CA2049803A1 - Serotonin 5ht1a agonists - Google Patents

Abstract

ABSTRACT The present invention is directed to a new class of compounds of the formula: in which B is represented a C1-4 alkylene bridging group, Alk is represented by a linear alkylene bridging group con-taining from 2-8 carbon atoms which may optionally be mono-substituted at one carbon atom with a C1-4 alkyl, phenyl, substituted phenyl, or alkylphenyl substituent in which the phenyl ring may be optionally substituted; D is represented by a bond or an ethenylene bridging group; X, Y and Z are each independently represented by hydrogen, C1-4 alkyl, phenyl, substituted phenyl or alkylphenyl in which the phenyl ring may be optionally substituted; R1 is represented by a substituent selected from the group consisting of hyd-rogen, halogen, C1-4 alkyl, C1-5 alkoxy, CF3, OCF3, OH, NO2, CN, -NR2R3, -CONR2R3, -COOR4, -CH2SO2NR2R3, -SO2NR2R3, and -OCH2COOR4; R2 and R3 are each independently represented by H or a C1-4 alkyl; R4 is represented by H, C1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; Het is represented by one of the following substituents: or which are serotonin 5HT1A and 5HTlD agonists and may be used in the treatment of anxiety, depression, migraine, stroke and hypertension as well as pharmaceutical and diagnostic compositions containing them.

Description

-1- z~ 3 SEROTONIN 5HTl A AGONI STS

The present invention is directed to a new class of serotonin 5HTlA and SHTlD agonists, their use in the 5 treatment of anxiety, depression, migraine, stroke and hypertension as well as pharmaceutical and diagnostic compositions containing them.

In accordance with the present invention, a new class of serotonin 5HTlA and lD agonists have been discovered which can be described by the following formula:

~ B-N-CH-Alk-D-CO-N ~ R1 X FORMULA I

in which B is represented by a Cl_4 alkylene bridgin~ group;
Alk is represented by a linear alkylene bridging group containing from 2-8 carbon atoms which may optionally be mono-substituted at one carbon atom with a Cl 4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; D is represented by a bond or an ethenylene bridging group; X, Y, and Z are each independently represented by hydrogen, Cl_4 .: . , , :

. :. : .
, :.. ` :' :' :: ` ` :
~, , . .: .

-2~

alkyl, phenyl, substituted phenyl or alkylphenyl in which the phenyl ring may be optionally substituted; Rl is represented by a substituent selected from the group consisting of hydrogen, halogen, Cl 4 alkyl, Cl-5 alkoxy, CF3, OCF~, OH, NO2, CN, -CONR2R~, -NR2R3, -COOR4, -OCH~COOR4, -CH2SO2NR2R3, and -SO2NR2R3; R2 and R3 are each independently represented by H or a Cl_4 alkyl; R4 is represented by H, Cl-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; Het is represented by one of the following substituents:

~ N ~ or ~ \ O ~

in which R is represented by a substituent selected from the group consisting of hydrogen, halogen, Cl-4 alkyl, Cl-4 alkoxy, O-CH2-C6H5, CF3, OCF3, OH, NO2, CN, -CONR5R6, -CH2SO2NR5R6, -SO2NR5R6, -COOR7 or -~CH2COOR7; R5 and R6 are each independently represented by H or Cl_4 alkyl; R7 is represented by H, Cl-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; A is represented by H, or Cl_4 alkyl;
or a pharmaceutically acceptable salt thereof; with the proviso that when Het is an indolyl derivative, then Rl is not a carbonyl derivative.

The compounds encompassed by Formula I above may also be represented by the following subgeneric formulae:
in which R, A, B, Alk, D, X,Y, Z, and Rl are as defined above.

. , ; ~ ~ , , B-N-CH-Alk-D-CO-N

R ~\~ Z R
A FORMULA Ia B-N-CH-Alk-D-CO-N ~
~ R 1 R FO~MULA Ib These compounds mimic the effects of serotonin at the 5HTlA and lD receptor. They are useful in the treatment of anxiety, depression, migraine, stroke and hypertension.

As used in this application:
a) the term "halogen" refers to a fluorine, chlorine, or bromine atom;

bj the terms "lower alkyl group and Cl-4 alkyl" refer to a branched or straight chained alkyl group containing from 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.;

c) the terms "lower alkoxy group and Cl 4 alkoxy" refer to :'~

_4_ ~5~ 3 a straight or branched alkoxy group containing from 1-4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, etc.;

d) the term "substituted phenyl ring" refers to a phenyl moiety (C6Hs) which is substituted with up to 3 substituents, each substituent is independently selected from the group consisting o~ halogens, Cl_4 allcyl, Cl_4 alkoxy, CF3, OCF3, OH, CN, and ~2- These substituents may be the same or different and may be located at any of the ortho, meta, or para positions.

e) the term "alkylphenyl substituent" refers to the following structure, ~(CH2)m-C6H5, in which m is an integer from 1-3. This phenyl ring may be substituted in the manner described immediately above.

f) the term "pharmaceutically acceptable salt" refers to either a basic addition salt or an acid addition salt.

g) the phrase "Cl-4 alkylene bridging group" refers to a methylene, ethylene, propylene, butylene, l~methyl-ethylene, -2-methyl-ethylene, 2-methyl-propylene, 2-ethyl-ethylene, 1-ethyl-ethylene, etc.

h) the term "ethenylene bridging group" refers to the following substituent:-CH=CH-.

i) the term "Alk" refers to a linear alkylene group which may be represented by the following structure:
-(CH2)p-CHL-(CH2)s, in which p and s are each independently represented by an integer from 0-7 and L is represented by H, Cl_4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted, with the proviso that the sum p and s is from 5~

1-7. Representative examples of such linear alkylene groups include ethylene, propylene, butylene, hexylene, ~-benzyl-pentylene, ~-ethyl-heptylene, ~i-phenyl-propylene, ~-benzyl-pentylene, ~i-methylpentylene, ai-methylbutylene, etc. For the purposes of this application, the ~-carbon should be considered to be the carbon atom immediately adjacent to the carbon atom bearing the Y-substituent.

j) the term "indolyl derivative" refers to a compound in which Het is represented by:

1 5 R~3 k) the term "benzodioxan" derivative refers to a compound in which Het is represented by:

~ \ O ~

1) the term carbonyl derivative refers to one of the following substituents: -CONR2R3, ~COOR4, -OCH2COOR4, -CONR5R6, -COOR7, -OCH2COOR7.

m~ the term Cl_5 alkoxy refers to:
a straight or branched alkoxy group containing from 1-5 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentoxy, etc.

, -6~ ¢~

The expression "pharmaceutically acceptable acid addi-tion salts" is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates.
Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as methanesulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
The expression "pharmaceutically acceptable basic addition salts" is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by Formula I or any of its intermediates.
Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides;
ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. Either the mono- or di~basic salts can be formed with those compounds.

7 ~d ~7 ~ v 3 Some of the compounds of Formula I contain one or more asymmetric centers and will therefore exist as enantiomers and diastereomers. Any reference in this application to one of the compounds represented by Formula I, or any intermediate thereof, should be construed as covering a specific optical isomer, a racemic mixture or a diastereomeric mixture. The specific optical isomers can be synthesized or can be separated and recovered by techniques known in the art such as chromatography on chiral stationary phases, resolution via chiral salt formation and subsequent separation by selective crystalli~ation, or enzymatic hydrolysis using stereoselective esterases as is known in the art. Alternatively, a chirally pure starting material may be utilized.

Those compounds of Formula I in whlch D is an ethenylene bridging group will also exist as geometric isomers. Any reference to these compounds should be construed as referring to either the cis isomer, the trans isomer or a mixture of these isomers.

All of the compounds of Formula Ia contain an indole.
This indole may be optionally substituted as is indicated by the presence of the R substituent. When R is represented by a substituent other than hydrogen, there can be up to 3 such non-hydrogen substituents occurring on the indole ring.
These substituents may appear at any of positions 2, 4, 5, 6, or 7. The l-position of the indole may also be optionally substituted as indicated by the A substituent.

All of the compounds represented by Formula Ib contain a benzodioxan. This benzodioxan may be optionally substituted as indicated by the R substituent. When R is represented by a substituent other than hydrogen, there can be up to 3 such . ~ ;
.

. " . . :. ..
.: . , -~ :

-8~ $(~3 non-hydrogen substituents occurring on the benzodioxan.
These substituent may be located at any of positions 3, 5, 6, 7 or 8.

All of the compounds of Formula I contain a phenyl ring adJacent to the amide substituent. This phenyl ring may also be substituted as is indicated by the Rl substituent.
When R~ is represented by a substituent other than hydrogen, there can be up to 3 such non-hydrogen substituents occurring on the phenyl ring. These substituents can be the same or different and can be located at any of the ortho, meta, or para positions. As noted above, if Het is represented by an indolyl derivative, then Rl should not be represented by a carbonyl derivative.

The amino-alkylene chain connecting the benzodioxan or indole with the terminal phenyl ring may be further substituted as indicated by the X, Y, and Z substituents.
X, Y, and Z may be represented by the same substituents or differing substituents. As noted above, Alk is represented by a linear alkyiene yroup. This alkylene group may be further substituted with only one alkyl, phenyl or alkylphenyl substituent. This one substituent may occur on any one carbon atom of the alkylene chain.

Examples of compounds encompassed by the present invention include:

a) 6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]-heptanamide;

b) 7-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-octanamide, :

c) 6-[~2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-phenyl-heptanamide;

5 d) 5-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-~trifluoromethyl)phenyl]-hexanamide;

e) 6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-t4-methoxyphenyl)-heptanamide;
f) 4-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]-pentanamide;

g) 6-[[2-(5-methoxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl] heptanamide;

h) 6-[[2-(5-hydroxy-1~-indol-3-yl)ethyl]methylamino]-N-[4-(trifluoromethyl)phenyl]-heptanamide;

20 i) 6-[[2-(5-hydroxy-lH-indol--3-yl)ethyl]amino]-N-(2-methoxyphenyl)-heptanamide;

j) 6-[[2-(5-carboxamido-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-heptanamide;
k) 6-~2-(lH-indol-3-yl)ethyl]amino]-N-~4-(tri~luoro-methyl)phenyl]-hexanamide;

1) 6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(1-propyl)phenyl]-hexanamide;

m~ 5-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(1-propyloxy)phenyl]-hexanamide;

n) 6-[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)ethyl]amino]-N-phenyl-hexanamide;

:., . : :: :
,. .
: i :

-10- ~ 33~

o) 6-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4-(trifluoromethyl)phenyl]-heptanamide;

p) 6-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4-methoxyphenyl)-heptanam.ide;

q) 6-[[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-methyl amino]-N-[4-(trifluoromethyl)phenyl]-hexanamide;

r) 6-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[2-(trifluoromethyl)phenyl]-hexanamide;

15 s) 7-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyyl)-heptanamide;

t) 7-[[2-~5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(2-methoxyphenyl)-heptanamide;
u3 6-[[2-(4-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-heptanamide;

v) 6-[[2-(S-chloro-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-heptanamide;

w) 7-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(3-methoxyphenyl)-octanamide;

3~ x) 6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[2-(trifluoromethyl)phenyl]-hexanamide;

y) 6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[3-(trifluoromethyl)phenyl]-hexanamide;

.
.~, '' ` , , , 3~

z) 6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-4-methyl-N-(4-methoxyphenyl)-hexanamide;

aa) 6-[[3-(5-hydroxy-lH-indol-3-yl)propyl]amino]-N-(4-methoxyphenyl)-hexanamide;

bb) 6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(3-methoxyphenyl)-hexanamide;
cc) 6-[[2-(5-hydroxy-1-methyl-indol-3 yl)ethyl]amino]-N-(4-methoxyphenyl)-hexanamide;

dd) 6-[(2,3-dihydro-8-methoxy-1,4-benzodioxin-2-yl)methylamino]-N-(4-methoxyphenyl)-hexanamide;

ee) 5-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4-(trifluoromethyl)phenyl]-pentanamide;

ff) 4-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4-methoxyphenyl)-butanamide;

~9) 7-[[2-(5-methoxy-lH-indol-3-yl)ethyl]-methylamino]-N-(4-methoxyphenyl)-octanamide;
hh) 6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-2-hexenamide.

ii) 7-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4-trifluoromethyl)phenyl]-heptanamide.

Examples of preferred 5HTlA agonists inslude: -a) 5-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4-(tri~luoromethyl)phenyl]-pentanamide;

M01533A -ll-: : ,-, . ~,. . . ~ . - .
:. ,, :,: .

-12~ ,~J~

b) 6-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino] N-[2-(trifluoromethyl)phenyl]-hexanamide;

c) 6-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]-heptanamide;

d) 7-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-octanamide;
e) 6-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-phenyl-heptanamide;

f) 5-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl~phenyl]-hexanamide;

g) 6-[[2-(S-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-heptanamide;

h) 6-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]-hexanamide;

i) 6-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-(3,4-dimethoxyphenyl)-heptanamide;
j) 6-[[2-(S-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-octanamide;

k) 4-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-~4-~(trifluoromethyl)phenyl]-pentanamide;

1) 6-[[2-(5 Hydroxy-lH-indol-3-yl)ethyl]amino]-N-(2-methoxyphenyl)-heptanamide;

m) 5-[(2,3-dihydro-1,4-benzodioxin-2(S)-yl)methyl amino]-N-(4-chlorophenyl~-pentanamide;

- - : ; ., - . :

, ~

~d~r~ 33 n) 5-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(3,4-dichlorophenyl)-pentanamide;

o) 5-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4-dimethylaminophenyl)-pentanamide;

p) 6-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4-methoxyphenyl)-hexanamide;

q) 7-[2-[(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-phenyl-heptanamide.

Preferred 5HTlD Agonists include:

a) 5-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4-(trifluoromethyl)phenyl]-pentanamide;

20 b) 5-[(2,3-dihydro-1,4-benzodioxin-2(S)-yl)methylamino]-N-(4-chlorophenyl)-pentanamide;

c) 5-[(2,3-dihydro-1,4-benzodioxin-2(S)-yl)methyl amino]-N-[4-(trifluoromethyl)phenyl]-~entanamide;
d) 6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[3-(trifluoromethyl)phenyl]-hexanamide;

e) 6-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]-hexanamide.

The compounds of Formula Ia can be prepared using techniques known in the art. One suitable method is disclosed below in Reaction Scheme I:

-14- ~ 3 REACTION SCHEME I
STEP A
AMIDATION
8 r\ CH3NHOCH3 HO-C-Alk-D-CO-N ~ R1 2 STEP B

CH3N-CAlk-D-CO~ YMgHal C-Alk-D-CO-OCH3 Z Cl or I
3 ~ 5 STEP C

C-Alk-D-CO-N~ R +~ B-l H

REDUCTIVE AMINATION I Q
B-N-CH-Alk-D-CO-N ~ R

A Formula Ia .

.

-1 s~ $~3 As is depicted, the initial step in the reaction is to carry out an amidation reaction between the acid derivative of structure 1 and N,O-dimethylhydroxylamine, thereby producing the amido-derivative depicted by structure 3. This amido-derivative is subjected to a Grignard reaction thereby producing the compound of structure 5. The desired product of Formula Ia is then produced by carrying out a reductive amination between the compound of structure 5 and the indole derivative of structure 6.

The appropriate acid derivative to utilize as a starting material is one in which Alk, D, Rl, and Z are represented by the same substituents as is desired in the final product of Formula Ia. Methods for producing these acid derivatives are known in the art. For example, see Leznoff, C.C. and Goldwasser, J.M. Tetrahedron Letters, 1875-1878 (1977) and Leznoff C.C. and Goldwasser, J.M., Can. J. Chem., 56, 1562-1568 (1978).

