Naphthyridine compounds Number:7,417,054 from the United States Patent and Trademark Office (PTO) owispatent Certain naphthyridine compounds are histamine H.sub.3 receptor and serotonin transporter modulators useful in the treatment of histamine H.sub.3 receptor- and serotonin-mediated diseases.<H Naphthyridine, compounds, Naphthyridine, c, 7417054.html, Patent, pto, 7417054

Title: Naphthyridine compounds

Abstract: Certain naphthyridine compounds are histamine H.sub.3 receptor and serotonin transporter modulators useful in the treatment of histamine H.sub.3 receptor- and serotonin-mediated diseases.

Patent Number: 7,417,054 Issued on 08/26/2008 to Carruthers, et al.

Inventors: Carruthers; Nicholas I. (Poway, CA), Keith; John M. (San Diego, CA), Letavic; Michael A. (San Diego, CA), Shah; Chandravadan R. (San Diego, CA)
Assignee: Janssen Pharmaceutica N.V. (BG)

Appl. No.: 11/424,751

Filed: June 16, 2006

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
60692003	Jun., 2005

Current U.S. Class: 514/300 ; 546/122

Current International Class: A01N 43/42 (20060101); A61K 31/44 (20060101); C07D 471/02 (20060101)

Field of Search: 546/122 514/300

References Cited [Referenced By]

U.S. Patent Documents


4113869	September 1978	Gardner
2006/0194837	August 2006	Carruthers

Foreign Patent Documents


0978512	Feb., 2000	EP
1113007	Jul., 2001	EP
1335261	Oct., 1973	GB
9640142	Dec., 1996	WO
WO 01/32624	May., 2001	WO
WO 2005/111036	Nov., 2005	WO

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Primary Examiner: Seaman; D. Margaret
Assistant Examiner: Rahmani; Niloofar

Parent Case Text

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. .sctn. 119(e) of provisional application Ser. No. 60/692,003, filed on Jun. 17, 2005, which is incorporated herein by reference in its entirety.

Claims

What is claimed is:

1. A compound of formula (I): ##STR00082## wherein one or two of X, Y, and Z is N, and the remaining of X, Y, and Z are CR.sup.5; L is --O-- or --CH.sub.2-- and n is 1 or 2; or L is --C.ident.C-- and n is 0 or 1; m is 0, 1, or 2; R.sup.1 is --H; or is --C.sub.1-6alkyl, --C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, --COOC.sub.1-6alkyl, or --COObenzyl, each optionally mono-, di-, or tri-substituted with R.sup.a; R.sup.a is selected from the group consisting of --OH, --OC.sub.1-6alkyl, phenyl optionally substituted with --OC.sub.1-4alkyl or halo, --CN, --NO.sub.2, --N(R.sup.b)R.sup.c (wherein R.sup.b and R.sup.c are independently --H or --C.sub.1-6alkyl), --C(O)N(R.sup.b)R.sup.c, --N(R.sup.b)C(O)R.sup.b, --N(R.sup.b)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.b)R.sup.c, --SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --COOH, and --COOC.sub.1-6alkyl; R.sup.2 and R.sup.3 are independently selected from --H, or from the group consisting of: A) --C.sub.1-6alkyl, --C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, benzyl; B) phenyl or pyridyl, optionally fused at two adjacent carbon ring members to a three- or four-membered hydrocarbon moiety to form a fused five- or six-membered aromatic ring, which moiety has one carbon atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), and which moiety has up to one additional carbon atom optionally replaced by --N.dbd.; C) a 4-8 membered heterocyclic ring, said heterocyclic ring having a carbon atom which is the point of attachment, having 1 or 2 heteroatom members selected from >O, >S(O).sub.0-2, and >NH, and having 0 or 1 double bonds; and D) a monocyclic aromatic hydrocarbon group having five or six ring atoms, having a carbon atom which is the point of attachment, having one carbon atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), having up to one additional carbon atom optionally replaced by --N.dbd., and optionally benzofused or pyridofused; where each of A)-D) is optionally mono-, di-, or tri-substituted with a moiety selected from the group consisting of --OH, --C.sub.1-4alkylOH, --OC.sub.1-6alkyl, --CN, --NO.sub.2, --N(R.sup.d)R.sup.e (wherein R.sup.d and R.sup.e are independently --H or --C.sub.1-6alkyl), --C(O)N(R.sup.d)R.sup.e, --N(R.sup.d)C(O)R.sup.d, --N(R.sup.d)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.d)R.sup.e, --SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --COOH, --COOC.sub.1-6alkyl, --OC(O)N(R.sup.d)R.sup.e, and --OC(O)OR.sup.d; or, alternatively, R.sup.2 and R.sup.3 may be taken together with the nitrogen to which they are attached to form a 4-8 membered heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from >O, >S(O).sub.0-2, >NH, and >NR.sup.f, having 0 or 1 double bonds, having 0, 1, or 2 carbon members separated from the nitrogen of attachment by at least one carbon member which is a carbonyl, optionally benzo or pyrido fused, optionally having one carbon member that forms a bridge, and having 0-5 carbon member substituents R.sup.ff, R.sup.f is selected from the group consisting of --C.sub.1-6alkyl optionally mono-, di-, or tri-substituted with halo, --C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, --C.sub.2-6alkylOH, --C(O)N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h are independently --H or --C.sub.1-6alkyl), --C(O)R.sup.i (where R.sup.i is --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5- or 6-membered aromatic heterocyclyl, each optionally mono-, di-, or tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl, --CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl, and --COOC.sub.1-6alkyl; R.sup.ff is selected from the group consisting of --C.sub.1-6alkyl optionally mono-, di-, or tri-substituted with halo, --C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, halo, --OH, --C.sub.1-6alkylOH, --OC.sub.1-6alkyl, --OC.sub.2-3alkylO-, --CN, --NO.sub.2, --N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h are independently --H or --C.sub.1-6alkyl), --C(O)N(R.sup.g)R.sup.h, --N(R.sup.g)C(O)R.sup.g, --N(R.sup.g)SO.sub.2C.sub.1-6alkyl, --C(O)R.sup.i (where R.sup.i is --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5- or 6-membered aromatic heterocyclyl, each optionally mono-, di-, or tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl, --CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.y)R.sup.z, --SCF.sub.3, --OCF.sub.3, --COOH, and --COOC.sub.1-6alkyl; R.sup.4 is --OH, --OC.sub.1-6alkyl, --CF.sub.3, --C.sub.1-6alkyl, or halo; two R.sup.4 substituents may be taken together to form methylene or ethylene; or one of R.sup.4 is taken together with R.sup.2 to form methylene, ethylene, or propylene; wherein each methylene, ethylene, or propylene is optionally substituted with --OH, --OC.sub.1-6alkyl, --SC.sub.1-6alkyl, --CF.sub.3, --C.sub.1-6alkyl, amino, or halo; R.sup.5 is selected from the group consisting of --H, --C.sub.1-6alkyl, --OH, --OC.sub.1-6alkyl, --SC.sub.1-6alkyl, and halo; Ar.sup.1 is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di-, or tri-substituted with R.sup.j or di-substituted on adjacent carbons with --OC.sub.1-4alkyleneO- optionally mono- or di-substituted with fluoro, --(CH.sub.2).sub.2-3NH--, --(CH.sub.2).sub.1-2NH(CH.sub.2)--, --(CH.sub.2).sub.2-3N(C.sub.1-4alkyl)-, or --(CH.sub.2).sub.1-2N(C.sub.1-4alkyl)(CH.sub.2)--; R.sup.j is selected from the group consisting of 1) --OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl optionally mono-, di-, or tri-substituted with halo, --C.sub.2-6alkenyl, --OC.sub.3-6alkenyl, --C.sub.2-6alkynyl, --OC.sub.3-6alkynyl, --C.sub.3-6cycloalkyl, --OC.sub.3-6cycloalkyl, --CN, --NO.sub.2, --N(R.sup.k)R.sup.l (wherein R.sup.k and R.sup.l are independently --H or --C.sub.1-6alkyl), --N(R.sup.k)COR.sup.l, --N(R.sup.k)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl, --C(O)N(R.sup.m)R.sup.n (wherein R.sup.m and R.sup.n are independently --H or --C.sub.1-6alkyl, or R.sup.m and R.sup.n taken together with their nitrogen of attachment form a 4-8 membered heterocyclic ring having 1 or 2 heteroatom members selected from >O, >S(O).sub.0-2, >NH, and >NC.sub.1-6alkyl, having 0 or 1 double bonds, having 0 or 1 carbonyl members), --SO.sub.2N(R.sup.m)R.sup.n, --SCF.sub.3, halo, --CF.sub.3, --COOH, --COOC.sub.1-6alkyl, and --COOC.sub.3-7cycloalkyl; and 2) a 4-8 membered saturated or partially saturated heterocyclic ring, having 1 or 2 heteroatom members selected from >O, >S(O).sub.0-2, >NH, and >NC.sub.1-6alkyl, having 0 or 1 carbonyl members; said ring optionally mono-, di-, or tri-substituted with R.sup.p; R.sup.p is a substituent independently selected from the group consisting of --OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN, --NO.sub.2, --N(R.sup.q)R.sup.r (wherein R.sup.q and R.sup.r are independently --H, --C.sub.1-6alkyl, or --C.sub.2-6alkenyl), --C(O)N(R.sup.q)R.sup.r, --N(R.sup.q)C(O)R.sup.r, --N(R.sup.q)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.q)R.sup.r, --SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --COOH, and --COOC.sub.1-6alkyl; b) phenyl or pyridyl fused at two adjacent carbon ring members to a three membered hydrocarbon moiety to form a fused five membered aromatic ring, which moiety has one carbon atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), and which moiety has up to one additional carbon atom optionally replaced by --N.dbd., the fused rings optionally mono-, di-, or tri-substituted with R.sup.t; R.sup.t is a substituent independently selected from the group consisting of --OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN, --NO.sub.2, --N(R.sup.u)R.sup.v (wherein R.sup.u and R.sup.v are independently --H or --C.sub.1-6alkyl), --C(O)N(R.sup.u)R.sup.v, --N(R.sup.u)C(O)R.sup.v, --N(R.sup.u)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.u)R.sup.v, --SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --COOH, and --COOC.sub.1-6alkyl; c) phenyl fused at two adjacent ring members to a four membered hydrocarbon moiety to form a fused six membered aromatic ring, which moiety has 0, 1, or 2 carbon atoms replaced by --N.dbd., the fused rings optionally mono-, di-, or tri-substituted with R.sup.t; d) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom which is the point of attachment, having one carbon atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), having up to one additional carbon atom optionally replaced by --N.dbd., optionally mono- or di-substituted with R.sup.t, and optionally benzofused or pyridofused at two adjacent carbon atoms, where the benzofused or pyridofused moiety is optionally mono-, di-, or tri-substituted with R.sup.t; and e) a monocyclic aromatic hydrocarbon group having six ring atoms, having a carbon atom which is the point of attachment, having one or two carbon atoms replaced by --N.dbd., optionally mono- or di-substituted with R.sup.t, and optionally benzofused or pyridofused at two adjacent carbon atoms, where the benzofused or pyridofused moiety is optionally mono- or di-substituted with R.sup.t; and enantiomers, diastereomers, hydrates, solvates thereof, and pharmaceutically acceptable salts, esters and amides thereof.

2. The compound of claim 1 wherein X is N.

3. The compound of claim 1 wherein Y is N.

4. The compound of claim 1 wherein Z is N.

5. The compound of claim 1 wherein Y and Z are N.

6. The compound of claim 1 wherein L is --O-- and n is 1.

7. The compound of claim 1 wherein L is --CH.sub.2-- and n is 1.

8. The compound of claim 1 wherein L is --C.ident.C-- and n is 0.

9. The compound of claim 1 wherein m is 0 or 1.

10. The compound of claim 1 wherein R.sup.1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, benzyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, --COOCH.sub.3, --COO-t-butyl, and --COObenzyl.

