CA2185236A1 - Method for treating 5ht2b receptor related conditions - Google Patents

Abstract

The present invention provides methods for binding a 5-HT2B receptor in mammals using both known and novel compounds.
Further, the invention provides a method for treating or preventing 5-HT2B related conditions. Finally, the invention provides an article of manufacture.

Description

WO 95/24200 . ~ 3~

2 ~ 85236 TITLE

Field of the Tnvention The present invention relates to a method for treating 5HT2B receptor related conditions. Further, this application discloses new compounds of Formulas XI and XII infra.
Backarollnd of the Invention This invention is directed to a method for treating a mammal suffering from or:susceptible to a condition associated with modulation of a 5-HT2B receptor.
Blocking serotonin receptors has been shown to result in a number of beneficial pharmacological effects, including reduction in disease states such as hypertension, depression, anxiety, and the like; see U.S. Patent No 5,141,944. Nelson et al., Psvchor-h~rm;3coloav iln~l BiochGmistrv of Nellrotr;3ncmitter Rece~tors, eds. ~.I
Yamamura et al., Elsevier/North ~olland Inc., p 325, have rrn~i rm~ that there are multiple serotonin recognition sites. The general class of serotonin receptors are referred to as the 5-HT receptors.

W0 95/24200 P~ O
;~ 2185236 Specific 5-HT receptor sites include 5-HTlA, 5-HTlB, 5-HTlD, 5-HT2.~, 5 -HT2g, 5-HT2C, 5-HT3, and 5-HT4 sites . Each of these receptors mediates certain physiolPgical effects. See Leonard, B.E., Inter~tion~l Clin;cal Psvnhor-h~rm~cQlD~v, 7:13-21 (1992).
This invention provides a method for using =
compounds which are active at the 5-HT2~3 receptor= to treat or prevent 5-HT2B related conditions. Further, this invention provides a method for selectively blocking the 5-HT2s receptor. Additionally, this invention provides a method for blocking human 5-HT2g receptorS. ~ The 5-HT2B receptor active compounds provide a useful tool for characterizing the 5-HT2s receptor .
This invention provides a group of compounds which are 5HT2g receptor antagonists. Applicants have discovered that such compounds are potent competitive inhibitors of serotonin-induced contraction of the colon. Thus, this invention provides compounds which can act to normalize gastrointestinal motility and be useful in the treatment of Functional Bowel Disorders.
Further, it has been discovered the 5-HT2B receptor is localized in the rat lung, stomach fundus, uterus, bladder, and colon. Interesting areas of 5-HT2B receptor localization in the human include but are not limited to the brain and blood vessels. Thus, conditions which can be treated using a compound which modulates a 5-HT2B receptor includes, for~examp~e, psychosis, depression, anxiety disorders, uterine diseases such as endometriosis, fibrosis, and other Ahnnrm~l uterine contractivity, panic attack, migraine, eating d~sorders, seasonal affective disorder, consumption disorders, cardiovascular conditions, ~ such as thrombosis, hypertension, angina, vasospasm, and other vascular occlusive diseases, incontinence, bladder dysfunction, respira~ory/airway disorders including asthma, and the like.

~ WO 95/24200 PCrll~S95/03099 ~V of the Invention This invention provides a method for treating a mammal suf f ering f rom or susceptible to a condition associated with dysfunctionaI or abnormal 5-HT2B receptor stimulation, comprising administering an effective amount of a compound interacting with the 5HT2g receptor as an agonist, partial agonist or antagonist selected from the group consisting of a compound of the Formula I
(~NRl I

wherein:
Q is hydrogen or (CHR2)R~
Rl is hydrogen or Cl-C3 alkyl;
R2 is hydrogen or Cl-C3 alkyl;
R3 is hydrogen or Cl-C3 alkyl;
R4 is Cs-c8 cycloalkyl, substituted Cs-c8 cycloalkyl, Cs-C8 cycloalkenyl, subsl~ituted Cs-Cg cycloalkenyl, bicyclic or substituted bicyclic;
A is selected f rom the group consisting of R7~ (IIa) f ~ ~ (IIIa) R7--~
R8 ' and WO 95/24200 r ~ oss R
6~
R7-- ( IVa ) R8 ; J
wherein R6 and R7 are, independently, hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, halo, halo(Cl-C6)alkyl, halo(C2-C6~alkenyl, CORs, Cl-Clo alkanoyl, CO2Rs~, (Cl-C6 alkyl)mamino, NO2, -SR5, or ORs;
m is 1 or 2;
Rs is independently hydrogen or Cl-C4 alkyl;
Rs~ is Cl-C4 alkyl;
R8 is independently selected from the group consisting of an R6 group, substituted C3-c8 cycloalkyl, C3-C8 cycloalkyl, C3-Cg cycloalkyl- (Cl-C3) alkyl, Cs-Cg cycloalkenyl, substituted Cs-C8 cycloalkenyl, Cs-C8 cycloalkenyl- (Cl-C3 ) alkyl, C7-C20 arylalkyl; or R6 and R7 toyether with the ~carbon atoms of group A form a 5- to 8-member carbon ring;, a compound of Formula II

~NRgR10 II

H

wherein R8 is selected from the group consisting of~
hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, halo, halo(C2-C6)alkyl, halo(Cl-C6)alkenyl, CORs, Cl-Clo alkanoyl, CO2R5~~ (Cl-C6 alkyl)mamino, NO2, -SRs, ORs, substituted C3-Cg cycloalkyl, C3-C8 cycloalkyl, C3-C8 Cycloalkyl-(cl-c3)alkyl~ CS-C8 cycloalkenyl, substituted Cs-c8 cycloalkenyl, C5-C8 cycloalkenyl-(Cl-C3)alkyl, and C7-C20 arylalkyl;
Rs is independently hydrogen or Cl-C4 alkyl;
Rs~ is Cl-C4 alkyl;

~ W0 95/24200 . ~
`` ~ i 2~ 85236 Rg and Rlo are independently selected from the group consisting of hydrogen, Cl-c6 alkyl, substituted C3-c8 cycloalkyl, C3-Cg cycloalkyl, C3-Cg cycloalkyl- (Cl-C3 ) alkyl, Cs-Cg cycloalkenyl-(Cl-C3)alkyl, C7-C20 arylalkyl;
Rll is selected from the group consisting of Cl-C4 alkyl, ORs1, fluoro, bromo, iodo, and chloro;
Rl2- is selected from the group consisting of hydrogen and Cl-C4 alkyl;
a compound of Formula III

~NR12 ~ m N
wherein:
Rl2 is Cl-C4 alkyl or allyl;
Rl3 is -O- or -~ (Rls ) -;
Rl5 is hydrogen or Cl-C~ alkyl;
Rl4 is Cl-C4 alkyl, hydroxy Cl-C4 alkyl, C3-C7 cycloalkyl, and C3-C7 cycloalkyl substituted with hydroxy or methoxy;
O a compound of Formula IV

WO 9S/24200 PCr/US95/03099 ~

C - N~ H2)m' N1s, wherein:
R15 is Cl-C4 alkyl;
R16 is allyl or Cl-C4 strai~ht chain alkyl;
R17 is hydrogen or Cl-C4 straight chain alkyl;
Rl8 is hydrogen, Cl-C4 alkyl, hydroxy, or Cl-C4 alkyloxy;
m~ is 0, 1, 2, or 3;
a compound o~ Formula V
o R21 I -N--(alk)--R22 /~
~ NR20 V

wherein:
Rl9 is Cl-C4 alkyl;
R20 is allyl or Cl-C4 straight c~ain alkyl;

,~ W09~/24200 R21 is hydrogen or C1-C4 straight chain alkyl;
R22 is pyridinyl or imidazolyl;
alk is a divalent organic radical derived from a straight or branched C1-Cs alkane;
a compound of Fo~mula VI
COO--CHRZ4_ R2s wherein:
R23 is C1-C3 alkyl or allyl;
R2~ is C1-C3 hydroxyalkyl or C1-C3 dihydroxyalkyl;
R25 is hydrogen or CE~3;
a compound of Formula VII
~CH3 .

W0 95/2420~ r~
"f ~' r~f~ ~ ~ 21 85236 a compound of Formula VIII
N
R25' is hydrogen or metho~qr;
a compound of Formula Ig wherei~:
yb, in combination with the carbon atom to which it is joined, defines a substituted or unsubtituted aromatic heterocyclic 5-membered ring selected from the group consisting of ~ =
R2a R2a ~7 R29 1~ R29 --CH, R26 is hydrogen, Cl-C3 alkyl, allyl, or .

~I woss/24200 r~"~ 099 i 2185236 R27 is hydrogen, C1-C3 alkyl, allyl, , or (CH2) n~ ~X;
n' is 1 to 5;
X" is an optionally substitutea phenyl, C1-C3 alkoxy, or C1-C3 alkylthio;
R28 and R29 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, C1-C3 alkylthio, halo, CN, phenyl; or together are - (CX2) p" ~ i p" is 3 to 6;
Y~ is -CX2-, -O-, ~S()m~~;
m~ is O, 1, or 2; and a compound of the Formula X
'?~
N ~
h~ NH X
C~
or a pharmaceutically acceptable salt or solvate thereof.
This invention provides a method for treating a ma~nmal suffering from or susceptible to a condition associated with dysfunctional or abnormal 5-XT2B receptor stimulation, comprising administering an effective amount of a compound interacting with the 5XT2g receptor as an agonist, partial agonist or antagonist selected from the group consisting of a compound of the Formula XI
.

Wo95124200 PCr/US95/03099 2~ 85236 ,~i I",,~.j~. ~ C 10 ~X~ ;
R3 a wherein Q ' is selected from the group consisting of hydrogen, R34, and CXR2 ) R4;
R34 is selected from the group consisting of s~iro- ~
bicyclic, substituted sI)iro-bicyclic, bicyclic or substituted bicyclic;
Rl is hydrogen or Cl-C3 alkyl;
R2 is hydrogen or Cl-C6 alkyl;
R3 is hydrogen or Cl-C3 alkyl;
R~ is Cs-Cg cycloalkyl, substituted Cs-Cs cycloalkyl, Cs-C8 cycloalkenyl, substituted Cs-cg cycloalkenyl, bicyclic or substituted bicyclic;
A is selected from the group consisting of R,~ (IIa) R6~
~ ( IIIa ) R~ ~J
, and f'\~
R7 1 ( IVa ) R8~

~ W0 95124200 r~ O99 .. . .
11 2!85236 wherein R6 and R7 are, independently, hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, halo, halo(Cl-C6)alkyl, halo~C2-C6)alkenyl, CORs, Cl-Clo alkanoyl, C02Rs~, (Cl-C6 alkyl)mamino, N02, -SR5, or OR5;
m is 1 or 2;
R5 is independently hydrogen or Cl-C4 alkyl;
R5, is Cl-C~, alkyl;
R8 is independently selected from the group consisting of an R6 group, substituted C3-c8 eycloalkyl, C3-C8 cycloalkyl, C3-Cg cycloalkyl- (Cl-C3 ) alkyl, Cs-Cg cycloalkenyl, substituted Cs-C8 cyeloalkenyl, C5-C8 cycloalkenyl- (Cl-C3 ) alkyl, C7-C20 arylalkyl; or R6 and R7 together with the carbon atoms of group A form a 5- to 8-member carbon ring;
R30 and R31 join to form a 3 to 8 member carbon ring; or R30 and R31 are independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; or a pharmaceutically acceptable salt or solvate thereof.
This invention provides a method for treating a mammal suffering from or suseeptible to a condition assoeiated with dysfunetional or abnormal 5-E~T2B reeeptor stimulation, eomprising administering an effeetive amount of a eompound interaeting with the 5~T2B reeeptor as an agonist, partial agonist or antagonist seleeted from the group consisting of a eompound of the Formula XII

H
Xll A is seleeted from the group eonsisting of WO 95/24200 P~ /Q~099 0 12 ~ 2 ~ 8 ~ 2 3 6 R7~ ~IIa) R6~C~
~ (IIIa) ~\
R~ , and R7 l ( IVa ) wherein R6 and R7 are, independently, hydrogen, Cl-C6 aIkyl, C2-C6 alkenyl, halo, halo(Cl-C6)alkyl, halo(C2-C6)alkenyl, CORs, C1-Clo alkanoyl, CO2Rs., (Cl-C6 alkyl)mamino, NO2, -SR5, or ORs;
m is 1 or 2;
R8 is selected from the group consisting of hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, halc, halo(C2-C6)alkyl, halo(Cl-C6)alkenyl, CORs, Cl-Clo a1kanoyl, CO2R5~ (cl-c6 alkyl)mamino, NO2, -SRs, ORs, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, c3-c8~cycloalkyl-(cl-c3)alkyl~ Cs-c8 cycloalkenyl, substituted C5-C8 cycloalkenyl, Cs-c8 cycloalkenyl-(Cl-C3)alkyl, and C7-C20 arylalkyl;
R5 is independently hydrogen or Cl-C4 alkyl;
R5, is C1-C~ alkyl;
R6 and R7 together with the carbon atoms of group A
form a 5- to 8-member carbon ring;
Rg and Rlo ~are independéntly selected from the group consisting of hydro~en, Cl-C6 alkyl, su~stituted C3-C8 WO 95/24200 ~ 1)99 . ~I t ~`
13 2~85236 cycloalkyl, C3-Cg cycloalkyl, C3-C3 cycloalkyl-~C1-C3)alkyl, Cs-C3 cycloalkenyl-rCl-C3~alkyl, C7-c20 arylalkyl;
Rll is selected from the group consisting of Cl-C~, alkyl, ORs, fluoro, bromo, iodo, and chloro;
R30 and R31 join to form a 3 to 8 member carbon ring; or ~ ~ =
R30 and R31 are independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; or a pharmaceutically acceptable salt or solvate thereof.
Second, this invention provides a method for blocking a 5HT2B receptor in a mammal, comprising administering a 5HT2g receptor occupying dose of a compound selected from the group consisting of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X supra.; or a pharmaceutically acceptable salt or solvate thereof.
This invention provides a method for blocking a 5HT2B receptor in a mammal, comprising administering a 5HT2s receptor occupving dose of a compound selected from the group consisting of Formula XI, and XII supra.; or a pharmaceutically acceptable salt or solvate thereof.
Third, this invention provides a method for selectively interacting with the 5-HT2B receptor in a mammal, comprising administering a 5-HT2B selective compound selected from the group consisting of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X supra.; or a pharmaceutically acceptable salt or solvate thereof to a mammal.
This invention provides a method for selectively interacting with the 5-HT2g receptor in a mammal, comprising administering a 5-HT2g selective compound selected from the group consisting of of Formula XI and XII; or a pharmaceutically acceptable salt or solvate thereof to a mammal .
The present invention provides compounds of the Formula XI

WO 95/24200 r~ IIL ,,, r, ~, O
t~ 21 85236 C~ R31 wherein Q ~ is selected from the yroup consisting of hydroyen, R30" and ( C~IR2 ) R4;
R34 is selected from the yro~p consistiny of spiro-~:
bicyclic, substituted sE~iro-bicyclic, bicyclic or substituted bicyclic i R1 is hydrogen or C1-C3 alkyl;
R2 is hydroyen or C1-C6 alkyl;
R3 is hydro~ren or C1-C3 alkyl;
R4 is Cs-Cg cycloalkyl, substituted Cs-Cs cycloalkyl, Cs-C8 cycloalkenyl, substituted Cs-cs cycloalkenyl, bicyclic or ~=.
substituted bicyclic;
A is selected from the yroup~ consisting of R7 ~)~ ( I I a ) `1~
Ra ~ ( IIIa) R7 ~,J
Ra , and R7-- ( IVa ) R8~

~WO 9~il24200 r~"~ J, 5'~ f' 2~85236 wherein R6 and R7 are, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, halo~C1-C6)alkyl, halo(C2-C6)alkenyl, COR5, C1-C1o aIkanoyl, CO2Rsl, (C1-C6 alkyl)mamino, NO2, -SR5, or ORs;
m is 1 or 2;
R5 is independently hydrogen or C1-C4 alkyl;
R5, is C1-C~, alkyl;
R8 is independently selected from the group consisting of an R6 group, substituted C3-c8 cycloalkyl, C3-C8 cycloalkyl, C3-Cg cycloalkyl- (C1-C3 ) alkyl, Cs-C8 cycloalkenyl, substituted Cs-c8 cycloalkenyl, Cs-c8 cycloalkenyl- (C1-C3 ) alkyl, C7-C20 arylalkyl; or R6 and R7 together ~7ith the carbon atoms of yroup A form a 5- to 8-member carbon ring;
R30 and R31 join to form a 3 to 8 member carbon ring; or R30 and R31 are independently selected from the group consisting of Cl-C6 alkyl and C2-C6 alkenyl; or a pharmaceutically acceptable salt or solvate thereof.
This invention provides compounds of Formula XII

~ R R10 Xll A is selected from the group consisting of F~ ~ ( I Ia ) W0 95/24200 l ~llu., ~/0~099 ~ 2 1 8 5 2 3 6 \
~ ( IIIa ) R7--~J
R8 , and R7-- ( IVa ) ~/~

wherein R6 and R7 are, independently, hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, halo, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, CORs, C1-Ç1o alkanoyl, CO2Rs~, ~C1-C6 alkyl)mamino, NO2, -SR5, or OR5;
m is 1 or 2;
R8 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, halo~C2-C6)alkyl, halo~C1-C6)alkenyl, CORs, Cl-Clo alkanoyl, Co2Rs~, ~ (C1-C6~
alkyl)mamino, NO2, -SR5, ORs, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-c8 cycloalkyl- (C1-C3 ) alkyl, C5-C8 cycloalkenyl, substituted C5-C8 cycloalkenyl, C5-C8 cycloalkenyl - (C1-C3 ~ alkyl, and C7-C20 arylalkyl;
R5 is independently hydrogen or C1-C4 alkyl;
R5. is C1-C4 alkyl;
R6 and R7 together with the carbon atoms of group A
form a 5- to 8-m-em~er carbon ring;
Rg and R1o are independently selected from the group consisting of hydrogen, Cl-c6 alkyl, substituted C3-C8 cycloalkyl, C3-Cg cycloalkyl, C3-Cg cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, C7-C20 arylalkyl; t R11 is selected from the group consisting of C1-C4 alkyl, ORs-, fluoro, bromo, iodo, and chloro;

~ WO 95/24200 PCTn~S95J03099 R30 and R31 join to form a 3 to 8 member carbon ring; or R30 and R3l are independently selected from the group consisting of C1-C6 alkyl and C2-C~ alkenyl; or a pharmaceutical~y acceptable salt or solvate thereof.
Finally this invention provides a method for interacting with a human 5-HT2g receptor in a human, comprising administering a 5-HT2g blocking dose of a compound selected from the group consisting of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X supra.; or a pharmaceutically acceptable salt or solvate thereof to a human.
This invention provides a method for interacting with a human 5-HT2g recepto~ in a human, comprising administering a 5-HT2g blocking dose of a compound selected from the group consisting of Eormula XI and XII; or a pharmaceutically acceptable salt or solvate thereof.
A further embodiment of this invention is an article of manufacture comprising packaging material and one or more pharmaceutical agents contained within said packaging material, wherein said pharmaceutical agent is effective for the treatment of a condition re(auiring 5-HT2B receptor occupation and is selected from the group consisting of a compound of Formula I, II, III; IV, V, VI, VII, VIII, IX, and X supra.; or a pharmaceutically acceptable salt or solvate thereof; and said packaging material comprises a label which indicates that said pharmaceutical agent can be used for the treatment of a condition rerluiring 5-HT2B receptor modulation.
Another embodiment of this invention is an article of manufacture comprising packaging material and one or more pharmaceutical agents rnn~in,o~ within said packaging material, wherein said pharmaceutical agent is effective for the treatment of a condition rer~uiring 5-HT2B receptor occupation and is selected from the group consisting of a compound of Formula XI, and XII supra.; or a pharmaceutically acceptable salt or solvate thereof; and said packaging material comprises a label which indicates that said .. _ _ _ _ _ . . . .. .

W0 95124200 P~ '0~099 0 ? ~ C ?i~ r pharmaceutical agent can be used for the treatment of a condition requiring 5-~T2B receptor modulation.
DetAi led ~escriotion of the Invention The term " treating " as used herein includes ~~
prophylaxis of the named physical and/or mental condition or amelioration or ~l;m;nAt;on of the developed physical and/or mental condition once it has been established.
The terms "Cl-Cn alkyl~' wherein n= 2-10, as used herein, represent a branched or linear alkyl group having from one to the specified num.ber ~of carbon atoms. Typical C1-C6 alkyl groups include methyl, ethyl, n-propyi, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like .
As used herein, the term "R30 and R31 join to form a

3 to 8 member carbon ring" shall mean that R30 and R31 are most preferably independently seIected from the group consisting of C1-C6 alkyl and C2-C6 alkenyI. ~The carbon ring thus formed may be saturated or unsaturated. As used herein, such ring may be illustrated as: ~
13 n; wherein n30 shall refer-to the total number of carbon atoms in the ring thus formed. Such carbon ring may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, C1-C6 alkyl, NO2, halo, halo~C1-C6)alkyl, halo(C2-C6)alkenyl, C2-C6 alkenyl, CO2Rs, ~C1-C6 alkyl)mamino, -SRs, and ORs.: A
preferred embodiment is when R30 and R31 join to form a C3-C6 member saturated carbon ring. It is another preferred embodiment that R30 and R31 join to form a C3-Cs member saturated carbon ring. ~
When R30 and R31 do not join to form a carbon ring, it is a preferred embodiment that R30 and R31 are _ independently selected from the group consisting of C1-C3 alkyl .
The terms l'C2-Cn alkenyl" wherein n= 3-10, as used herein, represents an ole~inically unsaturated branched or J~ WO 9~/24200 ~ ,,S. ,, ~, ~
- - ' 2 ~ 85236 linear group having from 2 to 10 carbon atoms and at least one double bond. The group~ can be branched or straight chain. Examples of such groups include 1-propenyl, 2-propenyl ( -C~2-CH=CH2 ), 1 , 3 -butadienyl ( -CH=CHCH=CH2 ), 1-butenyl ~ -CH=CHCH2CH3 ), hexenyl , pentenyl , and the like.

The terms "halide", '~halogen~, and "halo" include fluorine, chlorine, bromine, and iodine. The preferred halogen is chlorine.

The terms "halo (cl-c6) alkyl " and ~halo (C2-C6)alkenyl" refer to alkyl or alkenyl substituents having one or more independently selected halo atoms attached at one or more available carbon atoms. These terms include chloromethyl, bromoethyl, trifluoroethyl, trifluoromethyl, trifluoroethylenyl, 3-bL~ ~L~)lJyl, 3-bromo-1-propenyl, 2-bromopropyl, 2-bromo-l-propenyl, 3-chlorobutyl, 3-chloro-2-butenyl, 2,3-dichlorobutyl, chloroethylenyl, 5-fluoro-3-pentenyl, 3-chloro-2-bromo-5-hexenyl, 3-chloro-2-bromo-butyl, trichloromethyl, dichloroethyl, 1, 4-dichlorobutyl, 3-bromopentyl, 1, 3-dichlorobutyl, 1,1-dichloropropyl, and the like. More preferred halo- (C1-C6) alkyl groups are trichloromethyl, trichloroethyl, and trifluoromethyl. The most preferred halo-(C1-C6)alkyl is trifluoromethyl.

The term "Cl-C1o alkanoyl" represents a group of the formula C(O) (Cl-Cg) alkyl. Typical Cl-Clo alkanoyl groups include acetyl, propanoyl, butanoyl, and the like.

The term " (Cl-C6 alkyl)mamino~ wherein m=1-2;

refers to either a mono- or a dialkylamino group in which the alkyl portion of the group may be straight or branched.

Examples o~ such groups are methylamino, dimethylamino, ethylamino, diethylamino, 2-propylamino, 1-propylamino, di (n-propyl ) amino, di ( iso-propyl ) amino, methyl -n-propylamino, t-butylamino, and the like.

The term "C3-Cn cycloalkyl" wherein n=4-8, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Wo 9~/24200 ,~ ~Z3~ ~ 2185236 The term ''substituted(Cs-Cn) cycloalkyl" refers to a cycloalkyl group as described supra wherein the cycloalkyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, C1-C6 alkyl, NO2, halo, halo(Cl-C6)alkyl, halo(C2-C6)alkenyl, C2-C6 alkenyl, Co2Rs~ (Cl-C6 alkyl)mamino, -SRs, and ORs The term "C3-Cg cycloalkyl-(C1-C3)alkyl" represents a linear alkyl group substituted at a terminal carbon with a C3-Cg cycloalkyl group. Typical cycloalkylalkyl groups include cyclohexylethyl, cyclohexylmethyl, 3-cyclopentylpropyl, and the like.
The term ~Cs-C8 cycloalkenyl" represents an olefinically unsaturated ring having five to eight carbon atoms, eg., phenyl, cyclohexadienyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, cyclooctatrienyl and the like.
The term "substituted (Cs-Cg) cycloalkenyl'' refers to a cycloalkenyl group as described supra wherein the cycloalkenyl group may be substituted with from one to four substituents independently selected from the group consi:sting of hydrogen, Cl-C6 alkyl, NO2, halo, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, C2-C6 alkenyl, CORs, Cl-Clo alkanoyl, C7-C20 arylalkyl, C2Rs, (Cl-C6 alkyl~mamino, -SRs, and ORs.
The term "Cs-Cg cycloalkenyl-(Cl-C3)alkyl"
represents a linear Cl-C3 alkyl group substituted~ at a terminal carbon with a Cs-c8 cycloalkenyl grouP.
The term " aryl " represents phenyl or naphthyl .
The aryl group can be unsubstituted or can have one or two substituents independently selected from the group consisting of Cl-C6 alkyI, Ci=c8 cycloalkyl, substituted C3-C8 cycloalkyl, C2-C6 alkenyl, C3-Cg cycloalkyl-(C1-C3)alkyl, phenyl, Cs-Cg cycloalkenyl, substituted Cs-C8 cycloalkenyl, Cs-Cg cycloalkenyl-(C1-C3)alkyl, CORs, C1-C10 alkanoyl, OR5, and C7-C16 arylalkyl. The substituents may be located at any available position on the aryl ring.
The term ''C7-C20 arylalkyl" represents an aryl- (C1-Clo)alkyl substituent wherein the alkyl group is linear, such ~ WO 9~/24200 I ~ 099 ? '~ ~ 21 2 1 8 5 2 3 6 as benzyl, phenethyl, 3-phenylpropyl, or phenyl- t-butyl; or branched .
- The term ~bicyclic~ represents either an unsaturated or saturated stable 7- to 12-membered bridged or fused bicyclic carbon ring. The bicyclic ring may be attached at any carbon atom which af fords a stable structure .
The term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like.
The term "unsaturated bicyclic~' represents a stable bicyclic ring of 7 to 12 carbon atoms. The unsaturated bicyclic ring may be attached at any carbon atom which affords a stable structure. The unsaturated bicyclic ring may be substituted with from one to four substituents as defined for~"substituted bicyclic" infra.
The general term "substituted bicyclic" refers to a bicyclic ring system with up to 4 substituents attached at any desired positions on the bicyclic ring system. The bicyclic substituents may be independently selected from the group consisting of hydrogen, Cl-c6 alkyl, NO2, halo, halo (Cl-C6)alkyl, halo(C2-C6)alkenyl, C2-c6 alkenyl, COR5, Cl-C1o alkanoyl, C7 -C20 arylalkyl, CO2R5, (Cl-C6 alkyl ) mamino, -SR5, and ORs; wherein Rs is def ined supra . It is intended that the substituted bicyclic substituent may bond to the C~R2 group through any available carbon atom in the bicyclic ring system. The term includes, but is not limited to compounds such as, 2-methyldicyclohexyl, 3-hydroxydicyclohexyl, benzocyclohexyl, benzocyclohexenyl, 2-methoxybenzocyclohexyl, 6-chlorobenzocyclohexenyl, 8-ethenylbenzocyclohexyl, and the like .
The term ~spiro-bicyclic'~ and "substituted spiro-bicyclic~ refer to a bicyclic or substituted bicyclic (as defined supra. ) airectly attached to the carbon of the parent ring at substituent Q ' . For illustration purposes, a spiro-bicyclic is attached as shown:

Wo9~/24200 .~"-J.,,~r ~3 t ~

~X R31 R~
The term ~naphthyl~ refers to a n~3phth;l1 ene ring system substituent, as commonly used in organic chemistry.
The naphthyl substituent may bond to the CHR2 group through any available carbon atom in the naphthyl ring system. The term "substituted naphthyl" refers to a naphthyl ring system with up to 5 substituents attached at any desired positions on the naphthyl ring system. The naphthyl substituents may be independently selected from the ~'substituted bicyclic~
group supra.
The term Uphenyl'' as used herein refers to an unsubstituted benzene ring system. The term " substituted phenyl~ refers to a benzene ring system with from one to three substituents independently selected from the group of bicyclic substituents defined supra; Rs is defined supra.
The term "Cl-C4 alkoxy~ represents a straight or branched alkoxy chain having from one to four carbon atoms.
Cl-C4 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and the like.
In a compound of Formula IV when m' is 0, the ring attached to the amide nitrogen atom is cyclopentyl; when m is 1, the ring is cyclohexyl; when m' is 2, the ring is cycloheptyl; and when m' is 3, the ring is cyclooctyl. If the cycloalkyl ring is substituted, the substituent may be at an available position on the ring.
The term '~pyridinyl~' refers to 2-, 3-, or 4-pyridinyl. The term "imidazolyl" refers to 1-, 2-, or 4-imi dazolyl .

~ WO 95/24200 The term "alk" refers to a divalent organic radical derived from a straight sr branched C1-Cs alkane. Such groups include but are not limited to -CH2-, -CH(CH3)-, -C(CH3)2-, -CH ( C2Hs ) -, -CH2CH2 -, =CH2C~I ( CH3 ) -, -CH2C ( CH3 ) 2 -, -CH2CH (CH3 ) CH2-, -CH (CH3 ) CH (CH3 ) -, -CX (CH3 ) CH2CH (CH3 ) -, and the like.
The term "optionally substituted phenyl " refers to a phenyl ring which may contain one or two substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halo, NO2, and CN.
The term " selective interaction with a 5-XT2s receptor" refers to a method of interacting with the 5-HT2s receptor to a greater extent than the 5-xT2A or 5-HT2c receptor. :_ The term "protic acid" refers to an acid having an acidic hydrogen. Preferred protic acids include hydrochloric acid, formic acid, perchloric acid, sulfuric acid, and phosphoric acid in an aqueous medium. The most preferred protic acids are hydrochloric acid, sulfuric acid, and formic acid .
The term Uorganic solvent" includes solvents containing carbon, such as halogenated hydrocarbons, ether, toluene, xylene, benzene, and tetrahydrofuran.
The term "agitate" includes such techni~ues as stirring, centrifugation, mixing, and other similar methods.
The term "aprotic solvent" refers to polar solvents of moderately high dielectric constant which do not contain an acidic hydrogen. Examples of common aprotic solvents are dimethyl sulfoxide (DMSO), dimethylformamide, sulfolane, tetrahydrofuran, diethylether, methyl-t-butyl ether, or 1,Z-dimethoxyethane .
The term ~protic solvent" refers to a solvent containing hydrogen that is attached to oxygen, and hence is appreciably acidic. Common protic solvents include such solvents as water, methanol, ethanolt 2-propanol, and 1-butanol .

Wo 9~l24200 r~~ ogs ù ~ ~ 2 ~ '~ ' 2 1 8 5236 The term ~ inert atmosphere " ref ers to reaction conditions in which the mixture is covered with a layer :of inert gas such as nitrogen or argon.
Abbre~iations used herein have their accepted meaning, unless stated otherwise For example, "Me'' and "Et~' refer to methyl, ethyl respectively, and "t-Bu" refers to tertiary-butyl. The abbreviation ''RT" refers to room temperature or ambient conditions unless indicated other~7ise.
The term "ligand" refers to comp~unds that are bound by the indicated receptor ~ Compounds useful as selective ligands may be used to selectively occupy the specific receptor site or may act as a selective a~onist at the specific receptor site. ~ ~
The term "substantially pure" is intended to mean at least about 90 mole percent, more preferably at least about 95 mole percent, and most preferably at least about 98 mole percent of the desired enantiomer or stereoisomer is present compared to other possible configurations.
Compounds which are contemplated for use in modulating a 5-XT2B receptor include, but are not limited to 7-bromo-8-methyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6-isopropyl-8-methoxy-1, 2, 3, 4 -tetrahydro-9H-pyrido [ 3, 4b] -indole, 5-chloro-8-ethoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-cbloro-7-methyl-8-fluoro-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 5-dimethylamino-8-hydroxy-1, 2, 3, 4-tetrahydro-9H-pyrido[3,~b~-indole, 6-nitro-8-butyl-1,2,3,4-tetrahydro-9H-pyrido [3, 4b] -indole, 7-cyclohexyl-8-hydroxy-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-[3-methyl-cyclohexyl] -8-methyl-l,Z,3,4-tetrahydro-9H-pyrido[3,4b] -indole, 6-benzyl-8-fluoro-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 5-cyclohexylmethyl-8-chloro-1, 2, 3, 4-tetrahydro-9H-pyrido r3, 4b] -indole, 6-carboxyl-8-bromo-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6-ethoxy-8-isopropyl-3 -methyl-1, 2, 3, 4-tetrahydro-9H-pyrido [ 3, 4b] -indole, 6, 8-dichloro-4 -naphthylmethyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6,8-dimethyl-3,4-dimethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b] -indole, 7, 8-difluoro-2 (N) -methyl-1, 2, 3, 4-tetrahydro-9H-WO 9512420D r ~ J / IJ ', ' 'A~D99 I ~ ' ~ ` 2~ 85236 pyrido [3, 4b] -indole, 6, 8-dibutyl-2 (N) -cyclopropylmethyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6, 8-dibromo-2 (N) -cyclohexenylmethyl-l, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 8-chloro-2 (N) -benzyl-l, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 8-f luoro-4-methyl-2 (N) -cyclohexyl-1, 2, 3, 4-tetrahydro-9H-pyrido[3,4b]-indole, 6-methylamine-8-chloro-1,2,3,4-tetrahydro-9H-pyrido [3, 4b] -indole, 6-chloromethyl-8-chloro-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 7-methoxy-1-naphthylpiperazine, l-naphthylpiperazine, 7-bromo-lH-indole-3-~thAnAmine, 7-fluoro-lH-indole-3-ethAnAmine~ 7-methoxy-lH-indole-3-f'thAnAmi n~, 7-chloro-lH-indole-3-~thAnAmi ne, 5-methyl-7-chloro-lH-indole-3-~thAnAmi ne, l-H-Benz (G) indole-3-ethAnAmi ne, 6-methyl-7-chloro-lH-indole-3-ethAnAmi ne, 6-bromo-7-methyl-lH-indole-3 -ethAnAm; n.~, 6-methyl-lH-indole-3 -ethAnAmi n~, 5-methyl-7-bromo-lH-indole-3-ethAnAmi ne, 6, 7 -dimethyl-lH-indole-3-ethAnAmine, 6-methyl-7-bromo-lH-indole-3-ethAnAmi ne, ( 8~)-N-cyclohexyl-l-isopropyl-6-n-butyl-ergoline-8-carboxamide, ~8,~)-N-cyclohexyl-N-ethyl-l-isopr 6-methylergoline-8-carboxamide, other (8~)-l~lkyl-6-~substituted)ergolines described in U.S. Patent 4,931,447,cycloalkyIamides of (8,B)-I-alkyl-6- (substituted) eryolines described in U.S. Patent 4,981,859, compounds described in U.S. Patent 4,563,461, compounds described in U.S. Patent

4,902,691, wherein the four aforementioned U.S. Patents are herein incorporated by reference, 1, 2-dimethyl-3-ethyl-5-(dimethylamino) -indole, 2- (di-n-propylamino) -8- (isothiazol-3-yl)-1,2,3,4-tetrahydronaphthalene, 2-ethylamino-8-(isoxazol-3 -yl ) -1, 2, 3, 4-tetrahydrnnA~hthA l ene, 2- (N-methyl-N-benzylamino) -8-(5-n-propyl-1,2,3-oxadiazol-4-yl) -1,2,3,4-tetrahydrnnA~hthAl ene, 2-diallylamino-8- (pyrazol-3-yl) -1, 2, 3, 4-tetrahydrnnArhthA 1 er,e, 2 -diethylamino-8 - ( 1, 3, 4 -oxadiazol-2-yl) -1, 2, 3, 4-tetrahydrnnAphthAl ene, 2- (di-n-prppylamino) -8 - (3 -methoxypyrid-2 -yl ) -1, 2, 3, 4-tetrahydrnn~hthAl ene, 2-benzylmethylamino-8- (3-methoxypyrid-2 -yl ) -1, 2, 3, 4 -tetrahydrnnA~hthA l ene, 2 -benzylmethylamino-8 -(benzofuran-2 -yl ) -1, 2, 3, 4-tetrahydrnnArhthA 1 ene, 2 -dimethylamino-8-(1,3,5-triazin-2-yl) -1,2,3,4-Wo 95/24200 , ~ 099 o tetrahydronaphthalene, 2- (di-cyclopropylmethylamino) -8-~oxazol-4-yl) -1, 2, 3, 4-tetrahydronaphthalene, 2-ethylamino-8-(1,2,3-oxadiazol-4-yl)-thio-1,2,3,4-tetrahydrnn~rhthAlene, 2-n-butylamino-8 - ( 5-methoxypyrimidin-2 -yl ) -1, 2, 3, 4 -tetrahydr~n~phth~1 ene, 2- (di-n-propylamino) -8- (5- Y
chlorooxazol-2-yl)-1,2,3,4-tetrahydrnn~rhth~1ene, 2-(di-n-propylamino) -8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydrnn~rhth~l ene, 2- (di-n-propylamino) -8- (2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydrnn;~hth~lene, 2-(di-n-propylamino)-8-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,2,3,4-tetrahydrnn~rhth~l ene, 2- (di-n-propylamino) -8- (3-methyl-1,2,4-oxadiazol-5-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino ) - 8 - ( pyraz in-2 -yl ) -1, 2, 3, 4 -tetrahydrnn~rh th~ n P, 2 - ( di-n-propylamino ) -6- (bromopyrazin-2 -yl ) -1, 2, 3, 4-tetrahydronaphthalene, 2- (di-n-propylamino) -8- (benzothiazol-2-yl)-1,2,3,4-tetrahydmn~rhth~lene, 2-(di-n-propylamino)-8-(benzoxazol-2-yl)-1,2,3,~-tetrahydrnn~rhth~lene, 2-(di-n-propylamino) -8- (indol-3-yl) -1, 2, 3, 4-tetrahydrnn~rhth~1 ene, 3-(di-n-propylamino) -5- (isoxazol-2-yl) -1, 2, 3, 4-tetrahydronaphthalene, 3- ~di-n-propylamino) -5- ~isoxazol-2-yl) -chromane, 5- ~isoxazol-5-yl) -3- (dipropylamino) chromane, 5-(3-methylisoxazol-5-yl) -3- (dipropylamino) chromane, 5- (4-methylisoxazol-5-yl) -3- (dipropylamino) chromane, 5- (3, 4-dimethylisoxazol-5-yl) -3- (dipropylamino) chromane, 5- (3-methylisoxazol-S-yI) -3- ~dipropylamino) thiochromane, 5- (4-methylisoxazol-5-yl) -3- (dipropylamino) thiochromane, 5- (3, 4-dimethylisoxazol-5-yl) -3- (dipropylamino) thiochromane, 8-(4,5,6, 7-tetrahydrobenz[c]isoxazol-1-yl)-2-(dimethylamino) tetrahydrnn~rhth~l ene, and the like.
Especially pre:Eerred compounds for use in modulating a 5-HT2g receptor include 7-bromo-8-methyl-1, 2, 3, 4-tetrahydro-9E~-pyrido[3,4b]-indole, 6-isopropyl-8-methoxy-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 5-chloro-8-ethoxy-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6-chloro-7-methyl-8-fluoro-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole1 5-dimethylamino-8-hydroxy-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6-nitro-8-butyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -~ W0 95/24200 Y ~ ' 'Q~099 indole, 7-cyclohexyl-8-hydroxy-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6- [3-methyl-cyclohexyl] -8-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-benzyl-8-fluoro-l, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 5-cyclohexylmethyl-8-chloro-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6-carboxyl-8-bromo-1,2,3,4-tetrahydro-9H-pyrido [3, 4b] -indole, 6-ethoxy-8-isopropyl-l, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6, 8-dichlorQ-4-naphthylmethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6,8-dimethyl-3,4-dimethyl-1, 2, 3, 4-tetrahydro-9X-pyrido [3, 4b] -indole, 7, 8-difluoro-2 (N) -methyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6, 8-dibutyl-2 (N) -cyclopropylmethyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6, 8-dibromo-2 (~) -cyclohexenylmethyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 8-chloro~2 (N) -benzyl -1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 8-fluoro-4-methyl-2 (N) -cyclohexyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6-methylamine-8-chloro-3-isopropyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 6-chloromethyl-8-chloro-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, 7-methoxy-1-naphthylpiperazine, 1-naphthylpipera2ine, 7-bromo-lH-indole-3-~thAn~min~, 7-fluoro-lH-indole-3-eth~n~min~, 7-methoxy-lH-indole-3-P~hAnAm;np~ 7-chloro-lH-indole-3-ethAn~min~, 5-methyl-7-chloro-lX-indole-3-ethAnAmin~, 1-H-Benz ( G ) indole-3 -e~hAnAm; n~, 6-methyl -7 -chloro-lH-indole-3 -ethAnAmi n~, 6-bromo-7-methyl-lX-indole-3-F~thAnAmi ne, 6-methyl-lH-indole-3-ethAnAmine~ 5-methyl-7-bromo-lH-indole-3-ethAn~mi ne, 6, 7-dimethyl-lH-indole-3 -ethAnAmi nf~, 6-methyl-7-bromo-lH-indole-3 -ethAn~mi ne, 1, 2-dimethyl-3 -ethyl-5-(dimethylamino) -indole, 2- (di-n-propylamino) -8- ~isothiazol-3-yl) -1, 2, 3, 4-tetrahydr~-n~hth~l ene, 2-ethylamino-8- (isoxazol-3 -yl ) -1, 2, 3, 4 -tetrahydrr~ArlhthA l ene, 2 - (N-methyl-N-benzylamino) -8-(5-n-propyl-1,2,3-oxadiazol-4-yl) -1,2,3,4-tetrahydrf~nAphthAl ene, 2-diallylamino-8- (pyrazol-3-yl) -1, 2, 3, 4 -tetrahydr~nArhth~ 1 ene, 2 -diethylamino-8- ( 1, 3, 4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino) -8-(3-methoxypyrid-2-yl) -1,2,3,4-tetrahydronaphthalene, 2-benzylmethylamino-8- (3-methoxypyrid-WO 95/24200 r~,lllJ.,9! . _,, ~

