HRP950259A2 - Hydroxamic acid and amino acid derivatives and their use as anti-arthritic agents - Google Patents

Hydroxamic acid and amino acid derivatives and their use as anti-arthritic agents Download PDF

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HRP950259A2
HRP950259A2 HRP950259A HRP950259A2 HR P950259 A2 HRP950259 A2 HR P950259A2 HR P950259 A HRP950259 A HR P950259A HR P950259 A2 HRP950259 A2 HR P950259A2
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David John Nelson
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David John Nelson
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Područje tehnike The field of technology

Predmet ovog izuma su male molekule koje inhibiraju metaloproteinaze matriksa, farmaceutski pripravci koji ili sadrže i njihova upotreba kao farmaceutskih sredstava. The subject of this invention are small molecules that inhibit matrix metalloproteinases, pharmaceutical preparations that contain or contain them, and their use as pharmaceutical agents.

Stanje tehnike State of the art

Postoje dokazi da stromelizin (MMP-3) i druge metaloproteinaze (MMP) imaju veliku ulogu u nekoniroliranom propadanju vezivnog tkiva, uključujući i proteoglikan i kolagen, što dovodi do resorpcije izvanstaničnog matriksa. To je svojstveno mnogim patološkim stanjima, kao što su reumatoidni ili osteoartrilis, rožnični ulkus, epidermalni ili želučani ulkus; tumorske metastaze ili invazija; bolesti periodonta ili kostiju. Obično se regulacija tih kataboličkih enzima vrši tijekom njihove sinteze, kao i za vrijeme njihove izvanstanične aktivnosti putem djelovanja specifičnih inhibitora, kao što su alfa-2-makroglobulini i TIMP (tkivni inhibitor metaloproteinaze matriksa), koji stvaraju neaktivne komplekse s MMP-ovima. There is evidence that stromelysin (MMP-3) and other metalloproteinases (MMPs) play a major role in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to extracellular matrix resorption. This is characteristic of many pathological conditions, such as rheumatoid or osteoarthritis, corneal ulcer, epidermal or gastric ulcer; tumor metastasis or invasion; periodontal or bone diseases. Usually, the regulation of these catabolic enzymes is carried out during their synthesis, as well as during their extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of matrix metalloproteinase), which create inactive complexes with MMPs.

Osteo- i reumatoidni artritis (odnosno OA i RA) su bolesti koje razgrađuju zglobne hrskavice, a obilježava ih lokalizirana erozija hrskavične površine. Istraživanja su pokazala da je zglobna hrskavica glave bedrene kosti kod ljudi koji su imali OA, na primjer, pokazivala tijekom kontrola smanjeno spajanje radiooznačenog sulfata, što je ukazivalo na činjenicu da mora postojati povećani stupanj razgradnje hrskavice kod OA-a (Mankin i sur., J. Bone Joint Surg. 52A, 1970, 424-434). Postoje četiri vrste razgradnih enzima proteina u stanicama sisavaca: serin, cistein, asparaginska kiselina i metaloproteinaza. Postojeće spoznaje dokazuju da su metaloproteinaze odgovorne za razgradnju izvanstaničnog matriksa zglobne hrskavice kod OA i RA. Uvećana aktivnost kolagenaze i stromelizina otkrivena je u OA hrsksvici i povezana je s ozbiljnošću oštećenja (Mankin i sur., Arthrilis Rehum. 21, 1978, 761-766, Woessner i sur., Arthrilis Rheum. 26, 1983, 63-68 i Ibid. 27, 1984, 305-312). Povrh toga, imunohistokemijska istraživanja (Okada i sur. Ann. Rheum. 48, 1989, 645) pokazala su da se stromelizin sintetizira i izlučuje putem stanica sinovijske ovojnice kod RA. Također su otkrivene veće razine stromelizina u hondrocilima u 90% OA hrskavica, kod kojih je bojanje stromelizinom bilo povezno s histološkim nalazima patologije i nestajanjem proteoglikana (Okada i sur. Lab Invest. 66, 1992, 680). Osteo- and rheumatoid arthritis (that is, OA and RA) are diseases that break down articular cartilage, and are characterized by localized erosion of the cartilage surface. Studies have shown that the articular cartilage of the femoral head in people who had OA, for example, showed reduced binding of radiolabeled sulfate during controls, suggesting that there must be an increased level of cartilage breakdown in OA (Mankin et al., J. Bone Joint Surg. 52A, 1970, 424-434). There are four types of protein-degrading enzymes in mammalian cells: serine, cysteine, aspartic acid, and metalloproteinase. Existing knowledge proves that metalloproteinases are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activity of collagenase and stromelysin was detected in OA cartilage and correlated with the severity of damage (Mankin et al., Arthrilis Rheum. 21, 1978, 761-766, Woessner et al., Arthrilis Rheum. 26, 1983, 63-68 and Ibid 27, 1984, 305-312). In addition, immunohistochemical studies (Okada et al. Ann. Rheum. 48, 1989, 645) have shown that stromelysin is synthesized and secreted by synovial cells in RA. Higher levels of stromelysin were also detected in chondrocytes in 90% of OA cartilages, where stromelysin staining was associated with histological findings of pathology and disappearance of proteoglycans (Okada et al. Lab Invest. 66, 1992, 680).

Stoga je stromelizin, metaloproteinaza matriksa (MMP-3), okarakteriziran kao jedan od ključnih enzima koji uzrokuju oštećenja kostiju i hrskavice kod sisavaca. Može se očekivati da će se patogeneza takvih bolesti poboljšati uzimanjem MMP inhibitora, a predloženo je već mnogo spojeva koji bi se mogli koristih u tu svrhu (vidi Wahl i sur. Ann. Rep. Med. Chem. 25., 175-184, AP, San Diego, 1990). Therefore, stromelysin, a matrix metalloproteinase (MMP-3), has been characterized as one of the key enzymes that cause bone and cartilage damage in mammals. The pathogenesis of such diseases can be expected to be improved by taking MMP inhibitors, and many compounds have already been proposed that could be used for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25., 175-184, AP , San Diego, 1990).

PCT međunarodna prijava broj WO 92/213260 opisuje N-karboksialkilpeptidilne spojeve opće formule: PCT International Application No. WO 92/213260 describes N-carboxyalkylpeptidyl compounds of the general formula:

[image] [image]

u kojoj je SA amino kiselina, a koji djeluju kao inhibitori botesti uzrokovanili metaloproteinazom matriksa. in which SA is an amino acid, and which act as inhibitors of bottesti caused by matrix metalloproteinase.

PCT međunarodna prijava br. WO 90/05716 opisuje inhibitore kolagenaze na bazi hidroksamske kiseline opće formule: PCT international application no. WO 90/05716 describes collagenase inhibitors based on hydroxamic acid of the general formula:

[image] [image]

PCT međunarodna prijava bf. WO 92/13831 opisuje srodne hidroksamske kiseline koje inhibiraju kolagenazu, opće formule: PCT international application bf. WO 92/13831 describes related collagenase-inhibiting hydroxamic acids of the general formula:

[image] [image]

PCT međunarodna prijava br. WO 94/02446 opisuje inhibitore metaloproteinaze koji su prirodni derivati amino kiseline opće formule: PCT international application no. WO 94/02446 describes metalloproteinase inhibitors which are natural amino acid derivatives of the general formula:

[image] [image]

PCT međunarodna prijava br. WO 93/09097 opisuje derivate piperazinske kiseline opće formule: PCT international application no. WO 93/09097 describes piperazine acid derivatives of the general formula:

[image] [image]

koji imaju inhibirajuće djelovanje na kolagenazu tipa IV, i korisni su kao supresivi metastaza raka. which have an inhibitory effect on collagenase type IV, and are useful as cancer metastasis suppressors.

Ogita i sur. (J. Anti. 1992, 45, 1723-1732) opisuju izolaciju strukturalno srodne vrste metabolita mikroba, matlistatina, koji su otkriveni pretraživanjem kao inhibitori kolagenaze tipa IV i prikazani su općom formulom: Ogita et al. (J. Anti. 1992, 45, 1723-1732) describe the isolation of a structurally related species of microbial metabolites, matlistatins, which were discovered by screening as type IV collagenase inhibitors and represented by the general formula:

[image] [image]

Europska patentna prijava objavljena pod br. 574,758 Al, opisuje derivate hidroksamske kiseline kao inhibitore kolagenaze opće formule: European patent application published under no. 574,758 Al, describes hydroxamic acid derivatives as collagenase inhibitors of the general formula:

[image] [image]

Spojevi opisani u ovom izumu djeluju kao inhibitori stromelizina, i na taj način sprečavaju gubitak i razgradnju hrskavice. Hidroksamske i karboksilne kiseline i njihovi derivati opisani u ovom izumu su bioraspoloživi nakon peroralne primjene. Određen broj spojeva opisanih kao inhibitori metaloproteinaze, kao što je na primjer kolagenaza, nisu dovoljno bioraspoloživi, te se stoga ne mogu koristiti kao terapijski agensi, posebno ukoliko je poželjna peroralna primjena. Slaba oralna aktivnost pripisana je relativno velikoj molekularnoj masi, neadekvatnoj topivosti i prisutnosti peptidnih veza, koje su osjetljive na cijepanje uzrokovano proteazama sisavaca in vivo i koje općenito djeluju na izrazito vezanje molekula u ljudskom serumu. Hidroksamske i karbocikličke kiseline i njihovi derivati opisani u ovom izumu imaju u tom smislu značajnu prednost, budući da one ne sadrže peptidne veze koje se mogu cijepati, niske su molekularne mase i mogu bili hidrofilne, a ipak inhibiraju metaloproteinaze matriksa. The compounds described in the present invention act as stromelysin inhibitors, thereby preventing the loss and degradation of cartilage. The hydroxamic and carboxylic acids and their derivatives described in this invention are bioavailable after oral administration. A certain number of compounds described as inhibitors of metalloproteinases, such as for example collagenase, are not sufficiently bioavailable, and therefore cannot be used as therapeutic agents, especially if oral administration is desired. Weak oral activity has been attributed to relatively high molecular weight, inadequate solubility, and the presence of peptide bonds, which are susceptible to cleavage by mammalian proteases in vivo and which generally act to strongly bind molecules in human serum. Hydroxamic and carbocyclic acids and their derivatives described in this invention have a significant advantage in this sense, since they do not contain cleavable peptide bonds, have low molecular weight and may be hydrophilic, yet inhibit matrix metalloproteinases.

Izlaganje biti izuma Presentation of the essence of the invention

Predmet ovog izuma su nove hidroksamske i karbocikličke kiseline i njihovi derivati koji inhibiraju stromelizin, i stoga su korisne u liječenju artritisa. Skupina koristi u ovom postupku liječenja predstavljena je općom formulom I: The subject of this invention are new hydroxamic and carbocyclic acids and their derivatives that inhibit stromelysin, and are therefore useful in the treatment of arthritis. The group of benefits in this treatment procedure is represented by the general formula I:

[image] [image]

ili njihove farmaceutski pogodne soli ili prodrug oblici, n kojoj je: or their pharmaceutically suitable salts or prodrug forms, in which:

A izabran iz -N(R8)CH(R9)CO2H ili -CH(R1)CONHOH; A selected from -N(R8)CH(R9)CO2H or -CH(R1)CONHOH;

Q je izabran je: Q is chosen is:

C5-C14 karbocikličkog prstena supstituiranog s 0-4 skupine izabrane iz R5, R6, R18 ili, -C(=O)R3, ili 5- do 10-članog heterocikličkog prstena koji sadrži 1 do 4 heteroatoma, koji su nezsvisno izabrani iz kisika, dušika ili sumpora, a navedeni heterociklički prsten supstituiran je s 0-4 skupine izabrane iz R5, R6, R8, R18 ili -C(=O)R3; of a C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 or, -C(=O)R3, or a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen , nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or -C(=O)R3;

R1 je izabran iz: R1 is selected from:

H, OR17, S(O)mR17a; H, OR17, S(O)mR17a;

C1-C4 alkila supstituiranog s 0-3 R4, C1-C4 alkyl substituted with 0-3 R4,

C2-C4 alkenila supstituiranog s 0-3 R4, C2-C4 alkenyl substituted with 0-3 R4,

C2-C4 alkinila supstituiranog s 0-3 R4, C2-C4 alkynyl substituted with 0-3 R4,

R2 je izabran iz: R2 is selected from:

H, H,

C1-C6 alkila supstituiranog s 0-3 R17b, C1-C6 alkyl substituted with 0-3 R17b,

-O-(C1-C8 alkil)-R20, -O-(C1-C8 alkyl)-R20,

-S-(C1-C8 alkil)-R20, -S-(C1-C8 alkyl)-R20,

-CH2O-( C1-C8 alkil)-R20, ili -CH2O-(C1-C8 alkyl)-R20, or

-CH2S-(C1-C8 alkil)-R20; -CH2S-(C1-C8 alkyl)-R20;

R3 je izabran iz: OR11, NHCH(R12)COR13, R3 is selected from: OR11, NHCH(R12)COR13,

NHCH(R12)COOR11, NHCH(R12)CONR14R15, NR10R10a; NHCH(R12)COOR11, NHCH(R12)CONR14R15, NR10R10a;

R4 je izabran iz: R4 is selected from:

-OR17, -SOmR17, -OR17, -SOmR17,

-NR8R10, -NHC(=NR8)N(R8)R10, -NR8R10, -NHC(=NR8)N(R8)R10,

C1-C4 alkila, C1-C4 alkyl,

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikloalkila, ili C3-C8 cycloalkyl, or

heterocikla izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil, a navedeni heterociklički prsten supstituiran je s 0-2 R19; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, and said heterocyclic ring is substituted with 0-2 R19;

R4a je izabran iz: R4a is selected from:

-OR17, -SOmR17, -OR17, -SOmR17,

C1-C4 alkila, C1-C4 alkyl,

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikloalkila, ili C3-C8 cycloalkyl, or

heterocikla izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil, pirolidinil, ftalimido, triazolidinil, oksadiazolidinil, imidazolidinil, piperidinil, a navedeni heterociklički prsten supstituiran je s 0-5 R18; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, pyrrolidinyl, phthalimido, triazolidinyl, oxadiazolidinyl, imidazolidinyl, piperidinyl, and said heterocyclic ring is substituted with 0-5 R18;

R5 i R6 su nezsvisno izabrani iz: R5 and R6 are independently selected from:

vodika, hydrogen,

hidroksi, hydroxy,

C1-C6 alkila supstituiranog s 0-3 R20, C1-C6 alkyl substituted with 0-3 R20,

C1-C4 alkoksi, -NR14R15, -COOR11, C1-C4 Alkoxy, -NR14R15, -COOR11,

C1-C4 alkoksikarbonila, hidroksimetila, -CH2OR13, C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13,

C1-C4 alkilaminokarbonila, -C(=NOH)R14 C1-C4 alkylaminocarbonyl, -C(=NOH)R14

=O, =S, ili njihovog ketalnog ili tioketalnog oblika kada su R5 ili R6 spojeni na zasićeni ugilikov atom, ili = 0 kada su R5 ili R6 spojeni na sumpor; =O, =S, or their ketal or thioketal form when R5 or R6 is attached to a saturated carbon atom, or = 0 when R5 or R6 is attached to sulfur;

R5 i R6 kada su povezani sa susjednim atomima prstena mogu se povezati kako bi tvorili 5-7-člani karbociklički ili heterociklički prsten, gdje navedeni karbociklički prsten sadrži jedan ili dva N, O ili S atoma, i navedeni karbociklički ili heterociklički prsten supstituiran je s 0-2 R18; R 5 and R 6 when linked to adjacent ring atoms may be linked to form a 5-7 membered carbocyclic or heterocyclic ring, wherein said carbocyclic ring contains one or two N, O or S atoms, and said carbocyclic or heterocyclic ring is substituted with 0-2 R18;

R8 je supstituent na dušiku i izabran je iz vodika, R8 is a substituent on nitrogen and is selected from hydrogen,

C1-C6 alkila supstituiranog s 0-3 R20, C1-C6 alkyl substituted with 0-3 R20,

C1-C6 alkilkarbonila, C1-C6 alkylcarbonyl,

alkoksikarbonila, alkoxycarbonyl,

arilalkoksikarbonila, arylalkyloxycarbonyl,

alkilaminokarbonila; alkylaminocarbonyl;

R9 je izabran iz: R9 is selected from:

H, H,

C1-C8 alkila supstituiranog s 0-3 R4a, C1-C8 alkyl substituted with 0-3 R4a,

C2-C8 alkenila supstituiranog s 0-3 R4a, C2-C8 alkenyl substituted with 0-3 R4a,

C2-C8 alkinila supstituiranog s 0-3 R4a; C2-C8 alkynyl substituted with 0-3 R4a;

R10 je izabran iz: R10 is selected from:

vodika, hydrogen,

C1-C4 alkoksi, C1-C4 Alkoxy,

C1-C6 alkila supstituiranog s 0-4 R4; C1-C6 alkyl substituted with 0-4 R4;

R10a je izabran iz vodika ili C1-C4 alkila; R 10a is selected from hydrogen or C 1 -C 4 alkyl;

R10 i R10a se mogu spojiti kako bi tvorili -(CH2)4-, -(CH2)5-, -CH2CH2N(R16)CH2CH2- ili -CH2CH2OCH2CH2-; R10 and R10a can be joined to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R16)CH2CH2- or -CH2CH2OCH2CH2-;

R11 je H, benzil ili C1-C4 alkil; R 11 is H, benzyl or C 1 -C 4 alkyl;

R12 je izabran iz: R12 is selected from:

H, H,

C1-C4 alkila supstituiranog s 0-3 R4, C1-C4 alkyl substituted with 0-3 R4,

C2-C4 alkenila supstituiranog s 0-3 R4, C2-C4 alkenyl substituted with 0-3 R4,

C2-C4 alkinila supstituiranog s 0-3 R4; C2-C4 alkynyl substituted with 0-3 R4;

R13 je C1-C4 alkil; R 13 is C 1 -C 4 alkyl;

R14 i R15 su nezsvisno izabrani iz H ili C1-C4 alkila; R 14 and R 15 are independently selected from H or C 1 -C 4 alkyl;

R16 je vodik ili metil; R 16 is hydrogen or methyl;

R17 je izabran iz: R17 is selected from:

vodika, hydrogen,

C1-C6 alkila supstituiranog s 0-3 R17a, C1-C6 alkyl substituted with 0-3 R17a,

C1-C6 alkilkarbonila supstituiranog s 0-3 R17a, C1-C6 alkylcarbonyl substituted with 0-3 R17a,

C1-C6 alkoksikarbonila supstituiranog s 0-3 R17a, C1-C6 alkoxycarbonyl substituted with 0-3 R17a,

fenoksikarbonila supstituiranog s 0-3 R18; phenoxycarbonyl substituted with 0-3 R18;

R17a je izabran iz: R17a is selected from:

H, H,

C1-C4 alkila; C1-C4 alkyl;

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikloalkila, C3-C8 cycloalkyl,

heterocikla izabranog iz skupina koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, pirolil, pirazolil, piperidinil, pirolidinil, pirimidinil ili piridazinil, benzofuranil, benzotienil, indolil, tetrahidrofuranil, ili piranil, navedeni heterociklički prsten supstituiran je s 0-2 R18; heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, piperidinyl, pyrrolidinyl, pyrimidinyl or pyridazinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R17b je izabran iz: R17b is selected from:

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikloalkila, C3-C8 cycloalkyl,

heterocikla izabranog iz skupine koja sadrži tienil, furanil, tiazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, pirolil, pirazolil, piridazinil, pirimidinil, benzofuranil, benzotienil, indolil, tetrahidrofuranil ili piranil, navedeni heterociklički prsten supstituiran je s 0-2 R18; a heterocycle selected from the group consisting of thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R18, kada je supstituent ugljik, je izabran iz jednog ili više od slijedećih spojeva: R18, when the substituent is carbon, is selected from one or more of the following compounds:

fenoksi, benziloksi, halogen, hidroksi, nitro, cijano, C1-C4 alkil, C1-C4 alkoksi, -CO2H, sulfonamid, C1-C4 alkil supstituiran s -NR10R10a,-NR10R10a C1-C4 hidroksialkil, metilendioksi, etilendioksi, C1-C4 haloalkil, C1-C4 haloalkoksi, C1-C4 alkoksikarbonil, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil, C1-C4 alkilkarbonilamino, -S(O)mR11 –NHSO2R11, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a, -NR10R10a C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11 –NHSO2R11,

heterocikla izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

ili R18 može biti lanac s 3 ili 4 ugljika spojen sa susjednim ugljicima na prstenu kako bi tvorio stopljeni 5- ili 6-člani prsten, navedeni 5- in 6-člani prsten može bili supstituiran s halogenom, C1-C4 alkilom, C1-C4 alkoksi, hidroksi, NR10OR10a -O ili -S kada je spojen sa zasićenim ugljikovim atomom, ili =O kada je spojen sa sumporom; or R 18 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, NR10OR10a -O or -S when attached to a saturated carbon atom, or =O when attached to sulfur;

R18 kada je supstituent dušik, je izabran iz jednog ili više od slijedećih spojeva: R18 when the substituent is nitrogen, is selected from one or more of the following compounds:

fenil, benzil, fenetil, hidroksi, C1-C4 hidroksialkil, C1 C4 alkoksi, C1-C4 alkil, C3-C6 cikloalkil C3-C6 cikloalkilmetil-CH2NR10R10a, -NR10R10a, C2-C6 alkoksialkil, C1-C4 haloalkil, C1-C4 alkoksikarbonil, -CO2H, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil; Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl-CH2NR10R10a, -NR10R10a, C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C4 Alkoxycarbonyl , -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R19, kada je supstituent ugljik, je izabran iz jednog ili više od slijedećih spojeva: R19, when the substituent is carbon, is selected from one or more of the following compounds:

fenil, benziloksi, halogen, hidroksi, nitro, cijano, C1-C4 alkil, C1-C4 alkoksi, -CO2H, sulfonamid, C1-C4 alkil supstituiran s -NR10R10a, -NR10R10a, C1-C4 hidroksialkil, metilendioksi, etilendioksi, C1-C4 haloalkil, C1-C4 haloalkoksi, C1-C4 alkoksikarbonil, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil, C1-C4 alkilkarbonilamino, -S(O)mR11, -NHSO2R11, phenyl, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a, -NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1- C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11,

heterocikla izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

ili R19 može biti lanac s 3 ili 4 ugljika spojen sa susjednim ugljicima na prstenu kako bi tvorio stopljeni 5- ili 6-člani prsten, navedeni 5- ili 6-člani prsten može biti supstituiran s halogenom, C1-C4 alkilom, C1-C4 alkoksi, hidroksi,-NR10R10a; or R 19 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a;

R19, kada je supstituent dušik, je izabran iz jednog ili više od slijedećih: R19, when the substituent is nitrogen, is selected from one or more of the following:

fenil, benzil, fenetil, hidroksi, C1-C4 hidroksialkil, C1-C4 alkoksi, C1-C4 alkil, C3-C6 cikloalkil C3-C6 cikloalkilmetil, -CH2NR10R10a, -NR10R10a, C2-C6 alkoksialkil, C1-C4 haloalkil, C1-C4 alkoksikarbonil, -CO2H, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil; Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C6 C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R20 je izabran iz: R20 is selected from:

arila supstituiranog s 0-5 R18, heterocikla izabranog iz skupine koja sadrži: aryl substituted with 0-5 R18, a heterocycle selected from the group consisting of:

tienil, furanil, tiazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, pirolil, pirazolil, piridazinil, pirimidinil, benzofuranil, benzotienil, indolil, tetrahidrofuranil, ili piranil, navedeni heterociklički prsten supstituiran je s 0-2 R18. thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18.

Jedan aspekt ovog izuma odnosi se na novu skupinu spojeva koji se mogu svrstati unutar skupine spojeva formule I i na farmaceutske pripravke koji ili sadrže i načine upotrebe navedenih spojeva za inhibiranje stromelizina i za liječenje OA i RA. Ti novi spojevi prikazani su formulom II: One aspect of this invention relates to a new group of compounds that can be classified within the group of compounds of formula I and to pharmaceutical preparations that contain or contain methods of using said compounds to inhibit stromelysin and to treat OA and RA. These new compounds are represented by formula II:

[image] [image]

ili njihove farmaceutski pogodne soli ili prodrug oblici, gdje je: or their pharmaceutically acceptable salts or prodrug forms, where:

Q izabran iz: Q selected from:

C5-C14 karbocikličkog prstena supstituiranog s 0-4 skupine izabrane iz R5, R6, R18 ili -C(O)R3, ili 5- do 10-članog heterocikličkog prstena koji sadrži 1 do 4 heteroatoma nezsvisno izabranih iz kisika, dušika ili sumpora, a navedeni heterociklički prsten supstituiran je s 0-4 skupine izabrane iz R5, R6, R8, R18 ili -C(=O)R3; C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 or -C(O)R3, or a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or -C(=O)R3;

R1 je izabran iz: R1 is selected from:

H, OR17, S(O)mR17a, H, OR17, S(O)mR17a,

C1-C4 alkila supstituiranog s 0-3 R4, C1-C4 alkyl substituted with 0-3 R4,

C2-C4 alkenila supstituiranog s 0-3 R4, C2-C4 alkenyl substituted with 0-3 R4,

C2-C4 alkinila supstituiranog s 0-3 R4, C2-C4 alkynyl substituted with 0-3 R4,

R2 je izabran iz: R2 is selected from:

C1-C6 alkila supstituiranog s 0-3 R17a, C1-C6 alkyl substituted with 0-3 R17a,

-O-(C1-C8 alkil)-R20, -O-(C1-C8 alkyl)-R20,

-S-(C1-C8 alkil)-R20, -S-(C1-C8 alkyl)-R20,

-CH2O-(C1-C8 alkil)-R20, ili -CH2O-(C1-C8 alkyl)-R20, or

-CH2S-(C1-C8 alkil)-R20; -CH2S-(C1-C8 alkyl)-R20;

R3 je izabran iz -NR10R10a; R3 is selected from -NR10R10a;

R4 je izabran iz: R4 is selected from:

-OR17, -SOmR17, -OR17, -SOmR17,

-NR8R10, -NHC(=NR8)N(R8)R10, -NR8R10, -NHC(=NR8)N(R8)R10,

C1-C4 alkila, C1-C4 alkyl,

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikloalkila, ili C3-C8 cycloalkyl, or

heterocikla izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil, a navedeni heterociklički prsten supstituiran je s 0-2 R18; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, and said heterocyclic ring is substituted with 0-2 R18;

R5 i R6 su nezsvisno izabrani iz: R5 and R6 are independently selected from:

vodika, hidroksi, C1-C6 alkila supstituiranog s 0-3 R20, hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 R20,

C1-C4 alkoksi, -NR14R15, -COOR11, C1-C4 Alkoxy, -NR14R15, -COOR11,

C1-C4 alkoksikarbonila, hidroksimetila, -CH2OR13, C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13,

C1-C4 alkilaminokarbonila, -C(=NOH)R14, C1-C4 alkylaminocarbonyl, -C(=NOH)R14,

Kada su R5 i R6 povezani sa susjednim atomima prstena mogu se povezati kako bi tvorili 5-7-člani karbociklički ili heterociklički prsten, gdje navedeni karbociklički prsten sadrži jedan do dva N, O ili S atoma, i navedeni karbociklički ili heterociklički prsten supstituiran je s 0-2 R18; When R 5 and R 6 are attached to adjacent ring atoms they may be linked to form a 5-7 membered carbocyclic or heterocyclic ring, wherein said carbocyclic ring contains one to two N, O or S atoms, and said carbocyclic or heterocyclic ring is substituted with 0-2 R18;

R8 je supstituent na dušiku i izabran je iz vodika, R8 is a substituent on nitrogen and is selected from hydrogen,

C1-C6 alkila supstituiranog s 0-3 R20, C1-C6 alkyl substituted with 0-3 R20,

C1-C6 alkilkarbonila, C1-C6 alkylcarbonyl,

alkoksikarbonila, alkoxycarbonyl,

arilalkoksikarbonila, arylalkyloxycarbonyl,

alkilaminokarbonila; alkylaminocarbonyl;

R10 je izabran iz: R10 is selected from:

vodika, hydrogen,

C1-C4 alkoksi, C1-C4 Alkoxy,

C1-C6 alkila supstituiranog s 0-4 R4; C1-C6 alkyl substituted with 0-4 R4;

R10a je izabran iz vodika ili C1-C4 alkila; R 10a is selected from hydrogen or C 1 -C 4 alkyl;

R10 i R10a se mogu spojiti kako bi tvorili -(CH2)4-, -(CH2)5-, -CH2CH2N(R16)CH2CH2- ili –CH2CH2OCH2CH2-; R10 and R10a can be joined to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R16)CH2CH2- or –CH2CH2OCH2CH2-;

R11 je H, benzil ili C1-C4 alkil; R 11 is H, benzyl or C 1 -C 4 alkyl;

R12 je izabran je: R12 is selected:

H, H,

C1-C4 alkila supstituiranog s 0-3 R4, C1-C4 alkyl substituted with 0-3 R4,

C2-C4 alkenila supstituiranog s 0-3 R4, C2-C4 alkenyl substituted with 0-3 R4,

C2-C4 alkinila supstituiranog s 0-3 R4; C2-C4 alkynyl substituted with 0-3 R4;

R13 je C1-C4 alkil; R 13 is C 1 -C 4 alkyl;

R14 i R15 su nezsvisno izabrani iz H ili C1-C4 alkila; R 14 and R 15 are independently selected from H or C 1 -C 4 alkyl;

R16 je vodik ili metil; R 16 is hydrogen or methyl;

R17 je izabran iz: R17 is selected from:

vodika, hydrogen,

C1-C6 alkila supstituiranog s 0-3 R17a, C1-C6 alkyl substituted with 0-3 R17a,

C1-C6 alkilkarbonila supstituiranog s 0-3 R17a, C1-C6 alkylcarbonyl substituted with 0-3 R17a,