11. The compound of claim 1 wherein R.sup.1 is methyl, ethyl, propyl, allyl, propargyl, or benzyl.

12. The compound of claim 1 wherein R.sup.1 is hydrogen or methyl.

13. The compound of claim 1 wherein R.sup.2 and R.sup.3 are independently selected from --H, or, optionally substituted, from the group consisting of: A) methyl, ethyl, isopropyl, butyl, pentyl, hexyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, benzyl, B) phenyl, pyridyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl, imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl, C) azetidinyl, pyrrolidinyl, piperidinyl, and D) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, and 3-indazolyl.

14. The compound of claim 1 wherein R.sup.2 and R.sup.3, optionally substituted, are independently selected from methyl, ethyl, isopropyl, pyrrolidinyl, piperidinyl, 2-benzothiazolyl, and methoxyethyl.

15. The compound of claim 1 wherein R.sup.2 and R.sup.3 are, independently, ethyl, isopropyl, methoxyethyl, or 2-benzothiazolyl.

16. The compound of claim 1 wherein R.sup.2 and R.sup.3, optionally substituted, are taken together with the nitrogen to which they are attached to form a ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, 1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, and 1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl.

17. The compound of claim 1 wherein R.sup.2 and R.sup.3 are taken together with the nitrogen to which they are attached to form a 4-8 membered heterocyclic ring, said heterocyclic ring selected from piperidine, pyrrolidine, and morpholine, said ring substituted with 1 or 2 substituents R.sup.ff.

18. The compound of claim 1 wherein R.sup.ff is selected from the group consisting of methyl, ethyl, isopropyl, butyl, hexyl, --CF.sub.3, --CHF.sub.2, vinyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclobutylethyl, bromo, chloro, fluoro, iodo, --OH, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, isopropoxy, pentyloxy, --O(CH.sub.2).sub.2O--, --O(CH.sub.2).sub.3O--, --CN, amino, methylamino, dimethylamino, diethylamino, diethylcarbamoyl, methanesulfanyl, methanesulfonyl, methanesulfonamido, --C(O)R.sup.i, --COOH, and ethoxycarbonyl.

19. The compound of claim 1 wherein R.sup.ff is selected from the group consisting of methyl, fluoro, --OH, --CF.sub.3, hydroxymethyl, hydroxyethyl, dimethylamino, ethoxycarbonyl, and --O(CH.sub.2).sub.2O--.

20. The compound of claim 1 wherein R.sup.i is selected from the group consisting of methyl, pyridyl, isopropyl, cyclobutyl, cyclopropyl, N-methylpyrrolyl, and 1-methyl imidazolyl.

21. The compound of claim 1 wherein R.sup.2 and R.sup.3 are taken together with the nitrogen to which they are attached to form azetidinyl, 2-methylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3-dimethylaminopyrrolidinyl, 2,5-dimethylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl, 2- hydroxymethylpyrrolidinyl, piperidinyl, 4-fluoropiperidinyl, 3,3-difluoropiperidinyl, 4,4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl, 4-trifluoromethylpiperidinyl, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, morpholinyl, 4-cyanopiperidinyl, 4-carboethoxypiperidinyl, 3-hydroxypiperidinyl, 4-hydroxypiperidinyl, 2-hydroxymethylpiperidinyl, 3-hydroxymethylpiperidinyl, 4-hydroxymethylpiperidinyl, 4-hydroxyethylpiperidinyl, 3-methylmorpholin-4-yl, 3-hydroxymethylmorpholin-4-yl, 2-hydroxymethylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl, 1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, 1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl, or 2-methylmorpholin-4-yl.

22. The compound of claim 1 wherein R.sup.2 and R.sup.3 are taken together with the nitrogen to which they are attached to form piperidinyl, 4-fluoropiperidinyl, 4,4-difluoropiperidinyl, morpholinyl, or 3-methylmorpholin-4-yl.

23. The compound of claim 1 wherein R.sup.4 is methoxy, ethoxy, isopropoxy, pentyloxy, --CF.sub.3, methyl, ethyl, propyl, isobutyl, pentyl, chloro, or fluoro.

24. The compound of claim 1 wherein R.sup.4 is hydroxy, methyl, methoxy, fluoro, or --CF.sub.3.

25. The compound of claim 1 wherein two R.sup.4 are taken together to form methylene.

26. The compound of claim 1 wherein R.sup.2 and one of R.sup.4 are taken together to form ethylene or propylene.

27. The compound of claim 1 wherein R.sup.5 is hydrogen, methyl, ethyl, isopropyl, hexyl, hydroxyl, methoxy, ethoxy, isopropoxy, methylsulfanyl, bromo, chloro, fluoro, or iodo.

28. The compound of claim 1 wherein R.sup.5 is hydrogen.

29. The compound of claim 1 wherein Ar.sup.1, optionally substituted, is selected from the group consisting of: a) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-, 7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-, 7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl, 1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl, b) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl, imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl, c) naphthyl, 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl, d) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, 3-indazolyl, and e) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or 4-quinolinyl, 2- or 3-quinoxalinyl, 2- or 4-quinazolinyl, [1,5], [1,6], [1,7], or [1,8]naphthyridin-2-, 3-, or 4-yl, [2,5], [2,6], [2,7], [2,8]naphthyridin-1-, 3-, or 4-yl.

30. The compound of claim 1 wherein Ar.sup.1, optionally substituted, is selected from the group consisting of phenyl, pyridyl, pyrazinyl, thiazolyl, pyrazolyl, and thiophenyl.

31. The compound of claim 1 wherein Ar.sup.1 is selected from the group consisting of phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl, 4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl, 3-chloro-4-difluoromethoxyphenyl, 3-fluoro-4-chlorophenyl, benzo[1,3]dioxol-4 or 5-yl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl, 4-methanesulfanylphenyl, 4-methanesulfinylphenyl, 4-methanesulfonylphenyl, 4-trifluoromethanesulfanylphenyl, thiophen-2-yl, thiophen-3-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-chloro-5-pyridinyl, 2-dimethylamino-5-pyridinyl, 2-methoxy-5-pyridinyl, 2-thiomethyl-5-pyridinyl, 2-hydroxy-5-pyridinyl, oxazol-5-yl, thiazol-5-yl, thiazol-2-yl, 2H-pyrazol-3-yl, pyrazin-2-yl, 1-naphthyl, 2-naphthyl, 4-imidazol-1-ylphenyl, 4-pyrazol-1-ylphenyl, 1H-indol-5-yl, 1H-benzimidazol-5-yl, benzo[b]thiophen-7-yl, and 4-biphenyl.

