HRP20020223A2 - Triphenylalkene derivatives and their use as selective estrogen receptor modulators - Google Patents
Triphenylalkene derivatives and their use as selective estrogen receptor modulators Download PDFInfo
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- HRP20020223A2 HRP20020223A2 HR20020223A HRP20020223A HRP20020223A2 HR P20020223 A2 HRP20020223 A2 HR P20020223A2 HR 20020223 A HR20020223 A HR 20020223A HR P20020223 A HRP20020223 A HR P20020223A HR P20020223 A2 HRP20020223 A2 HR P20020223A2
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- Croatia
- Prior art keywords
- phenyl
- chloro
- enyl
- phenoxy
- nmr
- Prior art date
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- 229940095743 selective estrogen receptor modulator Drugs 0.000 title claims abstract description 6
- 239000000333 selective estrogen receptor modulator Substances 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 239000000203 mixture Substances 0.000 claims abstract description 62
- -1 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy Chemical group 0.000 claims abstract description 27
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 9
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 76
- 230000001076 estrogenic effect Effects 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 230000001833 anti-estrogenic effect Effects 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- MKYQPGPNVYRMHI-UHFFFAOYSA-N Triphenylethylene Chemical group C=1C=CC=CC=1C=C(C=1C=CC=CC=1)C1=CC=CC=C1 MKYQPGPNVYRMHI-UHFFFAOYSA-N 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 7
- 102000015694 estrogen receptors Human genes 0.000 claims description 7
- 108010038795 estrogen receptors Proteins 0.000 claims description 7
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000006012 2-chloroethoxy group Chemical group 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- SPVZKKXRIUEYLX-UHFFFAOYSA-N 1-[2-[4-[4-chloro-2-(2-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy]ethyl]piperidine Chemical compound COC1=CC=CC=C1C(CCCl)=C(C=1C=CC(OCCN2CCCCC2)=CC=1)C1=CC=CC=C1 SPVZKKXRIUEYLX-UHFFFAOYSA-N 0.000 claims description 2
- OZWNGONMPMQBOK-UHFFFAOYSA-N 1-[2-[4-[4-chloro-2-(3-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy]ethyl]piperidine Chemical compound COC1=CC=CC(C(CCCl)=C(C=2C=CC=CC=2)C=2C=CC(OCCN3CCCCC3)=CC=2)=C1 OZWNGONMPMQBOK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 claims description 2
- UHXWJNBAEKBKEO-UHFFFAOYSA-N 1-chloro-4-[4-chloro-1-[4-(2-chloroethoxy)phenyl]-2-(4-chlorophenyl)but-1-enyl]benzene Chemical compound C1=CC(OCCCl)=CC=C1C(C=1C=CC(Cl)=CC=1)=C(CCCl)C1=CC=C(Cl)C=C1 UHXWJNBAEKBKEO-UHFFFAOYSA-N 0.000 claims description 2
- ATNHJRWRNIUZLA-UHFFFAOYSA-N 2-[4-[4-chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy]-n,n-dimethylethanamine Chemical compound C1=CC(OCCN(C)C)=CC=C1C(C=1C=CC(Cl)=CC=1)=C(CCCl)C1=CC=C(Cl)C=C1 ATNHJRWRNIUZLA-UHFFFAOYSA-N 0.000 claims description 2
- KFYFANIEZDOFFJ-UHFFFAOYSA-N n-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenyl]-n',n'-dimethylethane-1,2-diamine Chemical compound C1=CC(NCCN(C)C)=CC=C1C(C=1C=CC=CC=1)=C(CCCl)C1=CC=CC=C1 KFYFANIEZDOFFJ-UHFFFAOYSA-N 0.000 claims description 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 claims 2
- JQXONNSWMJOKNO-UHFFFAOYSA-N 1-(4-chloro-1,2-diphenylbut-1-enyl)-4-(2-methylsulfanylethoxy)benzene Chemical compound C1=CC(OCCSC)=CC=C1C(C=1C=CC=CC=1)=C(CCCl)C1=CC=CC=C1 JQXONNSWMJOKNO-UHFFFAOYSA-N 0.000 claims 1
- APEDQWZNVLWQRQ-UHFFFAOYSA-N 1-[2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethyl]imidazole Chemical compound C=1C=CC=CC=1C(CCCl)=C(C=1C=CC(OCCN2C=NC=C2)=CC=1)C1=CC=CC=C1 APEDQWZNVLWQRQ-UHFFFAOYSA-N 0.000 claims 1
- KKSTUOBPNIQOQW-UHFFFAOYSA-N 1-[2-[4-[4-chloro-2-(2-chlorophenyl)-1-phenylbut-1-enyl]phenoxy]ethyl]piperidine Chemical compound C=1C=CC=C(Cl)C=1C(CCCl)=C(C=1C=CC(OCCN2CCCCC2)=CC=1)C1=CC=CC=C1 KKSTUOBPNIQOQW-UHFFFAOYSA-N 0.000 claims 1
- NKZTZAQIKKGTDB-UHFFFAOYSA-N 2-[2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy]ethanol Chemical compound C1=CC(OCCOCCO)=CC=C1C(C=1C=CC=CC=1)=C(CCCl)C1=CC=CC=C1 NKZTZAQIKKGTDB-UHFFFAOYSA-N 0.000 claims 1
- JTTIEHQAQHMYJD-UHFFFAOYSA-N 2-[3-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]-n,n-dimethylethanamine Chemical compound CN(C)CCOC1=CC=CC(C(=C(CCCl)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 JTTIEHQAQHMYJD-UHFFFAOYSA-N 0.000 claims 1
- VYYWCVMTGYXAQJ-UHFFFAOYSA-N 2-[3-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethanol Chemical compound OCCOC1=CC=CC(C(=C(CCCl)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 VYYWCVMTGYXAQJ-UHFFFAOYSA-N 0.000 claims 1
- ASMPIVJNWYFPGW-UHFFFAOYSA-N 2-[4-(4-chloro-1,2-diphenylbut-1-enyl)anilino]ethanol Chemical compound C1=CC(NCCO)=CC=C1C(C=1C=CC=CC=1)=C(CCCl)C1=CC=CC=C1 ASMPIVJNWYFPGW-UHFFFAOYSA-N 0.000 claims 1
- FPDFGJBIULRCBC-UHFFFAOYSA-N 2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]butan-1-ol Chemical compound C1=CC(OC(CO)CC)=CC=C1C(C=1C=CC=CC=1)=C(CCCl)C1=CC=CC=C1 FPDFGJBIULRCBC-UHFFFAOYSA-N 0.000 claims 1
- FEXRUSQUTLWESL-UHFFFAOYSA-N 2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenyl]sulfanyl-n,n-dimethylethanamine Chemical compound C1=CC(SCCN(C)C)=CC=C1C(C=1C=CC=CC=1)=C(CCCl)C1=CC=CC=C1 FEXRUSQUTLWESL-UHFFFAOYSA-N 0.000 claims 1
- BHNDRXNBYHXZQX-UHFFFAOYSA-N 2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenyl]sulfanylethanol Chemical compound C1=CC(SCCO)=CC=C1C(C=1C=CC=CC=1)=C(CCCl)C1=CC=CC=C1 BHNDRXNBYHXZQX-UHFFFAOYSA-N 0.000 claims 1
- RAQMMGPTKYEDNQ-UHFFFAOYSA-N 2-[4-[4-chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy]ethanol Chemical compound C1=CC(OCCO)=CC=C1C(C=1C=CC(Cl)=CC=1)=C(CCCl)C1=CC=C(Cl)C=C1 RAQMMGPTKYEDNQ-UHFFFAOYSA-N 0.000 claims 1
- DZGBSCMWMPKXAZ-UHFFFAOYSA-N 2-[4-[4-chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy]-n,n-dimethylethanamine Chemical compound C1=CC(OCCN(C)C)=CC=C1C(C=1C=CC(Cl)=CC=1)=C(CCCl)C1=CC=CC=C1 DZGBSCMWMPKXAZ-UHFFFAOYSA-N 0.000 claims 1
- DHYBSJUFZKJDRO-UHFFFAOYSA-N 2-[4-[4-chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy]acetic acid Chemical compound C1=CC(OCC(=O)O)=CC=C1C(C=1C=CC(Cl)=CC=1)=C(CCCl)C1=CC=CC=C1 DHYBSJUFZKJDRO-UHFFFAOYSA-N 0.000 claims 1
- XEAITSYRXXCXQQ-UHFFFAOYSA-N 2-[4-[4-chloro-1-(4-fluorophenyl)-2-phenylbut-1-enyl]phenoxy]-n,n-dimethylethanamine Chemical compound C1=CC(OCCN(C)C)=CC=C1C(C=1C=CC(F)=CC=1)=C(CCCl)C1=CC=CC=C1 XEAITSYRXXCXQQ-UHFFFAOYSA-N 0.000 claims 1
- RVAVCGMKBBTXAT-UHFFFAOYSA-N 2-[4-[4-chloro-1-(4-fluorophenyl)-2-phenylbut-1-enyl]phenoxy]ethanol Chemical compound C1=CC(OCCO)=CC=C1C(C=1C=CC(F)=CC=1)=C(CCCl)C1=CC=CC=C1 RVAVCGMKBBTXAT-UHFFFAOYSA-N 0.000 claims 1
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- GGUFILQMOPZGEV-UHFFFAOYSA-N 3-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]propan-1-ol Chemical compound C1=CC(OCCCO)=CC=C1C(C=1C=CC=CC=1)=C(CCCl)C1=CC=CC=C1 GGUFILQMOPZGEV-UHFFFAOYSA-N 0.000 claims 1
- YSRHQKVVQONCBO-UHFFFAOYSA-N 3-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]propane-1,2-diol Chemical compound C1=CC(OCC(O)CO)=CC=C1C(C=1C=CC=CC=1)=C(CCCl)C1=CC=CC=C1 YSRHQKVVQONCBO-UHFFFAOYSA-N 0.000 claims 1
- XJLKGBOMSXXMEK-UHFFFAOYSA-N 3-[4-[4-chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy]propane-1,2-diol Chemical compound C1=CC(OCC(O)CO)=CC=C1C(C=1C=CC(Cl)=CC=1)=C(CCCl)C1=CC=CC=C1 XJLKGBOMSXXMEK-UHFFFAOYSA-N 0.000 claims 1
- XZYDRUBEVFWAQF-UHFFFAOYSA-N 3-[4-chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenylbut-1-enyl]phenol Chemical compound C1=CC(OCCO)=CC=C1C(C=1C=C(O)C=CC=1)=C(CCCl)C1=CC=CC=C1 XZYDRUBEVFWAQF-UHFFFAOYSA-N 0.000 claims 1
- IANRKXFMAWMYFE-UHFFFAOYSA-N 3-[[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]methyl]pentan-3-ol Chemical compound C1=CC(OCC(O)(CC)CC)=CC=C1C(C=1C=CC=CC=1)=C(CCCl)C1=CC=CC=C1 IANRKXFMAWMYFE-UHFFFAOYSA-N 0.000 claims 1
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- 230000000144 pharmacologic effect Effects 0.000 abstract 1
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Classifications
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- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
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- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Description
Područje izuma
Ovaj se izum odnosi na derivate trifenilalkena i na njihovu uporabu kao selektivnih modulatora estrogenih receptora (SMER).
Podloga izuma
Publikacije i ostali materijali ovdje korišteni da bi se rasvjetlila podloga izuma, a napose slučajevi s dodatnim potankostima iz prakse, u tekstu se iznose kao literaturni navodi.
Estrogeni su poznati kao ženski spolni hormoni. U posljednje su vrijeme, međutim, brojne tkivne značajke specifične za estrogene opisane u organima koji se u klasičnom smislu ne drže osjetljivima na estrogene, niti na njih reagiraju. Tijekom menopauze lučenje estrogena dramatično se smanjuje. Kasnije se u starijih žena razviju uobičajeni simptomi klimakterija, uključivši napadaje vrućine, znojenje, nesanicu, depresiju, glavobolju, suhoću rodnice, kardiovaskularne simptome, inkontinenciju urina, osjećaj otečenosti, osjetljvost dojki i umor. Dugotrajniji nedostatak estrogena izaziva kardiovaskularne poremećaje i osteoporozu, koji povećavaju rizik od loma kostiju i hospitalizacije, što je za društvo vrlo skupo. Estrogeni se sve više rabe za rješavanje klimakterijskih simptoma, no s druge strane, uzimanjem estrogena povećava se rizik pojave karcinoma maternice i dojke (Lobo, 1995). Pokazalo se da estrogeni djeluju povoljno i u prevenciji Alzheimerove bolesti (Henderson, 1997), te da snižavaju vrijednosti kolesterola iz LDL i tako sprječavaju nastanak kardiovaskularnih bolesti (Grodstein & Stampfer, 1998). Stoga se očekuju novi terapijski pristupi u kojima bi se iskoristili povoljni učinci estrogena, ali bez rizika od pojave karcinoma. Razvijeni su selektivni modulatori estrogenih receptora (SMER) koji ispunjavaju te zahtjeve (Macgregor & Jordan, 1998). Ipak, SMER koji su danas u uporabi,daleko su od optimalnih. Na primjer, uporaba raloksifena ograničena je njegovim izraženim antiestrogenim svojstvima, zbog kojih uzrokuje ili pogoršava klimakterijske simptome, premda je njegov utjecaj na kosti povoljan (Khovidhunkit & Shoback, 1999). Bilo bi najpoželjnije razviti tkivnospecifične estrogene koji bi se mogli u žena rabiti za rješavanje klimakterijskih simptoma, osteoporoze, Alzheimerove bolesti i/ili kardiovaskularnih bolesti, a bez rizika od karcinogeneze. Novi bi se SMER mogli davati muškarcima za zaštitu od osteoporoze, kardiovaskularnih bolesti Alzheimerove bolesti, a bez estrogenih nuspojava (ginekomastije, smanjenog libida itd,).
Cilj i sažetak izuma
Jeadan od ciljeva ovog izuma je ponuditi nove, selektivne modulatore estrogenih receptora.
Drugi je cilj ovog izuma osigurati farmaceutski sastav koji će sadržavati dovoljnu količinu tvari da osigura njeno efikasno tkivnospecifično estrogeno i/ili antiestrogeno djelovanje kao gore navedenog novog selektivnog modulatora estrogenih receptora, ili netoksične, farmaceutski prihvatljive soli te tvari, kao i njenog farmaceutski kompatibilnog i prihvatljivog nosača.
Dodatni cilj ovog izuma je ponuditi metodu za postizanje tkivnospecifičnog estrogenog i/ili antiestrogenog djelovanja u osobe u koje je takvo djelovanje poželjno, koja se sastoji od davanja takvoj osobi tvari koja djeluje kao novi, selektivni modulator estrogenih receptora, ili netoksične, farmaceutski prihvatljive soli te tvari, u količini dostatnoj da se postigne željeni učinak.
U skladu s prvim ciljem izuma, riječ je o novim tvarima koje djeluju kao selektivni modulatori estrogenih receptora, opće formule:
[image] ( I )
gdje su R1 i R2, koji mogu biti jednaki ili različiti:
a) H,halogen,OCH3,OH; ili
[image]
gdje X jest O, NH ili S; a n je cijeli broj od 1 do 4; a
R4 i R5, koji mogu biti jednaki ili različiti, su 1 do 4 ugljikova alkila, H, -CH2C≡CH ili -CH2CH2OH; ili
R4 i R5 tvore peteročlani ili šesteročlani prsten ili heteroaromatski prsten koji sadrže N; ili
b) -Y-(CH2)nCH2-O-R6
gdje Y jest O, NH ili S, a n je cijeli broj od 1 do 4; a
R6 je H, -CH2CH2OH, ili -CH2CH2Cl; ili
c) 2,3-dihidroksipropoksi, 2-metilsulfamiletoksi, 2-kloroetoksi, 1-etil-2-hidroksietoksi, 2,2-dietil-2-hidroksietoksi ili karboksimetoksi; i
R3 je H, halogen, OH ili -OCH3; i
njihove netoksične, farmaceutski prihvatljive soli i esteri i njihove smjese,
pod uvjetom da
a) gdje R2 je [image] na položaju 4 fenila
gdje R4 i R5
i) su jednaki, metil ili etil; ili ii) stvaraju peteročlani prsten koji sadrži N ;
tada R1 i R3 ne mogu istodobno biti H; i
b) gdje R2 je [image] na položaju 4 fenila
gdje R4 i R5, koji su jednaki ili različiti,
jesu metil ili H; ili
gdje R2 je -O-CH2CH2-OH ili -O-CH2COOH na položaju 4 fenila,
tada R1 i R3 ne mogu istodobno biti H, ili OH na položaju 4 fenila; i
ako R1 je OH na položaju 4 fenila, R3 ne može biti H.
Prema drugom cilju izuma, želi se osigurati farmaceutski sastav koji će sadržavati dovoljnu količinu tvari da osigura njeno efikasno tkivnospecifično estrogeno i/ili antiestrogeno djelovanje kao gore navedenog novog selektivnog modulatora estrogenih receptora, ili netoksične, farmaceutski prihvatljive soli te tvari, kao i njenog farmaceutski kompatibilnog i prihvatljivog nosača.
Prema dodatnom cilju izuma, želi se ponuditi metodu za postizanje tkivnospecifičnog estrogenog i/ili antiestrogenog djelovanja u osobe u koje je takvo djelovanje poželjno, koja se sastoji od davanja takvoj osobi tvari koja djeluje kao novi, selektivni modulator estrogenih receptora, ili netoksične, farmaceutski prihvatljive soli te tvari u količini dostatnoj da se postigne željeni učinak.
Detaljni opis izuma
Ovaj se izum odnosi na uporabu novih selektivnih modulatora estrogenih receptora (SMER) i njihovih farmaceutskih pripravaka u muškaraca i žena, za liječenje degenerativnih bolesti i simptoma prouzročenih nedostatkom estrogena. U tipičnom slučaju, SMER djeluju kao estrogeni na koštani i kardiovaskularni sustav, dok na tkivo dojke djeluju kao antiestrogeni. SMER mogu imati agonističke i antagonistične učinke i na druga tkiva. Ovisno o njihovoj kemijskoj građi i hormonskim svojstvima, neke tvari mogu biti posebno prikladne za prevenciju osteoporoze u starijih žena, dok se druge (koje nisu estrogeni s feminizirajućim djelovanjem) mogu rabiti i u muškaraca za prevenciju osteoporoze, kardiovaskularnih bolesti i Alzheimerove bolesti. Nek su tvari specfično proizvedene za liječenje klimakterijskih simptoma žena menopauzi. Zajedničko je svojstvo novih opisanih tvari da djeluju antiestrogeno na mliječne žlijezde i da koče proliferaciju stanica karcinoma dojke. Djeluju i kao slabi estrogeni u maternici i ne uzrokuju karcinom maternice, što je inače jedna od nuspojava dobro poznatog SMER tamoksifena.
Novi SMER koji su predmetom ovog izuma iskazuju tkivnospecifično estrogeno i/ili antiestrogeno djelovanje in vitro i in vivo i korisni su za sprječavanje i liječenje osteoporoze, kardiovaskularnih bolesti i Alzheimerove bolesti u muškaraca i žena, kao i za liječenje klimakterijskih simptoma i karcinoma dojke u žena.
