Antidepressant arylpiperazine derivatives of hetrocycle-fused benzodioxans Number:7,153,849 from the United States Patent and Trademark Office (PTO) owispatent Compounds of the formula I: ##STR00001## are useful for the treatment of depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive-compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction and related illnesses.<H arylpiperazine, Antidepressant, Antidepressant, , 7153849.html, Patent, pto, 7153849

Title: Antidepressant arylpiperazine derivatives of hetrocycle-fused benzodioxans

Abstract: Compounds of the formula I: ##STR00001## are useful for the treatment of depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive-compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction and related illnesses.

Patent Number: 7,153,849 Issued on 12/26/2006 to Evrard, et al.

Inventors: Evrard; Deborah Ann (Hamilton Square, NJ), Zhou; Dahui (East Brunswick, NJ), Stack; Gary Paul (Ambler, PA), Venkatesan; Aranapakam Madumbai (Regopark, NY), Failli; Amedeo A. (Princeton Junction, NJ), Croce; Susan Christman (Lambertville, NJ)
Assignee: Wyeth (Madison, NJ)

Appl. No.: 10/659,537

Filed: September 10, 2003

Current U.S. Class: 514/218 ; 514/253.03; 540/575; 544/361

Current International Class: A61K 31/55 (20060101); A61K 31/497 (20060101); C07D 243/06 (20060101); C07D 401/06 (20060101)

Field of Search: 544/361 540/575 514/218,253.03

References Cited [Referenced By]

U.S. Patent Documents


5869490	February 1999	Stack

Foreign Patent Documents


91/13872	Sep., 1991	WO
98/16530	Apr., 1998	WO

Other References

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Primary Examiner: Richter; Johann
Assistant Examiner: Sackey; Ebenezer
Attorney, Agent or Firm: Woodcock Washburn LLP

Parent Case Text

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. application Ser. No. 60/410,082, filed Sep. 12, 2002, the disclosure of which is incorporated herein by reference in its entirety.

Claims

What is claimed is:

1. A compound of formula I: ##STR00031## wherein R.sup.1 is hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; the group X--Y is --N.dbd.C(R.sup.2)--C(R.sup.3)N--, --N.dbd.C(R.sup.2)--C(R.sup.4).dbd.CH--, --N.dbd.C(R.sup.2)--N.dbd.CH--, --N.dbd.C(R.sup.2)--O--, or --NH--C(R.sup.5).dbd.CH--; R.sup.2 and R.sup.3 are, independently, hydrogen, halo, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms; R.sup.4 is hydrogen or alkyl of 1 to 6 carbon atoms; R.sup.5 is hydrogen, halo, trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms; Ar is phenyl, naphthyl, indolyl, indazolyl, thienyl, pyridinyl, pyrimidinyl, quinolinyl, benzofuranyl, benzothienyl, benzoisothiazolyl, or benzisoxazolyl, each optionally substituted with one to three substituents independently selected from hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; and n is 1 or 2; or pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein R.sup.1 is hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.

3. A compound according to claim 1, wherein R.sup.1 is hydrogen, halo or alkoxy of 1 to 6 carbon atoms.

4. A compound according to claim 1, wherein R.sup.1 is hydrogen.

5. A compound according to claim 1, wherein Ar is phenyl, quinolinyl, benzofuranyl, benzothienyl, or indolyl, each optionally substituted.

6. A compound according to claim 1, wherein X--Y is --N.dbd.C(R.sup.2)--C(R.sup.4).dbd.CH-- and R.sup.4 is hydrogen or alkyl of 1 to 3 carbon atoms.

7. A compound according to claim 1, wherein R.sup.2 and R.sup.3 when present are independently selected from hydrogen, amino or alkyl of 1 to 6 carbon atoms.

8. A compound according to claim 1, wherein R.sup.2 and R.sup.3 when present are independently hydrogen or alkyl of 1 to 3 carbon atoms.

9. A compound according to claim 1, wherein R.sup.5 is hydrogen, trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms.

10. A compound according to claim 1, wherein R.sup.5 is hydrogen, trifluoromethyl or alkyl of 1 to 3 carbon atoms.

11. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(3-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,- 4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,- 4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl[methyl}-8-methyl-2,3-dihydr- o[1,4]dioxine [2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1- ,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(3-methoxyphenyl)piperazin-1-yl]methyl-2,3}-8-methyl-2,3-dihyd- ro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1- ,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]methyl}-8-methyl-- 2,3-dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

18. A compound according to claim 1, wherein said compound is (2S)-8-methyl-2-[4-(3-trifluoromethyl-phenyl)piperazin-1-ylmethyl]-2,3-di- hydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

19. A compound according to claim 1, wherein said compound is (2S)-8-methyl-2-[4-(3-fluorophenyl)piperazin-1-ylmethyl]-2,3-dihydro[1,4]- dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

20. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr- o[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

21. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(3,4-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr- o[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

22. A compound according to claim 1, wherein said compound is (2S)-8-methyl-2-[(4-quinolin-2-ylpiperazin-1-yl)methyl]-2,3-dihydro[1,4]d- ioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

23. A compound according to claim 1, wherein said compound is ((2S)-8-methyl-2-{4-(6-nitroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihy- dro [1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

24. A compound according to claim 1, wherein said compound is (2S)-8-methyl-2-{4-(6-chloroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihy- dro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

25. A compound according to claim 1, wherein said compound is2-(4-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl- }piperazin-1-yl}quinoline-6-carbonitrile or a pharmaceutically acceptable salt thereof.

26. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro- [1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

27. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(5-fluoro-1-benzofuran-3-yl)-l -piperazinyl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

28. A compound according to claim 1, wherein said compound is ((2S)-2-{[4-(7-methoxy-1-benzofuran-3-yl)-l -piperazinyl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

29. A compound according to claim 1, wherein said compound is (2S)-8-methyl-2-{[(2S)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3- -dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

30. A compound according to claim 1, wherein said compound is2-((3R)-3-methyl-4-{[(2S))-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quino- lin-2-yl]methyl}piperazin-1-yl]quinoline-6-carbonitrile or a pharmaceutically acceptable salt thereof.

31. A compound according to claim 1, wherein said compound is (2S)-8-methyl-2-{[(2R)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3- -dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

32. A compound according to claim 1, wherein said compound is (2S)-8-methyl-2-{[4-(2-naphthyl)piperazin-1-yl]methyl}-2,3-dihydro[1,4]di- oxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

33. A compound according to claim 1, wherein said compound is (2S)-2-[4-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl)-piperazi- n-1-yl]-quinoline-6-carboxylic acid amide or a pharmaceutically acceptable salt thereof.

34. A compound according to claim 1, wherein said compound is (2S)-2-[4-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazin-- 1-yl]-quinoline-6-carbonitrile or a pharmaceutically acceptable salt thereof.

35. A compound according to claim 1, wherein said compound is (2S)-2-[4-(8-Ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-pi- perazin-1-yl]-quinoline-6-carbonitrile or a pharmaceutically acceptable salt thereof.

36. A compound according to claim 1, wherein said compound is (2S)-2-[4-(2-Methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[.alpha.]nap- hthalen-8-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile or a pharmaceutically acceptable salt thereof.

37. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihy- dro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

38. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihy- dro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

39. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(6-methoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methyl-2,3-di- hydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

40. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(6-Trifluoromethoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-meth- yl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

41. A compound according to claim 1, wherein said compound is 2-[4-(6-Fluoro-quinolin-2-yl)-piperazin-1-ylmethyl]-8-methyl-2,3-dihydro-- [1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

42. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(6-methoxyquinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,- 3-dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

43. A compound according to claim 1, wherein said compound is2-(4-{[(2S)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl- }1,4-diazepan-1-yl)quinoline-6-carbonitrile or a pharmaceutically acceptable salt thereof.

44. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(6-Trifluoromethoxy-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8- -methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

45. A compound according to claim 1, wherein said compound is 2-[4-(6-Fluoro-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-8-methyl-2,3-dihy- dro-[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

46. A compound according to claim 1, wherein said compound is (2S)-2-{[4-(6-Bromo-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3- -dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

47. A compound according to claim 1, wherein said compound is 8-Methyl-2-(4-quinolin-2-yl-[1,4]diazepan-1-ylmethyl)-2,3-dihydro-[1,4]di- oxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

48. A compound according to claim 1, wherein said compound is 8-Methyl-2-[4-(4-methyl-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-2,3-dihy- dro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.

49. A method of treating a subject suffering from a condition selected from depression, anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, obsessive-compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders, vasomotor flushing, alcohol addiction, and sexual dysfunction, comprising the step of: providing to said subject suffering from said condition, a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

50. A method according to claim 49, wherein the condition is depression.

51. A method according to claim 49, wherein the condition is selected from the group consisting of obsessive-compulsive disorder, panic attacks, generalized anxiety disorder, and social anxiety disorder.

52. A pharmaceutical composition, comprising: an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.

Description

FIELD OF THE INVENTION

This invention relates to antidepressant arylpiperazine derivatives of heterocycle-fused benzodioxans, to processes for preparing them, methods of using them and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Major depression is a serious health problem affecting more than 5% of the population, with a lifetime prevalence of 15 20%.

Selective serotonin reuptake inhibitors have produced success in treating depression and related illnesses and have become among the most prescribed drugs. They nonetheless have a slow onset of action, often taking several weeks to produce their full therapeutic effect. Furthermore, they are effective in less than two-thirds of patients.

Serotonin selective reuptake inhibitors (SSRIs) are well known for the treatment of depression and other conditions. SSRIs work by blocking the neuronal reuptake of serotonin, thereby increasing the concentration of serotonin in the synaptic space, and thus increasing the activation of postsynaptic serotonin receptors.

However, although a single dose of an SSRI can inhibit the neuronal serotonin transporter which would be expected to increase synaptic serotonin, long-term treatment is required before clinical improvement is achieved.

It has been suggested that the SSRIs increase the serotonin levels in the vicinity of the serotonergic cell bodies and that the excess serotonin activates somatodendritic autoreceptors, 5HT.sub.1A receptors, causing a decrease in serotonin release in major forebrain areas. This negative feedback limits the increment of synaptic serotonin that can be induced by antidepressants.

A 5HT.sub.1A antagonist would limit the negative feedback and should improve the efficacy of the serotonin reuptake mechanism (Perez, V., et al., The Lancet, 349:1594 1597 (1997)). Such a combination therapy would be expected to speed up the effect of the serotonin reuptake inhibitor.