32. The compound of claim 1 wherein Ar.sup.1, optionally substituted with halo, is 4-methoxyphenyl or 4-methanesulfanylphenyl.

33. A compound selected from the group consisting of: 4-(2-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]- naphthyridine; 4-(2-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy- dro-[2,6]-naphthyridine; 2-Methyl-4-phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-n- aphthyridine; 4-Phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]naphthyridi- ne; Diethyl-[3-(8-phenyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-yloxy)-pro- pyl]-amine; 4-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6- ]-naphthyridine; Diethyl-[3-(6-methyl-8-phenyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-ylox- y)-propyl]-amine; 4-(4-Methoxy-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrah- ydro-[2,6]-naphthyridine; 4-(4-Methoxy-phenyl)-7-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-1,2,3,4-tetr- ahydro-[2,6]-naphthyridine; 4-(4-Methoxy-phenyl)-2-methyl-7-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-1,2- ,3,4-tetrahydro-[2,6]-naphthyridine; 4-(4-Methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-[2,6- ]-naphthyridine; 4-(4-Methoxy-phenyl)-2-methyl-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrah- ydro-[2,6]-naphthyridine; 4-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6- ]-naphthyridine; 4-(3-Methoxy-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrah- ydro-[2,6]-naphthyridine; 4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[- 2,6]-naphthyridine; 4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperid in-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-naphthyridine; 4-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]- naphthyridine; 4-(4-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy- dro-[2,6]-naphthyridine; 7-[3-(4,4-Difluoro-piperidin-1-yl)-propoxy]-4-(4-methoxy-phenyl)-1,2,3,4-- tetrahydro-[2,6]-naphthyridine; Diethyl-{3-[8-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-y- loxy]-propyl}-amine; {3-[8-(3,4-Dichloro-phenyl)-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-yloxy]- -propyl}-diethyl-amine; 7-(1-Benzyl-piperidin-4-yloxy)-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydro-[2- ,6]-naphthyridine; 4-(4-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]- naphthyridine; 4-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]- naphthyridine; 4-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]- naphthyridine; 4-(3,4-Dichloro-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-[- 2,6]-naphthyridine; 4-(3-Chloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy- dro-[2,6]-naphthyridine; 7-[3-(4,4-Difluoro-piperidin-1-yl)-propoxy]-4-(4-methoxy-phenyl)-2-methyl- -1,2,3,4-tetrahydro-[2,6]naphthyridine; Diethyl-{3-[8-(4-methoxy-phenyl)-6-methyl-5,6,7,8-tetrahydro-[2,6]naphthy- ridin-3-yloxy]-propyl}-amine; {3-[8-(3,4-Dichloro-phenyl)-6-methyl-5,6,7,8-tetrahydro-[2,6]naphthyridin- -3-yloxy]-propyl}-diethyl-amine; 7-(1-Isopropyl-piperidin-4-ylmethoxy)-4-(4-methoxy-phenyl)-1,2,3,4-tetrah- ydro-[2,6]-naphthyridine; 4-(3-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]- naphthyridine; 4-(3-Chloro-4-fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy- dro-[2,6]naphthyridine; 4-(3-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy- dro-[2,6]-naphthyridine; 4-(3-Chloro-4-fluoro-phenyl)-2-methyl-7-(3-piperid in-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]naphthyridine; 4-(4-Chloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy- dro-[2,6]naphthyridine; 4-(3,4-Dichloro-phenyl)-7-(1-isopropyl-piperidin-4-ylmethoxy)-1,2,3,4-tet- rahydro-[2,6]naphthyridine; 4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tet- rahydro-[2,6]-naphthyridine (enantiomer A); 4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tet- rahydro-[2,6]-naphthyridine (enantiomer B); 7-(1-Isopropyl-piperidin-4-ylmethoxy)-4-(4-methoxy-phenyl)-2-methyl-1,2,3- ,4-tetrahydro-[2,6]-naphthyridine; 4-(3,4-Dichloro-phenyl)-7-(1-isopropyl-piperidin-4-ylmethoxy)-2-methyl-1,- 2,3,4-tetrahydro-[2,6]naphthyridine; 4-(4-Methoxy-phenyl)-7-(piperidin-4-yloxy)-1,2,3,4-tetrahydro-[2,6]naphth- yridine; 4-(4-Methoxy-phenyl)-2-methyl-7-(1-methyl-piperidin-4-yloxy)-1,2,- 3,4-tetrahydro-[2,6]naphthyridine; 7-(3-Piperidin-1-yl-propoxy)-4-(4-trifluoromethoxy-phenyl)-1,2,3,4-tetrah- ydro-[2,6]naphthyridine; 4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[- 2,6]-naphthyridine (enantiomer A); 4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[- 2,6]-naphthyridine (enantiomer B); 7-(3-Morpholin-4-yl-propoxy)-4-phenyl-1,2,3,4-tetrahydro-[2,6]naphthyridi- ne; 8-(4-Methoxy-phenyl)-6-methyl-3-(4-piperidin-1-yl-but-1-ynyl)-5,6,7,8-- tetrahydro-[1,6]naphthyridine; 8-(4-Methoxy-phenyl)-6-methyl-3-(4-piperidin-1-yl-butyl)-5,6,7,8-tetrahyd- ro-[1,6]-naphthyridine; 5-(4-Methoxy-phenyl)-7-methyl-2-(3-piperidin-1-yl-propoxy)-5,6,7,8-tetrah- ydro-[1,7]naphthyridine; and 5-(4-Methoxy-phenyl)-7-methyl-2-(4-piperidin-1-yl-but-1-ynyl)-5,6,7,8-tet- rahydro-[1,7]naphthyridine.

34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound of formula (I).