282-yl)-1,2,3,4-tetrahydronaphthalene, 2-benzylmethylamino-8-(benzofuran-2-yl)-1,2,3,4-tetrahydrnnAphthAlene, 2-dimethylamino-8- ( 1, 3, 5 -triazin-2 -yl ) -1, 2, 3, 4 -tetrahydrnnA~hthA l ene, 2- ~di-cyclopropylmethylamino) -8-(oxazol-4-yl)-1,2,3,4-tetrahydronaphthalene, 2-ethy1amino-8-( 1, 2, 3 -oxadiazol-4-yl ) -thio-1, 2, 3, 4 -tetr~hydronAphthA 1 ene, 2 -n-butylamino-8- (5-methoxypyrimidin-2-yl) -1, 2, 3, 4-tetrahydronaphthalene, 2- (di-n-propylamino) -8- (5-chlorooxazol-2 -yl ) -1, Z, 3, 4 -tetrahydrnn~phthA 1 ene, 2 - ( di -n-propylamino) -8-(pyrimidin-2-yl)-1,2,3,4-tetrahydrnnA~hthAl ene, 2- (di-n-propylamino) -8- (2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydrnnis~hthAlene, 2-(di-n-propylamino) -8-(3-phenyl-1,2,4-oxadiazol-5-yl) -1,2,3,4-tetrahydrnn~hthAl ene, 2- (di-n-propylamino) -8- (3-methyl-1, 2, 4-oxadiazol-5-yl) -1, 2, 3, 4-tetrahydrnnArhthA 1 eae, 2- (di-n-propylamino) -8- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydrnnA~hthAl ene, 2- (di-n-propylamino) -6- (bromopyrazin-2-yl) -1, 2, 3, 4-tetrahydrnnAr~hth~l ene, 2- (di-n-propylamino) -8- (benzothiazol-2-yl) -1, 2, 3, 4-tetrahydrnnAphthAl ene, 2- (di-n-propylamino) -8-(benzoxazo~-2-yl)-1,2,3,4-tetrahydrnn~phthAlPne, 2-(di-n-propylamino)-8-(indol-3-yl)-1,2,3,4-tetrahy~lrnnAphthAlene, 5-(isoxazol-5-yl) -3- (dipropylamino) chromane, 5- (3-methylisoxazol-5-yl) -3- (dipropylamino) chromane, 5- (4-methylisoxazol-5-yl) -3- (dipropylamino) ~:~lL~ '', 5- (3, 4- ~:
dimethylisoxazol-5-yl) -3- (dipropylamino) chromane, 5- (3-methylisoxazol-5-yl) -3-(dipropylamino) thiochromane, 5- (4-methylisoxazol-5-yl) -3- (dipropylamino) thiochromane, 5- (3, 4-dimethylisoxazol -5 -yl ) -3 - ( dipropylamino ) thiochromane, 8-(4,5,6,7-tetra_ydrobenz[c]isoxazol-1-yl)-2-(dimethylamino) tetrahydronaphthalene, and 3- (di-n-propylamino)-5-(isoxazol-2-yl) -1,2,3,4-tetrahydronaphthalene.
A preferred compound of Formula IX has the following structure: ;

~ W095/24200 r~

N=~
\~
T Rl 26 ~O~N_ F,27 Wherein R26, R27, R28, R29, and Y~ are as defined supra.
When Q is hydrogen, preferred compounds of Formula I
have the followlng structure: ~
Rs ~NRt I ' Wherein R6 is selected from the group consisting of Cl-C4 alkyl, ORs;, f luoro, bromo, and chloro;
Rs~ is Cl-C4 alkyl; and Rl, R7, and R8 are -as def ined supra .
The 5-HT2B receptor has been identified in various tissues and organs in the rat. The primary areas of 5-HT2s receptor localization in the rat include lung, uterus, bladder, stomach, and colon. Further, the 5-HT2g receptor has been identified in various tissues and organs in the human.
Interesting areas of 5-HT2B receptor localization in the human include but are not limited to the brain and blood vessels.
In light of the receptor localization, physiological conditions which can be mediated by the 5-HT2s receptor include incontinence, bladder dysfunction, Functional Bowel Disorders, stomach emptying disorders, respiratory disorders including asthma, uterine dysfunction including endometriosis, fibrosis, and motility disorders such as but not limited to induction of labor, sleeping Wo 95/24200 r~ 099 0 disorders, eating disorders, incIuding bulimia and obesity, consumption disorders, thermoregulation, sexual disorders, hyperactivity, excessive aggression, alcoholism, anxiety, obsessive-compulsive disorders, depression, psychosis, schizophrenia and schizophreniform disorders, panic disorders, Gilles de la Tourette syndrome, and Alzheimer's disease and cardiovascular diseases such as thrombosis, hypertension, vasospasm (peripheral and/or central) such as stroke, angina, and other vascular occlusive diseases.
Further, migraine hc;q~ rhf~q can be treated using 5-HT2s receptor stimulating compounds of this invention.= Preferred examples of such condition5 which may be treated using 5-HT2s modulators include cardiovascular disorders, uterine dysfunction, sleep disorders, hallucinogenic activity, psychosis, anxiety, depression, thermoregulation, feeding disorders, and hypotension. See ~eonard, B.E., International Cl;nical Psvcho~h?rm~colorY, 7, 13-21 (1992) . It is particularly preferred to use a 5-HT2g antagonist for treating a Functional Bowel Disorder.
Several examples of more specific CNS disorders which may be treated using 5-HT2g modulating compounds of this invention include, but are not limited to: (numerals in parenthesis refer to the DS~-III-R Classification Codes) Attention-deficit hyperactivity disorder (314 . 01), conduct disorders (312.20, 312.00, 312.90), primary degenerative dementia of the Alzheimer type, senile onset (290.30, 290.20, 290.21, 290.00), primary degenerative dementia of ~the Alzheimer type, presenile onset (290.11, 290.12, 290.13, 290.10), alcohol withdrawal delirium (291.00), alcohol hallucinosis (291.30), alcohol, dementia associated with alrnhnliqm (291.20), cannabis, delusional disorder (292.11), cocaine, intoxication (305 . 60), hallucinogen, mood disorder (292.84), nicotine withdrawal (292.00), phencyclidine or=
similarly acting arylcyclohexylamine intoxication (305.90), other psychoactive substance into~ication (305.90), delirium (293.00), dementia (294.10), organic delusional disorder ~293.81), organic hallucinosis (293.82), organic mood ~ WO 95/24200 , ,.~ . . ~
31 2 ~ 852~6 disorder (293 83), oraanic anxiety disorder ~294.80), organic personality disorder (310.10), organic mental disorder (294.80), schizophrenia, catatonic (295.21, 295.22, 295.23, 295.24, 295.25, 295.20), schizophrenia, disorganized (295.11, 295.12, 295.13, 295.14, 295.15, 295.00), schizophrenia, paranoid (295.31, 295~32, 295.33, 295.34, 295.35, 295.00), schizophrenia, undiffertiated (295.91, 295.92, 295.93, 295.94, 295.95, 295.00), schizophrenia, residual (295.61, 295 62, 295.63, 295 64, 295.65, 295.60), delusional (paranoid disorder (297.10), schizophreniform disorder (295.40), schizoaffective disorder (295_70), induced psychotic disorder (297.30), bipolar disorder, mixed (296.61, 296.62, 296.63, 296.64, 296.65, 296.66, 296.60), bipolar disorder, manic (296.41, 296.42,- 296.43, 2g~.44, 296.45, 296.46, 296.40), bipolar disorder, depressed (296.51, 296.52, 296.53, 296.54, 296.55, 296.56, 296.50), major depression, single episode (296.21, 296.22, 296.23, 296.24, 296.25, 296.26, 296.20), major depression, recurrent (296.31, 296.32, 296.33, 296.34, 296.35, 296.36, 296.3~), obsessive compulsive disorder (300.30), ~ost-traumatic stress disorder (309.89), g~n~r~li7ed anxiety disorder (300.02), hypochondriasis ( 3 0 0 . 0 7 ), s omat i zation disorder ( 3 0 0 . 81 ), mal e erect ile disorder (302.72), intermittent explosive disorder (312.34), impulse control disorder (312_39), paranoid (301.00), schizoi~ (301.20), schizotypal (301.22), antisocial (301.70), and borderline (301.83). Diaanostic and Statistical Manual of Mental Pisorders, 3rd ~d. Revised, (1980), prepared by the Task Force on N~m~n~l ~ture and Statistics of the American Psychiatric Association Thus, the present invention also provides methods for treating or preventing the above-named conditions.
The skilled artisan will recognize that psychosis or psychotic conditions are characterized by hallucinations, delusions, or grossly disorganized behavior which indicate that the patient suffers from gross imr;li ~^nt in reality testing Therefore, drugs having antipsychotic activity can WO 95/24200 ~J~ O99 `` ., 2185236 t~ ! !

be useful for treating a variety of important psychotic conditions .
As used herein the term "Functional Bowel Disorder"
refers to a =functional gastrointestinal disorder manifested by (1) Ah~min~l pain and/or (2) symptoms of disturbed 5 defecation (urgency, straining, feeling of incomplete:
evacuation, altered stool form [consistency] and altered bowel frequency/timing) and/or (3) bloating (di5tention).
The term "Functional Bowel Disorder" i~cludes but is not limited to irritable bowel syndrome, hypermotility, ichlasia, hypertonic lower esophogeal sphinctor, tachygastria, constipation, hypermotility associated with irritable bowel syndrome .
Functional Bowel Disorders are characterized by Ahnorr-l bowel function without detectable structural AhnnrmAl ities. Ahnr~rr-~l bowel function includes diarrhea, constipation, mucorrhea, and pain or discomfort over the course of the sigmoid colon. Such disorders are influenced by psychological factors and stressful life situations.
The Functional Bowel Disorder, Irritable Bowel:
Syndrome ( IBS ), is one of the most commonly encountered gastrointestinal disorders. Between 2096 and 50% of patients referred to gastrointestinal clinics suffer from IBS.
Symptoms of IBS occur in approximately 1496 of otherwise apparently healthy people. IBS is a complex condition, in part because it is not a disease but a syndrome composed of a number of conditions with similar manifestations.
Current therapy for Functional Bowel Disorders ls restricted to drugs which treat only a small proportion of patients. For exa~ple, anticholinergic drugs reduce spasticity, therefy relieving some of the abdominal pain.
Histamine B2 receptor antagonists inhibit gastric acid secretion and my relieve some dyspeptic symptoms. A
therapeutic agent that relieves most of the Functional Bowel Disorder symptoms is currently not available.
The term Functional Bowel Disorder ' nr] ~ q conditions such as Irritable Bowel:Syndrome, ichlasia, ~ W0 95/24200 r~
~ . i,; ~

hypertonic lower esophogeal sphincter, tachygastria, hypermotility associated with irritable bowel syndrome, and constipation .
The compounds described herein can form acid addition salts with a wide variety of inorganic and organic acids. Typical acids which can be used include sulfuric, hydrochloric, hydrobromic, phosphoric, hypophosphoric, hydroiodic, sulfamic, citric, acetic, maleic, malic, succinic, tartaric, rlnn~mir, benzoic, ascorbic, m~ndelic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, trifluoroacetic, hippuric and the like. The pharmaceutically acceptable acid addition salts are especially preferred for the treatment of 5-HT2B receptor related conditions.
Certain compounds are preferred for use in treating conditions related to the modulation of a 5-XT2B receptor.
The following invention embodiments and compound characteristics listed in tabular form may be independently combined to produce a variety of preferred compounds and embodiments of the invention. The following list of embodiments of this invention is in no way intended to limit the scope of this invention in any way:
A) Rl is hydrogen;
B) R2 is hydrogen or methyl;
C) R3 iS 11YdLUÇ~ 1 or methyl;
D) R4 is Cs-Cg cycloalkenyl or substituted C5-C8 cycloalkenyl, bicyclic or substituted bicyclic, wherein the substituents are selected from the group consisting of hydrogen, Cl-C6 alkyl, NO2, halo, halo(cl-c6)alkyl~ C2-C6 alkenyl, CORs, (Cl-C6 alkyl)mamino, -SR5, and OR5 E) A is a group of formula III;
F) A is a group of formula IV wherein R6 and R7 are C1 C6 alkyl or halo, and R8 is hydrogen, Cl-cs alkyl, halo, C5-C8 cycloalkyl, phenyl or substituted-phenyl;
G) The compound interacting with the 5-HT2B receptor is a 5-HT2g receptor antagonist;
E~) The compound interacting witht he 5-~lT2B receptor is a

5-HT2B receptor partial agonist i WO 95/24200 r ~ 099 I ) R4 is substituted Cs-c8 cycloalkenyl; wherein the substituents are selected from the group consisting of hydrogen, NO2, halo, (Cl-C6 alkyl)mamino, and ORs;
J) A is a group of formula IV wherein R6 is hydrogen, R7 and Ra are independently selected rom the group consisting of halo and Cl-C4 alkyl;
K) R4 is naphthyl or substituted naphthyl wherein the naphthyl substituents are selected from the group consisting of (Cl-C6 alkyl)mamino and ORs;
L) Y~ is CX2, R26 and R27 are each C2-C3 alkyl; and R2a and R29 are each hydrogen;
M) Compounds of the ~Formula I, II, III, IV, and V;
N) Compounds af the Formula II, III, and VIII;
O) Compounds of the Formula VI, VIII, IX, XI, and XII;
P) A compound of the Formula X;
Q) Compounds of wherein R6 is methyl, R2 is methyl, and R4 is substituted alkenyl wherein the alkenyl group is phenyl and there are~two substituents which are each methQxy;
R) The 5-HT2B modulated condtion is a Functional Bowel Disorder .
S) The Functional Bowel Disorder is irritable boweI
syndrome .
T) The 5-XT2g modulated condition is psychosis.
U) The 5-HT2g selective compound has a greater affinity for 5-HT2g receptors than it has for 5-HT2A receptors.
V) The 5-HT2B selective compound has a greater af finity for 5-HT2g receptors than it has for 5-HT2C receptors.
W) The 5-HT2g modulated condtion is selected from the group consisting of urinary incontinence, bladder dysfunction, uterine dysfunction, cardiovascular disorder, and respiratory disorder.
X) The compound is administered in a unit dosage form.
Y) The label on the article of manufacture states that WO 95/24200 ~ 5~ 099 the compound is useful for treating a condition selected from the group consisting of urinary incontinence, bladder dysfunction, uterine dysfunction, cardiovascular disorder, respiratory disorder, and Functional Bowel Disorder.
Z) A pharmaceutical formulation comprising one or more pharmaceutically acceptable exipients and a 5-HT2B receptor morl~ t i n!J compound;
Z1) A compound wherein Rl is aromatic;
Z2) A compound wherein R4 is an aromatic bicyclic Z3 ) A compound of Formula VII.
Certain compounds of Formula II are useful for morl-ll;3tin~ 5EI2B receptors. Certain compounds of Formula II
within the scope of this invention are preferred for that use. The following invention embodiments and compound characteristics listed in tabular form may be independently combined to produce a variety of preferred compounds and embodiments of the invention. The following list of embodiments of this invention is in no way intended to limit the scope of this invention in any way.
A) Rg and Rlo are each hydrogen.
B) R11 is Cl-C3 alkyl.
C) Rll is chloro, fluoro, or bromo.
D) Rll is -OCH3.
E) R6 is Cl-C4 alkyl.
F) R6 is methyl.
G) A method for binding a 5HT2B receptor using one or more compounds of Formula I and/or II.
H) A method of using one or more compounds of Formula I
and/or II for treating a functional bowel disorder.
I) A method of using one or more compounds of Formula I
and/or II which are useful for stimulation of the 5HT2s receptor for treating a condition selected from the group consisting of urinary inc-~ntin~n~e, bladder dysfunction, uterine dysfunction, cardiovascular disorders, and respiratory disorders.
J) A method for using one or more compounds of Formula I
and/or II for treating Irritable Bowel Syndrome.
_ _ _ _ . . . ..... .. . . .

WO 95/24200 1 ~ 099 K) A pharmaceutical formulation comprising a compo~nd of Formula I or II and one or more pharmaceutically acceptable excipients .
The compounds of the present invention are useful for modulating or blocking the 5-HT2 receptor. Certain of f the present compounds of Formula XI and XII are preferred for that use. The following invention embodiments and compound characteristics listed in tabular~ form may be independently selected or combined to produce a variety of pref erred compounds and em.~bodiments of the invention. The following list of f~mh~ nts of this in~lention is in no way intended to limit the scope of this invention in any way.
A) Rl is hydrogen;
B) R2 is hydrogen or methyl;
C) R3 is hydrogen or methyl;
D) R4 is Cs-c8 cy(-7~Alkf~nyl Qr substituted CS-C8 cycloalkenyl, wherein the substituents are selected from the group consisting of hydrogen, Cl-c6 alkyl, NO2, halo, halo(C1-C6)alkyl, C2-C6 alkenyl, CORs, (Cl-C6 alkyl)m amino, -SR5, and ORs;
E) A is a group of formula III;
F) A is a group of formula IV wherein R6 and R7 are C1-C6 alkyl or halo, and R8 is hydrogen, Cl-cs alkyl, halo, C5-C8 cycloalkyl, phenyl or substituted-phenyl;
G) R2 is hydrogen;
H) R3 is hydrogen;
I) R4 is substituted Cs-c8 cycloalkenyl; wherein the substituents are selected from the group consisting of hydrogen, NO2, halo, (C1-C6 alkyl~m amino, and ORs;
J) A is a group of formula IV wherein R6 is hydrogen, R~
and R8 are independently selected from the group consisting of halo and C1-C4 alkyl.
K) Q' is (CHR2)R~;
L) R30 and R31 join to form a 3 to 6 member carbon ring;
M) R30 and R31 join to form a 3 to 5 member carbon ring;
N) R30 and R31 ~re each methyl;
o) R4 is naphthyl;

W0 95/24200 T ~ 099 37 2~85236 P) R4 is an optionally substituted bicyclic hydrocarbon ring system having 7 to 12 carbon atoms and 0, 1, 2, or 5 double bonds;
Q) R4 is a 6 to 10 carbon atom unsaturated bicyclic ring system;
R) Q' is bicyclic or substituted bicyclic;
S) R34 is ~;
T) R34 is an optionally substituted bicyclic ring substituent;
U) Rg and R1o are each hydrogen;
V) Rg is selected from the group consisting of C1-C6 alkyl, substituted C3-c8 cycloalkyl, C3-ca cycloalkyl, C3-C8 cycloalkyl-(C1-C3)alkyl, C~-Cg cycloalkenyl-(C1-C3)alkyl, C7-C20 arylalkyl;
W) R4 is aromatic;
X) R34 is spiro-bicyclic or substituted spiro-bicyclis;
Y) Q ~ is hydrogen .
The more preferred classes have the following f eatures:
A-C, E or F, I, L, N, P, R, and W.
The most preferred class of compounds has the following features:
A, G-J, M, and Q.
The preferred classes of compounds for use as selective 5-~T2B ligands have the following features:
A-D, E or J, M, and 0.
The most preferred class of compounds for use as selective 5-~IT~g ligands has the following features.
A, G-J, M, and 0.
Compounds of Formulas XI and XII are particularly use~ul for modulating 5E~T2g receptors. Certain compounds Wo 9~/Z4200 p~ "~" _ ,J
2 ~ 85236 within the scope of this invention are ~pre~erred for that use. The following invention embodiments and compound characteristics listed in tabular form may be independently selected or comhined to produce a variety of=preferred compounds and em.bodiments of the invention. The following list of l~mho~lim~nts of this invention is in no way intended to limit the scope of this invention in any way.
A) Rg and R1o are each hydrogen;
B) R1l is C1-C3 alkyl;
C) R11 is chloro, fluoro, or bromo;
D ) R1 1 i s -OCH3;
E) R30 and R31 join to form a 3 to 8 member carbon ring;
F) R30 and R31 join to form a 3 tQ 6 member carbon ring;
G) A compound having preferred characteristics described supra .;
H) A method for binding a 5HT2B receptor using one or more compounds of Formula XI and/or XI~;
I ) A method of usiny one or more compounds of Formula XI
and/or XII for treating a functional bowel disorder.
I) A method of using one or more compounds of Formula XI
and/or XII which are useful for modulatation of the 5E~T2s receptor for treating a function bowel disorder.
J) A method for~ using one or more compounds of Formula XI and/or XII for treating Irritable Bowel Syndrome.
K) A pharmaceutical formulation comprising a compound of Formula XI and/or XII and one or ~Lore pharmaceutically acceptable excipients.
Examples of compounds of Formula XI include but are~
not limited to: ~
10-methyl-2,3,4,4a,5,6,7,11c-octahydro-lH-indolo[2,3-c] quinoline, 8-chloro-2, 3, 4, 4a, 5, 6, 7, llc-octahydro-lH-indolo [2, 3-c] quinoline, 6- (2, 4-dimethoxybenzyl) -10-methyl-2~3~4~4a~5~6~7~llc-octahydro-l}~-indolo[2~3-c]Q~l;nt~lin~ 7-fluoro-6-(2,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-lH-indolo [2, 3-c] quinoline, 8-methoxy-6- (2, 4-dimethoxybenzyl) -10-methyl-2,3,4,4a,5, 6,7, llc-octahydro-lH-indolo [2, 3 -c] quinoline, 7-nitro-6- (3, 4-dimethoxybenzyl) -10-~ W0 95/24200 r~

methyl-2,3,4,4a,5,6,7,11c-octahydro-lH-indolo[2,3-c] quinoline, 5- (2, 4-dimethoxybenzyl ) -10 -methyl-2,3,4,4a,5,6,7,11c-octahydro-lH-indolo[2,3-c]quinoline, 7-bromo-5-(2,4-dimethoxybenzyl) -10-methyl-2,3,4,4a,5,6,7,11c-octahydro-lH-indolo [ 2, 3 -c] quinoline, 6 -e~hoxy-5- ( 3, 4 -dimethoxybenzyl) -lo-methyl-2~3~4~4a~5~6~7~llc-octahydro-lH-indolo [2, 3 -c] quinoline, 7-nitro-6- (3, 4-dimethoxybenzyl ) -10-methyl-2,3,4,4a,5, 6,7,10c-octahydro-lH-indolo[2,3-c] quinoline, 7- (3, 4-dimethoxybenzyl) -10-methyl-2,3,4,4a,5,6,7,11c-octahydro-lH-indolo[2,3-c]quinoline, 7-nitro-6- (3, 4 -diethoxybenzyl ) -10 -methyl-2, 3, 4, 4a, 5, 6, 7, llc-octahydro-lH-indolo [ 2, 3 -c] quinoline, 6-methyl -8-bromo-1-[ (3,4-dimethoxyphenyl) -10-methyl-2,3,4,4a,5,6,7,11c-octahydro-lH-indolo [2, 3-c] quinoline, 7- (1,1-dimethylethyl) -5-~1-n~rhth~lenyl-1-ethyl)-1,2,3,4,4a,5,6,10c-pyrido [3,4-b]
indole hydrochloride, 7-methyloxy-1- (2-methyl~min~n~r~hth~lenyl)-1-ethyl) -1,2,3,4,4a,5,6,10c-octahydrocyclopenta[a]pyrido [3,4-b] indole, (Z) 2-butenedioate, 6- ( 1, 1-dimethylethyl ) -1- ( 1- ( 3 -diethyl~min~n~hth~lenyl) -1-ethyl) -1,2,3,4,4a,5,6,10c-octahydrocyclopenta [a] pyrido- [3, 4-b] indole hydrochloride, and

6 -methyl -5 - [ ( 4 -dimethylamino-n~rhth~ l enyl ) -methyl ] -1, 2, 3, 4, 4a, 5, 6, lOc-octahydrocyclopenta [a] pyrido- [3, 4-b] indole dihydrochloride .
Examples of compounds of Formula X}I include but are not limited to:
3-(2-amine-cyclopentyl)-6,7-dimethylindole, 3-(2-amine- ~=
cyclopentyl) -5-methyl-7-bromoindole, 3- (2-amine-cyclopentyl) -6 -methyl-7 -chloroindole, 3 - ( 2 -amine-cyclopentyl ) -6-bromo-7 -methylindole, 3- (2-amine-cyclopentyl) -Benz (G) indole, 3- (2-amine-cyclohexyl ) -5 -methyl -7 -chloroindole, 3 - ( 2 -amine-cyclohexyl ) -7 -chloroindole, 3 - ( 2 -amine-cyclopropyl ) -7 -methoxyindole, 3- (2-amine-cycloheptyl) -7-fluoroindole, 3- (2-amine-cyclohexyl ) -7-bromoindole, 3 - (2-amine-cyclopropyl ) -6-methyl-7-bromoindole, 3- (2-amine-cyclopentyl) -5-fluoro-7-methoxyindole, 3- (2-amine-cyclopentyl) -5-nitro-7-Wo ss/24200 , ~ /Q~n!~g .

40chloroindole, 3- (2-amine-cyclooctyl) -2-ethyl-7-fluoroindole, and 3- (2-amine-cycloheptyl) -2-methyl-7-fluoroindole.
The compounds which are usef~ul for blocking 5-HT2s receptors contemplates racemic mixtures as well as the ~ ,t substantially pure stereoisomers~ of the compounds of Formulas I through XII . The term " enantiomer" is used herein as commonly used in organic chemistry to denote a compound which rotates the plane of polarization. Thus, the "- enantiomer"
rotates the plane of polarized light to the lef t, and contemplates the levorotary compound of Formulas I through XII. The + and - enantiomers can be isolated using well-known classical resolution tech~iques. One particularly useful reference which describes such methods is JAcQuEs et.
al. ENANTIOME~S, RAcEMATEs, AND RES~LUTIONS (John Wiley and Sons 1981). Appropriate resolution methods include direct crystallization, entrainment, and crystallization by optically active solvents. Chrisey, L.A. Heterocvcles, 267, 30 (1990). A preferred resolution method is crystallization with an optically active acid or~ by chiral synthesis as described in Example 46 using the method of A.I. Meyers Loewe, M.F. et al., Tetrahedron Letters, 3291, 26 (1485), Meyers, A.I. et al., J. Am. Chem. Soc., 4778, 110 (1988) .
Preferred optically active acids include camphorsulfonic and derivatives of tartaric acid.
The present invention encompasses both the R and the S configurations. The terms "R" and "S" are used herein as commonly used in organic chemistry to denote the specific~
configuration of a chiral center. See, R.T. Morrison and R.N. Boyd, Orcanic C~hemistrv, pp 138-139 ~4th Ed. Allyn &
Bacon, Inc., Boston) and Orchin, et al. The Vocabularv of Qrc~anic Chemistrv, p. 126, (John Wiley and Sons, Inc. ) .
For example, the present invention includes, but is not limited to, the use of compounds such as (-) - (S) -7-methyl - 8 -bromo -1- [ ( 3, 4 -dimethoxyphenyl ) methyl ] - l, 2, 3, 4 -tetrahydro-9H-pyrido[3,4-b]indole; (-)-(S)-5,7-dimethyl-1,2,3,4-tetrahydro-l-[ (3,4-dimethoxyphenyl)methyl]-9H-~ W095l24200 r~
2 ~ ~5236 41pyrido [3, 4-b] indole; ( -) - (S) -5-fluoro-6-methyl-1- [ (2-chloro-3,4-dimethoxyphenyl)methyl] -1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; and (-)-(5)-6-methyl-1,2,3,4-tetrahydro-1-[(3,4-dimethylphenyl)methyl]-9H-pyrido[3,4-b]indole. The invention also includes, but is not limited to, the use of (+) - (S) -7-methyl-8-bromo-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; (+)-(5)-5,7-dimethyl-1,2,3,4-tetrahydro-1-[ (3,4-dimethoxyphenyl)methyl]-9H-pyrido [3, 4-b] indole; (+) - (S) -5-fluoro-6-methyl-1- [ (2-chloro-3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-9X-pyrido[3,4-b] indole; ( - ) - (R) -7-methyl-8-bromo-1- [ (3, 4-dimethoxyphenyl)methyl~ -1, 2, 3, 4-tetrahydro-9E~-pyrido [3, 4-b]inaole; (-)-(R)-5,7-dimethyl-1,2,3,4-tetrahydro-1-[ (3,4-dimethoxyphenyl)methyl]-9H-pyrido[3,4-b]indole; (-)-(R)-5-fluoro-6-methyl-1-[(2-chloro-3,4--1imf~thn~cyphenyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; and (-)-(R)-6-methyl-1,2,3,4-tetrahydro-1-[(3,4-dimethylphenyl)methyl]-9H-pyri do [ 3, 4 -b ] indo l e; ( + ) - ( R ) - 7 -me thy l - 8 -bromo - 1 - [ ( 3, 4 -dimethoxyphenyl ) methyl ] -1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4 -b]indole; ~+)-(R)-5,7-dimethyl-1,2,3,4-tetrahydro-1-[(3,4-dimethoxyphenyl)methyl] -9H-pyrido [3, 4-b] indole; (+) - (R) -5-fluoro-6-methyl-1-[(2-chloro-3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; and ~+)-(S)-6-methyl -1, 2, 3, 4 -tetrahydro-1- [ (3, 4 -dimethylphenyl ) methyl ] -9H-pyrido [3, 4-b] indole.
The compounds which are useful for interaction with 5-HT2B receptors are known to form hydrates and solvates with appropriate solvents. Preferred solvents for the preparation of solvate forms include water, alcohols, tetrahydrofuran, DMF, and DMSO. Preferred alcohols are methanol and ethanol.
other appropriate solvents may be selected based on the size of the solvent molecule. Small solvent molecules are preferred to facilitate the corresponding solvate formation.
The solvate or hydrate is typically formed in the course of recrystallization or in the course of salt formation. One useful reference concerning solvates is Sykes, Peter, A
~uidebook to Mech~nl sm in O~cranic ChemistrY, 6, 56, (1986, Wo gs/24200 r~ ogg ~

John Wiley & Sons, New York). The term ~solvate~ as used herein includes hydrate forms such as monohydrate and dihydrat es .
Some of the compounds which are useful for interaction with 5-~IT2g receptors are either known in the art or readily available by routine synthetic processes. For example, compounds of Formula III can be prepared using the methods taught in Semonsky et al., U.K. Patent No. 816,273 (July 8, 1959), U.S. Patent Nos. 2,736,728 and 2,77~,763 which U. S . Patents are hereby incorporated by reference.
C`~ UlldS of FormuIa IV may be prepared as described in ~. S .
Patent Nos. 4,981,859 and 4,931,447 which are hereby incorporated by reference. A process for preparing compounds of Formula V is described in U.S. Patent No. 4,902,691 which is hereby incorporated by reference. A process for preparing compounds of Formula VI is described in U.S. Patent No.
4,563,461 which is hereby incorporated by reference. A
compound of Formula VII can be prepared as described in Forbes, I.T., J. Med. Chem., 36:1104-1107 (1993). A compound of Formula VIII is known in the art and may be purchased or prepared by recognized methods. A process for preparing compounds of Formula IX is available to the artisan in tfie published European Patent application. The European Publication number is 0498590 A1 (August 12, 1992; Bulliten 92/33) and is readily available to the United States artisan in the English language. A compound of Formula g is known in the art and can be prepared by recognized methods.
The compounds of the present invention can be prepared using chemical processes that are understood in the art; however, the most preferred method for preparing the formula I compounds of this invention utilizes the process of Scheme V. The most preferred method for preparing a compound of Formula II is using the general method illustrated in Scheme II in~ra. Compounds of EDrmula II wherein Rg, R12, and/or RlC are not hydrogen can be prepared using accepted chem.~ical methods such as reductive alkylation and direct alkylation of the corresponding tryptamine.

~ WO95124200 p~ "~ ,, r ~j 2 1 8 5 2 3 6 4~
A compound of Formula I, wherein Q is hydrogen, may be prepared by contacting glyoxylic compound of formula (i) with an amine of formula (h~. This Pictet-Spengler type reaction is generally applicable, provides desirable yields, and produces stable intermediates. Further, the product of the reaction typically may be directly isolated as the desired salt.
The compounds of formula ~a) which may be used as starting materials for the compounds of the instant invention can be purchased from art-reco~nized vendors or may be prepared using well-known chemical techniSIues. The compounds of formula (b) which are useful as s~arting materials for the compounds of this invention may be prepared as represented by Scheme I. The R4 group is as defined herein above.
The process for preparing the compounds of this invention will be discussed in greater detail in the following paragraphs.

WO 95~24200 ~ i 5/A't099 Q ~, 21 85236 S rh F~m~
~-H J~N/~CO2H
Compound (a) in Scheme I may be substituted or unsubstituted depending on the desired product. Most formula ~a) compounds necessary for the preparation of the azalactone (b) starting materials are commercially available.
Additional substituted formula (a) compounds may prepare~
using common chemical methods . Furniss, B . S . et al ., Voael ' s T,-~ctbook of Practical Ora~n- c Ch~ri ~trY (John Wiley, New York, N.Y. 1989) see especially p,o 989 through 993.
Generally, the Scheme I reac~ion is begun by preparing a solution of compound (a), acetylglycine and sodium acetate in acetic anhydride. The reaction is commonly heated from about 90C to about liOC for a period of about 2-15 hours. The reaction mixture is cooled to about ambient temperature and stirred for a period of about O-10 hours under inert conditions. The reaction time will vary depending on the degree o~ substitution on the R4 group and the completion of reaction desired. -- -When the re ction is complete, the mixture ispoured onto ice with stirring. The azalactone (b) may be isolated by standard isolation techniaues such as f iltration and may be dried under reduced pressure.
Compound (d) in Scheme II is used as a starting material for compounds of Formula I. These compounds are commercially available or may be prepared using the well-known Fischer indole synthesis applied to tryptamines. The Fischer synthesis is represented by Scheme II. ~'A" is as hereinabove def ined .

~ WO 95/24200 1~ 099 t ~' Scheme II
~NHNH2 r ~ 2 Cl--~H H
The chlorobutanal compound used in Scheme II may be prepared through the hydrogenation of chlorobutyryl chloride. The hydrogenation may be facilitated by the use of a catalyst such as Pd/C. Other halobutanal compounds may be suitable for the Scheme II process. The starting compounds (c) in Scheme II may be purchased or prepared using known methods . March, J ., Advanced Or~ni c (~~l~mi strv Reacti~-nq, Mech~3n; qmq, and Struct~re, 3rd (John Wiley & Sons, New York, 1985) see especially page 1163.
The Fischer synthesis is commonly begun by adding a suitable saturated base like sodium carbonate to a stirred suspension of the hydrazine salt in an organic solvent like chloroform. The hydrazine hydrochloride salt is one especially preferred hydrazine salt. The desired hydrazine free base is extracted with the organic phase. The oil is placed in an alcohol and water solution and treated with an a~L~ iate base like sodium acetate. The halobutanal is added and the tube purged with an inert gas like nitrogen.
The resulting mixture is placed in an oil bath which has been heated to about 90C-110C. The mixture should be heated for about 17 to 19 hours. The mixture is allowed to cool to ambient temperature and is concentrated under reduced pressure. The residue is partitioned between a suitable organic and basic ao,ueous phase, such as chloroform/methanol and a(lueous sodium carbonate. The organic phase may be concentrated and the resulting compound (d) purified by standard methods such as flash chromatography. If chromatography is used, fractions containing product may be .

Wo 95/24200 .
, i3 ~ 2 1 8 5 23 6 combined and concentrated. The oil is dissolved~ in an appropriate solvent, such as diethyl ether c~nt~ining about 1% alcohol. A preferred alcohol is methanol The mixture may be treated with dry acid gas, such as dry HCl gas to produce the corresponding acid addition salt of the desired compound ( d ) .
One method for preparing Formula I compounds uses the Pictet-Spengler reaction as represented by Scheme III.
The substituents are as defined hereinabove.

~ WO 95124200 r~

St~ m~ III
2 R2~ ~C~I0 (e) (f ~
Generally, the Scheme III reaction is carried out by reacting compound (e) with the selected aldehyde in a suitable solvent such as ethanol or methanol for a period of about 1 to 5 0 hours depending on the desired product . The reaction may be refluxed if necessary. The precipitated reaction product is collected by common isolation methods, such as filtration and may be purified by recrystallization.
If a compound with an R1 substituent is desired, the reaction may be followed by a reductive alkylation. The reductive alkylation is represented by Scheme IV.
Scl-ll~m~ IV
alkylation ~N-R3 R4 R2 R3 R4 R2 ( g ) A protic acid and aldehyde solution is commonly added to an aqueous solution of compound ( f ) . The most preferred protic acid is formic acid. The most preferred aldehyde is formaldehyde. The artisan can readily choose P other appropriate reagents to facilitate the reductive alkylation. The resulting solution is refluxed for a period of about 4 to 80 hours. After reflux the solution should be made basic using an a~ iate base such as potassium carbonate. The desired product can then be extracted with an appropriate organic phase, such as chlorof orm. The product WO 95124200 P~~ J~
! t~ 2 ~ 8 5 2 3 6 can be dried, concentrated, and purified by known methods such as flash chromatography A preferred method for~ preparing certain Formula I
compounds, wherein R2 is hydrogen, utilizes the modified Pictet-Spengler reaction described supra, as represented by Scheme V . The substituents are as def ined hereinabove .
S-~hf~mo V
Pr tic, (~
N ~ h ) ( i ) R3 R
Compound (h) and compound ~i) are contacted in a suitable protic aqueous acid solution. When compounds having hydrogen at the 1-position are desired, glyoxylic acid may be used in place of ~i). This step may be completed under inert conditions. Compound (h) and compound (i) may be refluxed under atmospheric or inert conditions for a period of about 20 to about 30 hours Preferred ~protic acids include sulfuric acid and hydrochloric acid. The most preferred acid solution is 1 N ~Cl. If direct isolation is not effective, then the reaction mixture may be neutralized with an appropriate base, such as potassium carbonate, followea by extraction with an organic phase, such as chloroform. The product can be isolated through solvent removal followed by chromatographic isolation, such as silica gel chromatography, or other common isolation techniques. Typically the product is isolated as the acid addition salt. Appropriate salt forms are discussed supra.
As noted above, the compounds of the present invention can exist as resolved enantiomers. The single ( - ) enantiomer may be prepared by the che~3ical resolution method of A I. Meyers as represented by Scheme VI infra. The ~+)enantiomer may be prepared using known resolution J5!o~n99 2~ 85236 technigues described su~r~. All substituents are as de~ined hereinabove . - -- Scheme VI
~5e Me tBu e~ e ~e2U (1) ~1) NH N N OtBu ~5ey~5e ~ml (~N N OtBu KH, T~{F, DA, ( 2 ) I MoMCl , Me~Me Me~Me ~;~N N QtBu ~ ~n-F~ ~N~N otBu R4 (O) OMe Q~le (n) r~duce 14 ) H2~H~, acid solvent ~NH
H }~4 (P) heme VI, CSA represents camphorsul~onic acid.
~.
star~d~rd isolation method ' th t ~urther puri~lcation.

WO g5124200 r~

Compound (m) prepared in step 1, can be added to a suspension of potassium hydride (KH) in tetrahydrofuran (THF) . Tetramethylethyl-n~ min~ (TMEDA) and then chloromethylmethyl ether (MOMCl) are added to the solution, as represented by step 2 The mixture is stirred for a period of about 1 hour. The mixture can be treated with water and partitioned between an appropriate organic, such as diethyl ether, and water. The product should be extracted with the organic phase, dried over potassium carbonate, and concentrated. The resulting oil may be used in subsequent steps without further purification.
In step 3, n-BuLi is slowly added dropwise to a stirred, cooled (about -76C to -o0C) solution of the forr-~i n,o in dry THF . The solution is stirred for a period of about 1 hour followed by addition of the chloro compound in dry THF. The solution is stirred for an additional period:
of about 4-5 hours at the reduced temperature. The mixture is allowed to cool to room temperature for a period of about 4 to 14 hours. Wet THF is added and the solution concentrated. The residue is dissolved in an appropriate organic solvent such as chloroform and washed with water.
The organic phase is dried over a suitable drying ayent, such as sodium carbonate, and concentrated to facilitate purification of the desired product. The product may be isolated by f lash chromatography and concentrated. The resulting oil may be used in subse~uent steps without further puri f ication .
The deprotection reaction represented in step 4 is begun at reduced temperature (about 0C). Water, acetic acid, and hydrazine hydrate are added to compound (o) The reaction temperature is decreased to about -10C to -20C for a period of about 60-120 hours. ~The mixture is allowed to warm to ambient temperature and is concentrated The product is dissolved in an appropriate organic phase, such as chloroform, and washed with water. The organic phase is dried over a suitable drying agent, such as sodium carbonate, and concentrated to a viscous oil. The oil is dissolved in ~ Wo 95/24200 r~ 59 ~_ 5 1 an appropriate solvent, such as diethyl ether and treated with a suitable organic or inorganic acid to afford the - desired acid addition salt. The salt can be isolated and purified by common chemical methods.
If the desired product has an alkyl group at the R3 position, the reaction represented by Scheme vrI may be employed .
Scheme VII
(Step ~) base, solvent H (~) phthAlic anhydride (r) ~ _ base, THF, Fi3 h~lo, TMEDA
2NNH2, ~lcohol ~J~O
In Scheme VII, an appropriate saturated base solution, such as sodium carbonate, is added to compound (g).
The desired compound (q) salt may be prepared by the method of Scheme II, above. The mixture is stirred at about ambient temperature f or a period of about l hour . The layers are separated, and the a(Iueous layer is extracted with an appropriate organic solvent, such as chloroform. The organic layers are dried over an appropriate drying agent, such as sodium sulfate, and concentrated. The residue is dissolved in a suitable solvent such as toluene and treated with phthalic anhydride. The solution is refluxed for a period of a})out 12 to 2 0 hours with azeotropic drying . The solution is cooled, concentrated, and recrystallized to give compound (r) .