C1-C6 alkoksikarbonila supstituiranog s 0-3 R17a, fenoksikarbonila supstituiranog s 0-3 R18; C1-C6 alkoxycarbonyl substituted with 0-3 R17a, phenoxycarbonyl substituted with 0-3 R18;

R17a je izabran iz: R17a is selected from:

H, H,

C1-C4 alkila; C1-C4 alkyl;

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikloalkila, C3-C8 cycloalkyl,

heterocikla izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, pirolil, pirazolil, piperidinil, pirolidinil, pirimidinil ili piridazinil, benzofuranil, benzotienil, indolil, tetrahidrofuranil, ili piranil, navedeni heterociklički prsten supstituiran je s 0-2 R18; heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, piperidinyl, pyrrolidinyl, pyrimidinyl or pyridazinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R17b je izabran iz: R17b is selected from:

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikloalkila, C3-C8 cycloalkyl,

heterocikla izabranog iz skupine koja sadrži tienil, furanil, tiazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, pirolil, pirazolil, piridazinil, pirimidinil, benzofuranil, benzotienil, indolil, tetrahidrofuranil ili piranil, navedeni heterociklički prsten supstituiran je s 0-2 R18; a heterocycle selected from the group consisting of thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R18, kada je supstituent ugljik, je izabran iz jednog od slijedećih spojeva: R18, when the substituent is carbon, is selected from one of the following compounds:

fenoksi, benziloksi, halogen, hidroksi, nitro, cijano, C1-C4 alkil, C1-C4 alkoksi, -CO2H, sulfonamid, C1-C4 alkil supstituiran s -NR10R10a, -NR10R10a, C1-C4 hidroksialkil, metilendioksi, etilendioksi, C1-C4 haloalkil, C1-C4 haloalkoksi, C1-C4 alkoksikarbonil, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil, C1-C4 alkilkarbonilamino, -S(O)mR11, -NHSO2R11, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a, -NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1- C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11,

heterocikla izabranog iz skupine koja sadfži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

ili R18 može biti lanac s 3 ili 4 ugljika spojen sa susjednim ugljicima na prstenu kako bi tvorio stopljeni 5- ili 6-člani prsten, navedeni 5- ili 6-člani prsten može biti supstituiran s halogenom, C1-C4 alkilom, C1-C4 alkoksi, hidroksi, NR10R10a, -O ili -S kada je spojen sa zasićenim ugljikovim atomom, ili =O kada je spojen sa sumporom; or R 18 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, NR10R10a, -O or -S when attached to a saturated carbon atom, or =O when attached to sulfur;

R18, kada je supstituent dušik, je izabran iz jednog ili više od slijedećih spojeva: R18, when the substituent is nitrogen, is selected from one or more of the following compounds:

fenil, benzil, fenetil, hidroksi, C1-C4 hidroksialkil, C1-C4 alkoksi, C1-C4 alkil, C3-C6 cikloalkil C3-C6 cikloalkilmetil,-CH2NR10R10a, -NR10R10a, C2-C6 alkoksialkil, C1-C4 haloalkil, C1-C4 alkoksikarbonil, -CO2H, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil; Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C6 C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R19, kada je supstituent ugljik, je izabran iz jednog ili više od slijedećih spojeva: R19, when the substituent is carbon, is selected from one or more of the following compounds:

fenil, benziloksi, halogen, hidroksi, nitro, cijano, C1-C4 alkil, C1-C4 alkoksi, -CO2H, sulfonamid, C1-C4 alkil supstituiran s -NR10R10a, -NR10R10a, C1-C4 hidroksialkil, metilendioksi, etilendioksi, C1-C4 haloalkil, C1-C4 haloalkoksi, C1-C4 alkoksikarbonil, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil, C1-C4 alkilkarbonilamino, -S(O)mR11, -NHSO2R11, phenyl, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a, -NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1- C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11,

heterocikla izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

ili R19 može biti lanac s 3 ili 4 ugljika spojen sa susjednim ugljicima na prstenu kako bi tvorio stopljeni 5- ili 6-člani prsten, navedeni 5- ili 6-člani prsten može biti supstituiran s halogenom, C1-C4 alkilom, C1-C4 alkoksi, hidroksi, NR10R10a; or R 19 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, NR10R10a;

R19, kada je supstituent dušik, je izabran iz jednog ili više od slijedećih: R19, when the substituent is nitrogen, is selected from one or more of the following:

fenil, benzil, fenetil, hidroksi, C1-C4 hidroksialkil, C1-C4 alkoksi, C1-C4 alkil, C3-C6 cikloalkil C3-C6 cikloalkilmetil,-CH2NR10R10a, -NR10R10a, C2-C6 alkoksialkil, C1-C4 haloalkil, C1-C4 alkoksikarbonil, -CO2H, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil; Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C6 C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R20 je izabran iz: R20 is selected from:

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

heterocikla izabranog iz skupine koja sadrži: heterocycle selected from the group consisting of:

tienil, furanil, tiazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, pirolil, pirazolil, piridazinil, pirimidinil, benzofuranil, benzotienil, indolil, tetrahidrofuranil, ili piranil, navedeni heterociklički prsten supstituiran je s 0-2 R18. thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18.

pod uvjetom da: under condition:

kada je R1 jednako vodik, a Q je when R1 is hydrogen and Q is

[image] [image]

tada R2 nije vodik, C3-C10 alkil ili (C1-C4 alkil)aril. then R 2 is not hydrogen, C 3 -C 10 alkyl or (C 1 -C 4 alkyl)aryl.

Poželjni spojevi ovog aspekta izuma su spojevi formule II u kojoj: Preferred compounds of this aspect of the invention are compounds of formula II wherein:

Q je 5-7-člani zasićeni heterociklički prsten koji sadrži barem jedan dušik, a može sadržavati i dodatni heteroatom izabran iz kisika, dušika ili sumpora, a navedeni heterociklički prsten je supstituiran s 0-4 skupine izabrane iz R5, 6, R8, R18 ili, -C(=O)R3; Q is a 5-7-membered saturated heterocyclic ring containing at least one nitrogen, and may also contain an additional heteroatom selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, 6, R8, R18 or, -C(=O)R 3 ;

R1 je izaban iz: R1 is elected from:

H, H,

C1-C4 alkila supstituiranog s 0-3 R4; C1-C4 alkyl substituted with 0-3 R4;

R2 je izabran iz: R2 is selected from:

C1-C6 alkila supstituiranog s 0-3 R17b, C1-C6 alkyl substituted with 0-3 R17b,

-O-(C1-C6 alkil)-R20, -O-(C1-C6 alkyl)-R20,

-S-(C1-C6 alkil)-R20, -S-(C1-C6 alkyl)-R20,

-CH2O-(C1-C5 alkil)-R20, ili -CH2O-(C1-C5 alkyl)-R20, or

-CH2S-(C1-C5 alkil)-R20; -CH2S-(C1-C5 alkyl)-R20;

R8 je vodik; R 8 is hydrogen;

R10 je izabran iz: R10 is selected from:

Vodika Hydrogen

C1-C6 alkila supstituiranog s 0-4 R4; C1-C6 alkyl substituted with 0-4 R4;

Više poželjni spojevi ovog aspekta izuma su oni spojevi formule II u kojoj je: More preferred compounds of this aspect of the invention are those compounds of formula II wherein:

Q heterocikl izabran iz slijedećih spojeva heksahidro-1-piridazinil, 2-tetrahidro-1,2-oksazinil, 1-morfolinil, 1-piperidinil, 1-pirolidinil, 1-piperazinil, 4-metilpiperazinil, tetrahidro-1,4-tiazin-4-il, tetrahidro-1,4-tiazin-4-il-1oksid, tetrahidro-1,4-tiazin-4-il-1,1-dioksid, 1-oksa-2-piperidinil, navedeni heterocikl je supstituiran s 0-3 skupine izabrane iz-C(=O)R3, R5, R6 ili, R8. Q heterocycle selected from the following compounds hexahydro-1-pyridazinyl, 2-tetrahydro-1,2-oxazinyl, 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-piperazinyl, 4-methylpiperazinyl, tetrahydro-1,4-thiazine- 4-yl, tetrahydro-1,4-thiazin-4-yl-1oxide, tetrahydro-1,4-thiazin-4-yl-1,1-dioxide, 1-oxa-2-piperidinyl, said heterocycle is substituted with 0 -3 groups selected from -C(=O)R 3 , R 5 , R 6 or, R 8 .

Nadalje poželjni spojevi su oni spojevi formule II u kojoj: Further preferred compounds are those compounds of formula II in which:

Q je: Q is:

[image] [image]

Zje N ili O; Is N or O;

R7 je izabran iz: R7 is selected from:

vodika, hidroksi, C1-C3 alkila supstituiranog s 0-3 R20, C1-C4 alkoksi, -NR14R15, -COOR11, hydrogen, hydroxy, C1-C3 alkyl substituted with 0-3 R20, C1-C4 alkoxy, -NR14R15, -COOR11,

C1-C4 alkoksikarbonila, hidroksimetila, -CH2OR13, C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13,

C1-C4 alkilaminokarbonila, -C(=NOH)R14; C1-C4 alkylaminocarbonyl, -C(=NOH)R14;

pod uvjetom da R8 nije prisutan kada je Z jednako O. provided that R8 is not present when Z equals O.

Posebno poželjni spojevi ovog aspekta izuma su izabrani iz: Particularly preferred compounds of this aspect of the invention are selected from:

[4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-beznzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metoksifenilsukcinil]-N-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methoxyphenylsuccinyl]-N-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metoksibenzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methoxybenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino]-2R-izobutil-3S-metiltiofenilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino]-2R-isobutyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metiltiobenzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-(metiltio-2-tienil)sukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-(methylthio-2-thienyl)succinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metilacetat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylacetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metihzopropanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylisopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metil-terc-butanoat]-N-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-tert-butanoate]-N-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metil-tioacetat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-thioacetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-(2-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-(2-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-(3-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-(3-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-(4-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-(4-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metiltio-terc-butanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metilsukcinit]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methylsuccinite]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-benzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metoksifenilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methoxyphenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metoksibenzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methoxybenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metiltiofenilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metiltiobenzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-(metiltio-2-tienil)sukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-(methylthio-2-thienyl)succinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-benzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metil-acetat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methyl-acetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metil-izopropanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methyl-isopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metil-terc-butanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methyl-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metil-tioacetat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methyl-thioacetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metil-tioizopropanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methyl-thioisopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metiltio-terc-butanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metil-(2-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(2-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metil-(3-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(3-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-heksil-3S-metil-(4-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(4-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-metilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-benzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-metoksifenilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methoxyphenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-metoksibenzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methoxybenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-metiltiofenilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-metiltiobenzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-(metiltio-2-tienil)sukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-(methylthio-2-thienyl)succinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-benzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino]-2R-etilfenil-3S-metil-acetat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino]-2R-ethylphenyl-3S-methyl-acetate]-N2-(S)-piperazine acid-N-methyl-amide;

(4-(N-hidroksiamino)-2R-etilfenil-3S-metil-izopropanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; (4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl-isopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-metil-terc-butanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-metil-tioacetat]-N2-(S)-piperazinska kiselina-N-metil amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl-thioacetate]-N2-(S)-piperazine acid-N-methyl amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-metil-tioizopropanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl-thioisopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-etilfenil-3S-metiltio-terc-butanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metiltiofenilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metiltiobenzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-(metiltio-2-tienil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-(methylthio-2-thienyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metil-acetat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methyl-acetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metil-izopropanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methyl-isopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metil-terc-butanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methyl-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metil-tioacetat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methyl-thioacetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metil-tioizopropanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methyl-thioisopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metiltio-terc-butanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidrokstamino)-2R-oktil-3S-metil-(2-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxtamino)-2R-octyl-3S-methyl-(2-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metil-(3-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methyl-(3-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-oktil-3S-metil-(4-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-octyl-3S-methyl-(4-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-4”(S/R)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-4”(S/R)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinit]-N2-(S)-5”(S/R)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinite]-N2-(S)-5”(S/R)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-6”(S/R)-piperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6”(S/R)-piperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-6”(S/R)-(4-metoksifenil)piperazinska kiselina-N-metil- [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6”(S/R)-(4-methoxyphenyl)piperazine acid-N-methyl-

amida; amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-4”(S/R)-benzilpiperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-4”(S/R)-benzylpiperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-5”(S/R)-benzilpiperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-5”(S/R)-benzylpiperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-6”(S/R)-benzilpiperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6”(S/R)-benzylpiperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-[4”,5”] benzopiperazinska kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-[4”,5”]benzopiperazine acid-N-methyl-amide;

[4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-[5”,6”] benzopiperazinaka kiselina-N-metil-amida; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-[5”,6”]benzopiperazine acid-N-methyl-amide;

Drugi aspekt ovog izuma uključuje skupinu novih spojeva koji također spadaju u skupinu spojeva formule I i njihovih farmaceutskih pripravaka i postupaka korištenja tih spojeva u inhibiranju stromelizina i u liječenju OA i RA. Navedeni spojevi prikazani su formulom III: Another aspect of this invention includes a group of novel compounds that also fall within the group of compounds of formula I and their pharmaceutical preparations and methods of using these compounds in inhibiting stromelysin and in the treatment of OA and RA. The mentioned compounds are represented by formula III:

[image] [image]

ili njihove farmaceutski pogodne soli ili prodrug oblici, u kojoj: or their pharmaceutically acceptable salts or prodrug forms, in which:

Q je izabran je: Q is chosen is:

C5-C14 karbocikličkog prstena supstituiranog s 0-4 skupine izabrane iz R5, R6, R18 ili -C(=O)R3, ili 5- do 10- članog heterocikličkog prstena koji sadrži 1 do 4 heteroatoma koji su nezsvisno izabrani iz kisika, dušika ili sumpora, a navedeni heterociklički prsten supstituiran je s 0-4 skupine izabrane iz R5, R6, R8, R18 ili -C(=O)R3; C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 or -C(=O)R3, or a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or -C(=O)R3;

R2 je izabran iz: R2 is selected from:

C1-C6 alkila supstituiranog s 0-3 R17b, C1-C6 alkyl substituted with 0-3 R17b,

-O-(C1-C8 alkil)-R20, -O-(C1-C8 alkyl)-R20,

-S-(C1-C8 alkil)-R20, -S-(C1-C8 alkyl)-R20,

-CH2O-(C1-C8 alkil)-R20, ili -CH2O-(C1-C8 alkyl)-R20, or

-CH2S-(C1-C8 alkil)-R20; -CH2S-(C1-C8 alkyl)-R20;

R3 je NR10R10a; R3 is NR10R10a;

R4 je izabran iz: R4 is selected from:

-OR17, -SOmR17, -OR17, -SOmR17,

-NR8RlO, -NHC(=NR8)N(R8)R10, -NR8R1O, -NHC(=NR8)N(R8)R10,

C1-C4 alkila, C1-C4 alkyl,

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikioalkila, ili C3-C8 cycloalkyl, or

heterocikla izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil, a navedeni heterociklički prsten supstituiran je s 0-2 R19; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, and said heterocyclic ring is substituted with 0-2 R19;

R4a je izabran iz: R4a is selected from:

-OR17, -SOmR17, -OR17, -SOmR17,

C1-C4 alkila, C1-C4 alkyl,

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikloalkila, ili C3-C8 cycloalkyl, or

heterocikla izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil, pirolidinil, ftalimido, triazolidinil, oksadiazolidinil, imidazolidinil, piperidinil, a navedeni heterociklički prsten supstituiran je s 0-5 R18; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, pyrrolidinyl, phthalimido, triazolidinyl, oxadiazolidinyl, imidazolidinyl, piperidinyl, and said heterocyclic ring is substituted with 0-5 R18;

R5 i R6 su nezsvisno izabrani iz: R5 and R6 are independently selected from:

vodika, hidroksi, C1-C6 alkila supstituiranog s 0-3 R20, C1-C4 alkoksi, -NR14R15, -COOR11, C1-C4 alkoksikarbonila, hidroksimetila, -CH2OR13, C1-C4 alkilaminokarbonila, -C(=NOH)R14, =O, =S, ili njhovog ketalnog ili tioketalnog oblika kada su R5 ili R6 spojeni na zasićeni ugljikov atom, ili = O kada su R5 ili R6 spojeni na sumpor; hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 R20, C1-C4 alkoxy, -NR14R15, -COOR11, C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13, C1-C4 alkylaminocarbonyl, -C(=NOH)R14, = O, =S, or its ketal or thioketal form when R 5 or R 6 are attached to a saturated carbon atom, or = O when R 5 or R 6 are attached to sulfur;

Kada su R5 i R6 povezani sa susjednim atomima prstena mogu se povezati kako bi tvorili 5-7-člani karbociklički ili heterociklički prsten, gdje navedeni karbociklički prsten sadrži jedan ili dva N, O ili S atoma, i navedeni karbociklički ili heterociklički prsten supstituiran je s 0-2 R18; When R5 and R6 are attached to adjacent ring atoms they may be linked to form a 5-7 membered carbocyclic or heterocyclic ring, wherein said carbocyclic ring contains one or two N, O or S atoms, and said carbocyclic or heterocyclic ring is substituted with 0-2 R18;

R8 je supstituent na dušiku i izabran je iz vodika, R8 is a substituent on nitrogen and is selected from hydrogen,

C1-C6 alkila supstituiranog s 0-3 R20, C1-C6 alkyl substituted with 0-3 R20,

C1-C6 alkilkarbonila, C1-C6 alkylcarbonyl,

alkoksikarbonila, alkoxycarbonyl,

arilalkoksikarbonila, arylalkyloxycarbonyl,

alkilaminokarbonila; alkylaminocarbonyl;

R9 je izabran iz: R9 is selected from:

H, H,

C1-C8 alkila supstituiranog s 0-3 R4a, C1-C8 alkyl substituted with 0-3 R4a,

C2-C8 alkenila supstituiranog s 0-3 R4a, C2-C8 alkenyl substituted with 0-3 R4a,

C2-C8 alkinila supstituiranog s 0-3 R4a, C2-C8 alkynyl substituted with 0-3 R4a,

R10 je izabran iz: R10 is selected from:

vodika, hydrogen,

C1-C4 alkoksi, C1-C4 Alkoxy,

C1-C6 alkila supstituiranog s 0-4 R4; C1-C6 alkyl substituted with 0-4 R4;

R10a je izabran iz vodika ili C1-C4 alkila; R 10a is selected from hydrogen or C 1 -C 4 alkyl;

R10 , R10a se mogu spojiti kako bi tvorili -(CH2)4-, -(CH2)5-, R10 , R10a can be joined to form -(CH2)4-, -(CH2)5-,

-CH2CH2N(R16)CH2CH2- ili –CH2CH2OCH2CH2-; -CH2CH2N(R16)CH2CH2- or –CH2CH2OCH2CH2-;

R11 je H, benzil ili C1-C4 alkil; R 11 is H, benzyl or C 1 -C 4 alkyl;

R12 je izabran je: R12 is selected:

H, H,

C1-C8 alkila supstituiranog a 0-3 R4, C1-C8 alkyl substituted with 0-3 R4,

C2-C8 alkenila supstituiranog s 0-3 R4, C2-C8 alkenyl substituted with 0-3 R4,

C2-C8 alkinila supstituiranog s 0-3 R4; C2-C8 alkynyl substituted with 0-3 R4;

R13 je C1-C4 alkil; R 13 is C 1 -C 4 alkyl;

R14 i R15 su nezsvisno izabrani iz H ili C1-C4 alkila; R 14 and R 15 are independently selected from H or C 1 -C 4 alkyl;

R16 je vodik ili metil; R 16 is hydrogen or methyl;

R17 je izabran iz: R17 is selected from:

vodika, hydrogen,

C1-C6 alkila supstituiranog s 0-3 R17a, C1-C6 alkyl substituted with 0-3 R17a,

C1-C6 alkilkarbonila supstituiranog s 0-3 R17a, C1-C6 alkylcarbonyl substituted with 0-3 R17a,

C1-C6 alkoksikarbonila supstituiranog s 0-3 R17a, C1-C6 alkoxycarbonyl substituted with 0-3 R17a,

fenoksikarbonila supstituiranog s 0-3 R18; phenoxycarbonyl substituted with 0-3 R18;

R17a je izabran iz: R17a is selected from:

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikloalkila, C3-C8 cycloalkyl,

heterocikla izabranog iz skupina koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, pirolil, pirazolil, piperidinil, pirolidinil, pirimidinil ili piridazinil, benzofuranil, benzotienil, indolil, tetrahidrofuranil, ili piranil, navedeni heterociklički prsten supstituiran je s 0-2 R18; heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, piperidinyl, pyrrolidinyl, pyrimidinyl or pyridazinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R17b je izabran iz: R17b is selected from:

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

C3-C8 cikloalkila, C3-C8 cycloalkyl,

heterocikla izabranog iz skupine koja sadrži tienil, furanil, tiazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, pirolil, pirazolil, piridazinil, pirimidinil, benzofuranil, benzotienil, indolil, tetrahidrofuranil ili piranil, navedeni heterociklički prsten supstituiran je s 0-2 R18; a heterocycle selected from the group consisting of thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R18, kada je supstituent ugljik, je izabran iz jednog od slijedećih spojeva: R18, when the substituent is carbon, is selected from one of the following compounds:

fenoksi, benziloksi, halogen, hidroksi, nitro, cijano, C1-C4 alkil, C1-C4 alkoksi, -CO2H, sulfonamid, C1-C4 alkil supstituiran s -NR10R10a, -NR10R10a, C1-C4 hidroksialkil, metilendioksi, etilendioksi, C1-C4 haloalkil, C1-C4 haloalkoksi, C1-C4 alkoksikarbonil, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil, C1-C4 alkilkarbonilamino, -S(O)mR11, -NHSO2R11, heterocikia izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil; phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a, -NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1- C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, heterocyclic selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

ili R18 može bili lanac s 3 ili 4 ugljika spojen sa susjednim ugljicima na prstenu kako bi tvorio stopljeni 5- ili 6-člani prsten, navedeni 5- ili 6-člani prsten može biti supstituiran a halogenom, C1-C4 alkilom, C1-C4 alkoksi, hidroksi, NR10R10a -O ili -S kada je spojen sa zasićenim ugljikovim atomom, ili =O kada je spojen sa sumporom; or R 18 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, NR10R10a -O or -S when attached to a saturated carbon atom, or =O when attached to sulfur;

R18, kada je supstituent dušik, je izabran iz jednog ili više od slijedećih spojeva: R18, when the substituent is nitrogen, is selected from one or more of the following compounds:

fenil, benzil, fenetil, hidroksi, C1-C4 hidroksialkil, C1-C4 alkoksi, C1-C4 alkil, C3-C6 cikloalkil C3-C6 cikloalkilmetil, -CH2NR10R10a, -NR10R10a,C2-C6 alkoksialkil, C1-C4 haloalkil, C1-C4 alkoksikarbonil, -CO2H, C1-C4 alkilkarboniloksi,C1-C4 alkilkarbonil; Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl, -CH2NR10R10a, -NR10R10a,C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C6 C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R19, kada je supstituent ugljik, je izabran iz jednog ili više od slijedećih spojeva: R19, when the substituent is carbon, is selected from one or more of the following compounds:

fenil, benziloksi, halogen, hidroksi, nitro, cijano, C1-C4 alkil, C1-C4 alkoksi, -CO2H, sulfonamid, C1-C4 alkil supstituiran s - NR10R10a, NR10R10a, C1-C4 hidroksialkil, metilendioksi, etilendioksi, C1-C4 haloalkil, C1-C4 haloalkoksi, C1-C4 alkoksikarbonil, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil, C1-C4 alkilkarbonilamino, -S(O)mR11, -NHSO2R11, phenyl, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with - NR10R10a, NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11,

heterocikla izabranog iz skupine koja sadrži tienil, piridinil, morfolinil, furil, tiazolil, piperidinil, pirimidinil ili piridazinil; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

ili R19 može biti lanac s 3 ili 4 ugljika spojen sa susjednim ugljicima na prstenu kako bi tvorio stopljeni 5- ili 6-člani prsten, navedeni 5- ili 6-člani prsten može bili supstituiran s halogenom, C1-C4 alkilom, C1-C4 alkoksi, hidroksi, NR10R10a, ili or R19 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, NR10R10a, or

R19, kada je supstituent dušik, je izabran iz jednog ili više od slijedećih: R19, when the substituent is nitrogen, is selected from one or more of the following:

fenil, benzil, fenetil, hidroksi, C1-C4 hidroksialkil, C1-C4 alkoksi, C1-C4 alkil, C3-C6 cikloalkil C3-C6 cikloalkilmetil,-CH2NR10R10a, -NR10R10a, C2-C6 alkoksialkil, C1-C4 haloaikil, C1-C4 alkoksikarbonil, -CO2H, C1-C4 alkilkarboniloksi, C1-C4 alkilkarbonil; Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C6 C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R20 je izabran iz: R20 is selected from:

arila supstituiranog s 0-5 R18, aryl substituted with 0-5 R18,

heterocikla izabranog iz skupine koja sadrži: heterocycle selected from the group consisting of:

tienil, furanil, tiazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, pirolil, pirazolil, piridazinil, pirimidinil, benzofuranil, benzotienil, indolil, tetrahidrofuranil, ili piranil, navedeni heterociklički prsten supstituiran je s 0-2 R18. thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18.

Poželjni spojevi drugog aspekta ovog izuma su oni spojevi formule III u kojima; Preferred compounds of the second aspect of this invention are those compounds of formula III in which;

Q je heterocikl izabran iz heksahidro-1-piridazinila, 2-tetrahidro-1,2-oksazini!a, 1-morfolinila, t-piperidinila, 1-pirolidinila, 1-piperazinila, 4-metilpiperazinila, tetrahidro-1,4-tiazin-4-ila, tetrahidro-1,4-tiazin-4-il-1-oksida, tetrahidro-1,4-tiazin-4-il-1,1-dioksida, a navedeni heterocikl supstituiran je s 0-3 skupine izabrane iz R5, R6, R8 ili-C(=O)R3; Q is a heterocycle selected from hexahydro-1-pyridazinyl, 2-tetrahydro-1,2-oxazinyl, 1-morpholinyl, t-piperidinyl, 1-pyrrolidinyl, 1-piperazinyl, 4-methylpiperazinyl, tetrahydro-1,4-thiazine -4-yl, tetrahydro-1,4-thiazin-4-yl-1-oxide, tetrahydro-1,4-thiazin-4-yl-1,1-dioxide, and the mentioned heterocycle is substituted with 0-3 groups selected from R5, R6, R8 or -C(=O)R3;

R2 je izabran iz: R2 is selected from:

C2-C4 alkila supstituiranog s 0-3 R17b, C2-C4 alkyl substituted with 0-3 R17b,

-O-(C1-C6 alkil)-R20, -O-(C1-C6 alkyl)-R20,

-S-(C1-C6 alkil)-R20, -S-(C1-C6 alkyl)-R20,

-CH2O-(C1-C5 alkil)-R20 ili, -CH2O-(C1-C5 alkyl)-R20 or,

-CH2S-(C1-C5 alkil)-R20; -CH2S-(C1-C5 alkyl)-R20;

R8 je vodik; R 8 is hydrogen;

R9 je izabran iz: R9 is selected from:

H, H,

C1-C4 alkila supstituiranog s 0-3 R4a, C1-C4 alkyl substituted with 0-3 R4a,

Više poželjni spojevi drugog aspekta ovog izuma su oni spojevi formule III u kojoj: More preferred compounds of the second aspect of this invention are those compounds of formula III in which:

Q je Q is

[image] [image]

Z je N ili O; Z is N or O;

pod uvjetom da R8 nije prisutan kada je Z jednako O. provided that R8 is not present when Z equals O.

Posebno poželjni spojevi drugog aspekta ovog izuma izabrani su iz slijedećih: Particularly preferred compounds of the second aspect of this invention are selected from the following:

Metil amid N-[1-(R)-karboksi-etil]-α-(S)-izobutilglicin-(S)-N2-piperazinske kiseline; N-[1-(R)-carboxy-ethyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etil]-α-(S)-heksilglicin-(S)-N2-piperazinake kiseline; N-[1-(R)-carboxy-ethyl]-α-(S)-hexylglycine-(S)-N2-piperazinic acid methyl amide;

Metil amid N-[1-(R)-karboksi-etil]-α-(S)-heptilglicin-(S)-N2-piperazinske kiseline; N-[1-(R)-carboxy-ethyl]-α-(S)-heptylglycine-(S)-N2-piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etil]-α-(S)-oktilglicin-(S)-N2-piperazinske kiseline; N-[1-(R)-carboxy-ethyl]-α-(S)-octylglycine-(S)-N2-piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etil]-α-(S)-etilfenilglicin-(S)-N2-piperazinske kiseline; N-[1-(R)-carboxy-ethyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etil]-α-(S)-propilfenilglicin-(S)-N2-piperazinske kiseline; N-[1-(R)-carboxy-ethyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etiltiobenzil]-α-(S)-izobutilglicin-(S)-N2-piperazinske kiseline; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etiltiobenzil]-α-(S)-heksilglicin-(S)-N2-piperazinske kiseline; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etiltiobenzil]-α-(S)-etilfenilglicin-(S)-N2 piperazinske kiseline; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-ethylphenylglycine-(S)-N2 piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etiltiobenzil]-α-(S)-propilfenilglicin-(S)-N2-piperazinske kiseline; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etiloksibenzil]-α-(S)-izobutilglicin-(S)-N2-piperazinske kiseline; N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etiloksibenzil]-α-(S)-heksilglicin-(S)-N2 piperazinske kiseline; N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etiloksibenzil]-α-(S)-etilfenilglicin-(S)-N2 piperazinske kiseline; N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-ethylphenylglycine-(S)-N2 piperazine acid methyl amide;

Metil amid N-[1-(R)-karboksi-etiloksibenzil]-α-(S)-propilfenilglicin-(S)-N2-piperazinske kiseline; N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide;

Treći aspekt ovog izuma su spojevi formule IV ili njihove farmaceutaki pogodne soli ili prodrug oblici koji se koriste u postupku liječenja OA i RA u kojem se koristi inhibitor stromelizina kao zaštitno sredstvo hrskavice: A third aspect of the present invention is the compounds of formula IV or their pharmaceutically acceptable salts or prodrugs used in the treatment of OA and RA in which a stromelysin inhibitor is used as a cartilage protective agent:

[image] [image]

u kojoj: where:

R2 je izabran iz: R2 is selected from:

H, H,

C3-C10 alkila, ili C3-C10 alkyl, or

aril-(C1-C4 alkil)-; aryl-(C1-C4 alkyl)-;

R3 je izabran iz OR11, NHCH(R12)COR13, NR10R10a, R3 is selected from OR11, NHCH(R12)COR13, NR10R10a,

NHCH(R12)COOR11, ili NHCH(R12)CONR14R15; NHCH(R 12 )COOR 11 , or NHCH(R 12 )CONR 14 R 15 ;

R10 i R10a su nezsvisno izabrani iz vodika, C1-C4 alkila, ili C1-C4 alkoksi; R 10 and R 10a are independently selected from hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;

R11, R12 i R15 su nezsvisno izabrani iz vodika ili C1-C4 alkila; R 11 , R 12 and R 15 are independently selected from hydrogen or C 1 -C 4 alkyl;

R13 i R14 su C1-C4 alkil. R 13 and R 14 are C 1 -C 4 alkyl.

