FI113176B - Pyrazino[2',1':6,1]pyrido[3,4-b]indol-1,4-dionderivater, förfarande för framställning därav och deras användning - Google Patents

Pyrazino[2',1':6,1]pyrido[3,4-b]indol-1,4-dionderivater, förfarande för framställning därav och deras användning Download PDF

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FI113176B
FI113176B FI962927A FI962927A FI113176B FI 113176 B FI113176 B FI 113176B FI 962927 A FI962927 A FI 962927A FI 962927 A FI962927 A FI 962927A FI 113176 B FI113176 B FI 113176B
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pyrido
indole
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Alain Claude-Marie Daugan
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Claims (15)

1. Pyrazino[2' , 1' :6, l]pyrido[3,4-b]indol-l, 4-dionde-rivat med formeln R 10 och salter och soivat därav, varvid R° betecknar väte, halogen eller Ci-6_alkyl; R1 betecknar väte, Ci_6-alkyl, C2-6_all<:enyl, C2-6-alkynyl, halogen-Ci-6-alkyl, C3_8-cykloalkyl, C3_8-cyklo-15 alkyl-Cx-3-alkyl, aryl-Cx-3-alkyl eller heteroaryl-Ci-3-alkyl, varvid aryl betecknar fenyl eller fenyl som är sub-stituerad med en eller flera (t.ex. 1, 2 eller 3) sub- stituenter som är valda bland halogen, Ci_6-alkyl, Ci_6~ alkoxi och metylendioxi och heteroaryl betecknar en 20 tienyl-, furyl- eller pyridylgrupp som kan vara sub- stituerad med en eller flera (t.ex. 1, 2 eller 3) sub- : ’·· stituenter som är valda bland halogen, Ci_6-alkyl, Ci_6~ !,'·{ alkoxi; R2 är fenyl som kan vara substituerad med en eller 25 flera (t.ex. 1, 2 eller 3) atomer eller en grupp som är » · . halogen, hydroxi, Ci-6-alkyl, Ci-6-alkoxi, -C02Rb, halogen- * I » , Ci-6-alkyl, halogen-Ci-6-alkoxi, cyan, nitro, NRaR eller en « * · ovan definierad aryl-Ci_3-alkyl, eller R2 är en eventuellt ... substituerad tiofen-, furan-, pyridin- eller naftalenring » · ' 30 eller en eventuellt :;r: r^Vx^ : substituerad bicyklisk ring i (Ctt,) , där n är 1 eller 2 och X och Y vardera är CH2 eller 0, 35 varvid den eventuella substituenten är en eller flera 1 1 * 113176 99 (t.ex. 1, 2 eller 3) bland halogen, Ch-6-alkyl, Ci-6-alkoxi och ovan definerade aryl-Ci-3-alkyl; R3 betecknar väte eller Ci-3-alkyl eller R1 och R3 betecknar tillsammans en 3- eller 4-ledad alkyl- eller al-5 kenylkedja; och Ra och Rb betecknar oberoende av varandra väte eller Ci-6-alkyl eller Ra kan även vara C2-7-alkanoyl eller Ci_6-alkylsulfonyl.
2. Pyrazino[2' , 1' : 6, l]pyrido[3,4-b]indol-l, 4-dionde-10 rivat med formeln r°—(T^yV1 (la) H R2 °
15 R och salter och soivat därav, varvid R° betecknar väte, halogen eller Ci-6-alkyl; R1 betecknar väte, Ci_6-alkyl, halogen-Ci-6~alkyl, C3-8-cykloalkyl, C3-8-cykloalkyl-Ci-3-alkyl, aryl-Ci-3-alkyl 20 eller heteroaryl-Ci-3-alkyl, varvid aryl betecknar fenyl eller fenyl som är substituerad med en eller flera (t.ex. ;‘-tt 1, 2 eller 3) substituenter som är valda bland halogen, .·- ; Ci-6-alkyl, Ci_6-alkoxi och metylendioxi och heteroaryl be- * · tecknar en tienyl-, furyl- eller pyridylgrupp som kan vara ! . 25 substituerad med en eller flera (t.ex. 1, 2 eller 3) sub- • * · * stituenter som är valda bland halogen, Ci_6-alkyl, C1-6- • » t ·’*’ alkoxi; < ‘ » * R2 är fenyl som kan vara substituerad med en eller flera (t.ex. 1, 2 eller 3) atomer eller en grupp som är • V 30 halogen, hydroxi, Ci_s-alkyl, Ci-6-alkoxi, -C02Rb, halogen- Ci-6-alkyl, halogen-Ci_6-alkoxi, cyan, nitro, NRaRb eller en ,·’ ; ovan definierad aryl-Ci-3-alkyl, eller R2 är en eventuellt ! substituerad tiofen-, furan-, pyridin- eller naftalenring , eller en eventuellt :i; 35 ^?