HRP20010078A2 - Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases - Google Patents
Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases Download PDFInfo
- Publication number
- HRP20010078A2 HRP20010078A2 HR20010078A HRP20010078A HRP20010078A2 HR P20010078 A2 HRP20010078 A2 HR P20010078A2 HR 20010078 A HR20010078 A HR 20010078A HR P20010078 A HRP20010078 A HR P20010078A HR P20010078 A2 HRP20010078 A2 HR P20010078A2
- Authority
- HR
- Croatia
- Prior art keywords
- sulfonylamino
- tetrahydro
- dibenzofuran
- acid
- hydroxy
- Prior art date
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- 102000002274 Matrix Metalloproteinases Human genes 0.000 title description 25
- 108010000684 Matrix Metalloproteinases Proteins 0.000 title description 25
- 239000003112 inhibitor Substances 0.000 title description 18
- 229940124530 sulfonamide Drugs 0.000 title description 3
- 150000003456 sulfonamides Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 112
- 125000000217 alkyl group Chemical group 0.000 claims description 89
- -1 alkyltsulfonylalkyl Chemical group 0.000 claims description 50
- 238000002360 preparation method Methods 0.000 claims description 50
- 238000011282 treatment Methods 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 150000001413 amino acids Chemical class 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
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- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 18
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 claims description 16
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
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Description
Dosadašnje spoznaje
Ovaj izum odnosi se na nove triciklične sulfonamide i njihove derivate koji su pogodni kao farmaceutska sredstva, na metodu njihove priprave, na farmaceutske pripravke koji uključuju te spojeve i farmaceutski prihvatljive nosače, te na farmaceutske metode tretmana. Novi spojevi iz ovog izuma su inhibitori matričnih metaloproteinaza npr. želatinaze A (MMP-2), kolaenaze-3 (MMP-13), te strome-lizina-1 (MMP-3). Određenije, novi spojevi iz ovog izuma su korisni u tretmanu rupture aterosklerotičnog plaka, aneurizme aorte, zatajenja srca, dilatacija lijevog ventrikula, restenoze, periodontalne bolesti, ulceracije rožnice, u tretmanu opeklina, ulceracija izazvanih dekubitusom, zacjeljenja rana, karcinoma, upale, boli, artritisa, osteoporoze, multipla skleroze, bubrežne bolesti i ostalih autoimunih ili upalnih poremećaja koji ovise o invaziji tkiva leukocitima ili ostalim aktiviranim migrirajućim stanicama, akutnih i kroničnih neurodeenerativnih poremećaja uključujući udar, ozljedu glave, ozljedu kralježnice, Alzheimerovu bolest, amiotrofnu lateralnu sklerozu, cerebralnu amiloidnu angiopatiju, AIDS, Parkinsonovu bolest, Huntingtonovu bolest, bolesti uzrokovane ima, miasteniju gravis i Duchennovu mišićnu distrofiju.
Želatinaza A i stromelizin-1 spadaju u skupinu matričnih metaloproteinaza (MMP) (VVoessner J. F., FASEBJ., 1991;5:2145-2154). Ostali članovi skupine jesu fibroblast kolagenaza, neutrofilna kolagenaza, Želatinaza B (92 kDa Želatinaza), stromelizin-2, stromelizin-3, matrizilin, kolagenaza 3 (Freije J. M., Diez.ltxa L, Balbin M., Sanchez. M., Blasco R., Tovia J., i Lopez-Otin C., J. BioL Chem. 1994;269:16766-16773), te novo otkrivene matrične metaloproteinaze povezane s membranom (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Vamamoto E. i Seiki M., Nature, 1994;370:61-65).
Katalitični cink u matričnim metaloproteinazama je obično glavno mjesto o kojem se vodi računa pri dizajnu inhibitora. Modifikacijom supstrata, a uvođenjem skupina koje mogu kelatizirati, stavljaju se inhibitori kao što su peptidi koji sadrže hidroksamatnu i tiolnu skupinu. Peptidi s hidroksamatnom skupinom i prirodni endogeni inhibitori MMp (TIMP) uspješno su se koristili u tretmanu životinjskih modela karcinoma i upale.
Mogućnost matričnih metaloproteinaza da razaraju različite komponente vezivnog tkiva čini ih potencijalnim mjestom za kontrolu patoloških procesa. Primjerice, ruptura ateroskelrotičnog plaka je najuobičajeniji događaj koji inicira koronarnu trombozu. Pretpostavljeno je da destabilizacija i degradacija ekstracelularnnog matriksa koji okružuje taj plak s MMP uzrokuje razbijanje plaka. Ramena i regije akumulacije pjenušavih stanica u humanom ateroskerotičnom plaku, pokazuju lokalno povećanje ekpresije želatinaze B, stromelizina-1, te interstinalne kolagenaze. In situ zimografija tih stanica pokazuje povećanje povećanu želatinolitičku i kaseinolitičku aktivnost (Galla Z. S., Sukhova G. K., Lark M. W. i Libby P. "Increased expression od matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atheroscleroric plaques", J. Clin. Invest, 1994;94:2494-2503). Nadalje, nađeno je da je visoka razina stromelizina u RNA poruci smještena u pojedinim stanicama u aterosklerotičnom plaku koji je uklonjen iz srčanih transplanta pacijenata za vrijeme operacije (Henney A. M. Wakeley P. R., Davies M. J., Foster K., Hembry R., Murphy G. i Humphries S. "Localization of stromelysin gene expression in atherosclerotic plagues by in situ hybridization", Proc. Nat'l. Acad. Sci., 1991;88:8154-8158).
Inhibitori matrične metaloprotinaze se koriste u tretmanu degenerativnih bolesti aorte povezane sa stanjivanjem stijenke medijalne aorte. Povećane razine proteolitičke aktivnosti MMP su identificirane kod pacijenata s aneurizmom aorte i stenozom aorte (Vine N. i Powell J. T., "Metallo-proteinases in degenerative aortic diseases", Clin. Sci., 1991;81:233-239).
Zatajenje srca nastaje zbog različitih uzroka bolesti, ali zajedničko svojstvo je kardijalna dilatacija za koju je utvrđeno da je neovisni faktor rizika za smrt (Lee T. H., Hamilton M. A., Stevenson L W., Moriguchi J. D., Fonarovv G. C., Child J. S., Laks H. i Walden J. A. "Inpact of left ventricular siže on the survival in advanced heart failure" Am. J. Cardiol., 1993;72:672-676). Ovo ponovno modeliranje srca sa zatajenjem obuhvaća razbijanje ekstracelularnog matriksa. Koncentracija matričnih metaloproteinaza je povećana kod pacijenata s idiopatskim i ishemičnim zatajenjem srca (Reddy H. K., Tyagi S. C., Campbell S. E. i VVeber K. T. "Activated myocarrdial collagenase in idiopathic dilated cardiomyopathy", Clin. Res., 1993;41:660A; Tyagi S. C., Reddy H. K., Voelker D. J., Tjara l. E. i VVeber K. T. "Miocardinal collagenase in failig human heart", Clin. Res., 1993:41.681 A). Životinjski modeli zatajenja srca pokazuju da je indukcija želatinaze važna u kardijalnoj dilataciji (Armstrong, P. W., Moe G. W., Howard R. J., Grima E. A. i Cruz T. F. "Structural modeling in heart failure: gelatinbase induction", Can. J. Cardiol., 1994;10:214-220), te da kardijalna dilatacija prethodi izrazitom smanjivanju srčanih funkcija (Sabbah N. H., Kono T., Stein P. D., Mancini G. B. i Goldstein S. "Left ventricular shape changes during the course of evlolving heart failure", Am. J. Physiol., 1992;263:H266-H270).
Neointimalna proliferacija koja vodi restenozi se često razvija nakon korobarne angioplastije. Migracija vaskulatnih stanica glatkih mišića (VSMC) iz medija tunike u sloj neointime je ključni događaj u razvijanju vaskularnih bolesti i posljedica toga je mogućnost predviđanja mehaničkog oštećenja krvnih žila (Bendek M. P., Zempo N., Clovves A. W., Galardy R. E. i Reidy M. "Smooth muscle ćeli migration and matrix metalloproteinase expression anftr arterial injury in the rat", Circulation Research, 1994;75:539-545). Northen bloting i zimogrfska analiza pokazuju da je uglavnom želatinaza A je bila eksprimirana MMP i eliminirana iz ovih stanicama. Nadalje, antiserumi s mogućnošću selektivne neutralizacije aktivnosti želatinaze A također su inhibirali VSMC migracije preko barijere bazalne membrane. Nakon ozljede žile, aktivnost želatinaze A povećana je više nego 20 puta, dok je VSMC prešao iz stanja mirovanja u proliferirani pokretan fenotip (Pauly R. R., Passanati A., Bialto C., Monticone R., Cheng L, Papadopulos N., Gluzband Y. S., Smith L., Weinstein C., Lakatta E. i Ceow M. T. "Migration of culturated vascular smooth muscle cells through a basement membrane barrier reguires type IV collagenase activity and is inhibited by cellular differentitation", Circulation Research, 1994;75:41-54).
Aktivnosti kolagenaze i stromelizina su utvrđene u fibroblastima izoliranim iz upaljene gingive (Uitto V. J., Applegren R. i Robinson P. J. "Collagenase and neutral metalloproteinase activity in extracts from inflamed human gingiva"J. Periodontal Res, 1981;16:417-424), te je razina enzima korelirana s ozbiljnosti paradentoze (Overall C. M., Wiebkin O. W. i Thonard J. C. "Demonstration of tissue collagenase activity in vivo and its realtionship to inflamation severity in human gingiva" J. Periodontal Res., 1987;22:81-88). Proteolitička degradacija ekstracelularnog matriksa je primijećena pri ulceraciji rožnice nakon opekline rožnice alkalijama (Brown S. l., Weller C. A i Wassweman H. E. "Collagenolytic activity of alkali burned corneas", Arch. Opthalmol., 1969;81:370-373). Peptidi koji sadrže tiol inhibiraju kolagenazu izoliranu iz zečjih rožnica poslije opekline alkalijama "Burns F. R., Stack M. S., Gray R. D. i Paterson C. A. Invest. Opthalmol., 1989;30:1569-1575).
Stromelizin potječe od bazalnog keratinocita u raznim kroničnim ulceracijama (Saarialho-Kere U. K., Ulpu K., Pentland A. P., Birkedal-Hansen H., Parks W. C., VVelgus H. G. "Distinct populations on basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds" J. Clin. Invest, 1994;94:79-88).
Stromelizin-1 mRNA i protein su nađeni u bazanlnom keratinocitu koji je u susjedstvu ali distalno od ruba rane, a to vjerojatno predstavlja mjesto prolifracije epiderma. Stromelizin-1 može, stoga spriječiti zacijeljenje epiderme.
Davis et al. (Cancer Res., 1993;53:2087-2091) prikazali su da peptid s hidroksamatnom skupinom, BB-94, smanjuje tegobu izazvanu tumorom i produžuje preživljavanje miševa koji nose ksenofag humanog karcinoma ovarija. Peptid od sačuvane MMP sekvencije propeptida je bio slab inhibitor želatinaze A i inhibirao je humane tumorske stanice, a invazijom preko sloja koji je rekonstituirane bazalne membrane (Melchiori A., Albili A., Ray J. M. i Stetalr-Stevenson W. G., Cancer Res. 1992;52:2353-2356), i prirodni inhibitor metaloproteinaze-2 (TIMP-2) u stanicama također blokira invaziju tumorskih stanica in vitro modela (DeCIerck Y. A., Perez N., Shimada H., Boone T. C., Langley K. E. i Taylor S. M., Cancer Res., 1992;52:701-708). Istraživanja humanog karcinoma pokazuju da je želatinaza A aktivirana na površinama invazivnih tumornih stanica (Strongin A. Y., Marmer B. L., Grant G. A. i Goldberg G. l. J. Biol. Chem., 1993;268:14033-14039), te je tamo zadržana zbog interakcije s molekulom receptorskog tipa (Monsky S. C. i Chen W.-T., Cancer Res., 1993;53:3159-3164).
Inhibitori MMP pokazali su aktivnost u modelima tumorne angiogeneze (Taraboletti G., Garofalo A., Belotti D., DrudisT., Borsotti P. Scanziani E., Brovvn P. D. i Giavazzi R., Journal of the National Cancer Institute, 1995;87:293, te Benelli R., Adatia R., Ensoli B., Stetler-Stevenson W. G., Santi L. i Albini A., Oncology Research, 1994;6:251-257).
Neka istraživanja pokazuju dosljedno podizanje razine stromelizina i kolagenaze u sinovijalnim tekućinama kod pacijenata s reumatoidnim artritisom i osteoartritisom u usporedbi s kontrolom (Walakovits L. A., Moore V. L., Bhardwaj N., Gallick G. S. i Lark M. W. "Detection od strolelizin and collagenase in synovial fluid from patioens with rheumatoid arthritis and post-traumatic knee injury", Arthritis Rheum., 1992;35:35-42; Zafarullah M., Pellerier J. P., Cloutier J. M. i Marcel-Peiietier J., "Elevated metalloproteinases and tissues inhibitor of metalloproteinase mRNA in human osteoarthritic synovia", J. Rheumatol., 1993;20:693-697). TIMP-1 i TIMP-2 sprječavaju stvaranje fragmenata kolagena, ali ne proteoglikanskih fragmenta nastalih od degradacije hrskavice na modelu artritisa goveđe nazalne i svinjske zglobne hrskavice, a dok sintetski hidroksamartni peptid može spriječiti stvaranje oba fragmenta (Andrews H. J., Plumpton T. A., Harper G. P. i Cavvston T. E., Agents Actions, 1992;37:147-154; Ellis A. J., Curry V. A., Powell E. K., i Cavvston T. E. Biochem. Biophysic. Res. Commun., 1994;210:94-101).
