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LV11614B - Substituted n-(indole-2-carbonyl)-©-alaninamides and derivatives as antidiabetic agents - Google Patents

Substituted n-(indole-2-carbonyl)-©-alaninamides and derivatives as antidiabetic agents Download PDF

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Publication number
LV11614B
LV11614B LVP-96-173A LV960173A LV11614B LV 11614 B LV11614 B LV 11614B LV 960173 A LV960173 A LV 960173A LV 11614 B LV11614 B LV 11614B
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alkyl
hydroxy
hydrogen
indole
alkoxy
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LVP-96-173A
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LV11614A (lv
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Bernard Hulin
Judith Lee Treadway
Martin William Holt
Dennis Jay Hoover
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Pfizer
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Publication of LV11614B publication Critical patent/LV11614B/en

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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Claims (38)

  1. -1- LV 11614 Izgudrojuma formula 1. Savienojums ar formulu (I)
    tā farmaceitiski pieņemamās sālīs un priekštečformas, kur: pātrauktā līnija (— ) apzīmē neobligātu saiti; A ir -C(H)=, -C(Cļ-4alkilgrupa)= vai -C(halogēna atoms)=, ja pātrauktā ITnija (—) ir saite, vai A ir metilēngrupa vai -CCH(Ci^alkilgrupa)-, ja pārtrauktā līnija (---) nav saite; Ri, R10 un R11t neatkarīgi viens no otra, ir ūdeņraža atoms, halogēna atoms, nitrogrupa stāvoklī 4-, 6- vai 7-, ciāngrupa, Ci^alkilgrupa, Ci.4alkoksi-grupa, fluormetilgrupa, difluormetilgrupa vai trifluormetilgrupa; R2 ir ūdeņraža atoms; R3 ir ūdeņraža atoms vai Ci_5alkilgrupa; R4 ir ūdeņraža atoms, metilgrupa, etilgrupa, n-propilgrupa, hidroksi-Ci-3alkil- grupa, Ci-3alkoksi-Ci-3alkilgrupa, fenil-Ci^alkilgrupa, fenilhidroksi-Ci. 4alkilgrupa, fenil(Ci-4alkoksi-Ci^alkilgrupa), tien-2-il- vai tien-3-il-Ci^alkilgrupa, -2- vai arī fur-2-il- vai fur-3-il-Ci-4alkilgrupa, kur R4 ietilpstošie cikli satur 1-3 neatkarīgi ņemtus, pie oglekļa atoma pievienotus aizvietotājus no rindas: ūdeņraža atoms, halogēna atoms, CMalkilgrupa, Cļ^alkoksigrupa, trifluormetilgrupa, hidroksilgrupa, aminogrupa, ciāngrupa; vai arī R4ir piridin-2-il-, piridin-3-il- vai piridin-4-il-CMalkilgrupa; tiazol-2-il-, tiazol-3-il-, tiazol-4-il- vai tiazol-5-il-Ci^alkilgrupa; imidazol-1-il-, imidazol-2-il-, imidazol-4-il- vai imidazol-5-il-Ci^alkilgrupa; pirol-2-il- vai pirol-3-il-Ci^alkilgrupa; oksazol- 2- il-, oksazol-4-il- vai oksazol-5-il-CMalkilgrupa; pirazol-3-il-, pirazol-4-il- vai pirazol-5-il-Ci^alkilgrupa; izoksazol-3-il-, izoksazol-4-il- vai izoksazol-5-il-Ci. 4alkilgrupa; izotiazol-3-il, izotiazol-4-il- vai izotiazol-5-il-Ci^alkilgrupa; piridazin- 3- il- vai piridazin-4-il-Ci^alkilgrupa; pirimidin-2-il-, pirimidim-4-il-, pirimidin-5-il vai pirimidin-6-il-Ci-4alkilgrupa; pirazin-2-il vai pirazin-3-il-Ci^alkilgrupa; 1,3,5-triazin-2-il-Ci^alkilgrupa, kur R4 ietilpstošie cikli satur 1-2 neatkarīgi ņemtus, pie oglekļa atoma pievienotus