mmol), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1, 91 grams, 4.3 mmol). the mixture was stirred at room temperature for 16 hours and then evaporated under vacuum. The residue was dissolved in ethyl acetate, and the solution was washed successively with 0.5 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and sodium chloride solution. After drying over magnesium sulfate, the solution was evaporated to give an oil. The desired product, 2,2-dimethylpropionic acid benzyloxycarbamoyl-[1-(4-methoxybenzenesulfonyl)cyclobutyl] methyl ester (0.87 grams, 46%) was isolated by flash chromatography on silica gel eluting with 30% ethyl acetate in hexane.

(G) N-Benziloksi-2-hidroksi-2[1-(4-metoksibenzensulfonil)ciklobutil] acetamid (G) N-Benzyloxy-2-hydroxy-2[1-(4-methoxybenzenesulfonyl)cyclobutyl] acetamide

Otopini benziloksikarbamoil-[1-(4-metoksibenzensulfonil)ciklobutil] metilnog estera Benzyloxycarbamoyl-[1-(4-methoxybenzenesulfonyl)cyclobutyl] methyl ester solutions

2,2-dimetilpropionske kiseline (0,87 grama, 1,78 mmola) u metanolu (10 ml), tetrahidrofuranu (5 ml) i vodi (5 ml) dodan je litijev hiroksid hidrat (0,37 grama, 8,8 mmola). Smjesa je miješana pri sobnoj temperaturi 24 sata. Zatim je dodan ionski izmjenjivač Amberlit IR-120 ispran metanolom (6 grama). Nakon 15 minuta miješanja smjesa je filtrirana. Filtrat je isparen, a ostatak je otopljen u etilacetatu. Dobivena otopina je oprana zasićenom otopinom natrij bikarbonata i otopinom natrijevog klorida, osušena na magnezijevom sulfatu i isparena do željenog produkta, N-benziloksi-2-hidroksi-2[1-(4-metoksibenzensulfonil) ciklobutil]acetamida u obliku ulja (0,72 grama, 100 %). To 2,2-dimethylpropionic acid (0.87 grams, 1.78 mmol) in methanol (10 mL), tetrahydrofuran (5 mL), and water (5 mL) was added lithium hydroxide hydrate (0.37 grams, 8.8 mmol ). The mixture was stirred at room temperature for 24 hours. Amberlit IR-120 ion exchanger washed with methanol (6 grams) was then added. After 15 minutes of mixing, the mixture was filtered. The filtrate was evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate solution and sodium chloride solution, dried over magnesium sulfate and evaporated to the desired product, N-benzyloxy-2-hydroxy-2[1-(4-methoxybenzenesulfonyl)cyclobutyl]acetamide in the form of an oil (0.72 grams, 100 %).

(H) 2,N-dihidroksi-2-[1-(4-metoksibenzensulfonil)ciklobutil]acetamid (H) 2,N-dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclobutyl]acetamide

Otopina N-benziloksi-2-hidroksi-2[1-(4-metoksibenzensulfonil)ciklobutil]acetamida (0,13 grama, 0,32 mmola) u metanolu (30 ml) tretirana je sa 5 % paladija na barijevom sulfatu (0,07 grama) i hidrogenirana pod tlakom od 3 bara tokom 4 sata u Parrovoj tresilici. Katalizator je izdvojen prolaskom kroz 0,45 µm najlonski filter i filtrat je koncentriran. Željeni produkt, 2,N-dihidroksi-2-[1-(4-metoksibenzensulfonil)ciklobutil]acetamid (0,061 grama, 65 %) je izoliran kao pjena flash kromatografijom na silikagelu uz eluiranje redom s kloroformom, 1 % metanolom u kloroformu i 2 % metanolom u kloroformu. MS m/z 314 (M-1). A solution of N-benzyloxy-2-hydroxy-2[1-(4-methoxybenzenesulfonyl)cyclobutyl]acetamide (0.13 grams, 0.32 mmol) in methanol (30 mL) was treated with 5% palladium on barium sulfate (0, 07 grams) and hydrogenated under a pressure of 3 bar for 4 hours in a Parr shaker. The catalyst was separated by passing through a 0.45 µm nylon filter and the filtrate was concentrated. The desired product, 2,N-dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclobutyl]acetamide (0.061 gram, 65%) was isolated as a foam by flash chromatography on silica gel eluting sequentially with chloroform, 1% methanol in chloroform, and 2 % methanol in chloroform. MS m/z 314 (M-1).

Primjer 4 Example 4

2,N-DIHIDROKSI-2-[1-(4-METOKSIBENZENSULFONIL)CIKLOPENTIL]ACETAMID 2,N-DIHYDROXY-2-[1-(4-METHOXYBENZENESULFONYL)CYCLOPENTYL]ACETAMIDE

2,N-dihidroksi-2-[1-(4-metoksibenzensulfonil)ciklopentil]acetamid je pripravljen metodom analognom onoj opisanoj u primjeru 3 korištenjem 4-metoksibenzentiola i ciklopentilbromida kao početnih materijala. MS m/z 328 (M-1). 2,N-dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclopentyl]acetamide was prepared by a method analogous to that described in Example 3 using 4-methoxybenzenethiol and cyclopentyl bromide as starting materials. MS m/z 328 (M-1).

Primjer 5 Example 5

2-{1-[4-(4-FLUOROFENOKSI)BENZENSULFONIL]CIKLOBUTIL}-2,N-DIHIDROKSIACETAMID 2-{1-[4-(4-FLUOROPHENOXY)BENZENESULFONYL]CYCLOBUTYL}-2,N-DIHYDROXYACETAMIDE

2-{1-[4-(4-Fluorofenoksi)benzensulfonil]ciklobutil}-2,N-dihidroksiacetamid je pripravljen metodom analognom onoj opisanoj u primjeru 3 korištenjem 4-(4-fluorofenoksi)benzenetiola i ciklobutil bromida kao početnih materijala. MS m/z 394 (M-1). 2-{1-[4-(4-Fluorophenoxy)benzenesulfonyl]cyclobutyl}-2,N-dihydroxyacetamide was prepared by a method analogous to that described in Example 3 using 4-(4-fluorophenoxy)benzenethiol and cyclobutyl bromide as starting materials. MS m/z 394 (M-1).

4-(4-Fluorofenoksi)benzentiol je dobiven kako slijedi. Klorosulfonska kiselina (26 ml, 0,392 mola) je dodana kap po kap ledom hlađenom 4-fluorofenoksibenzenu (36,9 grama, 0,196 mola) uz mehaničko miješanje. Kad je dodavanje dovršeno, smjesa je miješana pri sobnoj temperaturi 4 sata. Smjesa je tada izlivena u ledenu vodu. Produkt, 4-(4-fluorofenoksi)benzensulfonilklorid (18,6 grama, 33 %) je izdvojen filtracijom i osušen na zraku. 4-(4-Fluorophenoxy)benzenethiol was prepared as follows. Chlorosulfonic acid (26 mL, 0.392 mol) was added dropwise to ice-cooled 4-fluorophenoxybenzene (36.9 grams, 0.196 mol) with mechanical stirring. When the addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4-(4-fluorophenoxy)benzenesulfonyl chloride (18.6 grams, 33%) was isolated by filtration and air dried.

4-(4-Fluorofenoksi)benzensulfonilklorid (5,1 grama, 17,7 mmola) je dodan ledom hlađenoj smjesi koncentrirane sumporne kiseline (7 ml) i vode (37 ml) uz mehaničko miješanje. Zatim je polako dodavan cink u prahu (6,2 grama, 95 mmola). Kupka za hlađenje je uklonjena i mješavina je ostavljena da stoji pri sobnoj temperaturi 2 sata i tri sata pod refluksom. Nakon hlađenja do sobne temperature, reakcija je prekinuta dodavanjem leda. Dobivena smjesa je izdvojena toluenom. Organski sloj je opran vodom i zasićenom otopinom natrijevog klorida, osušen na magnezijevom sulfatu i isparen kako bi dao 4-(4-fluorofenoksi)benzenetiol kao bijelu krutinu (3,3 grama, 84 %). 4-(4-Fluorophenoxy)benzenesulfonyl chloride (5.1 grams, 17.7 mmol) was added to an ice-cooled mixture of concentrated sulfuric acid (7 mL) and water (37 mL) with mechanical stirring. Zinc powder (6.2 grams, 95 mmol) was then slowly added. The cooling bath was removed and the mixture was allowed to stand at room temperature for 2 hours and under reflux for three hours. After cooling to room temperature, the reaction was terminated by adding ice. The resulting mixture was extracted with toluene. The organic layer was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give 4-(4-fluorophenoxy)benzenethiol as a white solid (3.3 grams, 84%).