Gijbels et al. (J. Clin. Invest, 1994;94:2177-2182) je nedavno opisao hidroksamatni peptid, GM6001 koji sprječava razvitak ili povratak kliničke ekspresije eksperimentalnog alergijskog encefalomielitisa (EAE), ovisno o dozi, predlažući korištenje MMP inhibitora u tretmanu autoimunih upalnih poremećaja kao što je multipla skleroza.
U nedavnom istraživanju Madri je rasvijetlilo ulogu želatinaze A u T-stanicama izvan krvnih žila tijekom upale (Ramanic A. M. i Madri J. A., "The Induction of 72-kD Gelatinase in T Calls upon Adhesion to Endothelial Cells is VCAM-1 Dependent", J. Celi Biology, 1994;125:1165-1178). Ova transmigracija preko sloja endotelialnih stanica koordinirana je indukcijom želatinaze A, a održavana je adhezijom molekula-11 (VCAM-1) na vaskularne stanice. Kad je jedanput barijera savladana, edema i upala nastaju u CNS. Poznato je da su migracije leukocita kroz krvno-moždanu barijeru povezane s upalnim odgovorima u EAE. Inhibicijom metaloproteinaze želatinaze A, blokira se degradacija ekstracelularnih matričnih T-stanica koje su neophodne za penetraciju CNS.
Ova istraživanja zasnivaju se na vjerovanju da će inhibitor stromelizina i želatinaze A dobro djelovati na tretman bolesti koja obuhvaća razaranje ekstracelularnog matriksa nastalog od upale zbog infiltracije limfocita, nepogodne migracije metastatičnih ili aktiviranih stanica, ili gubitka strukturne značajke neophodne za organsku funkciju.
Neuroinflamatroni mehanizam je primijenjen u širokom rasponu akutnih i kroničnih neurodegenerativnih poremećaja, uključujući udar, traumu glave, multiple sklerozu, Alzheimerovu bolest (McGer E. G. i McGeer P. L, "Neurodegeneration and the immune systhem". u Calne D. B. ed. Neurodegenerative Diseases, W. B: Saunders, 1994:277-300). Ostali poremećaji koji mogu obuhvaćati neuroinfamatorni mehanizam uključuju amiotrfnu lateralnu sklerozu (Leigh P. N: "Patogenic Mechanism in amyotrophic lateral sclerosis and other motor neuron disorders" u Calne D. B. ed. Neurodegenerative Diseases, W. B: Saunders, 1994:473-488), cerebealnu amiolidnu angiopatiju (Mandybur T. l. i Balko., "Cerebrla amylolid angiopathy with ranulomatous angiitis ameiorated by steroid-cytoxan treatment", Clin, Neuropharm., 1992;15:241-247), AIDS (Gendelman H. E. i Tardeiu M., "Macrophages/microglia and the patophysiology of CNS injuries in AIDS", J. Eukocyte Biol., 1994;56:387-8), Parkinsonovu bolest, Huntingtonovu bolest, bolesti uzrokovane prionima, i neke poremećaje koji obuhvaćaju periferni nervni sustav kao što je miastenija gravis i Duchenova mišićna distrofija. Pokazano je da neuroinflamacija, koja se pojavljuje kao odgovor na ozljedu moza ili autoimuni poremećaj, uzrokuje uništavanje zdravog tkiva (Martin R., MacFarland H. F. i McFarlin D. E., "Immunological aspects of demyelinating diseases" Ann. Rev. Immunol., 1992;10:153-87; Clark R. K., Lee E. V., Fish C. J. et al "Development of tissue damage inflamation and resolution follovving stroke: an immunohistochemical and guantitative planimetric study", Brain Res. Buli., 1993;31:565-72; Giulian D. i Vaca K., "lnflammatory glia mediate delayed neuronal damage after ischemia in centra nervous system", Stroke, 1993;24(Suppl 12):184-90; Patterson P. H., "Cytokines in Alzheimer's disease and multiple sclerosis", Cur. Opinion Neurobio., 1995;5:642-6; Mceer P. L. Rogers J. i Me Geer E. "Neuroimmune mechansims in Alzheimer disease pathogenesis", Alzheimer Dis. Assoc. Disorders, 1994;8:149-58; Mertin R. i McFarand. "Immunological aspects of experimental allergic encephalomyelitis and multiple scerosis" Crit. Rev. Cin. Lab. Sci., 1995;32:121-82; Rogers J., Webster S., Lue. F. et al. "Inflammation and Alzheimer's disease pathogenesis" u Neurobiology of Aging, 1996;17:681-686; Rothwell N. J. i Reton J. K. "Involvment of cytokines in acute neurodegeneration in CNS" NeuroscL Biobehav. Rev., 1993; 17:217-27). Patološki profil i klinički tijek tih poremećaja se bitno razlikuje, ali svi imaju zajednico raspodjelu imunih/upalnih elemenata u procesu bolesti. Mnogi neurodegeneratvni poremećaju karakterizirani su velikim brojem reaktivnih mikroglia u uzorcima mozga nakon smrti, znakovit u aktivnom upalnom procesu (McGer E. G. i McGeer P. L, supra 1994).
Povećana pažnja je usmjerena prema upalnom mehanizmu u Alzheimerovoj bolesti. Neki dokazi podupiru prisustvo neuroinflamacije u Alzheimerovoj bolesti: 1) Postoji značajni porast upalnih markera u mozgu s Azheimerovom bolesti, uključujući reaktante akutne faze, citokine, komplementarne proteine i MHC molekule (McGer E. G. i McGeer P. L., supra 1994; Rogers et al. supra); 2) postoji dokaz da β-amiloidn inducira neurodegenerativne promjene primarno preko interakcija s upalnim molekulama, a upala sama je dovoljna da bi se inducirala neurodegeneracija (Rogers et al., supra); te 3) Porast epidemioliških podataka pokazuje da inti-inflamatorna terapija može odgoditi početak i usporiti progresiju Alzheimerove bolesti (McGeer P. L. i Rogers J., "Anti-inflamatory agents as therapeutic approach to Alzheimer's disease" Neuroloy, 1992;42:447-9; Kanadsko istraživanje zdravlja i starenja "Rsk factors for Alzheimer disease's in Canada", Neurology 1994;44:2073-80; ucca U., Tettmanti M., Forloni G., i Spagnoli A. "Nonsteroidal antiiflammatory dru use in Alzheimer disease" biol. Psychiatry, 1994;36:854-66; Hampel H. i Mueler N., "Inflammatory and immunoogical mechansims in Alzheimer's disease" DN&P, 1995;8:599-608; Breitenr J. C. S., Gau B. A., VVelsh K. A. et al. "Inverse association of anti-infamatory treatments and Alzheimer's disease: Initial results of a co-twin control study" Neurology, 1994;44:227-32; Breitner J. C. S., VVelsh K. A., Helms M. J. et al. "Deayed onser of Alzheimer's disease with nonsteroidal inti-inflamatory and hidtamine H2 bockin drugs" Neurobiol. Aing, 1995;16:523-30; Andersend K., Aluner L. J., Ott A., Hoes A. W., Breteer M. M. B. i Hofman A. "Do nonsteroidal anti-inflamatory drugs decrease the risk for Alzheimer's disease? The Rotterdam Study", Neurology, 1995;45:1441-5; Rich J. B., Rasmusson D. X., Folstein M. F., et al. "Nonsteroidal anti-infamatory drugs in Alzheimer's disease" Neurology1 1995;45:51-5;Aisen P. S. "Anti-infamatory therapy for Alzheimer's disease" Dementia, 1995;9:173-82; Rogers et al. supra). Kronična upotreba nesteroidnih antiupalnih lijekova (NSAID) se najčešće koristi za reumatoidni artritis, smanjuje vjerojatnost razvitka Alzheimerove bolesti, i postoji razlog da se vjeruje da ostala antiupalna sredstva mogu također biti učinkovita, mada izravnog dokaza za učinkovitost takvog tretmana nema (Hamper i Mueller, supra, 1995). Nadalje, zapravo svi spojevi koji su sad na raspolaganju, koji uključuju kortikosteroide, NSAID, antimalarike i kolhicin imaju ozbiljnih mana koje ih čine nepoželjnim u tretmanu kroničnih poremećaja. Glukokortikoidi koji imaju široku kliničku primjenu kao antiupalna sredstva i imunorepresivi mogu biti neurotoksični a također i toksični za sistemskim organe u umjereno visokim dozama. NSAID imaju gastointestinane i renalne nusefekte koji se pojavljuju nakon dugotrajne upotreba kod većine ljudi, a malo njih prolazi krvno-moždanu barijeru u značajnoj količini. Toksična svojstva kolhicinskih spojeva i kolhicina također su poznata. Antiupalni lijekovi koji se dobro toleriraju u pacijentima i koji prolaze krvno-moždanu barijeru u značajnoj dozi imaju veliku prednost u tretmanu akutnih i kroničnih degenerativnih bolesti centralnog nervnog sustava.
Normalna funkcija bubrega ovisi u održavanju tkiva stanica koje su nastale pri diferencijaciji visoko specijaliziranih bubrežnih stanica koje su dinamički balans skupa s njihovim ekstraceleularnim matriksom (ECM) (Davies M. et al. "Proteinases and glomerular matrix turnover" Kidney Int., 1992;41:671-678). Učinkovita glomrularna fitracija zahtjeva održavanje polupropusne glomerularne bazalna membrana (GBM) koja je sastavljena od kolagena, fibronektina, enaktin, laminin i protolikana. Strukturna razvnoteža je postignuta balansom kontinuiranog odlaganja ECM proteina degradacijom sa specifičnim metaloproteinazama (MMP). MMP pripada genskoj superobitelji cink endopeptidaza (Woessner J. F. "Matrix metaloproteinases and their inhibitors in connective tissue remodelling". FASEBJ. 1991;5:2145-2154). Ovi proteini su prvo izlučeni kao proenzini i zatim su aktivirani ekstracelularnim prostorom. Nasuprot tome, te proteinaze su podložne regulaciji putem prirodnih inhibitora koji se nazivaju TIMP (inhibitori metaoproteinaza u tkivima, enl. tissue inhibitors of metallopropeinases).
Manjak ili neispravnost u bio kojoj komponenti filtracijske barijere može imati katastrofalne posljedice na dugotrajnu funkciju bubrega. Primjerice, kod nasljednog nefritisa tipa Alport, povezanog s mutacijom gena koji kodiraju ECM proteine, nedostatak u nakuinasma kolagenskih vlakana vodi progresivnom zatajenju bubrega povezanog s podjelom GMB i konačno glomelarnoj ili interstibnalnoj fibrozi. Nasuprot tome, pri upali bubrega kao što je glomerulonefritis, stanična proliferacija komponenata glomerulusa četo prethodi očitoj utrastrukturanoj alteraciji ECM matriksa. Citokini i faktori rasta koji se odnose na proliferativni lomerulonefritis kao što je interleukin-1, faktor tumorne nekroze i transformirajući beta faktor rasta može povećati ekspresiju metaloproteinaze u renalnim mesingalnim stanicama (Martin J. et al. "Enhancement of lomerular mesingal cell neutral proteinase secretion by macrophaes: role of intereukin-1" J. Immunol. 1986;137:525-529; Marti H. P. et al "Homoloy cloning of rat 72 kDa type IV collagenase: Cytokine and second-messener inductibility in mesanial cells" Biochem. J. 1993;291:441-446; Marti H. P. et al. "Transforming growth factor-b stimulates glomerular mesangial ćeli synthesis at 72 kDa type IV collagenase" Am. J. Pathol., 1994;144:82-94). Za te metaloproteinaze se vjeruje da su obuhvaćeni u aberantnom remodeliranju tkiva i karakteristikama stanične proliferacije bubrežnih bolesti kao što je IgA nefropatija koja može napredovati preko procesa postupne glomerularne fibroze i gubitka funkcije GBM do zadnjeg stupnja bubrežne bolesti. Ekspresija metaoproteinaze je već dobro karakterizirana u eksperimentalnom imuno kompleksom održavanom gomerulonefritisu kao što je anti-Thy 1.1 model štakora (Bagchus W. M., Hoedemarker P. J., Rozin J., Bakker W. W. "Glomerulonephritis induces by monoconal anti-Thy 1.1 antibodies: A seguential histoloical and ultrastructural study in the rat", Lab. Invest 1986;55:680-687; lovett D. H., Johnson R. J., Marti H. P., Martin J., Davies M., Couse W. "Structura characterization of the mesengial ćeli type IV collaenase and enhanced expression in model of immune complex mediated glomeruloneohritis" Am. J. Pathol., 1992;141:85-98).
Nažalost, sada postoje vrlo ograničene terapijske strategije za modificiranje tijekom progresivne bubrežne bolesti. Mada mnoge bubrežne bolesti imaju upalnu komponentu, njihov odgovor na standardne imunosupresivne lijekove nije predvidljiv i potencijalno opasan na pojedine pacijente. Sekundarna posljedica postupnog zatajenja nefrona kao što je aktivacija renin-angiotenzinskog, praćenog individualnom nefronskom glomerularnom hiperfiltracijom u renalnom hipertenzijom, može biti učinkovito tretiran s ACE inhibitorima ili antagonistima receptora angiotenzina II. Međutim, u najboljem slučaju ovi spojevi mogu samo smanjiti brzinu GFR.