Description

FIELD OF THE INVENTION

The present invention provides compounds that are modulators of the histamine H.sub.3 receptor and the serotonin transporter. More particularly, the present invention provides naphtyridine compounds and methods for using them to treat disorders and conditions mediated by the histamine H.sub.3 receptor and the serotonin transporter. As a consequence of these activities the compounds of the present invention will have therapeutic utility for the treatment of depression and a range of related disorders.

BACKGROUND OF THE INVENTION

Depression is a chronic illness with an estimated lifetime prevalence of 17%. The total annual cost of depression in the USA is estimated at $44 billion. As such, it represents a major health problem with a serious pharmacoeconomic impact (Griffiths, R. I. et al. Pharmacoeconomics 1999, 15(5), 495-505). Although the biochemical basis of depression is not completely elucidated, the most commonly accepted hypothesis states that depression occurs when monoaminergic neurotransmission in the brain is impaired. This theory is largely based on the observation that compounds that improve noradrenergic and/or serotoninergic neurotransmission often have beneficial effects in depression. Such an improvement in monoaminergic neurotransmission can be achieved in several ways. The biological effect of noradrenaline is terminated by two mechanisms: reuptake from the synaptic cleft into the neuron via the norepinephrine transporter (NET), and degradation by monoamine oxidase (MAO). For serotonin, reuptake in the neuron via the serotonin transporter (SERT) likewise limits its availability in the synaptic cleft.

Currently, clinical treatment of depression relies mainly on four types of drugs: 1) MAO inhibitors; 2) tricyclic antidepressants (TCA); 3) selective serotonin reuptake inhibitors (SSRI); and 4) other drugs such as reboxetine and venlafaxine. MAOs have long been used as second-line drugs because of their potentially dangerous side effects, and more recently, reversible MAO-A selective inhibitors with improved profiles have been described (Bonnet, U. CNS Drug Rev. 2002, 8(3), 283-308). TCAs such as amitryptiline display complex pharmacological activities. They inhibit reuptake of noradrenaline and serotonin via their respective transporters, but also have affinity at muscarinic and histamine H.sub.1 receptors. Thus, their efficacy in treating depression is counterbalanced by numerous unwanted side effects. The SSRIs, which represent the largest and most successful group of antidepressants, show a higher selectivity for the SERT than for the NET, although the exact affinity ratio varies from drug to drug. This class of drugs is characterized by a milder side-effect profile than the MAO-inhibitors or the TCAs. Other drugs have been described, such as reboxetine, which preferentially targets the NET, and venlafaxine, which has dual activity at the SERT and NET (Olver, J. S. et al. CNS Drugs 2001, 15(12), 941-954).

Although remarkable progress has been made in the treatment of depression, there remains opportunity for improvement. The delay between start of treatment and subjective improvement is a case in point. Most drugs do not cause an improvement in the Hamilton Rating Scale for Depression until after several weeks of treatment, potentially leaving the patient subject to severe mental anguish during this time. Currently available drugs have a limited response rate and in most clinical trials only about 30% of patients show clinical improvement (Menza, M. A. et al. J. Clin. Psych. 2000, 61(5), 378-381). Psychiatrists frequently have to evaluate several drugs for individual patients before a satisfactory therapeutic response is observed. Consequently there is a significant therapeutic need for drugs with a faster onset of action, improved side effect profiles and higher response ratio.

In order to appreciate the rationale for a combined SERT/H.sub.3 antagonist, it is necessary to understand the physiology of the histamine H.sub.3 receptor. This receptor was described in 1983 (Arrang, J.-M. et al. Nature (London) 1983, 302(5911), 832-837) as a presynaptic, auto-inhibitory receptor on histaminergic neurons with a characteristic pharmacology. Activation of the H.sub.3 receptor was shown to decrease the amount of histamine released from the nerve terminals and to inhibit the activity of histidine decarboxylase, the rate-limiting enzyme in the synthesis of histamine. The cloning and characterization of the human H.sub.3 receptor made it possible to explore its pharmacology (Lovenberg, T. W. et al. Molec. Pharmacol. 1999, 55(6), 1101-1107). It is now known that the H.sub.3 receptor is expressed on a variety of neurons and thus, when activated, decreases the release of a number of other neurotransmitters including noradrenaline, dopamine, and acetylcholine (Hill, S. J. et al. Pharmacol. Rev. 1997, 49(3), 253-278). For the purpose of this discussion, we will focus on its known effects on the release of the neurotransmitters involved in depression, noradrenaline and serotonin. Although the serotoninergic cell bodies are found in the dorsal raphe nucleus while the histaminergic cells are located in the tuberomammillary nucleus of the hypothalamus, both systems have extensive projections throughout the brain. In several regions, such as the suprachiasmatic nucleus (Laitinen, K. S. M. et al. Eur. J. Pharmacol. 1995, 285(2), 159-164) and striatum both neurotransmitters are present. It is known that activation of the H.sub.3 receptor leads to a decreased release of serotonin, for instance in rat cortex slices (Fink, K. et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 1990, 342(5), 513-519; Schlicker, E. et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 1988, 337(5), 588-590). Functional antagonists of the H.sub.3 receptor lead to an increased release of noradrenaline in the central (mouse cortex slices, Leurs, R. et al. J. Pharmacol. Exp. Ther. 1996, 276(3), 1009-1015; the rat hippocampus, Alvez-Rodrigues, A. et al. Brain Res. 1998, 788(1-2), 179-186) and peripheral nervous system (human myocardial nerves, Hatta, E. et al. J. Pharmacol. Exp. Ther. 1997, 283(2), 494-500; guinea-pig intestinal sympathetic nerves, Blandizzi, C. et al. Br. J. Pharmacol. 2000, 129(7), 1387-1396). However, there is little evidence that H.sub.3 receptor antagonists alone are capable of increasing serotonin levels in vivo to those required for antidepressant effects. Microdialysis studies of the effect of H.sub.3 antagonists on serotonin levels in the brain of live animals are lacking. There are sparse reports indicating that thioperamide, an H.sub.3 receptor antagonist, may have an antidepressant effect per se in the mouse or rat forced swim test (Lamberti, C. et al. Br. J. Pharmacol. 1998, 123(7), 1331-1336; Perez-Garcia, C. et al. Psychopharmacology 1999, 142(2), 215-220).