aizvietotājus no rindas: halogēna atoms, trifluormetilgrupa, CMalkilgrupa, CMalkoksigrupa, aminogrupa, hidroksilgrupa; Rs ir ūdeņraža atoms, hidroksilgrupa, fluora atoms, CMalkilgrupa, C1-salkoksigrupa, Ci-6alkanoilgrupa, amino-CMalkoksigrupa, mono- vai di(Ci. 4alkil)amino-CMalkoksigrupa, karboksi-CMalkoksigrupa, C2-5alkoksikarbonil-CMalkoksigrupa, benziloksikarbonil-CMalkoksigrupa, karboniloksigrupa, kura ar C-C saiti savienota ar fenilgrupu, tiazolilgrupu, imidazolilgrupu, 1H-indolilgrupu, furilgrupu, pirolilgrupu, oksazolilgrupu, pirazolilgrupu, izoksazolilgrupu, izotiazolilgrupu, piridazinilgrupu, pirimidinilgrupu, pirazinilgrupu vai 1,3,5-triazinilgrupu, un kur R5 ietilpstošie cikli neobligāti aizvietoti pie oglekļa atoma ar: halogēna atomu, C-Malkilgrupu, Cv 4alkoksigrupu, hidroksilgrupu, aminogrupu vai trifluormetilgrupu; R7 ir ūdeņraža atoms, fluora atoms vai Ci-salkilgrupa; vai arī Rs un R7 abi kopā veido oksogrupu; R6 ir karboksilgrupa, Ci.8alkoksikarbonilgrupa, -C(0)NReR9 vai -C(0)R12, kur: Re ir ūdeņraža atoms, CMalkilgrupa, hidroksilgrupa vai Ci-8alkoksigrupa; R9 ir ūdeņraža atoms, Cļ.ealkilgrupa, hidroksilgrupa, Ci.8alkoksigrupa, perfluor-Ci.8-alkilmetilēngrupa, fenilgrupa, piridinilgrupa, tienilgrupa, furilgrupa, pirolilgrupa, pirolidinilgrupa, oksazolilgrupa, tiazolilgrupa, imidazolilgrupa, pirazolilgrupa, pirazolinilgrupa, pirazolidinilgrupa, izoksazolilgrupa, izotiazolilgrupa, piranilgrupa, piperidinilgrupa, morfolinilgrupa, piridazinilgrupa, pirimidinilgrupa, pirazinilgrupa, piperazinilgrupa vai 1,3,5-triazinilgrupa, kas pievienota ar C-N saiti; vai arī R9 ir C-|.5alkilgrupa, kas aizvietota ar 1-3 aizvietotājiem, kuri neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms, hidroksilgrupa, aminogrupa, mono-iCļ.salkiljaminogrupa, di-fCMalkiOaminogrupa; vai arī Rg ir Ci.5alkilgrupa, kas aizvietota ar 1-2 aizvietotājiem, kuri neatkarīgi viens no otra ņemti no rindas: fenilgrupa, piridinilgrupa, furilgrupa, pirolilgrupa, pirolidinilgrupa, oksazolilgrupa, tiazolilgrupa, imidazolilgrupa, pirazolilgrupa, -3- -3- LV 11614 pirazolinilgrupa, pirazolidinilgrupa, izoksazolilgrupa, izotiazolilgrupa, piranilgrupa, piperidinilgrupa, morfolinilgrupa, piridazinilgrupa, pirimidinilgrupa, pirazinilgrupa, piperazinilgrupa vai 1,3,5-triazinilgrupa, pie tam Rg ietilpstošie nearomātiskie slāpekļa heterocikli neobligāti aizvietoti pie oglekļa atoma ar aizvietotāju no rindas: Ci^alkilgrupa, benzilgrupa, benzoilgrupa, Ci^alkoksikarbonilgrupa, pie tam Rg ietilpstošie cikli papildus neobligāti aizvietoti pie oglekļa atoma ar aizvietotāju no rindas: halogēna atoms, Ci^alkilgrupa, Cī^alkoksigrupa, hidroksilgrupa, aminogrupa, mono-(Ci-5alkil)aminogrupa, di-(Ci-5alkii)aminogrupa, ar tādu noteikumu, ka Rg nesatur kvatemizētu slāpekļa atomu un nesatur saites N-O, N-N un N-halogēns; R12 ir piperazin-1-ilgrupa, 4-(Ci^alkil)piperazin-1-ilgrupa, 4-formilpiperazin-1 -ilgrupa, morfolinilgrupa, tiamorfolinilgrupa, 1-oksotiamorfolinilgrupa, 1,1-dioksotiamorfolinilgrupa, tiazolidin-3-ilgrupa, 1-oksotiazolidin-3-ilgrupa, 1,1 -dioksotiazolidin-3-ilgrupa, 2-(Ci. 