Nova strategija u tretmanu barem nekih bubrežnih bolesti je predložena na osnovu nedavnog opažanja o ponašanju MMP. Štakorske mesangialnih stanice MMP su klonirane (MMP-2), što je regulirano na specifični način u stanici, a nasuprot ostalim staničnim izvorima kao što su tumorske stanične linije, induciran je citokinom (Brown P. D., Levy A. T. Marulies L, Liotta L. A. Stetler.Stevenson W. "Independent expression and cellular processing of Mr 72,000 type IV collaenase and interstitial collagenase in human tumorienic cell lines" Cancer Res. 1990;50:6184-6191; Marti H. P. et al. "Homoloy cloning of rat 72 kDa type IV collagenase: Cytokine and second-messenger inducibility in mesanial cells" Biochem J. 1993;291:441-446). Dok MMP-2 može specifično degradirati okolni ECM, on također utječe na fenotip susjednih mesangialnih stanica. Inhibicija MMP-2 antisens oligonukleotidima ili tehnikama transfekcije može smanjiti povratak proliferativnog fenotipa kulture mesanglialnih stanica u stanicama koje se ne dijele ili ne-proliferativni fenotip koji imitira prirodno in vitro ponašanje tih stanica (Kitamura M. et al. "Gene transfer of metaloproteinase transin induces aberrant behaviour of cultured mesangial cells" Kidnylnt, 1994;45:1580-1586; Turck J. et al. "Matrix metaloproteinase 2 'gelatinase A) reulates lomerular mesanial cell proliferation and differentiation" J. Blol. Chem. 1996;271:15074-15083).
Jasno je da inhibitori MMP (MMPi) imaju mogućnost kliničke primjene u domaćinu koji ima bolest koja je karakterizira abnormalnim remodeliranjem stanica (Vincenti M. P. et al. "Usin inhibitors of metallopropeinases ti treat arthritis" Arthritis Rheum. 1994;8:1115-1126; rams F. et al. "X-ray structures of human neutrophil collagenase compexed with peptide hydroxamate and peptide thio inhibitors. Implications for substrate binding and rational drug design" Eur. J. Biochem. 1995;228:830-841).
Mi smo identificirali seriju tricikličnih sulfonamida i njihovih derivata koji inhibiraju matrične metaloproteinaze, posebice kolagenazu-3, stromelizin-1 i želatinazu A, pa su stoga korisni kao sredstva za tretman multipla skleroze, rupture ateroskelrotičnog plaka, restenoze, aneurizme aorte, zatajenja srca, dilatacija lijevog ventrikula, periodontalne bolesti, ulceracije rožnice, opeklina, ulceracija izazvana dekubitusom, zalječenja rane, karcinoma, upale, boli, artritisa, osteoporoze, bubrežne bolesti i drugih autoimunih ili upalnih bolesti koje ovise o invaziji tkiva leukocitima ili druih aktiviranih migrirajućih stanica, akutnih i kroničnih neurodegenerativnih poremećaja uključujući udar, ozljedu glave, ozljedu kralježnice, Alzheimerovom bolesti, amiotrofnu lateralnu sklerozu, cerebralni amiloidnu angiopatiju, AIDS, Parkinsonovu bolest, Huntingtonovu bolest, bolesti uzrokovane prionima, miastenik gravis i Duchennovu muskularnu distrofiju.
Sažetak izuma
Prema ovome, prvi aspekt ovo izuma je spoje formule I
[image]
u kojoj n jeste nula ili cijeli broj od 1 ili 2;
X je-O-,
-S(O)P gdje p jeste nula ili cijeli broj od 1 ili 2,
-NR2 gdje R2 jeste vodik,
alkil,
acil ili benzil,
CH2- ili
-CO-;
R je vodik,
alkil,
hidroksialkil,
alkoksialkil,
trifluormetil,
akanoiloksialkil,
alkanoilaminoalkil,
alkiltioalkil,
alkilsulfinilalkil,
alkiltsulfonilalkil,
aminoalkil,
alkilaminoalkil,
dialkilaminoalkil,
N-alkilpiperazinoalkil,
N-fenilalkilpiperazinoalkil,
morfolinoalkil,
tiomorfolinoalkil,
piperidinoalkil,
pirolidinoalkil,
N-alkilalkilpiperidinoalkil,
piridinilalkil,
tioenilaikil,
kinolinilalkil,
tiazolilalkil,
cikloalkil,
cikloalkilalkil,
fenil,
fenil supstituiran jednim ili tri supstituenta koji je:
hidroksi,
alkoksi,
alkil,
alkiltio,
alkilsulfinil,
alkilsulfonil,
amino,
alkilamino,
dialkilamino,
halogen,
cijano,
nitro,
trifluormetil ili na susjednom atomu ugljika alkenildioksi skupina s jednim ili dva atoma ugljika, alkenioksi skupina s dva ili tri atoma ugljika, fenilalkil, fenilalkil u kojem je fenil supstituiran s alkil,
alkoksi,
halogen, ili
trifluormetil, heteroaril, heteroaril supstituiran jednim ili dva supstituenta koji je:
alkil, ili
halogen, bifenil, bifenil supstituiran s alkil,
alkoksi,
halogen,
trifluormetil, ili
cijano, bifenilalkil ili bifenilalkil supstituiran s
alkil,
alkoksi,
halogen,
trifluormetil, ili
cijano;
D je nula ili cijeli broj od 1 do 3;
L je nula ili cijeli broj od 1 do 3;
R1 je vodik,
bočni lanac prirodne aminokiseline ili bočni lanac sintetske aminokiseline;
Y je OR3 gdje R3 jeste vodik,
metil, etil, ili
benzil, ili
NH-OR4 gdje R4 jeste vodik,
alkil ili
benzil;
u odgovarajući izomeri ili farmaceutski prihvatljiva sol.
Inhibitori matrične metaloproteinaze, spojevi formule I, korisni su u tretmanu mutipla skleroze. Također su korisni u tretmanu rupture ateroskelrotičnog plaka, aneurizme aorte, zatajenja srca, dilatacija lijevog ventrikula, periodontalne bolesti, ulceracije rožnice, opeklina, ulceracija izazvana dekubitusom, zalječenja rane, metastaze karcinoma, angiogenezu tumora, upale, bol, artritis, osteoporoza, bubrežna bolest, i ostalih autoimunih ili upalnih bolesti koje ovise o invaziji tkiva leukocitima ili drugih aktiviranih migrirajućih stanica, akutnih i kroničnih neurodeenerativnih poremećaja uključujući udar, ozljedu glave, ozljedu kralježnice, Alzheimerovom bolesti, amiotrofnu lateralnu sklerozu, cerebralni amiloidnu angiopatiju, AIDS, Parkinsonovu bolest, Huntingtonovu bolest, bolesti uzrokovane prionima, miastenik gravis i Duchennovu muskularnu distrofiju.
Daljnja cjelina ovog izuma je farmaceutski pripravak za davanje u učinkovitoj količini spoja formule I u jedinici doze za tretman gore spomenutih metoda. Konačno, u ovom izum je upućen na metodu priprave spojeva Formule I.
Detaljan opis izuma
U spojevima Formule l termin "alkil " označuje ravni ili razgranati lanac ugljikovodika koji ima 1 do 6 atoma ugljika, a uključuje, primjerice metil, etil, n-propil, izopropil, izobutil, n-butil, sec-butil, izobutil, terf-butil, n-pentil, n-heksil, i slično.
Termin "alkenil" označuje ravni ili razgranati lanac ugljikovodika koji ima 1 do 6 atoma ugljika, a uključuje, primjerice metil, etenil, 2-propenil, 1-butenil, 2-butenil, 1-pentenil, 2-pentenil, 3-metil-3-butenil, 1-heksenil, 2-heksenil, 3-heksenil i slično.
Termin "alkoksi" i "tioalkoksi" su -O-alkil ili -S-alkil od 1 do 6 atoma ugljika, kao što je gore definirano za "alkil".
Termin "cikloalkil" označuje zasićeni ugljikovodični prsten koji ima 3 do 7 atom ugljika, a koji može sadržavati atom kisika ili sumpora i uključuje, primjerice ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil i slično.
Termin "aril" označuje aromatski radikal koji je fenilna skupina, fenilna skupina supstituirana 1 do 4 supstituenta koji su odabrani od alkil kao što je gore definiran, alkoksi kao što je gore definiran, tioalkoksi kao što je gore definiran, hidroksi, halogen, trifluormetil, amino, alkilamino kao što je gore definirano za alkil, dialkilamino kao što je gore definirano za alkil, nitro, cijano, karboksi, gvanidino, amidino, SO3H, CHO, CO-alkil kao što je gore definirano za alkil, -CO-NH2, -CO-NH-alkil, NH-CO-alkil, kao što je gore definirano za alkil, -CO-N(alkil)2 kao što je gore definirano za alkil, -(CH2)n2-NH2 gdje n2, jeste cijeli broj od 1 do 5, -(CH2)n2-NH-alkil kao što je gore definirano za alkil i n2, -(CH2)n2-N(alkil)2 kao što je gore definirano za alkil i n2, -(CH2)n2-NH-CO-alkil, kao što je gore definirano za alkil i n2, te -(CH2)n2-N(alkil)-CO-alkil kao što je gore definirano za alkil i n2.
Termin "arilalkil" označuje aromatski radikal spojen na alkil radikal gdje aril i alkil jesu kao što je gore definirano, primjerice benzil, feniletil, 3-fenilpropil, (4-korfenil)metil i slično.
Termin "aciloskimetil11 označuje skupinu formule -CH2-O-CO-alkil gdje je alki kao što je gore definirano.
Termin "heteroaril" označuje petero- ili šesteročlane heteroaromatski radikal koji sadrži 1 do 3 heteroatoma koji su N, O i S, a uključuje primjerice hetero aromatski radikal koji je 2- ili 3-tienil, 2- ili 3-furanil, 2- ili 3-pirolil, 2-, 3- ili 4-piridinil, 2-pirazinil, 2-, 4- ili 5-pirimidinil, 3- ili 4-piradizinil, 1H-indol-6-il, 1H-indol-5-il, 1H-benzimidazol-6-il, 1H-benzimidazol-5-il, 2-, 4- ili 5-tiazolil, 3-, 4- ili 5-izotiazolil, 2-, 4- ili 5-imidazolil, 3-, 4- ili 5-pirazolil ili 2- ili 5-tiadizoil koji mogu biti supstituirani sa supstituenom koji je odabran iz sljedeće skupine: alkil kao što je gore definiran, alkoski kao što je gore definiran, tioalkoksi kao što je gore definiran, hidroksi, halogen, trifluormetil, amino, alkilamino kao što je gore definirano za alkil, dialkilamino kao što je gore definirano za alkil, nitro, cijano, karboksi, gvanidino, amidino, SO4H, CHO, CO-alkil kao što je gore definirano za alkil, -CO-NH2, -CO-NH-alkil, NH-CO-alkil, kao što je gore definirano za alkil, -CO-N(alkil)2 kao što je gore definirano za alkil, -(CH2)n2-NH2 gdje n2, jeste cijeli broj od 1 do 5, -(CH2)n2-NH-alkil kao što je gore definirano za alkil i n2, -(CH2)n2-N(alkil)2 kao što je gore definirano za alkil i n2, -(CH2)n2-NH-CO-alkil, kao što je gore definirano za alkil i N2, te -(CH2)n2-N(alkil)-CO-alkil kao što je gore definirano za alkil i n2.
Termin "heterocikl" označuje tro- do sedmeročlani cikloalkilni radikal koji sadrži 1 do 3 hetroatoma koji su N, O i S i uključuju, primjerice 2- i 3-azetidinil, 3- i 4-azetidinil-2-on, 4- i 5-imidazolidinil-2-on, 2,4-dioski-imidazolidini, 2,4-diokso-1,5,5-trimetil-imidazolidini, 2-, 4- i 5-tiazolidinil, 4- i 5-oksazolidinil-2-on, 2- i 3-tetrahidrofuranil, 2- i 3-pirolidinil, 2-, 3- i 4-piperidinil, 2- i 3-morfoinil, 2- i 3-piperazinil, 2-, 3- i 4-azacikloheptanil i slično.
Termin "heteroarilalkil" označuje heteroaromatski radikal koji je spojen na alkil radikal, a heteroaril i alkil jesu kao što je gore definirano.
Termin "heterocikloalkil" označuje heterociklični radikal koji je spojen na alkil radikal, a heterocikl i alkil jesu kao što je gore definirano.
Termin "pirolidinoalkil" označuje pirolidino skupinu koji je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "tienilalkil" označuje tienilnu skupinu koja je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "kinolinilalkil" označuje kinolinilnu skupinu koja je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "tiazolilalkil" označuje tiazolilnu skupinu koja je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "fenilalkil" označuje fenilnu skupinu koja je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "bifenilalkil" označuje bifenilnu skupinu koja je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "acil" označuje skupinu formule -CO-alkil, a alkil je kao što je gore definirano.
Termin "hidroksialkil" označuje hidroksilnu skupinu koja je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "alkoksialkil" označuje hidroksilnu skupinu koja je spojena na alkil radikal, a alkoksi i alkil jesu kao što je gore definirano.
Termin "aminoalkil" označuje amino skupinu koja je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "morfolinoalkil" označuje morfolino skupinu koja je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "tiomorfolinoalkil" označuje tiomorfolino skupinu koja je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "piperidinoalkil" označuje piperidino skupinu koja je spojena na alkil radikal, a alkil je kao što je gore definirano.
Termin "cikloalkilalkil" označuje cikloalkilnu skupinu koja je spojena na alkil radikal, a cikloalkil i alkil jesu kao što je gore definirano.
Termini "alkilaminoalkil" i "dialkilaminoalkil" označuju alkil-NH-alkil i (alkil)2N-alkil, a alkil je kao što je gore definirano.
Termini "alkilamino" i "dialkilaminol" označuju alkil-NH- i (alkil)2N-, a alkil je kao što je gore definirano.
Termini "alkiltioalkil", "alkilsufinilalkil" i "alkilsufonilalkil" označuju alkil-S-alkil, alkil-SO-alkil, te alkil-SO2-alkil, a alkil je kao stoje gore definirano.
Termini "alkiltio", "alkilsufinil" i "alkilsufonil" označuju alkil-S-, alkil-SO-, te alkil-SO2-, a alkil je kao što je gore definirano.
Termin "alkanoiloksialkil" označuje alkil-CO-O-alkil, a alkil je kao što je gore definirano.