Detaljan opis izuma Detailed description of the invention

Ovim izumom otkriveno je da su gore opisani spojevi korisni kao inhibitori stromelizina i sličnih metaloproteinaza matriksa, i korisni su u liječenju reumatodinog artritisa, osteoartritisa i sličnih patoloških stanja. The present invention has revealed that the compounds described above are useful as inhibitors of stromelysin and similar matrix metalloproteinases, and are useful in the treatment of rheumatoid arthritis, osteoarthritis and similar pathological conditions.

Ovaj izum također opisuje i postupke liječenja osteo- i reumatoidnog artritisa davanjem pacijentu farmaceutski ili terapijski učinkovite količine spoja formule (I) kao što je gore opisano. Terapijski učinkovita količina je ona količina spoja ovog izuma koja može inhibirati stromelizin ili liječiti simptome osteo- ili reumatoidnog artritisa kod bolesnika. This invention also describes methods of treating osteo- and rheumatoid arthritis by administering to a patient a pharmaceutically or therapeutically effective amount of a compound of formula (I) as described above. A therapeutically effective amount is that amount of a compound of the present invention that can inhibit stromelysin or treat symptoms of osteo- or rheumatoid arthritis in a patient.

Spojevi ovog izuma se također mogu uzimati u kombinaciji s jednim ili više dodatnih terapijskih agensa. Uzimanje spojeva formule I u kombinaciji s drugim terpijskim agensima omogućava uzimanje manje doze oba spoja. Snižena doza smanjuje moguće nuspojave i na taj način se povećava sigurnosna razina. The compounds of the present invention may also be taken in combination with one or more additional therapeutic agents. Taking the compounds of formula I in combination with other therapeutic agents allows taking a smaller dose of both compounds. A reduced dose reduces possible side effects and thus increases the safety level.

"Terapijski učinkovita količina" označava količinu spoja formule I koja kada se daje sama ili u kombinaciji s drugim terapijskim agensom sisavcu ili se ubrizgava u stanicu, učinkovito inhibira stromelizin i na taj način sprečava ili poboljšava upalna bolesna stanja ili razvitak bolesti. "Therapeutically effective amount" means an amount of a compound of formula I which, when administered alone or in combination with another therapeutic agent to a mammal or injected into a cell, effectively inhibits stromelysin and thereby prevents or ameliorates inflammatory disease states or disease development.

"Uzimanje u kombinaciji" ili "kombinirana terapija" označava da se spoj formule I i jedan drugi terapijski agens daju u isto vrijeme sisavcu koji se liječi. Kada se uzimaju u kombinaciji, mogu se uzimati u isto vrijeme ili jedan za drugim u bilo kojem vremenskoim razmaku. Na taj način se svaka komponenta može posebno uzeti, ali ipak u dovoljno kratkom vremenskom razmaku kako bi se postigao željeni terapijski učinak. "Combination administration" or "combination therapy" means that a compound of formula I and another therapeutic agent are administered at the same time to the mammal being treated. When taken in combination, they can be taken at the same time or one after the other at any time interval. In this way, each component can be taken separately, but still in a short enough time interval to achieve the desired therapeutic effect.

Spojevi opisani u ovom izumu mogu imati nesimetrične centre. Ukoliko nije drugačije naznačeno, svi kiralni, dijastereometrijski i racemički oblici uključeni su u ovaj izum. Mnogi geometrijski izomeri olefina, C=N dvostruke veze, i njima slične, također mogu biti prisutne u navedenim spojevima ovog izuma, i svi takvi stabilni izomeri su proučavani u ovom izumu. Značajno je da određeni spojevi iz ovog izuma sadržavaju nesimetrično supstituirani atom ugljika, i mogu se izolirati njihovi optički aktivni ili racemički oblici. Dobro je poznato kako se pripravljaju optički aktivni oblici, kao na primjer rastapanjem racemičkih oblika ili sintezom iz optički aktivnih početnih tvari. Svi kiralni, dijastereometrijski, racemički oblici i svi geometrijski izomerni oblici neke strukture su određeni, osim ako specifični stereokemijski ili izomerni oblici nisu posebno naznačeni. The compounds described in this invention may have asymmetric centers. Unless otherwise indicated, all chiral, diastereometric and racemic forms are included in this invention. Many geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds of this invention, and all such stable isomers are studied in this invention. It is significant that certain compounds of this invention contain an unsymmetrically substituted carbon atom, and their optically active or racemic forms can be isolated. It is well known how to prepare optically active forms, for example by dissolving racemic forms or by synthesis from optically active starting substances. All chiral, diastereometric, racemic forms and all geometric isomeric forms of a structure are defined, unless specific stereochemical or isomeric forms are specifically indicated.

Kada se neka varijabla (na primjer, R1 do R20, R10a, m, n, Z, X. itd.) pojsvi više puta u bilo kojem sastavnom dijelu ili formuli (I), njezina definicija pri svakom pojavljivanju je nezsvisna od svakog drugog pojavljivanja. Tako, na primjer, ukoliko je naznačeno da je skupina supstituirana s 0-3 R17, tada navedena skupina može biti supstituirana s nula do tri R17, a R17 je pri svakom pojavljivanju nezsvisno izabran iz definirane skupine mogućih R17. When a variable (for example, R1 to R20, R10a, m, n, Z, X, etc.) appears more than once in any component or formula (I), its definition at each occurrence is independent of every other occurrence . Thus, for example, if a group is indicated to be substituted with 0-3 R17, then said group may be substituted with zero to three R17, and R17 is independently selected at each occurrence from a defined group of possible R17.

Kada veza do supstituenta prelazi preko veze koja spaja dva atoma na prstenu, tada takav supstituent može biti povezan s bilo kojim atomom na prstenu. When the bond to a substituent crosses a bond connecting two atoms on a ring, then such a substituent can be bonded to any atom on the ring.

Kada je naveden supstituent, a nije naznačen atom preko kojeg je on povezan s ostalim dijelom spoja formule I, tada se takav supstituent može povezati putem bilo kojeg atoma na tom supstituentu. Na primjer, kada je supstituent piperazinil, piperidinil, ili tetrazolil, ukoliko nije drugačije naznačeno, navedena piperazinilna, piperidinilna, tetrazolilna skupina mogu biti povezane s ostalim dijelom spoja formule I putem bilo kojeg atoma piperazinilne, piperidinilne ili tetrazolilne skupine. When a substituent is specified, and the atom through which it is connected to the rest of the compound of formula I is not indicated, then such a substituent can be connected through any atom on that substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless otherwise indicated, said piperazinyl, piperidinyl, tetrazolyl group may be linked to the rest of the compound of formula I through any atom of the piperazinyl, piperidinyl, or tetrazolyl group.

Kombinacije i/ili varijable su dopustive ukoliko rezultiraju u stabilnim spojevima. “Stabilan spoj" ili “stabilna struktura” označavaju spoj koji je dovoljno postojan da može izdržati izolaciju iz reakcijske smjese do određenog stupnja čistoće i pripremanje terapijski učinkovitog agensa iz tog spoja. Combinations and/or variables are permissible if they result in stable compounds. "Stable compound" or "stable structure" means a compound that is stable enough to withstand isolation from a reaction mixture to a certain degree of purity and the preparation of a therapeutically effective agent from that compound.

Pojam "supstituiran", u tekstu označava da je jedan ili više vodika na označenom atomu zamijenjeno sa skupinom iz naznačene skupine, pod uvjetom da nije prijeđena normalna valencija označenog atoma, i da se supstitucijom dobiva stabilan spoj. Kada je supstituent keto (t.j. =O), tada su 2 vodika na atomu zamijenjena. The term "substituted" in the text means that one or more hydrogens on the indicated atom are replaced with a group from the indicated group, provided that the normal valence of the indicated atom is not exceeded, and that a stable compound is obtained by substitution. When the substituent is keto (ie =O), then 2 hydrogens on the atom are replaced.

"Alkil", u daljnjetn tekstu, uključuje i razgranate i ravne lance zasićenili alifatskih ugljikovodičnih skupina s određenim brojem ugljikovih atoma. "Alkenil" uključuje zasićene alifatske ugljikovodične lance ravnih ili razgranatih konfiguracija a određenim brojem ugljikovih atoma ( na primjer, C1-C10 označava alkil koji sadrži 1 do 10 ugljikovih atoma); "haloalkil" uključuje zasićene alifatske ugljikovodične skupine s razgranatim i ravnim lancima, s određenim brojem ugljikovih atoma, supstituiranih s 1 ili više halogena (na primjer -CvFw gdje je v=1 do 3, a w=1 do (2v+1)); ““alkoksi" predstavlja alkilnu skupinu s određenim brojem ugljikovih atoma spojenih kisikovom vezom; “cikloalkil" uključuje zasićene prstenaste skupine, uključujući mono-, bi- ili policikličke prstenaste sustave, kao što su ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil, ciklooktil i adamantil; i ““bicikloalkil" označava zasićene bicikličke prstenaste skupine kao što su [3.3.0]biciklooktan, [4.3.0.] biciklononan, [4.4.0.]biciklodekan (dekalin), [2.2.2.]biciklooktan i tako dalje. “Akenil" uključuje ugljikovodične lance razgranatih ili ravnih konfiguracija i jednu ili više zasićenih ugljik-ugljik veza koje se mogu nalaziti na bilo kojem stabilnom mjestu u lancu, kao što je etenil, propenil, i slična; "alkinil" uključuje ugljikovodične lance ravnih ili razgranatih konfiguracija i jednu ili više trostrukih ugljik-ugljik veza koje mogu biti na bilo kojem stabilnom mjestu u lancu, kao što je etinil, propinil, i slična. "Alkyl", hereinafter, includes both branched and straight chains of saturated aliphatic hydrocarbon groups with a certain number of carbon atoms. "Alkenyl" includes saturated aliphatic hydrocarbon chains of straight or branched configuration having a specified number of carbon atoms (for example, C1-C10 denotes an alkyl containing 1 to 10 carbon atoms); "haloalkyl" includes branched and straight chain saturated aliphatic hydrocarbon groups, having a specified number of carbon atoms, substituted with 1 or more halogens (for example -CvFw where v=1 to 3 and w=1 to (2v+1)); ""Alkoxy" represents an alkyl group with a certain number of carbon atoms connected by an oxygen bond; "cycloalkyl" includes saturated ring groups, including mono-, bi- or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl; and ““bicycloalkyl” means saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0.]bicyclononane, [4.4.0.]bicyclodecane (decalin), [2.2.2.]bicyclooctane, and so on. "Akenyl" includes hydrocarbon chains of branched or straight configuration and one or more saturated carbon-carbon bonds which may be located at any stable position in the chain, such as ethenyl, propenyl, and the like; "alkynyl" includes hydrocarbon chains of straight or branched configurations and one or more carbon-carbon triple bonds which may be at any stable position in the chain, such as ethynyl, propynyl, and the like.

“Alkilkarbonil" uključuje alkilnu skupinu s određenim brojem ugljikovih atoma spojenih preko karbonilne skupine s preostalim dijelom spoja na određenom mjestu. “Alkilkarbonilamino" označava atkilnu skupinu s određenim brojem ugljikovih atoma spojenih preko karbonilne skupine na amino vezu, gdje je navedena veza spojena s ostalim dijelom spoja na označenom mjestu. "Alkilkarboniloksi" označava alkilnu skupinu s određenim brojem ugljikovih atoma spojenih na karbonilnu skupinu, gdje je karbonilna skupina povezana putem kisikovog atoma na preostati dio spoja na određenom mjestu. "Alkylcarbonyl" includes an alkyl group with a certain number of carbon atoms connected via a carbonyl group to the remaining part of the compound at a specified position. "Alkylcarbonylamino" means an alkyl group with a certain number of carbon atoms connected via a carbonyl group to an amino bond, where said bond is connected to the rest of the moiety connection in the marked place. "Alkylcarbonyloxy" means an alkyl group having a certain number of carbon atoms attached to a carbonyl group, where the carbonyl group is attached through an oxygen atom to the remainder of the compound at a certain position.

Pojmovi "alkilen", "alkenilen", “fenilen”” i njima slični označavaju alkilne, alkenilne odnosno fenilne skupine, koje su dvjema vezama povezane s ostalim dijelom strukture formule I. Takvi "alkileni", "alkenileni", "fenileni" i slični se mogu isto tako označavati i kao "-(alkil)-“, "-(alkenil)-”” i “-(fenil)-" i slično. The terms "alkylene", "alkenylene", "phenylene" and the like denote alkyl, alkenyl or phenyl groups, which are linked by two bonds to the rest of the structure of formula I. Such "alkylenes", "alkenylenes", "phenylenes" and the like can also be designated as "-(alkyl)-", "-(alkenyl)-" and "-(phenyl)-" and the like.

"Halo" ili "halogen" se u tekstu odnosi na fluoro, kloro, bromo i jodo; a ““protuion” označava mali, negativno nabijeni ion kao što je klorid, bromid, hidroksid, acetat, sulfat i slični. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" means a small, negatively charged ion such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

U daljnjem tekstu “aril" ili "aromatski ostatak" označava fenil ili naftil; a pojam "arilalkil" označava arilnu skupinu spojenu s alkilnom vezom. Hereinafter, "aryl" or "aromatic residue" means phenyl or naphthyl; and the term "arylalkyl" means an aryl group connected with an alkyl bond.

U daljnjem tekstu, "ugljikocikl" ili “ugljikociklički ostatak” ili "ugiljkociklički prsten” označava bilo koji stabilan 3- do 7-člani monociklički ili biciklički ili 7- do 14-člani biciklički ili triciklički ili do 26-člani policiklički ugljikov prsten, od kojih svaki može biti zasićeni, djelomično zasićeni ili aromatski. Primjeri takvih ugljikocikla uključuju, ali nisu na njih ograničeni, ciklopropil, ciklopentil, cikloheksil, fenil, bifenil, naftil indanil, adamantil ili tetrahidronaftil (tetralin). In the following text, "carbon cycle" or "carbon cyclic residue" or "carbon cyclic ring" means any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or up to 26-membered polycyclic carbon ring, from each of which may be saturated, partially saturated, or aromatic.Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

U daljnjem tekstu, "heterocikl” ili “heteroaril" ili “heterociklički" označava stabilan 5- do 7-člani monociklički ili biciklički ili 7- do 10-člani biciklički heterociklički prsten, koji je ili zasićen ili nezasićen, i koji se sastoji od ugljikovih atoma i od 1 do 4 heteroatoma, nezsvisno izabranih iz skupine koja sadrži N, O ili S, i u kojoj dušikovi i sumporni heteroatomi mogu biti oksidirani, a dušik može također biti učetverostručen; uključujući i bilo koju bicikličku skupinu u kojoj bilo koji gore definirani heterociklički prsten može biti stopljen u benzenov prsten. Heterociklički prsten se može prispojiti nezasićenoj skupini na bilo kojem heteroatomu ili ugljikovom atomu, koji rezultira u stabilnoj strukturi. Heterociklički prstenovi opisani u tekstu mogu biti supstituirani na ugljikovom ili dušikovom atomu, ukoliko je dobiveni spoj stabilan. Primjeri takvih heterocikia uključuju, ali nisu ograničeni samo na njih, piridil, pirimidinil, furanil, tienil, pirolil, pirazolil, imidazolil, tetrazolil, benzofuranil, benzotiofenil, indolil, indolenil, kinolinil, izokinolinil ili benzimidazolil, piperidinil, 4-piperidonil, pirolidinil, 2-pirolidonil, pirolinil, tetiahidrofuranil, tetrahidroizokinolinil, tetrahidrokinolinil, dekahidrokinolinil ili oktahidroizokinolinil, azocinil, triazinil, 6H-1,2,5-tiadiazinil, 2H,6H-1,5,2-ditiazinil, tiofenil, tiantrenil, furanil, piranil, izobenzofuranil, kromenil, ksantenil, fenoksattinil, 2H-pirolil, pirolil, imidazolil, pirazolil, izotiazolil, izoksazolil, oksazolil piridinil, pirazinil, pirimidinil, piridazinil, indolizinil, izoindolil, 3H-indolil, indolil, 1H-indazolil, purinil, 4H-kinolizinil, izokinolinil, kinolinil, ftalazinil, naftiridinil, kinoksalinil, kinazolinil, cinolinil, pteridinil, 4aH-karbazolil, karbazolil, β-karbolinil, fenantridinil, akridinil, perimidinil, fenantrolinil, fenazinil, fenotiazinil, furazanil, fenoksazinil, izokromanil, kromanil, pirolidinil, pirolinil, imidazolidinil, imidazolinil, pirazolidinil, pirazolinil, piperidinil, piperazinil, indolinil, izoindolinil, kinuklidinil, morfolinil ili oksazolidinil. Također su uključeni i stopljeni prstenasti spojevi i spžio spojevi koji sadrže, na primjer, gore navedene heterocikle. Hereinafter, "heterocycle" or "heteroaryl" or "heterocyclic" means a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atom and from 1 to 4 heteroatoms, independently selected from the group consisting of N, O or S, and in which the nitrogen and sulfur heteroatoms may be oxidized and the nitrogen may also be quadrupled; including any bicyclic group in which any of the above-defined heterocyclic the ring can be fused to a benzene ring. The heterocyclic ring can be attached to an unsaturated group on any heteroatom or carbon atom, resulting in a stable structure. The heterocyclic rings described in the text can be substituted on the carbon or nitrogen atom, if the resulting compound is stable. Examples such heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imide zolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tethiahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1, 2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl pyridinyl , pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β -carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring compounds and fused compounds containing, for example, the above heterocycles.

Pojam “amino kiselina” označava organski spoj koji sadrži i bazičnu amino skupinu i kiselu karboksilnu skupinu. Ovaj pojam također uključuje i prirodne amino kiseline, promijenjene i neuobičajene amino kiseline, kao i amino kiseline koje se biološki pojsvijuju u slobodnom ili kombiniranom obliku, ali obično se ne pojavljuju u proteinima. Takve promijenjene i neuobičajene amino kiseline uključuju, na primjer, one opisane u tekstu "The Peptidea", autora Roberts-a i Vellaccio-a (1983), 5:342-429, koji je uključen u ovaj tekst. Promijenjene ili neuobičajene amino kiseline koje se mogu koristiti za izvođenje ovog izuma uključuju, ali nisu na njih ograničene, D-amino kiseline, hidroksilizin, 4-hidroksiprolin, N-Cbz-zaštićenu amino kiselinu, ornitin, 2,4-diaminobutiričnu kiselinu, homoarginin, norleucin,N-metilaminobutiričnu kiselinu, naftilalanin, N-metil-norleucin, 3,4-dehidroprolin, N,N-dimetilaminoglicin,N-metilaminoglicin, 4-aminopiperidin-4-karboksilnu kiselinu, 6-aminokaproičnu kiselinu, trans-4-(aminometil)-cikioheksankarboksilnu kiselinu, 2-, 3- i 4-(aminometil)-benzoičnu kiselinu, 1-aminociklopentankarboksilnu kiselinu,1-aminociklopropankarboksilnu kiselinu i 2-benzil-5-aminopentanoičnu kiselinu. The term "amino acid" means an organic compound that contains both a basic amino group and an acidic carboxyl group. This term also includes naturally occurring amino acids, altered and unusual amino acids, as well as amino acids that occur biologically in free or combined form but do not normally occur in proteins. Such altered and unusual amino acids include, for example, those described in "The Peptidea" by Roberts and Vellaccio (1983), 5:342-429, which is incorporated herein. Altered or unusual amino acids that can be used to practice this invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid, homoarginine , norleucine, N-methylaminobutyric acid, naphthylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4- (aminomethyl)-cyclohexanecarboxylic acid, 2-, 3- and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid and 2-benzyl-5-aminopentanoic acid.

Pojam “ostatak amino kiseline" označava dio amino kiseline (kao što je definirana) koji je prisutan n peptidu. The term "amino acid residue" means the portion of an amino acid (as defined) present in a peptide.

Pojam “peptid” u ovom izumu označava spoj koji se sastoji od dvije ili više amino kiseline (kao što su definirane), koje su spojene s peptidnom vezom. Pojam “peptid" također uključuje i spojeve koji sadrže i peptidne i ne-peptidne komponente, kao što su pseudopeptidni ili peptidomimetaki ostaci ili druge komponente koje ne sadrže amino kiseline. Takav spoj koji sadrži i komponente s peptidima i one koje ili ne sadrže, u tekstu je označen kao “analog peptida”. The term “peptide” as used herein means a compound consisting of two or more amino acids (as defined) joined by a peptide bond. The term "peptide" also includes compounds that contain both peptide and non-peptide components, such as pseudopeptide or peptidomimetic residues or other components that do not contain amino acids. Such a compound that contains both peptide and non-peptide components, in in the text it is marked as "peptide analog".

Pojam “peptidna veza” označava kovalentnu amidnu vezu nastalu gubitkom molekule vode između karboksilne skupine i jedne amino kiseline i amino skupine druge amino kiseline. The term "peptide bond" means a covalent amide bond formed by the loss of a water molecule between the carboxyl group of one amino acid and the amino group of another amino acid.

Pojam “farmaceutski pogodne soli" odnosi se na derivate opisanih spojeva, a dobivaju se mijenjanjem osnovnog spoja formule (I) stvaranjem kiselih ili lužnatih soli. Primjeri farmaceutski pogodnih soli uključuju, ali nisu na njih ograničene, soli mineralnih i organskih kiselina lužnatih ostataka, kao što su amini; alkalne ili organske soli kiselih ostataka, kao što su karboksilne kiseline i njima slične. The term "pharmaceutically suitable salts" refers to derivatives of the described compounds, which are obtained by changing the basic compound of formula (I) by forming acidic or alkaline salts. Examples of pharmaceutically suitable salts include, but are not limited to, salts of mineral and organic acids of alkaline residues, such as which are amines; alkaline or organic salts of acidic residues, such as carboxylic acids and the like.

“Prodrugs" su bilo koji kovalentno vezani nosači, koji otpuštaju aktivnu komponentu prema formuli (I) in vivo, kada sisavac primi takav prodrug. Prodrug oblici spojeva formule (I) pripravljaju se mijenjanjem funkcionalnih skupina prisutnih u spojevima, tako da se matični spojevi mijenjaju in vivo ili na već uobičajeni način. Prodrug uključuju spojeve formule (I) u kojima se hidroksi, amino ili sulfhidrilne skupine vežu na bilo koju skupinu koja se, kada ju sisavac primi, razgrađuje kako bi tvorita hidroksilnu, amino ili sulfhidrilnu skupinu. Primjeri prodrug uključuju, ali nisu na njih ograničeni, acetatne, formatne i benzoatne derivate alkohola i amino funkcionalne skupine u spojevima formule (I), fosfatne estere, dimetilglicinske estere, aminoalkilbenzilne estere, aminoalkilne estere i karboksialkilne estere alkoholnih i fenolnih funkcionlanih skupina spojeva formule (I); i njima slične. "Prodrugs" are any covalently bound carriers, which release the active component according to formula (I) in vivo, when a mammal receives such a prodrug. Prodrug forms of compounds of formula (I) are prepared by changing the functional groups present in the compounds, so that the parent compounds are changed in vivo or by conventional means.Prodrugs include compounds of formula (I) in which hydroxy, amino or sulfhydryl groups are attached to any group which, when received by a mammal, is degraded to form a hydroxyl, amino or sulfhydryl group.Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amino functional groups in compounds of formula (I), phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol and phenolic functional groups of compounds of formula (I) ; and similar to them.

Farmaceutski pogodne soli spojeva formule I uključuju konvencionalne netoksične soli ili kvartarne amonijeve soli spojeva formule I nastale, na primjer, iz netoksičnih anorganskih i organskih kiselina. Na primjer, takve konvencionalne netoksične soli uključuju derivate anorganskih kiselina kao što su klorovodična, bromovodična, sumporna, sulfamska, fosforna, nitratna i slične; i soli pripravljene iz organskih kiselina kao što su octena, propionska, sukcinska, glikolinska, stearinska, mliječna, jabučna, vinska, limunska, askorbinska, pamolčna, maleinska, hidroksimaleinska, feniloctena, glutaminska, benzoična, salicilna, sulfanilinska, 2-acetoksibenzoična, fumarna, toluensulfonska, metansulfonska,etan-disulfonska, oksalinska, izetionska, i slične. Pharmaceutically suitable salts of compounds of formula I include conventional non-toxic salts or quaternary ammonium salts of compounds of formula I formed, for example, from non-toxic inorganic and organic acids. For example, such conventional non-toxic salts include derivatives of inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfaniline, 2-acetoxybenzoic, fumaric , toluenesulfonic, methanesulfonic, ethane-disulfonic, oxaline, isethionic, and the like.

Farmaceutski pogodne soli ovog izuma mogu se sintetizirati uz pomoć već uobičajenih kemijskih postupaka iz spojeva formule I koji sadrže bazični ili kiseli dio. Općenito, soli se pripravljaju reakcijom slobodne baze ili kiseline sa stehiometrijskim iznosima ili sa suviškom poželjne anorganske ili organske kiseline ili baze iz koje nastale sol, u odgovarajućem otapalu ili kombinaciji različitih otapala. Pharmaceutically suitable salts of the present invention can be synthesized by conventional chemical methods from compounds of formula I containing a basic or acidic moiety. In general, salts are prepared by reacting a free base or acid with stoichiometric amounts or with an excess of the desired inorganic or organic acid or base from which the salt was formed, in a suitable solvent or a combination of different solvents.

Farmaceutski pogodne soli kiselina formule I s odgovarajućom količinom baze, kao što je zemno-alkalijski ili -alkalinski metalni hidroksid, kao na primjer natrij, kalij, litij, kalcij, ili magnezij, ili organska baza kao što je amin, na primjer, dibenziletilendiamin, trimetilamin, piperidin, pirolidin, benzilamin i slični, ili kvartarni amonij-hidroksid kao što je tetrametilamonij-hidroksid i slični. Pharmaceutically acceptable salts of the acids of formula I with an appropriate amount of a base, such as an alkaline-earth or -alkaline metal hydroxide, such as sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, for example, dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.

Farmaceutski pogodne soli spojeva ovog izuma mogu se priprsviti reakcijom slobodnih kiselih i lužnatih oblika ovih spojeva sa stehiometrijskim iznosom odgovarajuće baze ili kiseline u vodi ili u organakom otapalu, ili u njihovoj smjesi; općenito, poželjni su bezvodni mediji kao što su eter, etil-acetat, etanol, izopropanol ili acetonitril. Spisak odgovarajućih soli se nalazi u Remington’s Pharmaceutical Sciences, 17. izdanje, Mack Publishing Company, Easton, PA (1985) str. 1418. Pharmaceutically suitable salts of the compounds of this invention can be prepared by reacting the free acidic and basic forms of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent, or in their mixture; generally, anhydrous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA (1985) p. 1418

SINTEZA SYNTHESIS

Stručnjaci organske sinteze mogu priprsviti spojeve iz ovog izuma na mnogo već poznatih načina. Oni se mogu sintetizirati prema dolje opisanim postupcima, kao i prema postupcima sinteze poznatima u organskoj sintezi ili prema sličnim postupcima poznatima stručnjacima organske sinteze. Poželjni postupci uključuju one opisane u daljnjem tekstu. Sve navedene reference u potpunosti su uključene u tekst i čine njegov sastavni dio. Those skilled in the art of organic synthesis can prepare the compounds of the present invention in many known ways. They can be synthesized according to the procedures described below, as well as according to synthesis procedures known in organic synthesis or similar procedures known to those skilled in organic synthesis. Preferred procedures include those described below. All mentioned references are fully included in the text and form an integral part of it.

