Substituted indoles and uses thereof

This invention is directed to indole and benzothiazole compounds which are selective for cloned human alpha 2 receptors. This invention is also related to uses of these compounds for any indication where use of an alpha 2 agonist may be appropriate. Specifically, this includes use as analgesic, sedative and anaesthetic agents. In addition, this invention includes using such compounds for lowering intraocular pressure, presbyopia, treating migraine, hypertension, alcohol withdrawal, drug addiction, rheumatoid arthritis, ischemic pain, spasticity, diarrhea, nasal decongestion, urinary incontinence as well as for use as cognition enhancers and ocular vasoconstriction agents. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

 

What is claimed is:

1. A method of treating a subject suffering from a condition selected from the group consisting of migraine headache, hypertension, alcohol withdrawal, drug addiction, rheumatoid arthritis, presbyopia, ischemic pain, spasticity, diarrhea, nasal congestion, and urinary incontinence which comprises administering to the subject an amount of a compound effective to treat the condition wherein the compound has the structure: ##STR27##

wherein R.sub.2 is --H; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl;

wherein each of R.sub.4, R.sub.5 and R.sub.6 is independently --H, --F, --Cl, --Br, --I, --OH, --OR.sub.7, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2, --CN, --CO.sub.2 R.sub.7, --CON(R.sub.7).sub.2, or --COR.sub.7 ; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.7 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.7 is independently --H; --N(R.sub.10).sub.2, --NR.sub.10 COR.sub.10, --(CH.sub.2).sub.n OR.sub.10, --SO.sub.n R.sub.10, --SO.sub.n N(R.sub.10).sub.2, --(CH.sub.2).sub.n N(R.sub.10).sub.2, or --(CH.sub.2).sub.n NR.sub.10 COR.sub.10 ; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each n is independently an integer from 1 to 4;

wherein each R.sub.8 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein R.sub.9 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.10 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; and

wherein X is independently CH.sub.2, O, NH or S; or

a pharmaceutically acceptable salt thereof.

2. A method of treating a subject suffering from a condition selected from the group consisting of migraine headache, hypertension, alcohol withdrawal, drug addiction, rheumatoid arthritis, presbyopia, ischemic pain, spasticity, diarrhea, nasal congestion, and urinary incontinence which comprises administering to the subject an amount of a compound effective to treat the condition wherein the compound has the structure: ##STR28##

wherein R.sub.2 is --H; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl;

wherein each of R.sub.4, R.sub.5 and R.sub.6 is independently --H, --F, --Cl, --Br, --I, --OH, --OR.sub.7, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2, --CN, --CO.sub.2 R.sub.7, --CON(R.sub.7).sub.2, or --COR.sub.7 ; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10 ; or --CON(R.sub.10).sub.2 ;

wherein each R.sub.7 is independently --H; --N(R.sub.10).sub.2, --NR.sub.10 COR.sub.10, --(CH.sub.2).sub.n OR.sub.10, --SO.sub.n R.sub.10, --SO.sub.n N(R.sub.10).sub.2, --(CH.sub.2).sub.n N(R.sub.10).sub.2, or --(CH.sub.2).sub.n NR.sub.10 COR.sub.10 ; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each n is independently an integer from 1 to 4;

wherein each R.sub.8 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein R.sub.9 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.10 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; and

wherein X is independently CH.sub.2, O, NH or S; or

a pharmaceutically acceptable salt thereof.

3. A method of either claim 1 or 2, wherein the condition is migraine headache.

4. A method of either claim 1 or 2, wherein the condition is hypertension.

5. A method of either claim 1 or 2, wherein the condition is alcohol withdrawal.

6. A method of either claim 1 or 2, wherein the condition is drug addiction.

7. A method of either claim 1 or 2, wherein the condition is rheumatoid arthritis.

8. A method of either claim 1 or 2, wherein the condition is presbyopia.

9. A method of either claim 1 or 2, wherein the condition is ischemic pain.

10. A method of either claim 1 or 2, wherein the condition is spasticity.

11. A method of either claim 1 or 2, wherein the condition is diarrhea.

12. A method of either claim 1 or 2, wherein the condition is nasal congestion.

13. A method of either claim 1 or 2, wherein the condition is urinary incontinence.

14. A method for sedating a subject which comprises administering to the subject an amount of a compound effective to sedate the subject, wherein the compound has the structure: ##STR29##

wherein R.sub.2 is --H; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl;

