SI20268A - Nesteroidni ligandi za estrogenski receptor - Google Patents
Nesteroidni ligandi za estrogenski receptor Download PDFInfo
- Publication number
- SI20268A SI20268A SI9720098A SI9720098A SI20268A SI 20268 A SI20268 A SI 20268A SI 9720098 A SI9720098 A SI 9720098A SI 9720098 A SI9720098 A SI 9720098A SI 20268 A SI20268 A SI 20268A
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- Slovenia
- Prior art keywords
- phenyl
- enyl
- diphenyl
- compound according
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- 239000003446 ligand Substances 0.000 title abstract description 3
- 239000000262 estrogen Substances 0.000 title description 13
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- 239000000126 substance Substances 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 18
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- 125000000304 alkynyl group Chemical group 0.000 claims description 8
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
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Abstract
Novi nesteroidni ligandi za estrogenski receptor, ki imajo od tkiva odvisno estrogensko in antiestrogensko aktivnost, pa tudi metode za njihovo izdelavo in njihova uporaba pri zdravljenju različnih obolenj.ŕ
Description
Ta izum je povezan z novimi nesteroidnimi Ugandi za estrogenski receptor, ki imajo od tkiva odvisno estrogensko in antiestrogensko aktivnost, pa tudi z metodami za njihovo izdelavo in njihovo uporabo pri zdravljenju različnih oboljenj.
Estrogeni predstavljajo pomemben razred steroidnih hormonov, ki pospešujejo razvoj in vzdrževanje osnovnih spolnih lastnosti pri človeku. V preteklosti je bilo ugotovljeno, da so estrogeni uporabni pri zdravljenju določenih bolezenskih stanj in bolezni. Steroidni hormon estradiol, ki ga izloča jajčnik, je na primer uporaben pri zdravljenju osteoporoze, srčno20 žilnih bolezni, premenstrualnega sindroma, vazomotoričnih simptomov povezanih z menopavzo, atrofičnega vaginitisa, Kraurosis vulvae, ženskega hipogonadizma, primarnih motenj v delovanju jajčnika, prekomerne poraščenosti in raka na prostati. Na žalost je jemanje takšnih steroidov povezano z vrsto stranskih učinkov, ki vključujejo miokardni infarkt, trombembolijo, cerebrovaskularna oboljenja in karcinom endometrija.
Izkazalo se je na primer, da je hormonska nadomestna terapija z estrogenom klinično učinkovita pri zdravljenju osteoporoze pri ženskah po menopavzi, pa vendar le 15 % ustreznih žensk trenutno prejema hormonsko nadomestno terapijo, kljub temu da so klinični poizkusi pokazali 50 % zmanjšanje zlomov v kolku in 30 % zmanjšanje pojava srčno-žilnih bolezni. Odklanjanje te terapije izvira iz bolnikovega in io zdravnikovega strahu pred dvakrat večjim tveganjem za rak endometrija, ki so ga opazili pri hormonski nadomestni terapiji s samim estrogenom, pa tudi zaradi povezave med estrogensko terapijo in rakom na dojki. Čeprav tveganje klinično ni bilo dokazano, je bila zaradi domnevnega tveganja za rak na dojki hormonska nadomestna terapija kontraindicirana pri velikem deležu žensk po menopavzi. Vzporedna terapija z progestini dokazano ščiti maternico pred rakom in obenem vzdržuje osteoprotektivne učinke estrogena, vendar pa progestin povzroča druge stranske učinke, na primer krvavitev po prenehanju zdravljenja, bolečine v dojkah in nihanje razpoloženja.
Zaradi težav, povezanih z estrogensko terapijo, je bilo opravljenega veliko raziskovalnega dela, z namenom da bi odkrili učinkovito nesteroidno estrogensko in antiestrogensko spojino. V splošnem lahko takšne spojine označimo kot estrogenske in antiestrogenske hkrati, saj se vse vežejo na estrogenski receptor, pri čemer lahko izzovejo estrogenski ali antiestrogenski učinek, to pa je odvisno od lokacije receptorja. V preteklosti so predpostavljali, da vezavo različnih nesteroidnih estrogenskih in antiestrogenskih spojin na estrogenski receptor omogoča skupna farmakofora (prikazana spodaj na Shemi A), ki se ponavlja v kemijskih struktur teh spojin.
Shema A
Ta farmakofora je kasneje postala strukturno ogrodje, okoli katerega so sestavili nesteroidne estrogenske in antiestrogenske spojine. Njena prisotnost v zgradbi različnih spojin, na primer v heksestroiu, tamoksifenu, kromanu, trifeniletilenu, DES, klomifenu, centkromanu, nafoksidenu, trioksifenu, toremifenu, zindoksifenu, raloksifenu, droloksifenu, DABP, TAT-59 in drugih strukturno podobnih spojinah je postala na tem področju priznana kot molekularni ključ do specifičnosti vezave na estrogenski receptor.
Primer znamenitega nesteroidnega antiestrogena predstavlja tamoksifen (TAM), (Z)-1,2-difenil-1-[4-[2-(dimetilamino)etoksi]fenil]-1buten, ki je derivat trifeniletilena. Tamoksifen učinkovito nasprotuje rast spodbujajočemu učinku estrogena v primarnih tarčnih tkivih, na primer v dojki in jajčniku.
Do sedaj so razvili ta nesteroidni estrogen in strukturno podobno spojino raloksifen za zdravljenje oz. preprečevanje osteoporoze, srčnožilnih bolezni in raka na dojki, pa tudi za zdravljenje oz. preprečevanje vrste drugih oboljenj. Obe spojini sta pokazali osteoprotektiven učinek na kostno mineralno gostoto skupaj s pozitivnim učinkom na raven plazemskega holesterola in močno zmanjšano incidenco raka na dojki in raka na maternici. Na žalost se pri tamoksifenu in raloksifenu nesprejemljivo pogosto pojavljajo življenje ogrožujoči stranski učinki, na primer rak endometrija in hepatocelularni karcinom.
V skladu s tem bi bilo dobro razviti vrsto nesteroidnih spojin, ki bi ohranila ugodne lastnosti, na primer osteoprotektivno delovanje, medtem ko bi zmanjšala nezaželjene stranske učinke na minimum. Čeprav trenutno velja, da je zgoraj omenjeno farmakoforno ogrodje odgovorno za specifičnost vezave na estrogenski receptor, so zdaj odkrili, da je mogoče sestaviti določene nove nesteroidne ligande za vezavo na estrogenski receptor, kot je predstavljeno tukaj, ki vsebujejo določene skupine na takšnih farmakofornih spojinah, s čimer se ugodne lastnosti povečajo na maksimum, na primer osteoprotektivno delovanje, nezaželjene lastnosti pa zmanjšajo na minimum, na primer povečano tveganje za raka.
Slika 1 predstavlja podatke, ki kažejo uterotrofno delovanje spojin tega izuma na mladih podganah.
Slika 2 predstavlja podatke, ki kažejo spremembe v kostni mineralni gostoti v ledveni hrbtenici in tibiji podgan z odstranjenimi jajčniki.
Ta izum obsega rod spojin, kijih predstavlja Formula (I):
pri čemer so R1-R4 naknadno opredeljeni. Del tega izuma so farmacevtski pripravki, ki obsegajo eno ali več spojin Formule (I), pa tudi njihova uporaba, metode za pripravo in intermediati, ki so vključeni v njihovo sintezo.
Ta izum obsega red spojin, kijih predstavlja Formula (I):
pri čemer
R5 R5 je R1 enak -(CH2)nCR5=CR6R7; -(CH2)mC(X)NR8R9; ali —^J-R7 (CH2)p
R2 in R3 sta neodvisno H, -CH3, -OH, -OCH3, -OCH2CH3 ali -CH2(CH3)2,
R4 je -CN, -NO2, -CH3, -CH2CH3, -CH2CH2-Y ali -Y;
R5 in R6 sta neodvisno H, -C^alkil, -C2.4alkenil, -C2.4alkinil, -X-C1.3alkil, -X-C2.4alkenil, -X-C2_4alkinil ali -Y;
R7 je -CN, -C^alkil-OH, -C(O)O(CH3)3, -C(O)NR1°RH, -C(O)NR12R13, CMalkil-NRioRH, -C(O)RH -C(O)OR12, -C(O)NR12OR13, -C(O)NHC(O)R12, -C(O)NHCH2R12, -C(NH2)(NOR12), -S(O)R12, -S(O)(O)(OR12), 5 S(O)(O)(NHCO2R12), PO3R12, -P(O)(NR12R13)(NR12R13),
P(O)(NR12R13)(OR14), -CONR12(CH2)qOCH3, -CONR12(CH2)qNR8R9 ali oksadizol substituiran z metilno skupino.
R8 in R9 sta neodvisno vodik, -C1.7alkil, -C3.7cikloalkil, -O-C^alkil, -Cv 7alkil-Y ali fenil;
R10 in R11 sta neodvisno metil ali etil, ali pa povezana prek dušikovega atoma skupaj tvorita morfolinsko skupino;
R12, R13 in R14 so neodvisno H, -C1.12alkil, -C2.12alkenil, -C2.12alkinil, -OC^^alkil, -O-C2.12alkenil, -O-C2_12alkinil, -C3.7cikloalkil, -C3.7cikloalkenil, linearni ali ciklični heteroalkil, aril, heteroaril ali -Y;
X je kisik ali žveplo;
Y je halogen;
n celo število, izbrano izmed 0, 1, ali 2; m je celo število 1 ali 2; p celo število od 1 do 4; in q je celo število od 1 do 12.
V predstavljenem opisu je izraz alkil, uporabljen samostojno ali v povezavi, opredeljen kot ravna veriga ali razvejana veriga nasičenih ogljikovodikovih skupin od do C7, razen če je predhodno uporabljena kakšna druga oznaka dolžine verige. Izraz nižji alkil je tukaj opredeljen kot C1 do C4, razen če je predhodno uporabljena kakšna druga oznaka dolžine verige. Primeri alkilnih skupin vključujejo metilno, etilno, n-propilno, izopropilno, izobutilno, n-butilno, n-heksilno in podobne skupine.
Izraz haloalkil je tukaj opredeljen kot alkil, substituiran z enim ali večimi halogeni. Izraz cikloalkil po tukajšnji opredelitvi vključuje ciklične ogljikovodikove radikale od C3 do C7. Nekateri primeri cikloalkilnih radikalov vključujejo ciklopropil, ciklobutil in ciklopentil.
Izraz aril, uporabljen samostojno ali v povezavi, je tukaj opredeljen kot monociklična ali policiklična skupina, po možnosti monociklična ali biciklična skupina, t.j. fenil ali naftil, ki je lahko nesubstituirana ali substituirana, na primer z enim ali z večimi, zlasti z enim do tremi substituenti, izbranimi izmed halogena, alkilne, hidroksilne, alkoksilne, haloalkilne, nitro, amino, acilamino, alkiltio, alkilsulfinilne in alkilsulfonilne skupine. Nekateri primeri arilnih skupin vključujejo fenilno, 2-klorofenilno, 3-klorofenilno, 4-klorofenilno, 2-metilfenilno, 4-metoksifenilno, 320 trifluorometilfenilno, 4-nitrofenilno in podobne skupine.