Primjer 6 Example 6

2-{1-[4-(4-FLUOROFENOKSI)BENZENSULFONIL]CIKLOPENTIL}-2,N-DIHIDROKSIACETAMID 2-{1-[4-(4-FLUOROPHENOXY)BENZENESULFONYL]CYCLOPENTYL}-2,N-DIHYDROXYACETAMIDE

2-{1-[4-(4-Fluorofenoksi)benzensulfonil]ciklopentil}-2,N-dihidroksiacetamid je pripravljen metodom analognom onoj opisanoj u primjeru 3 korištenjem (4-fluorofenoksi)benzentiola i ciklopentilbromida kao početnih materijala. MS m/z 408 (M-1). 2-{1-[4-(4-Fluorophenoxy)benzenesulfonyl]cyclopentyl}-2,N-dihydroxyacetamide was prepared by a method analogous to that described in Example 3 using (4-fluorophenoxy)benzenethiol and cyclopentyl bromide as starting materials. MS m/z 408 (M-1).

Primjer 7 Example 7

2-[1-(4-CIKLOBUTOKSIBENZENSULFONIL)CIKLOBUTIL]-2,N-DIHIDROKSIACETAMID 2-[1-(4-CYCLOBUTOXYBENZENESULFONYL)CYCLOBUTYL]-2,N-DIHYDROXYACETAMIDE

2-[1-(4-Ciklobutoksibenzensulfonil)ciklobutil]-2,N-dihidroksiacetamid je pripravljen metodom analognom onoj opisanoj u primjeru 3 korištenjem 1-ciklobutoksi-4-ciklobutilsulfanilbenzen kao početni materijal u koraku B. MS: 354 (M-1). 2-[1-(4-Cyclobutoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide was prepared by a method analogous to that described in Example 3 using 1-cyclobutoxy-4-cyclobutylsulfanylbenzene as starting material in step B. MS: 354 (M-1) .

Primjer 8 Example 8

2-[1-(4-BUTOKSIBENZENSULFONIL)CIKLOBUTIL]-2,N-DIHIDROKSIACETAMID 2-[1-(4-BUTOXYBENZENESULFONYL)CYCLOBUTYL]-2,N-DIHYDROXYACETAMIDE

2-[1-(4-Butoksibenzensulfonil)ciklobutil]-2,N-dihidroksiacetamid je pripravljen metodom analognom onoj opisanoj u Primjeru 3 korištenjem 1-butoksi-4-ciklobutilsulfanilbenzena kao početnog materijala u koraku B. MS: 356 (M-1). 2-[1-(4-Butoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide was prepared by a method analogous to that described in Example 3 using 1-butoxy-4-cyclobutylsulfanylbenzene as starting material in step B. MS: 356 (M-1) .

Preparacija A Preparation A

4-(4-FLUOROFENOKSI)BENZENSULFONILKLORID 4-(4-FLUOROPHENOXY)BENZENESULPHONYL CHLORIDE

Klorsulfonska kiselina (26 ml, 0,392 mola) je dodana kap po kap ledom hlađenom 4-fluorofenoksibenzenu (36,9 grama, 0,196 mola) uz mehaničko miješanje. Kad je dodavanje završeno, smjesa je miješana pri sobnoj temperaturi 4 sata. Smjesa je tada izlivena u ledenu vodu. Naslovni spoj (18,6 grama, 33 %) je izdvojen filtracijom i osušen na zraku. Chlorosulfonic acid (26 mL, 0.392 mol) was added dropwise to ice-cooled 4-fluorophenoxybenzene (36.9 grams, 0.196 mol) with mechanical stirring. When the addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The title compound (18.6 grams, 33%) was isolated by filtration and dried in air.

Preparacija B Preparation B

4-(4-FLUOROFENOKSI)BENZENETIOL 4-(4-FLUOROPHENOXY)BENZENETHIOL

4-(4-Fluorofenoksi)benzensulfonilklorid (5,1 grama, 17,7 mmola) je dodan ledom hlađenoj smjesi koncentrirane sumporne kiseline (7 ml) i vode (37 ml) uz mehaničko miješanje. Zatim je polako dodavan cink u prahu (6,2 grama, 95 mmola). Kupka za hlađenje je uklonjena i mješavina je ostavljena da stoji pri sobnoj temperaturi 2 sata i tri sata pod refluksom. Nakon hlađenja do sobne temperature, reakcija je prekinuta dodavanjem leda. Dobivena smjesa je izdvojena toluenom. Organski sloj je opran vodom i zasićenom otopinom natrijevog klorida, osušen na magnezijevom sulfatu i isparen kako bi dao 4-(4-fluorofenoksi)benzenetiol kao bijelu krutinu. (3,3 grama, 84 %). 4-(4-Fluorophenoxy)benzenesulfonyl chloride (5.1 grams, 17.7 mmol) was added to an ice-cooled mixture of concentrated sulfuric acid (7 mL) and water (37 mL) with mechanical stirring. Zinc powder (6.2 grams, 95 mmol) was then slowly added. The cooling bath was removed and the mixture was allowed to stand at room temperature for 2 hours and under reflux for three hours. After cooling to room temperature, the reaction was terminated by adding ice. The resulting mixture was extracted with toluene. The organic layer was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give 4-(4-fluorophenoxy)benzenethiol as a white solid. (3.3 grams, 84%).

Preparacija C Preparation C

4-CIKLOBUTILSULFANILFENOL 4-CYCLOBUTYLSULPHANYLPHENOL

4-Hidroksibenzentiol (10,0 grama, 79,3 mmola) je dodan suspenziji natrijevog hidrida (1,9 grama, 79,2 mmola) u N,N-dimetilformamidu (50 ml). Kada je razvijanje vodika završeno i smjesa se ohladila do sobne temperature, dodan je ciklobutilbromid (11,4 grama, 84,4 mmola). Reakcijska smjesa je miješana pri sobnoj temperaturi 2,5 sata a onda je reakcija zaustavljena dodavanjem vode i 6 M(N) vodene otopine klorovodične kiseline. Smjesa je ekstrahirana sa dietileterom. Organski ekstrakt je opran otopinom natrijevog klorida, osušen iznad magnezijevog sulfata i koncentriran da kako bi dao žuto ulje. Otprilike pola ovog materijala je kromatografirano na silikagelu eluiranjem s 9:1:1 haksan/etilacetat/metilenklorid kako bi se dobilo spoj iz naslova u obliku prozirnog ulja (8,85 grama). 4-Hydroxybenzenethiol (10.0 grams, 79.3 mmol) was added to a suspension of sodium hydride (1.9 grams, 79.2 mmol) in N,N-dimethylformamide (50 mL). When hydrogen evolution was complete and the mixture cooled to room temperature, cyclobutyl bromide (11.4 grams, 84.4 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 hours and then the reaction was stopped by adding water and 6 M(N) aqueous solution of hydrochloric acid. The mixture was extracted with diethyl ether. The organic extract was washed with sodium chloride solution, dried over magnesium sulfate and concentrated to give a yellow oil. About half of this material was chromatographed on silica gel eluting with 9:1:1 hexane/ethyl acetate/methylene chloride to give the title compound as a clear oil (8.85 grams).