wherein each of R.sub.4, R.sub.5 and R.sub.6 is independently --H, --F, --Cl, --Br, --I, --OH, --OR.sub.7 , --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2, --CN, --CO.sub.2 R.sub.7, --CON(R.sub.7).sub.2, or --COR.sub.7 ; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.7 is independently --H; --N(R.sub.10).sub.2, --NR.sub.10 COR.sub.10, --(CH.sub.2).sub.n OR.sub.10, --SO.sub.n R.sub.10, --SO.sub.n N(R.sub.10).sub.2, --(CH.sub.2).sub.n N (R.sub.10).sub.2, or --(CH.sub.2).sub.n NR.sub.10 COR.sub.10 ; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each n is independently an integer from 1 to 4;

wherein each R.sub.8 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein R.sub.9 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.10 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; and

wherein X is independently CH.sub.2, O, NH or S; or

a pharmaceutically acceptable salt thereof.

15. A method for sedating a subject which comprises administering to the subject an amount of a compound effective to sedate the subject, wherein the compound has the structure: ##STR30##

wherein R.sub.2 is --H; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl;

wherein each of R.sub.4, R.sub.5 and R.sub.6 is independently --H, --F, --Cl, --Br, --I, --OH, --OR.sub.7, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2, --CN, --CO.sub.2 R.sub.7, --CON(R.sub.7).sub.2, or --COR.sub.7 ; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.7 is independently --H; --N(R.sub.10).sub.2, --NR.sub.10 COR.sub.10, --(CH.sub.2).sub.n OR.sub.10, --SO.sub.n R.sub.10, --SO.sub.n N(R.sub.10).sub.2, --(CH.sub.2).sub.n N(R.sub.10).sub.2, or --(CH.sub.2).sub.n NR.sub.10 COR.sub.10 ; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each n is independently an integer from 1 to 4;

wherein each R.sub.8 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein R.sub.9 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.10 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; and

wherein X is independently CH.sub.2, O, NH or S; or

a pharmaceutically acceptable salt thereof.

16. A method of producing ocular vasoconstriction in a subject which comprises administering to the subject an effective amount of a compound having the structure: ##STR31##

wherein R.sub.2 is --H; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl;

wherein each of R.sub.4, R.sub.5 and R.sub.6 is independently --H, --F, --Cl, --Br, --I, --OH, --OR.sub.7, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2, --CN, --CO.sub.2 R.sub.7, --CON(R.sub.7).sub.2, or --COR.sub.7 ; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.7 is independently --H; --N(R.sub.10).sub.2, --NR.sub.10 COR.sub.10, --(CH.sub.2).sub.n OR.sub.10, --SO.sub.n R.sub.10, --SO.sub.n N(R.sub.10).sub.2, --(CH.sub.2).sub.n N(R.sub.10).sub.2, or --(CH.sub.2).sub.n NR.sub.10 COR.sub.10 ; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each n is independently an integer from 1 to 4;

wherein each R.sub.8 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein R.sub.9 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.10 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; and

wherein X is independently CH.sub.2, O, NH or S; or

a pharmaceutically acceptable salt thereof.

17. A method of producing ocular vasoconstriction in a subject which comprises administering to the subject an effective amount of a compound having the structure: ##STR32##

wherein R.sub.2 is --H; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl;

wherein each of R.sub.4, R.sub.5 and R.sub.6 is independently --H, --F, --Cl, --Br, --I, --OH, --OR.sub.7, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2, --CN, --CO.sub.2 R.sub.7, --CON(R.sub.7).sub.2, or --COR.sub.7 ; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.7 is independently --H; --N(R.sub.10).sub.2, --NR.sub.10 COR.sub.10, --(CH.sub.2).sub.n OR.sub.10, --SO.sub.n R.sub.10, --SO.sub.n N(R.sub.10).sub.2, --(CH.sub.2).sub.n N(R.sub.10).sub.2, or --(CH.sub.2).sub.n NR.sub.10 COR.sub.10 ; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each n is independently an integer from 1 to 4;

wherein each R.sub.8 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein R.sub.9 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl wherein the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

wherein each R.sub.10 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; and

wherein X is independently CH.sub.2, O, NH or S; or

a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Alpha adrenergic receptors are plasma membrane receptors which are located in the peripheral and central nervous systems throughout the body. They are members of a diverse family of structurally related receptors which contain seven putative helical domains and transduce signals by coupling to guanine nucleotide binding proteins (G-proteins). These receptors are important for controlling many physiological functions and, thus, have been important targets for drug development during the past 40 years. Examples of alpha adrenergic drugs include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (for nasal decongestion), medetomidine (for veterinary analgesia), UK-14,304 and p-aminoclonidine (for glaucoma). However, most of these drugs produce undesirable side effects, possibly due to their interactions with other receptor subtypes. For example, clonidine is a well known centrally acting antihypertensive agent. However, it also produces untoward side effects such as analgesia, sedation, bradycardia and dry mouth which may be due to its lack of selectivity at .alpha..sub.2 receptors.

