Claims
- 1. A compound of the formula: ##STR348## wherein: R.sup.1 is hydrogen, or lower-alkyl;
- R.sup.2 and R.sup.3 are independently hydrogen, or lower-alkyl; or R.sup.2 and R.sup.3 together form a cycloalkyl ring, or a lower-alkylidene group;
- R.sup.4 and R.sup.5 are independently lower-alkynyl, lower-alkoxy, phenyl (or phenyl substituted by lower-alkoxy, halogen, lower-alkyl, polyfluorolower-alkyl, polychlorolower-alkyl, or hydroxy), a 5- or 6-membered monocyclic aromatic heterocyclic ring system containing from one to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (or said 5- or 6-membered monocyclic aromatic heterocyclic ring system substituted on any available carbon atom thereof by hydroxy, lower-alkyl, oxo, nitro, halogen, or lower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl, tri-lower-alkylsilyl, trilower-alkylsilyl-lower-alkoxy-lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl or halogen)); a 9- or 10-membered bicyclic aromatic heterocyclic ring system containing from one to two, the same or different, heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur (or said 9- or 10-membered bicyclic aromatic heterocyclic ring system substituted at any available carbon atom thereof by hydroxy, lower-alkyl, oxo, nitro, halogen, or lower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl, trilower-alkylsilyl, trilower-alkylsilyl-lower-alkoxy-lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl, or halogen)); or a 5- or 6-membered monocyclic nonaromatic heterocyclic ring system containing from one to two, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (or said 5- or 6-membered nonaromatic heterocyclic ring system substituted on any available carbon atom thereof by hydroxy, lower-alkyl, oxo, nitro, halogen, or lower-alkoxy, or on any available nitrogen atom thereof by lower-alkyl, trilower-alkylsilyl, trilower-alkylsilyl-lower-alkoxy-lower-alkyl, or phenyl-lower-alkyl (or said pheny-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl or halogen));
- or R.sup.2 and R.sup.4 and/or R.sup.3 and R.sup.5 taken together with the carbon atoms to which they are attached form a bicyclic ring system of the formula ##STR349## wherein B is: phenyl, or a 5- or 6-membered monocyclic aromatic heterocyclic ring system containing from one to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (or said B ring substituted on any available carbon atom thereof by lower-alkoxy, or lower-alkyl), and n is an integer from one to three;
- R.sup.6 is hydrogen, or from one to four, the same or different, substituents in any of the 7-, 8-, 9-, or 10-positions (if A is a six-membered ring), or in any of the 6-, 7-, 8-, or 9- position (if A is a five-membered ring) selected from the group consisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy, lower-alkoxy, methylenedioxy, polychlorolower-alkyl, OCO(CH.sub.2)m, C(O)O alkyl, OC(O)alkyl, C(O)Oalkyl, CO.sub.2.sup.-, carboxy, sulfo, SO.sub.3.sup.-, PO.sub.3 H, PO.sub.3.sup.-, cyano, polyfluorolower-alkyl, OC(O) alkyl-CH.dbd.CH-alkyl, OC(O)-lower-alkenyl-C(O)alkyl, alkoxy, OC(O)alkylC(O)Oalkyl, amino, and lower-alkylsulfonylamino, wherein m is an integer from one to four;
- A together with the carbon and nitrogen atoms to which it is attached forms a 5- or 6-membered monocyclic aromatic heterocycle containing from two to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (or said 5- or 6-membered monocyclic aromatic heterocycle substituted on any available carbon atom thereof by hydroxy, OC(O)alkyl-CH.dbd.CH-alkyl, OC(O)alkyl, OC(O)lower-alkenyl-C(O)Oalkyl, alkoxy, OC(O)alkylC(O)Oalkyl, nitro, amino, lower-alkylsulfonylamino, lower-alkyl, lower-alkoxy, or halogen; or on any available nitrogen atom thereof by phenyl (or said phenyl group substituted by lower-alkoxy, lower-alkyl or halogen), diphenylmethyl, naphthyl-lower-alkyl (or said naphthyl-lower-alkyl group substituted on the naphthyl group by lower-alkoxy, lower-alkyl or halogen), lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl or halogen));
- X.sup.- is an anion; and p is zero when R.sup.6 is a negatively charged radical, and p is one when R.sup.6 is other than a negatively charged radical; or a pharmaceutically acceptable acid-addition salt of basic members thereof; or a hydrate thereof; or a stereoisomer thereof.