Novi spojevi formule I se mogu pripraviti uz pomoć reakcija i tehnika opisanih u ovom dijelu. Reakcije se izvode u otapalima koja odgovaraju tvarima i reagensima koji se koriste i pogodne su za promjene koje se izvode. Također treba naglasiti da su u dolje navedenim postupcima sinteze svi predloženi uvjeti reakcije, uključujući i izbor otapala, atmosferu reakcije, temperaturu, trajanje pokusa i obradu, prikazani kao standardni uvjeti za navedenu reakciju, što bi stručnjaci odmah trebali prepoznati. Stručnjacima organske sinteze jasno je da prisutna funkcionalnost na različitim dijelovima izlučene molekule mora biti kompatibilna s reagensima i predloženom reakcijom. Nisu svi spojevi formule I koji spadaju u danu skupinu kompatibilni a nekim uvjetima reakcije potrebnima za izvođenje opisanih postupaka. Takve restrikcije supstituenata stručnjaci organske sinteze odmah moraju prepoznati i u skladu s time izabrati druge postupke. New compounds of formula I can be prepared using the reactions and techniques described in this section. The reactions are carried out in solvents appropriate to the substances and reagents used and suitable for the changes being carried out. It should also be emphasized that in the synthesis procedures listed below, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, temperature, duration of the experiment and processing, are presented as standard conditions for the specified reaction, which experts should immediately recognize. It is clear to experts in organic synthesis that the functionality present on different parts of the secreted molecule must be compatible with the reagents and the proposed reaction. Not all compounds of formula I belonging to the given group are compatible with some reaction conditions necessary for carrying out the described procedures. Specialists in organic synthesis must immediately recognize such substituent restrictions and choose other procedures accordingly.

Spojevi formule I u kojoj je A jednako HONHCOCH(R1) i Q je zsaićeni N-heterocikl povezan putem N atoma u prstenu, pripravljaju se kondenzacijom kiselina formule (V): Compounds of formula I in which A is equal to HONHCOCH(R1) and Q is a hydrogenated N-heterocycle connected via N atoms in the ring, are prepared by condensation of acids of formula (V):

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gdje je R jednako esterska zaštitna skupina, a R1 i R2 su definirani kao što je opisano u izlaganju biti izuma, spojevi vezani uz formulu I, s odgovarajuće supstituiranim N-heterociklom kako bi se dobila amidna veza između karbonila formule (V) i bazičnog dušika u prstenu navedenog heterocikla kako je prikazano u Shemi 1. wherein R is an ester protecting group and R1 and R2 are defined as described in the Summary of the Invention, compounds of formula I, with an appropriately substituted N-heterocycle to form an amide bond between the carbonyl of formula (V) and the basic nitrogen in the ring of said heterocycle as shown in Scheme 1.

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Kondenzacija se izvodi uz pomoć bilo kojeg postupka za stvaranje amidnih veza poznatih stručnjacima organake sinteze. Ti postupci uključuju pretvaranje kiseline (V) u odgovarajući kiseli klorid (Va) ili upotrebu standardnih postupaka vezanja kao što je azidska metoda, postupak miješanog kiselog karbonskog anhidrida (izobutil-kloroformat), postupak karbodiimida (dicikloheksailkarbodiimid, diizopropilkarbodiimid ili karbodiimidi topivi u vodi), postupak aktivnog estera (p-nitrofenil-ester, N-hidroksisukcinski imid ester), postupak karbonildiimidazola, fosfornih agensa kao što su BOP-Cl. Neki od navedenih postupaka (posebno karbodiimid) se mogu pojačati dodavanjem1-hidroksibenzotriazola. Poželjni postupak je tretiranje cikličkog amina s kiselim kloridom pripravljenim iz (V). Postupci mijenjanja karboksitnih kiselina u kisele kloride opisani su u (J. March, Adv. Org. Chem. 1985, p. 1146, J. Wiley & Son, USA) i uključuju, na primjer, tretiranje kiseline a oksalil-kloridom u prisustvu kataliličke količineN,N”-dimetilformamida. Uklanjanjem esterske zaštitne skupine, nakon čega slijedi aktiviranje dobivene kiseline, na primjer s izobutilklorofofmatom, i reakcijom s O-benzilhidroksilaminom dobiva se zaštićena hidroksamska kiselina. Deprotekcijom se dobiva hidroksamska kiselina. Condensation is carried out using any amide bond forming procedure known to those skilled in the art of organic synthesis. These procedures include converting the acid (V) to the corresponding acid chloride (Va) or using standard coupling procedures such as the azide method, the mixed acid carbonic anhydride (isobutyl-chloroformate) method, the carbodiimide method (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimides), active ester process (p-nitrophenyl-ester, N-hydroxysuccinic imide ester), carbonyldiimidazole process, phosphoric agents such as BOP-Cl. Some of the mentioned procedures (especially carbodiimide) can be enhanced by adding 1-hydroxybenzotriazole. A preferred procedure is to treat the cyclic amine with an acid chloride prepared from (V). Procedures for converting carboxylic acids into acid chlorides are described in (J. March, Adv. Org. Chem. 1985, p. 1146, J. Wiley & Son, USA) and include, for example, treating acid a with oxalyl chloride in the presence of a catalytic amounts of N,N”-dimethylformamide. Removal of the ester protecting group, followed by activation of the resulting acid, for example with isobutylchlorophosphate, and reaction with O-benzylhydroxylamine gives the protected hydroxamic acid. Hydroxamic acid is obtained by deprotection.

Spojevi formule I, u kojoj je A jednako HONHCOCH(R1), a Q je aril ili heteroaril, pripravljaju se tretiranjem kiselog klorida (Va) pripravljenog iz kiseline (V) s metaliziranim arilom ili hetefoarilom kao što je prikazano u Shemi 2, gdje su R, R1 i R2 kao što je gore definirano, Ar predstavlja aril ili heteroarilnu skupinu, a M je litij, magnezijev bromid ili trialkil ili triariltin. Organometalne skupine, Ar-M, se dobivaju tretiranjem arila ili heteroariljodida ili bromida s alkilom ili arillitijevim reagensom, magnezijem ili trialkiltinskim reagensom kako bi se dobio odgovarajući litij, magnezijbromid ili tin skupina, koristeći se postupcima poznatima stručnjacima u ovom polju. Kondenzaciju trialkiltinskih skupina s kiselim kloridima u prisutnosti katalitičke količine paladijevog (0) katalizatora opisali su Stille (Angew. Chem. Int. Ed. Engi., 1986, 25:508). U slučajevima kada su heteroarilne skupine dovoljno reaktivne, mogu se izvoditi ili direktna metalizacija ili direktna kondenzacija neaktiviranog heteroarilnog spoja navedenog klorida (vidi B. Oddo, Gazz. Chim. Itat., 1911, 41:234). Intermedijarni ester se zatim pretvara u željenu hidroksamsku kiselinu kao što je gore opisano. Compounds of formula I, wherein A is HONHCOCH(R1) and Q is aryl or heteroaryl, are prepared by treating an acid chloride (Va) prepared from an acid (V) with a metallated aryl or hetephoaryl as shown in Scheme 2, where R, R 1 and R 2 are as defined above, Ar represents an aryl or heteroaryl group and M is lithium, magnesium bromide or trialkyl or triaryltin. Organometallic groups, Ar-M, are obtained by treating an aryl or heteroaryl iodide or bromide with an alkyl or aryllithium reagent, magnesium or trialkyltin reagent to give the corresponding lithium, magnesium bromide or tin group, using procedures known to those skilled in the art. Condensation of trialkyltin groups with acid chlorides in the presence of a catalytic amount of palladium(0) catalyst was described by Stille (Angew. Chem. Int. Ed. Engi., 1986, 25:508). In cases where the heteroaryl groups are sufficiently reactive, either direct metallization or direct condensation of the unactivated heteroaryl compound of said chloride can be performed (see B. Oddo, Gazz. Chim. Itat., 1911, 41:234). The intermediate ester is then converted to the desired hydroxamic acid as described above.

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Kiseline formule (V) se priprave kao što jte gore opisano (Crimmin i sur. Synlett, 1993, 137; Tamaki i sur., Tetrahedron Lett. 1993, 34:683) ili prema uobičajenom postupku prikazanom u Shemi 3. Odgovarajuće supstituirana karboksilna kiselina (VIII) se pretvori u kiralni oksazolidinon (IX) uz pomoć Evansove deprotonacije s jakom bazom, nakon čega slijedi tretiranje s t-butilbromoacetatom, kako bi se dobio intermedijer (X). Transesterifikacijom kiralnog intermedijera s LiOBn, nakon čega slijedi tretiranje s kiselinom kako bi se uklonila terc-butil zaštitna skupina i pretvaranjem kiseline u trikloroetilester dobiva se spoj formule (Va)/ gdje je R1 vodik. Hidroliza kiralnog intermedijera se također može postići uz pomoć alkalinskog vodikovog peroksida kako bi se dobila kiselina (Vb). Acids of formula (V) are prepared as described above (Crimmin et al. Synlett, 1993, 137; Tamaki et al., Tetrahedron Lett. 1993, 34:683) or according to the usual procedure shown in Scheme 3. Appropriately substituted carboxylic acid (VIII) is converted to the chiral oxazolidinone (IX) by Evans deprotonation with a strong base, followed by treatment with t-butylbromoacetate to give intermediate (X). Transesterification of the chiral intermediate with LiOBn, followed by treatment with acid to remove the tert-butyl protecting group and conversion of the acid to the trichloroethyl ester gives a compound of formula (Va)/ where R1 is hydrogen. Hydrolysis of the chiral intermediate can also be achieved with alkaline hydrogen peroxide to give the acid (Vb).

Prema prikazu B, α-bromoester formule (IX) se može tretirati s kalijevom soli dibenzil-malonata kako bi se dobio triester (XII). Postupct priprave α-bromoestera amino-estera su poznati stručnjacima organske sinteze (R.S.Compagnone i H. Rapoport, J. Org. Chem. 1986, 51, 1713). Uklanjanjem benzil-estera i dekarboksilacijom se dobiva kiselina (XIII) koja se zatim može promijeniti u (Va) mijenjanjem funkcija kiseline uz pomoć standardnih postupaka. Kiseline (V) u kojima R1 nije vodik dobivaju se iz intermedijera (XII) Mannichovom reakcijom, nakon koje slijedi kvaternizacija i eliminacija kako bi se dobio metilenski spoj (XIV). Zatim se mijenjanjem funkcija kiseline dobiva željeni mono-trikloroetilester. Redukcijom alkena dobiva se (V) gdje je R1 jednako metil. Spojevi u kojima R1 nije vodik ili metil se dobivaju iz intermedijera (XIV) 1,4-adicijom odgovarajućih nukleofila α,β-nezasićenom dijelu kiseline. Odgovarajući nukleofili uključuju, alkillitije, alkilmagnezij-halide, tiole i alkokside i slične. According to scheme B, the α-bromoester of formula (IX) can be treated with the potassium salt of dibenzyl malonate to give the triester (XII). The procedure for the preparation of α-bromoesters of amino-esters is known to experts in organic synthesis (R.S. Compagnone and H. Rapoport, J. Org. Chem. 1986, 51, 1713). Removal of the benzyl ester and decarboxylation gives acid (XIII) which can then be changed to (Va) by changing the functions of the acid using standard procedures. Acids (V) in which R1 is not hydrogen are obtained from the intermediate (XII) by the Mannich reaction, followed by quaternization and elimination to give the methylene compound (XIV). Then, by changing the function of the acid, the desired mono-trichloroethyl ester is obtained. Alkene reduction yields (V) where R1 is methyl. Compounds in which R1 is not hydrogen or methyl are obtained from intermediate (XIV) by 1,4-addition of the corresponding nucleophiles to the α,β-unsaturated part of the acid. Suitable nucleophiles include, alkyllithiums, alkylmagnesium halides, thiols and alkoxides and the like.

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Spojevi formule II, u kojoj je Z jednako N mogu se pripraviti iz derivata piperazinske kiseline formule (XV), u kojoj su R5, R6, R7 definirani kao što je opisano u izlaganju biti izuma vezano uz spojeve formule II. Compounds of formula II, in which Z is equal to N, can be prepared from piperazine acid derivatives of formula (XV), in which R 5 , R 6 , R 7 are defined as described in the summary of the invention related to compounds of formula II.

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Nesupstituirani esteri piperazinske kiseline formule (XV) se mogu pripraviti kao što su to opisali Adams i sur. (Synth. Commun. 1988, 38, 2225) ili prema već poznatom postupku opisanom u Shemi 4. Unsubstituted piperazine esters of formula (XV) can be prepared as described by Adams et al. (Synth. Commun. 1988, 38, 2225) or according to the already known procedure described in Scheme 4.

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Asimetričnom adicijom di-t-butil dijazodikarboksilata do kiralnog oksazolidinona pripravljenog iz odgovarajuće supstituiranog derivata 5-bromovalerinske kiseline (K.J.Hale, V.M. 7613), nakon koje slijedi uklanjanje BOC skupina i hidroliza oksazolidinona dobivaju se derivati piperazinske kiseline (XVa). Poželjni postupci koji se koriste za uklanjanje BOC skupina su trifluorooctenom kiselinom, čistom ili u diklorometanu, ili HCl u dioksanu. Hidroliza oksazolidinona se po mogućnosti izvodi tretiranjem a vodenim litijevim hidroksidom. Spojevi formule (XVa) se mogu lako prevesti u spojeve formule (XV) pomoću poznatih postupaka stručnjacima organske sinteze, kao na primjer, tretiranjem benzilkloroformata u prisutnosti odgovarajuće baze kao što je vodeni natrij-hidfoksid nakon čega slijedi izlaganje izobutilenu pod kiselom katalizom. By asymmetric addition of di-t-butyl diazodicarboxylate to chiral oxazolidinone prepared from a suitably substituted derivative of 5-bromovaleric acid (K.J.Hale, V.M. 7613), followed by removal of BOC groups and hydrolysis of oxazolidinone, piperazine acid derivatives (XVa) are obtained. The preferred procedures used to remove BOC groups are trifluoroacetic acid, neat or in dichloromethane, or HCl in dioxane. Hydrolysis of oxazolidinone is preferably carried out by treatment with aqueous lithium hydroxide. Compounds of formula (XVa) can be readily converted to compounds of formula (XV) by procedures known to those skilled in the art of organic synthesis, for example, treatment of benzylchloroformate in the presence of an appropriate base such as aqueous sodium hydroxide followed by exposure to isobutylene under acid catalysis.

Postoje i drugi načini priprave spojeva formule (XV). Prema Diels-Alderovoj ciklizaciji 4-fenil-1,2,4-triazolin-3,4-diona s odgovarajuće supstituiranim dienom (Adams, vidi gore), dobiva se spoj koji nakon redukcije i alkalinske hidrolize daje derivate piperazinske kiseline (XVa) koji se prevode u (XV), kako je gore opisano. There are also other ways of preparing compounds of formula (XV). According to the Diels-Alder cyclization of 4-phenyl-1,2,4-triazoline-3,4-dione with an appropriately substituted diene (Adams, see above), a compound is obtained which after reduction and alkaline hydrolysis gives piperazine acid derivatives (XVa) which are translated into (XV), as described above.

Spojevi formule II u kojoj je Z jednako N, a R8 je H mogu se pripraviti iz piperazinskih estera formule (XV) i kiselina formule (V) kao što je prikazano u Shemi 5. Compounds of formula II wherein Z is N and R 8 is H can be prepared from piperazine esters of formula (XV) and acids of formula (V) as shown in Scheme 5.

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Piperazinski esteri (XV) se spajaju s kiselinama formule (V) kako bi se dobili amidi formule (VI) kao što je gore opisano. Za spojeve formule II u kojoj je Z jednako N, a R8 je H i R3 je –NR10R10a, nakon sinteze izvodi se hidroksiliza t-butil-estera spoja formule (VI), nakon koje slijedi aktiviranje dobivene kiseline s reagensom spajanja izabranim iz gore navedenog popisa standardnih postupaka, na primjer, izobutilkloroformat, i tretiranje sa suviškom amina formule R10(R10a)NH ili odgovarajućim alkoholom kako bi se dobio odgovarajući amid. Trikloroetil-ester se uklanja redukcijom nakon koje slijedi pretvaranje do hidroksamske kiseline kao što je ranije opisano. Poželjni postupci uklanjanja TCE estera su redukcija s cinkovim prahom ili blaga bazična hidroliza. Za uklanjanje benzila i Cbz skupina odjednom, koriste se slijedeći reagensi: hidrogenacijski uvjeti uz pomoć vodika pri atmosferskom tlaku, ili Parrovo uređaj uz povišeni vodikov tlak, ili cikloheksenov ili amonijev format uz paladij, paladijev hidroksid na kamenom ugljenu ili platinov oksid u metanolu, etanolu ili tetrahidrofuranu, ili u kombinaciji navedenih otapala (P.N.Rylander, Hydrogenaztion Methods, Academic Press, 1985). Kod spojeva u kojima R1 sadrži sumpor, uklanjanje benzila i Cbz zaštitne skupine se izvodi uz pomoć hidrogenacije u prisutnosti Witkinsonovog katalizatora ili tretiranjem s trimetilsililjodidom. Piperazine esters (XV) are coupled with acids of formula (V) to give amides of formula (VI) as described above. For the compounds of the formula II in which Z is N, R8 is H and R3 is –NR10R10a, after the synthesis, hydroxylysis of the t-butyl ester of the compound of the formula (VI) is performed, followed by activation of the obtained acid with a coupling reagent selected from the above of a list of standard procedures, for example, isobutylchloroformate, and treatment with an excess of an amine of the formula R10(R10a)NH or the corresponding alcohol to give the corresponding amide. The trichloroethyl ester is removed by reduction followed by conversion to hydroxamic acid as described earlier. Preferred methods for removing TCE esters are reduction with zinc dust or mild basic hydrolysis. To remove benzyl and Cbz groups at once, the following reagents are used: hydrogenation conditions with the help of hydrogen at atmospheric pressure, or Parr's device with elevated hydrogen pressure, or cyclohexene or ammonium formate with palladium, palladium hydroxide on coal or platinum oxide in methanol, ethanol or tetrahydrofuran, or in a combination of said solvents (P.N. Rylander, Hydrogenation Methods, Academic Press, 1985). For compounds in which R1 contains sulfur, removal of the benzyl and Cbz protecting groups is performed with the help of hydrogenation in the presence of a Witkinson catalyst or by treatment with trimethylsilyl iodide.

Drugi način dobivanja spojeva formule II u kojoj R1 nije vodik ili metil je prikazan u Shemi 6. Kiselina formule (XIV) se kondenzira sa spojem formule (XV) uz pomoć jednog od gore navedenih postupaka, kako bi se dobio (XVI). Taj intermedijer se dalje prevodi u kiselinu (XVII). Michaelovom adicijom odgovarajućeg nukteofila i pretvaranjem funkcionalnosti kiseline do hidroksamske kiseline dobivaju se spojevi formule II. Na taj način se mogu pripraviti i drugi spojevi formule II, zamjenom spoja (XV) u Shemi 6 sa heterocikličkim, arilnim i heteroarilnim reagensima, kako je gore opisano. Another method of preparing compounds of formula II in which R 1 is not hydrogen or methyl is shown in Scheme 6. An acid of formula (XIV) is condensed with a compound of formula (XV) by one of the above methods to give (XVI). This intermediate is further translated into acid (XVII). Compounds of formula II are obtained by Michael addition of the appropriate nucteophile and conversion of the acid functionality to hydroxamic acid. In this way, other compounds of formula II can be prepared by replacing compound (XV) in Scheme 6 with heterocyclic, aryl and heteroaryl reagents, as described above.

[image] [image]

Spojevi formule II se također mogu pripraviti prema Shemi 7. Compounds of formula II can also be prepared according to Scheme 7.

[image] [image]

Spojevi formule II u kojoj je Z jednako N, a R8 nije vodik pripravljaju se prema Shemi 8. Spojevi formule (VII) se oslobađaju kako je gore opisano, nakon čega slijedi alkilacija dobivenog slobodnog amina a alkilirajućim agensom u prisutnosti odgovarajuće baze. Alkilirajući agensi uključuju alkil-halide, mezilate, tozilate, itd. Odgovarajuće baze su trietilamin, N-metilmorfolin ili diizopropiletilamin. Spojevi u kojima je R8 jednako alkilkarbonilu se pripravljaju tretiranjem oslobođenih (VII) s acil-halidom kao što je acetil-klorid. Compounds of formula II wherein Z is N and R8 is not hydrogen are prepared according to Scheme 8. Compounds of formula (VII) are liberated as described above, followed by alkylation of the resulting free amine with an alkylating agent in the presence of a suitable base. Alkylating agents include alkyl halides, mesylates, tosylates, etc. Suitable bases are triethylamine, N-methylmorpholine or diisopropylethylamine. Compounds in which R 8 is alkylcarbonyl are prepared by treating the liberated (VII) with an acyl halide such as acetyl chloride.

[image] [image]

Spojevi formule II u kojoj je Z=O se pripravljaju iz hidroksamskih kiselina (XVII) prema prikazu u Shemi 9. Compounds of formula II in which Z=O are prepared from hydroxamic acids (XVII) as shown in Scheme 9.

[image] [image]

Hetero-Diels-Alderovom reakcijom hidroksamskih kiselina formule (XVII) i odgovarajuće supstituiranog diena u prisutnosti odgovarajućeg oksidansa dobivaju se spojevi formule (XVIII) iz kojih se nakon redukcije dobivaju spojevi formule II. Hetero-Diels-Alder reaction of hydroxamic acids of formula (XVII) and a suitably substituted diene in the presence of a suitable oxidant gives compounds of formula (XVIII) from which, after reduction, compounds of formula II are obtained.

[image] [image]

Spojevi formule I u kojoj je A jednako -NHCH(R9)CO2H se pripravljaju iz amino kiselina (XIX) prema Shemi 10. Compounds of formula I in which A is -NHCH(R9)CO2H are prepared from amino acids (XIX) according to Scheme 10.

[image] [image]

N-zaštićena amino kiselina (XIX) se spaja s piperazinskim esterima formule (XV) koristeći se standardnim ranije opisanim tehnikama spajanja, kako bi se dobio hidrazin (XX). Daljnjom obradom t-butil estera kako je ranije opisano i hidrogenacijom obaju Cbz-zaštitnih skupina dobiva se amin formule (XXI). Reduktivnom aminacijom primarne amino skupine s odgovarajuće supstituiranim α-ketobenzil esterima, uz pomoć stručnjacima već poznatih postupaka, dobivaju se spojevi opće formule III. Prema gore opisanim postupcima spoj (XV) se može zamijeniti s drugim N-heterociklima ili derivatima arila ili heteroarila kako bi se dobili drugi spojevi formule III. The N-protected amino acid (XIX) is coupled with the piperazine esters of formula (XV) using the standard coupling techniques previously described to give the hydrazine (XX). Further processing of the t-butyl ester as described earlier and hydrogenation of both Cbz-protecting groups yields the amine of formula (XXI). By reductive amination of the primary amino group with appropriately substituted α-ketobenzyl esters, with the help of procedures already known to experts, compounds of the general formula III are obtained. According to the procedures described above, compound (XV) can be substituted with other N-heterocycles or aryl or heteroaryl derivatives to obtain other compounds of formula III.

Neobične amino kiseline korištene u ovom izumu mogu se sintetizirati prema standardnim postupcima poznatima stručnjacima u ovom polju ("The Peptides: Analysis, Synthesis, Biology, Vol. 5, pp. 342-449, Academic Press, New York (1981)). N-alkil-amino kiseline se mogu pripraviti prema postupcima koje su opisati Cheung i sur. (Can. J. Chem. 55, 906, (1977)) i Freidinger i sur., (J. Org. Chem. 48, 77 (1982)), koji su uključeni u ovaj tekst prema referencama. The unusual amino acids used in this invention can be synthesized according to standard procedures known to those skilled in the art ("The Peptides: Analysis, Synthesis, Biology, Vol. 5, pp. 342-449, Academic Press, New York (1981)). N -alkyl-amino acids can be prepared according to the procedures described by Cheung et al. (Can. J. Chem. 55, 906, (1977)) and Freidinger et al., (J. Org. Chem. 48, 77 (1982 )), which are incorporated into this text by reference.

Funkcionalne skupine navedenih amino kiselina moraju bili zaštićene tijekom spajanja kako bi se spriječilo stvaranje nepoželjnih veza. Zaštitne skupine koje se mogu koristiti navedene su u priručniku Greenea, "Protective Groups in Organic Synthesis” John Wiley & Sons, New York (1981) i "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), navedeni tekstovi uključeni su u ovaj tekst prema referencama. The functional groups of the mentioned amino acids must be protected during coupling in order to prevent the formation of undesirable bonds. Protective groups that may be used are listed in Greene's handbook, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the texts of which are incorporated herein by reference.

U drugom aspektu ovog izuma, tvrdimo da su farmaceutski pripravci spojeva formule I (pod navedenim uvjetima) bioraspoloživi lijekovi za peroralnu primjenu korisni za liječenje artritisa, budući da djeluju kao zaštitnici hrskavice. In another aspect of this invention, we claim that the pharmaceutical compositions of the compounds of formula I (under the specified conditions) are bioavailable drugs for oral administration useful for the treatment of arthritis, since they act as cartilage protectors.

Spojevi opisani u ovom izumu i njihovi pripravci detaljnije su opisani u dolje navedenim primjerima i postupcima, koji samo služe kao primjer, ali ni na koji način ne sužavaju opseg ovog izuma. The compounds described in this invention and their preparations are described in more detail in the following examples and procedures, which are only intended to serve as examples, but in no way limit the scope of this invention.

Primjeri Examples

Slijedeće kratice korištene su u dolje navedenim primjerima: "1X" za jedanput, "2X”” za dvaput, "3X”” za triput, "bs” za široki singlet, "°C" za stupnjeva Celzijusa, “Cbz" za benziloksikarbonil, "d" za dublet, "dd”” za dvostruki dublet, ““eq" za ekvivalent ekvivalenta, "g”” za gram ili grame, “ml" za mililitar ili mililitre, “H” za vodik ili vodike, “1H" za proton, "hr" za sat ili sate, “m” za multiplet, “M” za mol, “min" za minutu ili minute, “mp" za točku topivosti, "MHz" za The following abbreviations are used in the examples below: "1X" for single, "2X" for twice, "3X" for triple, "bs" for broad singlet, "°C" for degrees Celsius, "Cbz" for benzyloxycarbonyl, "d" for doublet, "dd"" for double doublet, ""eq" for equivalent equivalent, "g"" for gram or grams, "ml" for milliliter or milliliters, "H" for hydrogen or hydrogens, "1H" for proton, "hr" for hour or hours, "m" for multiplet, "M" for mole, "min" for minute or minutes, "mp" for melting point, "MHz" for

megaherz, "MS" za masenu spektroskopiju, "nmr” ili “NMR" za nuklearnu magnetsku rezonancu, “t" za triplet, "tlc" za tankoslojnu kromatografiju, "v/v" za volumen u omjeru na volumen, "α", "β", "R" i "S" su stereokemijske oznake poznate stručnjacima iz tog polja. megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance, "t" for triplet, "tlc" for thin layer chromatography, "v/v" for volume to volume ratio, "α", "β", "R" and "S" are stereochemical designations known to those skilled in the art.

Postupak 1 Procedure 1

Priprava terc-butilestera N1-benziloksikarbonil-S-piperazinske kiseline Preparation of tert-butyl ester of N1-benzyloxycarbonyl-S-piperazine acid

A. [4R-(fenilmetil)-2-oksazolidinil)]-5-bromovaleramid A. [4R-(phenylmethyl)-2-oxazolidinyl]-5-bromovaleramide

Bromovalerinska kiselina (68 g, 0.38 g) je rastopljena u suhom metilen-kloridu (640 ml) i dodan je bezvodni DMF (1 ml). Otopina je ohlađena na 0°C u atmosferi dušika. Oksalil-klorid (36.8 ml, 0.413 mol) je ukapavan tijekom 20 min., nakon čega je smjesa miješana 1 h na 0°C, a zatim na sobnoj temperaturi dok se nije ispario sav plin (6h). Otapalo je uklonjeno in vivo kako bi se dobio sirovi kiseli klorid. Bromovaleric acid (68 g, 0.38 g) was dissolved in dry methylene chloride (640 ml) and anhydrous DMF (1 ml) was added. The solution was cooled to 0°C under a nitrogen atmosphere. Oxalyl chloride (36.8 ml, 0.413 mol) was added dropwise over 20 min., after which the mixture was stirred for 1 h at 0°C and then at room temperature until all the gas had evaporated (6 h). The solvent was removed in vivo to give the crude acid chloride.

Otopini (+)-(S)-4-benziloksazolidinona (66.56 g, 0.376 mol) u tetrahidrofuranu (900 ml), ohlađenoj na -78°C, dodavan je n-butillitij (164 ml, 2.29 M u heksanu) tijekom 1 sata uz mehaničko miješanje. Zatim je uklonjena rashladna kupelj, a otopina je miješana još 18 h. Reakcija je zatim ugašena s 10%-tnom limunskom kiselinom (400 ml) i vodom (600 ml). Faze su razdvojene, vodena faza je ekstrahirana s eterom (3 x 300 ml). Kombinirane organske tvari su oprane sa zasićenom vodenom otopinom natrij-hidrogenkarbonata (2 x 600 ml), 10%-tnom limunskom kiselinom (2 x 300 ml), vodom i otopinom soli, a zatim su osušene na bezvodnom magnezij-sulfatu. Filtracijom i uklanjanjem otapala dobiven je sirovi proizvod (124.0 g, 97%). To a solution of (+)-(S)-4-benzyloxazolidinone (66.56 g, 0.376 mol) in tetrahydrofuran (900 ml), cooled to -78°C, was added n-butyllithium (164 ml, 2.29 M in hexane) over 1 hour. with mechanical stirring. Then the cooling bath was removed, and the solution was stirred for another 18 h. The reaction was then quenched with 10% citric acid (400 ml) and water (600 ml). The phases were separated, the aqueous phase was extracted with ether (3 x 300 ml). The combined organics were washed with saturated aqueous sodium hydrogen carbonate solution (2 x 600 ml), 10% citric acid (2 x 300 ml), water and brine, and then dried over anhydrous magnesium sulfate. Filtration and removal of the solvent gave the crude product (124.0 g, 97%).