6alkoksikarbonil)pirolidin-1-ilgrupa, oksazolidin-3-ilgrupa vai 2(R)-hidroksimetilpirolidin-1-ilgrupa; vai arī R12 ir 3- un/vai 4- vien- vai divaizvietota oksazetidin-2-ilgrupa, 2-, 4- un/vai 5-vien- vai divaizvietota oksazolidin-3-ilgrupa, 2-, 4- un/vai 5- vien- vai divaizvietota tiazolidin-3-ilgrupa, 2-, 4- un/vai 5- vien- vai divaizvietota 1-oksotiazolidin-3-ilgrupa, 2-, 4- un/vai 5- vien- vai divaizvietota 1,1-doksotiazolidin-3-ilgrupa, 3- un/vai 4- vien- vai divaizvietota pirolidin-1 -ilgrupa, 3- , 4- un/vai 5- vien-, div- vai trīsaizvietota piperidin-1 -ilgrupa, 3-, 4- un/vai 5-vien-, div- vai trīsaizvietota piperazin-1-ilgrupa, 3-aizvietota azetidin-1-ilgrupa, 4- un/vai 5- vien- vai divaizvietota 1,2-oksazinan-2-ilgrupa, 3- un/vai 4- vien-vai divaizvietota pirazolidin-1-ilgrupa, 4- un/vai 5- vien- vai divaizvietota izoksazolidin-2-ilgrupa, 4- un/vai 5- vien- vai divaizvietota izotiazolidin-2-ilgrupa, kurās minētie aizvietotāji neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms, halogēna atoms, Ci-salkilgrupa, hidroksilgrupa, aminogrupa, mono-(Ci.5alkil)aminogrupa, di-(Ci-5alkil)aminogrupa, formilgrupa, oksogrupa, hidroksiliminogrupa, Ci.5alkoksigrupa, karboksilgrupa, karbamoilgrupa, mono-vai di-(Ci-4alkil)karbamoilgrupa, Ci^alkoksiiminogrupa, Ci-4alkoksimetoksigrupa, Ci-6alkoksikarbonilgrupa, karboksi-Ci-salkilgrupa, hidroksi-Ci.5alkilgrupa; ar noteikumu, ka tad, kad R4 ir ūdeņraža atoms, metilgrupa, etilgrupa vai n-propilgrupa, R5 ir hidroksilgrupa; ar tādu noteikumu, ka tad, kad R5 un R7 ir ūdeņraža atoms, R4 nav ūdeņraža atoms, metilgrupa, etilgrupa, n-propilgrupa, hidroksiI-Ci_3alkilgrupa vai Ci-3alkoksi-Ci.3alkilgrupa un R6 ir C(0)NR8Rg , C(0)R12 vai C1. 4alkoksikarbonilgrupa.
  2. 2. Savienojums pēc 1. punkta, kurā: R1 ir ūdeņraža atoms, halogēna atoms, metilgrupa, trifluormetilgrupa vai ciāngrupa stāvoklī 5; R10 un Rn neatkarīgi viens no otra ir ūdeņraža atoms vai halogēna atoms; Air-CH=; -4- R2 un R3 ir ūdeņraža atoms; R4 ir fenil-Ci-2alkilgrupa, pie tam fenilgrupa aizvietota ar 1-3 aizvietotājiem, kas neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms, halogēna atoms, vai ar 1-2 aizvietotājiem no rindas: ūdeņraža atoms, halogēna atoms, Ci^alkilgrupa, Ci^alkoksigrupa, trifluormetilgrupa, hidroksilgrupa, aminogrupa, ciāngrupa; vai R4 ir tien-2-il- vai tien-3-il-Ci_2a!kilgrupa; piridin-2-il-, piridin-3-il- vai piridin-4-il-C-i.2alkilgrupa; tiazol-2-il-, tiazol-3-il-, tiazol-4-il- vai tiazol-5-il-C 1.2aIkiIgrupa; imidazol-1-il-, imidazol-2-il-, imidazol-4-il- vai imidazol-5-il-Ci-2alkilgrupa; fur-2-il- vai fur-3-il-Ci-2alkilgrupa; pirol-2-il- vai pirol-3-il-Ci_2alkilgrupa; oksazol-2-il-, oksazol-4-il- vai oksazol-5-il-Ci.2alkilgrupa; pirazol-3-il-, pirazol-4-il- vai pirazol-5-il-Ci.2alkilgrupa; izoksazol-3-il-, izoksazol-4-il- vai izoksazol-5-il-Ci. 2alkilgrupa, kur R4 ietilpstošie heterocikli neobligāti satur 1-2 neatkarīgi ņemtus, pie oglekļa atoma pievienotus aizvietotājus no rindas: halogēna atoms, trifluormetilgrupa, Ci^alkilgrupa, Ci-4alkoksigrupa, aminogrupa un hidroksilgrupa; Rs ir ūdeņraža atoms; R6 ir -C(0)NRsR9 vai -C(0)Ri2. R7 ir ūdeņraža atoms.