Termin "alkanoilaminoialkil" označuje alkil-CO-NH-alkil, a alkil je kao što je gore definirano.
Termin "N-akilpiperazinoalkil" označuje [image] u kojem je alkil kao što je gore definirano.
Termin "N-fenilalkilpiperazinoalkil" označuje [image] u kojem je alkil kao što je gore definirano.
Termin "N-akilalkilpiperidinoalkil označuje [image] u kojem je alkil kao što je gore definirano.
Termin "alkenilendioksi" označuje -O-alkil-O-, gdje je alkil kao što je gore definirano.
Termin "alkenilenoksi" označuje -alkil-O-, gdje je alkil kao što je gore definirano.
Termin "bočni lanac prirodne aminokiseline" (prirodna α-aminokiselina) označuje grupu Q prirodne aminokiseline formule H2N-CH(Q)-COOH. Primjeri bočnih lanaca prirodne a-aminokiseline uključuju one od alanina, arginina, asparagina, asparaginske kiseline, cisteina, glutaminske kiseline, glicina, histidina izoleucina, leucina, lizina, metionina, fenilalanina, prolina, serina, treonina, triptofana, tirozina i valina.
Prirodne α-aminokiseline su aminokiseline nađene u živim organizmima. Primjeri takvih aminokiselina su glicin, alanin, valin, leucin, izoleucin, fenilalanin, prolin, serin, treonin, tirozin, asparain, lutamin, lizin, arinin, triptofan, histidin, cistein, metionin, asparainska kiselina i glutaminska kiselina.
Funkcionalne skupine aminokiselinskog bočnog lanca mogu biti zaštićene. Primjerice karboksilne skupine mogu biti
esterificirane, amino skupine mogu biti prevedene u amide ili karbamate, hidroksilne skupine mogu biti prevedene u etere ili estere, a tio skupine mogu biti prevedene u tioetere ili tioestere.
Termin "bočni lanac sintetske aminokiseline" označuje skupinu R1a sintetskoj aminokiselini formule
[image]
u kojoj
R jeste alkil,
hidroksialkil,
alkoksialkil,
trifluormetil,
alkanoiloksialkil,
alkanoilaminoalkil,
alkiltioalkil,
alkilsulfinilalkil,
alkilsulfonilalkil,
aminoalkil,
dialkilaminoalkil,
N-alkilpiperazinoalkil,
N-fenilalkilpiperazinoalkil,
morfolinoalkil,
tiomorfolinoalkil,
piperidinoalkil,
pirolidinoalkil,
N-alkilalkilpiperidinoalkil,
piridilalkil,
tienilalkil,
kinolinilalkil,
tiazolilalkil,
ciklalkil,
cikloalkilalkil,
fenil supstituiran jednim ili tri supstituenta koji je:
hidroksi,
alkoksi,
alkil,
alkiltio,
alkilsulfinil,
alkilsulfonil,
amino,
alkilamino,
dialkilamino,
halogen,
cijano,
nitro,
trifluormetil ili na susjednom atomu ugljika alkenildioksi skupina s jednim ili dva atoma ugljika, alkeniloksi skupina s dva ili tri atoma ugljika,
fenilalkil,
fenilalkil u kojem je fenil supstituiran s alkil,
alkoksi,
halogen, ili
trifluormetil,
heteroaril,
heteroaril supstituiran jednim ili dva supstituenta koji je:
alkil, ili
halogen,
bifenil,
bifenil supstituiran s alkil,
alkoksi,
halogen,
trifluormetil, ili
cijano,
bifenilalkil ili
bifenilalkil supstituiran s
alkil,
alkoksi,
halogen,
trifluormetil, ili
cijano;
D je nula ili cijeli broj od 1 do 3;
L je nula ili cijeli broj od 1 do 3;
R1a je bočni lanac sintetske aminokiseline. Sintetske aminokiseline su dobro poznate, npr. Roberts et al., "Unusual Amino Acids i Peptide Synthesis" The Peptides, 1993;5:341-429, ali nisu nađeni u živim organizmima. Bočni lanac sintetskih aminokiselina uključuje sljedeća, ali nije ne njih ograničen:
vodik,
-(CH2)n-naftalimid gdje n jeste nula ili cijeli broj od 1 do 2,
-(CH2)n-ftalimid gdje n jeste kao što je gore definirano,
-(CH2)n -aril gdje n jeste kao što je gore definirano,
alkil,
supstituirani alkil, pri čemu je supstituent odabran od sljedećih:
SH,
OR5 gdje R5 jeste vodik, alkil, fenil ili benzil,
SR5 gdje R5 jeste kao što je gore definirano,
halogen,
R5-N-R5a, gdje R5 i R5a isti ili različiti jesu kao što je gore definirano za R5,
CO2H,
COR5 gdje R5 jeste kao što je gore definirano,
CHO, ili
CO-N(R5a)R5 gdje R5 i R5a isti ili različiti jesu kao što je gore definirano za R5,
aril,
-(CH2)n-fenil gdje n jeste kao što je gore definirano, alkenil,
-(CH2)n-heteroaril gdje n jeste kao što je gore definirano, heterociklil,
-(CH2)m-NH-Z-R5 gdje m jeste cijeli broj od 1 do 6, Z je -CO-,
-CS- ili -SO2, a R5 jeste kao što je gore definirano,
-(CH2)m-NH-Z-R5 gdje m jeste cijeli broj od 1 do 6, Z je -CO-,
-CS- ili –SO2, a R5 jeste kao što je gore definirano,
-(CH2)m-O-(CH2)La-fenil gdje La jeste cijeli broj od 1 do 6, a m jeste kao što je gore definirano,
-(CH2)m-CO-R5 gdje m i R5 jesu kao što je gore definirano,
-(CH2)m-NHSO2-aril gdje m jeste kao što je gore definirano,
-(CH2)m-cikloalkil gdje m jeste kao što je gore definirano,
-(CH2)m-CO-aril gdje m jeste kao što je gore definirano,
-(CH2)m-CO-NH-R5 gdje m i R5 jeste kao što je gore definirano,
-(CH2)m-CO-OR5 gdje m i R5 jeste kao što je gore definirano,
[image] gdje m jeste kao što je gore definirano,
Y je OR3 gdje R3 jeste vodik,
metil,
etil, ili
benzil, ili
NH-OR4 gdje R4 jeste vodik,
alkil ili
benzil;
s ograničenjem da R1a nije bočni lanac prirodne a-aminokiseline kao što je gore definirano.
Nadalje, bočni lanac prirodne a-aminokiseline i sintetske aminokiseline koje imaju D ili R konfiguraciju uključene su u ovaj termin.
Funkcionalne skupine aminokiselinskih lanaca mogu biti zaštićene. Primjerice, karboksilna skupine može biti esterificirana, amino-skupina može biti prevedene u amide ili karbamate, hidroksilna skupina može biti prevedena u etere ili estere, a tiolna skupina može biti prevedena u tioetere i tioestere.
"Halogen" je fluor, klor, brom ili jod.
"Alkalijski metal" je metal iz IA grupe periodnog sustava i uključuje, primjerice litij, natrij, kalij i slično.
Aciloksimetilni esteri spojeva Formule I se mogu pripraviti stručnjaci po dobro poznatim metodama. Primjerice, odgovarajuće karboksilne kiseline se mogu ostaviti da reagiraju prvo s pogodnom bazom pri čemu nastaje karboksilat anion, nakon čega slijedi reakcija s karboksilnim halometilnim esterom, koji se može dobiti od komercijalnih dobavljača ili pripraviti stručnjacima dobro poznatim metodama, a može u prisutnosti pogodnog reagensa za aktiviranje karbosilnog halometilno estera, a koji su poznati stručnjacima, pri čemu nastaju acioksimetil esteri.
Neki spojevi Formule I mogu tvoriti daljnje farmaceutski prihvatljive soli adicijom kiselina i/ili adicijom baza. Svi ti oblici su obuhvaćeni predstavljenim izumom.
Farmaceutsko prihvatljive soli nastale adicijom kiseline uključuju soli izvedene iz netoksičnih anorganskih kiselina kao što su: solna, dušična, fosforna, sumporna, bromovodična, jodovodična, fluorovodična i slične, te soli izvedene iz netoksičnih organskih kiselina, kao što su alifatske mono- i dikarbosksilne kiseline, fenilom supstituirane alkan kiseline, hidroksialkan kiseline, alken dikiseline, aromatske kiseline, alifatske i aromatske sulfonske kiseline, itd. Takve soli stoga uključuju sulfate, pirosulfate, bisulfate, sulfite, nisulfite, nitrate, fosfate, monohidrogenfosfate, dihirogenfosfate, metafosfate, pirofosfate, kloride, bromide, jodide, acetate, trifluoracetate, propionate, kaprilate, izobutirate, oksalate, malonate, sukcinate, suberate, fumarate, maleate, mandetate, benzoate, klorbenzoate, metilbenzoate, dinitrobenzoate, ftalate, benzensulfonate, toluensulfonate, fenilacetate, citrate, laktate, maleate, tartarate, metansulfonate i slične. Također su razmatrane soli aminokiselina kao što su glukonati, galakturati (vidi primjerice Berge S. M. et al., "Pharmaceutical Salts", J. of Pharma. Sci., 1977;66,:1).
Soli nastale adicijom kiseline navedenih bazičnih spojeva se pripravljaju djelovanjem suviška željene kiseline na slobodnu bazu, pri čemu nastaje sol na uobičajeni način. Oblik slobodne baze se može regenerirati djelovanjem na takvu sol s bazom i izoliranjem slobodne baze na uobičajeni način. Oblik slobodne baze razlikuje se od odgovarajuće soli u nekim fizičkim svojstvima, kao što su topljivost u polarnim otapalima, ali inače su soli ekvivalentne odgovarajućoj slobodnoj bazi za svrhe predstavljene u izumu.
Farmaceutsko prihvatljive soli nastaje adicijom baze, ako što su soli alkalijskih i zemnoalkalijskih metala ili organskih amina. Primjeri metala su kationi natrija, kalija, magnezija, kalcija i slične. Primjeri pogodnih amina su N,N'-dibenzil-etilendiamin, klorprokain, kolin, dietanolamin, dicikloheksilamin, etilendiamin, N-metilglukamin, dicikloheksilamin, etilendiamin, N-metilglukamin i prokailn (vidi primjerice Berge S. M. et al., "Pharmaceutical Salts", J. of Pharma. Sci., 1977;66,:1).
Soli nastale adicijom baze bazičnih spojeva se pripravljaju djelovanjem suviška željene baze na slobodnu kiselinu pri čemu nastaje sol na uobičajeni način. Oblik slobodne kiseline se može regenerirati djelovanjem na takvu sol s kiselinom i izoliranjem slobodne kiseline na uobičajeni način. Oblik slobodne kiseline razlikuje se od odgovarajuće soli u nekim fizičkim svojstvima, kao što su topljivost u polarnim otapalima, ali inače su soli ekvivalentne odgovarajućoj slobodnoj kiselini za svrhe predstavljene u izumu.
Neki spojevi iz predstavljenog izuma mogu postajati u nesolvatiziranom kao i solvatiziranom obliku, uključujući i hidrate. Općenito, solvatizirani oblici uključujući i hidrate su ekvivalentni nesolvatiziranim oblicima i dio su cjeline ovog izuma.
Neki spojevi iz predstavljenog izuma imaju jedan ili više kiralnih ugljikovih centara i takvi centri mogu imati R ili S konfiguraciju. Predstavljeni izum uključuje diastereomere, enantionerne i epimerne oblike, kao i njihove smjese. Nadalje, spojevi iz ovog izuma mogu postojati kao geometrijski izomeri. Ovaj izum uključuje sve cis, trans, syn, and, entgegen (E) i zusammen (Z) izomere, kao i njihove smjese.
Preferirani spoj Formule I je:
[image]
u kojoj n jeste nula ili cijeli broj 1, te X je -O-, ili -CH2-.
Sljedeći preferirani spoj Formule I je:
[image]
u kojoj n jeste nula ili cijeli broj 1, te
X je -O-, ili
-CH2-, te
R jeste vodik.
Sljedeći preferirani spoj Formule I je:
[image]
u kojoj n jeste nula ili cijeli broj 1,
te X je -O-, ili
-CH2-,
R jeste vodik, te
Y jeste OH.
Slijedeći preferirani spoj Formule I je:
[image]
u kojoj n jeste nula ili cijeli broj 1,
te X je -O-, ili
-CH2-,
R jeste vodik,
te Y jeste NHOH.