The amidation reaction of Step A can be carried out using techniques known in the art. Typically approximately equivalent amounts of the acid derivative and N,O-dimethyl-hydroxylamine are contacted in the presence of an approximately equivalent amount of a peptide coupling reagent such as isobutylchloroformate. The amidation is also typically carried out in the presence of an approximately equivalent amount of a base such as triethylamine, 4-ethylmorpholine, or 4-methylmorpholine. The reaction is typically carried out in an aprotic solvent such as tetrahydrofuran or dichloromethane for a period of time ranging from 1 to 24 hours. The reaction is typically carried out at a temperature range of from -20 to 20C.

: ; . , ,,"
'; . ,' , . . ; i ! ~ .

' ' . ', ' ' ' : ' ' ~

-16- 2~$~

The resulting amide derivative of structure 3 can De recovered from the reaction zone by extraction with dichloromethane. It may then be purified by recrystallization from a solvent system such as ethyl acetate/hexane. Alternatively, it may be purified by flash chromatography utilizing an eluting agent such as a mixture of ethyl acetate and hexane.

In Step B, this amide derivative is subjected to a Grignard reaction in which the Grignard reagent is as described by structure 4 in which Y is as in Formula Ia and is represented by the same substituent as is desired in the final product. Typically, the amide of structure 3 is contacted with an excess of the Grignard reagent (2.0 to 3.0 equivalents) in an ethereal solvent such as ether or tetrahydrofuran at -78C. The reaction is warmed to room temperature and stirred for 8 to 36 hours. The resulting ketone derivative of structure 5 can be recovered by extraction. It may then be purified by ~lash chromatography with an eluting agent such as a 50:50 mixture of ethyl acetate and hexane.

In Step C, a reductive amination is carried out between the ketone or aldehyde derivative of structure 5 and the indole derivative of structure 6 in which R, A, ~, and B are as in Formula Ia and are re~resented by the same substituents as is desired in the final product. Several of these indoles are items of commerce and methods for producing other indole derivatives are known in the art.
For example, see Lloyd, D.H., Nichols, ~. Orq. Chem. 51, 4294-4295 (1986); Naito, T. et al., Sy_thesis, 778-780 (1989); Webb, C., US Patent 4,252,803; Abramovitch, R.A., Shapiro, D., J. Chem. Soc. 4589 (1956); Demerson, C.A. et _ al;, J. Med. Chem. 31, 1344-50 (1988).

.

The reductive amination is carried out using techniques known in the art. Typically the hydrochloric acid or maleic acid salt of the indole derivative of structure 6 is contacted with an equivalent or a slight excess of the compound of structure 5. The reductive amination is carried out in the presence of an excess of sodium cyanoborohydride (about 1.5 equivalents). The reaction is typically carried out in an alcoholic solvent such as methanol at a concentration of 0.1 molar. The reaction is carried out at room temperature for a period of time ranging from 1 to 7 days. The resulting product of Formula Ia can be recovered by the addition of sodium bicarbonate and water followed by extraction with a 1:4 mixture of 2-propanol and dichloro-methane. It may be purified by flash chromatography with aneluting system such as 5:20:80 triethylamine:ethanol:ethyl acetate.

Alternatively, the compounds of structure 5 can also be prepared according to the procedures described in Journal of Medicinal Chemistry, 26(4~, 494 (19~3) and in Int. J. Pept.
Protein Res., 22, 284 (1983).

Those compounds of structure 5 wherein Y = H can be made from the bromides of structure 8 (depicted below in Reaction Scheme II)by procedures known in the art. For example see Kornblum, N. et al., J. Am. Chem. Soc., 81, 4113-4114 (19593 and Ganem, B., Boeckman, R.K., Tetrahedron Letters, 917-920 (1974). In a typical procedure, approximately equimolar amounts of bromides of structure 8 (where Y = H and Alk, D, Z, and Rl, are as required structure 5) and sodium bicarbonate are stirred in dimethylsulfoxide (0.1-0.3 M) with a catalytic amount of potassium iodide. The mixture is typically heated under a nitrogen atmosphere at a temperature of from 100 to 150C for 2 - 10 hours. The resulting aldehyde derivative of structure 5 ~Y=H) can be , ~ , . - ~ . . .: , .
. , . . - . :
- . ,:

:

~18~ 3~

recovered by addition of water and extraction with diethyl ether. It may be purified by flash chromatography utilizing an eluant mixture such as 50:50 ethyl acetate:hexane.

The benzodioxan derivatives of Formula Ib can also be prepared by techniques known in the art. One suitable method is disclosed below in Reaction Scheme II:

; REACTIONSCHEMEII

Olg-NH Hal--CH-Alk-D-CO-N~ R

N-ALKYLATION
R \ O \ B-N-CH-Alk-D-CO-N ~ R
X Z

Formula Ib As is depicted above, the compounds of Formula Ib are prepared by carrying out an N-alkylation between a benzodioxan derivative as described by structure 7 in which R, X and B are as in Formula Ib and an alkylhalide derivative as described by structure 8 in which Alk, D, R1, Y and Z are as in Formula Ib and Hal is a halogen. The appropriate benzodioxan derivative to use is one in which R, X and B are represented by the same substituents as is desired in the final product~ Methods for producing these ', '~

, ..; .

-19~ 3 benzodioxans are known in the art. For example, see Dewar, G.H. et al., Eur. J. Med. Chem. Chim. Ther. 18, 286-289 (1983); Shapero, M., et al., J. Med. Chem. 12, 326-329. The appropriate alkylhalide derivative of structure 8 to use is one in which Y, Z, Alk, D and Rl are represented by the same substituents as is desired in the final product. Methods for producing the alkylhalide derivatives are known in the art. For example, see Stirling, C.J.M., Journal_of the Chemical Society, 4531-4536 (1958), and Stirling, C.J.M., Journal of the Chemical SocietY, 255-262 (1960).

The N-alkylation reaction is carried out using techniques known in the art. Typically approximately equimolar amounts of the reactants are contacted in a polar, aprotic solvent such as dimethylformamide or dimethyl-sulfoxide. The reaction is usually carried out for a period of time ranging from 30 minutes to 8 hours at a temperature range of 50 to 100C. The desired product of Formula Ib can be recovered by extraction after saturated aqueous sodium bicarbonate has been added to the reaction. It may then be purified by recrystallization from a solvent system such as ethanol:ethyl acetate and/or it may be purified by flash chromatography with an eluting agent such as 10:90 ethanol:ethyl acetate.

Alternatively, the compounds of Formula Ib can be prepared by the procedure outlined above in Reaction Scheme I. The only modification is that the benzodioxan derivative of structure 7 is utilized rather than the indole derivative of structure 6. Likewise, the compounds of Formula Ia in which R is H can be prepared by th~ method disclosed in Reaction Scheme II, but substituting the appropriate indole starting material for the benzodioxan of structure 7.

:

The compounds of Formula I are serotonin 5HTlA agonists and are therefore useful in the treatment of anxiety, hyper-tension, and depression. The affinity of the compounds for the 5HTlA receptor can be demonstrated by receptor binding assay procedures such as described by Gozlan et al. in Nature, Volume 305, at pages 140-142 (1983). The procedure of Sleight et al., as reported in the Euro~ean Journal of Pharmacoloqy, Volume 154, pages 255-261 (1988) can be utilized to show that this affinity results in an agonistic effect upon the receptor.

The compounds slow the firing of neurons in the dorsal raphe nucleus which contains one of the highest densities of 5HTlA receptors in the CNS. Inhibition of cell firing results in a reduction in the amount of serotonin released in brain regions receiving input from the dorsal raphe, thereby altering serotonin tone in the system. A slowing of the firing rate can be demonstrated by applying the compounds to rodent brain slices containing the dorsal raphe and measuring the activity of individual neurons. This procedure has been described by Sprouse et al., in the European Journal of Pharmacolo~y, Vol. 167, pp 375-383 (1989). Other 5HTlA agonists such as buspirone have been shown to inhibit raphe cell firing, an effect apparently common to all members of this pharmacologic class (Vandermaelen et al., European Journal of PharmaGoloqy, Vol.
129, pp 123-130 (1986)).

3D It has been reported that 5HTlA agonists are effective in the treatment of depression. The 5HTlA agonist, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH DPAT) was shown to be effective in rodent models for depression. European Journal of Pharmacoloqy, Vol 144., pages 223-229 (1987), Ceroo et al. and European Journal of Pharmacoloqy, Vol.
15B, pages 53-59 (1988), Ceroo et al~ Schweizer et al.

-21- 2~f~

reported that buspirone, a partial 5HTlA agonist, was useful in the treatment of depression. PharmacoloqY Bulletin, Vol.
22, No. 1 (1986). Since the compounds of the instant invention are 5HTlA agonists, they will be useful in the treatment of depression.

In order to exhibit an antidepressant effect, it is necessary that the compounds be administered to the patient in an effective amount. The dosage range at which these compounds exhibit this antidepressant effect can vary widely depending upon the severity of the patient's depression, the particular compound being administered, the route of administration, the co-administration of other therapeutic agents r and the presence of other underlying disease states.
Typically, the compounds will be administered at a dosage range of from 0.5 mg/kg/day to about 100 mg/k~/day.
Repetitive daily administration may be desirable and will vary with the conditions described above. However, the compounds are typically administered from 1 to 4 times daily.

The compounds of Formula I will elevate the patient's mood if they are suffering from depression and either relieve or alleviate the physical complaints which the patient is experiencing.

As noted above, the compounds of Formula I are serotonin SHTlA agonists. Compounds producing this effect at the sHTlA
receptor have also been found to exhibit anxiolytic properties. European Journal of Pharmocoloqy, Vol. 88, pages 137-138 (1983) Gloser et al. and Druqs of the Future Vol._13 pages 429-439 (1988) Glaseat. A SHTlA partial agonist known as buspirone is currently being marketed as an anxiolytic ayent. Since the compounds of the instant invention are are 5HT1A agonists, they will be useful in the treatment of anxiety.

It is also possible to demonstrate the anxiolytic activity of these compounds by their ability to block distress vocalizations in rat pups. This test is based upon the phenomenon that when a rat pup is removed from its litter, it will emit an ultrasonic vocalization. It was discovered that anxiolytic agents block these vocalizations.
The testing method has been described by Gardner, C.R., ~istress vocalization in rat pups: a simple screening method for anxiolytic drugs., J. PharmacolO Methods 14:181-1879 (19~5), and Insel et al., Rat pup ultrasonic isolation calls: Possible mediation by the benzodiazepine receptor complex, Pharmacol. Biochem. Behav~, 24: 1263-1267 (1986~.

In order to exhibit this anxiolytic effect, it is necessary that the compounds be administered to the patient in an effective amount. The dosage range at which these compounds exhibit this an~iolytic effect can vary widely depending upon the severity of the patient's anxiety, the particular compound being administered, the route of administration, the co-administration of other therapeutic agents, and the presence of other underlying disease states.
Typically, the compounds will be administered at a dosage range of from about 0.5 mg/kg/day to about 100 mg/kg/day.
Repetitive daily administration may be desirable and will vary with the conditions described above. However, the compounds are typically administered from 1 to 4 times daily.

The compounds of Formula I exhibit a hypotensive effect and are therefore useful in the treatment of hypertension.
Other 5HTlA agonists such as 3-OH-DPAT and flesinoxan have been shown to be effective for the treatment of hypertension .

in rodent models European Journal of Pharmacoloqy, Vol. 180, -pages 339-349 (l990) and European Journal of Pharmacoloqy, Vol. 1~2, pages 63-72 (1990). It is also possible to demonstrate the antihypertensive effects of these compounds using rodent models such as the spontaneously hypertensive rat. In this model, vehicle is administered to the rat orally or intravenously and a baseline blood pressure is established. The test compound is then administered by the same route and the decrease in blood pressure is noted. The compounds of Formula I produce a hypotensive effect.

In order to produce an antihypertensive effect, it is necessary that the compounds be administered to the patient in an effective amount. The dosage range at which these compounds exhibit this hypotensive effect can vary widely depending upon the severity of the patient's hypertension, the particular compound being administered, the route of administration, the co-administration of other therapeutic agents, and the presence of other underlying disease states.
TypiGally, the compounds will be administered at a dosage range of from about 0.5 mg/kg/day to about lO0 mg/kg/day.
Repetitive daily administration may be desirable and will vary with the conditions described above. However, the compounds are typically administered from 1 to 4 times daily.

The compounds of the present invention may be administered by a variety of routes. They are effective if administered orally. The compounds may also be administered ; parenterally (i.e. subcutaneously, intravenously, intramuscularly, or intraperitoneally).

As used in this application:
3~

:

a~ the term "patient" refers to warm blooded animals such as, for example, guinea pigs, mice, rats, cats, rabbits, dogs, monkeys, chimpanzees, and humans;

b) the term "treat" refers to the ability of the compounds to either relieve, alleviate, or slow the progression of the patient's disease.

c) the term "anxiety" refers to the unpleasant emotional state consisting of psychophysiological responses to anticipation of unreal or imagined danger, ostensibly resulting from unrecognized intrapsychic conflict.
Physiological concomitants include increased heart rate, altered respiration rate, sweating, trembling, weakness, and fatigue; psychological concomitants include feelings of impending danger, powerlessness, apprehension, and tension.

d) the term "depression" should be construed as encompassing those conditions which the medical profession have referred to as major depression, endogenous depression, psychotic depression, involutional depression, involutional melancholia, etc.
These conditions are used to describe a condition in which patients typically experience intense sadness and despair, mental slowing, loss of concentration, pessimistic worry, despair, and agitation. The patients often experience physical complaints such as insomnia, anorexia, decreased energy, decreased libido, etc.

Serotonin SHTlA agonists have also been shown to be useful in the treatment of stroke. It has been discovered that these compounds exhibit a neuroprotective effect and will either relieve or inhibit the CNS damage that typically accompanies a stroke. This neuroprotective effect is ~........... :

-25~ 3 believed to be due to serotonin's inhibitory effect upon excitatory neurotransmission. For example, Bielenberg et al showed that the 5HTlA agonists 8-OH-DPAT, buspirone, gepirone, ipsapirone, and Bay R 1531 inhibited or decreased neuronal destruction in rodent models of stroke. Stroke Supplement IV, Volume 21, No. 12 (December, 1990). Since the compounds of Formula I are serotonin 5HTlA agonists, they will be useful in the treatment of stroke.
In order to exhibit this neuroprotective effect, it is necessary that the compounds be administered to the patient in an effective amount. The dosage range at which these compounds exhibit this effect can vary widely depending upon the severity of the patient's condition, the particular compound being administered, the route of administration, the co-administration of other therapeutic agents, and the presence of other underlying disease states. Typically, the compounds will be administered at a dosage range of from 0.01 mg/kg/day to about 100 r,g/kg/day. Repetitive daily administration may be desirable and will vary with the conditions described above. However, the compounds are typically administered from 1 to 4 times daily or as a continuous intravenous infusion~
Stroke is a condition in which injury to the brain results due to either ischemic or hemorrhagic lesions. It is also commonly referred to as a cerebrovascular accident.
The compounds of Formula I can be used to treat any of these conditions. As used herein, the phrase "treating stroke"
refers to the ability of the compounds to either inhibit or decrease the CNS damage that typically accompanies a stroke.

As is readily apparent to those skilled in the art, the compounds of Formula I will not correct any CNS damac,e that has already occurred as the result of the cerebrovascular .
- :........ . , ~ .

-26- ~ 3 accident. The compounds should be administered at the initiation of the cerebrovascular accident, or soon thereafter, prior to the occurrence of extensive CNS damage.

The compounds of Formula I are also serotonin 5HTlD
agonists. The affinity of the compounds for the 5HTlD site can be demonstrated in binding procedures such as those described by Peroutka et al in ~,uropean Journal of Pharmacoloqy, Vol. 163 at pages 133-166 (1989).