The rationale for combining H.sub.3 receptor blockade and SERT activity in one single molecule is the expectation that both mechanisms will contribute synergistically to enhanced concentrations of serotonin in the synaptic cleft. Antagonism at the H.sub.3 receptor will provide increased release of serotonin-containing vesicles into the synaptic cleft, and concomitant blockade of the SERT will decrease the neuronal reuptake of these neurotransmitter molecules. Thus, higher concentrations of serotonin will be achieved, leading to an enhanced therapeutic effect.

Among the prominent vegetative symptoms of depression are disturbed sleep and the daytime fatigue associated with it. Polysomnographic investigations have shown severe disturbances in the sleep architecture of depressed patients. Among the typical abnormalities observed are: discontinuous sleep, decreased slow-wave sleep, shorter latency to REM sleep and an increased intensity and duration of REM sleep (Riemann, D. et al. Neuropsychobiology 2002, 45(Suppl. 1), 7-12). It is believed that suppression of REM sleep is involved in antidepressant efficacy. This is illustrated by the dramatic success of overnight deprivation of (REM) sleep (Riemann et al. 2002). Another non-pharmacological treatment for depression, electroconvulsant therapy, likewise decreases REM sleep. Virtually all of the available antidepressant drugs, regardless of their neurochemical mechanism of action, suppress REM sleep, nefazodone (a 5-HT.sub.2A antagonist) being the exception (Sharpley, A. L., Cowen, P. J. Biol. Psych. 1995, 37(2), 85-98). Antidepressant drugs also affect slow-wave-sleep, although in a less clear manner. H.sub.3 antagonists share this REM-sleep suppressing property and one of the main biological effects of histamine H.sub.3 antagonists is to improve wakefulness. Administration of H.sub.3 antagonists has been shown to decrease REM and non-REM sleep in several animal species. For example, the H.sub.3 antagonist carboperamide induces waking in rats (Monti, J. M. et al. Neuropsychopharmacology 1996, 15(1), 31-35). Another H.sub.3 antagonist, thioperamide, decreased both REM and non-REM sleep in rats (Monti, J. M. et al. Eur. J. Pharmacol. 1991, 205(3), 283-287) and cats (Lin, J.-S. et al. Brain Res. 1990, 523(2), 325-330). It is of interest to note that although H.sub.3 antagonists promote wakefulness, they do so much less potently than amphetamine derivatives. They may thus be considered mild stimulants. The daytime correlate of disturbed sleep is fatigue. Indeed, fatigue and lethargy are prominent symptoms of depression, and there is considerable interest in the use of stimulants to augment antidepressant therapy (Menza et al., 2000). However, most of the available stimulants, like the amphetamine derivatives and methylphenidate, carry a considerable risk of abuse and are not ideal therapeutic choices. Modafinil, a wake-promoting compound of unknown mechanism with a lower addictive potential, is marketed for the treatment of narcolepsy. In a small series of patients it was shown that addition of a low dose of modafinil to traditional antidepressant therapy resulted in a faster onset of action. Fatigue was particularly responsive to this therapy, but the cognitive and physical subscales of the Hamilton Rating Scale for Depression also improved (Menza et al., 2000). The behavioral profile of H.sub.3 antagonists (suppression of sleep with no stimulation of locomotor activity and limited addictive potential) is much like that of modafinil. Therefore, a combined H.sub.3/SSRI compound would provide symptomatic relief for the fatigue during the first weeks of treatment, before the mood-elevating effect of the SSRI can be noticed.

Depression is also associated with a number of cognitive symptoms such as impaired memory and concentration difficulties. H.sub.3 antagonists have been shown to improve memory in a variety of memory tests, including the elevated plus maze in mice (Miyazaki, S. et al. Life Sci. 1995, 57(23), 2137-2144), a two-trial place recognition task (Orsetti, M. et al. Behav. Brain Res. 2001, 124(2), 235-242), the passive avoidance test in mice (Miyazaki, S. et al. Meth. Find. Exp. Clin. Pharmacol. 1995, 17(10), 653-658) and the radial maze in rats (Chen, Z. Acta Pharmacol. Sin. 2000, 21(10), 905-910). Also, in the spontaneously hypertensive rat, an animal model for the learning impairments in attention-deficit disorders, H.sub.3 antagonists were shown to improve memory (Fox, G. B. et al. Behav. Brain Res. 2002, 131(1-2), 151-161). Although no human studies are available, the evidence indicates that a combined SERT/H.sub.3 antagonist will provide additional benefit in combating the cognitive impairments associated with depression.

In summary, the combination of H.sub.3 receptor antagonism with SERT activity will result in the production of drugs with an improved antidepressant profile compared to an SSRI alone. These drugs will be especially efficacious in ameliorating the symptoms of fatigue, disturbed sleep and memory loss associated with depression.

The features and advantages of the invention are apparent to one of ordinary skill in the art. Based on this disclosure, including the summary, detailed description, background, examples, and claims, one of ordinary skill in the art will be able to make modifications and adaptations to various conditions and usages. Publications described herein are incorporated by reference in their entirety. In addition, U.S. Patent Appl. No. 60/637,173 is also incorporated by reference.