WO g~/24200 P~
rc In the next step, compound (r) is mixed in THF. A
cooled (about 0C~ suspension of an ap~rPpriate base, such as potassium hydride in dry THF, is slowly added to the compound (r) solution. After the addition of the the base, the mixture is stirred fQr a period of about 1 hour.
TetramethylethylenP~ min~o (TMEDA) is added, followed by a haloalkyl such as methyl iodide (MeI). After about 1 hour, the reaction is quenched by the addition of water, followed by extraction with an appropriate organic phase, such as diethyl ether. The organic phases are dried over an appropriate drying agent, such as magnesium sulfate and concentrated .
The solution of the concentrated compound (s) can be used directly in the next step. It is contacted with an appropriate solvent, such as methanol, and treated with hydrazine. The mixture is refluxed for a period of about 2 hours. The mixture is cooled to ambient temperature and treated with concentrated acid, such as HCl The mixture is then treated with an alcohol and refluxed for a period of about 12 to 20 hours. Preferred alcohols include methanol, ethanol, and butanol. After cooling to a-m-bient temperature, the mixture is partitioned between a suitable organic and an ~gueous phase. One suitable colnbination is chloroform ana concentrated sodium carbonate solution. The agueous layer may be further f~rtr~ , the organic phases combined, dried, and concentrated. The product may be purified by flash chromatography, concentrated, and converted to a desired salt. The resulting compound (t) may be used in Scheme III
or Scheme V to produce the desired Formula I compound.
Compounds of Formulas XI and XII may be prepared using the methods described supra. However, a preferred method for preparing compounds of Formula XI and XII is illustrated by Scheme VIII

WO 9~51r24200 PCTIUS9S103099 ' . ~ 53 21 85236 Soh~mn ~
1 R32Mg3r ~ NH2-add ,Q N~Fl32 ~scid R3~ R~1 NH mildsr~d NH Q' ' 60c 3' ¢
4.sdd wherein R32 is independently selected from Cl-C6 alkyl; A, and Q' are defined supra.
Further, compounds of Example 108 can be prepared as illustrated by the following Scheme:
M Me MeO~O M Me 2.Mer,S Cu~r ~NH2-HCI Mora Mo ~H-Ha 1- ~ 2d E~e OMe 10~
Similarly, compounds of Example 109 can be prepared as illustrated by the following Scheme:
Me~c~N H2-HCI ~ Me ~OMe H 40(110) OMe 3i (109) The f ollowing Examples further illustrate the preparatiQn of certain of the Formula I, II, XI, and XII
compounds. The examples are illustrative only, and are not intended to limit the scope of the invention.
The column chromatography procedures used standard flash chromatography techniques. One well-known reference _ _ _ _ _ _ . _ _ . . , , , .. . _ WO 95/24200 I ~ ~ ,, O
~ ~ x~ I ~ 2 1 8 5 2 3 6 describing appropriate flash chromotagraphy technioues is Still, W.C. Kahn, and Mitra, vT. Org. Chem. 1978, 43, 2932.
Fractions containing product were generally evaporated under reduced vacuum to pro~ide the product.
optical rotations were obtained using methanol, pyridine, or other suitable solvent.
The hydrochloride salt of the particular compound was prepared by placing the f ree base into diethyl ether containing an alcohol such as methanol or other suitable-solvent mixture. While stirring this ether solution, a solution of HCl in diethyl ether was added dropwise until the solution became acidlc. Alternatively, the ether solution was treated with dry HCl gas.
The maleate salt of the particular compound was prepared by placing the free base in ethyl acetate or other suitable solvent and treating with maleic acid. The precipitate formed was filtered and dried to provide the corresponding hydrochloride or maleate salt of the free base.
Compounds of Formulas I through VI and VIII
through XII are more preferred for treating a mammal suffering from or susceptible to a condition associated with ~hn~ 1 or dysfunctional S-HT2B receptor stimulation.
Additionally, compounds of Formulas I through VI and VIII
through XII are more preferred for blocking a 5-XT2B receptor in a mammal or in vitrQ. Finally, compounds of Formulas I
through VI and VIII through XII are more~ preferred for use in an article of manufacture ~W0 95/24200 I ~ QlQgg 2 M 25-Cu/~ "X~ ~ ~x~R R
N 2i~ n30= 4 3" or ~Iyoxylic acid 4 Boc 2cn3=5 1N HCI
4.HCI
bX'-7C b X' 7CI ~0~~ tX'=7-CI n~.~
eX=7-CI n =4(93) f X~=s-Me n3=4 R=3~4-(oMe)2Bn~ R'=H (100) ~=5,7-Me2 n3=4(94) gX"=7-CI n3=4R=3,4-(OMe)2Bn,R'=H(101) X =5-Me n3=5 h Xn=5,7-Me2 n3=4 R=3,4-(OMe)2Bn, R'=H(102) i X"=5-Me n3=5 R=3,4-(OMe)2Bn, R'=H (103) J X"=5-Me n3=3 R=1-lldyll-,: 't.,:, R'=H (104) k X"=5-Me n3=4 R=1 -lld~Jl I~l,,: '', ', R'=H (105) I X'=5,7-Me2 n3=4 R=1-1ld~JII'' ,' " ~I, R'=H (106) m X"=5-Me n3-4 R, R'= H (107) ~OMe OMe For Examples 90 through 109, where applicable, diethylether was distilled from sodium benzophenone ketyl prior to use. All reactions were performed under a positive pressure of argon. 1H-NMR and 13C-NMR data were recorded on a Bruker AC-200P (200 MHz) . IR spectra were obtained on Nicolet 510 P-FT (film and KBr) . Melting points were determined on a Buchi apparatus and are not corrected Analytical TLC was performed on Merck TLC ç~lass plates precoated with F254 silica gel 60 (W, 254 nm and Iodine). Chromatographic separations were performed by using 230-400 mesh silica gel (~erck). N-BOC-aziridine~ (2a-d~ were prepared from the corresponding alkenes following standard procedures.

Wo 95l24200 p~ O99 *
. . ,~ , ,, PreParation 1 Preparation of 4-chlorobutanal.
Cl ~CI THF,2,6-lutidine~ ~H
RT, 60 psi 4-Chlorobutyryl chloride (300 g, 2.13 mol.) was dissolved in dry THF (3 L) . To this -solution was added 2, 6-lutidine (252 mL) followed by 5% Pd/C (30 g). This mixture was placed in a Parr hydrogenator and shaken under 60 psi of hydrogen for 6 hours. The mixture was purged with nitrogen, filtered, washing the catalyst with THF (500 mL), and concentrated at room temperature under- reduced pressure.
Distillation afforded 4-chlorobutanal (148.3 g) as a colorless liquid.
r le 1 pr~.rAr~;nn of 8-methyl-1-~(3,4-A; h-~y~.k~.-yl)methyl]-1,2,3,4-tetrahydro-9H-~yrido[3,4-b]indole CHO 1l O
~ HN C02H MeO~
MeO~ Ac2o. N~OAc, 1~UC MeO N~Me OMe A solution of 3,4-dimethoxybenzaldehyde (24.5 g, 0.15 mol.), N-acetylglycine (17.4 g, 0.15 mo~.) and sodium acetate (12.1 g, 0.15 mol) in acetic anhydride (135 mL) was heated to 100C for 12 hours. The reaction mixture was - , cooled to ambient temperature poured onto ice (300 mL) with stirring. The product was isolated by filtration, washed with water (3 X 50 mL) and diethyl ether ~3 X 50 mL) and dried under reduced press~re (16.3g).

WO g5r24200 Ç~CS \NH, ~ICI ~NH m~le~te ' ,~/>~Me MeO
OMe MeO~
OMe A suspension of azalactone prepared above (1.35 g, 5.46 mmol. ) and 7-methyl-tryptamine hydrochloride (1.15 g, 5.46 mmol. ) in 1 N HCl (50 mL) was heated to reflux for 24 hours under nitrDgen atmosphere. The reaction mixture was cooled to ambient temperature neutralized with saturated a aueous potassium carbonate solution and extracted with chloroform. The combined or~anic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.2% NH40H as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate cr~nt~inin!r 1% methanol and treated with maleic acid.
The product was isolated as the maleate salt (730 mg) by filtration. (mp = 168C, dec. ) Analysis Calculated Found C 66.36 66.15 H 6.24 6.28 N 6.19 5.79 WO 95/24200 ~ ,u~
~, ~ /i C~ 8 2 t 8 5 2 3 6 r lf~ 2 Prq~n~t;nn of 8-bromo-1-[(3,4-A;~ -h~-~y~h~.lrl)methyl]-1, 2, 3, 4 -tetrahydro- 9}~-~yrido [ 3, 4 -b] indole hydrochloride To a stirred suspension of 2-bromophenyl-hydrazine hydrochloride (25.8 g, 115 mmol.) in chloroform (500 mL) was added saturated sodium carbonate solution (500 mL). The mixture was stirred for 30 minutes and extracted with chloroform (2X 200 mL). The combined organic phases were concentrated to afford the hydrazine free base as a yellow oil. This oil was dissolved in methanol (100 mL) and treated slowly with 4-chlorobutanal (12.3 g, 115 mmol) . The mixture was placed in a sealable tube and purged with nitrogen for lO
minutes. The tube was sealed and placed in an oil bath preheated to 95CC. EIeating was continued for 18 hours. -The resulting dark solution was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between chloroform/methanol (75/25 by volume) and a aueous sodium carbonate solution The organic phase was concentrated and the crude indole ethAnAm;ni~ was purified by flash chromatography on silica gel (0-25% methanol gradient in chloroform as eluent). Fractions containing product were combined and concentlated. The oil was dissolved in diethyl et~er (300 mL) cn~tA;nin~ 1% methanol and treated with dry HCl gas. The hydrochloride salt was isolated by filtration, washed with 2-propanol (50 mL) and diethyl ether (100 mL) and dried to afford 7-bromotryptamine~hydrochloride (3 . 6 g) as a pale solid, which was used without further purification.
A suspension of azalactone (prepared as described in Example 1) (1.16 g, 4.7 mmol. ) and 7-bromotryptamine hydrochloride (1.0 g, 3.6 mmol.) in 1 N HCl (100 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The brown solid was triturated with isopropyl alcohol ~ Wo 95/24200 p~ "~ c l5 (3 X 50 mL) and washed with diethyl ether (3 X 50 mL).
Recrystallization from ethanol afforded 860 mg of desired product as the hydrochloride salt. (mp = 279-281C, dec. ) Analysis Calculated Found C 54.87 54.75 H 5.07 5.20 N 6.40 6.23 1~ 3 Preparation of 6, 8-dibromo-1- ~ (3,4-~ hl .. yyh6.. yl)methyl] -1, 2, 3, 4 -tetrahydro - 9H-~yrido [ 3, 4 -b] indole To a stirred, cooled (-5C) solution of 2, 4-dibromoaniline (50.0 g,0.2 mol.) in concentrated HCl solution (110 mL) was added sodium Ilitrite (13.8 g, 0.2 mol.) in water (110 mL) dropwise at such a rate as to maintain temperature below 5C. After complete addition, the mixture was further stirred at 5C for 30 minutes. A solution of tin chloride monohydrate (135.4 g, 0.6 mol.) in concentrated HCl (total volume 170 mL) was added dropwise again r~int~;nin~
temperature below 5C . Af ter complete addition and 3 0 minutes of ~urther stirring, the mixture was placed in the freezer overnight. The light brown solid which precipitated was isolated by f iltration and washed with cold brine followed by a solution of petroleum ether/ diethyl ether (2/1 by volume). This solid was slowly added to an ice cooled mixture of 50% sodium hydroxide solution/ ethyl acetate. The mixture was extracted with ethyl acetate and the organic phase dried over magnesium sulfate. After filtration, the solution was concentrated to 400 mL total volume, diluted with diethyl ether (1.5 L) and treated with dry HC1. The product, 2,4-dibromophenyl-hydrazine hydrochloride (45.9 g) was isolated as a white solid and used without further purif ication .
To a stirred suspension of 2, 4-dibromophenyl-hydrazine hydrochloride (22.0 g, 83 mmol.) in chloro~orm (500 Wo 95/24200 P~ u.,,s,~Q~nsg `~i`'~i'~ 2f85236 mL) was added 5aturated potassium carbonate solution (500 mL) . The mixture was stirred for~ 30 minutes and extracted with chloroform (2X 200 mL). The combined organic phases were concentrated to af ford the hydrazine free base as a yellow oil. This oil was dissolved in methanol (163 mL) and 3 treated slowly with 4-chlorobutanal ( 8 . 8 g, 83 mmol . ) . The mixture was placed in a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oil bath preheated to 95C. E~eating was rontin~ l for 18 hours. The resulting dark solution was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between chloroform/methanol (75/25 by volume) and aqueous sodium carbonate solution. The organic phase was concentrated and the crude indole et~n~mi ne was purified by flash chromatography on silica gel (0-25%
methanol gradient in chloroform as eluent~. Fractions containing product were combined and concentrated. The oil was dissolved in diethyl ether (300 mL) rr~t~;ninJr 1%
methanol and treated with dry HCl gas. The hydrochloride salt was isolated by filtration, washed with 2-propanol (50 mL1 and diethyl ether (100 mL) and dried to afford 7-bromo-tryptamine hydrochloride (1.5 g) as a pale solid, which was used without further purification.
A suspension of azalactone (prepared as described in Example 1) ~0.45 g, 1.82 mmol. ) and 5,7-dibromotryptamine hydrochloride (0.58 g, 1.64 mmol.) in 1 N HCl (65 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated ar~ueous potassium carbonate solution and extracted with chloroform. The combined organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate~0.2%
NH40H as eluent) . The fractions cr,nt~;ning product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate rrnt~ininJr 1% methanol and treated with maleic acid. The product was isolated as the maleate salt (340 mg) by filtration. (mp = 177-179C, dec. ) ~W0 95l24200 P~ ~
~` ~ ` 21 85236 Analysis Calculated .. Found C 48 .34 48 . 61 H 4.06 4.17 N 4.70 4.69 Wo 95/24200 r~ 5, ~ ~
2 1 ~ 5 2 3 6 r 1-~ 4 Pr~ At~n o~ 6-methyl-~-bromo-1-[(3,4-~;- h--~y~h~:.yl)-mQthyl]-1,2,3,4-tetrahydro-9~-~yrido[3,4-b]indole hydrochloride To a stirredl cooled (-5C) solution of 2-bromo-4-methylaniline (50 .54 g, 0 .272 mol. ) in concentrated HC1 solution (200 mL) was added sodium nitrite (lô.9 g, 0.274 mol. ) in water (200 mL) dropwise at such a rate as to Tn~int;~in temperature below 5C. After complete addition, the mixture was further stirred at 5C for 30 minutes. A
solution of tin chloride monohydrate (185.4 g, 0.822 mol. ) in concentrated ~Cl (total volume 400 mL) was added dropwise again maintaining temperature below 5C . Af ter complete addition and 30 minutes of further stirring, the mixture was placed in the free2er overnight. The light brown solid which precipitated was isolated by filtration and washed with cold brine followed by a solution of petroleum ether/diethyl ether (2/1 by volume). This solid was slowly added to an ice cooled mixture of 5096 sodium hydroxide solution / ethyl acetate. The mixture was extracted with ethyl acetate and the organic phase dried o~er magnesium sulfate. After =-filtration, the solution was f-nnn~ntr~ted to 400 mL total volume, diluted with diethyl ether (1.5 Lj and treated with dry HCl. The product, 2-bromo-4-methyl~henylhydrazine hydrochloride (52.4 g) was isolated as a light brown solid and used without further purification.
5-Methyl-7-bromotryptamine hydrochloride t4.95 g) was prepared as described in Example 3, except using 2-bromo-4-methylphenyl hydrazine hydrochloride (21 g) as starting material.
A suspension of azalactone (prepared as described in Example 5) (1.44 g, 6.07 mmol.) and 5-methyl-7-bromotryptamine hydrochloride (1.12 g, 3.87 mmol.) in 1 N ~Cl (80 mL) was heated to reflux for 24 hours under nitrogen atmosphere The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration The brown solid was triturated with isopropyl alcohol (3 X 50 Wo 95/24200 r~.,. - ,, ~-` " 2185236 . .

mL) and washed with diethyl ether (3 X 50 mL).
Recrystallization from ethanol afforded 1.06 g of desired product as a pale solid. (mp = 2Sl-253C, dec. ) Analysis Calculated Found C 55 . 83 56 . 08 H 5.35 5.32 N 6.20 6.33 l~xamDle 5 Pr~r~ ra t; nn of 8 -methoxy- 1- ~ ( 3, 4 _,1; - hnryDhenyl ) methyl ] -1, 2, 3, 4 -tetrahydro - 9H-~?yrido [ 3, 4 -b] indole To a stirred, cooled (0C) suspension of 2-methoxyphenylhydrazine hydrochloride (14.44 g, 83 mmol. ) in THF (600 mL) was added 4-chlorobutanal ~9.0 g, 84 mmol. ) followed by dropwise addition of triethylamine (8.6 g, 85 mmol. ) in THF (20 mL) . Upon complete addition, the cooling bath was removed and the solution stirred for 1 hour. The reaction mixture was filtered and the filter cake washed with THF (100 mL) . The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) and water (5 mL). The solution was transferred to a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oilbath preheated to 95C . Af ter heating for 14 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure.
The residue was partitioned between saturated aqueous potassium carbonate and 3 :1 chloroform: 2-propanol. The organic phase was dried over sodium sulfate and concentrated.
The residue was purified by flash chromatography on silica gel (159c methanol, 0.296 NH40H, in chlorQform as eluent) . The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in methanol and treated with dry HCl and concentrated to afford

7-metho~ytryptamine hydrochloride (4 . 04 g) as a stable foam, which was used without further purification.

Wo 95/24200 P~llu . _ ls j i r 2 ~ & 5 2 3 6 A suspension of azalactone (prepared as described in Example 1) (1.20 g, 4.85 mmol.~ and 7-methoxytryptamine hydrochloride (1. 0 g, 4 4 mmol . ) in lN HCl (120 mL) was heated to reflux for 24 hours under nitrogen atmosphere ~ The reaction mixture was cooled to ambient temperature, neutralized with saturated a aueous potassium carbonate ~
solution and extracted with chloroform. The combined organic layers were concentrated u~der reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0_2%
NH4011 as eluent) . The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate cnnt~inin~ 1% methanol and treated with maleic acid. The product was isolated as the maleate salt (770 mg) by filtration. (mp = 219-220C, dec. ) .
Analysis Calculated Found ~:
C 64.09 64.04 H 6.02 6.i8 N 5.98 5.93 r 1~ 6 PrerAra~ of 6,8-dirluoro-1-[(3,4-~ ,y~h_.-yl)-methyl~-1,2,3,4-tetrahydro-9H-~yrido[3,4-b]indole F$~ MeOH NaOAc, 9~C; --G~NH2 HCl Cl~ Et20, MeOH, HCI H
O F
To a stirred suspension of 2,4-difluoro- , phenylhydrazine hydrochloride (18.5 g, 128 mmol . ) in chloroform (500 mL) was added saturated potassium carbonate solution (500 mL) . The mixture was stirred for 30 minutes and extracted with chloroform (2X 200 mL). The c~nmhinf~l organic phases were cDncentrated to afford the hydrazine free ~ Wo gs/24200 ~ 099 base as a yellow oil. This oil was dissolved in a solution of methanol (163 mL), water (36 mL) and sodium acetate (10.57 g) and treated slowly with 4-chlorobutanal (13.7 g, 128 mmol . ) . The mixture was placed in a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oil bath preheated to 95C. Heating was continued for 15 hours. The resulting dark solution was cooled to a-mbient temperature and concentrated under reduced pressure. The residue was partitioned between chloroform/methanol (75/25 by volume) and a~ueous sodium carbonate solution. The organic phase was concentrated and the crude indole e~h~n~m- nf~ was purified by flash chromatography on silica gel ( 0-25%
methanol gradient in chloroform as eluent). Fractions containing product were combined and concentrated. The oil was dissolved in diethyl ether (300 mL) containing 1%
methanol and treated with dry HCl gas. The hydrochloride salt was isolated by filtration, washed with 2-propanol (50 mL) and diethyl ether (100 mL) and dried to afford 7-bromotryptamine hydrochloride (6.3 g) as a pale solid, which was used without further purif ication.
le~!lte , MeO
OMe MeO~
OMe A suspension of azalactone ~prepared as described in Example 1) (1.07 g, 4.33 mmol.) and 5,7-difluorotryptamine hydrochloride (1.0 g, 4.3 mmol.) in 1 N HCl (70 mL) was heated to reflux for 65 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated a~ueous potassium carbonate WO 95/24200 PCr/U595/03099 0 solution and extracted with chloroform. The combined organic -layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.296 NH40H as eluent) . The fractions containing product were pooled and concentrated under reduced pressure. ~ The residue was dissolved in ethyl acetate cDntaining 1% methanol and treated with maleic acid. The product was isolated as the maleate salt (450 mg) by filtratiQn. (mp = 164-166C, dec. ) Analysis Calculated Found :~
C 60.76 60.63 H 5.10 5.14 N 5.90 5.82 r le 7 Prep~rati~n of 7-methyl-8-bromo-1-[(3,4-~ y~Jhel~yl)-methyl] -1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4-b] indole hydroc:hloride 2 - Bromo - 3 -methy lphenylhydra z ine hydro chl o ri de ( 2 3 g) was prepared as described for 2-bromo-4-methylphenylhydrazine hydrochloride in Example 4, except using 2-bromo-3-methylaniline as starting material.
6-Methyl-7-bromotryptamine hydrochloride was prepared (2.42 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2-bromo-3-methylphenylhydrazine hydrochloride as starting material.
A suspension of azalactone (prepared as described in Example 1) (3.63 g, 14.7 mmoi.) and 6-methyl-7-bromo-tryptamine hydrochloride (4.25 g, 4 .21 mmol. ) in 1 N HCI (150 mL) was heated to reflux for 18 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aclueous potassium carbonate solution and extracted-with chloroform. The combined organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.2% NH40H as eluent). The fractions containillg product were pooled and concentrated under reduced pressure.

The residue was dissolved in ethyl acetate containing 1%
methanol and treated with dry HC1. The product was isolated as the hydrochloride salt (3.11 g) by filtration. m/e=414.
Analysis Calculated Found C55 . 83 56 .13 H5.18 5.29 N6.20 6.31 r le 8 Pr~r~rat;~n of 6-(1,1-dimethylethyl)-1-~(3,4-~; h~y~h~ yl) methyl]1,2,3,4-tetr~hydro-1-9~}-pyrido-[3,4b]indole hydro~hloride 5~ dimethylethyl ) -tryptamine hydrochloride was prepared (2.95 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 4- (1,1-dimethylethyl)-phenylhydrazine hydrochloride (6.00 g) as starting material.
A suspension of azalactone (prepared as described in Example 1) (1.25 g, 5.26 mmol.) and 5-(1,1-dimethylethyl)-tryptamine hydrochloride (1.33 g, 5.26 mmol . ) in 1 N HCl (50 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, and the crude product isolated by filtration.
The brown solid was triturated with isopropyl alcohol (3 X 50 mL) and washed with diethyl ether (3 X 50 mL) .
Recrystallization from ethanol af~orded 0.74 g of desired product as a pale solid.
Analysis Calculated Found C 69.47 69.66 H 7.53 7.50 - N 6.75 6.71 r l~ g pre~r~t;nn of 5-fluoro-6-methyl-1-[(3,4-~; - hrYyphenyl)-methyl] -1,2,3,4-tetr~lhydro-9}}-pyrido[3,4-b]indole Wo 95l24200 P~,l/u., /0~099 o i c 2 ~ 85236 3-Fluoro=~-methylphenylhydrazine hydrochloride (21.4 g) was prepared as described for 2-bromo-4 methylphenylhydrazine hydrochloride in Example 4, except using 3-fluoro-4-methyl~nilinr~ as starting material.
4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) as described for 5-methyl-7-bromotryptamine -hydrochloride in Example 4, except using 3-fluoro-4-methylphenylhydrazine hydrochloride ( 6 . 00 g) as starting material .
A suspension of azalactone (prepared as descri~ed in Example 1) (0.76 g, 3.06 mmol.) and 4-fluoro-5-methyltryptamine hydrochloride (0.70 g, 3.06 mmoI.) in l N
HCl (40 mL) was heated to reflux:for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The - ' inocl organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel ~ethyl acetate / 0 2% NH40H as eluent). The fractions containing product were pooled and concentr~ted under reduced pressure.
The residue was dissolved in ethyl acetate t~ t~ining 1%
methanol and treated with maleic~acid. The product was isolated as the maleate salt (60 mg) by filtration. mp. 191-194C .
Analysis Calculated Found C 63 . 82 63 . 60 H 5.78 5.65 N 5.95 5.92 r l~ 10 pr-~p~rAt;~n of 7,8,9,10-tetrahydro-10-~(3,4-dime~hu.,y~,h~yl) methyl]~ -benzo[g~yrido[3,4-b]indole 6, 7-Benzotryptamine hydrochloride was prepared (2.85 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 1-naphthyl-hydrazine hydrochloride (6.00 g) as starting material.

Wo95/24200 I~ O99 2 ~ 8 5 2 3 6 A suspension of azalactone (prepared as described in Example 1) (1.51 g, 6.11 mmol ) and 6,7-benzotryptamine hydrochloride (1.50 g, 6.11 mmol ) in 1 N HCl (40 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated agueous potassium carbonate solution and extracted with chloroform. The combined organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.2%
NH40H as eluent) . The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 196 methanol and treated with maleic acid. The product was isolated as the maleate salt (240 mg) by filtration. m/e=373, mp. 187C
( dec . ) Analysis Calculated Found C 68 . 84 68 . 63 H 5.78 5.91 N 5.73 5.67 Examl~le 11 Pre~ n~t; ~n of 6 -cyclohexyl ~ ( 3, 4 -~ i - h~ y~)h~y l ~ -methyl ] -1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole hydrochloride 4-Cyclohexylphenylhydrazine hydrochloride (35 6 g) was prepared as described for 2-bromo-4-methyl-phenylhydrazine hydrochloride in Example 4, except using 4-cyclohexylaniline as starting material.
5-Cyclohexyltryptamine hydrochloride was prepared (1.29 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 4-cyclohexylphenylhydrazine hydrochloride as starting material.
- A suspension of azalactone (prepared as described in Example 1) (0 .54 g, 2 .18 mmol. ) and 5-cyclohexyltryptamine hydrochloride (0.6 g, 2.18 mmol.) in 1 N HCl (30 mL) was heated to _ref lux f or 14 hours under nitrogen atmosphere . The reaction mixture was cooled to ambient temperature, Wo g~l24200 P~
2 1 8~236 neutralized with saturated agueous potassium carbonate solution and extracted with chloroform. The combined organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / O.296 NH40H as eluent) . The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 1% methanol and treated with maleic acid. The product was isolated as the maleate salt ~140 mg) by filtration. m/e= 404.
Analysis Calculated Found C 69.21 69.17 ~
H 6.97 7.01 N 5.38~ 5.53 r le 12 Prepn~t;on of 5,8-dimethyl-1,2,3,4-tetrahydro-1-[(3,4-; h~ y~,h~ ~yl)methyl] -9~-~yrido [3, 4h] indole hydrochloride 4, 7-dimethyltryptamine hydrochloride was prepared (0.94 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2, 5-dimethyl-phenylhydrazine hydrochloride (16 . 8 g) as starting material .
A suspension of azalactone ~prepared as described in Example ~) (1.04 g, 4.21 mmol.) and 4,7-dimethyltryptamine hydrochloride iO.94 g, 4.21 mmol.) in 1 N HCl ~40 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated agueous potassium carbonate ~
solution and extracted with chloroform. The combined organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.2%
NH40H as eluent) . The fractions ct-nt~ining product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 1% methanol and treated with anhydrous HCl. The product was isolated as the hydrochloride salt (~70 mg) by filtration. m/e=349 ~ Wo 9~l24200 , ~

Analysis Calculated Found - C 68.29 68.59 H 7.03 6.92 N 7 .24 7 . 04 Exam~le 13 pr~rAr~t;~n of 6-(1-methylethyl)-1,2,3,4-tetrahydro-1-[(3,4-A; ~h.--y~,h_.~yl)methyl] -9~-~yrido[3,4b] indole To a stirred suspension of 4-isopropylphenyl-hydrazine hydrochloride monohydrate tl5.3 g, 91.95 mmol.) in chloroform (250 mL) was added saturated sodium carbonate solution (250 mL) . The mixture was stirred for 30 minutes and extracted with chloroform (2X 200 mL). The ~ in~
organic phases were concentrated to af ford the hydrazine free base as a yellow oil. This oil was dissolved in methanol (200 mL) and water (5 mL) and treated with sodium acetate (6.72 g, 82 mmol.) and 4-chlorobutanal (8.7 g, 82 mmol.).
The mixture was placed in a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oil bath preheated to 100C. Heating was continued for 18 hours. The resulting dark solution was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between chloroform/methanol (75/25 by volume) and agueous sodium carbonate solution. The organic phase was concentrated and the crude indole ~th~n~mi n~ was purified by flash chromatography on silica gel (0-25%
methanol gradient in chloroform as eluent). Fractions containing product were combined and concentrated. The oil was dissolved in diethyl ether (300 mL) containing 196 methanol and treated with dry HCl gas. The hydrochloride salt was isolated by filtration, washed with 2-propanol (50=
mL) and diethyl ether (100 mL) and dried to afford 5-isopropyltryptamine hydrochloride ( 9 . 8 gl as a pale solid, which was used without further purification.
A suspension of azalactone (prepared as described in Example 1) (1.55 g, 6.31 mmol.) and 5-isopropyltryptamine Wo 95/24200 1 ~, ~ 099 2 1 g 5 2 3 6 hydrochloride (1.76 g, 7 .37 mmol. ) in 1 DJ HCl (40 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The combined organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.2%
NH40H as eluent) . The fractions containing Erroduct were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate rr,nti!,ining 196 methanol and treated with maleic acid. The product was isolated as the maleate salt (310 mg) by filtra~iQn. m/e=365, mp. 196-200C.
Analysis Calculated Found C 67 . 48 67 . 74 X 6.71 6.75 N 5 83 5 . 92 Lx~mDle 14 Pr~r~rnt;nn of 6,8-dimethyl-1,2,3,4-tetrahydro-1-~(3,4-d~methoxyDhenyl)methyl]-9H-eDyrido~3,4b]indole hydrochloride 5,7-Dimethyltryptamine hydrochloride was prepared (2.86 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2, 4-dimethylphenylhydrazine hydrochloride (15.0 g) as starting material .
A suspension of azalactone (prepared as described in Example 1) (r.6~ g, 6.67 mmol.) and 5,7-dimethyltryptamine hydrochloride (1.50 g, 6.67 mmol.) in 1 N HCl (70 mL) was heated to reflux for 24 hours under nitrogen atmosphere The reaction mixture was cooled to ambient temperature and the crude product~ isolated by filtration. The solid was triturated with ethanol/hexanes (3 X 50 mL) and washed with hexanes (3 X 50 mL) . The product was isolated by filtration (820 mg). m/e=350.

~ W095/24200 r~ A~ogg i Analysis Calculated Found C 68.29 68.07 H 7.03 7.12 N 7.24 7.23 Exam~le 15 Pr~r~ rat ion 0~ 5, 7 -dimethyl -1, 2, 3, 4 -tetrAhydro -1- [ ( 3, 4 -A; ' h. ~y~,.h.~..yl)methyl] -9H-~yrido [3,4b] indole hydrochloride 4, 6-Dimethyltryptamine hydrochloride was prepared (1.06 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 3, 5-dimethylphenylhydrazine hydrochloride (7 . 65 g) as starting material .
A suspension of azalactone (prepared as described in Example 1) (1.16 g, 4.69 mmol.) and 4,6-dimethyltryptamine hydrochloride (1.05 g, 4.67 mmol.) in 1 N HCl (60 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was triturated with ethanol/hexanes (3 X 50 mL~ and washed with hexanés (3 X 50 mL). The product was isolated by filtration (770 mg). m/e=350.
Analysis Calculated Found C 68.29 68.09 H 7.03 7.12 N 7 .24 7 . 02 Bxam~le 16 ~
pr~rAr:~tion Of 6,7-aimethyl-1,2,3,4-tetrahydro-1-[(3,4-A~ ' h.~y~,he"yl)methyl] -9H-~yrido[3,4b]indole To a stirred, cooled (OaC) solution of 5, 6-dimethyl-indole (3.69 g, 25.4 mmol.) in dry diethyl ether (75 W0 95/24200 r ~ . ' 9~ ~
2~85236 m~) was added dropwise oxalyl ch~oride 13.8 mL, 43.0 mmol.) over 2 minutes. After further stirring for 30 minutes, the bright yellow acid chloride (5.99 g) was isolated by filtration and washed with dry diethyl ether. This acid chloride was added in portions to a rapidly stirred solution of aqueous (3096) ammonium hydroxide (100 mL). After the addition was complete, the mixture was further stirred at ambient temperature,for 30 minutes and the crude product isolated by filtration. Recrystallization from THF/diethyl ether afforded product (3.05 g) as a tan solid.
To a stirred, refluxing solution of amide (prepared above) (3.05 g, 14.1 mmol.) in THF was added ~
dropwise a suspension of lithium aluminum hydride (3.07 g, 81.3 mmol. ) in THF over 1 H. Upon ccmplete addition, the mixture was further ~eated to reflux for 14 H. The reaction mixture was cooled to 0C and carefully treated with water (3.1 mL) followed by 15% sodium hydroxide solution (3.1 mL), followed by water (9.3 mL). The salts were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether (80 mL) with 5~6 ethyl acetate and treated with anhydrous HCl. The hydrochloride salt (2 . 65 g) was isolated by filtration and washed with dry ether.
A suspension of azalactone (prepared as described in Example 1) (1.10 g, 4 .45 mmol. ) and 5, 6-dimethyltryptamine hydrochloride (1.00 g, 4.45 mmol.) in 1 N HCl (60 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized ~with saturated a~ueous potassium carbonate solution and extracted with chloroform.
The c~mhi nPd organic layers were =concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.296 NH40H as eluent). The fractions containing product were pooled and concentrated under reduced pressure.
The residue was dissolved in ethyl acetate ~ nt~;n1n~ 1%
methanol and treated with maleic acid. The product was isolated as the maleate salt ~450 mg) by filtration. mp. 197-200C.
Analysis Calculated Found C 66 . 94 67 . 01 H 6.40 6.56 N 6.00 5.98 ~ :xamPle 17 Pre~aration of 6-ethyl-1,2,3,4-tetrahydro-l-t(3,4-t.h~y~,h_~lyl)methyl~-9~-~yrido[3,4b]indole To a stirred, cooled (0C) solution of 5-ethylindole (4.0 g, 27.5 mmol.) in dry diethyl ether (250 mL) was added dropwise oxalyl chloride (4.8 mL, 55.1 mmol.) over 2 minutes. After further stirring for 30 minutes, the bright yellow acid chloride was isolated by f iltration and washed with dry diethyl ether. This acid chloride was added in portions to a rapidly stirred solution of aqueous (30%) ammonium hydroxide (200 mL). After the addition was complete, the mixture was further stirred at ambient temperature for 30 minutes and the crude product isolated by filtration (4.7 g) as a tan solid.
To a stirred, refluxing solution of amide (prepared above) (4 .7 g, 21.7 mmol. ) in THF was added dropwise a suspension of lithium aluminum hydride (4 . 7 g, 121 mmol . ) in THF over 1 H. Upon complete addition, the mixture was further heated to reflux for 14 H. The reaction mixture was cooled to 0C and carefully treated with water (4.7 mL) followed by 15% sodium hydroxide solution (4.7 mL), followed by water (14.1 mL). The salts were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether (80 mL) with 5% ethyl acetate and treated with anhydrous HCl. The hydrochloride salt (4 . 02 g) was isolated by filtration and washed with dry ether .
A suspension of azalactone (prepared as described in Example 1) (1.10 g, 4.45 mmol. ) and 5, 6-dimethyltryptamine Wo gs/24200 P~
~ ~rl 2185236 hydrochloride (1.00 g, 4.45 mmol.) in 1 N HCl ~60 mL) was heated to reflux ~or 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloro~orm. The combined organic $
layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0_296 NH40H as eluent ) . The ~ractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 196 methanol and treated with maleic acid. The product was isolated as the maleate salt (520 mg) by filtration. mp. 185C (dec. ) .
Analysis Calculated Found C 66 . 94 66 . 95 H 6.48 6.55 N 6.01 5.99 ~le 18 Pr~p~ati~n of 6-bromo-1,2,3,4-tetrahydro-1-~(3,4-h~.Ay~,h~ )methyl]-g}l-pyrido[3~4b~indole A suspension o~ azalactone ~prepared as~described in Example 1) (0.91 g, 3.7 mmol.) and 5-bromotryptamine hydrochloride (1.01 g, 3.7 mmol.) in 1 N HCl (60 mL) was heated to reflux ~or 18 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloro~orm. The combined organic =
layers were concentrated under rbducea pressure and the residue chromatographed on silica gel (ethyl acetate / 0.296 NH4OH as eluent). The ~ractions containing product were pooled and concentrated under reduced pressuré. The residue was dissolved in ethyl acetate c~nt~inin~ 1% methanol and treated with maleic acid. The product was isolated as the maleate salt (800 mg) by ~iltration. (mp = 184-188C, de~. ) m/e= 403.
-~W0 95/24200 r~ o~oss Analysis Calculated Found C 55.72 55.51 H 4.87 5.09 N 5.41 5.36 EYam~le 19 pre~S~r~t;~n of 7,8-aimethyl-1,2,3,4-tetrahydro-1-[(3,4-dimeth~..y~,h~ yl)methyl~-9~-~yrido[3,4b]iAdole hydroc:hloride 6, 7-Dimethyltryptamine hydrochloride was prepared (2.26 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2,2-dimethyl-phenylhydrazine hydrochloride (15.0 g) as starting material.
A suspension of azalactone (prepared as described in Example 1) (1.39 g, 5.62 mmol.) and 6,7-dimethyltryptamine hydrochloride (1.26 g, 5 . 61 mmol . ) in 1 N HCl t70 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated a~ueous potassium carbonate solution and extracted with chloroform. The combined organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.2%
NH40H as eluent ) . The f ractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate ~ nti9;n;n~ 1% methanol and treated with anhydrous HCl. The product was isolated as the hydrochloride salt (290 mg) by filtration. m/e=350 Analysis Calculated Found C68.29 68.51 H7.03 6.87 N7.24 7.22 .
I2xamDle 2 0 .

Wo 95/24200 PCr/Uss5103099 ~ ~rii~I `; 2l85236 Preparation o~ 6-methyl-1, 2, 3, 4-tetr~hydro-1- ~ ( 3, 4-~imethoxy~henyl)methyl] -9H-~yrido [3, 4b] indole hydrochloride A suspension of azalactone (prepared as described in Example 1) (3.4 g, 12.4 mmol.) and 5-methyltryptamine hydrochloride (2.0 g, 9.9 mmol.) in 1 N HCl (100 mL) was heated to reflux for 24 hours under nitrogen atmosphere The reaction mixture was cooled to a~Loient temperature and ~he crude product is41ated by filtration. The solid was triturated with ethanol and washed with diethyl ether The product was isolated as ~WO 9SI24200 1 ~ I, u ~oss 2 1 ~ 523 6 the hydrochloride salt by filtration (3.2 g). mp. 245-246C
L ( dec . ) Analysis Calculated Found - C 67 . 64 67 . 42 H 6.67 6.66 N 7.51 7.25 r le 21 pr~r~r~ti~n of 6-methyl~ (3,4,5-trimeth~..y~he.~yl)-methyl]-1,2,3,4-tetrahydro-98-~yrido[3,4-b]indole hydrochloride A solution of 3,4,5-trimethoxyb~n7~ hyde (20.0 g, 0 .10 mol. ), N-acetylglycine (11.9 g, 0 .10 mol . ) and sodium acetate (8.4 ç~, 0.1 mol) in acetic anhydride (100 mL) was heated to 100C for 2 hours. The reaction mixture was cooled to ambient temperature poured onto ice (300 mL) with stirring. The product was isolated by filtration, washed with water (3 X 50 mL) and diethyl ether (3 X 50 mL) and dried under reduced pressure (5.6 g).
A suspension of azalactone (prepared above) (2 . 0 g, 7 .2 mmol. ) and 5-methyltryptamine hydrochloride (1.1 g, 5.4 mmol. ) in 1 N HCl (20 mL) was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was triturated with isopropanol and washed with diethyl ether . The product was isolated by filtration (650 mg). mp. 228-229C.
Analysis Calculated Found C65.58 65.38 H6.75 6.76 N6.95 6.92 WO 95/24200 ~ nsg .

r le 22 Pr r~rat;~ln of 6-methyl-1-[(2,3,4-trimethoxy~henyl)-methyl]-1, 2, 3, 4-tetrahydro-9~-~yrido ~3, 4-b] indole hydrochloride A~alactone (12.28 g) was prepared as in Example 21 except using 2,3,4-trimethoxyb~n7~ yde (20.0 ~
A suspension of azalactone (prepared above) (2 . 0 g, 7.2 mmol.) and 5-methyltryptamine hydrochloride (1.1 g, 5 .4 mmol . ) in l N HCl (20 mL) was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was triturated with isopropanol and washed with diethyl ether . The product was isolated by filtration (1.36 g). mp. 214.5C.
Analysis Calculated Found C 65 . 58 65 . 41 H 6.75 6.70 N 6.95 6.89 1~ 23 Preparation of 6-methyl-1-~(2-methoxy~henyl)methyl]-1,2,3,4-tetrahydro-9}}-~yrido ~3, 4-bl indole hydrochloride Azalactone (16.42 g) was prepared as in Example 21 except using 2-methoxybenzaldehyde (20.0 g).
A suspension of azalactone (prepared above) (2 . 0 g, 9 .2 mmol. ) and 5-methyltryptamine hydrochloride (1.5 g, 6 . 9 mmol . ) in 1 N HCl (20 mL) was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was triturated with isopropanol and washed with diethyl ether . The product was isolated by filtration (880 mg). mp. 252.8C.
Analysis Calculated Found C 70 . 06 70 . 15 -H 6.76 6.83 N 8.17 8.16 ~ WO 95/24200 r~ ,.,JQ~099 . ` , .~ ? 2 ! 85236 ExamDle 24 Pr~ at ~ nn o~ 6 -methyl -1- ~ ( 2, 4 -~ h' ~ - y~Jhe.. y 1 ) methyl ] -1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole hydrochloride Azalactone (7 . 55 g) was prepared as in Example 21 except using 2,4-dimethoxybenzaldehyde (20.0 g).
A suspension of azalactone (prepared above) (2.0 g, 8.1 mmol. ) and 5-methyltryptamine hydrochloride (1.3 g, 6.1 mmol. ) in 1 N HCl (20 mL) was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The combined organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate/0.2% NH40H as eluent) . The f ractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 19s methanol and treated with anhydrous HCl. The product was isolated as the hydrochloride salt (361 mg) by filtration. mp. 262 . 6C.
Analysis Calculated Found C67 . 6d, 67 . 73 H6.76 6.85 N7.51 7.50 Examrle 25 Preparation o~ 6-methyl-1-[(2,5-~ hnxyphenyl)methyl]-1, 2, 3, 4 -tetrahydro- 9H-pyrido [ 3, 4 -b] indole hydrochloride Azalactone (13.21 g) was prepared as in Example 21 except using 2,5-dimethoxybenzaldehyde (20.0 g).
A suspension of azalactone (prepared above) (2.0 g, 8.1 mmol. ) and 5-methyltryptamine hydrochloride (1.3 g, 6.1 m~ol. ) in 1 N HCl (20 mL) was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with WO 95/24200 , ~ 099 o <' t i 2~ 85236 chloroform. The co~nbined organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate/0.2% NH40H as eluent~. The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 196 methanol and treated with anhydrous HCl. The product was isolated as the hydrochloride salt ~1.14 g) by filtration. mp. 262 C.
Analysis Calculated Found C 67.64 67.36 H 6.76 6.71 N 7.51 7.25 Ex~mDle 2 6 Pr~D~ r~ t i ~n o~: 6 -methyl -1- [ ( 2, 4, 5 - trimeth "~y~"h~ ~ ~y 1 ) -me thyl ] -1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole hydrochloride AzalactoIIe (8.36 g) was prepared as in Example 21 except using 2,4,5-trimethoxyb~n7~1~ohyde (20.0 g).
A suspension of azalactone (prepared above) (2 . 0 g, 7.2 mmol.) and 5-methyltryptamine hydrochloride (1.1 g, 5.4 mmol. ) in 1 N HCl (20 mL) was heated to reflux for 48 hours under nitrogen atmosphere. :- The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solia was triturated with isopropanol and washed with diethyl ether . The product was isolated by filtration. RecrystAlli7~tion from ethanol/cyclohexane afforded product f2~3 mg). mp. 176.3C.
Analysis (~alculated Found C 65.50 65.51 -X 6.75 6.73 N 6.95 6.87 ~ W0 95l24200 F~ ~ gs ~ l~ 27 Preparation o f 6 ~ methylethyl ) -1- [ ( 2, 3, 4 -trimethoxy-~henyl )methyl] -1, 2, 3, 4 -tetrahydro-9H-~yrido ~3, 4-b] indole hydroc:hloride A suspension of azalactone (prepared as in Example 22) (1.0 g, 3.61 mmol.) and 5-isopropyltryptamine hydrochloride (prepared as in Example 13) (646 mg, 2.7 mmol.) in 1 N HC1 (20 mL) was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated a~ueous potassium carbonate solution and extracted with chloroform.
The cnmhi nc~l organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.2% NH40H as eluent). The fractions containing product were pooled and concentrated under reduced pressure.
The residue was dissolved in ethyl acetate containing 196 methanol and treated with anhydrous HCl. The product was isolated as the hydrochloride salt (315 mg) by filtration.
mp . 147 . 3C .
.