  3. 3. Savienojums pēc 2. punkta, kurā: oglekļa atomam a ir (S) stereoķīmija; oglekļa atomam b ir (R) stereoķīmija; R4 ir fenil-Ci.2alkilgrupa, tien-2-il- vai tien-3-il-Ci-2alkilgrupa, fur-2-il- vai fur-3-il-Ci-2alkilgrupa, kur aizvietotāja cikli aizvietoti ar 1-2 aizvietotājiem, kas neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms un fluora atoms; Re ir -C(0)NRgRg; R8 ir Cļ^alkilgrupa, hidroksilgrup vai Ci.3alkoksigrupa; R9 ir ūdeņraža atoms, Cļ^alkilgrupa, hidroksilgrupa, hidroksi-Ci^alkilgrupa, Ci-galkoksigrupa, piridinilgrupa, morfolinilgrupa, piperazinilgrupa, pirolidinilgrupa, piperidinilgrupa, imidazolilgrupa, tiazolilgrupa vai Cļ. 4alkilgrupa, kas neobligāti aizvietotas ar piridinilgrupu, morfolinilgrupu, piperazinilgrupu, pirolidinilgrupu, piperidinilgrupu, imidazolilgrupu vai tiazolilgrupu.
  4. 4. Savienojums pēc 3. punkta, kas ņemts no rindas: 5-hlor-1 H-indol-2-karbonskābes {(1S)-[(R)-hidroksi-(N,N- dimetilkarbamoil)metil]-2-feniletil]amīds, 5,6-dihlor-1 H-indol-2-karbonskābes {(1 S)-[(R)-hidroksi(N-metoksi-N-metil-karbamoil)-metil]-2-feniletil]amīds, -5- LV 11614 5-hlor-1 H-indol-2-karbonskābes karbamoil)-metil]-2-feniletil]amīds,. 5-hlor-1 H-indol-2-karbonskābes metilkarbamoil)-metil]-2-feniletil)amTds {(1S)-[(R)-hidroksi(N-metoksi-N-metil ((1S)-{(R)_hīdroksi[N-(2-hidroksietil)-N 5-hlor-1 H-indol-2-karbonskābes ((1SH(R).hjdroksi[N.meti|.N.(piridin.2.il). karbamoil]-metil}-2-feniletil)amTds, 5-hIor-1 H-indol-2-karbonskābes r{1S)-((R)_hidroksi{N.meti,.N.I2-pindīn-2- il)etil]-karbamoil}-metil)-2-feniletil]amīds.
  5. 5. Savienojums pēc 3. punkta, kurā· Ri ir 5-CI; R10 un Rn ir H, R4 ir benzilgrupa, Re ir metilgrupa, Rg ir metilgrupa.
  6. 6. Savienojums pēc 3. punkta, kurā: R1 ir 5-CI; R11 ir H, R10 ir 6-CI, R4 ir benzilgrupa, Re ir metilgrupa, Rg ir metoksigrupa.
  7. 7. Savienojums pēc 3. punkta, kurā: Rt ir 5-CI; R10 un Rn ir H, R4 ir benzilgrupa, Re ir metilgrupa, Rg ir metoksigrupa.
