Claims
- 1. A compound of structural formula: ##STR80## or a pharmaceutically acceptable salt thereof wherein Ar represents an aromatic heterocycle selected from R.sup.1, R.sup.2 -benzo[b]furo-, R.sup.1, R.sup.2 -benzo[b]thieno-, thieno- and furo-;
- R.sup.1 and R.sup.2 are independently:
- (1) hydrogen,
- (2) halo,
- (3) hydroxy,
- (4) C.sub.1-3 alkoxy, or
- (5) C.sub.1-6 alkyl;
- R.sup.3 is
- (1) hydrogen,
- (2) ##STR81## wherein R is hydrogen or C.sub.1-3 alkyl, (3) C.sub.1-6 alkyl, either unsubstituted or substituted with one or more of;
- (a) hydroxy,
- (b) carboxy,
- (c) C.sub.1-3 alkoxycarbonyl,
- (d) halo,
- (e) C.sub.1-3 alkoxy,
- (f) --CONR.sup.6 R.sup.7, wherein R.sup.6 and R.sup.7 are the same or different and are hydrogen or C.sub.1-5 alkyl, or joined together directly to form a pyrrolidino or piperidino ring or through a heteroatom to form a morpholino, piperazino or N-C.sub.1-3 alkylpiperazino heterocycle, or
- (g) --NR.sup.6 R.sup.7 ;
- (h) ##STR82## wherein X.sup.1 is ##STR83## and R.sup.9 is (i) C.sub.1-3 alkoxy,
- (ii) C.sub.1-3 alkyl, or
- (iii) NR.sup.6 R.sup.7 ;
- X is ##STR84## and R.sup.4 is
- (1) --OR.sup.8, wherein R.sup.8 is hydrogen or C.sub.1-6 alkyl, either unsubstituted or substituted with one or more of;
- (a) OR, or
- (b) --NRCOR;
- (2) --N(R.sup.8).sub.2,
- (3) --CO.sup.2 R.sup.8,
- (4) --CONR.sup.6 R.sup.7,
- (5) C.sub.1-6 alkyl, either unsubstituted or substituted with
- (a) OR8
- (b) halo,
- (c) CO.sub.2 R.sup.8
- (d) CONR.sup.6 R.sup.7,
- (6) C.sub.2-5 alkenyl,
- (7) C.sub.2-5 alkynyl,
- (8) C.sub.3-6 cycloalkyl,
- (9) 5 or 6-membered heterocycle selected from imidazo, thiazolo, oxazolo, furamyl piperidino, piperzino, pyridino and pyrazino, or phenyl or napthyl, either unsubstituted or substituted with one or more of;
- (a) halo, or
- (b) OR, or
- (c) C.sub.1-3 alkyl;
- R.sup.5 is independently
- (1) C.sub.1-6 alkyl, either unsubstituted or substituted with one or more of
- (a) --OR.sup.8,
- (b) --NR.sup.8 COR.sup.8, or
- (c) --CO.sub.2 R.sup.8,
- (2) --CO.sub.2 R.sup.8, or
- (3) --CONR.sup.6 R.sup.7 ;
- n is 0, 1, 2 or 3; and
- R.sup.3 and R.sup.4 taken together form a 2-oxazolidinon-1-yl or succinimidoyl group or;
- R.sup.3 and R.sup.5 or R.sup.4 and R.sup.5, if R.sup.5 is in the 1- or 3-position and both are alkyl, can be joined together to form a 5- or 6-membered ring.
- 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Ar is R.sup.1,R.sup.2 -benzo[b]furo- or R.sup.1,R.sup.2 -benzo[b]thieno-; R.sup.1 and R.sup.2 are hydrogen or halo; R.sup.3 is C.sub.1-6 alkyl, X is --SO.sub.2 --and R.sup.4 is C.sub.1-6 alkyl, di(C.sub.1-3 alkyl)amino, halo-C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl C.sub.2-5 alkenyl, C.sub.6-10 carbocyclic aryl, 5 or 6-membered heterocycle, --CO.sub.2 R.sup.8, --C.sub.1-5 alkyl-CO.sub.2 R.sup.8 or --C.sub.1-6 alkyl-CONR.sup.6 R.sup.7 ; and R.sup.5 is hydrogen or C.sub.1-6 alkyl.
- 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R.sup.1 and R.sup.2 are hydrogen, R.sup.3 is methyl, R.sup.4 is C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, di(C.sub.1-3 alkyl)amino, 2-furfuryl, or C.sub.1-3 alkoxycarbonylethyl and R.sup.5 is hydrogen.
- 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof wherein Ar is benzo[b]furo-, R.sup.3 is CH.sub.3, and R.sup.4 is --CH.sub.2 CH.sub.3, --N(CH.sub.3).sub.2, --CH.sub.2 CH.sub.2 OR or --wherein R.sup.5 is hydrogen or methyl. CH.sub.2 CH.sub.2 CH.sub.2 OR
- 5. The compound of claim 4 which is:
- (a) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-2-hydroxyethanesulfonamide;
- (b) (2RS,12bSR)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo-[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-3-hydroxypropanesulfonamide;
- (c) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]Furo[2,3-a]quinolizin-2-yl)-N-methyl-methanesulfonamide;
- (d) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N,N',N'-trimethylsulfamide; or
- (e) (2RS,12bSR)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]thieno[2,3-a]quinolizin-2-yl)-N-methyl-methanesulfonamide; or a pharmaceutically acceptable salt thereof.
