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SI9012429B - Novi derivati kromana in tiokromana - Google Patents

Novi derivati kromana in tiokromana Download PDF

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SI9012429B
SI9012429B SI9012429A SI9012429A SI9012429B SI 9012429 B SI9012429 B SI 9012429B SI 9012429 A SI9012429 A SI 9012429A SI 9012429 A SI9012429 A SI 9012429A SI 9012429 B SI9012429 B SI 9012429B
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alkyl
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alkenyl
compound
hydrogen
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Lars-Gunnar Larsson
Rolf Noreen
Lucy Anna Renyi
Svante Bertil Ross
Daniel Dungan Sohn
Bjoern Eric Svensson
Seth Olov Thorberg
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Aktiebolaget Astra
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Claims (24)

1 PATENTNI ZAHTEVKI 1. Spojina s formulo K 4
3 (I) označena s tem, da
X pomeni O ali (01 p je celo število O, 1 ali 2 R je vodik, tluoro ali Cj 6-alkil R, je vodik, C,^ alkil ali C2 6 alkenil R, je vodik, C,^ alkil, C2 6 alkenil, CM alkilaril, kjer aril lahko vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S, v danem primeru substituirana s halogenom, CN, CFj, C, ή alkilom, C2 6 alkenilom ali CM alkoksi, ali R3 je CN, S03CF3, Nv NRsR6, COR?, 5- ali 6-členski aril. ki lahko vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S, in pri čemer je bodisi (i) v danem primeru substituiran z enim ali več substituenti, neodvisno izbranimi izmed halogena. CN. CFV C, () alkila, C2 fj alkenila ali Ct alkoksi ali (ii) kondenziran pri dveh sosednjih atomih ogljika na arilni obroč, pri čemer je omenjeni arilni obroč v danem primeru substituiran z enim ali več substituenti, neodvisno izbranimi izmed halogena. CN. CF3, C{ (. alkila, C2 (> alkenila ali C^ alkoksi R4 je vodik ali halogen R5 je vodik, C, (i alki] ali C2 (t alkenil Rfi je C, 6 alkil ali C2 6 alkenil, ali R5 in R6 lahko skupaj tvorita 5- ali 6-členski obroč, ki lahko vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S R? je vodik, hidroksi, kloro, bromo, C, 6 alkil, C alkenil. CM alkoksi, NRsRg ali 5-ali 6-členski aril, ki lahko vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S, v danem primeru substituirana z enim ali več izmed halogena, CN, CF3, C 6 alkila, C, () alkenila ali C. , alkoksi Rg ali Rg sta vsak neodvisno vodik, Cf 6 alkil, C2 6 alkenil, 5- ali 6-členski aril, ki lahko vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S, v danem primeru substituirana s halogenom, CN, CF3, C 6 alkilom, C2 6 alkenilom, C, 4 alkoksi, ali lahko skupaj tvorita 5- ali 6-členski obroč, ki vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S, njen enantiomer ali njena sol.
2. Spojina po zahtevku 1, označena s tem, da X pomeni O.
3. Spojina po zahtevku 1, označena s tem, da X pomeni P (O) s in je p enak 0, 1 ali 2.
4. Spojina po enem od zahtevkov 1, 2 ali 3, označena s tem, da R3 pomeni NR5R6, COR7, 5- ali 6-členski aril. ki lahko vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S. in pri čemer je bodisi (i) v danem primeru substituiran z enim ali več sub-stituenti, neodvisno izbranimi izmed halogena. CN, CF,. C,_6 alkila, C,_ft alkenila ali CM alkoksi ali (ii) kondenziran pri dveh sosednjih atomih ogljika na arilni obroč, pri čemer je omenjeni arilni obroč v danem primeru substituiran z enim ali več sub-stituenti, neodvisno izbranimi izmed halogena, CN, CFV C,_ft alkila, C2(> alkenila ali C'M alkoksi: R? je vodik. CUi alkil. C2 g alkenil, C| 4 alkoksi. NRgR9 ali 5- ali 6-členski aril, ki lahko vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S, v danem primeru substituirana z enim ali več izmed halogena, CN, CF3, C,_6 alkila, C2(> alkenila ali C, 4 alkoksi; X, p, R, R(, R2, R4, Rv R6, Rs in R9 so, kot so definirani v zahtevku 1, njen enantiomer ali njena farmacevtsko sprejemljiva sol za uporabo pri terapiji.
5. Spojina po enem od zahtevkov 1-4, označena s tem, da sta R! in R2 enaka ali različna in sta izbrana izmed vodika, n-propila, i-propila in ciklopropila.