Izraz heteroaril je tukaj opredeljen kot 5-členska ali 6-členska heterociklična aromatska skupina, ki lahko nosi pripojen benzenski obroč in je lahko nesubstituirana ali substituirana, na primer z enim ali z večimi, zlasti z enim do tremi substituenti, izbranimi izmed halogena, alkilne, hidroksilne, alkoksilne, haloalkilne, nitro, amino, acilamino, alkilsulfinilne in alkilsulfonilne skupine.
Izraz halogen po tukajšnji opredelitvi vključuje fluor, klor, brom in jod.
Izraza linearni in ciklični heteroalkil sta opredeljena v skladu z izrazom alkil, z ustrezno nadomestitvijo ogljikovih atomov s kakšnim drugim atomom, ki tvori kemično stabilno spojino, na primer z dušikom, ali žveplom.
Poleg tega so zgoraj omenjene funkcionalne skupine podane tako, da določene atome ali skupine obdajajo oklepaji ( ), kjer je zaželjeno razjasniti strukturo ali način vezave. Zlasti en sam atom, na primer O, ali skupina atomov, na primer NH2, je v okviru formul ene od zgoraj podanih funkcionalnih skupin predstavljena v oklepajih [glej na primer, ko je R7 je .... -C(O)R12, -C(O)OR12, -C(O)NR12OR13, -C(NH2)(NOR12), itd. j. V takšnem primeru naj bi oklepaji ilustrirali, da je z njimi obdani atom ali skupina atomov vezana na najbližji predhodni kemično ustrezni atom, ki ni obdan z oklepaji.
Skupina -C(O)R12, naj bi na primer predstavljala funkcionalno skupino, kjer je kisik vezan na ogljik, najbližji predhodni atom, ki ni obdan z oklepaji in je kemično ustrezen glede na klasično teorijo vezave elektronskih orbital. Podobno naj bi -C(NH2)(NOR12) predstavljala funkcionalno skupino, kjer je dušik pri obeh skupinah NH2 in NOR12 vezan na ogljik, najbližji predhodni atom, ki ni obdan z oklepaji. Ta dva primera sta prikazana v (a) in (b) spodaj. Poznavalci tega področja bodo lahko ugotovili, da so ustrezni načini vezave (npr. enojna, dvojna, itd.) jasno izhajajo iz pravil tvorbe orbitalnih vezi.
-C-R12 -C-NOR12
H II o nh2 (a) (b)
Poleg tega so nekatere zgoraj omenjene funkcionalne skupine podane 10 tako, da določene atome ali skupine obdajajo oklepaji ( ), pri čemer oklepajem neposredno sledi črkovni ali številčni indeks [glej na primer, ko je R7 je .... -CONR12(CH2)qOCH3]. V takšnem primeru naj bi se z oklepaji obdani atom ali skupina atomov pojavila v funkcionalni skupini kot večkratnik indeksa. Na primer, če je q = 2 ko je R7 enak 15 CONR12(CH2)qOCH3, potem je R7 = -CONR12CH2CH2OCH3.
Poznavalci tega področja bodo lahko ugotovili, da v spojinah Formule (I) obstajajo stereocentri. V skladu s tem ta izum vključuje vse možne stereoizomere in geometrične izomere Formule (I) in vključuje ne samo racematne spojine, temveč tudi optično aktivne izomere. Kadar želimo dobiti spojino Formule (I) kot en sam enantiomer, to lahko dobimo z razkrojem končnega produkta ali s stereospecifično sintezo iz bodisi izomerno čiste začetne snovi ali iz kateregakoli ustreznega intermediata. Razkrojni ostanek končnega produkta, intermediat ali začetna snov se lahko obdelujejo s katerokoli ustrezno medoto, poznano na tem področju. Glej na primer Stereochemistrv of Carbon Compounds avtorja E. L. Eliel (Mcgraw Hill, 1962) in Tables of Resolving Agents avtorja S. H. VVilen. Poleg tega v primerih, ko so možni tavtomeri spojin Formule (I), ta izum vključuje vse tavtomerne oblike spojin.
Spodaj so naštete nekatere specifične spojine Formule (I), ki so bile sintetizirane v skladu s spodaj predstavljenim Poglavjem s primeri io Številka spojine
1. 3-(4-(1,2-difenil-but-1 -enil)-fenil]-N,N-dietil akrilamid
2. 3-(4-(1,2-difenil-but-1 -enil)-fenil]-N,N-dietil propionamid
3. 2-[4-(1,2-difenil-but-1-enil)-fenil] ciklopropankarboksilna kislina dietilamid
4. 3-(4-(1,2-difenil-but-1 -enil)-fenil]-N,N-dietil-2-metil-akrilamid
5. 3-[4-(1,2-difenil-but-1 -enil)-fenil]-but-2-enojska kislina dietilamid
6. 3-[4-(1,2-difenil-but-1 -enil)-fenil]-akrilna kislina metil ester
7. 3-(4-(1,2-d ifen i l-but-1 -en i l)-fe n i l]-akri Ion itri I
8. 3-[4-( 1,2-difenil-but-1 -enil)-fenil]-akrilna kislina tert-butil ester
9 . 3-[4-(1,2-difenil-but-1-enil)-fenil]-akrilna kislina
10. 3-(4-(1,2-d ifen i l-b ut-1 -en i l)-fen i I]-1 -morfolin-4-il-prop-2-en-1 -on
11. 3-(4-(1,2-difenil-but-1 -enil)-fenilj-N-(3-metoksi-propil)-akrilamid
12. N,N-dicikloheksil-3-[4-(1,2-difenil-but-1-enil)-fenil] akrilamid
13. N-(2-dimetilamino-etil)-3-[4-( 1,2-difenil-but-1 -enil)-fenil]-N-etil akrilamid
14. 3-(4-(1,2-difenil-but-1-enil)-fenil]-N-metil-N-oktil akrilamid
15. 3-(4-(1,2-difenil-but-1 -enil)-fenil] akrilamid
16. 3-[4-(1,2-difenil-but-1-enil)-fenil]-N-etil akrilamid
17.1 -amino-3-[4-(1,2-difenil-but-1 -enil)-fenil]-prop-2-en-1 -on oksim
18. 3-{2-[4-( 1,2-d ifen il-but-1 -en i l)-fen il]-vi n i l}-5-metil-[ 1,2,4]-oksadizol
19. 3-(4-(1,2-difenil-but-1 -enil)-fenil]-prop-2-en-1 -ol
20. {3-(4-(1,2-difenil-but-1 -enil)-fenil]-alil}-dimetilamin io 21. 3-(4-(1,2-difenil-but-1-enil)-fenil]-N,N-dietil tioakrilamid
22. 3-(4-(1,2-d ifen il-b ut-1 -en il)-fen i l]-N-(3-h id roksi-prop il)-akrilam id
V splošnem se spojine Formule (I) lahko pripravijo v skladu z naslednjimi sintetskimi postopki. Na tem področju je dobro znano, da se morajo pri vseh spodaj opisanih postopkih v skladu s splošnimi načeli kemije uporabiti zaščitne skupine, kadar je to potrebno. Te zaščitne skupine se odstranijo v zaključnih stopnjah sinteze v bazičnih, kislih ali hidrogenolitičnih pogojih, kar bo poznavalcem tega področja razumljivo. Z ustreznim ravnanjem in zaščito katerekoli kemijske lastnosti se lahko sintetizira katerakoli spojina Formule (I), ki tu ni specifično navedena, z uporabo metode, analogne tisti na spodaj predstavljenih Shemah B-G, pa tudi z metodami, predstavljenimi v Poglavju s primeri.
V splošnem je sinteza, uporabljena za nastanek spojin tega izuma, zastavljena tako, da omogoča dostop do analogov B-obroča z Ekonfiguracijo središčne tetra-substituirane dvojne vezi. Ena metoda za pripravo spojin Formule (I) vključuje spodaj predstavljeno Shemo B, pri čemer je ustrezni bromid, na primer bromid (b) [npr. (E)-1-bromo-2-fenil-1(trimetilsilil)-l -buten], sintetiziran v večgramskih količinah iz acetilena (a) z uporabo metode po Millerju (glej Miller, R.B.; Al-Hassan, M.l. Stereospecific Synthesis of (Z)-Tamoxifen via Carbometalation of Alkynylsilanes. J. Org. Chem. 1985, 50, 2121-2123). Bromid (b) se v io prisotnosti paladijevih katalizatorjev spoji z ustrezno arilno borovo kislino, na primer (c), s čimer nastane željeni aldehid (d) [npr. (Z)-1,2-difenil-1 -(4formilfenil)-1-buten], kot en sam izomer. Bromid (b) in aldehid (d) sta različna intermediata v sintezi analogov tamoksifena z B-obročem.
is Shema B
Kot je prikazano spodaj na Shemi C, s spojitvijo bromida (b) in arilne borove kisline (e) nastane a,b-nenasičen dietil amid (g), ki je naveden zgoraj kot Spojina št. 1 in je predstavljen spodaj v Primeru 2. Treba je poudariti, da s sintezo dietil amida po takšni poti zelo verjetno dobimo malo produkta, najbrž zaradi termične nestabilnosti arilne borove kisline (e). Poleg tega je bilo med razvijanjem spojin tega izuma ugotovljeno, da identifikacija dietil amida (g) kot iskane spojine (t.j. Spojina št. 1; 3-[4-(1,2difenil-but-1 -enil)-fenil]-N,N-dietil akrilamid) narekuje bolj učinkovito sintezo za pripravo analogov. V skladu s tem je bilo ugotovljeno, da pri io Horner-Emmonsovi reakciji aldehida (d) s fosfonatom (f) nastane dietil amid (g) v znatno večji količini.
Shema C Et2O3p\/CONEt2
g (spojina #1) h (spojina #21)
Stopnja IV
Poleg tega zgoraj predstavljena Shema C prikazuje, da se a,b20 nenasičeni dietil amid (g) lahko pretvori v:
(a), tioamid (h), [Spojina št. 21: 3-[4-(1,2-difenil-but-1-enil)-fenil]-N,Ndietil tioakrilamidj z Lawessonovim reagentom;
(b) . nasičeni amid (i), [Spojina št. 2: 3-[4-(1,2-difenil-but-l-enil)-fenil]Ν,Ν-dietil propionamid] s hidrogenacijo; ali v (c) , ciklopropil amid (j), [Spojina št. 3: 2-[4-(1,2-difenil-but-l-enil)-fenil] ciklopropankarboksilna kislina dietilamid] s Coreyevim ilidom.