Analysis Calculated Found C 66 . 89 66 . 80 H 7 .25 7 . 01 N 6.50 6.39 r le 28 Prel?ar2tion o~ 6-methyl-1-[(3,4-~; 'hn~ry-5-nitro~henyl)-methyl]-1,2,3,4-tetr2hydro-9H-~yrido[3,4-b]indole hydrochloride Azalactone (16.9 g) was prepared as in Example 21 except using 3,4-dimethoxy-5-nitrobenzaldehyde (23.5 g).
A suspension of azalactone (prepared above) ~2 . 8 g, 9 . 6 mmol . ) and 5-methyltryptamine hydrochloride (2 . 0 g, 9.5 mmol. ) in 1 N HCl (50 mL) was heated to reflux for 72 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was triturated with isopropanol W0 95/24200 P~ 099 o and washed with diethyl ether The product was isolated as the hydrochloride salt by filtration (3.441 mp. 239-2~3C, m/ e=3 81 .
Analysis Calculated Found C 60.36 60.54 H 5.79 5.66 N 10.06 10.12 r le 29 PrerJ~ ~t; ~n 0~ 6 -methyl -1- [ ( 3 - iodo-4, 5 - A; - ' h~lYy-~henyl ) -methyl]-1,2,3,4-tetrahydro-9~ yrido~3,4-b]indole To a stirred, cooled ~0C) solution of iodovanillin (10.0 g, 35.96 mmol.) in dimethyiformamide ~50 mL) was added anhydrous potassium carbonate (20.0 g, 143.86 mmol.) followed by iodomethane (3.11 mL, 50.0 mmol.). The mixture was allowed to warm to ambient temperature and stir ~or 14 H.
The mixture :was poured into diethyl ether (500 mL) and washed with water -(3 X 150 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure to afford~3-iodo-4,5-dimethoxybenzaldehyde (9.5 g) as a yellow oil which solidified upon standing and was used without further purification .
Azalactone (11.1 g) was prepared as in Example 21 except using 3-iodo-4, 5-dimethoxybenzaldehyde (9 .S g), and hippuric acid ( 6 . 41 g) instead of N-~cetylglycine .
A suspension of azalactone (prepared above) (2.2 g, 5 . 0 mmol . ) and 5-methyltryptamine hydrochloride (l. 0 g, 4 . 3 mmol . ) in 1 N HCl (100 mL) was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous sodium hydroxide solution and extracted with chloroform. The combined organic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.2% NH40H as eluent). The fractions containing product were pooled and concentrated under reduced pFessure. The residue was dissolved in ethyl WO 95/24200 PCrrUS95103099 ~ `,)2 ~ 2~85236 acetate containing 1~6 methanol and treated with maleic acid The product was isolated as the maleate salt (134 mg) by filtration. m/e=463.
Analysis Calculated Found C 51.92 52.15 EI 4.71 4.72 N 4.84 4.70 le 30 Prel;~aration of 6 -methyl -1- [ ( 3, 4 _A; ~h~`Yy- 5 -amino-~henyl ) -methyl]-1,2,3,4-tetrahydro-9}}-~yrido~3,4-~h]inaole dihydroc:hloride To a stirred solution of nitro compound (prepared in Example 28) (3.0 g, 7.2 mmol.) in acetic acid (40 mL) was added activated zinc dust (4.64 g). The reaction mixture was stirred at ambient temperature for 2 ~, diluted with water (200 mL) and filtered through celite. The filtrate was neutralized with a~Iueous ammonium hydroxide solution and extracted with chloroform. The organic phase was washed with brine and dried over magnesium sulfate. The combined organic phases were concentrated under reduced pressure and the residue dissolved in ethyl acetate and treated with anhydrous HCl. The product was isolated by filtration, washing with diethyl ether and trituration with ethyl acetate to afford product as the bis-hydrochloride salt (2.41 g).mp. 230-234C, m/e=351 .
Analysis Calculated Found C 59 . 44 58 . 47 ~I 6.41 6.31 N 9.90 9.68 W0 95/24200 r~ O
~ ~ r~ 21 8 5 2 3 6 Preparation o~ 6 -methyl-1- [ ( 3-methoxy-4-1?L~ ..y~ yl ) -methyl] -1, 2, 3, 4-tetrahydro-9H-~yrido ~3, 4-b] indole To a stirred solution of vanillin (30.0 g, lg7 mmol. ) in methanol (100 mL) was added anhydrous potassium carbonate (13.7 g, 99 mmol.) followed by allyl bromide (17.0 mL, 197 mmol. ) . The mixture was heated to reflux for 5 H.
The reaction mixture was filtered and concentrated under reduced pressure to afford the intermediate product (30.4 g) as an oily solid which was used without further purification.
Azalactone (32.2 g) was prepared as in Example 21 except using 3-methoxy-4-allyloxyb~n~ hyde (30.4 g), and hippuric acid (28.3 g) instead of N-acetyl glycine.
A suspension of azalactone (prepared above) (1.74 g, 5.2 mmol . ) and 5-methyltryptamine hydrochloride (1.1 g, 5.2 mmol. ) in 1 N HCl (40 mL) and ethanol (30 mL) was heated to reflux for 18 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The combined organic phases were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.2%
NH40H as eluent ) . The f ractions containing product were pooled and concentrated under reduced pressure. The residue ~ -was dissolved in ethyl acetate ~f)nt~inin~ 1% methanol and treated with maleic acid. The product was isolated as the maleate salt (560 mg) by filtration. m/e=362. The product was used without further purification.
To a suspension of maleate salt (560 mg, 1.7 mmol . ) in chloroform (100 mL) was added saturated potassium carbonate solution (100 mL) with vigorous stirring. The layers were separated and the aqueous phase was further extracted with chloroform (2 X 100 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The free base was dissolved in ethanol and hydrogenated (25C, 60 PSI) in the presence of raney nickel catalyst. The catalyst was removed ~ WO 9~/24200 . ~lllJ~'( ,9 ~. - 2 1 85236 by filtration and the solution concentrated under reduced pressure to af~ord a viscous oil, which was dissolved in ethyl acetate and treated with maleic acid (140 mg) . The crude product was isolated by filtration. Trituration with hot ethyl acetate and washing with diethyl ether afforded product (170 mg) as the maleate salt. mp. 188C, m/e=365.
Analysis Calculated Found C 67 . 48 67 . 62 H 6.71 6.66 N 5.83 5.80 r 1-~ 32 Prep~r~t; nn of 6-methyl-1- [ (4-dimethyl ~m;n~rh~nyl)methyl] -1,2,3,4-tetrahydro-9~ yrido~3,4-b]indole dihydrochloride To a stirred, cooled (-78C) suspension of methoxymethyltriphenylphosphonium chloride (13.79 g, 40.02 mmol . ) in dry THF (150 mL) was added n-BuLi solution (25.2 mL. 1. 6 M, 40 . 02 mmol . ) dropwise by syringe. The orange suspension was stirred at -78C for 15 min. A solution of 4-dimethylamino~enzaldehyde (5.00 g, 3.35 mmol.) in THF (75 mL) was added to the ylide dropwise=over 10 min. The reaction mixture was gradually warmed to ambient temperature and stirred 14 H. Saturated ammonium chloride solution (100 mL) was added and the mixture extracted with diethyl ether (3 X 50 mL) . The ~ mhi nP~i organic phases were dried over sodium sulfate and concentrated under reduced pressure.
Chromatography on silica gel, eluting with 1596 ethyl acetate/hexanes afforded product (4.70 g) as a mixture of olefin isomers which was used without further purification.
A mixture of 5-methyltryptamine hydrochloride (891 mg, 4.23 mmol.) and 1-methoxy-4'-dimethylaminostyrene (1.00 g, 5.64 mmol.) in acetonitrile (20 mL) and lN HCl solution (150 mL) was heated to reflux for 96 E~. The reaction mixture was cooled to amoient temperature, neutralized with saturated a(lueous potassium carbonate solution and extracted with chlorof orm. The combined organic phases were concentrated . = ~

W0 9~/24200 P~ 099 o under reduced pressure and the residue chromatographed on silica gel (2.5~ MeOH/chloroform/0.296 NH40X as eluent).~ The fractions cnnt~inin~ product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and treated with anhydrous HCl. The product was isolated as the dihydrochloride salt (354 mg) by filtration.
mp . 275 . 4C .
Analysis Calculated: Found C 64.2g 64.21 6.94 7.01 N 10.71 10.74 r 1~ 33 Preparation of 6-methyl-1-[(4-dibutyl~m;nr~h~nyl)methyl]-1,2,3,4-tetrahydro-9H-~yrido[3,4-b]indole dihydrochloride To a stirred, cooled (-78C) suspension of methoxymethyl-triphenylphosphonium chloride (8.81 g, 25.7 mmol . ) in dry TXF ( 150 mL~ was added n-Bu1i solutlon (16 .1 mL . 1. 6 ~, 25 . 7 mmol . ) dropwise by syringe . The orange suspension was stirred at -78C for 15 min. A solution of 4-dibutylaminobenzaldehyde (~.00 g, 2.14 mmoi. ) in TXF (75 mL) was added to the ylide dropwise over 10 min. The reaction mixture was gradually warmed to arnbient temperature and stirred 14 H. Saturated ammonium chloride solution (100 mL) was added and the mixture extracted with diethyl ether (3 X 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure.
Chromatography on silica yel, eluting with 15% ethyl acetate/hexanes afforded product_~3.47 g) as a mixture of olefin isomers which was used without further puri~i ~'At-i nn.
A mi~cture of 5-methyltryptamine hydrochloride ( 605 mg, 2.87 mmol.) and l-methoxy-4'-dibutylamino-styrene (1.00 g, 3.83 mmol.) in acetonitrile (20 mL) and lN XCl solution (150 mL) was heated to reflux for 96 X. The reaction mixture was cooled to ambient temperature, neutralized with saturated a~ueous potassium carbonate solution and extracted with W0 95/24200 P~ 099 , ` ,j ~, chloroform. The combined organic phases were concentrated under reduced pressure and the residue chromatographed on silica gel t2.596 MeOH/chloroform/0.2% NH40H as eluent) . The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and treated with anhydrous HCl. The product was isolated as the dihydrochloride salt (476 mg) by filtration.
mp . 2 6 6 . 6C .
Analysis Calculated Found C 60 . 05 67 . 92 H 8.25 8.22 N 8.82 8.74 r 1P 34 PrP~ratir~n of 6-methyl-1- [ ~3-fluoro-4-methoxyphenyl) -methyl]-1,2,3,4-tetrahydro-9H-~yrido[3,4-b]indole hydrochloride Azalactone (0.330 g) was prepared as in Example 21 except using 3-fluoro-4-methoxybenzaldehyde (5.0 g).
A suspension of azalactone prepared above (0.30 g, 1.3 mmol. ) and 5-methyltryptamine hydrochloride (0 .27 g, 1.3 mmol. ) in 1 N HCl (20 mlJ) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature neutralized with saturated a(aueous potassium carbonate solution and extracted with chloroform.
The combined organic phases were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate/0 296 MH40H as eluent) . The fractions containing product were pooled and concentrated under reduced pressure.
The residue was dissolved in ethyl acetate containing 196 methanol and treated with anhydrous HCl. The product was isolated as the hydrochloride salt (170 mg) by filtration.
m/e=324 .

Wo 95/24200 PCT/US95/03099 ~ ~ ~ r ~; 21 85236 90 .
Analysis Ca~culated Found C 66 57 66.37 H 6.15 6.16 N 7.76 7.5 r 1-~ 35 pr~p~r~l inn Of 6-methyl-1-[(3,4-dimethyl~henyl)methyl~-1, 2, 3, 4 -tetrahydro - 9H-~yrido [ 3, 4 -b] indole hydrochloride Azalactone (11.3 g) was prepared as in Example 21 except using 3, 4-dimethylbenzaldehyde (25 . 0 g) .
A suspension of azalactone prepared above (2 . 04 g, 9.5 mmol.) and 5-methyl-tryptamine hydrochloride (2.0 g, 9.5 mmol. ) in 1 N XCl (80 mL) was heated to reflux for 24 hours under nitro~en atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was triturated with ethanol and washed with diethyl ether . The product was isolated as the hydrochloride salt by filtration (1.89 g). m/e=304.
Analysis Calculated Found C73 . 9 9 73 . 84 H7.39 7.35 N8.21 8.48 }examole 36 pr~rAratinn 0~ 6-methyl-1-[(2-chloro-3,4-A;- -h~ y,~_e~yl)-methyl~-1,2,3,4-tetrahydro-9/E-ryrido[3,4-b]indole hydrochloride Azalactone (5.26g) was prepared as in Example~21 except using 2-chloro-3, 4-dimethoxybenzaldehyde ~10 . 45 g), A suspension of azalactone prepared above (1.34 g, 4.76 mmol.l and 5=methyltryptami~e hydrochloride (1.0 g, 4.75 mmol. ) in 1 N HCl (30 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was triturated with ethanol and washed ' with diethyl ether. The product was isolated oy filtration (l.19 g). m/e=370, mp. 244C (dec.).
Analysis Calculated Found C 61 . 92 61 . 67 EI 5 . 94 5 94 N 6.88 6.94 W0 95/24200 P~ 3 ,~ 2 ! 85236 -- lP 37 Pre~aration of 6-methyl-1- t (2-chloro-3-methoa-y-4-l.y.l,.,ay~,hc,lyl)methyl] -1,2,3,4-tetrahydro-9H-~yrido~3,4-b] -indole hydrochloride Azalactone (12.4 g) was prepared as in Example 21 except using 2-chloro-3-methoxy-4-hydroxybenzaldehyde (12 . 0 g) .
A suspension of azalactone prepared above (1.29 g, 4.8~ mmol.) and 5-methyl-tryptamine hydrochloride (1.0 g, 4 .75 mmol . ) in 1 N HCl (30 mL) was heated to reflux for 24 hours under nitrogen atmosphere.: The reaction mixture was cooled to ambient temperature an~d the crude product isolated by filtration. The solid was triturated with ethanol and washed with diethyl ether. The product was isolated by filtration (1. 07 g) . mp . 240C (dec. ) .
Analysis Calculated Found C 61. D7- 60 . 83 H 5.64 5.71 N 7.12 7.03 E le 30 PrP~ri~lt i nn oi~ 5-~luoro-6-methyl-1- t (2 -chloro-3, 4-A; h~ ~ ~ y~h_--y l ) methyl ] -1, 2, 3, 4 -tetrahydro- 9~-~yrido [ 3, 4 -b] indole hydrochloriae A suspension of azalactone (prepared in Example 36) (2.15 g, 7.63 mmol.) and 4-fluoro-5-methyl-tryptamine hydrochloride (prepared in Example 9) (1.0 g, 4.75 mmol.) in 1 N HCl (80 rnL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was ceoled to ambient temperature and the crude product isolated by filtration. The solid was triturated with ethanol and washed with diethyl ether. The product was isolated as the hydrochloride salt by filtration (1.39 g). m/e=388.

~ WO 95/24200 r~ oss -- .

Analysis Calculated Found C59.30 59.58 H5.45 5.47 N6.59 6.71 Exa l e 3 9 PrPrArat;~n of 6-methyl-1-(cyclohexy-lmethyl)-1,2,3,4-tetrahydro-9H-~yrido t3, 4-b] indole hydrochloride A suspension of cyclohexylacetaldehyde ( 631 mg , 5.0 mmol.) and 5-methyltryptamine hydrochloride (1.0 g, 4.3 mmol.) in ethanol ~20 mL) was heated to reflux for 36 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by f iltration . The solid was triturated with ethanol and washed with diethyl ether. The product was isolated by filtration (731 mg). m/e=282, mp 230C.
Analysis Calculated Found C71.56 71.27 H8.53 8.56 N8.78 8.64 r lP 40 Pr~r~rat;r~n o~ (+) 6-methyl-1-[~3,4-~ h~.ry~Jh_.~yl)~l~
ethyl]-1,2,3,4-tetrahydro-9E}-~yrido[3,4-b]indole (Z)-2-b~ltPn~l; oate To a stirred, cooled (-20C) suspension of methoxymethyltripheny]rh~s~h--n;um chloride (118.9 g, 347 mmol. ) in dry THF (2000 mL) was added potassium t-butoxide (39 .3 g, 350 mmol . ) in portions. The orange suspension was stirred at -20C for 30 mim. i~ solution of 3,4-dimethoxyacetophenone (50 . 0 g, 275 mmol . ) in THF (500 mL) was added to the ylide dropwise over 30 min. The reaction mixture was gradually warmed to ambient temperature and stirred 2 H. Saturated ammonium chloride solution (500 mL) ~ ~ ~ , . , _ _ _ _ _ _ _ _ _ _ . _ _ = = _ _ _ _ _ _ _ _ , _ _ _ _ _ _ _ _ Wo 95l24200 ~ 099 was added and the mlxture extracted with diethyl ether (3 X
500 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure.
Chromatography on silica yel, eluting with 15% ethyl acetate/hexanes afforded product~(48.4 g) as a mixture of olefin isomers which was used without further purification.
A mixture of 5-methyltryptamine hydrochloride (2.16 g, 10.3 mmol.) and 1-methoxy-2-methyl-3',4~-dimethoxystyrene (prepared above) (2 .13 g, 10 . 3 mmol . ) in methanol (12 mL) and lN HCl solution (108 mL) was heated to reflux for 96 H. The reaction mïxture was cooled to a-mbient temperature, neutralized with saturated a~Iueous potassium carbonate solution and extracted with chloroform. The combined orqanic phases were concentrated under reduced pressure and the residue chromatographed on silica gel ~2 . 596 ~eOH/chloroform/0.29~i NH40H as eluent). The fractions containing product (upper diastereomer) were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and treated with maleic acid. The product was isolated as the maleate salt (260 mg) by filtration. mp. 187-190C.
Analysis Calculated Found C66 . 94 = 66 . 95 H6.48 6.35 N6.00 5.81 1~ 41 Pr^p~tinn of (+) 6,7-dimethyl-1-[(3,4-~ o~henyl)-l-ethyl~-1,2,3,4-tetrahydro-~H-~yrido[3,4-b~i~dole (Z)-2-but-~n~ll; nAte 5, 6-dimethyltryptamine hydrochloride (prepared in Example 16) ( 1. 60 g, 7 .12 mmol . ) was convert~ed to its free base with aqueous potassium carbonate in chloroform. This solution was dried and treated with l-methoxy-2-methyl-3 ~, 4 ~ -~;mP~h~cystyrene (prepared above in Example 40) (1.49 g, 7.14 mmol.) and trifluororacetic acid (1.62 g, 14.2 mmol) and was ~ W095/24200 ~ .,51t ~S~
` ~ I 21 85236 heated to reflux for 96 H. The reaction mixture was cooled to ambient temperature, neutralized with saturated a~ueous potassium carbonate solution and extracted with chloroform.
The co-m-bined organic phases were concentrated under reduced pressure and the residue chromatographed on silica i gel (2 . 596 MeOX/chloroform/0.2% NH40H as eluent) . The fractions containing product (upper diastereomer) were pooled and concentrated under reduced pressure T~e residue was dissolved in~ ethyl acetate and treated with maleic acid. The product was isolated as the maleate salt (560 mg) by filtration.m/e=364 . mp. 177C (dec. ) .
Analysis Calculated Found C 67.48 67.34 X 6.71 6.68 N 5.83 5.74 r l~ 42:
Pr~ rAt;nn of (i) 6-ethyl-1-t(3,4-di~lletllul~y~ yl)-l-ethyl~-,2,3,4-tetrahydro-9H-~yridot3,4-b]indole (Z)-2-b~lt~n~ ate 5-ethylt~yptamine hydrûchloride (prepared in Example 17) (2.0 g, 8.9 mmol.) was converted to its free base with aqueous potassium carbonate in chloroform. This solution was dried and treated with 1-methoxy-2-methyl-3 ~, 4 ~ -dimethoxystyrene ~prepared above in Example 40) (1.86 g, 8.9 mmol.) and trifluroracetic acid (2.03 g, 17.8 mmol) and was heated to reflux for 96 H. The reaction mixture was cooled to ambient temperature, neutralized with saturated a~ueous potassium carbonate solution and extracted with chloroform.
The ~ mhi nPt~ organic phases were concentrated under reduced pressure and the re5idue cbromatographed on silica gel (2.5~6 MeOH/chloroform/0.296 NH40H as eluent). The fractions containing product (upper diastereomer) were pooled and r~n~Pntrated under reduced pressure. The residue was dissolved in ethyl acetate and treated with maleic acid. The product was isolated as the maleate salt (430 mg) by filtration.m/e=364 . mp. 192-194C (dec. ) .
. .

Wo 9s/24200 P~~ O99 `` ~ Q (~ 2!~5236 Analysis Calculated Found C67 48 67 . 32 H6.71 6 72 N5.83 5.76 r le 43 Prer~ati~n of (i) 6-methyl~ (3,4-dimeth -,-y~,h~LLyl) -l-~ro~yl ] -1, 2, 3, 4 -tetrahydro- 9H-~yrido [ 3, 4 -b] indole ( Z ) -2 -bl~tono~; onte To methanesulfonic acid (203 mL) was added phosphorus pentoxide (30 . 0 g) slowly with stirring. After the addition was complete, the mixture was further stirred under nitrogen atmosphere for 2 hours until homogenous. To this solution was added 3, 4-dimethoxyphenylacetonitrile (50 g, 0.28 mol. ) in a single portion, followed by 2-methyl-2,4-pentanediol (72.1 mL, 0.56 mol.) dropwise at such a rate as to maintain a temperature between 25 and 30C (1 hour).
After complete addition, the reaction mixture was stirred at ambient temperature for lO hours and poured onto ice (500 g).
The mixture was made basic with sodium hydroxide solution (50O), added at such a rate as to keep the temperature beLow 35C. The mixture was extracted=with diethyl ether (3 X 250 mL~ and the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to afford a green solid. Distillation (Kugelrohr~ afforded intermediate product (27.7 g~ which was used without further purification.
To a stirred, cool (-78C) solution of previously prepared intermediate product (27.2 g, 0.106 mol.) in THF
(400 mL) under argon atmosphere was added n-butyllithium solution ~ 68 . 7 mL, I . 6 M in hexanes, 0 .11 mol . ) dropwise via syringe over 15 minutes. After complete addition, the orange solution was stirred at -78C for 30 minutes. Ethyl bromide (8.18 mL, 0.10 mol.~ was added dropwise via syringe and the resulting solution further stirred at -78C for 45 minutes.
n-Butyllithium (68.7 mL, 1.6 M in hexanes, 0.11 mol.) was added dropwise over 15 minutes and the orange soIution =

~ WO 95/24200 , ~ 099 97 2 ~ 85236 stirred for 2 hours. The mixture was poured into ice/water (500 mL) and was acidified to pH 2-3 with 5N HCl solution.
The mixture was extracted with diethyl ether (2 X 100 mL) and these extracts were discarded. The aqueous phase was made basic with sodium hydroxide solution (5096), cooling the mixture with ice when necessary. The basic aqueous phase was extracted with diethyl ether (2 X 200 mL) and the ~-~mhinG~l organic extracts were dried over magnesium sulfate, filtered and concentrated to afford product as an oily solid (12.08 g), which was used without further purification.
To a stirred cooled (-40C) solution of previous product (12.0 g, 39.3 mmol.) in T~IF (90 mL) and ethyl alcohol (90 mL) was added 5 N HCl solution until pH 7. In a separate flask, a solution of sodium borohydride (2.12 g, 55.4 mmol. ) was dissolvea in water (20 mL) to which 1 drop of 50% sodium hydroxide had been added. Portions of the sodium borohydride solution and 5 N HCl solution were alternately added to the reaction mixture such that the pH remained 6-8, at such a rate as to m~in~in temperature between -35 and -45C. After complete addition, the reaction mixture was warmed to ambient temperature over about 2 hours. The reaction mixture was made basic with sodium hydroxide solution and extracted with diethyl ether (3 X 100 mL). The combined organic phases were washed with brine and dried over magnesium sulfate.
Filtration and removal of solvent af forded crude product (11.3 g) as a viscous oil, which was used without further puri f ication .
A mixture of crude product f rom the previous reaction (11.3 g, 36.8 mmol) and o~alic acid dihydrate (15.1 g, 120 mmol. ) in water (300 mL) was heated to reflux for 12 hours. The mixture was cooled to ambient temperature and extracted with chloroform (2 X 100 mL) . The combined organic phases were dried over magnesium sulfate, filtered and concentrated to af f ord aldehyde as an oran~e oil .
Distillation (Kugelrohr) under reduced pressure afforded pure aldehyde (4 . 97 g) as a pale oil .

Wo 9~/24200 ~ 099 98 2 1 8~236 A mixture of 5-methyltryptamine hydrochloride (2 .53 g, 12 . O mmol . ) and 2-ethyl-3 ', 4 ' -dimethoxyphenyl-acetaldehyde (prepared above) (2.49 g, 12.0 mmol.) in ethanol (30 mL) was heated to reflux for 48 H. The reaction mixture was cooled to ambient temperature, neutralized with saturated ac~ueous potassium carbonate solution and extracted with chloroform. The combined organic phases were concentrated under reduced pressure and the residue chromatographed on silica gel (2.596 MeOH/chloroform/0.29~i NH40H as eluent) . The fractions containing product (upper Rf diastereomer) were pooled and ~nnnp~trated under reduced pressure. The residue was dissolved in ethyl acetate and treated with maleic acid. The product was isolated as the maleate salt (1.51 g) by filtration. m/e=364.
Analysis Calculated Found C 67.48 67.35 H 6.71 6.96 N 5.83 5.77 r 1-~ 44 Prep~rAtj~n of 2,6-dimethyl-1-~(2-chloro-3,4-h~y~,h,..yl)methyl]-1,2,3,4-tetr~hydro-9~-pyridot3,4-b] indole hydrochloride An ac~ueou5 solution of ~6-methyl-1- [ (2-chloro-3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido [3,4-b]
indole hydrochloride (Prepared in Example 36)- ~500 mg, 1.23 mmol. ) was treated with sodium hydroxide (49 mg, 1.23 mmol. ), followed by formic acid (0.91 mL) and atIueous formaldehyde solution (0.18 mL). The mixture was heated to reflux for 4 H. The reaction mixture was cooled to= ambient temperature and concentrated under reduced pressure. The residue was partitioned between a~ueous potassium carbonate solution and diethyl ether. The organic phase was dried over potassium carbonate and concentrated under reduced pressure~ The residue was dissolved in ethyl acetate and treated with maleic acid. The maleate salt was isolated by filtration and ~ WO 95/24200 ~ ~' JJ
1 ~ 2 1 8 5 2 3 6 purified by recrystallization from ethyl acetate/hexanes to afford product (240 mg)~ m/e-385.
Analysis Calculated Found - C 62 34 62 . 47 H 5.84 5.71 N 5 .59 5 . 58 ~ xamDle 45 Pr~rA ~A t ir~r~ of 2 -methyl - 6 - ( 1 -methylethyl ) -1, 2, 3, 4 - tetrahydro -1-[(3,4-~;- h~xyrhenyl~methyl]-9H-~yrido-[3,4b]indole maleate An aqueous solution of 6-~1-methylethyl)-1-[(3,4-dimethoxyphenyl)methyl] -1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (Z)-2-butenedioate (prepared in Example 13) (500 mg, 1.04 mmol.) was treated with sodium hydroxide (83 mg, 2.08 mmol. ), followed by formic acid (0 .77 mL) and aqueous formaldehyde solution (0.15 mL). The mixture was heated to reflux for 4 ~. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The cn--~i n~l oryanic layers were concentrated under reduced pressure and the residue chromatographed on silica gel (ethyl acetate / 0.2% NH40H as eluent). The fractions containing product were pooled and concentrated under reduced pressure.
The residue was dissolved in ethyl acetate containing 1%
mGth; nnl and treated with maleic acid. The product was isolated as the maleate salt (130 mg) by filtration. m/e-376.
Analysis Calculated Found C 67.99 67.88 H 6 . 93 6 . 73 - N 5.66 5.69 Wo 95/2420û r~ J~ ~
" 21 ~ 5 2 3 6 r le 46 Pr~ri^ i?t~ n Or (-)-(S)-6-methyl-1,2,3,4-tetri~hydro-1-[(3,4-dimethyl~henyl)methyl]-9~-~?yrido[3,4-b]indole hydrochloride To a stirred solution of 6-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (3.14 g, 16.9 mmol.) in dry xylenes (65 mL~ was added (S) -N,N-dimethyl-N~ - (1-tert-butoxy-3-methyl) -2-butylformamidine (3 .79 g, 17.7 mmol. ) followed by camphorsulfonic acid (200 mg). The resulting solution was heated to reflux for 72 hours. The solution was cooled to ambient temperature and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (1:3:6 triethylamine:ethyl acetate:hexanes as eluent~.
The product containing fractions were pooled and concentrated to afford the product formamidine (5.99 g) as a viscous oil which was used without further purification.
To a stirred, cooled (0C) suspension of potassium hydride (25~i oil dispersion, 829 mg, 20.2 mmol. ) in THF (10 mL) was added formamidine prepared above (5.99 g~, 16.8 mmol. ) in THF (45 mL~ . To this mixture was added tetramethylethylenediamine (3.0 mL, 20.2 mmol.) followed by chloromethylmethyl ether (1.9 mL, 25.2 mmol. ) . The mixture was stirred for an additional 1 hour and treated with water (50 mL). The mixture was partitioned between diethyl ether and water and the layers separated. The aqueous phase was extracted with diethyl ether (2 X 100 ml,) and the organic phases combined, dried over potassium carbonate, and concentrated to afford product (6.73 g) as an orange oil, which was used without further purification.
To a stirred, cooled (-78C) solution o previously prepared formamidine (6.29 g, 8.4 mmol.) in dry THF (100 rn~) was added n-BuLi (1.7 M solution in hexanes, 10.1 mL, 17.1 mmol . ) dropwise over 5 minutes. The solution was further stirred at -78C solution for 1 hour and treated with 1-chloromethyl-3,4-dimethoxybenzene (3.35 g, 17.9 mmol.) in dry THF ~15 ml~) . The solution was further stirred for 4 hours at -78C and allowed to warm to room temperature overnight. Wet THF =as added ~50 m~) and the solution was concentrated under~

W0 9512420(~ P~ 5 ' 2 1 8~236 reduced pressure. The residue was dissolved in chloroform and washed with water. The organic phase was dried over sodium carbonate and concentrated. The crude product was purified by flash chromatography on silica gel ~1:3:6 triethylamine: ethyl acetate: hexanes as eluent ) . The product containing fractions (upper Rf ) were pooled and concentrated to afford product (3.92 g) as a viscous oil (m/e = 550) which was used without further purification.
To a stirred solution of methoxymethylindole prepared above (3 .g2 g, 7.13 mmol. ) in THF (70 mL) was added 2N HCl (20 mL). The mixture was stirred at ambient temperature for 24 hours, and partitioned between diethyl ether and water. The a~aueous phase was back extracted with diethyl ether (2 X 50 mL) and the combined organic phases were washed with brine, dried over sodium carbonate, and concentrated under reduced pressure. The residue was dissolved in THF= (20 mL) and treated with 2N sodium hydroxide solution (6 mL) . After 2 hours, the reaction mixture was extracted with chloroform (2 X 100 mL). The organic phase was dried over sodium carbonate and concentrated.
Chromatography on silica gel (1:3:6 triethylamine/ethyl acetate/hexanes as eluent) afforaed product (1.85 g) as a viscous oil (m/e= 505 ) .
To a stirred, cooled ( 0C) solution of previously prepared formamidine (1.37 g, 5.41 mmol.) in ethanol (50 mL) was added water (6 mL) fol:lowed by acetic acid (6 mL) and hydrazine hydrate (11 mL). The reaction vessel was placed in the freezer (-10C) for 72 hours. The mixture was warmed to a~abient temperature and concentrated under reduced pressure.
The crude product was dissolved in chloroform (300 mL) and washed with water (3 X 50 mL). The organic phase was dried over sodium carbonate and concentrated to a viscous oil. The oil was dissolved in diethyl ether and treated with anhydrous HCl. The hydrochloride salt (560 mg) was isolated by filtration. Recrystallization from ethanol (2 X) afforded material of constant rotation. Chiral HPLC confirmed enantiomeric purity as > 98% ee. m/e=336) Wo 95124200 r~ o~ogg O

specific rotation @ 589 ~nM = -118.0 (pyridine, C=1) specific rotation @ 365 nM = -401.0 (pyridine, C=1) Analysis Calculated Found C 67 . 64 67 . 65 H 6.76 6.70 N 7.51 7.52 r le 47 Pror~ ~at; on of ( I / - ) 6 -methyl -1- ~1- ( 4 -methoxy-nArhthAl~nyl)n~ethyl)-1,2,3,4-tetrahydro-9H-~yrido [3,4-b]-indole hydrochloride o~o CHO J~
N~CO
OMe OMe A solution of g-methoxy-1-nAphthAldehyde ( 20.0 g, 0.107 mol. ), N-acetylglycine ~ 12.58 g, 0.107 mol. ) and sodium acetate ( 8.81 g, 0.107 mol ) in acetic anhydride ( 100 mL ) was heated to 100C for~ 2 hours. The reaction mixture was cooled to ambient temperature and stirred for 10 hours under nitroyen atmosphere. The mixture was poured onto ice ( 250 mL ) with stirring. The product was isolated by filtration, washed with water ~ 3 X 50 mL ) and diethyl ether ( 3 X 50 mL ) and dried under reduced pressure ( 3.16 g ).

~ WO 9S/24200 r~
2 ~ 8 5 2 3 6 Me~N +\ I~N >-- --C~H HCI
H~1 lN HCl, [~
OMe OMe A suspension of azalactone prepared above (2 . 00 g, 7 . 5 mmol . ) and 5-methyl-tryptamine hydrochloride (1 18 g, 5 . 62 mmol . ) in lN HCl (20 mL) was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated hy filtration. The brown solid was triturated with isopropyl alcohoI (3 X 50 mL) and washed with diethyl ether (3 X 50 mL). Recrystallization from ethanol afforded 1.42 g of desired produc as a pale solid. (mp 271.7C) An~lvsis: CalCl~lated E5 C 73 .36 73 . 60 ~1 6.41 6.51 N 7.13 7.20 Pr~Araf;c~ of (1/-) 6-methyl-1-(1-(2-methoxy--A~h~-hAl~nyl) methyl~1,2,3,4-tetrahydro-9~ ?yrido~3,4-b~- indole hydrochloride To a stirred, cooled (-78C) solution of methoxymethyl-triphenylphosphonium chloride (11.05 g, 32.2 mmol. ) in 150 mL of anhydrous T~F was added n-butyllithium (20.14 mL of 1.6 M solution in hexanes, 32.2 mmol) dropwise via syringe. After complete addition, the solution was stirred at this temperature for 15 min. A solution of 2-methoxy-l-n~rhth~ ohyde (5.0 g, 26.9 mmol.) in THF (75 mL) WO 9S/24200 r~ V
`3 ~ 2 1 8 5 2 3 6 was added to the soIution dropwise by addition funnel. After complete addition, the s-olution was allowed to warm to ambient temperature and stir for 14 hours. A saturated solution of ammonium chloride~100 mL) was added and the mixture was partitioned between diethyl ether and~ water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. :~ The crude residue was purified by plug filtration (silica gel, eluent 40~6 ethyl acetate/hexanes) and afforded 5.0 g of product as a mixture of enol ethers, which was used without further purification.
A solution of enol ethers prepared above (5 . O g, 23 .3 mmol . ) in diethyl ether (50 mL) was treated with water (1.0 mL) and perchloric acid (1.5 mL of 60% solution). The solution was stirred at ambient temperature for 72 hours.
The solution was diluted with chloroform (100 mL) and neutralized with saturated sodium bicarbonate solution. ~he mixture was extracted with chloroform (3 X 100 mL) and the combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica ge1 (596 diethyl ether~hexanes as eluent) to afford (2-methoxy-1-naphthyl)-acetaldehyde (1.79 g) as a colorless oil.
To a stirred solution of 5-methyltryptamine hydrochloride (947 mg, 4 .49 mmol. ) in 20 mL of ethyl alcohol was added (2-methoxy-1-naphthyl)-acetaldehyde (l.Og, 4.99 mmol ). The solution was heated to reflux under nitrogen atmosphere for 40 hours. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. Recrystallization from ethyl alcohol/2-butanone afforded product as a pale solid (705 mg). (mp. 245.3C).
An ~ l vS i S: (';' l culat ed Found C 73.36 73.29 H 6.41 6.64 ~ W095/24200 ~ )99 ` ` '~` ; 2 1 85236 lD5 N7.13 7.12 r 1-~ 49 pr~ral ;-~n oE (+/-) 6-methyl-1-(1-n~hth~l~nyl-1-ethyl)-1,2,3,4-tetrahydro-9H-~yrido [3,4-b] indole (Z) 2-bvt~n~l; oate Me ol ~CN OH OH ~N~Me ~205,~eSo,U ~ ~e To m~thAn~qulfonic acid ~2l5 mL) was added phosphorus pentoxide (31. 8 g) slowly with stirring . After the addition was complete, the mixture was further stirred under nitrogen atmosphere for 2 hours until homogeneous. To this solution was added 1-naphthyl acetonitrile (50 g, 0.3 mol.) in a single portion, followed by 2-methyl-2,4-pentanediol (76.4 mL, 0.6 mol.) dropwise at such a rate as to maintain a temperature between 25 and 30C (1 hour). After complete addition, the reaction mixture was stirred at ambient temperature for lO hours and poured onto ice (500 g) . The mixture was made basic with sodium hydroxide solution (5096), added at such a rate as to keep the temperature ~elow 3 5C . The mixture was extracted with diethyl ether (3 X 250 m~L) and the ~X~mhin~d organic phases were dried over magnesium sulfate and concentrated under reduced pressure to afford a green solid. Recrystallization from ethyl acetate afforded product (28.29 g which was used without further purification.

WO 95/24200 r~
l.` ',i-~,, ! " 106 2185236 Me Me ol ~J~N~Me Mo~ Me e ~le t-BuLi,THF,-78~C, ~ ~
To a stirred, cooled ~-78C~ solution of previously prepared "isoxazan?" (28.3 g, 0.106 mol.) in THF (475 mL) under argon atmosphere was added t-butylllthium solution (68.4 mL, 1.7 M in pentane, 0.116 mol.) dropwise via syringe over 15 minutes. After complete addition, the orange solution was stirred at -78C for 30 minutes. ~ Methyl iodide ( 6 . 6 mL, 0 .106 mol . ) was added dropwise via syringe and the resulting solution further stirred at -78C for 45 minutes.
t-Butyllithium (68.4 mL, 1.7 M in pentane, 0.116 mol.) was added dropwise over 15 minutes and the orange solution stirred for 2 hours. The mixture was poured into ica/water (500 mL) and was acidified to pH 2-3 with 5M HCl solution.
The mixture was extracted with diethyl ether (2 X 100 mL) and these extracts were discarded. The aqueous phase was made basic with sodium hydroxide solution (50%), cooling the mixture with ice when necessary. The basic aqueous phase was extracted with diethyl ether (2 X 200 mL) and the combined organic extracts were dried over magnesium sulfate, ~iltered and concentrated to afford produc~ as an oily solid (13.15 g), which was used without further purification.