SUMMARY OF THE INVENTION

The invention features a compound of formula (I):

##STR00001## wherein one or two of X, Y, and Z is N, and the remaining of X, Y, and Z are CR.sup.5; L is --O-- or --CH.sub.2-- and n is 1 or 2; or L is --C.ident.C-- and n is 0 or 1; m is 0, 1, or 2; R.sup.1 is --H; or is --C.sub.1-6alkyl, --C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, --COOC.sub.1-6alkyl, or --COObenzyl, each optionally mono-, di-, or tri-substituted with R.sup.a; R.sup.a is selected from the group consisting of --OH, --OC.sub.1-6alkyl, phenyl optionally substituted with --OC.sub.1-4alkyl or halo, --CN, --NO.sub.2, --N(R.sup.b)R.sup.c (wherein R.sup.b and R.sup.c are independently --H or --C.sub.1-6alkyl), --C(O)N(R.sup.b)R.sup.c, --N(R.sup.b)C(O)R.sup.b, --N(R.sup.b)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.b)R.sup.c, --SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --COOH, and --COOC.sub.1-6alkyl; R.sup.2 and R.sup.3 are independently selected from --H, or from the group consisting of: A) --C.sub.1-6alkyl, --C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, benzyl; B) phenyl or pyridyl, optionally fused at two adjacent carbon ring members to a three- or four-membered hydrocarbon moiety to form a fused five- or six-membered aromatic ring, which moiety has one carbon atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), and which moiety has up to one additional carbon atom optionally replaced by --N.dbd.; C) a 4-8 membered heterocyclic ring, said heterocyclic ring having a carbon atom which is the point of attachment, having 1 or 2 heteroatom members selected from >O, >S(O).sub.0-2, and >NH, and having 0 or 1 double bonds; and D) a monocyclic aromatic hydrocarbon group having five or six ring atoms, having a carbon atom which is the point of attachment, having one carbon atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), having up to one additional carbon atom optionally replaced by --N.dbd., and optionally benzofused or pyridofused; where each of A)-D) is optionally mono-, di-, or tri-substituted with a moiety selected from the group consisting of --OH, --C.sub.1-4alkylOH, --OC.sub.1-6alkyl, --CN, --NO.sub.2, --N(R.sup.d)R.sup.e (wherein R.sup.d and R.sup.e are independently --H or --C.sub.1-6alkyl), --C(O)N(R.sup.d)R.sup.e, --N(R.sup.d)C(O)R.sup.d, --N(R.sup.d)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.d)R.sup.e, --SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --COOH, --COOC.sub.1-6alkyl, --OC(O)N(R.sup.d)R.sup.e, and --OC(O)OR.sup.d; or, alternatively, R.sup.2 and R.sup.3 may be taken together with the nitrogen to which they are attached to form a 4-8 membered heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from >O, >S(O).sub.0-2, >NH, and >NR.sup.f, having 0 or 1 double bonds, having 0, 1, or 2 carbon members separated from the nitrogen of attachment by at least one carbon member which is a carbonyl, optionally benzo or pyrido fused, optionally having one carbon member that forms a bridge, and having 0-5 carbon member substituents R.sup.ff, R.sup.f is selected from the group consisting of --C.sub.1-6alkyl optionally mono-, di-, or tri-substituted with halo, --C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, --C.sub.2-6alkylOH, --C(O)N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h are independently --H or --C.sub.1-6alkyl), --C(O)R.sup.i (where R.sup.i is --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5- or 6-membered aromatic heterocyclyl, each optionally mono-, di-, or tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl, --CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl, and --COOC.sub.1-6alkyl; R.sup.ff is selected from the group consisting of --C.sub.1-6alkyl optionally mono-, di-, or tri-substituted with halo, --C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, halo, --OH, --C.sub.1-6alkylOH, --OC.sub.1-6alkyl, --OC.sub.2-3alkylO--, --CN, --NO.sub.2, --N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h are independently --H or --C.sub.1-6alkyl), --C(O)N(R.sup.g)R.sup.h, --N(R.sup.g)C(O)R.sup.g, --N(R.sup.g)SO.sub.2C.sub.1-6alkyl, --C(O)R.sup.i (where R.sup.i is --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5- or 6-membered aromatic heterocyclyl, each optionally mono-, di-, or tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl, --CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.y)R.sup.z, --SCF.sub.3, --OCF.sub.3, --COOH, and --COOC.sub.1-6alkyl; R.sup.4 is --OH, --OC.sub.1-6alkyl, --CF.sub.3, --C.sub.1-6alkyl, or halo; two R.sup.4 substituents may be taken together to form methylene or ethylene; or one of R.sup.4 is taken together with R.sup.2 to form methylene, ethylene, or propylene; wherein each methylene, ethylene, or propylene is optionally substituted with --OH, --OC.sub.1-6alkyl, --SC.sub.1-6alkyl, --CF.sub.3, --C.sub.1-6alkyl, amino, or halo; R.sup.5 is selected from the group consisting of --H, --C.sub.1-6alkyl, --OH, --OC.sub.1-6alkyl, --SC.sub.1-6alkyl, and halo; Ar.sup.1 is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di-, or tri-substituted with R.sup.j or di-substituted on adjacent carbons with --OC.sub.1-4alkyleneO-- optionally mono- or di-substituted with fluoro, --(CH.sub.2).sub.2-3NH--, --(CH.sub.2).sub.1-2NH(CH.sub.2)--, --(CH.sub.2).sub.2-3N(C.sub.1-4alkyl)-, or --(CH.sub.2).sub.1-2N(C.sub.1-4alkyl)(CH.sub.2)--; R.sup.j is selected from the group consisting of 1) --OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl optionally mono-, di-, or tri-substituted with halo, --C.sub.2-6alkenyl, --OC.sub.3-6alkenyl, --C.sub.2-6alkynyl, --OC.sub.3-6alkynyl, --C.sub.3-6cycloalkyl, --OC.sub.3-6cycloalkyl, --CN, --NO.sub.2, --N(R.sup.k)R.sup.l (wherein R.sup.k and R.sup.l are independently --H or --C.sub.1-6alkyl), --N(R.sup.k)COR.sup.l, --N(R.sup.k)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl, --C(O)N(R.sup.m)R.sup.n (wherein R.sup.m and R.sup.n are independently --H or --C.sub.1-6alkyl, or R.sup.m and R.sup.n taken together with their nitrogen of attachment form a 4-8 membered heterocyclic ring having 1 or 2 heteroatom members selected from >O, >S(O).sub.0-2, >NH, and >NC.sub.1-6alkyl, having 0 or 1 double bonds, having 0 or 1 carbonyl members), --SO.sub.2N(R.sup.m)R.sup.n, --SCF.sub.3, halo, --CF.sub.3, --COOH, --COOC.sub.1-6alkyl, and --COOC.sub.3-7cycloalkyl; and 2) a 4-8 membered saturated or partially saturated heterocyclic ring, having 1 or 2 heteroatom members selected from >O, >S(O).sub.0-2, >NH, and >NC.sub.1-6alkyl, having 0 or 1 carbonyl members; said ring optionally mono-, di-, or tri-substituted with R.sup.p; R.sup.p is a substituent independently selected from the group consisting of --OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN, --NO.sub.2, --N(R.sup.q)R.sup.r (wherein R.sup.q and R.sup.r are independently --H, --C.sub.1-6alkyl, or --C.sub.2-6alkenyl), --C(O)N(R.sup.q)R.sup.r, --N(R.sup.q)C(O)R.sup.r, --N(R.sup.q)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.q)R.sup.r, --SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --COOH, and --COOC.sub.1-6alkyl; b) phenyl or pyridyl fused at two adjacent carbon ring members to a three membered hydrocarbon moiety to form a fused five membered aromatic ring, which moiety has one carbon atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), and which moiety has up to one additional carbon atom optionally replaced by --N.dbd., the fused rings optionally mono-, di-, or tri-substituted with R.sup.t; R.sup.t is a substituent independently selected from the group consisting of --OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN, --NO.sub.2, --N(R.sup.u)R.sup.v (wherein R.sup.u and R.sup.v are independently --H or --C.sub.1-6alkyl), --C(O)N(R.sup.u)R.sup.v, --N(R.sup.u)C(O)R.sup.v, --N(R.sup.u)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.u)R.sup.v, --SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --COOH, and --COOC.sub.1-6alkyl; c) phenyl fused at two adjacent ring members to a four membered hydrocarbon moiety to form a fused six membered aromatic ring, which moiety has 0, 1, or 2 carbon atoms replaced by --N.dbd., the fused rings optionally mono-, di-, or tri-substituted with R.sup.t; d) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom which is the point of attachment, having one carbon atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), having up to one additional carbon atom optionally replaced by --N.dbd., optionally mono- or di-substituted with R.sup.t, and optionally benzofused or pyridofused at two adjacent carbon atoms, where the benzofused or pyridofused moiety is optionally mono-, di-, or tri-substituted with R.sup.t; and e) a monocyclic aromatic hydrocarbon group having six ring atoms, having a carbon atom which is the point of attachment, having one or two carbon atoms replaced by --N.dbd., optionally mono- or di-substituted with R.sup.t, and optionally benzofused or pyridofused at two adjacent carbon atoms, where the benzofused or pyridofused moiety is optionally mono- or di-substituted with R.sup.t; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters, and amides thereof.