Po spodaj predstavljeni Shemi D se analogi dietil amida (g), ki vključujejo tri-substituirano a,b-nenasičeno dvojno vez, lahko sintetizirajo iz ustreznega aldehida, na primer iz (d), ali iz ustreznega ketona, na primer iz (n). Za nastanek a-metil amida (I) [Spojina št. 4: 3-[4-(1,2-difenilbut-l -enil)-fenil]-N,N-dietil-2-metil-akrilamid] kot enega samega izomera io se lahko uporabi zlasti Horner-Emmonsova reakcija metil fosfonata (k) z aldehidom (d), reakcija fosfonata (f) s ketonom (n) pa se lahko uporabi za nastanek zmesi E in Z-b-metil amidov (o, p) [Spojina št. 5: 3-[4-(1,2-difenilbut-l -enil)-fenil]-but-2-enojska kislina dietilamid — (Z) in (E) izomera], ki ju lahko ločimo s kromatografijo, pri čemer njuno relativno stereokemično zgradbo določimo z nadaljno 1H NMR NOE preiskavo.
Shema D
I (spojina #4) (b) +
(HO)2B
Stopnja lil
Po spodaj predstavljeni Shemi E karboksilna kislina (r) [Spojina št. 9: 3[4-(1,2-difenil-but-1-enil)-fenil]-akrilna kislina] lahko nastane s saponifikacijo metil estra (q) [Spojina št. 6: 3-[4-(1,2-difenil-but-1 -enil)fenil]-akrilna kislina metil ester], slednji pa se lahko sintetizira s kondenzacijo aldehida (d) s trimetil fosfonoacetatom, kot je prikazano na Shemi D. Poleg tega Shema E prikazuje, kako se karboksilna kislina (r) po spojitvi z vrsto linearnih in cikličnih alkilnih in heteroalkilnih aminov lahko uporabi kot ključni intermediat za sintezo različnih vrst a,b-nenasičenih amidov.
ΙΟ
Shema E
q (spojina #6)
Ι5 r (spojina #9)
Po spodaj predstavljeni Shemi F se oksadiazol (v) [Spojina št. 18: 3-{2[4-(1,2-d ifen i l-but-1 -enil)-feni l]-vin il}-5-metil-[ 1,2,4]-oksad izol] lahko sintetizira iz nitrila (t) [Spojina št. 7: 3-[4-(1,2-difenil-but-1 -enil)-fenil]akrilonitril] z reakcijo s hidroksilaminom, pri čemer nastane amid oksim (u) [Spojina št. 18: 3-{2-[4-(1,2-difenil-but-1 -enil)-fenil]-vinil}-5-metil-[1,2,4]oksadizolj, čemur sledi ciklizacija z ocetnim anhidridom.
Shema F
Stopnja il
Me
u (spojina #17) v (spojina #18)
Po spodaj predstavljeni Shemo G se alkohol (x) [Spojina št. 19: 3-[4(1,2-difenil-but-1 -enil)-fenil]-prop-2-en-1-olj in dimetil amin (y) [Spojina št. 20: {3-(4-(1,2-difenil-but-1-enil)-fenil]-alil}-dimetilamin] lahko sintetizirata iz t-butil estra (w) [Spojina št. 8: 3-(4-(1,2-difenil-but-1-enil)-fenil]-akrilna kislina tert-butil ester] s hidridno redukcijo, ki ji sledi mezilacija in alkilacija z dimetil aminom.
Shema G
Stopnja II
x (spojina #19)
SPLOŠNI POSTOPKI y (spojina #20)
Vse začetne snovi so bile pridobljene pri komercialnih dobaviteljih in 20 uporabljene brez nadaljnega prečiščenja, razen v primerih, kjer je navedeno drugače. Vrednosti tališč so bile ugotovljene s kapilarnimi cevkami na napravi Mel-Temp in so nekorigirane. Spektra 1H NMR in 13C NMR sta bila ugotovljena s spektrometroma Varian Unity-300 in Varian
XRL-300 s TMS in internim standardom v CDCI3. Kemijski premiki so navedeni v ppm (s); multiplicitete so označene s s(singlet), d(duplet), t(triplet), q(kvadriplet), m(multiplet), br(razširjena). Konstante spajanja (J) so navedene v Hz. Mikroanalize so bile opravljene v Atlantic Microlabs,
Inc. in vse vrednosti so odstopale od teoretičnih vrednosti za manj kot ±0,4 %. Masni spektri so bili posneti z JEOL JMS-AX505HA masnim spektrometrom z ionizacijo prek bombardiranja hitrih atomov. Infrardeči spektri so bili posneti s Perkin-Elmer 1280 infrardečim spektrometrom. Analitična tankoplastna kromatografija je bila opravljena s EM Science io silikat 60 F254 s steklom prevlečenimi ploščami, vizualizacija pa je bila dosežena z UV svetlobo, jodom, ali amonijevim molibdatom. Kromatografija je bila opravljena z EM Science 230-400 mrežico in silikagelom. MPLC je bil opravljen s Pharmacia LKB Series sistemom skupaj z Rainin Dynamax UV-C detektorjem in Merck Lobar Si60 (40-63 mm) stolpcem siiikagela. HPLC je bil opravljen s Shimadzu LC-6A Series HPLC skupaj z bodisi Rainin Dynamax C18 RP stolpcem ali z Rainin Dynamax Siliča stolpcem. Vsa topila so bila na reagenčni ravni in so bila uporabljena brez nadaljnega prešiščenja. (£)-1-bromo-2-fenil-1(trimetilsilil)-l-buten [glej (b), Shema B, zgoraj] je bil pripravljen z metodo po Millerju, kot je navedeno zgoraj, 4-formilborova kislina pa je bila pripravljena z metodo po Nothu (glej Feulner, H.; Linti, G.; Noth, H. Preparation and Structural Characterization of p-Formylbenzeneboronic Acid. Chem. Ber. 1990, 123, 1841-1843). Borovi kislini [glej (e) oz. (m) na
Shemi C oz. D] sta bili pripravljeni v Glaxo Group research Ltd., Hertfordshire, UK iz 3-(4-bromofenil)-N,N-dietilakrilamida oziroma iz 4bromoacetofenona z metodo po Gilmanu (glej Gilman, H.; Santucci, L.; Swayampati, D. R.; Ranck, R. O. Hydroxybenzeneboronic Acids and
Anhydrides. J. Am. Chem. Soc. 1957, 79 3077-3082).
PRIMERI
Naslednje spojine so bile pripravljene v skladu z zgoraj predstavljenimi splošnimi sintetskimi postopki in so tukaj opisane za boljšo predstavo, io kako se izdela različne spojine tega izuma. Naslednji Primeri so ilustrativni in ne omejujejo obsega tega izuma.
Primer 1 (Z)-1,2-difenil-1 -(4-formilfenil)-1 -buten
Raztopino 1,0 g (3,5 mmol) (£)-1-bromo-2-fenil-1-(trimetilsilil)-1-butena, 625 mg (4,2 mmol, 1,2 Eq) borove kisline [glej (c), Shema Β] in 400 mg (0,35 mmol, 0,1 Eq) Pd(PPh3)4 v 10 ml DME smo obdelali z 2ml 2N Na2CO3, potem smo jo 6 ur segrevali pri temperaturi vrelišča ob uporabi povratnega hladilnika. Raztopina je bila ohlajena na sobno temperaturo, nato smo jo vlili v NaHCO3 (40 ml), ekstrahirali z etil acetatom (2 x 40 ml), posušili (MgSO4), topilo je bilo odstranjeno in vacuo. Po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eluenta heksana / etil acetata 20 / 1 smo dobili 700 mg (69 %) zgoraj omenjene željene spojine v obliki rumene trdne snovi: 1H NMR (CDCI3, 300 MHz) s 9,82 (s, 1 H), 7,55-7,00 (m, 14 H), 2,48 (q, 2 H), 0,97 (t, 3 H); MS z nizko resolucijo m/e 313 (MH+). [glej na primer (d), Shema B, zgoraj].
Primer 2
3-[4-(1,2-difenil-but-1-enil)-fenil1-N,N-dietil akrilamid
Postopek A Raztopina 51 mg (0,18 mmol, 1,1 Eq) (E)-1-bromo-2-fenil1-(trimetilsilil)-l-buten, 40 mg (0,16 mmol) arilne borove kisline [glej (e), Shema C], in 20 mg (16,2 mmol, 0,1 Eq) Pd(PPh3)4 v 5ml DME smo io obdelali z 0,5 ml 2N Na2CO3, potem pa smo jo 2 uri segrevali pri temperaturi vrelišča ob uporabi povratnega hladilnika. Raztopina je bila ohlajena na sobno temperaturo, nato prelita v NaHCO3 (20 ml), ekstrahirana z etil acetatom (2 x 20 ml), posušena (MgSO4), topilo je bilo odstranjeno in vacuo. Po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eluenta heksana / etil acetata 3 /1 smo dobili 10 mg (15 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 138-140°C; 1H NMR (CDCI3 , 300 MHz) s 7,53 (d, 1 H, J = 15,4), 7,38-7,11 (m, 12 H), 6,86 (d, 2 H, J = 8,3), 6,66 (d, 1 H, J = 15,4), 3,40 (m, 4 H), 2,47 (q, 2 H, J = 7,3), 1,19 (m, 6 H), 0,93 (t, 3 H, J = 7,3); MS z visoko resolucijo izračunano 410,2483, izmerjeno 410,2484.
Postopek B Z uporabo dietil dietilkarbamoilmetilenfosfonata [glej (f), Shema C], kot je opisano v splošnem postopku za spajanje po Horner24
Emmonsu (glej Primer 7, spodaj), z aldehidom, (Z)-1,2-difenil-1-(4formilfenil)-1-butenom, po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo gradienta heksana / etil acetata 20 /1 do 2 / 1 smo dobili 110 mg (42 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 137-138°C; 1H NMR (CDCI3,300 MHz) s 7,53 (d, 1 H, J = 15,4), 7,36-7,11 (m, 12 H), 6,86 (d, 2 H, J = 8,3), 6,66 (d, 1 H, J = 15,4), 3,42 (m, 4 H), 2,47 (q, 2 H, J = 7,3), 1,19 (m, 6 H), 0,93 (t, 3 H, J = 7,3); Anal. (C29H31NO) C, H, N. [glej na primer (g), Shema C, zgoraj].
io Primer 3
3-[4-(1,2-difenil-but-1-enil)-fenil|-N,N-dietil tioakrilamid
Zmes 65 mg (0,16 mmol) 3-[4-(1,2-difenil-but-1-enil)fenil]-N,N-dietil akrilamida (glej Primer 2) in 39 mg (95,2 mmol, 0,6 Eq) Lavvessonovega reagenta je bila segrevana v 2ml suhega toluena pri 85°C 2 uri. Raztopina je bila ohlajena na sobno temperaturo in neposredno položena na kromatografski stolpec s silikagelom. Po prečiščenju s heksanom / etil acetatom 10/1 smo dobili 54 mg (83 %) tioamida zgoraj omenjene zaželjene spojine v obliki rumerne pene: m.p. 43-61°C; 1H NMR (CDCI3 , 300 MHz) s 7,85 (d, 0,5 H), 7,75 (d, 0,5 H), 7,65 (d, 0,5 H), 7,40-6,80 (m,
13,5 H), 4,05 (m, 2 H), 3,70 (m, 2 H), 2,45 (m, 2 H), 1,30 (m, 6 H), 0,95 (m, 3 H); 13C NMR (CDCI3 , 75 MHz) s 193,83, 144,56, 143,96, 143,18, 143,11, 141,92, 138,26, 133,00, 131,22, 130,83, 129,66, 128,28, 128,01, 127,91, 127,86, 127,70, 127,48, 127,02, 126,83, 126,45, 124,04, 48,45,
46,40, 29,19, 13,86, 13,67, 13,62, 11,66; IR (CHCI3) 3050, 1520, 1210, 950, 750; Anal. (C29H31NS) C, H, N. [glej na primer (h), Shema C, zgoraj].