~ WO 95/24200 r~ O99 ~ ~ }>~ 107 2185236 Me Me Me~ ~tMe Me~N~Me NaBH4, ~H~, EtOH H ule pH 6-8 ~ ~ ~
To a stirred cooled ~-40C) solution of previous product (13 .15 g, 46.7 mmol . ) in THF (100 mL) and ethyl alcohoL (100 mL) was added 5N HCl solution until pH 7. In a separate flask, a solution of sodium borohydride (2.52 g, 65.8 mmol.) was dissolved in water: (20 mL) to which 1 drop of 5096 sodium hydroxide had been added. Portions of the sodium borohydride solution and 5 N HCl solution were alternately added to the reaction mixture such that the pH remained 6-8, at such a rate as to maintain temperature between -35 and -45C. After complete addition, the reaction mixture was warmed to ambient temperature over about 2 hours. The reaction mixture was made basic with sodium hydroxide solution and extracted with diethyl ether (3 X lO0 mL). The combined organic phases were washed with brine and dried over magnesium sulfate. Filtration and removal of solvent afforded crude product (13.2 g) as a viscous oil, which was used without further purification.
Me ol Me~N-- MeyCHO
H vle ox~llic ~cid, H2~0 W095/24200 l~1/~ 5 ~
1t~ 108 2185236 A mixture sf crude product from the previous reaction ~13.2 g, 46.6 mmol) and oxalic acid dihydrate (19.1 g, 152 mmol. ) in water (380 mL) was heated to reflux for 12 hours . The mixture was cooled to . ambient temperature and extracted with chloroform (2 X 100 mL). The combined organic~
phases were dried over magnesium sulfate, filtered and concentrated to afford aldehyde as an orange oil.
Distillation (Kugelrohr) under reduced pressure afforded pure aldehyde (1. 97 g) as a pale oil .
Me~NH m~leate ~_~ Me_CHO L~ Me Me_~_( NH2 HCI 1 EtOE~, re~lu~ N
W~N [~ maleic ~cid A ~
Me ~Hmale~te racemic ~
A solution of 5-methyl tryptamine hydrochloride (1.11 g, 5.27 mmol.) and 2-~1-naphthyl )-propionaldehyde ~0.97 g, 5.26 mmol.) in 9596 ethyl alcohol was heated to reflux for 48 hours under nitrogen atmosphere. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between at~ueous potassium carbonate solution and chloroform. The chloroform phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (2596 methyl alcohol in chloroform as eluent), affording 529 mg of the higher rf isomer and 200 mg of the lower rf isomer. Each diastereomer, independently, was dissolved in ethyl acetate and treated with excess maleic acid. The maleate :salts were ~ WO 95/24200 P~l/IJ.. m~O99 109 ~ t 85236 isolated by filtration affording~ 570 mg of isomer A and 30 mg of isomer B.
f isomer A data: m~e = 340 An~lvSiS (~;3lculated Found C 73.66 73.64 H 6.18 6.13 N 6.14 6.4 isomer B data: m/e =~340 Analvsis Calc~ ted FQund C 73.66 73.41 H 6.18 6.04 1~ 6.14 5.89 r l-~ 50 PrPp:~At;~n of (~/-) 6~ imethylethyl)-l-( l-ethyl)-1,2,3,4-tetrahydro-9H-ryrido [3,4-b] indole hydrochloride 4-Chlorobutyryl chloride (300 g, 2 .13 mol. ) was dissolved in dry THF ~3 L) . To this solution was added 2, 6-lutidine (252 mL) followed by 596 Pd/C (30 g). This mixture was placed in a Parr hydrogenator and shaken under 60 psi of hydrogen for 6 hours. The mixture was purged with nitrogen, filtered, washing the catalyst with THF
(500 mL), and concentrated at room temperature under reduced pressure Distillation afforded 4-chlornhl-t~n~l (148.3 g) as a colorless liquid.
To a stirred suspension of 4-isopropyl-phenylhydrazine hydrochloride monohydrate (15.3 g, 91.95 mmol. ) in chloroform (250 mL) was added saturated sodium carbonate solution (250 mL). The mixture was stirred for 30 minutes until the organic phase appeared homogeneous, Wo 95/24200 1 ~
`~? ~ o 21 85236 and extracted with chloroform (2X 200 mL) . The combined organic phases were concentrated to afford the hydrazine free~
base as a yellow oil. This oil was dissolved in methanol ~200 mL) and water (5 mL) and treated with sodium acetate (6.72 g, 82 mmol. ) and 4-chlorobutanal (8 .7 g, 82 mmol . ) .
The mixture was placed in a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oil bath preheated to 100C. Heating was continued for 18 hours. The resulting dark solution was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between chloroform/methanol (75/25 by volume) and agueous sodium carbonate solution. The organic phase was concentrated and the crude indole ~th; n~mi ne was purified by flash chromatography on silica gel (0-2596 methanol gradient in chloroform as eluent). Fractions containing product were combined and concentrated. The oil was dissolved in diethyl ether (300 m~) containing 1%
methanol and treated with dry HCl gas. The hydrochloride salt was isolated by filtration, washed with 2-propanol ~50 mL) and diethyl ether (100 mL) and dried to afford 5-isopropyl -tryptamine hydrochloride ( 9 . 8 g) as a pale solid, which was used without further purification.
A solution of 5-isopropyltryptamine hydrochloride (1.24 g, 5.19 mmol.) and 2-(1-naphthyl)-propionaldehyde (0.95 g, 5.16 mmol. ) in 9596 ethyl alcohol was heated to reflux for 48 hours under nitrogen atmosphere. The mixture was cooled to ambient temperature and ~n~ ~ntrated under red~ced pressure. The resldue was partitioned between agueous potassium carbonate solution and shloroform. The chloroform phase was dried over magnesium sulfate and concentrated under reduced pressure~ The residue was subject~d to flash chromatography on silica gel (25% methyl alcohol in chloroform as eluent), affording 500 mg of the higher rf isomer along with 400 mg of impure lower rf isomer. The major diastereomer was dissolved in ethyl acetate=and treated with excess maleic acid. The maleate salt was isolated by filtration affording 400 mg of named product as a pale solid.

~ W095l24200 r~ S~

m/ e=3 6 9 .
~n~lvSiS Calculated C74.36 74 58 H6.66 6.64 N5.78 5.81 Exam~le 51 pr~r~r~t;~n of (I/-) 6-methyl-1-(1-n~rhlh~ nylmethyl)-1,2,3,4-tetrahydro-9H-~yrido [3,4-b] indole hydrochloride A solution of l-niqphth;~l dehyde (25.0 g, 0.16 mol.), N-acetylglycine (19.0 g, 0.162 mol.) and sodium acetate ~13.1 g, 0.160 mol) in acetic anhydride ~147 mL) was heated to 100C for 4 hours. The reaction mixture was cooled to ambient temperature poured onto ice ~300 mL) with stirring.
The product was isolated by filtration, washed with water ~3 X 50 mL) and diethyl ether ~3 X 50 mL) and dried under reduced pressure ( 11. 82 g ) .
A suspension of azalactone prepared above ~3 .15 g, 13 .3 mmol. ) and 5-methyl-tryptamine hydrochloride ~2.0 g, 9.5 mmol.) in lN HC1 (50 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The brown solid was triturated with isopropyl alcohol (3 X 50 mL) and washed with diethyl ether (3 X 50 mL) . Rec--stallization from W0 95/24200 r~
2~ 85236 ethanol afforded 1.94 g of desire=d product as~ a pale solid.
~n~lysis Calc~lated FQ~uad C 76.12 76.03 H 6.39 6.22 N 7 . 72 7 . 52 r 1~ 52 pre~r~ n of (+/-) 8-bromo-1-(1-n~rhl h~ nylmethyl) -1, 2, 3, 4 -tetrahydro - 9H -~yrido [ 3, 4 -b ] indole hydrochloride --NHNH2 MKeCOH3 '95C ~NH2 HCI
'~ H Et2orMeoH~Hcl H
O ~r To a stirred suspension of 2-bromophenyl-hydrazine hydrochloride (25.8 g, 115 mmol. ) in chloroform (500 mL) was added saturated sodium carbonate solution (500 mL). The mixture was stirred for 30 minutes until the organic phase appeared homogenous, and extracted with chloroform (2 X 200 mL). The co~bined organic phases were concentrated to afford the hydrazine free base as a yellow oil_ This oil was dissolved in methanol ( 100 mL) and treated slowly with 4-chlorobutanal (prepared as described in Example 4) (12.3 g, 115 mmol.). The mixture was placed in a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oil bath preheated to 95C. Heating was continued for 18 hours. The resulting dark solution was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between chloroform/methanol (75/25 bY volume) and aqueous sodium ~ WO9~l24200 r~ 3099 carbonate solution. The organic phase was concentrated and the crude indole eth~n~mine was purified by flash chromatography on silica gel ( 0-25% methanol gradient in chloroform as eluent). Fractions containing product were ~ ~ in~od and concentrated. ~he oil was dissolved in diethyl ether (300 mL) c~nt~inin~ 1% methanol and treated with dry HCl gas. The hydrochloride salt was isolated by filtration, washed with 2-propanol (50 mL) and diethyl ether ~100 mL) and dried to afford 7-~romo-tryptamine hydrochloride (3 . 6 g) as a pale solid, which was used without further purification.
A suspension of azalactone (prepared as described in Example 5) (55 g, 6.53 mmol. ) and 7-bromo-tryptamine hydrochloride (1.50 g, 5.44 mmol. ) in lN E~Cl (100 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was coolf~d to a-mbient temperature and the crude product isolated by filtration. The brown solid was triturated with isopropyl alcohol (3 X 50 mL) and washed with diethyl ether (3 X 50 mL).
Recrystallization from ethanol afforded 260 mg of desired product as a pale solid. (mp = 231-233C, dec. ) ~ni~lvsis Calculated Found C 61.77 61.48 H 4 . 71 4 . 63 N 6.55 6.73 D:xamDle 53 Pr~r~r~t;on of ( I/-) 8-bro-1-(1-n~rhthAl~nylmethyl)-1,2,3,4-tetrahydro-9H-~yrido [3,4-b] indole hydrochloride To a stirred suspension of 2-bromophenyl-hydrazine hydrochloride (25.8 g, 115 mmol.) in chloroform (500 mL) was added saturated sodium carbonate solution (500 mL). The mixture was stirred for 30 minutes until the organic phase appeared homogenous, and extracted with chloroform (2 X 200 mL). The combined organic phases were WO 95/24200 r~l",~ O99 `, 2 1 ~ 5 2 3 6 concentrated to af f or~ the hydrazine free base as a yellow oil. This oil was dissolved in methanol ~100 mL) and treated slowly with 4-chlorobutanal (prepared as described in Example 4) (12.3 g, 115 mmol.~. The mixture was placed in a sea~able tube and purged with nitrogen for= 10 minutes. The tube was sealed and placed in an oil bath preheated to 95C Heating was continued for 18 hours. The resulting dark solution was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between chloroform/methanol (75/25 by vol~Tle) and aqueous sodium carbonate.solution. The organic phase was concentrated and the crude indole ,~ n~minf~ was purified by flash chromatography on silica gel (0-25% methanol gradient in chloroform as eluent). Fractions containing product were combined and concentrated. The oil was dissolved in diethyl ether (300 IrL) containing 1% methanol and treated with dry HCl gas. The hydrochloride salt was isolated by filtration, washed with 2-propanol (50 mL) and diethyl ether (100 mL) and dried to afford ~-bromo-tryptamine hydrochloride ~3~. 6 g~ as a pale solid, which was used without further purification.
A suspension of azalactone (prepared as described in Example 5) ~55 g, 6.53 mmol. ) and 7-bromo-tryptamine =
hydrochloride (1.50 g, 5.44 mmol. ) in lN HCl ~100 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The brown solid was triturated with isopropyl alcohol (3 X 50 mL) and washed with diethyl ether (3 X 50 mL).
Recrystallization from ethanol afforded 260 mg of desired product as a pale solid. ~mp = 231-233C, dec. ) An~lvsis C~l c~ ted E5~d C - 61.77 61.48 H 4 .71 4 . 63 N 6.55 6.73 ~ WO 95/24200 P~

R.xa.mDle 54 a Pre~ f;~n Of (1/~) 8-methoxy-l-(l-n~rhthll~nylmethyl)-1,2,3,4-tetrahydro-9H-pyrido [3,4-b~ indole (Z)-2-~n c~1; oAt e To a stirred, cooled (0C) suspension of 2-methoxyphenylhydrazine hydrochloride (14.44 g, 83 mmol. ~ in THF ( 600 mL) was~ added 4-chlorobutanal prepared as described in Example 5 (9 . 0 g, 84 mmol . ~ followed by dropwise addition of triethylamine (8.6 g, 85 mmol.~ in THF (20 mL) . Upon complete addition, the cooling bath was removed and the solution stirred for 1 hour. The reaction mixture was filtered and the filter cake washed with THF (100 mL). The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) and water (5 mL). The solution was transferred to a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oilbath preheated to ~5C. After heating for 14 hours, the reaction mixture was cooled to ambient temperature and concentrat~d under reduced pressure. The residue was partitioned between saturated aqueous potassium carbonate and 3 :1 chloroform: 2-propanol . The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (15% methanol, 0.296 NH~LOH, in chloroform as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in methanol and treated with dry HCl and concentrated to afford 7-methoxytryptamine hydrochloride (4 . 04 g) as a stable foam, which was used without further purif ication .
A suspension of azalactone (prepared as described in Example 5) (1.30 g, 5.5 mmol. ~ and 7-methoxytryptamine hydrochloride (1.08 g, 4.8 mmol.) in lN HCl (100 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and e~tracted with chloroform. The solvent was WO 95/24200 PCr/lUS95/03099 o ~ ~ ~ Y i S 2 1 8 5 2 3 6 removed under reduced pressure and the residue chromatographed on silica gel (ethyl acetate~0.2% NH40H as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved: in ethyl acetate containing 1% methanoL and treated with maleic acid. The product was isolated as the maleate salt (880 mg ) bY filtration.
(mp = 226-227C, dec. ) An~lYsis ~ ulated Found C 70.73 70.61 H 5.72 5.77 N 6.11 6.03 ~ 3xaml~le S5 Preparation of (~/-) 6-bromo-1-~1-n~rh~-hAl~nylmethyl)-1, 2, 3, 4 -tetrAhydro- 9H-pyrido [ 3, 4 -b] indole ( Z ) -2 -~n~ te A suspension of azalactone (prepared as described in Example 5) (1.4 g, 5.9 mmol.) and 5-bromotryptamine hydrochloride (1.77 g, 6.4 mmol. ) in lN HCl (100 mL) was heated to re~lux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated a~Iueous potassium carbonate solution and extracted with chloroform. The solvent was removed under reduced pressure and the residue chromatographed on si~ica gel (ethyl acetate/0.2% NH40H as eluent ) . The fractions containing product were pooled and concentrated under reduced pressu~e. The residue was dissolved in ethyl acetate contai~ing 1% methanol and treated with maleic acid. The product was isolated as the maleate salt (540 mg) by filtration.
(mp = 234-235C, dec. ) m/e= 390.

WO 95/24200 P ~ ~
` ` 21 85236 Analvsis Calculated Found C 61.55 61.38 H 4.57 4.64 N 5.52 5.29 r le 56 Pr~rArat; r~n o~ ) 7-methyl-8-bromo~ 1-n~rh~hA1 ~nyl methyl ) -1, 2, 3, 4 -tetrahydro - 9H-pyrido [ 3, 4 -b ] indole hydrochloride 2-Bromo-3-methylphenylhydrazine hydrochloride (23 g) was prepared as described for 2-bromo-4 methylphenylhydrazine hydrochloride in Example 7, except using 2=bromo-3-methylaniline as starting material.
MeJ~3~ 2 MeOH, 95C, ~,~\NH2 HCI
t20,MeOH,HCl ~
6-Methyl-7-bromotryptamine hydrochloride was prepared (2 . 42 g) as described for 5-methyl-7-bromo-tryptamine hydrochloride in Example 7, except using 2-bromo-3-methyl phenylhydrazine hydrochloride as starting material.
A suspension of. azalactone (prepared as described in Example 5) (1.07 g, 4.51 mmol.) and 6-methyl-7-bromotryptamine hydrochloride (1.22 g, 4.21 mmol.) in lN HCl (70 mL) was heated to reflux for 65 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutrali2ed with saturated ar~ueous potassium carbonate solution and extracted with chloroform. The solvent was removed under reduced pressure and the residue chromatographed on silica gel (ethyl acetate/0.29ei NH40H as eluent). The fractions rnnt~ining product were pooled and WO 95n4200 r~"~ o .`~ " ~, 2~ 85236 concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 196 methanol and treated with dry HCl. The product was isolated as the hydrochloride salt (840 mg) by filtration. (mp = 276-279CC, dec. ) An~lvsis Calculated ~nd C 62.53 62.79 H 5.02 4.96 N 6.34 6.19 Pre~aration of ( +/ - ) 6-cyclohexyl-1- ~ l-n~rhth~ nylmethyl ) -1,2,3,4-tetrahydro-9H-l?yrido [3,4-b] indole hydrochloride 4-Cyclohexyl phenylhydrazine hydrochloride (35.6 g) was prepared as described ~or 2-bromo-4 methyl-phenylhydrazine hydrochloride in Example 7, except using 4-cyclohexyl-aniline as starting material.
C~3 2 ~eOH, ~NH2 HCI
E:t20 3~eOH, HCl HN
Cl ~H
5-Cyclohexyltryptamine hydrochloride was prepared ~1.29 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 4-cyclohexylphenylhydrazine hydrochloride as starting material.
A suspension of azalactone (prepared as described in Example 5) (1.09 g, 4.59 mmol. ) and 5-cyclohexyltryptamine hydrochloride (1 2~ g, 4.59 mmol.) in 1 N HCl (70 mL) was heated to re~lux ~or 14 hours under nitrogen atmosphere. ~ The ~ W0 95/24200 r~ ogg :`- 21 8~236 reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was recrystallized from ethanol ~2X) to afford 690 mg of desired product as a pale solid hydrochloride salt. m/e= 395 An;llvSiS ~-~lc~ ted und C 78.03 78.26 H 7.25 7.06 N 6.50 6.48 EXAmD1e 58 pr~rAr~t;r~n of (+/-) 2,6-dimethyl-l-(l-nArhtl~Al~nylmethyl)-1,2,3,4-tetrahydro-9H-~yrido [3,4-b] indole hydrochloride To an aqueous solution (200 mL) of 5-methyl-1- (1-n~ph~hAlenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido [3,4-b~
indole hydrochloride (2.00 g, 5.51 mmol.) previously prepared in ~xample 5, was added formic acid (4.1 mL) and formaldehyde solution (0.8 mL of 37% a~ueous solution) . The mixture was heated to reflux for 72 hours. The solution was made basic with saturated potassium carbonate solution and extracted with chloroform (2 X 100 mL). The combined organic phases were dried over potassium carbonate and concentrated under reduced E)ressure. The crude product was purified by flash chromatography on silica gel (chloroform as eluent) . The fractions containing product were pooled and concentrated to a viscous oil. The oil was dissolved in diethyl ether and treated with anhydrous HCl and the resulting hydrochloride salt was isolated by filtration. Drying afforded the named product (1.34 g). m/e = 340.
;

AnalYsis ('~ l culated ~Ld C 76.48 76.58 H 6.68 6.63 N 7.43 7.28 WO 95/24200 1 ~ *
''` ;`''' 2185236 le 59 Pre~aration of (+/-) 5-fluoro-6-methyl-1-(1-n~rh~-h~l~nyl-methyl)-1,2,3,4-tetrahydro-9H-~yrido [3,4-b] indole (Z)-2-b~t~n~l; onte 3 -f luoro-4-methyl -phenylhydrazine hydrochloride (21.4 g -) was prepared as described for 2-bromo-4 methyl-phenylhydrazine hydrochloride in Example 7, except using 3-fluoro-4-methyl aniline as starting material.
Me F NHNH2 M2COOH3 9C5HCc 3; M~NH2 HCI
+ Et20,MeOH,HCl Cl ~H ~ H
4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) as described for 5-methyl-7-bromo-tryptamine hydrochloride in Example 7, except using 3-fluoro-4-methyl-phenylhydrazine hydrochloride (6.00 g) as starting material. ~ ~ ~
A suspension of azalactone (prepared as described in Example 5) ~2.3 g, 9.6 mmol.) and 4-fluoro-5-methyltryptamine hydrochloride (2.2 g, 9.6 mmol.) in lN HCl ~40 m~ was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The solvent was removed under reauced pressure and the residue chromatographed on silica gel (ethyl acetate/0.2% NH40H as eluent). The fractions containirig product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 1% methanol~ and treated with maleic acid. The product was isolated as the ~ WO9S/24200 r~ ,. r ~5~
2 ' ~5236 maleate salt ~520 mg) by filtration.
An~lvsis r~l culated Found C70.42 70.45 H5.47 5.41 N6.08 6.10 le 60 Pr~'~A-r21t;~n of ( 1/-) 7,8,9,10-tetrahydro-10-(1-n~rh~hAl~nylmethyl)-llH-benzO ~g] ryrido [3,4-b] indole (Z)-2-bllt~nc~ oate --NHNH /--~\
K2CO3, CHC13; ,~ NH2 HCI
+ Et20, MeOH HCl ~ 11--H
6, 7 -benzotryptamine hydrochloride was prepared ~2.85 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 1-naphthyl-hydrazine hydrochloride (6`.00 g) as starting material.
A suspension of azalactone (prepared as described in Example 5) (2.75 g, 11.6 mmol.~ and 6,7-benzotryptamine hydrochloride (2.85 g, 11.6 mmol.) in lN Hcl (50 mL) was heated to reflux for 24 hours under nitrogen atmosphere. ~he reaction mixture was cooled to ambient temperature, neutralized with saturated a~ueous potassium carbonate solution and extracted with chloroform. The solvent was removed under reduced pressure and the residue chromatographed on silica ~rel (ethyl acetate/0.2% NH40H as eluent ) . The fractions containing product were pooled and _ . _ _ _ . ... ... . . .. ~ . -- --W0 95/24200 ~ Q99 concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 1% methanol and treated with maleic acid. The product was isolated as the maleate salt ( 3 0 0 mg ) by f iltration .
m/e = 363.
An~lvsis Calcll1 ated Found C 75.30 75 04 H 5.48 5.36 N 5.85 5.76 r le 61 Pre~aration of ( +/ - ) 6 - ( 1, 1 -dimethylethyl ) - l, 2, 3, 4 -tetrahydro-l-(l-n~rh~h~lPnylmethyl)-9H-~yrido [3,4b] indole (Z) -2-b~t~n~ ; oat~
t-~u ~,~
~NHNH2 HCI K2C03, CHCl3; ~\NH2 HCI
~eOH, 95C;
~~H Et20,MeOH,HCL~ ~i--N

5- ~1,1-dimethylethyl) -tryptamine hydrochloride was prepared (2 . 95 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 4-(1,1-dimethylethyl)-phenyl hydrazine hydrochloride (6.00 g~ as starting materlal.
A suspension of azalactone (prepared as described in Example S) (1.25 g, 5.26 mmol.) and 5-(1,1-dimethylethyl)-tryptamine hydrochloride (1.33 -g, 5 .26 mmol. ) in 1~ HCl (50 m~) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chlorof orm. The golvent was removed under reduced pressure and the residue ~ WO9~/24200 r~

chromatographed on silica gel (ethyl acetate/0 . 2% NH40H as eluent ) . The ~ractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 1% methanol and treated with maleic acid. The product was isolated as the maleate salt (700 mg) by filtration. m/e=369 AnAlvsis r~lc,llated EQIm~
C74.36 74. 08 H6.66 6.69 N5.78 5.69 r 1-~ 62 Pr~r~ t;~n of (~/-) 6-(1-methylethyl)-1,2,3,4-tetrahydro-1-(1-nAphth~ nylmethyl)-9/}-~yrido [3,4b] indole (Z)-2-b~lt~ne~; oate A suspension of azalactone (prepared as described in Example 5) (1.75 g, 7.38 mmol.) and 5-isopropyltryptamine hydrochloride (prepared as describea in Example 4) (1.76 g, 7 .37 mmol . ) in lN HCl (40 mL) was heated to reflux for 24 hours under nitrogen atmosphere The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The solvent was removed under reduced pressure and the residue chromatographed on silica gel (ethyl acetate/0.2% NE~40H as eluent). The fractions rnn~inin~
product were pooled and concentrated under reduced pressure.
The residue was dissolved in ethyl acetate containing 1%
methanol and treated with maleic acid. The product was isolated as the maleate salt ( 671 mg ) by filtration.
m/e=355 ,~n~lvsiS ('~lc1l1ated Found C74 . 02 74 . 08 H6.43 6.21 N5.95 5.83 W0 95/24200 r~ ogg &I1` 21~5236 r 1P 63 Pre~aration o~ (+/-) 6,9-dimethyl-1,2,3,4-tetrahydro-1-(1-n~ hth~-lPnylmethyl)-9H-~?yrido [3,4-b] indole hydrochloride To a stirred suspension of 5-methyltryptamine ~`
hydrochloride (10.0 g, 43.2 mmol ) in chloroform (300 m~ was added saturated sodium carbonate ~ solution (300 mL) . The mixture was stirred at ambient temperature for 1 hour. The layers were separated and the aSIueous layer was back extracted with chloroform (2 X 100 mL). The combined organic layers were dried ov~r sodium sulfate and concentrated. The residue was dissolved in toluene (300 mL) and treated with phthalic anhydride (7.05 g, 47 . 6 mmol. ) . The solution was heated to reflux for 14 hours with azeotropic removal of water (by Dean-Stark trap). The solution was cooled to ambient temperature and concentrated to afford crude product as a pale foam. Recrystallization from ethanol afforded product phthalimide (13.52 g) as a white solid, which was used without further purification.
To a stirred, cooled (0C) suspension of potassium hydride (2596 oil dispersion, 8.24 g, 51.3 mmol . ) in dry THF
(50 mL) was added a solution of phthalimide prepared above (13.02 g, 42.8 mmol.) in THF (150 mL) over 30 minutes. ~After complete addition, the mixture was further stirred for 1 hour . Tetramethylethylen~ mi n~ (7 . 7 mL , 51. 3 mmol . ) was added, followed by methyl iodide (4 . 0 mL, 63 . 8 mmol . ) . After 1 hour, the reaction was ~uenched by addition of water (200 mL), followed by extraction with diethyl ether (2 X 100 mL).
The combined organic phases were- dried over magnesium sulfate and concentrated under reduced pressure to afford product as a yellow solid (14 g) which was used without further purif ication .
A solution of phalimide prepared in the previous step (14 g, 42.8 mmol.) in methanol (85 mL) was treated with hydrazine (3 . 4 mL, 109 mmol . ) . The mixture was heated to reflux for 2 hours. The mixture~was cooled to ambient temperature, treated with con~::entrated E~Cl (7 mL) and ~ W0 95/24200 2 ! ~5236 methanol (25 mL), and further heated to reflux for 14 hours.
After cooling to ambient temperature, the mixture was partitioned between chloroform (200 mL) and saturated aqueous sodium carbonate solution (200 mL). The aqueous layer was further extracted with chloroform (2 X 100 mL) and the organic phases combined, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel ~ 0-2S96 methanol in chloroform/0.2% NH40H as eluent). The product containing fractions were pooled and concentrat~ed under reducea pressure. The residue was dissolved in diethyl ether and treated with anhydrous HCl. The product 1, 5-dimethyl-tryptamine hydrochloride (6.08 g) was isolated by filtration as a tan solid and used without further purification.
A suspension of azalactone prepared as described in Example 5 (1.06 g, 4.45 mmol.) and 1,5-dimethyl-tryptamine hydrochloride (1.00 g, 4.47 mmol.) in lN HCl (50 mL) was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperatur~ and the crude product isolated by filtration.
The brown solid was triturated with isopropyl alcohol (3 X 50 mL) and washed with diethyl ether (3 X 50 mL).
Recrystalli2ation from ethanol afforded 710 mg of desired product as a pale solid.
m/e=340 .
An;llysis C~lculated Found C 76.48 76.78 H 6 . 68 6.58 N 7.43 7.50 -~ ExamDle 64 Pr~r~-at;on of (-)-(S)-6-methyl-1,2,3,4-tetrahydro-1-(1-nArh~h~l~nylmethyl)-g~-~yrido [3,4-b~ indole hydro~hloride To a stirred solution of 6-methyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3,4-b]indole (3.14 g, 16.9 mmol.) in W0 95124200 1 ~ ~ 099 ~ ' (` ~i' i ~` 126 21 85236 dry xylenes ~ 65 mL ) was added (S) -N,N-dimethyl-N' - (1-tert-butoxy-3-methyl) -2-butylformamidine (3 .79 g, 17.7 mmol. ) followed by camphor sulfonic acid (200 mg). The resulting solution was heated to reflux for 72 hours The solution was cooled to ambient temperature and concentrated under reduced -pressure. The residue was purified by flash chromatography on silica gel (1:3:6 triethylamine:ethyl acetate:hexanes as eluent). The product containing fractions were pooled and concentrated to afford the product formamidine (5.g9 g) as a viscous oil which was used without further purification.
To a stirred, cooled ( 0C) suspension of potassium hydride (2596 oil dispersion, 829 mg, 20.2 mmol . ) in THF (10 mL ) was added f ormamidine prepared above (5.99 g, 16.8 mmol. ) in T~IF (~5 mL) . To this mixture was added tetramethylethylenediamine (3.0 mL, 20.2 mmol.) followed by chloromethylmethyl ether (1.9 mL, 25.2 mmol . ) .
The mixture was stirred for an additional 1 hour and treated with water ( 5 0 mL ) . The mixture was partitio~ed between diethyl ether and water and the layers separated. The aS~ueous phase was extracted with diethyl ether (2 X 100 mL) and the organic phases combined, dried over potassium carbonate, and concentrated to afford product (6.73 g) as an orange Dil, which was used without further purification.
To a stirred, cooled (-78C) solution of previously prepared formamidine (3 .36 g, 8.4 mmol. ) in dry THF (55 mL) was added n-BuLi (1.7M solution in hexanes, 5.4 mL, 9.18 mmol. ) dropwise over 5 minutes. The solution was further stirred at -78C solution for 1 hour and treated with l-chloromethyl-ni~rh~hi~lene (1.62 g, 9.18 mmol.) in dry THF ~10 mL). The solution was further stirred for 4 hours at -78C and allowed to warm to room temperature overnight. Wet THF was added (50 mL) and the solution was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with water. The organic phase was dried over _ sodium carbonate and concentrated. The crude product was purified by flash chromatography on silica gel (1:3:6 triethylamine:ethyl acetate:hexanes as eluent) . The product ~ W095/24200 ~ J',.,!0~099 ; r` 127 2 1 ~ 5 2 3 6 c~ntAining fractions were pooled and concentrated to afford product (3.48 g ) as a viscous oil (m/e = 539) which was used without further purification.
To a stirred solution of methoxymethyl indole prepared above (3.48 g, 6.45 mmol.) in THF (30 mL) was added 2N HCl (30 mL) . The mixture was stirred at ambient temperature for 24 hours, and partitioned between diethyl ether and water. The aqueous phase was back extracted with diethyl ether (2 X 50 mL) and the combined organic phases were washed with brine, dried over sodium carbonate, and concentrated under reduced pressure. The residue was dissolved in THF (20 mL) and treated with 2N sodium hydroxide solution (6 mL~ . After 2 hours, the reaction mixture was extracted with chloroform (2 X 100 mL). The organic phase was dried over sodium carbonate and concentrated to afford product (2.68 g) as a viscous oil (m/e= 495 )-To a stirred, cooled ( 0C) solution of previouslyprepared formamidine (2.68 g, 5.41 mmol.) in ethanol (100 mL) was added water (12 mL) followed by acetic acid (12 mL) and hydrazine hydrate (22 mL) . The reaction vessel was placed in the fre~ezer (-10C) for 72-hours. The mixture was warmed to ambient temperature and concentrated under reduced pressure.
The crude product was dissolved in chloroform (300 mL) and washed with water (3 X 50 mL). The organic phase was dried over sodium carbonate and concentrated to a viscous oil. The oil was dissolved in diethyl ether and treated with anhydrous HCl. The hydrochloride salt (1.50 g) was isolated by filtration. Recrystallization from ethanol (2 X) afforded material of constant rotation. Chiral HPLC confirmed enantiomeric purity as > 95% ee. m/e=326 ) specific rotation ~ 589 nM = -40.21 (pyridine, C=1 ) specific rotation ~ 365 nM = +80.43 ( pyridine, C=1) W095/24200 r~ l",~,.,.. .~ ~
` r ~ ; 2 1 8 5 2 3 6 An~ 5iS ~Al c~ ted FQund C 76 . 12 75 . 96 H 6.39 6.56 N 7.72 7.44 r le 65 Pr~r~ral~ n of 6-methyl-1-t(4-dimethylamino-n~hth~l~nyl)-methyl] -1,2,3,4-tetrahydro-9H-~yrido[3,4-b]indole dihydroehloride ~ -' y~- .,te To a stirred, coolea (-78C) suspension- of methoxymethyl-triphenylphosphonium chloride ( 10.32 g, 30.1 mmol. ) in dry THF ( 150 m~ ) was added n-BuLi solution ( 18.8 m~. 1.6 M, 30.1 mmol. ) dropwise by syringe. The orange suspension was stirred at -78C for 15 min. A solution of 4-dimethylamino-1-ni~phth~l-lPhyde ( 5.00 g, 25.1 mmol. ) in THF ( 75 mL ) was added to the ylide dropwise over 10 min.
The reaction mixture was gradually warmed to ambient temeeratur~ and stirred 14 H. Saturated ammonium chloride solution ( 100 m~ ) was added and the mixture extracted with diethyl ether ( 3 X 50 mL ). The combined organic phases were dried over sodium sulfate ana r~nrPnt~ated under reduced pressure. Chromatography on silica gel, eluting with 1596 ethyl acetate/hexanes afforded product ( 5.43 g ) as a mixture of olefi~ isomers which was used without further purif ication .
A mixture of 5-methyltryptamine hydrochloride ( 695 mg, 3 .3 mmol. ) and 1-methoxy-4 ' -dimethylamino-benzostyrene ( 1.00 g, 4.4 mmol. ) in acetonitrile ( 20 mL ) and lN HCl solution ( 150 mL ) was heated to reflux for 96 H, with addition of 1 mL of conc HCl added at 4 H The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The combined organic phases were concentrated under reduced pressure and the residue chromatographed on silica gel ( 2.5% MeOH/chlorofQrm/0.2%

~ W0 95/24200 T~~
- ~ 21 85236 NH40X as eluent ) . The f ractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and treated with anhydrous HCl. The product was isolated as the dihydrochloride salt monohydrate( 1.22 g ) by filtration. mp. 231.3C.
analysis: calculated ~ourld C 6~.21 65.30 H 6.79 6. 60 N 9.13 9.03 le 66 7 -methyl-8-bromo-1, 2, 3, 4-tetrahydro-9E~-~yrido [3, 4b] -indole ~CI ~ ~HCI
Br Br A 3 . O g sample of 6-methyl-7-bromo-lH-indole-3-e~h~n~mi ne hydrochloride was dissolved in warm water . A
solution of glyoxylic acid monohydrate (1.0 g) in water was added. The solution was adjusted to pX 4 using either potassium hydroxide or hydrochloride acid. A solid was suspended in water and concentrated HCl was added slowly.
The mixture was boiled. A solid was collected, washed with water, and vacuum dried. The solid was partitioned between 1 N NaOH and chloroform. The organic portion was dried and concentrated to a residue which was chromatographed on silica gel using methanol in chloroform. The desired fractions were pooled and concentrated to a solid which was dissolved in methanol, treated with gaseous HCl, and diluted with ether.
A solid was collected, washed with ether, and dried.
Yield: 48%
Melting Point: 321C
Elemental Analysis: C 47.83; H 4.8g, N 9.30.

8 "~ 2 1 85236 - 1~ 67 8-methoxy-1,2,3,4-tetrahydro-9H-~yrido[3,4b]-i~dole The desired product was prepared using substantially the process of Example ~6, except that the starting material was 7-methoxy-lH-indole-e~71;3ni~mi ne .
Melting Point: 2 07 -2 0 9C
Elemental Analysis: C 60.17; H 5.56; N 8.60.
r le 68 8-methoYy-Z (N) -~ro~yl-1, 2, 3, 4-teSrahydro-9~ yrido [3, 4b~ -i~lole 1~0 ~1 OMe OMe A sa-mple of 8-methoxy-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole was prepared substantially as described in Example 66. A 0.36 g sample of the indole was contacted with 1 g K2CO3 and the mixture was purged with nitrogen. - A 40 mL sample of CH3CN was added to the resulting mixture. 1~ -0.12 mL sample of 1-iodopropane was added. The mixture was maintained under nitrogen and stirred in the dark. The resulting mixture was extracted. The organic :phase was dried, evaporated, and chromatographed. The desired fractions were evaporated, taken up into methanol:ethyl acetate. The resulting mixture was added to a stirring ether solution through which gaseous HCl was bubbled. The resulting solid was vacuum dried, recrystallized, and evaporated to yield the desired product.
Yield: 0 . lOg ~ -Melting Poi~t: 282-284C
Elemental Analysis: C 64.45; H 7.67; N 9.91.

~ W0 95l24200 I ~ ~
131 2 ~ 85236 r 1~ 69 8-methoxy-2(N) -methyl-1,2,3,4-tetrahydro-9H-~yrido[3,4b] -indole ¢~ JR ~H
OMe OMe A sample of 8-methoxy-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole was prepared substantially as described in Example 66. The indole (1 g), NaOAc (0.34 g), Na8H3CN
(O.53 g), methanol (50 mL), and HOAc ~1.0 g) were stirred. A
1.36 g (37% in 10 mL methanol) sample of CH20 was added to the indole mixture.
The reaction was ~uenched using an acid, then made basic, and extracted. The organic was dried, evaporated, and chromatographed. The desired fractions were evaporated and taken up into methanol/ethyl acetate. The resulting mixture was added to ethereal HCl. The resulting solid was collected and vacuum dried.
Yield: 0.84 g (79%) Melting Point: 291-2g4C
Elemental Analysis: C 62.06; H 6.97; N 11.32.
r Wo 95l24200 ~ ).,,5,~0~099 2 ~ 85236 - 1~ 70 8-methoxy-2 (N) -cyclopropylmethyl-1, 2, 3, 4-tetrahydro-9}~-pyrido ~3, 4b] -indole ~r ~
OMe OMe The desired product was prepared using appro~riate reagents and the p~ocess substantially as described in Example 69.
Yield: o88%
Melting Point: 285-287C
Elemental Analysis: C 65.7$; H 7.47; N 9.47.
r le 71 HO~CI ~l1 The desired product can be prepared using appropriate reagents and the process substantially as described in Example 69.
Yield: 489ei Melting Point: 321C
Elemental Analysis: C 47.83; H 4.89; N 9.30.

~ WO 95/24200 Y~
` ~ ! ` 2~ 85236 r l~ 72 7,8-dimethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b] -indole A 2.30 g sample of 6,7-dimethyl-lH-indole-e~h;ln~mi n~ was dissolved in a mixture of water and isopropanol with heating. A 1. 03 g sample of glyoxilic acid monohydrate in 10 mL of water was added to the flask. The solution was allowed to cool and made basic by the addition of potassium hydroxide. The reaction was stirred for 48 hours.- The resulting solid was isolated by filtration and washed with water. The solid was dissolved in 50 mL of water and the solution was acidified by the slow addition of concentrated HCl. Heating was initiated and an additional 5 mL of concentrated HCl was added. The resulting solid was isolated by decanting and dissolved in 10 mL of water. This solution was made basic by the addition of potassium hydroxide and extracted using 1:3 isopropanol:CHCl3.
Separation and concentration of the organic layer gave a viscous oil which was purified via chromatography. The oil was dissol~ed in ethyl acetate and gaseous HCl was bubbled into the solution to form the hydrochloride salt. The solid hydrochloride salt was isolated by filtration and dried in a vacuum oven.
Yield: 5496 Melting Point: 330 C
Elemental Analysis: C 65.75; H 7.29; N lI.62.
r l., 73-methyl-8-bromo-1,2,3,4-tetr~hydro-9H-~yrido~3,4b]-i dole The desired 6-methyl-8-bromo-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole was prepared using appropriate reagents and the process substantially as described in Example 72 .
Yield: 5796 Melting Point: 346C
Elemental Analysis: C 48.04; H 4.68; N 9.3~) W095l24200 r IlU ~ ~ o r le 74 6,8-dif~luoro-1,2,3,4-tetrahydro-9}~-~yrido[3,4b] -indole The desired 6, 8-difluoro-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole was prepared using appropriate reagents and the process substantially as described in Example 72.
Yield: 596 Melting Point: 350C
Elemental Analysis: C 53 90; H 4.49; N 11.23.
r le 75 8-bromo-1,2,3,4-tetrahydro-9H-~yrido[3,4b] -indole The desired 8-bromo-l, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole was prepared using appropriate reagents and the process substantially as described in Example 72.
Yield: 496 Melting Point: 337 . 8C
Elemental Anal~ysis: C 46.17; H 4.26; N 9.52.
The following were prepared by the process substantially as described in Example 72.
8-fluoro-1,2,3,4-tetrahydro-9H-pyrido[3,4b] -indole Yield: 489~i Melting Point: 329 5C
Elemental Analysis: C 58 . 58; H 5 . 43; N 12 . 37 .
6-chloro-1, 2, 3, 4-tetrahydro-9H-pyrido [ 3, 4b] -indole;
Yield: 63 96 Melting Point: 317 . 9C
6-bromo-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole;
Yield: 19~
Melting Point: 310 . 9C
6-~luoro-1, 2, 3, 4-tet~ahydro-9H-pyrido [3, 4b] -indole;
Yield: 38 Melting Point: 316. 6C

WO 9S/24200 I ~ ~ O99 ` ` 21 85236 Yield: 5496 Melting Point: 33 0 C
Elemental ~nalysis: C 65.75; H 7.29; N 11.62.
Exam~le 76 7-methyl-8-chloro-1,2,3,4-tetrahydro-9EI-pyrido[3,4b] -indole ~HCI
Cl H
Cl The desired product was prepared using the process substantially as described in Exam?le 1 except that the starting material was 6-methyl-7-chloro-lH-indole-3-e~h~n~mi ne hydrochloride.
Yiela: 7096 The resulting material was boiled in ethanol The resulting product was collected, washed with ethanol, and vacuum dried.
Yield: 5 8 96 Melting Point: 330-334C
Elemental Analysis: C 55.88; X 5.47; N 10.93.
The ollowing were prepared using the process substantially as described abo~e in Example 76.
7-methyl-8-chloro-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole Melti ng Point: 350-352C
Elemental Analysis: C 55.65; H 5.68; N 10.39.
8-chloro-1, 2, 3, 4-tetrahydro-gH-pyrido [3, 4b] -indole Melting Point: 335-337C
Elemental Analysis: C 53.g3; H 4.88; N 11.09.

WO 9S/24200 1 ~ I/~J~.,~ 099 7-bromo-8-methyl-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole Melting Point: 323-325C
Elemental Analysis: C ~7 . 85; H 4 . 84; N 9 . 08 .
E 1~ 77 7-methyl-1,2,3,4-tetrahydro-9H-~yridot3,4b] -indole ~HCI ~HCI
A sample of 7-methyl-8-oromo-1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] -indole was reacted with hydrogen in the presence o~ Pd/C, ethanol, and triethylamine. The resulting material was filtered, concentrated and extracted. The organic phase was dried, concentrated, and vacuum dried. The resulting solid was taken up into methanol and added to ethereal XCl. A white solid was collected, washed with Et2~
and vacuum dried.
Yield: 56%
Mel ting Point: 3 1 0 -3 12 C
Elemental Analysis: C 64.79; H 6.89; N 12.47.
r le 78 8-methyl-1,2,3,4-tetrahydro-9H-~yrido[3,4b]-i~dole The desired product was prepared using the process substantially as described in Example 77.
Yield: 4696 Melting Point: 318-320C
Elemental Analysis: C 64.53; H 6.94; N 12.43.

~ WO95/24200 I_l"n,,~ ngg ` 21 85236 r le 79 7 -bromo~ -indole-3 _ethAn:~m; n~
'. ~ Cl ~H /~--~NHHCl NHNH2 ~ N
HCI T H
Br Br A 25 . 8 g sample of 2-bromophenylhydrazine hydrochloride was partitioned between 1 N NaOH and chloroform. The organic layer was separated and the aaueous portion was extracted with chloroform. The '-f~i nl~l organic extracts were dried (Na2SO~,) and concentrated to yield the f ree hydra z ine as an o i l .
The oil was stirred in 100 mL of methanol while 4-chlorobutyraldehyde ~12.3 g) was added. The resulting solution was transferred to a sealable tube and purged with nitrogen. The tube was sealed and the reaction mixture was heated in an oil bath maintained at 95C for 14 hours. The resulting mixture was allowed to cool and concentrated to a residue which was partitioned between lN NaOH and chloroform.
The combined organic extracts were dried and concentrated to an oil. The oil was chromatographed on silica gel using a gradient of 0-10% methanol in chloroform. Fractions containing product were concentrated to an oil which was taken up in a small amount of methanol and added to ethereal HCl_ 2~ solid was collected, washed with diethyl ether and vacuum dried at 50C.
Yield: 7.32 g 9r Yield: 23%
- M.P.: 260-262C
ElementaI Analysis: C 43.55: H 4.41: N 10.03.