Tvari formule (I) mogu se pripraviti postupkom koji obuhvaća reakciju tvari formule
[image] ( II )
gdje je R7 isto što i R1 ili R2 kako su definirane ranije, ili je takva zaštićena skupina, R3’ je R3 kako je definirana ranije ili je zaštićena OH, R8 je benzil ili tetrahidropiranil, s organometalnom skupinom formule
[image] ( III )
gdje R9 je H , R1 ili R2 kako su definirane ranije, ili je zaštićena takva skupina, a M je Mg-halogen ili Li, koje daju tvar formule
[image] ( IV )
gdje su R3’, R7, R8 i R9 kako je gore definirano, R8 je tetrahidropiranil kad su R7 ili R9 -X-(CH2)nCH2-OR6 gdje su X i n kao što je definirano u (I). Tvar (IV) je dehidrirana odgovarajućim kiselim katalizatorom, po mogućnosti acetanhidridom / acetil-kloridom, čime nastaje derivat trifeniletilena formule
[image] ( V )
gdje R8' je H ili benzil, R7' i R9' su R1 i R2 ili benzilom zaštićena OH ili benzilom zaštićena -XCH2CH2OR6. Moguće zaštitne tetrahidropiranilne skupine u R3, R7, R8 i R9 uklanjaju se u tom procesu, dajući radikale R3, R7', R8' i R9',
Uklanjanje mogućeg benzilnog R8' može se izvesti tretmanom sa Zn i acetil-kloridom u toluenu, čime se dobiva trifenilbutenol formule
[image] ( VI )
Hidroksi-spoj (VI) može se prevesti u odgovarajući klorid tretmanom tionil-kloridom ili trifenilfosfin-ugljičnim tetrakloridom u organskom otapalu, čime se dobije spoj formule
[image] ( VII )
Spojevi koji su predmetom patenta (I) pripravljaju se iz spojeva formule (VII) gdje je R7' i/ili R9' benzilom zaštićena -XCH2CH2OR6 dobivena tretmanom sa Zn i acetil-kloridom u organskom otapalu ili katalitičkom hidrogenacijom.
Drugi proces za pripravu spojeva formule (IV) je reakcija hidroaluminacije derivata "stirena" formule
[image] ( VIII )
gdje R10 je -CHO, -CH2OH, -COOH ili odgovarajući ester, a R3 je definiran ranije derivatom benzofenona formule
[image] ( IX )
Još jedan proces za pripravu spojeva ovog izuma sastoji se od O-alkilacije spoja formule (V) gdje R7' i/ili R9' je OH s derivatom alkilnog halida formule
R11-(CH2)m-halogen ( X )
gdje je m cijeli broj od 1 do 5, a R11 je halogen, [image] or -OR6' gdje R6' je R6 ili zaštićeni R6, ili -COOR, pri čemu se dobije spoj formule
[image] ( XI )
Spoj formule ( XI ) gdje je R11 halogen, reagira s aminom formule [image] čime se dobiva spoj fomule
[image] ( XII )
Još jedan proces za pripravu spojeva formule (VII) obuhvaća McMurryjevu reakciju derivata benzofenona formule
[image] ( XIII )
gdje su R7' i R9' kao što je definirano ranije, s derivatom 3-kloropropiofenona formule
[image] ( XIV )
gdje je R3 kao što je definirano ranije.
Spoj koji je predmetom patenta, formule (I) gdje R1 ili R2 je 2,2-dietil-2-hidroksietoksi, može se pripraviti reakcijom spoja formule (XI), gdje m je 1 a R11 je -COOR, s etilmagnezijevim bromidom.
Spoj koji je predmetom patenta, formule (I) gdje R1 ili R2 je 1-etil-2-hidroksietoksi, može se pripraviti O-alkilacijom spoja formule (V), gdje R7' ili R9' je OH s etil �-bromobutiratom i redukcijom nastalog estera litijevim aluminijevim hidridom.
Eksperimentalni dio
Metode
Evaluacija estrogenih i antiestrogenih svojstava spojeva in vitro na staničnoj kulturi MCF-7
Stanična linija ljudskog karcinoma dojke, MCF-7 (McGrathov klon), osjetljiva na estrogen, održavana je u mediju za staničnu kulturu RPMI-1640, kojem je dodano 10 % fetalnog telećeg seruma, 2 mM L-glutamin, 10 μg/ml inzulina i 10 μg/ml gentamicina. Stanice su uzgajane u jednoslojnoj kulturi u plastičnim bočicama za staničnu kulturu površine 75 cm² (Nunc, Roskilde, Denmark) u 25 ml medija pri 37 °C u atmosferi od 95 % zraka i 5 % CO2, a rasađivane su dva puta na tjedan.
U pokusima koji su obuhvaćali hormonski i antihormonski tretman, stanice su u eksponencijalnoj fazi rasta, tijekom jednog dana predkultivirane u odsutnosti estradiola. Potom su pipetirane u mikrotitarske pločice s 96 bunarića (Nunclon, Roskilde, Denmark) u količini od 3,5 x 103 stanica po bunariću i inkubirane 24 sata pri 37 °C, 95 % zraka i 5 % CO2 u mediju RPMI-1640 (L-glutamin i gentamicin kao gore) s 5 % pročišćenog fetalnog telećeg serum (pročišćenog dva puta dekstranom vezanim na aktivni ugljen, da se uklone steroidi) i bez fenolnog crvenila. Nakon razdoblja inkubacije, medij je uklonjen. Odmah potom stanice su izložene djelovanju istraživanih lijekova, tako što im je dodan svježi medij s 5 % pročišćenog seruma. Polovina stanica uzgajana je uz dodatak estradiola, a polovina bez njega. Dodani su istraživani spojevi (otopljeni u etanolu u koncentraciji od 0,01 M i do potrebne koncentracije razrijeđeni medijem za staničnu kulturu). Finalna koncentracija spojeva bila je 1, 10, i 100 nM, te 1 i 10 μM. Stanice su inkubirane četiri dana.
Broj živih stanica određivan je nakon četiri dana luminometrom, na osnovi količine ATP-a i rekacije s luciferazom, kao što su opisali Kangas i sur., 1984. Ta metoda omogućava određivanje estrogenosti na osnovi sposobnosti spojeva da pospješuju rast stanica ovisnih o ostrogenu u odsutnosti estradiola. Estrogenost se određivala u postotku maksimalne stimulacije staničnog rasta postignute istraživanim spojem (pri bilo kojoj koncentraciji) u odnosu na rast stimuliran estradiolom (100 % stimulacije). U opisanim se istraživanjima antagonizam mjerio pri koncentraciji od 1 μmol/l i izražavao u postotku od teoretskog, potpunog (100 %) antagonizma, koji je značio potpunu inhibiciju stimulacije estradiolom. Pri visokim koncentracijama molekule mogu iskazivati i toksičnost. Toksičnost se izražavala udjelom mrtvih stanica (tj. 100 % znači da su pri izlaganju spoju sve stanice uginule). Rezultati su prikazani u Tablici 2.
Određivanje estrogenosti i iantiestrogenosti in vivo
Klasična metoda evaluacije estrogenog i antiestrogenog djelovanja je nezreli mišji ili štakorski uterus (Terenius, 1971). Životinje stare 18 dana, tijekom tri dana bile su izlagane djelovanju istraživanih spojeva. Četvrtog dana žrtvovane su asfiksijom s CO2, te je zabilježena njihova tjelesna težina i težina uterusa. Estrogeni povećavaju veličinu i težinu uterusa (uterotropni učinak), a antiestrogeni koče to djelovanje. Stoga su se spojevi davali sami i s estradiolom, kako bi se procijenilo i agonističko i antagonističko djelovanje. Rezultati su prikazani u Tablici 3, u % od estrogene stimulacije (100 %) i inhibicije estrogenog djelovanja (potpuna inhibicija 100 %). Prikazani su rezultati rada s dvjema dozama, niskom, t.j. 3-5 mg/kg i visokom, tj. 10–50 mg/kg. Estrogena se aktivnost može određivati i mjerenjem veličine uterusa nakon četiri mjeseca tretmana u ovariektomiranih štakora. Taj je pokus izveden pri radu s odabranim spojevima, kao što prikazuje Tablica 4.
Mjerenje učinaka na kolesterol i na kosti
Spojevi seu peroralno davani ženkama štakora svakog dana tijekom četiri ili pet tjedana. Na kraju je uzet uzorak krvi. Serum je odvojen centrifugiranjem i zamrznut do određivanje ukupne količine kolesterola. Uzeti su uzorci kosti s kralješnice i tibije. Fizička snaga kosti mjerila se kao što su opisali Peng i sur., 1994. Procjena kosti uključivala je:
Određivanje težine pepela tibijskih epifiza
Pažljivo su preparirane epifize jedne tibije, te su spaljene. Uzorci su spaljeni da se uklone voda i organski materijal. Težina pepela odražava mineralni sadržaj kosti. Uz to, uzeti su i uzorci kosti za histomorfometrijsku analizu. U nekim je slučajevima stvaranje kosti analizirano injiciranjem tetraciklina (50 mg/kg i.p. 10 dana prije sekcije) i kalceina (20 mg/kg i.p. 3 dana prije sekcije). Metoda se zasniva na stalnom vezanju tetraciklina na kost koja raste, te njegovoj detekciji fluorescencijom (Peng i sur,, 1994).
Mehaničko testiranje kostiju
Mehaničko testiranje kostiju obavljalo se uređajem za testiranje materijala koji je konstruiran u kućnoj izradi na Oulu University (Technical Services Department of the Medical Faculty). Uređaj za testiranje zasniva se na načelu poluge. Jedan je kraj čelične poluge fiksiran. Potisna šipka i pogonski motor povezani su s polugom omjerom moenata od 12,5 cm/50 cm = 1⁄4. Kao pogonski motor služi linearni aktuator (SEY 10 Magnetic Elektromotoren AG, Switzerland) kojim se postiže stalno vertikalno kretanje (0,62 cm/s). Na potisnu je šipku montirana izmjenjiva kompresijska glava za prijenos različito jakih sila kompresije na testirani uzorak, koja se okreće stalnom brzinom od 0,155 mm/s, do maksimalnog opterećenja od 1200 N. Potisnom se šipkom upravlja putem aksijalne kugle koja osigurava vertikalno pokretanje. Sila kompresije mjeri se senzorom sile s kompenzacijom temperature, koji je pričvršćen na nepokretni dio kompresijske konstrukcije. Mjerna elektronika raspolaže sustavom za namještanje i baždarenje senzora.
Snaga vrata femura
Maksimalno opterećenje što ga može podnijeti vrat femura mjereno je testom konzolnog savijanja. Podloga za kost je debela ploča od polimetilmetakrilata, u kojoj je izbušeno nekoliko otvora različitih veličina. Na jednoj strani svakog otvora urezana je brazda za treći trohanter femura. Femur je prerezan točno između srednje i donje trećine njegove epifize. Kost je postavljena okomito i čvrsto umetnuta u odgovarajući otvor podloge. Najmanji trohanter svake kosti dodirivao je površinu ploče. Taj je postupak omogućio brzu i stabilnu fiksaciju kosti, bez uporabe ikakvog drugog materijala za uklapanje. Konkavna kompresijska glava promjera 2,5 mm izrađena je od aluminija. Kompleks glava-vrat femura testiran je primjenom sile paralelno s dijafizom femur.
Određivanje protutumoske aktivnosti in vivo
Protutumorska se aktivnost određivala modelom DMBA (dimetilbenz[a]antracen). Jednokratnom peroralnom dozom DMBA (12 mg) pokrene se karcinogeneza mliječne žlijezde. Novi su se spojevi davali tijekom pet tjedana, do pojave palpabilnih tumora. Veličina tumora i broj novih tumora pažljivo su se određivali jednom na tjedan, do okončanja pokusa. Model su potanko opisali Kangas i sur, 1986. Rast tumora mjerio se jednom na tjedan. Svi su se tumori razvrstavali na temelju njihovih svojstava rasta, t.j. njihove sposobnosti progresije, stabilnosti i regresije. Posebno su kategoriziranbi tumori koji su posve nestali. Uzelo se da tumor progredira ako se njegov volumen povećao za više od osam puta tijekom pet mjeseci doziranja, te da regredira ako mu se volumen smanjio na četvrtinu ili manje od volumena koji je imao na početku. Ako se volumen tumora promijenio manje, ili se uopće nije promijenio, uzimao se kao stabilan.
Rezultati
Gore opisanim metodama ukupno je evaluirano 46 spojeva, uključenih u popis spojeva za primjer, te numeriranih i navedenih u Tablici 1.
[image]
Strukture spojeva navedenih kao primjer mogu se sažeto prikazati ovako:
[image]
[image]
[image]
[image]
[image]
Estrogeno i antiestrogeno, kao i citotoksično djelovanje nekoliko spojeva prikazano je u Tablici 2. Vidi se da spektar hormonske aktivnosti spojeva varira i tako pruža mogućnosti njihova korištenja u različitim kliničkim uvjetima.
Spojevi slabe hormoske aktivnosti, koji djelotvorno ubijaju MCF-7 stanice (stanice ljudskog karcinoma dojke) pri najvišoj testiranoj koncentraciji (10 μM) mogli bi se pretežno rabiti za liječenje karcinoma dojke. To su, između ostalih, spojevi Br. 1, 3, 16, 19, 26, 27, 39 i 40 (Tablica 2). Ti spojevi, i neki drugi, djeluju manje estrogeno i antiestrogeno od tamoksifena i toremifena, dobro poznatih lijekova protiv karcinoma (Tablica 3). Posebno je zanimljiv spoj Br. 19, jer se in vivo, na modelu tumora mliječnih žlijezda u štakora induciranih s DMBA, pokazao djelotvornijim protutumorskim lijekom od tamoksifena i toremifena, čak i u vrlo niskim dozama (Table 6).
Spojevi slabog estrogenog djelovanja, a bez antiestrogenog djelovanja, mogli bi biti osobito prikladni za prevenciju i liječenje osteoporoze i klimakterijskih simptoma. Takvi su spojevi (između ostalih) oni navedeni pod Br. 3, 10, 11, 18, 19, 20, 25, 32, 36 i 44 (Tablice 2, 3 i 4).
Spojevi koji snizuju kolesterol mogli bi biti korisni kardiovaskularni lijekovi. U žena bi se mogla tolerirati stanovita razina njihova estrogenog djelovanja, no spojevi koji uopće nisu estrogeni ili su vrlo slabi estrogeni, a snizuju kolesterol, mogli bi se rabiti i u muškaraca u prevenciji i liječenju kardiovaskularnih bolesti. Takvi su spojevi (između ostalih) oni navedeni pod Br., 3, 19, 20 (i za muškarce) i 33 (za žene) (Tablica 4). Za očekivati je da ti isti spojevi budu korisni i u liječenju ili prevenciji Alzheimerove bolesti. U ovom potonjem slučaju, citotoksično djelovanje spojeva mora biti slabo, kao npr. u spoja Br. 33 (Tablica 2). Valja napomenuti da spoj Br. 19 nije iskazao nikakvo antiestrogeno djelovanje na težinu prostate u dozama koje su bile djelatne u indukciji tumora dojke s DMBA, (Tablice 6 i 7). To bi moglo biti posebno korisno u muškaraca, a moglo bi se pokazati i dodatno korisnim, uz gore spomenutu mogućnost liječenja karcinoma prostate.
Hormonski profil nekih spojeva in vivo može se razlikovati od onog in vitro, kao npr. spoja Br. 1, koji nije pokazao estrogeno djelovanje in vitro (Tablica 2), ali je pokazao slabo estrogeno djelovanje in vivo (Tablica 3). Stoga gore navedene primjere treba uzimati kao primjere djelotvornosti u različitim uvjetima. Gore izneseno ne smije se shvaćati kao ograničenje njihove moguće uporabe u različitim kliničkim situacijama.
TABLICA 2,Estrogeno, antiestrogeno i citotoksično djelovanje istraživanjih spojeva na stanice MCF-7. Potankosti određivanja iznesene su u tekstu. Maksimalni estrogeni agonizam u odsutnosti estradiola izražavao se u postotku stimulacije estradiolom (100 %). Antiestrogena su svojstva evaluirana pri koncentraciji od of 1 μmol/l, uzimajući teoretski potpuni antagonizm kao 100 %. Toksičnost pri koncentraciji od 10 μmol/l evaliurala se kao frakcija mrtvih stanica u usporedbi s kontrolom (tj. 100 znači da su sve stanice mrtve). Kao referentni uzeti su poznati estrogeni.
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TABLICA 3 Uterotropno (npr, estrogeno) i estrogenu antagonističko djelovanje istraživanih spojeva u trodnevnom pokusu uterotropnosti u nezrelih štakorica. Estrogeno se djelovanje izražavalo u postotku od maksimalnog djelovanja izazvanog estrogenom. Antiestrogeno djelovanje je prikazano u postotku od teoretski potpune inhibicije estrogenog djelovanja (100 %).
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TABLICA 4 Utjecaj spojeva Br. 3, 19 i 20 na razinu serumskog kolesterola u ovarijektomiranih štakorica (OVX) nakon četiri tjedna doziranja. Za usporedbu, jedna je skupina primala estradiol. Rezultati pokazuju da je ovarijektomija uzrokovala porast razine kolesterola. Estradiol, te spojevi Br. 3, 19 i 20 mogli su sprječiti taj porast čak i pri vrlo niskoj dozi, te su snizili razinu kolesterola ispod one u lažno operiranih životinja. U svakoj je skupini bilo po osam životinja.
[image] TABLICA 5 Utjecaj spojeva Br. 3, 19 i 20 na kosti ovarijektomiranih štakorica nakon četiri tjedna doziranja. Štakorice su bile ovarijektomirane (kontrolnu su skupinu činile one lažno operirane). Spojevi su davani peroralno tijekom četiri tjedna u niže navedenim dozama (mg/kg), počevši tjedan dana nakon ovarijektomije. Za određivanje kvalitete kostiju preparirane su epifize tibije i vratovi femura.
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TABLICA 6 Protutumorsko djelovanje spoja br. 19 na karcinom mliječne žlijezde induciran s DMBA u štakorice. Spoj br. 19 davan je peroralno svakoga dana tijekom pet dana u niže navedenim dozama. Tumori su svrstavani kao oni koji rastu, stabilni, koji regrediraju i koji su nestali, kao što je opisano u tekstu. U svakoj je skupini zabilježen broj tumora, te je izračunat njihov postotak u odnosu na ukupni broj tumora. U svakoj je skupini bilo sedam životinja. Spoj br. 19 nije utjecao na tjelesnu težinu životinja u usporedbi s kontrolnim životinjama.
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TABLICA 7: Utjecaj spoja br. 19 na težinu prostate u intaktnih i kastriranih mužjaka štakora nakon što su četiri dana svakodnevno primali dvije različite doze. Kastracija je znatno smanjila težinu prostate, a poznato je da estrogeni djeluju jednako. Spoj br. 19 nije iskazao estrogeno djelovanje u dozi od 0,5 mg/kg, a iskazao je slabo estrogeno djelovanje u dozi od 5,0 mg/kg. Valja uočiti da taj spoj u dozi od 0,5 mg/kg ima znatno protutumorsko djelovanje u životinja s karcinomom dojke induciranim s DMBA (Tablica 6).
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Za potrebe ovog izuma, novi SMER ili njihove farmaceutski prihvatljive soli mogu se uzimati na različite načine. Prikladni načini uzimanja uključuju npr. pripravke za peroralnu uporabu, injekcije za parenteralnu primjenu, uključivši intravenske, intramuskularne, intradermalne i subkutane injekcije; te pripravke za transdermalnu i rektalnu primjenu. Prikladni pripravci za peroralnu primjenu uključuju npr. konvencionalne tablete i one s usporenim oslobađanjem, te želatinske kapsule.
Potrebne doze novih SMER razlikovat će se s obzirom na stanje zbog kojeg se uzimaju, težinu stanja, trajanje liječenja, način uzimanja i specifični spoj koji se uzima. U tipičnom slučaju, dnevna doza za odraslu osobu iznosi 5-200 mg, po mogućnosti 20–100 mg. SMER se mogu uzimati u obliku tableta ili drugih vrsta pripravaka, npr. želatinskih kapsula, sami ili pomiješani s bilo kojim klinički prihvatljivim, nedjelatnim sastojkom koji se rabi u farmaceutskoj industriji.
PRIMJERI
Primjer 1
a) O-alkiliranje derivata 4-hidroksibenzofenona
U uvjetima katalize faznog prijenosa (phase transfer catalysis, PTC)
[4-(2-dimetilaminoetoksi)fenil]-(4-fluorofenil)metanon
4-Hidroksibenzofenon (28,1 g, 0,13 mol) se otopi u toluenu (140 ml). Doda se tetrabutilamonijev bromid (TBABr) (2,1 g). Doda se vodeni 48 % natrijev hidroksid (140 ml) pri 50–55 °C. Smjesa se zagrije do 80 °C, te se u malim porcijama dodaje 2-kloroetildimetilamin-hdroklorid (ukupno 20,0 g, 0,14 mol) i reakcijska se smjesa miješa 3 h pri 97-100 °C . Odvoje se slojevi i organski se sloj ispere vodom, osuši iznad natrijeva sulfata i otpari do suha. Dobije se 33,0 g, 88 % produkta. Proizvod se bez daljeg pročišćavanja koristi u idućoj fazi.
