ZA200502040B - Antidepressant indolealkyl derivatves of heterocyclefused benzodioxan methylamines - Google Patents

Description

ANTIDEPRESSANT INDOLEALKYL DERIVATIVES OF HETEROCYCLE-FUSED

BENZODIOXAN METHYLAMINES

Cross-Reference to Related Applications

[0001] This application is a continuation-in-part application of U.S. Application

Serial No. 60/410,347, filed September 12, 2002, the disclosure of which is incorporated herein by reference in its entirety.

Background of the Invention

[0002] Major depression is a serious health problem affecting more than 5% of the population, with a lifetime prevalence of 15-20%.

[0003] 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.

[0004] 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.

[0005] 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.

[0006] 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.a 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.

[0007] A 5HT,, 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.

[0008] Thus, it is highly desirable to provide improved compounds which both inhibit serotonin reuptake and which are antagonists of the 5HT 4 receptor.

Description of the Invention :

[0009] In accordance with this invention, there is provided a group of novel compounds of Formula I:

R! 3

TT

(CHy), == N ~

N 0 ~~ Y )—X R'

R2 wherein

Y is u.

Zz N 6 6 = —

R° R®

X is O, N=CH, CR’=CH or CR’=N, in which R’ is hydrogen or alkyl of 1 to 6 carbon atoms;

Z is O, Sor NR? in which R® is hydrogen or alkyl of 1 to 6 carbon atoms;

R', R® and R® are, independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 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, alkanesulfonyl of 1 to 6 carbon atoms or alkanesulfonamido of 1 to 6 carbon atoms;

R? is 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;

R3 and R* are, independently, hydrogen or alkyl of 1 to 6 carbon atoms; n is1,2o0r3; or a pharmaceutically acceptable salt thereof.

[0010] R'is preferably hydrogen, halo, cyano, trifluoromethyl, alky! of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms. More preferably, R' is hydrogen, halo or alkoxy of 1 to 6 carbon atoms. In stil more preferred embodimants of the present invention, R' is hydrogen.

[0011] R? is preferably hydrogen, amino or alkyl of 1 to 6 carbon atoms. More preferably, R? is hydrogen or alkyl! of 1 to 3 carbon atoms.

[0012] R3 R* R’ and R® are preferably independently selected from hydrogen or alkyl of 1 to 3 carbon atoms. More preterably, R? is hydrogen or alkyl of 1 to 3 carbon atoms and R* is hydrogen.

[0013] R® and R® are preferably independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms. In still more preferred embodiments of the present invention R® and R® are : preferably independently selected from hydrogen, cyano or halogen. .

[0014] X is preferably O or CR’=CH. When X is CR’=CH, R’ is preferably hydrogen or alkyl of 1to 3 carbon atoms.

[0015] Zs preferably NR® . When Z is NR®, R® is preferably hydrogen or alkyl of 1 to 3 carbon atoms.

[0016] nis preferably 2 or 3.

[0017] In other preferred embodiments of the invention is provided compounds of

Formula la:

R! 3 1 Bg

CH,)

N ( 2/n 4

R2 F R la wherein R’, R?, R® R’, R°, R®, n, and Y are as described above.

[0018] In still other preferred embodiments of the invention is provided compounds of Formula Ib:

R! Io) 3 » 1] (CHy), = N ~

N 0 ~N Y 0 R*

R2 ib wherein R', R?, R® R* R® R® n, and Y are as described above.

[0019] This invention relates to both the R and S stereoisomers of the aminomethyl-2,3-dihydro-1,4-dioxinof2,3-flquinolines, -quinazolines, quinoxalines and aminomethyl-7,8-dihydro{1,4]dioxino[2,3-g][1,3]benzoxazoles 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. Certain of the compounds of this invention (i.e., R* is alkyl) contain two stereogenic centers and thus may exist as diastereomers. This invention relates to both diastereomers, as well as to mixtures of diastereomers.

[0020] Where a stereoisomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. “Substantially free,” as used herein, means that the compound is made up of a significantly greater proportion of one sterecisomer. In preferred embodiments the compound is made up of at least about 90% by weight of a preferred sterecisomer. 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 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, IN 1972).

[0021] “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.

[0022] “Alkanamido,” as used herein, refers to the group R-C(=0)-NH- where R is an alkyl group of 1 to 5 carbon atoms.

[0023] “Alkanoyl,” as used herein, refers to the group R-C(=0)- where R is an alky! group of 1 to 5 carbon atoms.

[0024] “Alkanoyloxy,” as used herein, refers to the group R-C(=0)-O- where Ris an alkyl group of 1 to 5 carbon atoms.

[0025] “Alkanesulfonamido,” as used herein, refers to the group R-S(O),-NH- where R is an alkyl group of 1 to 6 carbon atoms.

[0026] “Alkanesulfonyl,” as used herein, refers to the group R-S(O),- where Ris an alkyl group of 1 to 6 carbon atoms.

[0027] “Alkoxy,” as used herein, refers to the group R-O- where R is an alkyl group of 1 to 6 carbon atoms.

[0028] “Carboxamido,” as used herein, refers to the group NH,-C(=0)- .

[0029] “Carboalkoxy,” as used herein, refers to the group R-O-C(=O)- where R is an alkyl group of 1 to 5 carbon atoms.

[0030] “Halogen” (or “halo”), as used herein, refers to chlorine, bromine, fluorine and iodine.

[0031] 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.

[0032] Specific examples of compounds of Formula | are:

N-[2-(5-Methoxy-1H-indol-3-yl)-ethyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3- flquinolin-2-ylmethyl)-amine;

N-[2-(5-Chloro-1H-indol-3-yl)ethyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3- flquinolin-2-ylmethyl)amine;

N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2, 3- flquinolin-2-ylimethyl)amine;

N-{2-(5-Fluoro-1H-indol-3-yl)ethyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino{2,3-flquinolin- 2-ylmethyl)amine;

N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-(8-ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin- 2-ylmethyl)amine;

N-[3-(1H-Indol-3-yl)propyl}-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2- ylmethyl)amine;

N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-methyl-N-(8-methyl-2,3-dihydro- [1,4])dioxino[2,3-flquinolin-2-yImethyl)amine;

N-[3-(7-Fluoro-1H-indol-3-yl)propyl}-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3- flquinolin-2-yimethyl)amine;

N-[4-(1H-Indol-3-yl)butyl}-N-(8-methyl-2,3-dihydro-{1,4]dioxino[2,3-f]quinolin-2- ylmethyl)amine;

N-[4-(5-Fluoro-1H-indol-3-yl)butyl}-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin- 2-yimethyl)amine;

N-[4-(5-Fluoro-1H-indol-3-yl)-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2- ylmethyl)butan-2-amine;

N-[3-(5-Fluoro-1-methyl-1H-indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro- [1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine;

N-[3-(5,7-Difluoro-1H-indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-{1,4]dioxino[2,3- flquinolin-2-yimethyl)amine;

N-(2,3-Dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)-N-{3-(5-fluoro-1H-indol-3- yl)propyllamine;

N-(2,3-Dihydro-[1,4]dioxino[2,3-flquinolin-2-yimethyl)-N-[3-(5-fluoro-1H-indol-3- yl)propyl]-N-methylamine;

N-[3-(5,7-Difluoro-1H-indol-3-yl)propyl]-N-methyl-N-(8-methyi-2,3-dihydro- [1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine;

N-[2-(1-Benzofuran-3-yl)ethyl]-N-(8-methyi-2,3-dihydro-[1,4]dioxino{2,3-f]quinolin-2- ylmethyl)amine;

N-[3-(1-Benzofuran-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2- yimethyl)amine;

N-[3-(7-Methoxy-1-benzofuran-3-yl)propyi}-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3- flquinolin-2-ylmethyl)amine;