    7. Savienojums pēc 3. punkta, kurā: R1 ir 5-CI; R10 un Rn ir H, R12 ir 1,1-dioksotiazolidin-1-ilgrupa.
  8. 8. Savienojums pēc 3. punkta, kurā: R1 ir 5-CI; R10 un Rn ir H, R4 ir benzilgrupa, Re ir metilgrupa, Rg ir 2-oksietilgrupa.
  9. 9. Savienojums pēc 3. punkta, kurā: R1 ir 5-CI; 6- Rio un Rn ir H, R4 ir benzilgrupa, Re ir metilgrupa, R9 ir piridin-2-ilgrupa.
  10. 10. Savienojums pēc 3. punkta, kurā: Ri ir 5-CI; Rio un Rn ir H, R4 ir benzilgrupa, Re ir metilgrupa, Rg ir 2-(piridin-2-il)etilgrupa.
  11. 11. Savienojums pēc 2. punkta, kurā: oglekļa atoma a stereoķīmija ir (S), oglekļa atoma b stereoķīmija ir (R), R4 ir fenil-Ci.2alkilgrupa, tien-2-il- vai tien-3-il-Ci-2alkilgrupa, fur-2-il- vai fur-3-il-Ci.2alkilgrupa, kur aizvietotāja R4 cikli aizvietoti ar 1-2 aizvietotājiem, kas neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms un fluora atoms; Re ir C(0)Ri2; R12 ir morfolinilgrupa, 4-(Ci-4alkil)-piperazin-1-ilgrupa, 3-aizvietota azetidin-1-ilgrupa, 3- un/vai 4- vien- vai divaizvietota pirilidin-1 -ilgrupa, 4- un/vai 5- vien-vai divaizvietota izoksazolidin-2-ilgrupa, 4- un/vai 5- vien- vai divaizvietota 1,2-oksazinan-2-ilgrupa, kur minētie aizvietotāji neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms, halogēna atoms, hidroksilgrupa, aminogrupa, mono-(Cļ^alkiOaminogrupa, di-(Ci-6alkil)aminogrupa, oksogrupa, hidroksiliminogrupa, alkoksigrupa.
  12. 12. Savienojums pēc 1. punkta, kas ņemts no rindas: 5-hlor-1 H-indol-2-karbonskābes [(1 S)-benzil-(2R)-hidroksi-3-(4-metilpiperazin-1 -il)-3-oksopropil]amīda hidrogenhlorīds, 5-hlor-1 H-indol-2-karbonskābes [(1S)-benzil-(2R)-hidroksi-3-(3- hidroksiazetidin-1-il)-3-oksopropil]amīds, 5-hlor-1 H-indol-2-karbonskābes [(1S)-benzil-(2R)-hidroksi-3-(izoksazolidin-2-il)-3-oksopropil]amīda hidrogenhlorīds, 5-hlor-1 H-indol-2-karbonskābes [(1 S)-benzil-(2R)-hidroksi-3-(1,2-oksazinan-2-il)-3-oksopropil]amīda hidrogenhlorīds, 5-hlor-1 H-indol-2-karbonskābes [(1 S)-benzil-(2R)-hidroksi-3-((3S)- hidroksipirolidin-1-il)-3-oksopropiljamīds, 5-hlor-1 H-indol-2-karbonskābes [(1S)-benzil-3-((3S,4S)-dihidroksipirolidin-1-il)- (2R)-hidroksi-3-oksopropil]amīds, 5-hlor-1 H-indol-2-karbonskābes [(1 S)-benzil-3-((3R,4S)-dihidroksipirolidin-1-il)- (2R)-hidroksi-3-oksopropil]amīds, -7- LV 11614 5-hlor-1 H-indol-2-karbonskābes [(1 S)-benzil-(2R)-hidroksi-3-(morfolin-4-il)-3-oksopropiljamīds.
  13. 13. Savienojums pēc 11. punkta, kurā: Ri ir 5-CI; R10 un Rn ir H; R4 ir benzilgrupa; R 12 ir 4-metilpiperazin-1-ilgrupa.
  14. 14. Savienojums pēc 11. punkta, kurā: Rļ ir 5-CI; R10 un Rn ir H; R4 ir benzilgrupa; R12 ir 3-hidroksiazetidin-1-ilgrupa.
  15. 15. Savienojums pēc 11. punkta, kurā: Ri ir 5-CI; Rio un Rn ir H; R4 ir benzilgrupa; R12 ir izoksazolidin-2-ilgrupa.