1H NMR (CDCl3): 2,36 (s, 6H), 2,77 (t, 2H), 4,15 (t, 2H), 6,99 (d, 2H), 7,15 (t, 2H), 7,27–7,83 (m, 4H)
Istom se metodom pripravljaju sljedeći spojevi:
(4-klorofenil)-[4-(2-dimetilaminoetoksi)fenil]metanon
1H NMR (CDCl3): 2,36 (s, 6H), 2,77 (t, 2H ), 4,15 (t, 2H), 6,98 (d, 2H), 7,45 (2H), 7,71 (d, 2H), 7,79 (d, 2H)
[4-(2-benziloksietoksi)fenil]-(4-fluorofenil)metanon
1H NMR (CDCl3): 3,87 (dist.t, 2H), 4,24 (dist.t, 2H), 4,65 (s, 2H), 6,99 (d, 2H), 7,15 (t, 2H), 7,32-7,39 (m, 5H), 7,76-7,83 (m, 4H)
[4-(2-benziloksietoksi)fenil]-(4-klorofenil)metanon
1H NMR (CDCl3): 3,86 (t, 2H), 4,24 (t, 2H), 4,65 (s, 2H), 6,99 (d, 2H), 7,3-7,4 (m, 5H), 7,45 (d, 2H), 7,70 (d, 2H), 7,78 (d, 2H )
Kiselom katalizom
(4-klorofenil)-[4-(tetrahidropiraniloksi)fenil]metanon
4-kloro-4'-hidroksibenzofenon (50 g, 0,215 mol) se otopi u diklorometanu (400 ml). Otopini se dodaju 3,4-dihidro-2H-piran (21,7 g, 0,257 mol) i katalitička količina p-toluensulfonske kiseline. Otopina se miješa šest sati pri sobnoj temperaturi i potom ostavi stajati preko noći. Reakcijskoj se smjesi doda 1 N vodena otopina natrijeva hidroksida (100 ml) i miješa 15 minuta. Odvoji se organski sloj i ispere dva puta 1 N vodenom otopinom natrijeva hidroksida, te jednom vodom. Otopina diklorometana se osuši i pusti da otpari do suha. Dobije se 68,6 g produkta.
1H NMR (CDCl3): 1,52–2,20 (m, 6H), 3,60-3,67 (m, 1H), 3,8–3,94 (m, 1H), 5,5–5,6 (m, 1H), 7,10 (d, 2H), 7,45 (d, 2H), 7,72 (d, 2H ), 7,78 (d, 2H)
Istom se metodom pripravljaju sljedeći spojevi:
Bis[4-(tetrahidropiraniloksi)fenil]metanon
1H NMR (CDCl3): 1,55–2,20 (m, 12H), 3,6–3,7 (m, 2H), 3,8–4,0 (m, 2H), 5,5–5,6 (m, 2H), 711 (d, 4H), 7,78 (d, 4H)
NaH kao baza
(4-klorofenil)-[4-(2,2-dimetil-[1,3]dioksolan-4-ilmetoksi)-fenil]-metanon
Natrijev hidrid (3,4 g, 0,072 mol) u ulju ispere se heptanom i pomiješa s dimetilformamidom (DMF) (120 ml). Otopini se, kap po kap, dodaje 4-kloro-4'-hidroksibenzofenon (12 g, 0,052 mol) u DMF, te se reakcijska smjesa miješa jedan sat pri sobnoj temperaturi. Potom se otopini tijekom jednog sata, kap po kap, dodaje 2,2-dimetil-[1,3]dioksolan-4-il metil ester (17,7 g, 0,0618 mol, pripravljen iz S1,2Oizopropilglicerola i p-toluensulfonil-klorida) toluen-4-sulfonske kiseline u DMF. Smjesa se zagrije do 60 °C i miješa dva dana pri toj temperaturi. Reakcijskoj se smjesi doda 1 N vodena otopina natrijeva hidroksida (200 ml), te se otopina ekstrahira tri puta toluenom (60 ml). Toluenski se slojevi spoje i isperu dva puta vodom (60 ml), osuše i otpare do suha. Ostatak se kristalizira metanolom. Dobije se 13,7 g, 76,7 % produkta.
1H NMR (CDCl3): 1,42 (s, 3H), 1,48 (s, 3H), 3,90–4,24 (m, 4H), 4,52 (kvintet, 1H), 6,99 (d, 2H), 7,46 (d, 2H ), 7,71 (d, 2H), 7,79 (d, 2H)
b) Reakcija hidroaluminacije derivata benzofenona cinamaldehidom ili metil-cinamatom
1-[4-(2-N,N-dimetilaminoetoksi)fenil]-1-(4-fluorofenil)-2-fenilbutan-1,4diol
Litij-aluminij-hidrid (2,6 g, 0,068 mol) se doda suhom tetrahidrofuranu (120 ml) u atmosferi dušika. Cinamaldehid (13,8 g, 0,1 mol) u suhom tetrahidrofuranu (30 ml) doda se pri 24–28 °C. Reakcijska se smjesa miješa jedan sat pri sobnoj temperaturi. Doda se [4-(2-dimetilaminoetoksi)fenil]-(4-fluorofenil)- metanona (29,6 g, 0,103 mol) u suhom tetrahidrofuranu (60 ml) pri 50–55 °C. Reakcijska se smjesa miješa tri sata pri 60 °C. Veći dio tetrahidrofurana ispari. Dodaju se toluen (300 ml), 48 % vodena otopina natrijeva hidroksida (118 ml) i voda (30 ml). Smjesa se podvrgne povratnom strujanju tijekom 10 min, a vodeni se sloj odvoji dok je još vruća. Ponovi se tretman s NaOH. Toluenski se sloj opere dva puta vrućon vodom. Proizvod se, kao smjesa stereoizomera, kristalizira iz toluena (26,4 g, 62 %).
1H NMR (CDCl3 + MeOH-d4): 1,95–2,12 (m, 2H), 2,30 i 2,37 (2s, zajedno 6H), 2,68 i 2,77 (2t, zajedno 2H), 3,31–3,48 (m, 2H) gdje signal CHCH2 drugog dijastereoizomera, 3,80 (dd, CHCH2 drugi dijastereoizomer), 3,95 i 4,08 (2t, zajedno 2H), 6,62 i 6,91 (2d, zajedno 2H), 7,03 i 6,72 (2t, zajedno 2H), 7,05–7,20 (m, 7H), 7,51 (m, 2H)
Istom se metodom pripravljaju sljedeći spojevi:
1-(4-klorofenil)-1-[4-(2-N,N-dimetilaminoetoksi)fenil]-2-fenilbutan 1,4-diol , smjesa stereoizomera.
1H NMR (CDCl3 + MeOH-d4): 1,85–2,10 (m, 2H), 2,27 i 2,33 (2s, zajedno 6H), 2,66 i 2,75 (2t, zajedno 2H), 3,25–3,50 (m, 2H), 3,62 i 3,84 (t i dd, zajedno 1H), 3,93 i 4,04 (2t, zajedno 2H), 6,6–7,6 (13H)
1-[4-(2-benziloksietoksi)fenil]-1-(4-fluorofenil)-2-fenilbutan-1,4-diol, smjesa stereoizomera.
1H NMR (CDCl3): 1,92–2,15 (m, 2H), 3,30–3,48 i 3,48–3,66 (2m, zajedno 2H), 3,74 i 3,83 (2 dist.t, zajedno 2H), 4,02 i 4,15 (2 dist.t, zajedno 2H), uz dvije zadnje signalne skupine CHCH2, 4,58 i 4,63 (2s, zajedno 2H), 6,6-7,6 (18H)
1-[4-(2-Benziloksietoksi)fenil]-1,2-bis(4-klorofenil)butan-1,4-diol, smjesa stereoizomera.
Umjesto cinamaldehida uzima se metilni ester 4-klorocimetne kiseline,
1H NMR (CDCl3): 1,80–2,15 (m, 2H), 3,2–3,4 and 3,4–3,6 (2m, zajedno 2H), 3,75 i 3,82 (2 t, zajedno 2H), 3,95 (dist.t, 1H) , 4,00 i 4,14 (2 t, zajedno 2H), 4,59 i 4,63 (2s, zajedno 2H), 6,80–7,55 (17 H)
1,2-bis(4-klorofenil)-1-[4-(2-dimetilaminoetoksi)fenil]butan-1,4-diol, smjesa stereoizomera.
Umjesto cinamaldehida uzima se ester 4-klorocimetne kiseline.
1H NMR (CDCl3 + MeOH-d4): 1,85–2,20 (m, 2H), 2,35 i 2,37 (2s, zajedno 6H), 2,77 i 2,82 (2t, zajedno 2H), 3,20-3,45 (m, zajedno 2H), 3,81 i 3,85 (2 dist, t, zajedno 1H), 4,10 i 4,21 (2 t, zajedno 2H), 6,9–7,8 (m, 12 H)
1,1-Bis[4-(tetrahidropiraniloksi)fenil]-2-fenilbutan-1,4-diol
1H NMR (CDCl3): 1,5–2,1 (m, 14 H), 3,3–4,1 (m, 7H), 5,25-5,28 (m, 1H), 6,77 (d, 2H), 7,00 (d, 2H), 7,1–7,2 (m, 9H), 7,47 (d, 2H)
1-(4-klorofenil)-2-fenil-1-[4-(tetrahidropiraniloksi)fenil]-butan-1,4-diol
1H NMR (CDCl3 ): 1,5–2,1 (m, 8H), 3,2–4,0 (m, 5H), 5,27 (m, 1H), 6,79 (d, 2 H), 6,9–7,32 (m, 9H), 7,5 (d, 2H)
1-(4-klorofenil))-[4-(2,2-dimetil-[1,3]dioksolan-4-ilmetoksi)-fenil]-2-fenilbutan-1,4-diol
1H NMR (CDCl3 ): 1,37 i 1,40 i 1,42 and 1,46 (4s, zajedno 6H), 1,9–2,1 (m, 2H), 3,2-4,5 (m, 8H), 6,6–7,55 (m, 13H)
1,2-difenil-1-[3-(tetrahidropiraniloksi)fenil]-butan-1,4-diol
se pripravlja počevši od fenil-[3-(tetrahidropiraniloksi)fenil]metanona i cinamaldehida Spoj se u idućoj reakciji koristi bez daljeg pročišćavanja.
c) Dehidracija derivata 1,1,2-triarilbutan-1,4-diola
4-[4-(2-dimetilaminoetoksi)fenil]-4-(4-fluorofenil)-3-fenilbut-3-en-1-ol
1-[4-(2-N,N-Dimetilaminoetoksi)fenil]-1-(4-fluorofenil)-2-fenilbutan-1,4diol (8,46 g, 0,02 mol) se podvrgne povratnom strujanju u 80 ml acetanhidrida tijekom tri sata. Smjesa se ohladi do 60 °C i doda acetil-klorid (7,85 g, 0,1 mol), Smjesa se miješa četiri sata pri 80–90 °C. Otapala se otpare. Doda se otopina koja sadrži 5 % natrijev hidroksid u 80 % vodenom metanolu, te se miješa dva sata pri sobnoj temperaturi. Metanol se otpari. Doda se voda, a produkt se ekstrahira etilacetatom. Organski se sloj ispere vodom, osuši i otpari. Ostatak (9,5 g) je smjesa E- i Z- izomera produkta. Izomeri se odvoje plamenom kromatografijom (eluens - toluen:trietilamin 9:1).
E-izomer, 1H NMR (CDCl3): 2,27 (s, 6H), 2,64 (t, 2H), 2,74 (t, 2H), 3,57 (t, 2H), 3,92 (t, 2H), 6,57 (d, 2H), 6,75 (d, 2H), 7,03 (t, 2H), 7,10–7,18 (m, 5H), 7,27 (dd, 2H)
Z-izomer, 1H NMR (CDCl3): 2,34 (s, 6H), 2,74 (t, 2H), 2,79 (t, 2H), 3,60 (t, 2H), 4,05 (t, 2H), 6,69 (t, 2H), 6,84 (dd, 2H), 6,91 (d, 2H), 7,09–7,17 (m, 5H), 7,20 (d, 2H)
Istom se metodom pripravljaju sljedeći spojevi:
4-(4-klorofenil)-4-[4-(2-dimetilaminoetoksi)fenil]-3-fenilbut-3-en-1-ol
E-izomer, 1H NMR (CDCl3): 2,27 (s, 6H), 2,64 (t, 2H), 2,73 (t, 2H), 3,56 (t, 2H), 3,91 (t, 2H), 6,56 (d, 2H), 6,74 (d, 2H), 7,10–7,34 (m, 9H)
4-[4-(2-benziloksietoksi)fenil]-4-(4-fluorofenil)-3-fenilbut-3-en-1-ol
E-izomer, 1H NMR (CDCl3): 2,74 (t, 2H), 3,57 (m, 2H), 3,74 (dist.t, 2H), 4,01 (dist.t, 2H), 4,58 (s, 2H), 6,57 (d, 2H ), 6,75 (d, 2H), 7,00–7,40 (m, 14H) iz kojeg se može identificirati signal 7,03 (t, 2H).
Z-izomer, 1H NMR (CDCl3): 2,79 (t, 2H), 3,60 (m, 2H), 3,84 (dist.t, 2H), 4,17 (dist.t, 2H), 4,65 (s, 2H), 6,69 (t, 2H), 6,83 (dd, 2H), 6,91 (d, 2H ), 7,00–7,45 (m, 14H) iz kojeg se može identificirati signal 7,20 (d, 2H).
4-[4-(2-Benziloksietoksi)fenil]-3,4-bis(4-klorofenil)-but-3-en-1-ol
E-izomer, 1H NMR (CDCl3): 2,70 (t, 2H), 3,50-3,65 (m, 2H), 3,75 (dist.t, 2H), 4,03 (dist.t, 2H), 4,59 (s, 2H), 6,59 (d, 2H), 6,73 (d, 2H), 7,00–7,40 (m, 13H)
3,4-bis(4-klorofenil)-4-[4-(2-hidroksietoksi)fenil]but-3-en-1-ol
se dobiva kao nusprodukt u reakciji dehidracije of 1-[4-(2-benziloksietoksi)fenil]-1,2-bis(4-klorofenil)butan-1,4-diola.
E-izomer, 1H NMR (CDCl3): 2,72 (t, 2H), 3,50-3,65 (m, 2H), 3,80–3,96 (m, 4H), 6,59 (d, 2H), 6,75 (d, 2H), 7,00–7,40 (m, 8H)
Z-izomer, 1H NMR (CDCl3 + MeOH-d4): 2,75 (t, 2H), 3,56 (t, 2H), 3,95 (t, 2H), 4,09 (t, 2H), 6,79 (d, 2H), 6,91 (d, 2H), 7,01 (d, 2H), 7,05 (d, 2H), 7,16 (d, 2H), 7,19 (d, 2H).
3,4-bis(4-klorofenil)-4-[4-(2-dimetilaminoetoksi)fenil]but-3-en-1-ol
E-izomer, 1H NMR (CDCl3): 2,29 (s, 6H), 2,66 (t, 2H), 2,72 (t, 2H), 3,57 (t, 2H), 3,94 (t, 2H), 6,60 (d, 2H), 6,73 (d, 2H), 7,06 (d, 2H), 7,15 (d, 2H), 7,23 (d, 2H), 7,32 (d, 2H)
Z-izomer, HCl-sol, 1H NMR (MeOH-d4):), 2,77 (t, 2H), 3,03 (s, 6H ), 3,53 (t, 2H), 3,65 (t, 2H), 4,42 (t, 2H), 6,89 (d, 2H), 7,08 (d, 2H), 7,10 (d, 2H), 7,16 (d, 2H), 7,23 (d, 2H), 7,31 (d, 2H)
4,4-bis(4-hidroksifenil)-3-fenilbut-3-en-1-ol
Zaštitne tetrahidropiranilne (THP) skupine uklanjaju se reakcijom dehidracije.
1H NMR (CDCl3): 2,76 (t, 2H), 3,54 (m, 2H), 6,46 (d, 2H), 6,70 (d, 2H), 6,80 (d, 2H), 7,0–7,2 (m, 7H)
4-(4-klorofenil)-4-(4-hidroksifenil)-3-fenilbut-3-en-1-ol
Zaštitna THP skupina uklanja se reakcijom dehidracije.
E-izomer 1H NMR (CDCl3): 2,65 (t, 2H), 3,45 (t, 2H), 6,29 (d, 2H), 6,49 (d, 2H), 7,00–7,15 (m, 5H), 7,24 (d, 2H), 7,33 (d, 2H)
Z-izomer 1H NMR (CDCl3): 2,79 (t, 2H), 3,58 (t, 2H), 6,80 (d, 2H), 6,81 (d, 2H), 6,97 (d, 2H), 7,1–7,2 (m, 7H)
4-(4-klorofenil)-4-[4-(2,3-dihidroksipropiloksi)fenil]-3-fenilbut-3-en-1-ol
U reakciji se kida 2,2-dimetil-[1,3]dioksolanski prsten.
E-izomer 1H NMR (CDCl3): 2,73 (t, 2H), 3,55 (t, 2H), 3,60–3,77 (m, 2H), 3,87–4,05 (m, 3H), 6,56 (d, 2H), 6,76 (d, 2H), 7,1–7,35 (m, 9H)
3-(4-hidroksi-1,2-difenilbut-1-enil)fenol
Zaštitna THP skupina uklanja se reakcijom dehidracije.
Z-izomer 1H NMR (CDCl3): 2,73 (t, 2H), 3,55 (t, 2H), 6,4–7,4 (m, 12H)
d) Konverzija hidroksi-skupine 3,3,4-triarilbut-3-en-1-ola u klor.
Tionil-kloridom
(E)-(2-{4-[4-kloro-1-(4-fluorofenil)-2-fenilbut-1-enil]fenoksi}etildimetilamin (Br.1)
(E)-4-[4-(2-dimetilaminoetoksi)fenil]-4-(4-fluorofenil)-3-fenilbut-3-en1ol (0,8 g, 2 mmol) se otopi u toluenu (30 ml), te se doda tionil-klorid (0,7 g, 6 mmol). Smjesa se podvrgne povratnom strujanju tijekom jednog sata. Toluen djelomice ispari. Proizvod u obliku kristalizirane hidrokloridne soli se odfiltrira, a precipitat ispere toluenom. Dobije se 0,79 g, 86 % produkta.