Isomeric forms of the compounds of formula (I), and of their pharmaceutically acceptable salts, esters, and amides, are encompassed within the present invention, and reference herein to one of such isomeric forms is meant to refer to at least one of such isomeric forms. One of ordinary skill in the art will recognize that compounds according to this invention may exist, for example in a single isomeric form whereas other compounds may exist in the form of a regioisomeric mixture.

The invention also features pharmaceutical compositions containing such compounds and methods of using such compounds and compositions in the treatment or prevention of disease states mediated by the histamine H.sub.3 receptor and the serotonin transporter.

Compounds of the present invention are useful in combination with other therapeutic agents as a combination therapy method, including use in combination with H.sub.1 receptor antagonists, H.sub.2 receptor antagonists, H.sub.3 receptor antagonists, and neurotransmitter modulators such as serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), noradrenergic reuptake inhibitors, non-selective serotonin re-uptake inhibitors (NSSRIs), and modafinil.

Additional features and advantages of the invention will become apparent from the detailed description and examples below, and the appended claims.

DETAILED DESCRIPTION

Particular preferred compounds of the invention comprise a compound of formula (I), or an enantiomer, diastereomer, hydrate, solvate thereof, or a pharmaceutically acceptable salt, amide or ester thereof, wherein n, m, L, X, Y, Z, R.sup.1-4, and Ar.sup.1 have any of the meanings defined hereinabove and equivalents thereof, or at least one of the following assignments and equivalents thereof. Such assignments may be used where appropriate with any of the definitions, claims or embodiments defined herein:

Preferably, X is N.

Preferably, Y is N.

Preferably, Z is N.

Preferably, Y and Z are N.

Preferably, L is --O-- and n is 1.

Preferably, L is --CH.sub.2-- and n is 1.

Preferably, L is --C.ident.C-- and n is 0.

Preferably, m is 0 or 1.

Preferably, R.sup.1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, benzyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, --COOCH.sub.3, --COO-t-butyl, and --COObenzyl.

More preferably, R.sup.1 is methyl, ethyl, propyl, allyl, propargyl, or benzyl.

Even more preferably, R.sup.1 is hydrogen or methyl.

Preferably, R.sup.2 and R.sup.3 are independently selected from --H, or, optionally substituted, from the group consisting of: A) methyl, ethyl, isopropyl, butyl, pentyl, hexyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, benzyl, B) phenyl, pyridyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl, imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl, C) azetidinyl, pyrrolidinyl, piperidinyl, and D) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, and 3-indazolyl.

More preferably, R.sup.2 and R.sup.3, optionally substituted, are independently selected from methyl, ethyl, isopropyl, pyrrolidinyl, piperidinyl, 2-benzothiazolyl, and methoxyethyl.

Even more preferably, R.sup.2 and R.sup.3 are, independently, ethyl, isopropyl, methoxyethyl, or 2-benzothiazolyl.

In a preferred embodiment, R.sup.2 and R.sup.3, optionally substituted, are taken together with the nitrogen to which they are attached to form a ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, 1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, and 1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl.

In an alternative embodiment, R.sup.2 and R.sup.3 are taken together with the nitrogen to which they are attached to form a 4-8 membered heterocyclic ring, said heterocyclic ring selected from piperidine, pyrrolidine, and morpholine, said ring substituted with 1 or 2 substituents R.sup.ff.

Preferably, R.sup.ff is selected from the group consisting of methyl, ethyl, isopropyl, butyl, hexyl, --CF.sub.3, --CHF.sub.2, vinyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclobutylethyl, bromo, chloro, fluoro, iodo, --OH, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, isop