N-[3-(1-Benzothien-3-yl)propyl]-N-(8-methyi-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2- yimethyl)amine;

N-[2-(1-Benzothien-3-yl)ethyl}-N-(8-methyl-2,3-dihydro-[1,4]dioxino{2,3-f]quinolin-2- ylmethyl)amine;

N-[3-(1-Benzothien-3-yl)propyl}-N-methyl-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3- flquinolin-2-ylmethyl)amine;

N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-(2-methyl-7,8-dihydro-[1,4]dioxino[2,3- g][1,3]benzoxazol-8-yimethyl)amine;

N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-methyl-N-(2-methyl-7,8-dihydro- [1,4]dioxino[2,3-g]{1,3]benzoxazol-8-yimethyl)amine;

N-Ethyl-N-[3-(5-Fluoro-1H-indol-3-yl)propyl}-N-(8-methyl-2,3-dihydro-[1,4]dioxino(2,3- flquinolin-2-ylmethyl)amine;

N-{3-(5,7-Difluoro-1-methyl-1H-indol-3-yl)propyl]-N-(8-methyi-2,3-dihydro- [1,4]dioxino[2,3-flquinolin-2-yimethyl)amine;

N-[3-(5,7-Difluoro-1-methyl-1H-indol-3-yl)propyl}-N-methyl-N-(8-methyl-2,3-dihydro- [1,4]dioxino[2,3-flquinolin-2-yimethyl)amine;

N-[4-(1-Benzofuran-3-yl)butyl]-N-(8-methyl-2,3-dihydro-[ 1,4]dioxino[2,3-flquinolin-2- ylmethyl)amine; 3-{3-[(8-Methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yimethyl)-amino}-propyi}-1H- indole-5-carbonitrile; 3-{3-[(2-Methyl-7,8-dihydro-[1,4]dioxino[2,3-g][ 1,3]benzoxazol-8-yimethyl)amino]- propyl}-1H-indole-5-carbonitrile; 3-{3-[Methyl-(2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl)- amino]-propyl}-1H-indole-5-carbonitrile; 3-{3-[Methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-aminoj}- propyl}-1H-indole-5-carbonitrile; [3-(6-Fluoro-indol-1-yl)-propyl}-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2- ylmethyl)-amine; [3-(6-Fluoro-indol-1-yl)-propyl}-methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3- flquinolin-2-ylmethyl)-amine;

[4-(5-Fluoro-1-methyl-1H-indol-3-yl)-butyl]-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3- flquinolin-2-yimethyl)-amine;

Ethyl-[3-(5-fluoro-1H-indol-3-yl)-propyl]-(2-methyl-7,8-dihydro-{1,4]dioxino[2,3- g][1,3]benzoxazol-8-ylmethyl)-amine; 1-Methyl-3-{3-[(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)-amino]- propyl}-1H-indole-5-carbonitrile; [4-(6-Fluoro-indol-1-yl)-butyl]-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2- - ylmethyl)-amine; 3-{4-[(8-Methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yImethyl)-amino]-butyl}- 1H- indole-5-carbonitrile; 1-Methyl-3-{3-[methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)- aminoj-propyl}-1H-indole-5-carbonitrile; 3-{4-[Methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]- butyl}-1H-indole-5-carbonitrile; [3-(5-Fluoro-1-methyl-1H-indol-3-yl)-propyl]-methyl-(8-methyl-2,3-dihydro- [1,4]dioxino[2,3-flquinolin-2-yimethyl)-amine; [4-(5-Fluoro-1H-indol-3-yl)-butyl]-methyl-(8-methyl-2,3-dihydro-{1,4]dioxino[2,3- flquinolin-2-ylmethyl)-amine; [4-(5-Fluoro-1-methyl-1H-indol-3-yl)-butyl]-methyl-(8-methyl-2,3-dihydro- [1,4]dioxino[2,3-f]quinolin-2-yimethyl)-amine; [3-(5-Fluoro-1H-indol-3-yl)-propyl}-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2- ylmethyl)-propyl-amine;

[3-(4-Fluoro-indol-1-yl)-propyli]-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2- yimethyl)-amine; [4-(6-Fluoro-indol-1-yl)-butyl]-methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin- 2-ylmethyl)-amine; [3-(4-Fluoro-indol-1-yl)-propyl]-methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3- flquinolin-2-yimethyl)-amine;

N-[4[(5-Chloro-1-benzothien-3-yl)butyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3- flquinolin-2-yljmethyl};

N-[3-(5-Chloro-1-benzothien-3-yl)propyl]-N-{{(2S)-8-methyl-2,3- dihydro[1,4]dioxino[2,3-flquinolin-2-ylJmethyl}amine;

N-[3-(5-Fluoro-1-benzothien-3-yl)propyl]-N-{{(2S)-8-methyl-2,3- dihydro[1,4]dioxino[2,3-f]quinolin-2-yljmethyl}amine; and

N-[4-(1-Benzofuran-3-yl)butyl]-N-ethyl-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3- flquinolin-2-ylJmethyljamine.

[0033] Compounds of the present invention are prepared in accordance with the following general description and specific examples. Variables used are as defined for Formula |, unless otherwise noted. The 2,3-dihydro-1,4-dioxino[2,3-flquinolin-2- ylmethylamines in which R? is H are prepared as illustrated in Scheme 1 below.

Specifically, the appropriately substituted nitroguaiacol (1) is alkylated with allyl bromide in the presence of a suitable base such as sodium hydride and then demethylated by a reagent such as sodium hydroxide. The resulting 4-nitro-2- allyloxypheno! (3) is then alkylated with glycidyl! tosylate or an epihalohydrin in the presence of a base such as sodium hydride and heated in a high boiling solvent such as mesitylene or xylene to effect both rearrangement of the allyl group and cyclization of the dioxan ring. The resulting primary alcohol (5) is converted to the tosylate 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 isomerized by treatment with catalytic bis-acetonitrile palladium (il) chloride in refluxing methylene chloride or benzene.

Allylic oxidation of 6 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- methyltosylate (7) or halide.

Replacement of the tosylate or halide with the appropriately substituted indolealkylamine in some high boiling solvent such as dimethyl sulfoxide gives the title compounds of the invention.

R! Py R! or Br Sr NaOH, DMSO/H,0 —— ——

ON" > ONa® DMF O,N oF 80deg 1 2

R' OH Tso R' OO mesitylene

AX NOON yiene,

P P 145 deg = =

ON oF O,N oF

NaH 3 4

R' R'

AS be 1) TsCl, pyr (S “ =

ON" Fo OH 2) (CHCN)PAC, ON oo” OTs ’ CH,CI, NS 6

R3 al (CH, 1) SeO, Sg . 2) Fe/AcOH N Za 0 OTs R 7 DMSO

R!

Dey (CH), = N

N 0) AY i he = R

Scheme 1

[0034] The 2,3-dihydro-1,4-dioxino[2,3-flquinolin-2-yimethylamines of the invention in which R? is alkyl may be prepared from the nitro olefin described above in the following manner (Scheme 2). The rearranged olefin (6) is treated sequentially with ozone and a tertiary amine or with osmium tetroxide and sodium periodate to give the o-nitrobenzaldehyde (8). Condensation with the appropriate : triphenylphosphorylidene ketone under Wittig conditions gives the o-nitrocinnamyl ketone (9), which upon reduction by iron in acetic acid, cyclizes to the corresponding 2,3-dihydro-1,4-dioxino[2,3-flquinoline-2-methyltosylate (10). Replacement of the tosylate with the appropriately substituted indolealkylamine as above gives the title compounds of the invention. Substitution of trimethyl phosphonoacetate for the triphenylphosphorylidene ketone in the Wittig procedure above, followed by reduction of the nitro group with tin (11) chloride and cyclization in acid gives the compounds of the invention in which R? is hydroxy. 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? is halo. Substitution of diethyl cyanomethylphosphonate for the triphenylphosphorylidene ketone in the Wittig procedure above, followed by reduction of the nitro group with tin (ll) chloride and cyclization in acid gives the compounds of the invention in which R? is amino.