Rekristatizacijom iz 10:1 heptana u eteru dobiven je čisti proizvod u 85% iscrpka. mp 57-59°C. MS m/e 340 (M+H)+. [α]D +81.6. Recrystallization from 10:1 heptane in ether gave the pure product in 85% yield. mp 57-59°C. MS m/e 340 (M+H)+. [α]D +81.6.

B. N1,N2-[di-terc-butoksikarbonil]-S-piperazinska kiselina [4R-(fenilmetil)-2-oksazolidinonamid] B. N1,N2-[di-tert-butoxycarbonyl]-S-piperazine acid [4R-(phenylmethyl)-2-oxazolidinonamide]

Sličan postupak priprave ovog spoja opisan je u kemijskim priručnicima (Hale i sur., Tetrahedron Letters 1992, 33, 7613). U unaprijed pripravljenu otopinu litij-diizopropil-amida (0.2214 mol u 104 ml tetrahidrofurana), ohlađenoj, na -78°C, dodavan je spoj iz postupka A (76.8 g, 0.226 mol), ali tako da se temperatura održavala na ili ispod -70°C. Dobivena smjesa je miješana još 20 min. na -78°C. Ukapana je otopina di-terc-butil-dijazodikarboksiiata (62.44 g, 0.271 mol) u suhom metilen-kloridu (370 ml), uz održavanje temperature na -70°C. Dobivena smjesa je miješana 30 min, a zatim je dodan 0.1 ekvivalent tetrabutilamonij-jodida. Zatim je uklonjena rashlađna kupelj, a temperatura reakcije se podigla do -10°C uz miješanje tijekom 30 minuta. HPLC je pokazaia potpuno mijenjanje proizvoda. Sirova smjesa je izlivena u otopinu etera (800 ml), vode (2 ml) i kalij-dihidrogen-fosfata (50 g). Organski sloj je odvojen, a vodeni je još dalje ekstrahiran s eterom. Kombinirane organske tvari su oprane sa zasićenom vodenom otopinom natrij-hidrogen-bikarbonata (500 ml) i otopinom soli, nakon čega je slijedilo sušenje na bezvodnom magnezij-sulfatu. Filtracijom i isparavanjem otapala dobiveno je sirovo ulje koje je zatim pročišćeno MPLC-SiO2 (25% etil-acetat/heksanu) kako bi se dobio željeni proizvod (49 gm, 50%). MS m/e 507 (M+H)+. [α]D +35.95 (c 0.370, metanol). A similar procedure for the preparation of this compound is described in chemical handbooks (Hale et al., Tetrahedron Letters 1992, 33, 7613). To a previously prepared solution of lithium diisopropylamide (0.2214 mol in 104 ml of tetrahydrofuran), cooled to -78°C, the compound from procedure A (76.8 g, 0.226 mol) was added, but so that the temperature was maintained at or below - 70°C. The resulting mixture was stirred for another 20 min. at -78°C. A solution of di-tert-butyl-diazodicarboxylate (62.44 g, 0.271 mol) in dry methylene chloride (370 ml) was added dropwise, while maintaining the temperature at -70°C. The resulting mixture was stirred for 30 min, and then 0.1 equivalent of tetrabutylammonium iodide was added. The cooling bath was then removed, and the reaction temperature was raised to -10°C with stirring for 30 minutes. HPLC showed a complete change of product. The crude mixture was poured into a solution of ether (800 ml), water (2 ml) and potassium dihydrogen phosphate (50 g). The organic layer was separated, and the aqueous layer was further extracted with ether. The combined organics were washed with saturated aqueous sodium hydrogen bicarbonate solution (500 ml) and brine, followed by drying over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave a crude oil which was then purified by MPLC-SiO2 (25% ethyl acetate/hexane) to give the desired product (49 gm, 50%). MS m/e 507 (M+H)+. [α]D +35.95 (c 0.370, methanol).

C. S-piperazinska kiselina [4R-(fenilmetil)-2-oksazolidinonamid]dihidroklorid C. S-piperazine acid [4R-(phenylmethyl)-2-oxazolidinonamide]dihydrochloride

U ohlađenu otopinu 4N hidrogen-klorida u dioksanu (100 ml) dodana je otopina spoja iz postupka 1B (10 g, 0.02 ml) u dioksanu (10 ml). Rashladna kupelj je uklonjena, a otopina je miješana 4 sata na sobnoj temperaturi. Otapalo je uklonjeno in vacuo kako bi se dobila dihidrokloridna sol (7.3 g, 98%). MS m/e 290 (M+H)+. [α]D +89.29 (c0.224, metanol), ir 3434, 1782, 1698, 1HNMR (300 MHz) 7.25 (5H, m), 4.81 (1H, dd), 4.40 (1H, m), 4.22 (1H, dd), 3.01 (4H, m), 2.0-1.75 (3H, m), 1.6 (1H, m). A solution of the compound from procedure 1B (10 g, 0.02 ml) in dioxane (10 ml) was added to a cooled solution of 4N hydrogen chloride in dioxane (100 ml). The cooling bath was removed, and the solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo to give the dihydrochloride salt (7.3 g, 98%). MS m/e 290 (M+H)+. [α]D +89.29 (c0.224, methanol), ir 3434, 1782, 1698, 1HNMR (300 MHz) 7.25 (5H, m), 4.81 (1H, dd), 4.40 (1H, m), 4.22 (1H , dd), 3.01 (4H, m), 2.0-1.75 (3H, m), 1.6 (1H, m).

D. N1-(benziloksikarbonil)-S-piperazinska kiselina [4R-(fenilmetil)-2-oksazolidinonamid] D. N1-(benzyloxycarbonyl)-S-piperazine acid [4R-(phenylmethyl)-2-oxazolidinonamide]

Otopina spoja iz postupka 1C (8.03 g, 22.1 mmol) u DMF (45 ml) ohlađena na 0°C tretirana je s Hunigsovom bazom (15.8 ml, 90.4 mmol) i miješana 20 min. Benzil-kloroformat (3.76 g, 22.1 mmol) je ukapavan tijekom 20 min., nakon čega je uklonjena rashladna kupelj i miješanje je nastavljeno na 20°C još 18 sati. Isparavanjem hlapljivih tvari dobiveno je smeđe ulje koje je zatim stavljeno N etil-acetat. Bijeli precipitat (diizopropiletilamin-hidroklorid) je uklonjen filtracijom, a filirat je opran sa zasićenim natrij-hidrogenkarbonatom, vodom i otopinom soli, nakon čega je osušen na bezvodnom magnezij-sulfatu. Filtracijom i uklanjanjem otapala in vacuo dobivena je polukrutina koja je rekristalizirana iz pentan/etil-acetata kako bi se dobio željeni proizvod (6.36 g, 68%) mp 102-103°C. MS m/e 423 (M+H)+. [α]D +33.3 (c 0.664, MeOH). A solution of the compound from procedure 1C (8.03 g, 22.1 mmol) in DMF (45 ml) cooled to 0°C was treated with Hunig's base (15.8 ml, 90.4 mmol) and stirred for 20 min. Benzyl chloroformate (3.76 g, 22.1 mmol) was added dropwise over 20 min., after which the cooling bath was removed and stirring was continued at 20°C for another 18 h. Evaporation of the volatiles gave a brown oil, which was then treated with N ethyl acetate. The white precipitate (diisopropylethylamine hydrochloride) was removed by filtration, and the filtrate was washed with saturated sodium hydrogencarbonate, water and salt solution, after which it was dried over anhydrous magnesium sulfate. Filtration and removal of the solvent in vacuo gave a semi-solid which was recrystallized from pentane/ethyl acetate to give the desired product (6.36 g, 68%) mp 102-103°C. MS m/e 423 (M+H)+. [α]D +33.3 (c 0.664, MeOH).

E. M1-(benziloksikarbonil)-S-piperazinska kiselina E. M1-(benzyloxycarbonyl)-S-piperazine acid

Spoj iz postupka 1D (5 g, 11.8 mmol) je rastopljen u smjesi THF (50 ml) i vode (10.2 ml) i ohlađen na 0°C. Litij-hidroksid-monohidrat (1.16 g) je dodan smjesi, a zatim je nestajanje početnih tvari zabilježeno uz pomoć tlc (1:1 eter/heksan). Nakon završetka reakcija (otprilike 4 h) je ugašena s 10%-tnom limunskom kiselinom i ekstrahirana s etil-acetatom. Etil-acetat je zatim 5 puta ekstrahiran sa zasićenom otopinom natrij-hidrogenkarbonata. U vodenu bazičnu fazu je dodana limunska kiselina, a zatim je 4 puta ekstrahirana s etil-acetatom. Organska faza je oprana s vodom, otopinom soli i osušena je na bezvodnom magnezij-sutfatu. Isparavanjem otapala dobiven je željeni proizvod (2.9 g, 93%) koji je u slijedećoj fazi korišten bez pročišćavanja. MS m/e 282 (M+H)+. [α]D = -31.25 (c 0.0128, MeOH), ir 3200, br 1750, 1692 1HNMR (300 MHz) 7.28 (5H, m), 5.05 (2H, 2), 3.8 (1H, ddd), 3.28 (2H, m), 3.02 (1H, m), 1.85 (1H, m), 1.70 (1H, m), 1.5 (2H, m). The compound from procedure 1D (5 g, 11.8 mmol) was dissolved in a mixture of THF (50 ml) and water (10.2 ml) and cooled to 0°C. Lithium hydroxide monohydrate (1.16 g) was added to the mixture, and then the disappearance of the starting materials was recorded by tlc (1:1 ether/hexane). After completion of the reaction (approximately 4 h), it was quenched with 10% citric acid and extracted with ethyl acetate. Ethyl acetate was then extracted 5 times with saturated sodium bicarbonate solution. Citric acid was added to the aqueous basic phase, and then it was extracted 4 times with ethyl acetate. The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave the desired product (2.9 g, 93%) which was used in the next step without purification. MS m/e 282 (M+H)+. [α]D = -31.25 (c 0.0128, MeOH), ir 3200, br 1750, 1692 1HNMR (300 MHz) 7.28 (5H, m), 5.05 (2H, 2), 3.8 (1H, ddd), 3.28 (2H , m), 3.02 (1H, m), 1.85 (1H, m), 1.70 (1H, m), 1.5 (2H, m).

F. Terc-butil-ester N1-(benizloksikarbonil)-S-piperazinske kiseline F. N1-(Benzyloxycarbonyl)-S-piperazine acid tert-butyl ester

Otopini spoja iz postupka 1E (11 g) u metilen-kloridu (100 ml) dodan je N,N-diizopropil-O-terc-butil-imidat•CuCl2 (35 ml 3M otopine u metilen-kloridu), a zatim je smjesa miješana na 20°C 18 sati. Dodana je octena kiselina (20 ml), a otopina je zatim miješana još 30 min. Filtracijom, nakon koje je slijedilo razrijeđivanje s vodom (100 ml) i zasićenom otopinom natrij-hidrogenkarbonata do pH 9-10, dobivena je otopina koja je snažno miješana još 10 min. Izdvajanjem organske faze, nakon čega je slijedila ekstrakcija s metilen-kloridom dobiven je sloj proizvoda koji je trebalo dodatno filtrirati i ukloniti plavi želatinozni precipitat. Vodeni sloj je ekstrahiran još 3 puta s metilen-kloridom, a kombinirani organski sloj je opran s vodom, otopinom soli i osušen na bezvodnom magnezij-sulfatu. Otapalo je uklonjeno in vacuo kako bi se dobilo ulje koje je triturirano s heksanom i filtrirano kako bi se uklonile preostale krutine. Uklanjanjem heksana dobiven je željeni proizvod u obliku ulja (10.3 g, 88%) koje se stvrdnulo na -20°C. MS m/e 280 (M+H)+.[α]D = -33 (c 0.700, MeOH), ir 1732, 1698. To a solution of the compound from procedure 1E (11 g) in methylene chloride (100 ml) was added N,N-diisopropyl-O-tert-butylimidate•CuCl2 (35 ml of a 3M solution in methylene chloride), and then the mixture was stirred at 20°C for 18 hours. Acetic acid (20 ml) was added, and the solution was then stirred for another 30 min. Filtration, followed by dilution with water (100 ml) and saturated sodium hydrogencarbonate solution to pH 9-10, resulted in a solution that was vigorously stirred for another 10 min. By separating the organic phase, followed by extraction with methylene chloride, a product layer was obtained, which had to be additionally filtered and the blue gelatinous precipitate removed. The aqueous layer was extracted 3 more times with methylene chloride, and the combined organic layer was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give an oil which was triturated with hexane and filtered to remove residual solids. Removal of hexane gave the desired product in the form of an oil (10.3 g, 88%) which solidified at -20°C. MS m/e 280 (M+H)+.[α]D = -33 (c 0.700, MeOH), ir 1732, 1698.

Postupak 2 Procedure 2

Priprava terc-butil-estera N1-(benziloksikarbonil)-6-fenilpiperazinske kiseline Preparation of N1-(benzyloxycarbonyl)-6-phenylpiperazine tert-butyl ester

A. 2-karbometoksi-5,8-difenilbiciklo [4.3]-1,6,8-triaza-7,9-dioksonon-3-en A. 2-carbomethoxy-5,8-diphenylbicyclo [4.3]-1,6,8-triaza-7,9-dioxonon-3-ene

Otopini N-fenil-3,4-dioksourazola (9.55 g, 54.5 mmol) u metilen-kloridu (250 ml) dodavana je otopina metil 5-fenil-2,4-pentenoata (10.25 g, 54.5 mmol) u metilen-kloridu (100 ml) tijekom 20 minuta. Smjesa je miješana 18 sati na sobnoj temperaturi. Otapalo je uklonjeno uz pomoć rotacijskog isparivača kako bi se dobio polukruti proizvod koji je trituriran a 1:1 eterom u heksanu. Bijeli kristali su sakupljeni filtracijom kako bi se dobio proizvod (12.34 g, 65%). Trituracija je ponovljena na filtratu kako bi se dobilo još bijelog kristalnog proizvoda, u kombiniranom isrpku 14.16 g (75%). mp 155-156°C. MS m/e 364 (M+H)+. To a solution of N-phenyl-3,4-dioxourazole (9.55 g, 54.5 mmol) in methylene chloride (250 ml) was added a solution of methyl 5-phenyl-2,4-pentenoate (10.25 g, 54.5 mmol) in methylene chloride ( 100 ml) for 20 minutes. The mixture was stirred for 18 hours at room temperature. The solvent was removed using a rotary evaporator to give a semi-solid product which was triturated with 1:1 ether in hexane. White crystals were collected by filtration to give the product (12.34 g, 65%). The trituration was repeated on the filtrate to give more white crystalline product, in a combined yield of 14.16 g (75%). mp 155-156°C. MS m/e 364 (M+H)+.

B. 2-karbometoksi-5,8-difenilbiciklo [4.3]-1,6,8-triaza-7,9-dioksonanon B. 2-carbomethoxy-5,8-diphenylbicyclo [4.3]-1,6,8-triaza-7,9-dioxonanone

Proizvod iz postupka 2A (14.16 g, 39.9 mmol) je razrijeden u smjesi 3:1 etanola u etil-acetatu, i miješan u prisutnosti 10%-tnog paladija na ugljiku pod 1 atm. vodikovog tlaka tijekom 18 sati. Katalizator je uklonjen filtracijom i opran s metilen-kloridom. Otapalo je uklonjeno isparavanjem kako bi se dobila bijela kruta pjena (14.2 g, 100%). Trituracijom pjene s 1:1:1 etil-acetat/eter/heksan, filiracijom i sušenjem dobiven je proizvod (12.7 g, 90%). mp 126-128°C. MS 366 (M+H)+. The product from procedure 2A (14.16 g, 39.9 mmol) was diluted in a 3:1 mixture of ethanol in ethyl acetate, and stirred in the presence of 10% palladium on carbon under 1 atm. of hydrogen pressure for 18 hours. The catalyst was removed by filtration and washed with methylene chloride. The solvent was removed by evaporation to give a white solid foam (14.2 g, 100%). Trituration of the foam with 1:1:1 ethyl acetate/ether/hexane, filtration and drying gave the product (12.7 g, 90%). mp 126-128°C. MS 366 (M+H)+.

C. Dihidroklorid 6-fenilpiperazinske kiseline C. Dihydrochloride of 6-phenylpiperazine acid

Spoj iz postupka 2B (28.7 g, 78.6 mmol), butanol (210 ml) i kalij-hidroksid u prahu (28.7 g, 511 mmol) su kombinirani i zagrijavani uz refluks 24 sata. Smjesa je ohlađena na sobnu temperaturu i miješana još 24 sata. Dodana je voda (225 ml) i smjesa je miješana 30 minuta. Sloj butanola je izdvojen i opran s vodom (225 ml). Kombinirana vodena faza je jedanput oprana s metilen-kloridom. Zatim je vodenoj fazi dodano 6N HCl do pH 2. Isparavanjem hlapljivih tvari pod vakuumom dobiven je krutina koja je triturirana s metanolom. Kalij-klorid je isfiltriran i otapalo je uklonjeno kako bi se dobio željeni proizvod (21.5 g, 96%). MS m/e 207 (M+H)+ slobodne baze. The compound from procedure 2B (28.7 g, 78.6 mmol), butanol (210 mL) and potassium hydroxide powder (28.7 g, 511 mmol) were combined and heated at reflux for 24 hours. The mixture was cooled to room temperature and stirred for another 24 hours. Water (225 ml) was added and the mixture was stirred for 30 minutes. The butanol layer was separated and washed with water (225 ml). The combined aqueous phase was washed once with methylene chloride. Then 6N HCl was added to the aqueous phase to pH 2. Evaporation of the volatiles under vacuum gave a solid which was triturated with methanol. The potassium chloride was filtered off and the solvent was removed to give the desired product (21.5 g, 96%). MS m/e 207 (M+H)+ free base.

D. N1-(benziloksikarbonil) piperazinska kiselina D. N1-(benzyloxycarbonyl)piperazine acid

Spoj iz postupka 2C (1 g, 3.6 mmol) je rastopljen u vodi (15 ml) i uz dodavanje 2N natrij-hidroksida pH je podešen na 9-9.5. Dobivena smjesa je ohlađena na 5°C, a otopina benzilkloroformata (0.464 ml, 3.6 mmol) u toluenu (2 ml) i otopina natrij-hidroksida (3.58 mmol) u vodi (2 ml) su zajedno dodavani jednakom brzinom tijekom 5 minuta. Dvofazna otopina je miješana 18 sati. Otopini je zatim dodano 1N HCl do pH 3, a zatim je smjesa ekstrahirana s etil-acetatom (3X). Organska faza je oprana s otopinom soli i osušena s bezvodnim magnezij-sulfatom. Filtracijom, nakon koje je uslijedilo isparavanje in vacuo dobiven je naslovljeni spoj (1.16 g, 95%). U slijedećoj fazi je dobiveni sirovi proizvod korišten nepromijenjen. MS m/e 341 (M+H)+, 295 (M+-CO2), 251 (M+-benzil). The compound from procedure 2C (1 g, 3.6 mmol) was dissolved in water (15 ml) and with the addition of 2N sodium hydroxide the pH was adjusted to 9-9.5. The resulting mixture was cooled to 5°C, and a solution of benzyl chloroformate (0.464 ml, 3.6 mmol) in toluene (2 ml) and a solution of sodium hydroxide (3.58 mmol) in water (2 ml) were added together at the same rate over 5 minutes. The two-phase solution was stirred for 18 hours. 1N HCl was then added to the solution until pH 3, and then the mixture was extracted with ethyl acetate (3X). The organic phase was washed with brine and dried with anhydrous magnesium sulfate. Filtration followed by evaporation in vacuo afforded the title compound (1.16 g, 95%). In the next phase, the obtained raw product was used unchanged. MS m/e 341 (M+H)+, 295 (M+-CO2), 251 (M+-benzyl).

E. t-butil-ester N1-(benziloksikarbonil)-6-fenilpiperazinske kiseline E. N1-(benzyloxycarbonyl)-6-phenylpiperazine acid t-butyl ester

Otopina spoja iz postupka 2D (1.22 g, 3.6 mmol) u metilen-kloridu (10 ml), ohlađena na 0°C, tretirana je s N,N-diizopropil-O-terc-butilimidat•CuCl2 (3.5 ml, 3.5 M otopine). Rashladna kupelj je uklonjena, a otopina je miješana 4.5 sati na sobnoj temperaturi. Smjesa je obrađena kao šo je prije opisano u postupku 1F. Sirovi proizvod (1.24 g, 86%) je pročišćen s MPLC (SiO2, 4:1 heksan/etil-acetatu) kako bi se dobio proizvod u obliku smjese dijastereomera. MS 397 (M+H)+. A solution of the compound from procedure 2D (1.22 g, 3.6 mmol) in methylene chloride (10 ml), cooled to 0°C, was treated with N,N-diisopropyl-O-tert-butylimidate•CuCl2 (3.5 ml, 3.5 M solution ). The cooling bath was removed, and the solution was stirred for 4.5 hours at room temperature. The mixture was processed as previously described in procedure 1F. The crude product (1.24 g, 86%) was purified by MPLC (SiO 2 , 4:1 hexane/ethyl acetate) to give the product as a mixture of diastereomers. MS 397 (M+H)+.

Postupak 3 Procedure 3

Priprava (2S,3R)-2’2’2’-trikloroetil-3-karboksi-2,5-dimetilheksanoata Preparation of (2S,3R)-2'2'2'-trichloroethyl-3-carboxy-2,5-dimethylhexanoate

A. (R)-2-etenil-3 (t butoksikarbonil)-5-metilheksanoična kiselina A. (R)-2-ethenyl-3-(t-butoxycarbonyl)-5-methylhexanoic acid

(R)-benzil (2-benziloksikarbonil)-3-(terc-butiloksikarbonil)-5-metilheksanoat (2 g, 4.4 mmol) je pripravljen kao što je opisano u Europskoj patentnoj prijavi WO 90/05719) i rastopljen u etanolu (40 ml). Dodan je amonij-format (1.4 g, 21.3 mmol) nakon čega je slijedio 10% Pd-C (500 mg) u obliku otopine izopropanola. Nakon 90 minuta uklonjen je katalizator filtracijom na celitu kako bi se dobila otopina sirovog diacida. Dodan je piperidin (415 g) i smjesa je miješana 10 min. na sobnoj temperaturi. Dodan je vodeni formaldehid (2.1 ml, 40% otopine), a smjesa je miješana još 18 sati. Otopina je zagrijavana uz refluks tijekom 90 min., ohlađena na sobnu temperaturu i otapalo je ispareno. Sirova tvar je razdijeljena s etil-acetatom i 10% otopine limunske kiseline. Kiseli sloj je triput ekstrahiran s etil-acetatom, a kombinirani organski slojevi su oprani s otopinom soli, osuženi na bezvodnom magnezij-sulfatu, filtrirani i ispareni in vacuo kako bi se dobio nsalovljeni spoj (0.87 g, 82%) u obliku bezbojnog ulja. MS 242 (M+H)+ , IR 3500-2800, 1730, 1700, 1626 cm-1. (R)-Benzyl (2-benzyloxycarbonyl)-3-(tert-butyloxycarbonyl)-5-methylhexanoate (2 g, 4.4 mmol) was prepared as described in European Patent Application WO 90/05719) and dissolved in ethanol (40 ml). Ammonium formate (1.4 g, 21.3 mmol) was added followed by 10% Pd-C (500 mg) as an isopropanol solution. After 90 minutes, the catalyst was removed by filtration on celite to obtain a crude diacid solution. Piperidine (415 g) was added and the mixture was stirred for 10 min. at room temperature. Aqueous formaldehyde (2.1 ml, 40% solution) was added and the mixture was stirred for another 18 hours. The solution was heated under reflux for 90 min., cooled to room temperature and the solvent was evaporated. The crude material was partitioned with ethyl acetate and 10% citric acid solution. The acidic layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give the title compound (0.87 g, 82%) as a colorless oil. MS 242 (M+H)+ , IR 3500-2800, 1730, 1700, 1626 cm-1.

B. 2S-metil-3R-(terc-butoksikarbonil)-5-metilheksanoična kiselina B. 2S-methyl-3R-(tert-butoxycarbonyl)-5-methylhexanoic acid

Otopini spoja iz postupka 3A (0.86 g) u metanolu (40 ml) je dodan 10% Pd-C (120 cng), a zatim je heterogena smjesa miješana pod 1 atm vodikovog plina tijekom 12 sati. Katalizator je filtriran, a otapalo je ispareno kako bi se dobio zasićeni proizvod u obliku bezbojnog ulja (9:1 smjesa dijastereomera). MS m/e 244 (M+H)+, [α] +18.2 (c 0.406, metanol) To a solution of the compound from procedure 3A (0.86 g) in methanol (40 ml) was added 10% Pd-C (120 cng), and then the heterogeneous mixture was stirred under 1 atm of hydrogen gas for 12 hours. The catalyst was filtered and the solvent was evaporated to give the saturated product as a colorless oil (9:1 mixture of diastereomers). MS m/e 244 (M+H)+, [α] +18.2 (c 0.406, methanol)

C. 2’2’2’-trikloroetil 2S-metil-3R-(terc-butoksilkarbonil), 5 metilheksanoat C. 2'2'2'-trichloroethyl 2S-methyl-3R-(tert-butoxylcarbonyl), 5 methylhexanoate

Spoj iz postupka 3B (4.4 mmol), trikloroetanol (850 ml, 8.8 mmol) i DMAP (30 mg) su pomiješani u suhom metilen-kloridu (10 ml) i ohlađeni na 0°C. Dodan je dicikloheksilkarbodiimid (908 mg (4.4 mmol), rashladna kupelj je uklonjena nakon 5 minuta, a otopina je zatim miješana u atmosferi dušika tijekom 12 sati. Precipitat dicikloheksiluree je uklonjen filtracijom, nakon čega je organski stoj opran s 10%-tnom limunskom kiselinom i otopinom soli. Isparavanjem otapala dobivena je polukrutina koja je triturirana s heksanom kako bi se dobilo još uree, koja je sakupljena filtracijom. Sloj heksana je snažno miješan u jednakoj količini vode tijekom 2 sata kako bi se uklonio suvišak trikloroetanola. Sloj heksana je zatim izdvojen, opran s otopinom soli i osušea na MgSO4. Isparavanjem otapala dobiveno je sirovo ulje koje je pročišćeno MPLC na silikagelu (5% eter/heksan) kako bi se dobio željeni dijastereomer u obliku ulja (77%). MS m/e 376 (M+H)+, [α] +7.43 (c 0.350, metanol) The compound from procedure 3B (4.4 mmol), trichloroethanol (850 ml, 8.8 mmol) and DMAP (30 mg) were mixed in dry methylene chloride (10 ml) and cooled to 0°C. Dicyclohexylcarbodiimide (908 mg (4.4 mmol)) was added, the cooling bath was removed after 5 min, and the solution was then stirred under nitrogen for 12 h. The dicyclohexylurea precipitate was removed by filtration, after which the organic layer was washed with 10% citric acid. and brine. Evaporation of the solvent gave a semi-solid which was triturated with hexane to give more urea, which was collected by filtration. The hexane layer was stirred vigorously in an equal amount of water for 2 hours to remove excess trichloroethanol. The hexane layer was then separated , washed with brine and dried over MgSO4. Evaporation of the solvent gave a crude oil which was purified by MPLC on silica gel (5% ether/hexane) to give the desired diastereomer as an oil (77%). MS m/e 376 (M +H)+, [α] +7.43 (c 0.350, methanol)

Primjer 1 Example 1

[4-(N-hidrokaiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amid [4-(N-hydrocaamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide

A. Terc-butil-ester (2R,3S)-[4-(2’2’2’-triktoroetoksi)-2-izobutil-3-metilsukcinil]-N2-(N1-benziloksikarbonil) piperazinske kiseline A. Tert-butyl ester (2R,3S)-[4-(2'2'2'-trictoroethoxy)-2-isobutyl-3-methylsuccinyl]-N2-(N1-benzyloxycarbonyl)piperazine acid

Spoj iz postupka 3D (1 g, 3.1 mmol) je rastopljen u suhom metilen-kloridu (30 ml) koji je sadržavao 5 kapi suhog N,N-dimetilformamida. Otopina je ohlađena na 0°C pod N2 nakon čega je slijedila adicija oksalil-klorida (0.297 ml, 3.4 mmol). Otopina je miješana 30 min na 0°C, a zatim 1 h na RT. Otapalo je ispareno in vacuo i 3x isprano sa suhim metilen-kloridom kako bi se uklonio HCI. Sirovi kiseli klorid je rastopljen u 15 ml metilen-klorida i dodan je smjesi (+/-)-t-butilestera N1-benziloksikarbonilpiperazinske kiseline (992 mg, 3.1 mmol) i N-metilmorfolina (341 ul, 3.1 mmol) u metilen-kloridu (20 ml) na 0°C. Smjesa je zatim miješana 18 sati na sobnoj temperaturi, a zatim je razrijeđena s 10%-tnom limunskom kiselinom, nakon čega je slijedila separacija i ispiranje sa zasićenim vodenim natrij-hidrogenkarbonatom, otopinom soli i konačno sušenje na bezvodnom magnezij-sulfatu. The compound from procedure 3D (1 g, 3.1 mmol) was dissolved in dry methylene chloride (30 ml) containing 5 drops of dry N,N-dimethylformamide. The solution was cooled to 0°C under N2 followed by the addition of oxalyl chloride (0.297 ml, 3.4 mmol). The solution was stirred for 30 min at 0°C and then for 1 h at RT. The solvent was evaporated in vacuo and washed 3x with dry methylene chloride to remove HCl. The crude acid chloride was dissolved in 15 ml of methylene chloride and added to a mixture of N1-benzyloxycarbonylpiperazine acid (+/-)-t-butyl ester (992 mg, 3.1 mmol) and N-methylmorpholine (341 µl, 3.1 mmol) in methylene chloride. (20 ml) at 0°C. The mixture was then stirred for 18 hours at room temperature and then diluted with 10% citric acid, followed by separation and washing with saturated aqueous sodium bicarbonate, brine and finally drying over anhydrous magnesium sulfate.