It has been reported that 5HTlD agonists are effective in the treatment of migraine. The 5HTlD agonist, sumatriptan, was shown to produce antimigraine-like effects in animal models and to terminate acute migraine attacks in early clinical trials. Peroutka et al, id.; Saxena et al, TIPS- Vol. lO, page 200, May 1989; and Hamel et al, Br. J.
Pharmacol. (l991) 102,227-223. Since the compounds of Formula I are serotonin 5HTlD agonists, they may be utilized to terminate migraine attacks.

Migraine attacks are associated with excessive dilation of the extracerebral cranial vasculature. Since serotonin 5HTlD agonists constrict these vessels, it is currently believed that this is the mechanism by which they terminate migraine attacks. Saxena et al, id. The ability of the compounds of Formula I to produce constriction of these extracerebral cranial vessels can be demonstrated using the method of Boer et al, Br. J. Pharmacol. ~1931), 102, 323-330.

In addition to terminating acute migraine attacks, thecompounds can be administered on a prophylactic basis to prevent the occurrence of migraines. In order to produce these antimigraine effects, it is necessary that the compounds be administered to the patient in an effective .: ~

.

-27~ 3~ 3 amount. The dosage range a~ which these compounds exhibit these anti-migraine effects can vary widely depending upon the severity of the patient's migraine, the particular compound being administered, the route of administration, the co-administration of other therapeutic agents, and the presence of other underlying disease states. Typically, the compounds will be administered at a dosage range of from about 0.5 mg/kg/day to about 100 mg/kg/day. Repetitive daily administration may be desirable and will vary with the conditions described above. However, the compounds are typically administered from 1 to 4 times daily.

Pharmaceutical compositions can be manufactured utilizing techniques known in the art. Typically an anti-depressant, anxiolytic, anti-hypertenisve, anti-stroke, or anti-migraine amount of the compound will be admixed with a pharmaceutically acceptable carrier.

For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.
In another embodiment, the compounds of ~ormula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.

.
' -28- ~f~

For parenteral administration the compounds may be dissolved in a physiologically acceptable pharmaceutical 5 carrier and administered as either a solution or a suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art.

The compounds of Formula I may also be admixed with any inert carrier and utilized in laboratory assays in order to determine the concentration of the compounds within the serum, urine, etc., of the patient as is known in the art.

The following Examples are being presented in order to further illustrate the invention, but they should not be construed as limiting the scope of the invention in any manner.

:

-29~ 3 EXAMPLES

6-~[2-(5-HydroxY-lH-indol-3-yl)ethvl]amino~-N-[4-(trifluoro-methyl)phenyl]-tleptanamide~ monohydrochloride, hemihydrate Serotonin hydrochloride hemihydrate (200 mg) and N-[4-(trifluoromethyl)phenyl]-6-oxo-heptanamide (260 mg) were dissolved in methanol (8 mL) and treated with sodium cyanoborohydride (85 mg). After stirring for 45 hours in the dark at 23C, sodium bicarbonate (250 mg) and water (20 mL) were added and the reaction stirred 1 hour. The mixture was extracted with 1:4 2-propanol:dichloromethane (2 x 50 mL) and the combined e~tracts dried over Na2SO4 and concentrated in vacuo to an oil. This oil was chromatographed using 5:10:90, then 2.5:50:S0 triethylamine:ethanol:ethyl acetate as eluant, and the component with an Rf o~ 0.4 in the later solvent system was isolated as a slightly red, clear oil. This oil was reconc2ntrated from methanol (50 mL) three times, then dissolved in ethanol (50 mL) and treated with 1:9 concentrated hydrochloric acid:ethanol (1.1 mL). This solution was concentrated in vacuo and then reconcentrated ~irst from 1:1 ethanol:methanol (50 mL), then from 1:4 methanol:ethyl acetate (50 mL). Th2 title compound was obtained as a tan solid (370 mg).
Analysis calculated for C24H28F3N3O2 HC1 0~75 H20-0.05 CH3CH2OCOCH~: C, 57.92; H, 6~21; N, 8.37. Found: C, 57.91;
H, 6.22; N, 8.27.
IR(KBr): 3302, 1604, 1534, 1410, 1326, 1164, 1114, 1068 cm-1.
CIMS (CH4): 448 (100%), 428 (40%), 219 (28%).
lH NMR (d6-DMSO): 10.68 (lH, d; J = 2.1 Hz), 10.01 (lH, s), 8.92 (2H, bm)l 8.73 (lH, s), 7.86 (2H, d; J = 9.0 Hz), 7.64 .,~ . , . .. , . . . ~
, . : . ~. , :, ,~ :

-30~ 3 (2H, d; J = 8.9 Hz), 7.16 (2H, m), 6.88 (lH, d; J = 2.0 Hz), 6.63 (lH, dd; J = 2.0, 8.4 Hz), 3.27-2.95 (5H), 2.42 (2H, t;
J = 7.5 Hz), 1.82 (lH, m), 1.67-1.20 (5H), 1.24 (3H, d; J =
6.6 Hz) ppm.
13C NMR (d6-DMSO): 171.83, 150.40, 142.94, 130.76, 127.49, 126.23, 125.95, 123.58, 122.90 (m), 118.8A, 111.83, 111.57, 108.50, 102.07, 53.04, 44.16, 36.10, 31.93, 24.58, 24.37, 22.02, 15.56 Ppm.
19F NMR (d6-DMSO): -60.098 ppm.

2A) 7-Oxo-N-(4-methoxypheny~)-octanamide Prepared as in J. Med. Chem. 26, 492-439 (1383), Method C, except substituting p-anisidine for para-(n-butyl)-aniline. Recrystallized from hot ethyl acetate by the addition of 20:~0 ethyl acetate:hexanes. The title compound was isolated as a pale violet solid.
Anal. Calc. fo~ Cl5H2lNO3: C, 68.~2; H, 8004; N, 5.32.
Found: C, 68.57; H, 8.22; N, 5.32.
IR(KBr): 3312, 2942, 1708, 1658~ 1598, 1528, 1514, 1410, 1364, 1296, 1240, 823 cm-l.
CIMS;CH4): 264 (100%, M+H~) lH NMR(CDC13): 7.76 (lH, bs), 7.43 (2H, d; J = 9.0 Hz), 6.85 (2H, d; J = 8.9 Hz), 3.78 (3H, s), 2.44 (2H, t; J = 7.8 Hz), 2.31 (2H, t; J = 7.3 Hz), 2.13 (3~, s), 1.70 (2H, m), 1.59 (2H, m), 1.35 (2H, m) ppm.
13C NMR (CDC13): 210.13, 171.97, 156.81, 131.76, 122.21, 114.45, 55.66, 43.53, 37.20, 30.09, 28.68, 25.46, 23.33 ppm.
Melting point: 106.0-107.0C.

Mnl533A -30-.:
~ . . .
:
.:: .:

` -31- ~3~

2B) 7-[~2-(5-Hydroxy-lH-indol-3-yl~ethyl]amino]-N-(4-methoxyphenyl)-octanamide, monohydrochloride Serotonin hydrochloride hemihydrate (222 mg), N-(4-methoxyphenyl)-7-oxo-octan~mide (263.3 mg), and methanol (10 mL) were stirred in the dark and the resulting solution treated with sodium cyanoborohydride (95 mg). After 4 d at ca. 22C, sodium bicarbonate (350 mg) and water (10 mL) were added. After stirring 1.5 hours, the mixture was extracted with 1:4 2-propanol:dichloromethane (3 x 25 mL) and the combined extracts were dried (Na2SO4) and concentrated in vacuo. Chromatography eluting with 4:10:90, then 3:30:70 triethylamine:ethanol:ethyl acetate gav~ a component with an Rf of 0.3 in the latter solvent system. This oil was reconcentrated twice from ethanol (50 mL), then redissolved in ethanol (ca. 50 mL), treated with 1:9 concentrated hydrochloric acid:ethanol (1.2 mL), and reconcentrated in uacuo to a pale yellow oil which foamed to a solid. This was the title compound (352 mg), isolated as a pale yellow solidO
Analysis calculated for C25H33N3O3 HCl 0.9 H2O 0.1 ~H3CH2OH:
C, 62.95; H, 7.63; N, 8.74. Found: C, 62.99; H, 7.58; N, 8.71.
IR(KBr): 3266, 2938, 1652, 1538, 1512, 1462, 1242 cm-l.
CIMS (CH4): 424 (100%), 277 (24%).
lH NMR (d6-DMSO): 10.68 (lH, d; J = 2.0 Hz), 9.88 (lH, s), 8.92 (2H, bdj, 7.53 (2H, d; J = 9.0 Hz), 7.17-7.14 (2H), 6.87-6.83 (3H), 6.64 (lH, dd; J = 2.2, 8.5 Hz); 3.71 (3H, s), 3.24-2.96 (SH), 2.29 (2H, t; J = 7.2 Hz), 1.85-1.20 (8H), 1.24 (3H, d; J = 6.5 Hz) ppm.
3C NMR (d6-DM~O): 170.65; 154.92, 150.37, 132.56, 130.74, 127.46, 123.53, 120.52, 113.70, 111.79, 111.54, 108.48, 102.04, 55.11, 53.17, 44.13, 36~04, 32.06, 28.33, 24.92, 24.51, 21.98, 15.52 ppm.

~:

-32~

3A) 6-Oxo-N-PhenYl-heptanamide Prepared as in J. Med Chem., 26, 492-499 (1983), Method C, except substituting aniline for para-(n-butyl)-aniline.
The title compound was purified by dissolving in hot ethyl acetate and adding hexane to give a white solid. Anal.
Calc. for Cl3Hl~NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 70.94; ~, 7.77; N, 6.21.
IR(KBr): 3340, 2945, 1706, 1664, 1599, 1534, 1447, 1375, 766, 695 cm-l.
CIMS (CH4): 220 (100%, M-~H+), 127 (67%).
lH NMR (CDCl3): 7.80 (lH, bs), 7.56 (2H, d; J = 7.7 Hz), 7.31 (2H, app.t; J = 7.8 Hz), 7.09 (lH, t; J = 7.4 Hz), 2.50 (2H, t; J = 6.5 Hz), 2.73 (2H, t; J = 6.9 Hz), 2.15 (3H, s), 1.67 (4 H, m) ppm.
13C NMR (CDC13). 203.20, 171.01, 138.02, 128.89, 124.09, 119.80, 43.21, 37.25, 29.99, 24.82, 22.97 ppm.
Melting point: 85.5-86.5C.

3B) _[[2-(5-HYdroxy-lH-indol-3-yl)ethyl]amino]-N-phenyl- ~`~
heptanamide, monohydrochloride hydrate Serotonin hydrochloride (1.000 g) and N-phenyl-6-oxo-heptanamide (1.289 g) were stirred in methanol (47 mL) under a nitrogen atmosphere and treated with sodium cyanoborohydride (0.444 9), excluding light from the reaction. After 4 d at ca~ 23C, a solution of sodium bicarbonate (1.00 g) in water (25 mL) was added. One hour later, the reaction was diluted with water (75 mL) and extracted with 1:4 2-propanol:dichloromethane (3 x 75 mL).
The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo to a foaming oil which was chromatographed using 5:20:80 triethylamine:ethanol:ethyl i, , , - ; :-, ' ` ," -, ,.

acetate, isolating the component with an Rf of 0.3. The resulting oil was twice reconcentrated invacuo from ethanol tlO0 mL) and then redissolved in ethanol (100 mL). This solution was treated with 1:9 concentrated hydrochloric acid: ethanol (6 mL), concentrated inuacuo, reconcentrated from ethanol ~100 mL) to an oil, and the oil placed under vacuum to yield the title compound as a solid (1.80 g).
Anal. Calc. for C23H29N3O2.HC1 1 2 H2O: C, 63.13; H, 7.40; N, 9.60. Found: C, 63.37; H, 7.25; N, 9.57.
IR(KBr): 3404, 3274, 1660, 1598, 1542, 1442 cm-1.
CIMS(CH4): 380 (100%), 233 (20%).
H NMR (d6-DMSO): 10.70 (lH, d; J = 2.0 Hz), 10.07 (lH, s), 8.95 (2H, bm), ~.75 (lH, bs), 7.63 (lH, d; J = 7.5 ~z), 7.28 (2H, t; J = 8.0 Hz), 7.17-7.14 (2H, m), 7.02 (lH, t; J = 7.4 Hz), 6.88 (lH, d; J = 2.1 Hz), 6.65 (lH, dd; J = 2.2, 8.5 Hz), 3.48-3.32 (5H, bm), 3.20 (lH, bm), 3.11 (2H, bm), 3.03 (2H, bm), 2.36 (2H, t; J = 7.4 Hz), 1.81 (lH, bm), 1.70-1.20 (SH), 1.24 (3H, d; J = 6.5 Hz) ppm.
13C NMR (d6-DMSO): 171.11, 150.40, 139.39, 130.76, 123.63, 127.50, 123.57, 122.93, 119.03, 111.84, 111.57, 108.51, 102.08, 53.05, 44.15, 36.06, 31.95, 24.77, 24.42, 22.02, 15.56 ppm.

5-[[2-(5=Hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-~trifluoro-methyl)phenyl]-hexanamide~ monohYdrochloride Serotonin hydrochloride hemihydrate (200 mg) and N-[4-(trifluoromethyl)phenyl]-5-oxo-hexanamide ~246 mg) were stirred under nitrogen in methanol (8 mL) and treated with sodium cyanoborohydride (~5 mg). After stirring 66 hours at 23C, sodium bicarbonate (250 mg) and water (5 mL) were added. Thirty minutes later, the reaction was diluted with water (50 mL) and extracted with 1:4 2-propanol:dichlor-, ' , : , omethane (40 mL, 40 mL, 20 mL) and the extracts dried (Na2SO4) and concentrated ~n uacuo to an oil. The oil was chromatographed with 5:10:90, then 3:50:50 triethyl-amine:ethanol:ethyl acetate to isolate a component withR~ of 0.15 (5:10:90 triethylamine:ethanol:ethyl acetate).
This oil was dissolved in ethanol (50 mL), treated with 1:9 concentrated hydrochloric acid:ethanol (2 mL), and concentrated invacuo. Reconcentration from ethanol (50 mL) and placlng under vacuum gave the title compound as an off-white solid (272 mg).
IR(KBr): 3334, 1604, 1538, 1410, 1324, 1186, 1164, 1114, 1068 cm-l~
CIMS (CHq): 434 (100%) 414 (32%), 287 (34%) 142 (20%).
lH NMR (d6-DMSO): 10.69 (lH, d; J = 2.2 Hz), 10.56 (lH, s), 8.97 (lH, bs), 8.84 (lH, bs), 8.64 (lH, s), 7~86 (2H, d; J
= 9.1 Hz), 7.63 (2H, d; J = 9.0 Hz), 7.16 (2H, m), 6.97 (lH, d; J = 2.0 Hz), 6.64 (lH, dd; J = 2.1, 8.5 Hz), 3.26 (lH, m), 3.12 (2H, bm), 3.03 (2H, bm)r 2.43 (2H, t; J = 7.4 Hz), 1.90-1.47 (4H), 1.27 (3H, d; J = 6.6 Hz) ppm.
13C NMR (d6-DMSO): 171.60, 150.40, 142.87, 130.76, 127.49, 126.22, 125.97 (m), 123.58, 123.19, 122.76, 118.B7, 111.84, 111.57, 108.48, 102.08, 52.98, 44.20, 35.91, 31.77, 21.99, 20.81, 15.62 ppm.
19F NMR (d6-DMSO): -60.104 ppm.