  16. 16. Savienojums pēc 11. punkta, kurā: Ri ir 5-CI; R10 un Rn ir H; R4 ir benzilgrupa; Ri2ir 1,2-oksazinan-2-ilgrupa.
  17. 17. Savienojums pēc 11. punkta, kurā: Ri ir 5-CI; R10 un Rn ir H; R4 ir benzilgrupa; R12 ir 3(S)-hidroksipirolidin-1 -ilgrupa.
  18. 18. Savienojums pēc 11. punkta, kurā: Rļ ir 5-CI; R10 un Rn ir H; R4 ir benzilgrupa; R12 ir (3S,4S)-dihidroksipirolidin-1-ilgrupa.
  19. 19. Savienojums pēc 11. punkta, kurā: Ri ir 5-CI; R10 un Ru ir H; R4 ir benzilgrupa; R12 ir (3R,4S)-dihidroksipirolidin-1 -ilgrupa.
  20. 20. Savienojums pēc 11. punkta, kurā: Rļ ir 5-CI; R10 un Rn ir H; R4 ir benzilgrupa; -8- R12 ir morfolinilgrupa.
  21. 21. Savienojums pēc 1. punkta, kurā: Ri ir ūdeņraža atoms, halogēna atoms, metilgrupa vai ciāngrupa; R10 un Rn neatkarīgi viens no otra ir ūdeņraža atoms vai fluora atoms; A ir -CH=; _ R2 un R3 ir ūdeņraža atoms; R4 ir fenil-Ci.2alkilgrupa, aizvietota ar 1-3 aizvietotājiem, kas neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms un fluora atoms, vai ar 1-2 aizvietotājiem, kas neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms, halogēna atoms, Ci^alkilgrupa, Ci^alkoksigrupa, trifluormetilgrupa, hidroksilgrupa, aminogrupa, ciāngrupa; vai arī R4 ir tien-2-il- vai tien-3-il-Ci_2alkilgrupa; piridin-2-il-, piridin-3-il- vai piridin-4-il-Ci-2alkilgrupa; tiazol-2-il-, tiazol-3-il-, tiazol-4-il- vai tiazol-5-il-Ci-2alkilgrupa; imidazol-2-il-, imidazol-4-il- vai imidazol-5-il-Ci-2alkilgrupa; fur-2-il- vai fur-3-il-Ci-2alkilgrupa; pirol-2-il- vai pirol-3-il-Ci-2alkilgrupa; oksazol-2-il-, oksazol-4-il-vai oksazol-5-il-Ci-2alkilgrupa; pirazol-3-il-, pirazol-4-il- vai pirazol-5-il-Ci-2alkilgrupa; izoksazol-3-il-, izoksazol-4-il- vai izoksazol-5-il-Ci-2alkilgrupa; pie tam minētie heterocikli aizvietotājā R4 neobligāti aizvietoti pie oglekļa atoma ar 1-2 aizvietotājiem, kas neatkarīgi viens no otra ņemti no rindas: halogēna atoms, trifluormetilgrupa, Ci^alkilgrupa, Ci^alkoksigrupa, aminogrupa, hidroksilgrupa; Rs ir ūdeņraža atoms; R6 ir karboksilgrupa vai Ci.8alkoksikarbonilgrupa; R7 ir ūdeņraža atoms, fluora atoms vai Ci-ealkilgrupa.
  22. 22. Savienojums pēc 21. punkta, kurā: oglekļa atoma a stereoķīmija ir (S); oglekļa atoma b stereoķīmija ir (R); R4 ir fenil-Ci-2alkilgrupa, tien-2-il- vai tien-3-il-Ci-2alkilgrupa, fur-2-il- vai fur-3-il-Ci-2alkilgrupa, kur R4 ietilpstošie cikli satur 1-2 neatkarīgi ņemtus aizvietotājus no rindas: ūdeņraža atoms, fluora atoms; R10 un R11 ir H; R6 ir karboksilgrupa; R7 ir H.
  23. 23. Savienojums pēc 22. punkta, kurā: R1 ir 5-CI; R10 un Rn ir H; R4 ir benzilgrupa.