Otapalo je ispareno kako bi se dobila sirova tvar koja je pročišćena MPLC na silikagelu kako bi se dobio naslovljeni spoj (0.96 g, 50%) u obliku smjese 1:1 dijastereomera. MS m/e 623 (M+H)+. IR 1760 cm-1. The solvent was evaporated to give the crude material which was purified by MPLC on silica gel to give the title compound (0.96 g, 50%) as a 1:1 mixture of diastereomers. MS m/e 623 (M+H)+. IR 1760 cm-1.

B. N-metil-amid (2R,3S)-[4-(2’2’2’-trikloroetil)-2-izobutil-3-metilsukcinil]-N2-(N1-benziloksikarbonil)-piperazinsike kiseline B. N-methyl-amide (2R,3S)-[4-(2'2'2'-trichloroethyl)-2-isobutyl-3-methylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid

Spoj iz primjera 1A (0.96 g) je dodan otopini 4N HCl/dioksanu (35 ml), a smjesa je zatim miješana 8 sati na sobnoj temperaturi. Uklanjanjem otapala in vacuo dobivena je željena kiselina u kvantitativnom iscrpku. Sirova kiselina je rastopljena u CH2Cl2 (10 ml) i tretirana s N-metilmorfolinom (0.19 ml, 1.7 mmol) i ohlađena na -20°C. Nakon 10 min miješanja na -20, izobutilkloroformat (0.2 ml, 1.5 mmol) je ukapavan tijekom 5 min, i smjesa je miješana 1 sat na sobnoj temperaturi. Dobivena smjesa je tretirana s 5 ekvivalenata 40%-tnog vodenog metilamina, i otopina je miješana 30 min kako bi se ugrijala na sobnu temperaturu. Smjesa je zatim razrijeđena s etil-acetatom, oprana s 10%-tnom limunskom kiselinom, vodom i otopinom soli, a zatim osušena na bezvodnom magnezij-sulfatu. Isparavanjem otapala dobiveno je sirovo ulje koje je pročišćeno MPLC (5% MeOH/CH2Cl2) kako bi se dobio željeni amid u oblika smjese 1:1 dijastereomera (770 mg, 89%). MS m/e 578 (M+H)+, IR 3354, 1752, 1716, 1678, 1544 cm-1. The compound from Example 1A (0.96 g) was added to a solution of 4N HCl/dioxane (35 ml), and the mixture was then stirred for 8 hours at room temperature. By removing the solvent in vacuo, the desired acid was obtained in a quantitative extract. The crude acid was dissolved in CH2Cl2 (10 ml) and treated with N-methylmorpholine (0.19 ml, 1.7 mmol) and cooled to -20°C. After stirring for 10 min at -20, isobutylchloroformate (0.2 ml, 1.5 mmol) was added dropwise over 5 min, and the mixture was stirred for 1 h at room temperature. The resulting mixture was treated with 5 equivalents of 40% aqueous methylamine, and the solution was stirred for 30 min to warm to room temperature. The mixture was then diluted with ethyl acetate, washed with 10% citric acid, water and brine, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude oil which was purified by MPLC (5% MeOH/CH2Cl2) to give the desired amide as a 1:1 mixture of diastereomers (770 mg, 89%). MS m/e 578 (M+H)+, IR 3354, 1752, 1716, 1678, 1544 cm-1.

C. N-metil-amid (2R,3S)-[4-hidroksi-2-izobutil-3-metilsukcinil]-N2-(N1-benziloksikarbonil)-piperazinske kiseline C. N-methyl-amide (2R,3S)-[4-hydroxy-2-isobutyl-3-methylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid

Spoj iz primjera 1 B je rastopljen u tetrahidrofuranu (26 ml) i dodano je 5.2 ml 1M otopine amonij-acetata. Otopina je ohlađena na 0°C, a zatim je dodan cinkov prah (2.3 g, 3 ms. ekvival.) Heterogena otopina je snažno miješana 10 minuta na 0°C, a zatim 6 sati na sobnoj temperaturi. Sirova reakcijska smjesa je filtrirana i oprana s etil-acetatom. Otapalo je uklonjeno isparavanjem, a sirova tvar je razrijeđena s etil-acetatom i oprana s vodom, 10%-tnom limunskom kiselinom (2x), otopinom soli i osušena na bezvodnom magnezij-sulfatu. Filtracijom i isparavanjem otapala, nakon čega je slijedila MPLC (10% MeOH/CH2Cl2) dobiven je željeni proizvod u omjeru 1:1 smjese dijastereomera u obliku bijele pjene (330 mg, 57%). MS m/e 465 (M+H)+, IR 3324, 2958, 1712, 1680, 1554 cm-1. The compound from Example 1 B was dissolved in tetrahydrofuran (26 ml) and 5.2 ml of 1 M ammonium acetate solution was added. The solution was cooled to 0°C and then zinc powder (2.3 g, 3 ms. equiv.) was added. The heterogeneous solution was stirred vigorously for 10 minutes at 0°C and then for 6 hours at room temperature. The crude reaction mixture was filtered and washed with ethyl acetate. The solvent was removed by evaporation, and the crude material was diluted with ethyl acetate and washed with water, 10% citric acid (2x), brine and dried over anhydrous magnesium sulfate. Filtration and solvent evaporation, followed by MPLC (10% MeOH/CH2Cl2) afforded the desired product as a 1:1 mixture of diastereomers as a white foam (330 mg, 57%). MS m/e 465 (M+H)+, IR 3324, 2958, 1712, 1680, 1554 cm-1.

D. N-metil-amid (2R,3S)-[4-benziloksiamino)-2-izobutil-3-metilsukcinil)-N2-(N1-benziloksikarbonil)-piperazinske kiseline D. N-methyl-amide (2R,3S)-[4-benzyloxyamino)-2-isobutyl-3-methylsuccinyl)-N2-(N1-benzyloxycarbonyl)-piperazine acid

Spoj iz primjera 1C (210 mg, 0.47 mmol) je pomiješan s N-metilmorfolinom (0.056 ml) u suhom metilen-klorida (15 ml) i ohlađen na -20°C pod N2. Dodan je izobutilkloroformat (0.061 )ml, 0.47 mmol), a otopina je zatim miješana 1 h. Otopina O-benzilhidroksilamin-hidroklorida (77 mg) i N-metilmorfolina (0.056 ml) u metilen-kloridu (3 ml) je dodana uz ispiranje s metilen-kloridom, zatim je smjesa miješana na sobnoj temperaturi 18 sati. Smjesa je razrijeđena s metilen-kloridom, oprana s 10%-tnom limunskom kiselinom (1 x 20 ml), otopinom soli, a zatim je osušena na bezvodnom magnezij-sulfatu. Isparavanjem otapala dobiven je O-benzil zaštićena hidroksamska kiselina (203 mg, 78%) u obliku smjese dijastereomera, koji su razdvojeni uz pomoć HPLC C18 kolona, 10% izopropanol/heksan. The compound from Example 1C (210 mg, 0.47 mmol) was mixed with N-methylmorpholine (0.056 ml) in dry methylene chloride (15 ml) and cooled to -20°C under N 2 . Isobutylchloroformate (0.061 ml, 0.47 mmol) was added, and the solution was then stirred for 1 h. A solution of O-benzylhydroxylamine hydrochloride (77 mg) and N-methylmorpholine (0.056 ml) in methylene chloride (3 ml) was added while washing with methylene chloride, then the mixture was stirred at room temperature for 18 hours. The mixture was diluted with methylene chloride, washed with 10% citric acid (1 x 20 ml), brine, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave O-benzyl protected hydroxamic acid (203 mg, 78%) in the form of a mixture of diastereomers, which were separated using HPLC C18 columns, 10% isopropanol/hexane.

Dijastereomer A 97 mg (prvi nastali proizvod) je preveden u odgovarajuću hidroksamsku kiselinu kao što je opisano u primjeru 1E. Diastereomer A 97 mg (the first product formed) was converted to the corresponding hydroxamic acid as described in Example 1E.

Dijastereomer B 95 mg (drugi nastali proizvod) je preveden u odgovarajuću hidroksamsku kiselinu kao što je opisano u primjeru 2. Diastereomer B 95 mg (the second product formed) was converted to the corresponding hydroxamic acid as described in Example 2.

E. (R)-[(2R,3S)-4-(N hidroksiamino)-2-izobutil-3-metilsukcinil]-N2-piperazinska kiselina-N-metil-amid E. (R)-[(2R,3S)-4-(N hydroxyamino)-2-isobutyl-3-methylsuccinyl]-N2-piperazine acid-N-methyl-amide

Dijastereomer A iz primjera 1D (29 mg, 0.052 mmol) je rastopljen u etanolu (5 ml) i dodan je 10% Pd na C ( 5 mg). Otopina je 1 h miješana pod balonom vodika. Heterogena smjesa je filtrirana kroz mikroporozni filter i isparena dok se potpuno nije osušila, kako bi se dobio naslovljeni spoj (18 mg, kvantitativni iscrpak). MS m/e 570 (M+H)+, [α]D +54.17 (c 0.216, MeOH), mp 120-130°C, ir 3224, 1624 br, 1HNMR (400 MHz, COSY, CD3OD) 5.1 (1H, dd), 4.08 (1H, dt), 3.09 (1H, ddd), 2.79 (3H, s), 2.4 (1H, ddd), 1.65 (1H, ddd), 2.25 (1H, ddd), 2.19 (1H, dddd), 1.8 (1H, dddd), 1.65 (1H, ddd), 1.55 (2H, m), 1.4 (1H, m), 1.2 (3H, d), 1.19 (1H, m), 0.92 (3H, d), 0.88 (3H, d), 13CNMR (100 MHz, DEPT, CD3OD) 178.7, 174.8, 173.6, 42.9, 41.7, 41.0, 27.5, 27.3, 26.3, 24.2, 22.3, 22.2, 15.5. Diastereomer A from Example 1D (29 mg, 0.052 mmol) was dissolved in ethanol (5 ml) and 10% Pd at C (5 mg) was added. The solution was stirred under a hydrogen balloon for 1 h. The heterogeneous mixture was filtered through a microporous filter and evaporated to complete dryness to afford the title compound (18 mg, quantitative extract). MS m/e 570 (M+H)+, [α]D +54.17 (c 0.216, MeOH), mp 120-130°C, ir 3224, 1624 br, 1HNMR (400 MHz, COSY, CD3OD) 5.1 (1H , dd), 4.08 (1H, dt), 3.09 (1H, ddd), 2.79 (3H, s), 2.4 (1H, ddd), 1.65 (1H, ddd), 2.25 (1H, ddd), 2.19 (1H, dddd), 1.8 (1H, dddd), 1.65 (1H, ddd), 1.55 (2H, m), 1.4 (1H, m), 1.2 (3H, d), 1.19 (1H, m), 0.92 (3H, d ), 0.88 (3H, d), 13CNMR (100 MHz, DEPT, CD3OD) 178.7, 174.8, 173.6, 42.9, 41.7, 41.0, 27.5, 27.3, 26.3, 24.2, 22.3, 22.2, 15.5.

Primjer 2 Example 2

(S)- [(2R,3S)-4-(N-butiloksiamino)-2-izobutil-3-metilsukcinil]-N2-piperazinska kiselina-N metil-amid (S)-[(2R,3S)-4-(N-butyloxyamino)-2-isobutyl-3-methylsuccinyl]-N2-piperazine acid-N methyl-amide

Dijastereomer iz primjera 1D (15 mg) je rastopljen u etanolu (5 ml) i dodan je 10%-tni Pd na C (5 mg). Otopina je miješana pod balonom vodika 1 sat. Heterogena smjesa je filtrirana kroz mikroporozni filter, isparena dok se smjesa nije osušila kako bi se dobio nastovljeni spoj (10 mg). mp 123-127°C, MS m/e 570 (M+H)+, [α]D +6.67 (c 0.009, MeOH), 1HNMR (400 MHz, COSY, CD3OD) 5.15 (1H, dd), 4.00 (1H, m), 3.05 (1H, m), 2.8 (1H, m), 2.79 (1H, s), 2.28 (1H, m), 2.10 (1H, m), 1.9 (1H, m), 1.7-1.5 (3H, m), 1.3 (1H, m), 1.05 (1H, m), 1-04 (3H, d), 0.92 (3H, d), 0.83 (3H, d), 13CNMR (100 MHz, DEPT, CD3OD) 180.8, 179.11, 174.6, 52.4, 42.6, 42.5, 28.1, 27.5, 27.1, 27.0, 26.2, 24.5, 22.4, 17.3, 17.1. The diastereomer from Example 1D (15 mg) was dissolved in ethanol (5 ml) and 10% Pd on C (5 mg) was added. The solution was stirred under a hydrogen balloon for 1 hour. The heterogeneous mixture was filtered through a microporous filter, evaporated to dryness to afford the title compound (10 mg). mp 123-127°C, MS m/e 570 (M+H)+, [α]D +6.67 (c 0.009, MeOH), 1HNMR (400 MHz, COSY, CD3OD) 5.15 (1H, dd), 4.00 ( 1H, m), 3.05 (1H, m), 2.8 (1H, m), 2.79 (1H, s), 2.28 (1H, m), 2.10 (1H, m), 1.9 (1H, m), 1.7-1.5 (3H, m), 1.3 (1H, m), 1.05 (1H, m), 1-04 (3H, d), 0.92 (3H, d), 0.83 (3H, d), 13CNMR (100 MHz, DEPT, CD3OD) 180.8, 179.11, 174.6, 52.4, 42.6, 42.5, 28.1, 27.5, 27.1, 27.0, 26.2, 24.5, 22.4, 17.3, 17.1.

Primjer 3 Example 3

Metil-amid N-[1(R)-karboksietil]-α-(S)-izobutilglicin-(S)-N1-piperazinske kiseline N-[1(R)-carboxyethyl]-α-(S)-isobutylglycine-(S)-N1-piperazine acid methyl-amide

Otopini Cbz-L-leucina (1 g, 3.77 mmol) i N,N-dimetilformamida (0.5 ml) u metilen-kloridu (45 ml) na 0°C, dodan je oksalil-klorid (0.329 ml). Otopina je miješana 1 h na 0°C, a zatim 2 h na sobnoj temperaturi. Zatim je isparena in vacuo. Sirovi kiseli klorid je stavljen u metilen-klorid (45 ml) i ohlađen na 0°C u atmosferi N2. Spoj iz postupka 1F (1.21 mg, 3.77 mmol) i N-metilmorfolin (0.458 ml) u metilen-kloridu je dodavan otopini kiselog klorida tijekom 10 minuta, a zatim je smjesa miješana 18 sati na RT. Smjesa je stavljena u metilen-klorid i oprana s 10%-tnom limunskom kiselinom, zasićenim vodenim natrij-hidrogenkarbonatom, vodom i otopinom soli, a zatim je osušena na bezvodnom magnezij-sutfatu. Filtracijom i isparavanjem otapala dobiven je amid u obliku ulja koji je pročišćen MPLC (1.7 g, 79%). To a solution of Cbz-L-leucine (1 g, 3.77 mmol) and N,N-dimethylformamide (0.5 ml) in methylene chloride (45 ml) at 0°C, oxalyl chloride (0.329 ml) was added. The solution was stirred for 1 h at 0°C and then for 2 h at room temperature. It was then evaporated in vacuo. The crude acid chloride was taken up in methylene chloride (45 ml) and cooled to 0°C under N 2 . The compound from procedure 1F (1.21 mg, 3.77 mmol) and N-methylmorpholine (0.458 ml) in methylene chloride was added to the acid chloride solution over 10 minutes, and then the mixture was stirred for 18 hours at RT. The mixture was taken up in methylene chloride and washed with 10% citric acid, saturated aqueous sodium hydrogencarbonate, water and brine, and then dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave the amide in the form of an oil, which was purified by MPLC (1.7 g, 79%).

Dobiveni amid (1.7 mg, 2.98 mmol) je tretiran s trifluorooctenom kiselinom tijekom 4 sata na sobnoj temperaturi. Isparavanjem otapala dobivena je prijelazna kiselina koja je korištena u slijedećoj fazi bez pročišćavanja. U otopinu sirove kiseline ohlađenu na -20°C (660 mg, 1.29 mmol) i N-metilmorfolina (0.145 ml, 1.37 mmol) u metilen-kloridu dodan je izobutilkloroformat (0.173 ml, 1.32 mmol). Otopina je miješana 1h na -20°C. Zatim je dodan vodeni metilamin (40%-tna otopina, 5 ekviv.) i temperatura je narasla do ambijentalne. Nakon 1 h otopina je ugašena s 10%-tnom limunskom kiselinom, razrijeđena s CH2Cl2 i oprana s vodom i otopinom soli, nakon čega je smjesa osušena na MgSO4. Filtracijom i isparivanjem otapala dobiven je metil-amid koji je pročišćen MPLC. The resulting amide (1.7 mg, 2.98 mmol) was treated with trifluoroacetic acid for 4 hours at room temperature. By evaporating the solvent, a transition acid was obtained, which was used in the next step without purification. Isobutylchloroformate (0.173 ml, 1.32 mmol) was added to a solution of the crude acid cooled to -20°C (660 mg, 1.29 mmol) and N-methylmorpholine (0.145 ml, 1.37 mmol) in methylene chloride. The solution was stirred for 1 hour at -20°C. Aqueous methylamine (40% solution, 5 equiv) was then added and the temperature was raised to ambient. After 1 h, the solution was quenched with 10% citric acid, diluted with CH2Cl2 and washed with water and brine, after which the mixture was dried over MgSO4. Filtration and evaporation of the solvent gave methyl-amide, which was purified by MPLC.

Bis-Cbz zaštićeni intermedijer je hidrogeniziran s H2 Pd-C u etanolu tijekom 4 sata na 1 atm. Heterogena smjesa je filtrirana i isparena in vacuo kako bi se dobio odgovarajući amin. Konačni proizvod je dobiven reduktivnom aminacijom a benzil-piruvatom kao što slijedi: amin u THF je tretilan s benzil-piruvatom na 20°C. Natrij-cijanoborohidrid je dodan, a ekvivalent p-toluensulfonske kiseline u THF je titriran više od 1 h. Otapalo je ispareno do 1/3 volumena, a etil-acetat i voda su zatim dodani. Organska faza je izdvojena, a vodena je oprana 3 puta a etil-acetatom. Kombinirane organske tvari su oprane s vodom i otopinom soli, a zatim osušene na MgSO4. Filtracijom i isparavanjem otapala dobivena je sirova amino kiselina u obliku smjese dijastereomera koja je pročišćena s MPLC (60% meOH/CH2Cl2). MS m/e 327 (M+H)+. The bis-Cbz protected intermediate was hydrogenated with H2 Pd-C in ethanol for 4 hours at 1 atm. The heterogeneous mixture was filtered and evaporated in vacuo to give the corresponding amine. The final product was obtained by reductive amination with benzylpyruvate as follows: the amine in THF was tritylated with benzylpyruvate at 20°C. Sodium cyanoborohydride was added and an equivalent of p-toluenesulfonic acid in THF was titrated over 1 h. The solvent was evaporated to 1/3 volume, and ethyl acetate and water were then added. The organic phase was separated, and the aqueous phase was washed 3 times with ethyl acetate. The combined organics were washed with water and brine and then dried over MgSO4. Filtration and evaporation of the solvent gave the crude amino acid in the form of a mixture of diastereomers, which was purified by MPLC (60% meOH/CH2Cl2). MS m/e 327 (M+H)+.

Primjer 45a Example 45a

(S)-[(2R,3S)-4-(N-hidroksiamino)-2-propilfenil-3-metilsukcinil]-N2-piperazinksa kiselina-N-metil-amid (S)-[(2R,3S)-4-(N-hydroxyamino)-2-propylphenyl-3-methylsuccinyl]-N2-piperazinic acid-N-methyl-amide

A. [4R-(fenilmetil)-2-oksazolidinil)j-5-fenilvaleramid A. [4R-(phenylmethyl)-2-oxazolidinyl)j-5-phenylvaleramide

Natrijeva sol 5-fenilvalerinske kiseline (53.5 mol) je rastopljena u THF (100 ml) i dodan je bezvodni DMF (1 ml). Otopina je ohlađena na 0°C u atmosferi dušika. Oksalil-klorid (4.67 ml) je ukapavan tijekom 20 min., nakon čega je slijedilo miješanje na 0°C tijekom 1 h, a zatim na sobnoj temperaturi sve do prestanka stvaranja plina (3 h). The sodium salt of 5-phenylvaleric acid (53.5 mol) was dissolved in THF (100 ml) and anhydrous DMF (1 ml) was added. The solution was cooled to 0°C under a nitrogen atmosphere. Oxalyl chloride (4.67 ml) was added dropwise over 20 min., followed by stirring at 0°C for 1 h, and then at room temperature until gas formation ceased (3 h).

U otopinu (+)-(S)-4-benziloksazolidinona (8.83 g, 53.5 mmol) u tetrahidrofuranu (100 ml) ohlađenu na -78°C je dodavan uz miješanje n-butil-litij (21.4 ml, 2.5 M u heksanu) tijekom 1 sata. Nakon 15 min miješanja, dodavan je tijekom 45 min kiseli klorid (unaprijed rashlađen na -78°C). Rashladna kupelj je uklonjena, a otopina je miješana još 18 sati. Reakcija je ugašena s 10%-tnom limunskom kiselinom (100 ml) i vodom (100 ml). Faze su razdvojene, a vodena faza je ekstrahirana s eterom (3 x 300 ml). Kombinirane organske tvari su oprane sa zasićenom vodenom otopinom natrij-hidrogenkarbonata (2 x 600 ml), 10%-tnom limunskom kiselinom (2 x 300 ml), vodom i otopinom soli, a zatim su osušene na bezvodnom magnezij-sulfatu. Filtracijom i uklanjanjem otapala dobiven je sirovi proizvod koji je zatim kromatorgafiran koristeći 20%-tni etil-acetat/heksanu kako bi se dobilo 14 g (77%) željenog proizvoda. MS m/e 338 (M+H). To a solution of (+)-(S)-4-benzyloxazolidinone (8.83 g, 53.5 mmol) in tetrahydrofuran (100 ml) cooled to -78°C, n-butyl lithium (21.4 ml, 2.5 M in hexane) was added with stirring. during 1 hour. After 15 min of mixing, acid chloride (precooled to -78°C) was added over 45 min. The cooling bath was removed, and the solution was stirred for another 18 hours. The reaction was quenched with 10% citric acid (100 ml) and water (100 ml). The phases were separated and the aqueous phase was extracted with ether (3 x 300 ml). The combined organics were washed with saturated aqueous sodium hydrogen carbonate solution (2 x 600 ml), 10% citric acid (2 x 300 ml), water and brine, and then dried over anhydrous magnesium sulfate. Filtration and removal of the solvent afforded the crude product which was then chromatographed using 20% ethyl acetate/hexane to afford 14 g (77%) of the desired product. MS m/e 338 (M+H).

B. [4R-(fenilmetil)-2-oksazolidinil)]-2S-(t-butilacetil)-5-fenilvaleramid B. [4R-(phenylmethyl)-2-oxazolidinyl)]-2S-(t-butylacetyl)-5-phenylvaleramide

Spoj iz dijela A (14 g, 41.5 mmol) je rastopljen u 150 ml bezvodnog THF i ohlađen na -78 pod N2. LDA (41.5 mmol) je dodavan tijekom 10 min., a otopina je miješana na -78 tijekom 30 min. Terc-butil-bromoacetat (8.1 g, 41.5 mmol) rastopljen u 30 ml THF je dodavan tijekom 20 min., a dobivena smjesa je miješana 30 min na .-78., a zatim zagrijana na ambijentalnu temperaturu uklanjanjem rashladne kupelji. Nakon 1 h, otopina je koncentrirana na rotacijskom isparivaću do 1/4 volumena. Zatim je dodan etil-acetat, nakon čega je smjesa isprana s 10%-tnom limunskom kiselinom, vodom i otopinom soli i osušena na MgSO4. Isparavanjem otapala dobiveno je ulje koje je pročišćeno uz pomoć MPLC 25% eter/heksan kako bi se dobilo 10.75 g (57%) proizvoda adicije. mp 73-75°C, MS m/e 452 (M+H)+, [α]D +74.3 (c 0.214, metanol) The compound from part A (14 g, 41.5 mmol) was dissolved in 150 ml of anhydrous THF and cooled to -78 under N 2 . LDA (41.5 mmol) was added over 10 min, and the solution was stirred at -78 for 30 min. Tert-butyl bromoacetate (8.1 g, 41.5 mmol) dissolved in 30 ml of THF was added over 20 min., and the resulting mixture was stirred for 30 min at .-78., and then warmed to ambient temperature by removing the cooling bath. After 1 h, the solution was concentrated on a rotary evaporator to 1/4 volume. Ethyl acetate was then added, after which the mixture was washed with 10% citric acid, water and brine and dried over MgSO4. Evaporation of the solvent gave an oil which was purified by MPLC 25% ether/hexane to give 10.75 g (57%) of the addition product. mp 73-75°C, MS m/e 452 (M+H)+, [α]D +74.3 (c 0.214, methanol)

C. Terc-butil-3S-(hidroksikarbonil)-6 fenilheksanoat C. Tert-butyl-3S-(hydroxycarbonyl)-6 phenylhexanoate

Ohlađenoj otopini (0°C) spoja iz dijela B (5 g, 11.1 mmol) rastopljenoj u 60 ml THF/H2O (4:1) je dodan vodikov peroksid (30% otopina, 4.5 ml, 44.4 mmol), a zatim vodeni LiOH (425 mg u 30 ml vode). Otopina je miješana 5 h na 0. Za to vrijeme je uz pomoć TLC zabilježeno potpuno rastapanje početnih tvari. THF je uklonjen pod sniženim tlakom, a dobivena vodena faza je oprana s CH2Cl2. Vodenoj fazi je pažljivo dodavana 10%-tna HCl do pH 1. Otopina je ekstrahirana a etil-acetatom, osušena na MgSO4, filtrirana i isparena kako bi se dobio sirovi proizvod. Dobiveni proizvod je pročišćen MPLC 7% meOH/CH2Cl2 kako bi se dobilo 2.90 g (90%) pročišćene kiseline. MS m/e 293 (M+H)+, [α]D +6.3 (c 0.322, metanol). To a cooled solution (0°C) of the compound from part B (5 g, 11.1 mmol) dissolved in 60 ml of THF/H2O (4:1) was added hydrogen peroxide (30% solution, 4.5 ml, 44.4 mmol), followed by aqueous LiOH (425 mg in 30 ml of water). The solution was stirred for 5 h at 0. During this time, the complete dissolution of the starting substances was recorded with the help of TLC. The THF was removed under reduced pressure, and the resulting aqueous phase was washed with CH2Cl2. 10% HCl was carefully added to the aqueous phase until pH 1. The solution was extracted with ethyl acetate, dried over MgSO4, filtered and evaporated to obtain the crude product. The resulting product was purified by MPLC 7% meOH/CH2Cl2 to give 2.90 g (90%) of the purified acid. MS m/e 293 (M+H)+, [α]D +6.3 (c 0.322, methanol).

D. (2R)-[4-(terc-butoksi)-2-propilfenilsukcinil]-N2-(N1-benziloksikarbonil)-S-piperazinska kiselina D. (2R)-[4-(tert-butoxy)-2-propylphenylsuccinyl]-N2-(N1-benzyloxycarbonyl)-S-piperazine acid

Spoj iz dijela C (2.50 g, 8.56 mmol) je rastopljen u 100 ml bezvodnog toluena i ohlađen na -10°C. Dodan je DMP (0.5 ml), a zatim oksatit-klorid (1.39 g). Dobivena otopina je miješana 1 h na -10, nakon čega je ispareno otapalo pod visokim vakuumom na -10. Sirovi kiseli klorid je razrijeđen s 50 ml CH2Cl2 a zatim ohlađen na 0°C pod N2. U posebnoj posudi je rastopljena N-benziloksikarbonil-S-piperazinska kiselina (2.26 g) u 35 ml CH2Cl2 i tretirana a 3.68 ml trietilatmna. Nakon 5 min., dobivena je otopina premiještana tijekom 10 min u drugu posudu. Miješanje je nastavljeno još 1 h na 0 i 1 h na ambijentalnoj temperaturi. Reakcija je ugašena s 10%-tnom limunskom kiselinom i ekstrahirana 3 puta s CH2Cl2. Organska taza je oprana s vodom, otopinom soli i osušena s MgSO4. Filtracijom i isparavanjem otapala nakon čega je slijedila MPLC (7% meOH/CH2Cl2) dobiveno je 1.95 g (42%) željenog proizvoda MS m/e 539 (M+H)+, [α]D -10.6 (c 1.002, metanol). The compound from part C (2.50 g, 8.56 mmol) was dissolved in 100 ml of anhydrous toluene and cooled to -10°C. DMP (0.5 ml) was added, followed by oxalate chloride (1.39 g). The resulting solution was stirred for 1 h at -10, after which the solvent was evaporated under high vacuum at -10. The crude acid chloride was diluted with 50 ml of CH2Cl2 and then cooled to 0°C under N2. In a separate vessel, N-benzyloxycarbonyl-S-piperazine acid (2.26 g) was dissolved in 35 ml of CH2Cl2 and treated with 3.68 ml of triethylamine. After 5 min., the resulting solution was transferred for 10 min to another container. Stirring was continued for another 1 h at 0 and 1 h at ambient temperature. The reaction was quenched with 10% citric acid and extracted 3 times with CH2Cl2. The organic phase was washed with water, brine and dried with MgSO4. Filtration and evaporation of the solvent followed by MPLC (7% meOH/CH2Cl2) afforded 1.95 g (42%) of the desired product MS m/e 539 (M+H)+, [α]D -10.6 (c 1.002, methanol) .