1H NMR (HCl soč, MeOH-d4): 2,90 (t, 2H), 2,92 (s, 6H), 3,40 (t, 2H), 3,49 (dist.t, 2H), 4,21 (dist.t, 2H), 6,70 (d, 2H), 6,85 (d, 2H), 7,11 (t, 2H), 7,12–7,22 (m, 5H), 7,32 (dd, 2H)
Istom se metodom propravljaju sljedeći spojevi:
(Z)-(2-{4-[4-kloro-1-(4-fluorofenil)-2-fenilbut-1-enil]fenoksi}etildimetilamin (Br. 2)
1H NMR (HCl sol, MeOH-d4): 2,93 (t, 2H), 2,99 (s, 6H), 3,42 (t, 2H), 3,61 (dist.t, 2H), 4,39 (dist.t, 2H), 6,73 (t, 2H), 6,88 (dd, 2H), 7,07 (d, 2H), 7,12–7,22 (m, 5H), 7,29 (d, 2H)
(E)-(2-{4-[4-kloro-1-(4-klorofenil)-2-fenilbut-1-enil]fenoksi}etil)dimetilamin (Br. 3)
1H NMR (CDCl3): 2,30 (s, 6H), 2,66 (t, 2H), 2,91 (t, 2H), 3,40 (t, 2H), 3,94 (t, 2H), 6,57 (d, 2H), 6,75 (d, 2H), 7,1–7,4 (m, 9H)
(2-{4-[4-kloro-1,2-bis(4-klorofenil)but-1-enil]fenoksi}etil)dimetilamin (Br. 4 i 5)
E-izomer (Br. 4), HCl-sol, 1H NMR (CDCl3): 2,90 (s, 6H), 2,94 (t, 2H), 3,40 (t, 4H), 4,38 (t, 2H), 6,59 (d, 2H), 6,78 (d, 2H), 7,06 (d, 2H), 7,19 (d, 2H), 7,23 (d, 2H), 7,35 (d, 2H)
Z-izomer (Br. 5), HCl-sol, 1H NMR (MeOH-d4):), 2,95 (t, 2H), 3,41 (s, 6H ), 3,41 (t, 2H), 3,48-3,58 (m, 2H) 4,56-4,65 (m, 2H), 6,79 (d, 2H), 6,92 (d, 2H), 7,02 (d, 2H), 7,05 (d, 2H), 7,19 (d, 2H), 7,22 (d, 2H)
(E)-1-[4-(2-benziloksietoksi)fenil]-4-kloro-1-(4-fluorofenil)-2-fenilbut1en
1H NMR (CDCl3): 2,92 (t, 2H), 3,41 (t, 2H), 3,74 (dist.t, 2H), 4,01 (dist.t, 2H), 4,59 (s, 2H), 6,58 (d, 2H), 6,76 (d, 2H), 7,06 (t, 2H), 7,10–7,40 (m, 12H)
(E)-1-[4-(2-benziloksietoksi)fenil]-4-kloro-1,2-bis(4-klorofenil)-but-1-en
1H NMR (CDCl3): 2,90 (t, 2H), 3,39 (t, 2H), 3,76 (dist.t, 2H), 4,04 (dist.t, 2H), 4,60 (s, 2H), 6,60 (d, 2H), 6,74 (d, 2H), 7,06 (d, 2H), 7,17 (d, 2H), 7,23 (d, 2H) 7,25–7,4 (m, 7H)
4-kloro-1-[4-(2-kloroetoksi)fenil]-1,2-bis(4-klorofenil)-but-1-en (Br. 6 i 7)
se pripravlja iz 3,4-bis(4-klorofenil)-4-[4-(2-hidroksietoksi)fenil]but-3en1ola.
E-izomer (No,6), 1H NMR (CDCl3): 2,90 (t, 2H), 3,39 (m, 2H), 3,73 (t, 2H), 4,10 (t, 2H), 6,59 (d, 2H), 6,76 (d, 2H), 7,10 (d, 2H), 7,17 (d, 2H), 7,23 (d, 2H), 7,33 (d, 2H)
Z-izomer (No, 7), 1H NMR (CDCl3): 2,94 (t, 2H), 3,40 (t, 2H), 3,83 (t, 2H), 4,25 (t, 2H), 6,79 (d, 2H), 6,92 (d, 2H), 7,02 (d, 2H), 7,05 (d, 2H), 7,18 (d, 2H), 7,20 (d, 2H)
Trifenilfosfin-ugljikovim tetrakloridom
1-(2,2-imetil-[1,3]dioksolan-4-ilmetoksi)fenil-4-kloro-1-(4-klorofenil)2fenil-but-1-en
Trifenilfosfin (0,19 g, 0,73 mmol) se otopi u acetonitrilu (4 ml). Otopini se dodaju ugljikov tetraklorid (0,237 g, 1,3 mmol) i trietilamin (0,043 g, 0,43 mmol), te se smjesa miješa pola sata pri sobnoj temperaturi. U acetonitrilu se otopi 4-(2,2-dimetil-[1,3]dioksolan-4-ilmetoksi)fenil-4-(4-klorofenil)-3-fenil-but-3-en-1-ol (0,2 g, 0,43 mmol, pripravljen iz 4-(4-klorofenil)-4-[4-(2,3dihidroksipropiloksi)fenil]-3-fenilbut-3-n-1-ola zaštitom diolne skupine kao acetonida), doda reakcijskoj smjesi i nneprekidno miješa još dva sata. Otapalo se potom otpari, a ostatak otopi u 20 ml otopine metanol-voda (8:2). Otopina se dva puta ekstrahira petroleum-eterom (20 ml) pri točki ključanja. Petroleum-eterske faze se spoje i još jednom isperu vrućom otopinom metanol-voda. Dobije se 0,07 g produkta.
E-izomer 1H NMR (CDCl3): 1,37 i 1,41 (2s, zajedno 6H), 2,91 (t, 2H), 3,40 (t, 2H), 3,70–4,14 (m, 4H), 4,39 (kvintet, 1H), 6,56 (d, 2H), 6,76 (d, 2H), 7,05–7,4 (m, 9H)
e) Uklanjanje zaštitnih skupina
(E)-2-{4-[4-kloro-2-fenil-1-(4-fluorofenil)but-1-enil]fenoksi}etanol (Br. 8)
(E)-1-[4-(2-benziloksietoksi)fenil]-4-kloro-1-(4-fluorofenil)-2-fenilbut-1-en (400 mg, 0,8 mmol) se otopi u toluenu. Dodaju se Zn (106 mg, 1,6 mmol) i acetil-klorid (126 mg, 1,6 mmol) u atmosferi dušika. Smjesa se miješa šest sati pri sobnoj temperaturi. Smjesa se filtrira i otapalo otpari. Ostatak se otopi u 80 % vodenom metanolu koji sadrži 5 % natrijeva hidroksida. Smjesa se miješa dva sata pri sobnoj temperaturi, a metanol otpari. Doda se nešto vode i proizvod se ekstrahira u etilacetatu. Smjesa se osuši i otapalo otpari. Proizvod se pročisti plamenom kromatografijom (eluens: toluen:metanol 9:1).
1H NMR (CDCl3): 2,92 (t, 2H, ), 3,41 (t, 2H), 3,87-3,95 (m, 4H), 6,57 (d, 2H), 6,78 (d, 2H), 7,06 (t, 2H), 7,10–7,31 (m, 7H)
Istom se metodom pripravljaju sljedeći spojevi sadržani u ovom izumu:
(E)-2-{4-[(Z)-4-kloro-1,2-bis(4-klorofenil)but-1-enil]fenoksi}etanol (Br. 9)
1H NMR (CDCl3): 2,90 (t, 2H), 3,39 (t, 2H), 3,85–4,05 (m, 4H), 6,61 (d, 2H), 6,77 (d, 2H), 7,07 (d, 2H), 7,1–7,26 (m, 4H), 7,35 (d, 2H)
(E)-3-{4-[(Z)-4-kloro-1-(4-klorofenil)-2-fenil-but-1-enil]fenoksi}propan-1,2diol (Br. 10)
1-(2,2-Dimetil-[1,3]dioksolan-4-ilmetoksi)fenil-4-kloro-1-(4-klorofenil)-2-fenil-but-1-en (0,5 g, 1,0 mmol) se otopi u etanolu i otopini se doda 2 N vodena otopina vodikova klorida (5 ml). Smjesa se zagrije do 40°C i neprekidno miješa jedan sat. Potom se etanol otpari, a proizvod ekstrahira u toluenu, ispere vodom, osuši i otpari do suha. Dobije ga se se 0,45 g.
1H NMR (CDCl3): 2,91 (t, 2H), 3,41 (t, 2H), 3,60-4,15 (m, 5H), 6,56 (d, 2H), 6,77 (d, 2H), 7,1–7,4 (m, 9H)
Primjer 2
a) O-alkilacija derivata 4-(1,2-diaril-4-hidroksibut-1-enil)fenola
4,4-bis[4-(2-benziloksietoksi)fenil]-3-fenil but-3-en-1-ol
se pripravlja iz 4,4-bis(4-hidroksifenil)-3-fenilbut-3-en-1-ol (primjer 1c) i benzil 2-bromoetiletera reakcijom PTC, metodom opisanom u primjeru 1a.
1H NMR (CDCl3): 2,78 (t, 2H), 3,59 (q, 2H), 3,74, 3,84, 4,02 i 4,17 (4 dist.t, zajedno 8H), 4,59 (s, 2H), 4,65 (s, 2H), 6,56 (d, 2H), 6,76 (d, 2H), 6,91 (d, 2H), 7,09–7,40 (m, 17H)
Istom se metodom pripravljaju sljedeći spojevi:
E)-4-[4-(2-benziloksietoksi)fenil]-4-(4-klorofenil)-3-fenil-but-3-en-1-ol
1H NMR (CDCl3): 2,74 (t, 2H), 3,56 (t, 2H), 3,71–3,76 (m, 2H), 3,98–4,03 (m, 2H), 4,60 (s, 2H), 6,57 (d, 2H), 6,75 (d, 2H), 7,10–7,40 (m, 14H)
(Z)-4-[3-(2-benziloksietoksi)fenil]-3,4-difenil-but-3-en-1-ol
1H NMR (CDCl3): 2,75 (t, 2H), 3,58 (t, 2H), 3,63–3,66 (m, 2H), 3,81-3,85 (m, 2H), 4,55 (s, 2H), 6,47–7,40 (m, 19H)
(Z)-4-[4-(2-metilsulfaniletoksi)fenil]-3,4-difenil-but-3-en-1-ol
Spoj se pripravlja metodom opisanom u primjeru 1a, počevši s 4-(4-hidroksifenil)-3,4-difenil-but-3-en-1-olom (priprava opisana u US patentu no. 4,996,225) i 2-kloroetilmetil-sulfidom.
1H NMR (CDCl3): 2,16 (s, 3H), 2,75 (t, 2H), 2,79 (t, 2H), 3,59 (q, 2H), 4,02 (t, 2H), 6,55 (d, 2H), 6,79 (d, 2H), 7,05-7,40 (m, 10H)
(Z)-4-[4-(3-benziloksipropoksi)fenil]-3,4-difenil-but-3-en-1-ol
se pripravlja istom metodom, koristeći se benzil 3-bromopropileterom kao reagensom.
1H NMR (CDCl3): 2,00 (kvint,, 2H), 2,75 (t, 2H), 3,59 (2x t, 4H), 3,95 (t, 2H), 4,48 (s, 2H), 6,54 (d, 2H), 6,78 (d, 2H), 7,11–7,40 (m, 15H)
(E)-4-(4-klorofenil)-3-fenil-4-(4-{2-[2-(tetrahidropiraniloksi)etoksi]etoksi}fenil)but-3-en-1-ol
NaH (0,09 g, 2,69 mmol) se pomiješa s dimetilformamidom (DMF) (30 ml). U otopini se otopi (E)-4(4klorofenil)-4-(4-hidroksifenil)-3-fenilbut-3-en-1-ol, smjesa se zagrije do 60 °C i miješa pola sata. Otopini se doda 2[(2(tetrahidropiraniloksi)etoksi]etil klorid (0,83 g, 4,03 mmol) otopljen u DMF (5 ml) i nastavlja se grijati tijekom tri sata. U ohlađenu reakcijsku smjesu dodaju se vodena otopina amonij-klorida (30 ml) i toluen (30 ml), te se nastavi miješati još10 minuta. Slojevi se odvoje i vodeni se sloj ekstrahira toluenom (30 ml). Toluenske faze se spoje i isperu 2N vodenom otopinom natrijeva hidroksida, te tri puta vodom. Organska se faza osuši i otpari do suha. Dobije se 1,4 g, 99 % produkta.
1H NMR (CDCl3): 1,40–1,90 (m, 6H), 2,70 (t, 2H), 3,4-3,94 (m, 10H), 3,95–4,05 (m, 2H), 4,55 (m, 1H), 6,56 (d, 2H), 6,74 (d, 2H), 7,05–7,35 (m, 9H)
Istom se metodom pripravljaju sljedeći spojevi:
(Z)-3,4-difenil-4-(4-{2-[(2-(tetrahidropiraniloksi)etoksi]etoksi}fenil)but3en1ol
se pripravlja istom metodom kao i prethodni spoj, počevši s 4(4hidroksifenil)-3,4-difenil-but-3-en-1-olom (priprava opisana u US patentu no. 4,996,225) i 2-[2-(tetrahidropiraniloksi)etoksi]etil-kloridom.
1H NMR (CDCl3): 1,40-1,91 (m, 6H), 2,74 (t, 2H), 3,4–4,0 (m, 12H), 4,61 (m, 1H), 6,55 (d, 2H), 6,77 (d, 2H), 7,05-7,35 (m, 10H)
4-(4-fluorofenil)-3-fenil-4-(4-{2-[2-(tetrahidropiraniloksi)etoksi]etoksi}fenil)but-3-en-1-ol
E-izomer 1H NMR (CDCl3): 1,38–1,90 (m, 6H), 2,75 (t, 2H), 3,32–4,03 (m, 10H), 4,00 (m, 2H), 4,62 (m, 1H), 6,56 (d, 2H), 6,75 (d, 2H), 7,04 (t, 2H), 7,00–7,20 (m, 5H), 7,27 (dd, 2H)
Z-izomer 1H NMR (CDCl3): 1,40–1,90 (m, 6H), 2,79 (t, 2H), 3,43-4,03 (m, 10H), 4,15 (m, 2H), 4,65 (m, 1H), 6,69 (t, 2H), 6,83 (dd, 2H), 6,90 (d, 2H), 7,05–7,20 (m, 5H), 7,19 (d, 2H)
(Z)-4-[4-(2,2-dimetil-[1,3]-dioksolan-4-ilmetoksi)fenil]-3,4-difenilbut-3-en-1-ol
1H NMR (CDCl3): 1,37 i 1,41 (2s, zajedno 6H), 2,75 (t, 2H), 3,58 (t, 2H), 3,70–4,10 (m, 4H), 4,39 (kvintet, 1H), 6,56 (d, 2H), 6,78 (d, 2H), 7,10–7,40 (m, 10H)
{4-[1-(4-klorofenil)-4-hidroksi-2-fenilbut-1-enil]fenoksi}etilester octene kiseline
se pripravlja iz 4-(4-klorofenil)-4-(4-hidroksifenil)-3-fenilbut-3-en-1-ola (primjer 1c) i etil-bromoacetata prema postupku opisanom u primjeru 1a, koristeći NaH kao bazu.
E-izomer 1H NMR (CDCl3): 1,25 (t, 3H), 2,74 (t, 2H), 3,57 (t, 2H), 4,22 (q, 2H), 4,48 (s, 2H), 6,56 (d, 2H), 6,77 (d, 2H), 7,0–7,4 (m, 9H)
Z-izomer 1H NMR (CDCl3): 1,31 (t, 3H), 2,78 (t, 2H), 3,58 (t, 2H), 4,29 (q, 2H), 4,63 (s, 2H), 6,79 (d, 2H), 6,89 (d, 2H), 6,98 (d, 2H), 7,15–7,30 (m, 7H)
b) Konverzija hidroksilne skupine i klor
1,1-bis[4-(2-benziloksietoksi)fenil]-4-kloro-2-fenil-but-1-en
Konverzija hidroksi-skupine u klor izvodi se korištenjem tionil-klorida kao reagensa, prema postupku opisanom u primjeru 1d.
1H NMR (CDCl3): 2,94 (t, 2H), 3,42 (t, 2H), 3,73 i 3,83 (2 dist.t,, zajedno 4H), 4,00 i 4,16 (2 dist.t,, zajedno 4H), 4,58 (s, 2H), 4,65 (s, 2H), 6,56 (d, 2H), 6,76 (d, 2H), 6,92 (d, 2H), 7,10–7,40 (m, 17H)
Istom se metodom pripravljaju sljedeći spojevi:
(E)-1-[4-(2-benziloksietoksi)fenil]-4-kloro-1-(4-klorofenil)-2-fenil-but-1-en
1H NMR (CDCl3): 2,91 (t, 2H), 3,40 (t, 2H), 3,71–3,76 (m, 2H), 3,98–4,03 (m, 2H), 4,60 (s, 2H), 6,57 (d, 2H), 6,75 (d, 2H), 7,10–7,40 (m, 14H)
(Z)-4-kloro-1-[4-(2-metilsulfaniletoksi)fenil]-1,2-difenil-but-1-en (Br. 11)
1H NMR (CDCl3): 2,16 (s, 3H), 2,79 (t, 2H), 2,92 (t, 2H), 3,42 (t, 2H), 4,01 (t, 2H), 6,55 (d, 2H), 6,78 (d, 2H), 7,05–7,45 (m, 10H)
(Z)-1-[3-(2-benziloksietoksi)fenil]-4-kloro-1,2-difenil-but-1-en
1H NMR (CDCl3): 2,92 (t, 2H), 3,41 (t, 2H), 3,63–3,67 (m, 2H), 3,81–3,85 (m, 2H), 4,55 (s, 2H), 6,47-7,40 (m, 19H)
(Z)-1-[4-(3-benziloksipropoksi)fenil]- 4-kloro-1,2-difenil-but-1-en
1H NMR (CDCl3): 2,0 (kvintet, 2H), 2,92 (t, 2H), 3,42 (t, 2H), 3,59 (t, 2H), 3,94 (t, 2H), 4,48 (s, 2H), 6,54 (d, 2H), 6,78 (d, 2H), 7,11–7,40 (m, 15H)
{4-[4-kloro-1-(4-klorofenil)-2-fenilbut-1-enil]fenoksi}etilester octene kiseline i odgovarajuća kiselina (Br. 12 i 13)
E-izomer, etilester 1H NMR (CDCl3): 1,25 (t, 3H), 2,91 (t, 2H), 3,41 (t, 2H), 4,21 (q, 2H), 4,49 (s, 2H), 6,57 (d, 2H), 6,77 (d, 2H), 7,0–7,4 (m, 9H)
Ester se hidrolizira do odgovarajuće kiseline u 80 % vodenom metanolu koji sadrži 5 % natrijeva hidroksida.
E-izomer, kiselina (No, 12)1H NMR (CDCl3): 2,91 (t, 2H), 3,41 (t, 2H), 4,47 (s, 2H), 6,58 (d, 2H), 6,78 (d, 2H), 7,0–7,4 (m, 9H)
Z-izomer, etilester 1H NMR (CDCl3): 1,31 (t, 3H), 2,95 (t, 2H), 3,42 (t, 2H), 4,30 (q, 2H), 4,65 (s, 2H), 6,79 (d, 2H), 6,91 (d, 2H), 6,98 (d, 2H), 7,15–7,30 (m, 7H)
Z-izomer, kiselina (No, 13) 1H NMR (CDCl3): 2,95 (t, 2H), 3,41 (t, 2H), 4,65 (s, 2H), 6,79 (d, 2H), 6,94 (d, 2H), 6,98 (d, 2H), 7,10–7,30 (m, 7H)
(Z)-1,2-difenil-4-kloro-4-(4-{2-[2-(tetrahidropiraniloksi)etoksi]etoksi}fenil)but-1-en
Konverzija hidroksi-skupine u klor izvodi se korištenjem Ph3P i CCl4 kao reagenasa, prema postupku opisanom u primjeru 1d.
1H NMR (CDCl3): 1,30–1,90 (m, 6H), 2,92 (t, 2H), 3,42 (t, 2H), 3,4–4,0 (m, 10H), 4,62–4,65 (m, 1H), 6,55 (d, 2H), 6,77 (d, 2H), 7,05–7,35 (m, 10H)
Istom se metodom pripravljaju sljedeći spojevi:
(Z)-4-[4-(4-kloro-1,2-difenil-but-1-enil)fenoksimetil]-2,2-dimetil-[1,3]dioksolan
1H NMR (CDCl3): 1,37 i 1,41 (2s, zajedno 6H), 2,91 (t, 2H), 3,41 (t, 2H), 3,7–4,1 (m, 4H), 4,39 (kvintet, 1H), 6,55 (d, 2H), 6,77 (d, 2H), 7,10–7,41 (m, 10H)
(E)-1-(4-{2-[(2-kloroetoksi]etoksi}fenil)-4-kloro-1-(4-klorofenil)2fenilbut-1-en (Br. 14)
U reakciji se zbiva i konverzija tetrahidropiraniloksi-skupine u klor.
1H NMR (CDCl3): 2,94 (t, 2H), 3,43 (t, 2H), 3,65 (dist, t, 2H), 3,8-3,85 (m, 4H), 4,0–4,06 (m, 2H), 6,60 (d, 2H), 6,78 (d, 2H), 7,10–7,40 (m, 9H)
(E)-1-(4-{2-[(2-kloroetoksi]etoksi}fenil)-4-kloro-1-(4-fluorofenil)2fenilbut-1-en (Br. 15)
U reakciji se zbiva i konverzija tetrahidropiraniloksi-skupine u klor.