- 6. The compound of claim 1, wherein X is --SO.sub.2 --; R.sup.4 is C.sub.1-3 alkyl, phenyl, or 2-furyl; R.sup.3 is C.sub.1-3 alkyl substituted with ##STR85##
- 7. The compound of claim 6, wherein X.sup.1 is --SO.sub.2 --.
- 8. The compound of claim 6, wherein X.sup.1 is ##STR86##
- 9. The compound of claim 6, wherein R.sup.4 and R.sup.9 are C.sub.1-3 alkyl, and R is hydrogen.
- 10. A pharmaceutical composition having .alpha..sub.2 -adrenoceptor antagonist activity comprising a pharmaceutically acceptable carrier and an effective .alpha..sub.2 -adrenoceptor antagonist amount of a compound of structural formula: ##STR87## or a pharmaceutically acceptable salt thereof, wherein Ar, R.sup.3, X, R.sup.5, and R.sup.4 are as defined in claim 1.
- 11. The composition of claim 10 wherein Ar is R.sup.1,R.sup.2 benzo[b]furo- or R.sup.1,R.sup.2 -benzo[b]thieno-; R.sup.1 and R.sup.2 are hydrogen or halo; R.sup.3 is C.sub.1-6 alkyl, X is --SO.sub.2 -- and R.sup.4 is C.sub.1-6 alkyl, di(C.sub.1-3 alkyl) amino, halo-C.sub.1-6 alkyl, hydroxyC.sub.1-6 alkyl, C.sub.2-5 alkenyl, C.sub.6-10 carbocyclic aryl, 5 or 6-membered heterocycle, --CO.sub.2 R.sup.8, --C.sub.1-5 alkyl--CO.sub.2 R.sup.8 or --C.sub.1-6 alkyl-CONR.sup.6 R.sup.7 ; and R.sup.5 is hydrogen or C.sub.1-6 alkyl.
- 12. The composition of claim 11 wherein R.sup.1 and R.sup.2 are hydrogen, R.sup.3 is methyl, R.sup.4 is C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, di(C.sub.1-3 alkyl)amino, 2-furfuryl, or C.sub.1-3 alkoxycarbonylethyl and R.sup.5 is hydrogen.
- 13. The composition of claim 12, wherein Ar is benzo[b]furo-, R.sup.3 is --CH.sub.3, X is --SO.sub.2, and R.sup.4 is --CH.sub.2 CH.sub.3, --N(CH.sub.3).sub.2 S--CH.sub.2 CH.sub.2 OR or --CH.sub.2 CH.sub.2 CH.sub.2 OR wherein R.sup.5 hydrogen or methyl.
- 14. The pharmaceutical composition of claim 10 wherein the compound is:
- (a) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-2-hydroxyethanesulfonamide;
- (b) (2RS,12bSR)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo-[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-3-hydroxypropanesulfonamide;
- (c) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-methanesulfonamide;
- (d) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N,N',N'-trimethylsulfamide; or
- (e) (2RS,12bSR)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]thieno[2,3-a]quinolizin-2-yl)-N-methyl-methanesulfonamide; or a pharmaceutically acceptable salt thereof.
- 15. The composition of claim 10 wherein X is --SO.sub.2 --; R.sup.4 is C.sub.1-3 alkyl, phenyl, or 2-furyl; and R.sup.3 is C.sub.1-3 alkyl substituted with ##STR88##
- 16. The composition of claim 15 wherein X.sup.1 is --SO.sub.2 --.
- 17. The composition of claim 15 wherein ##STR89##
- 18. The composition of claim 15 wherein R.sup.4 and R.sup.9 are C.sub.1-3 alkyl and R is hydrogen.
- 19. A method of antagonizing .alpha..sub.2 -adrenoceptors which comprises administering to a patient in need of such treatment an effective .alpha..sub.2 -adrenoceptor antagonist amount of a compound of structural formula: ##STR90## or a pharmaceutically acceptable salt thereof wherein Ar, R.sup.3, X, R.sup.4, and R.sup.5 are as defined in claim 1.
- 20. The method of claim 19 wherein Ar is R.sup.1,R.sup.2 -benzo[b]furo or R.sup.1 , R.sup.2 -benzo[b]thieno; R.sup.1 and R.sup.2 are hydrogen or halo; R.sup.3 is C.sub.1-6 alkyl; X is --SO.sub.2 --and R.sup.4 is C.sub.1-6 alkyl di(C.sub.1-3 alkyl)amino, halo-C.sub.1-6 hydroxyC.sub.1-6 alkyl, C.sub.2-5 alkenyl, C.sub.6-10 -carbocyclic aryl, 5 or 6-membered heterocycle, --CO.sub.2 R.sup.8, --C.sub.1-5 CO.sub.2 R.sup.8 or C.sub.1-6 alkyl-CONR.sup.6 R.sup.7 ; and R.sup.5 is hydrogen or C.sub.1-6 alkyl.