E. (2R)-[4-(terc-butoksi)-2-propilfenilsukcinil]-N2-(N1-benziloksikarbonil)-piperazinska kiselina -N-metil-amid E. (2R)-[4-(tert-butoxy)-2-propylphenylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid -N-methyl-amide

Spoju iz dijela D (1.90 g, 3.53 mmol) rastopljenom u 40 ml CH2Cl2, dodano je NMM (413 ul). Otopina je ohlađena na -20, a zatim je dodan IBCF (459 ul, 3.53 mmol). Smjesa je miješana 1.5 h, a zatim jje dodano 0.6 ml 40%-tnog vodenog metil-amina. Rashladna kupelj je uklonjena, a otopina je miješana 1 h na ambijentalnoj tempetaturi. Reakcija je ugašena dodavanjem 10%-tne limunske kiseline. Organska faza je izdvojena, oprana s vodom, otopinom soli i osušena na MgSO4. Filtracijom i isparavanjem otapala dobiven je sirovi proizvod koji je pročišćen s MPLC (75% MeOH/CH2Cl2) kako bi se dobilo 1.6 g (82%) proizvoda. MS m/e 552 (M+H)+, [α]D -29.9 (c 0.166, metanol). To the compound from part D (1.90 g, 3.53 mmol) dissolved in 40 mL of CH 2 Cl 2 , was added NMM (413 µl). The solution was cooled to -20 and then IBCF (459 µl, 3.53 mmol) was added. The mixture was stirred for 1.5 h, and then 0.6 ml of 40% aqueous methylamine was added. The cooling bath was removed, and the solution was stirred for 1 h at ambient temperature. The reaction was quenched by adding 10% citric acid. The organic phase was separated, washed with water, brine and dried over MgSO4. Filtration and evaporation of the solvent gave the crude product which was purified by MPLC (75% MeOH/CH2Cl2) to give 1.6 g (82%) of product. MS m/e 552 (M+H)+, [α]D -29.9 (c 0.166, methanol).

F. (2R)-[4-hidroksi-2-propilfenilsukcinil]-N2-(N1-benziloksikarbonil)-piperazinska kiselina-N-metil-amid F. (2R)-[4-hydroxy-2-propylphenylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid-N-methyl-amide

1.6 g spoja iz dijela E tretirano je a 50 ml 1N HCl u dioksanu tijekom 2 sata. Otapalo je zatim ispareno pod sniženim tlakom kako bi se dobila sirova kiselina, koja je pročišćena s MPLC (7% MeOH/CH2Cl2 do 13% MeOH/CH2Cl2). Dobiveno je 930 mg (65%) čistog željenog proizvoda. MS m/e 496 (M+H)+, [α]D =-34.8 (c 0.118, metanol). 1.6 g of the compound from part E was treated with 50 ml of 1N HCl in dioxane for 2 hours. The solvent was then evaporated under reduced pressure to give the crude acid, which was purified by MPLC (7% MeOH/CH2Cl2 to 13% MeOH/CH2Cl2). 930 mg (65%) of pure desired product was obtained. MS m/e 496 (M+H)+, [α]D =-34.8 (c 0.118, methanol).

G. (2R)-[4-(benznoksiamino)-2-propilfenilsukcinil]-N2-(N1-benziloksikarbonil)-piperazinska kiselina N-metil-amid G. (2R)-[4-(Benzoxyamino)-2-propylphenylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid N-methyl-amide

Na sličan način opisan u primjeru 1D pripravljen je naslovljeni spoj iz 930 mg spoja iz primjera 45a, dio F kako bi se dobilo 620 mg (54%) željenog proizvoda. MS m/e 601 (M-CH3)+, [α]D =-30.7 (c 0.114, metanol) In a manner similar to that described in Example 1D, the title compound was prepared from 930 mg of the compound of Example 45a, part F to give 620 mg (54%) of the desired product. MS m/e 601 (M-CH3)+, [α]D =-30.7 (c 0.114, methanol)

H. (2R)-[4-(hidroksiamino)-2-propilfenilsukcinill]-N2-(N1-benziloksikarbonil)-piperazinska kiselina-N-metil-amid H. (2R)-[4-(hydroxyamino)-2-propylphenylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid-N-methyl-amide

Na sličan način opisan u dijelu 1E, pripravljen je naslovljeni spoj u 80% iscrpka (40 mg). MS m/e 376 (M+H)+, [α]D =-12.5 (c 0.080, metanol) 1HNMR (MeOH-d4) 7.25-7.15 (5H, m), 5.05 (1H, m), 3.9 (1H, m), 2.95 (1H, m), 2.8 (1H, m), 2.76 (3H, s), 2.6 (2H, m), 2.5 (1H, dd), 2.19 (1H, dd), 2.01 (1H, m), 1.95 (1H, m), 1.7-1.4 (6H, m). In a similar manner to that described in Part 1E, the title compound was prepared in 80% yield (40 mg). MS m/e 376 (M+H)+, [α]D =-12.5 (c 0.080, methanol) 1HNMR (MeOH-d4) 7.25-7.15 (5H, m), 5.05 (1H, m), 3.9 (1H , m), 2.95 (1H, m), 2.8 (1H, m), 2.76 (3H, s), 2.6 (2H, m), 2.5 (1H, dd), 2.19 (1H, dd), 2.01 (1H, m), 1.95 (1H, m), 1.7-1.4 (6H, m).

Spojevi prikazani u tabelama od 1-3 (dolje prikazanim) mogu se pripraviti koristeći se gore opisanim postupcima i njihovim varijacijama. The compounds shown in Tables 1-3 (shown below) can be prepared using the procedures described above and variations thereof.

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ISKORISTIVOST USABILITY

Spojevi formule I imaju MMP-3 inhibirajuće djelovanje i stoga su korisni kao zaštitna sredstva za hraksvicu u liječenju upalnih bolesti. MMP-3 inhibirajuća aktivnost spojeva ovog izuma prikazana je uz pomoć izvedenih testova, na primjer, koristeći se dolje opisanim postupkom testiranja inhibitora MMP-3 aktivnosti. Spojevi ovog izuma su bioraspoloživi in vivo kao što je prikazano u dolje opisanom ex vivo testu. Spojevi formule I sprečavaju/inhibiraju razgradnju hraksvice in vivo, na primjer kao što se vidi iz dolje opisanog modela akutne razgradnje hrskavice kod životinja. The compounds of formula I have an MMP-3 inhibiting effect and are therefore useful as protective agents for the hyacinth in the treatment of inflammatory diseases. The MMP-3 inhibitory activity of the compounds of the present invention was demonstrated by assays performed, for example, using the MMP-3 activity inhibitor assay procedure described below. The compounds of this invention are bioavailable in vivo as shown in the ex vivo assay described below. Compounds of formula I prevent/inhibit cartilage degradation in vivo, for example as seen in the animal model of acute cartilage degradation described below.

Spojevi opisani u ovom izumu su korisni kao standardi i reagensi za određivanje snage potencijalnog farmaceutskog sredstva za inhibiranje MMP-3. Oni bi bili uključeni u komercijalni pribor koji uključuje spoj iz ovog izuma. The compounds described in the present invention are useful as standards and reagents for determining the potency of a potential pharmaceutical agent to inhibit MMP-3. These would be included in a commercial kit incorporating a compound of the present invention.

Metaloproteinaze matriksa su također odgovorne za razgradnju bazalnih membrana kako bi omogućile stanicama raka da uđu u cirkulaciju i kasnije u druga tkiva, što dovodi do metsataza tumora (Stetler-Stevenson, Cancer and Metastasis Reviews, 9, 289-303, 1990). Spojevi iz ovog izuma bt trebali biti korisni za prevenciju i liječenje invazivnih tumora, na taj način što inhibiraju metastaze. Matrix metalloproteinases are also responsible for breaking down basement membranes to allow cancer cells to enter the circulation and later into other tissues, leading to tumor metastases (Stetler-Stevenson, Cancer and Metastasis Reviews, 9, 289-303, 1990). The compounds of the present invention should be useful for the prevention and treatment of invasive tumors by inhibiting metastasis.

Spojevi ovog izuma bi također bili iskoristivi u liječenju i prevenciji osteopenije povezane s razgradnjom hrskavice i kosti uzrokovanom metaloproteinazama matriksa, koja se javlja kod pacijenata koji boluju od osteoporoze. The compounds of the present invention would also be useful in the treatment and prevention of osteopenia associated with the breakdown of cartilage and bone caused by matrix metalloproteinases, which occurs in patients suffering from osteoporosis.

“µg" u tekstu označava mikrogram, "mg" označava miligram, "g" označava gram, "µL" označava mikrolitar, "ml" mililitar, "1" litru, "nM” označava nanomolarni, "µM" mikromolarni, "mM" milimolarni, ““M" molarni, i “nm" nanometar. "Sigma” označava Sigma-Aldrich Corp. iz St. Louisa, MO. "µg" in the text means microgram, "mg" means milligram, "g" means gram, "µL" means microliter, "ml" means milliliter, "1" means liter, "nM" means nanomolar, "µM" means micromolar, "mM" millimolar, "M" molar, and "nm" nanometer. "Sigma" means Sigma-Aldrich Corp. of St. Louis, MO.

Spoj se smatra aktivnim ako je IC50 ili Ki vrijednoat manja od 1 mM za inhibiciju MMP-3. A compound is considered active if the IC50 or Ki value is less than 1 mM for MMP-3 inhibition.

Test fltuorescencije bisacetilirane tvari P/MMP-3 Fluorescence test of bisacetylated substance P/MMP-3

Enzimski test visokog kapacita napravljen je kako bi se otkrili potencijalni inhibitori MMP-3. U testu je korišten derivat peptidnog supstrata, tvar P (Arg-PrO-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met), koju MMP-3 cijepa isključivo na mjestu glutamin-fenilalaninske veze. Kako bi se test prilagodio široko primijenjljivom ispitivanju, razvili smo fluorimetrijsku metodu detekcije proizvoda. Proizvodnja produkta hidrolize, tvari P 7-11, mjeri se reakcijom s fluorescaminom, fluorogenskim spojem koji reagira s primarnim aminom iz ovog dijela. Tvar P supstrata je bisacetilirana kako bi se blokirali primarni amini netaknutog supstrata. Na taj način, dobivena fluorescencija predstavlja stvaranje proizvoda (7-11 peptid) nastalog nakon cijepanja putem MMP-3, i mjeri se uz upotrebu standardne krivulje izrađene uz pomoć poznatih koncentracija 7-11 peptida. Kinetička ispitivanja u kojima je korišten bisacetilirani supatrat dala su slijedeće parametre za MMP-3: Km = 769 +/- 52 µM; Vmax = 0.090 +/- 0.003 nmola 7-11 peptida/min A high-throughput enzyme assay was performed to detect potential MMP-3 inhibitors. The test used a derivative of the peptide substrate, substance P (Arg-PrO-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met), which is cleaved by MMP-3 exclusively at the place of the glutamine-phenylalanine bond. In order to adapt the test to widely applicable testing, we developed a fluorimetric product detection method. Production of the hydrolysis product, substance P 7-11, is measured by reaction with fluorescamine, a fluorogenic compound that reacts with the primary amine from this moiety. Substance P of the substrate is biacetylated to block the primary amines of the intact substrate. In this way, the obtained fluorescence represents the formation of the product (7-11 peptide) formed after cleavage by MMP-3, and is measured using a standard curve made with the help of known concentrations of the 7-11 peptide. Kinetic studies in which the bisacetylated counterpartate was used gave the following parameters for MMP-3: Km = 769 +/- 52 µM; Vmax = 0.090 +/- 0.003 nmole 7-11 peptides/min

Kako bi se procijenila inhibicija MMP-3, spojevi su pripravljeni u koncentracijama od 10 mM u 100%-tnom metanolu, i zatim su dalje razrijeđivani do 20X molarne mase. Pet mikrolitara od svake količine lijeka je dodano u ispitivanu smjesu c prisutnosti 20 nM fragmentiranog MMP-3 u 67.5 mM tricina (pH 7.5), 10 mM CaCl2. 40 mM NaCl, i 0.0005% Brij 35 u konačnom volumenu od 100 mikrolitara. Dodana je bisacetilirana tvar P (1000 mM), i test je trajao 1 sat na 25ºC. Reakcija je zatim ugašena s EDTA (20 mM), a proizvod je nakon adicije fluorescamina (0.075 mg/ml) detektiran fluorometrijski. Fluorescencija svakog uzorka pretvorena je u količinu proizvoda koja je nastala koristeći standardnu krivulju za tvar P 7-11. Pod tim uvjetima, test je linearan u odnosu na količinu MMP-3 do 10 pmola. Inhibicija MMP-3 je određena uspoređivanjem količine proizvoda nastalog u prisustvu i odsustvu spoja. To assess MMP-3 inhibition, compounds were prepared at concentrations of 10 mM in 100% methanol, and further diluted to 20X molar mass. Five microliters of each amount of drug was added to the test mixture in the presence of 20 nM fragmented MMP-3 in 67.5 mM tricine (pH 7.5), 10 mM CaCl2. 40 mM NaCl, and 0.0005% Brij 35 in a final volume of 100 microliters. Biacetylated substance P (1000 mM) was added, and the test was run for 1 hour at 25ºC. The reaction was then quenched with EDTA (20 mM), and the product was detected fluorometrically after the addition of fluorescamin (0.075 mg/ml). The fluorescence of each sample was converted to the amount of product formed using a standard curve for substance P 7-11. Under these conditions, the assay is linear in relation to the amount of MMP-3 up to 10 pmol. Inhibition of MMP-3 was determined by comparing the amount of product formed in the presence and absence of compound.

Aktivnosti reprezentativnih spojeva ovog izuma iz gore opisanog testa prikazane su u tabeli A. Ki vrijednosti su označene kako slijedi: +++=<50 nM; + +=50 nM do 100 nM; + =>100 nM. The activities of representative compounds of the present invention from the assay described above are shown in Table A. Ki values are indicated as follows: +++=<50 nM; + +=50 nM to 100 nM; + =>100 nM.

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Ex vivo test bioraspoloživosti MMP-3 inhibitora Ex vivo bioavailability test of MMP-3 inhibitors

Kardijalnom punkcijom uzeti su uzorci krvi iz štakora u različitim vremenskim razdobljima nakon doziranja J.V., J.P. ili P.O. sa spojem kako bi se odredile razine inhtbitora. Plazma je ekstrahirana s 10%-tnim TCA u 95% metanola i stavljena na led 10 minuta. Zatim je plazma centrifugirana 15 minuta na 14,000 rpm u Ependorfovoj mikrocentrifugi. Supernatanti su uklonjeni, ponovno centrifugirani, a dobiveni supernatant je razrijeđen u omjeru 1:10 M 50 mM tricina, pH 8.5. pH uzorka je podešen na 7.5, a zatim testiran u MMP-3 tvar P fluorescentnom enzimskom testu. Plazma štakora ekstrahirana je na isti način i korištena kao negativna kontrolna skupina. Ta plazma je također korištena kako bi se dobila krivulja plazme željenog spoja. Poznate koncentracije spoja dodane su kontrolnoj plazmi, koja je ekstrahirana na isti način, a zatim testirana u MMP-3 enzimskom testu. Dobivena je standardna krivulja koja je pokazivaia omjer postotka inhibicije u MMP-3 testu i koncentraciju lijeka dodanu uzorcima. Na temelju inhibicije u prisutnosti plazme doziranih štakora, određene su koncentracije spoja koristeći standardnu krivulju. Blood samples were taken from rats by cardiac puncture at different time periods after dosing J.V., J.P. or P.O. with compound to determine inhibitor levels. Plasma was extracted with 10% TCA in 95% methanol and placed on ice for 10 minutes. Then the plasma was centrifuged for 15 minutes at 14,000 rpm in an Eppendorf microcentrifuge. The supernatants were removed, centrifuged again, and the obtained supernatant was diluted in a ratio of 1:10 M with 50 mM tricine, pH 8.5. The pH of the sample was adjusted to 7.5 and then tested in the MMP-3 substance P fluorescent enzyme assay. Rat plasma was extracted in the same way and used as a negative control group. This plasma was also used to obtain a plasma curve of the desired compound. Known concentrations of the compound were added to control plasma, which was extracted in the same way and then tested in the MMP-3 enzyme assay. A standard curve was obtained showing the ratio of the percentage of inhibition in the MMP-3 test and the concentration of the drug added to the samples. Based on inhibition in the presence of plasma from dosed rats, compound concentrations were determined using a standard curve.

Tabela B pokazuje rezultate oralnog doziranja reprezentativnih spojeva ovog izuma na štakorima od po 100 mg/kg. Table B shows the results of oral dosing of representative compounds of this invention in rats at 100 mg/kg.

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Model akutne razgradnje hrskavice kod štakora A model of acute cartilage degradation in rats

In vivo model akutne razgradnje hrskavice kod štakora karakteriziran je kao postupak za utvrđivanje proteoglikanskog sadržaja u sinovijskoj tekućini nakon početka razgradnje hrskavice. Eksperimentalne skupine pokazale su povećane razine proteoglikanskog sadržaja u sinovijskoj tekućini nasuprot kontrolnim skupinama štakora. Kriterij za prikazivanje aktivnosti spoja kod ovog modela je mogućnost inhibicije razgradnje hrskavice, što se mjeri povećanim proteoglikanskim sadržajem u sinovijskoj tekućini štakora nakon uzimanja spoja. Indometacin, nesteroidni protuupalni tijek je neaktivan u ovom modelu. Prepisani indometacin ne ometa prikazivanje razgradnje hrskavice kod eksperimentalnih životinja. Nasuprot tome, uzimanjem spojeva ovog izuma značajno je inhibiralo prikazivanje razgradnje hrskavice u ovom modelu. An in vivo model of acute cartilage degradation in rats was characterized as a procedure for determining the proteoglycan content in the synovial fluid after the onset of cartilage degradation. Experimental groups showed increased levels of proteoglycan content in synovial fluid compared to control groups of rats. The criterion for showing the activity of the compound in this model is the possibility of inhibiting the breakdown of cartilage, which is measured by the increased proteoglycan content in the synovial fluid of rats after taking the compound. Indomethacin, a nonsteroidal anti-inflammatory drug, is inactive in this model. Prescribed indomethacin does not interfere with the display of cartilage degradation in experimental animals. In contrast, administration of the compounds of this invention significantly inhibited the display of cartilage degradation in this model.

Doziranje i formulacija Dosage and formulation

Spojevi opisani u ovom izumu se mogu uzimati peroralno koristeći bilo koji farmaceutaki prihvatljivi način doziranja poznat u ovom polju. Aktivna komponenta se može pripraviti u tvrdim dozama, kao što su suhi puderi, granule, tablete ili kapsule, ili u tekućim oblicima kao što su sirupi, ili vodene suspenzije. Aktivna komponenta se može uzimati sama, ali obično se uzima s farmaceutskim nosačem. Koristan priručnik farmaceutskih oblika doziranja je Remington’s Pharmaceutical Sciences, Mack Publishing. The compounds described in the present invention can be taken orally using any pharmaceutically acceptable dosage method known in the art. The active component can be prepared in hard doses, such as dry powders, granules, tablets or capsules, or in liquid forms such as syrups, or aqueous suspensions. The active component can be taken alone, but is usually taken with a pharmaceutical carrier. A useful handbook of pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.

Spojevi ovog izuma mogu se uzimati u obliku tableta, kapsula (koje uključuju i one sa zadržanim oslobađanjem i s vremenski određenim oslobađanjem), pilule, puderi, granule, eliksiri, tinkture, supsenzije, sirupi, i emulzije. Isto tako mogu se davati i intravenozno (bolusnom injekcijom ili infuzijski), intraperitonealno, subkutano ili intramuskularno. The compounds of this invention may be taken in the form of tablets, capsules (including both sustained release and timed release), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be given intravenously (bolus injection or infusion), intraperitoneally, subcutaneously or intramuscularly.

Učinkovita, ali ne i toksična količina željenog spoja se može koristiti kao protuupalno sredstvo ili sredstvo protiv artritisa. An effective but non-toxic amount of the desired compound can be used as an anti-inflammatory or anti-arthritic agent.

Spojevi ovog izuma se mogu uzimati na bilo koji način koji omogućava kontakt aktivne komponente s mjestom djelovanja agensa, MMP-3 u tijelu sisavca. Mogu se uzimati na bilo koji uobičajeni način zajedno s drugim farmaceutskim sastojcima, bilo kao samostalni terapijski aktivni sastojci ili u kombinaciji terapijski aktivnih sastojaka, s farmaceutskim nosačem odabranim na temelju standardne farmaceutske prakse. The compounds of this invention can be taken by any means that allows the active component to contact the site of action of the agent, MMP-3 in the body of a mammal. They may be taken in any conventional manner together with other pharmaceutical ingredients, either as single therapeutically active ingredients or in combination of therapeutically active ingredients, with a pharmaceutical carrier selected based on standard pharmaceutical practice.

Propisana doza varirat će ovisno o poznatim faktorima kao što su: farmakodinamičke karakteristike pojedine aktivne komponente, i način i oblik uzimanja; dob, zdravstveno stanje i tjelesna masa primatelja; priroda i duljina trajanja simptoma; vrsta istodobne terapije, učestatost postupka; renalna ili hepatička funkcija pacijenta i željeni učinak. Prosječno stručan veterinar ili liječnik će tako odrediti i prepisati učinkovitu količinu lijeka potrebnu za sprečavanje ili suzbijanje razvoja bolesnog stanja. The prescribed dose will vary depending on known factors such as: pharmacodynamic characteristics of individual active components, and the method and form of intake; recipient's age, state of health and body mass; nature and duration of symptoms; type of simultaneous therapy, frequency of the procedure; the patient's renal or hepatic function and the desired effect. An average expert veterinarian or doctor will thus determine and prescribe the effective amount of medicine necessary to prevent or suppress the development of the disease state.

Uobičajena dnevna doza aktivne komponente, kada se koristi za navedene učinke, iznosit će od 0.001 do 1000 mg/kg tjelesne težine, poželjeno bi bilo od 0.01 do 100 mg/kg tjelesne težine dnevno, a najbolje bi bilo od 1.0 do 20 mg/kg/dnevno. Za normalnog muškog odraslog čovjeka od otprilike 70 kg tjelesne težine, to bi iznosilo otprilike od 70 do 1400 mg na dan. Intravenzozno, najpoželjnije doze bile bi od 1 do 10 mg/kg na minutu uz konstantnu brzinu infuzije. Prednost je da se spojevi ovog izuma mogu uzimati u obliku jedne dnevne doze, ili se dnevna doza može raspodijeliti u dvije, tri ili četiri dnevno. The usual daily dose of the active component, when used for the stated effects, will be from 0.001 to 1000 mg/kg body weight, preferably from 0.01 to 100 mg/kg body weight per day, and best from 1.0 to 20 mg/kg /Daily. For a normal male adult of approximately 70 kg body weight, this would be approximately 70 to 1400 mg per day. Intravenously, the most preferred doses would be 1 to 10 mg/kg per minute at a constant infusion rate. It is an advantage that the compounds of this invention can be taken in the form of one daily dose, or the daily dose can be divided into two, three or four daily doses.

Spojevi ovog izuma se mogu uzimati intranazalno, putem lokalne primjene odgovarajućeg intranazalnog sredstva, ili transdermalnim putem, koristeći poznate transdermalne kožne flastere. Ako se daje u obliku transdermalnog sustava prijenosa, tada će doziranje biti konstantno radije nego isprekidano. The compounds of this invention can be taken intranasally, by local application of a suitable intranasal agent, or transdermally, using known transdermal skin patches. If given as a transdermal delivery system, then the dosage will be constant rather than intermittent.

U postupcima opisanima u ovom izumu, spojevi mogu tvoriti aktivnu komponentu i uzimaju se zajedno s odgovarajućim farmaceutskim razrijeđivačima, ekcipiensima ili nosačima (u tekstu zajednički nazvani nosači), odgovarajuće izabranima u odnosu na oblik uzimanja lijeka, tj. oralne tablete, kapsule, eliksire, sirupe i slično, i u skladu s farmaceutskom praksom. In the methods described in this invention, the compounds can form an active component and are taken together with suitable pharmaceutical diluents, excipients or carriers (in the text collectively called carriers), appropriately chosen in relation to the form of taking the drug, i.e. oral tablets, capsules, elixirs, syrups and the like, and in accordance with pharmaceutical practice.

Na primjer, za peroralnu primjenu u obliku tableta i kapsula, aktivna komponenta lijeka može se kombinirati s oralnim, netoksičnim, farmaceutski prihvatljivim, inertnim nosačem kao što je laktoza, škrob, saharoza, glukoza, metil-celuloza, magnezij-stearat, dikalcij-fosfat, kalcij-sulfat, manitol, sorbitol i slični; za peroralnu primjenu u tekućem obliku, oralne komponente lijeka mogu se kombinirati s oralnim, netoksičnim, farmaceustki pogodnim inertnim nosačem, kao što je etanol, glicerol, voda i slični. Štoviše, ukoliko je to poželjno ili potrebno, odgovarajuća vezivna sredstva, lubrikanti, dezintegrirajuća sredstva kao i sredstva za bojenje se također mogu staviti u smjesu. Odgovarajuća vezivna sredstva kao što su škrob, želatina, prirodni šećeri kao što su glukoza ili laktoza, kukuruzni zaslađivači, prirodne i sintetičke gume kao što su akacija, tragacanth ili natrij-alginat, karboksimetilceluloza, polietilen-glikol, voskovi, i slične. Lubrikanti uključeni u doze uključuju natrij-oleat, natrij-stearat, magnezij-stearat, natrij-benzoat, natrij-acetat, natrij-klorid, i slične. Dezintegrirajuća sredstva uključuju škrob, metil-celulozu, agar, bentonit, ksantan gumu, i slična. For example, for oral administration in the form of tablets and capsules, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate , calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, and the like. Moreover, if desired or necessary, appropriate binders, lubricants, disintegrants as well as coloring agents may also be incorporated into the mixture. Suitable binding agents such as starch, gelatin, natural sugars such as glucose or lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants included in the doses include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrating agents include starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

Spojevi ovog izuma se također mogu uzimati u obliku liposomskog prijenosnog sustava, kao što su mala unilamelarna tjelešca, velika unilamelarna tjelešca i multilamelarna tjelešca. Liposomi mogu nastati iz mnoštva fosfolipida, kao što su kolesterol, stearilamin ili fosfatidilkolini. The compounds of the present invention can also be administered in the form of a liposomal delivery system, such as small unilamellar bodies, large unilamellar bodies, and multilamellar bodies. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Spojevi ovog izuma se također mogu spajati s topivim polimerima kao ciljanim nosačima lijeka. Takvi polimeri uključuju polivinilpirolidon, piranov kopolimer, polihidroksipropilmetakrilamid-fenol, polihidroksietilaspartamidfenol, ili polietilendioksid-polilizin supstituiran s palmitoilnim ostacima. Nadalje, spojevi ovog izuma se mogu spojiti u skupinu bioraspoloživih polimera korisnih za postizanje kontroliranog otpuštanja lijeka, na primjer, polimliječna kiselina, poliglikolinska kiselina, kopolimeri polimliječne i poliglikolinkse kiseline, poliepsilon-kaprolakton, polihidroksi butirična kiselina, poliortoesteri, poliacetali, polidihidropirani, policijanoacilati, i križno vezani ili amfipatički blok kopolimeri hidrogela. The compounds of the present invention can also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylenedioxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of this invention can be combined into a group of bioavailable polymers useful for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon-caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and cross-linked or amphipathic hydrogel block copolymers.

Odgovarajuće doze lijeka (farmaceutski pripravci) mogu sadržavati od 1 mg do 100 mg aktivne komponente po jedinici. U tim farmaceutskim pripravcima aktivna komponenta će biti prisutna u iznosu od 0.5-95% od ukupne mase pripravka. Aktivna komponenta se može uzimati peroralno u krutim oblicima, kao što su kapsule, tablete i prašci ili u tekućim oblicima, kao što su eliksiri, sirupi i suspenzije. Također se može davati i parenteralno u obliku sterilnih tekućih doza. Appropriate doses of the drug (pharmaceutical preparations) may contain from 1 mg to 100 mg of the active component per unit. In these pharmaceutical preparations, the active component will be present in the amount of 0.5-95% of the total mass of the preparation. The active component can be taken orally in solid forms, such as capsules, tablets and powders, or in liquid forms, such as elixirs, syrups and suspensions. It can also be administered parenterally in the form of sterile liquid doses.