6-[[2-(5-Hydroxy-lH-indol-3-yl~ethyl]amino]-N-(4~methoxy-phenyll-heptanamide monohydrochloride In an aluminum foil-wrapped flask were placed N-(4-methoxyphenyl)-6-oxo-heptanamide (225 mg), 5-hydroxytryptamine hydrochloride hemihydrate (200 mg), sodium cyanoborohydride (85 mg) and methanol (8.0 mL). This mixture was stirred at room temperature (ca. 23C) for 67 :

' 3~3 hours. Solid sodium bicarbonate (500 mg) and water (45 mL) were added and after 5 minutes the reaction was extracted with 1:4 2-propanol:dichloromethane (3 x 35 mL). The combined extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to a foaming oil. This was chromatographed using 5:10:90, then 3:50:50 triethyl-amine:ethanol:ethyl acetate isolating the component with an Rf of 0.15 in 5:10:90 triethylamine:ethanol:ethyl acetate.
The product was twice reconcentrated from ethanol (100 mL), then redissolved in ethanol (100 mL) and treated with 1.0 M
aqueous hydrochloric acid (1.5 mL). This solution was concentrated inuacuo, then twice redissolved in ethanol (70 -mL) and reconcentrated. The resulting oil was placed under vacuum causing it to foam to a light tan solid (360 mg), the title compound.
Anal. Calc. C24H3lN3O3 HCl 0.05 C2H5OH-0.8 H2O:C, 62.56; H, 7.38; N, 9.08. Found: C, 62.41; H, 7.12; N, 8.9A.
IR(KBr): 3404, 3270, 1652, 1512, 1244 cm-l.
CIMS (CH4): 410 (100%), 263 (32%).
lH NMR (d6-DMSO): 10.69 (lH, d; J = 2.1 Hz), 9.91 (lH, s), 8.95 (~H, bd), 7.53 (2H, d; J = 9.1 Hz), 7.15 (2H, m), 6.85 (2H, d; J = 9.2 Hz), 6.86 (lH, d; J = 9.3 Hz), 6.64 (lH, dd; ~~
J = 2.2, 8.6 Hz), 3.70 (3H, s), 3.20 (lH, bm), 3.10 (2H, bm), 3.00 (2H, bm), 2.32 (2H, t; J = 7.4 Hz), 1.81 (lH, bm), 1.59 (2H, bm), 1.33 (2H, bm), 1.24 (3H, d; J = 6.5 Hz) ppm.
13C NMR (d6-DMSO): 170.55, 154.96, 150.40, 132.5B, 130.76, 127.50, 123.57, 113.73, 111O84, 111.57, 108.52, 102.07, 55.13, 53.05, ~4.15, 35.91, 31.94, 24.83, 24.43, 22.02, 15.56 ppm.

-36~

6A) 6-Bromo-N-[4-(trifluorometh~ll)Phenyl]-hexanamide s Triethylamine (1.30 mL) and 4-aminobenzotrifluoride (1.21 g) were stirred in dichloromethane (35 mL) at 0C
under nitrogen and treated with 6-bromohexanoyl chloride (1.15 mL). After 20 minutes, the reaction was allowed to warm to 20C and stirred an additional 40 minutes. The reaction was treated with a~ueous saturated sodium bicarbonate (40 mL), and extracted with dichloromethane.
The extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to a solid. This solid was dissolved in ethyl acetate and the title compound was precipitated out as fine white needles by addition of hexanes (2.35 g). M.p. 96-98C. Anal. Calc. for C13H15BrF3NO: C, 46.17; H, 4.47; N,

4.14. Found: C, 46.25; H, 4.59; N, 4.12.
IR(KBr): 3316, 1670, 1600, 1530, 1410, 1322, 1260, 1170, 1128, 1112, 1066, 842 cm-l.
CIMS(CH4): 340 (90%), 338 (100%), 320 (50%), 318 (55%), 258 (60%).
lH NMR (CDC13): 7.65 (2H, d; J = 8.5 ~z), 7.56 (2H, d; J =
8.5 Hz), 7.47 (lH, bs), 3.42 (2H, t; J = 6.5 Hz), 2.40 (lH, t; J = 6.6 Hz), 1.90 (2H, m), 1.75 (2H, m), 1.52 (2H, m) ppm.
13C NMR (CDCl3): 171.21, 140.83, 126.27, 119.32, 37.39, 33.49, 32.34, 27 64, 24.42 ppm.
l9F NMR (CDC13): -62.712 ppm.
6B) 6-Oxo-N-[4-(trifluoromethy~Lphenyl]-hexanamide A solution of sodium bicarbonate (0.250 g), potassium iodide (0.050 9), and 6-bromo-N-[4-(trifluoromethyl)phenyl]-hexanamide (1.00 g) in dimethylsulfoxide (15 mL) was heatedat 125-130C for 3.5 hours while stirring under a nitrogen . ~ ~
:- :

B~

atmosphere. The reaction was treated with water (75 mL) and extracted with ether. The ether extract was washed with brine (50 mL), dried over sodium sulfate after adding dichloromethane (30 mL), filtered, and concentrated invac~o.
Chromatography using 50/50 ethyl acetate/hexane gave a white solid (Rf = 0.2 in same solvent system, 0.326 g), identified as the title compound. m.p.: 129.S-131.0C.
Calc. Anal. for Cl3Hl4F3NO2: C, 57.14; ~, 5.16; N, 5.13.
Found: C, 57.00; H, 5.14; N, 5.01.
IR(KBr): 33.6~, 2944, 2844, 1716, 1702, 1614, 1602, 1542, 1466, 1408, 1388, 1372, 1320 1308, 1258, 1168, 1110, 1064, 862, 736 cm-l.
CIMS (CH4): 274 (100%)~ 254 (74%).
lH NMR (CDCl3): 9.83 (lH, s), 7.69 (2H, d; J = 9.5 Hz)~ 7.57 (2H, d; J = 8.5 Hz), 7.63 (lH, bs), 2.56 (2H, t; J = 7.
Hz), 2.44 (2H, t; J = 7.6 Hz), 1.83-1.65 (4H, m) ppm.
l9F NMR(CDC13): -60.159 ppm.
0 6C) 6-[[2-(5-Hydrox~-lH-indol-3-yl)ethYl]amino~-N-[4-(trifluoromethyl)phenYl]-hexanamide, monohydro-chloride, hemihydrate Serotonin hydrochloride hemihydrate (120 mg) and N-[4-(trifluoromethyl)phenyl]-6-oxo-hexanamide (14~ mg) were dissolved in methanol (5 mL) and treated with sodium cyanoborohydride (51 mg). The solution was stirred at ca 23C for 7 d in the dark. The reaction was treated with sodium bicarbonate (415 mg) and one hour later was diluted with water (50 mL) and extracted with 1:4 2~propanol:di-chloromethane (3 x 30 mL). After drying (Na2SO4), the eYtracts were concentrated in vacuo to a clear, slightly brown oil. This oil was chromatographed using 5:10;90, then

5;50:50 triethylamine:ethanol:ethyl acetate. The component with an Rf of 0.3 in the latter solvent system was isolated as an oil (140 mg), then dissolved in ethanol (20 mL) and .

' :

s,,~

treated with 1 M hydrochloric acid (0.4 mL). The resulting solution was concentrated in vaCuo~ reconcentrated from ethanol (20 mL), then reconcentrated from a methanol (20 mL) and water (5 mL) mixture to give, after placing under vacuum, the title compound as a tan powder (131 mg).
Anal. calc. for C23H26N3O2F3 HC1 0.5 H~O: C, 57.68; N, 5.89;
H, 8.77. Found: C, 57.44; H, 5.89; N, 8.64.
IR(KBr) 3346, 3264, 1602, 1532, 1460, 1410, 1324, 1184, 1164, 1116, 1066 cm-l.
CIMS (CH4): 434 (100%), 414 (34%), 287 (25%).
lH NMR (CD30D): 7.77 (2H, d; J = 9.1 Hz), 7.58 (2H, d; J =
9.0 Hz), 7.18 (lH, d; J = 9.0 Hz), 7.12 (lH, s), 6.95 (lH, d; J = 2.1 Hz), 6.69 (lH, dd; J = 2.0, 9.1 Hz), 3.35-3.25 (2H, m), 3.09-3.00 (4H, m), 2.44 (2H, t; J = 7.5 Hz), 1.69-1.55 (4H), 1.50-1.38 (2H) ppm.
13C NMR (CD30D): 174.50, 151.57, 133.22, 128.85, 127.09, 127.04, 126.99, 126.94, 124.98, 120.66, 113.05, 112.87, 109.28, 103.13, 49.18, 47.71, 37.44, 27.08, 26.95, 25.89, 23.48 ppm.
9F NMR (CD30D): -63.309 ppm-7A) 6-Oxo-N-(3,4-dimethoxyphenyl)-6-oxo-heptanamide Prepared as in J. Med. Chem. 26, 492~499 (1983), Method C, except substituting 4-amino-veratrole for p (n-butyl) aniline. N-Ethylmorpholine was used instead of N-methyl-morpholine. Title compound was purified by recrystalli-zation from hot ethyl acetate by the addition of 30:70 ethyl acetate:hexane. The title compound was obtained as a greyish-white solid.
Anal. Calc. for Cl5H2lNO4: C, 64.50; H, 7.58; N, 5.01.
Found: C, 64.40; H, 7.66; N, 5.00.
CIMS (CH4): 280 (100%), 127 (8%) ,, - : - :,;.: , 3~

IR(K~r): 3364, 2938, 2906, 1708, 1690, 1606, 1546, 1516, 1466, 1442, 1312, 1400, 1374, 1258, 1234, 1214, 1158, 1134, 1028, 764 cm-l.
5 lH NMR (CDC13): 7.53 (lH, bs), 7.41 (lH, d; J = 2.5 Hz), 6.91 (lH, dd; J = 2.5, 8.6 Hz), 6.80 (lH, d; J = 8.6 Hz), 3.88 (3H, s), 3.86 (3H, s), 2.51 (2H, bt; J = 6.7 Hz), 2.36 (2H, bt; J = 6.8 Hz), 2.16 (3H, s), 1.71-1.66 (4H, bm) ppm.
13C NMR (CDC13): 209.06, 170.71~ 148.98, 145.69, 131.69, 111.64, 111.27, 104.86, 56.09, 55.86, 43.21, 37.22, 29.99, 24.83, 22.98 ppm. Melting Point: 114-115C.

7B) 6-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-(3,4-dimethoxyphenyl)-heptanamide, monohydrochloride hydrate The compound was prepared as in Example 2B except using 178 mg of serotonin hydrochloride and using N-(3,4-dimethoxyphenyl)-6-oxo-heptanamide (225 mg), running the reaction 21 hours at ca. 25C. The compound as the free amine had an Rf of 0.5 in 10:90 ethanol:ethyl acetate. The title compound was obtained as a tan solid (247 mg).
Anal. Calc. for C25~33N3O4 HC1 0.3 H2O: C, 62.37; H, 7.24; N, 8.73. Found: C, 62.58; H, 7.41; N, 8.74.
IR(KBr): 3348, 1610, 1514, 1450, 1224, 1020/ 732 cm-l.
CIMS (CH4):440 (100~), 293 (37%) lH NMR (d6-DMSO): 10.67 (lH, d; J = 2.2 Hz), 9.84 (lH, s), 8.75 (lH, bs), 8.70 (lH, s), 7.33 (lH, d; J = 2.3 Hz), 7.17-7.09 (3H, m), 6.87-6.84 (2H, m), 6.63 (lH, dd; J = 2.2 Hz, 8.5 Hz), 3.70 (6H, s), 3.22 (1 H, bm), 3.22 (2H, bm), 2.98 2H, bm), 2.31 (2H, bt; J = 7.4 Hz), 1.85-1.70 (lH, bm), 1.63-1.32 (4H, bm), 1.23 (2H, d; J = 6.4 Hz) ppm.
13C ~MR (d6-DMSO): 172.41, 150.64, 149.10, 145.62, 132.90, 131.52, 128.10, 124.49, 112.88, 112.~2, 112.32, 109.01, 105.25, 102.77, 56.43, 56.13, 54.04, 44.88, 36.66, 32.68, 25.53, 24.96, 22.63, 16O26 ppm. Melting Point: 214-215C.

.

8A) 6-Oxo-6-(N,O-dimethylhydroxylamino~-N-(4-methoxyphenYl)hexanamide

6-Oxo-6-(4-methoxyphenylamino)hexanoic acid (509 mg), tetrahydrofuran (12 mL) and dimethylformamide (0.1 mL) were cooled to 0-5C. Oxalyl chloride (0.23 mL) was added and the reaction was allowed to stir for fifteen minutes before the addition of N,_-dimethylhydroxylamine hydrochloride (221 mg). After tw~nty minutes, pyridine (0.8 mL) was added and reaction was warmed to 20-25C. Saturated sodium bicarbonate solution (100 mL) w~s added and the reaction was extracted with dichloromethane (2 x 30 mL). The combined organic extracts were dried (Na2SO4) and concentrated invacuo to afford a brown oil which was purified by chromatography eluting with 95:5 ethyl acetate:hexanes. The resulting white solid was recrystallized from ethyl acetate:hexanes to give the title compound as white crystals (133 mg).
Anal. Calc. for Cl5H22N2O4: C, 61.21; H 7.53; N, 9.52.
Found: C, 61.45; H, 7.64; N, 9.35.
CIMS (CH4): 295 t85%), 234 (100%), 172 (70%) IR(KBr): 3354, 2952, 1688, 1659, 1602, 1546, 1510, 1472, 1238, 1174, 1032, 844, 526 cm-l.
lH NMR (d6-DMSO): 8.58 (lH, bs), 7.48 (2H, d; J = 9.0 Hz), 6.82 (2H, d; J = 9.0 Hz), 3.7Ç (3H, s), 3.66 (3H, s), 3.17 (3H, s), 2.47 (2H, bm), 2.38-2.34 (2H, bm~, 1.76-1.69 (4 H, bm) ppm.
13C NMR (d6-DMSO): 170.82, 131.36, 121.66, 114.05, 77.21, 77.15, 76.80, 61.22, 55.47, 37.17, 31.33, 25.22~ 23.60 ppm.
Melting point: 89-90C.