Pi

AR! R 0) PhsPa

S L 1) Og, CH,Cl, I 1 or R? . OsN 0)

ON" “0 OTS 2) (-PrEiN 2

H™ ~O 6 8 1 R!

R D NL Fe/AcOH A 0 = oT = )

ON 0 S N 0” OTs

NN =

R2 9 10

R70

Scheme 2

[0035] Compounds of the invention in which R’ is attached to position 6 of the 2,3- dihydro-1,4-dioxino[2,3-flquinolin-2-yimethylamines may be alternatively prepared by a variation of the Skraup quinoline synthesis according to Scheme 3 below. The appropriately substituted benzodioxan methyltosylate (11) is nitrated under standard conditions with nitric acid in a solvent such as dichloroethane and the resulting nitro compound (12) reduced by treatment with hydrogen in the presence of a catalyst such as platinum on sulfide carbon. Treatment of the resulting aniline (13) 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-flquinoline (14).

Replacement of the tosylate with the appropriately substituted indolealkylamine as above gives the title compounds of the invention. “CL HNO; Roe Hp, PYC-S _— -— o OTs ON om 11 12

CHO

R' o) = R! o) _—

LAO on p-chiorani, phon = 13 14

Scheme 3

[0036] The 2,3-dihydro-1,4-dioxino[2,3-flquinazolin-2-ylmethylamines of the invention are prepared as illustrated below (Scheme 4). The o-nitrobenzaldehyde (8) described above is converted to the oxime (15) 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 (16) 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-flquinazoline-2- methyltosylate or halide may be isolated by column chromatography. Replacement of the tosylate or halide with the appropriately substituted indolealkylamine in some high boiling solvent such as dimethyl sulfoxide gives the tite compounds of the invention.

R' R!

AS be 1) NH,OH, NaOAc AS 5S . = Z OTs

O,N o OTs HoN 0

NG 2) H,, Pd/C y . H 8 HIN H 15

OH

R! Ro oon iS 0 HN (GHeh, ) R*C(OR)s _ ors YX, 2) H,, Ra-Ni N 0] R rs Ns _

R

16 DMSO

R' 3

NGC

_ N (CHa)n_

N 0 NY

A ~ R* re” N

Scheme 4

[0037] The 2,3-dihydro-1,4-dioxino[2,3-flquinazolin-2-ylmethylamines of the invention may be alternatively prepared from the rearranged olefin described above by the method outlined in Scheme 5 below. The nitro olefin (6) 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 (17) is then converted to the aldehyde (18) 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- flquinazoline-2-methyltosylate (16) or halide is effected by treatment of the amido aldehyde (18) with ammonia and replacement of the tosylate or halide with the appropriately substituted indolealkylamine in some high boiling solvent such as dimethyl sulfoxide as described above gives the title compounds of the invention.

R' R'

Nx le) 1) SnCl, o Ax 0) 84 1 ors 2 A 84 1 ors

O.N 0 2) R°COCI R27” °N 0 x EtsN H 6 17

R! R!

OsQy, NalO, 0 ( 3S NH; he BY

RN A 0 OTs N a OTs

H ~O AN 18 16

Scheme 5

[0038] The 2,3-dihydro-1,4-dioxino[2,3-f]quinoxalin-2-yimethylamines of the invention are prepared as illustrated in Scheme 6 below. The o-nitrobenzaldehyde (8) described above is oxidized to the o-nitrobenzoic acid (19) by a suitable oxidant such as chromium trioxide (Jones’ oxidation) or sodium chlorite and the acid converted to the o-nitroaniline (20) with diphenylphosphoryl azide (DPPA) in the presence of a tertiary base such as diisopropylethylamine. Reduction of the resulting nitroaniline to the diamine (21) 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- flquinoxaline-2-methyltosylate (22) or halide. Replacement of the tosylate or halide with the appropriately substituted indolealkylamine in some high boiling solvent such as dimethyl sulfoxide gives the title compounds of the invention.

R! R' oS BY CrO,, H,S0, AS 3 Ph,PON;

ZZ ' = OTs

O2N 0) OTs acetone ON 0) (i-Pr),EtN 2

HO O" “oH 19 0)

A 3S Hy, Pd/C, HCI AS BE o as - = —

O,N o OTs H,N 0 OTs.

NH; NH: 2 HCl 21 3 al ®) I CH

TL on™

OTs

NF So R 2A —_—

AN 22 DMSO

R

1

PD J (CHola_ oY " "

Scheme 6

[0039] The o-nitrobenzaldehyde (8) used in the chemistry described above may be alternatively prepared as shown in scheme 7 below. The appropriate mono-allylated catechol (23) is elaborated with glycidyl tosylate as described above and rearranged in refluxing mesitylene. Cyclization to the benzodioxan methanol (25) is effected by treatment with sodium bicarbonate in ethanol and the alcohol is converted to the tosylate (26) or halide as described above. After rearrangement of the double bond by treatment with catalytic bis-acetonitrile palladium (ll) chloride in refluxing methylene chloride and cleavage with ozone or osmium tetroxide/sodium periodate as described above, the resulting aldehyde (27) is regioselectively nitrated with a combination of nitric acid and tin (IV) chloride.

R OH TsO <{ R' O 1) mesitylene » —_— ( ANA reflux 0 NaH O 2) NaHCO, EtOH 23 24

R' R'

Nx © 1) TsClL pyr Nx © O03, CHCl 0 OH 2) (CH3CN),PdCl, 0 S EtsN

CH,Cl, a lI 2s 26 1 1

R RES BY HNO, SnCl, ~~ R RS oO = OTs = 1 T 0 O,N o OTs

H™ ~O Ce 27 8

Scheme 7

[0040] The 7,8-dihydro[1,4]dioxino[2,3-g][1.3]benzoxazol-8-ylmethylamines of the invention are prepared as illustrated in Scheme 8 below. The amido olefin (17) described in Scheme 5 is cleaved to the corresponding o-amidobenzaldehyde (18) by treatment with catalytic osmium tetroxide in the presence of sodium periodate.

The aldehyde is converted to the phenol (28) 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 (29) is effected by treatment at reflux with an appropriate dehydrating agent such as an ortho ester or an acid catalyst such as p-toluenesulfonic acid. Replacement of the tosylate or halide with the appropriately substituted indolealkylamine in some high boiling solvent such as dimethyl! sulfoxide gives the title compounds of the invention.

R! R'

Yooh BYeul

ZZ

NP NIN R27 o OTs

H H

17 H™ ~O 18

R\ R!

Oo oO

X

1) m-CPBA 1 Jor R2C(OR)3 NE 1 or 7 Ss — FN 0 —~ NF To 2) Al,O,, MeOH OH »-0 28 R? 29

Re l (cH :

HN 2h R 3

Y Y \; SN Oo R a | | (CHa

R oo N ~ - N 0 NOY

DMSO >

R2

Scheme 8

[0041] Alternatively (Scheme 9), the nitro olefin (6) may be reduced with tin (11) chloride as described in Scheme 5 above and protected with a suitable protecting group such as carbobenzoxy (Cbz) before the olefin is cleaved to the aldehyde (31) by treatment with osmium tetroxide/sodium periodate and the aldehyde converted to a phenol (32) by the Baeyer-Villager procedure. Deprotection by treatment with hydrogen over palladium on carbon gives the o-aminophenol, (33) which is cyclized to the 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (29) 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? is amino. Treatment of the o-aminophenol with carbonyl diimidazole gives the oxazolone which leads to compounds of the invention in which R? is halo via treatment with an inorganic anhydride such as phosphoryl chloride or bromide. Replacement of the tosylate with the appropriately substituted indolealkylamine as above gives the title compounds of the invention.