Primer 4
3-[4-(1,2-difenil-but-1-enil)-fenilj-N,N-dietil propionamid
Raztopino 50 mg (0,12 mmol) 3-(4-(1,2-difenil-but-1-enil)-fenil]-N,Ndietil akrilamida (glej Primer 2) in 3 mg tris(trifenilfosfin)-rodijevega(l) klorida (VVilkinsonov katalizator) v 1 ml suhega toluena smo mešali pod atmosfero plina H2 pri 50°C 16 ur. Raztopina je bila ohlajena na sobno io temperaturo, toluen pa je bil odstranjen in vacuo. Po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eluenta heksana / etil acetata 2 / 1 smo dobili 48 mg (95 %) zgoraj omenjene željene spojine v obliki bistrega brezbarvnega olja: 1H NMR (CDCI3 , 300
MHz) s 7,37-7,11 (m, 10 H), 6,85 (d, 2 H, J = 8,3), 6,78 (d, 2 H, J = 8,3), 15 3,31 (q, 2 H, J = 7,1), 3,08 (q, 2 H, J = 7,3), 2,81 (t, 2 H, J = 8,3), 2,44 (m,
H), 1,03 (m, 6 H), 0,91 (t, 3 H, J = 7,3); MS z nizko resolucijo m / e 412 (MH+); Anal. (C29H33NO) C, H, N. [glej na primer (i), Shema C, zgoraj].
Primer 5
2-[4-(1,2-difenil-but-1-enil)-fenil1 ciklopropankarboksilna kislina dietilamid
Raztopino 12 mg (0,24 mmol, 2,0 Eq) natrijevega hidrida (50 % v olju) in 54 mg (0,24 mmol, 2,0 Eq) trimetiloksosulfonijevega jodida v 2 ml suhega dimetil sulfoksida smo mešali 30 minut pri sobni temperaturi, v tem času je plin prenehal izhajati. Nato smo dodali raztopino 50 mg (0,12 mmol) amida, pripravljenega v Primeru 2, in 0,5 ml dimetil sulfoksida, nastalo raztopino smo segrevali pri 50°C 16 ur. Reakcijska zmes je bila ohlajena na sobno temperaturo, prelita v 20 ml H2O in ekstrahirana z etil acetatom (2 x 20 ml). Organski plasti smo zmešali, posušili (MgSO4), topilo je bilo odstranjeno in vacuo. Po prečiščenju ostanka z MPLC s silikagelom z uporabo eluenta heksana / etil acetata 4 / 1 smo dobili 32 mg (62 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. io 42-44°C; 1H NMR (CDCI3,300 MHz) s 7,37-7,10 (m, 10 H), 6,76 (m, 4 H), 3,38 (q, 4 H, J = 7,1), 2,45 (q, 2 H, J = 7,4), 2,30 (m, 1 H), 1,79 (m, 1 H), 1,55 (m, 1 H), 1,11 (m, 7 H), 0,92 (t, 3 H, J = 7,4); MS z nizko resolucijo m / e 424 (MH+); Anal. (C30H33NO) C, H, N. [glej na primer (j), Shema C, zgoraj].
Primer 6 (Metil) dietil dietilkarbamoilmetilenfosfonat
Raztopina 4,4 ml (2,2 mmol, 1,1 Eq) KN(TMS)2 (0,5 M v toluenu) je bila dodana hladni (-78°C) raztopini 500 mg (2,0 mmol) dietil dietilkarbamoilmetilenfosfonata v 5 ml suhega THF. Nastalo raztopino smo mešali 10 minut, nato smo previdno dodali 0,15 ml (2,4 mmol, 1,2 Eq) metil jodida. Nastala raztopina se je segrela na sobno temperaturo, mešali smo jo 1 uro, nato je bila prelita v slano vodo (70 ml) in ekstrahirana z etil acetatom (2 x 60 ml). Organski plasti smo zmešali, posušili (MgSO4), topilo je bilo odstranjeno in vacuo. Po prečiščenju rumenega ostanka s Kugelrohrjevo destilacijo smo dobili 525 mg (100 %) zgoraj omenjene željene spojine v obliki bistrega brezbarvnega olja: b.p.
155°C pri 0,15 torr; 1H NMR (CDCI3,300 MHz) s 4,18 (m, 4 H), 3,60 (m, 1
H), 3,22 (m, 4 H), 1,37 (m, 9 H), 1,18 (m, 6 H), [glej na primer (k), Shema C, zgoraj].
Primer 1 io Splošni postopek za Horner-Emmonsovo reakcijo z (Z)-1,2-difenil-1-(4formilfenil)-1 -butenom Raztopina 1,2 Eq KN(TMS)2 (0,5 M v toluenu) je bila dodana raztopini 0°C 1,2 Eq ustreznega fosfonata v suhem THF, ki smo jo medtem mešali. Nastalo raztopino smo mešali 15 minut pri 0°C, jo nato ohladili na -78°C in po kapljicah dodali raztopino (Z)-1,2-difeni 1-1-(415 formilfenil)-1-butena v THF. Nastala raztopina se je segrela na sobno temperaturo, pri čemer smo jo mešali 4 ure, nato smo jo segreli na 50°C za 2 uri, da smo zagotovili potek reakcije do konca. Reakcijska zmes je bila ohlajena na sobno temperaturo, prelita v slano vodo in dvakrat ekstrahirana z etil acetatom. Organski plasti smo zmešali, posušili (MgSO4), topilo je bilo odstranjeno in vacuo, ostanek pa je bil prečiščen s hitro silikagelno kromatografijo pod povišanim tlakom.
Primer 8
3-[4-(1,2-difenil-but-1-enil)-fenil1-N,N-dietil-2-metil-akrilamid
Z uporabo (metil) dietil dietilkarbamoilmetilenfosfonata na enak način kot zgoraj in po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eluenta heksana / etil acetata 3 /1 smo dobili 36 mg (53 %) zgoraj omenjene željene spojine v obliki bistrega brezbarvnega olja: 1H NMR (CDCI3,300 MHz) s 7,39-7,11 (m, 10 H), 6,97 (d, 2 H, J = 8,0), 6,85 (d, 2 H, J = 8,3), 6,32 (s, 1 H), 3,38 (m, 4 H), 2,47 (q, 2 H, J = 7,3), 2,00 (s, 3 H), 1,14 (t, 6 H, J = 7,1), 0,93 (t, 3 H, J = 7,3); io MS z nizko resolucijo m/e 424; Anal. (C30H33NO) C, H, N. [glej na primer (I), Shema D, zgoraj].
Primer 9 (Z)- in (E)-3[4-(1,2-difenil-but-1-enil)-fenil1-but-2-enojska kislina dietilamid
Z uporabo dietil dietilkarbamoilmetilenfosfonata na enak način kot zgoraj in po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eluenta heksana / etil acetata 5 / 2 smo dobili 95 mg (49
%) (Z)-izomera zgoraj omenjene željene spojine v obliki bele trdne snovi in mg (6 %) (E)-izomera v obliki brezbarvnega olja. Analitični podatki za (Z)-izomer: m.p. 109-111°C; 1H NMR (CDCI3 , 300 MHz) s 7,39-7,09 (m,
H), 6,85 (d, 2 H, J = 8,3), 6,20 (d, 1 H, J = 1,0), 3,44 (q, 2 H, J = 7,1),
3,33 (q, 2 H, J = 7,1), 2,47 (q, 2 H, J = 7,5), 2,16 (d, 3 H, J = 1,0), 1,13 (m, 6 H), 0,93 (t, 3 H, J = 7,6); MS z nizko resolucijo m/e 424; Anal. (C30H33NO) C, H, N. Analitični podatki za (E)-izomer: 1H NMR (CDCI3,300 MHz) s 7,36-7,09 (m, 10 H), 7,00 (d, 2 H, J = 8,3), 6,81 (d, 2 H, J = 8,2),
5,80 (d, 1 H, J = 1,0), 3,22 (q, 2 H, J = 7,2), 2,91 (q, 2 H, J = 7,1), 2,45 (q,
H, J = 7,6), 2,04 (d, 3 H, J = 1,0), 0,89 (m, 6 H), 0,74 (t, 3 H, J = 7,6); MS z nizko resolucijo m/e 424. [glej na primer (o, p), Shema D, zgoraj].
Primer 10 io 3-f4-(1,2-difenil-but-1-enil)-fenin-akrilna kislina metil ester
Z uporabo trimetil fosfonoacetata, kot je bilo predstavljeno zgoraj, in po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eiuenta heksana / etil acetata 20 / 1 smo dobili 2,33 g (100 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 133-135°C;
1H NMR (CDCI3,300 MHz) s 7,53 (d, 1 H, J = 16,0), 7,39-7,10 (m, 12 H),
6,88 (d, 2 H, J = 8,3), 6,27 (d, 1 H, J = 16,0), 3,76 (s, 3 H), 2,48 (q, 2 H, J = 7,3), 0,93 (t, 3 H, J = 7,3); MS z nizko resolucijo m/e 369; Anal. (C26H 24O2) C, H, N. [glej na primer (q), Shema E, zgoraj].
Primer 11
3-[4-( 1,2-difenil-but-1 -eniD-fenilj-akrilonitril
Z uporabo dietil cianometilfosfonata, kot je bilo predstavljeno zgoraj, in po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eluenta heksana / etil acetata 10/1 smo dobili 125 mg (93 %) zgoraj omenjene željene spojine v obliki bistrega brezbarvnega olja, ki se po mirovanju strdi: m.p. 101-102°C; 1H NMR (CDCI3 , 300 MHz) s 7,707,07 (m, 13 H), 6,90 (d, 2 H, J = 8,6), 5,79 (d, 1 H, J = 16,6), 2,48 (q, 2 H,
J = 7,3), 0,93 (t, 3 H, J = 7,3); Anal. (C25H21N) C, H, N. [glej na primer (t), Shema F, zgoraj].
Primer 12
3-[4-(1,2-difenil-but-1-enil)-feniH-akrilna kislina tert-butil ester io Z uporabo t-butil dietilfosfonoacetata, kot je bilo predstavljeno zgoraj, in po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eluenta heksana / etil acetata 20 / 1 ter po rekristalizaciji iz vročega heksana smo dobili 52 mg (95 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 139-140°C; 1H NMR (CDCI3 , 300
MHz) s 7,44-7,09 (m, 13 H), 6,86 (d, 2 H, J = 8,3), 6,20 (d, 1 H, J = 16,1), 2,47 (q, 2 H, J = 7,4), 1,49 (s, 9 H), 0,93 (t, 3 H, J = 7,4); MS z nizko resolucijo m / e 373, brez MH+. Anal. (C29H30O2) C, H. [glej na primer (w), Shema G, zgoraj].