Thus, it is highly desirable to provide improved compounds which both inhibit serotonin reuptake and which are antagonists of the 5HT.sub.1A receptor.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a group of novel compounds of the Formula I:

##STR00002## wherein R.sup.1 is hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; the group X--Y is --N.dbd.C(R.sup.2)--C(R.sup.3).dbd.N--, --N.dbd.C(R.sup.2)--C(R.sup.4).dbd.CH--, --N.dbd.C(R.sup.2)--N.dbd.CH--, --N.dbd.C(R.sup.2)--O--, or --NH--C(R.sup.5).dbd.CH--; R.sup.2 and R.sup.3 are, independently, hydrogen, halo, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms; R.sup.4 is hydrogen or alkyl of 1 to 6 carbon atoms; R.sup.5 is hydrogen, halo, trifluoromethyl, pentafluoroethyl, or alkyl of 1 to 6 carbon atoms; Ar is phenyl, naphthyl, indolyl, indazolyl, thienyl, pyridinyl, pyrimidinyl, quinolinyl, benzofuranyl, benzothienyl, benzoisothiazolyl, or benzisoxazolyl, each optionally substituted with one to three substituents independently selected from hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; n is 1 or 2; or pharmaceutically acceptable salts thereof.

R.sup.1 is preferably hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms. More preferably, R.sup.1 is hydrogen, halo or alkoxy of 1 to 6 carbon atoms. In still more preferred embodiments of the present invention, R.sup.1 is hydrogen.

R.sup.4 is preferably hydrogen or alkyl of 1 to 3 carbon atoms.

R.sup.2 and R.sup.3 are preferably independently selected from hydrogen, amino or alkyl of 1 to 6 carbon atoms. More preferably, R.sup.2 and R.sup.3 are independently hydrogen or alkyl of 1 to 3 carbon atoms.

R.sup.5 is preferably hydrogen, trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms. More preferably, R.sup.5 is hydrogen, trifluoromethyl or alkyl of 1 to 3 carbon atoms.

Ar is preferably phenyl, quinolinyl, benzofuranyl, benzothienyl, or indolyl, each optionally substituted with one to three substituents independently selected from hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms.

This invention relates to both the R and S stereoisomers of the benzodioxan methylamines as well as to mixtures of the R and S stereoisomers. Throughout this application, the name of the product of this invention, where the absolute configuration of the compounds of the invention is not indicated, is intended to embrace the individual R and S enantiomers as well as mixtures of the two. In some embodiments of the present invention the S enantiomer is preferred.

Where a single stereoisomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer or diastereomers. Thus, a single stereoisomer substantially free of the corresponding enantiomer or diastereomers refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer or diastereomers. "Substantially free," as used herein, means that the compound is made up of a significantly greater proportion of one stereoisomer. In preferred embodiments, the compound is made up of at least about 90% by weight of a preferred stereoisomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred stereoisomer. Preferred stereoisomers may be isolated from racemic mixtures or diastereomeric mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

"Alkyl," as used herein, refers to an aliphatic hydrocarbon chain and includes straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1 to 3 carbon atoms.

"Alkanamido," as used herein, refers to the group R--C(.dbd.O)--NH-- where R is an alkyl group of 1 to 5 carbon atoms.

"Alkanoyloxy," as used herein, refers to the group R--C(.dbd.O)--O-- where R is an alkyl group of 1 to 5 carbon atoms.

"Alkanesulfonamido," as used herein, refers to the group R--S(O).sub.2--NH-- where R is an alkyl group of 1 to 6 carbon atoms.

"Alkoxy," as used herein, refers to the group R--O-- where R is an alkyl group of 1 to 6 carbon atoms.

"Carboxamido," as used herein, refers to the group NH.sub.2--C(.dbd.O)--.

"Carboalkoxy," as used herein refers to the group R--O--C(.dbd.O)-- where R is an alkyl group of 1 to 5 carbon atoms.

"Halogen" (or "halo"), as used herein, refers to chlorine, bromine, fluorine and iodine.

Pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids.

Specific examples of compounds of Formula I are: (2S)-2-{[4-(3-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,- 4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,- 4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr- o[1,4]dioxine[2,3-f]quinoline; (2S)-2-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1- ,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(3-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1- ,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1- ,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]methyl}-8-methyl-- 2,3-dihydro[1,4]dioxino[2,3-f]quinoline; (2S)-8-methyl-2-[4-(3-trifluoromethyl-phenyl)piperazin-1-ylmethyl]-2,3-di- hydro[1,4]dioxine[2,3-f]quinoline; (2S)-8-methyl-2-[4-(3-fluorophenyl)piperazin-1-ylmethyl]-2,3-dihydro[1,4]- dioxine[2,3-f]quinoline; (2S)-2-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr- o[1,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(3,4-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr- o[1,4]dioxino[2,3-f]quinoline; (2S)-8-methyl-2-[(4-quinolin-2-yl)piperazin-1-yl)methyl]-2,3-dihydro[1,4]- dioxino[2,3-f]quinoline; (2S)-8-methyl-2-{4-(6-nitroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihyd- ro[1,4]dioxino[2,3-f]quinoline; (2S)-8-methyl-2-{4-(6-chloroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihy- dro[1,4]dioxino[2,3-f]quinoline; 2-(4-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}p- iperazin-1-yl}quinoline-6-carbonitrile; (2S)-2-{[4-(1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro- [1,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(5-fluoro-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,- 3-dihydro[1,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(7-methoxy-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2- ,3-dihydro[1,4]dioxino[2,3-f]quinoline; (2S)-8-methyl-2-{[(2S)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3- -dihydro[1,4]dioxino[2,3-f]quinoline; 2-((3R)-3-methyl-4-{[(2S))-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoli- n-2-yl]methyl}piperazin-1-yl]quinoline-6-carbonitrile; (2S)-8-methyl-2-{[(2R)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3- -dihydro[1,4]dioxino[2,3-f]quinoline; (2S)-8-methyl-2-{[4-(2-naphthyl)piperazin-1-yl]methyl}-2,3-dihydro[1,4]di- oxino[2,3-f]quinoline; (2S)-2-[4-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl)-piperazi- n-1-yl]-quinoline-6-carboxylic acid amide; (2S)-2-[4-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazin-- 1-yl]-quinoline-6-carbonitrile; (2S)-2-[4-(8-Ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-pi- perazin-1-yl]-quinoline-6-carbonitrile; (2S)-2-[4-(2-Methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthale- n-8-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile; (2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihy- dro[1,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihy- dro[1,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(6-methoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methyl-2,3-di- hydro[1,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(6-Trifluoromethoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-meth- yl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline; 2-[4-(6-Fluoro-quinolin-2-yl)-piperazin-1-ylmethyl]-8-methyl-2,3-dihydro-- [1,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(6-methoxyquinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,- 3-dihydro[1,4]dioxino[2,3-f]quinoline; 2-(4-{[(2S)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}-- 1,4-diazepan-1-yl)quinoline-6-carbonitrile; (2S)-2-{[4-(6-Trifluoromethoxy-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8- -methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline; 2-[4-(6-Fluoro-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-8-methyl-2,3-dihy- dro-[1,4]dioxino[2,3-f]quinoline; (2S)-2-{[4-(6-Bromo-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3- -dihydro[1,4]dioxino[2,3-f]quinoline; 8-Methyl-2-(4-quinolin-2-yl-[1,4]diazepan-1-ylmethyl)-2,3-dihydro-[1,4]di- oxino[2,3-f]quinoline; and 8-Methyl-2-[4-(4-methyl-quinolin-2-yl)-[1,4]di azepan-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline; and pharmaceutically acceptable salts thereof.