., - , ., . ~ . ~ , ''` :

-41- ~ 3 8B) N-(4-Methoxyphenyl)-6-oxo-7-phenylheptanamide 6-Oxo-6-(_,O-dimethylhydroxylamino)-N-(4-methoxyphenyl) hexanamide (454 mg) was dissolved in tetrahydrofuran (13 mL~
and cooled to -78C. Benzylmagnesium chloride in tetrahydrofuran (2.0 M, 1.6 mL) was added and reaction was warmed to 20C. After 24 hours, additional benzylmagnesium chloride in tetrahydrofuran (2.0 M, 0.4 mL) was added.
After 24 hours, 1.0 M aqueous hydrochloric acid (10 mL) was added and reaction extracted using dichloromethane (2 x 15 mL). The combined organic extracts were dried (Na2SO4) and concentrated In vacuo. The resulting solid was chromatographed eluting with 30:70 ethyl acetate:hexanes to afford the title compound (Rf of 0.68 in 70:30 ethyl acetate-hexanes) as white crystals (200 mg).
Anal. Calc. for C20H23NO3: C, 73.82; H, 7.12; N, 4.30.
Found: C, 73.80; H, 7.21; N, 4.25.
CIMS (CH4): 326 (100~), 203 (8%).
IR(KBr): 3304, 2944, 1703, 1654, 1604, 1549, 1513, 1499, 1465, 1422, 1248, 1028, 832, 708 cm-l.
lH NMR (d6-DMSO): 7.62 (lH, bs), 7.43 (lH, d; J = 2.2 Hz),

7.40 (lH, d; J = 2.2 H~), 7.35-7.18 (5H, m), 6.84 (lH, d;
J = 2.3 H~), 6.82 (lH, d; ~ = 2.2 Hz), 3.77 (3~, s), 3.68 (2H, s), 2.50 (2H, bt; J = 6.5 Hz), 2.27 (2H, bt; J = 7.1 Hz), 1~62-1.60 (4H, m) ppm.
13C NMR (d6-DMSO): 209.19, 171.10, 156.58, 134.42, 131.29, 129.62, 129.01, 127.31, 121.90~ 114.25, 55.34, 50.lQ, 41.23, 36.91, 24.56, 22.62 ppm. Melting point: 131-132C.
8C) i~-[[2-L5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenylL~benzeneheptanamide, monohydrochloride The compound was prepared as in Example 2B except ~sing N-(4-methoxyphenyl)-6-oxo-7-phenyl-heptanamide (311 mg) and reacting components for 60 hours at 40-45C. Compound as the free amine had an Rf of 0.74 in 1:1:8 diethylamine:ethanol:ethyl acetate. The title compound was obtained as a tan solid (90 mg).
IR(KBr): 3410, 3270, 1652, 1512r 1242, 1180, 702 cm-l.
CIMS (CH4): 486 tlO0%), 394 (15%), 339 (20%) lH NMR (d6-DMSO): 10.68 (lH, s), 9.83 tlH, s), 9.15-9.12 tlH, bs), 8.94-8.91 tlH, bs), 8.72-8.71 tlH, bs), 7.51 t2H, d;
J = 9.1 Hz), 7.48-7.22 (5H, m), 7.17-7.11 (2H, m), 6.88-6.83 (3H, m), 6.64 tlH, dd; J = 2.0, 8.5 Hz), 3.71 t3H, s), 3.22-3.12 t3H, bm), 3.08-3.01 t2H, bm), 2.83 tlH, dd; J = 9.1, 13.0 Hz), 2.51 t2H, t; J = 1.8 Hz), 2.23 t2H, t; J = 6.9 Hz), 1.60-1.24 t6H, m) ppm.
l~C NMR (d6-DMSO): 213.26, 172.32, 156.16 150.69, 146.97, 137.02, 132.43, 131.57, 129.91, 129.83, 129.58, 128.08, 127.88, 124.57, 122.04, 11~.68, 112.94, 112.39, 108.94, 102.86, 59.07, 56.01, 45.45, 36.72, 36.3~, 29.97, 25.63, -24.24, 22.65 ppm.
Exact Mass (CIMS, CH4): Calc. for C30H36N3O3: 486.2757.
Found: 486.2754. Melting point: 109-110C tstarted to decompose at 100C.) 6-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]a _no]-N-(4-methoxyphenyl)octanamide, monohydrochloride The compound was prepared as in Example 2B except using N-(4-methoxyphenyl~-6-oxo-octanamide (300 mg) and running the reaction 60 hours at 35-40C. The compound as the ~ree amine had an Rf of 0.43 in 10.90 ethanol:ethyl acetate. The title compound was obtained as a tan solid (238 mg).
IR(KBr): 3264, 1654, 1540, 1512, 1460, 1242 cm-l.
CIMS (CH~): 424 (100%), 277 (35%) lH NMR (d6-DMSO): 10.68 (lH, d; J = 1.6 Hz), 9.84 (1~, s)

8.68 (2H, bs), 7.51 (2H, d; J = 8.9 Hz), 7.17-7.14 (2H, m), ,: ~

_43_ ~ 3~

6.86 (lH, s), 6.85 (2H, d; J = 8.8 Hz), 6.63 (lH, dd; J =
2.2 8.8 Hz), 3.7 (2H, s), 3.33-3.1 (3H, bm), 3.08-3.00 (2H, bm), 2.31 (2H, t; J = 7.2 Hz), 1.68-1.598 (5H, bm), 1.38-1.15 (2H, bm), 1.06 (lH, t; J = 6.9 Hz), 0.91 (3H, t;
J = 7.4 Hz) ppm.
13C NMR (d6-DMSO): 171.86, 155.85, 150.61, 132.45, 131.29, 127.96, 124.24, 121.62, 114.44, 112.63, 112.13, 108.87, 102.59, 58.57, 45.03, 41.99, 36.34, 28.91, 25.49, 24.34, 22.58, 22.39, 11.45 ppm.
Exact Mass (CIMS, CH4) Calc. for C25H34N3O3: 424.2600.
Found: 424.2621.

,'" ~ ;.: ':
, EXA~PLE 10 5-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4-(trifluoromethyl)phenyl~-pentanamide, monohydrochloride 2,3-Dihydro-1,4-benzodioxin-2-methanamine (350 mg) and 5-chloro-N-[4-(trlfluoromethyl)phenyl]-pentanamide (593 mq) were stirred in dimethylEormamide (7.0 mL) under a nitrogen atmosphere. Sodium bicarbonate (395 mg) and potassium iodide (40 mg) were added and mlxture was stirred for 60 -hours at 70-75C. Saturated sodium bicarbonate solution (50 mL) was added to the cooled reaction and the mlxture extracted with diethyl ether (3 x 30 mL). The combined extracts were dried (MgSO4), filtered, and concentrated in uacuo. The resulting oil was chromatographed eluting with 40:60 ethyl acetate:hexane, then 10:90 ethanol:ethyl acetate to give a yellow-white solid with an ~f of 0.15 in 50:50 ethyl acetate:ethanol. This solid was dissolved in ethanol (20 mL) and treated with 1.0 M aqueous HCl (1.0 mL). The solution was concentrated in vacuo to a white solid which after recrystallization from ethanol:ethyl acetate afforded the title compound as a white powder (117 mg).
Anal. Calc. for C21H23F3N2O3 HCl: C, 56.70; H, 5.44; N, 6.30.
Found: C, 56.57; H, 5.62; N, 6.03.
CIMS (CH4): 409 (100%), 273 (20~) IR (KBr): 3442, 3316, 2954, 2934, 2844, 1670, 1600, 1530, 1496, 1410, 1334, 1268, 1118, 1070, 836, 752 cm-l.
lH NMR (d6-DMSO): 10.49 (lH, s), 9.25 tlH, bs), 7.84 (2H, d;
J = 8.6 Hz), 7.66 (2H, d; J = 8.5 Hz), 6.94-6.85 (4H, m), 4.65-4.63 (lH, m), 4.36 (lH, dd; J = 2.5, 11.6 Hz), 4.06 (lH, dd; J = 6.7, 11.7 Hz), 3.30 (lH, m)~ 3.20 (lH, m), 3.03-2.98 (2H, bm), 2.41 (2H, bt), 1.68-1.64 (4H, bm) ppm.
13C NMR (d6-DMSO): 171.55, 142.a3, 141.82, 125.95 (m), 123.19, 122.75, 121.71, 118.~3, 117.35, 117.12, 69.16, 64.79, 47.14, 46.35, 35.70, 24.84, 21.94 ppm.

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~:

l9F NMR (d6-DMSO): -60.08 ppm (s). Melting point: 190-192C.

6-[(2,3-Dihydro-1,3-benzodioxin-2-yl)methylamino~-N-[3-(tri~luoromethyl)phenyl]-hexanamide, monohvdrochloride The title compound was prepared according to Example 10 except using 6-bromo-N-[3-(trifluoromethyl)phenyl]-hexanamide. The reaction required 57 hours at 40-45C. The title compound (Rf of 0.51 in 1:1:8 diethylamine:ethanol:ethyl acetate) was obtained as a yellow solid (380 mg).
Anal. Calc. for C22H2sF3N2O3 HCl: C, 57.58; H, 5.71; N, 6.10.
Found: C, 57.35; H, 5.94; N, 5.81.
IR (KBr): 3440, 2944, 2786, 1660, 1496, 1448, 1336, 1132, 1068, 756, 698 cm-l.
CIMS (CH4): ~23 (100~), 403 (29%), 2~7 (29%) lH NMR (d6-DMSO): 10.45 (lH, s), 9.35 (lH, bs), 9.07 (lH, bs), 8.16 (lH, s), 7.82 (lH, d; J = 8.2 Hz), 7.53 (lH, bt;
J - 8.2 Hz), 7.38 (lH, d; J = 8.0 Hæ), 6.93-6.85 (4H, m), 4.69-4.62 (lH, bm), 4.38 (lH, dd; J = 2.4, 11.7 Hz), 4.06 (lH, dd; J = 6.7, 11.7 Hz), 3.30 (lH, bs), 3.19 (1~, bs), 3.01-2.94 (2H, bm), 2.38 (2~, t; J = 7.1 Hz), 1.75-1.58 (4 H), 1.42-1.34 (2H) ppm.
3C NMR (d6-DMSO): 171.70, 142.68, 141.~3, 140.08, 129.85, 129.33 (q), 125.95, 122.46, 122.32, 121.69, 119.24, 117.34, 117.11, 115.00 (m), 6~.14, 64.80, 47.19, 46.27, 36.02, 25.53, 25.01, 24.38 ppm~
l9F NMR (d5-DMSO): -61.16 ppm (s).
Melting point: Compound became gummy at 105C, melted at 113-114C.

.,:

. . .

-4~-6-[(2,3-Dihydro-1,4-benzodioxin-2-~l)methylamino]-N-[4-(trifluoromethyl)phenyl]-hexanamide, monohydrochloride 2,3-Dihydro-1,4-benzodioxin-2-meth~namine (380 mg) and 6-bromo-N-[4-(trifluoromethyl)phenyl]-hexanamide (772 mg) were stirred in l-methyl-2-pyrrolidinone (7.8 mL) under a nitrogen atmosphere. Triethylamine (0.6 mL) was added and mixture was stirred for 36 hours at 20C, then heated at 40-50C for six hours. Saturated sodium bicarbonate solution (20 mL) was added to the cooled reaction and the mixture extracted with diethyl ether (2 x 20 mL). The combined extracts were dried (MgSO4), filtered, and concentrated in vac~o. The resulting clear liquid was chromatographed eluting with 50:50 ethyl acetate:hexane, then 5% ammonium hydroxide:ethyl acetate to give a clear oil with an Rf of 0.71 in the latter solvent system. This oil was dissolved in ethanol (50 mL) and treated with 1.0 M aqueous hydrochloric acid (3.0 mL). The solution was concentrated in vacu~ to a yellow solid which was triturated with ethyl aceta~e to give the title compound as a tan solid (400 mg). ~~
Anal. Calc. for C22H25F3N2O~ HCl: C, 57.58; H, 5.71; N, 6.10.
Found: C, 57.54; H, 5.81; N, 6.02.
IR (KBr): 3436, 2940, 1672, 1604, 1530, 1494, 1410, 1326, 1266, 1114, 1068, 750 cm-l.
lH NMR (d6-DMSO): 10.47 (lH, s), 9.17 (2H, bs), 7.85 (2H, d;
J = 8.5 Hz), 7.66 (2H, d; J = 8.7 Hz), 6.95-6.86 (4H, m)j 4.6~-4.63 (lH, bm), 4.38 (lH, dd; J = 2.3, 11.6 Hz), 4.06 (lH, dd; J = 6.7, 11.7 Hz), 3.27 (lH~ m), 3.20 (lH, m), 2.98 (2H, m), 2.40 (2H, t; J = 7.4 Hz), 1.73-1.61 (4H, m), 1.42-1.35 (2H, m) ppm.
CIMS (CHq): 423 (100%), 403 (30%).
l9F NMR (d6-DMSO): -60.112 ppm(s).
Melting point: 191.0-191.5C.

.. . .~ . .
.~ . .

-47~

6-[~(2,3-Dihydro-1,4-benzodioxin-2-yl)methyl]methylamino]-N-[4-(trifluoromethyl)phenvl]-hexanamide monohydrochloride 6-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4-(triEluoromethyl)phenyl]hexanamlde monohydrochloride (201 mg), 37~ aqueous formaldehyde (0.18 mL) and sodium cyanoborohydride (38 mg) were stirred in methanol (4.8 mL) for 96 hours at 20-25C under nitrogen atmosphere.
Saturated sodium bicarbonate (20 mL) was added to the reaction and extracted with dichloromethane (2 x 20 mL).
The combined extracts w~re dried (Na2SO4) and concentrated in uacuo. The resulting oil was chromatographed eluting with ethyl acetate and lO:gO ethanol:ethyl acetate to give a white solid (Rf of 0.52 in 10:90 ethanol:ethyl acetate) which was dissolved in ethanol and treated with 1.0 M
aqueous HCl (1 ml). The solution was concentrated ~n uacuo to give an oil which was dissolved in 70:30 ethyl acetate:hexane and concentrated. A hygroscopic white solid (151 mg) remained.
CIMS (CH4): 437 (100%), 301 (40%).
Exact Mass (CIMS, CH4): Calc. for C23H23F3N~O~: 437.2052.
Found: 437.2044.
IR (KBr): 3432, 1688, 1604, 1538, 1496, 1410, 1324, 1264, 1114, 1066, 846, 752 cm-l.
lH NMR (d6-DMSO): lO.B2 (lH, bs), 10.59 (lH, bs), 10.48 (lH, s), 7.85 (2X, d; J = 8.6 Hz), 7.66 (2H, d; J = 8.8 Hz), 6.95-6.86 (4H, m), 4.86 (lH, bs)~ 4.35 (lH, d; J = 10.7 Hz), 4.09-4.00 (lH, m), 3.60-3.10 (multiple broad multiplets~, 2.91-2.79 (3H, bs), 2.51 (2H, s), 2.41 (2H, t; J = 6.9 Hz), 1.74-1.58 (4H, bm), 1.40-1.29 (2H, bm) ppm.
l9F NM~ (d6-DMSO): -60.075 ppm(s).

, , : ' -48~ 3~

4-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoro-methyl)phenyl]-Pentanamide, hydrochloride, monohydrate Prepared as in Example 1 except substituting 4-oxo-N-[4-(trifluoromethyl)phenyl]-pentanamide for the keto amide.
The title compound was isolated as a tan solid.
Anal. Calc. for C22H24F3N3O2 HCl H2O: C, 55.76; H, 5.74;
N, 8.87. Found: C, 55.74; H, 6.59; N, 8.67.
IR(KBr): 3408, 1670, 1606, 1542, 1412, 1326, 1114, 1068 cm-l.
CIMS (CH4): 420 (100%~, 400 (20%), 273 (32%), 142 (92%).
lH NMR (d6 DMSO): 10.68 (lH, b~), 10.63 (lH, s), 9.06 (lH, bs), 8.95 (lH, bs), 8.69 (lH, bs), 7.86 (2H, d; J = 8.5 Hz), 7.68 (2H, d; J = 8.5 Hz), 7.17-7.11 (2H), 6.90 (lH, d; J =
1.0 Hz), 6.63 (lH, dd; J = 1.1, 8.3 Hz), 3.40 (4H, bs), 3.31 (lH, bs), 3.13 (2H, bm), 3.04 (2H, bm), 2.62-2.44 (2H), 2.16 (lH, bm), 1.80 (lH, m), 1.28 (3H, d; J = 6.7 Hz) ppm.
13C NMR (d6-DMSO): 171.36, 150.72, 143.08, 131.08, 127.82, 126.33 123.93, 123.61, 119.24, 112.15, 111.89, 107.76, 102.39, 53.15, 44.65, 32.56, 28.22, 22.33, 15.93 ppm.
l9F NMR (d6-DMSO): -60.125 ppm.

-, , : : :

-49- 2 ~ ~?~33 6-[~2-(5-Methoxy-l~-indol-3-yl)ethyl3amino]-N-[4-(trifluoro-methyl)phenyl]-heptanamide, hYdrochloride-3/4 hydrate Prepared as in Example 1 except substituting 2-(5-methoxy-lH-indol-3-yl)ethylamine hydrochloride for serotonin hydrochloride and substituting 3.35:65 triethyl-amine:ethanol:ethyl acetate for the second chromatographysolvent. The title compound was isolated as a tan solid.
Anal. Calc. for C25H30F3N3O2 HCl 3/4 H2O: C, 58.70; H, 6.40;
N, 8.21. Found: C, 58.82; H, 6.23; N, 8.40.
IR(KBr): 3417, 2946, 1671, 1605, 1537, 1487, 1410, 1325, 1165, 1114, 1067, 844 cm~l.
CIMS (CH4): 462 (100%), 442 (44%).
1~ NMR (d6-DMSO): 10.82 (lH, bs), 10.48 (lH, bs), 8.88 (2H, bs), 7.84 (2H, d; J = 8.0 Hz), 7.645 (2H, d; J = 8.1 Hz), 7.25 (lH, d; J = 8.2 Hz), 7.22 (lH, d; J = 1.2 Hz), 7.11 (lH, d; J = 1.0 Hz), 6.75 (lH, dd; J = 1.2, 8.2 Hz), 3.77 (3H, s), 3.27-3.02 (5~), 2.41 (2H, bt), 1.82 (lH, bm), 1.60-1.20 (5H), 1.24 (3H, d; J = 6.7 Hz) ppm.
l9F NMR (d6-DMSO): -60.094 ppm.