.alpha.-Adrenergic receptors were originally proposed to have only two (alpha and beta) subtypes (Berthelsen, S.; Pettinger W. Life Sci., 21, 595 (1977)). However, modern molecular biological and pharmacological techniques have led to the identification of at least 6 subtypes (.alpha..sub.1a, .alpha..sub.1b, .alpha..sub.1c, .alpha..sub.2a, .alpha..sub.2b and .alpha..sub.2c) of the adrenergic receptors (Bylund, D. B., Trends Pharmacol. Sci., 9, 356 (1988)).

Among many other therapeutic indications, .alpha..sub.2 receptors are believed to modulate pain and behavioral depression by regulating locus coeruleus firing. In addition, .alpha..sub.2 receptors are well known to be involved in effects on blood pressure, heart rate, vasoconstriction and on glaucoma. However, it is not known which therapeutic indications are controlled by each of these subtypes.

The effects of .alpha..sub.2 receptor agonists on analgesia, is anesthesia and sedation have been well documented for past 10 years (Pertovaara, A., Progress in Neurobiology, 40, 691 (1993)). For example, systematic administration of clonidine has been shown to produce antinociception in various species including human patients in addition to its well known sedative effects. Intrathecal and epidural administration of clonidine has also proved effective in producing antinociception. Another .alpha..sub.2 agonist, medetomidine, which has better .alpha..sub.2 /.alpha..sub.1 selectivity and is more potent at .alpha..sub.2 receptors than clonidine, has been extensively studied for its antinociception effect. In the spinally-initiated heat-induced tail flick test in rats, systemic administration of medetomidine produced a dose-dependent antinociception which could be totally reversed by .alpha..sub.2 receptor antagonists, atipamazole or idazoxan. Experimental studies of medetomidine on pain sensitivity in humans also indicated that this agent is very effective for ischemic pain, even though effective drug doses were high enough to produce sedation and considerable decreases in blood pressure.

Effects of .alpha..sub.2 receptor agonists in anaesthetic practice have also been investigated (Bloor, B. C.; Flacke, W. E., Anesth. Analg., 61, 741 (1982)). The sedative effect of .alpha..sub.2 agonists is regarded as good component of premedication. Another beneficial effect of .alpha..sub.2 agonists in anaesthetic practice is their ability to potentiate the anaesthetic action of other agents and to reduce anaesthetic requirements of other drugs during surgery. Studies shows that premedication with 5 .mu.g kg.sup.-1 of oral clonidine administration reduced fentanyl requirements for induction and intubation by 45% in patients undergoing aortocoronary bypass surgery (Ghingnone, M., et al., Anesthesiology, 64, 36 (1986)).

SUMMARY OF THE INVENTION

This invention is directed to novel indole and benzothiazole compounds which are selective for cloned human .alpha..sub.2 adrenergic receptors. This invention is also related to uses of these compounds for any indication where use of an .alpha..sub.2 adrenergic receptor agonist may be appropriate. Specifically, this includes use as analgesic, sedative and anaesthetic agents. In addition, this invention includes using such compounds for lowering intraocular pressure, treating migraine headache, hypertension, presbyopia, alcohol withdrawal, drug addiction, rheumatoid arthritis, ischemia, spasticity, diarrhea, nasal decongestion, urinary incontinence as well as for use as cognition enhancers and ocular vasoconstriction agents. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds having the structure: ##STR1##

where each of R.sub.1, R.sub.2 and R.sub.3 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl;

where each of R.sub.4, R.sub.5 and R.sub.6 is independently --H, --F, --Cl, --Br, --I, --OH, --OR.sub.7, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2, --CN, --CO.sub.2 R.sub.7, --CON(R.sub.7).sub.2, or --COR.sub.7 ; straight chained or branched C.sub.1 -C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl where the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

where each R.sub.7 is independently --H; --N(R.sub.10).sub.2, --NR.sub.10 COR.sub.10, --(CH.sub.2).sub.n OR.sub.10, --SO.sub.n R.sub.10, --SO.sub.n N(R.sub.10).sub.2, --(CH.sub.2).sub.n N(R.sub.10).sub.2, or --(CH.sub.2).sub.n NR.sub.10 COR.sub.10 ; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl where the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