Preparacija D Preparation D

1-CIKLOBUTOKSI-4-CIKLOBUTILSULFANILBENZEN 1-CYCLOBUTOXY-4-CYCLOBUTYLSULPHANYLBENZENE

60 % suspenzija natrijevog hidrida u ulju (1,97 grama, 49 mmola) je dodana otopini 4-ciklobutilsulfanilfenola (7,2 grama, 40 mmola) u N,N-dimetilformamidu (25 ml). Nakon što je završeno razvijanje vodika, dodan je ciklobutilbromid (6,4 grama, 47 mmola). Reakcijska smjesa je miješana pri sobnoj temperaturi 4 sata a onda 16 sati pri 70 °C u uljanoj kupki. Nakon hlađenja i prekida reakcije dodavanjem vode, smjesa je ekstrahirana s dietileterom. Organski ekstrakt je opran vodom i otopinom natrijevog klorida, osušen iznad magnezijevog sulfata i isparen, kako bi dao nečisti uzorak spoja iz naslova, ulje. Ono je korišteno bez pročišćavanja. A 60% suspension of sodium hydride in oil (1.97 grams, 49 mmol) was added to a solution of 4-cyclobutylsulfanylphenol (7.2 grams, 40 mmol) in N,N-dimethylformamide (25 mL). After hydrogen evolution was complete, cyclobutyl bromide (6.4 grams, 47 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours and then for 16 hours at 70 °C in an oil bath. After cooling and terminating the reaction by adding water, the mixture was extracted with diethyl ether. The organic extract was washed with water and sodium chloride solution, dried over magnesium sulfate and evaporated to give an impure sample of the title compound, an oil. It was used without purification.

Preparacija E Preparation E

1-BUTOKSI-4-CIKLOBUTILSULFANILBENZEN 1-BUTOXY-4-CYCLOBUTYLSULPHANYLBENZENE

60 % suspenzija natrijevog hidrida u ulju (2,2 grama, 55 mola) je dodana otopini 4-ciklobutilsulfanilfenol (8,85 grama, 49,1 mmola) u N,N-dimetilformamidu (35 ml) ohlađenoj ledom. Nakon što završeno razvijanje vodika, dodan je 1-bromobutan (6,7 ml, 58,9 mmola). Reakcijska smjesa je miješana pri sobnoj temperaturi 16 sati. Nakon hlađenja i prekida reakcije s vodom, smjesa je ekstrahirana sa dietileterom. Organski ekstrakt je opran vodom i otopinom natrijevog klorida, osušen iznad magnezijevog sulfata i isparen kako bi dao nečisti uzorak spoja iz naslova u obliku ulja (11,2 grama). Ovo je korišteno bez pročišćavanja. A 60% suspension of sodium hydride in oil (2.2 grams, 55 mol) was added to an ice-cooled solution of 4-cyclobutylsulfanylphenol (8.85 grams, 49.1 mmol) in N,N-dimethylformamide (35 mL). After hydrogen evolution was complete, 1-bromobutane (6.7 mL, 58.9 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After cooling and stopping the reaction with water, the mixture was extracted with diethyl ether. The organic extract was washed with water and sodium chloride solution, dried over magnesium sulfate and evaporated to give an impure sample of the title compound as an oil (11.2 grams). This was used without purification.