γχΝ ·;"· substituerad bicyklisk ring | (CH_)„ , 113176 100 där n är 1 eller 2 och X och Y vardera är CH2 eller 0, varvid den eventuella substituenten är en eller flera (t.ex. 1, 2 eller 3) bland halogen, Ci-6-alkyl, Ci-6-alkoxi och ovan definerade aryl-Ci-3-alkyl och 5 Ra och Rb betecknar oberoende av varandra väte el ler Ci-6-alkyl eller Ra kan även vara C2-7~alkanoyl eller Ci_ 6-alkylsulfonyl.
3. Förening enligt patentkrav 1 eller 2, där R° är väte. 10
4. Förening enligt nägot av patent kraven 1 - 3, där R1 är väte, Ci_4-alkyl, halogen-Ci-4-alkyl, C3-6-cyklo-alkyl, C3-6-cykloalkylmetyl, pyridyl-Cx-3-alkyl, furyl-Ci_3-alkyl eller eventuellt substituerad bensen.
5. Förening enligt nägot av patentkraven 1-3, 15 där R1 och R3 tillsammans betecknar en 3-ledad alkylkedja.
6. Förening enligt patentkrav 1, där R3 betecknar väte.
7. Cis-isomer av en förening med formeln (I), vilken cis-isomer har formeln
20 O —rr^Y'^N-R' !’·· <Ib) •v; “ r! 0 m·' j 25 och blandningar därav med dess optiska cis-enantiomer, • · · inklusive racemiska blandningar, och salter och solvater t 1 t ;;; av dessa föreningar, där R° är väte eller halogen och R1, *·’ * R2 och R3 betecknar samma som i föregäende patentkrav.
8. Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmet- ; *.· 30 yl)-6- (3,4-metylendioxifenyl) pyrazino[2’ , 1' : 6, ljpyrido- • [3,4-b]indol-l, 4-dion; » cis-2,3, 6, 7,12,12a-hexahydro-6-(2,3-dihydrobenso- [ [b]furan-5-yl) -2-metylpyrazino[2' , 1' : 6, l]pyrido[3,4-b]indol- 1,4-dion; :J.: 35 cis-2,3,6,7,12,12a-hexahydro-6-(5-brom-2-tienyl)- :· · 2-metylpyrazino[2' , 1' : 6, l]pyrido[3, 4-b]indol-l, 4-dion; 113176 101 cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-metyl-fenyl) pyrazino[2' , 1' :6, l]pyrido[3, 4-b]indol-l, 4-dion; (6R, 12aR)-2, 3, 6, 7,12,12a-hexahydro-2-isopropyl-6-(3,4-metylendioxifenyl) pyrazino[2' , 1' : 6, l]pyrido[3,4-b]in-5 dol-1,4-dion; (6 R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyklopentyl- 6-(3,4-metylendioxif enyl) pyrazino[2' , 1’ :6, l]pyrido[3,4-b]-indol-1,4-dion; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyklopropyl- 10 metyl-6- (4-metoxifenyl) pyrazino[2' , 1' :6, l]pyrido[3,4-b]-indol-1,4-dion; (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3-klor-4-metoxifenyl) -2-metylpyrazino[2' , 1' :6, l]pyrido[3,4-b]indol- 1,4-dion; 15 (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-metyl-6- (3,4 — metylendioxifenyl) pyrazino[2' , 1' :6, l]pyrido[3, 4-b]indol-l, 4-dion; (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3,4-metylen-dioxifenyl) pyrazino[2' ,1' :6, l]pyrido[3,4-b]indol-l, 4-dion; 20 (5aR,12R,14aS)-l,2,3,5,6,ll,12,14a-oktahydro-12- (3,4-metylendioxif enyl) pyrrolo[l", 2" : 4' , 5' ]pyrazino-[2' , 1' : 6, l]-pyrido-[3, 4-b]indol-l, 4-dion; ,-, ; och fysiologiskt godtagbara saler och solvater (./ därav. ( , 25 9. (6R, 12aR)-2,3, 6,7, 12,12a-hexahydro-2-metyl-6- * ' {3,4-metylendioxif enyl) pyrazino[2' , 1' : 6, l]pyrido[3,4-b]- '·<*.' indol-1, 4-dion; och fysiologiskt godtagbara salter och • t · V ’ soivat därav.