- 2. A compound according to claim 1 wherein:
- R.sup.1 is hydrogen, or lower-alkyl;
- R.sup.2 and R.sup.3 are independently hydrogen, or lower-alkyl; or R.sup.2 and R.sup.3 together form a cycloalkyl ring, or a lower-alkylidene group;
- R.sup.4 and R.sup.5 are independently lower-alkynyl, lower-alkoxy, phenyl (or phenyl substituted by lower-alkoxy, halogen, lower-alkyl, polyfluorolower-alkyl, polychlorolower-alkyl, or hydroxy), a 5- or 6-membered monocyclic aromatic heterocyclic ring system containing from one to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (or said 5- or 6-membered monocyclic aromatic heterocyclic ring system substituted on any available carbon atom thereof by lower-alkyl, oxo, nitro, halogen, or lower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl, tri-lower-alkylsilyl, trilower-alkylsilyl-lower-alkoxy-lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl or halogen)); a 9- or 10-membered bicyclic aromatic heterocyclic ring system containing from one to two, the same or different, heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur (or said 9- or 10-membered bicyclic aromatic heterocyclic ring system substituted at any available carbon atom thereof by lower-alkyl, oxo, nitro, halogen, or lower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl, trilower-alkylsilyl, trilower-alkylsilyl-lower-alkoxy-lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl, or halogen)); or a 5- or 6-membered monocyclic nonaromatic heterocyclic ring system containing from one to two, the same or different, heteroatom s selected from the group consisting of nitrogen, oxygen and sulfur (or said 5- or 6-membered nonaromatic heterocyclic ring system substituted on any available carbon atom thereof by lower-alkyl, oxo, nitro, halogen, or lower-alkoxy, or on any available nitrogen atom thereof by lower-alkyl, trilower-alkylsilyl, trilower-alkylsilyl-lower-alkoxy-lower-alkyl, or phenyl-lower-alkyl (or said pheny-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl or halogen));
- or R.sup.2 and R.sup.4 and/or R.sup.3 and R.sup.5 taken together with the carbon atoms to which they are attached form a bicyclic ring system of the formula ##STR350## wherein B is: phenyl, or a 5- or 6-membered monocyclic aromatic heterocyclic ring system containing from one to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (or said B ring substituted on any available carbon atom thereof by lower-alkoxy, or lower-alkyl), and n is an integer from one to three;
- R.sup.6 is hydrogen, or from one to four, the same or different, substituents in any of the 7-, 8-, 9-, or 10-positions (if A is a six-membered ring), or in any of the 6-, 7-, 8-, or 9- position (if A is a five-membered ring) selected from the group consisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy, lower-alkoxy, methylenedioxy, polychlorolower-alkyl, OCO(CH.sub.2)m, C(O)O alkyl, OC(O)alkyl, C(O)Oalkyl, CO.sub.2.sup.-, carboxy, sulfo, SO.sub.3.sup.-, PO.sub.3 H, PO.sub.3.sup.-, cyano, and polyfluorolower-alkyl, wherein m is an integer from one to four;
- A together with the carbon and nitrogen atoms to which it is attached forms a 5- or 6-membered monocyclic aromatic heterocycle containing from two to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (or said 5- or 6-membered monocyclic aromatic heterocycle substituted on any available carbon atom thereof by lower-alkyl, lower-alkoxy, or halogen; or on any available nitrogen atom thereof by lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl or halogen));
- X.sup.- is an anion; and p is zero when R.sup.6 is a negatively charged radical, and p is one when R.sup.6 is other than a negatively charged radical; or a pharmaceutically acceptable acid-addition salt of basic members thereof; or a hydrate thereof; or a stereoisomer thereof.
- 3. A compound according to claim 2 wherein R.sup.2 and R.sup.3 are independently hydrogen, or lower-alkyl; and R.sup.6 is hydrogen, or from one to two, the same or different, substitutents in any of the 7-,8-,9-, or 10-positions (if A is a six-membered ring), or in any of the 6-,7-,8 or 9-positions (if A is a five-membered ring) selected from the group consisting of lower-alkyl, halogen, hydroxy, lower-alkoxy and polyfluorolower-alkyl.
- 4. A compound according to claim 3 wherein R.sup.6 is hydrogen, or one substituent in any of the 7-,8-,9- or 10-positions (if A is a six-membered ring), or in any of the 6-,7-,8 or 9-positions (if A is a five-membered ring) selected from the group consisting of lower-alkyl, halogen, hydroxy, and lower-alkoxy.
- 5. A compound according to claim 4 wherein R.sup.6 is hydrogen, or one lower-alkoxy substituent in any of the 7-,8-,9- or 10-positions (if A is a six-membered ring), or in any of the 6-,7-,8 or 9-positions (if A is a five-membered ring); and R.sup.1 is hydrogen.