where each n is independently an integer from 1 to 4;

where each R.sub.8 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl where the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

where R.sub.9 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; C.sub.3 -C.sub.7 cycloalkyl or cycloalkenyl; C.sub.4 -C.sub.7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl where the substituted phenyl or phenyl substituted C.sub.1 -C.sub.4 alkyl is substituted with --H, --F, --Cl, --Br, --I, --NO.sub.2, --CN, straight chained or branched C.sub.1 -C.sub.7 alkyl, straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl, --NR.sub.10, --OR.sub.10, --COR.sub.10, --CO.sub.2 R.sub.10, or --CON(R.sub.10).sub.2 ;

where each R.sub.10 is independently --H; straight chained or branched C.sub.1 -C.sub.7 alkyl; straight chained or branched C.sub.2 -C.sub.7 alkenyl or alkynyl; and

where X is independently CH.sub.2, O, NH or S; or a pharmaceutically acceptable salt thereof.

Note that when R.sub.9 is H, the H undergoes exchange between the adjacent amine and imidazole nitrogen atoms, in a phenomenon called "tautomerization." Throughout this application, the pictorial representation of this structure where R.sub.9 is H places the exchangeable H on the amine nitrogen atom.

In a preferred embodiment, the compounds may have the structure: ##STR2##

where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as defined above.

In preferred embodiments, the invention includes compounds having the structures: ##STR3##

EXAMPLE 1

4-Methyl-5-(2-imidazolin-2-ylamino)indole

##STR4##

EXAMPLE 2

7-Bromo-5-(2-imidazolin-2-ylamino)indole

##STR5##

EXAMPLE 3

7-Chloro-5-(2-imidazolin-2-ylamino)indole

##STR6##

EXAMPLE 4

7-Methyl-5-(2-imidazolin-2-ylamino)indole

##STR7##

EXAMPLE 5

7-Cyano-5-(2-imidazolin-2-ylamino)indole

##STR8##

EXAMPLE 6

7-Acetyl-5-(2-imidazolin-2-ylamino)indole

##STR9##

EXAMPLE 10

7-Isopropanyl-5-(2-imidazolin-2-ylamino)indole

In another embodiment, the compounds may have the structures: ##STR10##

where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as defined above.

Another embodiment of the invention includes the compound having the following structure: ##STR11##

EXAMPLE 8

7-Methyl-5-(2-thiazolin-2-ylamino)indole

In still another embodiment, the compounds may have the structure: ##STR12##

where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and X are as defined above.

In one embodiment, the compounds may have the structure: ##STR13##

where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and X are as defined above.

In another embodiment, the compounds may have the structures: ##STR14##

where R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and X are as defined above.

In another embodiment, the compounds may have the structure: ##STR15##

where R.sub.2, R.sub.4, R.sub.5, R.sub.6, and X are as defined above.

In one preferred embodiment, the compound may have the structure: ##STR16##

EXAMPLE 13

5-(2-Imidazolin-2-ylamino)benzothiazole

In another embodiment, the compounds may have the structure: ##STR17##

where R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and X are as defined above.

In another embodiment, the compounds may have the structure: ##STR18##

where R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.9, and X are as defined above.

In one preferred embodiment, the compound may have the structure: ##STR19##

EXAMPLE 14

6-(2-Imidazolin-2-ylamino)benzothiazole

In another preferred embodiment, the compound may have the structure: ##STR20##

EXAMPLE 15

6-(2-Thiazolin-2-ylamino)benzothiazole

The invention also provides for the (-) and (+) enantiomers of the compounds of the subject application described herein. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the following acids and bases. The following inorganic acids; hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The organic acids; acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The following inorganic bases; ammonia, hydroxyethylamine and hydrazine. The following organic bases; methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein.

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds described above and a pharmaceutically acceptable carrier. In the subject invention a "therapeutically effective amount" is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. In one embodiment the therapeutically effective amount is an amount from about 0.01 mg per subject per day to about 500 mg per subject per day, preferably from about 0.1 mg per subject per day to about 50 mg per subject per day and most preferably from about 1 mg per subject per day to about 20 mg per subject per day. In the practice of this invention the "pharmaceutically acceptable carrier"0 is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.

In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.

A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.

The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.

The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.

The invention further provides a method for anaesthetic premedication which comprises administering to the subject an amount of any of the compounds described above effective to reduce in the subject the requirement for anaesthetic drugs.

