HRP20100339T1 - Derivati indola kao aktivatori ppar - Google Patents

Derivati indola kao aktivatori ppar Download PDF

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HRP20100339T1
HRP20100339T1 HR20100339T HRP20100339T HRP20100339T1 HR P20100339 T1 HRP20100339 T1 HR P20100339T1 HR 20100339 T HR20100339 T HR 20100339T HR P20100339 T HRP20100339 T HR P20100339T HR P20100339 T1 HRP20100339 T1 HR P20100339T1
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formula
compound
branched
linear
carbon atoms
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Binet Jean
Boubia Benaissa
Dodey Pierre
Legendre Christiane
Barth Martine
Poupardin-Olivier Olivia
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Laboratoires Fournier Sa
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Abstract

Derivat indola, naznačen time što je odabran od: i) spojeva formuleu kojoj: Ra i Rb su svaki nezavisno atom vodika, atom halogena, linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 6 atoma ugljika, CF3, CN, CO-R2 ili OR2 skupina ili fenil skupina po potrebi supstituirana s linearnim, razgranatim ili cikličkim lancem ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupinom; R2 je linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupina ili fenil skupina po potrebi supstituirana s linearnim, razgranatim ili cikličkim lancem ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupinom; R3 i R4 su svaki nezavisno atom vodika ili linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 4 atoma ugljika; R je atom vodika ili linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 3 atoma ugljika; n = 1, 2 ili 3; X je jednostruka veza, atom kisika ili atom sumpora; iAr je aromatski ili heteroaromatski prsten odabran od fenil, naftil, kinolinil, izokinolinil, piridinil, pirazolil, imidazolil, izoksazolil, tiazolil, benzimidazolil, benzotiazolil, 2,1,3-benzotiadiazolil, 3,4-dihidro-1,4-benzoksazinil, 5,6,7,8-tetrahidronaftalenil, 1,2,3,4-tetrahidrokinolinil, 1,2,3,4-tetrahidroizokinolinil, 1,2,3,4-tetrahidro-2-oksokinolinil, 3,4-dihidro-2H-benzopiranil, indolil, 2,3-dihidroindolil, benzofuranil, 2,3-dihidrobenzofuranil, 1,3-benzodioksolil, 1,4-benzodioksanil i benzoksazolil skupina po potrebi supstituiran s jednim ili više atoma ili skupina atoma odabranih od atoma halogena, linearnih, razgranatih ili cikličkih lanaca ugljikovodika koji imaju 1 do 6 atoma ugljika, fenil, CF3, CN, CO-R2, OR2, SR2, NH-COR2, morfolinil, amino i 4-morfolinosulfonil skupine; kao i5-klor-1-[(4-fluor-3-nitrofenil)sulfonil]-1H-indol-2-butan kiselina, metil ester1[(4-amino-3-nitrofenil)sulfonil]-5-klor-1H-indol-2-butan kiselina, metil ester, ii) njihovih farmaceutski prihvatljivih soli. Patent sadrži oš 12 patentnih zahtjeva.

Claims (13)

1. Derivat indola, naznačen time što je odabran od: i) spojeva formule [image] u kojoj: Ra i Rb su svaki nezavisno atom vodika, atom halogena, linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 6 atoma ugljika, CF3, CN, CO-R2 ili OR2 skupina ili fenil skupina po potrebi supstituirana s linearnim, razgranatim ili cikličkim lancem ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupinom; R2 je linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupina ili fenil skupina po potrebi supstituirana s linearnim, razgranatim ili cikličkim lancem ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupinom; R3 i R4 su svaki nezavisno atom vodika ili linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 4 atoma ugljika; R je atom vodika ili linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 3 atoma ugljika; n = 1, 2 ili 3; X je jednostruka veza, atom kisika ili atom sumpora; i Ar je aromatski ili heteroaromatski prsten odabran od fenil, naftil, kinolinil, izokinolinil, piridinil, pirazolil, imidazolil, izoksazolil, tiazolil, benzimidazolil, benzotiazolil, 2,1,3-benzotiadiazolil, 3,4-dihidro-1,4-benzoksazinil, 5,6,7,8-tetrahidronaftalenil, 1,2,3,4-tetrahidrokinolinil, 1,2,3,4-tetrahidroizokinolinil, 1,2,3,4-tetrahidro-2-oksokinolinil, 3,4-dihidro-2H-benzopiranil, indolil, 2,3-dihidroindolil, benzofuranil, 2,3-dihidrobenzofuranil, 1,3-benzodioksolil, 1,4-benzodioksanil i benzoksazolil skupina po potrebi supstituiran s jednim ili više atoma ili skupina atoma odabranih od atoma halogena, linearnih, razgranatih ili cikličkih lanaca ugljikovodika koji imaju 1 do 6 atoma ugljika, fenil, CF3, CN, CO-R2, OR2, SR2, NH-COR2, morfolinil, amino i 4-morfolinosulfonil skupine; kao i 5-klor-1-[(4-fluor-3-nitrofenil)sulfonil]-1H-indol-2-butan kiselina, metil ester 1[(4-amino-3-nitrofenil)sulfonil]-5-klor-1H-indol-2-butan kiselina, metil ester, ii) njihovih farmaceutski prihvatljivih soli.