Posebno vrijedna cjelina ovo izuma su spojevi iz sljedeće skupine:
(S)3-meti-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-jantarna kiselina,
(S) fenil-[(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)]-octena kiselina,
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-3-(3,4,4-trimeti1-2,5-diokso-imidazolidin-1-il)-propionska kiselina,
(S)3-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionska kiselina,
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-4-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-maslačna kiselina,
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-5-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-pentanska kiselina,
(S)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(S)4-fenilmetansulfinil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)4-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)5-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(S)6-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina,
(S)7-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina,
(S)8-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina,
(S)4-fenilsulfamoil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)4-fenilmetansulfonil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)4-benzilsulfanil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)3-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran--3-sulfonilamino)-propionska kiselina,
(S)4-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)5-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(S)6-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina,
(S)7-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina,
(S)8-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina,
(S)2-(2,3-dihidro-1H-8-oksa-ciklopenta[a]inden-6-sulfonilamino)-3-metil-maslačna kiselina,
(S)3-meti-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzo[a]azulen-2-sulfonilamino)-maslačna kiselina,
(S)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)N-hidroksi-3-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-sikcinamska kiselina,
(S)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-acetamid,
(S)N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-3-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-propionamid,
(S)3-(1,3-diokso-1,3-dihidro-izoindol-2-il)-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid,
(S)N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-4-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-butiramid,
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-5-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-pentan kiselina hidroksamid,
(S)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(S)N-hidroksi-4-fenilmetansulfinil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)4-(1,3-diokso-1,3-dihidro-izoindol-2-il)-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)5-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(S)6-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina hidroksamid,
(S)7-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina hidroksamid,
(S)8-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina hidroksamid,
(S)4-benzilsulfanil-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)N-hidroksi-4-fenilsufamoil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)N-hidroksi-4-fenilmetansulfonil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)N-hidroksi-3-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid,
(S)N-hidroksi-4-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)5-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(S)6-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina hidroksamid,
(S)7-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina hidroksamid,
(S)8-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina hidroksamid,
(S)2-(2,3-dihidro-1H-8-oksa-ciklopenta[a]inden-6-sulfonilamino)-N-hidroksi-3-metil-butiramid,
(S)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzo[a]azulen-2-sulfonilamino)-butiramid,
(S)3-metil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-maslačna kiselina,
(S)3-metil-2-(9-metil-6J,8,9-tetrahidro-5H-karbazol-2-sulfonilamino)-maslačna kiselina,
(S)4-fenil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-maslačna kiselina,
(S)4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-maslačna kiselina,
(S)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid,
(S)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-butiramid,
(S)N-hidroksi-3-metil-2-(9-metil-6,7,8,9-tetrahidro-5H-karbazol-2-sulfonilamino)-butiramid,
(S)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid,
(S)3-metil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-maslačna kiselina,
(S)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid,
(R)3-metil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)N-hidroksi-3-meti-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-jantarna kiselina,
(R) fenil-[(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)]-octena kiselina,
(R)2-(67,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-3-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-propionska kiselina,
(R)3-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionska kiselina,
(R) 2-(67,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-4-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-maslačna kiselina,
(R)2-(67,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-5-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-pentanska kiselina,
(R)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(R)4-fenilmetansulfinil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)4-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)5-(1,3-diokso-1,3-dihidro-izoindol-2-il)-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(R)6-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina,
(R)7-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina,
(R)8-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktnska kiselina,
(R)4-fenilsulfamoil-2-(67,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)4-fenilmetansulfonil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)4-benzilsulfanil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)3-(1H-indol-3-il)-2-(67,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionska kiselina,
(R)4-(1H-indol-3-il)-2-(67,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)5-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(R)6-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina,
(R)7-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina,
(R)8-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina,
(R)2-(2,3-dihidro-1H-8-oksa-ciklopenta[a]inden-6-sulfonilamino)-3-metil-maslačna kiselina,
(R)3-meti-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzo[a]azulen-2-sulfonilamino)-maslačna kiselina,
(R)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)N-hidroksi-3-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-sukcinamska kiselina,
(R)N-hidroksi-2-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-acetamid,
(R)N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-3-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-propionamid,
(R)3-(1,3-diokso-1,3-dihidro-izoindol-2-il)-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid,
(R)N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-4-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-butiramid,
(R)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-5-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-pentan kiselina hidroksamid,
(R)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(R)N-hidroksi-4-fenilmetansulfinil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)4-(1,3-diokso-1,3-dihidro-izoindol-2-il)-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)5-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(R)6-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina hidroksamid,
(R)7-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina hidroksamid,
(R)8-fenil-2-2-(6,7,8,9-tetrahidro-dibenzofuran-S-sulfonilamino)-oktanska kiselina hidroksamid,
(R)4-benzilsulfanil-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)N-hidroksi-4-fenilsufamoil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)N-hidroksi-4-fenilmetansulfonil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)N-hidroksi-3-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid,
(R)N-hidroksi-4-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)5-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(R)6-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina hidroksamid,
(R)7-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina hidroksamid,
(R)8-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina hidroksamid,
(R)2-(2,3-dihidro-1H-8-oksa-ciklopenta[a]inden-6-sulfonilamino)-N-hidroksi-3-metil-butiramid,
(R)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzo[a]azulen-2-sulfonilamino)-butiramid,
(R)3-metil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-maslačna kiselina,
(R)3-metil-2-(9-metil-6,7,8,9-tetrahidro-5H-karbazol-2-sulfonilamino)-maslačna kiselina,
(R)4-fenil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-maslačna kiselina,
(R)4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-maslačna kiselina,
(R)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid,
(R)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-butiramid,
(R)N-hidroksi-3-metil-2-(9-metil-6,7,8,9-tetrahidro-5H-karbazol-2-sulfonilamino)-butiramid,
(R)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid,
(R)3-metil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-maslačna kiselina, te
(R)N-hidroksi-3-metil-2-(67,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid, i odgovarajući izomeri ili odgovarajuće farmaceutski prihvatljive soli.
Spojevi Formule I su vrijedni inhibitori brojnih različitih metričnih metaloproteinaza. Prethodno je pokazano da efikasnost inhibitora matričnih metaloproteinaza su u modelima bolesnih stanja kao što je artritis ili metastaze ovisi o modeifikaciji vanstaničnog matriksa.
Provedeni su in vitro eksperimenti koji pokazuju efikasnost spojeva Formule l kao specifični inhibitori raznih matričnih metaloproteinaza. Eksperimenti su izvedeni s proteinazama pune duljine i katalitičke domene. Tablica l pokazuje aktivnost Primjera 1-4 prema MMP-1FL (kolagenaza pune duljine), MMP-2CD (želatinaza A katalitička domena, MMP-2FL (matrilizin pune duljine), MMP-9-FL (želatinaza B pune duljine), MMP-13CD (kolagenaza-3 katalitička domena) i MMP-14CD (MMP-1 membranskog tipa). IC50 vrijednosti određene su korištenjem tiopeptoidnog supstrata, Ac-Pro-Leu-Gly-tioester-Lue-Lue-Gy-OEt (Ye Q.-Z., Johnson L. L, Hupe D. J. i Baragi V. "Purification and Characterization of the Human Stromelysin Caralytic Domain Expressed in Escherichia coli, Biochemistry, 1992;31:1123111235, Ye Q.-Z- Johnson L L, Yu A. E. i Hupe D. "Reconstructed 19 kDa catalytic domain od gelatinase A in active proteinase" Biochemistry, 1995;34:4702-4708). MMP-13CD je eksprimirana iz sintetske gena i pročišćena iz stanične kulture Escherichia coli prema prethodno opisanoj metodi (Ye O.-Z-Johnson L. L. i Baragi V. "Gene synthesis and expression in E. coli for PUMP, a human matrix metalloproteinazse" Biochemical and Biophysical Research Communications, 1992; 186:143-149).
TABLICA 1. Biološka aktivnost spojeva Formule I
[image]
Sljedeća lista sadrži kratice ili akronime korištene unutar shema i teksta:
GBM Glomerularna bazalna membrana
ECM ekstracelularni matriks
CNS centrani nervni sustav
CH2Cl2 diklormetan
EAE eksperimentani autoimuni encefalimielitis
MMP matrična metaloproteinaza
TIMP tkivni inhibitori matričnih metaloproteinaza
VSMC stanica vaskuarnih gatkih mišića
TFA trifluoroctena kiselina
IC50 koncentracija spoja potrebna da 50% inhibira enzimsku aktivnost
HCl klorovodik
THF tetrahidrofuran
Pd paladij
Na natrij
NaH Natrijev hidrid
LiOH litijev hidroksid
LiCl litijev klorid
H2O voda
H2 vodik
CDl 1,1'-karbonilimidazol
hv svjetlo
SO3'·DMF sumporni trioksid dimetilformamid
SOCl2 tionil-klorid
t-Bu tercijarni butil
BOC tercijarni butoksikarbonil
LDA litijev diizopropilamid
MeOH metanol
DMF dimetilformamid
p-TsOH(p-TSA) para-toluensufonska kiselina
CHCl3klorofom
CDCla deuterirani koroform
E entgeen
Z zusammen
H2NOBz O-benzil hidroksilamin
TEA trietilamin
CH3CN acetonitril
DBU 1,8-diazabiciklo[5.4.0]undeka-7-en
DCC dicikloheksilkarbodiimid
PPA polifosforna kiselina
BaSO4 barijev sulfat
DMSO-d6 deuterirani dimetilsulfoksid
MgSO4 magnezijev sulfat
1H-NMR protonska nuklearna magnetska rezonancija
PPM dijelova po milion
MS spektar masa
Triciklični arilni i triciklični heteroarilni polazni spojevi formule (3)
[image]
u kojoj n jeste nula ili cijeli broj od 1 ili 2;
X je -O-,
-S-,
-NR2- gdje R2 jeste vodik, alkil,
acil ili
benzil,
se dobivaju iz komercijalnih izvora (X=N-R2 u kojoj R2 jeste kao što je gore definirano) ili se pripravljaju poznatim metodama, npr. Bachelet J. P. i Caubere P. J. Org. Chem. 1982;47:234-238; Ebel F. Helv. Chem. Acta, 1929;12:3-16; Vanrysselberhe V. et al. Ind. Eng. Chem. Res. 1996;35:3311-3318; Derouane D. et al. J. Chem. Soc., Chem. Commun, 1995; 10:993-994; Miki Y i Sugimoto Y. Seikiyu Gakkaishi, 1994;37:386-394; Miki Y et al. Seikiyu Gakkaishi, 1992;35:382-338; Rankel L A. Fuel Sci. Technol. Int., 1991;9:1435-1447; Siskin M. et al. Energy Fuels, 1990; M. A. et al. J. Org. Chem. 1988;53:596-600; Nagai M. et al., J. Catal. 1986;97:52-58; Miyake M. et al. Buli Chem. Soc. Japan, 1090;52:559-563; Ando W. et al. J. Chem. Soc., Chem. Commun., 1975; 17:704-705; Fraser P. S. et al. J. Org. Chem., 1974;39:2509-2513; Cagniant D. et al. Buli Soc. Chem. Fr. 1969;2:601-606; U. S Patenti 5.721.185, 5,670,680; Međunarodna publicirana patentna aplikacija WO 95/27717; Smith W. et al. J. Org. Chem., 1990;55:5301-5302; Mejer S., Pol. of Chem. 1979;53:2385-2388; Canonne P. et al., J. Or. Chem. 1980;45:1828-1835; Parham W. E., Synthesis, 1976;116-117; Japanski Patentna aplikacija JP 08191063 A2; Parhan W. E. J. Org. Chem., 1969;34:1899-1904; McCure K. R et. al., Bioor. Med. Chem. Alett., 1998;8:143-146.
Sinteza polaznog spoja za spoj Formule I u kojem X jeste -O- je prikazana u Shemi 1. Tako, spoj formule (1) u kojem n jeste nula ili cijeli broj od 1 ili 2 reagira s fenolom u prisutnosti natrija ili natrijevog hidrida i slično u prisutnosti otapala kao što je benzen, tetrahidrofuran i slično, pri čemu nastaje spoje formule (2). Ciklizacija spoja formule (2) u prisutnosti kiseline kao što je primjerice fosforna kiselina, p-toluensufonska kiselina i slično i prisutnosti otapala kao što je benzen i slično nastaje spoj formule (3).
Sinteza spojeva Ia, Ib, Ic i Id je prikazana u Shemi 2. Tako, spoj formule (3) u kojem n jeste kao što je n kao što je gore definirano je sulfoniran korištenjem sulonatnog reagensa, kao što je primjerice SO3-DMF i slično refluksiranjem u otapalu kao što je primjerice dikloretan i slično pri čemu nastaje spoj formule (4) u kojem je n kao što je gore definirano. Spoj formule (4) je kloriran sa sredstvom za kloriranje kao što je, primjerice, tioni-klorid i slično pri sobnoj temperaturi i dobiva se spoj formule (5) u kojem je n kao što je gore definirano. Spoj formule (5) reagira s aminokselinom formule (R1) u kojoj R1 jeste vodik, bočni lanac prirodne aminokiseline ili bočni lanac sintetske aminokiseline u prisutnosti baze kao što je, primjerice trietilamin i slično u otapalu kao što je, primjerice, tetrahidrofuran/voda i slično kod oko sobne temperature, pri čemu nastaje spoj Formule Ia u kojem je R1 kao što je gore definirano. Alternativno, spoj formule (5) je reagirao s C-zaštićenom aminokiselinom formule (7) u kojoj je R1 kao što je gore definirano, u prisutnosti baze kao što je, primjerice, trietilamin i slično u prisutnosti otapala kao što je, primjerice, diklormetan i slično, pri čemu nastaje spoj formule (8) u kojem n i R1 jesu kao što je gore definirano. Spoju formule (8) se može ukloniti zaštitna skupina u prisutnosti kiseline kao što je primjerice trifluoroctena kiselina i slično, u otapalu kao što je primerice diklormetan i slično kod oko sobne temperature pri čemu nastaje spoj Formule Ia. Reakcijom kiselinskog korida Formule Ia s O-benzilnim hidroksilaminom u otapalu kao što je, primjerice, tetrahidrofuran i slično, pri od oko -10 °C do oko 40 °C, nastaje spoj formule Ic u kojem n i R1 jesu kao što je gore definirano. Reakcija spoja Formule Ic s plinovitim vodikom u prisutnosti katalizatora kao što je primjerice paladij na barijevom sulfatu i slično u otapalu kao što je primjerice metanol, tetrahidrofuran i slično, nastaje spoj Formule Id u kojem n i R1 jesu kao što je gore definirano. Reakcija spoja formule (8) sa spojem formule
R-hal
u kojoj R jeste
vodik,
alkil,
hidroksialkil,
alkoksialkil,
trifluormetil,
akanoiloksialkil,
alkanoilaminoalkil,
alkiltioalkil,
alkilsulfinilalkil,
alkiltsulfonilalkil,
aminoalkil,
alkilaminoalkil,
dialkilaminoalkil,
N-alkilpiperazinoalkil,
N-fenilalkilpiperazinoalkil,
morfolinoalkil,
tiomorfolinoalkil,
piperidinoalkil,
pirolidinoalkil,
N-alkilalkilpiperidinoalkil,
piridinilalkil,
tienilalkil,
kinolinilalkil,
tiazolilalkil,
cikloalkil,
cikloalkilalkil,
fenil,
fenil supstituiran jednim do tri supstituenta koji je:
hidroksi,
alkoksi,
alkil,
alkiltio,
alkilsulfinil,
alkilsulfonil,
amino,
alkilamino,
dialkilamino,
halogen,
cijano,
nitro,
trifluormetil ili na susjednom atomu ugljika alkenildioksi skupina s jednim ili dva atoma ugljika, alkenioksi skupina s dva ili tri atoma ugljika, fenilalkil, fenilalkil u kojem je fenil supstituiran s alkil,
alkoksi,
halogen, ili
trifluormetil, heteroaril, heteroaril supstituiran jednim ili dva supstituenta koji je:
alkil, ili
halogen,
bifenil, ili
bifenil supstituiran s alkil,
alkoksi,
halogen,
trifluormetil, ili
cijano,
bifenilalkil ili
bifenilalkil supstituiran s
alkil,
alkoksi,
halogen,
trifluormetil, ili
cijano;
a hal jeste klor, brom ili jod u prisutnosti baze kao što je primjerice DBU i slično u otapalu kao što je primjerice acetonitril i slično, pri čemu nastaje spoj formule (9) u kojoj n, R i R1 jesu kao što je gore definirano. Reakcijom spoja formule (9) s kiselinom primjerice trifluoroctenom kiselinom i slično u prisutnosti otapala kao što je, primjerice, diklormetan nastaje spoj Formule lb u u kojoj n, R i R1 jesu kao što je gore definirano.