Compounds of the present invention are prepared in accordance with the following general description and specific examples. Variables used are as defined for Formula I, unless otherwise noted. Specifically (Scheme 1), the appropriately substituted arylpiperazine is combined with a suitably substituted benzodioxanmethyl sulfonate (e.g., R is 4-methylphenyl or 4-bromopheneyl) or halide in a solvent such as dimethyl sulfoxide and heated to a temperature of 50 100.degree. C. for several hours as illustrated below.

##STR00003##

The arylpiperazines appropriate to the chemistry of Scheme 1 are known in the literature or may be prepared by those skilled in the art.

The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethyltosylates in which R.sup.2 is hydrogen (R is 4-methylphenyl) appropriate to the chemistry in Scheme 1 can be prepared as illustrated in Scheme 2 below. Specifically, the appropriately substituted nitroguaiacol (2) is alkylated with allyl bromide in the presence of a suitable base such as sodium hydride to produce (3) and then demethylated by a reagent such as sodium hydroxide. The resulting 4-nitro-2-allyloxyphenol (4) is then alkylated with glycidyl tosylate or an epihalohydrin in the presence of a base such as sodium hydride to produce (5) and heated in a high boiling solvent such as mesitylene or xylene to effect both rearrangement of the allyl group and cyclization to the dioxan ring. The resulting primary alcohol (6) is converted to the tosylate by reaction with p-toluenesulfonyl chloride in the presence of a tertiary amine or alternatively to a halide by reaction with carbon tetrabromide or carbon tetrachloride in combination with triphenylphosphine. The allyl side chain is then isomerized by treatment with catalytic bis-acetonitrile palladium (II) chloride in refluxing methylene chloride or benzene to produce (7). Allylic oxidation with selenium dioxide in refluxing dioxane/water gives the o-nitrocinnamaldehyde, which upon reduction with iron in acetic acid cyclizes to the 2,3-dihydro-1,4-dioxino[2,3-f]quinoline-2-methyl-tosylate (8).

##STR00004##

The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethyltosylates in which R.sup.2 is alkyl may be prepared from the nitro olefin described above in the manner described in Scheme 3. The rearranged olefin (7) is treated sequentially with ozone and a tertiary amine or with osmium tetroxide and sodium periodate to give the o-nitrobenzaldehyde (9). Condensation with the appropriate triphenyl phosphoranylidene ketone under Wittig conditions gives the o-nitrostyryl ketone (10), which upon reduction by iron in acetic acid, cyclizes to the corresponding 2,3-dihydro-1,4-dioxino[2,3-f]-quinoline-2-methyltosylate (11). Replacement of the tosylate with the appropriately substituted arylpiperazine as above gives the title compounds of the invention.

##STR00005##

Substitution of trimethyl phosphonoacetate for the triphenylphosphoranylidene ketone in the Wittig procedure above, followed by reduction of the nitro group with tin (II) chloride and cyclization in acid gives the compounds of the invention in which R.sup.2 is hydroxy. Alkylation of this hydroxy derivative by a suitable alkyl halide or tosylate in the presence of base gives the compounds of the invention in which R.sup.2 is alkoxy. Treatment of the hydroxy derivative with an inorganic acid chloride such as phosphoryl chloride or bromide gives the compounds of the invention in which R.sup.2 is halo. Substitution of diethyl cyanomethylphosphonate for the triphenyl-phosphoranylidene ketone in the Wittig procedure above, followed by reduction of the nitro group with tin (II) chloride and cyclization in acid gives the compounds of the invention in which R.sup.2 is amino.

The o-nitrobenzaldehyde (9) used in the Wittig chemistry described in Scheme 3 may be alternatively prepared as shown in Scheme 4. The appropriate mono-allylated catechol (12) is elaborated with glycidyl tosylate as described above to produce (13) and rearranged in refluxing mesitylene. Cyclization to the benzodioxan methanol is effected by treatment with sodium bicarbonate in ethanol and the alcohol (14) is converted to the tosylate. After rearrangement of the double bond by treatment with catalytic bis-acetonitrile palladium chloride in refluxing methylene chloride to produce 15 and cleavage with ozone or osmium tetroxide/sodium periodate as described above, the resulting aldehyde (16) is regioselectively nitrated with a combination of nitric acid and tin (IV) chloride to produce (9).