16A) 5-Oxo-N-(2-methoxyphenyl)-hexanamide Prepared as in J. Med. Chem. 26, 492-49g (1983), Method C, except substituting orthoanisidine for p-(n-butyl)-aniline. Title compound was purified by chromatography using 50:50 ethyl acetate:hex~nes and then recrystallizing from hot ethyl acetate by the addition of 20:80 ethyl acetate:hexanes. The title compound was isolated as white needles. Melting point: 101.0-101.5C.

, -50~

Anal. Calc. for Cl4HlgNO3: C, 67.45; H, 7.68; N, 5.62.
Found: C, 67.21; ~, 7.69; N, 5.45.

16B~ 6-~[2-(5-Hydroxy-lH-indol-3-yl)ethYl]amino]-N-(2-methoxyphenyl)-heptanamide hydrochloride monohYdrate Prepared as in Example 1 except substituting 6-oxo-N-(2-methoxyphenyl)-heptanamide for the keto amide and using dichloromethane to extract the crude product. The crude product was purified by chromatography using 4:10:90, then 3:30:70 triethylamine:ethanol:ethyl acetate to elute. The title compound was isolated as a tan solid.
Anal. Calc. for C24H3lN3O3 HCl H2O: C, 62.13; H, 7.39; N,

9.06. Found: C, 61.91; H, 7.33; N, 8.96.
IR(KBr): 3406, 3284, 2944, 1658, 1598, 1528, 1488, 1460, 1434, 1254, 1218, 754 cm-l.
CIMS (CH4); 410 (100~,), 263 (26~).
lH NMR (d6-DMSO): 10.68 (lH, bs)r 9.08 (lH, s)~ 8.94 (2H, bm), 7.92 (H, d; J = 7.5 Hz), 7.15 (2H, m), 7.09-7.00 (2H), 6.90-6.85 (2H, m), 6.64 (lH, dd; J = 1.3, 7O5 Hz), 3.82 (3H, s), 3.60 (2H, bm), 3.20 (lH, bm), 3.11 (2H, bm), 3.00 (2H, bm), 2.38 (2H, bt; J = 7.2 Hæ), 1.80 (lH, bm), 1.67-1.25 (3H), 1.26 (3H, d; J = 6.5 Hz) ppm.
13C NMR (d6-DMSO): 171.16, 150.37, 149.63, 130.74, 127.47, 127.31, 124.23, 123.51, 122.11, 120O12, 111.79, 111.55, 111.07, 108.51, 102.06, 55.59, 53.03, 44O10, 35.77, 31.91, 24.88, 24.42, 21.98, 15.54 ppm.

17A) 6-Bromo-N-[2-(trifluoromethyl)phenylJ-hexanamide Prepared according to procedure of example 6A except using 2-aminobenzotrifluoride. The reaction took 24 hours :,. , ~ .', ''': ', . .

. . , ' , -51~ 3.~

at 20-25C. The title compound (Rf of 0.40 in 30:70 ethyl acetate:hexane) ~as obtained as white crystals (2.40 g).
Anal. Calc. for C13H15BrF3NO: C, 46.17i H, 4.47; N, 4.14.
Found: C, 46.31; H, 4.53; N, 4.12.
IR(KBr): 3274, 1662, 1590, 1524, 1456, 1320, 1280, 1258, 1176l 1120, 1060, 1038, 766 cm-l.
CIMS ~CH4): 338 (30~), 320 (10%), 258 (50~), 203 ~40%)l 161 ( 100~ ) .
lH NMR (CDC13): 8.00 (lH, bd; J = 8.0 Hz), 7.67 (lH, bs), 7.59 (lH, d; J = 7.9 Hz), 7.51 (lH, t; J = 7.9 Hz), 7.22 (lH, t; J = 7.6 Hz), 3.39 (2H, t; J = 6.7 Hz), 2.38 (2H, t;
J = 7.2 Hz), 1.91-1081 (2H, m), 1.77-1.66 (2H, m), 1.54-1.46 (2H, m) ppm.
13C NMR (CDC13): 170.99, 135.12, 132.86, 126.06 (m), 124.56, 124.47, 37.47, 33.42, 32.40, 27.61, 24.47 ppm.
l9F NMR (CDC13): -61.27(s) ppm.
Melting point: 50-51C.

17B) 6-[(2~3-Dihydro-1,4-benzodioxin-2-y~)methylamino]-N-[2-(trifluoromethYl)phenyl]-hexanamide, monohydrochloride Prepared according to procedure of Example 10 except using 6-bromo-N-[2-(trifluoromethyl)phenyl]-hexanamide.
Reaction took 48 hours at 35-40C. The title compound (R~ of 0.65 in 1:1:8 diethylamine:ethanol:ethyl acetate) was obtained as a yellow solid (158 mg).
Anal. Calc. for C22H25F3N2O3 HCl: C, 57.58; H, 5.75; N, 6.10.
Found: C, 57.26; H, 5.75; N, 6.47.
IR(KBr): 3432, 2942, 2778, 1670, 1592, 1526, 1496, 1454, 1320, 1268, 1170, 1126, 750 cm-l.
CIMS (CH4): 423 (100%), 287 ~20%).
lH NMR (d6-DMSO): 9.61 (lH, s), 9.47 (lH, bs), 9.22 (lH, bs;, 7.75-7.51 (2H, m), 7.47 (2H, m), 6.97-6.84 (4H, m), 4.72-4.64 (lH, m), 4.38 (lH, dd; J = 2.4, 11.7 Hz), 4.07 (lH, dd;

-52~

J = 6.7 Hz, 11.7 Hz), 3.32 (lH, m), 3.23-3.16 (lH, m), 3.04-2.91 (2H, m), 2.36 (2H, m), 1.71-1.45 (4H), 1.38-1.31 (2H, m) ppm.
13C NMR (d6-DMSO): 172.45, 143.08, 142.22, 135.94, 135.91, 133.27, 130~81, 127.02, 126.60 (m), 126.47, 125.73, 122.03, 117.64, 117.43, 69.29, 64.90, 47.26, 46.29, 35.17, 25.47, 24.99, 24.57 ppm.
l9F NMR (d6-DMSO): -59.10(s) ppm.
Melting point: Title compound melted at 174-175C.

6-[[2-(lH-Indol-3-Yl)ethyl]amino]-N-[4-(trifluoromethyl)-phenyl]-hexanamide, monoh~drochloride Tryptamine-HCl (648 mg), 6-bromo-N-[4-(trifluoromethyl)phenyl]-hexanamide (543 mg) (prepared in Example 6A) and triethylamine (0.7 mL) were stirred in dimethylformamide (16 mL) for 60 hours at 55-60C under a nitrogen atmosphere. Saturated sodium bicarbonate solution (100 mL) was added to reaction and the mixture was extracted with diethyl ether (3 x 50 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The resulting brown liquid was chromatog~aphed eluting with 70:30 ethyl acetate:hexane and then 1:1:8 diethylamine:ethanol:ethyl acetate (Rf of 0.45 in 1:1:8 dethylamine:ethanol:ethyl acetate) to give a yellow oil which was dissolved in ethanol and treated with 1.0 M aqueous HCl (4.5 mL). The solution was concentrated in uacuo to give the title compound as a tan solid (284 mg).
CIMS (CH4): 418 (100~), 287 (25%) Exact Mass (CIMS, CH4): Calc. for C23H27F3N3O: 418.2106.
Found: 418.2102.
IR~KBr): 3418, 3314, 2948, 2788, 1666, 1604, 1538, 1458, 1410, 1342, 1326, 1114, 1068, 740, 580 cm-l.

.
., ~, ~ .
'' . i~, ,: :
, , -53- ~

lH N~R (d6-DMSO): 10.99 (lH, s), 10.50 (lH, s), 9.01 (2H, bs), 7.85 (2H, d; J = 8.5 Hz), 7.65 (2H, d; J = 8.6 Hz), 7.60 (lH, d; J = 7.8 Hz), 7.37 (lH, d; J = 8.1 Hz), 7.24 (lH, d; J = 2.1 Hz), 7.09 (lH, app.t.; J = 7.0 Hz), 7.00 (lH, app.t.; J = 6.9 Hz), 3.40 (lH, bs), 3.11 (4H, bm), 2.96-2.91 (2H, bm), 2.40 (2H, t; J = 7.2 Hz), 1.71-1.60 (4H, bm), 1.39-1.34 (2EI, bm) ppm.
13C NMR (d6-DMSO): 173.62, 147.03, 142.91, 136.92, 127.42, 126.92 (m), 124.02, 122.42, 120.17, 119.74, 118.97, 112.49, 109.92, 48.00 47.51, 36.85, 26.21 26.03, 25.21, 22.47 ppm.
l9F NMR (d6-DMSO): -60~06 ppm(s). Melting point: 180-181C.

l9A) 5-Iodo-N-~4-~trifluoromethyl)phenyl]-pentanamide 5-Chloro-N-[4-(trifluoromethyl)phenyl]-pentanamide (2.795 9) and sodium iodide (3~32 9) were stirred in acetone (20 ml) at 22C for 3d, then heated at reflux for 16h, all under nitrogen. The cooled reaction mixture was chromatographed with 50:50 ethyl acetate:hexane to isolate product with Rf=0.30 in 35:65 ethyl acetate:hexane by addition of hexane and evaporation of solvent under a stream of nitrogen afforded, after suction filtration, a white solid (2.887 9).
The product iodide contained ca. 5% starting chloride and was used without further purification.

:: ,.
:: , - :. ~: : -.
: . . : . .

., , . , :

J~

l9B) 5-[2,3-Dihydro-1,4-benzodioxin-2~-yl)methylamino]-N-[4-~trifluoromethyl)phenyl]-pentanamide, monohydro-chloride 2,3-Dihydro-1,4-benzodioxin-2(R)-methanamine (455 mg) and 5-iodo-N-[4-(trifluoromethyl)phenyl]-pentanamide (1220 mg) were dissolved in dry dimethylformamide (24 mL) under nitrogen and heated at 65-70C for 9h. The reaction was cooled, treated with saturated aqueous sodium bicarbonate (10 mL) and water (100 mL) and the resulting mixture extracted with ether (2 X 100 mL). The ether extracts were washed with brine, dried over MgSOq/Na2SO4, and concentrated in vacuo to an oil. Chromatography with 0:20:80, then 5:20:80 triethyla~ine:ethanol:ethyl acetate gave a solid (Rf ca.
0.45 in the latter system, 570 mg). This was dissolved in ethanol (15 mL), treated with 1.0 M aqueous hydrochloric acid (2 mL) and concentrated in vacuo. This solid was crystallized from warm ethanol (10 mL) by addition of ether (10 mL) and cooling (0C). Suction filtration afforded the title compound (350 mg) as a white solid.
Anal.Calc. for C2lH23F3N2O~ HC1: C, 56.70;
H, 5.44; N/ 6.30. Found: C, 56.74; H, 5.56; N, 6.10.
IR(KBr): 2946, 2776, 1668, 1604, 1534, 1496, 1410, 1328, 1264, 1166, 1114, 1068 cm-l.

lH NMR (d6-DMSO3: 10.51 (lH, 5), 9.20 (2H, bd)~
7.84 (2H, d; J= 8.6 Hz), 7.66 (2H, d; J= 8.7 Hz~, 6.94-6.85 (4H, m), 4.64 (lH, m), 4.37 (lH, dd;
J = 2.4, 11.6 Hz), 4.06 (lH, dd; J = 6.7, 11.6 Hz), 3.30 (lH, m)~ 3.20 (lH, m), 3.01 (2H, bm), 2.41 (2H, bt), 1.66 (4H, bm) ppm.
3C NMR (d6-DMSO): 171.55, 142.85, 142.69, 141.83, 125.98, 123.18, 122.75, 121.71, 118.83, 117.35, 117.12, 69.15, 64.79, 47.11, 46.33, 35.71, 24.83, 21.95 ppm " ;~

~, :
, , , l9F NMR ~d6-DMSO): -60.072 ppm(s).
Melting point: 190.5-192.0C.
Optical rotation: [~D =+4 4 8 (c=1.08, methanol).

5-[t2,3-Dihydro-1,4-benzodioxin-2~S)-yl)methylamino]-N-[4-(trifluoromethyl)phenyl]-pentanamide, monohydrochloride Prepared essentially as in Example l9B except substituting 2,3-dihydro-1,4-benzodioxin-2(S)-methanamine for the R-enantiomerO

Anal. Calc. for C21Hz3F3N2O3 HCl: C, 56.70; H, 5.44; N, 6.30.
Found: C, 56.30; H, 5.62; N, 6.09.
All spectral data was essentially identical to Example 20B.
Optical rotation: [~ =-44.8 (c=0.89, methanol).

Example 21 5-[(2,3-Dihydro-1,4-benzodioxin-2(S)-yl)methylamino]-N-(4-chloroPhenyl)-Pentanamide, monohydrochlo_ de Prepared as in Example 19 except using 5-iodo-N-(4-chlorophenyl)-pentanamide as the alkylating ayent and heating at 80C for 6 hours, then 70C for 16 hours. Crude product was chromatographed using 0~10:90, then 5:10:90 triethylamine:ethanol:ethyl acetate. Component with an R~
of ca. 0.40 was isolated, converted to the hydrochloride salt, and recrystallized as in Example 19 to afford a white solid.
Anal. Calc. for C20H23ClN~O3 HCl: C, 58.40; H, 5.88; N, 6.81. Found- C, 58.11; H, 6.03; N, 6.71.
CIMS (CH4~: 377 (37%), 375 (100%3, 239 (31%), 111 (30%).

., , , - , ;. , i, .

:

-56 ~ i&~

IR(Kbr):2944, 2782, 1654, 1596, 1536, 1494, 1400, 1266 cm-l.
lH NMR (d~-DMSO): 10.26 (lH, s), 9.31 (lH, bs), 5 9.09 (lH, bs), 7.67 (2H, d; J = 8.4 Hz), 7.34 (2H, d; J =
8.3 Hz), 6.94-6.86 (4H), 4.65 (lH, m), 4.37 (lH, dd; J =
2.3, 11.-7 Hz), 4.06 (lH, dd; J = 6.8, 11.8 Hæ), 3.29 (lH, bm), 3.19 (lH, bm), 3.00 (lH, bm), 2.38 (2H, bt; J = 7.0 Hz), 1.67 (4H, m) ppm.
13C NMR (d6-DMSO): 170~99, 142.67, 141.82, 138.25, 128.53, 126.47, 121.71, 120.50, 120.42, 117.35, 117.12, 69.14, 64.78, 47.13, 46.32, 35.62, 24.84, 22.02 ppm.
Melting point: 200-202C.
Optical rotation: [~D =-48.6 (c=0.69, methanol).

6-[(2,3-Dih~dro-1,4-benzodioxin-2-yl)methylamino]-N-(4-methoxyphenyl)-hexanamide, monohydrochloride.