Claims

1. Spoj formule [image] karakteriziran time da je R1 vodik, hidroksi, (C6-C10)aril(C1-C6)alkoksi, (C1-C6) alkoksi, (C1-C6) alkil(C=O)O-, (C1-C6)alkoksi(C=O)O-, (C6-C10)aril(C=O)O-, (C6-C10)ariloksi(C=O)O-, (C6-C10)aril(C1-C6) alkil(C=O)O- ili (C6-C10)aril(C1-C6)alkoksi(C=O)O-; gdje je spomenuti aril u spomenutom (C6-C10)aril(C1-C6) alkoksi, (C6-C10)aril(C=O)O-, (C6-C10)ariloksi(C=O)O-, (C6-C10)aril(C1-C6)alkil(C=O)O- ili (C6-C10)aril(C1-C6) alkoksi(C=O)O-, gdje se arilna jedinica tih svih grupa opcionalno zamjenjuje s jednim ili više supstituenata (preferirano jedan do tri supstituenata) neovisno izabranih od fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6) alkoksi, perfluoro(C1-C3)alkil perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi; R2 je vodik ili (C1-C6)alkil; R3 i R4 se neovisno biraju iz grupe koja se sastoji od vodika, (C1-C6)alkil, trifluorometil, trifluorometil(C1-C6) alkil, (C1-C6)alkil(difluorometilen), (C1-C3)alkil(difluorometilen)(C1-C3)alkil, (C6-C10)aril, (C2-C9) heteroaril, (C6-C10)aril(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkil, (C6-C10)aril(C6-C10)aril, (C6-C10)aril(C6-C10)aril(C1-C6) alkil, hidroksi(C1-C6)alkil, (C1-C6)alkil(C=O)O-(C1-C6)alkil, (C1-C6)alkoksi(C=O)O-(C1-C6)alkil, (C6-C10) aril(C=O)O-(C1-C6)alkil, (C6-C10)ariloksi(C=O)O-(C1-C6)alkil, (C6-C10)aril(C1-C6)alkil(C=O)O-(C1-C6)alkil, (C6-C10)aril(C1-C6)alkoksi(C=O)O-(C1-C6)alkil, (C1-C6)alkoksi(C1-C6)alkil, (C6-C10)ariloksi(C1-C6)alkil, (C6-C10)aril(C1-C6)alkoksi(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkoksi(C1-C6)alkil, amino(C1-C6)alkil, (C1-C6) alkilamino(C1-C6)alkil, [(C1-C6)alkil]2amino(C1-C6)alkil, (C1-C6)alkil(C=O)NH(C1-C6)alkil, (C1-C6) alkoksi(C=O)NH(C1-C6)alkil, (C6-C10)aril(C=O)NH(C1-C6)alkil, (C6-C10)ariloksi(C=O)NH(C1-C6)alkil, (C6-C10) aril(C1-C6)alkil(C=O)NH(C1-C6)alkil, (C6-C10)aril(C1-C6)alkoksi(C=O)NH(C1-C6)alkil, (C1-C6) alkilsulfonil(C1-C6)alkil, (C6-C10)arilsulfonil(C1-C6)alkil, R5CO(C1-C6)alkil ili R8(C1-C6)alkil; ili R3 i R4 mogu biti uzeti zajedno s ugljikovim atomom na kojeg su vezani kako bi stvorili (C3-C6)cikloalkil ili benzo(C3-C6) cikloalkil prsten ili grupu formule [image] gdje je atom ugljika obilježen zvjezdicom ugljik na koji su vezani R3 i R4, "n" i "m" se neovisno biraju od brojeva 1 i 2, a X je CF2, O, SO2, ili NR9 gdje je R9 vodik, (C1-C6)alkil, (C6-C10)aril, (C2-C9)heteroaril, (C6-C10) aril(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkil, (C1-C6)alkilsulfonil, (C6-C10)arilsulfonil, (C1-C6)alkil(C=O)-, (C1-C6)alkoksi(C=O)-, (C6-C10)aril(C=O)-, (C6-C10)ariloksi(C=O)-, (C6-C10)aril(C1-C6)alkil(C=O)- ili (C6-C10) aril(C1-C6)alkoksi(C=O)-; gdje je svaki od navedenih (C6-C10)aril, (C2-C9)heteroaril ili (C3-C6)cikloalkil jedinica gdje se svaka od navedenih (C6-C10)aril, (C2-C9)heteroaril, (C6-C10)aril(C1-C6)alkil, (C2-C9) heteroaril(C1-C6) alkil, (C6-C10)aril(C6-C10)aril, (C6-C10)aril(C6-C10)aril(C1-C6)alkil, (C6-C10)aril(C=O)O-(C1-C6)alkil, (C6-C10)aril (C1-C6)alkil(C=O)O-(C1-C6)alkil, (C6-C10)aril(C1-C6)alkoksi(C=O)O-(C1-C6)alkil, (C6-C10)ariloksi-(C1-C6)alkil, (C6-C10)aril(C1-C6)alkoksi(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkoksi(C1-C6)alkil, (C6-C10)aril(C=O)NH(C1-C6)alkil, (C6-C10)aril(C1-C6)alkil(C=O)NH(C1-C6)alkil, (C6-C10)aril(C1-C6)alkoksi(C=O)NH(C1-C6)alkil, (C6-C10)arilsulfonil, (C6-C10)arilsulfonil(C1-C6)alkil, (C6-C10)aril(C=O)-, (C6-C10)aril(C1-C6)alkil(C=O)-, (C6-C10)aril(C1-C6)alkoksi (C=O)-, (C3-C6)cikloalkil ili benzo-(C3-C6)cikloalkil prsten može po volji biti zamijenjen na bilo kojem atomu prstena koji je sposoban formirati dodatnu vezu pomoću supstituenta (po mogućnosti jedan do tri supstituenta po prstenu) neovisno odabranog iz grupe fluoro, kloro, bromo, (C1-C6) alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi; ili kad su R3 i R4 uzeti zajedno s atomom ugljika na kojeg su spojeni čineći grupu formule [image] tada bilo koji atom ugljika gore navedenog prstena, koji je sposoban stvarati dodatnu vezu, može biti po volji zamijenjen supstiuentom (po mogućnosti od nula do tri supstituenta) neovisno odabranim iz grupe koja sadrži fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, perfluoro(C1-C3)alkoksi i (C6-C10) ariloksi; R5 je R6O ili R6R7N gdje su R6 i R7 svaki neovisno odabrani iz grupe vodik, (C1-C6)alkil, (C6-C10)aril(C1-C6) alkil ili (C2-C9)heteroaril(C1-C6)alkil; gdje je svaki od rečenih (C6-C10)aril i (C2-C9)heteroaril jedinka rečenog (C6-C10)aril(C1-C6)alkil ili (C2-C9)heteroaril(C1-C6)alkil grupe mogu biti po volji zamijenjene sa jednim ili više supstituenata neovisno odabranim iz grupe koja sadrži fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi; ili R6 i R7 uzeti zajedno s atomom dušika za kojeg su vezani formiraju opcionalno supstituirane heterocikličke spojeve kao npr. piperazinil, (C1-C6)alkilpiperazinil, (C6-C10)arilpiperazinil, (C2-C9)heteroarilpiperazinil, (C6-C10)aril(C1-C6)alkilpiperazinil, (C2-C9)heteroaril(C1-C6)alkilpiperazinil; (C1-C6)alkil(C=O)-piperazinil, (C1-C6)alkoksi(C=O)-piperazinil, (C6-C10)aril(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkil(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkoksi(C=O)-piperazinil, morfolinil, piperidinil, pirrolidinil ili azetidinil; gdje je svaki od rečenih piperazinil, (C1-C6)alkilpiperazinil, (C6-C10)arilpiperazinil, (C2-C9)heteroarilpiperazinil, (C6-C10) aril(C1-C6)alkilpiperazinil, (C2-C9)heteroaril(C1-C6)alkilpiperazinil; (C1-C6)alkil(C=O)-piperazinil, (C1-C6) alkoksi(C=O)-piperazinil, (C6-C10)aril(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkil(C=O)-piperazinil, (C6-C10) aril(C1-C6)alkoksi(C=O)-piperazinil, morfolinil, piperidinil, pirolidinil ili azetidinil mogu biti po volji zamijenjeni na bilo koji atom prstena ugljika, koji je sposoban stvarati dodatnu vezu, sa supstiuentom (po mogućnosti jedan do tri supstituenta po prstenu) neovisno odabranim iz grupe koja sadrži fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, ili perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi.; R8 je piperazinil, (C1-C6)alkilpiperazinil, (C6-C10)arilpiperazinil, (C2-C9)heteroarilpiperazinil, (C6-C10)aril(C1-C6) alkilpiperazinil, (C2-C9)heteroaril(C1-C6)alkilpiperazinil; (C1-C6)alkil(C=O)-piperazinil, (C1-C6) alkoksi(C=O)-piperazinil, (C6-C10)aril(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkil(C=O)-piperazinil, (C6-C10) aril(C1-C6) alkoksi(C=O)-piperazinil, morfolinil, piperidinil, pirolidinil, azetidinil, piperidil, (C1-C6) alkilpiperidil, (C6-C10) arilpiperidil, (C2-C9)heteroarilpiperidil, (C6-C10)aril(C1-C6)alkilpiperidil, (C2-C9) heteroaril(C1-C6)alkilpiperidil; (C1-C6)alkil(C=O)-piperidil, (C1-C6)alkoksi(C=O)-piperidil, (C6-C10)aril(C=O)-piperidi, (C6-C10)aril(C1-C6) alkil(C=O)-piperidil ili (C6-C10)aril(C1-C6)alkoksi(C=O)-piperidil, gdje