R' 1) SnCl R} ( 3 ) 2 (ES BS

Et

NN 3 NN 6 30

R! R! 0s0,, NalO, 5 0 1) m-CPBA Ne © — + Cbz 1 — « Cbz 1 \ 7 OTs “N = o OTs N o

H Ao 2) Al;03, MeOH OH : 31 32

R' R!

Hy, PAIC Nx © , NS

R°C(OR’)3

HN 0) —_— N (9)

OH »o

R2 33 29

Scheme 9

[0042] Compounds of the invention in which R' is hydrogen and R? is alkyl are most conveniently prepared according to scheme 10 below. The appropriate 2',3',4'- trihydroxyacylphenone (34) 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 (35). Following conversion of the ketone to the oxime (36) by reaction with hydroxylamine hydrochloride and sodium acetate, cyclization to the oxazole (37) is effected by treatment with phosphory! chloride in the appropriate dimethylalkanoic acid amide. The resulting 7.8-dihydro-1,6,9-trioxa-3-aza-cyclopentalajnaphthalene-8-methanol is converted to the tosylate (38) by treatment with p-toluenesulfonyl chloride in pyridine and combined with the appropriate indolealkylamines as described to give the title compounds of the invention.

TsO 0

OH NN o) NH,OH, NaOAC

RA v CX J

Yi OH Na,COj ©

O OH O OH

34 35

Oo POCI, oO

R? Jon )§

CL R°CCONMe; ~~ N/ o” OH _NH OH >*o

HO R2 36 37 (0)

TsCl, pyridine ) _— N o OTs )-o

R2 38

Scheme 10

[0043] The compounds of the invention may be resolved into their enantiomers by conventional methods or, preferably, the individual enantiomers may be prepared directly by substitution of (2R)-(-)-glycidyl 3-nitrobenzene-sulfonate or tosylate (for the S benzodioxan methanamine) or (2S)-(+)-glycidyl 3-nitrobenzene-sulfonate or tosylate (for the R enantiomer) in place of epihalohydrin or racemic glycidyl tosylate in the procedures above.

In yet another method, compounds of the present invention may be prepared in accordance with Scheme 11. The synthesis of compound | is comprised of steps that begin with halogenation of 39 where R’ is alkyl of 1-6 carbon atoms, with reagents such as N-halosuccinimide in acetonitrile to give 40 (where Hal is halogen such as Br, Cl or 1). Deprotecting 40 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 HCI gives the salt 41. Free base 41 may be obtained by neutralization with an

Amberlyst A-21 resin slurry in polar solvents such as ethanol or methanol.

[0044] Alkylation of 41, either as the free base or as the sait, with benzyl or

[0] substituted benzyl protected glycidyl ethers (NOR 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 DMSO, DMF, or DMA in the presence of bases such as sodium carbonate, potassium carbonate, or triethylamine gives 42. 42 was 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, (x) Tol-BINAP and separate enantiomers thereof; 1-1’- bis(diphenyiphosphino) ferrocene, 1,3-bis(diphenyiphosphino)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 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 43.

R’ R’

NS OR’ N-halosuccinimide oS OR Lewis acid/CH,Cl,

N = CH5CN N = Hal or strong protic acid x *x

R2 39 R2 40 ; . OH

PR OH NOR" BRN oN OR’ Pd cat/ligand 1X IX or Cu cat = E—— ZZ —nt

Hal

N, Hal Base, polar solvent \ Base, toluene x )x

R2 41 R? 42

R! Co R'

NN B Lewis acid/CH,Cl,, XS *)

I = +, OR” or strong protic acid Z “,, OH

N © or hydrogenolysis N o xX >—X

R2 43 R2 44

R3 (CH

R' HN ain

Sry ET

Arylsulfonyl chloride N p> o yy JOR” \

Base, CHCl, >—X Base, polar solvent

R2 ~ 45

R! le} 3

IX

(CH), — N ~

N 9) Y y—X hd

R2

Scheme 11

[0045] Deprotection of quinoline 43 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 HCI or under reductive cleavage conditions using Pd catalyst and hydrogen transfer reagents such as hydrogen, cyclohexene, methyl cyclohexene, or ammonium formate gives the heterocycle-fused benzodioxanmethanol 44. The hydroxyl moiety of 44 can be activated with an aryl- or alkylsulfonyl chloride such as p-toluenesulfonyl chloride, methanesulfony! chloride, 2-, 3- or 4-nitrobenzenesulfonyl chloride, or 2- or 4-bromobenzenesulfony! chloride in the presence of bases such as triethylamine or pyridine in suitable solvents such as methylene chloride, THF, or toluene to afford 45 where R™ is a sulfonate such as p-toluenesulfonate, methanesulfonate, 2-, 3-, or 4-nitrobenzenesulfonate, or 2- or 4- bromobenzenesulfonate. The final coupling of 45 with indolealkylamines appropriate to the invention, in the presence of bases such as Hiinig's base (diisopropyl ethylamine), potassium carbonate, or sodium carbonate in polar solvents such as

THF, dioxane, DMSO, DMF, or DMA affords the compounds of Formula |.

[0046] The compounds of the invention may alternatively be prepared from the heterocycle-fused benzodioxan methyltosylate (45) by the method outlined below in

Scheme 11. The tosylate is heated with sodium azide in an appropriate solvent such as DMF to give the azide 46, which is then reduced to the primary amine (47) by a suitable reducing agent such as hydrogen over palladium on carbon, sodium borohydride in isopropanol or triphenylphosphine. The primary amine 47 may either be reductively alkylated by treatment with a suitably substituted aldehyde or ketone in the presence of a reducing agent such as sodium cyanoborohydride or alkylated with a suitably substituted indolealkyl halide, alkylsulfonate or arylsulfonate in the presence of a base such as triethylamine or

Hunig’s base to give the compounds of the invention in which R? is hydrogen. The secondary amines thus derived may be further alkylated if desired by treatment with the appropriate alkyl halide in the presence of a tertiary base or alkanal in the presence of a reducing agent such as sodium cyanoborohydride to give the compunds of the invention in which R% is alkyl.

R? R! oS 3 NaN,, DMF A ”) Hg, Pd/C

N 0 vn, OTs -_— N ZZ (0) “uy, Ng — x x

R? 45 R2 46 (CH2)q

R* N (CHa)n_

R' N, ~ © NY Y

Ax O _— >—X rR? ) NaCNBH; R2

N 7 0] “ur NH \ »—X

Et;N

R? 47 ~~

R! 0 (CH) i J

Br n Nn (CHa), *x

R2

Scheme 12

[0047] The guaiacols, catechols, 2’,3',4'-trihydroxyacylphenones and benzodioxan methyltosylates appropriate to the above chemistry are known compounds or can be prepared by one schooled in the art. The indole alkyl ketones, halides, alkylsulfonates and arylsulfonates are known compounds or they can readily be prepared by one schooled in the art using the procedures outlined by Smith, Yocca,

Yevich and Matson in EP 464 558 A1 or by Bathe and Tilly in WO 0035872 A1. The indolealkylamines are known compounds or can readily be prepared by one schooled in the art from the halides or sulfonates by treatment with sodium azide or sodium cyanide, followed by reduction with hydrogen over the appropriate catalyst, either palladium on carbon or rhodium on alumina. The benzofuranylalkylamines and benzothiophenylalkylamines are known compounds or can readily be prepared by one schooled in the art from the known alcohols by first converting them to the bromides by treatment with triphenylphosphine and carbon tetrabromide, then displacing the bromide with either sodium azide or sodium cyanide and finally by reduction with hydrogen as described above for the indolealkylamines.