6. Spojina po enem od zahtevkov 1-5, označena s tem, da R3 pomeni CORr
7. Spojina po zahtevku 6, označena s tem, da R? pomeni CM alkil, fenil, furanil, ali tienil, v danem primeru substituiran s halogenom, NRgR9, kjer sta Rg in R9 vsak neodvisno izbrana izmed vodika ali C, . alkila ali C, . alkoksi.
8. Spojina po zahtevku 6, označena s tem, da sta R in R4 vodik, Rt in R2 sta n-propil in R? pomeni metil, etil, n-propil, i-propil, ciklopropil, n-butil, i-butil, t-butil, cik-lobutil, tienil, furanil, fenil, N-metilamino, metoksi ali fluorofenil.
9. Spojina po enem od zahtevkov 1-5, označena s tem, da R3 pomeni fenil, furanil. tienil ali fluorofenil.
10. Spojina po enem od zahtevkov 1-7 in 9, označena s tem, da R4 pomeni halogen v položaju 8.
11. Spojina po zahtevku 1, označena s tem, daje 3-dipropilamino-5-acetilkroman, njegov enantiomer ali njegova sol.
12. Spojina po zahtevku 1, označena s tem, da je 3-dipropilamino-5-karbamoilkroman, njegov enantiomer ali njegova sol.
13. Spojina po zahtevku 1, označena s tem, da je 3-dipropilamino-5-N-metilkarbamoilkroman. njegov enantiomer ali njegova sol.
14. Spojina po zahtevku 1, označena s tem. da je 3-dipropilamino-5-(2-tienilkurbonilkroman). njegov enantiomer ali njegova sol. 4
15. Spojina po zahtevku 1, označena s tem, da R3 pomeni CN, COOH, COC1, COBr, N., ali S03CF3 in so X, R, Rp R2 in R4, kot so definirani v zahtevku 1, njen enan-tiomer ali njena sol.
16. Spojina po zahtevku 15, označena s tem, da sta R( in R2 enaka ali različna in sta izbrana izmed vodika, n-propila, i-propila in ciklopropila.
17. Spojina po zahtevku 16, označena s tem, da sta R in R4 vodik, R in R? sta n-propil in R3 pomeni S03CF3.
18. Farmacevtski pripravek, označen s tem, da vsebuje kot aktivno sestavino spojino s formulo I
v kateri X pomeni O ali P (O) II s; p je celo število 0,1 ali 2 R je vodik, fluoro ali C( 6-alkil R, je vodik, C, 6 alkil ali C2 (. alkenil R, je vodik. C, () alkil, C2 (. alkenil, C,.4 alkilaril, kjer aril lahko vsebuje 1 ali 2 heteroatoma. izbrana izmed N, O ali S, v danem primeru substituirana s halogenom, CN. CF.. C. alkilom, C., alkenilom ali C. alkoksi > j -i» ' J-n 1-4 R3 je NRSR(>. CORr 5- ali 6-členski aril, ki lahko vsebuje 1 ali 2 heteroatoma, izbrana 5 izmed N, O ali S, in pri čemer je bodisi (i) v danem primeru substituiran z enim ali več substituenti, neodvisno izbranimi izmed halogena, CN, CF3, CU) alkila, C26 alkenila ali C, 4 alkoksi ali (ii) kondenziran pri dveh sosednjih atomih ogljika na arilni obroč, pri čemer je omenjeni arilni obroč v danem primeru substituiran z enim ali več substituenti, neodvisno izbranimi izmed halogena, CN, CF3, C, 6 alkila, C2 6 alkenila ali Cj 4 alkoksi R4 je vodik ali halogen R5 je vodik, C,_6 alkil ali C2 6 alkenil Rr> je C 6 alkil ali C alkenil, ali R5 in R6 lahko skupaj tvorita 5- ali 6-členski obroč, ki lahko vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S R? je vodik, Cj_6 alkil, C2 6 alkenil, CM alkoksi, NRgR9 ali 5- ali 6-členski aril, ki lahko vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S, v danem primeru substituirana z enim ali več izmed halogena, CN, CF3, C, 6 alkila, C24, alkenila ali C3 4 alkoksi R8 in R9 sta vsak neodvisno vodik, C,_6 alkil, C2 6 alkenil, 5- ali 6-členski aril, ki lahko vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S, v danem primeru substituirana s halogenom, CN, CF3, C, 6 alkilom, C2 6 alkenilom, 4 alkoksi, ali lahko skupaj tvorita 5- ali 6-členski obroč, ki vsebuje 1 ali 2 heteroatoma, izbrana izmed N, O ali S, njen enantiomer ali njeno farmacevtsko sprejemljivo sol.
