FI114801B - Borester- och -syraföreningar samt syntes och användning därav - Google Patents
Borester- och -syraföreningar samt syntes och användning därav Download PDFInfo
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- FI114801B FI114801B FI971746A FI971746A FI114801B FI 114801 B FI114801 B FI 114801B FI 971746 A FI971746 A FI 971746A FI 971746 A FI971746 A FI 971746A FI 114801 B FI114801 B FI 114801B
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- 238000007910 systemic administration Methods 0.000 description 1
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- DTWNKTDZTLVHLG-RDJZCZTQSA-N tert-butyl (2s,3s)-3-hydroxy-2-naphthalen-1-yl-5-oxopyrrolidine-1-carboxylate Chemical compound O[C@H]1CC(=O)N(C(=O)OC(C)(C)C)[C@H]1C1=CC=CC2=CC=CC=C12 DTWNKTDZTLVHLG-RDJZCZTQSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
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- 125000004306 triazinyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 230000001810 trypsinlike Effects 0.000 description 1
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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Claims (27)
1. Förening kännetecknad av formeln P--N- -tf-X'- -CH-X2-CH—ΒίΖ’χΖ*) (la) B A' R2 A* JA 5 I eller ett farmaceutiskt godtagbart sait därav; där P betecknar R7-C(0)-, R7-NH-C(0)-, R70-C (O) - eller R7-S02-, där R7 betecknar heteroaryl eller heteroarylalkyl; eller där R7 ocksä kan beteckna N-morfolinyl när P betecknar R7-C(0)-; 10 där Bl vid varje förekomst oberoende betecknar N eller CH; där X1 vid varje förekomst oberoende betecknar -C(0)-NH-, -CH2-NH-, -CH(OH)-CH2, -CH(OH)-CH(OH)-, -CH(OH)-CH2-NH-, -CH~CH-, -C(0)-CH2-, -S02-NH-, —S02—CH2— eller -CH (OH) -CH2-C (O) -NH-, med det förebehället att när B1 betecknar N, sä är den grupp X1 som f 15 är fästad vid Bl -C(0)-NH-; där X2 betecknar -C(0)-NH-, -CH(OH)-CH2-, -CH(OH)-CH(OH-, : -C(0)-CH2-, -SO2-NH-, -S02-CH2- eller -CH (OH) -CH2-C (O) -NH-; där R betecknar väte eller alkyl, eller där R tillsammans med den angränsande R1, eller tillsammans med den angränsande R2 20 när A är lika med noll, bildar ett kväve-innehällande mono-, di- eller tricykliskt, mättat eller partiellt mättat ringsy-:·! stem innehällande 4-14 ringatomer, varvid detta ringsystem .*' > eventuellt kan vara substituerat med en eller tvä ketogrupper, hydroxigrupper, alkylgrupper, arylgrupper, aralkylgrupper, al-25 koxigrupper eller aryloxigrupper; > · ! 114801 där R1 vid varje förekomst oberoende betecknar väte, alkyl, cykloalkyl, aryl, en 5-10-ledad, mättad, partiellt omättad el-ler aromatisk heterocyklisk grupp eller -CH2-R5, där ringdelen av en eventuell arylgrupp, aralkylgrupp, alkarylgrupp eller 5 heterocyklisk grupp eventuellt kan vara substituerad; där R2 betecknar väte, alkyl, cykloalkyl, aryl, en 5-10-ledad, , mättad, partiellt omättad eller aromatisk heterocyklisk grupp eller -CH2-R5, där ringdelen av en eventuell arylgrupp, aralkylgrupp, alkarylgrupp eller heterocyklisk grupp eventuellt 10 kan vara substituerad; där R3 betecknar väte, alkyl, cykloalkyl, aryl, en 5-10-ledad, mättad, partiellt omättad eller aromatisk heterocyklisk grupp eller -CH2-R5, där ringdelen av en eventuell arylgrupp, aralkylgrupp, alkarylgrupp eller heterocyklisk grupp eventuellt 15 kan vara substituerad; där R5 vid varje förekomst betecknar aryl, aralkyl, alkaryl, cykloalkyl, en 5-10-ledad, mättad, partiellt omättad eller • .1 aromatisk heterocyklisk grupp eller W-R6, där W betecknar en kalkogen och R6 betecknar alkyl, varvid ringdelen av en eventu-20 eli arylgrupp, aralkylgrupp, alkarylgrupp eller heterocyklisk grupp eventuellt kan vara substituerad; där Z1 och Z2 oberoende av varandra betecknar alkyl, hydroxi, alkoxi eller aryloxi, eller där Z1 och Z2 tillsammans bildar en grupp härrörande frän en dihydroxiförening med minst tvä hyd-,25 roxigrupper separerade medelst minst tvä sammanbindande atomer i en kedja eller ring, varvid kedjän eller ringen innefattar kolatomer och eventuellt en eller flera heteroatomer valda :·/. bland N, S och O; > och där A betecknar 0, 1 eller 2. 101 1 1 4801
2. Förening enligt krav 1, kännetecknad av att heteroarylgruppen R7 ör vald bland tienyl, benso[b]tienyl, nafto[2,3~b]tienyl, tiantrenyl, furyl, pyranyl, isobensofuranyl, bensoxazolyl, kromenyl, xan-5 tenyl, fenoxatiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyra-zolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrdazinyl, indolizi-nyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-kinolizinyl, isokinolyl, kinolyl, ftalazinyl, naftyridinyl, kinazolinyl, cinnolinyl, pteridinyl, 4aH-karbazolyl, karbazo-10 lyl, β-karbolinyl, fenantridinyl, akridinyl, perimidinyl, fe-nantrolinyl, fenazinyl, isotiazolyl, fenotiazinyl, isoxazolyl, furazanyl och fenoxazinyl.