WO 95l24200 ~ 099 o ,j , , ~ " , ~
~i ~ ' 138 2 1 85236 7 -~luoro-1~-indole-3 _eth~nslm; n~
EtO ~ ¢~~ HCI ~`

F HCI F
The desired 7-fluoro-lH-indole-3-ethAnAmin~ was prepared substantially as described in Example 81 infra.
except that 2-fluorophenylhydrazine hydrochloride (25.5 g) was used. Additionally, reverse phase HPLC was required for ::
final purification.
Yield: 4 g Melting point: 187-189C ~ - ~
Elemental AnaIysis: C 55.12; H 5.48; N 12.60.
E le 81 7 -methoxy-l~-iudole-3_eth~n,~.n; n~
Cl ¢;~--NHHC

HCI NH
OMe OMe A 15 . 8 g sample of 2 -methoxyphenylhydrazine hydrochloride and a 26.3 g sample of 4-~thAlimidobutyraldehyde diethyl acetal were stirred in ethanol. The mixture was heated at reflux for 2 hours. The reaction mixture was allowed to cool and was concentrated to a residue The resulting residue was dissolved in 750 mL
ethanol and 15 . 5 g hydrazine hydrate was added . The mixture was heated at reflux for 14 hours. A 70 mL sample of 5N HCl was added and the mixture was allowed to cool. The cooled W0 95/24200 r~ A~ogg *

mixture was concentrated to a residue. The residue was partitioned between lM NaOH and chloroform. The organic portion was separated and the aqueous portion was extracted with chloroform. The combined organic extracts were dried (Na2SO4) and concentrated to an oil The oil was chromatographed on silica gel using a gradient of 0-10%
methanol in chloroform. Fractions con~aining product were concentrated to an oil which was taken up into a small amount of methanol and added 'co ethereal HCl. A solid was collected, washed with diethyl ether, and vacuum dried at 50C to af~ord a white solid.
Yield: 7 5 g (37%) melting point: 198_200C
Elemental Analysis: C 57.51; H 6.75; N 12.10.
r 1~ 82 7 -chloro-lH-indole-3 -e~hs~n~; n~
~~ ~
A 10 . 0 g sample of 2-chlorophenylhydrazine hydrochloride and 17 . 9 g of 4-phthalimidobutyraldehyde diethyl acetal were stirred in 200 mL ethanol with 1 mL 5 N
HCl The mixture was concentrated to a residue which was slurried in a small amount of methylene chloride A yellow solid was collected and vacuum dried at 40C The solid was stirred in 500 mI ethanol. Hydrazine hydrate (14 g) was added and the mixture was heated at reflux for 14 hours. A
60 mL sample of 5 N HCl was added and the mi~cture was heated at re1ux for 1 hour. The mixture was allowed to cool and was concentrated to a residue The residue was partitioned Wo gs/24200 PCT/US95103099 i '; 2 1 8 5 2 3 6 between 1 N NaOH and chloroform. The organic layer was separated and the a~aueous layer was extracted with chloroform. The combined extracts were dried ~Na2SO4) and concentrated to an oil. The oil was chromatographed on silica gel using a gradieFIt of 0-10% methanol in chloroform containing 0.2% ammonium hydroxide. Fractions C~n~Ainin~
product were concentrated to an oil which was taken up in a small amount of methanol and added to ethereal XCl. A solid was collected, washed with diethyl ether, and vacuum dried at 50C .
Yield: 3.2 g ~25%) Melting Point: 227-229C
Elemental AnaIysis: ~ 51.76; H 5.29; N 11.97.
~ xamDle 83 5-methyl-7 -chloro-1}~-indole-3 _ethAnAm; nc.
The desired product was prepared substantially as described in Example 82.
Yield: 4.3 g (34%) Melting Point: 279-281C
Elemental Analysis: C 54.05; X 5.85; N 11.33.
r le 84 l-}I-Ben~(G)indole-3-eth ~n~m;nA

~ Wo 95/24200 T ~
-~ .. - ! '1 i 1-H-Benz (G) indole-3 -~tll~n~mi nP was prepared using substantially the process described in Example 82 Yield: 3.5 g ~I7%) Melting Point: 305-307C
Elemental Analysis: C 68.43; H 6.30; N 11.08.
r le 85 6 -methyl-7 -chloro-1/}-indole-3 _e~h~nAm; n~6 -bromo-7 -methyl indole-3-eth:~n,-m; n~-~~
Cl 6-methyl-7-chloro-lH-indole-3 -eth~n~m; ne was prepared using substantially the same process described in Example 82 .
Yield: 3 . 0 g (24%) Melting Point: 290C
Elemental Anal~sis_ C 54.10; H 5.88; N 11.66.
6-bromo-7-methyl-lH-indole-3-et~n~mi n~ was prepared substantially as described in Example 82 using appropriate starting materials.

WO 95124200 r~ ogg r~ 2 1 8 5 2 3 6 Yield: 1.6 g ~5696) Melting Point: 251 C
Elemental Analysis: C 45.85; H 4.97; N 9.71.
le 86 6-methyl-lH-indole-3-el-hAn~m; n~
~CI ~1 A sample of 6-methyl-7-bromo-lH-indole-3-eth;~n;~mine was contacted with Pd/C H2 in the presence of ethanol and triethylamine. The resulting material was evaporated and partitioned between base/CHCl3. The organic phase was dried, concentrated, and dried. The resulting material was taken up into methanol and added to ethereal HCl. The resulting material was washed and vacuum dried.
Melting Point: 232-2360C
Elemental Analysis: C 62.84; H 7.24; N 13.20.
r 1~ 87 5-methyl-7 -bromo-lH-indole-3 -e1-hAn~--n; n~
A sample of 5-methyl-7-bromo-lH-indole-3-e~h~n~mi ne was prepared using appropriate starting materials and substantially the process described in Example 79.
Yield: 16%
A 0 . 6 g sample of 5-methyl-7-bromo-lH-indole-3-eth~n~mi ne hydrochloride salt was converted to the free base and chromatographed on silica. The desired fractions were pooled and evaporated. The resulting material was taken up into ethyl acetate, filtered, diluted with ether, and maleic acid in methanol. The product was crystallized using ether, f i 1 t ered, and dri ed .

~WO95/24200 r~

lG3 Yield: 6796 Melting Point: 185-187C
Elemental Analysis: C 49.09; H 4.85; N 7.71.
~x lmle 88 6, 7 -dlmethyl -lH-indole-3 -e~-h~n~m; no A sample of 6,7-dimethyl-lH-indole-3-eth;ln~mine was prepared using c-~L,L..~Liate starting materials and substantially the process described in Example 79. The 6,7-dimethyl-lH-indole-3-~oth~n~mi ne was purified by treating with K2CO3 and extracting with 3:1 CHCl3/isopropanol. The organic phase was dried, evaporated, and chromatographed. The desired fractions were pooled, evaporated, and mixed with ethyl acetate. The resulting material was diluted with ether and maleic acid in methanol. The solid was triturated in ether and dried.
Melting Point: 171-173C
Elemental Analysis: C 63.20; H 6.75; N 8.98.
/Zx~mDle 89 6-methyl-7-bromo-1}}-indole-3-e~h,-n--m;n., A sample of 6-methyl-7-bromo-lH-indole-3 -eth~n~m; n was prepared using appropriate starting materials and substantially the process described in Example 79.
Yield: 8 . 696 The 6-methyl-7-bromo-lH-indole-3-eth~n~mi n~ was dissolved in boiling ethanol and slowly cooled to room temperature. The solvent was reduced, the resulting material was filtered, and washed with ether. The resulting material was again filtered and washed with ether to afford the desired compound.
Melting Point: 288-290C
Elemental Analysis: C 45.54; H 4.80; N 9.47.
For Examples 90 through 110, where applicable, diethylether was distilled from sodium benzophenone ketyl prior to use. All reactions were performed under a positive Wo 95l24200 1~ r~osg i i 2 1 8 5 2 3 6 pressure of argon. ~ NMR and 13C-N~R data were recorded on a Bruker AC-200P (200 MHz). IR spectra were obtained on Nicolet 510 P-FT ( film and KBr) . Melting points were determined on a BiLchi apparatus and are not corrected. Analytical TLC was performed on Merck TLC glass plates precoated with F254 silica gel 60 (W, 254 nm and Iodine) . Chromatographic separations were performed by uslng 230-400 mesh silica gel (Merck) . N-BOC-aziridines (2a-d) were prepared from the:
corresponding alkenes following standard procedures.
Pr~rnrat~n 2 Indole ~tartin~ material~
The indole starting materials (la, lb, and lc) infra. were purchased (la), prepared accordin~ to Bartoli's procedure (lb) [Bartoli, G. et al. Tetrahedron Lett., 1989, 30, 2129~ or (lc) synthesized from 2-iodo-~, 6-dimethylaniline (5'~ ~ ) . The process is illustrated by the following Scheme:
Scheme IV
SiMe3 Me~Me Cull(pph3)2pdcl2 _~
6n 1c The 2-Iodo-4, 6-dimethylaniline (5" ' ) synthesis can be completed as follows To a suspension of 5" ' (24 mmol. ), CuI (0.05 equiv.) and (PPh3)2PdC12 (0.05 equiv.) in 30 ml of dry triethylamine under Ar atmosphere was added trimethylsilylacetylene (1.1 equiv. ) and the resulting mixture was stirred for 3 hours. Then, the solvent was eliminated under vacuum and the residue purified by flash chromatography using hexane/ethyl acetate ~3 :1) as eluent t~ . ~
yield 6" in quantitative yield. A slurry of 6" ' (23 mmol. ) and CuI (2 e~uiv. ) in 50 ~Ll of dry dimethylformamide was heated for 2.5 h. under Ar atmosphere at 100 C After cooling down to room temperature the reaction mi~cture was W0 95/24200 1 ~ 099 filtered off and the solid washed twlce with ether (20 ml. ) .
The organic phase was washed with water (3x 50 ml. ), dried over Na2SO4 and the solvent evaporated to dryness. The crude product was purifIed by flash chromatoyraphy using hexane/ethyl acetate (3:1) as eluent to afford lc (1.5 g., 4596 ) .
The process for preparing compounds of Examples 90 through 107 is illustrated by the following Scheme:
n20 X'-S-Me X"=S-Me n3=3 (90) X =5 M3 n30_4 R R';H (95) cX 5,7-diMe b X~=7-CI n20=3(91) cX"=S-Me n30=3 R=3,4-(OMe)2Bn,R'=H(97) c X"=5,7-Me2n3=3 d X .7-CI n30=3 R=3,4-(OMe)2Bn, R'-H (98) d X"_S-Me n30=4 (92) r X''=S 7-Me2 n3=3 R=3 4-(OMe)2Bn R'=H (99) X"~7-a n30=4(93) IX"=SMe n30=4R=34-(OMe)2Bn R'=H(100) I X~.5,7-Me2 n30=4 (94) 9 X'-7-a n30 4 R=3,4-(OMekBn, R'-H (101) D X''~Mo n30=5 h X'=5,7-Me2 n30=4 R=3,4-(OMe)2Bn, R' H(102) i X' S-Me n30=S R=3,4-(OMe)2Bn, R'=H (103) ¦ X' S Me n30=3 R_1 , ' ', ' ", I, R'-H (104) k X"S-Me n3=4 R=1 , ' ", ' ", I, R'-H (10s) IX'~5,7-Me2n3=4R=1~ ,' b`' ',I,R' H(106) m X'=S-Me n3-4 R, R'= (107) \~ OMe OMe r 19 90 Trans-3-(2-amino-.~ lyl)-5 " ~Iil.~ole,hydrochloride To a suspension of the corresponding indole la (5 mmol ) in 10 ml of anhydrous ether under Ar a~mnq~h~re was added a 3M solution of methylmagnesium bromide ( 1. 5 ecluiv . ) The resulting mixture was stirred for 45 min. at room temperature. Then, this mixture was cannulated to a slurry of WO 9~l24200 r~
~ ~ ~ ,,, 2185236 Copper (I) bromide-dimethylsulfide complex (0 .2 equiv. ) in 5 ml. of dry ether under Ar atmosphere at -30 C The reaction mixture was stirred for 30 min. at the same temperature.
After this time the mixture was cooled down to -78 C and the corresponding aziridine 2a ( 1. 5 e~uiv . ) dissolved in l0 ml .
of dry ether was added. The whole mixture was allowed to reach room temperature and stirring was kept overnight. The reaction was s~uenched with l0 ml. of a saturated solution of ammonium chloride. The layers were separated and the a~ueous phase was extracted with ether/ethyl acetate (l:l) (2xl0 ml. ) . The combined organic extracs were dried over anhydrous sodium sulfate, the solvent was eliminated under vacuum and the residue was purif ied by f lash chromatography using hexane/ethyl acetate (3 :l) . The corresponding N-BOC protected tryptamine was dissolved~in dichloromethane/ether. The solution was saturated with dry hydrogen chloride and stirred overnight at room temperature. Finally, the solvent was evaporated and the crude title tryptamines purified by washing with dichoromethane~ether~methanol mixture (2:3:1).
The produc~ was identified as the title compound (3a).
Yield: 85%. Mp: >200 C. 1HNMR(CD30D),~:7.35(s,lH),7.23-7.12(m, 2H), 6.91 (d, J= 7.5 HZ, lH), 3.73 (m, lH), 3.27 (m, lH), 238-2.10 (m, 5H), 2.05-1.70 (m, 4H). 13c NMR (CD30D), ~: 136.98,128.93,127.84,124.27,123.13,119.01, 114.19,112.37, 58.56, 43.93, 33.10, 31.30, 23.07, 21.73. IR (KBr): 3304, 2963,1593, 1510,1481, 800 cm~1. MS (EI): 214 (M+-HCl, 28),197 (70),170 (14),144 (42),126 (49), 105 (33), 84 (100).
~xam~le ~l Trans-3-(2-amino ~lu~...1.~1)-7-chloro~ndole, hy-1rnrhlnri~ie The title compound (3b) was prepared using substantially the same procedure as described by Example 90;
however, the indole starting material was a compound of Formula lb.
Yield: 37%. Mp: >200 C. 1HNMR(CD30D),~:7,56(d,J=7.7Hz,1H), 7.31 (s, lH), 7.12 (d J = 7.3 Hz, lH), 7.01 (t, J = 7.8 Hz, lH), 3.77 (q, J= 7.9 Hz, lH), 3.40-3.25 (m, lH), 2.40-2.15 (m, 2H), 2.05-1.70 (m, 4H). 13C NMR (CD30D), ~:

~ Wo s~/24200 ~ 3099 ~` 2185236 135.48, 129.53, 124.28, 122.13, 120.79, 118.40, 118.02, 116.18, 58.55, 43.79, 33.32, 31.36, 23.11. IR (KBr): 3422, 3298, 3040, 2972, 2909,1495 cm~l. MS (EI): 235 (M+-Cl, 100), 218 (28), 165 (7).
r le 92 Trans-3-(2-amino-cycloheYyl)-5 ' ~ .dole, 1~
The title compound (3d) was prepared using subst;~nt;~1 ly the same procedure as described by Example 90.
Yield: 80%. Mp: >200 C. lHNMR(CD30D),~:7,44(s,1H),7.27(d,J=8.3 Hz, lH), 7.18 (s, lH), 6.95 (dd, J = 8.3 and 1.2 Hz, lH), 3.55-3.40 (m, lH), 2.86 (dt, J= 4.3 and 11.3 Hz, lH), 2.42 (s, 3H), 2.25-2.12 (m, lH), 2.10-1.79 (m, 4H), 1.75-1.40 (m, 3H). 13c NMR (CD30D), ~: 136.97, 129.12, 127.74, 124.42,123.73, 119.09, 114.77, 112.48, 56.22, 41.61, 34.75, 32.42, 26.93, 25.79, 21.73. lR (KBr): 3400, 3283, 3021, 2936, 2861,1491 cm-l. MS (EI): 229 (M+-CI, 100).
r ~-94 Trans-3-(2-amino-..~ Ayl)-7-~ hl.,..~ -.lr, hy~lrn~hlnri~1P (3e) The title compound (3e)was prepared using substantially the same procedure as described by Example 9 0 .
. Yield: 43~. Mp: >200 C. lHNMR(CD30D),o:7,63(d,J=7.8Hz,lH), 7.35 (s, lH), 7.14 (d, J = 7.4 Hz, lH), 7.02 (t, J = 7.7 Hz, lH), 3.60-3.40 (s, lH), 3.08-2.91 (m, lH), 2.30-2.10 (m, lH), 2.05-1.80 (m, 4H), 1.75-1.45 (m, 3H). 13C NMR
(CD30D), ~: 135.43,129.41 125.00,122.15~120.87,118.53,118.09,116.70,56.12, 41.43, 34.74, 32.37, 26.80, 25.68. IR (KBr): 2938, 2859,1429,1341, 779, 735 cm~l. MS
(EI): 249 (M+-Cl, 100).
FY~m~le 94 Trans-3-(2-amino~ h.Ayl)-5~7-dimethylindole~ hy~1rorhlnri~1P
Trans-3-(2-amino-cyclopentyl)-5,7-~' ' yl . . ~dole, hydrochloride The title compound (3f) was prepared using - substantially the procedure o~ Example 90; however, the indole was lc and the aziridine was 2b.
Yield: 4536. Mp: >200 C. lHN~(CD30D),~:7,27(s,1H),7.19(s,1H), 6.77 (s, lH), 3.42 (dt, J = 11.0 and 4.2 Hz, lH), 2.85 (dt, J= 11.4 and 4.2 Hz, lH), 2.44 (s, 3H), 2.39 (s, 3H), 2.30-2.10 (m, lH), 2.08-1.83 (m, 4H), 1.70-1.40 (m, 3H).
13C NMR (CD30D), ~: 136.39,129.37,127.39, 125.01, 123.56,121.94,116.78, Wo95/24200 PCrrUS95/03099 115.16, 56.28, 41.70, 34.71, 32.40, 26.g3, 25.80, 21.72,16.93. IR (KBr): 3420, 3279, 3013, 2934, 2861,1505 cm~l. MS (EI): 242 (M+-HCl, 62), 225 (25),199 (23),184 (20), 171 (38), 158 (lO0), 145 (18), 128 (12), 115 (12), 97 (12).
Substantially the same procedure was used to prepare Tran~- 3 - ( 2 -amine -cyc1o~entyl ) - 5, 7 -dimethylindole, hydrochloride (3c); however, the aziridine was 2a.
Yield: 63 96, lH NMR (DMSO-d6), o: 10.8 (s, lH), 8.12 (broad s, 3H), 7.30-7.20 (m, 2H), 6.70 (s, lH), 3.70-3.55 (m, lH), 3.55-3.20 (m, lH), 2.38 (s, 3H), 2.36 (s, 3H), 2.30-2.10 (m, 2H), 2.00-1.60 (m, 4H).
r l~ 95 Tr~ns-10-methyI-2,3,4f4a,5,6,7,11c-octahydro-lH-indolo[2,3-c].l~ -' e, lly ~l ~ u~
A suspension of tryptamine hydrochloride (3a) (1.3 mmol. ) in 10 ml. of distilled water was dissolved by heating.
To this solution glyoxylic acid ~1.43 mmol. ) in 1 ml. of water was added. Subsequently, a solution of =KOH (1.3 mmol . ) in 1 ml. of distilled water was slowly added to reach pH= 4.
The resulting solution was stirred at room temperature for l h. A~ter this time, commercially available hydrochloric acid ( 0 . 5 ml . ) was added dropwise and the resulting mixture was refluxed for 30 rnin. Another portion of hydrochloric acid (0.5 ml.) was added and the reaction further~refluxed for 15 min. Finally, the reaction mixture was cooled down to room temperature and ~iltered of f . The title tetrahydro-b-carboline (4a) was subsequently washed with water and ethanol .
Yield: 8196. Mp: >200 C. lHNMR(DMSO-c~ :>ll.O(s,lH),9.92 (broad s, lH), 9.68 ( broad s, lH), 7.38 (s, lH), 7.23 (d, J = 8.3 Hz, lH), 6.88 (d, J=
7.8 Hz, lH), 4.50-4.22 (m, 2H), 3.18-2.95 (m, 2H), 2.80-2.65 (m, lH), 2.34 (s, 3H), 2.30-2.15 (m, lH), 1.98-1.80 (m, 2H), 1-80-I.20 (4H) 13C NMR (DMSO-d6), ~:
134.75 127.31, 126.49, 125.64, 122.65, 119.11, 111.14, 108.82, 58.99, 37.18, 29.42, 28.84, 24.94, 24.43, 21.28. IR (KBr): 3391, 3266, 2936, 2861, 2801, 2762 cm~l MS(EI): 241 (M+-CI, 100).

Wo 95/24200 r~ .
` - - 21 85236 FY Irr~le 96 Trans-8-chloro-2,3,4,4a,5,6,7,11c-octahydro-lH-indolo[2,3 ~ ]qll;nnli~
hyrlrs)rhl-lri/le (4b) A suspension of tryptamine hydrochloride ~3b) (1.3 mmol. ) in 10 ml. of distilled water~ was dissolved by heating To this solution gliQxylic acid ~1.43 mmol. ) in 1 ml. of water was added. SubsecLuently, a solution of KOH (1.3 mmol.) in 1 ml. of distilled water was slowly added to reach pH= 4.
The resulting solution was stirred at room temperature for l h. After this time, commercially available hydrochloric acid ( 0 . 5 ml . ) was added dropwise and the resulting mixture was refluxed for 30 min. Another portion of hydrochloric acid (0.5 ml.) was added and the reaction further refluxed for 15 min. Finally, the reaction mixture was cooled down to room temperature and filtered off. The title tetrahydro-b-carboline (4b) was subse~uently washed with water and ethanol .
Yield: 4596: Mp: >200 C lHN~ (DMSO-~6), o: >11.0 (s, lH), 10.05 (broad s, lH), 9.87 ( broad s, lH), 7.58 (d, J= 7.8 Hz, lH), 7.16 (d, J = 7.6 Hz, lH), 6.98 (t, J= 7.9 Hz, lH), 4.60-4.20 (m, 2H), 3.18-æ95 (m, 2H), 2.90-æ70 (m, lH), 2.25-2.18 (m, lH), 1.98-1.75 (m, 2H), 1.65-1.20 (4H). 13C NMR (DMSO-d6), o: 133.17 128.18, 127.23, 120.65, 120.03, 118.55, 115.78, 110.73, 58.74, 36.93, 29.16, 28.77, 24.88, 24.36. IR (KBr): 3422, 3231, 2936, 2861, 2760,1429 c}n~l. MS (EI): 261 (M+~l, 30), 241 (100).
r ~-97 Trans-5-(3,4-di...L~ yl,...,,~ 9 '' yl-1,2,3,4,4a,5,6,10c-Oclal~ u~ r ' 'a]pyrido [3,4-b]indole, hy~lrothlnritle (4c) A suspension of the corrPcponrlin~ tryptamine hydrochloride (3a) (1 mmol) and the correponding ~aLkylidene-2-methyloxazolin-5-one (1.2 mmol) in lN hydrochloric acid (3 ml.) was refluxed under Ar ~trnn~phPre during 72 h.
After this time the reaction mixture was allowed to reach room temperature and W0 9~/24200 r~ s o '~ ~ \ r~ ~ t r 150 2 1 8 5236 filtered off. The crude solid was purified by f~ash chromatography using dichloromethane/methanol (9:1) as eluent.
Yield: 88%. Mp: 187-191 C. lH~MR(DMSO-d6),o:>11.0(s,1H),10.38 (broad s, lH), 9~5 ( broad s, lH), 7.50-7.15 (m, 3H), 7.15-6.80 (m, 3H), 5.0-4.70 (broad s, lH), 3.75 (s, 6H), 3.40-2.80 (m), 2.49 (s, 3H), 2.20-~70 (m, 4H), 1.55-1.30 (broad s, lH). 13c NMR (DMSO-d6), o: 148.73147.90,134.45,130.24,128.17, 127.64, 125.44, 123.03, 121.78, 118.43, 113.69, 111.95, 111.27, 110.64, 62.01, 57.50, 55.51, 37.49, 2552, 25.14, 21.30, 20.73. IR (KBr): 3438, 3237, 2942,1518,1264,1248 cm~l. MS (EI): 377 (M+-CI, 100).
FY In~ple 98 Trans-7-chloro-5-(3,4-dimL~ ,,,y~ 2~3~4~d 1 ~,6 lr;
ocllLyd.u.~rlnpPnt~[a]pyrido [3,4-blindole, hyrlrn~hlnrirlP (4d) A suspension of the corresponding tryptamine hydrochloride (3b) ~1 mmol) and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in lN
hydrochloric acid (3 ml . ) was refluxed under Ar atmosphere during 72 h. After this time the reaction mixture was allowed to reach room temperature and filtered off. The crude solid was purified by flash chromatography using dichloromethane/methanol (9:1) as eluent.
Yield: 52%. Mp: >230 C dec. lHNMR(DMSO-~j),o:>ll.O(s,lH), 10.40 (broad s, lH), 9.30 ( broad s, lH), 7.60-7.42 (m, lH), 7.38-6.90 (m, 5H), 4.90-4.75 (broad s, lH), 3.78 (s, 3H), 3.76 (s, 3H), 3.40-3.00 (m), 2.15-1.80 (m, 4H), 1.60-1.35 (broad s, lH). 13c NMR (DMSO-d6), o: 148.70,147.91,132.95,131.78,128.25, 127.02, 121.75, 121.11, 120.41, 117.96, 116.05, 113.54, 112.72, 111.99, 61.74, 57.45, 55.50, 37.27, 25.24, 25.07, 20.77. IR (KBr): 3588, 3438,1518,1290 cm~l. MS (EI): 398 (M++2-HCI, 40), 396 (M+-HCl, 100).
FYIn~yle 99 Trans-5-(3,4-l- ' yb~ yl)-7~9-dimethyl-l~2~3~4~4a~5~6~loc-o~ ydlu~lopenta[a]pyrido [3,4-b]irldole, hytlror~hlnri~lP (4e) A suspension o the corresponding tryptamine hydrochloride (3c) (1 mmol) and the correponding 4-~ WO 95/24200 P~ 5 ,t i~ ' 2 ~ 85236 151alkylidene-2-methyloxazo~in-5-one ~1 2 mmol) in lN
hydrochloric acid (3 ml. ) was refluxed under Ar atmosphere during 72 h. After this time the reaction mixture was allowed to reach room temperature and filtered off. The crude solid was purified by flash chromatography using dichloromethane/methanol ( 9 :1 ) as eluent .
Yield: 87%. Mp: >200 C. lHNMR(DMSO~ >11.0(s,lH),1020 (broad s, lH), 9.20 ( broad s, lH), 7.29 (s, lH), 7.20-6.95 (m, 3H), 6.75 (s, lH), 4.90-4.70 (broad s, lH), 3.78 (s, 6H), 3.30-2.90 (m), 2.48 (s, 3H), 2.34 (s, 3H), 2.10-1.70 (m, 4H), 1.60-1.30 (broad s, lH). 13c NMR (DMSO-d6), ~: 148.73147.90,134.01, 129.98, 128.31, 127.84, 125.10, 123.82, 121.75, 120.42, 116.03, 11358, 111.99, 111.21, 61.94, 57.62, 55.52, 37.60, 25.57, 25.17, 21.23, 20.75,17.07. IR (KBr): 3447, 2910,1520 cm-l. MS (EI): 391 (M~-CI,100), 239 (35).
E~ ~le 100 Trans-6-(3,4-~- ' y~ o-methyl-2~3~4~4a~5~6~7~llc-octahydro-lH
indo1o[2,3-,~.], ~ d~u~lllv~;de (4f) A suspension of the corresponding tryptamine hydrochloride ( 3d) ( 1 mmol ) and the correponding 4 -alkylidene-2-methyloxazolin-5-one (1.2 mmol) in lN
hydrochloric acid (3 ml . ) was refluxed under Ar atmosphere during 72 h. After this time the reaction mixture was allowed to reach room temperature and f iltered of f . The crude solid was purified by flash chromatography using dichloL~ ~~h~ne/methanol (9:1) as eluent.
Yield: 85%. Mp: 197-200 C lHNMR(DMSO-d~),o:>ll.O(s,lH),8.90 (broad s, lH), 7.42 (s, lH), 7.28 (d, J= 8.3 Hz, lH), 7.16 (s, lH), 7.05-6.90 (m, 3H), 4.95-4.80 (broad s, lH), 3.73 (s, 6H), 3.66-3.59 (m, lH), 3.25-2.80 (m, 4H), 2.35 (s, 3H), 2.20-2.10 (m, lH), 1.95-120 (m, 6H). 13c NMR (DMSO-d6), ~: 148.67147.91, 134.92, 134.76, 129.72, 127.85, 127.45, 125.43, 122.91, 121.85, 119.43, 113.59, 111.90, 111.30,109.45, 59.98, 55.47, 55.40, 37.08, 36.65, 29.48, 28.24, 24.94, 24.41, 21.32. IR
(KBr): 3439, 2936,1516,1464,1453,1265 cm~l. MS (EI): 391 (M-l-CI, 100).

WO 95/24200 Pl_ 1/ LI~SJ, ~099 FY~ e lnl Trans-8-chloro-6-(3,4-dimethuJ~ylJ..~yl)-2,3,4,4a,5,6,7,11c~octahydro-lH-jn-inln[7 ~-c]~ ,.oli,-e, hy~lrn--hlnri~ (4g) A suspension of rche corresponding- tryptamine hydrochloride (3e) (1 mmol) and the corr~rnnflin~ 4- - r alkylidene-~-methyloxazolin-5-one (1 2 mmol) in lN
hydrochloric acid (3 ml . ) was refluxed under~ Ar atmosphere during 72 h. After this time the reaction mixture was allowed to reach room temperature and filtered off. The crude solid was purified ~y flash chromatography using dichloromethane/methanol ( 9 :1 ) as eluent .
Yield: 47%. Mp: >250 C. lHNMR(DMSO-d5),o:>11.0(s,1H),9.75 (broad s, lH), 8.90 ( broad s, lH), 7.64 (d, J= 7.9 Hz, lH), 7.20 (d, J= 7.8 Hz lH), 7.15-7.00 (m, 4H), 4.90-4.80 (broad s, lH), 3.74 (s, 6H),3.70-3.60 (m, lH), 3.25-2.85 (m, 4H), 2.20-2.15 (m, lH),1.95-1.25 (m, 6H). 13C NMR (DMSO-d6), c~: 148.72, 148.00, 133.46, 131.35, 128.00, 127.08, 121.86, 121.13, 120.28, 119.01, 115.99, 113.41, 111.98, 111.66, 59.62, 55.53, 55.42, 54.98, 37.24, 36.49, 29.23, 28.25, 24.88, 24.34. IR
(KBr): 3428, 2938,1518,1250 cm~l. MS (EI): 410 (M+-HCI, 100).
r ~^ ln7 Trans-6-(3,4-d~.c~u~yL,~ yl)-8,10-dimethyl-2,3,4,4a,5,6,7,11c-octahydro-lH-in~lnln[7 ~-~]~ , hydrochloride (4h) A suspension of the corresponding tryptamine hydrochloride (3f) (1 mmol) and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in lN
hydrochloric acid (3 ml. ) was refluxed under Ar atmosphere during 72 h. After this time the reaction mixture~was allowed to reach room temperature and-filtered off. The crude solid was purified 3~y flash chromatography using dichloromethane/methanol ( g :1 ) as eluent .
Yield: 7896. Mp: 198-202 C. lHNMR(DMSO-d6),c1:10.88~s,1H),9.81 (broad s, lH), 8.78 ( broad s, lH), 7.24 (s, lH), 7.20 (s, lH), 7.10-6.90 (m, 2H), 6.73 (s, lH), 4.90-4.75 (broad s, lH), 3.74 (s, 6H), 3.25-3.10 (m, 2H), 3.10-2.80 (m, 2H), 2.45 (s, 3H), 2.32 (s, 3H), 2.20-2.10 (m, lH), 2.00-1.80 (m, 3H), 1.60-1.10 (m, 3H).

Wo 9S/24200 F~ 9st'v~
` ` ' 21 8523~t 13c NMR (DMSO-d6), ~: 148.65147.87,134.44,12g55, 128.17,127.59,125.13, 123.68, 121.90, 120.36, 117.05, 113.64, 111.89, 110.04, 59.89, 55.78, 55.41, 37.17, 36.56, 29.47, 28.21, 24.94, 24.43, 21.26,17.09. IR (KBr): 3450, 2936,1516,1493,1264, 1240 cm~l. MS (EI): 405 (M+-C1,100).
FY~n~ e 103 Trans-7-(3,4-l' " yb~ y~ l-methyl-l~2~3~4~5~5a~6~7~8~l2a-d~all~ Lu.~ lohepta[a]py~idot3,4-blirldole, hydrorhlnri~ (4i) A suspension of the corresponding tryptamine hydrochloride (3~) (l mmol) and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in lN
hydrochloric acid ( 3 ml . ) was ref luxed under Ar atmosphere during 72 h. After this time the reaction mixture was allowed to reach room temperature and filtered off. The crude solid was purified by flash chromatography using dichloromethane/methanol ( 9: l ) as eluent .
Yield: 35% . Mp: 187-190 C lHNMR (DMSO-d6), ~: >11.0 (s, lH), 9.66 (broad s, lH`t, 7.29-7.25 (m, 2H), 6.92 (d, J= 7.8 Hz, lH), 6.81 (d, J= 8.2 Hz, lH), 6.65-6.56 (m, ZH) 4.80-4.70 (broad s, lH), 3.66 (s, 3H), 3.43 (s, 3H), 3.00-2.90 (m, lH),2.90-2.70 (m, lH), 2.35 (s, 3H), 2.35-2.20 (m, lH), 1.80-1.30 (m, 8H), 0.85-0.65 (m, lH). 13c NMR (DMSO-d6), D: 14856147.96,135.12,128.81,128.05,127.27, 125.32, 123.09, 121.73, 118.97, 113.32, 111.85, 111.31, 110.51, 55.60, 55.08, 54.97, 51.48, 36.97, 36.24, 32 74, 31.88, 26.37, 24.88, 24.14, 21.30. IR (KBr): 3414, 3343, 2932, 2859,1516,1265 cm~1. MS (EI): 405 (M+-Cl, 100), 335 (20).
EY~T~Ie 104 T""", ~ hYI-5-(1-naPhll,YI~._LIIYI) 1,2,3,4,4a,5,6,10C-OCtal~Y~U~YdO1,~1a[a]PYridO ~3,4-blirldOle, hYr1rD~h1Or;~ (4j) A suspension of the corresponding tryptamine hydrochloride (3a) (l mmol) and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in lN
hydrochloric acid (3 ml. ) was refluxed under Ar atmosphere during 72 h. After this time the reaction mixture was allowed to reach room temperature and f iltered of f . ~he crude solid WO 95/24200 1 ~

was purified by flash chromatography using dichloromethane/methanol ~ 9 :1 ) as eluent .
Yield: 78%. ~Ip: >200 C. lHNMR(DMSO~ >11.0(s,1H),10.45 (broad s, lH), 9.03 ( broad s, lH), 8.46 (d, J= 7.9 Hz, lH), 8.12-7.90 (m, 3H), 7.70-7.40 (m, 3H), 7.40-7.25 (m, 2H), 6.96 (d, J= 8.0 Hz, lH), 5.154.90 (broad s, lH), 4.45-4.30 (m, lH), 3.65-3.50 (m), 3.15-2.95 (m, lH), 2.38 (s, 3H), 2.00-1.70 (m, 4H), 1.60-135 (broad s, lH). 13c NMR (DMSO-d6), ~: 134.59,133.86,131.63,131.32, 129.92, 129.18, 128.86, 128.07, 127.74, 126.38, 125.96, 125.83, 125.48, 124.08, 123.20, 118.52,111.31,110.97, 61.78, 55.76, 37.40, 35.13, 25.49, 25.12, 21.32, 20.67. IR (KBr):
3445, 3231, 2949, 2878, 2780, 793 cm~l. MS (EI): 367 (~+-CI, 100).
EY~Ie 105 Tr~ns-10-methyl-6-(1-na~ Ll.yl.l.~ll.yl)-2,3,4,4a,5,6,7,11c-octahydro-lH-indolo[2,3-c]~lui..ol~ y~ (4k) A suspension of the corresponding tryptamine hydrochloride (3d) ~1 mmol) and the correponding 4-alkylidene-2-methyloxazolin-5-one~ ~1.2 mmol) in lN
hydrochloric acid ~3 ml. ) was refluxed under Ar atmosphere during 72 h. After this time the reaction rlixture was alIowed to reach room temperature and fiItered off. The crude solid was purified by flash chromatography using dichloromethane/methanol ~ 9 :1 ) as eluent .
Yield: 80%. Mp: >200 C. 1HNMR(DMSO-d6),~:>11.0(s,1H),8.40(d, J= 7.8 Hz, lH), 8.01 (d, J= 7.5 Hz, lH), 7.92 (d, J= 8,2 Hz, lH), 7.74 (d, J= 6.8 Hz, lH), 7.70-7.40 (m, 4H), 7.35 (d, J= 8.4 Hz, lH), 6.97 (d, J= 8.2 Hz, lH), 5.15-4.90 (broad s, lH), 4.50-4.30 (m, lH), 3.50-3.10 (m, 2H), 3.10-2.82 (m, 2H), 2.38 (s, 3H), 2.10-1.20 (m, 7H). 13c NMR (DMSO-d6), ~: 135.05,134.90,133.85,131.79,131.28, 129.36, 128.93, 128.07, 127.56, 126.33, 125.94, 125.83, 125.41, 124.02, 123.10, 11954, 111.27,109.61, 59.72, 53.97, 36.73, 35.27, 29.47, 28.37, 24.92, 24.36, 21.34. IR (KBr):
3447, 3235, 2936, 2857,1450, 790 cm~l. MS (EI): 381 (~+-Cl, 100).

~ WO 95/24200 ~ 5~
`` - `` 2185236 F l^ 1()6 Trans-8,10-dimethyl-6-(1-~ yhl~ yl)-2,3,4,4a,5,6,7,11c-octahydro-lH- irldolo[2,3 ]~l; .......... nl ... , hy-lro.^hlnri~l r (41) A suspension of the corresponding tryptamine hydrochloride ~3f ) (1 mmol) and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in lN
hydrochloric acid (3 ml. ) was refluxed under Ar atmosphere during 72 h. After this time the reaction mixture was allowed to reach room temperature and filtered off. The crude solid was purified by flash chromatography using dichloromethane/methanol ( 9 :1 ) as eluent .
Yield: 77%. Mp: >200 C. lHNMR(DMSO-dJ),cî:>ll.O(s,lH),10.11 (broad s, lH), 8.æ (d, J= 8.2 Hz, lH), 8.35 (broad s, lH), 8.02 (d, J= 7.3 Hz, lH), 7.92 (d, J= 7.9 Hz, lH), 7.82 (d, J= 6.9 Hz, lH), 7.71-7.46 (m, 3H), 7.29 (s, lH), 6.78 (s, lH), 5.10-4.90 (broad s, lH), 4.70-4.50 (m, lH), 3.40-3.20 (m, 2H), 3.10-2.80 (m, 2H), 2.51 (s, 3H), 2.34 (s, 3H), 2.05-1.90 (m, lH), 1.80-1.70 (m, 2H), 1.60-1.20 (m, 4H). 13c NMR (DMSO-d6), ~: 134.57,133.87,131.95, 131.42,129.29,129.11, 128.81, 128.04, 127.71, 126.21, 125.91, 125.83, 125.14, 124.46, 123.91, 120.46, 117.14, 110.25, 59.65, 54.03, 36.66, 35.25, 29.47, 28.32, 24.94, 24.35, 21.26,17.30. D~ (KBr): 3449, 2934, 2859, 2791,1449, 779 cm~l. MS (EI): 395 (M+-Cl, 100).
EY~r~ 107 Trans-spiro-6,6-[2-(3,4-l' ' y)-1,2,3,q ~ yll~ l .yl]-10-methyl-2,3,4,4a,5,6,7,11a-octahydro-lH-indolot2,3-c]quinid~ne, l~yLu~hlc~l;de (4m) A suspension of the corresponding tryptamine hydrochloride (3a) (1 mmol) and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in lN
hydrochloric acid (3 ml . ) was refluxed under Ar atmosphere during 72 h. After ~his time the reaction mixture was allowed to reach room temperature and filtered off. rî-he crude solid was purified by flash chromatography using dichloromethane/methanol ( 9 :1 ) as eluent .