[0048] 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 *H-paroxetine from male rat frontal cortical: membranes was determined using a Tom Tech filtration device to separate bound from free *H-paroxetine and a Wallac 1205 Beta Plate® counter to quantitate bound radioactivity. Kis 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 *H-paroxetine binding in rat frontal cortex and *H-serotonin uptake inhibition.

[0049] High affinity for the serotonin 5-HT,. receptor was established by testing the claimed compound's ability to displace [3H] 8-OHDPAT (dipropylaminotetralin) from the 5-HT, 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 5-HT,a receptors. The 5-HT,, affinities for the compounds of the invention are reported below as Kj's.

[0050] Antagonist activity at 5-HT,, receptors was established by using a %S-

GTPyS 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 *S-

GTPyS to membranes containing cloned human 5-HT,. receptors was determined.

Agonists produce an increase in binding whereas antagonists produce no increase but rather reverse the effects of the standard agonist 8-OHDPAT. The test compound’s maximum inhibitory effect is represented as the Ina, while its potency is defined by the ICsg. . [0051] The results of the three standard experimental test procedures described in the preceding three paragraphs were as follows:

5-HT Transporter Affinity 5-HT1A Receptor Affinity 5-HT1A Function

Compound Kl (nM) Kl (nM) 1C50 (nM) (Imax)

Example 1 31.00 2.03 88.6 (80.3)

Example 2 34.00 19.89 49.4 (37.0)

Example 3 0.41 0.27 10.6 (98.7)

Example 4 47.00 4.19 909.1 (58.0)

Example 5 0.96 0.64 92.5 (76.8)

Example 6 3.57 0.39 31.3 (86.6)

Example 7 0.38 3.43 | 73.9 (100)

Example 8 2.07 0.22 25.8 (94.1)

Example 9 4.70 0.46 23.7 (95.2)

Example 10 1.29 1.78 71.1 (61.5)

Example 11 Isomer A 1.62 1.68 27.8 (78.3) isomer B0.43 4.65

Example 12 13.00 1.55 137.6 (81.6)

Example 13 1.05 0.32 64.6 (95.0)

Example 14 1.00 1.03 507.3 (100)

Example 15 1.60 5.16 411.8 (100)

Example 16 1.80 2.51 125.1 (100)

Example 17 46.00 0.63 52.0 (78.0)

Example 18 6.60 0.35 10.4 (59.3)

Example 19 14.60 0.20 50.1 (95.4)

Example 20° 2.82 0.38 188.3 (100)

Example 21 62.00 0.60 25.9 (37.5)

Example 22 4.30 7.12 878.0 (85.5)

Example 23 1.85 0.70 19.3 (85.8)

Example 24 1.40 4.45 156.9 (100)

Example 25 0.60 5.47 43.5 (94.0)

Example 26 5.90 3.26 180.4 (90.2)

Example 27 6.70 52.85 340.6 (100) . Example 28 5.50 0.28

Example 29 0.90 1.64 55.8 (94.0) . Example 30 1.80 5.35 68.0 (73.1)

Example 31 2.40 35.30 205.4 (97.7)

5-HT Transporter Affinity 5-HT1A Receptor Affinity 5-HT1A Function

Compound KL(nM) KI (nM) C50 (0M) (Imax)

Example 32 1.00 5.46 232.7 (100) ) Example 33 2.20 21.21 200.1 (73.5)

Example 34 8.10 0.29 193.1 (100) ) Example 35 2.40 0.56 66.6 (78.9)

Example 36 1.90 16.29 486.2 (91.9)

Example 37 2.60 1.12 21.4 (100)

Example 38 1.31 0.06 25.8 (85.5)

Example 39 0.50 0.85 263.2 (78.5)

Example 40 7.00 17.67 1980.0 (100)

Example 41 0.24 20.99

Example 42 2.75 35.96

Example 43 0.50 13.09 343.7 (100)

Example 44 3.40 9.99 372.3 (100)

Example 45 1.00 108.11 1086.0 (100)

Example 46 6.70 0.05 31.4 (85.6)

Exmaple 47 1.00 4.42 191.1 (75.2)

Example 48 4.20 24.66 500.0 (100)

Example 49 23.0 0.73 99 (33)

Example 50 9.7 0.45 69 (50)

Example 51 2.35 0.78 19 (82)

Example 52 nd 2.08 ECs0=526 (Emax=97)

[0052] 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, bulimia nervosa, vasomotor flushing, cocaine and alcoho! ) 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,, 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; x 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.

[0053] 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.

[0054] 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 |, 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.

[0055] 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, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] The present invention includes prodrugs of compounds of Formula |, la and

Ib. 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).

[0062] The following examples illustrate the production of representative compounds of this invention.

INTERMEDIATE 1 3-Allyloxy-4-methoxynitrobenzene

[0063] 97.5 g (0.51 mole) of the sodium salt of 5-nitroguaiacol was dissolved in one liter of DMF and 1.5 equivalents of allyl bromide added. The reaction was heated to 65°C for two hours, after which time much of the dark color had discharged and tlc (1:1 CH2Clo/hexane) indicated loss of starting material. The solvent was concentrated in vacuum and the residue washed with water. The product was isolated by filtration and dried in a vacuum. This gave 112 g of pale yellow solid. A sample recrystallized from methanol, gave m.p. 93-94 °C.

INTERMEDIATE 2 2-Allyloxy-4-nitrophenol

[0064] To one liter of dimethyl sulfoxide was added 750 mL of 2 N aqueous sodium hydroxide and the mixture was heated to 65°C. The pale yellow solid 3-allyloxy-4- methoxynitrobenzene prepared above was added in portions over a 30 minute period and then the temperature was raised to 95°C and maintained for 3 hours, after which time the starting material had been consumed. The mixture was allowed to cool and poured into a mixture of 1 L ice and 1 L 2 N HCI. 73 Grams of crude but homogeneous (by tic 1:1 CH2Clo/hexane) desired product was isolated as a light } brown solid by filtration. This material was subsequently dissolved in 1:1 hexane/methylene chloride and filtered through silica gel to give 68 g of pale yellow . solid, which, when recrystallized from ethyl/acetate/hexane, gave m.p. 61-62°C. The aqueous mother liquors from the initial crystallization above were extracted with 2 L of ethyl acetate. This was dried over sodium sulfate, filtered and evaporated to a dark oil. Column chromatography on silica with 1:1 CH2Clo/hexane gave an . additional 12 g of the title compound as a yellow solid. Elution with 2% MeOH in

CHCI3 gave 12 g of a dark oil which slowly crystallized in vacuum. This proved to be the Claisen product, 3-allyl-4-nitrocatechal. - INTERMEDIATE 3 2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane

[0065] 20g (0.50 mole) of 60% NaH/mineral oil was placed in a two liter flask and washed with 500 mL of hexane. 1 L of DMF was added, followed by 77 g (0.40 mole) of the 2-allyloxy-4-nitrophenol prepared in the previous step. Addition of the phenol was performed in portions under argon. After stirring the mixture for 30 minutes at room temperature under argon, 108 g (0.48 moles) of (R)-glycidyl tosylate was added and the mixture heated at 70-75°C under nitrogen overnight. Upon cooling, the DMF was removed in vacuum and replaced with one liter of methylene chloride. This was washed with 500 mL portions of 2 N HCI, saturated sodium bicarbonate and saturated brine and dried over sodium sulfate. The mixture was filtered, concentrated to an oil in vacuum and column chromatographed on silica gel using 1:1 hexane/methylene chloride as eluant. This gave 43 g of product contaminated with traces of the two starting materials, followed by 21 g of pure product as a pale yellow solid. The impure material was recrystallized from 1.2 L of 10% ethyl acetate/hexane to give 34 g of pure (homogeneous on silica gel tic with 1:1 hexane/methylene chloride) (R)-2-(2-allyloxy-4-nitrophenoxymethyl)-oxirane (m.p. 64°C).