  24. 24. Savienojums pēc 1. punkta, kurā: R1 ir ūdeņraža atoms, halogēna atoms, metilgrupa vai ciāngrupa; R10 un R11 neatkarīgi viens no otra ir ūdeņraža atoms vai halogēna atoms; A ir -CH=; R2 un R3 ir H; R4 ir fenil-Ci-2alkilgrupa, kurā fenilgrupa satur 1-3 aizvietotājus, kas neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms, halogēna atoms; vai 1-2 aizvietotājus, kas neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms, -9- -9- LV 11614 halogēna atoms, Ci^alkilgrupa, Ci^alkoksigrupa, trifluormetilgrupa, hidroksilgrupa, aminogrupa, ciāngrupa; vai arī R4 ir tien-2-il- vai tien-3-il-Gļ_2alkiIgrupa; piridin-2-il-, piridin-3-il- vai piridin-4-il-Ci-2alkilgrupa; tiazol-2-il-, tiazol-3-il-, tiazol-4-il- vai tiazol-5-il-Ci-2alkilgrupa; imidazol-2-il-, imidazol-4-il- vai imidazol-5-il-Ci-2alkilgrupa; fur-2-il- vai fur-3-il-Ci^alkilgrupa; pirol-2-il- vai pirol-3-il-Ci-2alkilgrupa; oksazol-2-il-, oksazol-4-il-vai oksazol-5-il-Ci-2alkilgrupa; pirazol-3-il-, pirazol-4-il- vai pirazol-5-il-Ci^alkilgrupa; izoksazol-3-il-, izoksazol-4-il- vai izoksazol-5-il-Ci-2alkilgrupa; pie tam minētie heterocikli aizvietotājā R4 neobligāti aizvietoti pie oglekļa atoma ar 1-2 aizvietotājiem, kas neatkarīgi viens no otra ņemti no rindas: halogēna atoms, trifluormetilgrupa, Ci^alkilgrupa, CMalkoksigrupa, aminogrupa, hidroksilgrupa; R5 ir fluora atoms, Ci^alkilgrupa, C-i-salkoksigrupa, amino-Ci^alkoksigrupa, mono- vai d^Ci^alkiOamino-CMalkoksigrupa, karboksi-CMalkoksigrupa, Ci. salkoksikarbonil-CMalkoksigrupa, benziloksikarbonil-Cļ^alkoksigrupa; R6 ir karboksilgrupa vai Ci.8alkoksikarbonilgrupa; R7 ir ūdeņraža atoms, fluora atoms vai Cļ-ealkilgrupa.
  25. 25. Savienojums pēc 1. punkta, kurā: R1 ir ūdeņraža atoms, halogēna atoms, metilgrupa vai ciāngrupa; R10 un R11 neatkarīgi viens no otra ir ūdeņraža atoms vai halogēna atoms; A ir -CH=; R2 un R3 ir H; R4 ir fenil-Ci.2alkilgrupa, kurā fenilgrupa satur 1-3 aizvietotājus, kas neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms, halogēna atoms; vai 1-2 aizvietotājus, kas neatkarīgi viens no otra ņemti no rindas: ūdeņraža atoms, halogēna atoms, Ci-4alkilgrupa, Ci^alkoksigrupa, trifluormetilgrupa, hidroksilgrupa, aminogrupa, ciāngrupa; vai arī R4 ir tien-2-il- vai tien-3-il-Ci.2alkilgrupa; piridin-2-il-, piridin-3-il- vai piridin-4-il-Ci^alkilgrupa; tiazol-2-il-, tiazol-3-il-, tiazol-4-il- vai tiazol-5-il-C1_2alkilgrupa; imidazol-2-il-, imidazol-4-il- vai imidazol-5-il-Ci-2alkilgrupa; fur-2-il- vai fur-3-il-C-i^alkilgrupa; pirol-2-il- vai pirol-3-il-Ci-2alkilgrupa; oksazol-2-il-, oksazol-4-il-vai oksazol-5-il-Ci-2alkilgrupa; pirazol-3-il-, pirazol-4-il- vai pirazol-5-il-Ci-2alkilgrupa; izoksazol-3-il-, izoksazol-4-il- vai izoksazol-S-il-C^alkilgrupa; pie tam minētie heterocikli aizvietotājā R4 neobligāti aizvietoti pie oglekļa atoma ar 1-2 aizvietotājiem, kas neatkarīgi viens no otra ņemti no rindas: halogēna atoms, trifluormetilgrupa, Ci^alkilgrupa, Ci^alkoksigrupa, aminogrupa, hidroksilgrupa; R5 ir fluora atoms, Ci-ļalkilgrupa, Ci.salkoksigrupa, amino-CMalkoksigrupa, mono- vai di(CMalkil)amino-Ci-4alkoksigrupa, karboksi-CMalkoksigrupa, Ci. 5alkoksikarbonil-CMalkoksigrupa,.benziloksikarbonil-CMalkoksigrupa; R6 ir C(0)NR8R9 vai C(0)Ri2; R7 ir ūdeņraža atoms, fluora atoms vai Ci.6alkilgrupa.