Prepared as in Example 19 except using 2,3-dihydro-1,4-benzodioxin-2-methanamine (nonchiral) and using 6-iodo-N-(4-methoxyphenyl)-hexanamide as the alkylating agent. The reaction was run at 80C for 19 hours. The produc~ was isolated as a white solid after chromatography, conversion to the monohydrochloride salt, and drying.
Anal. Calc. for C22H2~N2O4 Hcl. HCl: C,62.77; H, 6.94; N, 6.66. Found: C, 62.57; H, 6.96; N, 6.68.
CIMS (CH4): 385 (100%), 249 (42%).
IR (KBr): 2944, 1656, 1530, 1514, 1496, 1268, 1250, 1238 cm-l. lH NM~ (d6-DMSO): 9.87 (lH, S), 9.4 (lH, vbs), 9.2 (lH, vbs, 7.52 (2H, d; J = 9.2 Hz), 6095-6.85 (4H, m), 6.85 (2H, d; J= 9.0 Hz), 4.66 (lH, m), 4.38 (lH, dd; J =
2.4, 11.7 Hz), 4.06 (lH, dd; J = 6.7, 11.6 Hz), 3.71 ... , :.

., .

(3H, s), 3.19 (lH, m), 3.18 (lH, m), 2.98 (2H, m), 2.30 (2H, bt; J - 7.3 Hz), 1.70 (2H, m), 1.60 (2H, m), 1.35 (2H, m) ppm.
13C NMR (d6-DMSO): 170.39, 154.94, 142.68, 141.84, 132.55, 121.70, 120.53, 120.43, 117.35, 117.11, 113.71, 69.13, 64.82, 55.11, 47.16, 46.21, 35.89, 25.61, 25.00, 24.61 ppm.
Melting point: 154.5-155.5C.

5-[(2,3-D-hYdro-1,4-benzodioxin-2-yl)methylamino]-N-(3,4-dichlorophenyl)-Pentanamide, monohydrochloride.

15Prepared as in Example 19 except using 5-iodo-N-(3,4-dichlorophenyl)-pentanamide as the alkylating agent and using 10:90 ethanol:ethyl acetate as the eluant in the chromatography. The product was recrystallized from 50:50 methanol:ethanol by evaporation of methanol under a steam of nitrogen followed by addition of ether and isolation of the white solid.
Anal. Calc. for C2oH22cl2N2o3 HCl: C, 53.89,; H, 5.20; N, 6.28. Found: C, 53.76; H, 5.41; N, 6.09.
CIMS (CH4); 411 (56~), 409 (100%).
IR (KBr): 2948, 1666, 1592, 1524, 1494, 1476, 1268, 750 cm-l.
1H NMR(d6-DMSO): 10.44 (lH~ S)r 9.20 (lH~ bS)r 9-05 (lH, bs)~
8.04 (lH, d; J = 1.9 Hz), 7.58-7.50 (2H), 6.g4-6.86 (4H), 4.62 (lH, m), 4.36 (lH, dd; J = 2.6, 11.6 Hz), 4.06 (lH, dd;
J = 6.8, 11.8 Hz), 3.31 (lH, m), 3.20 (lH, m), 3.00 (2H, m), 2.39 (lH, bt; J = 6.4 Hz), 1.67 (4H) ppm.
13C NMR ( d6-DMSO): 171.39, 142.67, 141.79, 139.35, 130O87, 130.61, 124.34, 121.71, 120.13, 119.00, 118.92, 117.33, 117.13, 69.13, 64.74, 47.09, 46.30, 35.60, 24.77, 21.87 ppm.
Melting Point. 177-179C.

? ~ :

~ ' ` .

6-[[2-(2,3-~ihydro-1,4-benzodioxin-2-yl)ethyl]amino]-N-phenvl-hexanamide, monohydrochloride.

2-(2,3-Dihydro-1,4-benzodioxin-2-yl)ethylamine hydrochloride (1,057 mg) and 6-o~o-N-phenyl-hexanamide (403 mg) were stirred in dry methanol (25 mL) at 22C and treated with s~dium cyanoborohydride (148 mg). A~ter 68 hours, the reaction was treated with lM hydrochloric acid (ca. 20 mL) and stirred 1 hour. The pH was then brought to 13 using l.OM aqueous sodium hydroxide. Extraction with dichloro-methane, drying with sodium sulfate, and concentration afforded an oil. Chromatography with 0:20:80, then 5:20:80 diethylamine:ethanol:ethyl acetate, and isolation of the component with an Rf of ca. 0.25 in the latter system gave a clear oil (305 mg). This was converted to the hydrochloride salt with l.OM hydrochloric acid and the resulting solid recrystallized from ethanol:ethyl acetate.
Anal. Calc. for C22H28N203 HCl: C, 65.26,; H, 7.22; N, 6.92.
Found: C, 65.06; H, 7.29; N, 6.86.
; CIMS (CH4): 369 (100%).
IR (KBr): 3434, 2946, 1656, 1598, lS40, 1494, 1266, 754 cm-lH NMR (d6-DMSO): 10.00 (lH, S), 8.89 (2H, bs), 7.60 (2H, d; J = 8.6 Hz), 7.28 (2H, t; J = 8.7 Hz), 7.02 (lH, t;
J = 8.5 Hz), 6.90-6.80 (4H), 4.35-4.27 (2H), 3.92 (lH, dd; J
= 6.8, 11.6 Hz), 3.10 (2H, bt~, 2.92 (2H, bt), 2.33 (2H, t; J = 6.7 Hz), 2.00 (2H), 1.70~1.55 (4H), 1.33 (2H) ppm.
13C NM~ (d6-DMSO): 171.05, 142.90, 142.56, 139.35, 128.62, 122.92, 121.42, 121.34, 119,00, 117,15, 116.92, 70.32, 66.78, 46.63, 43.04, 36.06, 26.79, 25.62, 25.29, 24.56 ppm.

,:

~59-6-[[2-(5-Carboxamido-lH-indol 3-yl)ethyl]amino]-N-(4-methoxyphenyl)-heptanamide~ hemifumarate.

2-(5-Carboxamido-lH-indol-3-yl)ethylamine maleate (798 mg) and 6--oxo-N-(4-methoxyphenyl)-heptanamide (623 mg) were stirred in methanol ~15 mL) under nitrogen and treated with sodium cyanoborohydride (190 mg). After 20 hours at 22C, the reaction was treated with saturated aqueous sodium bicarbonate and stirred an additional hour. The reaction was extracted with 20:80 2 propanol:dichloromethane, the extracts dried (Na2SO4), and concentrated to a foam.
Chromatography (0:20:80, then 5O20 80 diethylamine:ethanol:ethyl acetate) gave a component with an Rf of ca. 0.45 which was converted to its hemifumarate salt, a tan solid (870 mg).
Anal. Calc. for C25H32N4O3 0.5 C4H4040 C,65.57; H, 6.93; N, 11.33. Found: C, 65.27; H, 7.24; N, 11.16.
CIMS (CH4): 437 (100%), 263 (45%), 117 (100%).
IR (KB~): 3382, 3190, 2946, 1656, 1602, 1568, 1512, 1366, 1234 cm-l.

lH NMR (d6-DMSO): 11.15 (lH, bs), 9.80 (lH, bs), 8.27 (lH, bs), 7.96 (lH, bs), 7.66 (lH, dd; J = 1.5, 8.5 Hz), 7.49 (2H, d; J = 9.1 Hz~, 7.35 (lH, d; J = 8.5 Hz), 7.27 (lH, d; J = 1.9), 7.10 (lH, bs), 6.84 (2H, d; J = 9.1 Hz), 6.46 (lH, s), 3.70 (3H, s), 3.04-2.93 (5H), 2.27 (2H, bt; J = 7.4 Hz~, 1.69-1.52 (2H), 1.49-1.25 (2H), 1.11 (3H, d; J = 6.4 Hz) ppm.
13C NMR (d6-DMSO): 170.59, 169.01, 168.63, 154.94, 137.81, 132.55, 126.48, 124.61, 124.19, 120.91, 120.56, 118.75, 113.72, 112.28, 110.73, 55.11, 52.54, 45.55, 36.06, 33.91, 25.12, 24.70, 23.57, 17.60 ppm.
Melting point: 236-239C.

.

-60~

7-[[2-(lH-indol-3-yl)ethyl]amino]-N-phenyl-heptanamide, hemifumarate.

Prepared as in Example 25 except using 2-(lH-indol-3-yl)ethylamine hydrochloride and 7-bromo-N-phenyl-heptanamide as the amine and allcylhalide. The component with an Rf of ca. 0.5 in 5:20:80 diethylamine:ethanol:ethyl acetate was isolated Anal. Calc. for C23H2yN3O-0.5 C~H404: C, 71.23; H, 7.41; N, 9.97. Found: C, 70.94; H, 7.64; N, 9.70 CIMS (CH4): 364 (100%), 117 (100%).
IR(KBr): 3408, 3248, 2936, 1674, 1620, 1600, 1550, 1500, 1458, 1442, 1360, 752 cm-l.
lH NMR (d6-DMSO): 10.95 (lH, bs), 10.03 (lH, s), 7.61 (2H, dd; J= 1.1, 8.6 Hz), 7.56 (lH, d; J = 7.8 Hz), 7.35 (lH, d;
J = 7.9 Hz), 7.29-7.24 (2H), 7.18 (lH, d; J = 2.4 Hz), 7.09-6.95 (4H), 6.45 (lH, s), 2.99 (4H, bs), 2~78 (2~, bt; J =
7.3 Hz), 2.30 (2H, t; J = 7.2 Hz), 1.60-1.53 (4H), 1.32-1.27 (4H) ppm.
13C NMR (d6-DMSO): 171.28, 169.33, 139.44, 136.26, 128.65, 126.97, 122.99, 122.90, 121.04, 119.03, 118.35, 118.27, ~-111.4~, 110.64, 48.04, 47.27~ 36.30, 28.32, 26.71, 26.12, 25.00, 22.96 ppm.
Melting Point: 180-182C.

EXAMPI.E 27 5-[(2,3-Dihydro-1,4-benzodioxln-2(S)-yl)methylamino]-N- ~-carboxamidophenyl)-pentanamide, hydrochloride.

Prepared as in Example 19 except using 5-iodo-N-(4-carboxamidophenyl)-pentanamide as the alkylating agent. The product was isolated as an off-white solid.
CIMS (CH4): 384 (100%), 248 (28%).

.
.

.

~3~
IR(KBr): 3373, 1663, 1607, 1528, 1495, 1412, 1264, 755 cm-l.
lH NMR (d6-DMSO): 10.32 (lH, s), 9.29 (lH, bs), 9.07 (lH, bs), 7.85 (lH, bs), 7.82 (2H, d; J = 8.6 Hz), 7.68 (2H, d; J
= 8.6 Hz), 7.23 (lH, bs), 6.95-6.84 (4H), 4.64 (lH, m), 4.37 (lH, dd; J - 2.4, 11.6 Hz), 4.06 (lH, dd; J = 6.6, 11.4 Hz), 3.31 (lH, m), 3.20 (lH, m), 3.00 (lH, m), 2.40 (2H, bt), 1.79-1.63 (4H) ppm.
13C NMR (d6-DMSO): 171.20, 167.33, 142.66, 141.88, 128.51, 128.30, 121.70, 118.02, 117.34, 117.11, 69.14, 64.77, 47.14, 46.34, 35.68, 24.85, 21.99 ppm.
Melting Point: 154-156C. (dec.).
Optical rotation: [~]D =-32.3 (c=0.875, dimethyl sulfoxide).

5-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-L~=
methylphenyl)-pentanamide, monohydrochloride.

Prepared as in Example 20 except using 5-iodo-N-(4-methylphenyl)-pentamide as the alkylating agent and heating at 70C for 18 hours. The crude product was chromatographed using 20:80 ethanol:ethyl acetate. The component with an R~
of ca. 0.50 (in 5:20:80 triethyl amine:ethanol:ethyl acetate) was isolated, converted to the hydrochloride salt, and recrystallized as in Example 19 to afford a white solid.
Anal. calc. for C2lH26N2O3-HCl: C, 54.52; H, 6.98; N, 7.16.
Found: Ct 64.28; H, 7.00; N, 7.15.
CIMS (CH4): 355 (100%).
IR(KBr): 2944, 2716, 1661, 1596, 1524, 1496, 1265 cm-l.
lH NMR (d6-DMSO): 10.01 (lH, s), 7.51 (2H, d; J = 8.4 Hz), 7.08 (2H, d; J - 8.3 Hz) ~ -': '':' . ' ' ' : ,.

6.95-6.84 (4H, m), 4.68 (lH, m), 4.38 (lH, dd; J = 2.4, 11.6 Hz), 4.06 (lH, dd; J = 6.7, 11.7 Hz) 3.29 (lH, bm), 3.17 (lH, dd; J = 8.4, 13.3 Hz) 3.00 (2H, bm), 2.51 (lH, m), 2.35 (2H, t; J = 6.8 Hz) 2.24 (3H, s), 1.70 (4H, bm) ppm.
13C NMR (d6-DMSO): 170.58, 142.69, 141.86, 136.83, 131.79, 128.97, 121.70, 119.04, 117.37, 117.11, 69.15, 64.84, 47.14, 46.33, 35.63, 24.89, 22.19, 20.43 ppm.
Melting Point: 186-187C.

7-[[2 (5-HydroxY-lH-indol-3-yl)ethyl]amino]-N-phen heptanamide, hydrochloride Prepared as in Example 6 utilizing the appropriate reagents to obtain the title compound which was isolated as a brownish, hygroscopic solid.
CIMS (CH4): 380 (100%), 233 (20~), 221 (21%).
Exact mass (CI, C4Hlo) calc.: 380.2338 for free amine.
Found: 380.2332 IR(KBr): 3402, 3130, 2938, 1660, 1598, 1542, 1498, 1492, 1460, 1442, 758 cm-l.
lH NMR (d6-DMSO): 10.66 (lH, d; J = 2.2 Hz~, 9.97 (lH, s), 8.92-8.98 (2H), 7.61 (2H, d; J = 7.6 Hz), 7.28 (2H, app.t; J
= 7.9 Hz), 7.15 (lH, d; J = 8.6 Hz), 7.12 (lH), 7.01 (lH, app.t; J = 7.5 Hz), 6.86 (lH, d; J = 2.2 Hz), 6.Ç3 (lH, dd; J =2.2, 8.6 Hz), 3.14-3.06 (2H), 3.00-2.87 (4H), 2.32 (2H, t; J = 7.3 Hz), 1.65-1.55 (4H), 1.35-1.25 (4H) ppm.

6-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-[3-(trifluoromethyl)phenyl]-hexanamide ! hydrochloride The title compound was prepared as in Example 6 but using the appropriate reagents to obtain thte desired substitutions. The product was a brownish, hygroscopic solid.
Anal. Calc. for C23H26F3N3O2 HClØ8H20: C, 57.04; H, 5.95;
N, 8.68. Found: C, 57.00; H, 5.92; N, 8.69.
CIMS (CH4): 434 (100%).
1H NMR (d6-DMSO): 10.66 (lH, m), 10.39 (lH, s), 8.74-8.66 (2H), 8.5 (lH, s), 7.78 (lH, dd; J = 1.4, 7.8 Hz), 7~54 (lH, t; J = 7.B Hz), 7.38 (lH, d; J = 7.8 Hz), 7.14 (lH, d; J =
8.7 Hz), 7.12 (lH, d; J = 2.2 Hz), 6.85 (lH, d; J = 2.2 Hz), 6.63 (lH, dd; J = 2.2, 8.7 Hz), 3.15-3.05 (2H), 3.00-2.90 (4H), 2.38 (2H, t; J = 7.1 Hz), 1.70-1.60 (4H), 1.38-1.31 (2H) ppm.
l9F NMR (d6-DMSO): -61.149 (s) ppm.

6-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-[2-(trifluoromethyl)phenyl]-hexanamide, hYdrochloride The title compound was prepared as in Example 6 substituting the appropriate reactants as required in Scheme I. The product is a brown, hygroscopic solid.
CIMS (CH4): 434 (100%), 287 (26%). Exact mass (CIMS) calc.
for C23H26F3N3O2 (free amine of title: 43402055. Found:
434.2068.
IR(RBr): 3258, 2950, 1662, 1586, 1522, 1492, 1456, 1320, 1170, 1128, 1112, 770 cm-l.