Elemental Analysis for: C12H13NOs5

Calcd: C, 57.37; H,5.21; N, 5.58

Found: C, 57.50; H, 5.21; N, 5.43

INTERMEDIATE 4 (8-Allyl-7-nitro-2,3-dihydro-benzo(1.4)dioxin-2-yl)-methanol

[0066] (R)-2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80 mmol) prepared : as above was heated at 155°C in mesitylene for 24 hours under nitrogen. Filtration of the black solid that formed gave 1.5 g of very polar material. Evaporation of the solvent in vacuum followed by column chromatography on silica gel with methylene chloride as eluant gave 10 g of recovered starting material and 7.5 g of the desired rearranged (S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol, which slowly crystallized on standing in vacuum (m.p. 67°C). The yield based on recovered starting material is 75%.

Elemental Analysis for: C12H{13NOs

Calcd: C, 57.37; H, 5.21; N, 5.58

Found: C, 57.26; H, 5.20; N, 5.35

INTERMEDIATE 5

Toluene-4-sulfonic acid 8-allyl-7-nitro-2,.3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester

[0067] 9.55 g (38.0 mmol) of (S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)- methanol was dissolved in 465 mL of pyridine, 29.0 g (152 mmol) of p- toluenesulfonyl chloride was added and the mixture stirred at room temperature under nitrogen overnight. Water was then added to quench the excess tosyl chloride and the solvent was removed in vacuum and replaced with methylene chloride. This solution was washed with 2 N HCI, with saturated sodium bicarbonate, and with saturated brine, and dried over magnesium sulfate. Filtration, evaporation in vacuum and column chromatography on silica gel with 1:1 hexane/methylene chloride as eluant gave 126 g (92%) of toluene-4-sulfonic acid (R)-allyl-7-nitro-2,3- benzo(1,4)dioxin-2-yimethyl ester, which slowly crystallized to a tan solid (m.p. 60-62 °C) upon standing.

Elemental Analysis for: C1gH19NO7S } Calcd: C, 56.29; H, 4.72; N, 3.45

Found: C, 56.13; H, 4.58; N, 3.44

INTERMEDIATE 6 {7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4- methylbenzenesulfonate

[0068] To a solution of 10.0 g (24.0 mmol) of (R)-[8-allyl-7-nitro-2,3-dihydro-1,4- benzodioxin-2-yljmethyl 4-methylbenzenesulfonate in 700 mL of benzene was added 1.03 g of bis(acetonitrile)dichloropalladium (Il) and the mixture was refluxed under nitrogen for 48 hours. The catalyst was then removed by filtration and the filtrate concentrated in vacuum to a brown oil. Column chromatography on silica gel with methylene chloride as eluent gave 7.2 g of the title compound as a mixture of E and

Z isomers. A sample of {(2R)-7-nitro-8[(E)-1-propenyl}-2,3-dihydro-1,4-benzodioxin- 2-ylimethyl 4-methylbenzenesulfonate was obtained as a yellow solid (m.p. 105-106 °C) by evaporation of a pure E isomer-containing fraction.

Elemental Analysis for: C1gH1gNO7S

Calcd: C, 56.29; H, 4.72; N, 3.45

Found: C, 56.12; H, 4.64; N, 3.39

INTERMEDIATE 7 {7-Nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1.4-benzodioxin-2-ylimethyl 4- methylbenzenesulfonate

[0069] {(2R)-7-nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4- methy Ibenzenesulfonate (6.15 g, 15.2 mmol) was dissolved in 180 mL of dioxane.

Selenium dioxide (4.20 g, 37.9 mmol) was then added, followed by 0.70 mL of water.

The heterogeneous mixture was heated at reflux under nitrogen for 5 hours. Upon cooling, the reaction was filtered and concentrated in vacuum to yield a dark yellow solid. This was dissolved in minimal ethyl acetate and column chromatographed on silica gel using 30% ethyl! acetate in hexane as eluant to give 5.75 g of the (R)- enantiomer of the title compound as a light yellow solid (m.p. 138-140 °C).

Elemental Analysis for: C1gH17NOgS } Calcd: C, 54.41; H, 4.09; N, 3.34 "Found: C, 54.10; H, 3.85; N, 3.31

INTERMEDIATE 8 . 2,3-Dihydro[1,4]dioxino[2,3-flquinolin-2-ylmethyl 4-methylbenzenesulfonate : [0070] To a solution of {(2R)-7-nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1,4- benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (3.50 g, 8.35 mmol) in 200 mL of acetic acid/ethanol (1:1) was added 2.35 g (42.1 mmol) of iron powder and the mixture was heated at reflux under nitrogen for 8 hours. After the reaction was complete, 150 mL of water was added and the mixture filtered through a pad of celite. The filtrate was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel using a gradient elution commencing with 20% ethyl acetate/hexane and ending with 70% ethyl acetate/hexane to give 1.85 g of the (R)-enantiomer of the title compound as a yellow oil. . "H-NMR (CDCl,): doublet 8.8 & (1 H); doublet 8.2 § (1 H); doublet 7.8 8 (2 H); doublet 7.6 6 (1 H); multiplet 7.35 & (1 H); multiplet 7.25 & (3 H); multiplet 4.6 8 (1 H); multiplet 4.3-4.4 5 (3 H); multiplet 4.2 6 (1 H); singlet 2.4 5 (3 H).

INTERMEDIATE 9 (8-Formyl-7- nitro-2,3-dihydro-1.4-benzodioxin -2-yl)methyl 4- methylbenzenesulfonate - [0071] {(2R)-7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yljmethyl 4- methy |benzenesulfonate (10.5 g, 25.9 mmol) dissolved in 400 mL of methylene chloride was treated with excess ozone at -78°C. Diisopropylethylamine (11.5 mL, 66.0 mmol) was then added dropwise over 30 minutes and the mixture allowed to come to room temperature and stir overnight under a nitrogen atmosphere. The mixture was then diluted to 600 mL with methylene chloride, washed three times with 100 mL portions of 2N HCI (aq), twice with 200 mL portions of saturated aqueous sodium bicarbonate and with 200 mL of saturated brine. The solution was dried over magnesium sulfate, filtered and concentrated in vacuum to a crude brown oil, which was column chromatographed on silica gel with 10% hexane/methylene chloride to give 7.52 g of the (R)-enantiomer of the title compound as a yellow solid. "H-NMR

(CDCly): doublet 7.8 5 (2 H); doublet 7.62 § (1 H); doublet 7.4 § (2 H); doublet 7.0 & (1 H); multiplet 4.4-4.6 5 (2 H); multiplet 4.2 § (3 H); singlet 2.4 § (3 H).

INTERMEDIATE 10 ’ {7-Nitro-8-[(E)-3-0x0-1-butenyl]-2 3-dihydro-1.4-benzodioxin-2-yl}methyl 4- methylbenzenesulfonate

[0072] To a solution of 3.00 g (7.37 mmol) of [(2R)-8-formyl-7- nitro-2,3-dihydro- 1,4-benzodioxin -2-yllmethyl 4-methylbenzenesulfonate in 250 mL of toluene was added 2.90 g (9.10 mmol) of 1-triphenylphosphorylidene-2-propanone. The mixture was stirred at room temperature under nitrogen for 5 hours, during which time some product precipitated from solution. The solvent was removed in vacuum and the crude residue was column chromatographed on silica gel with methylene chloride as eluant to give 3.0 g of the (R)-enantiomer of the title compound as a yellow solid. 'H-

NMR (CDCl,): doublet 7.8 8 (2 H); doublet 7.6 & (1 H); doublet 7.5 § (2 H); doublet 7.4 5 (2 H); doublet 6.95 8 (1 H); doublet 6.6 § (1 H); multiplet 4.5 5 (1 H); doublet of doublets 4.0 § (1 H); multiplet 4.2 & (3 H); singlet 2.45 § (3 H); singlet 2.4 § (3 H).