je svaki od rečenih piperazinil, (C1-C6) alkilpiperazinil, (C6-C10)arilpiperazinil, (C2-C9)heteroarilpiperazinil, (C6-C10) aril(C1-C6)alkilpiperazinil, (C2-C9) heteroaril(C1-C6)alkilpiperazinil, (C1-C6)alkil(C=O)-piperazinil, (C1-C6) alkoksi(C=O)-piperazinil, (C6-C10) aril(C=O)-piperazinil, (C6-C10)aril(C1-C6)alkil(C=O)-piperazinil, (C6-C10) aril(C1-C6)alkoksi(C=O)-piperazinil, morfolinil, piperidinil, pirolidinil, azetidinil, piperidil, (C1-C6) alkilpiperidil, (C6-C10)arilpiperidil, (C2-C9) heteroarilpiperidil, (C6-C10)aril(C1-C6)alkilpiperidil, (C2-C9) heteroaril(C1-C6)alkilpiperidil; (C1-C6)alkil(C=O)-piperidil, (C1-C6)alkoksi(C=O)-piperidil, (C6-C10)aril(C=O)-piperidil, (C6-C10)aril(C1-C6)alkil(C=O)-piperidil i (C6-C10)aril(C1-C6)alkoksi(C=O)-piperidil mogu biti po volji zamijenjeni na bilo koji atom prstena ugljika, koji je sposoban stvarati dodatnu vezu, sa supstiuentom (po mogućnosti jedan do tri supstituenta po prstenu) neovisno odabranim iz grupe koja sadrži fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3) alkil ili perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi; Q je (C1-C6)alkil, (C6-C10)aril, (C6-C10)ariloksi(C6-C10)aril, (C6-C10)aril(C6-C10)aril, (C6-C10)aril(C6-C10) aril(C1-C6)alkil, (C6-C10)ariloksi(C2-C9)heteroaril, (C2-C9)heteroaril, (C2-C9)heteroaril(C2-C9)heteroaril, (C1-C6)alkil (C6-C10)aril, (C1-C6)alkoksi(C6-C10)aril, (C6-C10)aril(C1-C6)alkoksi(C6-C10)aril, (C6-C10)aril(C1-C6) alkoksi(C1-C6)alkil, (C2-C9)heteroariloksi(C6-C10)aril, (C1-C6)alkil(C2-C9)heteroaril, (C1-C6)alkoksi(C2-C9) heteroaril, (C6-C10)aril(C1-C6)alkoksi(C2-C9)heteroaril, (C2-C9)heteroariloksi(C2-C9)heteroaril, (C6-C10) ariloksi(C1-C6)alkil, (C2-C9)heteroariloksi(C1-C6)alkil, (C1-C6)alkil(C6-C10)ariloksi(C6-C10)aril, (C1-C6) alkil(C2-C9)heteroariloksi(C6-C10)aril, (C1-C6)alkil(C6-C10) (C2-C9)heteroaril, (C1-C6)alkoksi(C6-C10) ariloksi(C6-C10)aril, (C1-C6)alkoksi (C2-C9)heteroariloksi(C6-C10)aril ili (C1-C6)alkoksi(C6-C10)ariloksi(C2-C9) heteroaril gdje svaka (C6-C10)aril ili (C2-C9)heteroaril jedinica navedenih (C6-C10)aril, (C6-C10)ariloksi(C6-C10) aril, (C6-C10)aril(C6-C10)aril, (C6-C10) aril(C6-C10)aril(C1-C6)alkil, (C6-C10)ariloksi(C2-C9)heteroaril, (C2-C9) heteroaril, (C1-C6)alkil(C6-C10)aril, (C1-C6) alkoksi(C6-C10)aril, (C6-C10)aril(C1-C6)alkoksi(C6-C10)aril, (C6-C10) aril(C1-C6)alkoksi(C1-C6)alkil, (C2-C9) heteroariloksi(C6-C10)aril, (C1-C6)alkil(C2-C9)heteroaril, (C1-C6) alkoksi(C2-C9)heteroaril, (C6-C10)aril(C1-C6) alkoksi(C2-C9)heteroaril(C2-C9)heteroariloksi(C2-C9)heteroaril, (C6-C10)ariloksi(C1-C6)alkil, (C2-C9) heteroariloksi(C1-C6)alkil, (C1-C6)alkil(C6-C10)ariloksi(C6-C10)aril, (C1-C6)alkil(C2-C9)heteroariloksi(C6-C10)aril, (C1-C6)alkil(C6-C10) (C2-C9)heteroaril, (C1-C6)alkoksi(C6-C10) ariloksi(C6-C10)aril, (C1-C6)alkoksi(C2-C9) heteroariloksi(C6-C10)aril ili (C1-C6)alkoksi(C6-C10)ariloksi(C2-C9) heteroarila supstituirana na svakom atomu ugljika u prstenu koji je sposoban da stvori dodatnu vezu s jednim ili više supstituenata (preferirano jedan do tri supstituenta) neovisno odabranih između fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3) alkil, perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi; uzevši u obzir da ako su R3 ili R4 vodici, ili su oba R3 i R4 vodici, onda R1 i R2 ne mogu oba biti vodici, ili R1 mora biti hidroksi, (C1-C6)alkoksi, (C6-C10)aril(C1-C6)alkoksi, (C1-C6)alkil(C=O)O-(C1-C6)alkil, (C1-C6) alkoksi(C=O)O-(C1-C6)alkil, (C6-C10)aril(C=O)O-(C1-C6)alkil, (C6-C10)ariloksi(C=O)O-(C6-C10)arilalkil(C=O) O-(C1-C6)alkil ili (C6-C10)arilalkoksi(C=O)O-(C1-C6)alkil; ili njihova farmaceutski prihvatljiva sol.1. Compound formula [image] characterized in that R1 is hydrogen, hydroxy, (C6-C10) aryl(C1-C6) alkoxy, (C1-C6) alkoxy, (C1-C6) alkyl(C=O)O-, (C1-C6)alkoxy( C=O)O-, (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-, (C6-C10)aryl(C1-C6) alkyl(C= O)O- or (C6-C10)aryl(C1-C6)alkoxy(C=O)O-; wherein said aryl in said is (C6-C10)aryl(C1-C6) alkoxy, (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-, (C6- C10)aryl(C1-C6)alkyl(C=O)O- or (C6-C10)aryl(C1-C6) alkoxy(C=O)O-, where the aryl unit of all these groups is optionally replaced by one or more substituents (preferably one to three substituents) independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6) alkoxy, perfluoro(C1-C3)alkyl perfluoro(C1-C3)alkoxy and (C6-C10) )aryloxy; R 2 is hydrogen or (C 1 -C 6 )alkyl; R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, (C1-C6)alkyl(difluoromethylene), (C1-C3)alkyl(difluoromethylene) (C1-C3)alkyl, (C6-C10)aryl, (C2-C9) heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C6- C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6) alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkyl(C=O)O- (C1-C6)alkyl, (C1-C6)Alkoxy(C=O)O-(C1-C6)alkyl, (C6-C10) aryl(C=O)O-(C1-C6)alkyl, (C6- C10)aryloxy(C=O)O-(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl(C=O)O-(C1-C6)alkyl, (C6-C10)aryl( C1-C6)Alkoxy(C=O)O-(C1-C6)Alkyl, (C1-C6)Alkoxy(C1-C6)Alkyl, (C6-C10)Aryloxy(C1-C6)Alkyl, (C6-C10) Aryl(C1-C6)Alkoxy(C1-C6)Alkyl, (C2-C9)Heteroaryl(C1-C6)Alkoxy(C1-C6)Alkyl, Amino(C1-C6)Alkyl, (C1-C6)Alkylamino(C1- C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, (C1-C6)alkyl(C=O)NH(C1-C6)alkyl, (C1-C6) alkoxy(C=O) NH(C1-C6)alkyl, (C6-C10)aryl(C=O)NH(C1-C6)alkyl, (C6-C10)aryloxy(C=O)NH(C1-C6)alkyl, (C6-C10 ) aryl(C1-C6)alkyl(C= O)NH(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C=O)NH(C1-C6)alkyl, (C1-C6) alkylsulfonyl(C1-C6)alkyl, (C6 -C10)arylsulfonyl(C1-C6)alkyl, R5CO(C1-C6)alkyl or R8(C1-C6)alkyl; or R3 and R4 may be taken together with the carbon atom to which they are attached to form a (C3-C6)cycloalkyl or benzo(C3-C6)cycloalkyl ring or group of the formula [image] where the asterisked carbon atom is the carbon to which R3 and R4 are attached, "n" and "m" are independently selected from 1 and 2, and X is CF2, O, SO2, or NR9 where R9 is hydrogen, (C1- C6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C1-C6)alkylsulfonyl , (C6-C10)arylsulfonyl, (C1-C6)alkyl(C=O)-, (C1-C6)alkoxy(C=O)-, (C6-C10)aryl(C=O)-, (C6- C10)aryloxy(C=O)-, (C6-C10)aryl(C1-C6)alkyl(C=O)- or (C6-C10)aryl(C1-C6)alkoxy(C=O)-; where each of said (C6-C10)aryl, (C2-C9)heteroaryl or (C3-C6)cycloalkyl units where each of said (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10) aryl(C1-C6)alkyl, (C2-C9) heteroaryl(C1-C6) alkyl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6 )alkyl, (C6-C10)aryl(C=O)O-(C1-C6)alkyl, (C6-C10)aryl (C1-C6)alkyl(C=O)O-(C1-C6)alkyl, ( C6-C10)aryl(C1-C6)Alkoxy(C=O)O-(C1-C6)alkyl, (C6-C10)aryloxy-(C1-C6)alkyl, (C6-C10)aryl(C1-C6) Alkoxy(C1-C6)alkyl, (C2-C9)Heteroaryl(C1-C6)Alkoxy(C1-C6)Alkyl, (C6-C10)Aryl(C=O)NH(C1-C6)Alkyl, (C6-C10 )aryl(C1-C6)alkyl(C=O)NH(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C=O)NH(C1-C6)alkyl, (C6-C10 )arylsulfonyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, (C6-C10)aryl(C=O)-, (C6-C10)aryl(C1-C6)alkyl(C=O)-, (C6 The -C10)aryl(C1-C6)alkoxy (C=O)-, (C3-C6)cycloalkyl or benzo-(C3-C6)cycloalkyl ring may optionally be substituted on any ring atom capable of forming an additional bond by of substituents (preferably one to three substituents per ex rock) independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6) alkyl, (C1-C6) alkoxy, perfluoro(C1-C3) alkyl, perfluoro(C1-C3) alkoxy and (C6-C10) aryloxy; or when R 3 and R 4 are taken together with the carbon atom to which they are attached to form a group of the formula [image] then any carbon atom of the above ring, which is capable of forming an additional bond, may be optionally replaced by a substituent (preferably from zero to three substituents) independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 3 )alkyl, perfluoro(C 1 -C 3 )alkoxy and (C 6 -C 10 )aryloxy; R 5 is R 6 O or R 6 R 7 N where R 6 and R 7 are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein each of said (C6-C10)aryl and (C2-C9)heteroaryl units of said (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl groups may be optional substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 3 )alkyl, perfluoro (C 1 -C 3 ) alkoxy and (C 6 -C10)aryloxy; or R6 and R7 taken together with the nitrogen atom to which they are attached form optionally substituted heterocyclic compounds such as piperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (C6-C10)aryl (C1-C6)alkylpiperazinyl, (C2-C9)heteroaryl(C1-C6)alkylpiperazinyl; (C1-C6)Alkyl(C=O)-piperazinyl, (C1-C6)Alkoxy(C=O)-piperazinyl, (C6-C10)aryl(C=O)-piperazinyl, (C6-C10)aryl(C1 -C6)alkyl(C=O)-piperazinyl, (C6-C10)aryl(C1-C6)alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl; wherein each of said piperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (C6-C10)aryl(C1-C6)alkylpiperazinyl, (C2-C9)heteroaryl(C1- C6)alkylpiperazinyl; (C1-C6)alkyl(C=O)-piperazinyl, (C1-C6) alkoxy(C=O)-piperazinyl, (C6-C10)aryl(C=O)-piperazinyl, (C6-C10)aryl(C1 -C6)alkyl(C=O)-piperazinyl, (C6-C10)aryl(C1-C6)alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl may be optionally substituted at any carbon ring atom , which is capable of forming an additional bond, with a substituent (preferably one to three substituents per ring) independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, perfluoro(C1- C3)alkyl, or perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy.; R8 is piperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (C6-C10)aryl(C1-C6)alkylpiperazinyl, (C2-C9)heteroaryl(C1-C6)alkylpiperazinyl ; (C1-C6)alkyl(C=O)-piperazinyl, (C1-C6) alkoxy(C=O)-piperazinyl, (C6-C10)aryl(C=O)-piperazinyl, (C6-C10)aryl(C1 -C6)alkyl(C=O)-piperazinyl, (C6-C10) aryl(C1-C6) alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperidyl, (C1-C6) alkylpiperidyl, ( C6-C10) arylpiperidyl, (C2-C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C2-C9)heteroaryl(C1-C6)alkylpiperidyl; (C1-C6)alkyl(C=O)-piperidyl, (C1-C6)alkoxy(C=O)-piperidyl, (C6-C10)aryl(C=O)-piperidyl, (C6-C10)aryl(C1 -C6) alkyl(C=O)-piperidyl or (C6-C10)aryl(C1-C6)alkoxy(C=O)-piperidyl, wherein each of said piperazinyl, (C1-C6) alkylpiperazinyl, (C6-C10 )arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (C6-C10)aryl(C1-C6)alkylpiperazinyl, (C2-C9)heteroaryl(C1-C6)alkylpiperazinyl, (C1-C6)alkyl(C=O)-piperazinyl, (C1-C6) alkoxy(C=O)-piperazinyl, (C6-C10) aryl(C=O)-piperazinyl, (C6-C10)aryl(C1-C6)alkyl(C=O)-piperazinyl, (C6 -C10) aryl(C1-C6)alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperidyl, (C1-C6) alkylpiperidyl, (C6-C10)arylpiperidyl, (C2-C9) heteroarylpiperidyl, ( C6-C10)aryl(C1-C6)alkylpiperidyl, (C2-C9)heteroaryl(C1-C6)alkylpiperidyl; (C1-C6)alkyl(C=O)-piperidyl, (C1-C6)alkoxy(C=O)-piperidyl, (C6-C10)aryl(C=O)-piperidyl, (C6-C10)aryl(C1 -C6)alkyl(C=O)-piperidyl and (C6-C10)aryl(C1-C6)alkoxy(C=O)-piperidyl can be optionally substituted on any carbon ring atom, which is capable of forming an additional bond, with a substituent (preferably one to three substituents per ring) independently selected from the group consisting of fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, perfluoro(C 1 -C 3 )alkyl or perfluoro(C 1 - C3) alkoxy and (C6-C10) aryloxy; Q is (C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6 -C10) aryl(C1-C6)alkyl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C1-C6)alkyl (C6-C10)Aryl, (C1-C6)Alkoxy(C6-C10)Aryl, (C6-C10)Aryl(C1-C6)Alkoxy(C6-C10)Aryl, (C6-C10)Aryl(C1-C6) Alkoxy(C1-C6)alkyl, (C2-C9)Heteroaryloxy(C6-C10)aryl, (C1-C6)Alkyl(C2-C9)Heteroaryl, (C1-C6)Alkoxy(C2-C9) Heteroaryl, (C6- C10)Aryl(C1-C6)Alkoxy(C2-C9)Heteroaryl, (C2-C9)Heteroaryloxy(C2-C9)Heteroaryl, (C6-C10) Aryloxy(C1-C6)Alkyl, (C2-C9)Heteroaryloxy(C1 -C6)alkyl, (C1-C6)alkyl(C6-C10)aryloxy(C6-C10)aryl, (C1-C6)alkyl(C2-C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl( C6-C10) (C2-C9)heteroaryl, (C1-C6)Alkoxy(C6-C10) aryloxy(C6-C10)aryl, (C1-C6)Alkoxy (C2-C9)heteroaryloxy(C6-C10)aryl or ( C1-C6)Alkoxy(C6-C10)aryloxy(C2-C9) heteroaryl where each (C6-C10)aryl or (C2-C9)heteroaryl unit of said (C6-C10)aryl, (C6-C10)aryloxy(C6- C10) aryl, (C6-C10) aryl(C6-C10)aryl, (C6-C10) aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9) heteroaryl, (C1- C6)Alkyl(C6-C10)aryl, (C1-C6)Alkoxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)Alkoxy(C6-C10)aryl, (C6-C10) aryl(C1 -C6)Alkoxy(C1-C6)alkyl, (C2-C9)Heteroaryloxy(C6-C10)Aryl, (C1-C6)Alkyl(C2-C9)Heteroaryl, (C1-C6)Alkoxy(C2-C9)Heteroaryl, (C6-C10)Aryl(C1-C6)Alkoxy(C2-C9)Heteroaryl(C2-C9)Heteroaryloxy(C2-C9)Heteroaryl, (C6-C10)Aryloxy(C1-C6)Alkyl, (C2-C9)Heteroaryloxy (C1-C6)alkyl, (C1-C6)alkyl(C6-C10)aryloxy(C6-C10)aryl, (C1-C6)alkyl(C2-C9)heteroaryloxy(C6-C10)aryl, (C1-C6) alkyl(C6-C10) (C2-C9) heteroaryl, (C1-C6) alkoxy(C6-C10) aryloxy(C6-C10) aryl, (C1-C6) alkoxy(C2-C9) heteroaryloxy(C6-C10) aryl or (C1-C6)Alkoxy(C6-C10)aryloxy(C2-C9) heteroaryl substituted at each ring carbon atom capable of forming an additional bond with one or more substituents (preferably one to three substituents) independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C 1-C6)Alkoxy, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)Alkoxy and (C6-C10)aryloxy; provided that if R 3 or R 4 is hydrogen, or both R 3 and R 4 are hydrogen, then R 1 and R 2 cannot both be hydrogen, or R 1 must be hydroxy, (C 1 -C 6 ) alkoxy, (C 6 -C 10 )aryl(C 1 -C6)Alkoxy, (C1-C6)Alkyl(C=O)O-(C1-C6)Alkyl, (C1-C6)Alkoxy(C=O)O-(C1-C6)Alkyl, (C6-C10) aryl(C=O)O-(C1-C6)alkyl, (C6-C10)aryloxy(C=O)O-(C6-C10)arylalkyl(C=O)O-(C1-C6)alkyl or (C6 -C 10 ) arylalkoxy (C=O) O -(C 1 -C 6 ) alkyl; or a pharmaceutically acceptable salt thereof.