.. . ~. . , ~, . , . . .

lH NMR (d6-DMSO): 10.67 (lH, bs), 9.59 (lH, s), 8.82-8.72 (2H), 7.73 (lH, d; J = 7.6 Hz), 7.67 (lH, t; J = 7.6 Hz), 7.48 - 7.43 (2H), 7.15 (lH, d; J = 8.7 Hz), 7.12 (lH, d; J
= 2.1 Hz), 6.85 (lH, d; J = 2.3 Hz), 6.63 (lH, dd; J = 2.4, 8.6 Hz), 3.16-3.09 (2H), 2.98-2.89 (4H), 2.35 (2H, bt), 1.67-1.55 (4H), 1.38-1.30 (2H) ppm.
l9F NMR (d6-DMSO): -59.104 5-[(2,3-DihYdro-1,4-benzodioxin-2-yl)methylamino]-N-[_-(dimethylaminoLphenyl]-pentanamide, dihydrochloride The title compound was prepared as in Example 19 substituting the appropriate alkylating reactant. The product was a very hygroscopic white solid.
IR(KBr): 3434, 1550, 1516, 1494, 1266, 840 cm-l.
CIMS (CH4): 384 (100%).
lH NMR (d6-DMSO + D2O): 7.67 (2H, d; J = 9.1 Hz), 7041 (2H, d; J = 9.1 Hz), 7.00-6.91 (4H), 4.55 (lH, bm)~ 4.34 (lH, dd;
J = 2.2, 11.7 Hz), 4.02 (lH, dd; J = 6.8, 11.6 Hz), 3.31 (lH, dd; J = 3.1, 13.6 Hz), 3.22 (1~, dd; J = 9.2, 13.6 Hz), 3.10 (6H, s), 3.04 (2H, bt), 2.39 (2H, bt), 1.68 (4H) ppm.
13C NMR (d6-DMSO ~ D2O): 172.56, 143.24, 142.33, 138.02, 122.)37, 122.76, 121.37, 120.12, 118.30, 117.94, 69.72, 65037, 47.94, 47.13, 45.56, 36.16, 25.47, 22.60 ppm.

7-[(2,3-DihYdro-1,4-benzodioxin-2-yl)methylamino~-N-[4-(trifluoromethyl)phenvl]-he~tanamide, hYdrochloride The title compound was prepared as in Example 19, except using 7-bromo-N-[4-(trifluoromethyl)phenyl]-heptanamide as , .
. . . .
, , the alkylating agentO The product is a white so~
Melting point: 208-210C.

Anal. Calc for C23H27F3N2O3 HCl: C, 58.41; H, 5.97; N, 5.92.
Found: C, 58.35; H, 6.07; N, 5.76.

5-[(2,3-Dihydro-1,4 benzodioxin-2-yl)methylamino~-N-Phenyl-pentanamide, monohydrochloride Prepared as in Example 19 except using 5-iodo-N-phenyl-pentamide as the alkylating agent and heating at 82C for 15.5 hours. The crude product was chromatographed using 3:10:90 diethylamine:ethanol:ethyl acetate. The component with an Rf of ca. 0.50 (in 5:20:80 triethyl amine:ethanol:ethyl acetate) was isolated, converted to the hydrochloride salt, and recrystallized as in Example 19 to afford a white solid.
Anal. calc. for C20H24~2O3 HCl: C, 63.73; H, 6.70; N, 7:43.
Found: C, 63.72; H, 6.67; N, 7.47.
CIMS (CH4): 341 (100%).
IR(KBr): 3434, 2944, 1663, 1598, 1528, 1496, 1476, 1264 cm-l.
lH NMR (d6-DMSO: 10.04, (lH, s), 9~10 (2H, bd) 7.61 (2H, d; J
= 7.6 Hz), 7.29 (2H, t; J = 8.0 Hz), 7.02 (lH, t; J = 6.4 Hz3, 6.92 (4H, m), 4.63 (lH, m), 4.37 (lH, dd; J = 11.6, 2.4 Hz), 4.06 (lH, dd; J = 11.6, 6.7 Hz), 3.30 (lH, m), 3.25 (lH, m), 3.01 (2H, bm), 2.37 (2H, t; J = 6.7 Hz), 1.68 (4H, bm) ppm.
13C NMR (d6-DMSO): 170.79, 142.67, 141~81, 139.27, 128.62, 122.98, 121.71, 119.00, 117.35, 117.12, 69.15, 64.77, 47.17, 46.34, 35.63, 24.89, 22.09 ppm.
Melting Point: 180.5-lB1.5C.

:~ , . .: :
.
.. :

-66- ~ ~ ~a~

5-[(2,3-Dihydro-1,4-benzodioxin-2(S)-yl)methylamino]-N-~4-methoxyphenyl)pentanamide, monohYdrochloride Prepared as in Example 19 except using the 5-iodo-N-(4-methoxyphen~l)-pentamide as the alkylating agent and heating at 62C for 24 hours. The crude product was chromatographed using 0: ln: 90 then 3:10:90 diethylamine:ethanol:ethyl acetate. The component with an Rf of ca. 0.50 (in 5:20:80 triethylamine:ethanol:ethyl acetate) was isolated, converted to the hydrochloride salt and recrystallized as in Example 19 to afford a pale yellow solid.
Anal. Calc. for C2lH26N2O4-HCl: C, 61.98; H, 6.70; N, 6:88.
Found: C, 62.00; H, 6.85; N, 6.74.
CIMS (CH4): 371 (100%).
IR(KBr): 3132, 2941, 165~, 1597, 1527, 1518, 1496 cm-l.
lH NMR (d6-DMSO): 9.88 (lH, s), 9.20 (lH, bs), 9.00 (lH, bs) 7.51 (2H, d; J = 9.1 Hz3, 6.90 (6H, m), 4.62 (lH, m)~ 4.36 (lH, dd; J = 11.7, 2.4 Hz), 4.06 (lH, dd; J = 11.7, 6.7 Hz), 3.71 (3H, s), 3.33 (lH, bs), 3.20 (lH, m~, 3.00 (2H, bs), 2.33 (2H, t; J = 6.6 Hz), 1.66 (4H, bm) ppm.
l~C NMR (d6-DMSO): 170.23, 155.00, 142.68, 141.81, 132.46, 121.73, 120.5, 120.4, 117.4, 117.1, 113.8, 69.2, 64.8, 55.1, 47.2, 46.36, 35.49, 24.92, 22.15 ppm.
Melting point: 198-199C.

~01533A -66-, ,. ;

5-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4-fluorophenyl)-pentanamide, monohydrochloride Prepared as in Example 19 except using the 5-iodo-N-(4-fluorophenyl)-pentamide as the alkylating agent and heating at 60C for 20 hours. The crude product was chromatographed using 0:10:90 then 3:10:90 diethylamine: ethanol:ethyl acetate. The component with an Rf of ca. 0.50 (in 5:20:80 triethylamine:ethanol:ethyl acetate) was isolated, converted to the hydrochloride salt and recrystallized as in Example 19 to afford a tan solid.
Anal. Calc for C20H23N2O3 HCl: C, 60.83; H, 6.14;
N, 7:09.
Found: C, 60.87; H, 6.32; N, 6.98.
CIMS (CH4): 359 (100~).
IR(KBr): 3294, 2943, 1653, 1510t 1495 cm-l.
lH NMR (d6-DMSO): 10.17 (lH, s), 9.35 (lH, bs), 9.12 (lH, bs), 7.64 (2H, dd; J = 9.1, 5.1 Hz), 7.13 (2H, t; J = 8.9 Y.z), 6.89 (4H, m), 4.65 (1~, m), 4.37 (lH, dd; J = 11.6, 2.4 Hz), 4.06 (lH, dd; J = 11.7, 6.8 Hz), 3.32 (lH, bs), 3.29 (lH, bs), 3.01 (2H, bs), 2.36 (2H, t; J = 6.7 Hz), 1.67 (4H, bs) ppm.
13C (d6-DMSO): 170.70, 159.37, 156.20, 142.68, 141.83, 135.70, 121.71, 120.74, 120.64, 117.36, 117.12, 115.31, 115.01, 69.15, 64.80, 47.15, 46.34, 35.55, 24.86, 22.10 ppm.
Melting pointO 167-169C.

, . . . . . .. .
,. , ~ ~ . .. .
' ~ , '. .. !, . . .

' , '~ ' '~` . ' :

6-[[2-(5-Hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(1-pentyloxy)phenyl]-hexanamide hYdrochloride hydrate.

The title comopund was prepared as described in Example 6, with the appropriate reagents to give the desired substitution. The compound was a tan solid.
IR(KBr): 3280, 2956, 2936, 1654, 1540, 1512, 1468, 1238, 832, 801 cm-l.
CIMS: (CH4): 452 (100%), 305 (34%).
lH NMR (d6-DMSO): 10.66 (lH, bs), 9.83 (lH,S), 8.84 (2H, bs), 8.69 (lH, bs), 7.50 (2H, d; J = 9.1 Hz), 7.13-7.10 (2H), 6.87-6.80 (3H), 6.62 (lH, dd; J = 2.2, 8.6 Hz), 3.89 (2H, t; J = 7.2 Hæ), 3.15-3.06 (2H), 3.00-2.89 (4H), 2.30 (2H, t; J = 7.4 Hz), 1.70-1.53 (6H~, 1.35-1.28 (6H), 0.88 (3H, ; J = 6.7 Hz) ppm.
l3C NMR (d6-DMSO): 170.48, 154.39, 150.38, 132.44, 130.78, 127.46, 123.58, 120.52, 114.31, 111.82, 111.56, 108.35, 102.08, 67.48, 47.03, 46.53, 35.94, 28.43, 27~74, 25.69, 25.32, 24.67, 21.92, 21.81, 13.94, ppm.

. .

Claims (34)

WHAT IS CLAIMED IS:

1. A compound of the formula:

in which B is represented a C1-4 alkylene bridging group;
Alk is represented by a linear alkylene bridging group containing from 2-8 carbon atoms which may optionally be monosubstituted at one carbon atom with a C1-4 alkyl, phenyl, substituted phenyl, or alkylphenyl substituent in which the phenyl ring may be optionally substituted; D is represented by a bond or an ethenylene bridging group; X, Y, and Z are each independently represented by hydrogen, C1-4 alkyl, phenyl, substituted phenyl or alkylphenyl in which the phenyl ring may be optionally substituted; R1 is represented by a substituent selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-5 alkoxy, CF3, OCF3, OH, NO2, CN, -NR2R3, -CONR2R3, -COOR4, -CH2SO2NR2R3, SO2NR2R3, and -OCH2COOR4; R2 and R3 are each independently represented by H or a C1-4 alkyl; R4 is represented by H, C1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; Het is represented by one of the following substituents:

or in which R is represented by a substituent selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-5 alkoxy, CF3, OCF3, OH, NO2, CN, -CH2SO2NR5R6, -SO2NR5R6, OCH2C6H5, -CONR5R6, -COOR7 and -OCH2COOR7; R5 and R6 are each independently represented by H or C1-4 alkyl; R7 is represented by H, C1-4 alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in which the phenyl ring may be optionally substituted; A is represented by H, or C1-4 alkyl;
or a pharmaceutically acceptable salt thereof; with the proviso that when Het is an indolyl derivative, then R1 is not a carbonyl derivative.

2. A compound according to claim 1 in which Het is represented by

3. A compound according to claim 1 in which Het is represented by:

4. A compound according to claim 1 in which D is a direct bond.

5. A compound according to claim 1 in which B is ethylene.

6. A compound according to claim 2 in which R is OH.

7. A compound accoring to claim 6 in which X is H and B
is ethylene.

8. A compound according to claim 7 in which X is H, CH3 or -CH2CH3.

9. A compound according to claim 8 in which Alk is butylene or pentylene.

10. A compound according to claim 9 in which R1 is a 4-substituent.

11. A compound according to claim 10 in which R1 is -CF3 or -OCH3.

12. A compound accoring to Claim 3 in which R is H.

13. A compound according to claim 12 in which B is methylene.

14. A compound according to claim 13 in which X is H.

15. A compound according to claim 14 in which Y is H.

16. A compound according to claim 15 in which Alk is propylene or butylene.

17. A compound according to claim 16 in which D is a bond and Z is H.

18. A compound according to claim 11 in which D is a bond and Z is H.

19. A compound which is selected from the group consis-ting of:
5-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4-(trifluoromethyl)phenyl]pentanamide;
6-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[2-(trifluoromethyl)phenyl]hexanamide;
6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]heptanamide;
7-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)octanamide;
6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-phenyl-heptanamide;
5-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]hexanamide;
6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)heptanamide;
6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]hexanamide;
6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(3,4-dimethoxyphenyl)heptanamide;
6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)octanamide;
4-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]pentanamide;
6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-(2-methoxyphenyl)heptanamide;
5-[(2,3-dihydro-1,4-benzodioxin-2(S)-yl)methylamino]-N-(4-chlorophenyl)pentanamide;
5-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(3,4-dichlorophenyl)pentanamide;
5-[(2,3-dihydro-1 r 4-benzodioxin-2-yl)methylamino]-N-(4-dimethylaminophenyl)pentanamide;
6-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4-methoxyphenyl)hexanamide;
7-[2-[(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-phenyl-heptanamide;
5-[(2,3-dihydro-1,4-benzodioxin-2(S)-yl)methylamino]-N-[4-(trifluoromethyl)phenyl]pentanamide; and 6-[[2-(5-hydroxy-lH-indol-3-yl)ethyl]amino]-N-[3-(tri-fluoromethyl)phenyl]hexanamide;
or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising an effec-tive amount of a compound, as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.

21. A pharmaceutical composition for use in the treat-ment of depression which comprises an effective antidepres-sant amount of a compound, as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.

22. A pharmaceutical composition for use in the treat-ment of anxiety which comprises an effective anxiolytic amount of a compound, as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.

23. A pharmaceutical composition for use in producing an agonist effect at the 5HTlA or 5HTlD receptor in a pat-ient which comprises an effective agonist effect producing amount of a compound, as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.

24. A pharmaceutical composition for use in the treat-ment of hypertension which comprises an effective anti-hypertensive amount of a compound, as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.

25. A process for producing a compound as defined in claim 2 comprising carrying out the reaction depicted below in Reaction Scheme I in which:
a) an amidation reaction is carried out between an acid derivative of structure 1 and N,O-dimethylhy-droxylamine thereby producing an amido-derivative depicted by structure 3;
b) subjecting said amido-derivative of structure 3 to a Grignard reaction as depicted, thereby producing a compound of structure 5; and c) subjecting said compound of structure 5 to a reduc-tive amination with an indole derivative of struc-ture 6 to produce a compound of Formula Ia as shown below:

REACTION SCHEME I
STEP A
STEP B

STEP C
Formula Ia

26. A process for producing a compound as defined in claim 3 comprising carrying out the reaction depicted below in Reaction Scheme II in which an N-alkylation is carried out between a benzodioxan derivative of structure 7 and an alkylhalide derivative of structure 8 to produce a compound of Formula Ib as shown below:

Formula Ib

27. A method for the treatment of depression comprising administering an antidepressant amount of a compound according to claim 1.

28. A method for the treatment of anxiety comprising administering an anxiolytic amount of a compound according to claim 1.

29. A method for producing an agonist effect at the 5HTlA or 5HTlD receptor comprising administering a compound according to claim 1 to a patient in need thereof.

30. A method for the treatment of hypertension compris-ing the administration to a patient in need thereof an ef-fective amount of a compound according to claim 1.

31. A composition comprising a compound according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 in admixture with an inert carrier.

32. A composition according to claim 31 wherein said composition is a pharmaceutical composition.

33. Use of a compound according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 as a medicine.

34. Use of a compound according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 as a medicine in the treatment of anxiety, depression, stroke, hypertension, or migraine.