Primer 13 l-d-d^-difenil-but-l-enilj-fenill-etanon
Raztopina 172 mg (0,60 mmol) (E)-1-bromo-2-fenil-1-(trimetilsilil)-1butena [glej (b), Shema B, zgoraj], 125 mg (0,60 mmol, 1,0 Eq) borove kisline [glej (m), Shema D] in 70 mg (0,06 mmol, 0,1 Eq) Pd(PPh3)4 v 8 ml DME je bila obdelana z 0,4 ml 2 N Na2CO3, potem smo jo 18 ur segrevali pri temperaturi vrelišča ob uporabi povratnega hladilnika. Raztopina je bila ohlajena na sobno temperaturo, prelita v slano vodo (20 ml), ekstrahirana z etil acetatom (2 x 20 ml), posušena (MgSO4), topilo pa je bilo odstranjeno in vacuo. Po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eluenta heksana / etil acetata 20 / 1 smo dobili 152 mg (78 %) zgoraj omenjene željene spojine v obliki rumene trdne snovi: 1H NMR (CDCI3 , 300 MHz) s 7,6 (d, 2 H), 7,45-7,10 (m, 10 io H), 6,98 (d, 2 H), 2,48 (m, 3 H), 0,94 (t, 3 H), [glej na primer (n), Shema D, zgoraj].
Primer 14
3-[4-(1,2-difenil-but-1-enil)-fenil1-akrilna kislina
Raztopina 50 ml (16 mmol, 10,0 Eq) 2,0 M KOH je bila v času 2 minut po kapljicah dodana raztopini 600 mg estra, pripravljenega tako kot v Primeru 10, (1,6 mmol, 1,0 Eq) v 90 ml metanola / THF 1 / 2. Nastalo raztopino smo mešali 18 ur pri sobni temperaturi, topilo je bilo nato odstranjeno in vacuo. Ostanek smo raztopili v 30 ml 1 M HCI in ekstrahirali z etil acetatom (2 x 60 ml). Organski plasti smo zmešali, posušili (MgSO4), topila pa so bila odstranjena in vacuo. Po prečiščenju ostanka s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eluenta metilen klorida / metanola 95 / 5 smo dobili 370 mg (63 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 148-150°C; 1H NMR (CDCI3 , 300 MHz) s 7,60 (d, 1 H, J = 15,9), 7,39-7,10 (m, 12 H),
6,89 (d, 2 H, J = 8,1), 6,27 (d, 1 H, J = 15,9), 2,48 (q, 2 H, J = 7,3), 0,93 (t, 3 H, J = 7,4); MS z nizko resolucijo m / e 355; Anal. (C25H22O2) C, H. [glej na primer (r), Shema E, zgoraj].
Primer 15
Splošni postopek za spojitvene reakcije s 3-[4-(1,2-difenil-but-1-enil)fenill-akrilno kislino io Raztopini 1,0 Eq kisline (20) in suhega metilen klorida je bilo dodano 1,0 Eq EDC, 1,3 Eq HOBT in 1,0 Eq Et3N, nato pa še 1,2 Eq ustreznega amina. Nastalo raztopino smo mešali 18 ur pri sobni temperaturi, nato je bila prelita v 20 ml H2O in dvakrat ekstrahirana z etil acetatom (2 x 60 ml). Organski plasti smo zmešali, izprali s H2O (1 x 20 ml), posušili (MgSO4), topilo je bilo odstranjeno in vacuo, ostanek pa je bil prečiščen s hitro silikagelno kromatografijo pod povišanim tlakom MPLC ali z rekristalizacijo.
Primer 16
3-[4-(1,2-difenil-but-1-enil)-fenil1-1-morfolin-4-il-prop-2-en-1-on
Z uporabo morfolina in po prečiščenju z MPLC s silikagelom z uporabo eluenta heksana / etil acetata 2/1, čemur je sledila rekristalizacija iz heksana, smo dobili 12 mg (14 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 150-154°C; 1H NMR (CDCI3,300 MHz) s 7,53 (d, 1 H, J = 15,4), 7,39-7,10 (m, 12 H), 6,87 (d, 2 H, J = 8,3), 6,67 (d, 1 H, J = 15,4), 3,65 (m, 8 H), 2,48 (q, 2 H, J = 7,3), 0,93 (t, 3 H, J = 7,3); MS z nizko resolucijo m / e 424; Anal. (C29H29NO2) C, H, N. [glej na primer (s),
Shema E, zgoraj].
Primer 17
3-[4-(1,2-difenil-but-1-enil)-fenin-N-(3-metoksi-propil)-akrilamid Z uporabo 3-metoksipropilamina in po prečiščenju z rekristalizacijo iz io vročega heksana / etil acetata 2 /1, ter po MPLC s silikagelom z uporabo eluenta heksana / etil acetata 1 / 2 smo dobili 20 mg (30 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 132-135°C; 1H NMR (CDCI3 , 300 MHz) s 7,43 (d, 1 H, J = 15,7), 7,36-7,10 (m, 12 H), 7,86 (d, 2 H, J = 8,3), 6,20 (d, 1 H, J = 15,7), 3,46 (m, 4 H), 3,34 (s, 1 H),
2,48 (q, 2 H, J = 7,5), 1,80 (m, 2 H), 0,92 (t, 3 H, J = 7,5); MS z nizko resolucijo m/e 426; Anal. (C29H31NO2) C, H, N. [glej na primer (s), Shema E, zgoraj].
Primer 18
N.N-dicikloheksil-S-^-G^-difenil-but-l-eniD-fenin akrilamid
Z uporabo dicikloheksilamina in po prečiščenju z rekristalizacijo iz vročega heksana / etil acetata 2 / 1 smo dobili 29 mg (28 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 194-200°C; 1H
NMR (CDCIg, 300 MHz) s 7,43-7,11 (m, 13 H), 6,86 (d, 2 H, J = 8,3), 6,69 (d, 1 H, J= 15,4), 3,50 (m, 2 H), 2,48 (q, 2 H, J = 7,3), 1,77-1,62 (2 m, 12 H), 1,30-1,10 (m, 8 H), 0,93 (t, 3 H, J = 7,3); MS z nizko resolucijo m/e 518; Anal. (C37H43NO) C, H, N. [glej na primer (s), Shema E, zgoraj].
Primer 19
N-(2-dietilamino-etil)-3-[4-( 1,2-difenil-but-1 -enil)-fenil]-N-etil akrilamid vodikov oksalat
Z uporabo 2-dimetilaminoetilamina in po prečiščenju s hitro silikagelno io kromatografijo pod povišanim tlakom z uporabo eluenta metilen klorida / metanola 15/1, čemur je sledila tvorba soli vodikovega oksalata z 1,1 Eq oksalno kislino v Et2O, smo dobili 58 mg (53 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 145-147°C; 1H NMR (CDCI3 , 300 MHz) s 7,51 (d, 1 H, J= 15,1), 7,38-7,10 (m, 12 H), 6,88 (d, 2 H), 6,60 (d,
2 H, J = 15,1), 6,12 (m, 2 H), 3,70 (m, 2 H), 3,47 (m, 3 H), 3,35 (m, 2 H),
2,90 (m, 4 H), 2,48 (q, 2 H, J = 7,4), 1,20 (m, 2 H), 0,93 (t, 3 H, J = 7,4); MS z nizko resolucijo m I e 453; Anal. (C31H36N2O C2H2O4) C, H, N. [glej na primer (s), Shema E, zgoraj].
Primer 20
3-[4-(1,2-difenil-but-1-enil)-feniH-N-(3-hidroksi-propil)-akrilamid Z uporabo 3-hidroksipropilamina in po prečiščenju z MPLC s silikagelom z uporabo gradienta heksana / etil acetata od 2 / 1 do 100 % etil acetata, ter po rekristalizaciji iz vročega heksana, smo dobili 14 mg (15 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 144146°C; 1H NMR (CDCI3,300 MHz) s 7,47 (d, 1 H, J = 15,6), 7,36-7,10 (m, 12 H), 7,68 (d, 2 H, J = 8,3), 6,22 (d, 1 H, J = 15,6), 3,62 (m, 2 H), 3,51 (m, 2 H), 3,25 (t, 1 H), 2,47 (q, 2 H, J = 7,3), 1,71 (m, 2 H), 0,94 (t, 3 H, J =
7,3); MS z nizko resolucijo m / e 421; Anal. (C28H29NO2) C, H, N. [glej na primer (s), Shema E, zgoraj].
Primer 21 io 3-[4-(1,2-difenil-but-l-enil)-fenil1-N-metil-N-oktil akrilamid
Z uporabo N-metil-N-oktilamina in po prečiščenju z MPLC s silikagelom z uporabo eluenta heksana / etil acetata 3 / 1 smo dobili 56 mg (41 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 108-109°C; 1H NMR (CDCI3 , 300 MHz) s 7,52 (d, 1 H, J = 15,4), 7,38-7,14 (m, 12 H),
6,86 (d, 2 H, J = 7,8), 6,68 (dd, 1 H, J = 15,4), 3,00 (d, 4 H), 2,48 (q, 2 H, J = 7,3), 1,26 (m, 8 H), 0,93 (t, 3 H, J = 7,3), 0,86 (m, 6 H); MS z nizko resolucijo m / e 480; Anal. (C34H41NO) C, H, N. [glej na primer (s), Shema E, zgoraj].
Primer 22
3-[4-( 1,2-difenil-but-l -enilj-fenill akrilamid
Z uporabo nasičene raztopine amonija v CH2CI2 in po prečiščenju z MPLC s silikagelom z uporabo eluenta heksana / etil acetata 2 / 1 smo dobili 39 mg (39 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 200-202°C; 1H NMR (CDCI3 , 300 MHz) s 7,47 (d, 1 H, J = 15,6), 7,39-7,10 (m, 12 H), 6,87 (d, 2 H, J = 8,3), 6,27 (d, 1 H, J = 15,6), 2,48 (q, 2 H, J = 7,3), 0,93 (t, 3 H, J = 7,3); MS z nizko resolucijo m/e
354; Anal. (C25H23NO) C, H, N.