2. Spoj prema zahtjevu 1, naznačen time što najmanje jedan od supstituenata Ra i Rb nije atom vodika.
3. Spoj prema zahtjevu 1 ili 2, naznačen time što Ar je fenil ili heteroaromatska skupina koja sadržava dušik.
4. Spoj prema jednom od zahtjeva 1 do 3, naznačen time što n je jednak 1 ili 2.
5. Spoj prema jednom od zahtjeva 1 do 4, naznačen time što se upotrebljava kao farmakološki aktivna tvar.
6. Upotreba spoja prema jednom od zahtjeva 1 do 4, naznačena time što se upotrebljava za proizvodnju lijeka namijenjenog za liječenje hipertrigliceridemije, hiperlipidemije, hiperkolesterolemije, pretilosti i dijabetesa.
7. Upotreba spoja prema jednom od zahtjeva 1 do 4, naznačena time što se upotrebljava za proizvodnju lijeka namijenjenog za liječenje endotelne disfunkcije.
8. Upotreba spoja prema jednom od zahtjeva 1 do 4, naznačena time što se upotrebljava za proizvodnju lijeka namijenjenog za liječenje kardiovaskularne bolesti, upalne bolesti i neurodegeneracije kao što su, naročito, Alzheimerova bolest ili Parkinsonova bolest.
9. Farmaceutski pripravak, naznačen time što sadržava najmanje jedan spoj prema jednom od zahtjeva 1 do 4 kao aktivnu tvar.
10. Postupak za dobivanje spoja prema zahtjevu 1, naznačen time što sadržava korake koji se sastoje od a) upotrebe SONOGASHIRA reakcije za reakciju spoja formule [image] u kojoj: Ra i Rb su svaki nezavisno atom vodika, fluora, klora ili broma ili linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 6 atoma ugljika, CF3, CN, CO-R2 ili OR2 skupinu; i R2 je linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupinu ili fenil skupinu po potrebi supstituiranu s linearnim, razgranatim ili cikličkim lancem ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupinu, s acetilenskim derivatom formule [image] u kojoj: n = 1, 2 ili 3; R3 i R4 su svaki nezavisno atom vodika ili linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 4 atoma ugljika; R je linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 3 atoma ugljika; i X je jednostruka veza, atom kisika ili atom sumpora, u prisutnosti bakar jodida, katalizatora na bazi platine, npr. tetrakis-(trifenilfosfin)paladija, i organske baze, u otapalu, pri temperaturi između 0 i 60 ̊C, 2 do 24 sata, da nastane spoj formule [image] u kojoj: Ra, Rb, n, X, R3, R4 i R su kao što je definirano u početnim spojevima; b) reduciranja "nitro" skupine koju nosi spoj formule IV iznad, npr. reakcijom s kositar kloridom u prisutnosti etanola, u otapalu, pri temperaturi blizu sobne temperature, 1 do 24 sata, da nastane anilin formule [image] u kojoj: Ra, Rb, n, X, R3, R4 i R su kao što je definirano u početnom spoju; c) reakcije spoja formule V s arilsulfonil kloridom formule Ar-SO2-Cl (VI) u kojoj: Ar je aromatski ili heteroaromatski prsten odabran od fenil, naftil, kinolinil, izokinolinil, piridinil, pirazolil, imidazolil, izoksazolil, tiazolil, benzimidazolil, benzotiazolil, 2,1,3-benzotiadiazolil, 3,4-dihidro-1,4-benzoksazinil, 5,6,7,8-tetrahidronaftalenil, 1,2,3,4-tetrahidrokinolinil, 1,2,3,4-tetrahidroizokinolinil, 1,2,3,4-tetrahidro-2-oksokinolinil, 3,4-dihidro-2H-benzopiranil, indolil, 2,3-dihidroindolil, benzofuranil, 2,3-dihidrobenzofuranil, 1,3-benzodioksolil, 1,4-benzodioksanil i benzoksazolil skupina po potrebi supstituiran s jednim ili više atoma ili skupina atoma odabranih od atoma halogena, linearnih, razgranatih