WO 95/24200 1 ~ ~ 099 o 13~ !' 156 2185236 Epimeric mixture. Yield: 89%. 1HNMR(DMSO-O,o:>11.0(s,1H), 10.12 (broad s, lH), 8.72 (broad s, lH), 7.42 (s, lH), 7.21 (s, lH), 6.90-6.60 (s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.30-2.80 (m, 5H), 2.35 (s, 3H), 2.00-1.20 (m, 6H). 13C
NMR (DMSO-d6), o: 147.44,134.84,134.32,133.98,127.42,126.53,126.35,125.25, 125.13,123.60,123.25,122.98,119.56,119.43, I12.05, 111.48,111.27,108.78,108.60, 57.83, 57.50, 56.07, 55.56, 36.40, 31.91, 30.74, 29.39, 29.21, 28.73, 28.41, 24.92, 24.38, 23.83, 2130. IR (KBr): 3440, 2950,1518,1200,1110, cm~l. MS (EI): 41;' (M+-CI, 100).
EY~ 108 Trans-1-(3,4-dime~l.v,~yl~ /1)-3,4,6-trimethyl-1,2,3,1 t~l~al.r.l.u-9H-pyrido[3,4-blindole,l.~Lu.Lluiide (4n) Trans-3-(2-i~mirle-1,2-' ' ~l~tl~rl)-e rlilldole~
hy-1rn~hlnri~e (3h) was prepared using substantially the procedure of~Example 90; however, the aziridine was 2c:.
Yield: 71%. 1HNMR(CD30D),o:7,45(s,1H),7.32(d,J=8.3Hz,lH),7.19(s, lH), 7.00 (dd, J= 8.4 and 15 Hz, lH), 3.66 ~t, J - 6.9 Hz, lH), 3.28 (t, J= 7.3 Hz, lH), 2.47(s, 3H), 1.48 (d, J= 7.2 Hz, 3H), 1.38 (d, J= 6.6 Hz, 3H). 13C NMR (CD30D), ~:
136.89, 129.19, 127.68, 124.46, 123.69, 119.09, 115.41, 112.44, 53.51, 36.62, 21.71, 17.06, 16.49.
A suspension of the corresponding tryptamine hydrochloride ~3h) (1 mmol) and 6,7-dimethoxytetralin-2-one (1.2 mmol) in lN hydrochloric acid (3 ml. ) was refluxed under Ar atmosphere during 72 h. After this time the reaction mixture was allowed to reach room temperature and filtered off. The crude solid was purified by flash chromatography using dichloromethane/methanol ( 9 :1 ) as eluent .
Yield: 32%. Mp: 195-199 C. lHNMR(DMSO-dj),o:>ll.O(s,lH),9.40 (broad s, lH), 8.90 ( broad s, lH), 7.40 (s, lH), 7.30 (d, J= 8.2 Hz, lH), 7.08 (s, lH), 6.96-6.90 (m, 3H), 4.90-4.80 (broad s, lH), 3.73 (s, 3H),3.72 (s, 3H), 3.70-3.60 (m, 2H), 3.20-3.00 (m, 3H), 2.37 (s, 3H), 1.46 (broad s, 3H), 1.40 (broad s, 3H). 13C
NMR (DMSO-d6), o: 148.66147.93,135.00,12g.21, 127.40,125.40,122.97,121.82, 119.07, 113.56, 111.95, 111.24, 110.34, 5732, 55.43, 55.33, 54.60, 36.46, 32.56, 21.24, ~ W095/24200 P~ O99 ~i 21 85236 >~, l 5 7 17.06,15.9æ IR (KBr): 3438, 2936,1518,1464,1265,1242,1040 cm~l. MS (EI): 365 (M+-C1, 100).
s E~ l~?le 109 Cis-3-(2-amirle-~Jcloll~Ayl)-5-mLll,y~ ~ 'e, }ly.l.... hl~ iP
~, Cis-6-(3,4-dimethuAyl~.~yl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-lH-inr2nlc~[7 ~-c].~u,llol..le, hy~1rorhlrri-.2P (4O) The title compound (3i) was prepared following the procedure described by Scmuszkovicz, J. et al. Tetrahedron, l99l, 47, 8653 starting from 5-methylindole (la).
Mp: 86-90 C. lHNMR(CD30D),~:7,38(s,1H),7.26(d,J=8.3Hz,lH),7.11 (s, lH), 6.96 ~d, J = 8.2, lH), 3.90-3.70 (m, lH), 3.55-3.38 (m, lH), æ42 (s, 3H), 2.40-2.35 (m, lH), 2.10-1.79 (m, 4H), 1.75-1.50 (m, 3H). 13C NMR (CD30D), ~: 136.75, 129.27,127.88,124.63,12351,118.71,114.49, llæ34, 52.60, 36.79, 29.52, 26.44, 25.85, 21.68, 21.00. IR (KBr): 3401, 3017, 2932, 2863,1561,1489 cm~1. MS (EI): 229 (M+-CI, 100).
The process for preparing the final product ~4O) is illustrated by the following Scheme:
. MoO)}~ Mo M~ ~OMe Mp: 167-171 C . lH NMR (DMSO-d6), o: >11.0 (s, lH), 8.87 (broad s, 2H), 7.29-7.20 (m, 3H), 7.12-6.85 (m, 3H), 4.95-4.80 (broad s, lH), 3.76 (s, 3H), 3.75 (s, 3H), 3.70-3.60 (m), 3.25-3.00 (m, lH), 2.36 (s, 3H), 2.40-2.00 (m), 1.95-1.20 (m, 6H). 13C
NMR (DMSO-d6), o: 148.67147.87,134.80,128.71,128.43,127.63,125.45,123.32, 121.75, 117.82, 113.59, 111.91, 111.30, 111.34, 56.99, 55.46, 55.12, 36.12, 36.65, 28.42, 27.49, 24.94, 24.39, 2123,1917. ~ (KBr): 3439, 2934,1516,1263 cm~l. MS (EI): 390(M+-CIH, 100).
As noted above, the compounds of the present invention are useful in blocking the effect of serotonin or other agonists at 5-XT2Ar 5-HT2g and/or 5-HTlC receptors.
Thus, the present invention also provides a method for blocking 5-HT2A, 5-HT2~, or 5-XT1C receptors in mar~lmals comprising administering to a mammal requiring blocking of a W0 95/24200 ~ 099 ' ' 158 ~185236 5-HT2A, 5-HT2g, or 5-HTlC receptor, respectively, a receptor blocking dose of a compound of the invention.
One particularly useful embodiment of this inventio~ is that it provides selective ligands for the 5-HT2s receptor. Compounds with a high_affinity for the 5-HT2s receptor generally are cross-reactive with the 5-HT2C receptor as well. Now 5-HT2g receptors can be selectively modulated using compounds of tl:lis inventio~ at rates set folth above for blocking the effects of agonists at 5-HT2g receptors. The selective affinity may provide treatments with fewer side effects and will facilitate the development of additional therapeutic agents.
Compounds exhibiting activity at the 5HT2g receptor are useful for treating disorders related to the modulation of the 5HT2g receptor. For exaIr~le, compounds having 5HT2s antagonist activity reduce the spasticity of the colon.
Thus, these compounds are useful for the treatment of functional bowel disorders including irritable bowel syndrome and irritable bowel syndrome-related symptoms. The antispasmo~ic effect of such compounds can reduce abdominal pain associated with functional bowel disorders.
Additionally, the 5HT2g receptor is localized in other organs such as the brain, bladder, blood vessels, stomach, and uterus, indicating that additional conditions are 5HT2s mediated .
Compounds demonstrating activity at the 5~3T2A
receptor can be utilized in the treatment or prevention of conditions related to modulation of the 5HT2A receptor.
Examples of such conditions include hypertension, sleep disorders, hallucinogenic activity, psychosis, anxiety, depression, thermoregulation, feeding disorders, and hypotension. Leonard, B.E., Int~nati-ln;~l ~l;nical Psv-h~-~h~ colo~, 7, 13-21 (1992) .
The term "receptor blocking dose", means an amount of compound necessary to block a targeted receptor, selected from the group consisting of 5-HT2A~ 5-HT2g~ and 5-HTlc WO 95/24200 T ~
~; ' ~ ' 159 2185236 receptor in a mammal The active compounds are ef f ective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0 . 05 to about 250 mg/kg of body weight. In the treatment of adult humans, the range of about 0.5 to 100 mg/kg, in single or divided doses, is preferred. The ranges of about 5 mg/kg to about 60 mg/kg and about 10 mg/kg to about 50 mg/kg are especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician in light of the relevant circumstances, including the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient ' s symptoms, and the chosen route of administration, and therefore the above dosage ranges are not lnt~n~lP~l to limit the scope of the invention in any way The compounds may be administered by a variety of routes such as oral, transdermal, subcutaneous, intranasal, intramuscular, and intravenous routes.
While it is possible to administer a compound of the invention directly without any formlllA~ion~ the compounds are preferably employed in the form of a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one compound of the invention. Such compositions contain from about 0.1 percent by weight to about 90 . 0 percent by weight of a present compound. As such, the present invention also provides phArmA~ tical formulations comprising a compound of the invention and a pharmaceutically acceptable excipient therefor.
In making the compositions of the present invention, the active ingredient is usually mixed with an excipient which can be a carrier, or a diluent or be diluted by a carrier, -or~ enclosed within a carrier which can be in the form of a capsule, sachet, paper or other cnn~Aln,~r When the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient Thus, the composition can be in the form of tablets, pills, powders, WO 95/24200 P~ 5~ 0 160 2 ~ 85236 lozenges, sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in a lic~uid medium), and sof t and hard gelatin capsules .
The compounds of the invention may be delivered ~ransdermally, if desired. Transdermal permeation enhancers ~' and delivery systems, including patches and the like, are well known to the skilled artisan.
Examples of suitable carriers, -excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, ~calcium phosphate,: alginates, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propylhydroxy- benzoates, talc, magnesium stearate, water, and mineral oil. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The formulations of the invention may be formulated so as to provide (auick, sustained, or delayed release of ~the active ingredient af ter administration to the patient by employing procedures well known in the art.
The compounds of this invention may be delivered transdermally using known transdermal delivery systems and excipients. Most preferrably, a compound of this invention is admixed with permeation Pnh~nrprs including, but not limited to, ~rropylene glycol, polyethylene glycol monolaurate, and azacycloalkan-2-ones, and incorporated into a patch or similar delivery system. Additional excipients including gelling age~ts, emulsifiers, and buffers may be added to the transdermal formulation as desired.
For oral administration, a compound of this invention ideally can be admixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules.
The compositions are preferably formulated in a unit dosage form, each dosage cnnt~-n;ng from about 1 to e about 500 mg, more usually about 5 to about 300 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for ~ W0 95/24200 T ~ ).. r 'l , j human subj ects and other maInmals, each unit containing a predetermined ~uantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical carrier. ~~
The active compounds are~ effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0 . 05 to about 250 mg/kg of body weight. In the treatment of adult humans, the range of about 0.5 to 100 mg/kg, in single or divided doses, is preferred. The ranges of about 5 mg/kg to about 60 mg/kg and about 10 mg/kg to about 50 mg/kg are especially preferred.
However, it will be understood that the amount of the compound actually administered will be determined by a physician in light of the reIevant circumstances, including the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient ' s symptoms, and the chosen route of ~administration, and therefore the above dosage ranges are not ;nt-~n~ to limit the scope of the invention in any way. The compounds may be administered by a variety of routes such as oral, tr~n~ , subcutaneous, intranasal, intramuscular, rectally, and intravenous routes.
Pharmaceutical compositions of a compound of the present invention or~ its salts or solvates are most preferrably produced by formulating an active compound in unit dosage form with a pharmaceutical carrier. Some examples of unit dosage forms are tablets, pills, powders, aqueous and non-acrueous oral solutions and suspensions, transdermal delivery devices and patches, and parenteral - solutions packaged in containers containing either one or t more unit dosages and may be capable of being subdivided into individual doses. Some examples of suitable pharmaceutical carriers and/or diluents include gelatin capsules, sugars including lactose and sucrose, starches such as corn starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, Wo ss/z4zoo P~ Q3099 *
,~ 'jr~ ' 162 ~ 2~ 85236 and cellulose acetate phthalate, gelatin, talc, stearic acid, magnesium stearate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive~oil, corn oil, and oil of theobroma, propylene glycol, glycerin, so~bitol, polyethylene glycol, water, agar, alginic acid, isotonic saline, phosphate ~' buffer solutions, lactic acid, glycolic acid, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, magnesium stearate, croscarmellose, alginic acid, sodium starch glycolate, lauryl sulfate. as well as other compatible substances used in pharmaceutical formulations. The active compound may be prepared as a microparticle using biodegradable polymers or other known methods. The composition may be prepared using known formulation technology to provide a rapidly dissolving, sustained release, or targeted delivery compositions. The compositions of this invnetion may contaln other components such as coloring agents, flavoring, and/or preservatives.
The compositions may contain other therapeutic agents, for example an antacid or analgesic. ~
The article of manufacture will include packaging material. Packaging material will preferably include a cnnt;l;n~r. The preferred container and packaging material can be selected using the characteristics of the compound to be packaged. For example, the preferred rflnt~inl~r may be glass, plastic, foil, sealed bubble packaging, clear, amber, and may incorporate other known pharmaceutical packaging technology. The packaging may include features such as cotton, silica or other drying agents, and/or a meaSuring~
device. The article of manufacture shall include a label indicating that the composition is useful for the treatment of an a condition associated with 5-~IT2g receptor stimulation malfunction. Most preferably, the condition is selected from the group consisting of urinary incontinence, bladder dysfunction, uterine dysfunction, cardiovascular disorder, and respiratory disorder.
In order t~ illustrate more fully the operation of this invention, the follo~ing formulation examples are ~ W095l24200 r~ , s: lS~
' ` ' 163 21 85236 provided. The examples are illustrati~7e only, and are not intended to limit the scope of the invention. The formulations may employ as active compounds any of the compounds of the present invention.

WO 95/24200 r~
" ,, !~ " ~ 16 4 2 1 8 5 2 3 6 FQ~n111 atio~ 1 E~ard gelatin capsules are prepared using the following ingredients: :-Concer,tration Amount Per by Weight (-~nsule (l~ercent (+/-) 6-ethyl-8-chloro-1- .-[ ( 3, 4 - dimethoxypheny l ) me t hy l ]
-1, 2, 3, 4-tetrahydro-9EI-pyrido [ 3, 4 -b] indole hydrochloride 250 mg 55 0 starch dried 200 mg 43 o magnesium stearate - ~LL~g 2 . O
460 mg 100 . 0 The abo~e ingredients are mixed and filled into hard gelatin capsules in 460 mg tluantities.

~ WOg~/24200 r~ o~
~ ' 165 2 1 ~5236 Forml~l ation 2 Capsules each containing 20 mg of medicament are made as follows:
Concentration Amount Per by Weight Cal~sule ~ercent ) 6-methyl -8-ethyl -1-[ (3-bromo-4-chloro-phenyl) -methyl ) -1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4b] indole :~
(Z)-2-butenedioate 20 mg 10.0 starch 89 mg 44 . 5 microcrystalline cellulose 89 mg 44 . 5 maqnesium stearate 2 mq ~2 200 mg 100 . 0 The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a Mo. 45 mesh b.S. sieve and ~illed into ~I h~d gel~tin c~psule.

Wo95/24200 , ~ "~)~, /Q;~099 166 ~
For~ ~1 at ion 3 .:
Capsules each containing 100 mg of medicament are made as follows: -Concentration Amount Per by Weight Car~sule (~ercPnt ) 5 - f luoro- 6 -methyl-1- ( 1- ( 3 -methylaminophenyl ) - ~
methyl) -1,2,3,4-tetrahydro-9H-pyrido-[3, 4-b] indole (Z) -2-butenedioate lOD mg 30 . 0 polyoxyethylene sorbitan monooleate 50 mg 0 . 02 starch powder 250 mc~ 69 . 98 400 m~ 100 . 00 The above ingredients are thoroughly mixed and placed in an empty gelatin capsule.

~ WO 95/24200 A .~
-' ~ ` 2~ 85236 Form-llation 4 Tablets con~Ainin~ 10 mg of active ingredient are made as f ollows:
Concentration Amount Per :~ by Weight ~Ansule (~f~rcent ) 6 - f Iuoro - 8 -phenoxy -4-ethoxy-phenyl)-methyl) -1,2, 3,4-tetrahydro - 9H-pyrido -[3, 4-b] indole ~Z) -2-butenedioate 10 mg 10 . 0 starch 45 mg 45 . 0 microcrystalline cellulose 35 mg 35 . 0 polyvinylpyrrolidone ~as 10% solution in water) 4 mg 4 . 0 sodium carboxyrnethyl starch 4 . 5 mg 4 . 5 magnesium stearate 0 . 5 mg 0 . 5 talc 1 m~ 1. 0 100 mg 100 . 0 The active ingredient, starch and cellulose are passed through a No . 45 mesh U. S . sieve and mixed thoroughly.
The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No 14 mesh U.S. sieve. The granule so produced is dried at 50-60 C and passed through a No 18 mesh U S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No . 60 mesh U. S sieve, are then added to WO 95124200 p~ J, ,/Qtogg ~ . . . ! ~ 168 the granule which, after mixing, is compressed on a tablet machine to yield a tablet weighing 100 mg.
Forlmll aticn 5 A tablet f ormulation may be prepared using the ~~
ingredients below:
Concentration Amount Per by Weight Ca~s--1 e (l~erc,-nt) 5, 6-difluoro-l- ( 1- ( 3 -dimethylamino-phenyl ) -methyl) -1,2,3,4-tetrahydro - 9H-pyrido -[ 3, 4 -b] indole ( Z ) -2 -butanedioate 250 mg 38 . 0 microcrystalline cellulose 400 mg 60 . 0 silicon dioxide f umed 10 mg 1 . 5 stearic acid 665 mg 100 . 0 The components are blended and compressed to ~orm tablets each weighing 665 mg.

~WO 95/24200 F~~ O99 - - ` 21 85236 Formulati~n 6 -Suspensions each containing 5 mg of medicament per 5 ml dose are as follows:
per 5 ml of slls~ension 3 -methyl -5-chloro-6-methyl -1- (1- (3-dimethylamino-phenyl) -methyl) -1,2,3,4-tetrahydro-9H-pyrido-[3, 4-b] indole (Z) -2-butenedioate 5 mg sodium carboxymethyl cellulose 50 mS~

syrup 1. 2 5 ml benzoic acid solution O.10 ml flavor q.v.

color = q.v.

water q. s . to 5 ml The medicament is passed through a No. 45 mesh U. S . sieve and mixed with the sodium carboxymethylcellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color is diluted with some of the water and added to the paste with stirring. Sufficient water is then added to produce the required volume.

W0 95/24200 r ~ .. /Q:~099 ~ 170 2 1 8 5 2 3 6 Formulation 7 An aerosol solution is ~prepared corLtaining the folIowing components: ,~
Concentration by WP; aht (~ercPnt ) 5 -propyl - 6-ethyl -1- [ ( 3 4 -dimethoxy-phenyl ) -methyi)-1,2,3,4-tetrahydro-9H-pyrido-[3, 4-b] indole hydrochloride = 0 .25 ethanol 2 9 . 7 5 Propellant 22 (chlorodifluoromethane) _ZQ~
100 . 00 The active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -30C and transferred to a filling device. The reauired amount is then fed to a stainless~steel c~n~inPr and diluted further with the r~ining amount of propellant. The valve units are then f itted to the container .

~ WO 9~/24200 1 ~ ~ 099 Formulation 8 Injectables may be prepared as follows:
- Amount Per Batch 6~ methylethyl ) -1,2,3,4-tetrahydro-1-( 1- ( 4 -dimethylaminonAphth~ 1 enyl ) -methyl ) -9:~-pyrido [3, 4b] indole ( Z ) -2 -butenedioate 50 mg Devazepide ~or Injection q.s The compound or a suitable salt thereo~ is dissolved in, for example, ethanol, and passed through a 0.2 micron f ilter . Ali~uots of f iltered solution are added to ampoules or vials, sealed and sterilized.

--WO 95l24200 P~
J 2 t 8 5 2 3 6 Formlllation 9 Tablets containing 10 mg of active ingredient are made as follows:
Concentration Amount Per by Weight TAhl et ( oercent ) 7, 8, 9, 10-tetrahydro-10--(1- (2--dimethyl Ami nnnArhthyleneyl ) -methyl)-llH-benzo[gl-pyrido [3, 4-b] indole (Z)-2-butenedioate 6 g 2.0 corn starch 200 g 78 . 0 microcrystalline cellulose 46 g 18 . 0 Sterotex Powder HM 4 g l . 5 Puri f ied Wat er 3 0 0 mT, 100 mg 100 . 0 The active ingredient, starch and cellulose are combined together in a planetary mixer and mixed for 2 minutes. Water is added to the combination and mixed for 1 minute. The resulting mix is spread on trays and dried in a hot air oven at 50C until a moisture level of 1 to 2 percent is obtained. The dried mix then milled with a Fitzmill through a #RH2B screen, and added back to the milling mixture. The mixture is drum rolled for 5 minutes.
Compressed tablets of 50 mg, 150 mg, and 200 mg are formed wlth appropriate sized punches.

~WO 95/24200 I ~ 'Q~099 ForTmll ation 10 Capsules are prepared using the following - ingredients:
Concentration Amount Per by Weight Ca~su I e (~erc~nt ) (+/-) 6-methyl-1- (1- (3-ethylamino naphthalenyl ) -1 -ethyl ) -1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (Z) 2-butenedioate 200 mg 49.0 lactose US~ . 2 0 0 mg 49 . 0 Serotex Powder 10 mc~ 2 . O
410 mg 100 . 0 The above ingredients are mixed and filled into h~rci gol~ci- c.~ps~l1es in 410 mg q~ tiCies.

Wo 95/24200 PCTiU595/03099 r~ 174 21 85236 For~lll ation 11 Hard gelatin capsules are prepared using the folIowing ingredients:
Concentration Amount Per by Weight (~n~:llle (~rC~nt) Trans-9-methyl-5- (1-naphthylmethyl) -1, 2, 3, 4-4a,5,6,10c,octahydrocyclo-penta [a] pyrido [3, 4 -b]
indole, hydrochloride 250 mg 55 . 0 starch dried 200 mg 43 . 0 magnesium stearate . ~L mg ~Q
460 mg 100 . 0 The above ingredients are mixed and filled into hard gelatin capsules in 460 mg ~uantities.

WO 95/24200 r~
,. ~ . .

Forml~l ation 12 Capsules each containing 2 0 mg of medicament are made as f ollows:
Concentration Amount Per by Weight Ca~sule (~ercl-nt ) spiro-6, 6 [2- (3, 5-dimethoxy) -1, 2, 3, 4-tetrahydronaphthyl~ -10-methyl-2,3,4,4a,5,6,7,11a- :
octahydro-lH-indolo [2, 3-c] -~uinuclidine, hydrochloride 20 mg 10 . 0 starch 89 mg 44 5 microcrystalline cellulose 89 mg 44.5 magnesium stearate 2 mc ~,~
200 mg 100 . 0 The active ingredient, cellulose, starch, andmagnesium stearate are blended, passed through a No. 45 mesh U.s. sieve ~nd filled ineo ~ rd ~elatin callsule.

W095/24200 P~l/UL,''~ .~, o For~ l ation 13 Capsules each c~nt~inin~ 100 mg of medicament are made as follows ~
Concentrat ion Amount Per by Weight ( ~nSll 1 e (~ercent sp iro-6, 6 [2- (3 -fluoro-4-methoxy ) -1, 2, 3, 4-tetrahydronaphthyl ] -10-methyl-2,3,4,4a,5,6,7,11a-octahydro-lE~-indolo [2, 3-c] -quinuclidi~e, hydrochloride 100 mg 30 . 00 polyoxyethyl ene - -sorbitan monooleate ~ . : 50 mg 0.02 starch powder ~ 250 m~ 69.98 350 mg 100 . 00 The above ingredients are thoroughly mixed and placed in an empty gelatin capsule.

~ WO 9~/24ZOû l~

Forrm11 ation I4 Tablets containing 10 mg of active ingredient are ~=
made as follows:
Concentration Amount Per by Weight T~hlet (l~erc--nt ) 8-fluoro-10-pheno 6- ( 1-naphthylmethyl ~ -2,3,4,4a,5,6,7,11c-octahydro -lH-indolo-[2,3-c]quinoline, tartrate 10 mg lO.0 starch 45 mg 45 . 0 microcrystalline cellulose 35 mg - 35 0 polyvinylpyrrolidone (as 1096 solution in water) 4 mg 4 . 0 sodium carboxymethyl starch 4 . 5 mg 4 . 5 magnesium stearate 0.5 mg 0.5 talc 1 mq 1. 0 100 mg 100 . 0 The active ingredient, starch and cellulose are passed through a No . 45 mesh U. S . sieve and mixed thoroughly .
The solution of polyvinylpyrrolidone is mixed wiht the resultant powders which are then passed through a No 14 mesh U . S . sieve . The granule so produced is dried at 50-60 C and passed through a No . 18 mesh U . S . sieve The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No . 60 mesh U. S . sieve, are then added to the granule which, after mixing, is compressed on a tablet machine to yield a tablet weighing 100 mg.

WO 9!;/24200 1~ O
~3 r; ^ 5~ ~ ~ 17 8 2 1 8 5 2 3 6 Forml~l ation 15 A tablet formulation may be prepared using the ingredients below:
Concentration Amount ~er by Weight T~hl et ( oercen t ) 8-methyl-10 -metho 6 - ( l-naphthylethyl ) -2,3,4,4a,5,6,7,11c-octahydro-lH-indolo -[2, 3-c] ~uinoline 250 mg 38 . 0 microcrystalline cellulose 400 mg 60 . 0 silicon dioxide fumed 10 mg 1. 5 stearic acid - - - 5 m~ 0 . 5 665 mg 100 . 0 The components are blended and compressed to orm tablets each weighing 665 mg.

~ WO 9~/24200 1 ~ '03099 ; ~ r . 2~ 85236 Fo nml 7 ation 16 c Suspensions each containing 5 mg of medicament per 5 ml dose are as fo~lows: ~ ~
per 5 ml of sllq7~ension 8-chloro-lû -cyclopropyl -6- ( 1 -naphthyl ethyl ) -2,3,4,4a,5,6,7,11c-octahydro-l~I-indolo-[2, 3-c,7 quinoline 5 mg sodium carboxymethyl cellulose 50 mg syrup 1. 25 ml benzoic acid solution O.10 ml f lavor ~:~ g . v .

color ~ : q.v.

water . ~ = ~. s .~ to 5 ml The medicament is passed through a No. 45 mesh U. S . sieve and mixed with the sodium carboxymethylcellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color is diluted with some of the water and added to the paste with stirring. Suffic1ent water is then added to produce the re~uired volume.

Wo 95/24200 r~ 3099 0 ` ' ~' 21 85236 Formulation 17 An aerosol solution is prepared containing the following components Concentration oy We i ~ht ( 1~ e rc Pn t ) spiro-6, 6 [2- ( 3 -ethyl-4-ethoxy) -1, 2, 3, 4 -tetrahydronaphthyl ] -10-methyl-2,3,4,4a,5,6,7,11a-octahydro-lH-indolo [2, 3-c] -~uinuclidine, maleate ~ 0.25 ethanol 29.75 Propellant 22 (chlorodifluoromethane) 70 . 00 100 . 00 The active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -30C and transferred to a filling device. The re~uired amount is then f ed to a stainless steel container and diluted further with the l. ;n;n~ amount of propellant. The valve units are then fitted to the C~-n~i~;n~r.

~ W095/2~200 l~,lJ~

Fo~n~l a~ion 18 c A tablet formulation may be prepared using the ingredients below:
Concentration Amount Per by Weight T~hlet (I~ercent) spiro-6, 6 [2- ( 3 -ethyl -4-ethoxy) -1, 2, 3, 4 -tetrahydro-6-methyl-naphthyl ] -10-methyl-2,3,4,4a,5,6,7,11a-octahydro-lH-indolo [2, 3-c] -quinuclidine, maleate 250 mg 38.0 microcrystalline cellulose 400 mg 60 . 0 silicon dioxide f umed 10 mg 1 . 5 stearic acid ~mg 665 mg 100 . 0 The components are blended and compressed to formtablets each weighins~ 665 mg.
Compounds of the present invention were tested for 5-HT1C receptor affinity using the following procedure:
IA. Biological Reagent Preparation.
Beef brain was removed immediately af ter slaughter, and choroid plexus were dissected over ice. ~ale Sprague-Dawley rats weighing 125-150 g (Harlan Industries, Cumberland, IN) were kiiled by decapitation. The brain of each was immediately removed and the cerebral cortex was dissected over ice. Tissues were homogenized in 9 volumes of 0.32 mol/L sucrose and centrifuged at 1, 000 x g for lD
minutes. The supèrnatant was centrifuged at 17, 000 x g for 20 minutes. The pellet was suspended in 100 volumes of 50 mM

WO 95/24200 r~ 099 Tris-HCl (pH7.4), incubated at 37C for 10 minutes and centrifuged at S0, 000 x g for 10 minutes, and the process was repeated three times. The final pellets were frozen at -70C
and used within 2 weeks. Pellets were rehydrated with physiological buf fer prior to use.
II. Assay Procedure. _ Radioligand binding assays for 5-HTlc and 5-HT2 receptors were conducted according to described methods. The assays can be co~ducted as described by Hoyer D, Functional correlates of serotonin 5-HTl recDgnition sites, J. Rece~tor 8, 59-81 (1988) and Hoyer D, Engel G, Kalkman HO
Molecular pharmacology of 5-HTl and 5-HT2 recognition sites in rat and pig brain me.mbranes: ~adio-ligand binding studies with l3H~5-HT, ~3H]8-oH-DPAT, (-) [l25I] iodocyanopindolol, r3H]mesuler~ine and ~3H]ketanserin, Eur. ~. PhRrmAcol. 118, 13-23 ~1985).
For 5-HTlC receptor assays increasing concentrations of experimental compound, 50 m,~l Tris HCl buffer pH 7.4, and tritiated mesulergine (2.0 nM) (3H
ligand) were f~mhi nl~fl in polystyrene tubes at room temperature The reaction was initiated by the addition of the resuspended choroid plexus tissue which had been preincubated at 37C for 20 minutes. The reaction mixture was incubated in a 37C water bath for 15 minutes.
The reactions were term.~inated by rapid filtration, (Brandel Cell Harvestor), through Whatman GF/B glass filters that had been presoaked in Tris buffer pH 7.4. The filters were then washed 2 times with 5 ml of ice cold Tris buffer pH
7.4. Washed filters were placed in s(-in~illRtion vials and 10 ml RedySolv, (Brandel), was added and samples were counted in a Searle D-300 beta counter. Means and standard error . -statistics were calculated for triplicate experimental:
determinations in certain cases. Mean values were obtained from three or more separate determinations. The incubation time for the reaction mixture was 15 minutes at 37C.

~ Wo 95/24200 r~ ,,s/~os9 2 1 8 5 ~ 3 6 Concentrations that caused a 50% inhibition of radioligand binding (ICso) and Hill coe~ficient were obtained by computer-assisted regression analysis Radioligand Binding Studies:
Membrane preparation from transformed cells.
Suspension cells expressing the cloned rat 5-HT2g receptor were harvested by centrifugation at 2,200 x g for 15 min at 4C. Kursar, J. D., D. L. Nelson, D. B. Wainscott, M. L.
Cohen, and M. Baez, Mol. Phannacol. 42: 549-557 (1992).
Membranes for the binding assays were prepared by vortexing the pellet in 50 mM Tris-HCl, pH 7.4 (0.5 x 109 cells/30 ml) .
The tissue suspension was then centrifuged at 39,800 x g for 10 min at 4C. This procedure was repeated for a total of three washes, with a 10 minute incubation at 37C between the first and second wash. The final pellet was homogenized in 67 mM Tris-HCl, pH 7.4 (at 20 - 40 and 12.5 million cells/ml, original cell number, for cells expressing low and relatively high levels of the 5-HT2g receptor, respectively) using a Tissumizer (Tekmar, Cincinnati, OH), setting 65 for 15 seconds .
[3H] 5 HT binding studies. Binding assays were automated using a Biomek 1000 (Beckman Instruments, Fullerton, Q) and were performed in triplicate in 0.8 ml total volume. Membrane suspension, 200 1ll, (0.04-0.27 mg protein) and 200 ~Ll of drug dilution in water were added to 400 1ll of 67 ~I Tris-HC1, pH 7.4, containing [3H]5-HT, pargyline, CaCl2, and L-ascorbic acid. Final concentrations of pargyline, CaC12 and L-ascorbic acid were 10 llM, 3 mM and 0.1%, respectively. Tubes were incubated at 37C for 15 min or at 0C for 2 hours (binding e(luilibria were verified for both of these conditions), then rapidly filtered using a Brandel cell harvester (Model MB-48R; Brandel, Gaithersburg, MD) through Whatman GF/B filters which had been presoaked in 0.5% polyethylenimine and precooled with ice-cold 50 mM
Tris-HCl, pH 7.4. The filters were then washed rapidly four times with one ml ice-cold 50 mM Tris-HC1, pH 7.4. The Wo 95/24200 P~
2 ~ 85236 amount of [3H]5-HT trapped on the filters was rlptprmined by liquid scintillation spectrometry (Ready Protein) and automated using a Biomek 1000 (Beckman Instruments, Fullerton, CA~ and were performed in triplicate in 0 . 8 ml total volume. Membrane suspension, 200 111, (0.04-0.27 mg protein) and 200 111 of drug dilution in water were added to 400 111 of 67 mM Tris-HCl, pH 7.4, containing [3H]5-HT, pargyline, CaCl2, and L-ascorbic acid. Final concentrat1ons of pargyline, CaC12 and L-ascorbic acid were lO ~LM, 3 mM and 0.196, respectively. Tubes were incubated at 37C for 15 min or at 0C for 2 hours (binding eQuilibria were verified fQr both of these conditions), then rapidly filtered using a~
Brandel cell harvester (Model MB-48R; Brandel, Gaithersburg, MD) through Whatman GF/B filters which had been presoaked in 0.596 polyethylenimine and precooled with ice-cold 50 mM
Tris-HCl, pH 7.4. The filters were then washed rapidly four times with one ml ice-cold 50 mM Tris-HCl, pH 7.4. The amount of [3H] 5-HT trapped on the filters was determined by liquid scintillation spectrometry (Ready Protein and Beckman) and determihed for best fit to a one-site or a two-site binding model using a partial F-test. De Lear" A., A. A.
Hancock, and R. J. Lefkowitz, l~ol. Pha~nacol. 21: 5-16 (1981). The following equation was used for a one-site binding model, Bmnx x [L]
Kd + [L]
where Bound = amount of [3H] 5-HT specifically bound, Bma~ =
maximum number of ~inding sites, Kd = equilibrium dissociation constant and [L] = free concentration of [3H] 5-HT, or a two-site binding model, B und=Bmnxlx[L] Bm~2x[L]
K~l+[L] Kd2+[L]
where Bound = amount of [3H] 5-HT specifically bound, Bmaxl =
maximum number of high affinity binding sites, BmaX2 =
maximum number of low affinity binding sites, Kd1 = -~equilibrium dissociation constant for the high affinity site, Kd2 = e~uilibrium dissociation coIIstant for the low affinity -~ W095/24200 1~

site and [L] = free concentration of [3HJ 5-HT- The IC50 values from the competition assays, the binding parameters for the IP3 standard curve and the ECso and EmaX values from the IP3 assays were dete~mined by nonlinear regression analysis of four parameter logistic e~uations (Systat, Systat Inc, Evanston, IL) . De Lean, A., A. A. Hancock, and R. J. Lefkowitz, Mol. Pharmacol. 21: 5-16 (1981)- The IC50 values were converted to Ki values using the Cheng-Prusoff e~uation. Cheng, Y., and W. H. Prusoff, Biochem. Pharmacol.
22: 3099-3108 (1973).
Compounds of this invention were tested using substantially the procedure describe in the Radioligand assay supra. and are summarized in Table I infra. The values in Table I are expressed as Ki values calculated as described supra. The blank values in Table I indicate that the compo~md w~s not tested in the corresponding ossoy.
-WO 95/24200 r~
` 21 85236 TæF~ C~ 5-F~Tæ~
r~.,.v~.. :.. rl2~nnol Ki Rat Ki Hums-n Ki ~uman Ki Rat ~_0 r NH
~N~ AVG. = 6.62 N SEM = 0.09 N =4 ~OH
o NH
H~H
OH ¢~ AVG. = 6.28 N SEM = 0.91 N =4 ~
$~ AVG. = 12.20 /~' ~q = 1.54 N~Y N = 3 O
N~
a~ ~ AVG. = 6.87 SEM = 0.65 N =3 ~ ~095124200 ,~""~
f'~ i;r~h 1 '`' 21 85236 ~CaklQl 5-FrTæR Cf~ 5-~Tæ~
r~nc~.vl.. :.. rl~nnoI
Ki Rat Ki Human Ki Human Ki Rat . 0~NH~
¢~ ~1 AVG. = 18.98 = Q90 = 6.12 oHSEM =7.56 = 0.32 =1.21 193525 N = 6 = 5 = 5 0~N~o ¢~,N~
N AVG. = 15.11 = 15.09 =2.05 ~ SEM = 2 43 = 2 26 = 0.29 237733 N = 6 = 5 = 5 0~N~
AVG. = 24A9 ,N~ SEM - ?
0~N~
AVG. = 35.13 ~ SEM = ?
-N~ N = 1 r wo 9s/24200 r~ ,, O

~T~p~ Cell~ 5-E~rT~,~
r~nr.~.~,o.. ;.. rl~nnoI
Ki Rat Ki Human Ki Human Ki Rat N
0~,~}
AVG. = 16.63 N SEM = ?
N = I
o,~N~H
¢~N~
N

~ AVG = 10.24 = 74.49 = 8.91 215403 SEM = 5.05 =6.34 =064 CIS ISOMERL N = 4 = 3 = 3 H OH
O~Nb ~N~
N AVG. = 11.36 = 107.74 = 12.44 ~ SEM = 4.21 = 1632 = 229 215047 ISOMER L N = 4 = 3 = 3 H OH
~Nb ~,N~
AVG. = 8.61 = 16.80 = 2.39 SEM = 421 = 3.03 = 026 215046 ISOMER U N = 4 = 3 = 3 wo 95/24200 r~ 5, 2 1 8~236 ~a~QI 5~ ~ C.qll~ 5-HT~A
r~n~ ... ;.. rl~nDoI
Ki Rat Ki Human Ei Human Ki Rat H OH
~Nb ~`
AVG. = 9.36 = 18.60 = 2.44 ~ SEM = 4 36 = 2.42 = 0.35 216404 CIS ISOMER u N = 4 = 3 = 3 f N~3 ~NJ
0~
6~N3 AVG. = 11.87 = 32.71 )_ SEM = 1.93 = 0.84 N = 2 = 2 .

WO 95/24200 r~ J~ ~

rT~F~ C~ 5-RrT~,~
r~ .vlu.. ~ rl~nnOI
Ki Rat Ki ~uman Ki Human Ki Rat OH
¢~o,N~
AVG. = 4115.29 8-OH-DPAT SEM = 311.55 ~Br N = 3 NH
H~
AVG. = 6153.15 SEM = ?
~ HCI N = 1 I~F
~ I
¢~ AVG. = 3019.67 SEM = ?
~ICI N = 1 J~ AVG. = 1501.95 SEM = ?
~Cl N = 1 ~ w09s/24200 I~ 099 2 1 ~5236 ~Cak~ 5-FrT2R Cells 5 r~ ,t.. ;.. rl~nDoI
Ki Rat l~i Human Ki Human Ki Rat O
AVG. = 862Al SEM = ?
HCl N = 1 --N
O
AVG. = 936.34 SEM = ?
HCl N = 1 ~0 ~\ ~ AVG. = 1752.56 \~--N SEM = ?
HCl \ N= 1 OH
~0 N=~ I OH
~N AVG. = 79.27 = 215.15 = 6158.98 N - 6 _ 2 - 2084.19 WO95/24200 F~~
~s, ` j" 2 1 85236 ~ahle 1 ~-~rT~R C~ HT~7A
r~n~ u.. ;.. rl~nnoI
Rat Ki Human Ki Human Ki Rat STRUCTURE 6-HT2B 5-HT2B 6-HT2A 6~HT2A
~0 ~N
AVG. = Q00 = 4749.52 = 2229.48 SEM = ? = ? = ?
Isomer 1 E~Br N = 1 = 1 = 1 N OH
~J-~ ~0 AVG = = 608.94 = 364.03 W ~ N - _ 3 ~ 41.34 N~ ~
¢~[ N~ AVG. = = 784.17 = 127.21 SEM = = 32.35 = 28 34 HCl N = = 3 = 3 o N~ ~
WN~ AVG. = = 266.63 = 6690.86 SEM = = 9.56 = 560.80 HCI N = = 3 = 3 ~wo g~/24200 Ql 5-RrT~R Cf~ 5 r.~n~eroto~in rl~nDol Ki Rat l~i ~Iuman l~i Human Ei Rat STRUCTURE 5-HT2B 6-EIT2B 5-Hlr2A 5-HT2A
.

, o~
H
AVG.= = 1018.01 =6028.85 SEM = = ? = ?
HCI N = = 1 = 1 o AVG. = = 1789.87 = 0.00 SEM = = ? = ?
HCI N = = 1 = 1 WO 9~/24200 r~ ogg O
` ' ' 21 85236 }~ T~R C~ ~2A
r2~lr,~.~,t.. ;.. rl~nDoI
KiRat Ki Human Ki Human KiRat STRUCTURE 5-HT2B 5~IIT2B 6-HT2A 5-ET2A
NH2 ~' ~ ' NH o CH~
J AVG. = 37.58 SEM = 4 76 CH N = 3 Br AVG.= 11.34 = 33.67 =14.22 SEM = 2.24 = 2.01 = 236 HCl N = 3 = 3 = 3 B r AVG. = 32.03 SEM = 3 49 HCl N = 4 HO~N ~ H AVG. = 283.84 8SEM = 13.48 OHN = 3 wo 95124200 P~1/IJ SJA~99 ~Ca~Q~. 5-~rTæR Cell~ 2rTæA
r~n~,~.vt.. ;.. rl~nDoI
Ki Rat Ki Human Ki Human Ki Rat STRUCTURE 5-HT2B 5-HT2B 5-HT2A s-lHT2A
'.o ~
¢~ oH ~O~
,~ AVG. = 10.~7 = 11.91 I ~J SEM = 1.46 = 1.09 H~N = 4 = 3 N~
AVG. = 130.79 B r SEM = 18.70 HCI N = 4 ~2 f~AVG. = 10.19 = 9.84 = 7.77 = 15.80 ~ SEM = 1.99 = 2.33 = 0.59 = 1.90 HO\~ N = 6 = 5 = 3 = 3 NH,2 AVG. = 9.15 - O SEM = 1.47 \ HCI N = 3 WO 9!jJ24200 ~ J~,~ 0!~9 o 2 ~ 85236 ~ahl~l 5-~T~R C~ 5-~IT~,A
r~ erot- nin ri2snDol Ki Rat Ki Human ~i Human Ki Rat STRUCTURE s H~r2B s-HT2B 5 HT2A s HT2A
NH
O
~OH=~ AVG. = 146.84 = 127.84 = 120.16 o SEM = 13.49 = 15.96 = ?
H2N N = 7 = 3 = 1 ~N OHo~
,~ AVG. = 169.22 SEM = 60.27 N = 4 ~NH
~ AVG =
HCI >=/ . 39 28 Br N = 4 NH~
~3/ AVG. = 112.90 SE~I = 5.61 HCI N = 3 ~ WO95/24200 r~ .,,31f ~

~CaklQ1 5 ~rTæR CP11~ 5 RrTæ~
r~ otonin rl25IlDOI
Ki Rat Ei Human Ei Hllman Ki K2nt ~NAVG. = 474.74 Br ~ SEM = 80.54 I~CI N = 6 --N
~\,, NH
HO~,J AVG.= 6Q96 SEM = 16.54 HCl N = 5 ~' ~NLI
~\ ~ AVG. = 32.78 HC~ SEM - 4 99 ~\NH
~ .
AVG. = 5.65 HCl ~=~ SEM = 0.65 FN =3 W095/24200 P~,lll '/'`~099 o .~ r ~
I ~ 198 2 1 85236 ~Lakh~ 5-E~rTæR (~ell~ ~-F~rT~, F~l''.. vt.. ; .. rl ~IlDOI
Ki l~at l~i Human Ki Euman Ei Rat STRUCTURE 5-ElT2B 5-HT2B 5-El'r2A 6-HT2A
N~ 2 .' ~\ -NH
~ AVG. = 6.21 J~SEM = 0.55 ~I EICI N = 6 N~H2 ` ' S~
~NH
AVG. = 40.64 SEM = 4.45 F EICI N = 3 o NH2 (1 ~ a~
NH
~( AVG. = 15.37 ~ F SEM = L67 F N = 3 ~NH
AVG. = 30.18 SEM = 0.90 N = 3 ~ wo gs/24200 ; ~ ` 21 85236 ~Cal~l 6-FrTæR C~ 5-FrT~
r~2~lseroton;n rl~lDOI
Ki Rat KiHuman KiHuman Ki Rat STRUCTURE 6-ET2B 6-HT2B 5-~2A 5-ET2A
,N~
~NH
o OH
~0 ~
> AVG. = 84.49 -N
O~,,OH ~`
,NH
HO O ~
J AVG. = 38.48 SEM = 3.77 N = 3 NH2 ~1 ~NH
0,~ AVG. = 49.29 SEM = ?
,ON = 1 NH~
\~NH
~' ~ AVG. = 6.52 )~/ SEM = 0.60 F N = 2 WO 95124200 r~ S3 0 200 2~85236 ~ ~-~T9.R C~ ~2A
r.~lSerotnnin r]~nDOI
Ri Rat Ki Human Ri Human Ri Rat STRUCTURE 5-HT2B 6-HT2B 6-~T2A 5-E~T2A
NH2 .`
,~
NH AVG. = 4g.92 ,~ SEM = 11.09 F N = 2 ~ ' = ~
HO AVG. = 41.62 creatinine SEM = 10.13 sulfate ~alt N = 2 N~ 2 HOJ~OH AVr = 4571.89 rv~Ga~ ~v SEM = 499 67 ~ulfate salt N = 2 ~NH AVG. = 164.84 SEM = ~
EICI N = i w0 95/24200 r~ Atoss ~ ! 2 ~a~ 5-FrTæR Cell.e ~-~T~
r~nu~.v~ rl~nDol Ki Rat Ki Human Ki HumPn Ki Rat STE~UCTURE 5~HT2B 5-HT2B 5-HT2A 5~HT2A

,~
NH
AVG. = 20.85 SEM = 5.29 rlcl _ N = 2 FAVG. = 62.43 SEM = 7.52 rlcl N = 3 ~NH2 ~,.. . .
\~J AVG. = 102.06 HCI ~ SEM _ 162 --N
~, ~< ~
1~ AVG. = 14.78 o~ ~ SEM = ?
N = 1 WO 95/24200 J ~, J I ~),,,,,.'Q~09g 2 ~ 8 5 2 3 6 Takl~l 5-FrTy~R C~ 5-Frl~
r~lTn~elotoDiD. rl~nDoI
Ki Rat l~i ~uman Ki Human Ki Rat STRUCTI~RE 5.1IT2B 5-HT2B 6'HT2A 5-HT2A

~}~Q AVG.= 7.94 = 11.21 = 27.55 = 20.70 NH SEM = 0.52 = ? = 0.62 = 3.48 Cl N = 6 = I = 3 = 3 N~
~ OH~b ~ Oq~
F~\ OH
~,NH AVG. = 336.55 \~ SEl~I = ?
F N = 1 .