- 21. The method of claim 20 wherein R.sup.1 and R.sup.2 are hydrogen, R.sup.3 is methyl, Rphu 4 is C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, di(C.sub.1-3 alkyl)amino, 2-furfuryl, or C.sub.1-3 alkoxycarbonylethyl and R.sup.5 hydrogen.
- 22. The method of claim 21 wherein Ar is benzo[b]furo-, R.sub.3 is --CH.sub.3, X is --SO.sub.2 --, and R.sup.4 is --CH.sub.2 CH.sub.3, --N(CH.sub.3).sub.2,--CH.sub.2 CH.sub.2 OR or --CH.sub.2 CH.sub.2 CH .sub.2 OR wherein R.sup.5 is hydrogen or methyl.
- 23. The method of claim 22 wherein the compound is:
- (a) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-2-hydroxyethanesulfonamide;
- (b) (2RS,12bSR)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-3-hydroxypropanesulfonamide;
- (c) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-methanesulfonamide;
- (d) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo-[b]furo[2,3-a]quinolizin-2-yl)-N,N',N'-trimethylsulfamide; or
- (e) (2RS,12bSR)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo [b]thieno[2,3-a]quinolizin-2-yl)-N-methyl-methanesulfonamide; or a pharmaceutically acceptable salt thereof.
- 24. The method of claim 19, wherein X is --SO.sub.2 --; R.sup.4 is C.sub.1-3 alkyl, phenyl, or 2-furyl; and R.sup.3 is C.sub.1-3 alkyl substituted with ##STR91##
- 25. The method of claim 24, wherein X.sup.1 is --SO.sub.2 --.
- 26. The method of claim 24, wherein X.sup.1 is ##STR92##
- 27. The method of claim 24 wherein R.sup.4 and R.sup.9 are C.sub.1-3 alkyl and R is hydrogen.
- 28. The compound of claim 1 or a pharmaceutically acceptable salt thereof where the hydrogen,at C-12b and the nitrogen at C-2 are trans, or an enantiomer.
- 29. The compound of claim 2 or a pharmaceutically acceptable salt thereof where the hydrogen at- C-12b and the nitrogen at C-2 are trans, and or an enantiomer.
- 30. The compound of claim 3 or a pharmaceutically acceptable salt thereof where the hydrogen at C-12b and the nitrogen at C-2 are trans, or an enantiomer.
- 31. The compound of claim 4 or a pharmaceutically acceptable salt thereof where the hydrogen at C-12b and the nitrogen at C-2 are trans, or an enantiomer.
- 32. The compound of claim 6 or a pharmaceutically acceptable salt thereof wherein the hydrogen, at C-12b and the nitrogen at C-2 are trans or an enantiomer.
- 33. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein the hydrogen-at C-12b and the nitrogen at C-2 are trans or an enantiomer.
- 34. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein the hydrogen at C-12b and the nitrogen at C-2 are trans or an enantiomer.
- 35. The compounds of claim 9 or a pharmaceutically acceptable salt thereof wherein the hydrogen at C-12b and the nitrogen at C-2 are trans or an enantiomer.
- 36. The composition of claim 10 wherein the compound or a pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer,
- 37. The composition of claim 11 wherein the compound or a pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
- 38. The composition of claim 12 wherein the compound or a pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomers.
- 39. The composition of claim 13 wherein the compound or a pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
- 40. The composition of claim 15 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
- 41. The composition of claim 16 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or and enantiomer.
- 42. The composition of claim 17 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
- 43. The composition of claim 18 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
- 44. The method of claim 19 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
- 45. The method of claim 20 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
- 46. The method of claim 21 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
- 47. The method of claim 22 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
- 48. The method of claim 24 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented, or an enantiomer.
- 49. The method of claim 25 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented, or an enantiomer.
- 50. The method of claim 26 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented, or an enantiomer.
- 51. The method of claim 27 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented, or an enantiomer.
BACKGROUND OF THE INVENTION
This is a continuation-in-part of copending application, Ser. No. 755,863, filed July 17, 1985, now abandoned, which in turn is a continuation-in-part of application, Ser. No. 680,678, filed Dec. 12, 1984, now abandoned, which in turn is a continuation-in-part of application Ser. No. 576,233 filed Feb. 2, 1984, now abandoned.
Foreign Referenced Citations (3)
Number |
Date |
Country |
1435573 |
May 1976 |
GBX |
2083029A |
Mar 1982 |
GBX |
2106909 |
Apr 1983 |
GBX |
Non-Patent Literature Citations (3)
Entry |
Burger's Medicinal Chemistry, 4th ed. Pt. III, pp. 307-310. |
Opalko et al., Chem. Abst. 96:162676j (1982). |
Kluze et al., Chem. Abstr. 91:204200d (1979). |
Continuation in Parts (3)
|
Number |
Date |
Country |
Parent |
755863 |
Jul 1985 |
|
Parent |
680678 |
Dec 1984 |
|
Parent |
576233 |
Feb 1984 |
|