The invention further provides a method for sedating a subject which comprises administering to the subject an amount of any of the compounds described above effective to sedate the subject.

This invention also provides a method for ocular vasoconstriction in a subject which comprises administering to the subject an amount of any of the compounds described above effective to produce ocular vasoconstriction in the subject.

This invention also provides a method of treating a subject suffering from a disorder associated with elevated intraocular pressure which comprises administering to the subject an amount of any of the compounds described above effective to lower the subject's intraocular pressure.

This invention also provides a method of treating a subject suffering from migraine headache which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's migraine headache.

This invention also provides a method of treating a subject suffering from hypertension which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's hypertension.

This invention also provides a method of treating a subject suffering from alcohol withdrawal which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's alcohol withdrawal.

This invention also provides a method of treating a subject suffering from drug addiction which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's drug addiction.

This invention also provides a method of treating a subject suffering from rheumatoid arthritis which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's rheumatoid arthritis.

This invention also provides a method of treating a subject suffering from presbyopia which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's presbyopia.

This invention also provides a method of treating a subject suffering from ischemic pain which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's ischemic pain.

This invention also provides a method of treating a subject suffering from spasticity which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's spasticity.

This invention also provides a method of treating a subject suffering from diarrhea which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's diarrhea.

This invention also provides a method of treating a subject suffering from nasal congestion which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's nasal congestion.

This invention also provides a method of treating a subject suffering from urinary incontinence which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's urinary incontinence.

This invention also provides a method of treating a disease which is susceptible to treatment by agonism of the .alpha..sub.2 adrenergic receptor which comprises administering to the subject an amount of any of the compounds described above effective to treat the disease.

This invention also provides a method of treating a subject suffering from pain which comprises administering to the subject an amount of any of the compounds described above effective to treat the subject's pain.

One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for treating the above noted disorders.

This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.

Experimental Details

The compounds claimed have been prepared using the synthetic sequences shown in Schemes 1-6. Detailed synthetic procedures for specific compounds are as described in the Examples below. All NMRs were obtained using a 300 MHz GE QEPLUS NMR machine.

Pharmacological profiles of the claimed compounds at cloned human alpha adrenergic receptors were determined in vitro binding and functional assays using cultured cell lines that selectively express the receptor of interest. Equilibrium competition binding assays were performed with membrane preparations from cultured LM(tk.sup.-) cells stably transfected with the cloned human alpha adrenoreceptor subtypes except for .alpha..sub.2b, which was expressed in Y-1 cells, using [.sup.3 H] prazosin for .alpha..sub.1 receptors and [.sup.3 H] rauwolscine for .alpha..sub.2 receptors. Further details of pharmacological evaluations of claimed compounds are described in Example 21.

EXAMPLE 1

4-Methyl-5-(2-imidazolin-2-ylamino)indole

4-Methyl-5-nitroindole

To a solution of 5-nitroindole (from Aldrich, 0.82 g, 5.1 mmol) in 20 mL of dry THF was added 5.0 mL (15 mmol) of methylmagnesium bromide for 0.5 h period and the resulting reaction mixture was stirred for 1 h at 25.degree. C. Reaction was the quenched by adding a THF solution of tetrachloro-1,4-benzoquinone (1.2 g, 4.9 mmol). Reaction mixture was concentrated in vacuo, yielding a dark solid which was subjected to column chromatography (30% EtOAc/n-Hexane) to yield 0.72 g (4.1 mmol, 80%) of the desired product.

4-Methyl-5-aminoindole

A solution of 4-methyl-5-nitroindole (0.72 g, 4.1 mmol) in 50 mL of methanol was stirred with 50 mg of 10% Pd/C under H.sub.2 for 12 h. Reaction mixture was filtered and concentrated in vacuo to provide an oil (0.61 g, >95%) which was characterized as the desired product by NMR analysis and subjected to a following reaction without further purification.

2-Imidazoline-2-sulfonic acid (ISA)

ISA was prepared according to the procedure described in literature (Gluchowski, C. U.S. Pat. No. 5,130,441, 1992). To a solution of 2-imidazolinethione (6.6 g, 65 mmol), sodium molybdate(IV) dihydrate (0.5 g, 2.1 mmol) and NaCl (1.5 g) in 150 mL of distilled water was added 30% of H.sub.2 O.sub.2 (50 mL, 450 mmol) for 1 h at -10.degree. C. The reaction mixture was stored at -20.degree. C. for 12 h and then reaction temperature was slowly warmed up to 25.degree. C. The white crystal obtained was filtered and dried in vacuo to provide 2.8 g (21 mmol, 32%) of the acid. The compound was used in many of the examples noted below.