Primer 23
3-[4-(1,2-difenil-but-1-enil)-fenil1-N-etil-akrilamid
Raztopina 0,2 ml (0,4 mmol, 1,2 Eq) oksalil klorida (2 M v CH2CI2) je io bila dodana raztopini 0°C 120 mg (0,3 mmol) kisline, pripravljene enako kot zgoraj v Primeru 14, raztopljene v 2 ml suhega metilen klorida, ki smo jo medtem mešali. Nastala raztopina se je segrela do sobne temperature, nato smo jo preko noči mešali. Topilo je bilo odstranjeno in vacuo, ostanek pa je bil raztopljen v 2 ml etra in nato dodan raztopini 23 ml etilamina (70 % utežni v H2O) (0,4 mmol, 1,2 Eq) v 2 ml 1 M NaOH, ki smo jo medtem hitro mešali. Nastalo raztopino smo mešali pri sobni temperaturi 2 uri. Reakcijska zmes je bila prelita v etil acetat in ekstrahirana; vodna plast je bila izprana z etil acetatom (3 x 10 ml). Organski plasti smo zmešali, posušili (MgSO4), topilo je bilo odstranjeno in vacuo, po prečiščenju ostanka z rekristalizacijo iz vročega etil acetata smo dobili 45 mg (35 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 192-193°C; 1H NMR (CDCI3 , 300 MHz) s 7,45 (d, 1 H, J = 15,6), 7,39-7,10 (m, 12 H), 6,86 (d, 2 H, J = 8,1), 6,20 (d, 1 H, J = 15,6),
3,38 (m, 2 H, J = 7,3), 2,48 (q, 2 H, J = 7,3), 1,17 (t, 3 H, J = 7,3), 0,93 (t, 3 H, J = 7,3); MS z nizko resolucijo m / e 382; Anal. (C27H27NO) C, H, N. [glej na primer (s), Shema E, zgoraj].
Primer 24
-amino-3-[4-( 1,2-difenil-but-1 -enil)-fenill-prop-2-en-1 -on oksim Raztopina 1,16 ml (1,16 mmol, 3,1 Eq) natrijevega metoksida v metanolu (1,0 M) je bila dodana raztopini 78 mg (1,12 mmol, 3,0 Eq) hidroksilamina hidroklorida v 4 ml suhega metanola. Nastalo raztopino io smo 15 minut segrevali pri temperaturi vrelišča ob uporabi povratnega hladilnika, nato je bila ohlajena na sobno temperaturo. Dodana je bila raztopina 125 mg (0,37 mmol) nitrila, pripravljenega enako kot v Primeru
11, raztopljenega v 2 ml suhega metanola / THF 2/1, reakcijsko zmes smo potem 16 ur segrevali pri temperaturi vrelišča ob uporabi povratnega hladilnika. Reakcijska zmes je bila ohlajena, prelita v 20 ml slane vode in ekstrahirana z etil acetatom (2 x 20 ml), posušena (MgSO4), topila pa so bila odstranjena in vacuo. Po prečiščenju s hitro silikagelno kromatografijo pod povišanim tlakom smo dobili 61 mg (47 %) zgoraj omenjene željene spojine v obliki bele trdne snovi: m.p. 182-185°C; 1H NMR (CDCI3 , 300
MHz) s 7,38-7,07 (m, 12 H), 6,85 (d, 2 H, J = 8,0), 6,68 (d, 1 H, J = 16,7), 6,32 (d, 1 H, J = 16,7), 4,60 (s, br, 2 H), 2,47 (q, 2 H, J = 7,6), 2,17 (s, 1 H), 0,93 (t, 3 H, J = 7,6); MS z nizko resolucijo m / e 369; Anal. (C25H 24N2O) C, H, N. [glej na primer (u), Shema F, zgoraj].
Primer 25
3-(244-(1,2-difenil-but-1-enil)-fenil]-vinil)-5-metil-[1,2,41-oksadiazol
Raztopina 60 mg (0,16 mmol) amid oksima, pripravljenega enako kot zgoraj v Primeru 24, raztopljenega v 5 ml ocetnega anhidrida, je bila segrevana pri 80°C 18 ur, ohlajena na sobno temperaturo, prelita v 10 ml 4 N NaOH in ekstrahirana z etil acetatom (2 x 20 ml). Organski plasti smo zmešali, posušili (MgSO4), topilo je bilo odstranjeno in vacuo. Po prečiščenju neobdelane snovi s hitro kromatografijo pod povišanim tlakom z uporabo eluenta heksana / etil acetata 10/1 smo dobili 21 mg deloma io nečistega produkta, ki se je nato rekristalizal iz vročega metanola / etil acetata 10/1, pri čemer je nastalo 13 mg (20 %) zgoraj omenjene željene spojine v obliki bele trdne kristalne snovi: m.p. 158-159°C; 1H NMR (CDCI3 , 300 MHz) s 7,50 (d, 1 H, J = 16,4), 7,37-7,12 (m, 13 H), 6,87 (m, 2 H), 2,58 (s, 3 H), 2,47 (q, 2 H, J = 7,3), 0,93 (t, 3 H, J = 7,3); MS z nizko resolucijo m / e 392; Anal. (C27H24N2O) C, H, N. [glej na primer (v), Shema F, zgoraj].
Primer 26
34441,2-difenil-but-1-enil)-fenil]-prop-2-en-1-ol
Raztopina 1,35 ml (1,35 mmol, 2,5 Eq) 1,0 M DIBAL-H v THF je bila po kapljicah dodana -78°C raztopini estra, pripravljenega enako kot zgoraj v Primeru 12, raztopljenega v 3 ml THF. Nastalo raztopino smo mešali 30 minut pri -78°C, jo potem segreli na sobno temperaturo in mešali 16 ur.
Odvečna DIBAL-H je bila na hitro ohlajena z 1 N HCI, reakcijska zmes je bila prelita v 20 ml 1 N HCI in ekstrahirana z etil acetatom (2 x 20 ml). Organski plasti smo zmešali, posušili (MgSO4), topila pa so bila odstranjena in vacuo. Po prečiščenju ostanka s hitro silikagelno kromatografijo pod povišanim tlakom z uporabo eluenta heksana / etil acetata 5 /1 smo dobili 94 mg (60 %) zgoraj omenjene željene spojine v obliki bele trdne kristalne snovi: m.p. 80-83°C; 1H NMR (CDCI3,300 MHz) s 7,41-7,02 (m, 12 H), 6,82 (d, 2 H, J = 8,3), 6,45 (d, 1 H, J = 15,8), 6,32 (dt, 1 H, J =5,8, 15,9),4,24 (m, 2 H), 2,47 (q, 2 H, J = 7,6), 1,31 (t, 1 H, J io = 5,9), 0,93 (t, 3 H, J = 7,6); MS z nizko resolucijo m / e 340; Anal.
(C25H 24O) C, H. [glej na primer (x), Shema G, zgoraj].
Primer 27 {3-[4-(1,2-difenil-but-1-enil)-fenil1-alil)-dimetilamin
Raztopina 90 mg (0,27 mmol) alkohola, pripravljenega enako kot zgoraj v Primeru 26, in 41 mg (0,32 mmol, 1,2 Eq) diizopropiletilamina v 2 ml suhega diklorometana je bila obdelana z 33 mg (0,29 mmol, 1,1 Eq) metansulfonil klorida, nastalo raztopino smo mešali pri sobni temperaturi 3 ure. Raztopina je bila potem prelita v 10 ml etil acetata in ekstrahirana z
10 ml slane vode, posušena (MgSO4), topila so bila odstranjena in vacuo, s čimer smo dobili 108 mg (97 %) gostega olja zlate barve. Ta snov je bila takoj raztopljena v 3 ml suhega metanola, potem je bil dodan 1 ml dimetilamina. Nastalo raztopino smo mešali 16 ur pri sobni temperaturi, potem so bila topila odstranjena in vacuo. Ostanek je bil raztopljen v 10 ml etil acetata in ekstrahiran z 1 N HCI. Vodna plast smo ločili in naalkalili z dodatkom 3 N NaOH, ter potem ekstrahirali z etil acetatom (2x10 ml). Bazične ekstrakte smo zmešali, posušili (MgSO4), topilo pa je bilo odstranjeno in vacuo. Po prečiščenju ostanka z MPLC s silikagelom z uporabo eluenta diklormetana / metanola 15/1 smo dobili 37 mg (40 %) zgoraj omenjene željene spojine v obliki bistrega brezbarvnega olja: 1H NMR (CDCI3,300 MHz) s 7,37-7,09 (m, 10 H), 7,02 (d, 2 H, J = 8,5), 6,81 (d, 2 H, J = 8,1), 6,34 (d, 1 H, J = 15,9), 6,14 (dt, 1 H, J = 6,6, 15,9), 3,17 io (d, 2 H, J = 6,6), 2,59-2,42 (m, 6 H), 1,01 (t, 6 H, J = 7,3), 0,92 (t, 3 H, J = 7,4); MS z nizko resolucijo m / e 396; Anal. (C29H33N) C, H, N. [glej na primer (y), Shema G, zgoraj].
Spojine Formule (I), ki vsebujejo kisle skupine, lahko tvorijo farmacevtsko sprejemljive soli z ustreznimi kationi. Ustrezni farmacevtsko sprejemljivi kationi vključujejo alkalne kovinske (npr. natrijeve, kalijeve) ali alkalne zemeljske kovinske (npr. kalcijeve ali magnezijeve) katione. Glede na prej opisano vsaka navedba tukaj navedenih spojin tega izuma vključuje tako spojine Formule (I) kot tudi njihove farmacevtsko sprejemljive soli in raztopine.
Že predhodno je bilo omenjeno, da so spojine tega izuma uporabne za zdravljenje oziroma preprečevanje vrste oboljenj in stanj, na primer srčnožilnih bolezni, raka na dojki, osteoporoze in artritičnih stanj. Nekateri drugi primeri oboljenj ali stanj, pri katerih so spojine tega izuma ravno tako uporabne v smislu zdravljenja oziroma preprečevanja, vključujejo premenstrualni sindrom, vazomotorični simptomi povezani z menopavzo, atrofični vaginitis, Kraurosis vulvae, ženski hipogonadizem, primarne motnje delovanja jajčnika, prekomerno poraščenost in raka na prostati.
Poznavalci tega področja bodo upoštevali, da pojem zdravljenja obsega tako profilakso kot tudi zdravljenje že razvite bolezni ali simptomov. Nadalje je treba upoštevati, da je količina spojine tega izuma, ki je potrebna za zdravljenje, odvisna od narave oboljenja, ki ga zdravimo, in od stanja bolnika, ter bo v končni fazi odvisna od presoje lečečega zdravnika ali veterinarja. V splošnem pa bodo pri zdravljenju odraslih ljudi uporabljeni odmerki običajno znašali od 0,001 mg/kg do približno 100 mg/kg na dan. Željeni odmerek se lahko priročno uporabi v eni samem odmerku, ali pa se razdeljene odmerke uporabi v ustreznih razmakih, na primer kot dva, trije, štirje ali več manjših odmerkov na dan.
Ta izum omogoča tudi nove farmacevtske pripravke spojin Formule (I).
Čeprav se spojine tega izuma lahko terapevtsko uporabljajo kot surova snov, je ugodneje, če se aktivna sestavina uporabi v okviru farmacevtskega pripravka. V skladu s tem ta izum omogoča farmacevtske pripravke, ki obsegajo spojino Formule (I) ali njeno farmacevtsko sprejemljivo sol skupaj z enim ali večimi farmacevtsko sprejemljivimi nosilci, dodatno pa lahko tudi druge terapevtske oziroma profilaktične sestavine. Nosilec (nosilci) mora biti sprejemljiv, kar pomeni, da mora biti združljiv z ostalimi sestavinami pripravka in ne sme biti škodljiv za prejemnika.