- 6. A compound according to claim 2 wherein:
- R.sup.4 and R.sup.5 are independently lower-alkynyl, lower-alkoxy, phenyl (or phenyl substituted by lower-alkoxy, halogen, lower-alkyl, polyfluorolower-alkyl, polychlorolower-alkyl, or hydroxy), a 5- or 6-membered monocyclic aromatic heterocyclic ring system containing from one to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (or said 5- or 6-member monocyclic aromatic heterocyclic ring system substituted on any available carbon atom thereof by lower-alkyl, oxo, or lower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl or halogen); or a 9- or 10-membered bicyclic aromatic heterocyclic ring system containing from one to two, the same or different, heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur (or said 9- or 10-membered bicyclic aromatic heterocyclic ring substituted at any available carbon atom thereof by lower-alkyl, oxo, or lower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower alkyl, or halogen.
- 7. A compound according to claim 6 wherein R.sup.4 and R.sup.5 are independently lower-alkoxy, phenyl (or phenyl substituted by lower-alkoxy, halogen, lower-alkyl, polyfluorolower-alkyl, polychlorolower-alkyl, or hydroxy), or a 5- or 6-membered monocyclic aromatic heterocyclic ring system containing from one to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (or said 5- or 6-membered monocyclic aromatic heterocyclic ring system substituted on any available carbon atom thereof by lower-alkyl, oxo, or lower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl or halogen).
- 8. A compound according to claim 7 wherein:
- R.sup.4 and R.sup.5 are independently lower-alkoxy, phenyl (or phenyl substituted by lower-alkoxy, halogen, lower-alkyl, polyfluorolower-alkyl, polychlorolower-alkyl, or hydroxy), or a 5-membered monocyclic aromatic heterocyclic ring system containing from one to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur (or said 5-membered monocyclic aromatic heterocyclic ring system substituted on any available carbon atom thereof by lower-alkyl, oxo, or lower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower-alkyl or halogen); and
- A together with the carbon and nitrogen atoms to which it is attached forms a 5-membered monocyclic aromatic heterocycle containing from two-to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (or said 5-membered monocyclic aromatic heterocycle substituted on any available carbon atom thereof by lower-alkyl, lower-alkoxy, or halogen; or on any availabe nitrogen atom thereof by lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy, lower alkyl or halogen).
- 9. A compound according to claim 8 wherein R.sup.2 and R.sup.3 are independently hydrogen, or lower-alkyl; and R.sup.6 is hydrogen, or from one to two, the same or different, substitutents in any of the 6-,7-,8 or 9-positions selected from the group consisting of lower-alkyl, halogen, hydroxy, lower-alkoxy and polyfluorolower-alkyl.
- 10. A compound according to claim 9 wherein R.sup.6 is hydrogen, or one substituent in any of the 6-,7-,8 or 9-positions selected from the group consisting of lower-alkyl, halogen, hydroxy, and lower-alkoxy.
- 11. A compound according to claim 10 wherein:
- R.sup.4 and R.sup.5 are independently lower-alkoxy, phenyl, or a 5-membered monocyclic aromatic heterocyclic ring system containing from one to two, the same or different, heteroatoms selected from the group consisting of nitrogen and oxygen (or said 5-membered monocyclic aromatic heterocyclic ring system substituted on any available carbon atom thereof by oxo, or on any available nitrogen atom thereof by phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower-alkoxy); and
- A together with the carbon and nitrogen atoms to which it it attached forms a 5-membered monocyclic aromatic heterocycle containing from two to three, the same or different, heteroatoms selected from the group consisting of nitrogen and sulfur (or said 5-membered monocyclic aromatic heterocycle substituted on any available carbon atom thereof by lower-alkyl; or on any available nitrogen atom thereof by lower-alkyl, or phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on the phenyl group by lower alkoxy).
- 12. A compound according to claim 11 wherein R.sup.6 in hydrogen, or one lower-alkoxy substituent in any of the 6-,7-,8-, or 9opositions; and R.sup.1 is hydrogen.
- 13. A compound according to claim 12 wherein:
- R.sup.4 and R.sup.5 are independently ethoxy, phenyl, or a 5-membered monocyclic aromatic heterocyclic ring system selected from furanyl, or pyrazolyl (or said 5-membered aromatic heterocyclic ring system substituted on any available carbon atom thereof by oxo, or on any available nitrogen atom thereof by methoxyphenylmethyl); and A together with the carbon and nitrogen atoms to which it is attached forms a 5-membered monocyclic aromatic heterocycle selected from thiazolyl, imidazolyl, or triazolyl (or said 5-membered monocyclic aromatic heterocycle substituted on any available carbon atom thereof by methyl; or on any available nitrogen atom thereof by methyl, phenylmethyl, or methoxyphenylmethyl.
- 14. A compound according to claim 13 wherein R.sup.2 and R.sup.3 are independently hydrogen or methyl, and R.sup.6 is hydrogen, or 9-methoxy.