Želatinozne kapsule mogu sadržavati aktivnu komponentu i usitnjene nosače, kao što su laktoza, škrob, derivati celuloze, magnezij-stearat, stearinska kiselina i slični. Slični razrijeđivači se mogu upotrebljavati i za komprimirane tablete. Tablete i kapsule se mogu proizvoditi u obliku proizvoda sa zadržanim oslobađanjem kako bi se omogućilo kontinuirano oslobađanje lijeka tijekom nekoliko sati. Komprimirane tablete se mogu obložiti sa šećerom ili nekim drugim oblogom kako se ne bi osjetio neugodan okus i kako bi se zaštitile od atmosferskih utjecaja, ili se mogu enterički obložiti za selektivno oslobađanje u probavnom traktu. Tekući oblici za peroralnu primjenu mogu biti obojani ili zaslađeni kako bi ih pacijent lakše prihvatio. Općenito voda, odgovarajuće ulje, solna otopina, vodena dekstroza (glukoza) i srodne šećerne otopine i glikoli, kao što su propilen-glikol ili polietilen-glikoli, pogodni su nosači parenteralnih otopina. Otopine za parenteralnu primjenu sadržavaju aktivnu komponentu, pogodni stabilizator, i ako je potrebno puferske tvari. Antioksidansi, kao što su natrij-bisulfit, natrij-sulfit, ili askorbinska kiselina, sami ili u kombinaciji, pogodni su stabilizatori. Također se koriste limunska kiselina i njene soli kao i EDTA. Povrh toga, parenteralne otopine mogu sadržavati konzervanse kao što su benzalkonij-klorid, metil-ili propil-paraben i klorobutanol. Gelatinous capsules can contain the active component and pulverized carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used for compressed tablets. Tablets and capsules can be manufactured as sustained-release products to allow continuous release of the drug over several hours. Compressed tablets can be coated with sugar or some other coating to avoid unpleasant taste and to protect them from atmospheric influences, or they can be enteric-coated for selective release in the digestive tract. Liquid forms for oral administration can be colored or sweetened to make them easier for the patient to accept. Generally water, suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols, such as propylene glycol or polyethylene glycols, are suitable carriers for parenteral solutions. Solutions for parenteral administration contain the active component, a suitable stabilizer and, if necessary, buffer substances. Antioxidants, such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, are suitable stabilizers. Citric acid and its salts as well as EDTA are also used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Pogodni farmaceutski nosači opisani su u Remington’s Pharmaceutical Sciences, A. Osol, uobičajenom priručniku iz ovog područja. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference in the art.

Korisni farmaceutski pripravci za davanje spojeva ovog izuma su slijedeći: Useful pharmaceutical preparations for administering the compounds of this invention are as follows:

Kapsule Capsules

Kapsule se mogu pripraviti uobičajenim postupcima, tako da doza sadrži 500 mg aktivne komponente, 100 mg celuloze i 10 mg magnezij-stearata. Capsules can be prepared by usual procedures, so that the dose contains 500 mg of active component, 100 mg of cellulose and 10 mg of magnesium stearate.

Veliki broj pojedinačnih kapsula se može pripraviti tako da se standardne tvrde dvodjelne želatinozne kapsule napune s po 100 mg aktivne komponente u prahu, 150 mg laktoze, 50 mg celuloze i 6 mg magnezij-stearata. A large number of individual capsules can be prepared by filling standard hard two-part gelatin capsules with 100 mg of active ingredient powder, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Sirup Syrup

Masa %. Mass %.

Aktivna komponenta 10 Active component 10

Tekući šećer 50 Liquid sugar 50

Sorbitol 20 Sorbitol 20

Glicerine 5 Glycerin 5

Arome, boje, i Aromas, colors, and

konzervansi prema potrebi preservatives as needed

Voda prema potrebi Water as needed

Konačni volumen od 100% postiže se dodavanjem destilirane vode. A final volume of 100% is achieved by adding distilled water.

Vodena suspenzija Aqueous suspension

Masa %. Mass %.

Aktivna komponenta 10 Active component 10

Natrij-saharin 0.01 Sodium saccharin 0.01

Keltrol® (Jestiva ksantan guma) 0.2 Keltrol® (Edible xanthan gum) 0.2

Tekući šećer 5 Liquid sugar 5

Arome, boje, i Aromas, colors, and

konzervansi prema potrebi preservatives as needed

Voda prema potrebi Water as needed

Ksantan guma se polagano dodaje M destiliranu vodu prije dodavanja aktivne komponente i ostalih sastojaka. Konačna suspenzija prolazi kroz homogenizator kako bi se postigla kvaliteta konačnog proizvoda. Xanthan gum is slowly added to distilled water before adding the active ingredient and other ingredients. The final suspension is passed through a homogenizer to achieve the quality of the final product.

Resuspendirajući prah Resuspending powder

Masa % mass %

Aktivna komponenta 50.0 Active component 50.0

Laktoza 35.0 Lactose 35.0

šećer 10.0 sugar 10.0

Akacija 4.7 Acacia 4.7

Natrij-karboksimetilceluloza 0.3 Sodium carboxymethylcellulose 0.3

Svaki se sastojak na kraju pretvara u prah i miješa. Puder se također može pripraviti u obliku suspenzije, a zatim se sprejanjem osušiti. Each ingredient is finally turned into a powder and mixed. The powder can also be prepared in the form of a suspension and then dried by spraying.

Polutvrdi gel Semi-hard gel

Masa % mass %

Aktivna komponenta 10 Active component 10

Natrij-saharin 0.02 Sodium saccharin 0.02

Želatina 2 Gelatin 2

Arome, boje i Aromas, colors and

konzervansi prema potrebi preservatives as needed

Voda prema potrebi Water as needed

Želatina se pripravlja u vrućoj vodi. Aktivna komponenta u prahu se suspendira u želatinoznu otopinu, a zatim se umiješaju ostali sastojci. Suspenzija se napuni u odgovarajuće spremnike i hladi kako bi se dobo gel. Gelatin is prepared in hot water. The active component in powder is suspended in a gelatinous solution, and then the other ingredients are mixed in. The suspension is filled into appropriate containers and cooled to form a gel.

Polutvrda pasta Semi-hard paste

Masa % mass %

Aktivna komponenta 10 Active component 10

Gelcarin® (Carrageenin guma) 1 Gelcarin® (Carrageenan gum) 1

Natrij-saharin 0.01 Sodium saccharin 0.01

Želatina 2 Gelatin 2

Arome, boje i Aromas, colors and

konzervansi prema potrebi preservatives as needed

Voda prema potrebi Water as needed

Gelcarin® se rastopi u vrućoj vodi (otprilike 80°C), a zatim se fini prah aktivne komponente suspendira u toj otopini. Natrij-saharin i ostali sastojci se dodaju u tu suspenziju dok je još topla. Suspenzija se homogenizira i puni u odgovarajuće spremnike. Gelcarin® is dissolved in hot water (approximately 80°C), and then the fine powder of the active component is suspended in that solution. Sodium saccharin and other ingredients are added to this suspension while it is still warm. The suspension is homogenized and filled into appropriate containers.

Emuizijska pasta Emulsion paste

Masa % mass %

Aktivna komponenta 30 Active component 30

Tween® 80 i Span® 80 6 Tween® 80 and Span® 80 6

Keltrol® 0.5 Keltrol® 0.5

Mineralno ulje 63.5 Mineral oil 63.5

Svi se sastojci pažljivo miješaju kako bi se dobila homogena pasta. All ingredients are carefully mixed to obtain a homogeneous paste.

Mekane želatinozne kapsule Soft gelatin capsules

Pripravi se mješavina aktivne komponente u jestivom ulju, kao što je sojino, maslinovo ili ulje sjemenki pamuka, i ubrizga se uz pomoć posebne pumpe (“positive displacement pump”) u želatinu, kako bi se dobile mekane želatinozne kapsule a po 100 mg aktivne komponente. Kapsule se operu i osuše. A mixture of the active component in edible oil, such as soybean, olive or cottonseed oil, is prepared and injected with the help of a special pump ("positive displacement pump") into the gelatin, in order to obtain soft gelatinous capsules with 100 mg of the active component each . The capsules are washed and dried.

Tablete Pills

Tablete se mogu pripraviti uobičajenim postupcima tako da se pripremi doza od 500 mg aktivne komponente, 150 mg laktoze, 50 mg celuloze i 10 mg magnezij-stearata. Tablets can be prepared by the usual procedures by preparing a dose of 500 mg of the active component, 150 mg of lactose, 50 mg of cellulose and 10 mg of magnesium stearate.

Velika količina tabteta pripravlja se na uobičajen način, miješanjem 100 mg aktivne komponente, 0.2 mg koloidalnog silikon-dioksida, 5 mg magnezij-stearata, 275 mg mikrokristalinične celuloze, 11 miligrama škroba i 98.8 mg laktoze. Odgovarajući ovoj se može nanijeti kako bi se olakšalo gutanje ili odgodilo otapanje. A large amount of tabtet is prepared in the usual way, by mixing 100 mg of the active component, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 milligrams of starch and 98.8 mg of lactose. Correspondingly, it can be applied to facilitate swallowing or delay dissolution.

Injekcije Injections

Parenteralni pripravci pogodni za injiciranje se pripravljaju miješanjem 1.5% mase aktivne komponente s 10% volumena propilen-glikola i vode. Otopina se izotonira uz dodavanje natrij-klorida, a zatim se sterilizira. Parenteral preparations suitable for injection are prepared by mixing 1.5% of the mass of the active component with 10% of the volume of propylene glycol and water. The solution is isotonized with the addition of sodium chloride, and then sterilized.

Suspenzija Suspension

Vodena suspenzija se pripravlja za petoralnu primjenu tako da svakih 5 ml sadrži 100 mg konačno podijeljene aktivne komponente, 200 mg natrij-karboksimetil-celuloze, 5 mg natrij-benzoata, 1.0 g otopine sorbitola, U.S.P. i 0.025 ml vanilije. The aqueous suspension is prepared for petoral administration so that each 5 ml contains 100 mg of the finally divided active component, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P. and 0.025 ml of vanilla.

Spojevi ovog izuma mogu se davati u kombinaciji s drugim terapijskim agensom, posebno nesterodinim protuupalnim lijekovima (NSAID). Spoj formule I i takav drugi terapijski agens se mogu davati odvojeno ili u kombinaciji u obliku jednog pripravka, u obliku bilo kakvog pripravka i načina primjene koji su gore opisani. The compounds of the present invention may be administered in combination with another therapeutic agent, particularly a non-steroidal anti-inflammatory drug (NSAID). The compound of formula I and such other therapeutic agent may be administered separately or in combination as a single formulation, in any of the formulations and routes of administration described above.

Spoj formule I se može pripraviti zajedno s drugim terapijskim agensom u jednom pripravku (t.j. kombinirati u kapsuli, tableti ili prahu, tekućini itd.). Kada spoj formule I i drugi terapijski agens nisu u jednom pripravku, mogu se uzimati u isto vrijeme, ili prema bilo kojem redoslijedu, na primjer spoj formule I prvi, a zatim drugi agens. Kada se ne uzimaju u isto vrijeme, poželjno je da razmak uzimanja spoja formule I i drugog terapijskog agensa ne bude veći od jednog sata, a bilo bi bolje manji od 5 do 30 minuta. A compound of formula I may be prepared together with another therapeutic agent in a single formulation (ie, combined in a capsule, tablet or powder, liquid, etc.). When the compound of formula I and the second therapeutic agent are not in the same preparation, they may be taken at the same time, or in any order, for example the compound of formula I first and then the second agent. When they are not taken at the same time, it is preferable that the interval between taking the compound of formula I and the other therapeutic agent is not more than one hour, and preferably less than 5 to 30 minutes.

Najbolji način uzimanja spoja formule I je peroralan. lako je požeijno da se spoj formute I i drugi terapijaki agens uzimaju na isti način (npr. peroralno) ukoliko je poželjno, mogu se uzimati na različite načine (npr. jedan peroralno, a drugi intravenozno). The best way to take a compound of formula I is orally. it is easily preferred that the compound of formula I and the other therapeutic agent are taken in the same way (eg, perorally) if desired, they can be taken in different ways (eg, one orally and the other intravenously).

Propisana doza spoja formule I kada se uzima sam ili u kombinaciji s drugim terapijskim agensom varirat će ovisno o poznatim faktorima kao što su: farmakodinamičke karakteristike pojedine aktivne komponente, i način i oblik uzimanja; dob, zdravstveno stanje i tjelesna masa primatelja; priroda i duljina trajanja simptoma; vrata istodobne terapije, učestalost postupka, i željeni učinak. Zbog toga kada se spoj formule I i drugi agens uzimaju u istom pripravku, oni se pripravljaju na taj način da je fizički kontakt između aktivnih komponenti minimalan. Na primjer, jedna aktivna komponenta se može enterički obložiti. Enteričkim oblaganjem jedne aktivne komponente smanjuje se fizički kontakt između dviju komponentata, a također se kontrolira oslobađanje jedne komponente u probavnom traktu, na taj način da se jedna komponenta ne oslobađa u želucu, već u crijevima. Jedna aktivna komponenta se može obložiti s tvari za odgođeno oslobađanje kako bi se odgodilo oslobađanje kroz probavni trakt i smanjio fizički kontakt dvaju komponentata. Nadalje, komponenta sa zadržanim oslobađanjem se može enterički obložiti kako bi oslobađanje komponente bilo u crijevima. Postoji i drugih načina, kao na primjer, priprava kombiniranog proizvoda u kojem bi jedna komponenta bila obložena sa polimerom za odgođeno oslobađanje ili enteričkim polimerom, a druga bi bila obložena s polimerom kao što je niskoviskozna hidroksipropil-metilceiuloza (HPMC) ili sličnim odgovarajućim tvarima poznatima u kemiji, kako bi se još bolje odvojile komponente. Polimerno oblaganje služi kao dodatna prepreka interakcije dvaju komponenti. The prescribed dose of a compound of formula I when taken alone or in combination with another therapeutic agent will vary depending on known factors such as: the pharmacodynamic characteristics of the individual active component, and the route and form of administration; recipient's age, state of health and body mass; nature and duration of symptoms; door of simultaneous therapy, the frequency of the procedure, and the desired effect. Therefore, when a compound of formula I and another agent are taken in the same preparation, they are prepared in such a way that physical contact between the active components is minimal. For example, one active component can be enteric coated. Enteric coating of one active component reduces the physical contact between the two components, and also controls the release of one component in the digestive tract, so that one component is not released in the stomach, but in the intestines. One active component can be coated with a delayed release agent to delay release through the digestive tract and reduce physical contact between the two components. Furthermore, the sustained release component can be enteric coated to allow the release of the component to be in the intestine. There are other ways, such as the preparation of a combination product in which one component would be coated with a delayed release polymer or an enteric polymer and the other would be coated with a polymer such as low viscosity hydroxypropyl methylcellulose (HPMC) or similar suitable substances known in chemistry, in order to separate the components even better. The polymer coating serves as an additional barrier to the interaction of the two components.

Stručnjacima će nakon proučavanja ovog izuma biti vrlo očiti načini smanjivanja kontakta između komponenti u kombiniranim proizvodima, bilo da se uzimaju u pojedinačnim pripravcima ili kao zasebni oblici, ali u isto vrijeme i na isti način. It will be very apparent to those skilled in the art after studying the present invention that there are ways to reduce the contact between the components in the combination products, whether they are taken in individual preparations or as separate forms, but at the same time and in the same manner.

Ovaj izum također uključuje i farmaceutaki pribor koji se koristi, na primjer, za liječenje i sprečavanje osteoartritisa i reumatoidnog artritisa, koji uključuje jedan ili više spremnika koji sadrže pripravak sa terapijski učinkovitom količinom spoja formule I. Takav pribor može nadalje uključivati, ukoliko je to potrebno, jednu ili više različitih konvencionalnih komponenti farmaceutskog pribora, kao što su, na primjer, spremnici s jednim ili više farmaceutski pogodnih nosača, dodatne spremnike, itd., što će stručnjacima odmah biti jasno. Upute, bilo umetnute ili u obliku naljepnica, koje ukazuju na količine komponenti koje se trebaju uzeti, načine uzimanja i/ili miješanja komponenti, mogu također biti uključene u pribor. The present invention also includes a pharmaceutical kit used, for example, for the treatment and prevention of osteoarthritis and rheumatoid arthritis, which includes one or more containers containing a composition with a therapeutically effective amount of a compound of formula I. Such kit may further include, if necessary , one or more different conventional components of a pharmaceutical kit, such as, for example, containers with one or more pharmaceutically suitable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, whether inserted or in the form of labels, indicating the quantities of components to be taken, methods of taking and/or mixing the components, may also be included in the kit.

Na kraju treba napomenuti da su navedene tvari i uvjeti važni za izvođenje ovog izuma, ali nenavedene tvari i uvjeti nisu isključeni ukoliko ne sprečavaju ostvarivanje biti izuma. Finally, it should be noted that the listed substances and conditions are important for the implementation of this invention, but unlisted substances and conditions are not excluded if they do not prevent the realization of the essence of the invention.

Pojam “koji se prvenstveno sastoji od” u ovom izumu znači da su sve specificirane tvari i uvjeti važni za izvođenje ovog izuma, ali da nespecificirane tvari i uvjeti nisu isključeni ukoliko ne predstavljaju prepreku za ostvarivanje ovog izuma. The term "consisting primarily of" in this invention means that all specified substances and conditions are important for carrying out this invention, but that unspecified substances and conditions are not excluded unless they represent an obstacle to the realization of this invention.

U ovom se opisu nalaze sve potrebne informacije koje će omogućih stručnjacima izvođenje ovog izuma. Budući da citirane reference mogu pridonijeti boljem razumijevanju uključene su u ovaj tekst. This description contains all the necessary information that will enable those skilled in the art to carry out this invention. Since the cited references can contribute to a better understanding, they are included in this text.

Iako su u ovom izumu opisani određeni aspekti, detalji tih aspekata ni na koji način ne ograničavaju izum. Razni ekvivalenti, izmjene i promjene se mogu primijeniti bez da se udalji od same biti izuma, te se stoga podrazumijeva da i takvi slični aspekti čine dio ovog izuma. Although certain aspects are described in this invention, the details of those aspects are not intended to limit the invention in any way. Various equivalents, modifications and changes may be applied without departing from the spirit of the invention, and it is therefore intended that such similar aspects form part of the present invention.

Claims (27)

1. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, uključujući i davanje terapijski učinkovite količine agensa za zaštitu hrskavice formule I, sisavcu kojemu je potrebno liječenje: [image] ili njegove farmaceutski pogodne soli ili prodrug oblika, naznačene time, da A je -N(R8)CH(R9)CO2H ili -CH(R1)CONHOH; Q je: C5-C14 karbociklički prsten supstituiran s 0-4 skupine izabrane iz R5, R6, R18 ili -C(=O)R3, ili 5- do 10-člani heterociklički prsten koji sadrži 1 do 4 heteroatoma, koji su nezavisno izabrani iz kisika, dušika ili sumpora, a navedeni heterociklički prsten supstituiran je s 0-4 skupine izabrane iz R5, R6, R8, R18 ili -C(=O)R3; R1 je: H, OR17, S(O)mR17a; C1-C4 alkil supstituiran s 0-3 R4, C2-C4 alkenil supstituiran a 0-3 R4, C2-C4 alkinil supstituiran a 0-3 R4, arila supstituiranog s 0-5 R18, heterocikla izabranog iz skupine koja sadrži: tienil, furanil, tiazolil, oksazolil, izoksazolinil, izotiazolil, triazolil, pirolil, pirazolil, piridazinil, pirimidinil, benzofuranil, benzotienil, indolil, tetrahidrofuranil, ili piranil, navedeni heterociklički prsten supstituiran je s 0-2 R18.1. A method of treating rheumatoid and osteoarthritis in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a cartilage protecting agent of formula I: [image] or a pharmaceutically acceptable salt or prodrug form thereof, indicated by that A is -N(R8)CH(R9)CO2H or -CH(R1)CONHOH; Q is: C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 or -C(=O)R3, or A 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms, which are independently selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or -C( =O)R3; R1 is: H, OR17, S(O)mR17a; C1-C4 alkyl substituted with 0-3 R4, C2-C4 alkenyl substituted with 0-3 R4, C2-C4 alkynyl substituted with 0-3 R4, aryl substituted with 0-5 R18, heterocycle selected from the group consisting of: thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18. 2. Spoj formule II: [image] ili njegove farmaceutski pogodne soli ili prodrug oblici, naznačen time, da. Q: C5-C14 karbociklički prsten supstituiran s 0-4 skupine izabrane iz R5, R6, R18 ili -C(O)R3, ili 5- do 10-člani heterociklički prsten koji sadrži 1 do 4 heteroatoma nezavisno izabranih iz kisika, dušika ili sumpora, a navedeni heterociklički prsten supstituiran je s 0-4 skupine izabrane iz R5, R6, R8, R18 ili -C(=O)R3; R1 je: H, C1-C4 alkil supstituiran s 0-3 R4, C2-C4 alkenil supstituiran s 0-3 R4, C2-C4 alkinil supstituiran s 0-3 R4, R2 je: C1-C6 alkil supstituiran s 0-3 R17b, -O-(C1-C8 alkil)-R20, pod uvjetom da R8 nije prisutan kada je W jednako O.2. Compound of formula II: [image] or its pharmaceutically acceptable salts or prodrug forms, indicated by that. Q: C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 or -C(O)R3, or A 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or -C(=O) R3; R1 is: H, C1-C4 alkyl substituted with 0-3 R4, C2-C4 alkenyl substituted with 0-3 R4, C2-C4 alkynyl substituted with 0-3 R4, R2 is: C1-C6 alkyl substituted with 0-3 R17b, -O-(C1-C8 alkyl)-R20, provided that R8 is not present when W is equal to O. 3. Spoj iz zahtjeva 2 , naznačen time,da.je izabran iz [4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-beznzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metoksifenilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metoksibenzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metiltiofenilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metiltiobenzilsukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-(metiltio-2-tienil)sukcinil]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metilacetat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metilizopropanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metil-terc-butanoat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metil-tioacetat]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-(2-piridil)-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-(3-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-(4-piridil)]-N2-(S)-piperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-6’(S/R)-(4-metoksifenil)piperazinska kiselina-N-metil- amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-4’(S/R)-benzilpiperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-5’(S/R)-benzilpiperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-6’(S/R)-benzilpiperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)- [4’,5’] benzopiperazinska kiselina-N-metil-amida; [4-(N-hidroksiamino)-2R-izobutil-3S-metilsukcinil]-N2-(S)-[5’,6’) benzopiperazinska kiselina-N-metil-amida;3. The compound from claim 2, indicated by the fact that it is selected from [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methoxyphenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methoxybenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-(methylthio-2-thienyl)succinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylacetate]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylisopropanoate]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-thioacetate]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-(2-pyridyl)-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-(3-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-(4-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6'(S/R)-(4-methoxyphenyl)piperazine acid-N-methyl- amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-4'(S/R)-benzylpiperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-5'(S/R)-benzylpiperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6'(S/R)-benzylpiperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)- [4',5'] benzopiperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-[5',6') benzopiperazine acid-N-methyl-amide; 4. Spoj formule III: [image] ili njegove farmaceutski pogodne soli ili prodrug oblici, naznačen time, da Q je: C5-C14 karbociklički prsten supstituiran s 0-4 skupine izabrane iz R5, R6, R18 -C(=O)R3, ili 5- do 10-člani heterociklički prsten koji sadrži 1 do 4 heteroatoma koji su nezavisno izabrani iz kisika, dušika ili sumpora, a navedeni heterociklički prsten supstituiran je s 0-4 skupine izabrane iz R5, R6, R8, R18 ili ,C(=O)R3; R2 je: C1-C6 alkil supstituiran s 0-3 R17b, -O-(C1-C8 alkil)-R20, -S-(C1-C8 alkil)-R20,4. Compound of formula III: [image] or its pharmaceutically acceptable salts or prodrug forms, indicated by that Q is: C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 -C(=O)R3, or A 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or ,C(= O)R3; R2 is: C1-C6 alkyl substituted with 0-3 R17b, -O-(C1-C8 alkyl)-R20, -S-(C1-C8 alkyl)-R20, 5. Spoj iz zahtjeva 7 naznačen time,da je izabran iz skupine koja sadrži slijedeće spojeve Metil amid N-[1-(R)-karboksi-etil]-α-(S)-izobutilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etil]-α-(S)-heksilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etil]-α-(S]-heptilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etil]-α-(S)-oktilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etil]-α-(S)-etilfenilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etil]-α-(S)-propilfenilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etiltiobenzil]-α-(S)-izobutilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etiltiobenzil]-α-(S)-heksilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etiltiobenzil]-α-(S)-etilfenilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etiltiobenzil]-α-(S)-propilfenilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etiloksibenzil]-α-(S)-izobutilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etiloksibenzil]-α-(S)-heksilglicin-(S)-N2-piperazinske kiseline; Metil amid N-(1-(R)-karboksi-etiloksibenzil]-α-(S)-etilfenilglicin-(S)-N2-piperazinske kiseline; Metil amid N-[1-(R)-karboksi-etiloksibenzil]-α-(S)-propilfenilglicin-(S)-N2-piperazinske kiseline;5. The compound from claim 7 characterized in that it is selected from the group containing the following compounds N-[1-(R)-carboxy-ethyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyl]-α-(S]-heptylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyl]-α-(S)-octylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methyl amide; N-(1-(R)-carboxy-ethyloxybenzyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide; 6. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, uključujući i davanje terapijski učinkovite količine spoja za zaštitu hrskavice formule IV, sisavcu kojemu je to potrebno: [image] ili farmaceutski pogodne soli ili prodrug oblici, naznačene time, da R2 je: H, C3-C10 alkil, ili aril-(C1-C4 alkil)-; R3 te OR11, NHCH(R12)COR13, NR10R10a, NHCH(R12)COOR11, ili NHCH(R12)CONR14R15, R10 i R10a su nezavisno vodik, C1-C4 alkil, ili C1-C4 alkoksi; R11, R12 i R15 su nezavisno vodik ili C1-C4 alkil; R13 i R14 su C1-C4 alkil.6. A method of treating rheumatoid and osteoarthritis in a mammal, including administering to a mammal in need thereof a therapeutically effective amount of a cartilage protecting compound of formula IV: [image] or pharmaceutically acceptable salts or prodrug forms, indicated by that R2 is: H, C3-C10 alkyl, or aryl-(C1-C4 alkyl)-; R3 and OR11, NHCH(R12)COR13, NR10R10a, NHCH(R12)COOR11, or NHCH(R12)CONR14R15, R 10 and R 10a are independently hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; R 11 , R 12 and R 15 are independently hydrogen or C 1 -C 4 alkyl; R 13 and R 14 are C 1 -C 4 alkyl. 7. Farmaceutski pripravak, naznačen time, da sadrži spoj iz zahtjeva 2 i farmaceutski pogodni nosač.7. Pharmaceutical preparation, characterized in that it contains the compound of claim 2 and a pharmaceutically suitable carrier. 8. Farmaceutski pripravak, naznačen time, da sadrži spoj iz zahtjeva 3 i farmaceutski pogodni nosač.8. Pharmaceutical preparation, characterized in that it contains the compound of claim 3 and a pharmaceutically suitable carrier. 9. Farmaceutski pripravak, naznačen time, da sadrži spoj iz zahtjeva 4 i farmaceutski pogodni nosač.9. Pharmaceutical preparation, characterized in that it contains the compound of claim 4 and a pharmaceutically suitable carrier. 10. Farmaceutski pripravak, naznačen time, da sadrži spoj iz zahtjeva 5 i farmaceutski pogodni nosač.10. Pharmaceutical preparation, characterized in that it contains the compound of claim 5 and a pharmaceutically suitable carrier. 11. Farmaceutski pripravak, naznačen time, da sadrži spoj iz zahtjeva 6 i farmaceutski pogodni nosač.11. Pharmaceutical preparation, characterized in that it contains the compound of claim 6 and a pharmaceutically suitable carrier. 12. Farmaceutski pripravak, naznačen time, da sadrži spoj iz zahtjeva 7 i farmaceutski pogodni nosač.12. Pharmaceutical preparation, characterized in that it contains the compound of claim 7 and a pharmaceutically suitable carrier. 13. Farmaceutski pripravak, naznačen time, da sadrži spoj iz zahtjeva 8 i farmaceutski pogodni nosač.13. Pharmaceutical preparation, characterized in that it contains the compound of claim 8 and a pharmaceutically suitable carrier. 14. Farmaceutski pripravak, naznačen time, da sadrži spoj iz zahtjeva 9 i farmaceutski pogodni nosač.14. Pharmaceutical preparation, characterized in that it contains the compound of claim 9 and a pharmaceutically suitable carrier. 15. Farmaceutski pripravak, naznačen time, da sadrži spoj iz zahtjeva 10 i farmaceutski pogodni nosač.15. Pharmaceutical preparation, characterized in that it contains the compound of claim 10 and a pharmaceutically suitable carrier. 16. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine agensa za zaštitu hrskavice iz zahtjeva 2.16. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 2. 17. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine agensa za zaštitu hrskavice iz zahtjeva 3.17. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 3. 18. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine agensa za zaštitu hrskavice iz zahtjeva 4.18. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 4. 19. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine agensa za zaštitu hrskavice iz zahtjeva 5.19. A method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 5. 20. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine agensa za zaštitu hrskavice iz zahtjeva 6.20. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 6. 21. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine agensa za zaštitu hrskavice iz zahtjeva 7.21. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 7. 22. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine agensa za zaštitu hrskavice iz zahtjeva 8.22. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 8. 23. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine agensa za zaštitu hrskavice iz zahtjeva 9.23. A method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 9. 24. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine agensa za zaštitu hrskavice iz zahtjeva 10.24. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 10. 25. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine nesteroidnog protuupalnog agensa u kombinaciji sa spojem za zaštitu hrskavice iz zahtjeva 2.25. A method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of a non-steroidal anti-inflammatory agent in combination with the cartilage protection compound of claim 2. 26. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine nesteroidnog protuupalnog agensa u kombinaciji sa spojem za zaštitu hrskavice iz zahtjeva 7.26. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of a non-steroidal anti-inflammatory agent in combination with the cartilage protection compound of claim 7. 27. Postupak liječenja reumatoidnog i osteoartritisa kod sisavaca, naznačen time, da uključuje i davanje terapijski učinkovite količine nesteroidnog protuupalnog agensa u kombinaciji sa spojem za zaštitu hrskavice iz zahtjeva 11.27. A method of treating rheumatoid and osteoarthritis in mammals, indicated by the fact that it also includes the administration of a therapeutically effective amount of a non-steroidal anti-inflammatory agent in combination with the cartilage protection compound of claim 11.
HRP950259 1994-04-28 1995-04-28 Hydroxamic acid and amino acid derivatives and their use as anti-arthritic agents HRP950259A2 (en)

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