##STR00006##

Compounds of the invention in which R.sup.1 is attached to position 6 of the 2,3-dihydro-1,4-dioxino[2,3-f]quinoline may be alternatively prepared by a variation of the Skraup quinoline synthesis according to Scheme 5. The appropriately substituted benzodioxan methyltosylate (17) is nitrated under standard conditions with nitric acid in a solvent such as dichloroethane and the resulting nitro compound (18) reduced by treatment with hydrogen in the presence of a catalyst such as platinum on sulfide carbon. Treatment of the resulting aniline (19) with acrolein in the presence of hydrogen chloride and an oxidant such as p-chloranil or naphthoquinone gives the corresponding 2,3-dihydro-1,4-dioxino[2,3-f]quinoline (20). Replacement of the tosylate with the appropriately substituted arylpiperazine as above gives the title compounds of the invention.

##STR00007##

The 2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines of the invention are prepared as illustrated below (Scheme 6). The o-nitrobenzaldehyde (9) described above is converted to the oxime (21) by treatment with hydroxylamine hydrochloride in the presence of a suitable base such as sodium acetate and the nitro group reduced to the amine by hydrogenation over palladium on carbon. Cyclization to the quinazoline N-oxide is effected by treatment at reflux with the appropriate ortho ester according to the method of Ostrowski (Heterocycles, vol. 43, No. 2, p. 389, 1996). The quinazoline N-oxide may be reduced to the quinazoline (22) by a suitable reducing agent such as hydrogen over Raney-nickel. Alternatively, an extended period of reflux in the ortho ester gives the reduced quinazoline directly via a disproportionation reaction and the 2,3-dihydro-1,4-dioxino[2,3-f]quinazoline-2-methyltosylate may be isolated by column chromatography. Replacement of the tosylate or halide with the appropriately substituted arylpiperazine in some high boiling solvent such as dimethyl sulfoxide gives the title compounds of the invention.

##STR00008##

The 2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines of the invention may be alternatively prepared from the rearranged olefin described above by the method outlined in Scheme 7 below. The nitro olefin (7) is first reduced to the aniline by treatment with a suitable reducing agent such as stannous chloride dihydrate in refuxing ethyl acetate and the resulting amine acylated with the appropriate acyl halide or anhydride. The olefin (23) is then converted to the aldehyde (24) by cleavage with catalytic osmium tetroxide in the presence of excess sodium periodate. Cyclization directly to the 2,3-dihydro-1,4-dioxino[2,3-f]quinazoline-2-methyltosylate (22) or halide is effected by treatment of the amido aldehyde (24) with ammonia and replacement of the tosylate or halide with the appropriately substituted piperazine in some high boiling solvent such as dimethyl sulfoxide as described above gives the title compounds of the invention.

##STR00009##

The 2,3-dihydro-1,4-dioxino[2,3-f]quinoxalin-2-ylmethylamines of the invention are prepared as illustrated in Scheme 8 below. The o-nitrobenzaldehyde (9) described above is oxidized to the o-nitrobenzoic acid (25) by a suitable oxidant such as chromium trioxide (Jones' oxidation) or sodium chlorite and the acid converted to the o-nitroaniline (26) with diphenylphosphoryl azide (DPPA) in the presence of a tertiary base such as diisopropylethylamine. Reduction of the resulting nitroaniline to the diamine (27) with hydrogen and palladium on carbon and cyclization by treatment with the appropriate dicarbonyl compound (for example, glyoxal, 2,3-butanedione, 3,4-hexanedione) gives the 2,3-dihydro-1,4-dioxino[2,3-f]quinoxaline-2-methyltosylate (28). Replacement of the tosylate with the appropriately substituted arylpiperazine in some high boiling solvent such as dimethyl sulfoxide gives the title compounds of the invention.

##STR00010##

The 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethylamines of the invention are prepared as illustrated in Scheme 9 below. The o-amidobenzaldehyde (24) described in Scheme 7 is converted to the phenol (29) by treatment with meta-chloroperoxybenzoic acid in a Baeyer-Villager reaction and cyclization to the 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (30) is effected by treatment at reflux with an appropriate dehydrating agent such as an ortho ester or an acid catalyst such as o-toluenesulfonic acid. Replacement of the tosylate with the appropriately substituted arylpiperazine in some high boiling solvent such as dimethyl sulfoxide gives the title compounds of the invention.

##STR00011##

Alternatively (Scheme 10), the nitro olefin (7) may be reduced with tin (II) chloride as described in Scheme 7 above and protected with a suitable protecting group such as carbobenzoxy (Cbz) before the olefin is cleaved to the aldehyde (32) by treatment with osmium tetroxide/sodium periodate and the aldehyde converted to a phenol (33) by the Baeyer-Villager procedure. Deprotection by treatment with hydrogen over palladium on carbon gives the o-aminophenol, (34) which is cyclized to the 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (30) by treatment with the appropriate ortho ester, carboxylic acid or anhydride. Treatment of the o-aminophenol with cyanogen bromide or chloride or a suitably substituted carbamoyl chloride leads to compounds of the invention in which R.sup.2 is amino. Treatment of the o-aminophenol with carbonyl diimidazole gives the oxazolone that leads to compounds of the invention in which R.sup.2 is halo via treatment with an inorganic anhydride such as phosphoryl chloride or bromide. Replacement of the tosylate with the appropriately substituted arylpiperazine as above gives the title compounds of the invention.