4-Methyl-5-(2-imidazolin-2-ylamino)indole

The amine (0.61 g, 4.1 mmol) and ISA (1.0 g, 7.6 mmol) in 10 mL of isobutanol were stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, providing an oily residue which was purified on column chromatography (20% NH.sub.3 saturated MeOH/EtOAc) to yield 0.52 g (2.4 mmol, 59%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.37 g (27%) of the product as a light brown solid: mp 215-218.degree. C.; .sup.1 H NMR (CD.sub.3 OD) .delta.7.28 (d, J=1.8 Hz, 1H), 7.25 (d, J=3.3 Hz, 1H), 6.92 (d, J=3.3 Hz, 1H), 6.52 (d, J=1.8 Hz, 1H), 3.68 (s, 4H), 2.42 (s, 3H); Anal. Calc. for C.sub.12 H.sub.14 N.sub.4.1.0C.sub.4 H.sub.4 O.sub.4 requires C, 58.18; H, 5.49; N, 16.96. Found: C, 58.87; H, 5.44; N, 16.77.

EXAMPLE 2

7-Bromo-5-(2-imidazolin-2-ylamino)indole

7-Bromo-5-nitroindoline

To a solution of 5-nitroindoline (from Aldrich, 2.0 g, 12.2 mmol) in 15 mL of AcOH was added Br.sub.2 (1.0 mL, 19.4 mmol) in a portion and the resulting solution was stirred for 1 h at 25.degree. C. Reaction mixture was concentrated in vacuo, yielding a yellow solid (3.9 g, >95%) of the desired product as a HBr salt, which was subjected to the following reaction without further purification.

7-Bromo-5-nitroindole

To a solution of 7-bromo-5-nitroindoline (3.0 g, 12.3 mmol) in 200 mL of acetone was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone until color of the solution turns to dark green. The reaction mixture was concentrated in vacuo and subjected to column chromatography (CHCl.sub.3, neat) to yield 2.7 g (11.2 mmol, 91%) of the indole.

7-Bromo-5-aminoindole

A solution of 7-bromo-5-nitroindole (0.68 g, 2.8 mmol) hydrazine (1.0 mL, 31 mmol) and 10% Pd/C (50 mg) in 50 mL of isopropanol was stirred at reflux for 2 h. The reaction mixture was filtered and concentrated in vacuo, yielding oily residue which was subjected to column chromatography (CHCl.sub.3, neat) to produce 0.41 g (2.0 mmol, 70%) of the desired product.

7-Bromo-5-(2-imidazolin-2-ylamino)indole

The amine (0.41 g, 2.0 mmol) and ISA (0.65 g, 4.9 mmol) were stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oil which was purified on column chromatography (20% NH.sub.3 saturated MeOH/EtOAc) to yield 0.26 g (0.91 mmol, 46%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.21 g (21%) of the product as a white solid: mp 272-273.degree. C.; .sup.1 H NMR (CD.sub.3 OD) .delta.7.45 (d, J=1.8 Hz, 1H), 7.36 (d, J=3.3 Hz, 1H), 7.20 (d, J=1.8 Hz, 1H), 6.56 (d, J=3.2 Hz, 1H), 3.68 (s, 4H); Anal. Calc. for C.sub.11 H.sub.11 BrN.sub.4.2.0C.sub.4 H.sub.4 O.sub.4 requires C, 44.63; H, 3.75; N, 10.96. Found: C, 45.25; H, 3.73; N, 11.53.

EXAMPLE 3

7-Chloro-5-(2-imidazolin-2-ylamino)indole

7-Chloro-5-nitroindoline

To a solution of 5-nitroindoline (0.5 g, 3.1 mmol) in 15 mL of AcOH was added a solution of Cl.sub.2 in AcOH dropwise until 30% of starting material was consumed. The reaction mixture was concentrated in vacuo, yielding an oil which was subjected to column chromatography (CHCl.sub.3, neat) to provide 0.23 g (1.2 mmol) of the desired product.

7-Chloro-5-nitroindole

To a solution of 7-chloro-5-nitroindoline (0.23 g, 1.2 mmol) in 20 mL of acetone was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone until color of the solution turns to dark green. Reaction mixture was concentrated in vacuo providing a dark residue which was subjected to column chromatography (CHCl.sub.3, neat) to yield 0.18 g (0.94 mmol, 79%) of the indole.