1H NMR (CDCl3): 2,91 (t, 2H), 3,41 (t, 2H), 3,62 (dist, t, 2H), 3,74–3,85 (m, 4H), 4,01 (dist.t, 2H ), 6,57 (d, 2H), 6,76 (d, 2H), 7,06 (t, 2H), 7,09–7,22 (m, 5H), 7,27 (dd, 2H)
c) uklanjanje zaštitnih skupina
2-(4-{4-kloro-1-[4-(2-hidroksietoksi)fenil]-2-fenil-but-1-enil}fenoksi)1etanol (Br. 16)
Benzilne se skupine uklanjaju korištenjem Zn i AcCl kao reagenasa, prema metodi opisanoj u primjeru 1e.
1H NMR (CDCl3): 2,95 (t, 2H), 3,42 (t, 2H), 3,80–4,20 (m, 8H), 6,56 (d, 2H), 6,78 (d, 2H), 6,92 (d, 2H), 7,10–7,26 (m, 7H)
Istom se metodom pripravljaju sljedeći spojevi sadržani u ovom izumu:
(E)-2-{4-[4-kloro-2-fenil-1-(4-klorofenil)but-1-enil]fenoksi}etanol (Br. 17)
1H NMR (CDCl3): 2,92 (t, 2H), 3,41 (t, 2H), 3,80–4,00 (m, 4H), 6,57 (d, 2H), 6,77 (d, 2H), 7,10–7,40 (m, 9H)
(Z)-2-[3-(4-kloro-1,2-difenil-but-1-enil)fenoksi]etanol (Br. 18)
1H NMR (CDCl3): 2,93 (t, 2H), 3,41 (t, 2H), 3,70–3,80 (m, 4H), 6,40–7,40 (m, 14 H)
(Z)-2-{2-[4-(4-kloro-1,2-difenilbut-1-enil)fenoksi]-etoksi}etanol (Br. 19)
Tetrahidropiranileter se cijepa pomoću H+/EtOH, metodom opisanom u primjeru 1e.
1H NMR (CDCl3): 2,92 (t, 2H), 3,41 (t, 2H), 3,61, 3,68, 3,77 (3 dist.t, 6H), 4,00 (dist.t, 2H), 6,56 (d, 2H), 6,78 (d, 2H), 7,1–7,4 (m, 10H)
Istom se metodom pripravljaju sljedeći spojevi sadržani u ovom izumu:
(Z)-3-[4-(4-kloro-1,2-difenil-but-1-enil)fenoksi]propan-1,2-diol (Br. 20)
1H NMR (CDCl3): 2,92 (t, 2H), 3,41 (t, 2H), 3,58–4,10 (m, 5H), 6,53 (d, 2H), 6,78 (d, 2H), 7,10–7,41 (m, 10H)
Primjer 3
a) (Z)-4-[4-(2-imidazol-1-il-etoksi)fenil]-3,4-difenil-but-3-en-1-ol
(Z)-4-[4-(2-Bromoetoksi)fenil]-3,4-difenilbut-3-en-1-ol (priprava opisana u US patentu no. 4,996,225) (4,97 g, 0,0117 mol) se otopi u metiletilketonu (50 ml) i kalijevu karbonatu (4,8 g, 0,035 mol), te se otopini doda imidazolna natrijeva sol (2,11 g, 0,0234 mol). Smjesa se miješa i podvrgne povratnom strujanju tijekom pet sati. Otopina se potom filtrira i filtrat otpari do suha. Ostatak se otopi u etilacetatu, ispere 2 N vodenom otopinom natrijeva hidroksida, osuši i otpari do suha. Ostatak se rekristalizira iz smjese toluena i acetonitrila.
1H NMR (CDCl3): 2,75 (t, 2H), 3,59 (dist, t, 2H), 4,07 (dist, t, 2H), 4,23 (dist, t, 2H), 6,51 (d, 2H), 6,79 (d, 2H), 6,97 (s, 1H), 7,03 (s, 1H), 7,05-7,40 (m, 10H), 7,51 (s, 1H)
(Z)-4-[4-(2-metilaminoetoksi)fenil]-3,4-difenilbut-3-en-1-ol
(Z)-4-[4-(2-kloroetoksi)fenil]-3,4-difenilbut-3-en-1-ol (pripravljen kao i (Z)4[4(2-bromoetoksi)fenil]-3,4-difenilbut-3-en-1-ol, a čija je priprava opisana u US patentu no. 4,996,225)(2,0 g, 0,0052 mol) i metilamin u 40 % vodenoj otopini (5 ml, 0,065 mol) pomiješaju se s dimetilformamidom (8 ml). Smjesa se grije u zatvorenoj epruveti osam sati pri 60 °C. Smjesi se doda 60 ml vode i ekstrahira se etilacetatom. Etilacetatna se faza ispere vodenom otopinom 2 N vodikova klorida. Vodena se faza zaluži dodavanjem 2 N otopine natrijeva hidroksida i ekstrahira etilacetatom. Etilacetatna se faza ispere vodom, osuši magnezijevim sulfatom i upari do suha. Dobije se 1,5 g produkta.
1H NMR (CDCl3): 2,39 (s, 3H), 2,70 (t, 2H), 2,84 (t, 2H), 3,48 (t, 2H), 3,93 (t, 2H), 6,59 (d, 2H), 6,77 (d, 2H), 7,10-7,40 (m, 10H )
b) (Z)-4-(4-{2-[(2-benziloksietil)metilamino]etoksi}fenil)-3,4-difenil-but3en1-ol
Pripravlja se istom PTC metodom koja je opisana u primjeru 1a, koristeći benzil 2bromoetileter kao reagens.
1H NMR (CDCl3): 2,35 (s, 3H), 2,70, 2,75, 2,79 (3 t, 6H), 3,56 (t, 2H), 3,60 (t, 2H), 3,94 (t, 2H), 4,50 (s, 2H), 6,54 (d, 2H), 6,77 (d, 2H), 7,10–7,20 (m, 5H), 7,25–7,35 (m, 10H )
c) (Z)-1-{2-[4-(4-kloro-1,2-difenilbut-1-enil)fenoksi]etil}-1H-imidazol (Br. 21)
se pripravlja kao što je opisano u primjeru 1d, koristeći se trifenilfosfinom i ugljikovim tetrakloridom kao reagensima. Proizvod se pročišćava otparavanjem acetonitrila i otapanjem ostatka u kiseloj otopini metanol-voda (8:2), te ekstrakcijom trifenilfosfina toluenom (tri puta pri sobnoj temperaturi). Otopina metanol-voda zaluži se i proizvod se ekstrahira toluenom. Toluenska se faza ispere dva puta vodom i otpari do suha. Proizvod se, u obliku soli HCl, kristalizira iz etilacetata. Dobije se 46 % proizvoda.
1H NMR (HCl-sol, MeOH-d4): 2,89 (t, 2H), 3,39 (t, 2H), 4,23 (t, 2H), 4,60 (t, 2H), 6,60 (d, 2H), 6,80 (d, 2H), 7,10-7,40 (m, 10H ), 7,54 (s, 1H), 7,67 (s, 1H), 8,98 (s, 1H)
(Z)-(2-benziloksietil)-{2-[4-(4-kloro-1,2-difenil-but-1-enil)fenoksi-etil}metilamin
se pripravlja kao što je opisano u primjeru 1d, korištenjem tionil-klorida kao reagensa.
1H NMR (CDCl3): 2,35 (s, 3H), 2,70, 2,79 (2 t, 4H), 2,92 (t, 2H), 3,42 (t, 2H), 3,56 (t, 2H), 3,93 (t, 2H), 4,51 (s, 2H), 6,54 (d, 2H), 6,77 (d, 2H), 7,10–7,40 (m, 15H)
d) (Z)-2-({2-[-4-(4-kloro-1,2-difenil-but-1enil)fenoksi]etil}metilamino)etanol (Br. 22)
se pripravlja istom metodom kao u primjeru 1e, koristeći Zn i acetil-klorid kao reagense.
1H NMR (CDCl3): 2,32 (s, 3H), 2,60 (t, 2H), 2,78 (t, 2H), 2,92 (t, 2H), 3,42 (t, 2H), 3,57 (t, 2H), 3,91 (t, 2H), 6,54 (d, 2H), 6,78 (d, 2H), 7,05–7,40 (m, 10H)
Primjer 4
a) 2-(4-klorofenil)-1-(4-metoksifenil)etanon
Anisol (13,9 g, 0,13 mol) se, uz miješanje, doda otopini 4-klorofeniloctene kiseline (20,0 g, 0,12 mol) u trifluoroctenom anhidridu (16,5 ml, 0,12 mol). Smjesa se miješa 24 sata pri sobnoj temperaturi. Doda se ledenohladna voda, kristalizirani se produkt skupi na sinter-pločici i ispere vodom. Proizvod se kristalizira iz etanola. Dobije ga se 20,4 g, 67 %.
1H NMR (CDCl3): 3,86 (s, 3H), 4,20 (s, 2H), 6,93 (d, 2H), 7,20 (d, 2H), 7,28 (d, 2H), 7,98 (d, 2H)
Istom se metodom pripravljaju sljedeći spojevi:
2-(4-fluorofenil)-1-(4-metoksifenil)etanon
1H NMR (CDCl3): 3,87 (s, 3H), 4,21 (s, 2H), 6,94 (d, 2H), 7,01 (t, 2H), 7,22 (dd, 2H), 7,99 (d, 2H)
1-(4-metoksifenil)-2-fenil-etanon
1H NMR (CDCl3): 3,84 (s, 3H), 4,23 (s, 2H), 6,92 (d, 2H), 7,20–7,40 (m, 5H), 7,99 (d, 2H)
b) 2-(4-klorofenil)-1-(4-hidroksifenil)etanon
Aluminijev klorid (29,8 g, 0,223 mol) u malim se porcijama dodaje se, uz miješanje, otopini 2-(4-klorofenil)-1-(4-metoksifenil)etanona (19,4 g, 0,074 mol) u toluenu (300 ml). Smjesa se zagrije do to 60 C i nastavi miješati neprekidno dva sata. Ohlađenoj se smjesi doda razrijeđena kloridna kiselina. Doda se etilacetat, da se proizvod otopi. Odvoje se slojevi i vodena se faza ekstrahira etilacetatom. Spojene organske faze se osuše, a otapala otpare. Produkt se rekristalizira iz toluena. Dobije ga se 17 g, 93 %.
1H NMR (CDCl3 + MeOH-d4): 4,19 (s, 2H), 6,85 (d, 2H), 7,19 (d, 2H), 7,28 (d, 2H), 7,90 (d, 2H)
Istom se metodom pripravljaju sljedeći spojevi:
2-(4-fluorofenil)-1-(4-hidroksifenil)etanon
1H NMR (CDCl3 + MeOH-d4): 4,20 (s, 2H), 6,86 (d, 2H), 7,00 (t, 2H), 7,22 (dd, 2H), 7,91 (d, 2H)
1-(4-hidroksifenil)-2-fenil etanon
1H NMR (CDCl3 + MeOH-d4): 4,20 (s, 2H), 6,84 (d, 2H), 7,2–7,4 (m, 5H ) 7,90 (d, 2H)
c) O-Alkiliranje derivata 4-hidroksidesoksibenzoina
U uvjetima PTC
2-(4-klorofenil)-1-[4-(2-dimetilaminoetoksi)fenil]etanon
10 % vodena otopina natrijeva hidroksida doda se smjesi koja sadrži 2-(4-klorofenil)-1-(4-hidroksifenil)etanon (6,0 g, 0,024 mol) i TBABr (0,9 g) u toluenu (60 ml) pri 60 °C. Smjesa se miješa 30 min. Doda se N,N-dimetilaminoetil-klorid-hidroklorid (3,6 g, 0,025 mol) i nastavi se miješati tri sata pri 70–75 °C. Slojevi se odvoje i vodena se faza ekstrahira toluenom. Produkt se dobije otparavanjem spojenih toluenskih faza (1,85 g, 24 %).
1H NMR (CDCl3): 2,34 (s, 6H), 2,75 (t, 2H), 4,12 (t, 2H), 4,20 (s, 2H), 6,95 (d, 2H), 7,19 (d, 2H), 7,29 (d, 2H), 7,97 (d, 2H)
Istom se metodom pripravljaju sljedeći spojevi:
1-[4-(2-dimetilaminoetoksi)fenil]-2-(4-fluorofenil)etanon
1H NMR (CDCl3): 2,34 (s, 6H), 2,75 (t, 2H), 4,12 (t, 2H), 4,21 (s, 2H), 6,96 (d, 2H), 7,01 (t, 2H), 7,22 (dd, 2H), 7,98 (d, 2H)
S K2CO3 u 2-butanonu
1-[4-(2-benziloksietoksi)fenil]-2-feniletanon
1-(4-Hidroksifenil)-2-feniletanon (17 g, 0,08 mol) se otopi u 2-butanonu (200 ml) i kalijevu arbonatu (33,1 g, 0,24 mol), te se otopini doda 2benziloksietilbromid (25,8 g, 0,12 mol). Smjesa se miješa i podvrgne povratnom strujanju tijekom tri sata. Otopina se potom filtrira i filtrat otpari do suha. Ostatak se otopi u toluenu, ispere 2 N otopinom natrijeva hidroksida i vodom, osuši i otpari do suha. Produkt se kristalizira iz etanola. Dobije ga se 23,2 g, 84 %.
1H NMR (CDCl3): 3,80-3,86 (m, 2H), 4,20-4,22 (m, 2H), 4,23 (s, 2H), 4,63 (s, 2H), 6,90 (d, 2H), 7,20-7,40 (m, 10H), 7,90 (d, 2H)
Istom se metodom pripravljaju sljedeći spojevi:
1-[4-(2-benziloksietoksi)fenil]-2-(4-klorofenil)etanon
1H NMR (CDCl3): 3,84 (dist.t, 2H), 4,20 (dist.t,, 2H), 4,20 (s, 2H), 4,63 (s, 2H), 6,95 (d, 2H), 7,19 (d, 2H), 7,29 (d, 2H), 7,30-7,45 (m, 5H), 7,96 (d, 2H)
2-(3-metoksifenil)-1-[4-(2-piperidin-1-iletoksi)fenil]etanon
Kao početni materijal koriste se 1-(4-hidroksifenil)-2-(3-metoksifenil)etanon i 1-(2-kloroetil)piperidin-hidroklorid.
1H NMR (CDCl3): 1,37-1,52 (m, 2H), 1,52–1,68 (m, 4H), 2,50 (Br.t, 4H), 2,78 (t, 2H), 3,77 (s, 3H), 4,14 (t, 2H), 4,19 (s, 2H), 6,73-6,90 (m, 3H), 6,90 (d, 2H), 7,22 (t, 1H), 7,96 (d, 2H)
2-(2-metoksifenil)-1-[4-(2-piperidin-1-iletoksi)fenil]etanon
Kao početni materijal koriste se 1-(4-hidroksifenil)-2-(2-metoksifenil)etanon i 1-(2-kloroetil)piperidin-hdroklorid.
1H NMR (CDCl3): 1,40-1,53 (m, 2H), 1,53-1,70 (m, 4H), 2,51 (Br.t, 4H), 2,79 (t, 2H), 3,79 (s, 3H), 4,16 (t, 2H), 4,22 (s, 2H), 6,84–7,00 (m, zajedno 4H) pod kojim 6,92 (d, 2H), 7,14-7,30 (m, 2H), 8,00 (d, 2H)
d) C-Alkiliranje derivata deoksibenzoina 4-benziloksi-2-(4-klorofenil)-1-[4-(2-dimetilaminoetoksi)fenil]butan-1-on
Smjesa koja sadrži 2-(4-klorofenil)-1-[4-(2-dimetilaminoetoksi)fenil]etanon (6,3 g, 0,020 mol) i TBABr (0,5 g) u toluenu (70 ml) zagrije se do 70 °C, te joj se doda 48 % vodena otopina natrijeva hidroksida (70 ml). Smjesa se miješa 30 min, te joj se, kap po kap, doda (2-bromoetoksimetil)benzen (5,5 g, 0,025 mol) pri 85-90 °C. Reakcijska se smjesa miješa tri sata pri 95-100 °C. Slojevi se odvoje i vodena se faza ekstrahira toluenom. Spojene organske faze isperu se vodom, a otapalo se otpari. Dobiveni proizvod (9,0 g ) bez daljeg se pročišćavanja koristi i udućoj reakciji.
1H NMR (CDCl3): 1,93–2,15 i 2,38–2,58 (2m, zajedno 2H), 2,32 (s, 6H), 2,72 (t, 2H), 3,25–3,55 (m, 2H), 4,08 (t, 2H), 4,42 (s, 2H), 4,82 (t, 1H), 6,88 (d, 2H), 7,15–7,40 (m, 9H), 7,92 (d, 2H)
Istom se metodom pripravljaju sljedeći spojevi:
4-benziloksi-1-[4-(2-dimetilaminoetoksi)fenil]-2-(4-fluorofenil)butan-1-on
1H NMR (CDCl3): 1,95–2,15 i 2,40-2,60 (2m, zajedno 2H), 2,31 (s, 6H), 2,71 (t, 2H), 3,25–3,55 (m, 2H), 4,07 (t, 2H), 4,42 (s, 2H), 4,83 (t, 1H), 6,88 (d, 2H), 6,94 (t, 2H ), 7,10–7,40 (m, 7H), 7,93 (d, 2H)
4-benziloksi-2-(4-klorofenil)-1-(4-metoksifenil)butan-1-on
1H NMR (CDCl3): 1,95–2,15 i 2,35-2,55 (2m, zajedno 2H), 3,30–3,55 (m, 2H), 3,82 (s, 3H), 4,42 (s, 2H), 4,82 (t, 1H), 6,85 (d, 2H), 7,10–7,40 (m, 9H), 7,93 (d, 2H)
1-[4-(2-benziloksietoksi)fenil]-2-fenil-4-(tetrahidropiraniloksi)butan-1-on
1H NMR (CDCl3 ): 1,4–1,9 (m, 6H), 2,0–2,2 (m, 1H), 2,4–2,65 (m, 1H), 3,2–4,05 (m, 6H), 4,1–4,2 (m, 2H), 4,45-4,5 (m, 1H), 4,60 (s, 2H), 4,80 (t, 1H), 6,88 (d, 2H), 7,1–7,4 (m, 10H), 7,96 (d, 2H)
1-[4-(2-benziloksietoksi)fenil]-2-(4-klorofenil)-4-(tetrahidropiraniloksi)butan-1-on
1H NMR (CDCl3 ): 1,30–1,90 (m, 6H), 1,95–2,15 i 2,38–2,58 (2m, zajedno 2H), 3,20–4,05 (m, 6H), 4,16 (dist.t, 2H), 4,75-4,85 (m, 1H), 4,61 (s, 2H), 4,80 (t, 1H), 6,88 (d, 2H), 7,13–7,40 (m, 9H ), 7,94 (d, 2H)
1,2-bisfenil-4-(tetrahidropiraniloksi)butan-1-on
1H NMR (CDCl3 ): 1,4–1,9 (m, 6H), 2,0–2,2 (m, 1H), 2,4–2,65 (m, 1H), 3,2–3,9 (m, 4H), 4,45–4,5 (m, 1H), 4,85 (t, 1H), 7,1–7,5 (m, 8H), 8,00 (d, 2H)
2-(3-metoksifenil)-1-[4-(2-piperidin-1-iletoksi)fenil]-4-(tetrahidropraniloksi)butan-1-on
1H NMR (CDCl3 ): 1,40–1,90 (m, 13H), 1,95–2,2 (m, 1H), 2,48 (Br.t, 4H), 2,75 (t, 2H), 3,20–3,90 (m, 4H) pod kojim 3,76 (s, 3H), 4,11 (t, 2H), 4,49 (m, 1H), 4,77 (m, 1H), 6,73 (dd, 2H), 6,80–6,95 (m, 4H), 7,21 (t, 1H), 7,96 (d, 2H)
2-(2-metoksifenil)-1-[4-(2-piperidin-1-iletoksi)fenil]-4-(tetrahidropiraniloksi)butan-1-on
1H NMR (CDCl3 ): 1,30–1,90 (m, 13H), 1,95-2,15 (m, 1H), 2,48 (m, 4H), 2,74 (t, 2H), 3,20–4,00 (m, 4H) pod kojim 3,88 (s, 3H), 4,09 (t, 2H), 4,45–4,55 (m, 1H), 5,22 (m, 1H), 6,73–6,90 (m, 4H) 7,14–7,30 (m, 2H), 7,97 (d, 2H)
e) Grignardova reakcija s derivatima deoksibenzoina
4-benziloksi-2-(4-klorofenil)-1-[4-(2-dimetilaminoetoksi)fenil]1fenilbutan-1-ol
4-Benziloksi-2-(4-klorofenil)-1-[4-(2-dimetilaminoetoksi)fenil]butan-1-on (9,4 g, 0,021 mol) se doda Grignardovu reagensu pripravljenom od bromobenzena (13,1 g, 0,083 mol) i strugotina Mg (2,0 g, 0,083 mol) u suhom tetrahidrofuranu. Smjesa se podvrgne povratnom strujanju tijekom tri sata. Ohlađenoj reakcijskoj smjesi doda se otopina amonijeva klorida, odvoji se THF sloj, a vodena se faza ekstrahira toluenom. Spojene organske faze isperu se vodom, a otapala otpare. Dobiveni produkt (10,7 g) koristi se bez daljeg pročišćavanja u idućoj reakciji.