##STR00012##

Compounds of the invention in which R.sup.1 is hydrogen and R.sup.2 is alkyl are most conveniently prepared according to Scheme 11 below. The appropriate 2',3',4'-trihydroxyacylphenone (35) is regioselectively alkylated with glycidyl tosylate or an epihalohydrin in the presence of a base such as sodium carbonate to give the corresponding 7-acyl-8-hydroxybenzodioxan-2-methanol (36). Following conversion of the ketone to the oxime (37) by reaction with hydroxylamine hydrochloride and sodium acetate, cyclization to the oxazole (38) is effected by treatment with phosphoryl chloride in the appropriate dimethylalkanoic acid amide. The resulting 7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene-8-methanol is converted to the tosylate (39) by treatment with p-toluenesulfonyl chloride in pyridine and combined with the appropriate arylpiperazine as described above to give the title compounds of the invention.

##STR00013##

The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the invention are prepared as illustrated in Scheme 12 below. Specifically, the primary alcohol (6) from the Claisen rearrangement described in Scheme 2 is converted to the tosylate (40) by reaction with p-toluenesulfonyl chloride in the presence of a tertiary amine or pyridine, or alternatively to a halide by reaction with carbon tetrabromide or carbon tetrachloride in combination with triphenylphosphine. The allyl side chain is then cleaved to the aldehyde (41) by treatment with ozone at low temperature, followed by work-up with a tertiary base such as diisopropylethylamine or triethylamine, or by treatment with catalytic osmium tetroxide and sodium periodate. Reduction of the nitro group with hydrogen over platinum oxide leads directly to formation of the indole (42) in which R.sup.5 is hydrogen. Alternatively, the aldehyde may be treated with an appropriate alkyl Grignard reagent or with trifluoromethyl trimethylsilane in the presence of cesium fluoride, then oxidized to a ketone with a suitable oxidant such as pyridinium chlorochromate (PCC) or the Swern reagent and reduced with hydrogen over platinum oxide to give the indoles in which R.sup.5 is alkyl or trifluoromethyl. Replacement of the tosylate with the appropriately substituted arylpiperazine in some high boiling solvent such as dimethyl sulfoxide gives the title compounds of the invention.

##STR00014##

The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the invention may alternatively be prepared following procedure (Scheme 13). The o-nitrobenzaldehyde (9) is condensed with the appropriate nitroalkane in the presence of a suitable base catalyst to yield the corresponding o,.beta.-dinitrostyrene (43). Reduction of both nitro groups with hydrogen over palladium on carbon is accompanied by cyclization to form the indole (44). Replacement of the tosylate with the appropriately substituted arylpiperazine as above gives the title compounds of the invention.

##STR00015##

In yet another method, compounds of the present invention may be prepared in accordance with Scheme 14. The synthesis of compound I is comprised of steps that begin with halogenation of 45 where R' is alkyl of 1 6 carbon atoms, with reagents such as N-halosuccinimide in acetonitrile to give 46 (where Hal is halogen such as Br, Cl or I). Deprotection of 46 with Lewis acids such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, or trimethylsilyl iodide in a suitable solvent such as methylene chloride, or with strong protic acids such as HBr and HCl gives the salt 47. Free base 47 may be obtained by neutralization with an Amberlyst A-21 resin slurry in polar solvents such as ethanol or methanol. Alkylation of 47, either as the free base or as the salt, with benzyl or substituted benzyl protected glycidyl ethers

##STR00016## where R'' is benzyl, substituted benzyl such as 4-bromobenzyl, 3,4-dimethoxybenzyl, 2- or 4-nitrobenzyl, or 4-methoxybenzyl) in suitable polar solvents such as dimethyl sulfoxide, dimethyl formamide, or dimethyl acetamide in the presence of bases such as sodium carbonate, potassium carbonate, or triethylamine gives 48. The compound 48 is then cyclized using palladium catalysts such as tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, or palladium acetate with ligands from the group consisting of (.+-.) BINAP and separate enantiomers thereof, (.+-.) Tol-BINAP and separate enantiomers thereof; 1-1'-bis(diphenylphosphino) ferrocene, 1,3-bis(diphenylphosphino)propane, and 1,2 bis(diphenyl-phosphino)ethane in the presence of bases such as NaH, LiH, KH, potassium carbonate, sodium carbonate, titanium carbonate, cesium carbonate, potassium t-butoxide or potassium phosphate tribasic in a suitable solvent such as toluene, or alternatively, with copper catalyst such as copper iodide in the presence of bases such NaH, LiH, KH in a suitable solvent such as toluene to afford 49. Deprotection of 49 with Lewis acids such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyl iodide in a suitable solvent such as methylene chloride, or with strong protic acids such as HBr and HCl or under reductive cleavage conditions using Pd catalyst and hydrogen transfer reagents such as hydrogen, cyclohexene, methyl cyclohexene, or ammonium formate gives 50. The hydroxyl moiety of 50 can be activated with an aryl- or alkyl-sulfonyl chloride such as p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or 4-nitrobenzenesulfonyl chloride, or 2- or 4-bromobenzenesulfonyl chloride in the presence of bases such as triethylamine or pyridine in suitable solvents such as methylene chloride, THF, or toluene to afford 51 where R''' is sulfonate such as p-toluenesulfonate, methanesulfonate, 2-, 3-, or 4-nitrobenzenesulfonate, or 2- or 4-bromobenzenesulfonate. The final coupling of 51 with arylpiperazines appropriate to the invention, in the presence of bases such as diisopropyl ethylamine, potassium carbonate, or sodium carbonate in polar solvents such as THF, dioxane, DMSO, DMF, or DMA affords compounds of Formula I.