3. Förening enligt krav 1, kännetecknad av att P betecknar kinolinkarbonyl,· pyridinkarbonyl, kinolinsulfonyl, 15 kinoxalinkarbonyl, kinoxalinsulfonyl, pyrazinkarbonyl, pyrazin-sulfonyl, furankarbonyl, ifuransulfonyl eller N-morfolinkarbonyl.
4. Förening enligt krav 1, kanne tecknad av att P betecknar 8-kinolinkarbohyl, 8-kinolinsulfonyl, 2-kinoxalin- j ♦ · | karbonyl, 2-kinoxalinsulfonyl, 2-pyrazinkarbonyl, 2-pyrazinsul-fonyl, 3-furankarbonyl, 3-furansulfonyl eller N-morfolinkarbonyl. ·· 20
5. Förening enligt krav 1, kännetecknad av att A betecknar 0.
6. Förening enligt krav 1, kännetecknad av att B1 vid varje förekomst betecknar CH.
7. Förening enligt krav 6, kännetecknad av att X1 vid varje förekomst betecknar -C(0)-NH-. Γ· . 25
: 8. Förening enligt krav 7rkännetecknad av att X2 betecknar -C(0)-NH-. • * I
] 9. Förening enligt krav 1, kännetecknad av att * * » ’ : R betecknar väte eller Ci-e~ alkyl. t 108 1 1 4801
10 R2, R3 eller R5 eventuellt kan vara substituerad med en eller tvä substituenter oberoende valda bland Ci-6-alkyl, C3-8-cyklo- alkyl, Ci_6-alkyl (C3-8) cykloalkyl, C2-8-alkenyl, C2-e-alkynyl, cy- ano, amino, Ci-6-alkylamino, di (Ci-β) -alkylamino, bensylamino, dibensylamino, nitro, karboxi, karbo(Ci-β)-alkoxi, trifluorme- 15 tyl, halogen, Ci-6-alkoxi, C6-io~aryl, C6-i0-aryl (Ca_6) -alkyl, C6-io-aryl (Ci_6)-alkoxi, hydroxi, Ci-6-alkyltio, Ci-6~alkylsulfi- nyl, Cj-6-alkylsulfonyl, C6-i0-aryltio, C6_io-arylsulfinyl, C6-x0- . arylsulfonyl, C6-io-aryl, Ci-6-alkyl (C6-i0) aryl och halo(C6-io)- • « aryl. 20
11. Förening enligt krav 1, kännetecknad av att A betecknar noll; där X2 betecknar -C(O) -NH-; där R betecknar väte eller Ci-8-alkyl; och där R3 betecknar Ci_6~alkyl. »
10. Förening enligt krav 1, kanne tecknad av att! k1 vid varje förekomst och R2 och R3 oberoende av varandra vardera betecknar väte, Ci-8-alkyl, en 5-, 6-, 9- eller 10-ledad heteroarylgrupp eller -CH2-R5; C3-i0-cykloalkyl, C6-io~aryl, 5 där R5 vid varje förekomst betecknar C6-io-aryl, Ci-io-ar (Ci-β) -alkyl, Ci_6-alk (C6-i0) aryl, C3-i0-cykloalkyl, Ci-8-alkoxi, Ci_8-alkyltio eller en 5-, 6-, 9- eller 10-ledad heteroarylgrupp; varvid ringdelen i en eventuell arylgrupp, aralkylgrupp, alka- rylgrupp eller 5-, 6-, 9- eller 10-ledad heteroarylgrupp R1,