  26. 26. Savienojuma pēc 1. punkta pielietojums tāda medikamenta ražošanai, kas paredzēts ar glikogēna fosforilāzi saistītu slimību vai stāvokļu profilaksei un/vai ārstēšanai zīdītājiem.
  27. 27. Pielietojums pēc 26. punkta, kas atšķiras ar to, ka medikaments paredzēts hiperglikēmijas ārstēšanai. -10-
  28. 28. Pielietojums pēc 26. punkta, kas atšķiras ar to, ka medikaments paredzēts diabēta ārstēšanai:
  29. 29. Pielietojums pēc 26. punkta, kas atšķiras ar to, ka medikaments paredzēts hiperholesterolēmijas ārstēšanai.
  30. 30. Pielietojums pēc 26. punkta, kas atšķiras ar to, ka medikaments paredzēts aterosklerozes ārstēšanai.
  31. 31. Pielietojums pēc 26. punkta, kas atšķiras ar to, ka medikaments paredzēts hiperinsulinēmijas ārstēšanai.
  32. 32. Pielietojums pēc 26. punkta, kas atšķiras ar to, ka medikaments paredzēts hipertenzijas ārstēšanai.
  33. 33. Pielietojums pēc 26. punkta, kas atšķiras ar to, ka medikaments paredzēts hiperlipidēmijas ārstēšanai.
  34. 34. Pielietojums pēc 26. punkta, kas atšķiras ar to, ka medikaments paredzēts miokarda išēmisko bojājumu profilaksei.
  35. 35. Glikogēna fosforilāzes inhibitora pielietojums tāda medikamenta ražošanai, kas paredzēts miokarda išēmisko bojājumu profilaksei.
  36. 36. Ārstnieciskais sastāvs, kas satur ārstnieciski iedarbīgu daudzumu savienojuma pēc 1. punkta un farmaceitiski pieņemamu nesēju.
  37. 37. Ārstnieciskais sastāvs pēc 36. punkta, kas paredzēts tādu slimību ārstēšanai, kuras saistītas ar glikogēna fosforilāzi.
  38. 38. Ārstnieciskais satāvs, kas satur: ārstnieciski iedarbīgus daudzumus - a) glikogēna fosforilāzes inhibitora; b) antidiabētiska līdzekļa, kas ņemts no rindas: insulīns un tā analogi; insulinotropīns; sulfonilurīnvielas un to analogi; biguanīdi; a2-antagonisti un imidazofīni; insulīna izdalīšanās veicinātāji; glitazoni; taukskābju oksidēšanas inhibitori; a-glikozidāzes inhibitori; b-agonisti; fosfodiesterāzes inhibitori; lipīdu līmeņa pazemināšanas līdzekļi; pretaptaukošanās līdzekļi; vanadātu un vanādija kompleksi un peroksivanādija kompleksi; amilīna antagonisti; glikagona antagonisti; glikoneoģenēzes inhibitori; somatostatīna analogi; antilipotiskie līdzekļi; kā arī neobligāti - c) farmaceitiski pieņemamu nesēju.
LVP-96-173A 1995-06-06 1996-06-04 Substituted n-(indole-2-carbonyl)-©-alaninamides and derivatives as antidiabetic agents LV11614B (en)

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CN1374082A (zh) 2002-10-16
DE69522718T2 (de) 2002-02-07
EP0832066A1 (en) 1998-04-01
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CO4700453A1 (es) 1998-12-29
WO1996039385A1 (en) 1996-12-12
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CA2223625A1 (en) 1996-12-12
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TNSN96075A1 (fr) 2005-03-15
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AP9600817A0 (en) 1996-07-31
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