9!;/~200 r~ ".J~9rlA~ogg r~ ,f 21 85236 ~03 ~21~1 5-ErT~R C~ ~2A
r~ vi(~ rl~nnoI
Ki E~at Ki Human Ki Hum Ki Rat STRUCAl'URE 5-HT2B 5-EIT2B 6-HT2A 6-HT2A
AVG. = 4.50 = 3.qg SEM = 0.47 = 0 80 HCI N = 12 = 8 ~1 AVG. = 3.58 q~ SEM = 167 ~ N = 3 ;

WO 95/24200 P~ )" r ~5 ~ ` 2~ ' '`` 204 2185236 ~a~ ~ 5-HT~12 Cf~ -HT~A
r~ .,.vt.. ;.. rl~nDoI
Ki Rat Ki Human Ki Human Ki Rat STRUCTURE 5-HT2B 5-HT2B 5-HT2A s-ElT2A
~ AVG. = 3.17 = 21.74 = 15.74 B r SEM = 0.36 = 0.74 = 141 ~CI N = 3 = 3 = 3 ~N~
$~,' AVG. = $4.49 SEM = 2.85 a~ N = 4 O _)-N
;;~ AVG. = 5.61 = 1.40 = 44.46 0~ , SEM = 0.91 = 0.08 = 0.75 ISOMER A N = 5 = 5 = 3 ;~0 ~ AVG. = ~0.07 = 5.55 = 372.81 OH ~ SEM = 8.51 = 0.40 = 23.51 ISOMER B N = 5 = 4 = 3 wo 95124200 r~ )5, i ~ 21 85236 ` ' ~ 205 T2R Cell.~ 5-HTæA
r~ ... ;.. r1~nDoI
Ki Rat Ri Human Ki llu}llan Ki Rat bl~U(;lU~; 5-HT2B 5-1IT2B 5-HT2A 5-HT2A
~ ' ~,N
~ _ AVG. = 8.16 = 1.50 = 23.39 HO ` SEM = 2.16 = 0 35 = 3.81 o N = 4 = 4 = 3 N~
~NH
AVG. = 3.10 = 0.79 = 28.07 ~' SEM = 0.20 = 0 06 = 2.30 O~ N = 3 = 7 = 3 AVG.= 539 ~ SEM = 0 68 HCI Q N = 3 N~,NH
OH~AVG.= 28.37 ~OH ` SEM = 2.08 O N = 3 wo gs/24200 r~ 33 ~ ~ 85236 ~Cakl~l 51:~T~,R C~
.. ;.. rl~nDol Ki Rat Ki Human Ki Human Ki Rat ~NH
~OH ~ AVG. = 3.94 = 1.29 = 6.68 OH ~ SEM = 0.88 = 0.12 = 0.63 O N = 3 = 3 = 3 N~NH
AVG. = 39.70 O~ N - 3 ~NH
~OH ~' AVG. = 1463.01 ~,,OH ` SEM = 110.95 O N = 4 ~NH
~OH ~) AVG.= 14.18 '~,,OH SEM = 1.74 O N = 4 ~1095124200 r~ vv C.~

r ~

5-~rT~R Cl?~; 5-RrT~
r~2T~ erot~nin r~ noI
Ki Rat Ki Human Ki I~uman E~i Rat STRUCTIJRE 5-EIT2B 6-HT2B 5-HT2A ~-HT2A
NH~ NH
¢~8~ ~3 SEM - 148 0 N = 3 G~ - AVG = ~.02 = 1.64 = 0.8.2 N SEM = 0.61 = 0.23 = 0.10 2 ~CI El2O N = 3 = 4 = 3 b~
o ~NH
~8H ~ AVG. = 4.82 NE~,NH
~1 AVG. = 2.16 'SEM = 0.33 0~ N = 3 WO 95/24200 ~ 099 r ~-~Ca~QI. 5-E~T~p~ Cell~ ~:~2A
r~ ;protonin rl~nDOI
Ri Rat Ki ~uman Ki Human Ki Rat N~NH
AVG. = 228.87 ~O SEM = 18.34 EICI ~ N = 3 N~.~
OH ~- AVG.= 6A2 = 2.01 = 23.08 ~o ~, SEM = 0.78 = ? = ?
OH N = 3 = 1 = 1 F

O ~
~OH /~ AVG.= 4.38 ~,OH ~I SEM = 1.25 O N = 3 ~NH
NH--~
~ AVG. = 3.31 = 0.74 = 4.63 HCI ~ ~ SEM = 0.31 = 0.04 = 0 26 ~ N = 3 = 3 = 3 WO g5/24200 r~

. . ., 1. . ~

Ta~ 5-HT~R C~ 5-~rT~
rs~nr~ .. ;" rl~nnol Ki Rat Ki Human ~i Human Ki Rat ,NH
~~o~ AVG. = 219.79 OH o\ SEM = 20.68 O N = 3 HO
AVG. = 4609.36 NH SEM = 316 40 E~Ci N = 3 \NH AVG. - 3'79.15 NH N = 3 0~
NH~
AVG. = 114.16 HCl '--~ SEM = 7.17 N = 3 WO 95/24200 r~ ogg Tahle 1 5-~rT~R C~ ~2A
r~ erotonin r~ nDOI
Ki Rat Ki Human Ki Human ~i Rat STRU~l-J~; 6 HT2B 5-HT2B s.HT2A s-HT2A
`O
AVG. = 404.85 SEM = 51.64 \--NH N = 3 ~0 NH~
NJ
HCI ~ AVG. = 9q.53 `r7 SEDI = ?
VN = 1 ~0~
NH I
HCI< / AVG.= 71.75 N-- SEM = ?
N = 1 Cl ~ AVG. = 70.71 HCI ~NH SEM - 10.08 ~ W095/U200 r~

Zll ~CaklQl 5-~ll'æR C.qllc ~:~2A
r.~.v~.. ;.. rl~'~nDOI
. KiRat Ki Human Ki ~uman ~i Rat STRUCTURE 5-HT2B 5-EIT2B 5-lIT2A 5-HT2A
- ~NH
J ~ ~ AVG. = 15.83 SEM = 1.73 EICI N = 3 ~--NH
/~ NH
,rAVG. = 13.98 = 16A3 = 41.71 = 4q.00 SEM = 1.00 = ? = 7.42 = 5.15 BrN = 3 = 1 = 4 = 3 --NH
/~ ' /~ NH
AVG. = 6.20 = 9.6~v = 22.72 = 25.61 Br SEM = 0.62 = 1.12 = 2.15 = 3.43 HCI N = 3 = 3 = 6 = 3 ~NH
NH
< '~ AVG. = 62.09 ~=/ SEM = 1.76 Br N = 3 ~a~21Ql 5-HT~R Cell~ ~:~2A
r3~nn.,.vl.. ,.. ;.. rl~nDoI
Ki R~t Ki Human Ki Human Ki Rat STRUCTt~RE 5-HT2B 5-HT2B 5-HT2A 5-HT2A
~NH
J~ AVG. = 57.89 F SEM = 7.60 HCI N = 3 r~
AVG. = 32.44 SEM = 3.48 Br HCl N = 3 ~ 1 )=/ AVG. = 322.26 SEM = 35.50 F HCl N = 3 ~`NH ' ~ ;
AVG.- 25.63 F SEM = 2.59 EICI N = 3 ~ WO 95/24200 r.l,~ 3~ ngg i `~ 1 8~236 ~-` 213 ~a~ç~ 5-F~T~R C 11 r~ ...... rl~nDol KiRat K Human KiHuman Ei Rat ~il~U(;l~; 5-HT2B F HT2g 5-ET2A 5-HT2A
's , -~NH
, y / \
~NH
AVG. = 78A6 SEM = 1.22 HCl N = 2 NH
AVG. = 60.10 SEM = 2.07 ECl N = 3 r ~
AVG. = 2.69 = 2.6~ = 20.61 = 15.49 Cl SEM = 0.24 = 0.24 = 1.28 = 0.79 lICl N = 6 = 4 = 4 = 3 Cl~_ HCI ~ AVG. = 3.19 = 0.84 = Q93 0 0_ SEM = 0.33 = 0.15 = 0.07 N = 3 = 4 = 3 -w095/24200 I~"~l~,3~q3099 ,t~ ,3 ~ ~ 21 85236 R Cell~ ~2A
r~ erot~nin rl~nnoI
lKi Rat Ki Human Ki Human Ki Rat STRUCTURE 5-HT2B 5-ET2B 5-ElkA 5-ElT2A
Br~
N~-->
~)-NH
O~ AVG. = 8.77 O 0-- SEM = ?
HCl ` N = 1 ~NH
NH
O~
AVG. = 5652.17 SEM = ?
HCl N = 1 ~NH
AVG. = 15.26 = 10.15 = 17.76 ~j/ I SEM = ? = 219 = 0 68 lHCl I N = 1 = 4 = 3 H ~--N
OH ~ H d ~ ~ AVG. = = 1.69 = 49.70 o O~ SEM = = ? = ?
OH ~ N = = 1 = 1 ~ WO9~/24200 ~ A ~, - - - ; 21 85236 ~Ca~Ql 5-E~rT~R C~ ~2A
r.2~ns.. vl.. ;.. rl~nnoI
l~i Rat Ki HumPn Ki Human Ki E2at STE?.UCTUB,E 5-HT2B 5-HT2B 5-HT2A 5-HT2A
N \_~
OH ~
~0 \~/ AVG. = = 2.08 = 6.71 ~ SEM = = ? = ?
OH N = = 1 = 1 Br~0, AVG.- ~ 0.37 _ 12.23 HCl ~ N = = 1 = i N
0}~ ~
_ AVG. = ~ 0.87 = 17A8 ÆM = = ? = ?
OH N = = l = 1 N~
AVG. =
~ 1.47 54.85 HCl H0 N = = i = i wo gs/24200 r~l"~ Og9 t ' 21 85236 ~a~ 5-EirT~R Cf~ ~2A
r~ erotonin rl~nDol Ki Rat ~i Huma~ Ei Human Ki Rat Y
HN~
~--N
_~ H
OH ~ AVG. = = 3.46 = 201.26 O ~ -- SEM = = ? = ?
OH N = = 1 = 1 .

~ wo95/24200 r. ~ J~ ~

~ak~ 6-RrT~lR Cells ~:~2A
r.2~.~.. vl/.. ;.. rl~nDoI
RiRat Ki Hum~n Ri Human Ri Rat STRUCTURE 6-HT2B 5-lIT2B 6-ET2A 5-HT2A
.
N~
0~
N--F\_ NAVG. = 4465 = 12.44 = 1.25 = ~.36 H SEM = 25.15 = 1.70 = 0.56 = 1.85 255747, Trans N = 6 = 3 ~ = 5 = 5 ~,0 HN--~J
0~
N--~' /~ AVG. =22.29 =4.30 = 11.33 = 1.57 SEM = 6.65 = 0.30 =3.26 = 0 49 278468, CIS N = 5 = 3 = 5 = 5 ~OH
HN--~J
0~
~3-~1~ AVG. = 80.90 =6.24 =2Ll8 = 2.82 SEM = 4.52 =0.29 =3.78 = 0.40 2~3~35 (TRANS) N = 3 = 3 WO 95/24200 1 ~,ll-J.,. _ 'Q~099 Table 1 5-F~rT2p~ Cf~ ~2A
r~ .v~,.. ;.. rl~nT-ol Ki Rat Ki Hum~n Ki EIum~n Ki Rat STRUCTURE 5-HT2B 5-~IT2B 5-~IT2A 5-HT2A
OlI
NHI'~
0~
N--AVG. - - 7 87 0.60 NH N = = 1 = 1 0:~
NE[O
0~
~N--AVG. = , 2.24 = 21.92 IICI I SE:l~q = =_ = _ ~\ N = =1 = 1 ~1~ W0 95/24200 r~ Qg9 ~ ~ ` '; ^' r '~. 219 2 ~ 8~236 ~I'hc~ f~ nrr ~'~l l A~gayg llC~C~ r-Comnol~n~ 5HT~R Cell~ SHT~z~CPl 1 q 5HT;~Cells Example 100 16.44 292.58 351.96 Example 105 22 . Oi 86 . 48 195 . 44 Example 102 168.4g 917.16 2172.86 Example 106 367.41 263.94 1108.87 Example 104 11.35 32.99 52.06 Example 97 9.56 123.g3 220.51 Example 99 106.17 556.40 1117.00 Example 107 177.89 362.79 325.10 Isomer 107(1) 142.80 152.65 137.76 Isomer 107 (2) 2894.33 1967.05 6211.80 Example 101 121.19 - 172.03 783.35 Example 98 52.54 53.65 202.60 Example 96 667.82 277.62 976.73 Example 95 839.63 3443.51 2641.21 Example 103 3520.31 1447.65 9247.06 Assay Methods 5-HT2g receptor in tissue in vitro:
Male Wistar rats (150-375 g; Laboratory Supply, Tnr~; ~n~rolis, IN) were sacrificed by cervical dislocation, and longitudinal section of the stomach fundus were prepared for in vitro examination. Four preparations were obtained from one rat fundus. Cohen, M.L. and J. Pharmacol. Exp.
Ther. 233 :75-79 (1985) . Tissues were mounted in organ baths containing 10 m~ of modified Krebs ' solution of the following composition (millimolar concentrations): NaCl, 118.2, KCl, 4 . 6 i CaC12 H2O, 1 . 6; KH2P04, 1 . 2; MgS04, 1. 2; dextrose, 10 . 0;
and NaHCO3, 24.8. Tissue bath solutions were maintained at 37C and equilibrated with 95~i O2 and 596 C02. Tissues were placed under optimum resting force (4 g) and were allowed to equilibrate for approximately 1 hour before exposure to the test compound. Isometric contractions were recorded as changes in grams of ~orce on a Beckman Dynograph with Statham Uc-3 transducers.

WO 95/24200 PCT/I~S95/03099 t~ r; t 2 2 0 2 1 8 5 2 3 6 Determination of Apparent Antagonist Dissociation Constant:
Noncumulative contractile collcentration-response curves for serotonin and other açlonists in the fundus were obtained by a stepwise increase in concentration af ter ~' washing out the preceding concentrations every 15-2 a minutes .
Each agonist concentration remained in contact with the tissue for approximateLy 2 minutes and maximum response to each compound conc~ntr~t1-~ was measured . EDso values were taken as the conce~Ltration of agonist that produced half-maximal contraction. Af~ter control responses were obtained, tissues were incubated with an appropriate concentration of buffer or antagonist for 1 hour. Responses to serotonin were then repeated in the presence of an antagonist.
Concentration responses utilized only one agonist and one antagonist concentration per tissue. In general, successive agonist responses in the presence of buffer treatment were unalte~ed (average dose ratio was 1.2~ +/- 0.21). ~-Apparent antagonist dissociation constants (KB) were determined for each concentration of antagonist according to the following e~Iuation:
KB= [B] / (dose ratio-1) where [B] is the concentration~ of the antagonist and dose ratio is the ED50 of the agonist in the presence of the antagonist divided by the control ED~. Generally, p~rallel shifts in the concentration-response curves occurred in the presence of antagonists. The results were expressed as the negative logarithm of the KB (i.e., -log KB) . Calculations were completed using known methods.
The results of the in vitro assay for~certain compounds of this invention are presented in Table II. The values in Table II are expressed as -log KB + standard error `
(number of data points). The 5=E~T2B value represents the negative log of the concentration of an antagonist that will produce a two fold de~tral shift in the concentration response curve to serotonin in the rat stomach fundus which is mediated by 5-XT2B receptors Likewise, the 5-HT2A value ~ WO 95l24200 1 ~ ,.,5,: ,~
~21 2 1 85236 represents the negative log of the c~n~-on~tion of an antagonist that will produce a two fold dextral shift in the concentration response curve to serotonin in the rat jugular vein which is mediated by 5-HT2A receptors. The blank values in Table II indicate that the compound was not tested in the indicated assay.

WO 95l24200 1 ~ .,5/~099 .. '' ~ab le I I
E~x~ # 5--~T2B 5--~T2A
( E undus ) ~ ~gular ) 9.00 i 0.07 (3) 3 8.78 ~ 0.24 (4) 4 8.92 + 0.29 (4) 6 9.60 -- 0.13 (7) 7 9.02 0.35 :~3) 8 8.45 ~ 0.24 (3) 9 9.30 ~- 0.12 :(7) 9.22 ' 0.05 (3) 11 <7 . 52 ( 4 ) 12 9.29 ~ 0.18 (4) 13 ~ 8.50 - 0.13 (4) 14 9.61 -- 0.22 (5) 9.34 - 0.12 (3) 16 9.71 - 0.14 (6) 8.15 + 0.28 (3) 17 9.46 -- 0.11 (6) 7.66 + 0.13 ~4) 18 8.80 :c 0.17 (3) 19 10.12 ~ 0.18 (3) 20 9.48 + 0.30 (4) 7.21 i: 0.20 (4) 22 8.21 + 0.43_(3) 28 8.55 -- 0.10 (4) 29 8.12 x 0.16 (7) 30 8.89 - 0.12 (4) 31 8.95 - 0.17 (3) 7.29 ~ 0.09 (4) WO 9S/24200 l ~ 099 Table II (~ont . ~
~3xampl~ # 5-HT2~ 5-HT2A
( Fundus ) ( JuSlular ) 34 9.as2 i 0.18 (5) *9.06 i 0.27 (3) 36 9.80 i 0.15 (4) 8.14 i 0.10 (6) 37 9.19 ~ 0.14 (4) 39 8.32 - 0.17 (3) 40 9.75 -- 0.11 (6) 41 9.81 J 0.18 (3) 7.94 i 0.15 (6) 42 9.56 - 0.22 (3) 43 9.44 - 0.16 (6) 44 8.40 0.40 (3) 45 8 . 14 -- 0 . 32 (3 ) 46 9.37 - 0.11 (8) 8.22 i 0.07 (12) 48 **
49 *10.4: i 0.22 (5) 8.40 - 0.28 (3) 51 9.75 ~ 0.11 (8) 8.07 i 0.10 (8) 52 *9.10 i 0.28 (3) 53 **
54 **
8.95 i 0.07 (4) 56 ~ *7.53 i 1.08 (4) 57 <8.0 (3) 58 c7.52 (4) 59 9.69 -- 0 21 (7) 8 . 92 - 0 . 04 (4) 61 8.44 ~ 0.22 (4) 62 8.58 -- 0.23 (3) 63 9 . 09 -' 0 .23 (3 ) 64 9.73 -- 0.05 (3) * Approximate value WO 95/24200 1 ~ 099 ** Non-competitive i~hibitors at 30 nM
Functional In vitro assay:
Sprague-Dawley rats (200-250g; ~aboratory Supply, Indianapolis, IN) were sacrificea by cervical dislocation and 8 cm segment of distal colon was removed and washed in ice cold moaified Kreb' s solution of _the following composition ~millimolarr: Nacl, 118.2; Kcl, 4.6; Cacl2. ~2O, 1.6;
KH2PO4, 1.2; MgSO4, 1.2; dextrose, 10.0; and NaHCO3, 24.8.
The colon was mounted on a glass rod and the longitudinal muscle layer with attached myenteric plexi was removed and mounted in organ baths, containing above described Kreb ~ s solution maintained at 37C and e~uilibrated with 95% 2 and 596 C02. Tissues were placed under 2 g~ tension and allowed to stabilize for 1 hour. Isometric contractions were recorded as changes in grams of force using grass FT03 transducers and MI2- computerized dynograph system. Cumulative concentration-response curves for serotonin were obtained by a stepwise increase in concentration after washing out t~e preceding cioncentration for 10-15 minutes. Each agonist concentration remained in contact with the tissue for 5 minutes. Maximum response to each concentration was determined and digitized. ECso values were taken as the concentration of agonist that ~roduced half maximal contraction. After control responses were obtained, tissues were incubated with an appropriate concentration of antagonist for 15 minutes. Resp~nse to serotonin were then repeated in the presence of an antagonist. Concentration-response l~t i 1 i ~ l only one concentration of antagonist per tissue. Apparent antagonist dissociation constants (Kg) were determined for each concentration of antagonist according to the following e~Iuation:
KB= ~B] / (dose ratio - 1), where rB] is the concentration of the antagonist and dose ratio is the EDso of the agonist in the presence of antagonist divided by the control EDso. The -~ WO95/24200 P~ O99 ~ ~ 21 85236 results were expressed as the negative logarithm of the KB
(i.e.,-log Kg) ~Br. J ph~rm~lrr~l . Methods 4:4165, (1980) .
The functional in vitro method described supra. was used to test compounds of this invention. Results obtained using the functional in vitro assay are presented in Tahle III. Values are expressed as PKi and pA2 (-log KB) . The following table illustrates the results obtained when the compounds were tested using the Radioligand assay supra.
(pKi) and the functional in vitro method described supra.
( PA2 ) ~able III
Crmnound ,n~; nA2 Example 73 7 . 85 8 . 9 Examp l e 4 9 - - 8 . 4 8 . 2 Example 20 8.51 7.8 Example 72 7 . 8 7 . 5 Example 41 8.19 7.2 Example 17 8.09 6.2 Example 22 8.27 4.8 7-methyl-8-chloro-1, 2, 3, 4-tetrahydro-9Ei-pyrido [3, 4b] -indole 8.57 8.3 6-bromo-1, 2, 3, 4-tetrahydro-9EI-pyrido[3,4b]-indole 7.21 8.2 6-chloro-1, 2, 3, 4-tetrahydro-9H-pyrido[3,4b]-indole 7.15 7.2 In vi vo S tudi es:
Sprague-Dawley Rats (250-300 g) were fasted overnight. The rats were anesthetized with urethane (250 mg) delivered intraperitoneally. The ~h~l~~in~l cavity was opened and strain guage transducers were sewn on the antimesenteric border of the colon. The transducers were oriented to record circular muscle contractions. The animal body temperature was maintained by a heating pad. An intravenous catheter was inserted into the jugular vein for drug adm.inistration. The carotid blood pressure was also monitored. Output of the Wo gs/24200 226 2 ! 8 ~236 strain guage transducers was graphed on a Beckman Dynograph.
Baseline motility was monitored for 30 minutes. At the end of the 3 0 minute period, a vehicle control dose was administered and motility was recorded for an additional 15 minutes. A serotonin dose response was developed.
Successively higher doses of serotonin were administered at 15 minute intervals. An EDso~ dose was calculated, which was the dose producing half maximal contraction. In antagoIlist experiments, historical EDsO dose was administered to ~alidate the experimental set up. Next, a dose of antagonist was given. The motility was monitored for 15 minutes. After the 15 minute monitoring, an EDsD dose was administered. Motility was evaluated by measuring the number of contractions and multiplying them by the amplitude of contractions over~a set time period to provide a Motility Index. The percent inhibition was calculated from the vehicle (no antagonist) treated group. A minimum of three rats were used for each concentration and data from different animals was pooled to determine EDso values. ~ ~
.Compounds of this invention proved to be active using the in vivo method described supra. For example, the compound of Example 73 produced =an EDsO value of ~3 .2 mglkg, i .v .

Claims (42)

Claims

1. A method for treating a mammal suffering from or susceptible to a condition associated with abnormal or dysfunctional 5-HT2B receptor stimulation, comprising administering an effective amount of a compound which interacts with the 5HT2B receptor selected from the group consisting of a compound of the Formula I
I
wherein:
Q is hydrogen or (CHR2)R4 R1 is hydrogen or C1-C3 alkyl;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen or C1-C3 alkyl;
R4 is C5-C8 cycloalkyl, substituted C5-C8 cycloalkyl, C5-C8 cycloalkenyl, substituted C5-C8 cycloalkenyl, bicyclic or substituted bicyclic;
A is selected from the group consisting of (IIa), (IIIa) , and (IVa);

wherein R6 and R7 are, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, COR5, C1-C10 alkanoyl, CO2R5', (C1-C6 alkyl)mamino, NO2, -SR5, or OR5;
m is 1 or 2;
R5 is independently hydrogen or C1-C4 alkyl;
R5' is C1-C4 alkyl;
R8 is independently selected from the group consisting of an R6 group, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl, substituted C5-C8 cycloalkenyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, C7-C20 arylalkyl; or R6 and R7 together with the carbon atoms of group A form a 5- to 8-member carbon ring;, a compound of Formula II
II
wherein R8 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, halo(C2-C6)alkyl, halo(C1-C6)alkenyl, COR5, C1-C10 alkanoyl, CO2R5, (C1-C6 alkyl)mamino, NO2, -SR5, OR5, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl, substituted C5-C8-cycloalkenyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, and C7-C20 arylalkyl;
R5 is independently hydrogen or C1-C4, alkyl;
R5' is C1-C4 alkyl;

R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, C7-C20 arylalkyl;
R11 is selected from the group consisting of C1-C4 alkyl, OR5', fluoro, bromo, iodo, and chloro;
R12' is selected from the group consisting of hydrogen, and C1-C4 alkyl;
a compound of Formula III
III

wherein:
R12 is C1-C4, alkyl or allyl;
Rl3 is -O- or -N(R15)-;
R15 is hydrogen or C1-C4 alkyl;
R14 is C1-C4 alkyl, hydroxy C1-C4 alkyl, C3-C7 cycloalkyl, and C3-C7 cycloalkyl substituted with hydroxy or methoxy;
a compound of Formula IV

IV

wherein:
R15' is C1-C4 alkyl;
R16 is allyl or C1-C4 straight chain alkyl;
R17 is hydrogen or C1-C4 straight chain alkyl;
R18 is hydrogen, C1-C4 alkyl, hydroxy, or C1-C4 alkyloxy;
m' is 0, 1, 2, or 3;
a compound of Formula V

V

wherein:
R19 is C1-C4 alkyl;
R20 is allyl or C1-C4 straight chain alkyl;
R21 is hydrogen or C1-C4 straight chain alkyl;

R22 is pyridinyl or imidazolyl;
alk is a divalent organic radical derived from a straight or branched C1-C5 alkane;

a compound of Formula VI
VI

wherein:
R23 is C1-C3 alkyl or allyl;
R24 is C1-C3 hydroxyalkyl or C1-C3 dihydroxyalkyl;
R25 is hydrogen or CH3;
a compound of Formula VII
VII;

a compound of Formula VIII
VIII;

wherein R25' is methoxy;

a compound of Formula IX
IX

wherein:
Yb, in combination with the carbon atom to which it is joined, defines a substituted or unsubtituted aromatic heterocyclic 5-membered ring selected from the group consisting of R26 is hydrogen, C1-C3 alkyl, allyl, or ;

R27 is hydrogen, C1-C3 alkyl, allyl, , or (CH2)n'-X";
n' is 1 to 5;
X" is an optionally substituted phenyl, C1-C3 alkoxy, or C1-C3 alkylthio;
R28 and R29 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, C1-C3 alkylthio, halo, CN, phenyl; or together are -(CH2)p"-;
p" is 3 to 6;
Ya is -CH2-, -O-, -S(O)m"-;
m" is 0, 1, or 2; and a compound of the Formula X
X;
or a pharmaceutically acceptable salt or solvate thereof.

2. A method of Claim 1 wherein the compound is selected from the group consisting of Formula I, II, and IX.

3. A method of Claim 2 wherein the compound of Formula IX has the following structure:
IX'.

Wherein R26, R27, R28, R29, and Ya are as defined supra.

4. A method of Claim 2 wherein the compound is selected from the group consisting of 2-(di-n-propylamino)-8-(isothiazol-3-yl)-1,2,3,4-tetrahydronaphthalene, 2-ethylamino-8-(isoxazol-3-yl)-1,2,3,4-tetrahydronaphthalene, 2-(N-methyl-N-benzylamino)-8-(5-n-propyl-1,2,3-oxadiazol-4-yl)-1,2,3,4-tetrahydronaphthalene, 2-diallylamino-8-(pyrazol-3-yl)-1,2,3,4-tetrahydronaphthalene, 2-diethylamino-8-(1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino)-8-(3-methoxypyrid-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-benzylmethylamino-8-(3-methoxypyrid-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-benzylmethylamino-8-(benzofuran-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-dimethylamino-8-(1,3,5-triazin-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-cyclopropylmethylamino)-8-(oxazol-4-yl)-1,2,3,4-tetrahydronaphthalene, 2-ethylamino-8-(1,2,3-oxadiazol-4-yl)-thio-1,2,3,4-tetrahydronaphthalene, 2-n-butylamino-8-(5-methoxypyrimidin-2-yl)-1,2,3,4-tetrahydronaphthalene, 2- (di-n-propylamino)-8-(5-chlorooxazol-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino)-8-(pyrimidin-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino)-8-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino)-8-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino)-8-(3-methyl-1,2,4-oxadiazol-5-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino)-8-(pyrazin-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino)-6-(bromopyrazin-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino)-8-(benzothiazol-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino)-8-(benzoxazol-2-yl)-1,2,3,4-tetrahydronaphthalene, 2-(di-n-propylamino)-8-(indol-3-yl)-1,2,3,4-tetrahydronaphthalene, 3-(di-n-propylamino)-5-(isoxazol-2-yl)-1,2,3,4-tetrahydronaphthalene, 3-(di-n-propylamino)-5-(isoxazol-2-yl)-chromane, 5-(isoxazol-5-yl)-3-(dipropylamino)chromane, 5-(3-methylisoxazol-5-yl)-3-(dipropylamino)chromane, 5-(4-methylisoxazol-5-yl)-3-(dipropylamino)chromane, 5-(3,4-dimethylisoxazol-5-yl)-3-(dipropylamino)chromane, 5-(3-methylisoxazol-5-yl)-3-(dipropylamino)thiochromane, 5-(4-methylisoxazol-5-yl)-3-(dipropylamino)thiochromane, 5-(3,4-dimethylisoxazol-5-yl)-3-(dipropylamino)thiochromane, and 8-(4,5,6,7-tetrahydrobenz[c]isoxazol-1-yl)-2-(dimethylamino)tetrahydronaphthalene; or a pharmaceutical salt or solvate thereof.

5. A method of Claim 2 wherein the compound is a compound of Formula I or II.

6. A method of Claim 1 wherein the compound interacting with the 5HT2B receptor is a 5-HT2B receptor antagonist.

7. A method of Claim 5 wherein the compound is selected from the group consisting of 7-bromo-8-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-isopropyl-8-methoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 5-chloro-8-ethoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-chloro-7-methyl-8-fluoro-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 5-dimethylamino-8-hydroxy-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-nitro-8-butyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 7-cyclohexyl-8-hydroxy-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-[3-methyl-cyclohexyl]-8-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-benzyl-8-fluoro-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 5-cyclohexylmethyl-8-chloro-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-carboxyl-8-bromo-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-ethoxy-8-isopropyl-3-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6,8-dichloro-4-naphthylmethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6,8-dimethyl-3,4-dimethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 7,8-difluoro-2(N)-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6,8-dibutyl-2(N)-cyclopropylmethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6,8-dibromo-2(N)-cyclohexenylmethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 8-chloro-2(N)-benzyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 8-fluoro-4-methyl-2(N)-cyclohexyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 6-methylamine-8-chloro-3-isopropyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, and 6-chloromethyl-8-chloro-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole; or a pharmaceutical salt or solvate thereof.

8. A method of Claim 1 wherein the condition is selected from the group consisting of a urinary incontinence, bladder dysfunction, uterine dysfunction, cardiovascular disorder, respiratory disorder, and Functional Bowel Disorder.

9. A method of Claim 8 wherein the condition is a Functional Bowel Disorder.

10. A method of Claim 9 wherein the Functional Bowel Disorder is one or more conditions selected from the group consisting of Irritable Bowel Syndrome, ichlasia, hypertonic lower esophogeal sphincter, tachygastria, hypermotility associated with irritable bowel syndrome, and constipation.

11. A method of Claim 2 wherein the condition is selected from the group consisting of a urinary incontinence, bladder dysfunction, uterine dysfunction, cardiovascular disorder, respiratory disorder, and Functional Bowel Disorder.

12. A method of Claim 8 wherein the condition is a cardiovascular disorder.

13. A method of Claim 8 wherein the condition is a bladder dysfunction or urinary incontinence.

14. A method of Claim 8 wherein the condition is a respiratory disorder.

15. A method of Claim 8 wherein the condition is migraine headaches.

16. A method of Claim 1 wherein the compound is selected from the group consisting of Formula III, IV, V, and VI.

17. A method for blocking a 5HT2B receptor in a mammal, comprising administering a 5HT2B receptor blocking dose of a compound selected from the group consisting of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X as defined in claim 1; or a pharmaceutically acceptable salt or solvate thereof.

18. A method for selectively blocking a 5-HT2B
receptor in a mammal, comprising administering a 5-HT2B
selective compound selected from the group consisting of Formula I, II, III, IV, V, VI, VII, IX, as defined in claim 1, and a compound of Formula VIII

VIII;

wherein R25' is hydrogen or methoxy;
or a pharmaceutically acceptable salt or solvate thereof to a mammal.

19. A method for blocking a human 5-HT2B receptor in a human, comprising administering a 5-HT2B blocking dose of a compound selected from the group consisting of Formula I, II, III, IV, V, VI, VII, VIII, and IX as defined in claim 1;
or a pharmaceutically acceptable salt or solvate thereof to a human.

20. An article of manufacture comprising packaging material and one or more pharmaceutical agents contained within said packaging material, wherein said pharmaceutical agent is effective for the treatment of a condition associated with 5-HT2B modulation and is selected from the group consisting of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X as defined in claim 1; or a pharmaceutically acceptable salt or solvate thereof; and said packaging material comprises a label which indicates that said pharmaceutical agent can be used for the treatment of a condition associated with dysfunctional or abnormal 5-HT2B
receptor stimulation.

21. A compound of the Formula XI

XI

wherein Q' is selected from the group consisting of hydrogen, R34, and (CHR2)R4;
R34 is selected from the group consisting of spiro-bicyclic, substituted spiro-bicyclic, bicyclic or substituted bicyclic;
R1 is hydrogen or C1-C3 alkyl;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen or C1-C3 alkyl;
R4 is C5-C8 cycloalkyl, substituted C5-C8 cycloalkyl, C5-C8 cycloalkenyl, substituted C5-C8 cycloalkenyl, bicyclic or substituted bicyclic;
A is selected from the group consisting of (IIa), (IIIa) , and (IVa);

wherein R6 and R7 are, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, COR5, C1-C10 alkanoyl, CO2R5', (C1-C6 alkyl)mamino, NO2, -SR5, or OR5;
m is 1 or 2;
R5 is independently hydrogen or C1-C4 alkyl;
R5' is C1-C4 alkyl;
R8 is independently selected from the group consisting of an R6 group, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl, substituted C5-C8 cycloalkenyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, C7-C20 arylalkyl; or R6 and R7 together with the carbon atoms of group A form a 5- to 8-member carbon ring;
R30 and R31 join to form a 3 to 8 member carbon ring; or R30 and R3l are independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; or a pharmaceutically acceptable salt or solvate thereof.

22. A compound of Claim 21 wherein R30 and R31 join to form a 3 to 8 member carbon ring.

23. A compound of Claim 22 wherein Q is (CHR2)R4

24. A compound of Claim 23 wherein R4 is bicyclic or substituted bicyclic.

25. A compound of Claim 22 wherein Q is R34.

26. A compound of Claim 25 wherein A is structure IV.

27. A compound of Claim 21 wherein R30 and R31 are independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; Q is (CHR2)R4.

28. A compound of Claim 27 wherein R4 is bicyclic or substituted bicyclic.

29. A compound of Claim 21 whererin R1 is selected from the group consisting of C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, and C5-C8 cycloalkenyl-(C1-C3)alkyl.

30. A compound of Claim 29 wherein wherein R30 and R31 are independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl.

31. A compound of the Formula XII
XII
A is selected from the group consisting of (IIa), (IIIa), and (IVa);
wherein R6 and R7 are, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, COR5, C1-C10 alkanoyl, CO2R5', (C1-C6 alkyl)mamino, NO2, -SR5, or OR5;
m is 1 or 2;

R8 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, halo(C2-C6)alkyl, halo(C1-C6)alkenyl, COR5, C1-C10 alkanoyl, CO2R5', (C1-C6 alkyl)mamino, NO2, -SR5, OR5, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl, substituted C5-C8 cycloalkenyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, and C7-C20 arylalkyl;
R5 is independently hydrogen or C1-C4 alkyl;
R5' is C1-C4 alkyl;
R6 and R7 together with the carbon atoms of group A
form a 5- to 8-member carbon ring;
R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, C7-C20 arylalkyl;
R11 is selected from the group consisting of C1-C4 alkyl, OR5', fluoro, bromo, iodo, and chloro;
R30 and R31 join to form a 3 to 8 member carbon ring; or R30 and R31 are independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; or a pharmaceutically acceptable salt or solvate thereof.

32. A compound of Claim 31 wherein R30 and R31 join to form a 3 to 8 member carbon ring.

33. A compound of Claim 32 whererin R9 and R10 are each hydrogen.

34. A compound of Claim 31 wherein A is IIa or IIIa.

35. A compound of Claim 31 wherein A is IV; R6, R7, and R8 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, COR5, C1-C10 alkanoyl, CO2R5', (C1-C6 alkyl)mamino, NO2, and -SR5, proyided that at least one of R6, R7, and R8 shall be selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, COR5, C1-C10 alkanoyl, CO2R5', (C1-C6 alkyl)mamino, NO2, and -SR5.

36. A compound of Claim 35 wherein R30 and R31 join to form a 3 to 8 member carbon ring.

37. A method for treating a mammal suffering from or susceptible to a condition associated with abnormal or dysfunctional 5-HT2B receptor stimulation, comprising administering an effective amount of a compound which interacts with the 5HT2B receptor selected from the group consisting of a compound of the Formula XI
XI
wherein Q' is selected from the group consisting of hydrogen, R34, and (CHR2)R4;
R34 is selected from the group consisting of spiro-bicyclic, substituted spiro-bicyclic, bicyclic or substituted bicyclic;
R1 is hydrogen or C1-C3 alkyl;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen or C1-C3 alkyl;
R4 is C5-C8 cycloalkyl, substituted C5-C8 cycloalkyl, C5-C8 cycloalkenyl, substituted C5-C8 cycloalkenyl, bicyclic or substituted bicyclic;
A is selected from the group consisting of (IIa), (IIIa), and (IVa);
wherein R6 and R7 are, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, COR5, C1-C10 alkanoyl, CO2R5', (C1-C6 alkyl)mamino, NO2, -SR5, or OR5;
m is 1 or 2;
R5 is independently hydrogen or C1-C4 alkyl;
R5' is C1-C4 alkyl;
R8 is independently selected from the group consisting of an R6 group, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl, substituted C5-C8 cycloalkenyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, C7-C20 arylalkyl; or R6 and R7 together with the carbon atoms of group A form a 5- to 8-member carbon ring;
R30 and R31 join to form a 3 to 8 member carbon ring; or R30 and R3l are independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; and a compound of Formula XII
XII

A is selected from the group consisting of (IIa), (IIIa), and (IVa);

wherein R6 and R7 are, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, COR5, C1-C10 alkanoyl, CO2R5', (C1-C6 alkyl)mamino, NO2, -SR5, or OR5;
m is 1 or 2;
R8 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, halo(C2-C6)alkyl, halo(C1-C6)alkenyl, COR5, C1-C10 alkanoyl, CO2R5', (C1-C6 alkyl)mamino, NO2, -SR5, OR5, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3 -C8 cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl, substituted C5-C8 cycloalkenyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, and C7-C20 arylalkyl;
R5 is independently hydrogen or C1-C4 alkyl;
R5' is C1-C4 alkyl;
R6 and R7 together with the carbon atoms of group A
form a 5- to 8-member carbon ring;

R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, C7-C20 arylalkyl;
R11 is selected from the group consisting of C1-C4 alkyl, OR5', fluoro, bromo, iodo, and chloro;
R30 and R31 join to form a 3 to 8 member carbon ring; or R30 and R31 are independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; or a pharmaceutically acceptable salt or solvate thereof.

38. A method of Claim 37 wherein the compound interacting with the 5HT2B receptor is a 5-HT2B receptor antagonist.

39 A method for blocking a 5HT2B receptor in a mammal, comprising administering a 5HT2B receptor blocking dose of a compound selected from the group consisting of Formula XI and XII supra.; or a pharmaceutically acceptable salt or solvate thereof.

40. A method for selectively blocking a 5-HT2B
receptor in a mammal, comprising administering a 5-HT2B
selective compound selected from the group consisting of Formula XI, and XII supra.; or a pharmaceutically acceptable salt or solvate thereof to a mammal.

41. A method for blocking a human 5-HT2B receptor in a human, comprising administering a 5-HT2B blocking dose of a compound selected from the group consisting of Formula XI, and XII supra.; or a pharmaceutically acceptable salt or solvate thereof to a human.

42. A pharmaceutical formulation comprising as an active ingredient a compound selected from the group consisting of a compound of Formula XI and XII supra.; or a pharmaceutically acceptable salt or solvate thereof;
associated with one or more pharmaceutically acceptable carriers therefor.