INTERMEDIATE 11 (8-Methyl-2 3-dihydrof[1 4]dioxino[2.3-flquinolin-2-yl)methyl 4- methylbenzenesulfonate

[0073] To a solution of {(2R)-7-nitro-8-[(E)-3-oxo-1-butenyl}-2,3-dihydro-1,4- benzodioxin-2-ylimethyl 4-methylbenzenesulfonate (3.40 g, 7.83 mmol) in 200 mL of acetic acid/ethanol (3:2) was added 2.25 g (40.2 mmol) of iron powder and the mixture was heated at reflux under nitrogen for 8 hours. After the reaction was complete, 150 mL of water was added and the mixture filtered through a pad of celite. The filtrate was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel using a gradient elution commencing with 20% ethyl acetate/hexane and ending with 70% ethyl acetate/hexane to give 2.5 g of the (R)-enantiomer of the title compound as a yellow oil. "H-NMR (CDCl,): doublet 8.1 5 (1 H); doublet 7.6 5 (2 H); doublet 7.45

Claims (84)

CLAIMS What is claimed is:

1. A compound of Formula I: R! 3 Po BY CH,) N ( 2/n N” OF SO Y 7 )—X RY R2 wherein Y is

2. Zz N 6 6 —_— — R® R° X is O, N=CH, CR’=CH or CR’=N, in which R’ is hydrogen or alkyl of 1 to 6 carbon atoms; Z is O, S or NR®, in which R® is hydrogen or alky! of 1 to 6 carbon atoms; R', R® and R® are, independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoy! of 2 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, alkanesulfony! of 1 to 6 carbon atoms or alkanesulfonamido of 1 to 6 carbon atoms; R? is 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® and R* are, independently, hydrogen or alkyl of 1 to 6 carbon atoms; n ist,2o0r3; or a pharmaceutically acceptable salt thereof.

2. A compound of Formula | as claimed in claim 1, wherein X is CR’=CH where R’ is hydrogen or alkyl of 1 to 3 carbon atoms.

3. A compound as claimed in claim 1 of Formula la: R! 0) 3 » 1 CH,) N ( 2/n N = 0 ~~ Sy R2 F R* la or a pharmaceutically acceptable salt thereof.

4. A compound as claimed in claim 1 of Formula Ib: R! 0) 3 ND 1

CH.) N ( 2/n NY TO NY 0 R* R2 Ib or a pharmaceutically acceptable salt thereof.

5. A compound as claimed in any one of claims 1 to 4, wherein R' is hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.

6. A compound as claimed in any one of claims 1 to 4, wherein R' is hydrogen, halo or alkoxy of 1 to 6 carbon atoms.

7. A compound as claimed in any one of claims 1 to 4, wherein R' is hydrogen.

. 8. A compound as claimed in any one of claims 1 to 7, wherein R? is hydrogen, amino or alkyl of 1 to 6 carbon atoms.

9. A compound as claimed in any one of claims 1 to 7, wherein R? is hydrogen or alkyl of 1 to 3 carbon atoms.

10. A compound as claimed in any one of claims 1 to 9, wherein R® and R* are independently selected from hydrogen or alkyl of 1 to 3 carbon atoms.

11. A compound as claimed in any one of claims 1 to 10, wherein R* is hydrogen.

12. A compound as claimed in any one of claims 1 to 11, wherein R” and R® are independently selected from hydrogen or alkyl of 1 to 3 carbon atoms.

13. A compound as claimed in any one of claims 1 to 12, wherein R® and Re are independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms.

14. A compound as claimed in any one of claims 1 to 12, wherein R® and R® are independently selected from hydrogen, cyano or halogen.

15. A compound as claimed in any one of claims 1 to 14, wherein Z is NR®

16. A compound as claimed in claim 15, wherein R® is hydrogen or alkyl of 1 to 3 carbon atoms.

17. A compound as claimed in any one of claims 1 to 16, wherein nis 2 or 3.

18. A compound of claim 1, wherein R' hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.

19. A compound of claim 1, wherein R'is hydrogen, halo or alkoxy of 1 to 6 carbon atoms, R%, R®, R” and R® are hydrogen or alkyl of 1 to 3 carbon atoms, R* is hydrogen, R® and R® are independently hydrogen, cyano or halogen, Z is NR® and n is 2 or 3.

20. The compound of claim 1 which is N-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-N-(8- methy!-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)-amine or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 which is N-[2-(5-chloro-1H-indol-3-yl)ethyl]-N-(8- methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

22, The compound of claim 1 which is N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-(8- methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-yimethyl)amine or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 which is N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-N-(8- methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-yimethyl)amine or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 which is N-[3-(5-fluoro-1H-indol-3-yl)propyl}-N-(8- ethyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 which is N-[3-(1H-indol-3-yl)propyl]-N-(8-methyl- 2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 which is N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N- methyl-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a : pharmaceutically acceptable salt thereof.

27. The compound of claim 1 which is N-[3-(7-fluoro-1H-indol-3-yl)propyl}-N-(8- methyi-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1 which is N-[4-(1H-indol-3-yl)butyl]-N-(8-methyl-2,3- dihydro-[1,4]dioxino[2,3-flquinolin-2-yimethyl)amine or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 which is N-[4-(5-fluoro-1H-indol-3-yl)butyl]-N-(8- methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1 which is N-[4-(5-fluoro-1H-indol-3-yl)-N-(8-methy!- 2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)butan-2-amine or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1 which is N-[3-(5-fluoro-1-methyl-1H-indol-3- yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1 which is N-[3-(5,7-difluoro-1H-indol-3-yl)propyl]-N- (8-methyl-2,3-dihydro-{1,4]dioxino[2,3-f]quinolin-2-yimethyl)amine or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1 which is N-(2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2- yimethyl)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]amine or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1 which is N-(2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2- ylmethyl)-N-{3-(5-fluoro-1H-indol-3-yl)propyl]-N-methylamine ora pharmaceutically acceptable salt thereof.

: 35. The compound of claim 1 which is N-[3-(5,7-difluoro-1H-indol-3-yl)propyl]-N- methyl-N-(8-methyl-2 3-dihydro-[1,4]dioxino[2,3-flquinolin-2-yimethyl)amine or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1 which is N-[2-(1-benzofuran-3-yl)ethyl]-N-(8-methyl- 2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1 which is N-[3-(1-benzofuran-3-yl)propyl}-N-(8- methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1 which is N-[3-(7-methoxy-1-benzofuran-3-yl)propyl]- N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

39. The compound of claim t which is N-[3-(1-benzothien-3-yl)propyl]-N-(8- methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1 which is N-[2-(1-benzothien-3-yl)ethyl]}-N-(8-methyi- 2,3-dihydro-[1,4]dioxino{2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

41. The compound of claim 1 which is N-[3-(1-benzothien-3-yl)propyl]-N-methyl- N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

42. The compound of claim 1 which is N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-(2- methyl-7,8-dihydro-[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

43. The compound of claim 1 which is N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N- methyl-N-(2-methyl-7,8-dihydro-[1,4]dioxinof2,3-g][1,3]benzoxazol-8-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

44. The compound of claim 1 which is N-ethyl-N-[3-(5-Fluoro-1H-indol-3- yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

45. The compound of claim 1 which is N-[3-(5,7-difluoro-1-methyl-1H-indol-3- yhpropyl]-N-(8-methyl-2,3-dihydro-{1,4]dioxino[2,3-f]guinolin-2-yimethyl)amine or a pharmaceutically acceptable salt thereof.