12. Förening enligt krav 1, kännetecknad av att R3 betecknar Ci_i2-alkyl.
13. Förening enligt krav 1, kännetecknad av att R3 betecknar Ci-6-alkyl. 25
14. Förening enligt krav 1, kännetecknad av att R3 betecknar C4-alkyl.
15. Förening enligt krav 1, kännetecknad av att • I : ·' R3 betecknar isobutyl.
16. Förening enligt krav 1, kännetecknad av att R2 betecknar isobutyl, 1-naftylmetyl, 2-naftylmetyl, 3-pyridyl"- 109 11 4801 metyl, 2-pyridylmetyl, 6-kinolinylmetyl, 3-indolylmetyl, bensyl, 4-fluorbensyl, 4-hydroxibensyl, 4-(2'-pyridylmetoxi)-bensyl, 4-(bensyloxi)bensyl, bensylnaftylmety1 eller fenetyl.
17. Förening enligt krav 1, kännetecknad av att 5 Z1 och 7} oberoende av varandra betecknar C1-6—alkyl, hydroxi, Ci-6-alkoxi eller Ci-io-aryloxi .
18. Förening enligt krav 17, kännetecknad av att Z1 och 7? bäda betecknar hydroxi.
19. Förening enligt krav 1, kännetecknad av att 10 Z1 och Z2 tillsammans bildar en grupp härrörande frän en dihyd- roxiförening vald bland pinakol, perfluorpinakol, pinandiol, etylenglykol, dietylenglykol, 1,2-cyklohexandiol, 1,3-propandiol, 2,3-butandiol, glycerol och dietanolamin.
20. Förening enligt krav 1, kännetecknad av att 15 P betecknar kinolinkarbonyl, pyridinkarbonyl, kinolinsulfonyl, kinoxalinkarbonyl, kinoxalinsulfonyl, pyrazinkarbonyl, pyrazin- • sulfonyl, furankarbonyl,furansulfonyl eller N—morfolinkarbonyl; .. där A betecknar noli; ♦ # där X2 betecknar -C(0)-NH-; 20 där R betecknar väte eller Ci-e-alkyl; där R2 och R3 oberoende av varandra vardera betecknar väte, : Ci-e-alkyl, C3-i0-cykloalkyl, C6-io-aryl, C6.10-ar(Ci_6)alkyl, pyri- dylmetyl eller kinolinylmetyl; ;>* och där Z och Z bäda betecknar hydroxi, Ci-6-alkoxi eller
21. Förening enligt krav 1, kännetecknad av att P betecknar 8-kinolinkarbonyl, 8-kinolinsulfonyl, 2-kinoxalin-5 karbonyl, 2-kinoxalinsulfonyl, 2-pyrazinkarbonyl, 2-pyrazin— sulfonyl, .3-pyridinkarbonyl, 3-pyridinsulfonyl, 3-furankarbonyl, 3-furansulfonyl eller N- morfolinkarbonyl; där A betecknar noli; där X2 betecknar -C(0)-NH-; 10 där R betecknar väte eller Ci-e-alkyl; där R3 betecknar isobutyl; där R2 betecknar isobutyl, 1-naftylmetyl, 2-naftylmetyl, 3-pyridylmetyl, 2-pyridylmetyl, 6-kinolinylmetyl, 3-indolyl-metyl, bensyl, 4-fluorbensyl, 4-hydroxibensyl, 4-(2' -pyridyl-15 metoxi)bensyl, 4-(bensyloxi)bensyl, bensylnaftylraetyl eller • · ;* fenetyl; och där Z1 och Z2 oberoende av varandra betecknar hydroxi, Οχ-6~ alkoxi eller C6-io~aryloxi, eller där Z1 och Z2 tillsammans bil-·. dar en grupp härrörande frän en dihydroxiförening vald bland : 20 pinakol, perfluorpinakol, pinandiol, etylenglykol, dietylen- glykol, 1,2-cyklohexandiol, 1,3-propandiol, 2,3-butandiol, :* glycerol och dietanolamin.
22. Förening enligt krav 1, kännetecknad av att den är ; 25 N- (2-pyrazin) karbonyl-L-fenylalanin-L-leucin-boronsyra; N- (2-kinolin) sulfonyl-L-homof enylalanin-L-leucin-boronsyra; N-(3-pyridin)karbonyl-L-fenylalanin-L-leucin-boronsyra; -N-(4-morfolin)karbonyl-L-fenylalanin-L-leucin-boronsyra; ) 114801 m υ u 1 N-(4-morfolin)karbonyl-β-(l-naftyl)-L-alanin-L-leucin-boronsyra; N-(8-kinolin) sulfonyl-β- (1-naftyl) -L-alanin-L-leucon-boronsyra; N-(4-morfoi in)karbonyl-(O-bensyl) -L-tyrosin-L-leucin-5 boronsyra; N-(4-morfolin)karbonyl-L-tyrosin-L-leucin-boronsyra; N-(4-morfolin)karbonyl-[O-(2-pyridylmetyl)]-L-tyrosin-L-leucin-boronsyra; eller ett farmaceutiskt godtagbart sait eller en boronatester 10 därav.