7-Chloro-5-aminoindole

A solution of 7-chloro-5-nitroindole (0.18 g, 0.94 mmol) hydrazine (0.25 mL, 7.7 mmol) and 10% Pd/C (10 mg) in 10 mL of methanol was stirred at reflux for 2 h. The reaction mixture was filtered and concentrated in vacuo, yielding an oil (0.16 g, >95%), which was characterized as the desired product by NMR analysis and subjected to the following reaction without further purification.

7-Chloro-5-(2-imidazolin-2-ylamino)indole

The amine (0.16 g, 0.95 mmol) and ISA (0.30 g, 2.2 mmol) was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oil which was purified on column chromatography (20% NH.sub.3 saturated MeOH/EtOAc) to yield 0.16 g (0.56 mmol, 59%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.17 g (86%) of the product as a white solid: mp 261-262.degree. C.; .sup.1 H NMR (CD.sub.3 OD) .delta.7.41 (d, J=1.8 Hz, 1H), 7.36 (d, J=3.3 Hz, 1H), 7.05 (d, J=1.8 Hz, 1H), 6.35 (d, J=3.2 Hz, 1H), 3.68 (s, 4H); Anal. Calc. for C.sub.11 H.sub.11 ClN.sub.4.1.0C.sub.4 H.sub.4 O.sub.4 requires C, 51.36; H, 4.31; N, 15.97. Found: C, 51.68; H, 4.41; N, 15.52.

EXAMPLE 4

7-Methyl-5-(2-imidazolin-2-ylamino)indole

7-Methyl-5-nitroindole

To a solution of 7-bromo-5-nitroindoline (0.65 g, 2.7 mmol) in 10 mL of DMF were added tetramethyltin (1.0 mL, 7.3 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.10 g) in a portion and resulting mixture was stirred in sealed tube for 12 h at 140.degree. C. The reaction mixture was concentrated in vacuo, providing a dark oily residue which was subjected to column chromatography (CHCl.sub.3, neat) to yield 0.35 g (2.0 mmol, 74%) of the desired product.

7-Methyl-5-aminoindole

A solution of 7-methyl-5-nitroindole (0.35 g, 2.0 mmol) and 10% Pd/c (50 mg) in 20 mL of MeOH was stirred under H.sub.2. The reaction mixture was filtered and concentrated in vacuo, yielding an oil (0.16 g, 1.1 mmol, 41%), which was characterized by NMR and subjected to the following reaction without further purification.

7-Methyl-5-(2-imidazolin-2-ylamino)indole

The amine (0.16 g, 1.1 mmol) and ISA (0.30 g, 2.2 mmol) in 10 mL of isobutanol was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding oily residue which was purified on column chromatography (20% NH.sub.3 saturated MeOH/EtOAc) to provide 0.16 g (0.75 mmol, 68%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.21 g (93%) of the product as a white solid: mp 224-226.degree. C.; .sup.1 H NMR (CD.sub.3 OD) .delta.7.27 (d, J=1.8 Hz, 1H), 7.26 (d, J=3.3 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 6.44 (d, J=3.3 Hz, 1H), 3.67 (s, 4H), 2.47 (s, 3H); Anal. Calc. for C.sub.12 H.sub.14 N.sub.4.1.0C.sub.4 H.sub.4 O.sub.4 requires C, 58.17; H, 5.49; N, 16.96. Found: C, 58.11; H, 5.40; N, 16.40.

EXAMPLE 5

7-Cyano-5-(2-imidazolin-2-ylamino)indole

7-Cyano-5-nitroindole

A solution of 7-bromo-5-nitroindole (2.5 g, 10.4 mmol), CuCN (3.0 g, 33.3 mmol) and KCN (3.0 g, 46.1 mmol) in 20 mL of DMF was stirred at 120.degree. C. for 24 h. The reaction mixture was diluted with 500 mL of EtOAc and washed with brine several times. Organic layer was dried over Na.sub.2 SO.sub.4 and concentrated in vacuo, yielding a brown oily residue which was subjected to column chromatography (CHCl.sub.3, neat) to provide 1.5 g (8.2 mmol, 77%) of the desired product.

7-Cyano-5-aminoindole

A solution of 7-cyano-5-nitroindole (1.5 g, 8.2 mmol), hydrazine (1.0 mL, 31.2 mmol) and 10% Pd/C (20 mg) in 30 mL of MeOH was stirred at reflux for 2 h. The reaction mixture was filtered and concentrated in vacuo to provide 1.3 g (>95%) of the amine.

