Heterocyclic compounds
The present invention relates to therapeutically active azacyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer's disease, severe painful conditions and glaucoma.
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Claims
1. A compound of formula I ##STR6## wherein Z.sup.1 is oxygen or sulphur;
- R.sup.1 is hydrogen, straight or branched C.sub.1-5 -alkyl, straight or branched C.sub.2-5 -alkenyl or straight or branched C.sub.2-5 -alkynyl; and
- R is -Z.sup.2 -R.sup.2 -X or -Z.sup.2 -R.sup.2 -Z.sup.3 -X, wherein Z.sup.2 and Z.sup.3 independently are oxygen or sulphur, R.sup.2 is straight or branched C.sub.1-15 -alkylene, straight or branched C.sub.2-15 -alkenylene, straight or branched C.sub.2-15 -alkynylene, each of which is.Iadd.optionally.Iaddend.substituted with halogen, --OH, --CN, --CF.sub.3, one or two phenyl, phenoxy, benzoyl, or benzyloxycarbonyl groups wherein each aromatic group is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl or C.sub.1-4 -alkoxy, and X is a heterocyclic group selected from the group consisting of 1,3-dioxolanyl, pyridyl, thienyl, pyrrolidonyl, oxazolidonyl, thiazolidonyl, pyrrolidinyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiazolyl and oxazolyl, which heterocyclic group is optionally substituted at a carbon or nitrogen atom with straight or branched C.sub.1-6 -alkyl, phenyl, benzyl or pyridine, or which heterocyclic group is optionally fused with a phenyl group; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein Z.sup.1 is sulphur.
3. A compound according to claim 2, wherein R is -Z.sup.2 -R.sup.2 -X or -Z.sup.2 -R.sup.2 -Z.sup.3 -X, wherein Z.sup.2 and Z.sup.3 independently are oxygen or sulphur, R.sup.2 is straight or branched C.sub.1-15 -alkylene, and X is thienyl.
4. A compound according to claim 2, wherein R is -Z.sup.2 -R.sup.2 -X or -Z.sup.2 -R.sup.2 -Z.sup.3 -X, wherein Z.sup.2 and Z.sup.3 independently are oxygen or sulphur, R.sup.2 is straight or branched C.sub.1-15 -alkylene, and X is oxazolidonyl.
5. A compound according to claim 2, wherein R is -Z.sup.2 -R.sup.2 -X or -Z.sup.2 -R.sup.2 -Z.sup.3 -X, wherein Z.sup.2 and Z.sup.3 independently are oxygen or sulphur, R.sup.2 is straight or branched C.sub.1-15 -alkylene, and X is thiazolidonyl.
6. A compound according to claim 2, wherein R is -Z.sup.2 -R.sup.2 -X or -Z.sup.2 -R.sup.2 -Z.sup.3 -X, wherein Z.sup.2 and Z.sup.3 independently are oxygen or sulphur, R.sup.2 is straight or branched C.sub.1-15 -alkylene, and X is 1,3,4-thiadiazolyl.
7. A compound according to claim 2, wherein R is -Z.sup.2 -R.sup.2 -X or -Z.sup.2 -R.sup.2 -Z.sup.3 -X, wherein Z.sup.2 and Z.sup.3 independently are oxygen or sulphur, R.sup.2 is straight or branched C.sub.1-15 -alkylene, and X is tetrazolyl.
8. A compound according to claim 2, wherein R is -Z.sup.2 -R.sup.2 -X or -Z.sup.2 -R.sup.2 -Z.sup.3 -X, wherein Z.sup.2 and Z.sup.3 independently are oxygen or sulphur, R.sup.2 is straight or branched C.sub.1-15 -alkylene, and X is thiazolyl.
9. A compound according to claim 1 which is:
- 3-(3-(2-(1,3-Dioxolane-2-yl)-ethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetr ahydro-1-methylpyridine;
- 3-(3-(4-Pyridylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-meth ylpyridine; or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1 which is:
- 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(2-thienyl)-1-propoxy)-1,2,5-thiadiazol -4-yl)pyridine;
- 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-thienyl)-1-ethoxy)-1,2,5-thiadiazol- 4-yl)pyridine;
- 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(3-thienyl)-1-ethoxy)-1,2,5-thiadiazol- 4-yl)pyridine;
- 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-thienylmethoxy)-1,2,5-thiadiazol-4-yl)p yridine;
- 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-thienylmethoxy)-1,2,5-thiadiazol-4-yl)p yridine;
- 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(2-pyrrolidon-1-yl)-1-propoxy)-1,2,5-th iadiazol-4-yl)pyridine;
- 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-pyrrolidon-1-yl)-1-ethoxy)-1,2,5-thi adiazol-4-yl)pyridine;
- 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-oxazolidon-3-yl)-1-ethoxy)-1,2,5-thi adiazol-4-yl)pyridine;
- 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(1-pyrrolidyl)-1-propoxy)-1,2,5-thiadia zol-4-yl)pyridine; or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 1 which is:
- 1-(3-(3-Pyridyl)-1,2,5-thiadiazol-4-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahyd ropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butane;
- 1-(1-Methyltetrazol-5-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl )-1,2,5-thiadiazol-4-ylthio)butane;
- 1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyr idin-3-yl)-1,2,5-thiadiazol-4-ylthio)butane;
- 1-(2-Thiazolin-2-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butane;
- 1-(2-Benzoxazolylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5 -thiadiazol-4-ylthio)butane;
- 1-(2-Methyl-1,3,4thiadiazol-5-ylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyri din-3-yl)-1,2,5-thiadiazol-4-ylthio)pentane;
- 1-(2-Benzthiazolylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2, 5-thiadiazol-4-ylthio)pentane;
- 1-(1-Methyltetrazol-5-ylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl )-1,2,5-thiadiazol-4-ylthio)pentane;
- 1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyr idin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexane;
- 1-(1-Methyltetrazol-5-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl )-1,2,5-thiadiazol-4-ylthio)hexane;
- 1-(2-Thiazolin-2-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexane; or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent.
14. The pharmaceutical composition according to claim 13 in the form of an oral dosage unit or a parenteral dosage unit.
15. The pharmaceutical composition according to claim 14, wherein said dosage unit comprises about 1 to about 100 mg of the compound.
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Type: Grant
Filed: Dec 20, 1996
Date of Patent: Jun 9, 1998
Assignee: Novo Nordisk A/S (Bagsvaerd)
Inventors: Per Sauerberg (Farum), Prebert H. Olesen (Copenhagen), Charles H. Mitch (Columbus, IN)
Primary Examiner: Jane Fan
Attorneys: Steve T. Zelson, Esq., Elias J. Lambiris, Esq.
Application Number: 8/770,484
International Classification: A61K 3144; C07D41304;