23. Förening enligt krav 22, kännetecknad av att den är N-(2-pyrazin)karbonyl-L-fenylalanin-L-leucin-boronsyra eller ett farmaceutiskt godtagbart sait eller en boronatester därav.
24. Farmaceutisk komposition, kännetecknad av att innefattäden en förening enligt nägot av de föregäende kraven, eller ett farmaceutiskt godtagbart sait därav, och en farma— ceutiskt godtagbar bärare eller ett farmaceutiskt godtagbart * utspädningsmedel. ·* 25. Farmaceutisk komposition enligt krav 24, kanne — * ’ 20 tecknad av att föreningen är närvarande i en mängd som ' hämmar proteasom-funktionen hos ett däggdjur.
25 C6-io~aryloxi, eller där Z1 och Z2 tillsammans bildar en grupp ,‘i härrörande frän en dihydroxiförening vald bland pinakol, per- fluorpinakol, pinandiol, etylenglykol, dietylenglykol, 1,2- „0 114801 cyklohexandiol, 1,3-propandiol, 2,3-butandiol, glycerol och dietanolamin.
26. Användning av en förening enligt nägot av kraven 1-23 ;· för framställning av en farmaceutisk komposition för (a) hämning av en cancercells tillväxt; 25 (b) minskning av den hastighet med vilken muskelprote- in nedbrytes; • · (c) minskning av aktiviteten av NF-κΒ i en cell; 114801 (d) minskning av den hastighet med vilken intracellu-lärt protein nedbrytes; (e) minskning av hastigheten av nedbrytning av p53; (f) hämning av cyklin-nedbrytning i en cell; 5 (g) förhindrande eller behandling av ett inflammato- riskt tillstAnd; (h) hämning av antigenpresentation i en cell; (i) hämning av inducerbar, NF-KB-beroende cellvidhäft-ning; eller 10 <j) hämning av HIV-replikation.
] 27. Användning enligt krav 26, kännetecknad av att en patient har diagnosticerats med eller riskerar att utveckla i ; ett tillständ valt bland avstötning av vävnad, avstötning av organ, artrit, infektioner, dermatoser, inflammatorisk tarmsjukdom, astma, 15 osteoporos, osteoartrit och autoimmuna sjukdomar. » · » »
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US33052594A | 1994-10-28 | 1994-10-28 | |
US33052594 | 1994-10-28 | ||
US08/442,581 US6083903A (en) | 1994-10-28 | 1995-05-16 | Boronic ester and acid compounds, synthesis and uses |
US44258195 | 1995-05-16 | ||
PCT/US1995/014117 WO1996013266A1 (en) | 1994-10-28 | 1995-10-27 | Boronic ester and acid compounds, synthesis and uses |
US9514117 | 1995-10-27 |
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FI20041415A FI120974B (sv) | 1994-10-28 | 2004-11-03 | Borester- och -syraföreningar samt användning därav |
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- 2004-06-09 LU LU91083C patent/LU91083I2/fr unknown
- 2004-08-06 NO NO2004004C patent/NO2004004I2/no not_active IP Right Cessation
- 2004-11-03 FI FI20041415A patent/FI120974B/sv not_active IP Right Cessation
- 2004-11-19 CY CY0400082A patent/CY2484B1/xx unknown
-
2005
- 2005-10-17 US US11/252,291 patent/US20060122390A1/en not_active Abandoned
-
2006
- 2006-07-11 HK HK06107756.3A patent/HK1087714A1/xx not_active IP Right Cessation
- 2006-12-20 US US11/642,372 patent/US20070282100A1/en not_active Abandoned
-
2008
- 2008-01-02 US US12/006,422 patent/US7531526B2/en not_active Expired - Lifetime
-
2009
- 2009-04-01 US US12/416,193 patent/US8003791B2/en not_active Expired - Fee Related
-
2011
- 2011-08-19 US US13/213,157 patent/US8378099B2/en not_active Expired - Fee Related
-
2013
- 2013-01-11 US US13/739,223 patent/US20130310320A1/en not_active Abandoned
-
2014
- 2014-04-08 US US14/247,711 patent/US20150072942A1/en not_active Abandoned
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Spc suppl protection certif: 253 Extension date: 20190428 |