##STR00017##

A protocol similar to that used by Cheetham et. al. (Neuropharmacol. 32:737, 1993) was used to determine the affinity of the compounds of the invention for the serotonin transporter. The compound's ability to displace .sup.3H-paroxetine from male rat frontal cortical membranes was determined using a Tom Tech filtration device to separate bound from free .sup.3H-paroxetine and a Wallac 1205 Beta Plates.RTM. counter to quantify bound radioactivity. K.sub.i's thus determined for standard clinical antidepressants are 1.96 nM for fluoxetine, 14.2 nM for imipramine and 67.6 nM for zimelidine. A strong correlation has been found between .sup.3H-paroxetine binding in rat frontal cortex and .sup.3H-serotonin uptake inhibition.

High affinity for the serotonin 5HT.sub.1A receptor was established by testing the claimed compound's ability to displace [.sup.3H] 8-OH-DPAT (dipropylamino-tetralin) from the 5HT.sub.1A serotonin receptor following a modification of the procedure of Hall et al., J. Neurochem. 44, 1685 (1985) which utilizes CHO cells stably transfected with human 5HT.sub.1A receptors. The 5HT.sub.1A affinities for the compounds of the invention are reported below as K.sub.i's.

Antagonist activity at 5HT.sub.1A receptors was established by using a .sup.35S-GTP.gamma.S binding assay similar to that used by Lazareno and Birdsall (Br. J. Pharmacol. 109:1120, 1993), in which the test compound's ability to affect the binding of .sup.35S-GTP.gamma.S to membranes containing cloned human 5HT.sub.1A receptors was determined. Agonists produce an increase in binding whereas antagonists produce no increase but rather reverse the effects of the standard agonist 8-OH-DPAT. The test compound's maximum inhibitory effect is represented as the I.sub.max, while its potency is defined by the IC.sub.50.

The results of the three standard experimental test procedures described in the preceding three paragraphs were as follows:

TABLE-US-00001 5-HT 5HT.sub.1A Transporter Receptor Affinity Affinity 5HT.sub.1A Function Compound K.sub.i (nM) K.sub.i (nM) IC.sub.50 (nM) (I.sub.max) Example 1 15.7 15.9 4564 (100) Example 2 565 22.9 632 (26) Example 3 76 1055? nd Example 4 34% @ 1 .mu.M 95% @ 1 .mu.M 994 (87) Example 5 35.5 80% @ 1 .mu.M 1715 (84) Example 6 0% @ 1 .mu.M 81% A1 .mu.M 3938 (37) Example 7 1.20 91% @ 1 .mu.M 557 (71) Example 8 21.6 31.4 3107 (100) Example 9 Example 10 88.5 82.5 403 (98) Example 11 85.5 18.2 345 (84) Example 12 48.0 47.3 3002 (100) Example 13 0.25 20.0 326 (70) Example 14 0.65 214 74.7 (58) Example 15 13.5 3.70 82.5 (87) Example 16 266 28.5 ND Example 17 74.0 718 ND Example 18 16.0 40.3 ND Example 19 123 167 3000 (90) Example 20 688 2.85 82.8 (92) Example 21 32.8 5.53 867 (83.5) Example 22 19.8 53.2 4539 (76) Example 23 56% @ 1 .mu.M 7.21 129 (71) Example 24 310 7.27 57 (58) Example 25 67 4.74 EC.sub.50 = 1135(E.sub.max = 67) Example 26 407 25.1 EC.sub.50 = 700 (E.sub.max = 64) Example 27 101 17.15 2412 (82) Example 29 200 1.26 1325 (100) Example 33 7.30 1.75 316 (92) Example 34 1.09 2.04

Like the antidepressants fluoxetine, paroxetine and sertraline, the compounds of this invention have the ability to potently block the reuptake of the brain neurotransmitter serotonin. They are thus useful for the treatment of diseases commonly treated by the administration of serotonin selective reuptake inhibitor (SSRI) antidepressants, such as depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive-compulsive disorders (including but not limited to trichotillomania), obsessive-compulsive spectrum disorders (including but not limited to autism), social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction (including but not limited to premature ejaculation), incontinence (including, but not limited to fecal incontinence, urge incontinence, overflow incontinence, passive incontinence, reflex incontinence, stress urinary incontinence urinary exertional incontinence and urinary incontinence), and pain (including, but not limited to migraine, chronic back pain, phantom limb pain, neuropathic pain such as diabetic neuropathy, and post herpetic neuropathy) and related illnesses. Moreover, the compounds of this invention have potent affinity for and antagonist activity at brain 5HT.sub.1A serotonin receptors. Recent clinical trials employing drug mixtures (e.g., fluoxetine and pindolol) have demonstrated a more rapid onset of antidepressant efficacy for a treatment combining SSRI activity and 5HT.sub.1A antagonism (Blier and Bergeron, 1995; F. Artigas, et al., 1996; M. B. Tome, et al., 1997). The compounds of the invention are thus exceedingly interesting and useful for treating depressive illnesses.

Thus the present invention provides methods of treating, preventing, inhibiting or alleviating each of the maladies listed above in a mammal, preferably in a human, the methods comprising providing a pharmaceutically effective amount of a compound of this invention to the mammal in need thereof.