Pripravki tega izuma se pri zdravljenju omenjenih bolezni lahko uporabljajo na standarden način, na primer oralno, parenteralno, sublingvalno, transdermalno, rektalno, prek vdihavanja ali v ustih. Za uporabo v ustih ima pripravek lahko obliko tablet ali pastil z običajno sestavo. Tablete in kapsule za oralno uporabo na primer lahko vsebujejo običajne inertne snovi, na primer vezavne snovi (na primer sirup, akacijo, želatino, sorbitol, tragakant, škrobno ali polivinilpirolidonsko sluz), polnila (na primer laktozo, sladkor, mikrokristalno celulozo, koruzni škrob, karcijev fosfat ali sorbitol), maziva (na primer magnezijev stearat, stearinsko kislino, talk, polietilen glikol ali silikat), razkrojila (na primer krompirjev škrob ali natrijev škrobov glikolat) ali vlažilne snovi, na primer natrijev lavril sulfat. Tablete so lahko prekrite v skladu z dobro poznanimi metodami na tem področju.
Podobno so spojine tega izuma lahko vključene v oralne tekoče pripravke, na primer v vodne ali oljne suspenzije, raztopine, emulzije, sirupe ali eliksirje. Poleg tega so pripravki, ki vsebujejo te spojine, lahko predstavljeni kot suhi produkt, ki ga je treba pred uporabo zmešati z vodo ali kakšnim drugim ustreznim vehiklom. Takšni tekoči pripravki lahko vsebujejo običajne aditive, na primer suspenzirajoče agense, na primer sorbitolni sirup, metil celulozo, glukozni/sladkorni sirup, želatino, hidroksietilcelulozo, karboksimetil celulozo, gel aluminijevega stearata ali hidrogenirane jedilne maščobe; emulgatorje, na primer lecitin, sorbitan monooleat ali akacijo; ne-vodne vehikle (ki lahko vključujejo jedilna olja), na primer mandljevo olje, frakcionirano kokosovo olje, oljne estre, propilen glikol ali etilni alkohol; in preservative, na primer metil ali propil β5 hidroksibenzoate ali sorbinsko kislino.
Takšni pripravki so lahko oblikovani tudi kot svečke, t.j. vsebujejo običajne podlage za svečke, na primer kakavovo maslo ali druge gliceride. Pripravki za vdihavanje so običajno izdelani v obliki raztopine, suspenzije ali emulzije in se lahko uporabijo kot suh prah ali v obliki areosola s pomočjo običajnega potisnega plina, na primer diklorodifluorometana ali triklorofluorometana. Tipični transdermalni pripravki se sestojijo iz običajnih vodnih ali ne-vodnih vehiklov, na primer krem, mazil, losionov, past ali so izdelani v obliki zdravilnega obliža, krpice ali membrane.
Poleg tega se pripravki tega izuma lahko oblikujejo za parenteralno uporabo z injekcijo ali neprekinjeno infuzijo. Pripravki za injekcijo so lahko v obliki suspenzij, raztopin, emulzij v oljnih ali vodnih vehiklih, in lahko vsebujejo pripravne snovi, na primer suspenzirajoče, stabilizirajoče ali oziroma razpršilne snovi. Podobno lahko aktivna sestavina nastopa v obliki prahu, ki ga je treba potem pred uporabo zmešati z ustreznim vehiklom (npr. sterilna voda brez pirogenov).
Pripravek je v skladu z izumom lahko oblikovan tudi kot depo preparat.
Takšni pripravki z dolgotrajnim učinkom se lahko uporabijo z vsaditvijo (na primer podkožno ali intramuskulamo) ali z intramuskulamo injekcijo. V skladu s tem so pripravki tega izuma lahko zmešani z ustreznimi polimernimi ali hidrofobnimi snovmi (na primer kot emulzija v ustreznem olju), z ionsko-izmenjevalnimi smolami ali pa so predstavljeni kot zmerno topni derivati, na primer kot zmerno topna sol.
Biološka aktivnost spojin Formule (I) je bila ocenjena v skladu s sledečimi protokoli, ustrezni rezultati so predstavljeni spodaj. Pri spojinah Formule (I) se lahko ocenjuje zlasti njihova osteoprotektivna aktivnost in njihove anti-uterotrofne lastnosti z uporabo metod, predstavljenih v sledečih protokolih.
Poznavalci tega področja bodo upoštevali, da je poznano in je na voljo več sprejemljivih vrst testov vezave na estrogenski receptor pri podgani za začetno pregledno testiranje spojin tega izuma glede na njihovo sposobnost vezave na ustrezni receptor. Spodaj je predstavljeno, kako so bile spojine najprej ocenjene s testom vezave na estrogenski receptor pri podgani glede na njihovo sposobnost inhibiranja vezave [3H]-estradiola. Spojine, pri katerih je bil IC50 < 10μΜ so bile nadalje ocenjene s spodaj predstavljenim funkcionalnim testom estrogenske aktivnosti in vitro na človeški endometriomski celični liniji lshikawa.
Slabo pritrjene lshikawa-Var I celice so bile odstranjene iz vzdrževalnih rastnih pogojev in v koncentraciji 58.500 celic/ml vstavljene v DMEM-F12 brez fenol-rdečega, ki je vseboval 5% FBS z nastrganim ogljem in 2 mM glutamin. Celice so bile položene na ploščice z gostoto 13.000 celic/cm2 in nameščene v inkubator (37°C, 5 % CO2) za tri dni. Celice so bile pobrane in v koncentraciji 83.000 celic/ml vstavljene v DMEM-F12 brez fenolrdečega, ki je vseboval 1% FBS z nastrganim ogljem, 2 mM glutamina, 100 enot/ml penicilina in 100 gg/ml streptomicina. Celice so bile nacepljene z gostoto 8300 celic/na jamico na 96 ploščic z jamicami in so se lahko pritrjevale preko noči. Ustrezna zdravila v 2x koncentracijah so bila dodana v 0,1 ml sredstva, ki je vsebovalo 0,2 % DMSO. Ploščice so bile v inkubatorju dva dni, sredstvo smo izsesali, ploščice pa so bile enkrat izprane z 300 μΙ 0,9 % sterilne slane vode. Ploščice smo zamrznili do 70°C in jih nato segreli do sobne temperature. Pritrjene celice smo testirali io s testom aktivnosti alkalne fosfataze tako, da smo dodali 200 μΙ 5mM pnitrofenilfosfata in 1 M dietanolamina, pH 10,4, ki je vseboval 0,1 % (w/v) Triton Χ-100, inkubirali pri 37°C za 30 minut in izmerili absorbcijo pri
405nm na ploščnem čitalniku Molecular Devices Thermo Max.
Spojine tega izuma smo po zgoraj opisanem postopku testirali zato, da bi ocenili njihovo sposobnost induciranja tvorbe alkalne fosfataze, kar je in vitro odgovor, ki je specifičen za estrogenske agoniste in za katerega je bilo pokazano, da korelira z uterotrofnim odzivom estrogenskih agonistov pri podganah in vivo . V spodaj prikazani Tabeli 1 so rezultati izraženi v obliki koncentracij različnih reprezentativnih spojin tega izuma, ki so inducirale 50 % lastne maksimalne aktivnosti alkalne fosfataze (Emax), pri čemer je maksimalna aktivnost izražena kot delež aktivnosti alkalne fosfataze, ki jo inducira nasičena koncentracija estradiola. V nadaljnih raziskavah se je izkazalo, da so vse spojine, katerih Emax je bil < 20% delovale kot antagonisti estradiola pri koncentracijah, ki so odražale njihovo afiniteto za vezavo na receptor.
Št. spojine | EC50 (nM)b | Emax (%)C |
estradiol | 0,01 | 100 |
tamoksifen | 33 | 16,5 ±0,6 |
1 | 2,3 | 11,9 ± 1,2 |
3 | 4,9 | 15,7 ± 1,8 |
4 | 20 | 18,8 ±2,3 |
5 | 7,3 | 15,0 ±3,0 |
9 | 58 | 3,8 ±0,9 |
10 | 6,9 | 14,8 ±2,4 |
11 | 11 | 14,0 ± 1,5 |
12 | 70 | 19,4 ±2,0 |
13 | 4,6 | 16,5 ± 1,7 |
14 | 12 | 6,3 ±2,1 |
15 | 8,6 | 8,9 ± 1,4 |
16 | 18 | 11,8 ± 1,9 |
21 | 6,9 | 18,8 ±2,6 |
22 | 17 | 15,3 ±2,4 |
Za spojino št. 1 je bilo ugotovljeno, da se veže na estrogenski receptor s približno 10 krat večjo afiniteto kot tamoksifen, kar se kaže v nižjem EC50 pri funkcionalnem celičnem testu lshikawa (glej Tabelo 1). Poleg tega je imela spojina št. 1 znatno nižjo agonistično aktivnost (Emax) kot tamoksifen. Ocenili smo vrsto amidnih analogov spojine št. 1, da bi ugotovili strukturne zahteve za znižanje EC50 in povečanje Emax pri funkcionalnem celičnem testu Ishikavva. Podatki so pokazali, da je v tem predelu molekule mogoč širok spekter strukturne raznolikosti (lipofilnost, sterična ovira, donorji in akceptorji vodikovih vezi) in samo velika spojina io št. 12 je kazala zmanjšano afiniteto za receptor. Spojina št. 1 je imela največjo afiniteto pri testu receptorske vezave in najmanjši EC50 pri funkcionalnem testu, vendar pa je analiza meritev Emax pokazala, da imajo spojine št. 9, 14 in 15 najnižjo rezidualno agonistično aktivnost.
Za oceno zgoraj predstavljenih spojin glede na njihovo anti-uterotrofno aktivnost in vivo smo stehtali skupine po pet 21 dni starih standardnih domačih podganjih samic (30-35 g) in izmerili povprečno težo vsake skupine, ki je dobila svoje zdravljenje, kot je prikazano na Sliki 1. Raztopine (10 x) trifeniletilenskih analogov v etanolu so bile razredčene z 0,5 % metil celulozo, živali so nato po gastrični sondi dobile odmerek 10 pmol/kg. Estradiol smo raztopili v sezamovem olju in dozirali 100 nmol/kg s podkožno injekcijo. Živali so prejemale odmerke 3 dni, na dan 4 pa so bile žrtvovane z zadušitvijo s CO2. Izmerili smo telesne teže, odstranili maternice, jih osušili in stehtali. Rezultati so izraženi kot teža maternice / telesna teža ± standardna napaka. Črni stolpci predstavljajo rezultate živali, ki so prejemale le odmerke s testno spojino. Beli stolpci predstavljajo rezultate živali, ki so prejemale testne spojine 6 ur pred odmerkom estradiola. Spojini 9 in 15 sta pokazali manj rezidualne agonistične aktivnosti kot tamoksifen.