Prethodna metodologija se može primijeniti na prirodne u sintetske α-aminokiseline formule (6) i (7), a koje se lako nabavljaju iz komercijalnih izvora ili se mogu pripraviti poznatim metodama. Alternativno se prirodne i sintetske aminokiseline formule (6) i (7) mogu pripraviti kao što je pokazano u Shemi 3. Tako se koristi metoda Evans D. A. et al. J. Am. Chem. Soc., 1982;104:1737-1739, po kojoj se N-Boc-glicin formule (10) kondenzira s kiralniom natrijevom soli benzilnog oksazolidina formule (ii) u prisutnosti sredstva za kondenzaciju kao što je, primjerice carbonildiimidazol i otapalu kao što je primjerice tetrahidrofuran i slično pri oko -10 °C do sobne temperature, pri čemu nastaje spoje formule (12). Enolat formule (12) reagira s litijevim diizopropilamidom a zatim sa sredstvom za alkiliranje formule
R1-hal
gdje hal jest kao što je gore definirano, pri čemu nastaje spoj formule (13) kao smjesa diastereomera. Diastereomeri se odvajaju kromatografijom korištenjem apsorbensa kao što je primjerice silikagel i slično pri čemu se dobiva čisti diastereomer. Čisti diastereomer reagira s plinovitim klorovodikom u otapalu kao što je diklormetan i slično pri sobnoj temperaturi, pri čemu nastaje spoj formule (14) u kojoj je R1 kao što je gore definirano. Reakcija spoja formule (14) sa spojem formule
ArSO2Cl
u kojoj Ar jeste
[image]
u kojoj n jeste nula ili cijeli broj od 1 ili 2;
X je-O-,
-S(O)P gdje p jeste nula ili cijeli broj od 1 ili 2,
-NR2- gdje R2 jeste vodik,
alkil.
acil ili benzil,
-CH2- ili
-CO-;
a n je kao što je gore definirano (pripravljen metodologijom prethodno opisanom za pripravu spoja formule (5) i formule (3)) u prisutnosti baze kao što je, primjerice trietilamin i slično u smjesi otapala kao što je primjerice tetrahidrofuran i voda i slično, pri oko 10 °C do oko sobne temperature nastaje spoj formule (15) u kojoj je R1 kao što je gore definirano. Kiralni oksazolidonski dodatak je uklonjen hidrolizom s bazom kao što je primjerice litijev hidroksid i slično u smjesi otapala kao što je primjerice dioksan/voda pri sobnoj temperaturi i nastaje spoj Formule Ie kojoj je R1 kao što je gore definirano.
Shema 4 pokazuje pripravu spoj Formule If korištenjem metodologije Myers A. et al. Tetraherdon Lett., 1995;36:4555-4558. Tako se enantiomerni pseudo-efedrin glicinamid formule (16) ili njegov enantiomer dodaje u smjesu litijevog klorida i litijevog diizopropilamida u otapalu kao što je primjerice tetrahidrofuran pri oko -78 °C gdje nastaje O,N-dianion koji je zagrijan do oko O °C i dodan je spoj formule
R1-hal
gdje R1 i hal jesu kao što je definirano za spoj formule (17) u kojoj R1 jeste kao što je gore definirano, koji ima visoki stupanj diastereoselektivnosti (>99% de.). Spoj formule (17) reagira sa spojem formule
ArSO2Cl
u kojoj Ar jeste kao što je gore definirano, u prisutnosti baze kao što je, primjerice trietilamin i slično u otapalu kao što je primjerice tetrahidrofuran/voda, pri od oko 10 °C do oko sobne temperature pri čemu nastaje spoj formule (18) u kojoj Ar i R1 jesu kao što je gore definirano. Kiralni oksazolidonski dodatak je uklonjen hidrolizom s bazom kao što je primjerice natrijev hidroksid ili smjesa vode i metanola pri oko temperature refluksiranja, pri čemu nastaje spoj Formule If u kojoj Ar i R1 jesu kao što je gore definirano. Alternativno se hidroliza može izvesti refluksiranjem vodene otopine spoja formule (18) bez dodatka baze.
Spojevi formula R-hal ili R1-hal su komercijalno pristupačni ili se mogu dobiti poznatim metodama.
Shema 1
[image]
Shema 2
[image]
[image]
Spojevi iz ovog izuma se mogu pripraviti i davati u širokom rasponu oralnih i parenteralnih oblika doze. Tako se spojevi mogu davati injekcijom, koja je intravenozna, intramuskularna, intrakutalna, subkutalna, intraduodenalna ili intraperitonalna. Također se spojevi iz ovog izuma mogu davati inhalacijom, primjerice intranasalno. Nadalje, spojevi se mogu davati transdermalno. Bit će očito stručnjacima da slijedeći oblici doze mogu kao aktivnu komponentu spoj Formule l ili odgovarajuću farmaceutski prihvatljivu sol spoja Formule I.
Za preparaciju farmaceutskih pripravaka iz ovog izuma, farmaceutski prihvatljivi nosači mogu biti kruti ili tekući. Čvrsti oblici pripravaka uključuju praške, tablete, pilule, kapsule, vrećice, supozitorije ili disperziven granule. Čvrsti nosač može biti jedna ili više tvari koji također djeluju kao razrjeđivači, sredstva za poboljšanje okusa, veziva, konzervansi, sredstva za dezintegraciju tableta ili sredstva za kapsuliranje.
U prašcima je nosač fino usitnjena krutina koja je u smjesi s fino usitnjenom aktivnom komponentom.
U tabletama, aktivna komponenta je miješana s nosačem koji neophodno ima svojstva veziva, a u pogodnom omjeru, te je prešana u željeni oblik i veličinu.
Prašci i tablete preferirano sadrže od 5 ili 10 do oko 70% aktivne tvari. Pogodni nosači su magnezijev karbonat, magenzijev stearat, talk, šećer, laktoza, pektin, dekstrin, škrob, želatina, tragakant, metilceluloza, natrijeva karboksimetil-celuloza, vosak niskog talište, kako maslac i slično. Termin "priprava" uključuje formulaciju aktivne tvari s tvari za kapsuliranje tako da se dobije kapsula u kojoj je aktivna komponenta s ili bez nosača okružena nosačem, koja je stoga s njim povezana. Slično je uključeno u vrećice i pastile. Tablete, prašci, kapsule pilule, vrećice i pastile se mogu koristiti kao čvrsti oblici doze pogodni za oralno davanje.
Za pripravu supozitorija, prvo se rastali vosak niskog talište kao što je smjesa glicerida masnih kiselina ili kako maslac, te se uz miješanje dodaje aktivna komponenta. Rastaljena homogena smjesa je zatim smješta u kalupe pogodne veličine, te se ostavi da se ohladi pri čemu očvrsne.
Tekući pripravci uključuju otopine, suspenzije i emulzije, primjerice vode ili otopine propilenglikola u vodi i/ili bilo koji dodatak koji se smatra sigurnim. Za parenteralne injekcije tekući pripravak se može formulirati u otopini u vodenoj otopini polietilenglikola.
Vodene otopine pogodne za oralnu upotrebu se mogu pripraviti otapanjem aktivne komponente u vodi i po želji dodavanjem pogodne boje, okusa, stabilizatora i ugušćivača.
Vodene suspenzije pogodne za oralnu upotrebu se mogu pripraviti disperzijom fino usitnjene aktivne komponente u vodi s viskoznim materijalnom, ako što su prirodne i sintetske gume, smole, metilceluloza, natrijeva karboksimetilceluloza, te druga dobro poznata sredstva za suspenziju.
Također su ovdje uključeni čvrsti pripravci koji se kratko prije upotrebe pretvaraju u tekuće pripravke za oralno davanje. Takvi tekući oblici uključuju otopine, suspenzije i emulzije. Ti pripravci uz aktivnu komponentu mogu sadržavati sredstva za obojenje i okus, stabilizatore, pufere, ugušćivače, solubilizatore i slično.
Farmaceutski pripravci su preferirano u jedinici doze. U takvom obliku pripravak je podijeljen u jedinice doze koje sadrže odgovarajuću količinu aktivne komponente. Oblik jedinice doze može biti pakirani pripravaka, pri čemu paket sadrži diskretne količine pripravka, kao što su pakirane tablete, kapsule i prašci u bočicama ili ampulama. Također oblik jedinice doze može biti sama kapsula, tableta, vrećica ili pastila, ili može biti odgovarajući broj svakog od ovih pakiranih oblika doze.
Količina aktivne komponente u jedinici doze pripravka može varirati i podešavati se od 1 mg do 1000 mg, preferirano 10 mg do 100 mg, a ovisno o određenoj primjeni i učinkovitosti aktivne komponente. Pripravak može po želji sadržavati i ostala kompatibilna terapeutska sredstva.
U terapeutske svrhe sredstava za tretman multipla skleroze, rupture aterosklerotičnog plaka, aneurizme aorte, zatajenja srca, restenoze, dilatacija lijevog ventrikula, periodontalne bolesti, ulceracije rožnice, tretman opeklina, ulceracija izazvana dekubitusom, zacijeljenja rane, karcinoma, upale, boli, artritisa, osteoporoze, i ostalih autoimunih ili upalnih poremećaja koji ovise o invaziji tkiva leukocitima ili aktiviranim minirajućim stanicama, akutnih i neurodegenerativnih poremećaja uključujući udar, ozljedu glave, ozljedu kralježnice, Alzheimerovu bolest, amiotrofnu lateralnu sklerozu, cerebralnu amiloidnu aniopatiju, AIDS, Parkinsonovu bolest, Hungtingtonovu bolest, bolesti uzrokovane prionima, miasteniju gravis i Duchenovu mišićnu distrofiju, spojevi koji se koriste u farmaceutskim metodama izuma se daju u početnoj dozi od oko 1 mg do oko 100 mg po kilogramu po danu. Preferirana dnevna doza je u rasponu od oko 25 mg do oko 75 mg po kilogramu. Doze se, međutim, mogu mijenjati ovisno o potrebama pacijenta, ozbiljnosti stanja koji je pod tretmanom i spoj koji se koristi. Određivanje odgovarajuće doze za određenu situaciju je očita stručnjacima. Općenito, tretman se započinje manjom dozom koja je manja od optimalne doze. Zatim se doza povećava pomalo sve do postizanja optimalnog efekta. Zbog pogodnosti, dnevna doza se po želji može podijeliti u obroke.
Sljedeći neograničavajući primjeri ilustriraju preferirane metode izumitelja za pripravu spojeva iz izuma.
PRIMJER 1
Priprava (R)3-metil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačne kiseline
Korak (a) Priprava 6,7,8,9-tetrahidro-dibenzofuran-3-sulfonske kiseline
U otopinu tetrahidrodibenzofurana (4 g, 0.023 mo) u diklormetanu (50 mL) dodan je u jednom obroku sumporni dioksid-DMF kompleks (6 g, 0.039 mol). Reakcijska smjesa je refluksirana 14 sati, ohlađena i uparena u vakuumu. Nastala sirova tekućina je otopljena u vrućem dietil-eter/etanolu, pri čemu se stvara talog. Krutina je odijeljena filtracijom, prana dietil-eterom i sušena u vakuumu, pri čemu nastaje produkt u obliku ružičaste krutine (2.3 g, 40%).
1H NMR (CDCl3) δ 7.9 (s, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 2.8 (m, 2H), 2.6 (m, 2H), 2.0-1.8 (m, 4H)ppm.
Korak (b) Priprava 6,7,8,9-tetrahidro-dibenzofuran-3-sulfonil klorida
6,7,8,9-Tetrahidro-dibenzofuran-3-sulfonska kiselina (2.1 g, 8.3 mmol) je suspendirana u tionil-kloridu (25 mL) i miješana je 6 sati pri sobnoj temperaturi. Otopina je uparena u vakuumu, nastala tekućina je obrađena etilnim acetatom, prana vodom, otopinom soli i sušena iznad magnezijevog sulfata. Otapalo je upareno do suha a sirovi produkt je razmuljen s heksanom i sakupljen filtracijom, pri čemu je dobiven sulfonil-klroid u obliku obojene krutine (1.3 g, 58%). 1H NMR (CDCl3) δ 8.0 (s, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 2.8 (m, 2H), 2.6 (m, 2H), 1.9-1.7 (m, 4H)ppm.