46. The compound of claim 1 which is N-{3-(5,7-difluoro-1-methyl-1H-indol-3- yl)propyl]-N-methyl-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2- yimethyl)amine or a pharmaceutically acceptable salt thereof.

47. The compound of claim 1 which is N-[4-(1-benzofuran-3-yl)butyl]-N-(8-methyl- 2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a pharmaceutically acceptable salt thereof.

48. The compound of claim 1 which is 3-{3-[(8-methyi-2,3-dihydro- [1,4]dioxino[2,3-flquinolin-2-ylmethyl)-amino]-propyl}-1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

49. The compound of claim 1 which is 3-{3-[(2-methyl-7,8-dihydro- [1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl)amino]-propyl}-1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

50. The compound of claim 1 which is 3-{3-[methyl-(2-methyl-7,8-dihydro- [1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl)-aminol}-propyl}-1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

51. The compound of claim 1 which is 3-{3-[methyl-(8-methyl-2,3-dihydro- [1,4]dioxino[2,3-flquinolin-2-ylmethyl)-amino)-propyl}- 1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

52. The compound of claim 1 which is [3-(6-fluoro-indol-1-yl)-propyl]-(8-methy!- 2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yimethyl)-amine or a pharmaceutically acceptable salt thereof.

583. The compound of claim 1 which is [3-(6-fluoro-indol-1-yl)-propyl]-methyl-(8- methyl-2,3-dihydro-[1,4]dioxino{2,3-fl]quinolin-2-yimethyl)-amine or a pharmaceutically acceptable salt thereof.

54. The compound of claim 1 which is [4-(5-fluoro-1-methyl-1H-indol-3-yl)-butyl]- (8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yimethyl)-amine or a pharmaceutically acceptable salt thereof.

55. The compound of claim 1 which is ethyl-[3-(5-fluoro-1H-indol-3-yl)-propyl]-(2- methyl-7,8-dihydro-[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl)-amine or a pharmaceutically acceptable salt thereof.

56. The compound of claim 1 which is 1-methyl-3-{3-[(8-methyi-2,3-dihydro- [1,4]dioxino[2,3-flquinolin-2-yImethyl)-amino]-propyl}-1H-indole-5-carbonitrile or a pharmaceutically acceptable slat thereof.

57. The compound of claim 1 which is [4-(6-fluoro-indol-1-yl)-butyl]-(8-methyl-2,3- dihydro-{1,4]dioxino[2,3-flquinolin-2-ylmethyl)-amine or a pharmaceutically acceptable salt thereof.

58. The compound of claim 1 which is 3-{4-[(8-methyl-2,3-dihydro- [1,4]dioxino[2,3-flquinolin-2-ylImethyl)-amino]-butyl}-1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

59. The compound of claim 1 which is 1-methyl-3-{3-[methyl-(8-methyl-2,3- dibydro-[1,4]dioxino[2,3-f]lquinolin-2-yimethyl)-amino]-propyl}-1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

60. The compound of claim 1 which is 3-{4-[methyi-(8-methyl-2,3-dihydro- [1,4]dioxino[2,3-f]quinolin-2-yimethyl)-amino]-butyl}-1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

61. The compound of claim 1 which is [3-(5-fluoro-1-methyi-1H-indol-3-yl)-propyl]- methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yimethyl)-amine or a pharmaceutically acceptable salt thereof.

62. The compound of claim 1 which is [4-(5-fluoro-1H-indol-3-y!)-butyl]-methyl-(8- methyl-2,3-dihydro-[1,4]1dioxino[2,3-flquinolin-2-yimethyl)-amine or a pharmaceutically acceptable salt thereof.

63. The compound of claim 1 which is [4-(5-fluoro-1-methyl-1H-indol-3-yl)-butyl}- methyl-(8-methyl-2,3-dihydro-{1,4]dioxino[2,3-flquinolin-2-yimethyl)-amine or a pharmaceutically acceptable salt thereof.

64. The compound of claim 1 which is [3-(5-fluoro-1H-indol-3-yl)-propyl]-(8- methyl-2,3-dihydro-[ 1,4]dioxino[2,3-f]quinolin-2-yimethyl)-propyl-amine or a pharmaceutically acceptable salt thereof.

65. The compound of claim 1 which is [3-(4-fluoro-indol-1-yi)-propyl]-(8-methyl- 2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylimethyl)-amine or a pharmaceutically acceptable salt thereof.

66. The compound of claim 1 which is {4-(6-fluoro-indol-1-yl)-butyl]-methyl-(8- methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)-amine or a pharmaceutically acceptable salt thereof.

PCT/IUS2003/028524

67. The compound of claim 1 which is {3-{4-fluoro-indol-yl)-propyll-methyl-(8- methyl -2,3-dihydro-[1,4]ldioxinol2,3-flquinolin-2-ylmethyl}-amine or a pharmaceutically acceptable salt thereof.

68. The compound of claim 1 which is N-[4[(5-Chloro-1-benzothien-3- yl) butyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-flquinolin-2- yllmethyl}amine or a pharmaceutically acceptable salt thereof.

69. The compound of claim 1 which is N-[3-(5-Chloro-1-benzothien-3- yl) propyll-N-{[{2S)-8-methyl-2,3-dihydro[1,4]dioxino{ 2, 3-flquinolin-2- ylimethyl}amine or a pharmaceutically acceptable salt thereof.

70. The compound of claim 1 which is N-[3-(5-Fluoro-1-benzothien-3- yl)propyl}-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[ 2, 3-flquinolin-2- yllmethyl}amine or a pharmaceutically acceptable salt thereof.

71. The compound of claim 1 which is N-[4-(1-Benzofuran-3-yl)butyl]-N-ethyl- N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-flquinolin-2-ylJmethyl}amine or a pharmaceutically acceptable salt thereof.

72. A compound of claim 1 which is the S enantiomer, substantially free of the R enantiomer of said compound.

73. A substance or composition for use in 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, cocaine and alcohol addiction, and sexual dysfunction, said substance or composition comprising a compound of Formula | as claimed in any one of claims 1 to 72 or a pharmaceutically acceptable salt thereof, and said method comprising providing to the subject suffering from said condition, a therapeutically effective amount of said substance or composition.

74. A substance or composition for use in a method of treatment of claim 73, wherein the condition is depression. 94 AMENDED SHEET

PCT/US2003/028524

75. A substance or composition for use in a method of treatment of claim 73, wherein the condition is selected from the group consisting of obsessive compulsive disorder, panic attacks, generalized anxiety disorder, and social anxiety disorder.

76. A pharmaceutical composition comprising a compound of Formula | as claimed in any one of claims 1 to 72 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

77. Use of a compound as claimed in any one of claims 1 to 72 in the preparation of a medicament for the treatment of 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, cocaine and alcohol addiction, and sexual dysfunction.

78. Use according to claim 77, wherein the condition is depression.

79. Use according to claim 77, wherein the condition is selected from the group consisting of obsessive compulsive disorder, panic disorder, generalized anxiety disorder, and social anxiety disorder.

80. A compound according to any one of claims 1 to 72, substantially as herein described and illustrated.

81. A substance or composition for use in a method of treatment according to any one of claims 73 to 75, substantially as herein described and illustrated.

82. A composition according to claim 76, substantially as herein described and illustrated.

83. Use according to any one of claims 77 to 79, substantially as herein described and illustrated.

84. A new compound, a substance or composition for a new use in a method of treatment, a new composition, or a new use of a compound as claimed in any one of claims 1 to 72, substantially as herein described. 95 AMENDED SHEET