Kot primer funkcionalnega učinkovanja teh spojin na kost smo pri 90 dni starih podganah s pomanjkanjem estrogena zaradi odstranjenih jajčnikov ocenjevali sposobnost spojine št. 9 za inhibicijo izgube mineralne kostne gostote. Devetdeset dni stare standardne domače podgane smo io razdelili v skupine po šest. Trem skupinam smo kirurško odstranili jajčnike.
Dva dni po odstranitvi jajčnikov so živali po gastrični sondi začele prejemati odmerek 10 μΐτιοΙ/kg spojine št. 9 in 0,5 % metil celuloze ali vehikla enkrat na dan 28 dni zapored. Ena skupina živali je bila lažno operirana in je 2 dni po odstranitvi jajčnikov začela prejemati vehikel enkrat na dan 28 dni zapored. Po 0, 14 in 28 dneh smo podgane anestezirali z izofluranom in jih položili na hrbet tako, da je bila njihova hrbtenica vzporedna z vzdolžno osjo mize plošče denzimetra. Pri snemanju ledvičnega dela hrbtenice so kot oporne točke služile medenične kosti. Za posnetek desne golenice smo nogo prilepili vzporedno z vzdolžno osjo plošče in jo posneli v smeri navzgor do stika s stegnenico. Analizo ledvične hrbtenice smo opravili tako, da smo z običajno analitično programsko opremo razdelili vretenca in medvretenčne prostore ter vključili samo tarčna vretenca v področju, ki nas je zanimalo.
Desno golenica je bila analizirana s podpodročno programsko opremo z visoko resolucijo, analiza se je osredotočila na predel 3-5 mm distalno od rastne plošče, za katerega je bilo predhodno ugotovljeno, da v njem zaradi odstranitve jajčnikov prihaja do pospešene izgube kosti. Rezultati po 14 in
28 dneh se niso znatno razlikovali. Na sliki 2 so prikazani rezultati po 28 dneh.
Na sliki 2 je oralno uporabljen odmerek 10 gmol/kg spojine št. 9 pokazal polno agonistično aktivnost in je vzdrževal kostno mineralno gostoto na ravni lažno operiranih podgan vseh 28 dni trajanja raziskave, io Biokemični podatki so pokazali, da je bil pri tem mehanizem delovanja inhibicija resorbcije kosti, kar se sklada z dejstvom, da v kosti deluje kot estrogenski agonist. Kostna mineralna gostota je bila izmerjena z dvojnoenergijsko rentgensko absorbciometrijo z uporabo Hologic QDR-2000 kostnega denzitometra in področne programske opreme z visoko resolucijo z osnovno nastavitvijo dolžine, širine, presledka med vrsticami in resolucije točk z zaporednimi vrednostmi 2, 0,75, 0,01 in 0,005 inča.
Claims (19)
- pri čemerR5 R620 je Ri enak -(CH2)nCR5=CR6R7; -(CH2)mC(X)NR8R9; ali —j~R7 (CH2)pR2 in R3 sta neodvisno H, -CH3, -OH, -OCH3, -OCH2CH3 ali -CH2(CH3)2R4 je -CN, -N02, -CH3, -CH2CH3, -CH2CH2-Y ali -Y;R5 in R6 sta neodvisno H, -COalkil, -C2.4alkenil,-C2_4alkinil, ^-C^alkil, -X-C2.4alkenil, -X-C2.4alkinil ali -Y;R7 je -CN, -CMalkil-OH, -C(O)O(CH3)3, -C(O)NR1°R/ -C(O)NR12R13, .5 CMalkil-NR1°Ri1,-C(O)R12, -C(O)OR12, -C(O)NR12OR13, -C(O)NHC(O)R12,C(O)NHCH2R12, -C(NH2)(NOR12), -S(O)R12, -S(O)(O)(OR12), S(O)(O)(NHCO2R12), PO3R12, -P(O)(NR12R13)(NR12R13),P(O)(NR12R13)(OR14), -CONR12(CH2)qOCH3, -CONR12(CH2)qNR8R9 ali oksadizol substituiran z metilno skupino.10 R8 in R9 sta neodvisno vodik, -C1.7alkil, -C3.7cikloalkil, -O-C^alkil, -Cv 7alkil-Y ali fenil;R10 in R11 sta neodvisno metil ali etil, ali pa povezana prek dušikovega atoma skupaj tvorita morfolinsko skupino;R12, R13 in R14 so neodvisno H, -C1.12alkil, -C2.12alkenil, -C2_12alkinil, -015 C1_12alkil, -O-C2.12alkenil, -O-C2.12alkinil, -C3.7cikloalkil, -C3.7cikloalkenil, linearni ali ciklični heteroalkil, aril, heteroaril ali -Y;X je kisik ali žveplo;Y je halogen;n celo število, izbrano izmed O, 1, ali 2;20 m je celo število 1 ali 2;p celo število od 1 do 4; in q je celo število od 1 do 12.
- 2. Spojina v skladu z zahtevkom 1, označena s tem, daje X enak O.
- 3. Spojina v skladu z zahtevkom 2, označena s tem, da je R1 enak -(CH2)nCR5=CR6R7.io
- 4. Spojina v skladu z zahtevkom 1, označena s tem, da sta R2 in R3 neodvisno izbrana izmed H, -OH, ali -OCH3
- 5. Spojina v skladu z zahtevkom 4,15 označena s tem, da sta R2 in R3 enaka H.
- 6. Spojina v skladu z zahtevkom 1, označena s tem,20 da je R4 bodisi -CH3, -CH2CH3 ali -CH2CH2-CI.
- 7. Spojina v skladu z zahtevkom 1, označena s tem, da sta R5 in R6 neodvisno H ali -C^alkil.
- 8. Spojina v skladu z zahtevkom 1, označena s tem,5 da sta R8 in R9 neodvisno vodik, -C-^alkil ali -C3.7cikloalkil.
- 9. Spojina v skladu z zahtevkom 3, označena s tem, da je R7 enak -C(O)O(CH3)3, -C(O)NRi°Rn, -C(O)NR11 12R13, -C(O)OR12, io -C(O)NHC(O)R12, -C(NH2)(NOR12), -S(O)(O)(NHCO2R12), PO3R12, P(O)(NR12R13)(NR12R13) ali -P(O)(NR12R13)(OR14).
- 10. Spojina v skladu z zahtevkom 1, označena s tem,15 da so R12, R13 in R14 neodvisno H, -C1_12alkil ali -C2.12alkenil.
- 11. Spojina v skladu z zahtevkom 1, označena s tem, da je spojina izbrana izmed naslednjih spojin:20 3-[4-(1,2-difenil-but-1 -enil)-fenil]-N,N-dietil akrilamid3-[4-(1,2-difenil-but-1-enil)-fenil]-N,N-dietil propionamid2- [4-(1,2-difenil-but-1 -enil)-fenil] ciklopropankarboksilna kislina dietilamid3- [4-(1,2-difenil-but-1 -enil)-fenil]-N,N-dietil-2-metil-akrilamid3-[4-(1,2-difenil-but-1 -enil)-fenil]-but-2-enojska kislina dietilamid 3-[4-(1,2-difenil-but-1-enil)-fenil]-akrilna kislina metil ester 3-(4-(1,2-difenil-but-1-enil)-fenil]-akrilonitril3-(4-(1,2-difenil-but-1 -enil)-fenil]-akrilna kislina tert-butil ester5 3-(4-(1,2-difenil-but-1 -enil)-fenil]-akriIna kislina3-(4-(1,2-difenil-but-1-enil)-fenil]-1-morfolin-4-il-prop-2-en-1-on 3-(4-(1,2-d ifenil-but-1-enil)-fenil]-N-(3-metoksi-propil)-akrilamid N,N-dicikloheksil-3-[4-(1,2-difenil-but-1-enil)-fenil]akrilamid N-(2-dimetilamino-etil)-3-[4-(1,2-d ifenil-b ut-1 -eni l)-feni l]-N-eti I akrilamid io 3-(4-(1,2-difenil-but-1 -enil)-fenil]-N-metil-N-oktil akrilamid 3-(4-(1,2-difenil-but-1 -enil)-fenil] akrilamid 3-(4-(1,2-d ifen i l-but-1 -en il)-fen i l]-N-etil akrilamid 1 -amino-3-[4-(1,2-difenil-but-1 -enil)-fenil]-prop-2-en-1 -on oksim 3-{2-[4-(1,2-difenil-but-1-enil)-fenil]-vinil}-5-metil-[1,2,4]-oksadizol15 3-(4-(1,2-difenil-but-1 -enil)-fenil]-prop-2-en-1 -ol {3-(4-(1,2-difenil-but-1-enil)-fenil]-alil}-dimetilamin 3-(4-(1,2-difenil-but-1 -enil)-fenil]-N, N-dietil tioakrilamid 3-(4-(1,2-difenil-but-1-enil)-fenil]-N-(3-hidroksi-propil)-akrilamid20
- 12. Priprava snovi za zdravljenje sesalca zaradi osteoporoze, ki obsega uporabo učinkovite količine spojine v skladu z zahtevkom 1 za pripravo snovi, ki se uporablja na omenjenem sesalcu.
- 13. Priprava snovi za zdravljenje sesalca zaradi artritičnih obolenj, ki obsega uporabo učinkovite količine spojine v skladu z zahtevkom 1 za pripravo snovi, ki se uporablja na omenjenem sesalcu.5
- 14. Priprava snovi za zdravljenje sesalca zaradi raka na dojki, ki obsega uporabo učinkovite količine spojine v skladu z zahtevkom 1 za pripravo snovi, ki se uporablja na omenjenem sesalcu.
- 15. Priprava snovi za zdravljenje sesalca zaradi srčno-žilnega obolenja, io ki obsega uporabo učinkovite količine spojine v skladu z zahtevkom 1 za pripravo snovi, ki se uporablja na omenjenem sesalcu.
- 16. Priprava snovi za preprečevanje osteoporoze pri sesalcu, ki obsega uporabo učinkovite količine spojine v skladu z zahtevkom 1 za pripravo15 snovi, ki se uporablja na omenjenem sesalcu.
- 17. Priprava snovi za preprečevanje artritičnih obolenj pri sesalcu, ki obsega uporabo učinkovite količine spojine v skladu z zahtevkom 1 za pripravo snovi, ki se uporablja na omenjenem sesalcu.
- 18. Priprava snovi za preprečevanje raka na dojki pri sesalcu, ki obsega uporabo učinkovite količine spojine v skladu z zahtevkom 1 za pripravo snovi, ki se uporablja na omenjenem sesalcu.
- 19. Priprava snovi za preprečevanje srčno-žilnega obolenja pri sesalcu, ki obsega uporabo učinkovite količine spojine v skladu z zahtevkom 1 za pripravo snovi, ki se uporablja na omenjenem sesalcu.
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US08/232,910 US5681835A (en) | 1994-04-25 | 1994-04-25 | Non-steroidal ligands for the estrogen receptor |
PCT/US1997/013975 WO1999007668A1 (en) | 1994-04-25 | 1997-08-12 | Non-steroidal ligands for the estrogen receptor |
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