Istom se metodom pripravljaju sljedeći spojevi:
4-benziloksi-1-[4-(2-dimetilaminoetoksi)fenil]-2-(4-fluorofenil)1fenilbutan-1-ol
koristi se bez daljeg pročišćavanja u idućoj reakciji.
4-benziloksi-2-(4-klorofenil)-1-[4-(2-dimetilaminoetoksi)fenil]1(4metoksifenil)butan-1-ol
koristi se bez daljeg pročišćavanja u idućoj reakciji.
1-(3-benziloksifenil)-1-[4-(2-benziloksietoksi)fenil]-2-fenil-4-(tetrahidropiraniloksi)butan-1-ol
koristi se bez daljeg pročišćavanja u idućoj reakciji.
1-[4-(benziloksietoksi)fenil]-2-(4-klorofenil)-1-(4-metoksifenil)4(tetrahidropiraniloksi)butan-1-ol
koristi se bez daljeg pročišćavanja u idućoj reakciji.
2-(3-metoksifenil)-1-fenil-1-[4-(2-piperidin-1-iletoksi)fenil]-4-(tetrahidropiraniloksi)butan-1-ol
koristi se bez daljeg pročišćavanja u idućoj reakciji.
2-(2-metoksifenil)-1-fenil-1-[4-(2-piperidin-1-iletoksi)fenil]4(tetrahidropiraniloksi)butan-1-ol
koristi se bez daljeg pročišćavanja u idućoj reakciji.
1-[3-(2-dimetilaminoetoksi)fenil]1,2-difenil-4-(tetrahidropiraniloksi)butan1-ol
koristi se bez daljeg pročišćavanja u idućoj reakciji.
1-[4-(2-benziloksietilsulfanil)fenil]1,2-difenil-4-(tetrahidropiraniloksi)butan-1-ol
koristi se bez daljeg pročišćavanja u idućoj reakciji.
1-[4-(2-dimetilaminoetilsulfanil)fenil]-1,2-difenil-4-(tetrahidropiraniloksi)butan-1-ol
koristi se bez daljeg pročišćavanja u idućoj reakciji.
f) Dehidracija derivata triarilbutandiola
(2-{4-[4-benziloksi-2-(4-klorofenil)-1-fenilbut-1-enil]fenoksi}etil)dimetilamin
4-Benziloksi-2-(4-klorofenil)-1-[4-(2-dimetilaminoetoksi)fenil]-1-fenilbutan-1-ol (10,7 g) se otopi u metanolu (70 ml), te se doda koncentrirana kloridna kiselina, da se otopina zakiseli. Smjesa se miješa 4,5 h pri sobnoj temperaturi, a potom jedan sat pri 50 °C. Otapalo se otpari i produkt se pročisti plamenom kromatografijom ( eluens: toluen:trietilamin 24:1). Dobije se 5,6 g, u obliku smjese E- and Z-izomera (1:2).
1H NMR (smjesa Z- i E-izomer, CDCl3): 2,28 i 2,34 (2s, 6H), 2,64 i 2,73 (2t, 2H), 2,78 i 2,83 (2t, 2H), 3,40 i 3,42 (2t, 2H), 3,93i 4,07 (2t, 2H), 4,36 i 4,38 (2s, 2H), 6,55-7,40 (m, 18H) iz čega se može identificirati 6,58 i 6,75 (2d, 4H).
Istom se metodom pripravljaju sljedeći spojevi:
(2-{4-[4-benziloksi-2-(4-fluorofenil)-1-fenilbut-1-enil]fenoksi}etil)dimetilamin
1H NMR (smjesa Z- i E-izomera, CDCl3): 2,28 i 2,34 (2s, 6H), 2,65i 2,74 (2t, 2H), 2,78 i 2,83 (2t, 2H), 3,41 i 3,43 (2t, 2H), 3,93 i 4,07 (2t, 2H), 4,37 i 4,39, (2s, 2H), 6,50-7,40 (m, 18 H) i čega se mogu identificirati 6,58 i 6,75 (2d, 4H).
(2-{4-[4-benziloksi-2-(4-klorofenil)-1-(4-metoksifenil)but-1-enil]fenoksi}etil)dimetilamin
1H NMR (smjesa Z- i E-izomera, CDCl3): 2,30 i 2,35 (2s, 6H), 2,67 i 2,76 (2t, 2H), 2,81 (t, 2H), 3,41 (t, 2H), 3,69 i 3,81 (2s, 3H), 4,38 (s, 2H), 6,56 i 6,86 (2d, 2H), 6,58 i 6,85 (2d, 2H), 6,75 (d, 2H), 6,76 (d, 2H), 7,0–7,4 (m, 11H)
4-[4-(2-benziloksietoksi)fenil]-3-(4-klorofenil)-4-(4-metoksifenil)but3en-1-ol
pripravlja se prema postupku opisanom u primjeru 1c. Izomeri Z i E odvoje se plamenom kromatografijom, uz eluens toluen:metanol 99:1.
Z-izomer 1H NMR (CDCl3): 2,76 (t, 2H), 3,57 (Br.t, 2H), 3,75 (dist.t, 2H), 3,81 (s, 3H), 4,03 (dist.t, 2H), 4,59 (s, 2H), 6,59 (d, 2H), 6,76 (d, 2H), 6,87 (d, 2H), 7,05 (d, 2H), 7,13 (d, 2H), 7,19 (d, 2H), 7,27–7,40 (m, 5H)
E-izomer 1H NMR (CDCl3): 2,76 (t, 2H), 3,58 (Br.t, 2H), 3,70 (s, 3H), 3,84 (dist.t, 2H), 4,17 (dist.t, 2H), 4,65 (s, 2H), 6,57 (d, 2H ), 6,77 (d, 2H), 6,90 (d, 2H), 7,06 (d, 2H), 7,15 (d, 2H), 7,18 (d, 2H), 7,27–7,40 (m, 5H)
Istom se metodom pripravljaju sljedeći spojevi:
3-(3-metoksifenil)-4-fenil-4-[4-(2-piperidin-1-iletoksi)fenil]but-3-en-1-ol
Z-izomer: 1H NMR (CDCl3):1,33–1,50 (m, 2H), 1,50-1,65 (m, 4H), 2,45 (Br.t,, 4H), 2,67 (t, 2H), 2,73 (t, 2H, ), 3,58 (t, 2H), 3,65 (s, 3H ), 3,96 (t, 2H), 6,55 (d, 2H), 6,63-6,77 (m, 3H), 6,79 (d, 2H), 7,10 (t, 1H), 7,20–7,40 (m, 5H)
E-izomer: 1H NMR (CDCl3): 1,40–1,55 (m, 2H), 1,55–1,70 (m, 4H), 2,51 (Br.t., 4H), 2,77 (t, 2H), 2,80 (t, 2H), 3,61 (s, 3H), 3,62 (t, 2H), 3,94 (t, 2H), 6,6–7,25 (m, 13H)
3-(2-metoksifenil)-4-fenil-4-[4-(2-piperidin-1-iletoksi)fenil]but-3-en-1-ol
Z-izomer: 1H NMR (CDCl3):1,33–1,48 (m, 2H), 1,48–1,65 (m, 4H), 2,43 (Br.t., 4H), 2,20–2,50 (t, 2H), 2,65 (t, 2H), 3,43–3,60 (t, 2H), 3,62 (s, 3H), 3,93 (t, 2H), 6,52 (d, 2H), 6,70–6,90 (m, 2H) pod kojim 6,82 (d, 2H), 7,05-7,43 (m, 7H)
E-izomer: 1H NMR (CDCl3): 1,38–1,52 (m, 2H), 1,52–1,70 (m, 4H), 2,51 (Br.t., 4H), 2,38–2,58 (t, 2H), 2,77 (t, 2H), 3,59 (s, 3H ), 3,45–3,65 (m, 2H), 4,10 (t, 2H), 6,6–7,35 (m, 13H)
(E)-4-(3-benziloksifenil)-4-[4-(2-benziloksietoksi)fenil]-3-fenil-but-3-en-1-ol
1H NMR (CDCl3 ): 2,73 (t, 2H), 3,5–3,6 (m, 2H), 3,7–3,76 (m, 2H), 4,0–4,03 (m, 2H), 4,60 (s, 2H), 5,05 (s, 2H), 6,56 (d, 2H), 6,78 (d, 2H), 6,8–6,95 (m, 2H), 7,05–7,35 (m, 17H)
(Z)-4-[4-(2-benziloksietilsulfanil)fenil]- 3,4-difenil-but-3-en-1-ol
1H NMR (CDCl3): 2,75 (t, 2H), 3,02 (t, 2H), 3,56 (t, 4H), 4,47 (s, 2H), 6,78 (d, 2H), 6,96 (d, 2H), 7,1-7,4 (m, 15H)
(Z)-4-[4-(2-dimetilaminoetilsulfanil)fenil]-3,4-difenil-but-3-en-1-ol
MS: EI, m/e 403 (M+, 1 %), 332 (1 %), 72 (12 %), 58 (100 %)
g) uklanjanje zaštitne benzilne skupine
3-(4-klorofenil)-4-[4-(2-dimetilaminoetoksi)fenil]-4-fenilbut-3-en-1-ol
(2-{4-[4-benziloksi-2-(4-klorofenil)-1-fenilbut-1-enil]fenoksi}etil)dimetilamin (1,1 g, 2,1 mmol) se otopi u toluenu, dodaju se Zn u prahu (0,4 g, 6,1 mmol) i acetil-klorid (0,6 g, 7,6 mmol), te se smjesa miješa tri sata pri 40 °C. Doda se još Zn (0,5 g) i acetil-klorida (0,6 g) i nastavi miješati tijekom još pet sati. Doda se etilacetat i precipitat se odfiltrira. Otapala se otpare, a ostatak otopi u metanolu. Acetatni ester produkta hidrolizira se zaluživanjem smjese 48 % vodenom otopinom natrijeva hidroksida i miješanjem smjese dva sata pri sobnoj temperaturi. Metanol se otpari, ostatak se otopi u toluenu i ispere vodom. Toluen se otpari, a izomeri odvoje plamenom kromatografijom. Dobije se 0,25 g Z-izomera i 0,15 g E-izomera.
Z-izomer: 1H NMR (CDCl3): 2,28 (s, 6H), 2,65 (t, 2H), 2,72 (t, 2H), 3,57 (t, 2H), 3,94 (t, 2H), 6,58 (d, 2H), 6,76 (d, 2H), 7,07 (d, 2H), 7,15 (d, 2H), 7,20-7,40 (m, 5H)
E-izomer: 1H NMR (CDCl3): 2,34 (s, 6H), 2,74 (t, 2H), 2,78 (t, 2H), 3,59 (t, 2H), 4,07 (t, 2H), 6,80–7,30 (m, 13H)
Istom se metodom pripravljaju sljedeći spojevi:
4-[4-(2-dimetilaminoetoksi)fenil]-3-(4-fluorofenil)-4-fenilbut-3-en-1-ol
Z-izomer: 1H NMR (CDCl3): 2,27 (s, 6H), 2,64 (t, 2H), 2,72 (t, 2H), 3,56 (t, 2H), 3,93 (t, 2H), 6,56 (d, 2H), 6,76 (d, 2H), 6,86 (t, 2H), 7,00-7,40 (m, 7H)
E-izomer: 1H NMR (E-izomer, CDCl3): 2,35 (s, 6H), 2,75 (t, 2H), 2,78 (t, 2H), 3,60 (t, 2H), 4,08 (t, 2H), 6,75-7,40 (m, 13H)
3-(4-klorofenil)-4-[4-(2-dimetilaminoetoksi)fenil]-4-(4-metoksifenil)but3-en-1-ol
Z-izomer: 1H NMR (CDCl3): 2,28 (s, 6H), 2,65 (t, 2H), 2,75 (t, 2H), 3,57 (t, 2H), 3,81 (s, 3H), 3,94 (t, 2H), 6,58 (d, 2H), 6,75 (d, 2H), 6,87 (d, 2H), 7,05 (d, 2H), 7,13 (d, 2H), 7,19 (d, 2H)
E-izomer: 1H NMR (CDCl3): 2,33 (s, 6H), 2,74 (t, 2H), 2,75 (t, 2H), 3,56 (t, 2H), 3,69 (s, 3H), 4,07 (t, 2H), 6,56 (d, 2H), 6,76 (d, 2H), 6,88 (d, 2H), 7,06 (d, 2H), 7,13 (d, 2H), 7,17 (d, 2H)
h) Konverzija hidroksilne skupine i klor
(Z)-(2-{4-[4-kloro-2-(4-klorofenil)-1-fenilbut-1-enil]fenoksi}etil)dimetilamin (Br. 23)
(Z)-3-(4-klorofenil)-4-[4-(2-dimetilaminoetoksi)fenil]-4-fenilbut-3-en-1-ol (0,22 g, 0,5 mmol) se otopi u toluenu, doda se tionil-klorid (0,2 g, 1,7 mmol) i smjesa se podvrgne povratnom hlađenju tijekom 45 minuta. Toluen se djelomice otpari, a precipitirana hidrokloridna sol produkta se filtrira. Dobije se 0,2 g produkta.
1H NMR (HCl salt, CDCl3): 2,88 i 2,90 (s, zajedno 6H), 2,91 (t, 2H), 3,40 (m, 4H), 4,40 (m, 2H), 6,58 (d, 2H), 6,81 (d, 2H), 7,07 (d, 2H), 7,19 (d, 2H), 7,20-7,50 (m, 5H)
Istom se metodom pripravljaju sljedeći spojevi:
(E)-(2-{4-[4-kloro-2-(4-klorofenil)-1-fenilbut-1-enil]fenoksi}etil)dimetilamin (Br. 24)
1H NMR (HCl sol, CDCl3): 2,35–3,02 (m, 2H), 2,95 (s, 6H), 3,35-3,55 (m, 4H), 4,46–4,60 (m, 2H), 6,75–7,30 (m, 13H)
(Z)-(2-{4-[4-kloro-2-(4-fluorofenil)-1-fenilbut-1-enil]fenoksi}etil)dimetilamin (Br. 25)
1H NMR (HCl sol, CDCl3): 2,88 (s, 6H), 2,94 (t, 2H, ), 3,41 (m, 4H), 4,39 (m, 2H), 6,56 (d, 2H), 6,80 (d, 2H), 6,91 (t, 2H), 7,10 (dd, 2H), 7,20–7,40 (m, 5H)
2-{4-[4-kloro-2-(4-klorofenil)-1-(4-metoksifenil)but-1-enil]fenoksi}etil)dimetilamin (Br. 26 i 27)
Z-izomer (No, 26): 1H NMR (HCl sol, CDCl3 + MeOH-d4): 2,89 (s, 6H), 2,94 (t, 2H), 3,41 (m, 4H), 3,84 (s, 3H), 4,34 (m, 2H), 6,59 (d, 2H), 6,81 (d, 2H), 6,90 (d, 2H), 7,06 (d, 2H), 7,18 (d, 2H), 7,19 (d, 2H)
E-izomer (Br. 27): 1H NMR (HCl sol, CDCl3 + MeOH-d4): 2,91 (t, 2H), 2,98 (s, 6H), 3,41 (t, H), 3,54 (m, 2H), 3,71 (s, 3H), 4,45 (m, 2H), 6,59 (d, 2H), 6,77 (d, 2H), 6,94 (d, 2H), 7,06 (d, 2H), 7,17–7,18 (d, 2H), 7,23 (d, 2H)
1-(2-{4-[4-kloro-2-(3-metoksifenil)-1-fenilbut-1-enil]fenoksi}etil)piperidin (Br. 28 i 29)
Z-izomer (Br. 28): 1H NMR (HCl sol, MeOH-d4): 1,45–2,10 (m, 6H), 2,92 (t, 2H), 3,06 (dt, 2H), 3,44 (t, 2H), 3,47-3,66 (m, 4H), 3,68 (s, 3H), 4,27 (dist.t., 2H), 6,70–6,85 (m, 5H), 6,92 (d, 2H), 7,15 (dt, 1H), 7,30–7,50 (m, 5H)
E-izomer (Br. 29): 1H NMR (HCl sol, MeOH-d4): 1,45-2,15 (m, 6H), 2,96 (t, 2H), 3,12 (dt, 2H), 3,47 (t, 2H), 3,58–3,75 (m, 4H), 3,62 (s, 3H), 4,44 (dist.t., 2H, 6,65–6,83 (m, 3H), 6,90-–6,97 (m, 2H), 7,01–7,18 (m, 6H), 7,31 (d, 2H)
1-(2-{4-[4-kloro-2-(2-metoksifenil)-1-fenilbut-1-enil]fenoksi}etil)piperidin (Br. 30 i 31)
Z-izomer (Br. 30): 1H NMR (HCl sol, MeOH-d4): 1,50–2,05 (m, 6H), 2,88 (t, 2H), 3,05 (dt, 2H), 3,41 (t, 2H), 3,45-3,65 (m, 4H), 3,86 (s, 3H), 4,25 (dist.t., 2H), 6,65-6,79 (m, 3H), 6,88-7,00 (m, 4H ), 7,20 (dt, 1H), 7,30-7,50 (m, 5H)
E-izomer (Br. 31): 1H NMR (HCl sol, MeOH-d4): 1,55–2,20 (m, 6H), 2,92 (t, 2H), 3,13 (dt, 2H), 3,43 (t, 2H), 3,58-3,75 (m, 4H), 3,84 (s, 3H), 4,45 (dist.t., 2H), 6,73 (dt, 1H), 6,89–7,30 (m, 7H), 7,08 (d, 2H), 7,18 (dt, 1H), 7,32 (d, 2H)
(Z)-1-[4-(2-benziloksietilsulfanil)fenil]- 1,2-difenil-4-kloro-but-1-en
1H NMR (CDCl3): 2,92 (t, 2H), 3,02 (t, 2H), 3,41 (t, 2H), 3,56 (t, 2H), 4,47 (s, 2H), 6,78 (d, 2H), 6,96 (d, 2H), 7,10-7,40 (m, 15H)
(Z)-1-[4-(2-dimetilaminoetilsulfanil)fenil]-1,2-difenil-4-kloro-but-1-en (Br. 32)
1H NMR (CDCl3): 2,28 (s, 6H), 2,46 (dist, t, 2H), 2,85–2,95 (m, 4H), 3,41 (dist, t, 2H), 6,79 (d, 2H), 6,96 (d, 2H), 7,00-7,40 (m, 10H)
1-[4-(2-benziloksietoksi)fenil]-4-kloro-2-(4-klorofenil)-1-(4-metoksifenil)but-1-en
Z-izomer, 1H NMR (CDCl3): 2,93 (t, 2H), 3,41 (t, 2H), 3,83 (s, 2H), 3,76 (dist.t, 2H), 4,04 (dist.t, 2H), 4,59 (s, 2H),6,59 (d, 2H), 6,77 (d, 2H), 6,87 (d, 2H), 7,05 (d, 2H), 7,15 (d, 2H), 7,19 (d, 2H), 7,27–7,40 (m, 5H)
E-izomer 1H NMR (CDCl3): 2,93 (t, 2H), 3,41 (t, 2H), 3,70 (s, 3H), 3,85 (dist.t, 2H), 4,18 (dist.t, 2H), 4,65 (s, 2H), 6,57 (d, 2H ), 6,79 (d, 2H), 6,92 (2H), 7,06 (d, 2H), 7,16 (d, 2H), 7,18 (d, 2H), 7,27–7,40 (m, 5H)
(E)-1-(3-benziloksifenil)-1-[4-(2-benziloksietoksi)fenil]-4-kloro-3fenilbut1en
Spoj se pripravlja metodom opisanom u primjeru 1d, koristeći se s Ph3P i CCl4 kao reagensima.