- 15. 11,11-Di(3-Furanyl)-5,10-ethano-5,10-dihydrothiazolo[3,2-b]isoquinolinium X.sup.- according to claim 14.
- 16. (+)-11,11-Di(3-furanyl)-5,10-ethano-5,10-dihydrothiazolo[3,2-b]isoquinolinium X.sup.- according to claim 15.
- 17.(+)-11,11-Di(3-furanyl)-5,10-ethano-5,10-dihydrothiazolo[3,2-b]isoquinolinium chloride according to claim 16.
- 18. A compound according to claim 1 wherein R.sup.6 is from one to four, the same or different, substituents in any of the 7-, 8-, 9-, or 10- positions (if A is a six-membered ring), or in any of the 6-, 7-, 8-, 9- positions (if A is a five-membered ring) selected from the group consisting of OC(O)alkyl-CH.dbd.CH-alkyl, OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy, OC(O)alkylC(O)Oalkyl, amino and lower-alkylsulfonylamino.
- 19. A compound according to claim 1 wherein A together with the carbon and nitrogen atoms to which it is attacked forms a 5- or 6-membered monocyclic aromatic heterocycle containing from two to three, the same or different, heteroatoms selected from the group consisting of nitrogen, oxygen sulfur with said 5- or 6-membered monocyclic aromatic heterocycle being substituted on any available carbon atom thereof by hydroxy, OC(O)alkyl-CH.dbd.CH-alkyl, CH-alkyl, OC(O)alkyl, OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy, OC(O)alkylC(O)Oalkyl, nitro, amino or lower-alkylsulfonylamino; or on any available nitrogen atom thereof by phenyl (or said phenyl group substituted by lower-alkoxy, lower-alkyl or halogen), diphenylmethyl, naphthyl-lower-alkyl (or said naphthyl-lower-alkyl group substituted on the naphthyl group by lower-alkoxy, lower-alkyl or halogen).
- 20. A compound according to claim 19 wherein:
- R.sup.4 and R.sup.5 are independently a 5-membered monocyclic aromatic heterocyclic ring system selected from the group consisting of furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrrolyl, imidazolyl, isoxazolyl, oxadiazolyl, and thiadiazolyl;
- R.sup.6 is hydrogen, or one substituent in any of the 6-, 7-, 8-, 9-positions selected from the group consisting of lower-alkoxy and hydroxy;
- A together with the carbon and nitrogen atoms to which it is attached forms a 5-membered monocyclic aromatic heterocycle selected from the group consisting of imidazolyl and triazolyl, with said 5-membered monocyclic aromatic heterocycle being substituted on any available nitrogen atom thereof by phenyl, diphenylmethyl, or naphthyl-lower-alkyl; and
- X.sup.- is an anion.
- 21. A compound according to claim 20 wherein:
- R.sup.1, R.sup.2, R.sup.3 and R.sup.6 are hydrogen;
- R.sup.4 and R.sup.5 are furanyl;
- A together with the carbon and nitrogen atoms to which it is attached forms an imidazole ring which is substituted on the available nitrogen atom thereof by phenyl, diphenylmethyl, or naphthylmethyl; and
- X.sup.- is an anion.
- 22. A pharmaceutical composition which comprises a compound according to claim 1 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 23. A pharmaceutical composition which comprises a compound according to claim 2 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 24. A pharmaceutical composition which comprises a compound according to claim 5 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 25. A pharmaceutical composition which comprises a compound according to claim 7 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 26. A pharmaceutical composition which comprises a compound according to claim 8 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 27. A pharmaceutical composition which comprises a compound according to claim 10 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 28. A pharmaceutical composition which comprises a compound according to claim 12 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 29. A pharmaceutical composition which comprises a compound according to claim 14 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 30. A pharmaceutical composition which comprises a compound according to claim 15 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 31. A pharmaceutical composition which comprises a compound according to claim 16 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 32. A pharmaceutical composition which comprises a compound according to claim 17 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 33. A pharmaceutical composition which comprises a compound according to claim 18 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 34. A pharmaceutical composition which comprises a compound according to claim 19 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 35. A pharmaceutical composition which comprises a compound according to claim 20 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
- 36. A pharmaceutical composition which comprises a compound according to claim 21 together with a pharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of our prior application Ser. No. 08/121,389, filed Sep. 14, 1993, now abandoned.
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
5180831 |
Powers et al. |
Jan 1993 |
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5240939 |
Demko |
Aug 1993 |
|
Non-Patent Literature Citations (1)
Entry |
Bradsher et al., J. Het. Chem. 1972, 9(2), 177-181. |
Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
121389 |
Sep 1993 |
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