2. Spoj iz zahtjeva 1, karakteriziran time da je R1 OH a R2 vodik.2. The compound of claim 1, characterized in that R1 is OH and R2 is hydrogen.

3. Spoj iz zahtjeva 1, karakteriziran time da su R3 i R4 uzeti zajedno s ugljikovim atomom na kojeg su vezani kako bi stvorili po volji supstituirani (C3-C6)cikloalkil ili benzo(C3-C6)cikloalkil prsten ili grupu formule [image] gdje su "n" i "m" se neovisno birani od brojeva 1 i 2 a X je CF2, O, SO2, ili NR9 gdje je R9 vodik, (C1-C6)alkil, (C6-C10)aril, (C2-C9)heteroaril, (C6-C10)aril(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkil, (C1-C6)alkilsulfonil, (C6-C10)arilsulfonil, (C1-C6)alkil(C=O)-, (C1-C6)alkoksi(C=O)-, (C6-C10)aril(C=O)-, (C6-C10)aril(C1-C6) alkil(C=O)- ili (C6-C10)aril(C1-C6)alkoksi(C=O)-; gdje se svaka od navedenih (C6-C10)aril i (C2-C9)heteroaril jedinica u navedenim (C6-C10)aril, (C2-C9)heteroaril, (C6-C10)aril(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkil, (C6-C10)arilsulfonil, (C6-C10)aril(C=O)-, (C6-C10)aril(C1-C6)alkil(C=O)-, (C6-C10)aril(C1-C6)alkoksi(C=O)-, grupama može po volji zamijeniti s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, perfluoro(C1-C3)alkoksi i (C6-C10) ariloksi.3. The compound of claim 1, characterized in that R3 and R4 are taken together with the carbon atom to which they are attached to form an optionally substituted (C3-C6)cycloalkyl or benzo(C3-C6)cycloalkyl ring or group of the formula [image] where "n" and "m" are independently selected from numbers 1 and 2 and X is CF2, O, SO2, or NR9 where R9 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C2- C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, (C1-C6)alkyl (C=O)-, (C1-C6)Alkoxy(C=O)-, (C6-C10)aryl(C=O)-, (C6-C10)aryl(C1-C6) alkyl(C=O) - or (C6-C10) aryl(C1-C6) alkoxy(C=O)-; where each of said (C6-C10)aryl and (C2-C9)heteroaryl units in said (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2 -C9)heteroaryl(C1-C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)aryl(C=O)-, (C6-C10)aryl(C1-C6)alkyl(C=O)-, (C6-C10)aryl(C1-C6) alkoxy (C=O)-, groups can be optionally replaced with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1 -C6)Alkoxy, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)Alkoxy and (C6-C10)aryloxy.

4. Spoj iz zahtjeva 2, karakteriziran time da su R3 i R4 oba (C1-C6)alkil, ili su R3 i R4 uzeti zajedno s ugljikovim atomom na kojeg su vezani kako bi stvorili po volji supstituirani (C3-C6)cikloalkil ili benzo(C3-C6)cikloalkil prsten ili grupu formule [image] gdje su "n" i "m" se neovisno odabrani od brojeva 1 i 2 a X je CF2, O, SO2, ili NR9 gdje je R9 vodik, (C1-C6) alkil, (C6-C10)aril, (C2-C9)heteroaril, (C6-C10)aril(C1-C6)alkil, (C2-C9)heteroaril(C1-C6)alkil, (C1-C6) alkilsulfonil, (C6-C10)arilsulfonil, (C1-C6)alkil(C=O)-, (C1-C6)alkoksi(C=O)-, (C6-C10)aril(C=O)-, (C6-C10) aril(C1-C6)alkil (C=O)- ili (C6-C10)aril(C1-C6)alkoksi(C=O)-; gdje se svaka od navedenih (C6-C10)aril ili (C2-C9)heteroaril jedinica u navedenim (C6-C10)aril, (C2-C9)heteroalkil, (C6-C10)aril(C1-C6)alkil, (C2-C9) heteroaril(C1-C6)alkil, (C6-C10)arilsulfonil, (C6-C10)aril(C=O)-, (C6-C10)aril(C1-C6)alkil(C=O)-, (C6-C10) aril(C1-C6)alkoksi(C=O)- grupama može po volji neovisno zamijeniti s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, perfluoro(C1-C3)alkil, perfluoro(C1-C3)alkoksi i (C6-C10)ariloksi.4. The compound of claim 2, characterized in that R 3 and R 4 are both (C 1 -C 6 )alkyl, or R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted (C 3 -C 6 )cycloalkyl or benzo (C3-C6)cycloalkyl ring or group of the formula [image] where "n" and "m" are independently selected from numbers 1 and 2 and X is CF2, O, SO2, or NR9 where R9 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C2- C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C1-C6) alkylsulfonyl, (C6-C10)arylsulfonyl, (C1-C6)alkyl (C=O)-, (C1-C6)Alkoxy(C=O)-, (C6-C10)aryl(C=O)-, (C6-C10) aryl(C1-C6)alkyl (C=O) - or (C6-C10) aryl(C1-C6) alkoxy(C=O)-; where each of said (C6-C10)aryl or (C2-C9)heteroaryl units in said (C6-C10)aryl, (C2-C9)heteroalkyl, (C6-C10)aryl(C1-C6)alkyl, (C2 -C9) heteroaryl(C1-C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)aryl(C=O)-, (C6-C10)aryl(C1-C6)alkyl(C=O)-, (C6-C10) aryl(C1-C6) alkoxy (C=O)- groups can be independently substituted at will with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1 -C6)Alkoxy, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)Alkoxy and (C6-C10)aryloxy.

5. Spoj iz zahtjeva 1, karakteriziran time da su R3 i R4 uzeti zajedno kako bi stvorili po volji supstituirani (C3-C6)cikloalkil prsten.5. The compound of claim 1, characterized in that R 3 and R 4 are taken together to form an optionally substituted (C 3 -C 6 )cycloalkyl ring.

6. Spoj iz zahtjeva 2, karakteriziran time da su R3 i R4 uzeti zajedno kako bi stvorili po volji supstituirani (C3-C6)cikloalkil prsten.6. The compound of claim 2, characterized in that R 3 and R 4 are taken together to form an optionally substituted (C 3 -C 6 )cycloalkyl ring.

7. Spoj iz zahtjeva 1, karakteriziran time da je Q (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril, gdje se svaka (C6-C10)aril jedinica navedenih (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril grupa može po volji zamijeniti s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, ili perfluoro(C1-C3)alkil.7. The compound of claim 1, characterized in that Q is (C6-C10)aryl or (C6-C10)aryloxy(C6-C10)aryl, where each (C6-C10)aryl unit of said (C6-C10)aryl or The (C 6 -C 10 )aryloxy (C 6 -C 10 )aryl group may optionally be substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or perfluoro (C1-C3)alkyl.

8. Spoj iz zahtjeva 2, karakteriziran time da je Q (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril, gdje se svaka (C6-C10)aril jedinica navedenih (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril grupa može po volji zamijeniti s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, ili perfluoro(C1-C3)alkil.8. The compound of claim 2, characterized in that Q is (C6-C10)aryl or (C6-C10)aryloxy(C6-C10)aryl, where each (C6-C10)aryl unit of said (C6-C10)aryl or The (C 6 -C 10 )aryloxy (C 6 -C 10 )aryl group may optionally be substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or perfluoro (C1-C3)alkyl.

9. Spoj iz zahtjeva 3, karakteriziran time da je Q (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril, gdje se svaka (C6-C10)aril jedinica navedenih (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril grupa može po volji zamijeniti s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, ili perfluoro(C1-C3)alkil.9. The compound of claim 3, characterized in that Q is (C6-C10)aryl or (C6-C10)aryloxy(C6-C10)aryl, where each (C6-C10)aryl unit of said (C6-C10)aryl or The (C 6 -C 10 )aryloxy (C 6 -C 10 )aryl group may optionally be substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or perfluoro (C1-C3)alkyl.

10. Spoj iz zahtjeva 4, karakteriziran time da je Q (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril, gdje se svaka (C6-C10)aril jedinica navedenih (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril grupa može po volji zamijeniti s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, Spoj iz zahtjeva 5, karakteriziran time da je Q (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril, gdje se svaka (C6-C10)aril jedinica navedenih (C6-C10)aril ili (C6-C10)ariloksi(C6-C10)aril grupa može po volji zamijeniti s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, ili perfluoro(C1-C3)alkil.10. The compound of claim 4, characterized in that Q is (C6-C10)aryl or (C6-C10)aryloxy(C6-C10)aryl, where each (C6-C10)aryl unit of said (C6-C10)aryl or The (C6-C10)aryloxy(C6-C10)aryl group can optionally be replaced by one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl. The compound of claim 5, characterized in that Q (C6-C10)aryl or (C6-C10)aryloxy(C6-C10)aryl, where each (C6-C10)aryl unit of said (C6-C10)aryl or (C6-C10)aryloxy(C6-C10) the aryl group may optionally be replaced by one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6) alkoxy, or perfluoro(C1-C3)alkyl.