Korak (c) Priprava (R) 3-metil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačne kiseline tert-butil estera
Otopini tert-butil estera (D)-vallina (0.13 g, 0.74 mmol) i trietilamina (0.075 g, 0.74 mmol) u tetrahidrofuran/vodi (5 mL, 1:1) dodan je u jednom obroku 6,7,8,9-tetrahidro-dibenzofuran-3-sulfonil klorid (0.20 g, 0.74 mmol) pri sobnoj temperaturi. Reakcijska smjesa je miješana 14 sati pri sobnoj temperaturi, nakon čega je dodana voden otopina HCl (1M, 5 mL) i eitlni acetat (10 mL). Organska faza je odijeljena i prana otopinom soli, sušena (MgSO4) i uparena do suha pri čemu je dobiven produkt kao bijela krutina (0.24 g, 80%).
1H NMR (CDCl3) δ 7.9 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 5.1 (d, 1H), 3.6 (dd, 1H), 2.8 (m, 2H), 2.6 (m, 2H), 2.0 (m, 1H), 1.9-1.8 (m, 4H), 1.1 (s, 9H), 1.0 (d, 3H) ppm.
Korak (d) Priprava (R) 3-metil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačne kiseline
U otopinu anisola (0.062 g, 0.57 mmol) u trifluoroctenoj kiselini (3 ml_) je dodan tert-butil ester (R) 3-meti-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonil-amino)-maslačne kiseline (0.23 g, 0.56 mmol). Hidroliza estera je završena nakon 4 sata, nakon kojeg vremena je kisela otopina izlivena na led i nastala krutina je sakupljena filtracijom. Kolač od filtriranja je sušen u vakuumu i krutina je prekristalizirana iz heksan/etil-acetat, pri čemu je dobiven prašak krem boje (0.12 g,71%),talište167-169°C.
1H NMR (CDCl3) δ 7.9 (s, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 5.4 (d, 1H), 3.7 (dd, 1H), 2.7 (m, 2H), 2.5 (m, 2H), 2.1 (m, 1H), 1.9-1.7 (m, 4H), 0.9 (d, 3H), 0.8 (d, 3H) ppm.
Na sličan način kao što je opisno u Primjeru 1 pripravljeni su sljedeći spojevi:
PRIMJER 2
(S)3-meti-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina
Talište 162-165 °C.
1H NMR (CDCl3) δ 7.9 (s, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 5.1 (d, 1H), 3.8 (dd, 1H), 2.8 (m, 2H), 2.6 (m, 2H), 2.1 (m, 1H), 2.0-1.8 (m, 4H), 0.9 (d, 3H), 0.8 (d, 3H) ppm.
PRIMJER 3
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-jantarna kiselina
Talište 176-179 °C.
1H NMR (CDCl3/DMSO-d6) δ 7.8 (s, 1H), 7.6 (d, 1H), 7.4 (d, 1H), 5.9 (d, 1H), 3.9 (m, 1H), 2.9-2.5 (m, 7H), 1.9-1.7 (m, 4H) ppm.
Na sličan način kao što je opisno u Primjeru 1, samo zamjenom tert-butilno estera D-valina s metilnim esterom L-homofenilalanina i korištenjem bazne hidrolize esterskog dijela, pripravljeni su sljedeći spojevi:
PRIMJER 4
(S)4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina
Talište 167-169-179 °C.
1H NMR (CDCl3) δ 7.9 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 7.2 (m, 3H), 7.1 (d. 2H), 5.2 (d, 1 H), 4.0 (m, 1H)ppm.
Koristeći postupak iz Primjera 1, pripravljeni su sljedeći spojevi Formule I
PRIMJER 5
(S) fenil-[(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)]-octena kiselina
PRIMJER 6
(S)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina.
PRIMJER 7
(S)2-(2,3-dihidro-1H-8-oksa-ciklopenta[a]inden-6-sulfonilamino)-3-metil-maslačna kiselina.
PRIMJER 8
(S)3-meti-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzofa1azulen-2-sulfonilamino)-maslačna kiselina.
PRIMJER 9
(S)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid.
PRIMJER 10
(S)N-hidroksi-3-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-sukcinamska kiselina.
PRIMJER 11
(R)4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina
PRIMJER 12
(R)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-jantarna kiselina
PRIMJER 13
(R)2-(2,3-dihidro-1H-8-oksa-ciklopentara1inden-6-sulfonilamino)-3-metil-maslačna kiselina
PRIMJER 14
(R)3-meti-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzofa1azulen-2-sulfonilamino)-maslačna kiselina
PRIMJER 15
(S)3-metil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-maslačna kiselina
PRIMJER 16
(S)3-metil-2-(9-metil-6,7,8,9-tetrahidro-5H-karbazol-2-sulfonilamino)-kiselina
PRIMJER 17
(S)4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino-maslačna kiselina
PRIMJER 18
(S)3-metil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-maslačna kiselina
OPĆI POSTUPAK ZA PRIPRAVU HIDROKSAMSKIH KISELINA FORMULE I (Z=NHOH)
Korak (a) Priprava derivata O-benzilhidroksilamina
U otopinu kiselinskog klorida karboksilne kiseline Formule I(Y=OH) u tetrahidrofuranu dodano je dva ekvivalenta O-benzhidroksilamina (kiselinski klorid je pripravljen iz odgovarajuće kiseline i tionil-korida ili oksalil-klorida). Smjesa je miješana 24 sata pri sobnoj temperaturi. Reakcijska smjesa je razrijeđena 1M etilnim acetatom. Slojevi su odijeljeni i sloj etilnog acetat je pran vodom i sušen iznad magnezijevog sulfata. Nakon filtracije, sirovi produkt je razmuljen u heksanu i nastala krutina je sakupljena filtracijom.
Korak (b) Priprava hidroksamske kiseline Formule I (Y=NHOH)
U otopinu produkta iz Koraka (a) u metanol/tetrahidrofuranu je dodan paladij na barijevom sulfatu. Otopina je izvođena u plinovitom vodiku ili pri atmosferskom tlaku pod balonom ili pri 50 funti po kvadratnom inču (psi) u Parrovoj aparaturi. Nakon što je hidriranje završeno, smjesa je filtrirana preko celita i koncentrirana u vakuumu pri čemu je dobiven hidroksamska kiselina.
Koristeći opći postupak za pripravu gore opisanih hidroksamskih kiselina, pripravljene su sljedeće hidroksamske kiseline Formule I.
PRIMJER 19
(S)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid
PRIMJER 20
(S)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid
PRIMJER 21
(S)-N-hidroksi-2-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-acetamid
PRIMJER 22
(R)N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-3-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-propionamid
PRIMJER 23
(R)3-(1,3-diokso-1,3-dihidro-izoindol-2-in-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid
PRIMJER 24
(R)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid
PRIMJER 25
(S)N-hidroksi-3-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid
PRIMJER 26
(S)2-(2,3-dihidro-1H-8-oksa-ciklopenta[a]inden-6-sulfonilamino)-N-hidroksi-3-metil-butiramid
PRIMJER 27
(S)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzo[a]azulen-2-sulfonilamino)-butiramid
PRIMJER 28
(S)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid
PRIMJER 29
(S)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid
PRIMJER 30
(R)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid
PRIMJER 31
(R)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid
PRIMJER 32
(R)N-hidroksi-2-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-acetamid
PRIMJER 33
(R)N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-3-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-propionamid
PRIMJER 34
(R)3-(1,3-diokso-1,3-dihidro-izoindol-2-il)-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid
PRIMJER 35
(R)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid
PRIMJER 36
(R)N-hidroksi-3-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid
PRIMJER 37
(R)2-(2,3-dihidro-1H-8-oksa-ciklopentefa1inden-6-sulfonilamino)-N-hidroksi-3-metil-butiramid
PRIMJER 38
(R)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzofa1azulen-2-sulfonilamino)-butiramid
PRIMJER 39
(R)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid
PRIMJER 40
(R)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid
Claims (31)
1. Spoj formule I
[image]
u kojoj n jeste nula ili cijeli broj od 1 ili 2;
X je-O-, -S(O)P gdje p jeste nula ili cijeli broj od 1 ili 2, -NR2- gdje
R2 jeste vodik, alkil, acil ili benzil,
CH2- ili -CO-;
R je vodik, alkil, hidroksialkil, alkoksialkil, trifluormetil, akanoiloksialkil, alkanoilaminoalkil, alkiltioalkil, alkilsulfinilalkil, alkiltsulfonilalkil, aminoalkil, alkilaminoalkil, dialkilaminoalkil, N-alkilpiperazinoalkil, N-fenilalkilpiperazinoalkil, morfolinoalkil, tiomorfolinoalkil, piperidinoalkil, pirolidinoalkil, N-alkilalkilpiperidinoalkil, piridinilalkil, tienilalkil, kinolinilalkil, tiazolilalkil, cikloalkil, cikloalkilalkil, fenil, fenil supstituiran jednim do tri supstituenta koji je:
hidroksi, alkoksi, alkil, alkiltio, alkilsulfinil, alkilsulfonil, amino, alkilamino, dialkilamino, halogen, cijano, nitro, trifluormetil ili na susjednom atomu ugljika alkenildioksi skupina s jednim ili dva atoma ugljika, alkenioksi skupina s dva ili tri atoma ugljika,
fenilalkil, fenilalkil u kojem je fenil supstituiran s
alkil, alkoksi, halogen, ili trifluormetil,
heteroaril, heteroaril supstituiran jednim ili dva supstituenta koji je:
alkil, ili halogen,
bifenil, bifenil supstituiran s
alkil, alkoksi, halogen, trifluormetil, ili cijano,
bifenilalkil ili bifenilalkil supstituiran s
alkil, alkoksi, halogen, trifluormetil, ili cijano;
D je nula ili cijeli broj od 1 do 3;
L je nula ili cijeli broj od 1 do 3;
R1 je vodik, bočni lanac prirodne aminokiseline ili bočni lanac sintetske aminokiseline;
Y je OR3 gdje R3 jeste vodik, metil, etil, ili benzil, ili NH-OR4 gdje R4 jeste vodik, alkil ili benzil;
i odgovarajući izomeri ili farmaceutski prihvatljiva sol.
2. Spoj prema patentnom zahtjevu 1, naznačeno time da je
[image]
3. Spoj prema patentnom zahtjevu 2, naznačeno time da n jeste nula ili cijeli broj 1, te X je -O-, ili -CH2-.
4. Spoj prema patentnom zahtjevu 3, naznačeno time da n jeste nula ili cijeli broj 1, X je -O-, ili -CH2-, te R jeste vodik.
5. 5 Spoj prema patentnom zahtjevu 4, naznačeno time da n jeste nula ili cijeli broj 1, X je -O-, ili -CH2-, R jeste vodik, te Y jeste OH.
6. Spoj prema patentnom zahtjevu 5, naznačeno time da n jeste nula ili cijeli broj 1, X je -O-, ili -CH2-, R jeste vodik, te Y jeste NHOH.