19. Farmacevtski pripravek po zahtevku 18, označen s tem, da so X, R, Rp R0. R3, R4, R7. Rg in R9 definirani kot v enem od zahtevkov 2-3, 5-14.
20. Spojina po enem od zahtekov 4-14 za uporabo pri zdravljenju motenj centralnega živčnega sistema, posebno motenj, ki so posredovane s 5-hidroksitriptaminom.
21. Spojina po zahtevku 20 za uporabo pri zdravljenju depresije, vznemirjenosti, anoreksije, senilne demence, migrene, Alzheimerjeve bolezni, hipertenzije. ter-moregulatornih in seksualnih motenj, bolečin in motenj v kardiovaskularnem sistemu. 6
22. Uporaba spojine po enem od zahtevkov 4-14 za izdelavo zdravila za zdravljenje motenj centralnega živčnega sistema, posebno motenj posredovanih s 5-hidroksitriptaminom.
23. Uporaba po zahtevku 22 za izdelavo zdravila za zdravljenje depresije, vznemirjenosti, anoreksije, senilne demence, migrene, Alzheimerjeve bolezni, ter-moregulatornih in seksualnih motenj, bolečin in motenj v kardiovaskularnem sistemu.
24. Postopek za pripravo spojine s formulo I po enem od zahtevkov 1-17, označen s tem, da izvedemo faze a) pretvorbo spojine s formulo II
v kateri je Y zapuščajoča skupina in so X, R, R,, R2 in R4, kot je definirano pri formuli I, s katalitičnim ciklusom z uporabo ničvalentne prehodne kovine (M°), ki jo izpostavimo oksidativni adiciji na aril-Y-vezi, obdelavo z ogljikovim monoksidom in nato z Z-H, kjer Z pomeni Cl, Br, OH, ORp, kjer Rp pomeni C, 6 alkil, in kar-boniliranega kompleksa o-aril-kovina-Y, tvorjenega na začetku, da nastane spojina s formulo I, kjer R4 pomeni COZ (IA). b) reakcijo s katalitični ciklusom z uporabo ničvalentne prehodne kovine (M°), ki jo izpostavimo oksidacijski adiciji na Z -Y, kjer je Z definiran kot Cl, Br, OH ali ORp, 7 kjer Rp pomeni CUj alkil in je Y zapuščajoča skupina, obdelavo z ogljikovim monoksidom in nato adicijo spojine s formulo III
III kjer so X, R, Rt, R2 in R4, kot je definirano pri formuli I, in je M' prehodna kovina, da se tvori spojina s formulo I, kjer R3 pomeni COZ (IA), ali c) pretvorbo spojine s formulo II
8 kjer so X, R, R,, R2 in R4, kot je definirano pri formuli I, Y je zapuščajoča skupina, kot je S03CFv halogenid, z obdelavo s cianidnim reagentom, da se tvori spojina s formulo I, kjer R3 pomeni CN (IB) d) aminiranje spojine s formulo IA
kjer so X, R, R1? R2 in R4, kot je definirano pri formuli I in Z pomeni Cl, OH ali ORp, kjer Rp pomeni Cl 6 alkil, z reakcijo z NHR8R9, da se tvori ustrezen amid s formulo I, kjer je R3 CONRgR9 (IC), ali e) substitucijo derivata 5-bromokromana/tiokromana
I kjer so X, R, R,, Rn in R4, kot so definirani pri formuli I, z obdelavo s kositrovim tri-alkilnim reagentom v prisotnosti ničvalentne kovine, npr. Pd(), da nastane spojina s formulo I, kjer R3 pomeni aril, ali v prisotnosti ogljikovega monoksida, da nastane spojina, kjer R3 pomeni COR7, kjer R7 pomeni C( alkil, G, ( alkenil ali aril, ali 9 f) pretvorbo derivata 5-karboksikromana/tiokromana s formulo IA
kjer so X, R, Rp R2 in R4, kot so definirani pri formuli I in Z pomeni Cl, Br, z uporabo R?Li, da nastane ustrezna spojina s formulo I, kjer R3 pomeni COR? (ID), kjer je R7 definiran kot C3 6 alkil, C2 6alkenil ali aril, ali g) hidrolizo spojine s formulo I, kjer R3 pomeni CN (IB)
kjer so X, R, Rp R2 in R4, kot so definirani pri formuli I. čemur v danem primeru sledi obdelava s tionil halogenidom, da nastane spojina s formulo I, kjer R3 pomeni COZ, kjer Z pomeni OH, Cl ali Br (IA), ali 10 h) substitucijo spojine s formulo I, kjer pomeni CN