11. Spoj iz zahtjeva 1, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, ili perfluoro(C1-C3)alkil.11. The compound of claim 1, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, or perfluoro(C1-C3)alkyl.

12. Spoj iz zahtjeva 2, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, ili perfluoro(C1-C3)alkil.12. The compound of claim 2, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, or perfluoro(C1-C3)alkyl.

13. Spoj iz zahtjeva 3, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, ili perfluoro(C1-C3)alkil.13. The compound of claim 3, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, or perfluoro(C1-C3)alkyl.

14. Spoj iz zahtjeva 4, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, ili perfluoro(C1-C3)alkil.14. The compound of claim 4, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, or perfluoro(C1-C3)alkyl.

15. Spoj iz zahtjeva 5, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, ili perfluoro(C1-C3)alkil.15. The compound of claim 5, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, or perfluoro(C1-C3)alkyl.

16. Spoj iz zahtjeva 8, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi, ili perfluoro(C1-C3)alkil.16. The compound of claim 8, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, or perfluoro(C1-C3)alkyl.

17. Spoj iz zahtjeva 1, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, (C1-C6)alkoksi, ili (C1-C6)alkil.17. The compound of claim 1, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6) alkoxy, or (C1-C6) alkyl.

18. Spoj iz zahtjeva 2, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, (C1-C6)alkoksi, ili (C1-C6)alkil.18. The compound of claim 2, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6) alkoxy, or (C1-C6) alkyl.

19. Spoj iz zahtjeva 5, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, (C1-C6)alkoksi, ili (C1-C6)alkil.19. The compound of claim 5, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6) alkoxy, or (C1-C6) alkyl.

20. Spoj iz zahtjeva 8, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, (C1-C6)alkoksi, ili (C1-C6)alkil.20. The compound of claim 8, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6) alkoxy, or (C1-C6) alkyl.

21. Spoj iz zahtjeva 1, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, (C1-C6)alkoksi, ili (C1-C6)alkil, s time da je supstituent u položaju 4.21. The compound of claim 1, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6) alkoxy, or (C1-C6) alkyl, with that the substituent is in position 4.

22. Spoj iz zahtjeva 2, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, (C1-C6)alkoksi, ili (C1-C6)alkil, s time da je supstituent u položaju 4.22. The compound of claim 2, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6) alkoxy, or (C1-C6) alkyl, with that the substituent is in position 4.

23. Spoj iz zahtjeva 5, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, (C1-C6)alkoksi, ili (C1-C6)alkil, s time da je supstituent u položaju 4.23. The compound of claim 5, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6) alkoxy, or (C1-C6) alkyl, with that the substituent is in position 4.

24. Spoj iz zahtjeva 8, karakteriziran time da je Q fenil ili fenoksifenil po volji supstituiran s jednim ili više supstituenata neovisno odabranih iz grupe koja obuhvaća fluoro, kloro, (C1-C6)alkoksi, ili (C1-C6)alkil, s time da je supstituent u položaju 4.24. The compound of claim 8, characterized in that Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6) alkoxy, or (C1-C6) alkyl, with that the substituent is in position 4.

25. Spoj iz zahtjeva 1, karakteriziran time da je odabran iz grupe koja obuhvaća: (2S)-2,N-dihidroksi-3-(4-metoksibenzensulfonil)propionamid; 3-[4-(4-fluorofenoksi)fenilsulfonil]2,N-dihidroksipropionamid; 2,N-dihidroksi-2-[1-(4-metoksibenzensulfonil)ciklobutil]acetamid; 2,N-dihidroksi-2-[1-(4-metoksibenzensulfonil)ciklopentil]acetamid; 2-[1-(4-ciklobutoksibenzensulfonil)ciklobutil]-2,N-dihidroksiacetamid; 2-[1-(4-butoksibenzensulfonil)ciklobutil]-2,N-dihidroksiacetamid; 2-{1-[4-(4-fluorofenoksi)benzensulfonil]ciklobutil}-2,N-dihidroksiacetamid; ili 2-{1-[4-(4-fluorofenoksi)benzensulfonil]ciklopentil}-2,N-dihidroksiacetamid.25. The compound of claim 1, characterized in that it is selected from the group comprising: (2S)-2,N-dihydroxy-3-(4-methoxybenzenesulfonyl)propionamide; 3-[4-(4-fluorophenoxy)phenylsulfonyl]2,N-dihydroxypropionamide; 2,N-dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclobutyl]acetamide; 2,N-dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclopentyl]acetamide; 2-[1-(4-cyclobutoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide; 2-[1-(4-butoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide; 2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclobutyl}-2,N-dihydroxyacetamide; or 2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclopentyl}-2,N-dihydroxyacetamide.

27. Farmaceutski pripravak karakteriziran time da služi za: (a) tretman stanja odabranih iz grupe koja sadrži artritis, osteoporozu, rak, sinergiju sa citotoksičnim antikancerogenim agensima, tkivni vrijed, makularnu degradaciju, restenozu, periodontalnu bolest, epidermolizis bullosa, skleritis, u kombinaciji sa standardnim NSAID'S i analgeticima i u ostalim bolestima karakteriziranim matriks metaloproteaznom aktivnošću, AIDS, sepsa, septički šok i ostale bolesti koje uključuju proizvodnju faktora nekroze tumora (TNF); ili (b) inhibiciju matriks metaloproteinaze ili proizvodnje faktora nekroze tumora (TNF) u sisavaca, uključujući čovjeka, a koji sadrži određenu količinu spoja formule I ili njegove farmaceutski prihvatljivu sol djelotvornog za takav tretman i farmaceutski prihvatljiv nosač.27. A pharmaceutical composition characterized in that it serves for: (a) treatment of conditions selected from the group consisting of arthritis, osteoporosis, cancer, synergy with cytotoxic anticancer agents, tissue ulcer, macular degradation, restenosis, periodontal disease, epidermolysis bullosa, scleritis, in combination with standard NSAIDs and analgesics and in other diseases characterized by matrix metalloprotease activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF); or (b) inhibition of matrix metalloproteinase or tumor necrosis factor (TNF) production in mammals, including humans, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective for such treatment and a pharmaceutically acceptable carrier.

28. Metoda inhibicije: (a) matriks metaloproteinaze; ili (b) proizvodnje faktora nekroze tumora (TNF) u sisavaca, uključujući čovjeka, karakterizirana time da se navedeni sisavac tretira djelotvornom količinom spoja formule I.28. Inhibition method: (a) matrix metalloproteinase; or (b) production of tumor necrosis factor (TNF) in a mammal, including a human, characterized by treating said mammal with an effective amount of a compound of formula I.

29. Metoda tretiranja stanja odabranih iz grupe koja sadrži artritis, osteoporozu, rak, tkivni vrijed, makularnu degradaciju, restenozu, periodontalnu bolest, epidremolizis bullosa, skleritis, spojevi formule I mogu se koristiti u kombinaciji sa standardnim NSAID'S i analgesticima u kombinaciji s citotoksičnim antitumorskim agensima, i kod ostalih bolesti karakteriziranih aktivnošću matriks metaloproteinaze, AIDS, sepsu, septički šok i ostale bolesti koje uključuju proizvodnju faktora nekroze tumora (TNF) u sisavaca, uključujući čovjeka, karakterizirana time što se navedeni sisavac tretira djelotvornom količinom spoja formule I ili njegove farmaceutski prihvatljive soli, djelotvornog u tretmanu takvog stanja.29. A method of treating conditions selected from the group consisting of arthritis, osteoporosis, cancer, tissue ulcer, macular degradation, restenosis, periodontal disease, epidremolisis bullosa, scleritis, compounds of formula I can be used in combination with standard NSAIDs and analgesics in combination with cytotoxic antitumor agents, and in other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in mammals, including humans, characterized in that said mammal is treated with an effective amount of a compound of formula I or its pharmaceutical acceptable salt, effective in the treatment of such a condition.