1H NMR (CDCl3): 2,93 (t, 2H), 3,40 (t, 2H), 3,71–3,76 (m, 2H), 3,98-4,05 (m, 2H), 4,58 (s, 2H), 5,06 (s, 2H), 6,60 (d, 2H), 6,78 (d, 2H), 6,85–7,50 (m, 19H)
(Z)-{2-[3-(4-kloro-1,2-difenilbut-1-enil)fenoksi]etil}dimetilamin (Br. 33)
1-[3-(2-Dimetilaminoetoksi)fenil]-1,2-difenil-4-(tetrahidropiraniloksi)butan-1-ol (0,93 g, 1,9 mmol) se otopi u toluenu (10 ml). Otopini se doda trietilamin (1,9 mmol) i smjesa se ohladi do -10°C, Smjesi se doda tionil- klorid (5,8 mmol) pri -10 - ±0°C. Smjesa se miješa jedan sat pri 0-5°C, ugrije do 80°C i miješa pri toj temperaturi tri sata. Otapalo se otpari, ostatak se otopi u toluenu, ispere s 2 N NaOH i vodom. Z-izomer produkta kristalizira se iz etilacetata u obliku soli HCl. Dobije ga se 0,15 g.
1H NMR (HCl sol, CDCl3): 2,79 (s, 6H), 2,94 (t, 2H), 3,20–3,29 (m, 2H), 3,42 (t, 2H), 4,12-4,20 (m, 2H), 6,40 (s, 1H), 6,51-6,62 (m, 2H), 6,98 (t, 1H), 7,10–7,45 (m, 10H)
i) Uklanjanje zaštitnih skupina
(E)-3-{4-kloro-1-[4-(2-hidroksietoksi)fenil]-2-fenil-but-1-enil}-fenol (Br. 34)
(E)-4-(3-benziloksifenil)-4-[4-(2-benziloksietoksi)fenil]-4-kloro-3-fenil-but-1-en (1,95 g, 3,39 mmol) se hidrogenira u etanol-etilacetatu (5 ml:20 ml) koji sadrži trietilamin (3,4 mmol) i 10 % paladij na ugljiku (0,195 g) kao katalizator. Katalizator se odfiltrira, a otapalo otpari. Proizvod se pročisti plamenom kromatografijom i kristalizira iz smjese toluen-metanol (9:1). Dobije ga se 0,23 g.
1H NMR (CDCl3 + MeOH-d4): 2,95 (t, 2H), 3,42 (t, 2H), 3,8–4,0 (m, 4H), 6,56 (d, 2H), 6,75–6,82 (m, 4H), 7,10–7,25 (m, 7H)
Istom se metodom pripravljaju sljedeći spojevi obuhvaćeni ovim patentom:
(Z)-3-[4-(4-kloro-1,2-difenilbut-1-enil)fenoksi]propan-1-ol (Br. 35)
1H NMR (CDCl3): 1,96 (kvint., 2H), 2,92 (t, 2H), 3,42 (t, 2H), 3,80 (q, 2H), 3,98 (t, 2H), 6,55 (d, 2H), 6,78 (d, 2H), 7,11–7,40 (m, 10H )
(Z)-2-[4-(4-kloro-1,2-difenil-but-1-enil)-fenilsulfanil]etanol (Br. 36)
se pripravlja postupkom opisanim u primjeru 2g.
1H NMR (CDCl3): 2,93 (t, 2H), 3,00 (t, 2H), 3,41 (t, 2H), 3,64 (t, 2H), 6,81 (d, 2H), 7,01 (d, 2H), 7,10-7,40 (m, 10H)
Istom se metodom pripravljaju sljedeći spojevi obuhvaćeni ovim patentom:
(Z)-2-{4-[4-kloro-2-(4-klorofenil)-1-(4-metoksifenil)but-1-enil]fenoksi}etanol (Br. 37)
1H NMR (CDCl3): 2,94 (t, 2H), 3,41 (t, 2H), 3,83 (s, 3H), 3,85–4,00 (m, 4H), 6,59 (d, 2H), 6,78 (d, 2H), 6,90 (d, 2H), 7,06 (d, 2H), 7,16 (d, 2H), 7,19 (d, 2H)
Primjer 5
a) 1-[4-(2-kloroetoksi)fenil]-2-(2-klorofenil)etanon
1-[4-(2-kloroetoksi)fenil]-2-(2-klorofenil)etanon se pripravlja metodom opisanom u primjer 4a, koristeći se 2-kloroetoksibenzenom i 2-klorofeniloctenom kiselinom kao početnim materijalom.
1H NMR (CDCl3): 3,85 (t, 2H), 4,30 (t, 2H), 4,39 (s, 2H), 6,98 (d, 2H), 7,22–7,26 (m, 3H), 7,39-7,50 (m, 1H), 8,04 (d, 2H)
Istom se metodom pripravljaju sljedeći spojevi:
1-[4-(2-kloroetoksi)fenil]-2-feniletanon
1H NMR (CDCl3): 3,83 (t, 2H), 4,24 (s, 2H), 4,28 (t, 2H), 6,94 (d, 2H), 7,2-7,4 (m, 5H), 8,00 (d, 2H)
b) 2-(2-klorofenil)-1-[4-(2-piperidiniletoksi)fenil]etanon
Smjesa 1-[4-(2-kloroetoksi)fenil]-2-(2-klorofenil)etanona (4 g, 13 mmol) i piperidina (5,8 g, 68 mmol) u 80% vodenom acetonu (50 ml) podvrgne se povratnom strujanju tijekom 12 h. Smjesi se još tri puta dodaju dodatne odvage od po 0,3 g piperidina u razmacima po četiri sata. Otapalo se otpari. Doda se dietileter i precipitirani piperidin-hidroklorid se odfiltrira. Dietileter se otpari, a dobiveni produkt pročisti plamenom kromatografijom (eluens: toluen:trietilamin 9:1). Dobije se 4,1 g, 89 % produkta.
1H NMR (CDCl3): 1,38–1,56 (m, 2H), 1,56-1,68 (m, 4H), 2,45–2,62 (m, 4H), 2,79 (t, 2H), 4,17 (t, 2H), 4,38 (s, 2H), 6,96 (d, 2H), 7,19–7,25 i 3,37–7,44 (2m, zajedno 4H), 8,01 (d, 2H)
1-[4-(2-Imidazol-1-il-etoksi)fenil]-2-fenil etanon
se pripravlja od 1-[4-(2-kloroetoksi)fenil]-2-feniletanona i imidazola u DMF, koristeći se natrijevim hidridom kao bazom, prema postupku opisanom u primjeru 1a.
1H NMR (CDCl3): 4,22 (s, 2H), 4,20–4,37 (m, 4H), 6,88 (d, 2H), 7,03 (s, 1H), 7,07 (s, 1H), 7,20-7,37 (m, 5H), 7,60 (s, 1H), 7,97 (d, 2H)
c) 2-(2-klorofenil-1-[4-(2-piperidiniletoksi)fenil]-4-(tetrahidropiraniloksi)butan1-on
2-(2-klorofenil-1-[4-(2-piperidiniletoksi)fenil]-4-(tetrahidropiraniloksi)butan-1-on se pripravlja reakcijom PTC, metodom opisanom u primjeru 4d, koristeći se 2-(2-klorofenil)-1-[4-(2-piperidiniletoksi)fenil]-etanonom (1,5 g, 4,2 mmol) i 2-tetrahidropiraniloksi-1-jodoetanom (1,3 g, 5,1 mmol) kao početnim materijalom. Produkt (1,6 g) se bez daljeg pročišćavanja koristi u idućoj reakciji.
1H NMR (CDCl3): spektar se može identificirati iz kompleksa 2,40-2,60 (m, 4H), 2,75 (t, 2H), 4,12 (t, 2H), 4,50-4,62 (m, 1H), 5,24-5,36 (m, 1H), 6,87 (d, 2H), 7,10-7,25 i 3,37-7,44 (2m, zajedno 4H), 7,98 (d, 2H)
Istom se metodom pripravlja sljedeći spoj:
1-[4-(2-imidazol-1-il-etoksi)fenil]-2-fenil-4-(tetrahidro-piraniloksi)butan1-on
1H NMR (CDCl3): 1,4-1,9 (m, 6H), 1,95-2,2 (m, 1H), 2,4-2,60 (m, 1H), 3,2-3,9 (m, 4H), 4,2-4,37 (m, 4H), 4,45-4,55 (m, 1H), 4,79 (dt, 1H), 6,80 (dd, 2H), 6,99 (s, 1H), 7,05 (s, 1H), 7,15-7,3 ( m, 5H), 7,55 (s, 1H), 7,95 (d, 2H)
d) 2-(2-klorofenil-1-fenil-1-[4-(2-piperidiniletoksi)fenil]-4-(tetrahidropiraniloksi)butan-1-ol
se pripravlja postupkom opisanim u primjeru 4e. Produkt se bez daljeg pročišćavanja koristi u idućoj reakciji.
Istom se metodom pripravljaju sljedeći spojevi:
1-[4-(2-imidazol-1-il-etoksi)fenil]-2-fenil-4-(tetrahidro-piraniloksi)-1-[3-(tetrahidro-piraniloksi)fenil]-butan-1-ol
Spoj se bez daljeg pročišćavanja koristi u idućoj reakciji.
e) 1-(2-{4-[-(2-klorofenil)-4-fenil-4-[4-(2-piperidin-1-iletoksi)fenil]but3en1-ol
2-(2-klorofenil-1-fenil-1-[4-(2-piperidiniletoksi)fenil]-4-(tetrahidropiraniloksi)butan-1-ol se dehidrira postupkom opisanim u 1c. Z-izomer produkta pročisti se plamenom kromatografijom (eluens: toluen-trietilamin 13:1)
Z-izomer: 1H NMR (CDCl3): 1,35–1,48 (m, 2H), 1,48-1,68 (m, 4H), 2,38–2,48 (m, 4H), 2,66 (t, 2H), 2,58-2,87 (m, 2H), 3,47–3,67 (m, 2H), 3,94 (t, 2H), 6,54 (d, 2H), 6,84 (d, 2H), 7,07–7,41 (m, 9H)
Istom se metodom pripravlja sljedeći spoj:
3-{4-hidroksi-1-[4-(2-imidazol-1-il-etoksi)fenil]-2-fenil-but-1-enil}-fenol
E-izomer: 1H NMR (CDCl3+MeOH-d4): 2,83 (t, 2H), 3,60 (t, 2H), 4,11 (dist, t, 2H), 4,20 (t, 2H), 6,48 (d, 2H), 6,76 (d, 2H), 6,66-6,9 (m, 4H), 6,92 (s, 1H), 6,98 (s, 1H), 7,08-7,32 ( m, 5H), 7,36 (s, 1H)
Z-izomer: 1H NMR (CDCl3+MeOH-d4): 2,73 (t, 2H), 3,54 (t, 2H), 4,23-4,4 (m, 4H), 6,35-7,23 (m, 15H), 7,55 (s, 1H)
f) (Z)-1-(2-{4-[4-kloro-2-(2-klorofenil)-1-fenilbut-1-enil]fenoksi}etil)piperidin (Br. 38)
se pripravlja postupkom opisanim u primjeru 1d.
1H NMR (CDCl3): 1,33-1,49 (m, 2H), 1,49-1,68 (m, 4H), 2,40-2,50 (m, 4H), 2,67 (t, 2H), 2,80-3,50 (m, 2H), 3,25-3,56 (m, 2H), 3,95 (t, 2H), 6,54 (d, 2H), 6,85 (d, 2H), 7,06–7,43 (m, 9H)
Istom se metodom pripravlja sljedeći spoj obuhvaćen ovim izumom:
3-{4-kloro-1-[4-(2-imidazol-1-il-etoksi)fenil]-2-fenil-but-1-enil}-fenol (Br. 39 i 40)
E-izomer (No, 39): 1H NMR (CDCl3): 2,94 (t, 2H), 3,41 (t, 2H), 4,07 (dist, t, 2H), 4,25 (t, 2H), 6,50 (d, 2H), 6,79 (d, 2H), 6,70-6,81 (m, 2H ), 6,98 (s, 2H), 7,10-7,24 (m, 7H), 7,51 (s, 1H)
Z-izomer (No, 40): 1H NMR (CDCl3+MeOH-d4, HCl-salt): 2,90 (dist.t, 2H), 3,40 (dist.t, 2H), 4,33 (dist, t, 2H), 4,65 (dist.t, 2H), 6,35-7,25 (m, 13H), 7,38 (s, 1H), 7,48 (s, 1H), 9,20 (s, 1H)
Primjer 6
a) (4-amino-fenil)fenil-metanon
4-Nitrobenzofenon (5,0 g, 0,022 mol) se otopi u etanol-diklorometanu (40 ml : 30 ml), te se hidrogenira pri sobnoj temperaturi, s 10 % paladijem na ugljiku (0,5 g) kao katalizatorom. Katalizator se odfiltrira, a filtrat otpari do suha. Proizvod se bez daljeg pročišćavanja koristi u idućoj reakciji, Dobije se 5,2 g.
1H NMR (CDCl3): 6,67 (d, 2H), 7,4-7,6 (m, 3H), 7,7-7,6 (m, 4H)
b) McMurryjeva reakcija
4-(4-kloro-1,2-difenil-but-1-enil)fenilamin
Cink (10,0 g, 0,154 mol) i tetrahidrofuran (THF) (120 ml) se stave u reakcijsku posudu i ohlade do-10°C. Smjesi se, kap po kap, doda titanov tetrahidroklorid (14,4 g, 0,076 mol) pri otprilike -10°C. Nakon što je dokapavanje dovršeno, smjesa se podvrgne povratnom hlađenju tijekom dva sata. Potom se ohladi do 40°C, te se (4-amino-fenil)fenil-metanon (5,1 g, 0,0258 mol) i 3-kloropropiofenon (4,36 g, 0,0258 mol) otope u THF (50 ml) i dodaju smjesi. Nastavi se povratno strujanje tijekom još 3,5 sata. Ohlađena reakcijska smjesa se izlije u vodenu otopinu kalijeva karbonata (14 g K2CO3 + 140 ml vode) i ostavi stajati preko noći. Smjesa se filtrira, a precipitat ispere tri puta s THF. Filtrat se upari do suha. Ostatak se otopi u etilacetatu i ispere vodom. Dobije se 9,6 g Z-izomera, koji je jedini izomer.
Z-izomer: 1H NMR (CDCl3): 2,90 (t, 2H), 3,41 (t, 2H), 6,32 (d, 2H), 6,64 (d, 2H), 7,0–7,4 (m, 10H)
Istom se metodom pripravlja sljedeći spoj obuhvaćen ovim izumom:
N-[4-(4-kloro-1,2-difenil-but-1-enil)-fenil]-N',N'-dimetiletan-1,2-diamin (Br. 47)
pri čemu se započne s [4-(2-dimetilaminoetilamino)fenil]fenil metanonom (priprava opisana u US patentu no. 5,693,674) i 3-kloropropiofenonom.
Z-izomer: 1H NMR (as HCl-sol, MeOH-d4): 2,95 (s, 6H), 2,99 (t, 2H), 3,44 (t, 2H), 3,47 (t, 2H), 3,68 (t, 2H), 6,90-7,10 (m, 4H), 7,15-7,40 (m, 10H)
c) (Z)-[4-(4-kloro-1,2-difenil-but-1-enil)fenilamino]etilester octene kiseline
(Z)-4-(4-kloro-1,2-difenil-but-1-enil)fenilamin (2,0 g, 5,99 mmol), etanol (30 ml), etilbromoacetat (2,5 g, 15 mmol) i natrijev acetat (2,4 g, 17,9 mmol) se stave u reakcijsku posudu i podvrgnu povratnom strujanju tijekom tri sata. Potom se otapalo otpari, a ostatak otopi u vodi i etilacetatu, etilacetatna se faza osuši i otpari do suha. Dobije se 2,9 g produkta.
1H NMR (CDCl3): 1,26 (t, 3H), 2,90 (t, 2H), 3,41 (t, 2H), 4,20 (q, 2H), 6,25 (d, 2H), 6,68 (d, 2H), 7,10-7,40 (m, 10H)
d) (Z)-2-[4-(4-kloro-1,2-difenil-but-1-enil)fenilamino]etanol (Br. 41)
(Z)-[4-(4-kloro-1,2-difenil-but-1-enil)fenilamino]etilester octene kiseline (2,9 g, 6,9 mmol) se otopi u tetrahidrofuranu, nakon čega se tijekom 15 minuta dodaje litijev aluminijev hidrid (0,34 g, 8,97 mmol) u malim porcijama. Smjesa se miješa dva sata pri sobnoj temperaturi. Potom se otapalo otpari do suha, a ostatak otopi u etilacetatu, te ispere vodom. Etilacetatna se faza otpari do suha, a produkt se pročisti plamenom kromatografijom s otopinom toluen:metanol:trietilamin (10:0,3:0,3) kao eluensom. Dobije se 0,47 g produkta.
1H NMR (CDCl3): 2,89 (t, 2H), 3,17 (t, 2H), 3,41 (t, 2H), 3,73 (t, 2H), 6,29 (d, 2H), 6,67 (d, 2H), 7,10–7,40 (m, 10H)
Primjer 7
a) 4-{2-[4-(2-benziloksietoksi)fenil]-1-(2-kloroetil)-2-fenilvinil}fenol
se pripravlja metodom opisanom u primjeru 6b, koristeći se [(4benziloksietoksi)fenil]fenilmetanonom i 3-kloro-1-(4-hidroksifenil)propan-1-onom kao početnim materijalom. Produkt je smjesa Z- i E-izomera.
1H NMR (CDCl3): 2,88 i 2,93 (2t, 2H), 3,42 i 3,43 (2t, 2H), 3,74 i 3,84 (2dist.t, 2H), 4,01 i 4,16 (2dist.t, 2H), 4,58 i 4,65 (2s, 2H), 6,55–7,40 (m, 18H)
b) 4-{1-(2-kloroetil)-2-[4-(2-hidroksietoksi)fenil]-2-fenilvinil}fenol (Br. 42 i 43)
se pripravlja postupkom opisanim u primjeru 1e. Izomeri se pročiste plamenom kromatografijom (eluens: diklorometan-metanol-trietilamin 98:2:1)
Z-izomer (No, 42): 1H NMR (CDCl3): 2,87 (t, 2H), 3,43 (t, 2H), 3,83-3,90 (m, 2H), 3,90-3,97 (m, 2H), 6,56 (d, 2H), 6,66 (d, 2H), 6,80 (d, 2H), 6,96 (d, 2H), 7,20-7,40 (m, 5H)
E-izomer (No, 43): 1H NMR (CDCl3): 2,92 (t, 2H), 3,38 (t, 2H), 3,90–4,02 (m, 2H), 4,03-4,14 (m, 2H), 6,63 (d, 2H), 6,89 (d, 2H), 6,95 (d, 2H), 7,20 (d, 2H), 6,85–7,17 (m, 5H)
Primjer 8
{2-[4-(4-kloro-1,2-difenilbut-1-enil)fenoksi]etil}metilprop-2-inilamin (Br. 44)
se pripravlja metodom opisanom u primjeru 1 a, počevši s Z-4-kloro-1,2-difenil-1[4[2(N-metilamino)etoksi]-fenil]-1-butenom (priprava opisana u US patentu no. 5,491173) i propargil-bromidom.