ili cikličkih lanaca ugljikovodika koji imaju 1 do 6 atoma ugljika, fenil, CF3, CN, CO-R2, OR2, SR2, NH-COR2, morfolinil, amino i 4-morfolinosulfonil skupine, u prisutnosti piridina, na sobnoj temperaturi, 10 do 120 minuta, da nastane spoj formule [image] u kojoj: Ra, Rb, n, X, R3, R4, R i Ar su kao što je definirano u početnim spojevima; d) cikliziranja spoj formule VII, npr. reakcijom s bakar(II) acetatom u otapalu pri temperaturi blizu temperature refluksa otapala, 4 do 24 sata, da nastane spoj formule [image] u kojoj: Ra, Rb, n, X, R3, R4, R i Ar su kao što je definirano u početnim spojevima; i e) ako je potrebno, hidroliziranja esterske skupine spoja formule Ia, i zatim obrade produkta s kiselinom da nastane spoj formule I u obliku slobodne kiseline: [image]
11. Postupak za dobivanje spoja prema zahtjevu 1, naznačen time što sadržava korake koji se sastoje od a) izvođenja reakcije halogeniranja, poželjno jodiranja, na anilinu formule [image] u kojoj: Ra i Rb su svaki nezavisno atom vodika, atom halogena ili linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 6 atoma ugljika, CF3, CN, CO-R2 ili OR2 skupinu, i R2 je linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupinu ili fenil skupinu po potrebi supstituiranu s linearnim, razgranatim ili cikličkim lancem ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupinu, pomoću sredstva za halogeniranje, npr. benziltrimetilamonij diklorjodata, u otapalu kao što je diklormetan ili metanol, na sobnoj temperaturi, 5 do 24 sata, da nastane spoj formule [image] u kojoj: Ra i Rb su kao što je definirano u početnim spojevima; b) reakcije spoja formule IX s acetilenskim derivatom formule [image] u kojoj: n = 1, 2 ili 3; R3 i R4 su svaki nezavisno atom vodika ili linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 4 atoma ugljika; R linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 3 atoma ugljika; i X je jednostruka veza, atom kisika ili atom sumpora, u uvjetima analognim onima opisanim za korak a) postupka opisanog u zahtjevu 10, da nastane spoj formule [image] u kojoj: Ra, Rb, n, X, R3, R4 i R su kao što je definirano u početnom spoju; c) cikliziranja spoja formule V iznad, u uvjetima analognim onima opisanim za izvođenje koraka (d) postupka opisanog u zahtjevu 10, da nastane indolski spoj formule [image] u kojoj: Ra, Rb, n, X, R3, R4 i R su kao što je definirano u početnom spoju; d) reakciju spoja formule (X) iznad s arilsulfonil kloridom formule Ar-SO2-Cl (VI) u kojoj: Ar je aromatski ili heteroaromatski prsten odabran od fenil, naftil, kinolinil, izokinolinil, piridinil, pirazolil, imidazolil, izoksazolil, tiazolil, benzimidazolil, benzotiazolil, 2,1,3-benzotiadiazolil, 3,4-dihidro-1,4-benzoksazinil, 5,6,7,8-tetrahidronaftalenil, 1,2,3,4-tetrahidrokinolinil, 1,2,3,4-tetrahidroizokinolinil, 1,2,3,4-tetrahidro-2-oksokinolinil, 3,4-dihidro-2H-benzopiranil, indolil, 2,3-dihidroindolil, benzofuranil, 2,3-dihidrobenzofuranil, 1,3-benzodioksolil, 1,4-benzodioksanil i benzoksazolil skupina po potrebi supstituiran s jednim ili više atoma ili skupina atoma odabranih od atoma halogena, linearnih, razgranatih ili cikličkih lanaca ugljikovodika koji imaju 1 do 6 atoma ugljika, fenil, CF3, CN, CO-R2, OR2, SR2, NH-COR2, morfolinil, amino i 4-morfolinosulfonil skupina, u otapalu, na sobnoj temperaturi, 1 do 12 sati, općenito nakon aktivacije indolskih spojeva formule (X) s natrij hidridom, da nastane spoj formule (Ia): [image] u kojoj: Ra, Rb, n, X, R3, R4, R i Ar su kao što je definirano u početnim spojevima; i e) ako je potrebno, hidroliziranja esterske skupine spoja formule Ia, npr. reakcijom s mineralnom bazom kao što je natrij hidroksid ili litij hidroksid, prema postupcima koji su dobro poznati stručnjacima, i zatim obrade produkta s kiselinom da nastane spoj formule I u obliku slobodne kiseline: [image]