7. Spoj, naznačeno time da je odabran iz sljedeće skupine:
(S)3-meti-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)N-hidroksi-3-meti-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-jantarna kiselina,
(S)fenil-[(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)]-octena kiselina,
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-3-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-propionska kiselina,
(S)3-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionska kiselina,
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-4-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-maslačna kiselina,
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-5-(3,4>4-trimetil-2,5-diokso-imidazolidin-1-il)-pentanska kiselina,
(S)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(S)4-fenilmetansulfinil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)4-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)5-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(S)6-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina,
(S)7-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina,
(S)8-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina,
(S)-4-fenilsulfamoil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)4-fenilmetansulfonil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)4-benzilsulfanil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)3-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionska kiselina,
(S)4-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(S)5-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(S)6-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina,
(S)7-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina,
(S)8-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina,
(S)2-(2,3-dihidro-1H-8-oksa-ciklopenta[a]inden-6-sulfonilamino)-3-metil-maslačna kiselina,
(S)3-metil-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzo[a]azulen-2-sulfonilamino)-maslačna kiselina,
(S)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)N-hidroksi-3-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-sikcinamska kiselina,
(S)N-hidroksi-2-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-acetamid,
(S)N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-3-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-propionamid,
(S)3-(1,3-diokso-1,3-dihidro-izoindol-2Hl)-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid,
(S)N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-4-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-butiramid,
(S)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-5-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-pentan kiselina hidroksamid,
(S)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(S)N-hidroksi-4-fenilmetansulfinil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)4-(1,3-diokso-1,3-dihidro-izoindol-2-il)-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)5-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(S)6-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-S-sulfonilamino)-heksanska kiselina hidroksamid,
(S)7-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina hidroksamid,
(S)8-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina hidroksamid,
(S)4-benzilsulfanil-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)N-hidroksi-4-fenilsufamoil-2-(6,7,8,9-tetrahidro-dibenzofuran-S-sulfonilamino)-butiramid,
(S)N-hidroksi-4-fenilmetansulfonil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)N-hidroksi-3-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid,
(S)N-hidroksi-4-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(S)5-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(S)6-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina hidroksamid,
(S)7-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina hidroksamid,
(S)8-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina hidroksamid,
(S)2-(2,3-dihidro-1H-8-oksa-ciklopenta[a]inden-6-sulfonilamino)-N-hidroksi-3-metil-butiramid,
(S)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzo[a]azulen-2-sulfonilamino)-butiramid,
(S)3-metil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-maslačna kiselina,
(S)3-metil-2-(9-metil-(6,7,8,9-tetrahidro-5H-karbazol-2-sulfonilamino)-maslačna kiselina,
(S)4-fenil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-maslačna kiselina,
(S)4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-maslačna kiselina,
(S)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid,
(S)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-butiramid,
(S)N-hidroksi-3-metil-2-(9-metil-6,7,8,9-tetrahidro-5H-karbazol-2-sulfonilamino)-butiramid,
(S)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid,
(S)3-metil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-maslačna kiselina,
(S)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid,
(R)3-metil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)N-hidroksi-3-meti-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-jantarna kiselina,
(R)fenil-[(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)]-octena kiselina,
(R)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-3-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-propionska kiselina,
(R)3-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionska kiselina,
(R)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-4-(3,4J4-trimetil-2,5-diokso-imidazolidin-1-il)-maslačna kiselina,
(R)2-(6,7l8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-5-(3,4J4-trimetil-2,5-diokso-imidazolidin-1-il)-pentanska kiselina,
(R)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(R)4-fenilmetansulfinil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)4-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)5-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(R)6-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina,
(R)7-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina,
(R)8-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina,
(R)4-fenilsulfamoil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)4-fenilmetansulfonil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)4-benzilsulfanil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)3-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionska kiselina,
(R)4-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-maslačna kiselina,
(R)5-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina,
(R)6-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina,
(R)7-(1 H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina,
(R)8-(1 H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina,
(R)2-(2,3-dihidro-1H-8-oksa-ciklopenta[a]inden-6-sulfonilamino)-3-metil-maslačna kiselina,
(R)3-metil-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzo[a]azulen-2-sulfonilamino)-maslačna kiselina,
(R)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)N-hidroksi-3-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-sukcinamska kiselina,
(R)N-hidroksi-2-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-acetamid,
(R)N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-3-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-propionamid,
(R)3-(1,3-diokso-1,3-dihidro-izoindol-2-il)-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid,
(R)N-hidroksi-2-(6,718)9-tetrahidro-dibenzofuran-3-sulfonilamino)-4-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-butiramid,
(R)2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-5-(3,4,4-trimetil-2,5-diokso-imidazolidin-1-il)-pentan kiselina hidroksamid,
(R)5-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(R)N-hidroksi-4-fenilmetansulfinil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)4-(1,3-diokso-1,3-dihidro-izoindol-2-il)-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)5-(1,3-diokso-1,3-dihidro-izoindol-2-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(R)6-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-S-sulfonilamino)-heksanska kiselina hidroksamid,
(R)7-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina hidroksamid,
(R)8-fenil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina hidroksamid,
(R)4-benzilsulfanil-N-hidroksi-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)N-hidroksi-4-fenilsufamoil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)N-hidroksi-4-fenilmetansulonil-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)N-hidroksi-3-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-propionamid,
(R)N-hidroksi-4- (1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-butiramid,
(R)5-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-pentanska kiselina hidroksamid,
(R)6-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heksanska kiselina hidroksamid,
(R)7-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-heptanska kiselina hidroksamid,
(R)8-(1H-indol-3-il)-2-(6,7,8,9-tetrahidro-dibenzofuran-3-sulfonilamino)-oktanska kiselina hidroksamid,
(R)2-(2,3-dihidro-1H-8-oksa-ciklopenta[a]inden-6-sulfonilamino)-N-hidroksi-3-metil-butiramid,
(R)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-10-oksa-benzo[a]azulen-2-sulfonilamino)-butiramid,
(R)3-metil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-maslačna kiselina,
(R)3-metil-2-(9-metil-6,7,8,9-tetrahidro-5H-karbazol-2-sulfonilamino)-maslačna kiselina,
(R)4-fenil-2-(6,7,8J9-tetrahidro-dibenzotiofen-3-sulfonilamino)-maslačna kiselina,
(R)4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-maslačna kiselina,
(R)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid,
(R)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-dibenzotiofen-3-sulfonilamino)-butiramid,
(R)N-hidroksi-3-metil-2-(9-metil-67,8,9-tetrahidro-5H-karbazol-2-sulfonilamino)-butiramid,
(R)N-hidroksi-4-fenil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid,
(R)3-metil-2-(6,7,819-tetrahidro-5H-fluoren-2-sulfonilamino)-maslačna kiselina, te
(R)N-hidroksi-3-metil-2-(6,7,8,9-tetrahidro-5H-fluoren-2-sulfonilamino)-butiramid, i odgovarajući izomeri ili odgovarajuće farmaceutski prihvatljive soli.
8. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji inhibira matrične proteinaze u domaćinu.
9. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji inhibira želatinaz u domaćinu.
10. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji inhibira stromelizin u domaćinu.
11. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji inhibira kolagenazu-3 u domaćinu.
12. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za prevenciju rupture aterosklerotičnog plaka u domaćinu koji od toga pati.
13. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji inhibira aneuriznu aorte kod domaćina koji od toga pati.
14. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji inhibira zatajenje srca kod domaćina koji od toga pati.
15. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za prevenciju restenoze kod domaćina koji od toga pati.
16. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za kontrolu periodontalne bolesti kod domaćina koji od toga pati.
17. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman ulceracije rožnice kod domaćina koji od toga pati.
18. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman opeklina kod domaćina koji od toga pati.
19. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman ulceracije od dekubitusa kod domaćina koji od toga pati.
20. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za zacijeljenje rana kod domaćina koji od toga pati.
21. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman karcinoma kod domaćina koji od toga pati.
22. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman artritisa kod domaćina koji od toga pati.
23. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretmanu osteoporoze kod domaćina koji od toga pati.
24. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman autoimunih ili upalnih poremećaja koji ovise o invaziji tkiva leukocitima kod domaćina koji od toga pati.
25. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman multipla skleroze kod domaćina koji od toga pati.
26. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman upale ili boli kod domaćina koji od toga pati.
27. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman akutnih i kroničnih neurodegenerativnih bolesti koje su sljedeće: udar, trauma glave, ozljeda kralježnice, Alzheimerova bolest, amiotrofna lateralna skleroza, cerebralna amiloidna angiopatija, AIDS, Parkinsonova bolest, Huntingtonova bolest, miastenija gravis i Duchennova mišićna distrofija kod domaćina koji od toga pati.
28. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman bubrežne bolesti ili boli kod domaćina koji od toga pati.
29. Upotreba terapijski učinkovite količine spoja prema bilo kojem patentnom zahtjevu od 1 do 7, naznačeno time da je za pripravu farmaceutskog pripravka koji je za tretman dilatacija lijevog ventrikula kod domaćina koji od toga pati.
30. Farmaceutski pripravak, naznačeno time da sadrži spoj prema bilo kojem patentnom zahtjevu od 1 do 7 u smjesi da farmaceutski prihvatljivim ekscipijensom, razrjeđivačem ili nosačem.
31. Metoda priprave spoja formule Ie
[image]
u kojoj n jeste nula ili cijeli broj 1 ili 2, X je-0-,
-S(O)P gdje p jeste nula ili cijeli broj od 1 ili 2,
-NR2- gdje R2 jeste vodik, alkil, acil ili benzil, ili CH2- ili -CO-; R1 je vodik, bočni lanac prirodne aminokiseline ili bočni lanac sintetske aminokiseline, ili odgovarajućeg izomera ili farmaceutski prihvatljive soli, naznačeno time da sadrži djelovanje na spoj formule (15)
[image]
u kojoj je Ph fenil, te n, X i R1 jesu kao što je gore definirano, s bazom u otapalu, pri čemu nastaje spoj Formule Ie, te po želji pretvorbu spoj Formule Ie u odgovarajuću farmaceutski prihvatljivu sol na uobičajeni način, te po želji pretvorbu farmaceutski prihvatljive soli u spoj Formule le na uobičajeni način.
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US9500698P | 1998-07-30 | 1998-07-30 | |
PCT/US1999/012273 WO2000006561A1 (en) | 1998-07-30 | 1999-06-02 | Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases |
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US (2) | US6420408B1 (hr) |
EP (1) | EP1100792B1 (hr) |
JP (1) | JP2002521478A (hr) |
KR (1) | KR20010072089A (hr) |
CN (1) | CN1310716A (hr) |
AP (1) | AP2001002037A0 (hr) |
AT (1) | ATE261954T1 (hr) |
AU (1) | AU758619B2 (hr) |
BG (1) | BG105185A (hr) |
BR (1) | BR9912600A (hr) |
CA (1) | CA2335077A1 (hr) |
DE (1) | DE69915634T2 (hr) |
DK (1) | DK1100792T3 (hr) |
EA (1) | EA200100158A1 (hr) |
EE (1) | EE200100063A (hr) |
ES (1) | ES2216614T3 (hr) |
GE (1) | GEP20033052B (hr) |
HR (1) | HRP20010078A2 (hr) |
HU (1) | HUP0102714A3 (hr) |
ID (1) | ID27192A (hr) |
IL (1) | IL140746A0 (hr) |
IS (1) | IS5810A (hr) |
NO (1) | NO20010479D0 (hr) |
NZ (1) | NZ509439A (hr) |
OA (1) | OA11589A (hr) |
PL (1) | PL345776A1 (hr) |
PT (1) | PT1100792E (hr) |
SK (1) | SK1192001A3 (hr) |
TR (1) | TR200100239T2 (hr) |
WO (1) | WO2000006561A1 (hr) |
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US6846799B1 (en) | 1998-08-18 | 2005-01-25 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
US7354894B2 (en) | 1998-08-18 | 2008-04-08 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
MXPA01013171A (es) * | 2001-02-14 | 2004-05-21 | Warner Lambert Co | Inhibidores triciclicos de sulfonamida de metaloproteinasa de matriz. |
ATE515495T1 (de) * | 2001-08-03 | 2011-07-15 | Schering Corp | Gamma sekretase inhibitoren |
EP1438036A2 (en) * | 2001-10-12 | 2004-07-21 | Eli Lilly And Company | Use of sulfonamide derivatives as pharmaceuticals compounds |
RS51155B (sr) * | 2001-12-20 | 2010-10-31 | Bristol-Myers Squibb Company | DERIVATI α -(N-SULFONAMIDO)ACETAMIDA KAO INHIBITORI β -AMILOIDA |
AU2003237518B8 (en) * | 2002-06-11 | 2009-03-12 | Arqule, Inc. | Substituted phenylsulfonamide inhibitors of beta amyloid production |
CA2495432A1 (en) * | 2002-07-17 | 2004-01-22 | Warner-Lambert Company Llc | Combination of an allosteric carboxylic inhibitor of matrix metalloproteinase-13 with celecoxib or valdecoxib |
US20050095267A1 (en) * | 2002-12-04 | 2005-05-05 | Todd Campbell | Nanoparticle-based controlled release polymer coatings for medical implants |
AU2003300076C1 (en) | 2002-12-30 | 2010-03-04 | Angiotech International Ag | Drug delivery from rapid gelling polymer composition |
US7524938B2 (en) | 2003-04-04 | 2009-04-28 | Yeda Research And Development Co., Ltd. | Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins |
ES2537514T3 (es) | 2003-04-04 | 2015-06-09 | Incyte Corporation | Composiciones, métodos y kits relacionados con la escisión de HER-2 |
WO2005061448A1 (en) * | 2003-12-24 | 2005-07-07 | Monash University | Compositions and methods for treating vascular conditions |
US20060112494A1 (en) * | 2004-12-01 | 2006-06-01 | David Oppong | Method of protecting an animal skin product from metalloproteinase activity |
CA2678304A1 (en) | 2007-02-23 | 2008-08-28 | Yeda Research And Development Co. Ltd. | Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins |
US8012947B2 (en) * | 2007-03-15 | 2011-09-06 | Hospital For Special Surgery | Methods and compositions for promoting wound healing |
US20090285840A1 (en) * | 2008-04-29 | 2009-11-19 | New York Society For The Ruptured And Crippled Maintaining The Hospital For Special Surgery | Methods for treating pathological neovascularization |
CA2676946A1 (en) | 2009-08-28 | 2011-02-28 | Lucie Peduto | Adam12 inhibitors and their use against inflammation-induced fibrosis |
CN103249719A (zh) | 2010-09-24 | 2013-08-14 | 兰贝克赛实验室有限公司 | 基质金属蛋白酶抑制剂 |
WO2017134265A1 (en) | 2016-02-05 | 2017-08-10 | Institut Pasteur | Use of inhibitors of adam12 as adjuvants in tumor therapies |
CN114981251B (zh) * | 2020-01-21 | 2023-11-21 | 深圳信立泰药业股份有限公司 | 一种二苯并呋喃类衍生物组织蛋白酶k抑制剂及其制备方法和医药用途 |
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CH517064A (de) * | 1969-07-09 | 1971-12-31 | Ciba Geigy Ag | Verfahren zur Herstellung von neuen Aryloxy- und Arylthioessigsäurederivaten |
CH531502A (de) * | 1970-03-20 | 1972-12-15 | Ciba Geigy Ag | Verfahren zur Herstellung von neuen Aryloxy- und Arylthioalkansäurealkylestern |
PH31294A (en) * | 1992-02-13 | 1998-07-06 | Thomae Gmbh Dr K | Benzimidazolyl derivatives, pharmaceutical compositions containing these compounds and process for preparing them. |
AU717570B2 (en) | 1995-06-02 | 2000-03-30 | Warner-Lambert Company | Tricyclic inhibitors of matrix metalloproteinases |
US5883940A (en) | 1996-07-01 | 1999-03-16 | Teledynamics Group, Inc. | Interactive method and apparatus for the generation of leads |
JP2000516607A (ja) | 1996-08-16 | 2000-12-12 | ワーナー―ランバート・コンパニー | 酪酸マトリックスメタロプロテイナーゼ阻害剤 |
AU736347B2 (en) * | 1996-09-04 | 2001-07-26 | Warner-Lambert Company | Compounds for and a method of inhibiting matrix metalloproteinases |
AU735013B2 (en) * | 1996-09-04 | 2001-06-28 | Warner-Lambert Company | Matrix metalloproteinase inhibitors and their therapeutic uses |
NZ335028A (en) * | 1996-10-16 | 2000-09-29 | American Cyanamid Co | Ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase (MMP) and TACE (TNF-alpha converting enzyme) inhibitors |
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