1H NMR (citratna sol, MeOH-d4): 2,74 (s, 3H), 2,82 i 2,86 (2s, 4H), 2,93 (t, 2H), 3,06 (t, 1H), 3,29 (dist, t, 2H), 3,44 (t, 2H), 3,85 (d, 2H), 4,16 (dist, t, 2H), 6,68 (d, 2H), 6,86 (d, 2H), 7,15–7,47 (m, 10H)
Primjer 9
a) (Z)-[4-(4-hidroksi-1,2-difenilbut-1-enil)feniloksi]etilester octene kiseline
se pripravlja iz (Z)-(4-hidroksi-1,2-difenilbut-1-enil)fenola (priprava opisana u US patentu no. 4,996,225) i etilbromoacetata, postupkom opisanim u primjeru 1a, koristeći se s NaH kao bazom.
1H NMR (CDCl3): 1,25 (t, 3H), 2,74 (t, 2H), 3,57 (t, 2H), 4,23 (q, 2H), 4,47 (s, 2H), 6,56 (d, 2H), 6,79 (d, 2H), 7,10-7,45 (m, 10H)
(Z)-2-[4-(4-hidroksi-1,2-difenilbut-1-enil)fenoksi]etilester maslačne kiseline
se pripravlja jednakim postupkom, služeći se etil -2-bromobutiratom kao alkilirajućim reagensom.
1H NMR (MeOH-d4): 0,98 (t, 3H), 1,17 (t, 3H), 1,86 (m, 2H), 2,70 (t, 2H), 3,47 (t, 2H), 4,12 (m, 2H), 4,50 (dd, 1H), 6,50 (d, 2H), 6,76 (d, 2H), 7,0–7,4 (m, 10H)
b) (Z)-[4-(4-kloro-1,2-difenilbut-1-enil]fenoksi)etilester octene kiseline
se pripravlja postupkom opisanim u primjeru 1d, služeći se s Ph3P i CCl4 kao reagensima.
1H NMR (CDCl3): 1,25 (t, 3H), 2,92 (t, 2H), 3,41 (t, 2H), 4,23 (q, 2H), 4,50 (s, 2H), 6,55 (d, 2H), 6,80 (d, 2H), 7,10-7,45 (m, 10H)
Istom se metodom pripravlja sljedeći spoj:
(Z)-2-[4-(4-kloro-1,2-difenilbut-1-enil)fenoksi]etilester maslačne kiseline
1H NMR (MeOH-d4): 1,01 (t, 3H), 1,16 (t, 3H), 1,89 (m, 2H), 2,91 (t, 2H), 3,40 (t, 2H), 4,15 (m, 2H), 4,40 (dd, 1H), 6,52 (d, 2H), 6,76 (d, 2H), 7,0–7,4 (m, 10H)
c) (Z)-3-[4-(4-kloro-1,2-difenilbut-1-enil)fenoksimetil]pentan-3-ol (Br. 45)
Grignardov se reagens pripravi od strugotina Mg (0,29 g, 12 mmol) i bromoetana (1,25 g, 12 mmol) u tetrahidrofuranu (4 ml), Doda se (Z)-[4-(4-kloro-1,2-difenilbut-1-enil]fenoksi)etilester octene kiseline (1,0 g, 23 mmol, iz primjera 9b) u tetrahidrofuranu (11 ml) pri sobnoj temperaturi, te se smjesa podvrgne povratnom strujanju tijekom dva sata. Doda se zasićeni amonijev klorid, a tetrahidrofuran se otpari. Produkt se ekstrahira u etilacetatu. Organski se sloj osuši i otpari do suha. Dobije se 1,0 g produkta.
1H NMR (CDCl3): 0,87 (t, 6H), 1,58 (q, 4H), 2,92 (t, 2H), 3,42 (t, 2H), 3,68 (s, 2H), 6,56 (d, 2H), 6,78 (d, 2H), 7,10-7,45 (m, 10H)
Primjer 10
(Z)-2-[4-(4-kloro-1,2-difenilbut-1-enil)fenoksi]butan-1-ol (Br. 46)
Z-2-[4-(4-kloro-1,2-difenilbut-1-enil)fenoksi]etilester maslačne kiseline (0,98 g, 2,2 mmol) reducira se litijevim aluminijvim hidridom (0,041 g, 1,1 mmol) u tetrahidrofuranu. Doda se ledenohladna voda, a tetrahidrofuran se otpari. Produkt se ekstrahira u etilacetatu, osuši, a otapalo otpari. Dobije se 0,55 g produkta.
1H NMR (CDCl3): 0,89 (t, 3H), 1,54-1,70 (m, 2H), 2,91 (t, 2H), 3,58-3,76 (m, 2H), 4,10-4,20 (m, 1H), 6,57 (d, 2H), 6,77 (d, 2H), 7,10-7,40 (m, 10H)
Primjer 11
E-3- (4-kloro-1-{4-[2-(2-hidroksietoksi)etoksi]fenil}-2-fenilbut-1-enil)fenol
a) 1-{4-[2-(2-benziloksietoksi)etoksi]fenil}-2-fenil etanon
se pripravlja postupkom opisanim u primjeru 4c, počevši s 1-(4-hidroksifenil)-2-fenil etanonom (pripravljenim kao što je opisano u primjeru 4 a-b)(10,0 g, 47,1 mmol) i 2-(2-benziloksietoksi)etil-kloridom (11,0 g, 51,8 mmol). Produkt se triturira tri puta toplim heptanom, da se uklone nusprodukti. Dobije se 9,6 g, 52 % produkta.
1H NMR (CDCl3): 3,60-3,79 (m, 4H), 3,85 (dist, t, 2H), 4,16 (dist, t, 2H), 4,20 (s, 2H), 4,56 (s, 2H), 6,92 (d, 2H), 7,20-7,41 (m, 10H), 7,96 (d, 2H)
b) 1-{4-[2-(2-benziloksietoksi)etoksi]fenil}-2-fenil-4-(tetrahidropiran-2-iloksi)butan-1-on
se pripravlja metodom opisanom u primjeru 4d, počevši s 1-{4-[2-(2-benziloksietoksi)etoksi]fenil}-2-feniletanonom (8,4g, 21,5 mmol) i 2-(tetrahidropiran-2-iloksi)etiljodidom (6,6 g, 25,8 mmol). Produkt (11,7 g) se u idućoj reakciji koristi bez daljeg pročišćavanja.
1H NMR (CDCl3 ): 1,40-1,95 (m, 6H), 2,00-2,20 and 2,40-2,60 (2m, zajedno 2H), 3,60–3,80 (m, 8H), 3,83 (dist.t, 2H), 4,13 (dist.t, 2H), 4,45-4,55 (m, 1H), 4,55 (s, 2H), 4,80 (t, 1H), 6,86 (d, 2H), 7,14-7,39 (m, 10H), 7,96 (d, 2H)
c) 1-{4-[2-(2-benziloksietoksi)etoksi]fenil}-2-fenil-4-(tetrahidropiran-2-iloksi)-1-[3-(tetrahidropiran-2-iloksi)fenil]butan-1-ol
se pripravlja metodom opisanom u primjeru 4e, počevši s 1-{4-[2-(2-benziloksietoksi)etoksi]fenil}-2-fenil-4-(tetrahidropiran-2-iloksi)butan-1-onom (10 g, 19,2 mmol) i 3-(tetrahidropiran-2-iloksi)fenilbromidom (9,8 g, 38 mmol). Produkt se pročisti plamenom kromatografijom, uz toluen-metanol (50:1) kao eluens. Dobije se 5,7 g, 43 % produkta.
1H NMR (CDCl3 ): 1,40–2,20 (m, 10H), 3,5-4,1 (m, 14H), 4,30-4,50 (2m, 1H), 4,52 (s, 1H), 4,53 (s, 1H), 6,60 (d, 2H), 6,90-7,40 (m, 16H),
d)Z,E-3-(1-{4-[2-(2-benziloksietoksi)etoksi]fenil}-4-hidroksi-2-fenilbut-1-enil)fenol
se pripravlja iz 1-{4-[2-(2-benziloksietoksi)etoksi]fenil}-2-fenil-4-(tetrahidropiran-2-iloksi)-1-[3-(tetrahidropiran-2-iloksi)fenil]butan-1-ola (5,7 g, 8,2 mmol), metodom opisanom u primjeru 1c, osim što se umjesto acetanhidrida (30 ml) rabi toluen, i što se dodaje trietilamin (0,91 g, 0,9 mmol). Produkt (3,8 g) se u idućoj reakciji koristi bez daljeg pročišćavanja.
1H NMR (CDCl3 ): 2,78 (t, 2H), 3,55-4,20 (m, 10H), 4,55 i 4,58 (2s, 2H), 6,56 (d, 2H), 6,73-6,93 (m, 3H), 7,1-7,4 (m, 13H),
e) Z,E-3- (1-{4-[2-(2-benziloksietoksi)etoksi]fenil}-4-kloro-2-fenilbut-1-enil)fenol
se pripravlja iz Z,E-3- (1-{4-[2-(2-benziloksietoksi)etoksi]fenil}-4-hidroksi-2-fenilbut-1-enil)fenola (3,8 g, 7,4 mmol), metodom opisanom u primjeru 4h, osim što se reakcijskoj smjesi dodaje trietilamin (1,64 g, 16,2 mmol). Produkt se pročisti plamenom kromatografijom. Dobije ga se 2,5 g.
1H NMR (CDCl3 ): 2,92 (t, 2H), 3,40 (t, 2H), 3,58-4,17 (m, 8H) 4,53 i 4,57 (2s, 2H), 6,53 (d, 2H), 6,71-6,9 (m, 6H), 7,1–7,4 (m, 10H),
f) E-3- (4-kloro-1-{4-[2-(2-hidroksietoksi)etoksi]fenil}-2-fenilbut-1-enil)fenol
Z,E-3-(1-{4-[2-(2-benziloksietoksi)etoksi]fenil}-4-kloro-2-fenilbut-1-enil)fenol (2,0 g, 3,78 mmol) se otopi u etilacetatu (30 ml), te se u atmosferi dušika dodaju Zn (0,062 g, 0,95 mmol) i acetilklorid (0,74 g, 9,5 mmol). Smjesa se miješa tri sata pri 50°C. Smjesa se filtrira, a otapalo otpari. Ostatak se otopi u 80 % vodenom metanolu koji sadrži 3% natrijeva hidroksida. Smjesa se miješa dva sata pri sobnoj temperaturi, a methanol otpari. Doda se voda (5 ml) i proizvod se ekstrahira u etilacetatu (10 ml). Smjesa se osuši, a otapalo otpari. Proizvod se najprije pročisti plamenom kromatografijom (eluens - toluen:metanol 9:1), a potom kristalizira iz toluena i rekristalizira iz smjese toluene-aceton. Dobije se 0,15 g proizvoda.
1H NMR (CDCl3 ): 2,94 (t, 2H), 3,41 (t, 2H), 3,59-3,63 (m, 2H), 3,67-3,72 (m, 2H), 3,78 (dist.t, 2H), 4,01 (dist.t, 2H), 6,56 (d, 2H), 6,78 (d, 2H), 6,70-6,90 (m, 3H), 7,1–7,3 (m, 6H).
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Claims (19)
1. Spoj formule:
[image]
( I )
gdje su R1 i R2, koji su jednaki ili različiti,
a) H, halogen, OCH3, OH; ili
b)
[image]
gdje X je O, NH ili S; a n je cijeli broj od 1 do 4; a
R4 i R5, koji su jednaki ili različiti, su 1 do 4 ugljikova alkila, H, -CH2C≡CH ili -CH2CH2OH; ili
R4 i R5 tvore peteročlani ili šesteročlani prsten, ili heteroaromatski prsten koji sadrže N; ili
c) -Y-(CH2)nCH2-O-R6
gdje Y je O, NH ili S, a n je cijeli broj od 1 do 4; a
R6 je H, -CH2CH2OH, ili -CH2CH2Cl; ili
d) 2,3-dihidroksipropoksi, 2-metilsulfamiletoksi, 2-kloroetoksi, 1-etil-2-hidroksietoksi, 2,2-dietil-2-hidroksietoksi ili karboksimetoksi; a
R3 je H, halogen, OH ili -OCH3; I
njihove netoksične, farmaceutski prihvatljive soli i esteri, ili njihove smjese,
pod uvjetom da
a) kad R2 je
[image]
na položaju 4 fenila
gdje R4 i R5
i) su jednaki, metil ili etil; ili
ii) tvore peteročlani prsten koji sadrži N;
tada R1 i R3 ne mogu istodobno biti H; a
b) kad R2 je
[image]
na položaju 4 fenila
gdje su R4 i R5, koji su jednaki ili različiti,
metil ili H; ili
kad R2 je -O-CH2CH2-OH ili -O-CH2COOH na položaju 4 fenila,
tada R1 i R3, ne mogu istodobno biti H, ili OH na položaju 4 fenila; a
ako R1 je OH na položaju 4 fenila, R3 ne može biti H.
2. Trifeniletilen prema zahtjevu 1, gdje R1 a R2 , koji su jednaki ili različiti, jesu
a) H, halogen, OCH3, OH; ili
b)
[image]
gdje X je O, NH ili S; a n je cijeli broj od 1 to 4; a R4 i R5, koji su jednaki ili različiti, jesu 1 do 4 ugljikova alkila, H,
-CH2C≡CH ili -CH2CH2OH; ili R4 i R5 tvore peteročlani ili šesteročlani prsten ili heteroaromatski prsten koji sadrže N.
3. Trifeniletilen prema zahtjevu 2, gdje X je O.
4. Trifeniletilen prema zahtjevu 3, gdje n je 1, a R4 i R5 su metil ili tvore piperidinski ili imidazolni prsten.
5. Trifeniletilen prema zahtjevu 2, gdje X je S.
6. Trifeniletilen prema zahtjevu 2, gdje X je NH.
7. Spoj prema zahtjevu 4, iz skupine kojoj pripadaju sljedeći spojevi:
(2-{4-[4-kloro-1-(4-fluorofenil)-2-fenilbut-1-enil]fenoksi}etil)-dimetilamin,
(2-{4-[4-kloro-1-(4-klorofenil)-2-fenilbut-1-enil]fenoksi}etil)-dimetilamin,
(2-{4-[4-kloro-1,2-bis(4-klorofenil)but-1-enil]fenoksi}etil)-dimetilamin,
(2-{4-[4-kloro-2-(4-fluorofenil)-1-fenilbut-1-enil]fenoksi}etil)-dimetilamin,
(2-{4-[4-kloro-2-(4-klorofenil)-1-fenilbut-1-enil]fenoksi}etil)-dimetilamin,
(2-{4-[4-kloro-2-(4-klorofenil)-1-(4-metoksifenil)but1enil]fen-oksi}etil)dimetilamin,
{2-[3-(4-kloro-1,2-difenilbut-1-enil)fenoksi]etil}dimetilamin,
1-{2-[4-(4-kloro-1,2-difenil-but-1-enil)fenoksi]etil}-1H-imidazol,
{2[4(4kloro-1,2-difenilbut-1-enil)fenoksi]etil}metilprop-2-inilamin,
2({2-[4-(4-kloro-1,2-difenil-but-1-enil)fenoksi]etil}metilamino)-etanol,
3{4-kloro-1-[4-(2-imidazol-1-il-etoksi)fenil]-2-fenil-but-1-enil}-fenol,
1(2-{4-[4-kloro-2-(2-klorofenil)-1-fenilbut-1-enil]fenoksi}etil)-piperidin,
1-(2-{4-[4-kloro-2-(3-metoksifenil)-1-fenilbut-1-enil]fenoksi}etil)-piperidin, i
1-(2-{4-[4-kloro-2-(2-metoksifenil)-1-fenilbut-1-enil]fenoksi}etil)-piperidin.
8. Spoj prema zahtjevu 5, koji je 1-[4-(2-dimetilaminoetilsulfanil)fenil]-1,2-difenil-4-kloro-but-1-en.
9. Spoj prema zahtjevu 6, koji je N-[4-(4-kloro-1,2-difenilbut-1-enil)fenil]-N’,N’-dimetilethan-1,2-diamin.
10. Trifeniletilen prema zahtjevu 1, gdje R1 i R2, koji su jednaki ili različiti, jesu
a) H, halogen, OCH3, OH; ili
b) -Y-(CH2)nCH2-O-R6
gdje Y je O, NH ili S a n je cijeli broj od 1 do 4; a R6 je H,
-CH2CH2OH, ili -CH2CH2Cl.
11. Trifeniletilen prema zahtjevu 10, gdje Y je O.
12. Trifeniletilen prema zahtjevu 10, gdje Y je S.
13. Trifeniletilen prema zahtjevu 10, gdje Y je NH.
14. Spoj prema zahtjevu 11, iz skupine kojoj pripadaju sljedeći spojevi:
2-{4-[4-kloro-2-fenil-1-(4-fluorofenil)but-1-enil]fenoksi}etanol,
2{4[4kloro-2-fenil-1-(4-klorofenil)but-1-enil]fenoksi}etanol,
3{4kloro-1-[4-(2-hidroksietoksi)fenil]-2-fenil-but-1-enil}-fenol,
4{1(2kloroetil)-2-[4-(2-hidroksietoksi)fenil]-2-fenilvinil}fenol,
2{4[4-kloro-1,2-bis(4-klorofenil)but-1-enil]fenoksi}etanol,
2-{4-[4-kloro-2-(4-klorofenil)-1-(4-metoksifenil)but-1-enil]fenoksi}etanol,
2(4{4kloro-1-[4-(2-hidroksietoksi)fenil]-2-fenil-but-1-enil}fenoksi)1etanol,
2-[3-(4-kloro-1,2-difenil-but-1-enil)fenoksi]etanol,
3[4(4kloro1,2difenilbut-1-enil)fenoksi]propan-1-ol,
2{2[4(4kloro1,2difenilbut1-enil)fenoksi]etoksi}etanol,
3[4(4kloro1,2difenilbut-1-enil)fenoksimetil]pentan-3-ol,
1(4{2[(2kloroetoksi]etoksi}fenil)-4-kloro-1-(4-klorofenil)-2-fenil-but1en i
1(4{2[(2kloroetoksi]etoksi}fenil)-4-kloro-1-(4-fluorofenil)-2-fenil-but1en.
15. Spoj prema zahtjevu 12, koji je 2-[4-(4-kloro-1,2-difenil-but-1-enil)-fenilsulfanil]etanol.
16. Spoj prema zahtjevu 13, koji je 2-[4-(4-kloro-1,2-difenil-but-1-enil)fenilamino]etanol.
17. Spoj prema zahtjevu 1, iz skupine kojoj pripadaju sljedeći spojevi:
3-[4-(4-kloro-1,2-difenilbut-1-enil)fenoksimetil]pentan-3-ol,
2-[4-(4-kloro-1,2-difenilbut-1-enil)fenoksi]butan-1-ol,
3-[4-(4-kloro-1,2-difenil-but-1-enil)fenoksi]propan-1,2-diol,
3-{4-[4-kloro-1-(4-klorofenil)-2-fenil-but-1-enil]fenoksi}propan 1,2 diol,
4-kloro-1-[4-(2-metilsulfanil-etoksi)fenil]-1,2-difenil-but-1-en,
4-kloro-1-[4-(2-kloroetoksi)fenil]-1,2-bis(4-klorofenil)-but-1-en, i
{4-[4-kloro-1-(4-klorofenil)-2-fenilbut-1-enil]fenoksi}octena kiselina.
18. Farmaceutski sastav koji sadrži količinu koja može polučiti tkivnospecifično estrogeno i/ili antiestrogeno djelovanje novog selektivnog modulatora estrogenih receptora, kao spoja iz zahtjeva 1, ili njegovu netoksičnu, farmaceutski prihvatljivu sol, kao i njegov farmaceutski kompatibilni, prihvatljivi nosač.
19. Metoda postizanja tkivnospecifičnog estrogenog i/ili antiestrogenog djelovanja u osobe u koje je to djelovanje poželjno, a koja se sastoji u davanju takvoj osobi novog selektivnog modulatora estrogenih receptora kao spoja iz zahtjeva 1, ili njegove netoksične, farmaceutski prihvatljive soli u količini dostatnoj da se poluči to djelovanje.
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PCT/FI2000/000946 WO2001036360A1 (en) | 1999-11-16 | 2000-11-01 | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
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HRP20020223C1 HRP20020223C1 (en) | 2012-12-31 |
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- 2003-04-08 US US10/408,303 patent/US6875775B2/en not_active Expired - Lifetime
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2009
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