12. Postupak za dobivanje spoja prema zahtjevu 1, naznačen time što sadržava korake koji se sastoje od a) reakcije spoja formule IX: [image] u kojoj: Ra i Rb su svaki nezavisno atom vodika, fluora, klora ili broma ili linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 6 atoma ugljika, CF3, CN, CO-R2 ili OR2 skupina; i R2 je linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupina ili fenil skupina po potrebi supstituirana s linearnim, razgranatim ili cikličkim lancem ugljikovodika koji ima 1 do 4 atoma ugljika ili CF3 skupinu, s arilsulfonil kloridom formule Ar-SO2-Cl (VI) u kojoj: Ar je aromatski ili heteroaromatski prsten odabran od fenil, naftil, kinolinil, izokinolinil, piridinil, pirazolil, imidazolil, izoksazolil, tiazolil, benzimidazolil, benzotiazolil, 2,1,3-benzotiadiazolil, 3,4-dihidro-1,4-benzoksazinil, 5,6,7,8-tetrahidronaftalenil, 1,2,3,4-tetrahidrokinolinil, 1,2,3,4-tetrahidroizokinolinil, 1,2,3,4-tetrahidro-2-oksokinolinil, 3,4-dihidro-2H-benzopiranil, indolil, 2,3-dihidroindolil, benzofuranil, 2,3-dihidrobenzofuranil, 1,3-benzodioksolil, 1,4-benzodioksanil i benzoksazolil skupina po potrebi supstituiran s jednim ili više atoma ili skupina atoma odabranih od atoma halogena, linearnih, razgranatih ili cikličkih lanaca ugljikovodika koji imaju 1 do 6 atoma ugljika, fenil, CF3, CN, CO-R2, OR2, SR2, NH-COR2, morfolinil, amino i 4-morfolinosulfonil skupina, u otapalu, na sobnoj temperaturi, 1 do 12 sati, da nastane spoj formule [image] u kojoj: Ra, Rb i Ar su kao što je definirano u početnim spojevima; b) reakcije spoja formule XI s acetilenskim derivatom formule [image] u kojoj: n = 1, 2 ili 3; R3 i R4 su svaki nezavisno atom vodika ili linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 4 atoma ugljika; R je linearni, razgranati ili ciklički lanac ugljikovodika koji ima 1 do 3 atoma ugljika; i X je jednostruka veza, atom kisika ili atom sumpora, u uvjetima analognim onima opisanim za korak a) postupka opisanog u zahtjevu 10, da nastane spoj formule [image] u kojoj: Ra, Rb, n, X, R3, R4, R i Ar su kao što je definirano u početnim spojevima; c) cikliziranja spoja formule VII iznad, u uvjetima analognim onima opisanim za izvođenje koraka (d) postupka opisanog u zahtjevu 10, da nastane indolski spoj formule [image] u kojoj: Ra, Rb, n, X, R3, R4, R i Ar su kao što je definirano u početnim spojevima; i d) ako je potrebno, hidroliziranja esterske skupine spoja formule Ia, npr. reakcijom s mineralnom bazom kao što je natrij hidroksid ili litij hidroksid, postupcima koji su dobro poznati stručnjacima, i zatim obrade produkta s kiselinom da nastane spoj formule I u obliku slobodne kiseline: [image]
13. Postupak prema zahtjevu 12 za dobivanje spoja prema zahtjevu 1, naznačen time što se dva koraka b) i c) izvode u jednoj radnji.
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