kjer so X, R, R , R2 in R4, kot je definirano pri formuli I, z obdelavo z or-ganokovinskim reagentom, čemur sledi hidroliza, da nastane spojina s formulo I. kjer R3 pomeni COR?, kjer R7 pomeni 6 alkil, C2 6 alkenil ali aril (ID), ali i) pretvorbo spojine s formulo (II)
kjer je Y zapuščajoča skupina in so X, R, R , R, in R4, kot je definirano pri formuli I, z reakcijo s prehodno kovino, da se tvori ligandni kompleks, ki ga izpostavimo ok-sidativni adiciji z obdelavo s trialkilaril stananom ali reagenti na osnovi aril borove kisline, da se tvori spojina s formulo I, kjer R, pomeni 5- ali 6-členski aril. ki lahko vsebuje l ali 2 heteroatoma, izbrana izmed N. O ali S, ki sta bodisi substituirana ali kondenzirana pri dveh sosednjih atomih ogljika, in nato, v danem primeru, pretvorbo dobljene baze v kislinsko adicijsko sol, ali dobljene soli v bazo ali drugačno kislinsko 11 adicijsko sol, ali, v danem primeru, ločitev dobljene izomerne zmesi v čisti enan-tiomer. Za Aktiebolaget Astra: LJUBLJANA, ČOPOVA 1
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SE8904361A SE8904361D0 (sv) 1989-12-22 1989-12-22 New chroman and thiochroman derivatives
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ATE149480T1 (de) * 1990-08-15 1997-03-15 Lilly Co Eli Ring-substituierte 2-amino-1,2,3,4-tetra- hydronaphthaline, 3-aminochromane und 3- aminothiochromane
ATE197145T1 (de) * 1991-02-08 2000-11-15 Lilly Co Eli Ringsubstituierte 2-amino-1,2,3,4- tetrahydronaphtahline und 3-aminochromane
HRP920935A2 (en) * 1991-10-08 1995-08-31 Astra Ab New therapeutically active compound
SE9103745D0 (sv) * 1991-12-18 1991-12-18 Wikstroem Haakan Aryl-triflates and related compounds
FR2691149B1 (fr) * 1992-05-18 1994-07-08 Adir Nouveaux composes thiochromaniques, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent.
US5434174A (en) * 1992-07-17 1995-07-18 Eli Lilly And Company Isoxazole derivatives for the treatment of irritable bowel syndrome
SE9301732D0 (sv) * 1993-05-18 1993-05-18 Haakan Wilhelm Wikstroem New centrally acting 5-,6-,7-, and 8-substituted sulphone esters of n-monosubstituted 2-aminotetralins
SE9703377D0 (sv) 1997-09-18 1997-09-18 Astra Ab New compounds
SE9703378D0 (sv) * 1997-09-18 1997-09-18 Astra Ab New compounds
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
IL156601A0 (en) * 2001-01-16 2004-01-04 Astrazeneca Ab Therapeutic chroman compounds
MXPA03006268A (es) 2001-01-16 2003-09-22 Astrazeneca Ab Compuestos terapeuticos de cromano.
NZ526697A (en) 2001-01-16 2005-05-27 Astrazeneca Ab Therapeutic heterocyclic compounds
JP5080716B2 (ja) 2001-07-20 2012-11-21 サイコジェニックス・インコーポレーテッド 注意欠陥・多動性障害の治療
US7125904B2 (en) 2002-10-11 2006-10-24 Portela & C.A., S.A. Peripherally-selective inhibitors of dopamine-β-hydroxylase and method of their preparation
SE0301795D0 (sv) * 2003-06-19 2003-06-19 Astrazeneca Ab New use I
SE0301796D0 (sv) * 2003-06-19 2003-06-19 Astrazeneca Ab New use II
WO2008080120A2 (en) * 2006-12-22 2008-07-03 Wyeth 3-amino chromane derivatives
SA08290245B1 (ar) * 2007-04-23 2012-02-12 استرازينيكا ايه بي مشتقات كربو كساميد جديدة من -n (8-اريل رباعي هيدرو نفثالين غير متجانس- 2- يل) أو -n (5-اريل كرومان غير متجانس -3-يل) لعلاج الألم
CN101712672B (zh) * 2008-10-06 2013-02-06 中国中医科学院中药研究所 一种治疗心脑血管系统疾病新化合物及其制备方法、用途
DE102010041948A1 (de) 2010-10-04 2012-04-05 Mahle International Gmbh Filtereinrichtung
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