10. Förening enligt nägot av patentkraven 1-9 • · » : * .* 30 för användning vid vard av stabil, instabil angina och variantangina, hypertoni, pulmonell hypertoni, kronisk , obstruktiv lungsjukdom, kongestivt hjärtfel, njursvikt, t i a • * a * ] ateroskleros, tillständ där blodkärlens öppenhet minskat, * » i » * perifer angiopati, cirkulationsstörningar, inflammations- : 35 sjukdomar, förlamning, bronkit, kronisk astma, allergisk .!#** » a 113176 102 astma, allergisk snuva, glaukom eller sjukdomar som kännetecknas av störningar i tarmmotilitet.
11. Förening enligt nägot av patentkraven 1-9 för användning vid framställning av ett läkemedel att 5 användas för värd av stabil, instabil angina och vari-antangina, hypertoni, pulmonell hypertoni, kronisk obstruktiv lungsjukdom, kongestivt hjärtfel, njursvikt, ateroskleros, tillständ där blodkärlens öppenhet minskat, perifer angiopati, cirkulationsstörningar, inflammations- 10 sjukdomar, förlamning, bronkit, kronisk astma, allergisk astma, allergisk snuva, glaukom eller sjukdomar som kännetecknas av störningar i tarmmotilitet.
12. Farmaceutisk komposition som innehäller en förening enligt nägot av patentkraven 1-9 tillsammans 15 med ett farmaceutiskt godtagbart utspädningsmedel eller en farmaceutiskt godtagbar bärare.
13. Förfarande för framställning av en farmaceutisk komposition som innehäller en förening enligt nägot av patentkraven 1-9 genom att blanda nämnda kom- 20 ponent med ett farmaceutiskt godtagbart utspädningsmedel eller en farmaceutiskt godtagbar bärare. ·' 14. Förfarande för framställning av ett pyrazi- no[2', 1' : 6, l]pyrido[3,4-b]indol-l, 4-dionderivat, känne- • t » i « *** tecknat av att t · » ! . 25 (A) för framställning av en förening med formeln » · · • 1 · o * / (I), där R är väte, behandlas en förening med formeln • 1 · 7 30 (II) ·::> H k o ‘ ; där Alk betecknar Ci-6_alkyl och Hai är en halogenatom, med » I 1 1 · en primär amin R1NH2; eller : : : 35 (B) för framställning av en förening med formeln ·;·· (I), där R1 och R3 tillsammans betecknar en 3- eller 4- 113176 103 ledad alkyl- eller alkenylkedja, cykliseras en förening med formeln O .. .. Vu-Alk H R4 O där Aik är Ci_6-alkyl och R1 och R3 tillsammans betecknar 10 en 3- eller 4-ledad kedja eller (C) för framställning av en förening med formeln (I), där R3 är Ci_3-alkyl, cykliseras en förening med formeln O 15 ^y^A-OAlk R2 O 20 där Alk är Ci-6-alkyl och Hai är en halogenatom, i närvaro av en primär amin; och om sä önskas utförs efter förfarandena (A), (B) och (C) i) bildning av sait; eller t % ii) bildning av soivat.
15. Pyrido[3,4-b]indol-3-karboxylatderivat med * * * formlerna • * · > t t o (II) 30 ν^Λβγ“,Μ O " k o * * ♦ ’ · O *:··: Λ Aik •ifv-TT " » "WrV' H R5 O 113176 104 O R0— H ' 3 (y)
5. T T RJ O varvid R° och R2 betecknar samma som i patentkrav 1, R1 och R3 bildar tillsammans en 3- eller 4-ledad alkyl- eller al-kenylkedja, Alk är Ci-6-alkyl och Hai är en halogenatom. ♦ · * » * : > ? » » ' i i ( »
FI962927A 1994-01-21 1996-07-19 Pyrazino[2',1':6,1]pyrido[3,4-b]indol-1,4-dionderivater, förfarande för framställning därav och deras användning FI113176B (sv)

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GB9401090 1994-01-21
GB9401090A GB9401090D0 (en) 1994-01-21 1994-01-21 Chemical compounds
PCT/EP1995/000183 WO1995019978A1 (en) 1994-01-21 1995-01-19 Tetracyclic derivatives, process of preparation and use
EP9500183 1995-01-19

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