Also encompassed by the present invention are pharmaceutical compositions for treating or controlling disease states or conditions of the central nervous system comprising at least one compound of Formula I, mixtures thereof, and or pharmaceutical salts thereof, and a pharmaceutically acceptable carrier therefore. Such compositions are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985). Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.

The compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances that may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid that 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, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups, and elixirs. The active ingredient of this invention 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 fat. 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 (particularly 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 used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The amount provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, and the state of the patient, the manner of administration, and the like. In therapeutic applications, compounds of the present invention are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a "therapeutically effective amount." The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age and response pattern of the patient. Generally, a starting dose is about 5 mg per day with gradual increase in the daily dose to about 150 mg per day, to provide the desired dosage level in the human.

"Provide," as used herein, means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.

The present invention includes prodrugs of compounds of Formula I and Ia. Prodrug, as used herein, means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113 191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1 38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).

The following examples illustrate the production of representative compounds of this invention.

Intermediate 1

5-Bromo-6-Methoxy-2-Methylquinoline

A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) in acetonitrile (1.77 L) was cooled to 0 3.degree. C. followed by portion-wise addition of N-bromo-succinimide (200 g, 1.12 mol) over a period of 30 minutes while maintaining the same temperature. The resulted brown slurry was warmed to ambient temperature and stirred for an additional 6 hours. The reaction was then quenched by a 10% NaHSO.sub.3 solution (211 mL). The reaction mixture was concentrated to a volume of 600 mL then slowly poured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred at room temperature for 1 hour then filtered, washed with water (2.times.1 L) and dried in a vacuum oven to give 253 g (98.6%) of the title compound as a brown solid: R.sub.f=0.39 (3:7) EtOAc:heptane; .sup.1H NMR (DMSO) .delta. 8.30 (d, J=6.5 Hz, 1H), 7.98 (d, J=6.9 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.47 (d, J=6.5 Hz, 1H), 4.02 (s, 3H), 2.66 (s, 3H).

Elemental Analysis for: C.sub.11H.sub.10NOBr Calc'd: C, 52.40; H, 3.97; N, 5.56. Found: C, 52.13; H, 3.94; N, 5.61.

Intermediate 2

5-Bromo-2-Methyl-6-Quinolinol Hydrobromide

A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12 mol) in 48% HBr (135 mL) was heated to reflux for 7 hours then cooled to 5.degree. C. in 1 hour to give a brown and thick slurry. The slurry was stirred at 0 5.degree. C. for 1 hour then filtered, washed with EtOAc (2.times.50 mL) and dried in a vacuum oven to give 34.9 g (92%) of the title compound as a brown solid: .sup.1H NMR (DMSO) .delta. 8.26 (d, J=8.7 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 2.64 (s, 3H); .sup.13C NMR (DMSO) .delta. 155.7, 152.0, 142.8, 133.3, 128.9, 126.4, 123.3, 121.2, 103.3, 24.1.

Intermediate 3

5-Bromo-2-Methyl-6-Quinolinol

A slurry of the hydrobromide salt of 5-bromo-2-methyl-6-quinolinol (3.4 g, 10.5 mmol) and Amberlyst A-21 ion-exchange resin (1.7 g, pre-washed with MeOH then dried in oven) in MeOH (35 mL) was stirred at room temperature for 3 hours. The mixture was then filtered and concentrated in vacuo to give 2.5 g (100%) of a yellow solid: R.sub.f=0.36(1:1) EtOAc:heptane; .sup.1H NMR (DMSO) .delta. 8.26 (d, J=8.4 Hz, 1H), 7.82 (d, J=9.3 Hz,1H), 7.47 (t, J=9.1 Hz, 2H), 2.66 (s, 3H).

Intermediate 4

(2S)-1-(Benzyloxy)-3-[(5-Brom-2-Methyl-6-Quinolinyl)Oxyl]-2-Pr Pan I

A solution of 5-bromo-2-methyl-6-quinolinol (30.1 g, 126 mmol), (R)-benzyl glycidyl ether (24.9 g, 152 mmol) and triethylamine (17.4 g, 172 mmol) in DMA (200 mL) was heated in a 95 98.degree. C. oil bath for 2 days. The solution was cooled and poured into water (300 mL) while stirring. The tan precipitate formed was filtered, washed with water (100 mL) and dried in a vacuum oven to give 37 g (73%) of the title compound as a tan solid: R.sub.f=0.35 (EtOAc); .sup.1H NMR (DMSO) .delta. 8.31 (d, J=8.8 Hz, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.72 (d, J=9.3 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.25 7.36 (m, 5H), 5.28 (d, J=5.1 Hz, 1H), 4.56 (s, 2H), 4.22 4.29 (m, 2H), 4.08 4.15 (m, 1H), 3.61 3.73 (m, 2H), 2.66 (s, 3H); [.alpha.].sub.D=+6.2.degree. (c=1, CH.sub.3OH).

Elemental Analysis for: C.sub.20H.sub.20BrNO.sub.3 Calc'd: C, 59.66; H, 4.97; N, 3.48. Found: C, 59.43; H, 4.97; N, 3.55.

Intermediate 5

(2S)-2[(Benzyloxy)methyl]-8-methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinoline

A solution of (2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol (10 g, 24.9 mmol), potassium phosphate tribasic (11.4 g, 50 mmol), Pd(OAc).sub.2 (280 mg, 1.25 mmol) and racemic BINAP (1.55 g, 2.49 mmol) in toluene (50 mL) was heated in a 100 102.degree. C. oil bath for 3 d. The solution was cooled to room temperature then EtOAc (50 mL) and water (50 mL) were added. The reaction mixture was filtered through a