7-Cyano-5-(2-imidazolin-2-ylamino)indole

The amine (0.11 g, 0.70 mmol) and ISA (0.20 g, 1.4 mmol) in 10 mL of isobutanol was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, providing oily residue which was purified on column chromatography (20% NH.sub.3 saturated MeOH/EtOAc) to yield 0.13 g (0.57 mmol, 82%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.02 g of the product as a white solid: mp 290-295.degree. C.; .sup.1 H NMR (DMSO-D6) .delta.7.64 (d, J=1.8 Hz, 1H), 7.47 (d, J=3.2 Hz, 1H), 7.37 (d, J=1.8 Hz, 1H), 6.55 (d, J=3.2 Hz, 1H), 3.51(s, 4H).

EXAMPLE 6

7-Acetyl-5-(2-imidazolin-2-ylamino)indole

7-Acetyl-5-nitroindole

To a solution of 7-cyano-5-nitroindole (0.7 g, 4.4 mmol) in 20 mL of THF was added 5.0 mL of MeMgBr (3.0 M) and the resulting reaction mixture was stirred for 12 h at 25.degree. C. Reaction was quenched by adding 10 mL of 1.0 N aqueous HCl. Reaction mixture was basified with 3 N aqueous NaOH and aqueous solution was extracted with EtOAc several times. Organic extracts were dried over MgSO.sub.4 and concentrated in vacuo to provide oily residue which was subjected to column chromatography (50% EtOAc/Cy.hexane) to yield 0.20 g (1.2 mmol, 26%) of the desired product.

7-Acetyl-5-aminoindole

A solution of 7-acetyl-5-nitroindole (0.2 g, 1.2 mmol) and 10% Pd/C (30 mg) in 20 mL of MeOH was stirred at reflux for 1 h. The reaction mixture was filtered and concentrated in vacuo, yielding oil (0.17 g, >95%), which was characterized by NMR and subjected to the following reaction without further purification.

7-Acetyl-5-(2-imidazolin-2-ylamino)indole

The amine (0.17 g, 1.2 mmol) and ISA (0.30 g, 2.2 mmol) were stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oil which was purified on column chromatography (20% NH.sub.3 saturated MeOH/EtOAc) to yield 0.08 g (0.33 mmol, 28%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.03 g of the product as a white solid: mp 238-240.degree. C.; .sup.1 H NMR (CD.sub.3 OD) .delta.7.77 (d, J=2.1 Hz, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 6.56 (d, J=3.2 Hz, 1H), 3.70 (s, 4H).

EXAMPLE 7

7-Amido-5-(2-imidazolin-2-ylamino)indole

7-amido-5-nitroindole

To a solution of 7-cyano-5-nitroindole (0.30 g, 1.9 mmol) in 5 mL of MeOH was added 5.0 mL of NH.sub.4 OH and 2 mL of H.sub.2 O.sub.2, and the resulting reaction mixture was stirred for 12 h at 25.degree. C. Reaction was concentrated in vacuo to get rid of MeOH. Remaining aqueous layer was then extracted with EtOAc several times. The organic extracts were dried over MgSO.sub.4 and concentrated in vacuo to provide an oil (0.27 g, >95%) which was identified as the desired product by NMR analysis and subjected to the following reaction without further purification.

7-Amido-5-aminoindole

A solution of 7-acetyl-5-nitroindole (0.28 g, 1.9 mmol), hydrazine (1.0 mL) and 10% Pd/C (30 mg) in 20 mL of MeOH was stirred at reflux for 1 h. The reaction mixture was filtered and concentrated in vacuo, yielding an oil (0.23 g, >95%), which was characterized as the amine by NMR analysis and subjected to a following reaction without further purification.

7-Amido-5-(2-imidazolin-2-ylamino)indole

The amine (0.23 g, 1.9 mmol) and ISA (0.50 g, 3.7 mmol) were stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oil which was purified on column chromatography (20% NH.sub.3 saturated MeOH/EtOAc) to yield 0.21 g (0.86 mmol, 45%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.22 g of the product as a white solid: mp 238-241.degree. C.; .sup.1 H NMR (CD.sub.3 OD) .delta.7.55 (d, J=1.8 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.40 (d, J=3.3 Hz, 1H), 6.52 (d, J=3.2 Hz, 1H), 3.72 (s, 4H); Anal. Calc. for C.sub.12 H.sub.13 N.sub.5 O.1.0C.sub.4 H.sub.4 O.sub.4 requires C, 53.48; H, 4.77; N, 19.49. Found: C, 52.80;